The health and psychological consequences of cannabis use
National Drug Strategy
Monograph Series No. 25
Wayne Hall,
Nadia Solowij and
Jim Lemon,
National Drug and Alcohol Research Centre
Prepared for the National Task Force on Cannabis
CONTENTS
Acknowledgments
Executive summary
Acute effects
Chronic effects
High risk groups
The health risks of alcohol, tobacco and cannabis use
1. Summary of report
2. Introduction
3. Evidential principles
4. Cannabis the drug
5. The accute effects of cannabis intoxication
6. The chronic effects of cannabis use on health
7. The psychological effects of chronic cannabis use
8. The therapeutic effects of cannabinoids
9. An overall appraisal of the health and psychological effects of
cannabis
Acknowledgments
The authors would like to acknowledge the assistance of the following
people in the preparation of this manuscript:
Dr Robert Ali, Chairman of the National Task Force on Cannabis, for
his encouragement and support at all stages of the project, and the
members of the Task Force for their feedback on earlier drafts of the
document.
Dr Mario Argandona (WHO Programme on Substance Abuse), Dr Greg
Chesher, (National Drug and Alcohol Research Centre), Paul Christie,
(Project Officer, National Task Force on Cannabis), Dr Bill Corrigal
(Senior Scientist, Addiction Research Foundation, Toronto), Emeritus
Professor Harold Kalant (Department of Pharmacology, University of
Toronto), and Dr Jean-Marie Ruel (Bureau of Dangerous Drugs, Health
and Welfare Canada) for their useful comments on the whole manuscript.
The following persons are acknowledged for their expert comments on
specific sections of the manuscript: Dr Peter Fried (Carleton
University, Ottawa, Ontario) for his comments on reproductive effects;
Dr Richard Mattick (National Drug and Alcohol Research Centre) for his
comments on the dependence syndrome; Dr Peter Nelson (Southern Cross
University, New South Wales) for his comments on psychological
effects); Dr Mehdi Paes (Department of Psychiatry, University of
Rabat, Morocco) and Professor S.M. Channabasavanna (Director, National
Institute of Mental Health and NeuroSciences, Bangalore, India) for
their comments on psychiatric disorders; and Professor Donald Tashkin
(Division of Pulmonary and Critical Care Medicine, University of
California, Los Angeles Medical School) for his comments on
cardiovascular and respiratory effects.
Eva Congreve, the Archivist at the National Drug and Alcohol Research
Centre, performed above and beyond the call of duty in uncomplainingly
and efficiently dealing with a plethora of requests for obscure
publications in esoteric journals. Without her assistance, this review
would not have been half as comprehensive as we hope it has been.
Peter Congreve and Keith Warren collected articles and books which
made the task of reading and writing easier.
Acknowledgment is given to the Centre's secretaries, Libby Barron,
Margaret Eagers and Gail Merlin, who undertook the thankless task of
checking the referencing and proof reading the manuscript.
Executive summary
The following is a summary of the major adverse health and
psychological effects of acute and chronic cannabis use, grouped
according to the degree of confidence in the view that the
relationship between cannabis use and the adverse effect is a causal
one.
Acute effects
• anxiety, dysphoria, panic and paranoia, especially in naive
users;
• cognitive impairment, especially of attention and memory, for the
duration of intoxication;
• psychomotor impairment, and probably an increased risk of
accident if an intoxicated person attempts to drive a motor vehicle,
or operate machinery;
• an increased risk of experiencing psychotic symptoms among those
who are vulnerable because of personal or family history of psychosis;
• an increased risk of low birth weight babies if cannabis is used
during pregnancy.
Chronic effects
The major health and psychological effects of chronic heavy cannabis
use, especially daily use over many years, remain uncertain. On the
available evidence, the major probable adverse effects appear to be:
• respiratory diseases associated with smoking as the method of
administration, such as chronic bronchitis, and the occurrence of
histopathological changes that may be precursors to the development of
malignancy.
• development of a cannabis dependence syndrome, characterised by
an inability to abstain from or to control cannabis use;
• subtle forms of cognitive impairment, most particularly of
attention and memory, which persist while the user remains chronically
intoxicated, and may or may not be reversible after prolonged
abstinence from cannabis.
The following are the major possible adverse effects of chronic, heavy
cannabis use which remain to be confirmed by further research:
• an increased risk of developing cancers of the aerodigestive
tract, i.e. oral cavity, pharynx, and oesophagus;
• an increased risk of leukemia among offspring exposed while in
utero;
• a decline in occupational performance marked by underachievement
in adults in occupations requiring high level cognitive skills, and
impaired educational attainment in adolescents;
• birth defects occurring among children of women who used cannabis
during their pregnancies.
High risk groups
Adolescents
• Adolescents with a history of poor school performance may have
their educational achievement further limited by the cognitive
impairments produced by chronic intoxication with cannabis.
• Adolescents who initiate cannabis use in the early teens are at
higher risk of progressing to heavy cannabis use and other illicit
drug use, and to the development of dependence on cannabis.
Women of childbearing age
• Pregnant women who continue to smoke cannabis are probably at
increased risk of giving birth to low birth weight babies, and perhaps
of shortening their period of gestation.
• Women of childbearing age who smoke cannabis at the time of
conception or while pregnant possibly increase the risk of their
children being born with birth defects.
Persons with pre-existing diseases
Persons with a number of pre-existing diseases who smoke cannabis are
probably at an increased risk of precipitating or exacerbating
symptoms of their diseases. These include:
• individuals with cardiovascular diseases, such as coronary artery
disease, cerebrovascular disease and hypertension;
• individuals with respiratory diseases, such as asthma,
bronchitis, and emphysema;
• individuals with schizophrenia, who are at increased risk of
precipitating or of exacerbating schizophrenic symptoms;
• individuals who are dependent on alcohol and other drugs, who are
probably at an increased risk of developing dependence on cannabis.
The health risks of alcohol, tobacco and cannabis use
Acute effects
Alcohol. The major risks of acute cannabis use are similar to the
acute risks of alcohol intoxication in a number of respects. First,
both drugs produce psychomotor and cognitive impairment. The
impairment produced by alcohol increases risks of various kinds of
accident. It remains to be determined whether cannabis intoxication
produces similar increases in accidental injury and death, although on
balance it probably does. Second, substantial doses of alcohol taken
during the first trimester of pregnancy can produce a foetal alcohol
syndrome. There is suggestive but far from conclusive evidence that
cannabis used during pregnancy may have similar adverse effects.
Third, there is a major health risk of acute alcohol use that is not
shared with cannabis. In large doses alcohol can cause death by
asphyxiation, alcohol poisoning, cardiomyopathy and cardiac infarct
whereas there are no recorded cases of fatalities attributable to
cannabis.
Tobacco. The major acute health risks that cannabis share with tobacco
are the irritant effects of smoke upon the respiratory system, and the
stimulating effects of both THC and nicotine on the cardiovascular
system, both of which can be detrimental to persons with
cardiovascular disease.
Chronic effects
Alcohol. Chronic cannabis use may share some of the risks of heavy
chronic alcohol use. First, heavy use of either drug increases the
risk of developing a dependence syndrome in which users experience
difficulty in stopping or controlling their use. There is strong
evidence for such a syndrome in the case of alcohol and reasonable
evidence in the case of cannabis. Second, there is reasonable clinical
evidence that the chronic heavy use of alcohol can produce psychotic
symptoms and psychoses in some individuals. There is suggestive
evidence that chronic heavy cannabis use may produce a toxic
psychosis, precipitate psychotic illnesses in predisposed individuals,
and exacerbate psychotic symptoms in individuals with schizophrenia.
Third, there is good evidence that chronic heavy alcohol use can
indirectly cause brain injury - the Wernicke-Korsakov syndrome - with
symptoms of severe memory defect and an impaired ability to plan and
organise. Chronic cannabis use does not produce cognitive impairment
of comparable severity but there is suggestive evidence that chronic
cannabis use may produce subtle defects in cognitive functioning, that
may or may not be reversible after abstinence. Fourth, there is
reasonable evidence that chronic heavy alcohol use produces impaired
occupational performance in adults and lowered educational
achievements in adolescents. There is at most suggestive evidence that
chronic heavy cannabis use produces similar, albeit more subtle
impairments in occupational and educational performance of adults.
Fifth, there is good evidence that chronic, heavy alcohol use
increases the risk of premature mortality from accidents, suicide and
violence. There is no comparable evidence for chronic cannabis use,
although it is likely that dependent cannabis users who frequently
drive while intoxicated with cannabis increase their risk of
accidental injury or death. Sixth, alcohol use has been accepted as a
contributory cause of cancer of the oropharangeal organs in men and
women. There is suggestive evidence that chronic cannabis smoking may
also be a contributory cause of cancers of the aerodigestive tract
(i.e. the mouth, tongue, throat, oesophagus, lungs).
Tobacco. The major adverse health effects shared by chronic cannabis
and tobacco smokers are chronic respiratory diseases, such as chronic
bronchitis, and probably, cancers of the aerodigestive tract. The
increased risk of cancer in the respiratory tract is a consequence of
the shared route of administration by smoking. It is possible that
chronic cannabis smoking also shares the cardiotoxic properties of
tobacco smoking, although this possibility remains to be investigated.
1. Summary of report
Introduction
This review of the literature on the health and psychological effects
of cannabis was undertaken at the initiative of the former Federal
Justice Minister, Senator Michael Tate, who requested a review of
knowledge relating to cannabis, to inform policy decisions. At Senator
Tate's urging, a National Task Force on Cannabis was established on 25
May 1992. The Task Force commissioned this review of the evidence on
the health and psychological effects of cannabis use. A new and
independent review was thought necessary because there has not been
any major international review of the literature on the health and
psychological effects of cannabis since 1981, when the Addiction
Research Foundation and World Health Organization jointly reviewed the
literature. The purpose of this review was to update the conclusions
of earlier reviews in the light of research undertaken during the past
decade.
Our approach to the literature
Our review of the literature was not intended to be as comprehensive
as the major review undertaken by the Addiction Research Foundation
and the World Health Organization. The literature is too large, and
the diversity of relevant disciplines represented in it beyond the
expertise we had available for the task. Unavoidably, we have relied
upon expert opinion in the areas that lie outside the authors'
collective expertise which is primarily in areas of epidemiology,
psychiatry, psychopharmacology, neurophysiology and neuropsychology.
In order to minimise the effects of our lack of expertise in certain
areas we have relied upon the consensus views expressed in the
literature by experts in the relevant fields. When there has been
controversy between the experts we have explicitly acknowledged areas
of disagreement. We have checked our understanding and representation
of these expert views by asking Australian and overseas researchers
with expertise in the relevant fields to critically review what we
have written.
Our approach to assessing the health effects of cannabis
The evaluation of the health hazards of any drug is difficult for a
number of reasons. First, causal inferences about the effects of drugs
on human health are difficult to make, especially when the interval
between use and alleged ill effects is a long one. It takes time for
adverse effects to develop and for research to identify such effects.
Second, in making causal inferences there is a tension between the
rigour and relevance of the evidence. The most rigorous evidence is
provided by laboratory investigations using animals or in vitro
preparations (e.g. cell preparations in a test tube) in which well
controlled drug doses are related to precisely specified biological
outcomes. The relevance of this evidence to human disease is
uncertain, however, because many inferences have to be made in linking
the occurrence of specific biological effects in laboratory animals to
the likely effects of human use. Epidemiological studies of
relationships between drug use and human disease are of greater
relevance to the appraisal of the health risks of human drug use, but
their relevance is purchased at the price of reduced rigour. Doses of
illicit drugs over periods of years are difficult to quantify because
of the varied dosages of blackmarket drugs and the stigma in admitting
to illicit drug use. Interpretation is further complicated by
correlations between cannabis use and alcohol, tobacco and other
illicit drug use.
Third, appraisals of the hazards of drug use are affected by the
social approval of the drugs in question. The countercultural
symbolism of cannabis use in the late 1960s has introduced an
unavoidable sociopolitical dimension to the debate about the severity
of its adverse health effects. Politically conservative opponents of
cannabis use justify continued prohibition by citing evidence of the
personal and social harms of cannabis use. When the evidence is
uncertain they resolve uncertainty by assuming that the drug is unsafe
until proven safe. Complementary behaviour is exhibited by proponents
of cannabis use. Evidence of harm is discounted and uncertainties
about the ill-effects of chronic cannabis use resolved by demanding
better evidence, arguing that until such evidence is available
individuals should be allowed to choose whether or not they use the
drug.
Such evidential standards are rarely applied consistently. The
politically conservative would reject a similar approach to the
appraisal of the health hazards of industrial processes. Similarly,
proponents of cannabis liberalisation rarely apply the principles used
in their risk assessment of cannabis to the appraisal of the health
effects of pharmaceutical drugs, industrial processes, and pesticides.
To guard against such double evidential standards we will be as
explicit as possible about the evidential standards we have used, and
attempt to be as even-handed as we can in their application.
Evidential desiderata
The burden of proof concerns who bears the responsibility for making a
case: those who make a claim of adverse health effects of cannabis, or
those who doubt it. If the burden falls on those who claim that it is
safe, uncertainty will be resolved by assuming that it is unsafe until
proved otherwise; conversely, if the burden falls on those who claim
that the drug is unsafe, then it will be assumed to be safe until
proven otherwise.
It is by no means agreed who bears the burden of proof in the debate
about the health effects of cannabis use. Proponents of continued
prohibition appeal to established practice, arguing that since the
drug is illegal the burden of proof falls upon those who want to
legalise it; opponents of existing policies argue that the burden of
proof falls upon those who wish to use the criminal law to prevent
adults from freely choosing to use a drug.
We will vary the burden of proof depending upon the state of the
evidence and argument. Once a prima facie case of harm has been made,
positive evidence of safety is required rather than the simple absence
of any evidence of ill effect. We will assume that a prima facie case
has been made when there is either direct evidence that the drug has
ill effects in humans or animals (e.g. from a case-control study), or
there is a compelling argument that it could, e.g. since tobacco
smoking causes lung cancer, and since cannabis and tobacco smoke are
similar in their constituents, it is probable that heavy cannabis
smoking also causes lung cancer.
Standard of proof reflects the degree of confidence required in an
inference that there is a causal connection between drug use and harm.
In courts of law, the standard of proof demanded depends upon the
seriousness of the offence at issue and the consequences of a verdict,
with a higher standard of proof, "beyond reasonable doubt", being
demanded in criminal cases, and the "balance of probabilities" being
acceptable in civil cases. Scientists generally require something
closer to the standard of "beyond reasonable doubt" than the balance
of probabilities before they draw confident conclusions of harm.
However, since there are few adverse health effects of cannabis use
which meet this standard, we will indicate when the evidence permits
an inference to be made on the balance of probabilities.
The criteria for causal inference that we will use are standard ones.
These are: (1) evidence that there is a relationship between cannabis
use and a health outcome provided by one of the accepted types of
research design (namely, case-control, cross-sectional, cohort, or
experiment); (2) evidence provided by a statistical test or confidence
interval that the relationship is unlikely to be due to chance; (3)
good evidence that drug use precedes the adverse effect (e.g. from a
cohort study); and (4) evidence either from experiment, or
observational studies with statistical or other form of control, which
makes it unlikely that the relationship is due to some other variable
which is related to both cannabis use and the adverse health effect.
In the trade-off between relevance and rigour, our preference will be
for human evidence, both experimental and epidemiological, over animal
and in vitro studies. In the absence of human evidence, in vitro and
animal experiments will be regarded as raising a suspicion that drug
use has an adverse effects on human health, with the degree of
suspicion being in proportion to the number of such studies, the
consistency of their results across different species and experimental
preparations, and the degree of expert consensus on the
trustworthiness of the inferences from effects in vitro and in vivo to
adverse effects on human health under existing patterns of usage.
Ideally, it would be desirable to quantify the magnitude of risk posed
by cannabis use by estimating both the relative and attributable risks
of specific health effects. However, since there is generally
insufficient evidence to estimate these risks for many putative
adverse effects of cannabis, the magnitude of a health risk posed by
cannabis use will be qualitatively assessed by a comparison of its
probable health effects with those of two other widely used
recreational drugs, alcohol and tobacco. The motive for such a
comparison is to minimise double standards in the appraisal of the
health effects of cannabis use by providing some kind of common
standard, however approximate, for making societal decisions about
cannabis use.
Cannabis the drug
Cannabis is a generic name for a variety of preparations derived from
the plant Cannabis sativa. A sticky resin which covers the flowering
tops and upper leaves, most abundantly in the female plant, contains
more than 60 cannabinoid substances. Laboratory research on animals
and humans has demonstrated that the primary psychoactive constituent
in cannabis is the cannabinoid, delta-9-tetrahydrocannabinol or THC.
The cannabinoid receptor
Cannabis resembles the opioid drugs in acting upon specific receptors
in the brain. In this respect it differs from alcohol, cocaine and
other illicit drugs which act by disrupting brain processes. The
determination and characterisation of a specific cannabinoid receptor
has made it possible to map its distribution in the brain, and to
demonstrate that its well-known psychoactive effects are receptor
mediated. Very recently an endogenous brain molecule has been
discovered which binds to the cannabinoid receptor and mimics the
action of cannabinoids. It has been called "anandamide", from the
Sanskrit word for bliss. Its discovery promises to stimulate a great
deal of research which will improve our understanding of the role
played by a cannabinoid-like system of the brain, and elucidate the
mechanism of action of cannabis.
Forms of cannabis
The concentration of THC varies between the three most common forms of
cannabis: marijuana, hashish and hash oil. Marijuana is prepared from
the dried flowering tops and leaves of the harvested plant. The
potency of the marijuana depends upon the growing conditions, the
genetic characteristics of the plant and the proportions of plant
matter. The flowering tops and bracts are highest in THC
concentration, with potency descending through the upper leaves, lower
leaves, stems and seeds. The concentration of THC in a batch of
marijuana containing mostly leaves and stems may range from 0.5-5 per
cent, while the "sinsemilla" variety with "heads" may have THC
concentrations of 7-14 per cent.
Hashish or hash consists of dried cannabis resin and compressed
flowers. The concentration of THC in hashish generally ranges from 2-8
per cent, although it can be as high as 10-20 per cent. Hash oil is a
highly potent and viscous substance obtained by extracting THC from
hashish (or marijuana) with an organic solvent, concentrating the
filtered extract, and in some cases subjecting it to further
purification. The concentration of the THC in hash oil is generally
between 15 per cent and 50 per cent.
Routes of administration
Almost all possible routes of administration have been used, but by
far the most common method is smoking (inhaling). Marijuana is most
often smoked as a hand-rolled "joint", the size of a cigarette or
larger. Tobacco is often added to assist burning, and a filter is
sometimes inserted. Hashish may also be mixed with tobacco and smoked
as a joint, but it is probably more frequently smoked through a pipe,
with or without tobacco. A water pipe known as a "bong" is a popular
implement for all cannabis preparations because the water cools the
hot smoke before it is inhaled and there is little loss of the drug
through sidestream smoke. Hash oil is used sparingly because of its
extremely high psychoactive potency; a few drops may be applied to a
cigarette or a joint, to the mixture in the pipe, or the oil may be
heated and the vapours inhaled. Whatever method is used, smokers
inhale deeply and hold their breath for several seconds in order to
ensure maximum absorption of THC by the lungs.
Hashish may also be cooked or baked in foods and eaten. When ingested
orally the onset of the psychoactive effects is delayed by about an
hour. The "high" may be of lesser intensity but the duration of
intoxication is longer by several hours. It is easier to titrate the
dose and achieve the desired level of intoxication by smoking than by
ingestion, since the effects from smoking are more immediate. Crude
aqueous extracts of cannabis have been very rarely injected
intravenously, but this route is unpopular since THC is insoluble in
water, and hence, little or no drug is actually present in these
extracts. Moreover, the injection of tiny undissolved particles may
cause severe pain and inflammation at the site of injection, and a
variety of toxic systemic effects.
Dosage
A typical joint contains between 0.5g and 1.0g of cannabis plant
matter, which may vary in THC content between 5mg and 150mg (i.e.
typically between 1 per cent and 15 per cent). The actual amount of
THC delivered in the smoke has been estimated at 20-70 per cent, the
rest being lost through combustion or sidestream smoke. The
bioavailability of THC (the fraction of THC in the cigarette which
reaches the bloodstream) from marijuana cigarettes in human subjects
has been reported to range from 5-24 per cent. Given all of these
variables, the actual dose of THC absorbed when cannabis is smoked is
not easily quantified.
In general, only a small amount of cannabis (e.g. 2-3mg of available
THC) is required to produce a brief pleasurable high for the
occasional user, and a single joint may be sufficient for two or three
individuals. A heavy smoker may consume five or more joints per day,
while heavy users in Jamaica, for example, may consume up to 420mg THC
per day. In clinical trials designed to assess the therapeutic
potential of THC, single doses have ranged up to 20mg in capsule form.
In human experimental research, THC doses of 10mg, 20mg and 25mg have
been administered as low, medium and high doses.
Patterns of use
Cannabis is the most widely used illicit drug in Australia, having
been tried by a third of the adult population, and by the majority of
young adults between the ages of 18 and 25. The most common route of
administration is by smoking, and the most widely used form of the
drug is marijuana. In the majority of cases cannabis use is
"experimental", that is, most users use the drug on a small number of
occasions, and either discontinue their use, or use intermittently and
episodically after first trying it. Even among those who continue to
use the drug over longer periods, the majority discontinue their use
in their mid to late 20s.
Only a small proportion of those who ever use cannabis use it on a
daily basis over an extended period such as several years. Because of
uncertainties about the dose received, there is no good information on
the amount of THC ingested by such regular users. "Heavy" use is
consequently defined approximately in terms of frequency of use rather
than the estimated average dose of THC received. The daily or near
daily use pattern over a period of years is the pattern that probably
places cannabis users at greatest risk of experiencing long-term
health and psychological consequences of use. Daily cannabis users are
more likely to be male and less well educated; they are also more
likely to regularly use alcohol and to have experimented with a
variety of other illicit drugs, such as, amphetamines, hallucinogens,
psychostimulants, sedatives and opioids.
Metabolism of cannabinoids
Different methods of ingesting cannabis give rise to differing
pharmacokinetics, i.e. patterns of absorption, metabolism and
excretion of the active agent. Upon inhalation, THC is absorbed from
the lungs into the bloodstream within minutes. After oral
administration absorption is much slower, taking one to three hours
for THC to enter the bloodstream, and delaying the onset of
psychoactive effects. When cannabis is smoked, the initial metabolism
of THC takes place in the lungs, followed by more extensive metabolism
by liver enzymes, with the transformation of THC to a number of
metabolites. The most rapidly produced metabolite is 9-carboxy-THC,
which is detectable in blood within minutes of smoking. Another major
metabolite produced is 11-hydroxy-THC, which is approximately 20 per
cent more potent than THC, and penetrates the blood-brain barrier more
rapidly. It is present at very low concentrations in the blood after
smoking, but at high concentrations after the oral route. THC and its
hydroxylated metabolites account for most of the observed effects of
the cannabinoids.
Peak blood levels of THC are usually reached within 10 minutes of
smoking, and decline rapidly thereafter to about 5-10 per cent of
their initial level within the first hour. This initial rapid decline
reflects both rapid conversion to its metabolites, as well as the
distribution of unchanged THC to lipid-rich tissues, including perhaps
the brain.
THC and its metabolites are highly fat soluble and may remain for long
periods in the fatty tissues of the body, from which they are slowly
released back into the bloodstream. The terminal half-life of THC (the
time required to clear half of the administered dose from the body) is
significantly shorter for experienced or daily users (19-27 hours)
than for inexperienced users (50-57 hours). Since tissue distribution
is similar for both users and non-users, it is the immediate and
subsequent metabolism that occurs more rapidly in experienced users.
Given the slow clearance of THC, repeated administration results in
the accumulation of THC and its metabolites in the body. Because of
its slow release from fatty tissues back into the bloodstream, THC and
its metabolites may be detectable in blood for several days, and
traces may persist for several weeks. Several studies have examined
measures of cannabinoids in fat, confirming that THC may be stored for
at least 28 days.
Detection of cannabinoids in body fluids
Cannabinoid levels in the body depend on both the dose given and the
smoking history of the individual, but are subject to a vast degree of
individual variability. Plasma levels of THC in man may range between
0-500ng/ml, depending on the potency of the cannabis ingested and the
time since smoking. The detection of THC in blood above 10-15ng/ml
provides evidence of recent consumption of the drug, although how
recent is not possible to determine. A more precise estimate of time
of consumption may be obtained from the ratio of THC to 9-carboxy-THC:
similar concentrations of both in blood indicate very recent use (in
the vicinity of 20-40 minutes) and a high probability of intoxication.
When the levels of 9-carboxy-THC are substantially higher than those
of THC itself, ingestion could be estimated to have occurred more than
half an hour ago. It is very difficult to determine the time of
administration from blood concentrations even if the smoking habits of
the individual and the exact dose consumed were known. Therefore, the
results of blood analyses are not easily interpreted and, at best,
only confirm the "recent" use of cannabis.
Intoxication and levels of cannabinoids
Since there is evidence that cannabis intoxication adversely affects
skills required to drive a motor vehicle (see below), it would be
desirable to have a reliable measure of impairment due to cannabis
intoxication that was comparable to the breath test of alcohol
intoxication. However, there is no clear relationship between blood
levels of THC or its metabolites and degree of either impairment or
subjective intoxication. A general consensus of forensic toxicologists
is that blood concentrations associated with impairment after smoking
cannabis have not been sufficiently established to provide a basis for
legal testimony in cases concerning driving a motor vehicle while
under the influence of cannabis.
Acute psychological and health effects
The major reason for the widespread recreational use of cannabis is
that it produces a "high", an altered state of consciousness which is
characterised by mild euphoria, relaxation, and perceptual
alterations, including time distortion and the intensification of
ordinary sensory experiences, such as eating, watching films, and
listening to music. When used in a social setting the high is often
accompanied by infectious laughter, and talkativeness. Cognitive
effects are also marked. They include impaired short-term memory, and
a loosening of associations, which make it possible for the user to
become lost in pleasant reverie and fantasy. Motor skills and reaction
time are also impaired, so skilled activity of various kinds is
frequently disrupted.
Not all the acute psychological effects of cannabis are welcomed by
users. The most common unpleasant psychological effects are anxiety,
sometimes producing frank panic reactions, or a fear of going mad, and
dysphoric or unpleasant depressive feelings. Psychotic symptoms such
as delusions and hallucinations may be more rarely experienced at very
high doses. These effects are most often reported by naive users who
are unfamiliar with the drug's effects, and by patients who have been
given oral THC for therapeutic purposes. More experienced users may
occasionally report these effects after oral ingestion of cannabis,
when the effects may be more pronounced and of longer duration than
those usually experienced after smoking cannabis. These effects can
usually be prevented by adequately informing users about the type of
effects they may experience, and once developed can be readily managed
by reassurance and support.
The inhalation of marijuana smoke, or the ingestion of THC has a
number of bodily effects. Among these the most dependable is an
increase in heart rate of 20-50 per cent over baseline, which occurs
within a few minutes to a quarter of an hour, and lasts for up to
three hours. Changes in blood pressure also occur, which depend upon
posture: blood pressure is increased while the person is sitting, and
decreases while standing. In healthy young users these cardiovascular
effects are unlikely to be of any clinical significance because
tolerance develops to the effects of THC, and young, healthy hearts
will only be mildly stressed.
The acute toxicity of cannabis, and cannabinoids more generally, is
very low. There are no confirmed cases of human deaths from cannabis
poisoning in the world medical literature. This is unlikely to be due
to a failure to detect such deaths, because animal studies indicate
that the dose of THC required to produce 50 per cent mortality in
rodents is extremely high by comparison with other commonly used
pharmaceutical and recreational drugs. The lethal dose also increases
as one moves up the phylogenetic tree, suggesting by extrapolation
that the lethal dose in humans could not be achieved by either smoking
or ingesting the drug.
Psychomotor effects and driving
The major potential health risk from the acute use of cannabis arises
from its effects on psychomotor performance. Intoxication produces
dose-related impairments in a wide range of cognitive and behavioural
functions that are involved in skilled performances like driving an
automobile or operating machinery. The negative effects of cannabis on
the performance of psychomotor tasks is almost always related to dose.
The effects are generally larger, more consistent and of increased
persistence in difficult tasks which involve sustained attention. The
acute effects of doses of cannabis which are subjectively equivalent
to or higher than usual recreational doses on driving performance in
laboratory simulators and over standardised driving courses, are
similar to those of doses of alcohol that achieve blood alchol
concentrations between 0.07 per cent and 0.10 per cent.
While cannabis impairs performance in laboratory and simulated driving
settings, it is difficult to relate the magnitude of these impairments
to the risk of being involved in motor vehicle accidents. Studies of
the effects of cannabis on on-road driving performance have found at
most modest impairments. Cannabis intoxicated persons drive more
slowly, and generally take fewer risks, than alcohol intoxicated
drinkers, probably because they are more aware of their level of
psychomotor impairment.
There is no controlled epidemiological evidence that cannabis users
are at increased risk of being involved in motor vehicle or other
accidents. This is in contrast to the case of alcohol use and
accidents, where case-control studies have shown that persons with
blood alcohol levels indicative of intoxication are over-represented
among accident victims. All that is available are studies of the
prevalence of cannabinoids in the blood of motor vehicle and other
accident victims, which have found that between 4 per cent and 37 per
cent of such blood samples have contained cannabinoids, typically in
association with blood alcohol levels indicative of intoxication.
These studies are difficult to evaluate for a number of reasons.
First, in the absence of information on the prevalence of cannabinoids
in the blood of non-accident victims, we do not know whether persons
with cannabinoids are over-represented among accident victims. Second,
the presence of cannabinoids in blood indicates only recent use, not
necessarily intoxication at the time of the accident. Third, there are
also serious problems of causal attribution, since more than 75 per
cent of drivers with cannabinoids in their blood also have blood
levels indicative of alcohol intoxication.
Attempts have been made to circumvent the first difficulty by using
NIDA Household survey data (from the United States) to estimate what
proportion of drivers might be expected to have cannabinoids in their
blood and urine. These suggest that cannabis users are two to four
times more likely to be represented among accident victims than
non-cannabis users; cannabis users who also use alcohol, rather than
cannabis only users, are even more likely to be over-represented among
accident victims. Other indirect support for an increased risk of
accidental death associated with cannabis use comes from surveys of
self-reported accidents among adolescent drug users, and from
epidemiological studies of the relationships between cannabis use and
mortality, and health service utilisation.
The known effects of interactions between cannabis and other drugs on
psychomotor performance are what would be predicted from their
separate effects. The drug most often used in combination with
cannabis is alcohol. The separate effects of alcohol and cannabis on
psychomotor impairment and driving performance are approximately
additive.
The effects of chronic cannabis use
Cellular effects and the immune system
There is reasonably consistent evidence that some cannabinoids, most
especially THC, can produce a variety of cellular changes, such as
alterations to cell metabolism, and DNA synthesis, in vitro (i.e. in
the test tube). There is stronger and more consistent evidence that
cannabis smoke is mutagenic in vitro, and in vivo (i.e. in live
animals), and hence, that it is potentially carcinogenic. If cannabis
smoke is carcinogenic then it is probably for the same reasons that
cigarette smoke is, rather than because it contains cannabinoids.
Hence, if chronic cannabis smoking causes cancer, it is most likely to
develop after long-term exposure at those sites which receive maximum
exposure, namely, the lung and upper aerodigestive tract (see below).
There is reasonably consistent evidence that cannabinoids impair both
the cell-mediated and humoral immune systems in rodents. Humoral
immune suppression is seen in decreased antibody formation responses
to antigens, and decreased lymphocyte response to B-cell mitogens.
Cell-mediated immune suppression is revealed by a reduction in
lymphocyte response to T-cell mitogens. These changes have produced
decreased resistance to infection by a bacteria and a virus. There is
also evidence that the non-cannabinoid components of cannabis smoke
impair the functioning of alveolar macrophages, the first line of the
body's defence system in the lungs. The clinical relevance of these
findings is uncertain, however. The doses required to produce these
effects have generally been very high, and the problem of
extrapolating to the effects of doses used by humans is complicated by
the possibility that tolerance may also develop to such effects.
The limited experimental and clinical evidence in humans is mixed,
with a small number of studies suggesting adverse effects that have
not been replicated by others. At present, there is no conclusive
evidence that consumption of cannabinoids predisposes man to immune
dysfunction, as measured by reduced numbers or impaired functioning of
T-lymphocytes, B-lymphocytes or macrophages, or reduced immunoglobulin
levels. There is suggestive evidence that THC impairs T-lymphocyte
responses to mitogens and allogenic lymphocytes.
The clinical and biological significance of these possible
immunological impairments in chronic cannabis users is uncertain. To
date there has been no epidemiological, or even anecdotal, evidence of
increased rates of disease among chronic heavy cannabis users, such as
was seen among young homosexual men in the early 1980s when the
Acquired Immune Deficiency Syndrome was first recognised. There is one
large prospective study of HIV-positive homosexual men which indicates
that continued cannabis use did not increase the risk of progression
to AIDS. Given the duration of large-scale cannabis use by young
adults in Western societies, the absence of any epidemics of
infectious disease makes it unlikely that cannabis smoking produces
major impairments in the immune system.
It is more difficult to exclude the possibility that chronic heavy
cannabis use produces a minor impairment in immunity. Such an effect
would be manifest in small increases in the rate of occurrence of
common bacterial and viral illnesses among chronic users which could
have escaped detection in the few studies that have attempted to
address the issue. Such an increase could nonetheless be of public
health significance because of the increased expenditure on health
services, and the loss of productivity that it would cause among the
young adults who are the heaviest users of cannabis.
The possibility that cannabinoids may produce minor impairments in the
immune system would also raise doubts about the therapeutic usefulness
of cannabinoids in immunologically compromised patients, such as those
undergoing cancer chemotherapy, or those with AIDS. AIDS patients may
provide one of the best populations in which to detect any such
effects. If it was ethical to conduct clinical trials of cannabinoids
to improve appetite and well-being in AIDS patients, then studies of
the impact of cannabis use on their compromised immune systems would
provide one way of evaluating the seriousness of this concern.
The cardiovascular system
There is insufficient new evidence to change the conclusions reached
by the Institute of Medicine in 1982, namely, that although the
smoking of marijuana "causes changes to the heart and circulation that
are characteristic of stress ... there is no evidence ... that it
exerts a permanently deleterious effect on the normal cardiovascular
system..." (p72). The situation may be less benign for patients with
hypertension, cerebrovascular disease and coronary atherosclerosis, in
which case there is evidence that marijuana poses a threat because it
increases the work of the heart. The "magnitude and incidence" of the
threat remains to be determined as the cohort of chronic cannabis
users of the late 1960s enters the age of maximum risk for
complications of atherosclerosis in the heart, brain and peripheral
blood vessels. In the interim, because any such effects could be life
threatening in patients with significant occlusion of the coronary
arteries or other cerebrovascular disease, patients with
cardiovascular disease should be advised not to consume cannabis, and
perhaps not to use THC therapeutically.
The respiratory system
Chronic heavy cannabis smoking impairs the functioning of the large
airways, and probably causes symptoms of chronic bronchitis such as
coughing, sputum production, and wheezing. Given the adverse effects
of tobacco smoke, which is qualitatively very similar in composition
to cannabis smoke, it is likely that chronic cannabis use predisposes
individuals to develop chronic bronchitis and respiratory cancer.
There is reasonable evidence for an increased risk of chronic
bronchitis, and evidence that chronic cannabis smoking may produce
histopathological changes in lung tissues of the kind that precede the
development of lung cancer.
More recently, concern about the possibility of cancers being induced
by chronic cannabis smoking has been heightened by case reports of
cancers of the aerodigestive tract in young adults with a history of
heavy cannabis use. Although these reports fall short of providing
convincing evidence because many of the cases concurrently used
alcohol and tobacco, they are clearly a major cause for concern, since
such cancers are usually rare in adults under the age of 60, even
among those who smoke tobacco and drink alcohol. The conduct of
case-control studies of these cancers should be a high priority for
research which aims to identify the possible adverse health effects of
chronic cannabis use.
Reproductive effects
Chronic cannabis use probably disrupts the male and female
reproductive systems in animals, reducing testosterone secretion, and
sperm production, motility, and viability in males, and disrupting the
ovulatory cycle in females. It is uncertain whether it is likely to
have these effects in humans, given the inconsistency in the limited
literature on human males, and the lack of research in the case of
human females. There is also uncertainty about the clinical
significance of these effects in normal healthy young adults. They may
be of greater concern among young adolescents, and among males with
fertility impaired for other reasons.
Cannabis use during pregnancy probably impairs foetal development,
leading to smaller birthweight, perhaps as a consequence of shorter
gestation, and probably by the same mechanism as cigarette smoking,
namely, foetal hypoxia. There is uncertainty about whether cannabis
use during pregnancy produces a small increase in the risk of birth
defects as a result of exposure of the foetus in utero. Prudence
demands that until this issue is resolved, women should be advised not
to use cannabis during pregnancy, or when attempting to conceive.
There is not a great deal of evidence that cannabis use can produce
chromosomal or genetic abnormalities in either parent which could be
transmitted to offspring. Such animal and in vitro evidence as exists
suggests that the mutagenic capacities of cannabis smoke are greater
than those of THC, and are probably of greater relevance to the risk
of users developing cancer than to the transmission of genetic defects
to children.
There is suggestive evidence that infants exposed in utero to cannabis
may experience transient behavioural and developmental effects during
the first few months after birth. There is a single study which
suggests an increased risk of childhood leukemia occurring among the
children born to women who used cannabis during their pregnancies. Its
replication is of some urgency.
Psychological effects of chronic cannabis use
Adolescent development
There is strong continuity of development from adolescence into early
adult life in which many indicators of adverse development which have
been attributed to cannabis use precede its use, and increase the
likelihood of using cannabis. These include minor delinquency, poor
educational performance, nonconformity, and poor adjustment. A
predictable sequence of initiation into the use of illicit drugs was
identified among American adolescents in the 1970s, in which the use
of licit drugs preceded experimentation with cannabis, which preceded
the use of hallucinogens and "pills", which in turn preceded the use
of heroin and cocaine. Generally, the earlier the age of initiation
into drug use, and the greater the involvement with any drug in the
sequence, the greater the likelihood of progression to the next drug
in the sequence.
The causal significance of these findings, and especially the role of
cannabis in the sequence of illicit drug use, remains controversial.
The hypothesis that the sequence of use represents a direct
pharmacological effect of cannabis use upon the use of later drugs in
the sequence is the least compelling. A more plausible and better
supported explanation is that it reflects a combination of two
processes: the selective recruitment into cannabis use of
nonconforming and deviant adolescents who have a propensity to use
illicit drugs; and the socialisation of cannabis users within an
illicit drug using subculture which increases the exposure,
opportunity, and encouragement to use other illicit drugs.
Although strong conclusions cannot be drawn, on the evidence from
cross-sectional and longitudinal studies of cohorts of American
adolescents in the 1970s and 1980s, there are suggestions that chronic
heavy cannabis use can adversely affect adolescent development in a
number of ways.
There has been suggestive support for the hypothesis that heavy
adolescent use of cannabis impairs educational performance. In
cross-sectional surveys, cannabis use is related to an increased risk
of failing to complete a high school education, and of job instability
in young adulthood. These relationships in cross-sectional studies are
exaggerated because those who are most likely to use cannabis have
lower pre-existing academic aspirations and high school performance
than those who do not use it. When pre-existing academic aptitude and
interest are taken into account, the relationship between cannabis use
and educational and occupational performance is much more modest. Even
though modest, the suggestive adverse effects of cannabis and other
drug use upon educational performance are important because they may
cascade throughout young adult life, affecting choice of occupation,
level of income, choice of mate, and quality of life of the user and
his or her children.
There is weaker but suggestive evidence that heavy cannabis use has
adverse effects upon family formation, mental health, and involvement
in drug-related (but not other types of) crime. In the case of each of
these outcomes, the apparently strong associations revealed in
cross-sectional data are much more modest in longitudinal studies,
after statistically controlling for associations between cannabis use
and other variables which predict these adverse outcomes.
On balance, there are sufficient indications that cannabis use in
adolescence probably adversely affects adolescent development to
conclude that it is desirable to discourage adolescent cannabis use,
and especially regular cannabis use.
Adult adjustment
The evidence that chronic heavy cannabis use produces an amotivational
syndrome among adults is equivocal. The positive evidence largely
consists of case histories, and observational reports. The small
number of controlled field and laboratory studies have not found
compelling evidence for such a syndrome, although their evidential
value is limited by the small sample sizes and limited
sociodemographic characteristics of the field studies, and by the
short periods of drug use, and the youthful good health and minimal
demands made of the volunteers observed in the laboratory studies. If
there is such a syndrome, it is a relatively rare occurrence, even
among heavy, chronic cannabis users.
A dependence syndrome
A cannabis dependence syndrome like that defined in DSM-III-R probably
occurs in heavy, chronic users of cannabis. There is good experimental
evidence that chronic heavy cannabis users can develop tolerance to
its subjective and cardiovascular effects, and there is suggestive
evidence that some users may experience a withdrawal syndrome on the
abrupt cessation of cannabis use. There is clinical and
epidemiological evidence that some heavy cannabis users experience
problems in controlling their cannabis use, and continue to use the
drug despite experiencing adverse personal consequences of use. There
is limited evidence in favour of a cannabis dependence syndrome
analogous to the alcohol dependence syndrome. If the estimates of the
community prevalence of drug dependence provided by the Epidemiologic
Catchment Area study are correct, then cannabis dependence is the most
common form of dependence on illicit drugs.
Recognition of the cannabis dependence syndrome has been delayed by a
number of factors. First, heavy daily cannabis use has been relatively
uncommon, and there have been few individuals who have requested
assistance in stopping their cannabis use. Second, an overemphasis on
evidence of tolerance and a withdrawal syndrome has hindered the
recognition of the syndrome among individuals who have presented for
treatment. Third, the occurrence of cannabis dependence has probably
been overshadowed because it is most common among persons who are
dependent on alcohol and opioids, forms of drug dependence which have
understandably been given higher treatment priority.
Given the widespread use of cannabis, and its continued reputation as
a drug free of the risk of dependence, the clinical features of
cannabis dependence deserve to be better defined. This would enable
the prevalence of a dependence syndrome to be better estimated and
individuals who are dependent on cannabis to be better recognised and
treated. Treatment should probably be on the same principles as other
forms of dependence, although this issue is also in need of research.
Although cannabis dependence is likely to be a larger problem than
previously thought, we should be wary of over-estimating its social
and public health importance. Estimates of the risk of users becoming
dependent suggest that it may be similar to that of alcohol, that it
will be highest among the minority of daily cannabis users, and that
even in this group the prevalence of drug-related problems may be
relatively low by comparison with those of alcohol dependence. There
is likely to be a high rate of remission of cannabis dependence
without formal treatment. While acknowledging the existence of the
syndrome, we should avoid exaggerating its prevalence and the severity
of its adverse effects on individuals. Better research on the
experiences of long-term cannabis users should provide more precise
estimates of the risk.
Cognitive effects
The weight of the available evidence suggests that the long-term heavy
use of cannabis does not produce any severe impairment of cognitive
function. There is reasonable clinical and experimental evidence,
however, that the long-term use of cannabis may produce more subtle
cognitive impairment in the higher cognitive functions of memory,
attention and organisation and integration of complex information.
While subtle, these impairments may affect everyday functioning,
particularly in adolescents with marginal educational aptitude, and
among adults in occupations that require high levels of cognitive
capacity. The evidence suggests that the longer the period that
cannabis has been used, the more pronounced is the cognitive
impairment. It remains to be seen whether the impairment can be
reversed by an extended period of abstinence from cannabis.
There is a need for research to identify the specific cognitive
functions affected by long-term cannabis use, to identify the precise
mechanisms that produce impairment and to relate them to biological
mechanisms, including the cannabinoid receptors and the endogenous
cannabinoid, anandamide. Such research also needs to investigate
individual differences in susceptibility to such effects, and the
impact of long-term cannabis use on adolescents and young adults.
Appropriate treatment programs for long-term dependent cannabis users
will also need to address the subtle cognitive impairments likely to
be found in this population.
Brain damage
A suspicion that chronic heavy cannabis use may cause gross structural
brain damage was provoked by a single poorly controlled study using an
outmoded method of investigation, which reported that cannabis users
had enlarged cerebral ventricles. This finding was widely and
uncritically publicised. Since then a number of better controlled
studies using more sophisticated methods of investigation have
consistently failed to demonstrate evidence of structural change in
the brains of heavy, long-term cannabis users. These negative results
are consistent with the evidence that any cognitive effects of chronic
cannabis use are subtle, and hence unlikely to be manifest as gross
structural changes in the brain. They do not exclude the possibility
that chronic, heavy cannabis use may cause ultrastructural changes at
the receptor level.
Psychotic disorders
There is suggestive evidence that heavy cannabis use can produce an
acute toxic psychosis in which confusion, amnesia, delusions,
hallucinations, anxiety, agitation and hypomanic symptoms predominate.
The evidence for an acute toxic cannabis psychosis comes from
laboratory studies of the effects of THC on normal volunteers and
clinical observations of psychotic symptoms in heavy cannabis users
which seem to resemble those of other toxic psychoses, and which remit
rapidly following abstinence.
There is less support for the hypothesis that cannabis use can cause
either an acute or a chronic functional psychosis which persists
beyond the period of intoxication. Such a possibility is difficult to
study because of the rarity of such psychoses, and the near
impossibility of distinguishing them from schizophrenia and manic
depressive psychoses occurring in individuals who also abuse cannabis.
There is strongly suggestive evidence that chronic cannabis use may
precipitate a latent psychosis in vulnerable individuals. This is only
strongly suggestive because in the best study conducted to date, the
use of cannabis was not documented at the time of diagnosis, there was
a possibility that cannabis use was confounded by amphetamine use, and
there are doubts about whether the study could reliably distinguish
between schizophrenia and acute cannabis-induced, or other
drug-induced, psychoses. Even if this relationship is causal, its
public health significance should not be overstated: the estimated
attributable risk of cannabis use is small (less than 10 per cent),
and even this seems an overestimate, since the incidence of
schizophrenia declined over the period when cannabis use increased
among young adults.
Therapeutic effects of cannabinoids
There is reasonable evidence that THC is an effective anti-emetic
agent for patients undergoing cancer chemotherapy, especially those
whose nausea has proven resistant to the anti-emetic drugs that were
widely used in the late 1970s and early 1980s, when most of the
research was conducted. It is uncertain whether THC is as effective as
newer anti-emetic drugs. Uncertainty also exists about the most
optimal method of dosing and the advantages and disadvantages of
different routes of administration. Nonetheless, there is probably
sufficient evidence to justify THC being made available in synthetic
form to cancer patients whose nausea has proven resistant to
conventional treatment.
There is also reasonable evidence for the potential efficacy of THC
and marijuana in the treatment of glaucoma, especially in cases which
have proved resistant to existing anti-glaucoma agents. Further
research is required to establish the effectiveness and safety of
long-term use, but this should not prevent its use under medical
supervision in individuals with poorly controlled glaucoma.
There is sufficient suggestive evidence of the potential usefulness of
various cannabinoids as anti-spasmodic, and anti-convulsant agents to
warrant further clinical research into their effectiveness. There are
other potential therapeutic uses which require more basic
pharmacological and experimental investigation, e.g. cannabinoids as
possible analgesic and anti-asthma agents.
There is a need for further research into the effectiveness of
cannabis and its derivatives in assisting patients with
HIV/AIDS-related conditions, and in particular, their value in
counteracting weight loss associated with these conditions, improving
mood and easing pain. Case reports have suggested that synthetic THC
may be effective in reducing nausea and stimulating appetite in
symptomatic AIDS patients. While there is a potential concern that
possible effects of cannabinoids on the immune system may have more
serious consequences for HIV positive individuals and AIDS patients, a
recent study has failed to find a relationship between the use of
cannabis, or any other psychoactive drugs, and the rate at which HIV
positive people progress to clinical AIDS.
Despite the basic and clinical research work which was undertaken in
late 1970s and early 1980s, the cannabinoids have not been widely used
therapeutically, nor has further investigation been conducted along
the lines suggested by the Institute of Medicine in 1982. This seems
attributable to the fact that, in the United States, where most
cannabis research has been conducted, clinical research on
cannabinoids has been discouraged by regulation and a lack of funding.
The discouragement of clinical cannabis research, in turn, derives
from the fact that THC, the most therapeutically effective
cannabinoid, is the one that produces the psychoactive effects sought
by recreational users. An unreasonable fear that the therapeutic use
of THC would send "mixed messages" to youth has motivated the
discouragement of research into the therapeutic effects of
cannabinoids.
The recent discovery of a specific cannabinoid receptor and the
endogenous cannabinoid-like substance anandamide may change this
situation by encouraging more basic research on the biology of
cannabinoids which may have therapeutic consequences. It may prove
possible to separate the psychoactive and therapeutic effects of
cannabis, fulfilling the ancient promise of "marijuana as medicine".
Overall appraisal of the health and psychological risks of cannabis
use
The following is a summary of the major adverse health and
psychological effects of acute and chronic cannabis use, classified by
the degree of confidence about the relationship between cannabis use
and the adverse effect.
Acute effects
The major acute adverse psychological and health effects of cannabis
intoxication are:
• anxiety, dysphoria, panic and paranoia, especially in naive
users;
• cognitive impairment, especially of attention and memory;
• psychomotor impairment, and possibly an increased risk of
accident if an intoxicated person attempts to drive a motor vehicle;
• an increased risk of experiencing psychotic symptoms among those
who are vulnerable because of personal or family history of psychosis;
and
• an increased risk of low birth weight babies if cannabis is used
during pregnancy.
Chronic effects
The major health and psychological effects of chronic heavy cannabis
use, especially daily use, over many years, remain uncertain. On the
available evidence, the major probable adverse effects appear to be:
• respiratory diseases associated with smoking as the method of
administration, such as chronic bronchitis, and the occurrence of
histopathological changes that may be precursors to the development of
malignancy;
• development of a cannabis dependence syndrome, characterised by
an inability to abstain from or to control cannabis use; and
• subtle forms of cognitive impairment, most particularly of
attention and memory, which persist while the user remains chronically
intoxicated, and may or may not be reversible after prolonged
abstinence from cannabis.
The following are the major possible adverse effects of chronic, heavy
cannabis use which remain to be confirmed by further research:
• an increased risk of developing cancers of the aerodigestive
tract, i.e. oral cavity, pharynx, and oesophagus;
• an increased risk of leukemia among offspring exposed in utero;
• a decline in occupational performance marked by underachievement
in adults in occupations requiring high level cognitive skills, and
impaired educational attainment in adolescents; and
• birth defects occurring among children of women who used cannabis
during their pregnancies.
High risk groups
A number of groups can be identified as being at increased risk of
experiencing some of these adverse effects.
Adolescents
• Adolescents with a history of poor school performance may have
their educational achievement further limited by the cognitive
impairments produced by chronic intoxication with cannabis.
• Adolescents who initiate cannabis use in the early teens are at
higher risk of progressing to heavy cannabis use and other illicit
drug use, and to the development of dependence on cannabis.
Women of childbearing age
• Pregnant women who continue to smoke cannabis are probably at
increased risk of giving birth to low birth weight babies, and perhaps
of shortening their period of gestation.
• Women of childbearing age who smoke cannabis at the time of
conception or while pregnant possibly increase the risk of their
children being born with birth defects.
Persons with pre-existing diseases
Persons with a number of pre-existing diseases who smoke cannabis are
probably at an increased risk of precipitating or exacerbating
symptoms of their diseases. These include:
• individuals with cardiovascular diseases, such as coronary artery
disease, cerebrovascular disease and hypertension;
• individuals with respiratory diseases, such as asthma, bronchitis
and emphysema;
• individuals with schizophrenia who are at increased risk of
precipitating or of exacerbating schizophrenic symptoms; and
• individuals who are dependent on alcohol and other drugs, who are
probably at an increased risk of developing dependence on cannabis.
Two special concerns
Storage of THC
There is good evidence that with repeated dosing of cannabis at
frequent intervals, THC can accumulate in fatty tissues in the human
body where it may remain for considerable periods of time. The health
significance of this fact is unclear. The storage of cannabinoids
would be serious cause for concern if THC were a highly toxic
substance which remained physiologically active while stored in body
fat. The evidence that THC is a highly toxic substance is weak and its
degree of activity while stored has not been investigated. One
potential health implication of THC storage is that stored
cannabinoids could be released into blood, producing a "flashback",
although this is likely to be a very rare event, if it occurs at all.
Whatever the uncertainties about health implications of THC storage,
all potential users of cannabis should be aware that it occurs.
Increases in the potency of cannabis?
It has been claimed that the existing medical literature on the health
effects of cannabis underestimates its adverse effects, because it was
based upon research conducted on less potent forms of marijuana than
became available in the USA in the past decade. This claim has been
repeated and interpreted in an alarmist fashion in the popular media
on the assumption that an increase in the THC potency of cannabis
necessarily means a substantial increase in the health risks of
cannabis use.
It is far from established that the average THC potency of cannabis
products has substantially increased over recent decades. If potency
has increased, it is even less certain that the average health risks
of cannabis use have materially changed as a consequence, since users
may titrate their dose to achieve the desired effects. Even if the
users are inefficient in titrating their dose of THC, it is not clear
that the probability of all adverse health effects will be thereby
increased. Given the existence of these concerns about THC potency, it
would be preferable to conduct some research on the issue rather than
to rely upon inferences about the likely effects of increased cannabis
potency. Studies of the ability of experienced users to titrate their
dose of THC would contribute to an evaluation of this issue.
A comparative appraisal of health risks: alcohol, tobacco and cannabis
use
The probable and possible adverse health and psychological effects of
cannabis need to be placed in comparative perspective to be fully
appreciated. A useful standard for such a comparison is what is known
about the health effects of alcohol and tobacco, two other widely used
psychoactive drugs. Cannabis shares with tobacco, smoking as the usual
route of administration, and resembles alcohol in being used for its
intoxicating and euphoriant effects. Although allowance has to be made
for the very different prevalence of use of the two drugs, and for the
fact that we know a great deal more about the adverse effects of
alcohol and tobacco use, the comparison serves the useful purpose of
reminding us of the risks we currently tolerate with our favourite
psychoactive drugs.
Acute effects
Alcohol. The major risks of acute cannabis use are similar to the
acute risks of alcohol intoxication in a number of respects. First,
both drugs produce psychomotor and cognitive impairment, especially of
memory and planning. The impairment produced by alcohol increases
risks of various kinds of accident, and the likelihood of engaging in
risky behaviour, such as dangerous driving, and unsafe sexual
practices. It remains to be determined whether cannabis intoxication
produces similar increases in accidental injury and death, although on
the balance of probability it does.
Second, there is good evidence that substantial doses of alcohol taken
during the first trimester of pregnancy can produce a foetal alcohol
syndrome. There is suggestive but far from conclusive evidence that
cannabis used during pregnancy may have similar adverse effects.
Third, there is a major health risk of acute alcohol use that is not
shared with cannabis. In large doses alcohol can cause death by
asphyxiation, alcohol poisoning, cardiomyopathy and cardiac infarct,
whereas there are no recorded cases of fatalities attributable to
cannabis.
Tobacco. The major acute health risks that cannabis share with tobacco
are the irritant effects of smoke upon the respiratory system, and the
stimulating effects of both THC and nicotine on the cardiovascular
system, both of which can be detrimental to persons with
cardiovascular disease.
Chronic effects
Alcohol. There are a number of risks of heavy chronic alcohol use,
some of which may be shared by chronic cannabis use. First, heavy use
of either drug increases the risk of developing a dependence syndrome
in which users experience difficulty in stopping or controlling their
use. There is strong evidence for such a syndrome in the case of
alcohol and reasonable evidence in the case of cannabis. A major
difference between the two is that it is uncertain whether a
withdrawal syndrome reliably occurs after dependent cannabis users
abruptly stop their cannabis use, whereas the abrupt cessation of
alcohol use in severely dependent drinkers produces a well defined
withdrawal syndrome which can be potentially fatal.
Second, there is reasonable clinical evidence that the chronic heavy
use of alcohol can produce psychotic symptoms and psychoses in some
individuals. There is suggestive evidence that chronic heavy cannabis
use may produce a toxic psychosis, precipitate psychotic illnesses in
predisposed individuals, and exacerbate psychotic symptoms in
individuals with schizophrenia.
Third, there is good evidence that chronic heavy alcohol use can
indirectly cause brain injury - the Wernicke-Korsakov syndrome - with
symptoms of severe memory defect and an impaired ability to plan and
organise. With continued heavy drinking, and in the absence of vitamin
supplementation, this injury may produce severe irreversible cognitive
impairment. There is good reason for concluding that chronic cannabis
use does not produce cognitive impairment of comparable severity.
There is suggestive evidence that chronic cannabis use may produce
subtle defects in cognitive functioning, that may or may not be
reversible after abstinence.
Fourth, there is reasonable evidence that chronic heavy alcohol use
produces impaired occupational performance in adults, and lowered
educational achievements in adolescents. There is at most suggestive
evidence that chronic heavy cannabis use produces similar, albeit more
subtle impairments in occupational and educational performance of
adults.
Fifth, there is good evidence that chronic, heavy alcohol use
increases the risk of premature mortality from accidents, suicide and
violence. There is no comparable evidence for chronic cannabis use,
although it is likely that dependent cannabis users who frequently
drive while intoxicated with cannabis increase their risk of
accidental injury or death.
Sixth, alcohol use has been accepted as a contributory cause of cancer
of the oropharangeal organs in men and women. There is suggestive
evidence that chronic cannabis smoking may also be a contributory
cause of cancers of the aerodigestive tract (i.e. the mouth, tongue,
throat, oesophagus, lungs).
Tobacco. The major adverse health effects shared by chronic cannabis
and tobacco smokers are chronic respiratory diseases, such as chronic
bronchitis, and probably, cancers of the aerodigestive tract. The
increased risk of cancer in the respiratory tract is a consequence of
the shared route of administration by smoking. It is possible that
chronic cannabis smoking also shares the cardiotoxic properties of
tobacco smoking, although this possibility remains to be investigated.
Implications for harm reduction
Anyone who wishes to avoid the probable acute and chronic adverse
health effects of cannabis should abstain from using the drug. This
advice is especially pertinent for persons with any of the diseases
(e.g. cardiovascular) or conditions (e.g. pregnancy) which would make
them more vulnerable to the adverse effects of cannabis.
Current cannabis users should be aware of the following risks of using
the drug. First, the risk of being involved in a motor vehicle
accident is likely to be increased when cannabis users drive while
intoxicated by cannabis. The combination of alcohol and cannabis
intoxication will substantially increase this risk. Second, the
chronic smoking of cannabis poses significant risks to the respiratory
system, apart from any specific effects of THC. Third, the respiratory
risks of cannabis smoking are amplified if deep inhalation and
breath-holding are used to maximise the absorption of THC in the
lungs. This technique greatly increases the delivery and retention of
particulate matter and tar. Fourth, daily or near daily use of
cannabis is to be avoided, as it has a high risk of producing
dependence.
2. Introduction
This review of the literature on the health and psychological effects
of cannabis was undertaken at the initiative of the former Federal
Justice Minister, Senator Michael Tate, who requested a review of
knowledge relating to cannabis, to inform policy decisions. At Senator
Tate's urging, a National Task Force on Cannabis was established on 25
May 1992. The Task Force commissioned this review of the evidence on
the health and psychological effects of cannabis use. A new and
independent review was thought necessary because there has not been
any major international review of the literature on the health and
psychological effects of cannabis since 1981, when the Addiction
Research Foundation and World Health Organization jointly reviewed the
literature. The purpose of this review was to update the conclusions
of earlier reviews in the light of research undertaken during the past
decade (ARF/WHO, 1981; Fehr and Kalant, 1983).
2.1 Our approach to the literature
Our review of the literature was not intended to be, and could not
hope to be, as comprehensive as the major review undertaken by the
Addiction Research Foundation and the World Health Organization. The
literature is too large, and the diversity of relevant disciplines
represented in it beyond the expertise we had available for the task.
Unavoidably, we have relied upon published expert opinion in the very
many areas which lie outside the authors' collective expertise, which
is primarily in epidemiology, psychopharmacology, neurophysiology and
neuropsychology. This fact is inevitably reflected in the relative
attention given to the literatures that lie within and beyond our
expertise. The literatures on the psychological consequences of acute
and chronic cannabis use, for example, are much more comprehensively
and critically reviewed than those pertaining to effects on the
reproductive and immune systems. In reviewing the literature that lies
outside our expertise, we have relied upon the consensus views
expressed in the literature by experts in the relevant fields. When
there has been controversy between the experts we have explicitly
acknowledged it. We have checked our understanding and representation
of these expert views by asking Australian and international
researchers with expertise in the relevant fields to critically review
what we have written.
3. Evidential principles
3.1 Issues in appraising health hazards
The evaluation of the health hazards of any drug is difficult for a
variety of scientific and sociopolitical reasons. First, causal
inferences about the effects of drugs on human health are not easy to
make (ARF/WHO, 1981). Even inferences about the relatively direct and
transient effects of acute drug use may be complicated by individual
variability in response to a standard dose of a drug, and by the fact
that serious adverse effects are relatively rare. Inference becomes
more difficult the longer the interval between use and alleged ill
effects: it takes time for such effects to develop, and it may take
considerably longer for the research technology to be developed that
enables these effects to be identified and confidently attributed to
the drug use rather than some other factor (Institute of Medicine,
1982). In the case of chronic tobacco use, for example, it has taken
over three hundred years to discover that it increases premature
mortality from cancer, and heart disease. Moreover, new health hazards
of tobacco use, such as passive smoking, continue to be discovered.
Second, in making causal inferences about drug use and its
consequences there is a tension between the rigour and relevance of
the evidence. The most rigorous evidence is provided by laboratory
investigations using experimental animals, or in vitro preparations of
animal cells and micro-organisms in which well controlled drug doses
are related to precisely measured biological outcomes. The relevance
of such research to human disease, however, is often problematic. A
great many inferences have to be made in linking the occurrence of
specific biological effects in laboratory animals or cell cultures to
the likely effects of the drug under existing patterns of human use.
Epidemiological studies of relationships between drug use and human
disease have manifestly greater relevance to the appraisal of the
health risks of human drug use, but this is purchased at the price of
reduced rigour. Doses of drugs over periods of years are difficult to
quantify in the best of circumstances. The vagaries of human memory
which make quantification of consumption difficult in the case of
tobacco and alcohol are magnified in the case of illicit drugs by the
non-standard doses and contaminants in blackmarket drugs, and the
reluctance of users to report illicit drug use. The fact that
different patterns of drug use and other life-style factors are often
correlated (e.g. alcohol and tobacco), makes attribution of
ill-effects to particular drugs even more difficult (Task Force on
Health Risk Assessment, 1986).
Third, appraisals of the hazards of recreational drug use are
unavoidably affected by the societal approval or disapproval of the
drug in question. As Room (1984) has observed, when evaluating the
impact of alcohol on non-industrialised societies, anthropologists
have often engaged in problem deflation in response to the problem
inflation of missionaries and colonial authorities. In our own
culture, the economic interests of tobacco and alcohol industries
provide a potent reason for problem deflation with these drugs. Such
problem deflationists often discount the adverse effects of alcohol
use, either by contesting the evidence for adverse effects, or by
denying that there is a causal connection between alcohol use and
particular adverse health effects.
Similar processes have been at work in the appraisal of the health
effects of recreational cannabis use. The countercultural symbolism of
cannabis use in the late 1960s has introduced a strong sociopolitical
dimension to the debate about the adverse health effects of cannabis.
Politically conservative opponents of cannabis use, for example,
justify its continued prohibition by citing evidence of the personal
and social harms of its use. When the evidence is uncertain, as it is
with many of the alleged effects of chronic use, they resolve the
uncertainty by assuming that the cannabis is unsafe until proven safe.
Complementary behaviour is exhibited by some proponents of
decriminalisation. Evidence of harm is discounted or discredited, and
uncertainties about the ill-effects of chronic cannabis use are
resolved by demanding more and better evidence, arguing that until
this uncertainty is resolved individuals should be allowed to exercise
their free choice about whether or not they use the drug.
Such approaches to the appraisal of evidence have not always been
consistently applied. Both sides of the debate would reject the
application of their own approaches to the appraisal of cannabis to
the appraisal of the health hazards of alcohol, pesticides,
herbicides, or chemical residues in food. While we do not claim to be
unaffected by these processes, we will be as explicit as possible
about the evidential standards that we have used, and as even-handed
as we can in their application.
3.2 Evidential desiderata
The following issues must be addressed in specifying what we have
taken to be the evidential desiderata in our appraisal of the health
risk of cannabis use: the burden of proof; standard of proof; criteria
for causal inference; preference for relevance or rigour; approaches
to estimating the magnitude of risk; and the desirability of a
comparative appraisal of the risks.
The burden of proof concerns who bears the responsibility for making a
case; those who make a claim of adverse health effects, or those who
doubt it (see Rescher, 1977, chapter XII). Who bears the burden of
proof determines the way in which an issue is decided in the face of
uncertainty: if the burden falls on those who claim that the drug is
safe, uncertainty will be resolved by assuming that it is unsafe until
proved otherwise; conversely, if the burden falls on those who claim
that the drug is unsafe, then it will be assumed to be safe until
proven otherwise.
It is by no means agreed who bears the burden of proof in the debate
about the health effects of cannabis use. Proponents of continued
prohibition appeal to established practice (Whately, 1846), arguing
that since the drug is illegal, the burden of proof falls upon those
who want to legalise it. Some proponents of its legalisation counter
that this begs the question, since there was no evidence, they argue,
that cannabis was harmful when its use was first made a criminal
offence. Others argue that the burden of proof falls upon those who
wish to use the criminal law to prevent adults from freely choosing to
use a drug (e.g. Husak, 1992).
We will vary the burden of proof on the basis of the state of the
evidence and argument. Once a prima facie case of harm has been made,
positive evidence of safety will be required rather than the simple
absence of any evidence of ill effect. We will assume that a prima
facie case has been made either when there is direct evidence that the
drug has ill effects in animals or humans (e.g. from a case-control
study), or when there is some compelling argument that it could, e.g.
the inference that since tobacco smoking causes lung cancer and
cannabis and tobacco smoke are similar in their constituents, it is
probable that heavy cannabis smoking also causes lung cancer.
The standard of proof reflects the degree of confidence required in an
inference that there is a causal connection between drug use and harm.
In courts of law, the standard of proof demanded depends upon the
seriousness of the offence at issue and the consequences of a verdict,
with a higher standard of proof, "beyond reasonable doubt", being
demanded in criminal cases, while the "balance of probabilities" is
acceptable in civil cases. Although these legal standards are not
directly translatable into scientific practice, scientists generally
require something closer to the standard of "beyond reasonable doubt"
than the balance of probabilities before drawing confident conclusions
that a drug causes harm.
If we were to demand that such a standard be met for the health
effects of cannabis, this review would be exceedingly brief.
Consequently, we will relax the criteria and indicate when the
evidence permits a causal inference to be made on the balance of
probabilities. We will take this standard to be exemplified in the
consensus of informed scientific opinion that sufficient evidence has
been provided to infer a probable causal connection between drug use
and a harm (e.g. Fehr and Kalant, 1983; Institute of Medicine, 1982).
In the trade-off between relevance and rigour, our preference will be
for human evidence, both experimental and epidemiological, rather than
animal and in vitro studies. In the absence of human evidence, in
vitro and animal experiments will be taken as raising a suspicion that
drug use has an adverse effects on human health. The degree of
suspicion raised will be in proportion to the number of such animal
studies, the consistency of their results across different species and
experimental preparations (Task Force on Health Risk Assessment,
1986), and the degree of expert consensus that the inferences from
effects in vitro and in vivo to adverse effects under existing
patterns of human use are valid. The degree of consensus on the latter
point will be indicated by the views expressed in authoritative
reviews in peer reviewed journals or contributions to international
consensus conferences (e.g. Fehr and Kalant, 1983; Institute of
Medicine, 1982).
The criteria for causal inference that we will use are standard ones
(see Hall, 1987), namely:
1. Evidence that there is a relationship between drug use and a
health outcome provided by one of the accepted types of
epidemiological research design (namely, case-control,
cross-sectional, cohort, or experiment).
2. Evidence (usually provided by a statistical significance test or
the construction of a confidence interval) that the relationship is
unlikely to be due to chance.
3. Good evidence that drug use precedes the adverse effect (e.g. a
cohort study).
4. Evidence either from experiment, or statistical or other form of
control, which makes it unlikely that the relationship is due to some
other variable which is related to both drug use and the adverse
effect.
In appraising a body of literature as a whole we determine the extent
to which the evidence meets the criteria outlined by Hill (1977).
Ideally, once a strong case has been made for a causal connection
between drug use and an adverse health effect, the magnitude of risk
needs to be estimated so the seriousness of the risk can be
quantified. For example, the consumption of large amounts of water
over a short period of time can kill human beings, but this is not a
good reason for counselling people against drinking water. The
quantities required to produce intoxication and death are so large
(e.g. 30 or more litres) that only diseased or psychotic individuals
consume them.
The standard epidemiological measures of risk magnitude are relative
risk and population attributable risk. The relative risk is the
increase in the odds of experiencing an adverse health outcome among
those who use the drug compared to those who do not (that is, the
number of times greater the risk of experiencing an effect is among
those who use the drug compared with those who do not). The population
attributable risk represents that proportion of cases with an adverse
outcome which is attributable to drug use. The two measures of risk
magnitude have different uses and implications. Relative risk is of
greatest relevance to individuals attempting to estimate the increase
in their risk of experiencing an adverse outcome if they use a drug.
Attributable risk is of most relevance to a societal appraisal of the
harms of drug use.
The importance of the two measures of risk magnitude depends upon the
prevalence of drug use and the base rate of the adverse outcome. An
exposure with a low relative risk may have a large public health
impact if a large proportion of the population is exposed (e.g.
cigarette smoking and heart disease). Conversely, an exposure with a
high relative risk may have little public health importance because
very few people are exposed to it. Accordingly, an appraisal of the
public health importance of illicit drug use must take some account
not only of the relative risk of harm, but also the prevalence of use
and the base rate of the adverse effect. As will become apparent in
the course of this review, it is very difficult to estimate either
relative or attributable risk of any probable adverse health effects
of cannabis use because few epidemiological studies have been
conducted.
A different way of assessing the health risk posed by cannabis use has
had to be used: a comparative qualitative appraisal of its risks with
those of other widely used recreational drugs such as alcohol and
tobacco (ARF/WHO, 1981). The motive for such comparisons is that they
reduce the operation of double-standards in the health appraisal of
drug use by reminding us that the drugs we currently tolerate pose
major health risks. They also help to put the risk of newer drugs into
perspective, so that we can use a common standard when making societal
decisions about whether or not to tolerate such drug use. The task of
comparison, however, is more difficult than it seems at first.
First, we know much more about the quantitative risks of acute and
chronic tobacco and alcohol use than we know about the health risks of
currently illicit drugs. This is largely because the legal drugs have
been consumed by substantial proportions of the population, over
centuries in the case of tobacco, and millennia in the case of
alcohol, and there have been more than 40 years of scientific studies
of the health consequences of their use. The contemporary illicit
drugs, by contrast, have been much less widely used in Western
society, and for a shorter period, primarily by healthy young adults;
there have also been few studies of their adverse health effects, and
there have been even fewer attempts to quantify the risks of their
use.
Second, the prevalence of use of currently legal and illegal drugs is
so different that any comparison based upon existing patterns of use
will disadvantage the legal drugs (Peterson, 1980). In principle, this
problem could be addressed by estimating what the health risks of
cannabis use might be if its prevalence was to approach that of
alcohol and tobacco. This approach has not been adopted here because
in the absence of good data on the quantitative risks of cannabis use,
a large number of contestable assumptions would have to be made to
permit such estimates to be made.
These obstacles provide strong reasons for cautiously interpreting
comparisons of the health hazards of cannabis with those of alcohol
and tobacco. They do not, however, provide insurmountable objections
to such comparisons. We will accordingly make some qualitative
comparisons with the health risks of alcohol and tobacco after we have
considered the evidence on the adverse health effects of cannabis.
References
Addiction Research Foundation/World Health Organization (1981) Report
of an ARF/WHO Scientific Meeting on the Adverse Health and Behavioral
Consequences of Cannabis Use. Toronto: Addiction Research Foundation,
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Fehr, K.O. and Kalant, H. (1983) (eds) Cannabis and Health Hazards.
Toronto: Addiction Research Foundation.
Hall, W. (1987) A simplified logic of causal inference. Australian and
New Zealand Journal of Psychiatry, 1987, 21, 507-513.
Hill, A.B. (1977). A Short Textbook of Statistics. London: Hodder and
Stoughton.
Husak, D.N. (1992) Drugs and Rights. Cambridge: Cambridge University
Press.
Institute of Medicine. (1982) Marijuana and Health. Washington DC:
National Academy Press.
Peterson, R (1980) (ed) Marijuana Research Findings: 1980 National
Institute on Drug Abuse Research Monograph Number 31. Rockville, MD:
U.S. Department of Health and Human Services.
Rescher, N. (1977) Methodological Pragmatism. Oxford, Blackwell.
Room, R. (1984) Alcohol and ethnography: A case of problem deflation?
Current Anthropology, 25, 169- 191.
Task Force on Health Risk Assessment, United States Department of
Health and Human Services (1986) Determining Risks to Health: Federal
Policy and Practice. Dover, MA: Auburn House Publishing Company.
Whately, R. (1846) Elements of Rhetoric. Originally published 1846.
(ed) D. Ehninger. Carnondale, Illinois: Illinois University Press,
1963.
4. Cannabis the drug
4.1 Cannabis the drug
Cannabis is the material derived from the herbaceous plant Cannabis
sativa, which grows vigorously throughout many regions of the world.
It occurs in male and female forms, with both sexes having large
leaves which consist of five to 11 leaflets with serrated margins. A
sticky resin which covers the flowering tops and upper leaves is
secreted most abundantly by the female plant and this resin contains
the active agents of the plant. While the cannabis plant contains more
than 60 cannabinoid compounds, such as cannabidiol and cannabinol, the
primary psychoactive constituent is delta-9-tetrahydrocannabinol or
THC (Gaoni and Mechoulam, 1964), the concentration of which largely
determines the potency of the cannabis preparation. Most of the other
cannabinoids are either inactive or only weakly active, although they
may increase or decrease potency by interacting with THC (Abood and
Martin, 1992).
Cannabis has been erroneously classified as a narcotic, as a sedative
and most recently as an hallucinogen. While the cannabinoids do
possess hallucinogenic properties, together with stimulant and
sedative effects, they in fact represent a unique pharmacological
class of compounds. Unlike many other drugs of abuse, cannabis acts
upon specific receptors in the brain and periphery. The discovery of
the receptors and the naturally occurring substances in the brain that
bind to these receptors is of great importance, in that it signifies
an entirely new pathway system in the brain.
4.2 The cannabinoid receptor
The desire to identify a specific biochemical pathway responsible for
the expression of the psychoactive effects of cannabis has prompted a
prodigious amount of cannabinoid research (Martin, 1986). Early
studies found that radioactively labelled THC would non-specifically
attach to all neural surfaces, suggesting that it produced its effects
by perturbing cell membranes (Martin, 1986). However, the work of
Howlett and colleagues (Howlett et al 1986; 1987; 1988) showed that
cannabinoids inhibit the enzyme that synthesizes cyclic AMP in
cultured nerve cells, and that the degree of inhibition was correlated
with the potency of the cannabinoid. Since many receptors relay their
signals to the cell interior by changing cellular cyclic AMP, this
finding strongly suggested that cannabinoids were not just dissolving
non-specifically in membranes. After eliminating all the known
receptors that act by inhibiting adenylate cyclase, it was concluded
that cannabinoids acted through their own receptor. The determination
and characterisation of a specific cannabinoid receptor in brain
followed soon after (Devane et al, 1988), paving the way for its
distribution in brain to be mapped (Bidaut-Russell et al, 1990;
Herkenham et al, 1990).
It is now accepted that cannabis acts on specific cannabinoid
receptors in the brain, conclusive evidence for which was provided by
the cloning of the gene for the cannabinoid receptor in rat brain
(Matsuda et al, 1990). A cDNA which encodes the human cannabinoid
receptor was also cloned (Gerard et al, 1991) and the human receptor
was found to exhibit more than 97 per cent identity with the rat
receptor. Cannabinoid receptors have also been found in the nervous
system of lower vertebrates, including chickens, turtles and trout
(Howlett et al, 1990) and there is preliminary evidence that they
exist in low concentration in fruit flies (Bonner quoted in Abbott,
1990; Howlett, Evans and Houston, 1992). This phylogenetic
distribution suggests that the gene must have been present early in
evolution, and its conservation implies that the receptor serves an
important biological function.
The localisation of cannabinoid receptors in the brain has elucidated
the pharmacology of the cannabinoids. Herkenham and colleagues
(Herkenham, et al 1990; 1991a; 1991b; 1992) used autoradiography to
localise receptors in fresh cut brain sections of a number of species,
including humans. Dense binding was detected in the cerebral cortex,
hippocampus, cerebellum and in outflow nuclei of the basal ganglia,
particularly the substantia nigra pars reticulata and globus pallidus.
Few receptors were present in the brainstem and spinal cord.
Bidaut-Russell and colleagues (Bidaut-Russell et al, 1990) located
cannabinoid receptors in greatest abundance in the rat cortex,
cerebellum, hippocampus and striatum, with smaller but significant
binding in the hypothalamus, brainstem and spinal cord.
High densities of receptors in the hippocampus and cortex suggest
roles for the cannabinoid receptor in cognitive functions. This is
consistent with evidence in humans that the dominant effects of
cannabis are cognitive: loosening of associations, fragmentation of
thought, and confusion on attempting to remember recent occurrences
(Hollister, 1986; Miller and Branconnier, 1983). High densities of
receptors in the basal ganglia and cerebellum suggested a role for the
cannabinoid receptor in movement control, a finding which is also
consistent with the ability of cannabinoids to interfere with
coordinated movements.
Cannabis has a mild effect on cardiovascular and respiratory function
in humans (Hollister, 1986) which is consistent with the observation
that the lower brainstem area has few cannabinoid receptors. The
absence of sites in the lower brainstem may in fact explain why high
doses of THC are not lethal. Cannabinoid receptors do not appear to
reside in the dopaminergic neurons or the mesolimbic dopamine cells
that have been suggested as a possible "reward" system in the brain.
These mappings of receptors have been broadly confirmed in recent work
by Matsuda and colleagues (1992, 1993) using a histochemistry
technique to neuroanatomically localise cannabinoid receptor mRNA.
Labelling intensities were highest in forebrain regions (olfactory
areas, caudate nucleus, hippocampus) and in the cerebellar cortex.
Clear labelling observed in the rat forebrain suggests several
potential sites in the human brain that could mediate an impairment of
memory function (Miller and Branconnier, 1983), such as the
hippocampus, medial septal complex, lateral nucleus of the mamillary
body, and the amygdaloid complex. Similarly, labelling was detected
clearly in rat forebrain regions that correspond to those that could
mediate cannabis-induced effects on human appetite and mood (namely,
the hypothalamus, amygdaloid complex, and anterior cingulate cortex).
It should be borne in mind that the regions where cannabinoid
receptors occur may have long projections to other areas, contributing
to the multiplicity of effects of the cannabinoids.
Since THC is not a naturally occurring substance within the brain, the
existence of a cannabinoid receptor implied the existence of a
naturally occurring or "endogenous" cannabinoid-like substance. Devane
and colleagues (1992) recently identified a brain molecule which binds
to the receptor and mimics the action of cannabinoids. The molecule,
arachidonylethanolamide, which is fat soluble like THC, has been named
"anandamide" from a Sanskrit word meaning "bliss". Anandamide has been
found to act on cells that express the cannabinoid receptor, but it
has no effect on identical cells which lack the receptor. Further
research is necessary to determine which neurons are responsible for
producing anandamide molecules and to determine what their role is.
The unique psychoactivity of cannabinoids may be described as a
composite of numerous effects which would not arise from a single
biochemical alteration, but rather from multiple actions (Martin,
1986). Thus, the diverse pharmacological actions of the various
cannabinoids implies the existence of receptor subtypes. Cannabinoid
receptor cDNA can be used to search for other members of the
hypothesised receptor family (Snyder, 1990). If the receptors with the
potential for mediating the therapeutic uses of cannabis are different
from those responsible for their psychoactive effects, cannabinoid
receptor cDNA cloning and new synthetic cannabinoids modelled on
anandamide may help to uncover the receptor subtypes and develop drugs
to target them, thus fulfilling the ancient promise of "marijuana as
medicine". If, however, it were the case that there was only one type
of cannabinoid receptor, then the psychoactive and therapeutic effects
would be inseparable. The evidence against this proposition mounts
with the recent cloning of a cannabinoid receptor in spleen that does
not exist in brain (Munro et al, 1993).
4.3 Forms of cannabis
The concentration of THC varies with the forms in which cannabis is
prepared for ingestion, the most common of which are marijuana,
hashish and hash oil. Marijuana is prepared from the dried flowering
tops and leaves of the harvested plant. Its potency depends upon the
growing conditions, the genetic characteristics of the plant and the
proportions of plant matter. The flowering tops and bracts (known as
"heads") are highest in THC concentration, with potency descending
through the upper leaves, lower leaves, stems and seeds. Some
varieties of the cannabis plant contain little or no THC, such as the
hemp varieties used for making rope, while others have been
specifically cultivated for their high THC content, such as
"sinsemilla".
Marijuana may range in colour from green to grey or brown, depending
on the variety and where it was grown, and in texture from a dry
powder or finely divided tea-like substance to a dry leafy material.
The concentration of THC in a batch of marijuana containing mostly
leaves and stems may range from 0.5-5 per cent, while the "sinsemilla"
variety with "heads" may result in concentrations from 7-14 per cent.
The potency of marijuana preparations being sold has probably
increased in the past decade (Jones, 1987), although the evidence for
this has been contested (Mikuriya and Aldrich, 1988).
Hashish or hash consists of dried cannabis resin and compressed
flowers. It ranges in colour from light blonde/brown to almost black,
and is usually sold in the form of hard chunks or cubes. The
concentration of THC in hashish generally ranges from 2-8 per cent,
although it can be as high as 10-20 per cent. Hash oil is a highly
potent and viscous substance obtained by using an organic solvent to
extract THC from hashish (or marijuana), concentrating the filtered
extract, and, in some cases, subjecting it to further purification.
The colour may range from clear to pale yellow/green, through brown to
black. The concentration of the THC in hash oil is generally between
15 per cent and 50 per cent, although samples as high as 70 per cent
have been detected.
4.4 Routes of administration
Almost all possible routes of administration have been used, but by
far the most common method is smoking (inhaling). Marijuana is most
often smoked as a hand-rolled "joint" the size of a cigarette or
larger, and usually thicker. Tobacco is often added to marijuana to
assist burning and "make it go further", and a filter may be inserted.
Hashish may be mixed with tobacco and smoked as a joint, but is more
often smoked through a pipe, either with or without tobacco. A water
pipe known as "bong" is a popular implement for all cannabis
preparations, because the water cools the hot smoke before it is
inhaled and there is little loss of the drug through sidestream smoke.
Hash oil is used sparingly because of its extremely high psychoactive
potency; a few drops may be applied to a cigarette or a joint, to the
mixture in the pipe, or the oil may be heated and the vapours inhaled.
Whatever method is used, smokers usually inhale deeply and hold their
breath for several seconds in order to ensure maximum absorption of
THC by the lungs.
Hashish may also be cooked or baked in foods and eaten. When ingested
orally the onset of the psychoactive effects is delayed by about an
hour. In clinical and experimental research, THC has often been
prepared in gelatine capsules and administered orally. In India, a
popular method of ingestion is in the form of a tea-like brew of the
leaves and stems, known as "bhang". The "high" is of lesser intensity
but the duration of intoxication is longer by several hours. It is
easier to titrate the dose and achieve the desired level of
intoxication by smoking than by oral ingestion since the effects are
more immediate.
Crude aqueous extracts of cannabis have on very rare occasions been
injected intravenously. THC is insoluble in water, so little or no
drug is actually present in these extracts, and the injection of tiny
undissolved particles may cause severe pain and inflammation at the
site of injection and a variety of toxic systemic effects. Injection
should not be considered as a route of cannabis administration, but
has been used in research to investigate pharmacokinetics.
Since different routes of administration give rise to differing
pharmacokinetics (see below), the reader should assume for the
remainder of this document that the method of ingestion is smoking
unless stated otherwise.
4.5 Dosage
A typical joint contains between 0.5g and 1.0g of cannabis plant
matter, which varies in THC content between 5mg and 150mg (i.e.
typically between 1 per cent and 15 per cent THC). Not all of the
available THC is ingested; the actual amount of THC delivered in the
smoke has been estimated at 20 per cent to 70 per cent of that in the
cigarette (Hawks, 1982), with the rest being lost through combustion
or escaping in sidestream smoke. The bioavailability of THC from
marijuana cigarettes (the fraction of THC in the cigarette which
reaches the bloodstream) has been reported to range between 5 per cent
and 24 per cent (mean 18.6 per cent) (Ohlsson et al, 1980). For all
these reasons, the actual dose of THC that is absorbed when cannabis
is smoked is not easily estimated.
In general, only a small amount of smoked cannabis (e.g. 2mg to 3mg of
available THC) is required to produce a brief pleasurable high for the
occasional user, and a single joint may be sufficient for two or three
individuals. A heavy smoker may consume five or more joints per day,
while heavy users in Jamaica, for example, may consume up to 420mg THC
per day (Ghodse, 1986). In clinical trials designed to assess the
therapeutic potential of THC, single doses have ranged up to 20mg in
capsule form. In human experimental research, THC doses of 10mg, 20mg
and 25mg have been administered as low, medium and high doses (Barnett
et al 1985; Perez-Reyes et al 1982).
Perez-Reyes et al (1974) determined the amount of THC required to
produce the desired effects by slow intravenous administration. They
estimated that the threshold for perception of an effect was 1.5mg
while a peak social "high" required 2-3mg THC. These levels did not
differ between frequent and infrequent users, so Perez-Reyes et al
concluded that tolerance or sensitivity to the perceived high does not
develop.
4.6 Patterns of use
Cannabis is the most widely used illicit drug in Australia, having
been tried by a third of the adult population, and by the majority of
young adults between the ages of 18 and 25 (see Donnelly and Hall,
1994). The most common route of administration is by smoking, and the
most widely used form of the drug is marijuana.
The majority of cannabis use in Australia and elsewhere is
"recreational". That is, most users use the drug to experience its
euphoric and relaxing effects rather than for its recognised
therapeutic effects. Unless explicitly stated to the contrary (as in
chapter 8) it should be assumed that the phrase "cannabis use" is a
short-hand term for the recreational use of cannabis products.
The majority of cannabis use is also "experimental" in that most of
those who have ever used cannabis either discontinue their use after a
number of uses, or if they continue to use, do so intermittently and
episodically whenever the drug is available. Only a small proportion
of those who ever use cannabis become regular cannabis users. The best
estimate from the available survey data is that about 10 per cent of
those who ever use cannabis become daily users, and a further 20-30
per cent use on a weekly basis (see Queensland Criminal Justice
Commission, 1993; Donnelly and Hall, 1994). Among those who continue
to use cannabis, the majority discontinue their use in their mid to
late 20s.
Because of uncertainties about the dose of THC contained in illicit
marijuana, there is no information on the amount of THC ingested by
regular Australian cannabis users. "Heavy" cannabis use is typically
defined in terms of the frequency of use rather than average dose of
THC received. Although it is possible that daily users could use small
quantities per day, this is unlikely to be true of the majority of
regular users because of the tolerance to drug effects which develops
with regular use. Evidence collected on chronic long-term users at the
National Drug and Alcohol Research Centre (Solowij, 1994), indicated
that they typically used more potent forms of cannabis (namely,
"heads" and hashish).
The daily or near daily use pattern is the pattern that probably
places users at greatest risk of experiencing long-term health and
psychological consequences of use. Such users are more likely to be
male and less well educated, and are more likely to regularly use
alcohol, and to have experimented with a variety of other illicit
drugs, such as amphetamines, hallucinogens, psychostimulants,
sedatives and opioids.
4.7 Metabolism of cannabinoids
"Cannabinoids" is the collective term for a variety of compounds which
can be extracted from the cannabis plant or are produced within the
body after ingestion and metabolism of cannabis. Some of these
compounds are psychoactive, that is, they have an effect upon the mind
of the users; others are pharmacologically or biologically active,
that is, have an effect upon cells or the function of other bodily
tissues and organs, but are not psychoactive. Animal and human
experimentation indicates that delta-9-tetrahydrocannabinol (THC) is
the major psychoactive constituent of cannabis.
THC is rapidly and extensively metabolised in humans. Different
methods of ingesting cannabis give rise to different patterns of
absorption, metabolism and excretion of THC. Upon inhalation, THC is
absorbed within minutes from the lungs into the bloodstream.
Absorption of THC is much slower after oral administration, entering
the bloodstream within one to three hours, and delaying the onset of
psychoactive effects.
After smoking, the initial metabolism of THC takes place in the lungs,
followed by more extensive metabolism by liver enzymes which transform
THC to a number of metabolites. The most rapidly produced metabolite
is 9-carboxy-THC (or THC-COOH) which is detectable in blood within
minutes of smoking cannabis. It is not psychoactive. Another major
metabolite of THC is 11-hydroxy-THC, which is approximately 20 per
cent more potent than THC, and which penetrates the blood-brain
barrier more rapidly than THC. 11-hydroxy-THC is only present at very
low concentrations in the blood after smoking, but at high
concentrations after the oral route (Hawks, 1982). THC and its
hydroxylated metabolites account for most of the psychoactive effects
of the cannabinoids.
Peak blood levels of THC are reached very rapidly, usually within 10
minutes of smoking and before a joint is fully smoked, and decline
rapidly to about 5-10 per cent of their initial level within the first
hour. This initial rapid decline reflects the rapid conversion of THC
to its metabolites, as well as the distribution of THC to lipid-rich
tissues, including the brain (Fehr and Kalant, 1983; Jones, 1980;
1987). THC and its metabolites are highly fat soluble and may remain
for long periods of time in the fatty tissues of the body, from which
they are slowly released back into the bloodstream. This phenomenon
slows the elimination of cannabinoids from the body.
The time required to clear half of the administered dose of THC from
the body has been found to be shorter for experienced or daily users
(19-27 hours) than for inexperienced users (50-57 hours) (Agurell, et
al 1986; Hunt and Jones, 1980; Lemberger et al, 1970; 1978; Ohlsson,
et al, 1980). Recent research using more sensitive detection
techniques suggests that the half-life in chronic users may be closer
to three to five days (Johansson et al, 1988). It is the immediate and
subsequent metabolism of THC that occurs more rapidly in experienced
users (Blum, 1984). Given the slow clearance, repeated administration
of cannabis results in the accumulation of THC and its metabolites in
the body. Because of its slow release from fatty tissues into the
bloodstream, THC and its metabolites may be detectable in blood for
several days, and traces may persist for several weeks.
While blood levels of THC peak within a few minutes, 9-carboxy-THC
levels peak approximately 20 minutes after commencing smoking and then
decline slowly. The elimination curve for THC crosses the
9-carboxy-THC curve around the time of the peak of the latter and
subjective intoxication also peaks around this time (i.e., 20-30
minutes later than peak THC blood levels), with acute effects
persisting for approximately two to three hours.
4.8 Detection of cannabinoids in body fluids
Cannabinoid levels in the body, which depend on both the dose given
and the smoking history of the individual, are subject to substantial
individual variability. Plasma levels of THC in man may range between
0-500ng/ml, depending on the potency of the cannabis ingested and the
time since smoking. For example, blood levels of THC may decline to
2ng/ml one hour after smoking a low potency cannabis cigarette, a
level that may be achieved only nine hours after smoking a high
potency cannabis cigarette. In habitual and chronic users such levels
may persist for several days after use because of the slow release of
accumulated THC.
The detection of THC in blood above 10-15ng/ml provides presumptive
evidence of "recent" consumption of cannabis, but it is not possible
to determine how recently it was consumed. A somewhat more precise
estimate of the time of consumption may be obtained from the ratio of
THC to 9-carboxy-THC: similar concentrations of each in blood could be
an indication of use within the last 20-40 minutes, and would predict
a high probability of the user being intoxicated. When the levels of
9-carboxy-THC are substantially higher than those of THC, ingestion
can be estimated to have occurred more than half an hour ago (Hawks,
1982; Perez-Reyes et al, 1982). However, such an interpretation
probably applies only to the naive users who have resting levels of
zero. Background levels of cannabinoids (particularly 9-carboxy-THC)
in habitual users make the estimation of time of ingestion almost
impossible. It is very difficult to determine the time of
administration from blood concentrations of THC and its metabolites,
even if the smoking habits of the individual and the exact dose
consumed are known. The results of blood analyses indicate, at best,
the "recent" use of cannabis.
Urinary cannabinoid levels provide an even weaker indicator of current
cannabis intake. In general, the greater the level of cannabinoid
metabolites in urine, the greater the possibility of recent use, but
it is impossible to be precise about how "recent" use has been (Hawks,
1982). Only minute traces of THC itself appear in the urine due to its
extensive metabolism, and most of the administered dose is excreted in
the form of metabolites in faeces and urine (Hunt and Jones, 1980).
9-carboxy-THC is detectable in urine within 30 minutes of smoking.
This and other metabolites may be present for several days in first
time or irregular cannabis users, while frequent users may continue to
excrete metabolites for weeks or months after last use because of the
accumulation and slow elimination of these compounds (Dackis et al,
1982; Ellis et al, 1985). As with blood levels, there is substantial
human variability in the metabolism of THC, and no simple relationship
between urinary levels of THC metabolites and time of consumption.
Hence, urinalyses results cannot be used to distinguish between use
within the last 24 hours and use more than a month ago.
Several studies have examined measures of cannabinoids in fat and
saliva. Analyses of human fat biopsies confirm storage of the drug for
at least 28 days (Johansson, et al, 1987). Detection of cannabinoids
in saliva holds more promise for forensic purposes, since it has the
capacity to reduce the time frame of "recent" use from days and weeks
to hours (Hawks, 1982; Gross et al 1985; Thompson and Cone, 1987).
Salivary THC levels have also been shown to correlate with subjective
intoxication and heart rate changes (Menkes et al, 1991).
4.9 Intoxication and levels of cannabinoids
Ingestion of cannabis produces a dose related impairment of a wide
range of cognitive and behavioural functions. Since there is evidence
that cannabis intoxication adversely affects skills required to drive
a motor vehicle (see below), it would be desirable to have a reliable
measure of impairment due to cannabis intoxication that was comparable
to the breath test of alcohol intoxication. For this reason, a
reliable measure for determining the degree of impairment due to
cannabis has been particularly sought after.
While the degree of impairment from alcohol can be determined from a
single blood alcohol estimate, a clear relationship between blood
levels of THC or its metabolites and degree of either impairment or
subjective intoxication has not been demonstrated (Agurell et al,
1986). The estimation of the degree of intoxication from a single
value of blood THC level is difficult, not only because of the time
delay between subjective high and blood THC, but also because of large
individual variations in the effects experienced at the same blood
levels. The difficulty is compounded by the distribution of THC to
body tissues, and its metabolism to other psychoactive compounds.
Blood levels of THC metabolites, such as 11-hydroxy-THC, correlate
temporally with subjective effects but are not readily detectable in
blood after smoking cannabis, while blood levels of THC correlate only
modestly with cannabis intoxication, in part because of its lipid
solubility (Barnett et al, 1985; McBay 1988; Ohlsson et al 1980). The
level of intoxication could only realistically be related to the total
sum of all the psychoactive cannabinoids present in body fluids and in
the brain and various tissues.
Due to large human variability, no realistic limit of cannabinoid
levels in blood has been set which can be related to an undesirable
level of intoxication. Tolerance also develops to many of the effects
of cannabis. Hence, a given dose consumed by a naive individual may
produce greater impairment on a task than the same dose consumed by a
chronic heavy user. THC may also be active in the nervous system long
after it is no longer detectable in the blood, so there may be
long-term subtle effects of cannabis on the cognitive functioning of
chronic users even in the unintoxicated state. To date, there is no
consistently demonstrated correlation between blood levels of THC and
its effect on human mind and performance. Thus, no practical method
has been developed as a forensic tool for determining levels of
intoxication based on detectable cannabinoids. A consensus conference
of forensic toxicologists has concluded that blood concentrations of
THC which cause impairment have not been sufficiently established to
provide a basis for legal testimony in cases concerning driving a
motor vehicle while under the influence of cannabis (Consensus Report,
1985).
4.10 Passive inhalation
In the United States, urine testing for drug traces and metabolites is
increasingly used to identify illicit drug users in the workplace
(Hayden, 1991). A technical concern raised by the opponents of this
practice has been the possibility of a person having a urine positive
for cannabinoids as the result of the passive inhalation of marijuana
smoke at a social event immediately prior to the provision of the
urine sample. A number of research studies have attempted to determine
the relationship between passive inhalation of marijuana smoke and
consequent production of urinary cannabinoids (Hayden, 1991).
In one of the first studies on passive inhalation, Perez-Reyes and
colleagues (1983) found that non-smokers who had been confined for
over an hour in a very small unventilated space containing the smoke
of at least eight cannabis cigarettes over three consecutive days had
insignificant amounts of urinary cannabinoids. Law and colleagues
(1984) and Mule et al (1988) also showed that passive inhalation
produced urinary cannabinoid concentrations well below the detection
limit of 20ng/ml 9-carboxy-THC used in workplace drug screens.
Morland et al (1985) produced urinary cannabinoid levels above 20ng/ml
in non-smokers but the conditions were extreme, namely, confinement in
a space the size of a packing box with exposure to the smoke of six
cannabis cigarettes. The studies of Cone and colleagues (1986; 1987a,
1987b) confirmed the necessity to apply extreme experimental
conditions, which they claimed non-smokers were unlikely to submit
themselves to for the long periods of time required to produce urinary
metabolites above 20ng/ml. They also showed that non-smokers with
significant amounts of cannabinoids in their urine experienced the
subjective effects of intoxication.
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5. The acute effects of cannabis intoxication
5.1 Psychological and physical effects
Any attempt to summarise the acute effects of cannabis, or of any
psychoactive drug, is necessarily an oversimplification. The effects
experienced by the user will depend upon: the dose, the mode of
administration, the user's prior experience with the drug, any
concurrent drug use, and the "set" - the user's expectations, mood
state and attitudes towards drug effects - and "setting" - the social
environment in which the drug is used (Jaffe, 1985). The following
descriptions of the typical effects of cannabis are made with this
qualification in mind.
The major motive for the widespread recreational use of cannabis is
the experience of a subjective "high", an altered state of
consciousness which is characterised by: emotional changes, such as
mild euphoria and relaxation; perceptual alterations, such as time
distortion, and; intensification of ordinary sensory experiences, such
as eating, watching films, listening to music, and engaging in sex
(Jaffe, 1985; Tart, 1970). When used in a social setting, the "high"
is often accompanied by infectious laughter, talkativeness, and
increased sociability.
Cognitive changes are usually marked during a "high". These include an
impaired short-term memory, and a loosening of associations, which
make it possible for the user to become lost in pleasant reverie and
fantasy, while making it difficult for the user to sustain
goal-directed mental activity. Motor skills, reaction time and motor
coordination are also affected, so many forms of skilled psychomotor
activity are impaired while the user is intoxicated (Jaffe, 1985).
Not all the effects of cannabis intoxication are welcomed by users.
Some users report unpleasant psychological reactions, ranging from a
feeling of anxiety to frank panic reactions, and a fear of going mad
to depressed mood (Smith, 1968; Weil, 1970; Thomas, 1993). These
effects are most often reported by naive users who are unfamiliar with
the effects of cannabis, and by some patients given THC for
therapeutic purposes. More experienced users may also report these
effects on occasion, especially after the oral ingestion of cannabis
when the effects may be more pronounced and of longer duration than
those usually experienced after smoking cannabis. These effects can
usually be successfully prevented by adequate preparation of users
about the type of effects they may experience. If these effects
develop they can be managed by reassurance and support (Smith, 1968;
Weil, 1970). Psychotic symptoms, such as delusions and hallucinations,
are very rare experiences that occur at very high doses of THC, and
perhaps in susceptible individuals at lower doses (Smith, 1968;
Thomas, 1993; Weil, 1970).
The inhalation of marijuana smoke, or the ingestion of THC, the
psychoactive derivative of cannabis, has a number of bodily effects.
Among these the most dependable are the effects on the heart and
vascular system. The most immediate effect of cannabis use by all
routes of administration is an increase in heart rate of 20-50 per
cent over baseline which occurs within a few minutes to a quarter of
an hour and lasts for up to three hours (Huber et al, 1988; Jones,
1984). Changes in blood pressure also occur which depend upon posture:
blood pressure is increased while the person is sitting, and decreases
while standing. A sudden change from a recumbent posture may produce
postural hypotension and fainting, an effect which may explain the
feeling of "light-headedness" and faintness that is often the earliest
indication of intoxication in naive users (Maykut, 1984). Increases
are also observed in the production of the catecholamine
norepinephrine, although these lag behind the cardiovascular changes,
and their mechanisms are not well understood (Hardman and Hosko,
1976).
In healthy young users these cardiovascular effects are unlikely to be
of any clinical significance. They may, however, magnify anxiety in
naive users. The cannabis-induced tachycardia and postural hypotension
may contribute to the panic attacks sometimes experienced by naive
users (Weil, 1970) who may mistakenly interpret the palpitations, and
the feeling of faintness, as symptoms of serious misadventure,
magnifying pre-existing anxiety in a positive feedback cycle that
leads to a panic attack.
5.2 Toxic dose levels
THC appears to be the component of cannabis which has the highest
direct toxicity in all animals so far tested. The toxic effects of
cannabis are mediated through its effects on neural systems. The cause
of death in experimental animals is almost invariably apnoea or
cardiac arrest, if apnoea is prevented (Rosencrantz, 1983). Due to the
development of tolerance, toxic doses depend upon the amount by which
they exceed the customary dose. In contrast to the increase in toxic
dose typical of many drugs when moving from primates to lower animals,
it appears that phylogenetically higher animals are less susceptible
to the acute toxicity of THC. Thus, the dose of THC which kills 50 per
cent of animals (LD50) when administered intravenously is 40mg/kg in
the rat but 130mg/kg in the dog and monkey (Rosencrantz, 1983).
For obvious ethical reasons there is no experimental evidence to
determine a lethal dose in humans. Nor is there any clinical evidence,
since there have been no reported cases of death attributable to
cannabis in the world medical literature (Blum, 1984; Nahas, 1984).
Extrapolation from the animal evidence suggests that the lethal human
dose of THC is at least as high as, and probably higher than, that
observed in the monkey. If this is so, then the toxic dose of THC in a
65kg adult would be 8.45kg.
A number of non-fatal toxic reactions occur in humans with higher than
normal doses. The tachycardia almost invariably produced in acute
intoxication, combined with the sensory alterations and increased
tremor commonly reported, probably contribute to the affective
components of these reactions. CNS and respiratory depression are
noted with high doses, which in severe overdose may be
life-threatening (Rosencrantz, 1983). These effects are, of course,
more dangerous to those with pre-existing cardiac irregularities.
Because of the large effective to lethal dose ratio in humans
(probably in excess of 1:1000 in non-tolerant users) the risk of
experiencing severe toxic effects of cannabis is limited by the
aversive psychotropic effects of high doses, which usually lead to
cessation of use before the onset of dangerous physical consequences.
5.3 Tolerance to acute effects
In animals, tolerance develops to the lethal, hypothermic and some of
the behavioural effects of cannabinoids. This has been attributed to
functional or pharmacodynamic adaptations of the CNS rather than to a
more rapid metabolic disposition (Jaffe, 1985). Laboratory studies in
humans involving daily dosing at high levels over periods of weeks
have demonstrated tolerance to mood effects, tachycardia, decrease in
skin temperature, increased body temperature, and impaired performance
on psychomotor tests. Abrupt discontinuation in these studies usually
produces a mild withdrawal syndrome (see below pp111-113).
5.4 Psychomotor effects
A major societal concern about cannabis intoxication is its potential
to impair psychomotor performance in ways which may directly affect
the well-being of non-users of cannabis. The prototype outcome is an
automobile accident caused by a cannabis user driving while
intoxicated. It is well known that individuals who drive while
intoxicated with alcohol are dangerous to others in proportion to
their level of intoxication. Is there evidence that intoxication with
cannabis produces impaired psychomotor performance of a nature and
degree sufficient to warrant restrictions upon its use by automobile
drivers? To what extent has cannabis intoxication contributed to road
accidents?
Psychoactive substances typically have both acute and chronic effects
on performance of a variety of tasks. Given the fact that most tasks
of interest to researchers require effort and concentration, only
those substances which enhance these very general abilities typically
improve performance. Recreational drugs are usually valued for effects
which remove the user from mundane concerns, produce relaxation, and
enhance experiences which would normally interfere with concentration
on a skilled task. Consequently, many societies enact restrictions on
the use of such drugs, either during specific tasks such as motor
vehicle driving, or at any time, as is the case with cannabis in most
Western societies, and with alcohol in many Islamic societies.
The subjective effects of cannabis include feelings of well-being and
relaxation, and sensory and temporal distortions which might be
expected to decrease performance in situations where perceptual
accuracy and attention are important. In deciding whether the
recreational use of cannabis presents a danger to the user and others
we need to consider two things: (1) the extent to which its use
disrupts the performance of potentially dangerous tasks such as motor
vehicle driving or the operation of machinery, and (2) the effect that
the drug has on the user's compliance with restrictions upon its use.
The second point refers to any disinhibitory effects of the drug which
might predispose users to ignore prohibitions on driving, or may
increase their willingness to take risks while intoxicated.
The risks of cannabis intoxication and driving will be assessed in the
following way. First, laboratory evidence on the effects of cannabis
on various psychomotor tasks will be reviewed. In the following review
of this evidence, when a number of studies have produced similar
results, only the most typical studies will be cited. (For a more
complete review of such studies see Chait and Pierri, 1992). Second,
the possible mechanisms of the psychomotor effects of cannabis will be
briefly discussed. Third, the literature on the effects of cannabis on
performance in driving and flying simulators will be briefly reviewed.
Fourth, the experimental literature on the effects of cannabis
intoxication on on-road driving will be reviewed. Finally, the limited
epidemiological evidence on the contribution of cannabis to motor
vehicle accidents will be considered.
5.4.1 Effects of cannabis on psychomotor tasks
Muscle control. Standing steadiness (Kiplinger et al, 1971) and hand
steadiness (Klonoff et al, 1973) are both adversely affected by
cannabis. Finger or toe tapping speed does not appear to be reliably
affected (Weckowicz et al, 1975; Evans et al, 1976; Milstein et al,
1975; Dalton et al, 1975), as only one study (Klonoff et al, 1973)
found a decrement in finger tapping.
Reaction time. Simple reaction time does not appear to be reliably
affected by cannabis. Some studies have reported decrements in mean
reaction time (Borg et al, 1975; Dornbush et al, 1971), or the
variability of reaction time (Braden et al, 1974), while others have
found no difference (Evans et al, 1973). Choice reaction time tasks,
in which the response is conditional not only upon the occurrence of a
stimulus, but also the presence of some other discriminant (such as
the pitch of a tone or the colour of a visual stimulus), have been
administered to determine the effect of cannabis. In a number of these
studies, reaction time was indeed slower after cannabis use (Borg et
al, 1975; Block & Wittenborn, 1984; 1986), although there were some
studies which found no change (Peeke et al, 1976; Block & Wittenborn,
1984). With only one exception (Low et al, 1973), errors in choice
reaction time were not increased by cannabis.
Single tasks of manual dexterity. Pursuit rotor tasks, in which the
subject attempts to follow a rotating target with a pointer, are
generally performed worse after cannabis use (Manno et al, 1971; Manno
et al, 1970), although studies employing regular users (Salvendy &
McCabe, 1975; Carlin et al, 1972) have found no effect, suggesting
that the regular users developed tolerance to the effects of cannabis.
Other tracking tasks are generally not affected (Zacny & Chait, 1991;
Heishman et al, 1989). Tests in which the subject must manipulate and
accurately place small items (Dalton et al, 1975; 1976; Evans et al,
1973) are usually affected, while sorting tasks may (Chait et al,
1985) or may not (Kelly et al, 1990) be performed less well.
Concurrent tasks. Most concurrent task studies use one task which
requires almost continuous attention, typically tracking, and one in
which significant stimuli occur sporadically, often within a larger
number of non-significant stimuli. The tasks are often referred to as
the central and peripheral tasks respectively. The performance of
concurrent tasks is almost always affected negatively by cannabis,
although the effects on the component tasks are not consistent. Number
or proportion of peripheral targets missed (MacAvoy & Marks, 1975;
Marks & MacAvoy, 1989; Casswell & Marks, 1973; Moskowitz et al, 1972),
proportion of hits (Moskowitz, Sharma & McGlothlin, 1972), false
alarms (Chait et al, 1988, MacAvoy & Marks, 1975; Moskowitz &
McGlothlin, 1974) or reaction time to peripheral targets (Perez-Reyes
et al, 1988; Evans et al, 1976; Moskowitz et al, 1976) may suffer, but
no interpretable pattern of decrements has emerged. It may be the case
that while overall performance on concurrent tasks is decreased during
cannabis intoxication, differences in the tasks used produce various
patterns of effect. While there has been some speculation as to
whether the effects of cannabis in concurrent tasks might be
concentrated on the central or peripheral tasks (Moskowitz, 1985), no
observed pattern has emerged to clearly support these conjectures.
5.4.2 Possible mechanisms of psychomotor effects
Sensory disturbances. Reports of the subjective experience of cannabis
intoxication include altered experience in all sensory modalities, as
well as in the perception of space and time (Tart, 1970). Since almost
all tasks of psychomotor performance include important visual and
auditory components, sensory disturbances might well affect the
ability to perform such tasks. Studies of the ability to discover
embedded figures within complex designs have shown that this is
impaired by cannabis (Carlin et al, 1972; Carlin et al, 1974; Pearl et
al, 1973). Performance decrements due to cannabis in the Stroop colour
naming test have been reported (Carlin et al, 1972; 1974), although it
is not clear whether disturbed perception has any significant effect
upon this task.
Central Nervous System depression. Both the toxic and behavioural
effects of cannabis indicate that it acts as a CNS depressant, at
least in moderate to high doses. It might seem reasonable to
hypothesise that this general effect might contribute to slowed
reaction times, inability to maintain concentration, and lapses in
attention. This is certainly the case with alcohol and other CNS
depressants. When compared to the relatively large and reliable
depressant effects of moderate doses of alcohol, it is clear that this
effect of cannabis is not the primary mediator of performance changes.
It must be stressed, however, that high doses of cannabis would make
this aspect of its action on psychomotor skills more important.
Motivational changes. A great deal has been written about the supposed
effects of cannabis on human motivation. Hypotheses concerning the
motivational effects of chronic cannabis use have been reviewed
separately (see chapter 7.2). Cannabis users routinely report reduced
desire for physical activity and increased difficulty of concentrating
on intellectually demanding tasks such as reading for study (Tart,
1970). Studies designed to test the effect of cannabis on the
willingness to perform laboratory "work" have found no striking
decrements (Mendelson, 1983). This is consistent with comparisons of
manual workers who used cannabis with those who did not (Rubin &
Comitas, 1975; Stefanis et al, 1977). Indeed, the counter-argument
that cannabis users can voluntarily compensate for some of the
impairing effects of the drug has received experimental support
(Cappell & Pliner, 1973; Robbe & O'Hanlon, 1993). As discussed below,
motivational changes are surely important in decisions made outside
the laboratory, but there appears to be no reliable evidence that
motivational changes are responsible for any major proportion of the
psychomotor effects of cannabis.
5.4.3 Effects of cannabis on simulated driving and flying
Simulated driving tasks. As the previous sections have shown, there is
considerable evidence that cannabis intoxication has some negative
effects upon performance which become more pronounced with increasing
task difficulty. Motor vehicle driving is a complex task, especially
in conditions of heavy traffic or poor road or weather conditions, and
as such, it might be expected to be adversely affected by cannabis.
Simulated driving tasks require skills which are similar to those
involved in driving, which can be performed under controlled
laboratory conditions. When special efforts are made to simulate the
performance characteristics of a car, simulations have two major
advantages (Smiley, 1986). First, cannabis users an be tested after
taking doses of cannabis which it would be unethical to use on the
road. Second, they can be placed in simulated emergency situations
which test their level of impairment in ways that would be
impermissible on the road. The disadvantage of simulator studies
derives from the difficulty of achieving sufficient fidelity to
on-road driving tasks.
One of the earliest studies by Crancer et al, (1969) found only that
"speedometer errors" increased in simulated driving after cannabis
use. In one of the more influential studies, Dott (1972) reported an
apparent decrease in the willingness to take risks in simulated
passing of another vehicle after cannabis use, while alcohol had the
opposite effect. Alcohol also tended to hamper the subjects' response
to stimuli signalling an emergency condition, while cannabis had
little effect on this response. Both, however, increased reaction time
to a more routine signal. A similar dissociation of the effects of
alcohol and cannabis was reported by Ellingstad, et al, (1973) who
found that cannabis did not appear to increase risk-taking, whereas
alcohol did. Cannabis affected the ability to judge the time taken to
pass another vehicle, while alcohol did not. Moskowitz et al (1976)
found that alcohol altered the visual search patterns of subjects
performing a simulated driving task, while cannabis did not. The
alterations found with alcohol were, in theory, consistent with a
reduced ability to scan for hazardous events, but no reliable
difference in task performance was found with either drug.
Smiley (1986) critically reviewed the research on the effects of
cannabis intoxication on simulated driving. She argued that the
earlier studies which showed fewer effects on car control than later
studies suffered because of their unrealistic car dynamics. Later
studies which used driving simulators with more realistic car dynamics
have shown impairments of lane control after cannabis use. Some of the
studies have also shown reductions in risk-taking as manifested in
slower speeds, and maintenance of a larger distance from the car in
front in following tasks (Smiley, 1986).
Simulated flying. Janowsky et al (1976) found substantial increases in
the number and magnitude of errors during a simulated flight after
taking cannabis. These were principally in keeping the plane at the
proper altitude and heading. Yesavage et al (1985) originally reported
negative effects of cannabis on some components of a simulated flying
task up to 24 hours after smoking, but this study did not include a
control group. A later study (Leirer et al, 1989) which attempted to
replicate this result with a control group found only an effect one to
four hours after smoking. A third study which also included a control
group (Leirer et al, 1991) again demonstrated decrements in the
composite performance score up to 24 hours after smoking cannabis.
Much has been made of these findings by critics of cannabis use, but
the effects are very small and of uncertain significance for flying
safety. Jones (1987) has argued that the use of cannabis by pilots in
the 24 hours preceding flying may be more an indicator of poor
judgment, rather than a cause for concern about the residual
psychomotor effects of cannabis.
5.4.4 Effects of cannabis on on-road driving
It is often remarked that the activity most often cited as dangerous
when performed under the influence of recreational drugs - motor
vehicle driving - is one of the least studied. Given the concern about
the safety of the experimental subject in drug and driving
experimentation, it is understandable that such studies have been
relatively uncommon. A review by Nichols (1971) found that there were
no well controlled observations of the effects of cannabis on driving
performance. This situation changed with research commissioned by the
Canadian Commission of Inquiry into the Non-Medical use of Drugs. A
comprehensive report published by Hansteen et al (1976) showed that a
moderate dose of alcohol (approximately 0.07 BAC) or THC (5.9mg)
impaired driving on a traffic-free course (as measured by the number
of times the lane-defining cones ("witch's hats") were struck).
Driving speed was decreased after cannabis but not after alcohol use.
Smiley et al (1975), using a different type of course, found that
reaction time to signal stimuli was increased with the combination of
cannabis and alcohol. Klonoff (1974) studied driving on a closed
course, and in city traffic, after a placebo and two doses of smoked
cannabis (4.9mg and 8.4mg THC). Closed course driving was scored by
the number of cones hit on a precisely laid out path. Driving in
traffic was scored by observation of eleven categories of driving
skill, similar to those used in some driving tests. Driving on the
closed course was impaired by both doses, as indicated by a higher
proportion of subjects whose performance declined after cannabis use.
Driving in traffic, however, while showing a trend toward poorer
performance, was not significantly affected, and the effects of
cannabis were much more variable. Sutton (1983) also found that
cannabis had little effect on actual driving performance. Peck et al
(1986) recorded performance on a range of driving tasks on a closed
circuit on four occasions after the administration of placebo, up to
19mg of smoked THC, 0.84g/kg of alcohol, and the combination of both
drugs. On most individual and derived composite measures, cannabis
impaired performance. This study is important in that there was a high
degree of concordance between objective performance measures (e.g.
number of traffic markers hit during manoeuvres), subjective estimates
of performance by the drivers, and ratings by police observers.
However, the conclusion reached was that the effects of cannabis on
driving performance were somewhat less than those of alcohol. Robbe
and O'Hanlon (1993), have reported the methodology, but not the
detailed results, of a study of driving in traffic. Their brief report
suggests that their results also indicated little impairment of actual
driving skills after cannabis. They speculated that since drivers were
aware of their intoxication, they had successfully attempted to
counter the impairment.
Overall, the effects of cannabis use on on-road driving have been
smaller than the comparable effects of intoxicating doses of alcohol
in the same settings (Smiley, 1986). The most consistent cannabis
effect has been that drivers reduce their risk by slowing down; a
finding that contrasts with the consistent finding that subjects
typically increase their speed when intoxicated with alcohol. It is
probably this compensatory behaviour by cannabis users that explains
the comparatively small effects of cannabis intoxication in on road
studies. For ethical reasons such studies have not been able to
adequately test the response of cannabis intoxicated drivers to
situations that require emergency decision, in which there is less
opportunity to compensate for impairment. The few studies which have
attempted to simulate this situation (e.g. by using subsidiary
reaction tasks in addition to driving) have shown that cannabis
intoxication impairs emergency decision-making (Smiley, 1986).
The small effects of cannabis on driving performance seem at odds with
its effects on laboratory tasks requiring divided attention. Peck et
al (1986) have pointed out, however, that the subtle performance
effects of drugs in laboratory divided attention tasks may be poor
predictors of driving performance. While the combination of
performance abilities which is tapped by the typical divided attention
task, such as concurrent pursuit tracking and visual discrimination,
is plausibly related to driving, the tracking task is usually a much
more difficult task than driving under normal conditions. Much more
attention must be allocated to the central task in most divided
attention tests, for example, leading to a substantial decrease in
performance when drugs such as cannabis are taken. In addition, in the
laboratory the subject is unable to vary a key task parameter, such as
driving speed, in order to compensate for any perceived impairment.
Hence, while laboratory divided attention tasks may be ideal for
detecting small drug effects, they may over-estimate the effects of
drugs on actual driving. It is not surprising then that many studies
which have used both types of test have reported less effect on actual
driving than on laboratory tasks or simulated driving.
5.4.5 Studies of cannabis use and accident risk
While cannabis produces decrements in psychomotor performance in
laboratory and controlled settings, it does not necessarily follow
that these decrements will increase the risk of being involved in
accidents. It may be, for example, that cannabis users are less likely
to drive than drinkers because they are more aware of their
intoxication. The survey evidence suggests that this is not the case.
Several surveys (e.g. Dalton et al, 1975; Thompson, 1975; Klonoff,
1974; Robbe & O'Hanlon, 1993) have found that cannabis users are
generally aware that their driving is impaired after using cannabis
but the majority had driven, or would drive, after using cannabis,
despite this recognition of impairment (Klonoff, 1974). This finding
is consistent with observations on the recreational use of alcohol
when driving (Smart, 1974).
Even if cannabis users drive when intoxicated it does not necessarily
follow that they will be over-represented among drivers involved in
accidents. It could be, for example, that cannabis users take special
care and avoid risk-taking when driving while intoxicated. This
possibility is difficult to investigate because there have been no
controlled epidemiological studies conducted to establish whether
cannabis users are at increased risk of being involved in motor
vehicle or other accidents. This is in contrast to the instance of
alcohol use and accidents, where case-control studies have shown that
persons with blood alcohol levels indicative of intoxication are
over-represented among accident victims (Holman et al, 1988).
In the case of cannabis, all that is available are studies of the
prevalence of cannabinoids in the blood of motor vehicle and other
accident victims (see McBay, 1986 for a review). Most often these have
been retrospective studies of the prevalence of cannabinoids in blood
tested post-mortem, which have found that between 4 per cent and 37
per cent of blood samples have contained cannabinoids, typically in
association with blood alcohol levels indicative of intoxication (e.g.
Cimbura et al, 1982; Mason and McBay, 1984; Williams et al, 1985).
Zimmerman et al (1983) have reported similar prevalence data on blood
cannabinoid levels among Californian motorists tested because of
suspicion of impairment by the Highway patrol. Soderstrom et al (1988)
have conducted one of the few prospective studies among trauma
patients rather than accident fatalities, which showed a high
prevalence of bloods positive for cannabinoids (35 per cent).
These studies are difficult to evaluate for a number of reasons.
First, in the absence of information on the prevalence of cannabinoids
in the blood of non-accident victims, we do not know whether persons
with cannabinoids are over-represented among accident victims
(Terhune, 1986). Although a prevalence of 35 per cent may seem high,
this is of the order of the prevalence of cannabis use among young
males who are at highest risk of involvement in motor vehicle and
other accidents (Soderstrom et al, 1988). Second, there are major
problems in using cannabinoid blood levels to determine whether a
driver or pedestrian was intoxicated with cannabis at the time of an
accident (Consensus Development Panel, 1985). The simple presence of
cannabinoids indicates only recent use, not necessarily intoxication
at the time of the accident (see above pp35-36). Third, there are also
serious problems of causal attribution, since more than 75 per cent of
drivers with cannabinoids in their blood also have blood levels
indicative of alcohol intoxication (McBay, 1986). On the basis of the
available evidence, it is accordingly difficult to draw any
conclusions about the contribution that cannabis intoxication may make
to the occurrence of motor vehicle accidents (Terhune, 1986).
One approach that has been used in an attempt to get around the
absence of data on the prevalence of cannabis use among drivers not
involved in accidents has been to perform "culpability analyses"
(Terhune, 1986). In such analyses, decisions are made as to which
drivers killed in fatal accidents are culpable (i.e. responsible for
the accident). Drivers with no alcohol or other drugs in their blood
are then used as the control group in analyses of the relationship
between the presence of drugs in blood and degree of culpability.
These studies have their problems: the culpability of the drug-free
drivers is usually high thereby reducing the ability to detect an
increase in culpability among drivers with alcohol and cannabis;
different studies use different criteria for deciding that when a
driver was intoxicated with cannabis; and as a consequence, different
studies have produced very different estimates of the relationship
between cannabinoids in blood and driver culpability (although most
have shown an increased culpability for drivers with intoxicating
levels of alcohol in their blood). As Simpson (1986) concluded after
reviewing the culpability literature: "the results are mixed and
inconclusive" (p28).
Gieringer (1988) used a different approach to circumvent the absence
of data on the prevalence of cannabinoids in drivers not involved in
accidents. He used data from a National Institute of Drug Abuse (NIDA)
household survey of drug abuse in the United States to estimate the
proportion of all drivers who might be expected to have blood and
urine samples positive for cannabinoids. On the basis of these data,
he estimated that cannabis users are two to four times more likely to
be represented among accident victims than non-cannabis users, and
that cannabis users who also used alcohol were even more likely to be
over-represented among the victims of motor vehicle accidents.
Gieringer's inference about the risks of combining alcohol and
cannabis when driving receive some support from the studies of Mason
and McBay (1984) and Williams et al (1985). Mason and McBay estimated
that at most one driver in their series of 600 drivers killed in
single-vehicle accidents was significantly impaired by cannabis use
alone, compared with between nine and 28 drivers who were impaired by
marijuana and alcohol, and 476 drivers who had blood alcohol
contentrations (BACs) greater than 0.10. Williams et al (1985)
investigated the relationship between alcohol and cannabis use and
driver responsibility for fatal accidents (as judged from police
investigations of each accident) involving young men in California.
Using the small drug-free group as the comparison, they found that
both alcohol (OR=4.7 [95 per cent CI: 2.1, 10.3]) and alcohol and
marijuana in combination (OR=8.6 [95 per cent CI: 3.3, 22.2])
significantly increased the odds of the driver being adjudged to be
responsible for the accident. Marijuana-only drivers, however, were
less likely to be adjudged responsible for their accident (OR=0.5 [95
per cent CI: 0.2, 1.3]), although numbers were small (N=19).
There is also indirect evidence that cannabis use produces an increase
in the risk of accidents, from surveys of self-reported accidents
among adolescent drug users. Two such surveys have found a
statistically significant relationship between marijuana use and
self-reported involvement in accidents, with marijuana smokers having
approximately twice the risk of being involved in accidents of
non-marijuana smokers (Hingson et al, 1982; Smart and Fejer, 1976).
More direct evidence of an association between cannabis use and
accidents is provided by two epidemiological studies, one of cannabis
use and mortality (Andreasson and Allebeck, 1990), and the other of
cannabis use and health service utilisation (Polen et al, 1993).
Andreasson and Allebeck reported a prospective study of mortality over
15 years among 50,465 Swedish military conscripts. They found an
increased risk of premature mortality among men who had smoked
cannabis 50 or more times by age 18 (RR=4.6, 95 per cent CI: 2.4,
8.5). Violent deaths were the major cause of death contributing to
this excess mortality, with 26 per cent of deaths being motor vehicle
and 7 per cent other accidents (e.g. drownings and falls). The
increased risk was no longer statistically significant (RR=1.2 [95 per
cent CI: 0.7, 1.9]) after multivariate statistical adjustment for
confounding variables such as anti-social behaviour, and alcohol and
other drug use in adolescence (Andreasson and Allebeck, 1990),
reinforcing Gieringer's suggestion that the combination of cannabis
and alcohol may be the important risk factor for accidents.
Polen et al (1993) compared health service utilisation by non-smokers
(N=450) and daily cannabis-only smokers (N=450) screened at Kaiser
Permanente Medical centres between July, 1979 and December, 1985. They
reported an increased rate of medical care utilisation by
cannabis-only smokers for respiratory conditions and accidental injury
over a one to two-year follow-up. There was also an interaction
between cannabis and alcohol use, in which cannabis users who were the
heaviest alcohol users showed the highest rates of utilisation. This
result is suggestive but minimally informative about the risks of
motor vehicle accidents, because all forms of accidental injury were
aggregated.
5.4.6 Conclusions on cannabis and driving
There is no doubt that cannabis adversely affects the performance of a
number of psychomotor tasks, an effect which is related to dose, and
which is larger, more consistent and persistent in difficult tasks
involving sustained attention. The acute effects on performance of
typical recreational doses of cannabis are similar to, if smaller
than, those of intoxicating doses of alcohol. Alcohol and cannabis
differ in their effects on the apparent willingness of intoxicated
users to take risks when driving, with persons intoxicated by cannabis
engaging in less risky behaviour than persons intoxicated by alcohol.
While cannabis produces decrements in performance under laboratory and
controlled on-road conditions, it has been difficult, for technical
and ethical reasons, to establish conclusively whether cannabis
intoxication increases the risk of involvement in motor vehicle
accidents. There is sufficient consistency and coherence in the
evidence from studies of cannabinoid levels among accident victims,
and a small number of epidemiological studies, to infer that there
probably is an increased risk of motor vehicle accidents among persons
who drive when intoxicated with cannabis. A crude estimate of the risk
is of the order of two to four times for persons driving under the
influence of cannabis. This increased risk may be largely explained by
the combined use of cannabis with intoxicating doses of alcohol.
Further research is required to elucidate this issue, although it will
not be easily resolved because of the technical obstacles to such
research. In the meantime, cannabis users should be urged not to drive
while intoxicated by cannabis, and they should be particularly warned
of the dangers of driving after combining alcohol and cannabis use.
5.5 Interactions between cannabis and other drugs
Cannabis is often taken in combination with other drugs. This is most
likely among those who use it frequently and in large quantities (Tec,
1973). The predominant drug of choice for use with cannabis is alcohol
(e.g. Carlin & Post, 1971; Hochhauser, 1977; McGlothlin et al, 1970;
Norton and Colliver, 1988) which supports the popular notion that this
combination enhances the degree of intoxication. Barbiturates, in
contrast, appear to produce an aversive intoxication when combined
with cannabis (Johnstone et al, 1975). The interactions of cannabis
with each type of drug will be considered in three ways; interactions
of toxicity, psychotropic effects and psychomotor impairment.
5.5.1 Other cannabinoids
There are slight interactions of THC with other cannabinoids found in
cannabis preparations. The two major cannabinoids other than THC which
have been extensively tested for interactions with THC and other drugs
are cannabidiol and cannabinol. Both of these compounds have been
found to have little psychoactivity when administered alone
(Hollister, 1986). In rather high doses (15-60mg), cannabidiol has
been reported to abolish the effects of 30mg of oral THC (Karniol et
al, 1975), whereas cannabinol had no apparent effect (Hollister &
Gillespie, 1975). Comparisons of smoked THC and smoked cannabis, the
latter containing the usual small amounts of cannabinol and
cannabidiol, indicate that there is, if anything, a slightly greater
psychoactive effect from the cannabis than from THC (Galanter et al,
1973; Lemberger et al, 1976). The psychotropic effects of THC also
appear to be slightly enhanced by the minor constituent cannabinoids
found in natural products when smoked (Galanter et al, 1973). No such
differences have been reported in the behavioural effects of smoked
cannabis.
5.5.2 Alcohol
Alcohol and cannabis have a number of effects in common, although the
mechanisms of these actions appear to be different. The recent
identification of the cannabinoid receptor (Howlett et al, 1990), and
an endogenous ligand for that receptor, have confirmed the hypothesis
that the central activity of cannabis is receptor-mediated (see pp
29-31 above). While the mechanism of action of alcohol is still in
question, most explanations are concerned with the effects of alcohol
upon the structure and chemistry of the cell membrane. Both drugs are
considered to be CNS depressants, especially in high doses, and both
have substantial analgesic properties. Since these effects of the two
drugs appear to be approximately additive (Siemens, 1980) it is
possible that the toxicity of high doses of Æ9-tetrahydrocannabinol
(THC) (Rosencrantz, 1983) may be potentiated by alcohol, although
there is very little evidence to support this conjecture. Neither the
metabolism of alcohol nor that of THC appears to be altered by the
presence of the other drug (Siemens & Khanna, 1977).
Alcohol and THC also appear to have similar psychotropic effects. The
perceived stimulation and euphoria at low doses are common effects, as
well as a tendency toward behavioural disinhibition over a range of
doses (Hollister & Gillespie, 1970). This interaction is generally
perceived by users as enhancing the intoxication produced by either
drug alone (Chesher et al, 1976), although contrary results have been
reported (Manno et al, 1971). However, larger doses in combination are
often reported to be aversive (Sulkowski & Vachon, 1977; Chesher et
al, 1986).
The effects of alcohol and cannabis combinations on psychomotor
performance are more complex. The majority of studies have reported
that both drugs produce impairment on a variety of psychomotor tasks,
and that the interaction is approximately additive. However, a number
of studies have reported that at low doses there is less than an
additive effect. Chesher et al (1976, 1977) found a reduction in
impairment late in intoxication after a combination of oral THC
(0.14-0.21mg/kg) and alcohol (0.5-0.6g/kg). A further study in which
the THC (0.32mg/kg) was administered one hour before the alcohol
(0.54g/kg) found no apparent antagonism (Belgrave et al, 1979).
Another study using three doses of smoked marijuana in combination
with alcohol showed a lower-than-expected impairment in the group
which received the lowest dose of THC (5mg) and the lowest dose of
alcohol (0.54g.kg) (Chesher et al, 1986). Peck et al (1986) also
reported an apparent antagonism, but only on a composite "stopping"
variable derived from driving performance. In most of their measures,
the combination of alcohol and cannabis produced additive impairments.
Siemens (1980) has proposed that alcohol may reduce the availability
of THC through a pharmacokinetic interaction demonstrated in animals
(Siemens & Khanna, 1977). Given that there is substantial evidence for
cross-tolerance between alcohol and THC (Newman et al, 1972), it is
possible that low doses of THC and alcohol in combination may enhance
the acute tolerance to alcohol (Hurst & Bagley, 1972) late in
intoxication.
5.5.3 Psychostimulants
The most characteristic effect of psychostimulants such as amphetamine
and cocaine is their activation of the sympathetic branch of the
autonomic nervous system, as indicated by increases in arousal, blood
pressure and respiratory rate. There are few actions which appear to
be common between cannabis and stimulants. The few effects on the
cardiovascular system, such as amphetamine-induced hypertension, and
THC-induced tachycardia, seem to occur independently (Zalcman et al,
1973). It is in the combined effect upon cardiac action that toxic
interactions of THC and stimulants could be dangerous, but there are
no clear indications in the literature for humans, and the evidence
from animal studies is mixed (Siemens, 1980).
The psychotropic effects of the combination of 0.14mg/kg amphetamine
and 0.05mg/kg THC have been reported as a longer and more intense
"high" (Evans et al, 1976), although a similar study using only
0.025mg/kg THC found no effect of the combination (Forney et al 1976).
While the concurrent use of cannabis and cocaine is often reported
(Miller et al, 1990), systematic study of their interaction is
lacking.
There is some evidence that amphetamine may antagonise the behavioural
impairments produced by cannabis (Zalcman et al, 1973), as a number of
stimulants appear to do in some animals (Consroe et al, 1976). The
infrequency of stimulant/cannabis combinations in recreational use
(Hollister, 1986) may be due to as yet unspecified negative
interactions experienced by users. It may be, for example, that
stimulants increase the probability of occurrence, or severity of the
acute panic reaction which sometimes occurs after cannabis use.
5.5.4 Depressants
A great deal of experimentation in animals has shown that cannabis in
general increases the depressant action of drugs such as the
barbiturates over a range of doses (Siemens, 1980). This is also the
case with oxymorphone (Johnstone et al, 1975) and diazepam (Smith &
Kulp, 1976). As with alcohol, it is likely that interactions between
these acute effects of depressant drugs would lead to the greatest
danger of acute toxicity. There is little human evidence at present,
however, to support this speculation.
The psychotropic effects produced by combinations of barbiturates with
cannabis appear to be additive (Dalton et al, 1975). As mentioned
previously, this intoxication is more likely to be aversive to the
user (Johnstone et al, 1975). The behavioural effects of the
interaction of depressant drugs with cannabis are, in almost all
reports, also additive.
5.5.5 Miscellaneous drugs
A number of other substances have been reported to antagonise various
effects of cannabis in animals, including phenitrone (Kudrin &
Davydova, 1968), pemoline (Howes, 1973) and even tamarind (Hollister,
1986). Only pemoline is acknowledged to counter the reduced motor
activity and hypoalgesia due to THC. Physostigmine has shown a complex
interaction which includes increasing the motor depression produced by
THC and antagonising the tachycardia (Freemon et al, 1975).
Propanolol, which would be expected to antagonise the tachycardia
characteristic of cannabis intoxication, also appears to abolish the
reduction in learning capacity produced by cannabis (Sulkowski et al,
1977), although an earlier study using smaller, spaced doses found no
effect (Drew et al, 1972). Recently, it has been reported that
indomethacin, a non-steroidal anti-inflammatory, reduced or eliminated
a number of physiological effects of THC, and attenuated the "high",
but did not affect the acute memory impairment (Perez-Reyes et al,
1991).
5.5.6 Conclusions on drug interactions
At present, the interactions between the effects of cannabis and other
drugs are what would be predicted from their separate actions, and are
generally relatively innocuous in recreational doses. There have been
a number of reports in which cannabis use has accompanied serious
consequences, typically when used in combination with one or more
other drugs in high doses, or over extended periods of intoxication.
However, there appears to be no evidence that cannabis is particularly
implicated in cases of heavy intoxication with other drugs. The
concurrent intoxication with alcohol and cannabis, which is the most
common combination of drugs, may have greatest relevance in motor
vehicle accidents. The separate impairments induced by the two drugs
appear to be approximately additive, and there are indications that
users of both drugs are over-represented among motor vehicle
accidents.
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Thompson, P. (1975) "Stoned" driving is unpleasant, say marijuana
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Yonge, K. A. (1975) Effect of marijuana on divergent and convergent
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6. The chronic effects of cannabis use on health
Cellular and immunological effects
The possible effects of chronic cannabis use on cellular processes and
the immune system are considered together because both effects may
influence a cannabis user's susceptibility to diseases. If cannabis
use affects cellular processes then users may be at increased risk of
developing various types of cancer, and if it affects the immune
system then cannabis users may be at increased risk of contracting
infectious diseases and developing cancer.
6.1 Mutagenicity and carcinogenicity
A major reason for research into the effects of cannabinoids on
cellular processes is to discover whether cannabinoids are mutagenic,
i.e. whether they may produce mutations in the genetic material in the
somatic and germ cells of users. If cannabinoid exposure affects the
genetic material of a user's somatic or bodily cells (such as those of
the lung, for example) then chronic cannabis use may cause cancer. If
it affects the genetic material of germ cells (the sperm and ova),
then genetic mutations could be transmitted to the children of
cannabis users.
There is experimental evidence from in vitro studies of animal cells
that some cannabinoids, including THC, can produce a variety of
changes in cellular processes in vitro (i.e. in the test tube). These
include alterations to cell metabolism, DNA synthesis, and cell
division (Nahas, 1984). The potential for cannabinoids to produce
genetic change in humans or animals is unclear. There is, at most,
mixed evidence that THC and other cannabinoids are mutagenic in
standard microbial assays, such as the Ames test, and there is
contradictory evidence on whether the cannabinoids are clastogenic,
i.e. produce breaks in chromosomes. According to Bloch (1983) who
reviewed the literature for the World Health Organisation: "in vivo
and in vitro exposure to purified cannabinoids or cannabis resin
failed to increase the frequency of chromosomal damage or mutagenesis"
(p412). Nahas (1984) reviewed the same evidence and concluded that
"cannabinoids and marihuana may exert a weak mutagenic effect" (p117).
More recently, Zimmerman and Zimmerman (1990/1991) concluded that
"cannabis mutagenicity remains unclear", but argued that there was
evidence that "cannabinoids induce chromosome aberrations in both in
vivo and in vitro studies" (p19).
There is stronger and more consistent evidence that cannabis smoke,
like smoke produced by most burning plant material, is mutagenic in
vitro, and hence, is potentially carcinogenic (Leuchtenberger, 1983).
According to Bloch (1983) "marijuana smoke exposure has been reported
to be associated with chromosomal aberrations ... [such as]
hypoploidy, mutagenicity in the Ames test ... " (Bloch, 1983, p413).
This is consistent with research indicating that cannabis smoke
contains many of the same carcinogens as cigarette smoke (Institute of
Medicine, 1982; Leuchtenberger, 1983), suggesting that if cannabis
smoke is carcinogenic it is more likely to be because of the
carcinogens it shares with cigarette smoke rather than because of the
cannabinoids it contains. If it is the non-cannabinoid components of
cannabis smoke that are mutagenic, then any cancers caused by cannabis
smoking are most likely to develop after long-term exposure to
cannabis smoke, and they are most likely to develop at sites which
have had the maximum exposure to that smoke, namely, the upper
aerodigestive tract and lung. This possibility is considered in more
detail below (see pp49-50).
6.2 Immunological effects
The possibility that cannabis reduces immune system function is
important for several reasons. First, tobacco smoking suppresses both
the humoral and cell-mediated immune systems. Given the similarities
between the constituents of cigarette and cannabis smoke (Institute of
Medicine, 1982; Leuchtenberger, 1983) it is reasonable to suspect that
cannabis may also be an immunosuppressant (Nahas, 1984). Second, even
a modest reduction in immunity caused by cannabis use could have
public health significance because of the relatively large number of
young adults who have used the drug (Munson and Fehr, 1983). Third, if
cannabinoids have immunosuppressive effects, then this would have
mixed implications for their therapeutic use. On the one hand, they
could be therapeutically useful as immunosuppressant drugs in patients
undergoing organ transplants. On the other hand, their therapeutic use
for other purposes would be limited in patients with impaired immune
systems, a restriction which would potentially preclude their use as
anti-emetic agents in cancer chemotherapy, or as appetite stimulants
and mood enhancers in patients with AIDS.
There are a number of difficulties in deciding whether cannabis
impairs the functioning of the immune system. First, the majority of
studies that have been conducted have been either in vitro studies in
which animal and human cell cultures have been exposed to cannabis
smoke or cannabinoids, or in vivo animal studies in which the effects
of cannabis and cannabinoid exposure on immune system function have
been assessed in live animals. The usual problems of extrapolation
from in vivo and in vitro studies to human users are complicated by
the fact that many of the effects of cannabinoids on the immune system
of animals are only obtained at very high doses which are rarely taken
by human beings. Second, the difficulties in interpreting these
studies are exacerbated because the results of the small number of
human in vivo studies have been conflicting. Third, there have been
very few epidemiological studies of immune system functioning and
disease susceptibility in heavy chronic cannabis users.
Given that the majority of the in vitro and in vivo animal work was
undertaken in the 1970s, we have relied upon the summary of findings
provided in the authoritative reviews of this literature undertaken by
the Addiction Research Foundation and World Health Organization
(Leuchtenberger, 1983; Munson and Fehr, 1983). This enables the
present review to focus upon on the clinical and public health
significance of the immunological effects observed in the experimental
studies. Before doing so, a brief and schematic review will be
provided of the components of the human immune system.
6.2.1 The immune system
The immune system in mammals is "an adaptive and a protective
mechanism against noxious foreign materials including pathogens and
cancer cells" (Munson and Fehr, 1983). Its multiple components
include: lymphoid tissues such as the spleen and lymph nodes; the bone
marrow and thymus, where lymphocytes and other important cells in the
immune system are manufactured; and the recirculating lymphocytes that
mediate cellular and humoral immunity (see Grossman and Wilson, 1992;
and Nossal, 1993).
Immunity may be either innate or acquired. Innate immunity consists of
those responses to foreign substances that do not require
sensitisation from previous exposure, such as the ingestion of
bacteria by macrophages, and the killing of tumour cells by natural
killer cells. Acquired immunity is that form of immunity in which the
recognition and destruction of foreign material depends upon processes
produced by a previous exposure to the material. It is mediated by the
cooperative functioning of two major systems of lymphocyte cells: the
B-cells (Thymus-independent lymphocytes) which control humoral
immunity, and T-cells (Thymus-dependent lymphocytes) the activity of
which controls cell-mediated immunity.
Humoral immunity involves the production of antibodies in response to
antigens, usually proteins, which are attached to the surface of
foreign cells. Antigens are recognised by the B-cells which
proliferate and differentiate into two types of cells, the first of
which synthesises and releases antibody, and the second of which
remains as antigen-sensitised cells that are able to respond to
subsequent exposure to the antigen by rapidly releasing large amounts
of antibody. The antibodies can act directly to inactivate the
pathogens or toxins by damaging cell membranes, or they can work
cooperatively with the cell-mediated immune system by enabling cells
called macrophages to recognise and destroy the foreign cells, either
by ingesting those cells which have antibodies attached, or by
releasing toxins which kill the cells. Cell-mediated immunity is
directed against foreign cells including many bacteria, viruses and
fungi. Macrophages are intimately involved in the early removal of
foreign materials directly by ingestion, or indirectly by altering
their antigens and presenting them to the T- and B-cells for the
further development of the immune response. They work in concert with
the humoral immune system to protect the organism from all pathogens
in its environment.
6.2.2 Effects of cannabinoids on lymphoid organs
A non-specific indication of an effect of cannabinoids on the immune
system would be a reduction in the weight of lymphoid organs, such as
the thymus and spleen, or a decrease in the number of circulating
lymphocytes. A substantial body of anatomical and histological studies
in animals bearing upon this possibility has been reviewed by Munson
and Fehr (1983). These studies reveal that cannabinoids in high doses
can affect the function of the stem cells which produce lymphocytes,
and can reduce the size of the spleen in rodents. It is uncertain what
the implications are for immune system competence because these
effects all occur after acute exposure, typically in response to very
high doses of cannabinoids. It is also unknown whether these effects
occur as the direct result of cannabinoids acting upon the lymphoid
cells, or whether they are an indirect effect of cannabinoids acting
on the adrenal-pituitary axis to increase the release of
corticosteroids which in turn shrink the spleen.
6.2.3 Effects of cannabinoids on humoral immunity
The effect of cannabinoids on humoral immunity has been assessed in
vitro by measuring the effect of cannabinoids on the number and
functioning of animal and human B-cells produced in response to the
presence of sheep red blood cells. Cannabinoids do not consistently
alter the number or percentage of B-cells (Munson and Fehr, 1983).
B-cell function has also been assessed in vitro by measuring the
proliferation of B-cells in response to chemicals which stimulate the
cells to divide, and by assessing antibody production in B-cells that
have previously been exposed to cannabinoids. While cannabinoids have
been consistently shown to impair the B-cell responses in mice, no
such effects have been consistently observed in humans, and the few
positive studies have produced results which are still within the
normal range (Munson and Fehr, 1983).
Antibody formation to THC has been demonstrated in animals. There are
also clinical reports in humans that cannabinoids can exacerbate
existing allergies, and there are several reports of demonstrated
allergy to cannabinoids in humans (e.g. Freeman, 1983). Munson and
Fehr (1983) concluded that: "it appears that cannabinoids can elicit
the formation of specific antibodies ... [and that THC] or a
metabolite is probably acting as a hapten, combining with a protein to
form an antigenic complex" (p289).
Hollister (1992), however, has questioned the clinical significance of
this evidence, arguing that:
While it is possible that a few persons may become truly allergic to
cannabinoids, it is far more likely that allergic reactions, which
have been extremely rare following the use of marijuana, are due to
contaminants .. (e.g. bacteria, fungi, molds, parasites, worms,
chemicals) that may be found in such field plants. That such impure
material, when smoked and inhaled into the lungs, causes so little
trouble is really a marvel (p163).
6.2.4 Effects of cannabinoids on cell-mediated immunity
Researchers have examined the effects of cannabinoids on both the
numbers and functioning of T-cells and macrophages. There are
considerable inconsistencies in the results of studies on the effects
of cannabinoids on T-cell numbers in humans, with some studies showing
reductions (e.g. Nahas et al, 1974) while others have not (e.g. Dax et
al, 1989). There is also mixed evidence on the effect of cannabinoids
on T-cell functioning as assessed by response to allogenic cells and
mitogens, chemicals which stimulate the cells to divide. A number of
the earliest studies suggested that T-cells from chronic cannabis
users showed a decreased responsiveness to such stimulation, but later
studies, including laboratory studies of chronic heavy dosing in
humans (e.g. Lau et al, 1976), have failed to replicate these results.
Studies of in vitro exposure of T-cells to cannabinoids have also
produced mixed results, while animal studies have showed a decreased
T-cell response to mitogens (Munson and Fehr, 1983).
Interpretations of this literature differ. Munson and Fehr (1983)
concluded that the fact that cannabinoids can affect T-cell function
in several species of animals "suggests that the same effects could
occur in humans given exposure to these substances" (pp306-307). Nahas
(1984) concluded that "there is only suggestive" evidence that
cannabinoids "exert an immunodepressive effect" (p156). Hollister
(1986) argued that even if there were such effects, they were of
limited clinical significance because they were probably transient
effects in healthy young adults, and there was no evidence of
increased susceptibility to disease in cannabis smokers. More
recently, Hollister (1992) has concluded that "... the effects of
cannabinoids on cell-mediated immunity are contradictory. Such
evidence as has been obtained to support such an effect has usually
involved doses and concentrations that are orders of magnitude greater
than those obtained when marijuana is used by human subjects. (p161)"
6.2.5 Effects of cannabinoids on host resistance
It is one thing to decide that in vitro exposure of the immune system
to high doses of cannabinoids impairs its functioning in various ways;
it is much more difficult to decide whether the small impairments in
immunity predicted by in vitro studies is likely to impair host
resistance to pathogens and infection with micro-organisms among human
cannabis users. There is a very small animal, and almost no human,
literature on which to make such a decision.
A small number of studies in rodents (mice and guinea pigs) has
suggested that high doses (200mg/kg) of cannabinoids decrease
resistance to infection (Friedman, 1991), e.g. with Lysteria
monocytogenes (Morahan et al, 1979), and herpes simplex type 2 virus
(Cabral et al, 1986; Mishkin and Cabral, 1985; Morahan et al, 1979). A
reasonably consistent finding in humans has been that exposure to
cannabis smoke adversely affects alveolar macrophages, cells in the
respiratory system that constitute a first line of bodily defence
against many pathogens and micro-organisms which enter the body via
the lungs (Leuchtenberger, 1983). Studies of these cells obtained from
cannabis smokers have demonstrated ultrastructural abnormalities
(Tennant, 1980), and studies of the in vitro exposure of alveolar
macrophages to cannabis smoke have demonstrated that their ability to
inactivate Staphylococcus aureus (Leuchtenberger, 1983; Munson and
Fehr, 1983), and more recently the fungus Candida albicans (Sherman et
al, 1991) has been impaired. In this case, however, it seems to be the
non-cannabinoid components of cannabis smoke that produce the effect
(Leuchtenbeger, 1983).
6.2.6 Human significance of immunological effects of cannabinoids
The animal evidence is reasonably consistent that cannabinoids produce
impairments of the cell-mediated and humoral immune systems, and in
several studies these changes have been reflected in decreased
resistance to bacteria and viruses. There is also evidence that the
non-cannabinoid components of cannabis smoke can impair the
functioning of alveolar macrophages, the first line of the body's
defence system. However, the doses required to produce these
immunological effects have varied from the behaviourally relevant to
very high doses. This raises the issue of whether their findings can
be extrapolated to the doses used by humans.
The possibility of tolerance developing to any immunological effects
of cannabinoids also makes the human significance of the results of in
vitro studies uncertain. If immunological tolerance develops with
chronic use, then the possibility of observing even the small effects
projected from the in vitro studies would be substantially reduced.
There have been no demonstrations that such tolerance occurs in
animals, in part because most studies have used short duration, high
dosing schedules rather than chronic high dosing required for
tolerance to be demonstrated. Given the large number of cannabinoid
effects to which tolerance has been shown to develop, it would not be
surprising if this were also true of its immunological effects.
The very limited human evidence from experimental studies of immune
function is mixed, with a small number of studies suggesting
immunosuppressant effects that have not been replicated by others. As
Munson and Fehr (1983) concluded: "At present, there is no conclusive
evidence that consumption of cannabinoids predisposes man to immune
dysfunction" (p338), as measured by reduced numbers or impaired
functioning of T-lymphocytes, B-lymphocytes or macrophages, or reduced
immunoglobulin levels. There was "suggestive evidence" of impaired
T-lymphocyte functioning reflected in an impaired reaction to mitogens
and allogenic lymphocytes (Munson and Fehr, 1983). More recently,
Wallace et al (1988, 1993 in press) have failed to find any impairment
of lymphocyte function in alveolar macrophages in marijuana smokers,
although they did find such impairment in tobacco smokers.
The clinical significance of these possible immunological impairments
in chronic cannabis users is uncertain. There have been sporadic
reports of ill health, including decreased resistance to disease,
among chronic heavy cannabis users in Asia and Africa (Munson and
Fehr, 1983). These reports are difficult to evaluate because of the
confounding effects of poor living conditions and nutritional status,
although it may be that the small human immunological impairment
predicted from the animal literature is most likely to be seen among
such populations (Munson and Fehr, 1983).
Three field studies of the effects of chronic cannabis use in Costa
Rica (Carter et al, 1980), Greece (Stefanis et al, 1977), and Jamaica
(Rubin and Costas, 1975), have failed to demonstrate any evidence of
increased susceptibility to infectious diseases among chronic cannabis
users. However, these negative findings are not very convincing. Less
than 100 users were studied overall, which is too small a sample in
which to detect a small increase in the incidence of common infectious
and bacterial diseases. While it is difficult to detect a small
increase in the incidence of infections in an individual or among a
small sample of people, such an increase may have great public health
significance. The type of large-scale epidemiological studies that are
needed to explore this issue have not been conducted until very
recently.
A recent study by Polen et al (1993) compared health service
utilisation by non-smokers and daily cannabis only smokers enrolled in
a health maintenance organisation. Their results provided the first
suggestive evidence of an increased rate of presentation for
respiratory conditions among cannabis-only smokers, although its
significance remains uncertain because infectious and non-infectious
respiratory conditions were aggregated. Nevertheless, further studies
of this type may enable a more informed decision to be made about the
seriousness of the risk that chronic heavy cannabis smoking poses to
the immune and respiratory systems.
Hollister (1992) has expressed a sceptical attitude towards the human
health implications of the literature on the immunological effects of
cannabis, arguing that:
... Clinically, one might assume that sustained impairment of
cell-mediated immunity might lead to an increased prevalence of
malignancy. No such clinical evidence has been discovered or has any
direct epidemiological data incriminated marijuana use with the
acquisition of human immunodeficiency virus or the clinical
development of AIDS. (p161)
Given the duration of large-scale cannabis use by young adults in
Western societies, the absence of an epidemic of infectious disease is
arguably sufficient to rule out the hypothesis that cannabis smoking
produces major impairments in the immune systems of users comparable
to those caused by AIDS. The absence of such epidemics among cannabis
users does not, however, exclude the possibility that chronic heavy
use may produce minor impairments in immunity, since this would
produce small increases in the rate of occurrence of common bacterial
and viral illnesses (Munson and Fehr, 1983) that would have escaped
the notice of clinical observers. Such an increase could nonetheless
be of public health significance because of the increased expenditure
on health services, and the loss of productivity among the young
adults who are the heaviest users of cannabis.
Clinical studies of patients with immune systems compromised by AIDS
may provide one of the best ways of detecting any adverse
immunological effects of cannabinoids. AIDS patients and gay advocacy
groups have proposed that cannabinoids should be used therapeutically
to improve appetite and well-being in AIDS patients (see below p195).
If it was ethical to conduct trials of the therapeutic use of
cannabinoids in AIDS patients, then monitoring the impact on immune
functioning would provide one way of evaluating the seriousness of the
immunological effects of cannabinoids, not only for AIDS patients, but
also for other immunologically compromised patients using cannabinoids
for therapeutic purposes. If there were no effects in patients with
compromised immune systems, it would also be a reasonable to infer
that there was little risk of immunological effects in long-term
recreational users.
An epidemiological study of predictors of progression to AIDS among
HIV positive homosexual men suggests that the risks may be
sufficiently small in the case of HIV positive patients to warrant
further research. Kaslow et al (1989) conducted a prospective study of
progression to AIDS among HIV positive men in a cohort of 4,954
homosexual and bisexual men. Among the predictor variables studied
were licit and illicit drug use, including cannabis use. Illicit drug
use predicted an increased risk of infection with HIV, as has been
consistently found in studies of risk factors for HIV infection.
However, neither cannabis use, nor any other psychoactive drug use,
predicted an increased rate of progression to AIDS among men who were
HIV positive. Nor was cannabis use related to changes in a limited
number of measures of immunological functioning.
6.2.7 Conclusions
There is reasonable evidence that cannabis smoke is mutagenic, and
hence, potentially carcinogenic, because of the many mutagenic and
carcinogenic substances it shares with tobacco smoke. THC is at most
weakly mutagenic. This suggests that the major cancer risk from
cannabis use is the development of cancers of the respiratory tract
arising from smoking as a route of administration, rather than from
the mutagenicity of the psychoactive components of cannabis.
There is reasonably consistent animal evidence that THC can impair
both the cell-mediated and humoral immune systems, producing decreased
resistance to infection by bacteria and viruses. The relevance of
these findings to human health is uncertain: the doses required to
produce these effects are often very high, and the problem of
extrapolating from the effects of these doses to those used by humans
is complicated by the possibility that tolerance develops to the
effects on the immune system.
The limited experimental evidence on immune effects in humans is
conflicting, with the small number of studies producing adverse
effects not being replicated. Even studies that have produced evidence
of adverse effects observe small changes that are still within the
normal range. The clinical and biological significance of even the
small positive effects in chronic cannabis users is uncertain. There
has not been any evidence of increased rates of disease among chronic
heavy cannabis users analogous to that seen among homosexual men in
the early 1980s. Given the duration of large-scale cannabis use by
young adults in Western societies, the absence of such epidemics makes
it unlikely that cannabis smoking produces major impairments in the
immune system.
It is more difficult to exclude the possibility that chronic heavy
cannabis use produces minor impairments in immunity. Such effects
would produce small increases in the rates of infectious diseases of
public health significance, because of the increased expenditure on
health services, and the loss of productivity among the young adults
who are the heaviest users. There is one large prospective study of
HIV-positive homosexual men which indicates that continued cannabis
use did not increase the risk of progression to AIDS (Kaslow et al,
1989). A recent epidemiological study by Polen et al (1993) which
compared health service utilisation by non-smokers and daily
cannabis-only smokers provided the first suggestive evidence of an
increased rate of medical care utilisation for respiratory conditions
among cannabis smokers. This remains suggestive, however, because
infectious and non-infectious respiratory conditions were not
distinguished. The most sensitive assay of any small immunological
effects of cannabis may come from studies of the therapeutic
usefulness of cannabinoids in immunologically compromised patients,
such as those undergoing cancer chemotherapy, or those with AIDS.
6.3 Cardiovascular effects
Both the inhalation of marijuana smoke and the ingestion of THC
reliably produces an increase in heart rate of 20 per cent to 50 per
cent over baseline (Huber et al, 1988; Jones, 1984). When cannabis is
smoked, the heart rate increases within two to three minutes, peaks
within 15 to 30 minutes, and may remain elevated for up to two hours.
When ingested, these effects are delayed for several hours, and last
for four to five hours (Maykut, 1984). There are also complex changes
in blood pressure which depend upon posture: blood pressure is
increased while the person is sitting or lying, but decreases on
standing, so that a sudden change from a recumbent to an upright
position may produce postural hypotension and, in extreme cases,
fainting (Maykut, 1984).
Young, healthy hearts are likely to be only mildly stressed by these
acute effects of cannabis (Tennant, 1983). The clinical significance
of the repeated occurrence of these effects in chronic heavy cannabis
users remains uncertain, because there is evidence from clinical and
experimental studies (Benowitz and Jones, 1975; Jones and Benowitz,
1976; Nowlan and Cohen, 1977) that tolerance develops to the acute
cardiovascular effects of cannabis. Clinical studies employing chronic
dosing over periods of up to nine weeks show that the increased heart
rate all but disappears, while the blood pressure increase is much
attenuated. Tolerance to the cardiovascular effects develops within
seven to 10 days in persons receiving high daily doses by the oral
route (Jones, 1984).
The field studies of chronic heavy users in Costa Rica (Carter et al,
1980), Greece (Stefanis et al, 1977), and Jamaica (Rubin and Costas,
1975) failed to disclose any evidence of cardiac toxicity, even in
those subjects with heart disease that was unrelated to their cannabis
use. The findings of the field studies have been supported by the fact
that electrocardiographic studies in conditions of both acute and
prolonged administration have rarely revealed pathological changes
(Benowitz and Jones, 1975; Jones, 1984). It seems reasonable to
conclude then that among healthy young adults who use cannabis
intermittently, cannabis use is not a major risk factor for
life-threatening cardiovascular events in the way that the use of
cocaine and other psychostimulants can be (Gawin and Ellinwood, 1988).
There is suggestive evidence of a small risk, however, since there
have been a number of case reports of myocardial infarction in young
men who were heavy cannabis smokers and had no personal history of
heart disease (Tennant, 1983; Choi and Pearl, 1989; Pearl and Choi,
1992; Podczeck et al, 1990). Such cases deserve close investigation to
exclude the role of other cardiotoxic drugs.
The possibility remains that chronic heavy cannabis smoking may have
more subtle effects on the cardiovascular system. Jones (1984) has
suggested, for example, that there is a possibility that "after years
of repeated exposure" there may be "lasting, perhaps even permanent,
alterations of the cardiovascular system function" (p331). Arguing by
analogy with the long-term cardiotoxic effects of tobacco smoking, he
suggests that there are "enough similarities between THC and nicotine
cardiovascular effects to make the possibility plausible" (p331).
Moreover, since many cannabis smokers are also cigarette smokers,
there is the possibility that there may be adverse interactions
between nicotine and cannabinoids in their effects on the
cardiovascular system.
6.3.1 Effects on patients with cardiovascular disease
The cardiovascular effects of cannabis may adversely affect patients
with pre-existing cardiovascular disease. As the Institute of Medicine
observed:
the possibility is great that the abnormal heart and circulation will
not be as tolerant of an agent that speeds up the heart, sometimes
unpredictably raises or drops blood pressure, and modifies the
activities of the autonomic nervous system (pp69-70).
There are a number of concerns about the potentially deleterious
effects of cannabis use on patients with ischaemic heart disease,
hypertension, and cerebrovascular disease (Jones, 1984; National
Academy of Science, 1982). First, THC appears to increase the
production of catecholamines which stimulate the activity of the
heart, thereby increasing the risk of cardiac arrhythmias in
susceptible patients. Second, THC increases heart rate, thereby
producing chest pain (angina pectoris) in patients with ischaemic
heart disease, and perhaps increasing the risk of a myocardial
infarction. Third, THC also has analgesic properties (see below p194)
which may attenuate chest pain, delaying treatment seeking, and
thereby perhaps increasing the risk of fatal arrhythmias. Fourth,
marijuana smoking increases the level of carboxyhaemoglobin, thereby
decreasing oxygen delivery to the heart, increasing the work of the
heart and, perhaps, the risk of atheroma formation. Moreover, the
reduced delivery of oxygen to the heart is compounded by a concomitant
increase in the work of the heart - and therefore its oxygen
requirements - because of the tachycardia induced by THC. Fifth,
patients with cerebrovascular disease may be put at risk of
experiencing strokes by unpredictable changes in blood pressure, and
patients with hypertension may experience exacerbations of their
disease for the same reason.
After considering the known cardiovascular effects of THC, and their
likely interactions with cardiovascular disease, the Institute of
Medicine (1982) concluded that it: " ... seems inescapable that this
increased work, coupled with stimulation by catecholamines, may tax
the heart to the point of clinical hazard" (p70). Despite the
plausibility of the reasoning, there is very little direct evidence of
the adverse effects of cannabis on persons with heart disease (Jones,
1984). Among the few relevant pieces of research evidence are two
laboratory studies of the acute cardiovascular effects of smoking
marijuana cigarettes on patients with occlusive heart disease. Aronow
and Cassidy (1974) conducted a double blind placebo control study
comparing the effect on heart rate and the time required to induce
chest pain during an exercise tolerance test, of smoking a single
marijuana cigarette containing 20mg of THC, with the effect of a
placebo marijuana cigarette. Heart rate increased by 43 per cent, and
the time taken to produce chest pain was approximately halved, after
smoking a marijuana cigarette. It appeared that cannabis increased the
myocardial oxygen demand while reducing the amount of oxygen delivered
to the heart (Aronow and Cassidy, 1974).
Aronow and Cassidy (1975) compared the effects of smoking a single
marijuana cigarette and a high nicotine cigarette in 10 men with
occlusive heart disease, all of whom were 20 a day cigarette smokers.
A 42 per cent increase in heart rate was observed after smoking the
marijuana cigarette compared with a 21 per cent increase after smoking
the tobacco cigarette. Exercise tolerance time was halved (49 per
cent) after smoking a marijuana cigarette by comparison with a 23 per
cent decline after smoking a tobacco cigarette.
Apart from these studies, there is very little direct evidence on the
risks of cannabis use by persons with cardiovascular disease. The
reasons for the absence of adverse effects of chronic cannabis use on
diseased cardiovascular systems are unclear. It should not be assumed
in the absence of evidence, however, that such effects do not exist.
The absence of evidence may simply reflect the lack of systematic
study. It may be that the development of tolerance to the
cardiovascular effects with chronic heavy dosing has protected the
heaviest users from experiencing such effects: it may be that there
has been an insufficient exposure to cannabis smoking of a
sufficiently large number of vulnerable individuals (National Academy
of Science, 1982); or it may be that cardiologists have missed any
such evidence because they have not inquired about cannabis use among
their patients.
On the face of it, the possibility of cannabis smokers developing
heart disease may seem "theoretical". Most cannabis users are healthy
young adults who smoke intermittently, most discontinue their use by
their late 20s, and very few of the minority who become heavy cannabis
users are likely to have clinical occlusive heart disease or other
atherosclerotic disease. But the possibility of such adverse effects
is not entirely theoretical.
First, any such effects would contraindicate the therapeutic uses of
cannabinoids among older patients, such as those with cancer and
glaucoma, who are at higher risk, because they are older, of having
significant heart disease (Jones, 1984).
Second, the chronic heavy cannabis users who were inducted into
cannabis use in the late 1960s and early 1970s are now entering the
period in which that minority who have continued to smoke cannabis are
at risk of experiencing symptoms of clinical heart disease. Among this
group cannabis use may contribute to an earlier expression of heart
disease, especially, if they have also been heavy cigarette smokers.
Because of the high rates of cessation of cannabis use with age,
however, this may be such a small number of persons that the effect is
difficult to detect clinically, especially if cannabis use is not
considered to be a risk factor about which cardiologists
systematically inquire. It may be worth exploring this possibility by
including questions on cannabis use in case-control studies of
cardiovascular disease among middle-aged adults.
6.3.2 Conclusions
On the available evidence, it is still appropriate to endorse the
conclusions reached by the expert committee appointed by the National
Academy of Science in 1982 that, although the smoking of marijuana
"causes changes to the heart and circulation that are characteristic
of stress ... there is no evidence ... that it exerts a permanently
deleterious effect on the normal cardiovascular system..." (p72). The
situation may be less benign for those with "abnormal heart or
circulation" since there is evidence that marijuana poses "a threat to
patients with hypertension, cerebrovascular disease and coronary
atherosclerosis" (p72) by increasing the work of the heart. The
"magnitude and incidence" of the threat remains to be determined as
the cohort of chronic cannabis users of the late 1960s enters the age
of maximum risk for complications of atherosclerosis of the cardiac,
brain and peripheral vessels. In the interim, because any such effects
could be life threatening in patients with significant occlusion of
the coronary arteries or other cerebrovascular disease, such persons
should be advised not to smoke cannabis (Tennant, 1983).
6.4 Effects on the respiratory system
The most reliable acute effect of exposure to cannabis smoke is
bronchodilation (National Academy of Science, 1982), which has
principally been of interest because of its possible therapeutic
effect upon asthma (see below pp193-194). Other than bronchodilation,
it has proved difficult to demonstrate any effects of acute cannabis
smoking on breathing "as measured by conventional pulmonary tests"
(National Academy of Science, 1982, p58).
The major concerns about the respiratory effects of cannabis use have
been the possible adverse effects of chronic, heavy cannabis smoking
(Tashkin, 1993). The two largest issues of concern have been the
production of chronic bronchitis as a precursor of irreversible
obstructive lung disease, and the possible causation of cancers of the
aerodigestive tract (including the lungs, mouth, pharynx, larynx, and
trachea) after 20 to 30 years of regular cannabis smoking. These risks
are the primary focus of this section of the review.
There is good reason to expect that chronic heavy cannabis smoking may
have adverse effects upon the respiratory system (Tashkin, 1993).
Cannabis smoke is similar in constitution to tobacco smoke, and
contains a substantially higher proportion of particulate matter and
of some carcinogens (e.g. benzpyrene) than does tobacco smoke
(Leuchtenberger, 1983; National Academy of Science, 1982). Hence, the
inhalation of cannabis smoke deposits irritating and potentially
carcinogenic particulate matter onto lung surfaces. Cigarette smoking
is known to cause diseases of the respiratory system, such as
bronchitis, emphysema, and various forms of cancer affecting the lung,
oral cavity, trachea, and oesophagus (Holman et al, 1988). Although
tobacco smokers smoke many more cigarettes than cannabis smokers,
cannabis smoke is typically inhaled more deeply, and the breath held
for longer, than tobacco smoke, thereby permitting greater deposition
of particulate matter on the lung surface (Hollister, 1986). It
therefore seems a reasonable inference that chronic daily cannabis
smoking may cause diseases of the respiratory system.
Despite the reasonableness of this hypothesis, it has nonetheless been
difficult to investigate the contribution of chronic heavy cannabis
smoking to diseases of the respiratory system (Huber et al, 1988;
National Academy of Science, 1982). A major problem is that most
marijuana smokers also smoke tobacco, which makes it difficult to
disentangle the effects of cannabis from those of tobacco smoking. The
problems in quantifying current and lifetime exposure to cannabis,
because of variations in quality and potency, make it difficult to
examine dose-response relationships between cannabis use and the risk
of developing various respiratory diseases. There is also likely to be
a long latency period between exposure and the development of these
diseases, especially in the case of cancers of the aerodigestive
tract. This period is approximately the length of time since cannabis
smoking became widespread in Western societies. There are also
technical difficulties in designing studies which are sufficiently
sensitive to detect increased risks of diseases arising from
relatively rare exposures, such as chronic daily cannabis use.
6.4.1 Bronchitis and airways obstruction
There is a small clinical literature containing case reports of acute
lung diseases among heavy cannabis smokers in the US military
stationed in West Germany during the early 1970s, when hashish was
cheap and freely available (Henderson et al, 1972; Tennant et al,
1971). Tennant et al studied 31 soldiers who had smoked 100g or more
of hashish monthly for six to 21 months, 21 of whom were also tobacco
smokers. Nine complained of bronchitis which had its onset three to
four months after they began to smoke hashish. Pulmonary function
tests of five cases (two of whom did not smoke tobacco) revealed mild
airflow obstruction that partially remitted after a reduction or
cessation of hashish use. Tennant (1980) also reported
histopathological studies of 23 of these patients in which all
patients were found to have atypical cells of the type (squamous
metaplasia in 21 cases) associated with chronic bronchitis and
carcinoma of the lung.
Henderson et al (1972) reported on 200 servicemen who sought treatment
for problems related to hashish use, 90 per cent of whom were also
cigarette smokers. Twenty men who smoked large doses of hashish on a
weekly basis presented with symptoms of chronic bronchitis, and on
testing had vital capacity that was 15-40 per cent below normal. Six
had a bronchoscopic examination which showed epithelial abnormalities.
The interpretation of these findings was complicated by the fact that
the majority of these hashish smokers were also tobacco smokers, as
were Tennant et al's subjects, and there was no adequate comparison
group.
The field studies of chronic cannabis smokers in Costa Rica (Carter et
al, 1980) and Jamaica (Rubin and Comitas, 1975), which included
comparison groups, have failed to support the clinical findings of
Henderson et al, and Tennant et al. Neither of these studies found any
statistically significant differences in lung function, or in the
prevalence of respiratory symptoms, between chronic cannabis users and
non-cannabis smoking controls. In both studies, however, the measures
of respiratory function were relatively unsophisticated, the sample
sizes were small, making it difficult to detect all but very large
differences, and the comparisons were often confounded by a failure to
control for tobacco smoking.
The most convincing evidence that chronic cannabis use may be a
contributory cause of impaired lung function and symptoms of
respiratory disease comes from a series of controlled studies which
have been conducted by Tashkin and his colleagues since the mid-1970s.
One of their early studies evaluated the subacute effects of heavy
daily marijuana smoking on respiratory function. The subjects were
young male marijuana smokers who were studied in a closed hospital
ward where they were allowed ad libitum access to marijuana for 47 to
59 days. The results of lung function tests showed a statistically
significant decrease in the function of large and medium-sized airways
over the course of the study. The degree of impairment was positively
correlated with the number of marijuana cigarettes smoked, suggesting
that the quantity of inhaled irritants was the important factor,
perhaps by producing an inflammatory reaction in the tracheobronchial
epithelium. Although the impairment was apparently small and values
were still within the normal range, these changes were of clinical
significance. If continued over a year, for example, the rate of
decline in lung function would be several times greater than the
normal rate.
Tashkin and his colleagues (1987) subsequently recruited a volunteer
sample of marijuana only smokers (MS, n=144), marijuana and tobacco
smokers (MTS, n=135), tobacco only smokers (TS, n=70), and non-smoking
controls (NS, n=97). A subset of these subjects were followed to
examine changes in lung function, signs and symptoms of respiratory
disease, and the occurrence of histopathological changes that may
precede the development of carcinoma.
In the baseline observations of their cohort, Tashkin et al (1987)
found significant differences in the prevalence of symptoms of
bronchitis (such as cough, bronchitic sputum production, wheeze and
shortness of breath) between all types of smokers (MS, MTS, TS) and
controls. There were no differences between cannabis and tobacco
smokers in the prevalence of these symptoms. Lung function tests
showed significantly poorer functioning and significantly greater
abnormalities in small airways among tobacco smokers (regardless of
concomitant cannabis use) while marijuana smokers showed poorer large
airways functioning than non-marijuana smokers (regardless of
concomitant tobacco use). These findings suggest that "habitual
smoking of marijuana or tobacco causes functional alterations at
different sites in the respiratory tract, with marijuana affecting
mainly the large airways and tobacco predominantly the peripheral
airways and alveolated regions of the lung" (Tashkin et al, 1990,
p67).
Follow-up studies of a subsample of this cohort have broadly supported
the results of the cross-sectional baseline study, while providing
more detail on some differences between marijuana and tobacco smoking
in their effects on lung function (Tashkin et al, 1990). The first
follow-up study was conducted two to three years after the baseline
study. Approximately half of these subjects were retested and most
remained in the same smoking categories as at baseline, namely, 40 of
the 54 MTS, 60 of the 71 MS, 30 of the 32 TS, and 56 of 58 NS,
respectively of those who were followed up.
The prevalence of bronchitic symptoms of cough, sputum, and wheeze was
higher in all smoking groups than among non-smokers at both time one
and time two, and there was no significant change in the respiratory
status of any of the smoking groups from time one to time two when
those individuals who ceased smoking were excluded. Substantially the
same results were obtained when the subjects were followed up three to
four years after initial assessment. In addition, there was evidence
of an additive adverse effect of marijuana and cigarette smoking, in
that the MTS group showed effects of both types of damage attributable
to marijuana and tobacco smoking alone.
Tashkin and his colleagues (Fligiel et al, 1988; Gong et al, 1987)
undertook histopathological studies of the lungs of a subsample of
their cohort. Fligiel et al (1988) compared the bronchial morphology
of males aged 25 to 49 years who were heavy smokers of marijuana only
(n=30), marijuana and tobacco (n=17), tobacco only (n=15) and
non-smoking controls (n=11). Bronchial biopsies were examined by
pathologists who were "blind" as to their smoking status, and analyses
were made of cellular inflammation. All subjects who smoked (whether
cannabis, tobacco or both) showed more prevalent and severe
histopathological abnormalities than non-smokers. Many of these
abnormalities were more prevalent in marijuana smokers, and they were
most marked in those who smoked both marijuana and tobacco.
These findings were especially striking because they were observed in
young adults who did not have respiratory symptoms, and they occurred
at a younger age on average in marijuana than tobacco smokers, despite
the fact that the marijuana smokers smoked less than a quarter as many
"joints" as the tobacco smokers smoked cigarettes. Fliegel et al
concluded that "marijuana smoking may be as damaging or perhaps even
more damaging to the respiratory epithelium than smoking of tobacco"
(p46), and there was "a very good possibility ... that marijuana
smoking combined with smoking of tobacco, leads to a more significant
mucosal alteration than either of these substances smoked alone"
(p47).
Evidence of inflammation was sought by examining the presence of
alveolar macrophages, lymphocytes, neutrophils and eosinophils in the
bronchial lavage of the same subjects. This examination revealed that
marijuana and tobacco smoking induced an inflammatory cellular
response in the alveoli, and that the combination of marijuana and
tobacco smoking produced the largest inflammatory response, "implying
an adverse effect of marijuana smoking on the lung that is independent
of and additive to that of tobacco" (Tashkin et al, 1990, p74).
Additional research by Tashkin and his colleagues (Tashkin et al,
1988; Wu et al, 1988) suggests that the most likely explanations of
the apparently greater toxicity of marijuana smoking are major
differences in the topography of marijuana and tobacco smoking.
Laboratory studies of the volume of inhaled smoke from tobacco and
marijuana, and analyses of its particulate content, indicated that
marijuana smokers inhaled a larger volume of smoke (40-54 per cent
more), inhaled more deeply, took in more particulate matter per puff,
and held their breath about four to five times longer, thereby
retaining more particulate matter, and absorbing three times more
carbon monoxide, than cigarette smokers (Wu et al, 1988).
Bloom et al (1987) have recently reported findings that broadly
confirm those of Tashkin and his colleagues. Bloom et al conducted a
cross-sectional study in a general population of the relationship
between smoking "non-tobacco" cigarettes and respiratory symptoms and
respiratory function. Their study sample was a community sample of 990
individuals aged under 40 years who were being followed as part of a
prospective community study of obstructive airways disease. Subjects
were asked about symptoms of cough, phlegm, wheeze and shortness of
breath, and they were also measured on a number of indicators of
respiratory function, including forced expiratory volume and forced
vital capacity.
The prevalence of ever having smoked a "non-tobacco" cigarette was 14
per cent (the same as the prevalence of marijuana smoking in general
population surveys), with 9 per cent being current smokers and 5 per
cent ex-smokers. Non-tobacco smokers were younger and more likely to
be male than non-smokers of non-tobacco. The mean frequency of current
non-tobacco smoking was seven times per week, and the average duration
of use was nine years. Non-tobacco smokers were more likely than
non-tobacco non-smokers to have smoked tobacco, and more likely to
inhale deeply than tobacco smokers.
Non-tobacco smoking was related to the prevalence of the self-reported
respiratory symptoms of cough, phlegm, and wheeze, regardless of
whether the person smoked tobacco or not. There were also mean
differences in forced expiratory volume and forced vital capacity,
with those who had never smoked having the best functioning, followed
in decreasing order of function by current cigarette smokers, current
non-tobacco smokers, and current smokers of both tobacco and
non-tobacco cigarettes. Non-tobacco smoking alone had a larger effect
on all flow indices than tobacco smoking alone, and the effect of both
types of smoking was additive.
Although there were some inconsistencies between the studies of
Tashkin and colleagues and those of Bloom and colleagues, there is
reasonable coherence in the available evidence on the respiratory
effects of cannabis use. Taken as a whole, it suggests that chronic
cannabis smoking increases the prevalence of bronchitic symptoms,
reduces respiratory function, and in very heavy smokers produces
histopathological changes that may portend the subsequent development
of bronchogenic carcinoma, a well known consequence of heavy tobacco
smoking. Although, "there is still no conclusive evidence in man of
clinically important pulmonary dysfunction produced by smoking
marihuana" (Huber et al, 1988; p8), it is nonetheless a reasonable
inference that chronic heavy cannabis smoking probably increases the
risk of developing respiratory tract cancer, and possibly influences
the development of irreversible obstructive pulmonary disease. Persons
who wish to reduce their risks of developing these diseases would be
wise to desist from cannabis smoking (Tashkin, 1993).
6.4.2 Cancers of the aerodigestive tract
Although "not a single case of bronchogenic carcinoma in man has been
directly attributable to marijuana" (Tashkin, 1988), it would be
unwise to infer from the absence of such cases that there is no such
an effect (Huber et al, 1988; National Academy of Science, 1982).
There is a 20 to 30-year latency period between the initiation of
regular smoking and the development of cancer, and cannabis smoking
only became widespread in Western societies in the early 1970s
(National Academy of Science, 1982). There has also been a lack of
clinical and epidemiological research on this question. Patients with
lung or of other types of cancer, for example, have rarely been asked
about their cannabis use as part of the clinical history-taking. No
cohort or case-control studies of cancers among cannabis smokers have
been reported, because the illegality of cannabis has made it
difficult to obtain reliable information on habits of the large
samples required, while the proportion of cannabis users who become
long-term heavy users is likely to be small (Huber et al, 1988).
Despite the absence of such evidence, there are good reasons for
suspecting that cannabis may contribute to the development of lung
cancer and cancers of the aerodigestive tract (the oropharynx, nasal
and sinus epithelium, and the larynx). A major reason is the
similarity between the constituents of cannabis and tobacco smoke, an
accepted cause of cancers in these organs (Doll and Peto, 1980;
International Agency for Research on Cancer, 1990). The major
qualitative differences between tobacco and cannabis smoke are the
presence of cannabinoids in cannabis smoke and of nicotine in tobacco.
There are also some quantitative differences in the amount of various
carcinogens with cannabis smoke typically containing higher levels
than tobacco smoke (Leuchtenberger, 1983; National Academy of Science,
1982).
The work of Fligiel et al (1988) has indicated that histopathological
changes of the type that are believed to be precursors of carcinoma
can be observed in the lung tissue of chronic marijuana smokers. These
results confirmed the earlier finding of Tennant (1980), who performed
bronchoscopies on 30 US servicemen stationed in Europe who had smoked
large quantities of hashish and experienced symptoms of bronchitis. He
found that 23 of these who also smoked tobacco had one or more
pathological changes "identical to those associated with the later
development of carcinoma of the lung when it occurs in tobacco
smokers" (Tennant, 1983, p78).
The results of these clinical and laboratory studies have recently
received suggestive support from case reports of cancers of the upper
aerodigestive tract in young adults who have been chronic cannabis
smokers. Donald (1991a, b) reported 13 cases of advanced head and neck
cancer occurring in young adults under 40 years of age among 3,000 of
his cancer patients. Their average age was 26 years (range 19-38
years), compared with an average age of 65 years among his other
patients. Eleven of the 13 had been daily cannabis smokers.
Interpretation is complicated by the fact that at least five of these
patients also smoked tobacco, and at least three were heavy alcohol
consumers, both known risk factors for cancers of the upper
aerodigestive tract (Holman et al, 1988; Vokes et al, 1993). Donald
acknowledged these facts, but emphasised that half of his cases
neither smoked tobacco nor consumed alcohol. Moreover, he argued, the
implication of marijuana as a cause of cancers of the upper
aerodigestive tract was strengthened by the observation that such
cancers are rare under the age of 40 years, even among tobacco smokers
who consume alcohol.
Similar findings have been reported by Taylor (1988) in a
retrospective analysis of cases of upper respiratory tract cancer
occurring in adults under the age of 40 years over a four-year period.
Because the medical records did not routinely report the patients' use
of cannabis, Taylor asked the attending clinicians to make judgments
about their patients' cannabis and other drug use. He found 10 cases
among the 887 cases of cancer that were treated over the study period.
They consisted of six males and four females with an average age of
33.5 years. Nine were cases of squamous cell carcinomas (of the
tongue, the larynx, and the lung). Five cases had a documented history
of heavy cannabis smoking, two patients were described as "regular"
cannabis users, one was classified as a "possible" cannabis user
because he was known to abuse other drugs, and two were judged not to
be cannabis users. As with Donald's case series, interpretation was
complicated by the fact that six out of 10 were heavy alcohol
consumers, and six were cigarette smokers (four out of the five heavy
cannabis users in each case).
Taylor argued "that the regular use of marijuana is a potent etiologic
factor, particularly in the presence of other risk factors, in
hastening the development of respiratory tract carcinomas" (p1216).
While he allowed that alcohol and tobacco use may have contributed to
the development of these cancer, he discounted their importance,
arguing like Donald, that the patients were well under 40 years of
age, while the peak incidence of such cancers in drinkers and smokers
is in the seventh decade of life.
Other investigators (e.g. Caplan and Brigham, 1989; Endicott and
Skipper, 1991, cited by Nahas and Latour, 1992) have also reported
cases of upper respiratory tract cancers in young adults with
histories of heavy cannabis use. Caplan and Brigham's (1989) report of
two cases of squamous cell carcinoma of the tongue in men aged 37 and
52 years was especially noteworthy because neither of their cases
smoked tobacco or consumed alcohol; a history of long-term daily
cannabis use was their only shared risk factor.
These case reports provide limited support for the hypothesis that
cannabis use is a cause of upper respiratory tract cancers. They did
not compare the prevalence of cannabis use in cases with that in a
control sample, and cannabis exposure was not assessed in a
standardised way or in ignorance of the case or control status, all of
which are standard controls to minimise bias in case-control studies
of cancer aetiology. Nonetheless, there is a worrying consistency
about the reports that should be addressed by case-control studies
which compare the proportions of cannabis smokers among patients with
cancers of the upper aerodigestive tract and appropriate controls
(National Academy of Science, 1982). Now may be the time to conduct
such studies, since chronic cannabis smokers who began their use in
early 1970s are now entering the period of risk for such cancers. If
carcinomatous changes occur earlier in heavy cannabis smokers, it may
be better to restrict attention to early onset cases (e.g. cases
occurring in individuals under 50 years of age). Information on
cannabis use should also be obtained prospectively in newly diagnosed
cases, because of the problems with retrospective assessment of
cannabis and other drug use from either clinical records or the
relatives of those who have died.
6.4.3 Conclusions
Chronic heavy cannabis smoking probably causes chronic bronchitis, and
impairs functioning of the large airways. Given the documented adverse
effects of cigarette smoking, it is likely that chronic cannabis use
predisposes individuals to develop irreversible obstructive lung
diseases. There is suggestive evidence that chronic cannabis smoking
produces histopathogical changes in lung tissues that are precursors
of lung cancer. Case studies raise a strong suspicion that cannabis
may cause cancers of the aerodigestive tract. The conduct of
case-control studies of these cancers is a high priority for research
into the possible adverse health effects of chronic cannabis smoking.
6.5 Reproductive effects of cannabis
In the mid-1970s there seemed to be good reason to suspect that
cannabis use had adverse effects on the human reproductive system.
There was some animal experimentation which suggested that cannabis
adversely affected the secretion of gonadal hormones in both sexes,
and the foetal development of animals administered crude marijuana
extract or THC during pregnancy (Bloch, 1983; Institute of Medicine,
1982; Nahas, 1984; Nahas and Frick, 1987; Wenger et al, 1992).
Cannabis was being widely used by adolescents who were undergoing
sexual maturation, and by young adults who were entering the peak age
for reproduction (Linn et al, 1983). The suspicion that cannabinoids
had adverse effects on the human reproductive system was first raised
by case reports of breast development (gynecomastia) in young men aged
23 to 26 years of age, all of whom had a history of heavy cannabis use
(Harman and Aliapoulios, 1972). The suspicion seemed confirmed by
human observations published shortly after by Kolodny et al (1974),
who reported that males who were chronic cannabis users had reduced
plasma testosterone, reduced sperm count and motility, and an
increased prevalence of abnormal sperm.
In the light of these observations, the widespread use of cannabis
among young adults which began in the early 1970s and continued well
into the mid-1980s raised understandable fears that fertility would be
impaired in men, and the rates of unfavourable pregnancy outcomes
would increase among women using cannabis during in their reproductive
years. These outcomes could possibly include greater foetal loss,
lower birth weight, and an increased risk of birth defects and
perinatal deaths. Later, concerns were also raised about the
possibility of adverse effects upon the subsequent behavioural
development and health of children exposed to marijuana in utero.
Evidence relevant to each of these concerns will be reviewed in this
section.
6.5.1 Effects on the male reproductive system
In animals, marijuana, crude marijuana extracts, THC and certain other
purified cannabinoids have been shown to "depress the functioning of
the male reproductive endocrine system" (Bloch, 1983, p355). If used
chronically, cannabis reduces plasma testosterone levels, retards
sperm maturation, reducing the sperm count and sperm motility, and
increasing the rate of abnormal sperm (Bloch, 1983, National Academy
of Science, 1982; Wenger et al, 1992). Although the mechanisms by
which cannabis produces these effects are uncertain, it is likely that
they occur both directly as a result of action of THC on the testis,
and indirectly via effects on the hypothalamic secretion of the
hormones that stimulate the testis to produce testosterone (Wenger et
al, 1992).
The small number of human studies on the effects of cannabis on male
reproductive function have produced mixed results. The findings of the
early study by Kolodny et al (1974) which reported reduced
testosterone, sperm production, and sperm motility and increased
abnormalities in sperm were contradicted shortly thereafter by the
results of a larger, well controlled study of chronic heavy users,
which failed to find any difference in plasma testosterone at study
entry, or after three weeks of heavy daily cannabis use (Mendelson et
al, 1974). Other studies have produced both positive and negative
evidence of an effect of cannabinoids on testosterone, for reasons
that are not well understood (Institute of Medicine, 1982). Hollister
(1986) has conjectured that reductions in testosterone and
spermatogenesis probably require long-term exposure. Even if there are
such effects of cannabis on male reproductive functioning, their
clinical significance in humans is uncertain (Institute of Medicine,
1982) since testosterone levels in the studies which have found
effects have generally remained within the normal range (Hollister,
1986).
The putative relationship between cannabis use and gynecomastia now
seems very doubtful. The magnitude of reductions observed in the
positive studies are too small to explain the case reports of
gynecomastia among heavy male cannabis smokers (Harman and
Aliapoulios, 1972), and a small case-control study failed to find any
relationship between cannabis use and gynecomastia in 11 cases and
controls (Cates and Pope, 1977). Although the small sample size of
this study did not exclude a four-fold higher risk of gynecomastia
among cannabis smokers, studies in humans and animals have not shown
any increased secretion of the hormone prolactin, the most likely
mechanism of such effects in males. As Mendelson et al (1984) have
argued, if chronic cannabis use caused gynecomastia, one would expect
many more cases to have been reported in the clinical literature,
given the widespread use of cannabis among young males during the past
few decades.
Hollister has argued that the reductions in testosterone and
spermatogenesis observed in the positive studies are probably of
"little consequence in adults", although he conceded that they could
be of "major importance in the prepubertal male who may use cannabis"
(p10). He cited a case of growth arrest in a 16-year-old male who
began heavy cannabis use at the age of 11, and who experienced a
retardation of growth and the development of secondary sexual
characteristics which partially remitted after three months abstinence
from cannabis (Copeland, Underwood and Van Wyck, 1980). The possible
effects of cannabis use on testosterone and spermatogenesis may
therefore be most relevant to males whose fertility is already
impaired for other reasons, e.g. a low sperm count.
6.5.2 Effects on the female reproductive system
The experimental animal studies suggests that cannabis use has similar
effects on female reproductive system to those found in males. The
acute effects of cannabis or THC exposure in the non-pregnant female
animal is to transiently interfere with the
hypothalamic-pituitary-gonadal axis (Bloch, 1983). Chronic cannabis
exposure delays oestrous and ovulation by reducing leutinising hormone
and increasing prolactin secretion.
There have been very few human studies of the effects of cannabis on
the female reproductive system because of fears that cannabis use may
produce teratogenic and genotoxic effects in women of childbearing age
who would be the experimental subjects in such studies (Rosenkrantz,
1985). Two studies have been reported with conflicting results. In an
unpublished study, Bauman (1980 cited by Nahas, 1984) compared the
menstrual cycles of 26 cannabis smokers with those of 17 controls, and
found a higher rate of anovulatory cycles among the cannabis users.
Mendelson and Mello (1984) observed hormonal levels in a group of
female cannabis users (all of whom had undergone a tubal ligation)
under controlled laboratory conditions. They failed to find any
evidence that sub-chronic cannabis use affected the cycling of the sex
hormones, or the duration of the cycle. In the absence of any other
human evidence, both Bloch (1983) and the Institute of Medicine (1982)
argued on the basis of the animal literature that cannabis use
probably had an inhibitory effect on human female reproductive
function which was similar to that which occurs in males.
6.5.3 Foetal development and birth defects
Given evidence that THC affects female reproductive function, one
might expect it to have a potentially adverse effect on the outcome of
pregnancy. The possibility of adverse pregnancy outcomes is increased
by evidence that THC crosses the placenta in animals (Bloch, 1983) and
humans (Blackard and Tennes, 1984). This raises the possibility that
THC, and possibly other cannabinoids, are teratogens, i.e. substances
that may interfere with the normal development of the foetus in utero.
The animal evidence indicates that in sufficient dosage cannabis can
"produce resorption, growth retardation, and malformations" in mice,
rats, rabbits, and hamsters (Bloch, 1983, p406). Growth resorption and
growth retardation have been more consistently reported than birth
malformations (Abel, 1985). There are also several caveats on the
evidence that cannabis increases rates of malformations. The doses
required to reliably produce malformations have been very high (Abel,
1985), and such effects have been observed more often after the
administration of crude marijuana extract than pure THC, suggesting
that other cannabinoids may be involved in producing any teratogenic
effects. There have also been doubts expressed about whether these
teratogenic effects can be directly attributed to THC. Some have
argued, for example, that the malformations may be a consequence of
reduced nutrition caused by the aversive properties of the large doses
of cannabis used in these studies (Abel, 1985; Bloch, 1983).
Hollister (1986) has also discounted the animal research data, arguing
that "virtually every drug that has ever been studied for
dysmorphogenic effects has been found to have them if the doses are
high enough, if enough species are tested, or if treatment is
prolonged" (p4). Similar views have been expressed by Abel (1985) and
by Bloch (1983), who concluded that THC was unlikely to be teratogenic
in humans because "the few reports of teratogenicity in rodents and
rabbits indicate that cannabinoids are, at most, weakly teratogenic in
these species" (p416).
6.5.3.1 Human studies
The findings from the small number of epidemiological studies of the
effects of cannabis use on human foetal development have been mixed
for a number of reasons. First, both the adverse reproductive outcomes
and the prevalence of heavy cannabis use during pregnancy are
relatively rare events. Hence, unless cannabis use produces a large
increase in the risk of abnormalities, very large sample sizes will be
required to detect adverse effects of cannabis use on foetal
development. Many of the studies that have been conducted to date have
been too small to detect effects of this size (e.g. Greenland et al,
1982 a,b; Fried, 1980).
There are also likely to be difficulties in identifying cannabis users
among pregnant women. The stigma associated with illicit drug use,
especially during pregnancy, may discourage honest reporting,
compounding the usual problem of women accurately recalling drug use
in early pregnancy, when they are asked about it late in their
pregnancy, or after the birth (Day et al, 1985). If, as seems likely,
a substantial proportion of cannabis users are misclassified as
non-users, any relationship between cannabis use and adverse outcomes
will be attenuated, requiring even larger samples to detect it
(Zuckerman, 1985).
Even when large sample sizes have been obtained, there are
difficulties in interpreting any associations found between adverse
pregnancy outcomes and cannabis use. Cannabis users are more likely to
use tobacco, alcohol and other illicit drugs during their pregnancy.
They also differ from non-users in social class, education, nutrition,
and other factors which predict an increased risk of experiencing an
adverse outcome of pregnancy (Fried, 1980, 1982; National Academy of
Science, 1982; Tennes et al, 1985). These sources of confounding make
it difficult to unequivocally attribute any relationship between
reproductive outcomes and cannabis use to cannabis use per se, rather
than to other drug use, or other variables correlated with cannabis
use, such as poor maternal nutrition, and lack of prenatal care.
Sophisticated forms of statistical control provide the only way of
assessing to what degree this may be the case, but its application is
limited by the small number of cannabis smokers identified in most
studies.
Given these difficulties, and the marked variation between studies in
the proportion of women who report cannabis use during pregnancy, the
degree of agreement between the small number of studies is more
impressive than the disagreement that seems at first sight to such be
a feature of this literature. There is reasonable consistency
(although not unanimity) in the finding that cannabis use in pregnancy
is associated with foetal growth retardation, as shown by reduced
birth weight (e.g. Gibson et al, 1983; Hatch and Bracken, 1986;
Zuckerman et al, 1989), and length at birth (Tennes et al, 1985). This
relationship has been found in the best controlled studies, and it has
persisted after statistically controlling for potential confounding
variables by sophisticated forms of statistical analysis (e.g. Hatch
and Bracken, 1986; Zuckerman et al, 1989).
Uncertainty remains about the interpretation of this finding. Is it
because the "marijuana products were toxic to foetal development", as
argued by Nahas and Latour (1992)? Is it because THC interferes with
the hormonal control of pregnancy shortening the gestation period, as
has been reported by Gibson et al (1983) and Zuckerman et al (1989)?
The fact that the lower birth weight among the children of women who
used cannabis disappears after controlling for gestation length is
supportive of the latter hypothesis. Is it because cannabis is
primarily smoked, since tobacco smoking has been consistently shown to
be associated with reduced birth weight (Fried, 1993)?
The findings on the relationship between cannabis use and birth
abnormalities are more mixed, and conclusions accordingly less
certain. Early case reports of children with features akin to the
Foetal Alcohol Syndrome born to women who had smoked cannabis but not
used alcohol during pregnancy (e.g. Milman, 1982, p42) suggested that
cannabis may increase the risk of birth defects. Subsequent controlled
studies have produced mixed results. Four studies have reported no
increased rate of major congenital abnormalities among children born
to women who use cannabis (Gibson et al, 1983; Hingson et al, 1982;
Tennes et al, 1985; Zuckerman et al, 1989).
One study has reported a five-fold increased risk of children with
foetal alcohol like features being born to women who reported using
cannabis (Hingson et al, 1982). The significance of this finding is
uncertain because the same study also found no relationship between
self-reported alcohol use and "foetal alcohol syndrome" features. This
is doubly surprising because of other evidence on the adverse effects
of alcohol, and because the epidemiological data indicates that
cannabis and alcohol use are associated (Norton and Colliver, 1988).
An additional study reported an increase in the crude rate of birth
abnormalities among children born to women who reported using
cannabis. This result was no longer statistically significant after
adjustment for confounders (Linn et al, 1983), although the confidence
interval around this adjusted risk (OR=1.36) only narrowly included
the null value (95 per cent CI: 0.97, 1.91).
The study by Zuckerman et al provides the most convincing failure to
find an increased risk of birth defects among women who used cannabis
during pregnancy. A large sample of women was obtained, among which
there was a substantial prevalence of cannabis use that was verified
by urinalysis. There was a low rate of birth abnormalities among the
cannabis users, and no suggestion of an increase by comparison with
the controls. On this finding, one might be tempted to attribute the
small increased risk in the positive study (Linn et al, 1983) to
recall bias, since the report of cannabis use during pregnancy was
obtained retrospectively after birth, when women who had given birth
to children with malformations may have been more likely to recall
cannabis use than those who did not. However, given the uncertainty
about the validity of self-reported cannabis use in many of the null
studies, it would be unwise to exonerate cannabis as a cause of birth
defects until larger, better controlled studies have been conducted.
6.5.4 Chromosomal abnormalities and genetic effects
Teratogenesis - interference with normal foetal development - is not
the only way in which cannabis use might adversely affect human
reproduction. Cannabis use could conceivably produce chromosomal
abnormalities or genetic change in either parent which could be
transmitted to their progeny. Although possible, there is no animal or
human evidence that such events occur. The experimental evidence
indicates that "in vivo and in vitro exposure to purified cannabinoids
or cannabis resin failed to increase the frequency of chromosomal
damage or mutagenesis" (Bloch, 1983, p412). Marijuana smoke exposure,
by contrast, "has been ... associated with chromosomal aberrations ...
[such as] hypoploidy, mutagenicity in the Ames test ... " (Bloch,
1983, p413). The latter fact is more relevant to an appraisal of the
risk of cannabis users developing cancers from exposure to cannabis
smoke rather than to the risks of transmissible genetic defects in
their offspring.
Hollister (1986) discounted the evidence from cytogenetic studies that
cannabinoids may be mutagenic, as did the Institute of Medicine
(1982). He also argued that assessing chromosomal damage was "more of
an art than a science", as indicated by poor inter-observer agreement,
and that the clinical significance remained unclear because "similar
types and degrees of chromosomal changes have been reported in
association with other drugs commonly used in medical practice without
any clinical evidence of harm ..." (p4). Hollister concluded that
"even if a small increase in chromosomal abnormalities is produced by
cannabis, the clinical significance is doubtful" (p4).
6.5.5 Post-natal development
A further possibility which needs to be considered is that cannabis
use by the mother during pregnancy and breast feeding may affect the
post-natal development of the child. This could occur either because
of the enduring effects of developmental impairment arising from in
utero exposure, or because the infant continued to be exposed to
cannabinoids via breast milk. These are not well investigated
possibilities, although there are a small number of animal studies
which provide suggestive evidence of such effects (Nahas, 1984; Nahas
and Frick, 1987).
The most extensive research evidence in humans comes from the Ottawa
Prospective Prenatal Study (OPPS), which studied developmental and
behavioural abnormalities in children born to women who reported using
cannabis during pregnancy (Fried and colleagues, 1980, 1982, 1983,
1985, 1986, 1989, 1990, 1992). In this study, mothers were assessed
about their drug use during pregnancy and their children were measured
on the Brazelton scales after birth, neurologically assessed at one
month, and assessed again by standardised scales of ability at six and
12 months. The results indicated that there was some developmental
delay shortly after birth in the infants' visual system, and there was
also an increased rate of tremors and startle among the children of
cannabis users.
The behavioural effects discernible after birth had faded by one
month, and no effects were detectable in performance on standardised
ability tests at six and 12 months. Effects were subsequently reported
at 36 and 48-month follow-ups (Fried and Watkinson, 1990) but these
did not persist in a more recent follow-up at 60 and 72 months (Fried,
O'Connell, and Watkinson, 1992). These results are suggestive of a
transient developmental impairment occurring among children who had
experienced a shorter gestation and prematurity. There is a
possibility that the tests used in later follow-ups are insufficiently
sensitive to the subtle effects of prenatal cannabis exposure,
although they were able to detect effects of maternal tobacco smoking
during pregnancy on behavioural development at 60 and 72 months (Fried
and Watkins, 1990, 1992).
Attempts to replicate the OPPS findings have been mixed. Tennes et al
(1985) conducted a prospective study of the relationship between
cannabis use during pregnancy and postnatal development in 756 women,
a third of whom reported using cannabis during pregnancy. The children
were assessed shortly after birth using the same measurement
instruments as Fried (1980), and a subset were followed up and
assessed at one year of age. The findings failed to detect any
differences in behavioural development between the children of users
and non-users after birth; i.e. there was no evidence of impaired
development of the visual system, and no increased risk of tremor or
startle among the children of users. There was also no evidence of any
differences at one year. More recently, Day et al (in press), have
followed up children at age three born to 655 women who were
questioned about their substance use during pregnancy. They found a
relationship between the mothers' cannabis use during pregnancy and
the children's performances on memory and verbal scales of the
Stanford-Binet Intelligence Scale.
There is suggestive evidence that cannabis use during pregnancy may
have a more serious and life threatening effect on post-natal
development. This emerged from a case-control study of Acute
Nonlymphoblastic Leukemia (ANLL), a rare form of childhood cancer
(Neglia et al, 1991; Robinson et al, 1989). The study was not designed
as a test of relationship between cannabis use and ANLL; it was
designed to examine the possible aetiological role of maternal and
paternal environmental exposures to petrochemicals, pesticides and
radiation. Maternal drug use, including marijuana use before and
during pregnancy, were assessed as possible covariates to be
statistically controlled in any relationships observed between ANLL
and environmental exposures.
An unexpected but strong association was observed between maternal
cannabis use and ANLL. The mothers of cases were 11 times more likely
to have used cannabis before and during their pregnancy than were the
mothers of controls. The relationship persisted after statistical
adjustment for many other risk factors. Comparisons of cases whose
mothers did and did not use cannabis during their pregnancies showed
that cases with cannabis exposure were younger, and had a higher
frequency of ANLL with cell types of a specific pathological origin
than did the cases without such exposure. The authors argued that
these differences made it unlikely that the relationship was due to
chance.
Reporting bias on the part of the mothers of cases is an alternative
explanation of the finding that is harder to discount. The reports of
cannabis use were obtained retrospectively after diagnosis of the
ANLL, so it is possible that the mothers of children who developed
ANLL were more likely to seek an explanation in something they did
during their pregnancies, and hence, may have been more likely to
report cannabis use than were mothers of controls. The authors
investigated this possibility by comparing the rates of cannabis use
reported in this study with the rates reported in several earlier
case-control studies of other childhood cancers that they had
conducted using the same methods. The rate was lower among controls in
the ANLL study, but even when the rate of cannabis use among the
controls in these other studies was used the odds ratio was still
greater than three and statistically significant. Nonetheless, since
this was an unexpected finding which emerged from a large number of
exploratory analyses conducted in a single study, it should be
replicated as a matter of some urgency.
6.5.6 Conclusions
On the balance of probabilities, high doses of THC probably disrupt
the male and female reproductive systems in animals by interfering
with hypothalamo-pituitary-gonadal system, reducing secretion of
testosterone, and hence reducing sperm production, motility, and
viability in males, and interfering with the ovulatory cycle in
females. It is uncertain whether these effects also occur in humans,
given the dose differences, the inconsistency in the literature on
human males and the absence of research on human females. Even if
cannabinoids have such effects in humans, their clinical significance
in normal healthy young adults is unclear. They may be of greater
concern among young adolescents who are now more likely to use, and
among males with fertility impaired for other reasons.
Cannabis use during pregnancy probably impairs foetal development,
leading to smaller birthweight, perhaps as a consequence of a shorter
period of gestation. It is possible although far from certain that
cannabis use during pregnancy produces a small increase in the risk of
birth defects as a result of exposure of the foetus in utero. Prudence
suggests that until this issue is resolved, we should err in the
conservative direction by recommending that women not use cannabis
during pregnancy, or when attempting to conceive (Hollister, 1986).
There is not a great deal of evidence that cannabis use can produce
chromosomal or genetic abnormalities in either parent which could be
transmitted to offspring. The available animal and in vitro evidence
suggests that the mutagenic properties of cannabis smoke are greater
than those of THC, and are probably of greater relevance to the risk
of users developing cancer than to the transmission of genetic defects
to children. There is suggestive evidence that infants exposed in
utero to cannabis may experience transient behavioural and
developmental effects during the first few months after birth. There
is also a single study which raises concern about an increased risk of
childhood leukemia occurring among the children born to women who used
cannabis during their pregnancies.
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7. The psychological effects of chronic cannabis use
A major concern about the psychological consequences of cannabis use
has been the possible effects of its chronic use on psychological
adjustment in general, and its impact upon motivation and performance
in occupational and social roles in particular. There have been two
variations on this concern depending upon the age of the cannabis
user. Among adults, an "amotivational syndrome" has been described, in
which chronic cannabis users become apathetic, socially withdrawn, and
perform at a level of everyday functioning well below their capacity
prior to their cannabis use. Among adolescents, the concern has been
about the effects of heavy cannabis use on motivation to undertake the
educational and other psychological tasks that are an essential part
of the transition from childhood to adulthood. The evidence for each
of these adverse outcomes of heavy cannabis use will be considered
separately, beginning with the effects on adolescent development,
which have understandably provoked the greatest concern, and prompted
the most research.
7.1 Effects on adolescent development
The effects of heavy cannabis use on adolescent development are of
special concern for a number of reasons. First, adolescents are minors
whose decisions about whether or not to use drugs are not
conventionally regarded as free and informed in the way that adult
choices are (Kleiman, 1989). Second, adolescence is an important
period of transition from childhood to adulthood, in which regular
cannabis intoxication may be expected to interfere with educational
achievement, the process of disengagement from dependence upon
parents, the development of relationships with peers, and making
important life choices, such as whether, whom and when to marry, and
what occupation to pursue (Baumrind and Moselle, 1985; Polich,
Ellickson, Reuter and Kahan, 1984). Third, the age at which drug use
begins has implications for subsequent drug use and health and
well-being. Early initiation of cannabis use predicts an increased
risk of escalation to heavier cannabis use, and to the use of other
illicit drugs. It also means a longer period of heavy use, and hence,
an increased risk of experiencing any adverse health effects that
chronic cannabis use may have in later adult life (Kleiman, 1989;
Polich, Ellickson, Reuter and Kahan, 1984). Fourth, since adolescence
is a time of risk-taking, the use of any intoxicant, whether alcohol
or cannabis while driving a car, increases the risks of accidental
injury, and hence of premature death (Kleiman, 1989; Polich,
Ellickson, Reuter and Kahan, 1984).
The type of evidence that initially excited concern about the effects
of chronic cannabis use on adolescents came from clinical case studies
in which bright adolescents' use of cannabis escalated to daily
cannabis use, and the use of other illicit drugs, leading to declining
social and educational performance, as evidenced by high school
drop-out, and immersion in the illicit drug subculture (e.g. Kolansky
and Moore, 1971; Lantner, 1982; Milman, 1982; Smith and Seymour,
1982). In some of these cases, the syndrome remitted after the
adolescent had been abstinent from cannabis for some months (Meeks,
1982; Smith and Seymour, 1982). Nonetheless, the evidence was largely
anecdotal and so of limited value in making causal inferences about
the contribution that cannabis made to the development of these
outcomes. It did not, that is, permit a decision to be made as to what
extent cannabis use was a symptom rather than a cause of personality,
or other psychiatric disorders, or a form of adolescent rebellion
against parental values.
The concern about the adverse effects of cannabis use on adolescent
development in the late 1970s prompted a number of large-scale
prospective epidemiological studies of the antecedents, and to a
limited degree, the consequences of adolescent drug use (e.g. Kandel,
1988; Kaplan, Martin and Robbins, 1982; Newcombe and Bentler, 1988).
These studies have attempted to tease out the contributions of the
users' pre-existing personal and social characteristics from the
specific effects of drug use. Some of these studies have also
attempted to examine the impact of illicit drug use in adolescence
upon a number of social and personal outcomes in early adult life
(e.g. Kandel, 1988; Newcombe and Bentler, 1988). The most important of
these studies are reviewed below.
7.1.1 Is cannabis a gateway drug?
A major concern about cannabis has been that its use in adolescence
may lead to, or increase the risk of using other more dangerous
illicit drugs, such as cocaine and heroin (DuPont, 1984; Goode, 1974;
Kleiman, 1992). The most popular evidence for this hypothesis is the
fact that the majority of heroin and cocaine users used cannabis
before heroin and cocaine. Such evidence is weak. In the absence of
comparative data on the prevalence of cannabis use by non-heroin
addicts we are unable to decide if there is an association between
cannabis and heroin use. Even if there is an association, alternative
explanations of its possible causal significance have to be evaluated
and excluded (Goode, 1974).
There is now abundant evidence of an association between cannabis and
heroin use from a series of cross-sectional studies of adolescent drug
use in the United States and elsewhere, including Australia. In the
late 1970s and into the 1990s in the United States there was a strong
relationship between degree of current involvement with cannabis and
the use of other illicit drugs such as heroin and cocaine users.
Kandel (1984), for example, found that the prevalence of other illicit
drug use increased with current degree of marijuana involvement: 7 per
cent of those who had never used marijuana, 33 per cent of those who
had used in the past, and 84 per cent of those who were currently
daily cannabis users, had used other illicit drugs. Current cannabis
users were also likely to have used a larger number of different types
of illicit drugs.
Cross-sectional data on drug use among Australian adults in 1993 have
also shown that those who have tried cannabis are more likely to have
used heroin, and the greater the frequency of cannabis use, the higher
the probability of their having tried heroin (see Donnelly and Hall,
1994). In the 1993 NCADA survey of drug use in Australia, for example,
the crude risk of using heroin was approximately 30 times higher among
those who have used cannabis than those who have not (even though 96
per cent of cannabis users had not used heroin) (see Donnelly and
Hall, 1994).
The relationships between cannabis and heroin use observed in the
cross-sectional studies have also been observed in the small number of
longitudinal studies of drug use. In one of the first such studies
Robins, Darvish and Murphy (1970) followed up a cohort of 222
African-American adolescents identified from school records at age 33,
and interviewed them retrospectively about their drug use in
adolescence and young adulthood, and their adult adjustment. They
found a higher rate of progression to heroin use among the young men
who had used cannabis before age 20.
These early results have been confirmed and elaborated upon in the
extensive research on adolescent drug use by Kandel and her colleagues
(e.g. Kandel et al, 1986). These investigators have identified a
predictable sequence of involvement with licit and illicit drugs among
American adolescents, in which progressively fewer adolescents tried
each drug class, but in which almost all of those who tried drug types
later in the sequence had used all drugs earlier in the sequence
(Kandel and Faust, 1975). Typically, psychoactive drug use began with
the use of the legal drugs alcohol and tobacco, which were almost
universally used. A smaller group of the alcohol and tobacco users
(although often the majority of adolescents) initiated cannabis use,
and those whose progressed to regular cannabis use were more likely to
use the hallucinogens and "pills" (amphetamines and tranquillisers).
The heaviest users of "pills", in turn, were more likely to use
cocaine and heroin. Generally, the earlier the initiation of any drug
use, and the heavier the use of any particular drug in the sequence,
the more likely the user was to use the next drug type in the sequence
(Kandel, 1978; Kandel et al, 1984; Kandel, 1988).
This sequence of drug involvement has largely been confirmed by other
researchers. Donovan and Jessor (1983), for example, found much the
same sequence of initiation, with the variation that when problematic
alcohol use was distinguished from non-problem alcohol use, then
marijuana use preceded problem drinking in the sequence of
progression. These sequences have also been observed in the small
number of prospective studies which have followed a cohort of
adolescents into early adulthood and examined the patterns of
progression in drug use (e.g. Kaplan et al, 1982; Yamaguchi and
Kandel, 1984a, b). For the majority (87 per cent) of men "the pattern
of progression is one in which the use of alcohol precedes marijuana;
alcohol and marijuana precede other illicit drugs; and alcohol,
cigarettes and marijuana precede the use of prescribed psychoactive
drugs" (Yamaguchi and Kandel, 1984a, p671). Among the majority of
women (86 per cent) the sequence was such that "either alcohol or
cigarettes precedes marijuana; alcohol, cigarettes and marijuana
precede other illicit drugs; alcohol and either cigarettes or
marijuana precede prescribed psychoactive drugs" (Yamaguchi and
Kandel, 1984a, p671).
Yamaguchi and Kandel (1984b) also examined variables which predicted
progression to illicit drug use beyond cannabis use. They were
specifically interested in "whether the use of certain drugs lower in
the sequence influences the initiation of higher drugs" (p673) and
used sophisticated statistical methods to discover if the statistical
relationship between cannabis use and subsequent illicit drug use
persisted after controlling for temporally prior variables, such as
pre-existing adolescent behaviours and attitudes, interpersonal
factors, and age of initiation into drug use. If the relationship
persisted after controlling for these variables, confidence was
increased that the relationship was a causal one.
Yamaguchi and Kandel found that the relationship between marijuana use
and progression to the use of other illicit drugs was not only
explained by friends' marijuana use (which also predicted
progression). Among men, the age of initiation of marijuana was an
important modifier of this relationship: men who initiated marijuana
use under the age of 16, were "even more likely to initiate other
illicit drugs than is expected from the longer period of risk
resulting from an early age of onset" (p677). Most importantly,
"persons who have not used marijuana have very small probabilities of
initiating other drugs, ranging from 0.01 to 0.03 (men) or 0.02
(women)" indicating that in their cohort, "marijuana appears to be a
necessary condition for the initiation of other illicit drugs" (p677).
The work of Kandel and her colleagues and that of other researchers
(e.g. O'Donnell and Clayton, 1982) has been interpreted by some as
confirming the "gateway drug" hypothesis or "the stepping stone theory
of drug use" (DuPont, 1984). Although it is not always clear what is
being claimed by proponents of this hypothesis, it does not imply that
a high proportion of those who experiment with marijuana will go on to
use heroin. Indeed, the overwhelming majority of cannabis users do not
use harder drugs like heroin. Kandel has explicitly disavowed this
interpretation of her work:
The notion of stages in drug behavior does not imply that these stages
are either obligatory or universal ... the model is not meant to be a
variant of the controversial `stepping-stone' theory of drug addiction
in which use of marijuana was assumed inexorably to lead to the use of
other illicit 'hard' drugs, especially heroin (Kandel, 1988, pp58-61).
The view that cannabis use generally leads to the use of other illicit
drugs is contradicted by the evidence from the studies of Kandel and
her colleagues. Cannabis use is largely a behaviour of late
adolescence and early adulthood. Kandel's research has shown that it
has been initiated by the age of 19 in 90 per cent of those who ever
used cannabis, and initiation is rare after 20 years. The frequency of
its use peaks in the early 20s, when 50 per cent of males and 33 per
cent of females reported using, and rapidly declines by age 23, with
"the assumption of the roles of adulthood .. getting married, entering
the labor force, or becoming a parent .. that may be incompatible with
involvement in illicit drugs and deviant lifestyles" (Kandel and
Logan, 1984, p665). Hence, although those who use cannabis are more
likely to use other illicit drugs than those who do not, it is more
usual for cannabis use to decline in early adult life, with only a
minority continuing to use regularly, or progressing to the use of
more dangerous illicit drugs. Even in the case of the minority (about
one in four) who progress to daily cannabis use, the majority cease
their use by the mid to late 20s (Kandel and Davies, 1992).
A better supported hypothesis is that cannabis use, especially heavy
cannabis use, greatly increases the chances of progressing to the use
of other illicit drugs. But even this type of relationship does not
necessarily mean that cannabis use "causes" heroin use. As Kandel
(1988) has stressed, the existence of sequential stages of progression
does not "necessarily imply causal linkages among different drugs".
The sequences "could simply reflect the association of each class of
drugs with different ages of initiation or [with pre-existing]
individual attributes, rather than the specific effects of the use of
one class of drug on the use of another" (Kandel, 1988, p61).
A plausible alternative hypothesis is that of selective recruitment.
That is, there is a selective recruitment to cannabis use of deviant
and nonconformist persons with a predilection for the use of
intoxicating substances. On this hypothesis, the sequence in which
drugs are typically used reflects their differential availability and
societal disapproval (e.g. Donovan and Jessor, 1983). Further, the
sequence of initiation into drug use is held to be a consequence of
the availability of different drugs at different ages, with the use of
the least available, and most strongly socially disapproved "hard"
drugs being last. This hypothesis exculpates cannabis use as a cause
of progression to other illicit drug use, since cannabis use and other
illicit drug use are the common consequences of adolescent deviance
and nonconformity (Kaplan et al, 1982; Newcombe and Bentler, 1988).
The selective recruitment hypothesis has received support from a
number of studies. There are substantial correlations between various
forms of nonconforming adolescent behaviour, such as, high school
drop-out, early premarital sexual experience and pregnancy,
delinquency, and alcohol and illicit drug use (Jessor and Jessor,
1977; Osgood et al, 1988). All such behaviours are correlated with
nonconformist and rebellious attitudes and anti-social conduct in
childhood (Shedler and Block, 1990) and early adolescence (Jessor and
Jessor, 1977; Newcombe and Bentler, 1988). Recent research indicates
that those who are most likely to use other illicit drugs, namely,
those who become regular cannabis users (Kandel and Davies, 1992), are
more likely to have a history of anti-social behaviour (Brook et al,
1992; McGee and Feehan, 1993), nonconformity and alienation (Brook et
al, 1992; Jessor and Jessor, 1978; Shedler and Block, 1990), perform
more poorly at school (Bailey et al, 1992; Hawkins et al, 1992; Kandel
and Davies, 1992), and use drugs to deal with personal distress and
negative affect (Kaplan and Johnson, 1992; Shedler and Block, 1990).
In general, the more of these risk factors that adolescents have, the
more likely they are to progress to more intensive involvement with
cannabis, and hence, to use other illicit drugs (Brook et al, 1992;
Newcombe, 1992; Scheier and Newcombe, 1991).
One way of testing the selective recruitment hypothesis is to discover
whether cannabis use continues to predict progression to "harder"
illicit drugs after statistically controlling for pre-existing
differences in personality and other characteristics (e.g. deviance)
between cannabis users and non-users. In several such studies (e.g.
Kandel et al, 1986; O'Donnell and Clayton, 1982; Robins et al, 1970)
the relationship between cannabis and heroin use has been reduced when
pre-existing differences have been controlled for, but in all cases
the relationship has persisted, albeit in attenuated form. O'Donnell
and Clayton (1982) have interpreted this type of finding as strong
evidence in favour of a causal connection between cannabis and heroin
use.
The credibility of such an argument for a causal interpretation of the
relationship between cannabis and heroin use depends upon whether the
most important prior characteristics have been adequately measured and
statistically controlled for in these studies. It would be difficult
to argue that this has been the case. Kandel et al (1986), for
example, were unable to measure the users' attitudes and family
characteristics at the time of drug initiation, or differential drug
availability, either or both of which "may account for the observed
relationships between the early and late stage drugs" (p679). In both
the studies of O'Donnell and Clayton (1982) and Robins et al (1970)
the measures of deviance "prior" to drug use were assessed
retrospectively with unknown validity. Baumrind (1983) has contested
the ability of these studies to exclude the alternative hypothesis
that personality differences which preceded cannabis use were the
causes of the progression to heroin use. She has argued that "it is
safer in the absence of evidence of external validity" of these
measures to assume that the relationship between marijuana use and
heroin use is spurious.
Even if we assume for the purpose of argument that the association
between cannabis and heroin use is not wholly explained by
pre-existing differences in deviant behaviour between cannabis users
and non-users, it remains to be explained how cannabis use "causes"
heroin use. It may seem superficially plausible to suggest that there
is something about the pharmacological effect of cannabis which
predisposes heavy users to progress to the use of other intoxicants,
but there is no obvious pharmacological mechanism for such
progression. Is it the development of tolerance to the positive
effects of cannabis, or to some form of experiential satiation with
its effects? Does the euphoria of cannabis awaken appetite for
intoxication by other drugs? These possibilities are difficult to
test.
Any pharmacological explanation in which more potent illicit drugs
serve as "substitutes" for less potent drugs like alcohol and cannabis
has to contend with a number of facts. As already indicated, there are
relatively low rates of progression from cannabis use to the sustained
use of other illicit drugs; experimentation and abandonment is more
the norm. Even those heavy cannabis users who use other illicit drugs
continue to use cannabis as well as the new illicit drugs. As Donovan
and Jessor (1983) have noted: "...`harder' drugs do not serve as
substitutes for `softer' drugs. Rather, a deepening of regular
substance use appears to go along with a widening of experience in the
drug domain" (p548-549).
There is also good reason for believing that the pattern of
progression observed among American adolescents in the 1970s was
conditioned by historical differences in drug availability (Kandel,
1978). Historical evidence from among earlier cohorts of heroin users
indicated that prior involvement with cannabis was confined to those
geographic areas of the US in which it was readily available (Goode,
1974). Research on African-American adolescents also showed a
variation in the sequence of drug use, with the use of more readily
available cocaine and heroin preceding the use of the less readily
available hallucinogens and "pills" (Kandel, 1978). Most dramatically,
American soldiers in Vietnam were more likely to use heroin than
alcohol because heroin was cheaper and more freely available than
alcohol to most American troops who were younger than the minimum
drinking age of 21 (Robins, 1993).
The historical and geographical variations in sequencing of illicit
drug use suggest a sociological explanation of both the sequencing of
illicit drug use and the higher rates of progression to heroin use
among heavy cannabis users. One of the most popular sociological
hypotheses is that cannabis use increases the chance of using other
illicit drugs by increasing contact with other drug users as part of a
drug using subculture. On this hypothesis, heavy cannabis use leads to
greater involvement in a drug using subculture which, in turn, exposes
cannabis users to the example of peers who have used other illicit
drugs. Such exposure also increases opportunities to use other illicit
drugs because of their increased availability within their social
circle, and places the individual in a social context in which illicit
drug use is encouraged and approved (e.g. Goode, 1974).
Although plausible, there is surprisingly little direct evidence on
the drug subculture hypothesis. Goode (1974) presented data from the
late 1960s indicating that the number of friends who used heroin was a
stronger predictor of heroin use than was frequency of cannabis use,
arguing that the "correlation between frequency of use and the use of
dangerous drugs ... [is] the result of interaction and involvement
with others who use" (p332). These observations have been supported by
Kandel's (1984) finding that the strongest predictor of continued
cannabis use in early adulthood was the number of friends who were
cannabis users.
The hypotheses of selective recruitment and socialisation in a
drug-using subculture are not mutually exclusive; both processes could
independently contribute to the relationship between regular marijuana
use and progression to heroin use (Goode, 1974). As already noted, the
selective recruitment hypothesis is supported by the consistent
finding of pre-existing differences between those who use marijuana
and those who do not, which are most marked in those whose continued
use of cannabis predicts their use of other illicit drugs. Once
initiated into cannabis use, heavy users become further distinguished
from non-users and those who have discontinued their use by the
intensity of their social relations and activities which involve the
use of marijuana, such as mixing with other drug users, and buying and
selling illicit drugs. The illegality of these activities confers on
the use, possession and sale of cannabis a socialising and subcultural
influence not possessed by the possession and use of the legal drugs
(Goode, 1974).
On the available evidence, the case for a pharmacological explanation
of the role of cannabis use in progression to other illicit drug use
is weak. A sociological explanation is more plausible than a
pharmacological one. The predictive value of cannabis use is more
likely to reflect a combination of: the selective recruitment to heavy
cannabis use of persons with combination of pre-existing personality
and attitudinal traits that predispose to the use of other
intoxicants; and the effects of socialisation into an illicit drug
subculture in which there is an increased availability of, and
encouragement to use, other illicit drugs.
7.1.2 Educational performance
A major concern about the effects of adolescent cannabis use has been
the possibility that its use impairs educational performance, and
increases the chances of students discontinuing their education. Such
a possibility is plausible: heavy cannabis use in the high school
years would impair memory and attention, thereby interfering with
learning in and out of the classroom (Baumrind and Moselle, 1985). If
use became chronic, persistently impaired learning would produce
poorer performance in high school and later in college, and increase
the chance of a student dropping out of school. If the adolescent's
school performance was marginal to begin with, as research reviewed
above suggests it is more likely to be among marijuana users, then
regular use could increase the pre-existing risk of high school
failure. Because of the importance of high school education to
occupational choice, this potential effect of adolescent cannabis use
could have consequences which ramified throughout the affected
individual's adult life.
Such a possibility has been supported by cross-sectional studies (e.g.
Kandel, 1984; Robins et al, 1970). These and other studies (see
Hawkins et al, 1992) have found a positive relationship between degree
of involvement with cannabis as an adult and the risk of dropping out
of high school. Studies of relationships between performance in
college and marijuana smoking have produced more equivocal results
(see below), usually failing to find consistent evidence that the
performance of cannabis users was more impaired than would be
predicted by their performance prior to cannabis use. These studies
have been criticised (Baumrind and Moselle, 1985; Cohen, 1982),
however. Baumrind and Moselle have argued that grade point average is
an insensitive measure of adverse educational effects among bright
high school and college students, while Cohen has argued that students
whose learning has been most adversely affected by their chronic heavy
cannabis use would not be found in college samples (Cohen, 1982).
Longitudinal studies of the effect of cannabis use on educational
achievement have produced mixed support for the hypothesis (e.g.
Kandel et al, 1986; Newcombe and Bentler, 1988). Kandel et al (1986),
for example, analysed the follow-up data from the cohort on which
their earlier cross-sectional finding of a relationship between
cannabis use and high school drop-out had been reported. They reported
a negative relationship between marijuana use in adolescence and years
of education completed in early adulthood but this relationship
disappeared once account was taken of the fact that those who used
cannabis in adolescence had much lower educational aspirations than
those who did not.
Newcombe and Bentler (1988) used a different approach to analysis in
their study of the effects of adolescent drug use on educational
pursuits in early adulthood. They used a composite measure of degree
of drug involvement, which measured frequency of use of alcohol,
cannabis and "hard drugs", and a measure of social conformity in
adolescence as a control variable in the analyses, which examined the
relationships between adolescent drug use and educational pursuits in
early adulthood. They found negative correlations between adolescent
drug use and high school completion, but after controlling for the
higher nonconformity and lower academic potential among adolescent
drug users, there was only a modest negative relationship between drug
use and college involvement. The only specific effect of any
particular type of drug use, over and above their measure of drug use
involvement, was a negative relationship between hard drug use in
adolescence and high school completion.
On the whole then, the available evidence from the longitudinal
studies suggests that there may be a modest statistical relationship
between cannabis and other illicit drug use in adolescence and poor
educational performance. The apparently strong relationship between
cannabis use and high school drop-out observed in cross-sectional
studies exaggerates the adverse impact of cannabis use on school
performance because adolescents who perform less well at school, and
have lower academic aspirations, are more likely to use cannabis. But
even if the relationship is statistically small, it may be
substantively important, especially among those whose educational
performance was marginal to begin with, because of the adverse effects
that educational underachievement has on subsequent life choices, such
as occupation, and the opportunities that they provide or exclude.
7.1.3 Occupational performance
Among those young adult cannabis users who enter the work-force, the
continued use of cannabis and other illicit drugs in young adulthood
might impair job performance for the same reasons that it has been
suspected of impairing school performance, namely, that chronic
intoxication impairs work performance. There is some suggestive
support for this expectation, in that cannabis users report higher
rates of unemployment than non-users (e.g. Kandel, 1984; Robins et al,
1970), but this comparison is likely to be confounded by the different
educational qualifications of the two groups. Longitudinal studies
have suggested that there is a relationship between adolescent
marijuana use and job instability among young adults which is not
explained by differences in education and other characteristics which
precede cannabis use (e.g. Kandel et al, 1986). Newcombe and Bentler
(1988) provided a more extensive analysis of the effects of adolescent
drug use on occupational performance in young adulthood. They examined
the relationships between adolescent drug use and income, job
instability, job satisfaction, and resort to public assistance in
young adulthood, while controlling for differences between users and
non-users in social conformity, academic potential and income in
adolescence. Their findings supported those of Kandel and colleagues
in that adolescent drug users had a larger number of changes of job
than non-drug users. Newcombe and Bentler conjectured that this
reflects either impaired work performance, or a failure of illicit
drug users to develop responsible employment behaviours such as
conscientiousness, thoroughness, and reliability.
7.1.4 Interpersonal relationships
There are developmental and empirical reasons for suspecting that
cannabis use may adversely affect interpersonal relationships. The
developmental reason is that heavy adolescent drug use may produce a
developmental lag, entrenching adolescent styles of thinking and
coping which would impair the ability to form adult interpersonal
relationships (Baumrind and Moselle, 1985). The empirical reason is
the strong positive correlation between drug use, precocious sexual
activity, and early marriage, which in turn predicts a high rate of
relationship failure (Newcombe and Bentler, 1988).
Cross-sectional studies of drug use in young adults have indicated
that a high degree of involvement with marijuana predicts a reduced
probability of marriage, an increased rate of cohabiting, an increased
risk of divorce or terminated de facto relationships, and a higher
rate of unplanned parenthood and pregnancy termination (Kandel, 1984;
Robins et al, 1970). Kandel (1984) also found that heavy cannabis
users were more likely to have a social network in which friends and
the spouse or partner were also cannabis users (Kandel, 1984). These
findings have been largely confirmed in analyses of the longitudinal
data from this cohort of young adults (Kandel et al, 1986).
Newcombe and Bentler (1988) found similar relationships between drug
use and early marriage in their analysis of the cross-sectional data
from their cohort of young adults in Los Angeles. Drug use in
adolescence predicted an increased rate of early family formation in
late adolescence and of divorce in early adulthood, which they
interpreted as evidence that: "early drug involvement leads to early
marriage and having children which then results in divorce" (p97).
Newcombe and Bentler argued that this finding provided evidence for
their theory of "precocious development", according to which drug use
accelerates development and "... drug users tend to bypass or
circumvent the typical maturational sequence of school, work and
marriage and become engaged in adult roles of jobs and family
prematurely without the necessary growth and development to enhance
success with these roles ... [developing] a pseudomaturity that ill
prepares them for the real difficulties of adult life" (pp35-36).
Less attention has been paid to the possibility that cannabis use has
adverse effects on the development of social relationships outside
marriage. Newcombe and Bentler (1988) have reported one of the few
such studies. They investigated the relationship between adolescent
drug use and degree of social support and the experience of loneliness
reported in young adulthood. Cross-sectional analyses of data on drug
use and degree of social support in adolescence showed that drug users
reported having less social support than non-users (Newcombe and
Bentler, 1988). But the effects of adolescent drug use on social
support and loneliness in young adulthood were minor. Alcohol use in
adolescence was associated with decreased loneliness in adulthood,
while only hard drug use in adolescence was associated with decreased
social support and increased loneliness in early adulthood.
7.1.5 Mental health
The impact of adolescent cannabis and other drug use on general health
in early adult life has not been investigated, in large part because
it will be difficult to detect any adverse effects of adolescent drug
use on adult health in the longitudinal studies that have been
conducted. In such cohorts, heavy cannabis use - the riskiest pattern
of use from the perspective of health effects - has generally been
observed to occur at low rates. In any case, young adulthood is too
soon to expect any adverse health effects to be evident, because of
the relatively short period of use by young adults.
For good reasons, the effects of cannabis use on mental health have
been the health outcomes most studied. Cannabis is a psychoactive drug
which effects the users' mood and feeling, so chronic heavy use could
possibly adversely affect mental health, especially among those whose
adjustment prior to their cannabis use was poor and who use cannabis
to modulate and control their negative mood states and emotions. The
relationships between cannabis use and the risks of developing
dependence upon cannabis or major mental illnesses such as
schizophrenia, are reviewed below (see pp110-122 and pp173-178
respectively). In this section attention is confined to non-psychotic
symptoms of depression and distress.
A number of studies have suggested an association between cannabis use
and poor mental health. Kandel's (1984) cross-sectional study found an
inverse association between the intensity of marijuana involvement and
degree of satisfaction with life, and a positive association between
marijuana involvement and a greater likelihood of having consulted a
mental health professional, and having been hospitalised for a
psychiatric disorder (Kandel, 1984). Longitudinal analyses of this
same cohort, however, found only weak associations between adolescent
drug use and these adult outcomes; the strongest relationship between
adolescent drug use and mental health, was a positive relationship
between cigarette smoking in adolescence and increased symptoms of
depression in adulthood (Kandel et al, 1986).
The cross sectional adult data in Newcombe and Bentler's (1988) study
showed strong relationships between adolescent drug use and emotional
distress, psychoticism and lack of a purpose in life. Emotional
distress in adolescence predicted emotional distress in young
adulthood, but there were no relationships between adolescent drug use
and the experience of emotional distress, depression and lack of a
sense of purpose in life in young adulthood. There were a number of
small but substantively significant effects of adolescent drug use on
mental health in young adulthood. Adolescent drug use predicted
psychotic symptoms in young adulthood, and hard drug use in
adolescence predicted increased suicidal ideation in young adulthood,
after controlling for general drug use and earlier emotional distress.
Newcombe and Bentler interpreted these findings as evidence that
adolescent drug use "interferes with organised cognitive functioning
and increases thought disorganisation into young adulthood" (p180).
7.1.6 Delinquency and crime
Since initiation into illicit drug use and the maintenance of regular
illicit drug use are both strongly related to degree of social
nonconformity or deviance (e.g. Donovan and Jessor, 1980; Newcombe and
Bentler, 1988; Polich et al, 1984) it is reasonable to expect
adolescent illicit drug use to predict social nonconformity and
various forms of delinquency and crime in young adulthood.
Cross-sectional studies of adult drug users seem to support this
hypothesis: they indicate that there is a relationship between the
extent of marijuana use as an adult and a history of lifetime
delinquency (e.g. Kandel, 1984; Robins et al, 1970), having been
convicted of an offence, and having had a motor vehicle accident while
intoxicated (Kandel, 1984).
Johnston et al (1978) reported a detailed analysis of the relationship
between intensity of drug use and delinquency across two waves of
interviews of adolescent males undertaken as part of the "Youth in
Transition" study. They found in their cross-sectional data that there
was a strong relationship between involvement in delinquency and
degree of involvement with illicit drugs, that is, self-reported rates
of delinquent activity increased steadily with increasing degree of
drug involvement. However, a series of analyses looking at changes in
drug use and crime over time indicated that the groups defined on
intensity of drug involvement differed strongly in their rate of
delinquent acts before their drug use. Moreover, the onset of illicit
drug use (including cannabis) had little effect on delinquent acts,
except perhaps among those who used heroin, among whom there was a
suggestion that the rates of delinquency increased. Finally, rates of
delinquent acts declined over time in all drug use groups and at about
the same rate. The findings were interpreted as delivering "a
substantial, if not mortal, blow" to the hypothesis that "drug use
somehow causes other kinds of delinquency" (p156).
Newcombe and Bentler (1988) reported a somewhat more complicated
although no less plausible picture in their longitudinal study. They
reported a positive relationship between drug use and criminal
involvement in adolescence, but found more mixed results in the
relationship between adolescent drug use and criminal activity in
young adulthood. Adolescent drug use predicted drug crime involvement
in young adulthood; but after controlling for other variables, it was
negatively correlated with violent crime, and general criminal
activities in young adulthood. Newcombe and Bentler argued that these
negative correlations indicated that the correlation between different
forms of delinquency in adolescence decreases with age, as criminal
activities become differentiated into drug-related and
non-drug-related offences. Hard drug use in adolescence also had a
specific effect on young adult crime over and above that of drug use
in general: it predicted an increased rate of criminal assaults in
young adulthood.
7.1.7 Conclusions
There are a number of clear outcomes of research on adolescent
cannabis and other illicit drug use. First, there is strong continuity
of development from adolescence into early adult life in which many of
the indicators of adverse development which have been attributed to
cannabis use precede its first use (Kandel, 1978). These include minor
delinquency, poor educational performance, nonconformity, and poor
adjustment. Second, there was a predictable sequence of initiation
into the use of illicit drugs among American adolescents in the 1970s
in which the use of licit drugs preceded experimentation with
cannabis, which preceded the use of hallucinogens and "pills", which
in turn preceded the use of heroin and cocaine. Generally, the earlier
the age of initiation into drug use, and the greater the involvement
with any drug in the sequence, the greater the likelihood of
progression to the next drug in sequence.
The causal significance of these findings, and especially the role of
cannabis in the sequence of illicit drug use, remains controversial.
The hypothesis that the sequence of use represents a direct
pharmacological effect of cannabis use upon the use of later drugs in
the sequence is the least compelling. A more plausible and better
supported explanation is that it reflects a combination of the
selective recruitment into cannabis use of nonconforming and deviant
adolescents who have a propensity to use illicit drugs, and the
socialisation of cannabis users within an illicit drug using
subculture which increases the exposure, opportunity, and
encouragement to use other illicit drugs.
There has been some support for the hypothesis that heavy adolescent
use of cannabis impairs educational performance. Cannabis use appears
to increase the risk of failing to complete a high school education,
and of job instability in young adulthood. The apparent strength of
these relationships in cross-sectional studies has been exaggerated
because those who are most likely to use cannabis have lower
pre-existing academic aspirations and high school performance than
those who do not. Even though more modest than has sometimes been
supposed, the apparently adverse effects of cannabis and other drug
use upon educational performance may cascade throughout young adult
life, affecting choice of occupation, level of income, choice of mate,
and quality of life of the user and his or her children.
There is weaker but suggestive evidence that heavy cannabis use has
adverse effects upon family formation, mental health, and involvement
in drug-related (but not other types of) crime. In the case of each of
these outcomes, the apparently strong associations revealed in
cross-sectional data are much more modest in longitudinal studies
after statistically controlling for associations between cannabis use
and other variables which predict these adverse outcomes.
On balance, there are sufficient indications that cannabis use in
adolescence adversely affects adolescent development to conclude that
it is a socially desirable goal to discourage adolescent cannabis use,
and especially regular cannabis use.
7.2 Psychological adjustment in adults
7.2.1 Is there an amotivational syndrome?
Anecdotal reports that chronic heavy cannabis use impairs motivation
and social performance have been described in the older literature on
cannabis use in societies with a long history of use, such as Egypt,
the Carribean and elsewhere (e.g. Brill and Nahas, 1984). In these
societies, heavy cannabis use is the prerogative of the poor,
impoverished and unemployed. With the increase of cannabis use among
young adults in the USA in the early 1970s, there were clinical
reports of a similar syndrome occurring among heavy cannabis users
(e.g. Kolansky and Moore, 1971; Millman and Sbriglio, 1986; Tennant
and Groesbeck, 1972). These investigators have typically described a
state among chronic, heavy cannabis users in which the users' focus of
interest narrowed, they became apathetic, withdrawn, lethargic,
unmotivated, and showed evidence of impaired memory, concentration and
judgment (Brill and Nahas, 1984; McGlothin and West, 1968). This
constellation of symptoms has been described as an "amotivational
syndrome" (e.g. McGlothin and West, 1968; Smith, 1968), which some
have claimed is an organic brain syndrome caused by the effects of
chronic cannabis intoxication (Tennant and Groesbeck, 1972). All these
reports have been uncontrolled, and often poorly documented, so that
it has not been possible to disentangle the effects of chronic
cannabis use from those of poverty and low socioeconomic status, or
pre-existing personality and other psychiatric disorders (Edwards,
1976; Millman and Sbriglio, 1986; National Academy of Science, 1982;
Negrete, 1983).
There is no research evidence which unequivocally demonstrates that
cannabis does or does not adversely affect the motivation of chronic
heavy adult cannabis users. It has proved singularly difficult to
provide better controlled research evidence which has permitted a
consensus to emerge upon the issue. Two types of investigation have
been carried out in an attempt to assess the motivational effects of
chronic heavy cannabis use: field studies of chronic heavy cannabis
using adults in societies with a tradition of such use, e.g. Costa
Rica (Carter et al, 1980) and Jamaica (Rubin and Comitas, 1975); and
laboratory studies of the effects on the motivation and performance of
volunteers who have been administered heavy doses of cannabis over
periods of up to 21 days (e.g. Mendelson et al, 1974). There has also
been some evidence on the prevalence of adverse psychological effects
of cannabis from a small number of studies of chronic cannabis users
(e.g. Halikas et al, 1982).
7.2.2 Field studies of motivation and performance
Rubin and Comitas (1975) examined the effects of ganja smoking on the
performance of Jamaican farmers who regularly smoked cannabis in the
belief that it enhanced their physical energy and work productivity.
They used videotapes to measure movement and biochemical measures of
exhaled breath to assess caloric expenditure before and after ganja
smoking. Four case histories were reported which indicated that the
level of physical activity increased immediately after smoking ganja,
as did caloric expenditure, but not productivity. It seemed to be that
after smoking ganja the workers engaged in more intense and
concentrated labour, but this was done less efficiently, especially by
heavy users. Contrary to the hypothesis that cannabis use produced an
impairment in motivation, they concluded: "In all Jamaican settings
observed, the workers are motivated to carry out difficult tasks with
no decrease in heavy physical exertion, and their [mistaken]
perception of increased output is a significant factor in bolstering
their motivation to work." (p79).
A study of Costa Rican cannabis smokers produced mixed evidence on the
impact of chronic cannabis use on job performance (Carter et al,
1980). A comparison was made of the employment histories of 41 pairs
of heavy users (10 marijuana cigarettes per day for 10 or more years)
and non-users who had been matched on age, marital status, education,
occupation, and alcohol and tobacco consumption. The comparison
indicated that non-users were more likely than users to have attained
a stable employment history, to have received promotions and raises,
and to be in full-time employment. Users were also more likely to
spend all or more than their incomes, and to be in debt. Among users,
however, the relationship between average daily marijuana consumption
and employment was the obverse of what the amotivational hypothesis
would predict, that is, those "who had steady jobs or who were
self-employed were smoking more than twice as many marijuana
cigarettes per day as those with more frequent job changes, or those
who were chronically unemployed" (p153), indicating that "the level of
consumption was related more to relative access than to individual
preference" (p154).
Evidence from these field studies is usually interpreted as failing to
demonstrate the existence of the amotivational syndrome (e.g.
Dornbush, 1974; Hollister, 1986; Negrete, 1988). There are critics,
however, who raise doubts about how convincing such apparently
negative evidence is. Cohen (1982), for example, has argued that the
chronic users in three field studies have come from socially marginal
groups, so that the cognitive and motivational demands of their
everyday lives were insufficient to detect any impairment caused by
chronic cannabis use. Moreover, the sample sizes of these studies have
been too small to exclude the possibility of an effect occurring among
a minority of heavy users.
Other evidence suggests that an amotivational syndrome is likely to be
a rare occurrence, if it exists. Halikas et al (1982), for example,
followed up 100 regular cannabis users six to eight years after
initially recruiting them and asked them about the experience of
symptoms suggestive of an amotivational syndrome. They found only
three individuals who had ever experienced such a cluster of symptoms
in the absence of significant symptoms of depression. These
individuals were not distinguished from the other smokers by their
heaviness of use. Nor was their experience of these symptoms obviously
related to changes in pattern of use; they seemed to come and go
independently of continued heavy cannabis use.
7.2.3 Laboratory studies of motivation and performance
In the light of Halikas et al's low estimate of the prevalence of
amotivational symptoms among chronic heavy cannabis users, it is
perhaps not surprising that the small number of laboratory studies of
long-term heavy cannabis use have failed to provide unequivocal
evidence of impaired motivation (Edwards, 1976). The early studies
conducted as part of the LaGuardia Commission inquiry (see Mendelson
et al, 1974) reported deterioration in behaviour among prisoners given
daily doses of cannabis over a period of some weeks, but these reports
were based upon largely uncontrolled observation. So too was the more
recent study of Georgotas and Zeidenberg (1979) in which it was
reported that five healthy male marijuana users who were placed on a
dose regimen of 210mg of THC per day for a month appeared "moderately
depressed, apathetic, at times dull and alienated from their
environment and with impaired concentration" (p430).
A study which used standardised measures of performance rather than
relying on observational data failed to observe such effects
(Mendelson et al, 1974). In this study 10 casual and 10 heavy cannabis
smokers were observed over a 31 days study period in a research
laboratory. For 21 of these days, subjects were given access to as
many marijuana cigarettes as they earned by performing a simple
operant task which involved pressing a button to move a counter. The
points could be exchanged for money (60 points equal to a cent),
packets of cigarettes (3,000 each), and marijuana cigarettes (6,000
each). Mendelson et al found that all subjects earned the maximum
number of points allowed per day (60,000) throughout the study and
that output was unaffected by marijuana smoking whereas ad libitum
access to alcohol by heavy drinking subjects in the same setting
profoundly disrupted performance of the same task. Mendelson et al
concluded that: "our data disclosed no indication of a relationship
between decrease in motivation to work at an operant task and acute or
repeat dose effects of marihuana" (p176).
A number of criticisms can be made of this study. First, the period of
heavy use was only 21 days by comparison with the life histories of 15
or more years daily use in heavy cannabis users in the field studies.
Second, the subjects in the study were volunteers who were all
healthy, young cannabis users with a mean IQ of 120 and nearly three
years of college education, and some of whom reported during
debriefing that they were motivated to perform well so as to
demonstrate that their cannabis use did not have any adverse effect on
their performance (Mendelson et al, 1974). Third, the tasks that users
were asked to perform (button presses) were undemanding. Mendelson et
al countered that these tasks had nonetheless been shown to detect the
deleterious effects of heavy alcohol use. Moreover, they argued, there
were other indicators that their subjects' performance and motivation
was unimpaired while using cannabis, namely, all subjects completed
the study, most undertook the daily assessments conducted throughout,
all complied with a roster for cleaning and house-keeping duties, and
all kept up their preferred recreational activities throughout the
study period.
A similar study was completed at the Addiction Research Foundation,
the results of which have not been fully published, although Campbell
(1976) has provided a brief account of its findings. In this study,
young cannabis users were studied in a residential token economy in
which they could earn tokens that could be exchanged for money and
other goods by manufacturing woven woollen belts. Unlike the Mendelson
study, subjects' cannabis doses were under the experimenters' control
and subjects were given mandatory high doses. The subjects showed no
gross behavioural changes, no social deterioration, and no alterations
in intellectual functioning, but the results suggested, contrary to
those of Mendleson et al, that chronic heavy cannabis use reduced
productivity, especially during the period of mandatory high dosing
(30mg of THC per day) which many subjects found aversive. It remains
unclear how applicable the results of performance with mandatory high
dosing are to the situation where users have control over their own
dose.
7.2.4 Discussion
The status of the amotivational syndrome remains contentious, in part
because of differences in the appraisal of evidence from clinical
observations and controlled studies. On the one hand, there are those
who find the small number of cases of "amotivational syndrome"
compelling clinical evidence of the marked deterioration in
functioning that chronic heavy cannabis use can produce. On the other,
there are those who are more impressed by the largely unsupportive
findings of the small number of field and laboratory studies. Although
the controlled studies have largely been interpreted as failing to
substantiate the clinical observations (e.g. Millman and Sbriglio,
1986), the possibility has been kept alive by suggestive reports that
regular cannabis users experience a loss of ambition and impaired
school and occupational performance as adverse effects of their use
(e.g. Hendin et al, 1987), and that some ex-cannabis users give
impaired occupational performance as a reason for stopping (Jones,
1984). It seems reasonable to conclude that if there is an
amotivational syndrome, it is a relatively rare consequence of
prolonged heavy cannabis use. If this is the case, then studies of
motivation and performance among dependent cannabis users may be the
most promising place to look for examples of the syndrome.
Even if we assume that chronic heavy cannabis use impairs adult
motivation and performance, there remains the question of mechanism
(Baumrind, 1983). Is there a specific amotivational syndrome caused by
the chronic intake of cannabinoids, or are we mistaking it for the
impaired cognitive and psychomotor performance of chronically
intoxicated dependent cannabis users (Edwards, 1976)? Are we perhaps
mistaking a depressive syndrome among heavy cannabis users for the
amotivational syndrome? (Cohen, 1982) Assuming that cases can be
identified, how easy is it to reverse the syndrome or behaviour
pattern after a period of abstinence from cannabis?
7.2.5 Conclusions
The evidence for an amotivational syndrome among adults is, at best,
equivocal. The positive evidence largely consists of case histories,
and observational reports. The small number of controlled field and
laboratory studies have not found compelling evidence for such a
syndrome, although their evidential value is limited by the small
sample sizes and limited sociodemographic characteristics of the field
studies, by the short periods of drug use, and the youthful good
health and minimal demands made of the volunteers observed in the
laboratory studies. It nonetheless is reasonable to conclude that if
there is such a syndrome, it is a relatively rare occurrence, even
among heavy, chronic cannabis users.
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7.3 Is there a cannabis dependence syndrome?
7.3.1 The significance of dependence
If there is a cannabis dependence syndrome, it has important
implications for both cannabis users and public health (Edwards,
1982). First, people who currently use cannabis, and young adults who
are considering whether to use it, should make decisions which are
informed by an appraisal of the risk of their becoming dependent on
the drug. If there is a risk of dependence, and cannabis continues to
be regarded as a drug that does not produce dependence, such decisions
cannot be informed.
Second, if there is a cannabis dependence syndrome, then persons who
become dependent on cannabis place themselves at an increased risk of
experiencing any adverse health effects attributable to cannabis use.
Dependent cannabis users typically smoke two or more cannabis
cigarettes daily over many years, putting themselves at risk of the
pulmonary hazards of smoking. A chronic state of cannabis intoxication
could place them at increased risk of accidents, and the THC they
absorb may accumulate in their bodies, placing them at increased risk
of experiencing any adverse health effects of THC (Edwards, 1982).
Third, although a dependent pattern of cannabis use may be rare in
comparison with the more prevalent pattern of experimental and
intermittent use, it may nonetheless have public health significance
because of the widespread experimentation with cannabis in many
Western societies. The public health significance of cannabis
dependence would also increase if the prevalence of use substantially
increased as a result of changes in the availability of the drug.
7.3.2 The nature of dependence
For much of the 1960s and 1970s the apparent absence of tolerance to
the effects of cannabis, and of a withdrawal syndrome analogous to
that seen in alcohol and opioid dependence, supported the consensus of
informed opinion that cannabis was not a drug of dependence. Expert
views on the nature of dependence changed during the late 1970s and
early 1980s, when the more liberal definition of drug dependence
embodied in Edwards and Gross's (1976) alcohol dependence syndrome was
extended to all psychoactive drugs (Edwards et al, 1981). The drug
dependence syndrome reduced the emphasis upon tolerance and
withdrawal, and attached greater importance to symptoms of a
compulsion to use, a narrowing of the drug using repertoire, rapid
reinstatement of dependence after abstinence, and the high salience of
drug use in the user's life. This new conception influenced the
development of the Third Revised Edition of the Diagnostic and
Statistical Manual of the American Psychiatric Association (1987)
(DSM-III-R), which reduced the importance of tolerance and withdrawal
symptoms in favour of a greater emphasis upon continued use of a drug
in the face of its adverse effects.
7.3.2.1 Drug dependence in DSM-III-R
"Psychoactive substance use disorders" include all forms of drug and
alcohol dependence in DSM-III-R (American Psychiatric Association,
1987; Kosten et al, 1987). "The essential feature of this disorder is
a cluster of cognitive, behavioral and physiologic symptoms that
indicate that the person has impaired control of psychoactive
substance use and continues use of the substance despite adverse
consequences" (p166). A diagnosis of psychoactive substance dependence
is made if any three of the nine criteria listed below have been
present for one month or longer:
1. the substance is often taken in larger amounts or over a longer
period than the person intended;
2. there is a persistent desire or one or more unsuccessful efforts
to cut down or control substance use;
3. a great deal of time is spent in activities necessary to get the
substance (e.g., theft), taking the substance..., or recovering from
its effects;
4. frequent intoxication or withdrawal symptoms when expected to
fulfil major role obligations at work, school, or home..., or when
substance use is physically hazardous...;
5. important social, occupational, or recreational activities given
up or reduced because of substance use;
6. continued substance use despite knowledge of having a persistent or
recurrent social, psychological, or physical problem that is caused or
exacerbated by the use of the substance;
7. marked tolerance;
8. characteristic withdrawal symptoms;
9. substance often taken to relieve or avoid withdrawal symptoms"
(American Psychiatric Association, 1987, pp167-8).
Criteria 8 and 9, are not required for the dependence syndromes of
cannabis, hallucinogens and PCP to be diagnosed.
These criteria may seem to conflict with community conceptions of drug
dependence, in that they explicitly include tobacco smoking as a form
of drug dependence, and could conceivably include caffeine dependence
(among heavy coffee drinkers). The fact that these forms of drug
taking are not usually be regarded as producing drug dependence is
less a reason for rejecting these diagnostic criteria than a signal of
the need to persuade the community to adopt a broader conception of
drug dependence, which reduces the emphasis upon "physical" dependence
as evidenced by the occurrence of a marked withdrawal syndrome on
abstinence.
7.3.2.2 Cannabis tolerance and withdrawal: experimental evidence
Although tolerance and withdrawal symptoms are not required within
DSM-III-R, there is evidence that both can occur under certain
conditions of dosing with cannabinoids. This should not be surprising
since, as Hollister (1986) has observed, cannabis "would have been an
exceptional centrally acting drug if tolerance/dependence were not one
of its properties" (p9). Yet for many years it was believed that there
was little tolerance to cannabis and no withdrawal syndrome. The
predominant recreational pattern of intermittent use in the community,
and the use of low doses of THC and short dosage schedules in
laboratory studies, contributed to this belief (Hollister, 1986), as
did the expectation that if there was a cannabis withdrawal syndrome,
it would be as readily recognised as the opioid withdrawal syndrome
(Edwards, 1982).
Since the middle 1970s evidence has emerged from human and animal
studies that chronic administration of high doses of THC results in
the development of marked tolerance to a wide variety of cannabinoid
effects, such as cardiovascular effects, and to the subjective high in
humans (Compton, Dewey, and Martin, 1990; Fehr and Kalant, 1983;
Hollister, 1986; Jones, Benowitz, and Herning, 1981; National Academy
of Science, 1982). Moreover, the abrupt cessation of chronic high
doses of THC generally produces a mild withdrawal syndrome like that
produced by other long-acting sedative drugs (Compton et al, 1990;
Jones and Benowitz, 1976; Jones et al, 1981).
Jones and Benowitz (1976) provided convincing evidence in humans of
the development of tolerance to the cardiovascular and subjective
effects of THC. They conducted human laboratory studies of the effects
of high doses of THC (210 mg per day) administered orally over a
period of 30 days on a fixed dosing schedule to healthy male
volunteers who had an extensive history of cannabis use. Clinical
observations of the subjects showed that as the duration of the high
dose regimen increased, there was a decline in the positive effects of
intoxication, and in the subjects' ratings of the "high". There was a
marked deterioration in the subjects' social functioning according to
nurses' ratings during the early days of the high dose regimen, but
there was almost complete recovery to baseline levels by the end of
the dosing period. There was similar evidence of recovery in cognitive
and psychomotor performance in the course of the high dose regimen.
The most convincing evidence of tolerance came from observations of
the cardiovascular and subjective effects of smoking a marijuana
cigarette at various points during the study. The magnitude of both
the cardiovascular and subjective responses to smoking a single
"joint" decreased with the length of time subjects had received a high
dose of THC. After a few days of high doses of THC, the increased
heart rate was replaced by a normal, and in some cases a slowed, heart
rate. Similarly, self-ratings indicated that the "high" produced by
the cigarette all but disappeared in the course of the high dose
regimen.
Similar observations of tolerance to the subjective effects of
cannabis have been made by Georgotas and Zeidenberg (1979). They
studied five healthy male marijuana smokers over a four-week period,
in which they smoked an average of 10 joints per day, providing an
average daily dose of 210mg of THC. In the course of this experiment,
subjects rapidly developed tolerance to the drug's effects:
Although initially they found the marijuana to be of good quality,
they now found it much weaker and inferior to what they were getting
outside. They felt it did not make them as high as often as they were
accustomed (p429).
An abstinence syndrome has been observed in monkeys maintained on a
schedule of chronic high doses of THC. Its symptoms consisted of:
"yawning, anorexia, piloerection, irritability, tremors and
photophobia" (Jones and Benowtiz, 1976). Similar symptoms were
observed by Jones and Benowitz (1976) after their subjects were
abruptly withdrawn from high doses of THC. Within six hours of
withdrawal subjects complained of "inner unrest", and by 12 hours,
"increased activity, irritability, insomnia, and restlessness were
reported by the subjects and obvious to staff" (p632). Common symptoms
reported were " `hot flashes', sweating, rhinorrhea, loose stools,
hiccups and anorexia" (p632) which many subjects compared to a bout of
influenza. These symptoms were reduced by the resumption of marijuana
use (Jones et al, 1981).
Georgotas and Zeidenberg (1979) reported similar withdrawal phenomena
in their long-term dosing study. During the first week of a four-week
wash-out period after four weeks of receiving 210mg of cannabis a day,
the subjects "became very irritable, uncooperative, resistant, and at
times hostile ... their desire for food decreased dramatically and
they had serious sleeping difficulties" (p430). These effects
disappeared during the final three weeks of the wash out. These
studies suggest that tolerance can develop to cannabis's effects and
that a withdrawal syndrome can occur on abstinence under certain
conditions, namely, chronic administration of doses as low as 10 mg
per day for 10 days (Jones et al, 1981).
The results of laboratory studies have received suggestive support
from a small number of studies of heavy cannabis users. Weller and
Halikas (1982), for example, found that the self-reported positive
effects of cannabis use diminished over a five to six-year period in
regular users of cannabis. The average reduction in the frequency of
experiencing the positive effects was small, perhaps because only 27
per cent were daily users, but they were consistent and included some
of the symptoms reported in laboratory studies.
The laboratory and observational studies raise the following
questions: How relevant are these observations to contemporary
cannabis users? How often does sufficient tolerance to cannabis
develop for users to experience a withdrawal syndrome? How often is
cannabis used to relieve or avoid withdrawal symptoms, and if so, does
such behaviour play any role in maintaining use and producing
dependence? These questions remain unanswered (Edwards, 1982; Jones,
1984), although (as will be seen below) there is clinical and
observational evidence that some heavy chronic users experience
tolerance and withdrawal symptoms, and that some use cannabis to
control these symptoms.
7.3.3 Clinical and observational evidence on dependence
There has not been an organised program of research on the cannabis
dependence syndrome comparable to that undertaken on the alcohol and
the opiate dependence syndromes. Instead, its existence and
characteristics have had to be inferred from a diverse body of
research studies. This comprises: limited data on the prevalence and
characteristics of persons seeking professional help in dealing with
their cannabis use and associated problems; a small number of
observational studies of problems reported by non-treatment samples of
long-term cannabis users; and a very small and recent literature
examining the validity of the cannabis dependence syndrome, usually as
part of larger investigations of the validity of the substance
dependence syndromes embodied in DSM-III-R and other classification
systems.
During the 1980s evidence began to emerge that there had been an
increase in the number of persons seeking help with cannabis as their
major drug problem. Jones (1984), for example, reported that 35,000
patients sought treatment in the United States in 1981 for drug
problems in which "cannabis was their primary drug" (p703), an
increase of 50 per cent over three years. Many of these patients
behaved "as if they were addicted to cannabis" and they presented
"some of the same problems as do compulsive users of other drugs"
(p711). More recently, Roffman and colleagues (1988) have reported a
strong response to a series of community advertisements offering help
to people who wanted to stop using marijuana.
Sweden, which has had a long history of hashish use, has also
experienced an increase in numbers of heavy hashish users presenting
to treatment services for assistance with problems caused by its use
(Engstrom et al, 1985). Tunving et al (1988) have described their
experience treating approximately 100 individuals per year who
presented to Swedish treatment services requesting help in controlling
their cannabis use. Although no data were reported on the proportion
of these individuals who satisfied the
DSM-III-R criteria for cannabis dependence, these patients typically
complained of symptoms which arguably would meet some of its criteria.
They reported, for example, that they had been unable to stop using
cannabis after having made several unsuccessful attempts to stop or
cut down, that they were frequently intoxicated, often every day, and
that they continued to use despite suffering adverse effects which
they recognised were connected with their cannabis use, such as
sleeplessness, depression, diminished ability to concentrate and
memorise, and blunting of emotions. Hannifin (1988) and Miller and
Gold (1989) have reported similar behaviour patterns among cannabis
users who have sought assistance.
In Australia, there are indications that some heavy cannabis users
request help in controlling their use. Didcott et al (1988), for
example, reported on the characteristics of 3,462 clients seen in 12
residential treatment services in New South Wales in 1985 and 1986.
They found that cannabis was identified as the "primary drug problem"
by 25 per cent of clients seen, second only to the opioid drugs, which
were so identified by 73 per cent of clients. Just over half of all
clients (52 per cent), the majority of whom were polydrug users,
identified their cannabis use as "a problem". The prevalence of
cannabis use as a principal drug problem was lower in a 1992 National
Census of Clients of Australian Treatment Service Agencies (Chen,
Mattick and Bailey, 1993). In this census cannabis use was the main
drug problem for 6 per cent of the 5,259 clients, fifth in order of
importance behind alcohol (52 per cent), opiates (26 per cent),
tobacco (9 per cent) and opiate/polydrug problems (7 per cent).
Suggestive evidence of cannabis dependence has emerged from a small
number of observational studies of regular cannabis users. Weller,
Halikas and Morse (1984), for example, followed up a cohort of 100
regular marijuana users who were first identified in 1970-1971, and
assessed them for alcohol and marijuana abuse using Feighner's
criteria for alcoholism and an analogous set of criteria for marijuana
(see Weller and Halikas, 1980). Their concept of abuse would arguably
have included most cases of dependence. They were able to interview 97
of their subjects about the amount and frequency of alcohol and
marijuana use, and their experience of problems related to the use of
both drugs. According to Feighner's criteria, 9 per cent of subjects
were alcoholic and 9 per cent were "abusers" of marijuana, with 2 per
cent qualifying for both diagnoses. The most common symptoms reported
among those classified as marijuana abusers were feeling "addicted", a
history of failed attempts to limit use, early morning use, and
traffic arrests related to marijuana use.
Hendin et al (1987) reported on the experiences of 150 long-term daily
cannabis users who had been recruited through newspaper
advertisements. Although they did not explicitly inquire about the
symptoms of a cannabis dependence syndrome, substantial proportions of
their sample reported experiencing various adverse effects of
long-term use, despite which they continued to use cannabis. These
included: impaired memory (67 per cent); an impaired ability to
concentrate on complex tasks (49 per cent); difficulty getting things
done (48 per cent); or thinking clearly (43 per cent); reduced energy
(43 per cent); ill health (36 per cent); and accidents (23 per cent).
Substantial minorities reported that it had impeded their educational
(31 per cent), and career achievements (28 per cent), and half of the
sample reported that they would like to cut down or stop their use.
These findings have been broadly supported by Kandel and Davies (1992)
and by Stephens and Roffman (1993). Kandel and Davies reported on the
characteristic problems reported by near daily cannabis users (aged
28-29 years) who were identified in a prospective study of the
consequences of adolescent drug use. The major adverse consequences of
use were: subjectively experienced cognitive deficits; reduced energy;
depression; and problems with spouse. Stephens and Roffman's sample of
users answering an advertisement offering assistance in quitting
cannabis complained of: "feeling bad about using"; procrastinating
because of their use; memory impairment; loss of self-esteem;
withdrawal symptoms; and spouse complaints about their use. In the
absence of control groups, however, it is impossible to be certain
that the prevalence of these symptoms is higher than in the community,
and that they were not present prior to cannabis use, as has been
reported in some longitudinal studies (e.g. Shedler and Block, 1990).
The most direct support for the validity of the cannabis abuse
dependence syndrome comes from a series of studies of the validity of
diagnostic criteria for substance dependence. Kosten et al (1987)
tested the extent to which the DSM-III-R psychoactive substance
dependence disorders for alcohol, cannabis, cocaine, hallucinogens,
opioids, sedatives and stimulants constituted syndromes. A sample of
83 persons (41 from an inpatient psychiatric unit and 42 from an
outpatient substance abuse treatment unit) was interviewed using a
standardised psychiatric interview schedule to elicit the symptoms of
drug dependence as defined in DSM-III-R for each of the drug classes.
Multiple diagnoses were allowed, so many individuals qualified for
more than one type of drug dependence.
There was consistent support for a unidimensional dependence syndrome
for alcohol, cocaine and opiates. The results were more equivocal in
the case of the cannabis dependence syndrome. All the items were
moderately positively correlated, had good internal consistency, and
seemed to comprise a Guttman scale, but a Principal Components
Analysis of the cannabis items suggested that (unlike alcohol, cocaine
and heroin, all of which had a single underlying factor) there seemed
to be three independent dimensions of dependence: compulsion indicated
by impaired social activity attributable to drug use, preoccupation
with drug use, giving up other interests, and using more than
intended; inability to stop use, indicated by not being able to cut
down the amount used, rapid reinstatement after abstinence, and
tolerance to drug effects; and withdrawal identified by withdrawal
symptoms, use of cannabis to relieve withdrawal symptoms, and
continued use despite problems.
Two more recent studies on much larger samples have provided stronger
support for the concept of a cannabis dependence syndrome. Newcombe
(1992) reported factor analyses of 29 questionnaire items designed to
measure DSM-III-R abuse and dependence for a community sample of 614
young adults reporting on their use of alcohol, cocaine, and cannabis.
He reported a strong common factor for all three drug types which
accounted for 36 per cent to 40 per cent of the item variance.
Rounsaville, Bryant, Babor, Kranzler and Kadden (1993) report the
results of factor analyses of items designed to assess dependence in
each of three diagnostic systems (DSM-III-R. DSM-IV and ICD-10) for
each of six drug classes (alcohol, cocaine, marijuana, opiates,
sedatives and stimulants). Their sample comprised 521 persons
recruited from inpatient and outpatient drug treatment, psychiatric
treatment services, and the general community. They found that a
single common factor explained the variation between diagnostic
criteria for all diagnostic systems, and for all drug types.
7.3.4 Epidemiological evidence on cannabis abuse and dependence
The best evidence on the prevalence of cannabis abuse and dependence
in the community comes from the Epidemiological Catchment Area (ECA)
study (Robins and Regier, 1991) which involved face-to-face interviews
with 20,000 Americans in five catchment areas: Baltimore, Maryland;
Los Angeles, California; New Haven, Connecticut; Durham, North
Carolina; and St Louis, Missouri. A standardised and validated
clinical interview schedule was used to elicit a history of
psychiatric symptoms found in 40 major psychiatric diagnoses,
including drug abuse and dependence. This information was used to
diagnose the presence or absence of a DSM-III diagnosis of drug
dependence (Anthony and Helzer, 1991). Although not a true random
sample of the American population, it is the best available data on
the prevalence of different types of drug dependence and their
correlates in a non-treatment population.
Illicit drug use was defined as "any non-prescription psychoactive
agents other than tobacco, alcohol and caffeine, or inappropriate use
of prescription drugs" (Anthony and Helzer, 1991, p116). To exclude
individuals who had only briefly experimented with illicit drugs,
individuals had to have used an illicit drug on more than five
occasions before they were asked about any symptoms of drug
dependence. The focus of the interview schedule was on the "consequent
psychiatric symptoms and behavioral changes that constitute the
syndromes of drug abuse and dependence" (p117).
The criteria used to define drug abuse and dependence were derived
from the DSM-III, which divided symptoms of abuse and dependence into
four main groups: (1) tolerance to drug effects; (2) withdrawal
symptoms; (3) pathological patterns of use; and (4) impairments in
social and occupational functioning due to drug use. Drug abuse
required a pattern of pathological use and impaired functioning. In
the case of cannabis, a diagnosis of dependence required pathological
use, or impaired social functioning, in addition to either signs of
tolerance or withdrawal. The problem had to have been present for at
least one month, although there was no requirement that all criteria
had to be met within the same period of time. In reporting the results
Anthony and Helzer report the prevalence of abuse and/or dependence
combined for all drug types.
Illicit drug use was relatively common in the sample, with 36 per cent
of persons having used at least one illicit drug. Cannabis was the
most commonly used illicit drug, having been used by 76 per cent of
those who had used any illicit drug more than five times. Drug abuse
and dependence were relatively common, with 6.2 per cent of the
population qualifying for such a diagnosis. Cannabis abuse and/or
dependence was the most common form of abuse and/or dependence, with
4.4 per cent of the population being so diagnosed compared with 1.7
per cent for stimulants, 1.2 per cent for sedatives, and 0.7 per cent
for opioid drugs. Two-thirds of cases of cannabis abuse and/or
dependence had used cannabis within the past year, and half had used
within the past month. "Almost two-fifths (38 per cent) of those with
a lifetime history of cannabis abuse and/or dependence reported active
problems in the prior year" (Anthony and Helzer, 1991, p123)
When DSM-III-R diagnoses of dependence and abuse were approximated,
three fifths of those with a diagnosis of dependence and/or abuse met
the criteria for dependence. The proportion of current users who were
dependent increased with age, from 57 per cent in the 18-29 year age
group to 82 per cent in the 45-64 year age group, reflecting the
remission of less severe drug abuse problems with age. Only a minority
of those who had a diagnosis of abuse and/or dependence (20 per cent
of men and 28 per cent of women) had mentioned their drug problem to a
health professional, even though 60-70 per cent had sought medical
treatment in the previous month. There were predictable age and gender
differentials in prevalence of drug abuse and/or dependence. Men had
higher prevalence than women (7.7 per cent versus 4.8 per cent). This
was largely due to differences in exposure to illicit drugs, since the
prevalence of a diagnosis of abuse and/or dependence among persons who
had used an illicit drug more than five times was the about the same
for men and women (21 per cent and 19 per cent). The highest
prevalence of abuse and/or dependence (13.5 per cent) was in the 18-29
year age group (16.0 per cent among men and 10.9 per cent among
women), declining steeply thereafter in both sexes.
It is difficult to make clear inferences about the prevalence of
cannabis dependence in the community from the ECA study, because
DSM-III rather than DSM-III-R criteria were used, and the data on the
prevalence of drug abuse and/or dependence have not been broken down
either by abuse and dependence or by drug class. The first of these
problems may not be too serious, since studies comparing DSM-III and
DSM-III-R criteria (e.g. Rounsaville et al, 1987) suggest that there
is reasonable agreement between a DSM-III diagnosis of abuse or
dependence and DSM-III-R dependence, in the case of cannabis
dependence. Any disagreements in diagnosis seem to be in the direction
of DSM-III-R identifying more cases as dependent than DSM-III,
suggesting that any errors in the prevalence of drug abuse in the ECA
study will be in the direction of underestimation.
The absence of detailed ECA reports on the separate prevalence of drug
abuse and dependence is more difficult to circumvent. If we assume
that any differences between drug types in the proportion of users who
became dependent would have been reported (and hence that the ratio of
cases of dependence to abuse for cannabis is 3:2), then the prevalence
of cannabis dependence in the USA in 1982-1983 would have been 2.6 per
cent of the population. If we also assume that the ratio of cases of
cannabis dependence to cases of cannabis abuse was the same for men
and women, then 3.2 per cent of men and 2.0 per cent of women would
have been diagnosed as cannabis dependent.
Similar estimates of the population prevalence of cannabis dependence
were produced by a community survey of psychiatric disorder conducted
in Christchurch, New Zealand, in 1986, using the same sampling
strategy and diagnostic interview as the ECA study (Wells et al,
1992). This survey used the DIS to diagnose a restricted range of
DSM-III diagnoses in a community sample of 1,498 adults aged 18-64
years of age. The prevalence of having used cannabis on five or more
occasions was 15.5 per cent, remarkably close to that of the ECA
estimate, as was the proportion who met DSM-III criteria for marijuana
abuse or dependence, namely 4.7 per cent. The fact that this survey
largely replicated the ECA findings for most other diagnoses,
including alcohol abuse and dependence, enhances confidence in the
validity of the ECA study findings.
7.3.5 The risk of cannabis dependence
It is important to put the existence of a cannabis dependence syndrome
into perspective to avoid a falsely alarmist impression that all
cannabis users run a high risk of becoming dependent upon cannabis. A
variety of estimates suggest that the crude risk is small, and
probably more like that for alcohol rather than nicotine or the
opioids. Other data suggests that certain characteristics of users
increase the risk of dependence developing, although in most cases it
is impossible to place quantitative estimates on the latter risks.
As with all drugs of dependence, persons who use cannabis on a daily
basis over periods of weeks to months are at greatest risk of becoming
dependent upon it. The ECA data suggested that approximately half of
those who used any illicit drug on a daily basis satisfied DSM-III
criteria for abuse or dependence (Anthony and Helzer, 1991). Since
this estimate was based upon drug abuse and dependence for all drug
types, including opioids, it probably overestimates the risks of
dependence among daily cannabis users. Kandel and Davis (1992)
estimated the risk of dependence among near daily cannabis (according
to approximated DSM-III criteria) at one in three.
The risk of developing dependence among less frequent users of
cannabis, including experimental and occasional users, would be
substantially less than that for daily users. A number of reasonably
consistent estimates of the risks of a broader spectrum of users
becoming dependent on cannabis can be obtained from recent studies. A
crude estimate from the ECA study was that approximately 20 per cent
of persons who used any illicit drug more than five times met DSM-III
criteria for drug abuse and dependence at some time. The specific rate
of abuse and dependence for cannabis (calculated by dividing the
proportion who met criteria for abuse and dependence by the proportion
who had used the drug more than five times) was 29 per cent. A more
conservative estimate which removed cases of abuse (40 per cent) from
the overall estimate of cannabis abuse and dependence would be that 17
per cent of those who used cannabis more than five times would meet
DSM-III criteria for dependence.
Estimates derived from a number of other studies suggest that the ECA
estimates of the risk of dependence are reasonable. The crude
percentage of cases of dependence and abuse among persons who had used
cannabis five or more times in the Christchurch epidemiology study
(Wells et al, 1992) was 30 per cent, while an estimate derived from
Newcombe's community survey of young adults was 25 per cent of those
who had ever used cannabis. A comparable estimate can be derived from
Kandel and Davies' (1992) study of near daily cannabis users. [This
was done by multiplying the ECA estimate of the proportion of daily
users who met criteria for abuse and dependence (50 per cent) by the
proportion of near daily users in Kandel and Davis sample (44 per
cent), and adding this to the ECA estimate of the proportion of
non-daily illicit drug users who met the criteria (30 per cent)
multiplied by their proportion in the Kandel and Davies sample (55 per
cent)]. On Kandel and Davies data the estimated rate of abuse and
dependence among those who had used cannabis 10 or more times was 39
per cent, the higher rate reflecting the higher number of times of use
required to be counted as a cannabis user in Kandel and Davies study
(10 times versus five times in ECA). A lower estimate of 12 per cent
for DSM-III-R cannabis dependence was obtained by McGee and colleagues
(1993) in a prospective study of 18-year-old youth in Dunedin, New
Zealand. A lower estimate was to be expected given the youth of the
sample, and the fact that the estimate is the proportion of dependent
users among those who had ever used cannabis.
Although one would not want to claim a great deal of precision for any
of these individual estimates of the risk of cannabis dependence, it
is reassuring that they are within a range of 12-37 per cent, and that
the estimates vary in predictable ways with the ages of the samples
and the stringency of the criteria used in defining cannabis use. The
reasonable consistency of the estimates suggests the following rules
of thumb about the risks of cannabis dependence. For those who have
ever used cannabis, the risks of developing dependence is probably of
the order of one chance in 10. The risk of dependence rises with the
frequency of cannabis use, as it does with all drugs, so that among
those who use the drug more than a few times the risk of developing
dependence is in the range of from one in five to one in three. The
range of the estimates reflects variations in the number of occasions
of use that is taken to reflect more than simple experimentation, with
the general rule being that the more often the drug has been used, and
the longer the period of use, the higher is the risk of becoming
dependent. Although there have been few formal comparisons of the
dependence potential of cannabis with that of other drugs, these risks
are probably more like those associated with alcohol than those
associated with tobacco and opiates (Woody, Cottler and Cacciola,
1993).
Apart from frequency of use, other risk factors have been identified
in the series of prospective studies of adolescent illicit drug use
reviewed above. These include the following factors which have been
shown to predict continued use and more intensive involvement with
illicit drugs: poor academic achievement; deviant behaviour in
childhood and adolescence; nonconformity and rebelliousness; personal
distress and maladjustment; poor parental relationships; earlier use;
and a parental history of drug and alcohol problems (Brook et al,
1992; Kandel and Davies, 1992; Newcombe, 1992; Shedler and Block,
1990). For most of these variables it is difficult to attach any
quantitative estimates to the increased risk of dependence, because
they have been measured in different ways in different studies.
These overall statements of the risks of cannabis dependence ignore
the fact that the risk of dependence is not equally distributed in the
population. The ECA study suggested that men have a higher risk of
developing dependence than women, and that the risk was highest among
the younger 18-29 year old cohort. In both cases, however, the most
likely explanation was the different rates of exposure to cannabis
among men and women, and among younger and older persons (Anthony and
Helzer, 1991). When this was controlled by looking at the rates of
dependence among daily users of the drug among men and women and
younger and older persons, the differences in the risk of dependence
largely disappeared (Anthony and Helzer, 1991).
7.3.6 The consequences of cannabis dependence
Another important issue that needs to be considered when placing the
risks of cannabis dependence into perspective is that of the
consequences of developing dependence. How easy or difficult is it for
those who decide to stop using cannabis to achieve and maintain
abstinence? This question is difficult to answer in the absence of
systematic research on the natural history of cannabis dependence. The
following are reasonable inferences about what the rate of remission
might be. First, cannabis dependence resembles alcohol dependence in
the risk of dependence, and the similarity in the age and gender
distributions of heaviest use, and abuse, and dependence. It seems
reasonable then to suppose that there is likely to be a high rate of
remission without treatment in cannabis dependence, as there is in as
in alcohol dependence in the community (Helzer, Burnham and McEvoy,
1991). The large discrepancy between the ECA estimates of cannabis
abuse and dependence in the community, and the proportions of cannabis
users among drug users seeking treatment provides indirect support for
this inference. Kandel and Davies' (1992) findings provide more direct
support. They found that 44 per cent of those who had used cannabis
more than 10 times became near daily users for an average period of
three years. Yet by age 28-29, less than 15 per cent of those who had
ever been daily users were still daily users, indicating a very high
rate of remission during the 20s.
Among those who develop cannabis dependence, how disruptive to
everyday life and functioning is it? This is even more difficult to
answer. All that can be said with confidence is that there are some
cannabis users who are sufficiently troubled by the consequences of
their dependence to seek assistance. The experience of Roffman and
colleagues suggests that this number may be increased if more effort
was made to attract dependent cannabis users into treatment. Among the
population of cannabis dependent persons seeking treatment, the major
complaints have been the loss of control over their drug use,
cognitive and motivational impairments which interfere with
occupational performance, lowered self-esteem and depression, and the
complaints of spouses and partners (see above). There is no doubt that
some dependent cannabis users report impaired performance and a
reduced enjoyment of everyday life, but more detailed research is
necessary to make a better judgment about how common this is, and how
severe the impairment typically produced by cannabis dependence is.
7.3.7 The treatment of cannabis dependence
Given the widespread scepticism about the existence of a cannabis
dependence syndrome, the question of what should be done to assist
those who present for help with their cannabis use has largely been
ignored (see Kleber, 1989). Indeed, Stephens and Roffman (1993) have
suggested that there is a widespread view among drug and alcohol
treatment practitioners that cannabis dependence does not require
treatment because the withdrawal syndrome is so mild that most users
can quit without assistance. Although, as argued above, it is likely
that rates of remission without treatment are substantial, the fact
that many users succeed without professional assistance does not mean
we should ignore requests for assistance from those who are unable to
stop on their own. As with persons who are nicotine dependent, those
dependent cannabis users who have repeatedly failed in attempts to
stop their cannabis use need professional assistance to do so. But
what types of treatment should be offered?
There is not a lot of information on which to base useful
recommendations. The available literature largely consists of
treatment suggestions based upon personal experience, or upon clinical
wisdom derived from opinions about the best forms of treatment for
other related forms of dependence, such as alcohol and tobacco (e.g.
de Silva, DuPont, and Russell, 1981). Jones (1984), for example,
suggested that because cannabis was usually smoked in social settings,
the treatment for cannabis dependence should be based upon principles
derived from successful forms of treatment for nicotine dependence.
Such treatment would include: assisted cessation of cannabis use
accompanied by education about the acute and chronic effects of the
drug; social skills training in resisting the social cues for cannabis
use; and the mobilisation of peer support to maintain abstinence
through self-help groups.
Others have preferred to adopt approaches adapted from those developed
to treat alcohol dependence. Hannifin (1988), in arguing for the
concept of "cannabism" by analogy to "alcoholism", implied that it be
managed in much the same way. Miller and his colleagues (Miller and
Gold, 1989; Miller, Gold and Pottash, 1989) have recommended a
treatment model based upon the preferred form of treatment for alcohol
dependence in the United States, namely, detoxification, a 12-step
program delivered during an extended inpatient stay, and enrolment in
Alcoholics Anonymous or Narcotics Anonymous after discharge. Stephens
and Roffman (1993) and Zweben and O'Connell (1992) have suggested
eclectic approaches combining management of withdrawal, relapse
prevention methods, and enrolment in 12-step programs. Tunving et al
(1988) have described their experience with a similar eclectic
outpatient program for cannabis users in Sweden. De Silva et al (1981)
provide short accounts of a variety of treatment approaches for
marijuana dependent adolescents.
There have been very few controlled evaluations of the effectiveness
of these recommendations. Smith et al (1988) reported a simple
pre-treatment and post-treatment comparison of cannabis use among
patients who received outpatient aversion therapy and group
self-management counselling. They found good self-reported rates of
abstinence, but these were obtained from telephone interviews
conducted by the therapists who delivered the treatment. Roffman et al
(1988) have reported a randomised controlled trial comparing group
based relapse prevention or social support. Subjects were 120 men and
women (average age 32 years with an average history of 16 years
marijuana use) who had answered advertisements publicising a treatment
program for adults seeking help to stop using marijuana. Their results
at one month follow-up were much less positive than those of Smith et
al: only 30 per cent of their patients were still abstinent, although
75 per cent had set abstinence as a treatment goal. By the end of a
year the abstinence rate had dropped to 17 per cent. Results were a
little more positive when evaluated in terms of average number of days
of use, and in problems experienced, suggesting that the outcome of
cannabis cessation treatment is much like that for alcohol and tobacco
(Heather and Tebbutt, 1989).
Much more research is clearly required before sensible advice can be
given about the best ways to achieve abstinence from cannabis. In the
absence of better evidence of treatment effectiveness, those who offer
treatment for cannabis dependence should avoid replicating experience
in the alcohol field, where intensive and expensive forms of inpatient
treatment have been widely adopted in the absence of any good evidence
that they are more effective than less intensive outpatient forms of
treatment (Heather and Tebbut, 1989; Miller and Hester, 1986).
7.3.8 Conclusions
In 1982 Edwards reviewed the available evidence on the question of
whether there was a cannabis dependence syndrome as defined by the
1981 World Health Organisation criteria. Although he argued that there
was good evidence of tolerance and a withdrawal syndrome, there was
insufficient evidence bearing on the criteria of compulsion, narrowing
of repertoire, reinstatement after abstinence, use to relieve or
prevent withdrawal symptoms and salience of cannabis use. He added
that although tolerance and withdrawal were insufficient to prove the
existence of a dependence syndrome, they nonetheless constituted
"grounds for believing that such a syndrome may exist" (p38). Until
these issues were resolved, he concluded, the question remained "very
open".
On the basis of evidence gathered since Edwards wrote, we conclude
that there probably is a cannabis dependence syndrome like that
defined in DSM-III-R which occurs in heavy chronic users of cannabis.
There is good experimental evidence that chronic heavy cannabis use
can produce tolerance and withdrawal symptoms, and some clinical and
epidemiological evidence that some heavy cannabis users experience
problems controlling their cannabis use, and continue to use despite
the experience of adverse personal consequences of use. There is
reasonable observational evidence that there is a cannabis dependence
syndrome like that for alcohol, cocaine and opioid dependence. If the
estimates of drug dependence from the ECA study are approximately
correct, cannabis dependence is the most common form of dependence on
illicit drugs, reflecting its high prevalence of use in the community.
The risk of developing the syndrome is probably of the order of: one
chance in ten among those who ever use the drug; between one in five
and one in three among those who use more than a few times; and around
one in two among those who become daily users of the drug.
Recognition of the cannabis dependence syndrome has been delayed
because of its apparent rarity in Western societies, which reflects a
number of factors. First, heavy daily cannabis use has been relatively
uncommon by comparison with the intermittent use of small quantities
of cannabis. Second, until recently there have been few individuals
who have presented requesting assistance for cannabis related
problems. This may have been because it is easier to stop using
cannabis than opioids or alcohol without specialist assistance, or it
may be that the impact of cannabis dependence on the user is not as
transparently adverse as that of alcohol or opioid problems to users
and their families. Third, an overemphasis on the occurrence of
tolerance and a withdrawal syndrome in the past has hindered its
recognition in those individuals who have presented for treatment.
Fourth, cannabis dependence (which is widespread among opioid
dependent persons) has been perceived to be a less serious problem
than dependence on alcohol, opioids and stimulants, which have
accordingly been given priority in treatment (Hannifin, 1988).
Given the widespread use of cannabis, and its continued reputation as
a drug which is free of the risk of dependence, the clinical features
of cannabis dependence deserve to be better delineated and studied.
This would enable its prevalence to be better estimated, and
individuals with this dependence to be better recognised and treated.
Treatment should probably be on the same principles as what is
effective for other forms of dependence. Treatment for tobacco
dependence may provide a better model than treatment for alcohol
dependence, although this area is in need of research.
Although cannabis dependence is likely to be a larger problem than
previously thought, we should be wary of over-estimating its social
and public health importance. It will be most common in the minority
of heavy chronic cannabis users. Even in this group, the prevalence of
drug-related problems may be relatively low by comparison with those
of alcohol dependence, and the rate of remission without formal
treatment is likely to be high. While acknowledging the existence of
the syndrome, we should avoid exaggerating its prevalence and the
severity of its adverse effects on individuals. Better research on the
experiences of long-term cannabis users should provide more precise
estimates of the risk.
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7.4 Effects of chronic cannabis use on cognitive functioning
Because cannabis use acutely impairs cognitive processes, a concern
has arisen that chronic cannabis use may cause chronic cognitive
impairment. Such a chronic effect need not necessarily be permanent,
but it would persist beyond the elimination of cannabinoids from the
body, and hence would be the result of secondary changes induced by
cumulative exposure to cannabinoids. Such chronic effects could
produce relatively enduring behavioural deficits which presumably
reflect changes in brain function.
This chapter deals with the evidence from a variety of different types
of study about the cognitive effects of chronic cannabis use. The
caveats mentioned in the introduction must be born in mind whilst
critically assessing this evidence: many other factors must be
controlled in order to confidently attribute any cognitive effects to
cannabis use. Among these, the most important are ensuring that the
cognitive impairment did not precede cannabis use, and ensuring that
the cognitive effects are not the result of the multiple drug use that
is especially common among heavy cannabis users (Carlin, 1986).
7.4.1 Clinical observations
Concerns about the cognitive effects of chronic cannabis use during
the early 1970s were first prompted by clinical reports of mental
deterioration in persons who had used cannabis heavily (at least
daily) for more than one year (Fehr and Kalant, 1983). Kolansky and
Moore (1971, 1972), for example, reported cases of psychiatric
disorder in adolescents and young adults (38 cases) and among adults
(13 cases) who had used marijuana at least twice per week. The
clinical picture was one of "very poor social judgment, poor attention
span, poor concentration, confusion, anxiety, depression, apathy,
passivity, indifference and often slowed and slurred speech" (Kolansky
and Moore, 1971). Cognitive symptoms included: apathetic and sluggish
mental and physical responses; mental confusion; difficulties with
recent memory; and incapability of completing thoughts during verbal
communication. These symptoms typically began after cannabis use and
disappeared within three to 24 months of abstinence. The course and
remission of symptoms also appeared to be correlated with past
frequency and duration of cannabis smoking. Those with a history of
less intensive use showed complete remission of symptoms within six
months; those with more intensive use took between six and nine months
to recover; while those with chronic intensive use were still
symptomatic nine months after discontinuation of drug use.
These clinical reports, similar observations by Tennant and Groesbeck
(1972) among hashish smoking US soldiers in West Germany, and a report
of cerebral atrophy in young cannabis users (Campbell et al, 1971)
excited substantial controversy about the cognitive effects of chronic
cannabis use. Critics were quick to object to the lack of objective
measures of impairment and the biased sampling from psychiatric
patient populations. It was also difficult to rule out alternative
explanations of the apparent association between cannabis use and
cognitive impairment, namely, that many of these effects either
preceded cannabis use, or were the result of other drug use. Whatever
their limitations, these clinical reports alerted the community to the
possible risks of using cannabis when it was becoming popular among
the young in Western countries; they also prompted better controlled
empirical research on the issue.
7.4.2 Cross-cultural studies
In response to public anxiety about the increase in marijuana use in
the late 1960s, the National Institute on Drug Abuse (NIDA) in the
United States commissioned three cross-cultural studies in Jamaica,
Greece and Costa Rica to assess the effects of chronic cannabis use on
cognitive functioning (among other things). The rationale for these
studies was that any cognitive effects of chronic daily cannabis use
would be most apparent in cultures with a long-standing tradition of
heavy cannabis use.
7.4.2.1 Jamaica
Bowman and Pihl (1973) conducted two field studies of chronic cannabis
use in Jamaica, one with a small sample of 16 users and 10 controls
from rural and semi-rural areas, and the other with a small urban slum
sample of 14 users and controls. Users had consumed cannabis daily for
a minimum of 10 years (current use of about 23 high potency
joints/day), while controls had no previous experience with cannabis.
Tests were selected on the basis of having previously been shown to be
sensitive to impairment following chronic heavy alcohol use (Bowman
and Pihl, 1973). The groups were matched for age, sex, social class,
alcohol use, education and "intelligence", but most subjects were
illiterate or semi-literate, with an average age of 30. No differences
were found between the users and non-users in either study, even when
the rural and urban samples were combined.
Soueif (1976b) argued that a null result would be expected according
to his hypothesis that cannabis-induced impairments require a minimum
level of literacy to be detected. Bowman and Pihl replied that the
controls were sufficiently literate to enable any impairment in the
users to manifest. Moreover, their study required only a minimum of
four hours abstinence prior to testing, which meant that some subjects
were still intoxicated at the time of testing. This possibility would
have biased the test results in favour of finding poorer performance
among the users.
A more extensive study of 60 working class males in Jamaica (Rubin and
Comitas, 1975) compared 30 users and 30 non-users matched on age,
socioeconomic status and residence. The users who were aged between 23
and 53 years with a mean age of 34 years, had used cannabis for an
average of 17.5 years (range seven to 37 years) at around seven joints
per day (range one to 24) containing an estimated 60mg of THC. They
had not used any other substances other than alcohol and tobacco.
While no control subject had used cannabis heavily in recent years,
nine were current "occasional" users of cannabis and all but 12 of the
controls had some experience with cannabis.
A battery of 19 psychological tests were administered after three days
of abstinence, as part of a six-day inpatient stay. The psychological
tests included three tests of intellectual and verbal abilities, and
15 neuropsychological tests measuring abilities previously shown to be
affected by acute cannabis intoxication. Comparisons of the users and
non-users on 47 test scores failed to reveal any consistent
significant differences. There were three statistically significant
results which were not easily interpreted and were considered chance
findings. There was no strong suggestion of differences that failed to
be detected because of a small sample size, since the user group
scored better than the non-user group on 29 variables, albeit
non-significantly.
The interpretation of these null results must be qualified because
several factors may have attenuated differences between users and
non-users. First, the tests used were not standardised for use in
Jamaica. The authors' argued that any cultural bias would be the same
for both users and controls and therefore would not obscure any group
differences (Rubin and Comitas, 1975, p111). Second, the Weschler
Adult Intelligence Scale (WAIS) subtests may have been too easy or too
difficult to allow detection of group differences. Third, the
inclusion of cannabis users in the control group may have further
reduced the chance of detecting group differences. Fourth, the
Jamaican sample were primarily farmers, fishermen and artisans from
rural areas, or casual urban labourers. The failure of cannabis to
impair their cognitive performance does not exclude the possibility
that the long-term use of cannabis may impair the performance of
persons required to perform at a cognitively more demanding level.
7.4.2.2 Greece
The Greek NIDA study (Stefanis et al 1976, 1977) compared the
cognitive performance of a sample of 47 chronic hashish users and 40
controls matched for age, sex, education, demographic region,
socioeconomic status and alcohol consumption. The subjects were mostly
refugees from Asia Minor, residing in a low income, working class area
of Athens. The average duration of hashish use was 23 years of 200mg
per day. Most users had smoked hashish on the day before testing, and
some had smoked several hours before the test session. Controls were
slightly better educated than users.
These researchers administered the Weschler Adult Intelligence Scale
(WAIS) and Raven's Progressive Matrices to assess general intelligence
and mental functioning (Kokkevi and Dornbush, 1977). Subtests of the
WAIS were used to evaluate impairment in specific cognitive and
perceptual functions. The Raven's test was considered to be a more
culture-free assessment of intelligence and was used for reliability
and validity purposes. The groups did not differ in global IQ score on
either the WAIS or Raven's Progressive Matrices, but non-users
obtained a higher verbal IQ score than users. The users' performance
was worse than controls on all but one of the subtests of the WAIS,
even if not significantly so. Significant differences in performance
between the two groups were obtained in three subtests of the WAIS,
indicating possible defects in verbal comprehension and expression,
verbal memory, abstraction and associative thinking, visual-motor
coordination and memorising capacity, and logical sequential thought.
The interpretation of these results was complicated by the lack of a
requirement that subjects abstain from hashish prior to testing.
Consequently, it was not clear whether the impairments found on these
subtests were related to long-term use of hashish, or were due to the
persistence of an acute drug effect at the time of testing. Because
the differences between verbal and performance IQ were similar in both
groups, the authors argued that there was no evidence of deterioration
in mental abilities in the hashish users.
7.4.2.3 Costa Rica
The NIDA study of chronic heavy cannabis users in Costa Rica was
modelled upon the Jamaican project, but with greater sensitivity to
cross-cultural issues. It involved an intensive physiological,
psychological, sociological and anthropological study of matched pairs
of users and non-users (Carter, 1980). Satz, Fletcher and Sutker
(1976) compared 41 male long-term heavy cannabis users (9.6 joints per
day for 17 years) with matched controls on an extensive test battery
designed to assess the impact of chronic cannabis use on
neuropsychological, intellectual and personality variables. The
educational level of the Costa Rican sample was slightly higher than
that of either the Greek or the Jamaican samples, although more than
half of the user group had not completed primary school, and both
users and non-users had left school at 12 years of age. The users were
working class, mostly tradesmen with lower than average income, who
reported that they often used cannabis to improve their work
performance.
Despite their long duration and heavy use, the Costa Rican users did
not differ significantly from controls on any test. Users scored
consistently lower, if not significantly so, than non-users on 11 of
16 neuropsychological tests. Although users' performance was poorer,
particularly in the mean number of errors made, learning curves were
similar for both groups. The authors concluded that there was
insufficient evidence for significant impairment of memory function in
the chronic cannabis users. Users performed slightly better on six of
the 11 WAIS subtests and had a slightly higher verbal and full-scale
IQ. There were no correlations between test results and the level of
marijuana use.
A 10-year follow-up of the Costa Rican sample was conducted by Page,
Fletcher and True (1988). By the time of follow-up, the users had an
average 30 years experience with cannabis, but the sample size had
dropped to 27 of the 41 original users and 30 of the 41 controls. The
test protocol included some of the original tests, as well as
additional tests which measured short-term memory and attention, and
which had been selected for their sensitivity in detecting subtle
changes in cognitive functioning.
No differences were detected on any of the original tests, but three
tests from the new battery yielded significant differences between
users and controls. In Buschke's Selective Reminding Test, the user
group retrieved significantly fewer words from long-term storage than
the non-user group, although the groups did not differ on a measure of
storage. Users performed more slowly than non-users in the Underlining
Test, with particularly poor performance in the most complex subtest.
The Continuous Performance Test also revealed users to be slower than
controls on measures requiring sustained attention and effortful
processing, although there were no differences in performance.
Page et al (1988) interpreted their results as evidence that long-term
consumption of cannabis was associated with difficulties in sustained
attention and short-term memory. They hypothesised that such tests
require more mental effort than the tests used in the original study,
and, as such, that long-term users of cannabis experience greater
difficulties with effortful processing. This study differs from
previous cross-cultural investigations in that it found differences
between users and non-users in tests of information processing,
sustained attention and short-term memory. Nevertheless, Page et al
(1988) emphasised that the differences they found were "quite subtle"
and "subclinical", with only a small number of subjects being
clinically impaired. Because the differences are so small and subtle,
it was difficult to exclude the alternative explanation that the
differences were due to acute intoxication or recent use, since
24-hour abstinence was requested but not verified.
7.4.2.4 Egypt
Soueif (1971) studied 850 Egyptian hashish smokers and 839 controls
obtained from a male prison population which was poorly educated,
largely illiterate and of low socioeconomic status. Significant
differences were found between users and controls on 10 out of 16
measures of perceptual speed and accuracy, distance and time
estimation, immediate memory, reaction time and visual-motor abilities
(Soueif, 1971; 1975; 1976a; 1976b). These differences were more marked
in those under 25 years and among the best educated urban users.
Soueif's study was subsequently criticised for methodological reasons
(Fletcher and Satz, 1977). A major criticism was that the groups
differed on a number of variables that were relevant to cognitive
performance, including education (with literate non-users being better
educated than illiterate users). There were also higher rates of
opiate and alcohol use among the cannabis users. Soueif (1977) later
reported that in his sample, differences between users and non-users
were not explained by education or polydrug use (Soueif, 1977). The
validity of these findings remain under doubt, however, because some
of the tests used did not have established neuropsychological validity
(Carlin, 1986).
7.4.2.5 India
Agarwal et al (1975) studied 40 subjects who had used bhang (a
tea-like infusion of cannabis leaves and stems) daily for about five
years. These users were less than 45 years of age, and reasonably well
educated: none were illiterate and 65 per cent had completed high
school. There was no control group, so scores were compared to
normative data on the tests used. By comparison with these norms, 18
per cent of the bhang users had memory impairment, 28 per cent showed
mild intellectual impairment on an intelligence test (IQs less than
90) and 20 per cent showed substantial cognitive disturbances on the
Bender-Gestalt Visuo-Motor Test. Wig and Varma (1977) substantially
replicated these results.
Mendhiratta, Wig and Verma (1978) compared 50 heavy cannabis users
(half bhang drinkers, half charas smokers of at least 25 days per
month for a mean of 10 years) with matched controls. The entire sample
was of low socioeconomic status. Tests were administered after 12
hours abstinence which was verified by overnight admission to a
hospital ward. The cannabis users reacted more slowly, and performed
more poorly in concentration and time estimation. The charas smokers
were the poorest performers, showing impaired memory function, lowered
psychomotor activity and poor size estimation. A follow-up of 11 of
the original bhang drinkers, 19 charas smokers and 15 controls nine to
10 years later (Mendhiratta et al, 1988) showed significant
deterioration on several of the tests.
Ray et al (1978) assessed the cognitive functioning of 30 chronic
cannabis users (aged 25-46) who had used bhang, ganja or charas for a
minimum of 11 times/month for at least five years. They compared their
performance to 50 randomly selected non-user controls of similar age,
occupation, socioeconomic status and educational background. Few
differences were found on tests of attention, visuomotor coordination,
or memory. Cannabis users' performance was impaired on one of the
subtests of the memory scale. However, the matching of subjects was
not rigorous, and the fact that all subjects were illiterate may have
produced a floor effect masking differences between groups.
Varma et al (1988) administered 13 psychological tests selected to
assess intelligence, memory and other cognitive functions, to 26 heavy
marijuana smokers and 26 controls matched on age, education and
occupation. The average daily intake of the cannabis users was
estimated as 150mg THC, with a frequency of at least 20 times per
month, and a mean duration of use 6.8 years (minimum five years).
Twelve hours abstinence was ensured by overnight hospitalisation.
Cannabis users were found to react more slowly on perceptuomotor
tasks, but did not differ from controls on the tests of intelligence.
When the scores of all the memory tests were combined, there was no
difference between the total scores of cannabis users and controls,
although cannabis users scored significantly more poorly on a subtest
of recent memory. There were trends toward poorer performance on
subtests of remote memory, immediate and delayed recall, retention and
recognition.
7.4.2.6 Summary
The results of the cross-cultural studies of long-term heavy cannabis
users provided at most equivocal evidence of an association between
cannabis use and more subtle long-term cognitive impairments. Given
that cognitive impairments are most likely to be found in subjects
with a long history of heavy use, it is reassuring that most such
studies have found few and typically small differences. It is unlikely
that the negative results of these studies can be attributed to an
insufficient duration or intensity of cannabis use within the samples
studied, since the duration of cannabis use ranged between 16.9-23
years, and the estimated amount of THC consumed daily ranged from
20-90mg daily in Rubin and Comitas's Jamaican study to 120-200mg daily
in the Greek sample.
The absence of differences is all the more surprising, since a number
of factors may have biased these studies toward finding poorer
performance among cannabis users. These include: higher rates of
polydrug use, poor nutrition, poor medical care, and illiteracy among
users; and the failure in many studies to ensure that subjects were
not intoxicated at the time of testing. Given the generally positive
biases in these studies, it has been argued that if cannabis use did
produce cognitive impairment, then these studies should have shown
positive results (Wert and Raulin, 1986b).
The force of this argument is weakened by the fact that most of these
studies also suffered from methodological difficulties which may have
operated against finding a difference. First, the instruments used
have been developed and standardised on Western populations. Second,
many of these studies were based on small samples of questionable
representativeness. Third, a number of studies failed to include a
control group, while others used inappropriate controls. Fourth,
generalisation of the results of these studies to users in the West or
other cultures is difficult, given the predominance of illiterate,
rural, older and less intelligent or less educated subjects in these
studies. Fifth, the studies were only capable of detecting gross
deficits. Sixth, few attempts were made to examine relationships
between neuropsychological test performance and frequency and duration
of cannabis use.
Despite all these problems, there was nonetheless suggestive evidence
of more subtle cognitive deficits. Slower psychomotor performance,
poorer perceptual motor coordination, and memory dysfunction were the
most consistently reported deficits. In terms of memory function, four
studies detected persistent short-term memory and attentional deficits
(Page et al, 1988; Soueif, 1976a; Varma et al, 1988; Wig and Varma,
1977), while three failed to detect such deficits (Bowman et al, 1973;
Satz et al, 1976; Mendhiratta et al, 1978). The measures of short-term
memory were often inadequate, failing to determine which processes may
be impaired (e.g. acquisition, storage, encoding, retrieval) and often
excluded higher mental loads and conditions of distraction. A proper
evaluation of the complexity of effects of long-term cannabis use on
higher cognitive functions requires greater specificity in the
selection of assessment methods, as well as the use of more sensitive
tests.
7.4.3 Studies of young Western users
A number of studies have been conducted on the cognitive performance
of American or Canadian cannabis users. These samples have generally
been young and well educated college students with relatively
short-term exposure to cannabis, by comparison with the long history
of use among chronic users in the cross-cultural studies.
In one of the earliest studies, Hochman and Brill (1973) surveyed
1,400 college students and compared the performance of non-users (66
per cent), occasional users (26 per cent) and chronic users (9 per
cent: defined as having used three times/week for three years or, had
used daily for two years). They found no relationship between either
frequency or duration of use and academic achievement. In about 1 per
cent of marijuana users there was impaired ability to function. In a
follow-up of the original sample over two consecutive years (1971:
N=1,133; 1972: N=901), Brill and Christie (1974) compared non-users,
occasional users (<2 times per week), frequent (2-4/week), and regular
users (ò5/week) by a self-report questionnaire. The majority of users
reported no effect of cannabis use on psychosocial adjustment. A small
proportion (12 per cent) who reported that their academic performance
had declined were likely to have either reduced their frequency of use
or quit. There were no significant differences between users,
non-users or former users in grade point average.
A series of studies conducted since then has largely confirmed the
results of Hochman and Brill's studies. Grant et al (1973), for
example, studied the effects of cannabis use on psychological test
performance on eight measures from the Halstead-Reitan Battery among
medical students. They found no differences between 29 cannabis users
(of median duration, four years and median frequency of use, three
times per month) and 29 age and intelligence matched non-users on
seven of the eight measures. The failure to find any difference in
sensory-motor integration or immediate sensory memory was later
replicated by Rochford, Grant and LaVigne (1977) in a comparison of 25
users (of at least 50 times over a mean 3.7 years) and 26 controls
matched on sex, age and scholastic aptitude scores.
Weckowicz and Janssen (1973) compared eleven male college students who
smoked cannabis three to five times per week for at least three years
with non-users who were matched on age, education and socioeconomic
and cultural backgrounds. They were assessed on a variety of tests of
cognitive function. Users performed better than controls on eight of
the 11 cognitive tests but performed more poorly on one which
suggested that chronic use may affect sequential information
processing. Otherwise, there was no evidence of gross impairment of
cognitive functioning. Weckowicz, Collier and Spreng (1977) largely
replicated these findings in a comparison of 24 heavy smokers (at
least daily for three years) belonging to the "hippie subculture" with
non-user controls matched for age, education, and social background.
Similar results were reported by Culver and King (1974) in a
comparison of the neuropsychological performance of three groups of
undergraduates (N=14) from classes in two successive years: marijuana
users (at least twice/month for 12 months); marijuana plus LSD users
(LSD use at least once/month for 12 months); and non-drug users. There
were no consistent differences between the groups across the different
years.
In 1981, Schaeffer et al (1981) reported no impairment of cognitive
function in one of the first studies of a prolonged heavy cannabis
using population in the United States, who used the drug for religious
reasons. They assessed 10 long-term heavy users of ganja, aged between
25 and 36 years, all of whom were Caucasian, and had been born, raised
and educated in the USA. All had smoked between 30gm and 60gm of
marijuana (>8 per cent THC) per day for a mean of 7.4 years. They had
not consumed alcohol or other psychoactive substances. This study was
also used a laboratory test to detect recent ingestion of cannabis.
Schaeffer et al reported that at the time of testing, all subjects had
at least 50ng/ml cannabinoids in their urines. Performance on a series
of tests of cognitive ability was compared with the
standardised-normative information available for each test. Overall,
WAIS IQ scores were in the superior to very superior range, and the
scores of all other tests were within normal limits. Despite the heavy
and prolonged use of cannabis, there was no evidence of impairment in
the cognitive functions assessed, namely, language function,
non-language function, auditory and visual memory, remote, recent and
immediate memory, or complex multimodal learning.
Carlin and Trupin (1977) assessed 10 normal subjects (mean age 24
years) who smoked marijuana daily for at least two years (mean five
years) and who denied other drug use. They administered the Halstead
Neuropsychological Test Battery after 24 hours abstinence. No
significant impairment was found by comparison with non-smoking
subjects matched for age, education and full-scale IQ. Cannabis users
performed better on a test sensitive to cerebral impairment than
non-users.
Not all studies have produced null results, however. Gianutsos and
Litwack (1976), for example, compared the verbal memory performance of
25 cannabis smokers who had used for two to six years and at least
twice/week for the last three months, with 25 non-smokers who had
never smoked cannabis. Subjects were drawn from an undergraduate
university student population and were matched on age, sex, year at
university, major and grade point average. Cannabis users reported
that they had not smoked prior to testing, although the length of
abstinence was not reported. Cannabis users recalled significantly
fewer words overall than non-users, and the difference in performance
increased as a function of the number of words they were required to
learn.
Entin and Goldzung (1973) also found evidence of impairment in two
studies of the residual impact of cannabis use on memory processes. In
the first study, verbal memory was assessed by the use of
paired-associate nonsense syllable learning lists. Twenty-six cannabis
users (defined as daily for at least six months) were compared to 37
non-users drawn from a student population. Cannabis users scored
significantly more poorly on both free recall (the number of words
recalled after a delay) and on acquisition, measured as improvement in
recall over repeated trials. In the second study, verbal and numerical
memory were tested by the presentation of word lists, interspersed
with arithmetic problems prior to recall. Cannabis users (N=37)
recalled significantly fewer words than non-users (N=37), but did not
differ from controls on arithmetic test scores. These findings were
interpreted as residual impairment of both the acquisition and recall
phases of long-term memory processes. The authors attributed the
impairments to either an enduring residual pharmacological effect on
the nervous system, or to an altered learning or attention pattern due
to repeated exposure to cannabis.
7.4.3.1 Summary
The results of these empirical studies served to allay fears that
cannabis smoking caused gross impairment of cognition and cerebral
function in young adults. The lack of consistent findings failed to
support Kolansky and Moore's (1971, 1972) clinical reports of an
organic impairment, although some critics (e.g. Cohen, 1982) argued
that the value of these studies was weakened by their small sample
sizes and the fact that by studying college students, they had sampled
from a population unlikely to contain many impaired persons. On
Cohen's hypothesis, the younger, brighter college cannabis users may
reflect the survivors, whereas Kolansky and Moore sampled the
casualties. Such an hypothesis conflicts with the explanations
provided for the failure to find impairment in the cross cultural
studies. Soueif's hypothesis, for example, was that the lower the
non-drug level of proficiency, the smaller the size of functional
deficit associated with drug usage. This would imply maximal
differences at the high end of cognitive ability.
A more pertinent explanation for the lack of impairment is that the
duration of cannabis use in these samples was quite brief, generally
less than five years. It has been argued that cannabis has not been
smoked long enough in Western countries for impairments to emerge.
Further, when psychometric testing was used as a metric of cognitive
function as opposed to self-report questionnaires, sample sizes were
often too small to permit the detection of all but very large
differences between groups.
Not all studies found negative results. A small number of studies did
find significant impairments in their cannabis users. It is noteworthy
that these studies selected tests to assess a specific cognitive
function (memory), and attempted to determine the specific stages of
processing where dysfunction occurred. Entin and Goldzung (1973), for
example, found that users were impaired on both verbal recall and
acquisition of long-term storage memory tasks, but not on arithmetic
manipulations which require short-term storage of information.
7.4.4 Controlled laboratory studies
A different approach to the investigation of the cognitive
consequences of chronic cannabis use is to examine the cognitive
effects of daily cannabis use over periods of weeks to months. Such
studies have attempted to control for variation in quantity, frequency
and duration of use, as well as other factors such as nutrition and
other drug use, by having subjects reside in a hospital ward while
receiving known quantities of cannabis. All such studies employed pre-
and post-drug observation periods. Because of their expense, sample
sizes in these studies have been small and the duration of cannabis
administration has ranged from 21 to 64 consecutive days.
Dornbush et al (1972) administered 1g of marijuana containing 14mg THC
to five regular smokers (all healthy young students) for 21
consecutive days. The subjects were tested immediately before and 60
minutes after drug administration. Data were collected on short-term
memory and digit symbol substitution tests. Performance on the
short-term memory test decreased on the first day of drug
administration but gradually improved until by the last day of the
study, performance had returned to baseline levels. On the
post-experimental day baseline performance was surpassed. Performance
on the digit symbol substitution test was unaffected by drug
administration and also improved with time, suggesting a practice
effect.
Mendelson, Rossi and Meyer (1974) reported a 31-day cannabis
administration study in which 20 healthy, young male subjects (10
casual and 10 heavy users, mean age 23) were confined in a research
ward and allowed 21 days of ad libitum marijuana smoking.
Psychological tests were administered during a five-day drug-free
baseline phase, the 21 day smoking period and a five-day drug-free
recovery phase. Acute and repeat dose effects of marijuana on
cognitive function were studied with a battery of psychological tests
known to be sensitive to organic brain dysfunction. There was no overt
impairment of performance prior to or following cannabis smoking, nor
was there any difference between the performance of the heavy and the
casual users. Short-term memory function, as assessed by digit span
forwards and backwards, was impaired while intoxicated, and there was
a relationship between performance and time elapsed since smoking.
Similar failures to detect cognitive effects have been reported by
three other groups of investigators. Frank et al (1976) assessed
short-term memory and goal directed serial alternation and computation
in healthy young males over 28 days of cannabis administration.
Harshman et al (1976) and Cohen (1976) conducted a 94-day cannabis
study in which 30 healthy moderate to heavy male cannabis users, aged
21-35, were administered on average 5.2 joints per day (mean 103mg
THC, range 35-198mg) for 64 days, and were assessed on brain
hemisphere dominance before, during and after cannabis administration.
Psychometric testing was not employed, but subjects were given two
work assignments with financial incentive: a "psychomotor" task
involving the addition of two columns of figures on a calculator, and
a "cognitive task" of learning a foreign language. No long-term
impairments were detected with these somewhat inadequate assessment
methods.
7.4.4.1 Summary
The experimental studies of daily cannabis usage for periods of up to
three months in young adult male volunteers have consistently failed
to demonstrate a relationship between marijuana use and
neuropsychological dysfunction. This is not surprising given the short
periods of exposure to the drug in these studies. Furthermore, since
subjects served as their own controls, and had all used cannabis for
at least one year prior to the study, it would be surprising if a few
additional weeks of cannabis use produced any significant decrements
in performance.
7.4.5 Recent research
The equivocal results of the early investigations into long-term
effects of cannabis on cognitive function led to something of a hiatus
in research on the cognitive effects of cannabis in the 1980s.
Although the accumulated evidence indicated that cannabis did not
severely affect intellectual functioning, uncertainty remained about
more subtle impairments. Their study required advances in methodology
and assessment techniques which were made in the field of cognitive
psychology and neuropsychology in the 1980s. Modern theories of
cognition, memory function and information processing were developed,
as were more sensitive measures of cognitive processes. By the late
1980s, interest in the cognitive effects of cannabis revived at a time
when cannabis had been widely used for more than 15 years, its use was
widespread and initiated at a progressively younger age among young
Americans.
Research from the late 1980s through the 1990s improved upon the
design and methodology of previous studies by using adequate control
groups, verifying abstinence from cannabis prior to testing, and
precisely measuring the quantity, frequency and duration of cannabis
use. In addition, greater attention was paid to investigating specific
cognitive processes and relating impairments in them to the quantity,
frequency and duration of cannabis use.
The greater specificity in study focus was made possible by
accumulating evidence that cannabis primarily exerts its effect upon
those areas of the brain responsible for attention and memory. Miller
and Branconnier (1983), for example, reviewed the literature and
concluded that impaired memory was the single most consistently
reported psychological deficit produced by cannabinoids acutely, and
the most consistently detected impairment in long-term cannabis use.
Intrusion errors were one of the most robust type of cannabis-induced
memory deficits in both recall and recognition (Miller and
Branconnier, 1983). Such errors involve the introduction of extraneous
items, word associations or new material during free recall of words,
or the false identification of previously unseen items in recognition
tasks. Miller and Branconnier conjectured that these intrusion errors
occurred because cannabis users were unable to exclude irrelevant
associations or extraneous stimuli during concentration of attention,
a process in which the hippocampus plays a major role. The finding of
high densities of the cannabinoid receptor in the cerebral cortex and
hippocampus (Herkenham et al, 1990) supports the hypothesis that
cannabinoids are involved in attentional and memory processes.
7.4.5.1 Studies of long-term adult users
Solowij et al (1991; 1992; 1993) conducted a series of studies of the
effects of long-term cannabis use on specific stages of information
processing. In keeping with Miller and Branconnier's hypothesis,
Solowij et al assessed the integrity of attentional processes in
long-term cannabis users using a combination of performance and brain
event-related potential measures. Event-related potential (ERP)
measures are sensitive markers of covert cognitive processes
underlying overt behaviour; the amplitude and latency of various ERP
components have been shown to reflect various stages of information
processing.
Solowij et al, (1991) studied a small and heterogeneous group of
long-term cannabis users (N=9), aged 19-40, who had used cannabis for
a mean of 11.2 years at the level of 4.8 days per week. The cannabis
users were matched on age, sex, years of education and alcohol
consumption with nine non-user controls who had either never used or
had limited experience with cannabis (maximum use 15 times). Strict
exclusion criteria were applied to any subjects with a history of head
injury, neurological or psychiatric illness, significant use of other
drugs, or high levels of alcohol consumption. The groups did not
differ in premorbid IQ, as estimated by the NART score (Nelson, 1984).
Subjects were instructed to abstain from cannabis and alcohol for 24
hours prior to testing and two urine samples were analysed to ensure
that subjects were not acutely intoxicated at the time of testing.
Subjects completed a multidimensional auditory selective attention
task in which random sequences of tones varying in location, pitch and
duration were delivered through headphones while brain electrical
activity (EEG) was recorded. They were instructed to attend to a
particular ear and a particular pitch, and to respond to the long
duration tones with a button press. This procedure enabled an
examination of the brain's response to attended and unattended tones.
Cannabis users performed significantly more poorly than controls, with
fewer correct detections, more errors and slightly longer reaction
times. Analysis of the ERP measures showed that cannabis users had
reduced P300 amplitudes compared to controls, reflecting dysfunction
in the allocation of attentional resources and stimulus evaluation
strategies. Further, cannabis users showed an inability to filter out
irrelevant information, while controls were able to reject this
irrelevant information from further processing at an early stage.
These results suggested that long-term cannabis use impairs the
ability to efficiently process complex information.
Solowij et al (1992; 1993) conducted a second study with a larger
sample to examine the relationships between degree of impairment and
the frequency and duration of use. Thirty-two cannabis users recruited
from the general community were split into four groups of equal size
(N=8) defined by frequency (light: ó twice/week vs heavy: ò three
times/week) and duration (short: 3-4 years vs long: ò five years) of
cannabis use. The mean number of years of use for the long duration
users was 10.1, and 3.3 for short duration users (range three to 28
years). The mean frequency of use was 18 days per month for the heavy
group and six for the light group (range: once/month to daily use).
Subjects were matched to a group of non-user controls (N=16) as in the
first study, and a similar methodology was employed.
Once again cannabis users performed worse than the controls, with the
greatest impairment observed in the heavy user group, thereby
replicating the earlier ERP findings. In addition, different cognitive
processes were differentially affected by frequency and duration of
cannabis use. The long duration user group showed significantly larger
processing negativity to irrelevant stimuli than did short duration
users and controls, who did not differ from each other. There were no
differences between groups defined on frequency of use. A significant
correlation between the ERP measure and duration of cannabis use
indicated that the ability to focus attention and filter out
irrelevant information was progressively impaired with the number of
years of use, but was unrelated to frequency of use. Frequency of use
affected the speed of information processing, as reflected in a
delayed P300 latency in the heavy user group compared to light users
and controls. There was a significant correlation between P300 latency
and increasing frequency of use, while this measure was unrelated to
duration of use.
These results suggest that different mechanisms underlie the
short-term and long-lasting actions of cannabinoids. The slowing of
information processing suggests a chronic build up of cannabinoids,
and reflected a residual effect which could be eliminated by reducing
the frequency of use. The inability to focus attention and reject
irrelevant information possibly reflected long-term changes at the
cannabinoid receptor site. The consequences of these impairments may
be apparent in high levels of distractability when driving, operating
complex machinery, and learning in the classroom situation, and
interference with efficient memory and general cognitive functions.
Solowij et al also conducted specific analyses to disentangle the
relationship between duration of cannabis use and age. The results of
these analyses indicated that impairment was greatest in younger
subjects. Further, the studies demonstrated the insensitivity of
performance measures to cannabinoid effects, emphasising the need to
use more sensitive measures to examine otherwise inaccessible, covert
cognitive processes.
Supportive evidence has emerged from a project funded by the National
Institute on Drug Abuse (NIDA) in the U.S. (principal investigator F.
Struve) that investigated persistent central nervous system sequelae
of chronic cannabis exposure. This research, which has focused upon
quantitative EEG, has found evidence of larger changes in EEG
frequency, primarily in frontal-central cortex, in daily cannabis
users of up to 30 years duration compared to short-term users and
non-users (e.g. Struve et al, 1993). The results also suggest a
dose-response relationship between EEG changes and the total
cumulative exposure (duration in years) of daily cannabis use which
may indicate organic changes. The major limitation of this research is
that changes in frequency of EEG spectra have not been shown to be
related to cognitive events.
One study from this research group has used cognitive event-related
potential measures. It found smaller P2 and N2 amplitudes in long-term
cannabis users (>15 years) compared to moderate users (of three to six
years). Cannabis users overall showed significantly smaller auditory
and visual P300 amplitudes than controls, but no significant latency
differences (Straumanis et al, 1992). Unfortunately, this study has
only been reported in abstract form, and results have not been
examined as a function of frequency of cannabis use.
This research group has also assessed cognitive functioning by
neuropsychological tests (e.g. Leavitt et al, 1991; 1992; 1993). These
investigations have been well controlled. Subjects were extensively
screened for current or past psychiatric or medical disease or CNS
injury, and underwent extensive drug history assessments, with eight
weeks of twice weekly drug screens. Groups were matched for age and
sex. Daily cannabis users who had at least three years to six years of
use were compared to a group who had used for six to 14 years, a group
who had used on a daily basis for 15 years or more, and a non-user
control group. Sample sizes varied from study to study, but averaged
15 per group.
An extensive battery of psychological tests included measures of
simple and complex reaction time, attention and memory span, language
and comprehension tasks, construction, verbal and visual learning and
memory, and mental abilities such as concept formation and logical
reasoning. The effects of age and education have been statistically
controlled for by multiple regression. Preliminary analyses have shown
a dose-response relationship between test performance and intensity of
cannabis use, with the best performance characterising controls,
followed by the daily cannabis users, and the worst mean scores
occurring in the very long-term group (Leavitt et al, 1991; 1992;
1993; Leavitt, personal communication). Tests sensitive to mild
cortical dysfunction were those most affected in the long-term user
groups.
The authors acknowledge that small sample sizes dictate caution, and
that there were no data available to assess premorbid cognitive
capacity of these subjects. Nevertheless, the results suggested that
long duration users seem to process some kinds of information more
slowly than non-users, and that the effects of long-term cannabis use
are most likely to surface under conditions of moderately heavy
cognitive load.
One crucial requirement for evaluating the performance of chronic
marijuana users is comparison with an appropriately matched group of
non-using subjects. Although the studies described have made
substantial progress in this regard, one concern remains that some of
these impairments may have been present in the cannabis users prior to
their cannabis use. Block et al (1990) used scores on the Iowa Tests
of Basic Skills collected in the fourth grade of grammar school as a
measure of premorbid cognitive ability. Block et al matched their user
and non-user samples on this test to ensure that they were comparable
in intellectual functioning before they began using marijuana. The
study aim was to determine whether chronic marijuana use produced
specific cognitive impairments, and if so, whether these impairments
depend on the frequency of use. Block and colleagues assessed: 144
cannabis users, 64 of whom were light users (one to four/week for 5.5
years) and 80 heavy users (òfive/week for 6.0 years), and compared
them with 72 controls. Subjects were aged 18-42. Twenty-four hours of
abstinence were required prior to testing.
Subjects participated in two sessions. In the first session they
completed the 12th grade version of the Iowa Tests of Educational
Development, which emphasise basic, general intellectual abilities and
academic skills and effective utilisation of previously acquired
information in verbal and mathematical areas. In the second session,
subjects were administered computerised tests that emphasise learning
and remembering new information, associative processes and semantic
memory retrieval, concept formation and psychomotor performance. These
tasks had been previously shown to be sensitive to the acute and
chronic effects of cannabis, and to relevant skills required in school
and work performance. The results showed that heavy users who were
matched to controls on fourth-grade Iowa scores, showed impairment on
two tests of verbal expression and mathematical skills when tested on
the 12th-grade Iowa test. No results have been reported to date from
the computerised tests.
7.4.5.2 Studies in children and adolescents
A very different approach to assessing the long-term consequences of
exposure to cannabis has been taken in a well controlled longitudinal
study of children who were exposed to cannabis in utero (Fried, 1993).
The levels of exposure to cannabis in the sample were approximately as
follows: 60 per cent of the mothers used cannabis irregularly, 10 per
cent reported smoking two to five joints per week, and 30 per cent
smoked a greater amount during each trimester of pregnancy. Prenatal
exposure to cannabis was associated with high pitched cries, disturbed
sleep cycles, increased tremors and exaggerated startles in response
to minimal stimulation in newborn to 30-day-old babies. The babies
showed poorer habituation to visual stimuli, consistent with the
sensitivity of the visual system to the teratogenic effects of
cannabis demonstrated in rhesus monkeys and rats. Fried hypothesised
that exposure to cannabis may affect the rate of development of the
central nervous system, slowing the maturation of the visual system.
This hypothesis was supported by visual evoked potential studies of
the children at four years of age, when children who had been exposed
to cannabis in utero showed greater variability and longer latency of
the evoked potential components, indicating immaturity in the system.
From one to three years of age, no adverse effects of prenatal
exposure were found. At two years it appeared that the children were
impaired on tests of language comprehension, but this effect did not
persist after controlling for other factors such as ratings of home
environment. At four years of age, however, the children of cannabis
using mothers were significantly inferior to controls on tests of
verbal ability and memory. The explanation for the failure to detect
impairments in the preceding age group was that the degree and types
of deficits observed may only be identifiable when cognitive
development has proceeded to a certain level of maturity.
At five and six years of age, the children were not impaired on global
tests of cognition and language. By age six, however, there was a
deficit in sustained attention on a task that differentiated between
impulsivity and vigilance. Fried proposed that "instruments that
provide a general description of cognitive abilities may be incapable
of identifying nuances in neurobehavior that may discriminate between
the marijuana-exposed and non-marijuana exposed children" (p332). He
suggested the need for tests which examine specific cognitive
characteristics and strategies, such as the test of sustained
attention. Fried concluded that cannabis "may affect a number of
neonatal behaviours and facets of cognitive behavior under conditions
in which complex demands are placed on nervous system functions".
The effects of long-term cannabis use on adolescents have not been
adequately addressed. This issue is of greater relevance with an
increase in the prevalence of cannabis use among adolescents and young
adults in Western society. In the first study of its kind with
adolescents, Schwartz et al (1989) reported the results of a small
controlled pilot study of persistent short-term memory impairment in
10 cannabis-dependent adolescents (aged 14-16 years). Schwartz's
clinical observations of adolescents in a drug-abuse treatment program
suggested that memory deficits were a major problem, which according
to the adolescents persisted for at least three to four weeks after
cessation of cannabis use. His sample was middle-class, North
American, matched for age, IQ and history of learning disabilities
with 17 controls, eight of whom were drug abusers who had not been
long-term users of cannabis, and another nine whom had never abused
any drug. The cannabis users consumed approximately 18g per week,
smoking at a frequency of at least four days per week (mean 5.9) for
at least four consecutive months (mean 7.6 months). Subjects with a
history of excessive alcohol or phencyclidine use were excluded from
the study. Cannabinoids were detected in the urines of eight of the 10
users over two to nine days.
Users were initially tested between two and five days after entry to
the treatment program, this length of time allowing for dissipation of
any short-term effects of cannabis intoxication on cognition and
memory. Subjects were assessed by a neuropsychological battery which
included the Wechsler Intelligence Scale for Children, and six tests
"to measure auditory/verbal and visual/spatial immediate and
short-term (delayed) memory and praxis (construction ability)"
(p1215). After six weeks of supervised abstinence with bi-weekly urine
screens for drugs of abuse, they were administered a parallel test
battery.
On the initial testing, there were statistically significant
differences between groups on two tests: cannabis users were
selectively impaired on the Benton Visual Retention Test and the
Wechsler Memory Scale Prose Passages. The differences were smaller but
were still detectable six weeks later. Cannabis users committed
significantly more errors than controls initially on the Benton Visual
Retention Test for both immediate and delayed conditions, but
differences in the six-week post-test were not significant. Users
scored lower than controls on both immediate and delayed recall in the
Wechsler Memory Prose Passages Test in both test sessions. The fact
that there was a trend toward improvement in the scores of cannabis
users suggests that the deficits observed were related to their past
cannabis use and that functioning may return to normal following a
longer period of abstinence.
Schwartz's study was the first controlled study to demonstrate
cognitive dysfunction in cannabis-using adolescents with a relatively
brief duration of use. The implications of these results are that
young people may be more vulnerable to any impairments resulting from
cannabis use. Unfortunately, like many of its predecessors, Schwartz's
team made little effort to interpret the significance of the
selectivity of their results. There was nothing to indicate which
specific elements of memory formation or retrieval were disrupted.
7.4.6 Discussion
Previous reviewers have generally concluded that there is insufficient
evidence that cannabis produces long-term cognitive deficits (e.g.
Wert and Raulin, 1986a; 1986b). This is a reasonable conclusion when
gross deficits are considered. However, the findings from recent, more
methodologically rigorous studies provide evidence of subtle cognitive
impairments which appear to increase with duration of cannabis use.
The evidence suggests that impairment on some neuropsychological tests
may become apparent only after 10-15 years of use, but very sensitive
measures of brain function are capable of detecting specific
impairments after five years of use.
Impairments appear to be specific to the organisation and integration
of complex information, involving various mechanisms of attention and
memory processes. The similarity between the kinds of subtle
impairments associated with long-term cannabis use and frontal lobe
dysfunction is becoming more apparent (e.g. short-term memory
deficits, increased susceptibility to interference, lack of impairment
on general tests of intelligence or IQ). Frontal lobe function is
difficult to measure, as indicated by the fact that patients with
known frontal lobe lesions do not differ from controls on a variety of
neuropsychological tests (Stuss, 1991), so the difficulty of assessing
frontal lobe functions is not unique to research into the long-term
effects of cannabis.
One of the functions of the frontal lobes is the temporal organisation
of behaviour, a key process in efficient memory function,
self-awareness and planning. The frontal lobe hypothesis of
impairments due to long-term use of cannabis is consistent with the
altered perception of time demonstrated in cannabis users and with
cerebral blood flow studies which demonstrate greatest alterations in
the region of the frontal lobes (see Section 7.5 brain damage).
The equivocal results of previous studies may be due primarily to poor
methodology and insensitive test measures. Wert and Raulin (1986b) had
rejected the possibility that tests used previously were not sensitive
enough to detect impairments, on the grounds that the same tests have
demonstrated impairment in alcoholics and heavy social drinkers.
However, the cognitive deficits produced by chronic alcohol
consumption may be very different to those produced by cannabis. The
mechanisms of action of the two substances are different, with
cannabis acting on its own specific receptor, and Solowij et al (1993)
showed that the attentional impairments detected in their long-term
cannabis users were not related to their alcohol consumption.
Furthermore, tests may have been selected inappropriately because they
were previously shown to be affected by acute intoxication, when the
consequences of chronic use may be very different. A priority for
future research is the identification of specific mechanisms of
impairment by making direct comparisons with the effects of a variety
of other substances.
Recent research has aimed at identifying specific cannabis effects by
using strict exclusion criteria, and carefully matching control groups
to ensure that any deficits observed are attributable to cannabis.
However, interactions between the effects of long-term cannabis use
concurrent with use of other substances need to be further explored.
Subjects have also been excluded if they have had a history of
childhood illness, learning disabilities, brain trauma or other
neurological or psychiatric illness. The effects of long-term cannabis
use on such individuals may be worthy of further investigation.
Cognitive deficits may not be an inevitable consequence of cannabis
use. The long-term effects of cannabis on healthy individuals may
differ from those in individuals with co-existing mental illness or
pre-existing cognitive impairments. On the other hand, some
individuals appear to function well even in cognitively demanding
occupations despite long-term cannabis use. Wert and Raulin (1986b)
suggested that some individuals may adapt and overcome some forms of
cognitive impairment by a process of relearning.
When users and non-users are compared, differences may not always
reach statistical significance due to large individual variability,
particularly when small sample sizes are used. Carlin (1986) proposed
that "studies that rely upon analysis of central tendency are likely
to overlook impairment by averaging away the differences among
subjects who have very different patterns of disability". Individual
differences in vulnerability to the acute effects of cannabis are well
recognised and are likely to be a factor in determining susceptibility
to a variety of cognitive dysfunctions associated with prolonged use
of cannabis.
There has been no research designed to identify individual differences
in susceptibility to the adverse effects of cannabis. A susceptibility
may be due to structural, biochemical or psychological factors, or as
Wert and Raulin suggested, to lack of the "cerebral reserve that most
of us call on when we experience mild cerebral damage", for example,
after a night of heavy drinking. Wert and Raulin suggested that
prospective studies are the ideal way to identify those subjects who
show real impairment in functioning by comparing pre- and post-
cannabis performance scores. However, even in a retrospective design
it is possible to compare the characteristics of subjects who show
impairment with those who do not, thereby identifying possible risk
factors. Insufficient consideration has been given to gender, age, IQ
and personality differences in the long-term consequences of cannabis
use.
Almost all of the studies reviewed have been retrospective studies of
naturally occurring groups (users vs. non-users). Although the
matching of control groups has become more stringent, and attempts to
obtain estimates of premorbid functioning have increased, prospective
studies where each subject is used as his/her own control would
eliminate the possibility of cannabis users having demonstrated poorer
performance before commencing their use of cannabis. A longitudinal
study in which several cohorts at risk for drug abuse are followed
over time would be the best way to assess the detrimental effects of
long-term cannabis use on cognition and behaviour.
Given the growing prevalence of cannabis use, and proposals to reduce
legal restrictions on cannabis use, it is essential that research into
cognitive effects of long-term cannabis use continues. According to US
survey data (Deahl, 1991), more than 29 million people in the United
States may be using cannabis, and more than seven million of these use
on a daily basis. While there is some controversy surrounding the
issue, it seems likely that the potency of cannabis has increased over
the years, as more potent strains have been developed for the black
market. Increased THC potency combined with decreased age of first use
may result in the more marked cognitive impairments in larger numbers
of individuals in the future.
Future research should adhere to rigorous methodology. This should
include the use of the best available techniques for detecting
cannabinoids in the body to provide greater precision in the
investigation of the effects of abstinence on performance. This would
permit a distinction to be made between those impairments which are
residual, and likely to resolve with abstinence over time, from those
of a more enduring or chronic nature, which would be associated with
cumulative exposure.
Given that recent research has identified cognitive impairments that
are associated with cumulative exposure, it is a priority to
investigate the extent and rate of recovery of function following
cessation of cannabis use. Furthermore, the parameters of drug use
require careful scrutiny in terms of evaluating how much cannabis must
be smoked and for how long, before impairments are manifest in
different kinds of individuals. One of the problems in assessing the
cannabis literature is the arbitrariness with which various groups of
users have been described as "heavy", "moderate" or "light",
"long-term", "moderate" or "short-term".
The use of very sensitive measures of cognitive function is important
for the detection of early signs of impairment, which may permit a
harm minimisation approach to be applied to cannabis use. With further
research, it may be possible to specify levels of cannabis use that
are "safe", "hazardous" and "harmful" in terms of the risk of
cognitive impairment. Further research examining the consequences of
cannabis use in comparison to other substances could provide users
with the ability to make an informed decision about whether or not to
use the drug, and if they use, how much and how often to use.
7.4.7 Conclusion
The weight of evidence suggests that the long-term use of cannabis
does not result in any severe or grossly debilitating impairment of
cognitive function. However, there is clinical and experimental
evidence which suggests that long-term use of cannabis produces more
subtle cognitive impairments in specific aspects of memory, attention
and the organisation and integration of complex information. While
these impairments may be subtle, they could potentially affect
functioning in daily life. The evidence suggests that increasing
duration of use leads to progressively greater impairment. It is not
known to what extent such impairment may recover with prolonged
abstinence.
It is apparent that not all individuals are affected equally by
prolonged exposure to cannabis. Individual differences in
susceptibility need to be identified and examined. For those who are
dysfunctional, there is a need to develop appropriate treatment
programs which address the subtle impairments in cognition and work
toward their resolution. There has been insufficient research on the
impact of long-term cannabis use on cognitive functioning in
adolescents and young adults, or on the effects of chronic use on the
cognitive decline that occurs with normal aging. Gender differences
have not been examined to date and may be important, given that such
differences have become apparent in differential responses to alcohol.
Future research should aim to identify with greater specificity those
aspects of cognitive functioning which are affected by long-term use
of cannabis, and to examine the degree to which they are reversible.
There is converging evidence that dysfunction due to chronic cannabis
use lies in the higher cognitive functions that are subserved by the
frontal lobes and which are important in organising, manipulating and
integrating a variety of information, and in structuring and
segregating events in memory.
Until better measures have been developed to investigate the
subtleties of dysfunction produced by chronic cannabis use, cannabis
may be viewed as posing a lesser threat to cognitive function than
other psychoactive substances such as alcohol. Nevertheless, the fact
remains that in spite of its illegal status, cannabis use is
widespread. We therefore have a continuing responsibility to minimise
drug-related harm by identifying potential risks, subtle though they
may be, and communicating the necessary information to the community.
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7.5 Chronic cannabis use and brain damage
A major concern about the recreational use of cannabis has been
whether it may lead to functional or structural neurotoxicity, or
"brain damage" in ordinary language. Fehr and Kalant (1983) defined
neurotoxicity as "functional aberrations qualitatively distinct from
the characteristic usual pattern of reversible acute and chronic
effects, and that may be caused by identified or identifiable neuronal
damage" (p27). On this definition, an enduring impairment of cognitive
functioning may be interpreted as a manifestation of neurotoxicity.
Since such impairments are discussed in the previous chapter on
chronic effects on cognitive functioning, this chapter will
concentrate on direct investigations of neurological function and
structural brain damage arising from exposure to cannabinoids. The
review begins with an examination of the evidence for behavioural
neurotoxicity from animal studies. Neurochemical, electrophysiological
and brain substrate investigations of functionality follow, and the
chapter concludes with the findings of more invasive examinations of
brain structure and morphology in animals, and of less invasive
techniques for imaging the human brain.
7.5.1 Behavioural neurotoxicity in animals
Animal research provides the ultimate degree of control over
extraneous variables; it is possible to eliminate factors known to
influence research findings in humans, e.g. nutritional status, age,
sex, previous drug history, and concurrent drug use. The results,
however, are often difficult to extrapolate to humans because of
between-species differences in brain and behaviour and in drug dose,
patterns of use, routes of administration and methods of assessment.
Animal research on the effects of cannabis on brain function has
typically administered known quantities of cannabinoids to animals for
an extended period of time and then examined performance on various
tasks assessing brain function, before using histological and
morphometric methods to study the brains of the exposed animals. In
general, the results of studies with primates produce results that
most closely resemble the likely effects in humans; the monkey is
physiologically similar to humans, while rats, for example, metabolise
drugs in a different way; and monkeys are able to perform complex
behavioural tasks. Nevertheless, every animal species examined to date
has been found to have cannabinoid receptors in the brain. In animal
models, non-targeted staring into space following administration of
cannabinoids is suggestive of psychoactivity comparable to that in
humans. The most characteristic responses to cannabinoids in animals
are mild behavioural aberrations following small doses, and signs of
gross neurotoxicity manifested by tremors and convulsions following
excessively large doses. Where small doses are given for a prolonged
period of time, evidence of behavioural neurotoxicity has emerged (see
Rosenkrantz, 1983). Chronic exposure produces lethargy, sedation and
depression in many species, and/or aggressive irritability in monkeys.
A clear manifestation of neurotoxicity in rats is what has been called
the "popcorn reaction" (Luthra, Rosenkrantz and Braude, 1976),
characterised by a pattern of sudden vertical jumping in rats exposed
to cannabinoids for five weeks or longer. It is also seen in young
animals exposed to cannabinoids in utero and then given a small dose
challenge at 30 days of age. Several studies of prenatal exposure
indicate that the offspring of cannabis treated animals show small
delays in various stages of post-natal development, such as eye
opening, various reflexes and open field exploration, although after
several weeks or months their development is indistinguishable from
normal (e.g. Fried and Charlebois, 1979). This means that either the
developmental delay was not chronic, the remaining damage is too
subtle to be detected by available measures, or the "plasticity of
nervous system organisation in the newborn permitted adequate
compensation for the loss of function of any damaged cells" (Fehr and
Kalant, 1983, p29).
Behavioural tests in rodents have included conventional and radial arm
maze learning, operant behaviour involving time discriminations, open
field exploration and two-way shuttle box avoidance learning. Correct
performance on these tests is dependent on spatial orientation or on
response inhibition, both of which are believed to depend heavily on
intact hippocampal functioning. Some studies have found decreased
learning ability on such tasks several months after long-term
treatment with cannabinoids (see Fehr and Kalant, 1983). For example,
Stiglick and Kalant (1982a, 1982b) reported altered learning behaviour
in rats one to six months after a three-month oral dosing regimen of
marijuana extract or THC. They claimed that the deficits were
reminiscent of behavioural changes seen after damage to the
hippocampus. Long lasting impairment of learning ability and
hippocampal dysfunction suggests that long-lasting damage may result
from exposure to cannabis. However, some studies have been carried out
too soon after last drug administration to exclude the possibility
that the observed effects are residual effects, that is, due to the
continued action of accumulated cannabinoids.
Memory function in monkeys has often been assessed by delayed
matching-to-sample tasks. In a recent study (Slikker et al, 1992),
rhesus monkeys were trained for one year to perform five operant tasks
before one year of chronic administration of cannabis commenced. One
group was exposed daily to the smoke of one standard joint, another on
weekends only, and control groups received sham smoke exposure (N=15
or 16 per group). Performance on the tasks indicated the induction of
an "amotivational syndrome" during chronic exposure to cannabis, as
manifested in a decrease in motivation to respond, regardless of
whether the monkeys were exposed daily or only on weekends. This led
the authors to suggest that motivational problems can occur at
relatively low or recreational levels of use (in fact the effect was
maximal with intermittent exposure). Task performance was grossly
impaired for more than a week following last exposure, although
performance returned to baseline levels two to three months after
cessation of use. Thus, the effects of chronic exposure were slowly
reversible with no long-term behavioural effects, and the authors
concluded that persistent exposure to compounds that are very slowly
cleared from the brain could account for their results. This
hypothesis is consistent with the long half life of THC in the body
(see Section 4.7 on metabolism).
One of the problems with these studies is that animals are often only
exposed for a relatively short period of time, for example, one year
or less. Slikker and colleagues acknowledge that it remains to be
determined whether longer or greater exposures would cause more severe
or additional behavioural effects. It may be that chronic dysfunction
becomes manifest only after many years of exposure. Nevertheless, it
is of concern that behavioural impairments have been shown to last for
several months after exposure, but reassuring that they have generally
resolved over time.
A further difficulty with animal studies is a consequence of
differences between animals and humans in route of cannabinoid
administration. In humans, the most common route of exposure to THC is
via the inhalation of marijuana smoke, whereas most animals studies
have relied upon the oral administration or injection of THC because
of the difficulty in efficiently delivering smoke to animals and the
concern about the complications introduced by carbon monoxide
toxicity. While it may well be impossible to evaluate the
pharmacological and toxicological consequences of exposure to the
hundreds of compounds in cannabis simultaneously, it is arguably
inappropriate to assess the long-term consequences of human cannabis
smoking by administering THC alone. Hundreds of additional compounds
are produced by pyrolysis when marijuana is smoked, which may
contribute either to acute effects or to long-term toxicity. Future
studies need to address these issues for comparability to human usage.
Appropriate controls, including those which mimic the carbon monoxide
exposure experienced during the smoking of marijuana may be necessary.
7.5.2 Neurochemistry
The discovery of the cannabinoid receptor and its endogenous ligand
anandamide revolutionised previous conceptions of the mode of action
of the cannabinoids. However, much further research is required before
the interactions between ingested cannabis, anandamide and the
cannabinoid receptor are fully understood. Nor should the anandamide
pathways be seen as responsible for all of the central effects of the
psychoactive cannabinoids. There is good evidence that cannabinoids
affect the concentration, turnover, or release of endogenous
substances (see Pertwee, 1988). Much research has been devoted to
examining the interactions between cannabinoids and several
neurotransmitter receptor systems (e.g. norepinephrine, dopamine,
5-hydroxytryptamine, acetylcholine, gamma-aminobutyric acid (GABA),
histamine, opioid peptides, and prostaglandins). The results suggest
that all these substances have some role in the neuropharmacology of
cannabinoids, although little is known about the precise nature of
this involvement. Cannabinoids may alter the activities of
neurochemical systems in the central nervous system by altering the
synaptic concentrations of these mediators through an effect on their
synthesis, release, or metabolism, and/or by modulating
mediator-receptor interactions. There have been numerous reports of
neurotransmitter perturbations in vitro and after short-term
administration (see Martin, 1986; Pertwee, 1988).
Domino (1981) demonstrated in cats that large doses of THC elevate
brain acetylcholine and reduce its turnover by producing a decrease in
acetylcholine release from the neocortex. At large doses, THC may
depress the brain stem activating system. With lower doses, brain
acetylcholine utilisation was reduced primarily only in the
hippocampus. Some of the potential undesirable side effects of
cannabinoids may be related to a decrease in acetylcholine release and
turnover. Domino also reported that THC decreased EEG activation and
induced slow wave activity: high voltage slow waves in neocortical EEG
were produced in frontal regions and tended to be exaggerated by small
doses but reduced by larger doses. These findings support the general
observation made in a variety of studies, that low doses of THC
stimulate, while high doses depress the noradrenergic and dopaminergic
system.
Bloom (1984) reported that cannabinoids increase the synthesis and
turnover of dopamine and norepinephrine in rat and mouse brain, while
producing little or no change in endogenous levels of catecholamines.
However, THC and other cannabinoids were reported to alter functional
aspects of catecholaminergic neurotransmission. THC was found to
increase the utilisation of the catecholamine neurotransmitters, to
alter the active uptake of biogenic amine neurotransmitters and their
precursors into synaptosomes, and to alter transmitter release from
synaptosomes. Further, THC was reported to alter the activity of
enzymes involved in the synthesis and degradation of the
catecholamines. THC and other cannabinoids can selectively alter the
binding of ligands to several different membrane-bound
neurotransmitter receptors.
Relatively few studies have examined whether long-term exposure to
cannabinoids results in lasting changes in brain neurotransmitter and
neuromodulator levels. An early study examined cerebral and cerebellar
neurochemical changes accompanying behavioural manifestations of
neurotoxicity (involuntary vertical jumping) in rats exposed to
marijuana smoke for up to 87 days (Luthra, Rosenkrantz and Braude,
1976). Sex differences emerged in the neurochemical consequences of
chronic exposure: in females, AChE showed a cyclic increase and
cerebellar enzyme activity declined. For both sexes cerebellar RNA
increased, but at different times for each sex, and at 87 days
remained elevated only in females. Some of these neurochemical changes
persisted during a 20-day recovery period, but the authors predicted
the return to normality after a much longer recovery period.
Cannabinoids administered prenatally not only impaired developmental
processes in rats, but produced significant decrements in RNA, DNA and
protein concentrations and reductions in amine concentrations
(dopamine, norepinephrine) in mice, which could be important in the
role of protein and nucleic acids in learning and memory (see Fehr and
Kalant, 1983). Bloom (1984) reported that chronic exposure to
cannabinoids has been shown to lead to increased activity of tyrosine
in rat brain.
However, recent evidence suggests that there are few, if any,
irreversible effects of THC on known brain chemistry. Ali and
colleagues (1989) administered various doses of THC to rats for 90
days and then assessed several brain neurotransmitter systems 24 hours
or two months after the last drug dose. Examination of dopamine,
serotonin, acetylcholine, GABA, benzodiazepine and opioid
neurotransmitter systems revealed that no significant changes
occurred. A larger study with both rats and monkeys examined receptor
binding of the above neurotransmitters and the tissue levels of
monoamines and their metabolites (Ali et al, 1991). No significant
irreversible changes were demonstrated in the rats chronically treated
with THC. Monkeys exposed to a chronic treatment of marijuana smoke
for one year and then sacrificed after a seven-month recovery period
were found to have no changes in neurotransmitter concentration in
caudate, frontal cortex, hypothalamus, or brainstem regions. The
authors concluded that there are no significant irreversible
alterations in major neuromodulator pathways in the rat and monkey
brain following long-term exposure to the active compounds in
marijuana.
Slikker et al (1992), reporting on the same series of studies, noted
that there were virtually no differences between placebo, low dose or
high dose groups of monkeys in blood chemistry values. The general
health of the monkeys was unaffected, but the exposure served as a
chronic physiological stressor, evidenced by increases in urinary
cortisol levels which were not subject to tolerance (although plasma
cortisol levels did not differ). Urinary cortisol elevation has not
been demonstrated in other studies with monkeys. Slikker et al
reported a 50 per cent reduction in circulating testosterone levels in
the high dosed group, with a dramatic (albeit non-significant) rebound
one to four weeks after cessation of treatment. It is worth noting
that these monkeys were three years of age at the commencement of the
study and would have experienced hormonal changes over the course of
entering adolescence during the study.
A recent pilot study compared monoamine levels in cerebrospinal fluid
(CSF) in a small sample of human cannabis users and age and
sex-matched normal controls (Musselman et al, 1993). The justification
for the study was that THC administered to animals has been shown to
produce increases in serotonin and decreases in dopamine activity. No
differences were found between the user and non-user groups in the CSF
concentration of HVA, 5HIAA, MHPG, ACTH and CRH. The authors proposed
a number of explanations for these results: (1) cannabis use has no
chronic effect on levels of brain monoamines; (2) those who use
cannabis have abnormal levels of brain monoamines which are normalised
over long periods of time by cannabis use; or (3) those who use
cannabis have normal levels of brain monoamines which are transiently
altered with cannabis use and then return to normal. However, there is
insufficient data from this study to permit a choice between these
hypotheses to be made. The frequency and duration of cannabis use, and
the time since last use in the user group could not be determined. All
users had denied using cannabis, having been drawn from a larger
normative sample and identified as cannabis users by the detection of
substantial levels of cannabinoids in urine screens. Furthermore, the
"normal" controls were assumed to be non-users on the basis of their
drug free urines, a far from adequate source of evidence for or
against cannabis use. Thus, the small sample size and faulty
methodology preclude any conclusions to be drawn from this study about
possible alterations in monoamine levels in cannabis users.
7.5.3 Electrophysiological effects
Cannabis is clearly capable of causing marked changes in brain
electrophysiology as determined by electroencephalographic (EEG)
recordings. Long-term residual abnormalities in EEG tracings from
cortex and hippocampus have been shown in cats (Barratt & Adams, 1972;
Domino, 1981; Hockman et al, 1971), rats (see Fehr and Kalant, 1983)
and monkeys (Heath et al, 1980) exposed to cannabinoids. Withdrawal
effects are also apparent in the EEG (see Fehr and Kalant, 1983), with
epileptiform and spike-like activity most often seen.
Shannon and Fried (1972) related EEG changes in rat to the
distribution of bound and unbound radioactive THC. Disposition of the
tracer was primarily in the extra-pyramidal motor system and some
limbic structures, and 0.8 per cent of the total injected drug which
was weakly bound in the brain accounted for the EEG changes. In
monkeys, serious subcortical EEG anomalies were observed in those
exposed to marijuana smoke for six months (Heath et al, 1980). The
septal region, hippocampus and amygdala were most profoundly affected,
showing bursts of high amplitude spindles and slow wave activity. Such
early studies often lacked critical quantitative analysis. The
definition of abnormal spike-like waveforms in EEG were not made to
rigorous criteria,and EEG frequency was not assessed quantitatively.
More recent studies have examined the effects of THC on extracellular
action potentials recorded from the dentate gyrus of the rat
hippocampus (Campbell et al, 1986a; 1986b). THC produced a suppression
of cell firing patterns and a decrease in the amplitude of
sensory-evoked potentials, also impairing performance on a tone
discrimination task. The evoked-potential changes recovered rapidly
(within four hours), but the spontaneous and tone-evoked cellular
activity remained significantly depressed, indicating an abnormal
state of hippocampal/limbic system operation. The authors proposed
that such changes accounted for decreased learning, memory function
and general cognitive performance following exposure to cannabis. The
long-lasting effects of prolonged cannabis administration on animal
electrophysiology has not been investigated to any degree of
specificity.
The waking or sleep EEG is increasingly recognised as a particularly
sensitive tool for evaluating the effects of drugs, especially drugs
that affect the CNS, since EEG signals are sensitive to variables
affecting the brain's neurophysiological substrate. The recording of
the EEG is one of the few reasonably direct, non-intrusive methods of
monitoring CNS activity in man. However, alterations in EEG activity
are difficult to interpret in a functional sense. Struve and
Straumanis (1990) provide a review of the human research dating from
1945 on the EEG and evoked potential studies of acute and chronic
effects of cannabis use. While the data have often been contradictory,
the most typical human alterations in EEG patterns include an increase
in alpha activity and a slowing of alpha waves with decreased peak
frequency of the alpha rhythm, and a decrease in beta activity (Fink,
1976; Fink et al, 1976). In general, this is consistent with a state
of drowsiness. Desynchronisation, variable changes in theta activity,
abnormal sleep EEG profiles and abnormal evoked responses have also
been reported (see Fehr and Kalant, 1983). Clinical reports have
associated cannabis with triggering seizures in epileptics (Feeney,
1979) and experimental studies have shown THC to trigger abnormal
spike waveforms in the hippocampus, whereas cannabidiol has an
opposite effect. Yet there is suggestive evidence that cannabis may be
useful in the treatment of convulsions. Feeney (1979) discusses these
paradoxical effects.
A number of studies have investigated EEG in chronic cannabis users.
The early cross-cultural studies were flawed in many respects (see
Section 7.4 on cognitive functioning) and also failed to used
quantitative techniques in analysing EEG spectra. No EEG abnormalities
were found in the resting EEG of chronic users from Greek, Jamaican or
Costa Rican populations compared to controls (Karacan et al, 1976;
Rubin and Comitas, 1975; Stefanis, 1976). In all of these studies,
only subjects who were in good health and who were functioning
adequately in the community, were selected, thereby systematically
eliminating subjects who may have been adversely affected by cannabis
use and who may therefore have shown residual EEG changes. The
evidence from many studies has been contradictory: users have been
found to show either higher or lower percentages of alpha-components
than non-users, and to have higher or lower visual evoked response
amplitudes (Richmon et al, 1974). Subjects in a 94-day cannabis
administration study (Cohen, 1976) showed lasting EEG changes. The
abnormalities were more marked in subjects who had taken heavier
doses, but it was observed that even in abstinence, cannabis users had
more EEG irregularities than non-using controls. It was not determined
for how long after cessation of use the EEG changes persisted. It has
also been reported that chronic users develop tolerance to some of the
acute EEG changes caused by cannabis (Feinberg et al, 1976). The
question as to why chronic cannabis users can continue to display
changes in EEG when tolerance is known to develop to such alterations
remains unanswered.
In a series of well controlled ongoing studies, Struve and colleagues
(1991, 1993) have been using quantitative techniques to investigate
persistent EEG changes in long-term cannabis users, characterised by a
"hyperfrontality of alpha". Significant increases in absolute power,
relative power and interhemispheric coherence of EEG alpha activity
over the bilateral frontal-central cortex in daily THC users compared
to non-users were demonstrated and replicated several times. The
quantitative EEGs of subjects with excessively long cumulative THC
exposures (>15 years) appear to be characterised by increases in
frontal-central theta activity in addition to the hyperfrontality of
alpha found in THC users in general (or those with much shorter
durations of use). Ultra-long-term users have shown significant
elevations of theta absolute power over frontal-central cortex
compared to short-term users and controls, and significant elevations
in relative power of frontal-central theta in comparison to short-term
users. Over most cortical regions, ultra-long-term users had
significantly higher levels of theta interhemispheric coherence than
short-term users or controls. Thus, excessively long duration of THC
exposure (15-30 years) appears to be associated with additional
topographic quantitative EEG features not seen with subjects using THC
for short to moderately long time periods.
These findings have led to the suspicion that there may be a gradient
of quantitative EEG change associated with progressive increases in
the total cumulative exposure (duration in years) of daily THC use.
Infrequent, sporadic or occasional THC use does not seem to be
associated with persistent quantitative EEG change. As daily THC use
begins and continues, the topographic quantitative EEG becomes
characterised by the hyperfrontality of alpha. While it is not known
at what point during cumulative exposure it occurs, at some stage
substantial durations of daily THC use become associated with a
downward shift in maximal EEG spectral power from the mid alpha range
to the upper theta/low alpha range. Excessively long duration
cumulative exposure of 15-30 years may be associated with increases of
absolute power, relative power and coherence of theta activity over
frontal-central cortex. One conjecture is that the EEG shift toward
theta frequencies, if confirmed, may suggest organic change. These
data are supplemented by neuropsychological test performance features
separating long-term users from moderate users and non-users, however
the relationship between neuropsychological test performance and EEG
changes has not been investigated.
While the EEG provides little interpretable information about brain
function, brain event-related potential measures are direct
electrophysiological markers of cognitive processes. Studies by
Herning et al (1979) demonstrated that THC administered orally to
volunteers alters event-related potentials according to dose, duration
of administration, and complexity of the task. Event-related potential
studies of chronic cannabis users in the unintoxicated state have
provided evidence for long-lasting functional brain impairment and
subtle cognitive deficits (see Section 7.4 on cognitive functioning).
7.5.4 Cerebral blood flow studies
Brain cerebral blood flow (CBF) is closely related to brain function.
The use of CBF may help to identify brain regions responsible for the
behavioural changes associated with drug intoxication. Since, however,
psychoactive drugs may induce CBF changes through mechanisms other
than alteration in brain function (e.g. by increasing carbon monoxide
levels, changing blood gases or vasoactive properties, affecting blood
viscosity, autonomic activation or inhibition of intraparenchymal
innervation, acting on vasoactive neuropeptides), any conclusions
drawn from drug-induced CBF changes must be treated with caution.
Mathew and Wilson (1992) report several studies of cannabis effects on
cerebral blood flow. Acutely, cannabis administration to inexperienced
users produced global CBF decreases, while acute intoxication
increased CBF in both hemispheres, at frontal and the left temporal
regions, in experienced users. There was an inverse relationship
between anxiety and CBF. The authors attributed the decrease in CBF in
naive subjects to their increased anxiety after cannabis
administration, while the increased CBF in experienced users was
attributed to the behavioural effects of cannabis. A further study
showed that the largest increases in CBF occurred 30 minutes after
smoking. The authors concluded that cannabis causes a dose related
increase in global CBF, but also appears to have regional effects,
with a greater increase in the frontal region and in particular in the
right hemisphere. CBF increases were correlated with the "high",
plasma THC levels and pulse rate, loss of time sense,
depersonalisation, anxiety and somatisation scores (positively with
frontal flow and inversely with parietal flow).
The authors claimed their results suggested that altered brain
function was mainly, if not exclusively, responsible for the CBF
changes. Carbon monoxide increased after both cannabis and placebo but
did not correlate with CBF. Cannabis induced "red eye" lasted for
several hours, but the CBF increases declined significantly within two
hours of smoking. Nevertheless, the possibility remains that the CBF
changes reflected drug-induced vascular (cerebral) change. Continued
reduction in cerebral blood velocity was demonstrated following
cannabis administration, and reports of dizziness but with normal
blood pressure suggested that cannabis may impair cerebral
autoregulation.
The time course of CBF changes resembled that of mood changes more
closely than plasma THC levels. Global CBF was closely related to
levels of arousal mediated by the reticular activating system. High
arousal states generally show CBF increases while low arousal states
show CBF decreases. Of all cortical regions, the frontal lobe has the
most intimate connections with the thalamus which mediates arousal,
and CBF increases after cannabis use were most pronounced in frontal
lobe regions. The right hemisphere is known to mediate emotions, and
the most marked changes after cannabis were seen there. Time sense and
depersonalisation, which are associated with the temporal lobe, were
severely affected, but there were no significant correlations between
these scores and temporal flow. Perhaps CBF techniques are not
sensitive enough in terms of spatial resolution to detect such
effects. The parietal lobes are associated with perception and
cognition. Cannabis reduces perceptual acuity, but during intoxication
subjects report increased awareness of tactile, visual and auditory
stimuli. Maybe their altered time sense and depersonalisation are
related to such altered awareness.
There have been a few investigations of chronic effects of cannabis on
CBF. Tunving et al, (1986) demonstrated globally reduced resting
levels of CBF in chronic heavy users of 10 years compared to non-user
controls, but no regional flow differences were observed. CBF
increased by 12 per cent between nine and 60 days later, indicating
reduced CBF in heavy users immediately after cessation of cannabis
use, with a return to normal levels with abstinence. This study was
flawed in that some subjects were given benzodiazepines (which are
known to lower CBF) prior to the first measurement. Mathew and
colleagues (1986) assessed chronic users of at least six months (mean
83 months) after two weeks of abstinence. No differences in CBF levels
were found between users and non-user controls. The number of studies
available on the effects of cannabis on CBF are relatively small. Use
of techniques with better spatial resolution and the ability to
quantify subcortical flow, such as positron emission tomography (PET),
would yield more useful findings.
7.5.5 Positron emission tomography (PET) studies
Positron emission tomography (PET) is a nuclear imaging technique
which allows the concentration of a positron-labelled tracer to be
imaged in the human brain. PET can measure the time course and
regional distribution of positron-labelled compounds in the living
human brain. Most PET studies have utilised an analog of glucose to
measure regional brain glucose metabolism, since nervous tissue uses
glucose as its main source of energy. Measurement of glucose
metabolism reflects brain function, since activation of a given brain
area is indicated by an increase in glucose consumption. PET may be
used to assess the effects of acute drug administration by using
regional brain glucose metabolism to determine the areas of the brain
which are activated by a given drug. Assessment of brain glucose
metabolism has been useful in identifying patterns of brain
dysfunction in patients with psychiatric and neurological diseases. It
is a direct and sensitive technique for identifying brain pathology,
since it can detect abnormalities in the functioning of brain regions
in the absence of structural changes, such as is likely to occur with
the neurotoxic effects of chronic drug use. It is accordingly more
sensitive than either computer-assisted tomography (CAT) scans or
magnetic resonance imaging (MRI) in detecting early pathological
changes in the brain.
Only one study to date has used the PET technique to investigate the
effects of cannabis use. Volkow et al (1991) reported preliminary data
from an investigation comparing the acute effects of cannabis in three
normal subjects (who had used cannabis no more than once or twice per
year) and in three chronic users (who had used at least twice a week
for at least 10 years). The regions of interest were the prefrontal
cortex, the left and right dorsolateral, temporal, and somatosensory
parietal cortices, the occipital cortex, basal ganglia, thalamus and
cerebellum. A measure of global brain metabolism was obtained using
the average for the five central brain slices, and relative measures
for each region were obtained using the ratios of region/global brain
metabolism. Due to the small number of subjects, descriptive rather
than inferential statistical procedures were used for comparison. The
relation between changes in metabolism due to cannabis and the
subjective sense of intoxication was tested with a regression
analysis.
In the normal subjects, administration of cannabis led to an increase
in metabolic activity in the prefrontal cortex and cerebellum; the
largest relative increase was in the cerebellum and the largest
relative decrease was in the occipital cortex. The degree of increase
in metabolism in the cerebellar cortex was highly correlated with the
subjective sense of intoxication. The cannabis users reported less
subjective effects than the normal controls and showed less changes in
regional brain metabolism, reflecting tolerance to the actions of
cannabis. However, the authors did not report comparisons of baseline
levels of activity in the users and controls, perhaps due to the
limitations of the small sample size. Such a comparison would have
enabled some evaluation of the consequences of long-term cannabis use
on resting levels of glucose metabolism. The increases in regional
metabolism are in accord with the increases in cerebral blood flow
reported by Mathew and Wilson (1992). The regional pattern of response
to cannabis in this study is consistent with the localisation of
cannabinoid receptors in brain. A further application of PET would be
to label cannabinoids themselves: labelling of cannabis with a
positron emitter has been achieved and preliminary biodistribution
studies have been carried out in mice and in the baboon (Charalambous
et al, 1991; Marciniak et al, 1991). The use of PET in future human
studies is promising.
7.5.6 Brain morphology
7.5.6.1 Animal studies
Early attempts to investigate the effects of chronic cannabinoid
exposure on brain morphology in animals failed to demonstrate any
effect on brain weight or histology under the light microscope.
Electron microscopic examination, however, has revealed alterations in
septal, hippocampal and amygdaloid morphology in monkeys after chronic
treatment with THC or cannabis. A series of studies from the same
laboratory (Harper et al, 1977; Myers and Heath, 1979; Heath et al,
1980 discussed below) reported widening of the synaptic cleft,
clumping of synaptic vesicles in axon terminals, and an increase in
intranuclear inclusions in the septum, hippocampus and amygdala. These
findings incited a great deal of controversy, and the studies were
criticised for possible technical flaws (Institute of Medicine, 1982),
with claims that such alterations are not easily quantifiable.
Harper et al (1977) examined the brains of three rhesus monkeys six
months after exposure to marijuana, THC or placebo, and two
non-exposed control monkeys. In the treated group, one monkey was
exposed to marijuana smoke three times each day, five days per week;
another was injected with THC once each day and the third was exposed
to placebo smoke conditions. The latter two had electrode implants for
EEG recording and had shown persistent EEG abnormalities following
their exposure to cannabis. Morphological differences were not
observed by light microscopy, but electron microscopy revealed a
widening of the synaptic cleft in the marijuana and THC treated
animals, with no abnormalities detected in the placebo or control
monkeys. Further, "clumping" of synaptic vesicles was observed in pre-
and post-synaptic regions in the cannabinoid treated monkeys, and
opaque granular material was present within the synaptic cleft. The
authors concluded that chronic heavy use of cannabis alters the
ultrastructure of the synapse, and proposed that the observed EEG
abnormalities may have been related to these changes.
Myers and Heath (1979) examined the septal region of the same two
cannabinoid treated monkeys, and found the volume density of the
organised rough endoplasmic reticulum to be significantly lower than
that of the controls, and fragmentation and disorganisation of the
rough endoplasmic reticulum patterns, free ribosomal clusters in the
cytoplasm, and swelling of the cisternal membranes was observed. The
authors noted that similar lesions have been observed following
administration of various toxins or after axonal damage, reflecting
disruptions in protein synthesis.
Heath et al (1980) extended the above findings by examining a larger
sample of rhesus monkeys (N=21) to determine the effects of marijuana
on brain function and ultrastructure. Some animals were exposed to
smoke of active marijuana, some were injected with THC and some were
exposed to inactive marijuana smoke. After two to three months of
exposure, those monkeys that were given moderate or heavy exposure to
marijuana smoke developed chronic EEG changes at deep brain sites,
which were most marked in the septal, hippocampal and amygdaloid
regions. These changes persisted throughout the six to eight month
exposure period, as well as the postexposure observation period of
between one and eight months. Brain ultrastructural alterations were
characterised by changes at the synapse, destruction of rough
endoplasmic reticulum and development of nuclear inclusion bodies. The
brains of the placebo and control monkeys showed no ultrastructural
changes. The authors claimed that at the doses used, which were
comparable to human usage, permanent alterations in brain function and
ultrastructure were observed in these monkeys.
Brain atrophy is a major non-specific organic alteration which must be
preceded by more subtle cellular and molecular changes. Rumbaugh et al
(1980) observed six human cases of cerebral atrophy in young male
substance abusers of primarily alcohol and amphetamines. They then
conducted an experimental study of six rhesus monkeys treated
chronically with various doses of cannabis extracts orally for eight
months and compared them to groups that were treated with barbiturates
or amphetamines, or untreated. No signs of cerebral atrophy were
demonstrated in the cannabis exposed group, and light microscopy
revealed no histological abnormalities in four of the animals, but
"equivocal" results for the other two. Brains were not examined under
the electron microscope. The amphetamine treated group showed the
greatest histological, cerebrovascular and atrophic changes.
More recently, McGahan et al (1984) used high resolution computerised
tomography scans in three groups of four rhesus monkeys. One was a
control group, a second was given 2.4mg/kg of oral THC per day for two
to 10 months, and a third group received a similar daily dose over a
five-year period. The dosage was considered the equivalent of smoking
one joint a day. The groups receiving THC were studied one year after
discontinuing the drug. There was a statistically significant
enlargement of the frontal horns and the bicaudate distance in the
brains of the five-year treated monkeys as compared to the control and
short-term THC groups. This finding suggests that the head of the
caudate nucleus and the frontal areas of the brain can atrophy after
long-term administration of THC in doses relevant to human exposure.
A number of rat studies have found similar results to those in rhesus
monkeys described above. Investigators have reported that after high
dose cannabinoid administration, there is a decrease in the mean
volume of rat hippocampal neurons and their nuclei, and that after low
dose administration, there is a shortening of hippocampal dendritic
spines. Scallet and coworkers (1987) used quantitative
neuropathological techniques to examine the brains of rats seven to
eight months after 90-day oral administration of THC. The anatomical
integrity of the CA3 area of rat hippocampus was examined using light
and electron microscopy. High doses of THC resulted in striking
ultrastructural alterations, with a significant reduction in
hippocampal neuronal and cytoplasmic volume, detached axodendritic
elements, disrupted membranes, increased extracellular space and a
reduction in the number of synapses per unit volume (i.e. decreased
synaptic density). These structural changes were present up to seven
months following treatment. Lower doses of THC produced a reduction in
the dendritic length of hippocampal pyramidal neurons two months after
the last dose, and a reduction in GABA receptor binding in the
hippocampus, although the ultrastructural appearance and synaptic
density appeared normal. The authors suggested that such hippocampal
changes may constitute a morphological basis for the persistent
behavioural effects demonstrated following chronic exposure to THC in
rats, effects which resemble those of hippocampal brain lesions. These
findings are in accord with those of Heath et al (1980) with rhesus
monkeys, and the doses administered correspond to daily use of
approximately six joints in humans.
A study by Landfield et al (1988) showed that chronic exposure to THC
reduced the number of nucleoli per unit length of the CA1 pyramidal
cell somal layer in the rat hippocampus. The brains of rats treated
five times per week for four or eight months with 4-10mg/kg injected
subcutaneously were examined by light and electron microscopy.
Significant THC-induced changes were found in hippocampal structure;
pyramidal neuronal cell density decreased and there was an increase in
glial reactivity, reflected by cytoplasmic inclusions similar to that
seen during normal aging or following experimentally induced brain
lesions. However, no effects were observed on ultrastructural
variables such as synaptic density. Adrenal-pituitary activity
increased, resulting in elevated ACTH and corticosterone elevations
during acute stress. The authors claimed that the observed hippocampal
morphometric changes produced by THC exposure were similar to
glucocorticoid-dependent changes that develop in rat hippocampus
during normal aging. They proposed that, given the chemical structural
similarity between cannabinoids and steroids, chronic exposure to THC
may alter hippocampal anatomical structure by interacting with adrenal
steroid activity. More recently, Eldridge et al (1992) reported that
delta-8-THC bound with the glucocorticoid receptors in the rat
hippocampus, and was displaced by corticosterone or delta-9-THC. A
glucocorticoid agonist action of delta-9-THC injections was
demonstrated. Injection of corticosterone increased hippocampal
cannabinoid receptor binding. These interactions suggest that
cannabinoids may accelerate brain aging.
It should be noted that where THC has been administered to monkeys for
six months, this represents only 2 per cent of their life span and may
not have been long enough to detect the gradual effects that could
arise from interactions with steroid systems (and affect the aging
process). In contrast, eight months administration to rats represents
approximately 30 per cent of their life span. The differences in the
ultrastructural findings of Landfield's and Scallet's studies may be
due to the largely different doses administered; the 8mg/kg of
Landfield's study was not sufficient to produce any marked behavioural
effects. Further, the two studies examined slightly different
hippocampal areas (CA1 or CA3).
Most recently, Slikker and colleagues (1992) reported the results of
their neurohistochemical and electronmicroscopic evaluation of the
rhesus monkeys whose dosing regime, behavioural and histochemical data
were reported above. They failed to replicate earlier findings: no
effects of drug exposure were found on the total area of hippocampus,
or any of its subfields; there were no differences in hippocampal
volume, neuronal size, number, length or degree of branching of CA3
pyramidal cell dendrites. Nor were there effects on synaptic length or
width, but there were trends toward increased synaptic density (the
number of synapses per cubic mm), increased soma size, and decreased
basilar dendrite number in the CA3 region with marijuana treatment.
Slikker et al (1992) were able to demonstrate an effect of enriched
environments upon neuroanatomy: daily performance of operant tasks
increased the total area of hippocampus and particularly the CA3
stratum oriens, producing longer, more highly branched dendrites and
less synaptic density, while the reverse occurred in the animals
deprived of the daily operant tasks. The extent of drug interaction
with these changes was not clear and may explain some of the
inconsistencies between this study and those described above. Clearly,
the question of whether prolonged exposure to cannabis results in
structural brain damage has not been fully resolved.
The development of tolerance following chronic administration of
psychoactive compounds is often mediated by a down-regulation of
receptors. Thus, chronic exposure to THC could result in a decreased
number of cannabinoid receptors in the brain. Such receptor
down-regulation and reduced binding has recently been demonstrated in
rats (Oviedo, Glowa and Herkenham, 1993). However, previously Westlake
et al (1991) found that cannabinoid receptor properties were not
irreversibly altered in rat brain 60 days following 90-day
administration of THC, nor in monkey brain seven months after one year
of exposure to marijuana smoke. It was argued that these recovery
periods were sufficient to allow the full recovery of any receptors
that would have been lost during treatment. Nevertheless, studies have
not yet confirmed the parameters of any alterations in cannabinoid
receptor number and function that may result from chronic exposure to
cannabinoids, and the extent of reversibility following longer
exposures has not been determined.
7.5.6.2 Human studies
There is very little evidence from human studies of structural brain
damage. In their controversial paper, Campbell et al (1971) were the
first to present evidence suggesting that structural/morphological
brain damage was associated with cannabis use. They used air
encephalography to measure cerebral ventricular size, and claimed to
have demonstrated evidence of cerebral atrophy in ten young males who
had used cannabis for three to 11 years, and who complained of
neurological symptoms, including headaches, memory dysfunction and
other cognitive impairment. Compared to controls, the cannabis users
showed significantly enlarged lateral and third ventricular areas.
Although this study was widely publicised in the media because of its
serious implications, it was heavily criticised on methodological
grounds. Most subjects had also used significant quantities of LSD and
amphetamines, and the measurement technique was claimed to be
inaccurate, particularly since there were great difficulties in
assessing ventricular size and volume to any degree of accuracy (e.g.
Bull, 1971; Susser, 1972; Brewer, 1972). Moreover, the findings could
not be replicated. Stefanis (1976) reported that echoencephalographic
measurements of the third ventricle in 14 chronic hashish users and 21
non-users did not support Campbell et al's pneumoencephalographic
findings of ventricular dilation.
The introduction of more accurate and non-invasive techniques, in the
form of computerised tomographic (CT) scans, (also known as
computer-assisted tomographic (CAT) scans), permitted better studies
of possible cerebral atrophy in chronic cannabis users (Co et al,
1977; Kuehnle et al, 1977). Co et al (1977), for example, compared 12
cannabis users recruited from the general community, with 34 non-drug
using controls, all within the ages of 20-30. The cannabis users had
used cannabis for at least five years at the level of at least five
joints per day, and most had also consumed significant quantities of a
variety of other drugs, particularly LSD. Kuehnle et al's (1977)
subjects were 19 heavy users aged 21-27 years, also recruited from the
general community who had used on average between 25 and 62 joints per
month in the preceding year, although their duration of use was not
reported. CT scans were obtained presumably at the end of a 31-day
study, which included 21 days of ad libitum smoking of marijuana
(generally five joints per day), and were compared against a separate
normative sample. No evidence for cerebral atrophy in terms of
ventricular size and subarachnoid space was found in either study.
Although these studies could also be criticised for their research
design (e.g. inappropriate control groups, and the fact that cannabis
users had used other drugs), these flaws would only have biased the
studies in the direction of detecting significant differences between
groups, yet none were found. The results were interpreted as a
refutation of Campbell's findings, and supporting the absence of
cortical atrophy demonstrated by Rumbaugh et al's (1980) CAT scans of
monkeys. A further study (Hannerz and Hindmarsh, 1983) investigated 12
subjects who had smoked on average 1g of cannabis daily for between
six and 20 years, by thorough clinical neurological examination and CT
scans. As in the studies above, no cannabis related abnormalities were
found on any assessment measure.
7.5.7 Discussion
Surprisingly few studies of neurotoxicity have been published, and the
results have been equivocal. There is convincing evidence that chronic
administration of large doses of THC leads to residual changes in
rodent behaviours which are believed to depend upon hippocampal
function. There is evidence for long-term changes in hippocampal
ultrastructure and morphology in rodents and monkeys. Animal
neurobehavioural toxicity is characterised by residual impairment in
learning, EEG and biochemical alterations, impaired motivation and
impaired ability to exhibit appropriate adaptive behaviour. Although
extrapolation to man is not possible, the results of these
experimental studies have demonstrated cannabinoid toxicity at doses
comparable to those consumed by humans using cannabis several times a
day. There is sufficient evidence from human research to suggest that
the cannabinoids act on the hippocampal region, producing behavioural
changes similar to those caused by traumatic injury to that region.
The cognitive, behavioural and functional responses to long-term
cannabis consumption in animals and man appear to be the most
consistent manifestation of its potential neurotoxicity. The extent of
damage appears to be more pronounced at two critical stages of central
nervous system development: in neonates when exposed to cannabis
during intrauterine life; and in adolescence, during puberty when
neuroendocrine, cognitive and affective functions and structures of
the brain are in the process of integration. As discussed in Section
7.4 on cognitive functioning, research needs to investigate the
possibility that more severe consequences may occur in adolescents
exposed to cannabinoids. Human research has defined a pattern of acute
CNS changes following cannabis administration; there is convincing
evidence for long-lasting changes in brain function after long-term
heavy use; whether or not these changes are permanent has not been
established.
Human studies of brain morphology have yielded generally negative
results, failing to find gross signs of "brain damage" after chronic
exposure to cannabis. Nevertheless, the results of many human studies
are indicative of more subtle brain dysfunction. It may be that
existing methods of brain imaging are not sensitive enough to
establish subcellular alterations produced in the CNS. Many
psychoactive substances exert their action through molecular
biochemical mechanisms which do not distort gross cell architecture.
The most convincing evidence on brain damage would come from
postmortem studies, but this type of information has not been
available.
In 1983, Fehr and Kalant concluded that "The state of the evidence at
the present time does not permit one either to conclude that cannabis
produces structural brain damage or to rule it out" (p602). Nahas
(1984) wrote "The brain is the organ of the mind. Can one repetitively
disturb the mental function without impairing brain mechanisms? The
brain, like all other organs of the human body, has very large
functional reserves which allow it to resist and adapt to stressful
abnormal demands. It seems that chronic use of cannabis derivatives
slowly erodes these reserves" (p299). In 1986, Wert and Raulin (1986)
proposed, that on the available evidence "there are no gross
structural or neurological deficits in marijuana-using subjects,
although subtle neurological features may be present. However, the
type of deficit most likely to occur would be a subtle, functional
deficit which could be assessed more easily with either psychological
or neuropsychological assessment techniques." (p624). In 1993, little
further evidence has emerged to challenge or refute these earlier
conclusions.
This conclusion was anticipated by the Parisian physician Moreau as
early as 1845 when he observed:
...unquestionably there are modifications (I do not dare use the word
"lesion") in the organ which is in charge of mental functions. But
these modifications are not those one would generally expect. They
will always escape the investigations of the researchers seeking
alleged or imagined structural changes. One must not look for
particular, abnormal changes in either the gross anatomical or the
fine histological structure of the brain; but one must look for any
alterations of its sensibility, that is to say, for an irregular,
enhanced, diminished or distorted activity of the specific mechanisms
upon which depends the performance of mental functions. (Moreau (de
Tours), 1845).
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7.6 Does cannabis use cause psychotic disorders?
There is a prima facie case for believing that cannabis use may in
certain circumstances be a contributory cause of major psychological
disorders such as psychotic disorders, i.e. illnesses in which
symptoms of hallucinations, delusions and impaired reality testing are
predominant features. First, THC is a psychoactive substance which
produces some of the symptoms found in psychotic disorders, namely,
euphoria, distorted time perception, cognitive and memory impairments
(Brill and Nahas, 1984; Halikas et al, 1971; Thornicroft, 1990).
Second, under controlled laboratory conditions with normal volunteers,
THC has been shown at high doses to produce psychotic symptoms which
include visual and auditory hallucinations, delusional ideas, thought
disorder, and symptoms of hypomania (Georgotas and Zeidenberg, 1979;
National Academy of Science, 1982). Third, a putative "cannabis
psychosis" has been identified by clinical observers in regions of the
world with a long history of chronic, heavy cannabis use, e.g. India,
Egypt, and the Carribean (Brill and Nahas, 1984; Ghodse, 1986).
7.6.1 The nature of the relationship
How might cannabis use causally contribute to the development of
psychosis? The following are the major mechanisms that have been
suggested by proponents of a relationship between cannabis use and
severe psychological disorder (Thornicroft, 1990).
7.6.1.1 Is there a 'cannabis psychosis'?
The first possibility is that acute or chronic cannabis use may
produce a "cannabis psychosis". Four possible variants of this
hypothesis can be distinguished. The first hypothesis is that the
acute use of large doses of cannabis may induce a "toxic" or organic
psychosis with prominent symptoms of confusion and hallucination,
which remit with abstinence from cannabis. The second hypothesis is
that cannabis use may produce an acute functional psychosis, similar
in its clinical presentation to paranoid schizophrenia, and lacking
the organic features of a toxic psychosis which remits after
abstinence from cannabis. A third hypothesis is that chronic cannabis
use may produce a chronic psychosis, i.e. a psychotic disorder which
persists beyond the period of intoxication. The fourth hypothesis (a
variant of the third) is that chronic cannabis use may induce an
organic psychosis which only partially remits with abstinence, leaving
in its train a residual deficit state with symptoms that are analogous
to the negative symptoms of schizophrenia, or a mild chronic brain
syndrome. This has also been described as "an amotivational syndrome"
which is characterised by withdrawal, lack of interest in others,
impaired performance and lack of motivation to perform one's social
responsibilities.
7.6.1.2 Does cannabis use precipitate a latent psychosis?
Cannabis use could conceivably precipitate a latent psychosis, i.e.
bring forward an episode of schizophrenia or manic depressive
psychosis in a vulnerable or predisposed individual. This could occur
either as a result of a specific pharmacological effect of THC (or
other constituents of cannabis preparations), or as the result of
stressful experiences while intoxicated, such as a panic attack or a
paranoid reaction to the acute effects of cannabis (Edwards, 1976).
Schizophrenia is the disorder about which concern has been most often
expressed in the case of cannabis use.
A related hypothesis would be that cannabis use exacerbates the
symptoms of a functional psychosis such as schizophrenia or manic
depressive psychosis. This could occur if cannabis use precipitated a
relapse in the same way that it has been hypothesised to precipitate
the onset of a latent psychosis. Alternatively, the pharmacological
effects of cannabis might impair the effectiveness of the neuroleptic
drugs used to treat major psychoses.
7.6.2 Methodological issues
Until recently, our ability to test these hypotheses has been hampered
by a lack of sophistication in research design (Mueser et al, 1990;
Thornicroft, 1990; Turner and Tsuang, 1990). First, the possible
mechanisms for a causal relationship between cannabis use and
psychosis have not always been clearly distinguished, and so have not
often informed the design of research studies purporting to test them.
Second, studies of the relationships between cannabis use and
psychological disorder have often been uncontrolled. Only rarely have
they compared cannabis use in psychotic patients and controls, or
compared the clinical characteristics and course of psychotic patients
who have and have not used cannabis. Third, the extent of cannabis and
other drug use, and its relationship to the onset of psychotic
symptoms, has often been poorly documented. There has been a heavy
reliance upon self-reported use, and few attempts have been made to
distinguish between use, abuse and dependence (Mueser et al, 1990).
Fourth, the diagnosis of a psychotic disorder, or of psychotic
symptoms, has only rarely used standardised diagnostic criteria such
DSM-III-R or ICD-9. Fifth, many studies have used small samples,
reducing the chances of detecting any association between cannabis use
and psychotic disorder. As a consequence of these deficiencies, many
studies have failed to provide convincing evidence of even an
association between cannabis use and psychotic symptoms or psychotic
syndromes.
Even when an association between cannabis use and psychosis has been
demonstrated, it has proved difficult to distinguish between
alternative explanations of it. There has been a readiness to assume
that the data supports the hypothesis that cannabis use is a
contributory cause of psychosis (whether that is a specific "cannabis
psychosis" or a functional psychosis such as schizophrenia). Only
recently have other hypotheses been acknowledged, and attempts made to
test them (e.g. Dixon et al, 1990, 1991; Turner and Tsuang, 1990).
There are a number of ways in which cannabis use could be associated
with psychotic disorders without being a contributory cause of such
disorders. One possibility is that the psychosis is a contributory
cause of cannabis use, and that cannabis is used to self-medicate
depression, anxiety, negative psychotic symptoms, or the side effects
of neuroleptic drugs. Another possibility is that drug use among
schizophrenic individuals is a consequence of pre-existing personality
characteristics which predispose them to use illicit drugs and to
develop schizophrenia. A third possibility is that heavy cannabis use
may be a marker of the use of amphetamine and cocaine for which there
is strong evidence for causing acute paranoid psychoses (Angrist,
1983; Bell, 1973; Connell, 1959).
In the review that follows, the best available clinical and
epidemiological studies bearing on these issues is reviewed. Although
we have preferred to cite controlled studies, we have not excluded all
the early uncontrolled studies which have been most often cited.
Attempts will also be made to distinguish the very different
non-causal explanations of the apparent association between cannabis
use and psychosis.
7.6.3 'Cannabis psychoses'
7.6.3.1 Toxic psychosis
Much of the literature on cannabis psychoses consists of case studies
(e.g. Carney, Bacelle and Robinson, 1984; Drummond, 1986; Edwards,
1983; Weil, 1970), case series (e.g. Bernardson and Gunne, 1972; Cohen
and Johnson, 1988; Kolansky and Moore, 1971; Onyango, 1986) and
reviews of such reports (e.g. Tunving, 1985) which often suffer from a
circularity in their argument (Thornicroft, 1990). Typically a group
of patients have been identified as having a toxic "cannabis
psychosis" (with little information given on how they came to be so
identified) and their behaviour and clinical history are then
presented as evidence for the existence of the diagnostic entity they
were meant to be testing. The better examples of these reports have
attempted to justify their inclusion of cases within this diagnosis,
and have attempted to assess the contribution of predisposition and
drug use to the development of the psychosis.
Chopra and Smith (1974) have presented one of the largest case series
of a toxic "cannabis psychosis". They described the characteristics of
200 East Indian patients who were admitted to a psychiatric hospital
in Calcutta between 1963 and 1968 with "psychotic symptoms following
the use of cannabis preparations" (p24). Their cases resembled cases
of acute organic brain disorder in that their major symptoms included
confusion and amnesia. The most common symptoms "were sudden onset of
confusion, generally associated with delusions, hallucinations
(usually visual) and emotional lability ... amnesia, disorientation,
depersonalisation and paranoid symptoms" (p24). Most psychoses were
preceded by the ingestion of a large dose of cannabis which produced
intoxication and amnesia for the period between ingestion and
hospitalisation.
Patients were classified into three groups on the basis of their
history of previous psychiatric disorder. The first consisted of a
third of patients who had no previous personality problems or
psychiatric disorder, whose only constant feature was "recent use of
cannabis preparations as the apparent precipitant of the psychotic
episode" (p25). They exhibited symptoms of excitement, confusion,
disorientation, delusions, visual hallucinations, depersonalisation,
emotional instability and delirium. These symptoms were usually of
short duration, varying between a few hours and several days, and all
these patients returned to their normal state after remission.
The second group consisted of 61 per cent of patients who did not have
a prior history of psychosis but had a history of schizoid,
sociopathic, and unstable personalities. Their clinical picture was
much like that of the first group, and they also had a high
probability of remission within a few days of admission. The third
group consisted of 10 patients with a prior history of psychosis (most
often schizophrenia) who rarely experienced a short remission and
usually required continued hospitalisation and treatment.
Chopra and Smith argued that their case series provided evidence for
the existence of the clinical entity of "cannabis psychosis". Although
they conceded that excessive drug use could be a sign of pre-existing
psychopathology, they argued that this was an unlikely explanation of
their findings, because at least a third of their cases had no prior
psychiatric history, the symptoms reported were remarkably uniform
regardless of prior psychiatric history, and there was evidence of a
dose-time relationship in that those who used the most potent cannabis
preparations experienced psychotic reactions after the shortest period
of use.
The findings of Chopra and Smith have received some support from case
series published in other countries (e.g. Bernardson and Gunne, 1972;
Onyango, 1986; Tennant and Groesbeck, 1972). Bernardson and Gunne
(1972) reported on 46 cases of putative cannabis psychosis admitted to
Swedish psychiatric hospitals between 1966 and 1970. These were
primary cannabis users who had no history of psychosis prior to their
cannabis use, and who presented with a clinical picture of paranoid
delusions, motor restlessness, auditory and visual hallucinations,
hypomania, aggression, anxiety and clouded consciousness. Their
symptoms usually remitted within five weeks of admission, and those
who returned to cannabis use after discharge were most likely to
relapse.
Tennant and Groesbeck (1972) report on psychoses they had treated
among US servicemen stationed in Germany between 1968 and 1971. During
this period, potent hashish was cheap and readily available and widely
used, with 46 per cent of servicemen reporting that they had used
hashish, and 16 per cent reporting using it three or more times per
week. They reported 18 cases of a short-term panic reaction or toxic
psychosis developing after a single high dose of hashish, and 85 cases
of toxic psychoses developing after the simultaneous consumption of
cannabis and other drugs. The toxic psychoses usually resolved within
three days on neuroleptic medication.
Onyango (1986) reported one of the few case series which used
biochemical measures of recent cannabis use to identify possible cases
of toxic cannabis psychosis among young adults who presented to a
London psychiatric hospital with psychotic symptoms. He screened the
urines of 25 such admissions and found that, although half reported
having used cannabis at some time, only four had cannabinoid
metabolites in their urines at the time of presentation. In three
cases the patients had a prior history of psychosis, their
phenomenology was unremarkable, and they did not respond rapidly to
treatment. Only one case seemed to fit the picture of a cannabis
psychosis. He had no prior history of psychosis, and a history of
chronic, heavy cannabis use prior to admission. He presented with
hallucinations, delusions, and labile, elated mood which responded
rapidly to haloperidol, and he had no further episodes during a
two-year follow-up.
All considered, there is a reasonable case for believing that large
doses of potent cannabis products can produce a toxic psychotic
illness in persons who do not have a personal history of psychotic
illness (Edwards, 1976; Negrete, 1983; Thomas, 1993). Such psychoses
are characterised by symptoms of confusion and amnesia, paranoid
delusions, and auditory and visual hallucinations, and they have a
relatively benign course in that they typically remit within a week of
abstinence (Chaudry et al, 1991; Thomas, 1993). They seem most likely
to occur in populations which use high doses of THC, and probably
occur rarely otherwise (Smith, 1968). Given the poor standards of
research design and lack of adequate controls in all but a few of
these studies, and the failure to use standardised diagnostic
criteria, it would be premature to claim that the existence of a toxic
"cannabis psychosis" has been established beyond reasonable doubt.
7.6.3.2 An acute functional psychosis
Other investigators have argued that heavy cannabis use may produce an
acute functional psychosis. That is, it produces an illness which does
not reflect an organic state produced by drug intoxication, but rather
a psychotic illness that resembles schizophrenia. Thacore and Shukla
(1976), for example, reported a case control study comparing cases
with a putatively functional cannabis psychosis with controls
diagnosed as having paranoid schizophrenia. Their 25 cases of cannabis
psychosis had a paranoid psychosis resembling schizophrenia, in which
"a clear temporal relationship between the prolonged use of cannabis
[longer than five years in all but one case] and the development of
psychosis has been observed on more than two occasions" (p384). Their
25 age and sex-matched controls were individuals with paranoid
schizophrenia who had no history of cannabis use.
The comparison revealed that the patients with a cannabis psychosis
displayed more odd and bizarre behaviour, violence, panic affect, and
insight and less evidence of thought disorder. They also responded
swiftly to neuroleptic drugs and recovered completely. According to
Thacore and Shukla, this functional psychotic disorder could be
distinguished from the toxic "cannabis psychosis" reported by Chopra
and Smith (1974), because there was no evidence of confusion and
amnesia, and the major presenting symptoms were delusions of
persecution, and auditory and visual hallucinations occurring in a
state of clear consciousness.
Rottanburg et al (1982) provide one of the most convincing research
studies in favour of the hypothesis that cannabis can produce an acute
functional psychosis. They conducted a case-control study in which
psychotic patients with cannabinoids in their urines were compared
with psychotic patients who did not have cannabinoids in their urines.
Both groups were assessed shortly after admission, and seven days
later, by psychiatrists who used a standardised psychiatric interview
schedule (PSE) and who were blind as to presence or absence of
cannabinoids in the patients' urine.
Every third admission of a Cape coloured man during a period of a year
(n=117) were screened for cannabinoids, alcohol and other toxins.
Sixty per cent (N=70) had urines that were positive for cannabinoids,
and 36 cases had levels which suggested heavy cannabis use prior to
admission. Sixteen patients left hospital before the study was
completed, leaving a group of 20 cases with psychoses and cannabinoids
only in their urines. They were compared with 20 psychotic controls,
matched for age and clinical diagnosis, whose urines were negative for
cannabinoids and other drugs and toxins.
The results showed that psychotic patients with cannabinoids in their
urine had more symptoms of hypomania and agitation, and less auditory
hallucinations, flattening of affect, incoherent speech and hysteria
than controls. They also showed strong improvements in symptoms by the
end of a week, as against no change in the controls despite receiving
comparable amounts of anti-psychotic drugs. They concluded that "heavy
cannabis intake is associated with a rapidly resolving psychotic
illness characterised by marked hypomanic features" (p1366).
Imade and Ebie (1991) conducted a retrospective comparison of the
symptoms reported by 70 patients with putatively cannabis-induced
psychosis, 163 patients with schizophrenia, and 39 patients with
mania. No details were provided on how these diagnoses were made, and
the ratings of symptoms were made retrospectively from case records by
psychiatrists who were not blind as to the patients' diagnoses. A
large number of statistical comparisons produced a number of
statistically significant differences in individual symptoms between
the three patient groups, although they did not differ in symptoms of
violence, panic and bizarre behaviour. Imade and Ebie argued that
there were no symptoms that were unique to cannabis psychosis, and
that there was no consistency of clinical picture that enabled them to
distinguish a "cannabis psychosis" from schizophrenia. This negative
study is unconvincing. The symptom ratings were made retrospectively
from clinical records of unknown quality, and the patients' diagnoses
were not made using standardised diagnostic criteria. There was no
information on how "cannabis psychosis" was diagnosed, or on the
clinical course of the psychoses. The authors also failed to use
appropriate statistical methods to test the claim that cannabis
psychosis can be distinguished from schizophrenia.
A number of cohort studies have been conducted on the prevalence of
psychotic symptoms in chronic cannabis users and controls. Beaubruhn
and Knight (1973) conducted a small study comparing the psychiatric
history and symptoms of 30 chronic daily Jamaican cannabis users (with
a history of at least seven years use) with that of 30 non-cannabis
using controls matched on social class, income, age and sex. Both
cases and controls were assessed by personal psychiatric interview and
personality questionnaires during a six day hospitalisation. There
were few statistically significant differences between the two groups,
only a higher rate of family history of psychiatric disorder and of
hallucinatory experiences in the cannabis users. Only one user and one
non-user reported a personal history of psychiatric disorder.
Similar results have been reported by Stefanis et al (1976) in a study
of 47 chronic cannabis users in Greece and 40 controls matched for
age, family origin, residence at birth and upbringing. They found a
higher incidence of personality disorders among their cannabis users,
but no statistically significant difference in the rates of
psychiatric disorder diagnosed by a personal interview with a
psychiatrist. Three cases of schizophrenia were diagnosed in the
cannabis using group, but a connection with cannabis use was
discounted on the ground that two of the three had a family history of
schizophrenia.
The small number of cases and the relative rarity of psychosis makes
these studies unconvincing. The authors interpreted their results far
too strongly, by inferring that a failure to find a difference in
rates of psychiatric disorder in sample sizes of 30 and 47 indicated
that there was no difference in prevalence between chronic cannabis
users and controls. In Beaubruhn and Knight's study (1973), for
example, the failure to detect a difference in the rate of psychosis
between 30 cannabis users and 30 controls does not rule out a 17 fold
higher rate of psychiatric disorder among cannabis users (as shown by
the upper limit of a 95 per cent confidence interval around the odds
ratio).
All considered, the case for believing that cannabis use can produce a
functional paranoid illness is much less compelling than that for a
toxic psychosis (Thomas, 1993; Thornicroft, 1990). The research
designs for studies of this diagnosis have more often included control
groups, but proponents of this hypothesis have not presented evidence
that satisfactorily distinguishes it from other functional psychoses
(Thornicroft, 1990).
If there is a toxic cannabis psychosis, then a strong case has not
been made for distinguishing it from the putatively functional
cannabis psychosis. Thacore and Shukla (1976) emphasised the history
of chronic heavy cannabis use among their cases of functional cannabis
psychoses, and the absence of the confusion and amnesia reported in
persons with the toxic psychosis.
The differentiation in terms of chronicity of drug use is
unconvincing. Some of the cases of the toxic cannabis psychosis
described by Chopra and Smith (1974), for example, had a long history
of heavy cannabis use. The hypothesised difference in symptoms is more
difficult to evaluate. Because few of the studies used standardised
assessments of symptoms, the absence of reports of confusion and
amnesia in the functional cases may indicate differences in diagnostic
practice. There are also strong similarities between the putatively
toxic and functional psychoses, namely, the occurrence of delusions,
and auditory and visual hallucinations, and a relatively benign
course, typically remitting within a week.
There is some recent support for the distinction between toxic and
functional cannabis-induced psychoses. Tsuang et al, (1982) compared
the demographic and clinical characteristics, and family histories of
four groups of patients: those with drug abuse who had experienced a
psychotic illness (DAP), those with diagnoses of drug abuse alone
(DA), those with schizophrenia (SC), and those with diagnoses of
atypical schizophrenia (AS). They subdivided the patients with drug
abuse and psychosis into those with shorter and longer duration of
symptoms. They found that the DAP patients were more likely to have
abused hallucinogens and cannabis, and less likely to have abused
sedative-hypnotics and opiates, than DA patients. The DAP patients
also had an earlier onset of illness, and better premorbid
personalities than the SC patients.
Comparisons of the DAP patients with short and long duration of
illness produced some interesting results. The patients with short
duration disorders had better premorbid personalties, fewer psychotic
symptoms, and fewer core schizophrenic symptoms, such as poor insight,
shallow and inappropriate affect, thought disorder, delusions and
Schneiderian "first rank symptoms". They were more likely to have
presented with "organic" symptoms such as confusion, disorientation,
visual hallucinations, and amnesia than the patients with long
duration disorders. By definition, the shorter duration patients had
shorter periods of admission; they also had shorter duration of drug
treatment, and more were discharged without being referred for further
treatment. The prevalence of family histories of schizophrenia among
the longer duration DAP patients was similar to that of the SC, while
the shorter duration DAP patients had no such family history.
On the basis of their comparisons, Tsuang et al argued that the short
duration disorders were drug-induced toxic psychoses, while the longer
duration disorders reflected functional psychoses precipitated by drug
use in predisposed individuals. If these findings are accepted, the
simplest explanation of the allegedly functional "cannabis psychoses"
is that they are functional psychoses occurring in heavy cannabis
users.
7.6.3.3 Chronic psychoses
If cannabis can produce an acute organic psychosis, the possibility
must be considered that chronic cannabis use may produce a chronic
psychosis in much the same way as chronic alcohol heavy use can
produce a chronic organic brain syndrome. As Ghodse (1986) has
suggested, it is "theoretically possible in a situation of easy
availability of cannabis, that regular, heavy users may suffer
repeated, short episodes of psychosis and effectively `maintain'
themselves in a chronic, psychotic state" (p477).
Although this is a possibility, there is no good evidence that chronic
cannabis use causes a psychotic illness which persists after
abstinence from cannabis (Thomas, 1993). This possibility is difficult
to study because of the near impossibility of distinguishing a chronic
cannabis psychosis from a functional psychosis such as schizophrenia
in which there is concurrent cannabis use (Negrete, 1983). Certainly
the findings of Tsuang et al (1982) suggest that the strong
presumption must be that individuals with a history of drug abuse and
a psychotic illness have a functional psychosis which has been
precipitated or exacerbated by drug use. Follow-up studies of patients
with acute cannabis psychoses, if they could be reliably identified,
would be the best way of throwing some light on this issue.
7.6.3.4 A residual state
A number of investigators have described a state among chronic, heavy
cannabis users in which the users' focus of interest narrows, they
become apathetic, withdrawn, lethargic, and unmotivated, and they have
impaired memory, concentration and judgment (Brill and Nahas, 1984;
McGlothin and West, 1968). This has been described as an
"amotivational state", which some have attributed to an organic
syndrome caused by the effects of chronic cannabis intoxication, from
which there is incomplete recovery after prolonged abstinence (Tennant
and Groesbeck, 1972).
The major clinical evidence in favour of such a hypothesis consists of
case series among contemporary chronic cannabis users (e.g. Kolansky
and Moore, 1971; Millman and Sbriglio, 1986), and historical reports
of the syndrome among chronic, heavy users in countries such as Egypt,
Greece, and the Carribean, where there has been a tradition of chronic
heavy cannabis use among the lower socioeconomic groups (Brill and
Nahas, 1984). These reports are often poorly documented and
uncontrolled, and do not permit the effects of chronic drug use to be
easily disentangled from those of poverty and low socioeconomic
status, or pre-existing personality disorders (Edwards, 1976; Millman
and Sbriglio, 1986; Negrete, 1983).
A small number of controlled studies of heavy chronic users in other
cultures have largely failed to substantiate the clinical observations
(Millman and Sbriglio, 1986), although there are enough reports of
regular users complaining of loss of ambition and impaired school and
occupational performance (e.g. Hendin et al, 1987), and of ex-users
giving this as a reason for stopping (Jones, 1984), to keep the
possibility alive. The small number of laboratory studies of long-term
heavy use have produced mixed evidence (Edwards, 1976). Georgotas and
Zeidenberg (1979), for example, reported that five healthy male
marijuana users on a dose regimen of 210mg of THC per day for a month
appeared "moderately depressed, apathetic, at times dull and alienated
from their environment and with impaired concentration" (p430). Others
have failed to observe such effects (e.g. Mendelson et al, 1974). The
status of the amotivational syndrome consequently remains uncertain
(see pp102-105).
7.6.4 Cannabis and schizophrenia
7.6.4.1 Precipitation
The possibility that heavy, chronic cannabis use may precipitate
schizophrenia was raised by Tennant and Groesbeck (1972) in their
study of the consequences of chronic heavy hashish use among American
servicemen in Germany between 1968 and 1971. They reported 112 cases
of "persistent schizophrenic reactions following prolonged hashish
use" (p134), and they presented evidence that there had been a four
fold increase in the incidence of schizophrenia among American
servicemen during the period in which hashish use became endemic. As
with all ecological evidence, a causal relationship is only one of the
possible explanations of the apparently concurrent increase in the
prevalence of hashish use and schizophrenia among American servicemen
in Germany. The attribution of the increase to hashish use alone was
also complicated by fact that many of their cases of schizophrenia
also used hallucinogens, amphetamines, and alcohol.
The precipitation hypothesis has received some support from a series
of case-control studies of cannabis and other psychoactive drug use
among schizophrenic patients (Schneier and Siris, 1987). The usual
finding has been that schizophrenic patients have higher rates of use
of psychomimetic drugs such as amphetamines, cocaine, and
hallucinogens than other patients (Dixon et al, 1990; Schneier and
Siris, 1987; Weller et al, 1988) or normal controls (Breakey et al,
1974; Rolfe et al, 1993). The results for cannabis use have been more
mixed, with some finding a higher prevalence of use or abuse (e.g.
Mathers et al, 1991) and others not having done so (Dixon et al, 1990;
Mueser et al, 1990; Schneier and Siris, 1987).
There is also good epidemiological evidence for an association between
schizophrenia and drug abuse and dependence in the Epidemiological
Catchment Area (ECA) study. In this study (Anthony and Helzer, 1991)
there was an increased risk of schizophrenia among men and women with
a diagnosis of any form of drug abuse and dependence: the excess risk
of schizophrenia was 6.2 for men and 6.4 for women. Although separate
estimates were not provided for cannabis abuse and dependence, it
seems reasonable to assume that the same sort of relationship applied.
Bland, Norman and Orn, (1987) have obtained a similar finding in a
population survey of the prevalence of psychiatric disorder in
Edmonton Alberta, using the same ECA interview schedule and diagnostic
criteria. They found that the odds of receiving a diagnosis of drug
abuse and dependence were 11.9 times higher among persons with
schizophrenia.
Many researchers have favoured a causal interpretation of the
increased prevalence of psychoactive drug use among schizophrenics,
that is, they have concluded that cannabis and other drug use
precipitates schizophrenic disorders in persons who may not otherwise
have experienced them. In support of this hypothesis are the common
findings that drug abusing schizophrenic patients have an earlier age
of onset of psychotic symptoms (with their drug use typically
preceding the onset of symptoms), a better premorbid adjustment, fewer
negative symptoms (e.g. withdrawal, anhedonia, lethargy), and a better
response to treatment and outcome than schizophrenic patients who do
not use drugs (Allebeck et al, 1993; Dixon et al, 1990; Schneier and
Siris, 1987).
There are other interpretations of these findings, however. Arndt et
al (1992), for example, have suggested that the association between
cannabis use and an early onset of schizophrenia in persons with a
good premorbid personality and outcome is spurious. According to Arndt
et al, schizophrenics with a better premorbid personality were simply
more likely to be exposed to illicit drug use among peers than those
with a withdrawn and socially inept premorbid personality, and because
of this prior exposure to drugs, they were also more likely to use
drugs to cope with the symptoms of an emerging psychosis. On this
account, cannabis and other illicit drug use is a correlate of a good
prognosis in schizophrenia, and pathological drug use is a response to
the unrelated emergence of psychotic symptoms.
A further possibility is that cannabis and other illicit drug use is a
consequence of schizophrenia. That is, such illicit drug use is a form
of self-medication to deal with some of the unpleasant symptoms of
schizophrenia, such as depression, anxiety, lethargy, and anhedonia,
and the side effects of the neuroleptic drugs used to treat it (Dixon
et al, 1990). There is some support for this hypothesis in the work of
Dixon et al (1990), who surveyed 83 patients with schizophrenia or
schizophreniform psychoses about the effects of various illicit drugs
on their mood and symptoms. Their patients reported that cannabis
reduced anxiety and depression, and increased a sense of calm, at the
cost of some increase in suspiciousness, and with mixed effects on
hallucinations and energy.
Prospective evidence. The most convincing evidence of an association
between cannabis use and the precipitation of schizophrenia has been
provided by a prospective study of cannabis use and schizophrenia in
Swedish conscripts undertaken by Andreasson et al (1987). These
investigators used data from a 15-year prospective study of 50,465
Swedish conscripts to investigate the relationship between
self-reported cannabis use at age 18 and the risk of receiving a
diagnosis of schizophrenia in the subsequent 15 years, as indicated by
inclusion in the Swedish psychiatric case register. Substantial data
were collected on the conscripts (such as family circumstances,
personal psychiatric disorder and other drug use) and statistical
methods were used to examine the effect of these potentially
confounding variables on the association between cannabis and
schizophrenia.
Their results showed that the relative risk of receiving a diagnosis
of schizophrenia was 2.4 times higher [95 per cent confidence interval
1.8, 3.3] for those who had ever tried cannabis compared to those who
had not. There was also a dose-response relationship between the risk
of a diagnosis of schizophrenia and the number of times that the
conscript had tried cannabis by age 18. The crude relative risk of
developing schizophrenia was 1.3 times higher [95 per cent confidence
interval 0.8, 2.3] for those who had used cannabis one to ten times,
3.0 times higher [95 per cent confidence interval 1.6, 5.5] for those
who had used cannabis between one and 50 times, and 6.0 times higher
[95 per cent confidence interval 4.0, 8.9] for those who had used
cannabis more than fifty times (compared in each case to those who had
not used cannabis).
The size of the risk was substantially reduced by statistical
adjustment for variables that were independently related to the risk
of developing schizophrenia (namely, having a psychiatric diagnosis at
conscription, and having parents who had divorced). Nevertheless, the
relationship between cannabis use and schizophrenia remained
statistically significant and still showed a dose response
relationship. The risk of a diagnosis of schizophrenia for those who
had smoked cannabis from one to ten times was 1.5 times that of those
who had never used, and the relative risk for those who had used 10 or
more times was 2.3 times that for those who had never used [95 per
cent confidence interval 1.0, 5.3].
Andreasson et al (1987) carefully scrutinised the validity of their
data on cannabis use and the diagnosis of schizophrenia. They
acknowledged that cannabis use was likely to have been under-reported
because the information was not confidential, but they argued this was
most likely to have under-estimated the relative risk of developing
schizophrenia among users and non-users. Self-reported cannabis use at
age 18 showed a strong dose-response relationship to the risk of
receiving a diagnosis of drug abuse in the subsequent 15 years. Data
from a small validity study indicated that 80 per cent of those
diagnosed as schizophrenic in the case register met the DSM-III
criteria for schizophrenia (which include a minimum duration of six
months).
Andreasson et al (1987) and Allebeck (1991) argued for a causal
interpretation of the association, conjecturing that cannabis use
precipitated schizophrenia in vulnerable individuals. They rejected as
implausible the hypothesis that cannabis consumption was a consequence
of emerging schizophrenia. The cannabis users who developed
schizophrenia had better premorbid personalities, a more abrupt onset,
and more positive symptoms than the non-users who developed
schizophrenia (Andreasson et al, 1989). Although over half of the
heavy cannabis users (58 per cent) had a psychiatric diagnosis at the
time of conscription, there was still a dose-response relationship
between cannabis use and schizophrenia among those conscripts who did
not have such a history. They stressed that cannabis use "only
accounts for a minority of all cases" (p1485) since most of the 274
conscripts who developed schizophrenia had not used cannabis, and only
21 of them were heavy cannabis users.
No single study ever settles an issue. Even a prospective study as
well designed, and as carefully interpreted as that of Andreasson et
al has been criticised (Johnson, Smith and Taylor, 1988; Negrete,
1989). Among these criticisms are the following, which raise a number
of alternative explanations to the causal one proposed by Andreasson
and his colleagues.
First, there was a large temporal gap between self-reported cannabis
use at age 18-20 and the development of schizophrenia over the next 15
years or so (Johnson, Smith and Taylor, 1988; Negrete, 1989). Because
the diagnosis was based upon a case register, there was no information
on whether the individuals continued to use cannabis up until the time
that their schizophrenia was diagnosed. Andreasson et al (1987)
anticipated and dealt with this criticism by showing that
self-reported cannabis use at age 18 was strongly related to the risk
of subsequently attracting a diagnosis of drug abuse. This suggests
that cannabis use at age 18 was predictive of continued drug use, and
the more so the more frequently it had been used by age 18.
A second possibility is that the excess rate of "schizophrenia" among
the heavy cannabis users was due to acute cannabis-induced toxic
psychoses which were mistakenly diagnosed as schizophrenia (Johnson et
al, 1988; Negrete, 1989). Andreasson et al (1989) attempted to address
this criticism by a study of the validity of the schizophrenia
diagnoses in 21 conscripts in the case register (8 of whom had used
cannabis and 13 of whom had not). This study indicated that 80 per
cent of these cases met the DSM-III requirement that the symptoms had
been present for at least six months, to exclude transient psychotic
symptoms. This sample size (21 case) was small, however, and the
confidence interval around a 20 per cent rate of misdiagnosis of
schizophrenia is between 3 per cent and 37 per cent. Even if the rate
of misdiagnosis was only 20 per cent, this could, if it varied between
cannabis and non-cannabis users, be large enough to explain the
relationship they observed.
A third, more serious concern about the causal interpretation of the
relationship between cannabis use and schizophrenia is that the
relationship may be a consequence of the use of other illicit
psychoactive drugs. Longitudinal studies of illicit drug use indicate
that intensity of cannabis use in late adolescence predicts the later
use of other illicit drugs. These drugs include amphetamine and
cocaine (Johnson, 1988; Kandel and Faust, 1975) which can produce an
acute paranoid psychosis (Angrist, 1983; Bell, 1973; Connell, 1959;
Gawin and Ellinwood, 1988; Grinspoon and Hedblom, 1975). There is also
good evidence that amphetamine was the major illicit drug of abuse in
Sweden during the study period (Inghe, 1969; Goldberg, 1968 a, b),
which suggests that intervening amphetamine use may have produced the
correlation between cannabis use and schizophrenia. Andreasson et al's
(1989) study reported that only two of their eight schizophrenic
cannabis users had also been abusers of amphetamines prior to the
diagnosis of their schizophrenia, but with a sample size as small as
this, the true rate (indicated by a 95 per cent confidence interval)
could be anywhere between 0 per cent and 55 per cent.
A fourth concern is that Andreasson et al (1987) have not ruled out
the possibility that cannabis use at age 18 was a symptom of emerging
schizophrenia. Statistical adjustment for a psychiatric diagnosis at
conscription did not eliminate the relationship between cannabis use
and schizophrenia, but it substantially reduced the size of the
relative risk, because over half of the heavy users of cannabis had
received a psychiatric diagnosis by age 18. Andreasson et al argued
that this hypothesis was implausible because the dose response
relationship between cannabis use and the risk of a schizophrenia
diagnosis held up among those who did not have a psychiatric history.
The persuasiveness of this argument depends upon how credible the
screening for psychiatric diagnosis was at the time of conscription,
and in particular, how confident we can be that a failure to identify
a psychiatric disorder at conscription means that no disorder was
present. This is difficult to evaluate.
The fifth and final criticism relates to the validity of self-reported
cannabis use at conscription. Andreasson et al (1987) acknowledged
that there was likely to be under-reporting of cannabis use because
this information was not collected anonymously, but they argued that
this was most likely to lead to an under-estimation of the
relationship between cannabis use and the risk of schizophrenia. This
will only be true, however, if the schizophrenic and
non-schizophrenics conscripts were equally likely to under-report. If,
however, pre-schizophrenic subjects were more candid about their drug
use, the apparent relationship between cannabis use and schizophrenia
would be due to response bias (Negrete, 1989). Although a possibility,
this seems unlikely in view of the strong dose-response relationship
with frequency of cannabis use, and the large size of the unadjusted
relative risk of schizophrenia among heavy users.
When all these criticisms are considered, the Andreasson et al (1987)
study still provides strong evidence of an association between
cannabis use and schizophrenia which is not completely explained by
prior psychiatric history. Uncertainty remains about the causal
significance of the association because it is unclear to what extent
the relationship is a result of drug-induced psychoses being mistaken
for schizophrenia, and to what extent it is attributable to
amphetamine rather than cannabis use.
Even if the relationship is causal, its public health significance
needs to be kept in perspective. Although they did not report
calculations of attributable risk, an estimate based upon the relative
risk adjusted for psychiatric disorder (Feinstein, 1985) indicates
that even if their association is causal, at most 7 per cent of cases
of schizophrenia would be attributable to cannabis use. That is, on
the prevalence rate of cannabis use reported by Andreasson et al,
cannabis use would have explained 7 per cent (at most) of cases of
schizophrenia occurring in Sweden during the period of study. Even
this small potential contribution to an increased incidence of
schizophrenia seems difficult to accept, since there is good
independent evidence that the incidence of schizophrenia, and
particularly of early onset, acute cases, declined during the 1970s,
the period when the prevalence of cannabis use increased among young
adults in Western Europe and North America (Der et al, 1990).
7.6.4.2 Exacerbation of schizophrenia
There is reason to be concerned about the effects of cannabis on
psychotic symptoms among individuals with schizophrenia. Cannabis is
psychoactive drug that is probably psychotomimetic in high doses, and
its use seems to be relatively common among schizophrenic patients, as
indicated above. There is also anecdotal clinical evidence that
schizophrenic patients who use cannabis and other drugs experience
exacerbations of symptoms (Weil, 1970), and have a worse clinical
course, with more frequent psychotic episodes, than those who do not
(Knudsen and Vilmar, 1984; Perkins et al, 1986; Turner and Tsuang,
1990).
However, there have been very few controlled studies of the
relationship between cannabis use and the clinical outcome of
schizophrenia. Negrete et al (1986) conducted a retrospective study
using clinical records of symptoms and treatment seeking among 137
schizophrenic patients with a disorder of at least six months
duration, and three visits to their psychiatric service during the
previous six months. The proportion of cannabis users among their
patients was the same as in the Canadian population, but heavy users
were over-represented, and the proportion of former users who had
stopped using was higher than in the general population. Negrete et al
(1986) compared the prevalence of hallucinations, delusions and
hospitalisations among the active users (N=25), the past users (n=51),
and those who had never used cannabis (N=61). The crude comparison
showed higher rates of continuous hallucinations and delusions, and of
hospitalisations among active users. This pattern of results persisted
after statistical control for differences in age and sex between the
three user groups.
Negrete et al argued that cannabis use exacerbated schizophrenic
symptoms. They rejected the alternative hypothesis that patients with
a poorer prognosis were more likely to use cannabis, because they
found that past cannabis users experienced fewer symptoms, and
reported a high rate of adverse effects when using (91 per cent). They
also discounted the possibility that these were toxic psychoses,
because in all cases the minimum duration of symptoms had been six
months. They left open the mechanism by which cannabis use exacerbated
schizophrenic symptoms, suggesting three possibilities: that cannabis
disorganises psychological functioning; that it causes a toxic
psychosis that accentuates schizophrenic symptomatology; or that it
interferes with the therapeutic action of anti-psychotic medication.
More recently, Cleghorn et al (1991) have provided supportive
evidence. They compared the symptom profiles of schizophrenic patients
with histories of substance abuse of varying severity (none, moderate,
and severe), among whom cannabis was the most heavily used drug.
Comparisons with a subset of the patients who were maintained on
neuroleptic drugs revealed that the drug abusers had a higher
prevalence of hallucinations, delusions and positive symptoms.
These studies provide a slender basis upon which to draw conclusions
about the effects of cannabis use on schizophrenic symptoms. One can
only agree with the conclusion of Turner and Tsuang (1990) that "the
impact of substance abuse on the course and outcome of schizophrenia
remains largely undefined" (p93), and that it will remain so until
large prospective studies in general population and clinical samples
recommended by Turner and Tsuang (1990) have been conducted. Until
such research has been undertaken, prudence would demand that
schizophrenic patients, and others at risk of schizophrenia by virtue
of family history, personality, or marginal social functioning, should
be strongly discouraged from using cannabis and other psychoactive
drugs, especially the psychostimulants amphetamine and cocaine.
7.6.5 Conclusions
There is reasonable evidence that heavy cannabis use, and perhaps
acute use in susceptible individuals, can produce an acute psychosis
in which confusion, amnesia, delusions, hallucinations, anxiety,
agitation and hypomanic symptoms predominate. The evidence for a toxic
cannabis psychosis comes from laboratory studies of the effects of THC
on normal volunteers and clinical observations of psychotic symptoms
in heavy cannabis users, which seem to comprise a toxic psychotic
syndrome and which remit rapidly following abstinence from cannabis.
There is also an argument by analogy with the fact that heavy chronic
amphetamine use has been shown to induce a paranoid psychosis
(Angrist, 1983).
There is little support for the hypothesis that cannabis use can cause
a chronic psychosis which persists beyond the period of intoxication.
Such a possibility is difficult to study because of the likely rarity
of such psychoses, and the near impossibility of distinguishing them
from individuals with schizophrenia and manic depressive psychoses who
also abuse cannabis (Negrete, 1983).
The occurrence of a chronic residual state, or "amotivational
syndrome", in chronic heavy cannabis users is not well supported by
research evidence. At best, a prima facie case has been made by
clinical observations, that withdrawal, lethargy, and apathy occur
among a minority of chronic, heavy users. This syndrome has proved
difficult to study in the laboratory, difficult to distinguish from
the effects of chronic intoxication (Negrete, 1988), and it so far
been impossible to rule out confounding effects of pre-existing
disease, malnutrition, personality disorder, and lifestyle.
There is strongly suggestive evidence that chronic cannabis use may
precipitate a latent psychosis in vulnerable individuals. This is
still strongly suggestive rather than established beyond reasonable
doubt, because in the best study conducted to date (Andreasson et al,
1987) the use of cannabis was not documented at the time of diagnosis,
there was a possibility that cannabis use was confounded by
amphetamine use, and there remains a question about the ability of the
study to reliably distinguish between schizophrenia and acute cannabis
or other drug-induced psychoses.
Even if the relationship between cannabis use and schizophrenia is a
causal one, its public health significance should not be overstated.
It is most likely to indicate that cannabis use can precipitate
schizophrenia in vulnerable individuals, since the estimated
attributable risk of cannabis use is small, and the incidence of
schizophrenia has declined during the period in which cannabis use has
increased among young adults.
The substantial prevalence of cannabis use among young adults in
Western societies makes the relationships between cannabis use and
psychosis deserving of further research. What are required are
case-control studies of people with schizophrenia and normals, and
case-control studies of psychotic individuals who do and do not have a
documented history of recent heavy cannabis use. Mueser et al (1990)
provide detailed suggestions for the types of controls that ought to
be incorporated in such studies. If the results of the case control
studies warrant it, prospective studies should be done. Longitudinal
studies like that undertaken by Andreason et al (1987) would be most
desirable, but can probably only be undertaken in exceptional
circumstances. Turner and Tsuang (1990) provide detailed suggestions
for prospective studies which would clarify the contribution of
cannabis and other drug use to the precipitation and exacerbation of
schizophrenia and other psychoses.
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8. The therapeutic effects of cannabinoids
8.1 Historical background
Cannabis has had a long history of medical and therapeutic use in
India and the Middle East (Grinspoon and Bakalar, 1993; Mechoulam,
1986; Nahas, 1984) where it has been variously used as an analgesic,
anti-convulsant, anti-spasmodic, anti-emetic, and hypnotic. Cannabis
was introduced to British medicine in the mid-nineteenth century by
O'Shaugnessy (1842) who had gained clinical experience with the drug
while an Army surgeon in India (Mechoulam, 1986; Nahas, 1984). He
recommended its use for the relief of pain, muscle spasms, and
convulsions occurring in tetanus, rabies, rheumatism and epilepsy
(Nahas, 1984). Partly as the result of his advocacy, cannabis came to
be widely used as an analgesic, anti-convulsant and anti-spasmodic
throughout the middle part of the 19th century in Britain and the USA.
The medical use of cannabis declined around the turn of the present
century. Because the active constituents of cannabis were not isolated
until the second half of the twentieth century, cannabis continued to
be used in the form of natural preparations which varied in purity
and, hence in effectiveness. The use of cannabis was largely
supplanted by other pharmaceutically purer drugs, which could be given
in standardised doses to produce more dependable effects. These
included the opiates, aspirin, chloral hydrate, and the barbiturates
(Mechoulam, 1986; Nahas, 1984). In the early part of the century, the
medical use of such crude cannabis preparations was further
discouraged by laws which treated cannabis as a "narcotic" drug and
severely restricted its availability. It finally disappeared from the
American pharmacopoeia in the early 1940s after the passage of the
Marijuana Tax Act (Grinspoon and Bakalar, 1993), although it continued
to be used in Australia into the 1960s (Casswell, 1992).
THC, the major psychoactive ingredient of cannabis, was not isolated
until 1964 (Goani and Mechoulam, 1964), shortly before cannabis
achieved widespread popularity as a recreational drug among American
youth. Its widespread recreational use, and its symbolic association
with a rejection of traditional social values, undoubtedly hindered
pharmaceutical research into its therapeutic uses. Consequently, the
rediscovery of some of its traditional therapeutic uses was largely
serendipitous, as was the discovery of some newer uses. For example,
its value as an anti-emetic agent in the treatment of nausea caused by
cancer chemotherapy seems to have been rediscovered by young adults
who had used cannabis recreationally prior to undergoing chemotherapy
for leukemia (Grinspoon, 1990).
From the mid-1970s some clinical research on the therapeutic value of
cannabis and cannabinoids was undertaken. On the whole, however, this
research has been very thin and uneven, and, consequently, many of the
claims for the therapeutic efficacy of cannabinoids rely heavily, and,
in the case of rare medical conditions, solely upon anecdotal
evidence, that is, the testimonies of individuals who claim to have
derived medical benefit from its use (e.g. Grinspoon and Bakalar,
1993; Randall, 1990), and small numbers of cases reported by
physicians (e.g. Consroe et al, 1975; Meinck et al, 1989).
Evidence will be reviewed for the best-supported therapeutic uses of
cannabinoids. The review begins with the evidence on the effectiveness
of cannabinoids as anti-emetic drugs for nausea caused by cancer
chemotherapy, and as agents to control intra-ocular pressure in
glaucoma. Briefer reviews are provided of the evidence in favour of
other putative therapeutic uses of cannabinoids which are less well
supported by clinical evidence, chief among which are its uses as an
anti-convulsant, an anti-spasmodic, and an analgesic agent. The value
and limitations of the largely anecdotal evidence of efficacy in these
latter conditions will also be briefly considered. The review will
include a discussion of the controversy in the United States about
"marijuana rescheduling" which has coloured much recent discussion of
the issue. This controversy concerns the vexatious issue of whether
smoked cannabis should be available for medical use in addition to
synthetic cannabinoids such as THC.
8.2 Cannabinoids as anti-emetic agents
Profound nausea and vomiting can be such serious complications of
chemotherapy and radiotherapy for cancer that patients may discontinue
potentially life-saving treatment (Institute of Medicine, 1982).
Although various types of drugs (e.g. the phenothiazines) have been
shown to be effective in controlling nausea and vomiting in cancer
patients, substantial minorities of patients do not benefit from these
drugs. The seriousness of the problem of chemotherapy-induced nausea,
and the incomplete success of existing treatments, prompted
oncologists in the late 1970s and early 1980s to take a particular
interest in the anti-emetic properties of cannabinoids (Institute of
Medicine, 1982).
8.2.1 Clinical trials
One of the earliest trials of the effectiveness of THC as an
anti-emetic was prompted by patient reports that smoking marijuana
relieved nausea and vomiting (Sallan et al, 1975). In this study, 22
patients (10 males and 12 females, average age 30 years) with a
variety of neoplasms were studied. In 20 patients, the nausea and
vomiting had proven resistant to existing anti-emetic drugs. A
randomised placebo-controlled trial with crossover was used, in which
patients were randomly assigned to receive oral THC (10mg per m2) and
placebo in one of four different orders (THC-placebo-THC; THC-
placebo-placebo; placebo-THC-placebo; placebo-THC-THC). Outcome was
assessed by grading patients' self-reports of nausea and vomiting
after THC and placebo into three categories: complete response if
there was vomiting after placebo but not after THC; partial response
if there was a greater than 50 per cent reduction in nausea and
vomiting after THC compared to placebo; and no response if there was a
less than 50 per cent reduction in nausea and vomiting.
Ten patients completed all three courses of THC and placebo and
vomited on at least one trial. After excluding one trial because of a
variation in the chemotherapy dose, there were 29 trails available for
analysis, 14 of placebo and 15 of THC. All 14 placebo trials resulted
in no response, while in the 15 THC trials there were five complete
responses, seven partial responses, and three no responses. This
difference was statistically significant when full and partial
responses were combined. Most patients (13/16) reported a "high" after
receiving THC, an experience which was correlated with the anti-emetic
effect. The most common side-effect was somnolence which curtailed
activities for two to six hours in a third of patients. Only two
patients experienced any symptoms of toxicity, (both after receiving
20mg doses of THC), namely, visual distortions and hallucinations and
depression lasting several hours. Sallan et al reported "preliminary"
observations from several patients that smoking marijuana produced an
equivalent anti-emetic effect to oral THC.
A trial by Chang et al (1979) largely supported the findings of Sallan
et al. In this study 15 patients with osteogenic sarcoma (10 males and
five females, average age 24 years) served as their own controls in
the course of monthly high dose methotrexate therapy. They were
assigned to receive three THC and three placebo trials in randomised
order during six treatment sessions. THC (10mg per m2 of body area)
and placebo were administered orally five times at three hourly
intervals, beginning two hours before chemotherapy. If the patients
vomited, the remaining doses of either THC or placebo were
administered by smoking a cigarette using a standardised smoking
technique. The effect of THC and placebo were assessed by nursing
staff who rated various endpoints (e.g. number of vomiting and
retching episodes, volume of emesis, degree and duration of nausea)
without being aware of which treatment patients had received. Patient
response was graded into three categories: excellent (greater then 80
per cent reduction after THC by comparison with placebo in each of
these endpoints); fair (greater than 30 per cent and less than 80 per
cent reduction), and no response (less than 30 per cent reduction).
The results showed that eight patients had an excellent response, six
a fair response, and one had no response. On all endpoints THC
produced a statistically significant reduction in nausea and vomiting
by comparison with placebo. There was also a dose-response
relationship between blood levels of THC and the incidence of nausea
and patient reports of feeling "high". Generally, higher THC blood
levels were achieved when marijuana was smoked than when THC was taken
orally. There were few side effects reported, with sedation being the
most common (12/15 patients). Four patients experienced five dysphoric
reactions in the course of 281 THC drug doses (2 per cent), none of
which lasted more than 30 minutes, and all of which were successfully
managed with simple reassurance.
In a second phase of the study, four patients who had an excellent
response to THC in the first phase were retested under double-blind
conditions using two placebo trials in the next 10 treatments. A small
number of patients who had a fair response were also studied using an
increased dose of THC. All patients showed a reduction in the average
anti-emetic benefit of THC, decreasing from excellent to fair in the
case of previous excellent responders, and from fair to no response in
the case of the fair responders. Chang et al hypothesised that the
decline in effect reflected either the development of tolerance to the
effects of THC, or the development of conditioned nausea and vomiting
that was resistant to the anti-emetic effects of THC.
Since these early studies, a large number of controlled clinical
studies have been conducted which compared the effectiveness of THC
with either a placebo or with other anti-emetic drugs (see Carey et
al, 1983; Poster et al, 1981; Levitt, 1986 for reviews). The results
of this literature have sometimes been unfairly described as
"confused" (e.g. Carey et al, 1983; Nahas, 1984). This description
betrays an unreasonably high expectation of the consistency of results
from studies which have generally used small samples of heterogenous
patients who have received various forms of chemotherapy. It also
ignores the fact that the cross-over studies comparing the anti-emetic
effects of THC with placebo have generally reported greater
anti-emetic effects for THC than placebo (Poster et al, 1981); the
single exception to this finding was a study which had a sample size
of only eight patients.
Comparisons of the effectiveness of oral THC with that of existing
anti-emetic agents have been less consistent than the results of
comparisons with placebo. Nonetheless, the results have generally
indicated that THC is at least equivalent in effectiveness to the
widely used anti-emetic drug prochlorperazine (Carey et al, 1983;
Levitt, 1986). The inconsistencies in this case arise because some
studies have shown THC to be superior, probably because of the
practice in some trials of enlisting patients whose nausea had
previously proven resistant to prochlorperazine (Carey et al, 1983).
The equivalence of THC and prochlorperazine has been supported by the
results of one of the largest and best conducted studies (Ungerleider
et al, 1982). In this study 214 patients with a variety of forms of
cancer (carcinomas, sarcomas, lymphomas and leukemias) were recruited
if they had already undergone chemotherapy and experienced nausea and
vomiting, or they were to receive a form of chemotherapy which had a
high emetic potential. Patients were randomly assigned to receive a
paired trial of either oral THC followed by prochlorperazine or vice
versa. The dose of THC was dependent on body surface area (7.5mg if
less than 1.4m2, 10mg for 1.4 to 1.8m2, and 12.5mg for greater than
1.8m2). Separate analyses were conducted on three groups of patients:
patients who received their cancer chemotherapy on a single day some
weeks apart (N=98); patients who received their chemotherapy on a
daily basis over several successive days (N=41); and patients who
discontinued the trial after a single episode of either THC or
prochlorperazine. Outcomes were patient self-ratings of nausea and
vomiting, and a variety of mood states and behaviours.
The results showed that there "were no statistically significant
differences in the anti-nausea/anti-emetic effect of THC and
prochlorperazine" (p640) in any of the three patient groups, even
though there were differences between patients in the single- and
multiple-day chemotherapy regimens in the time course of the nausea.
There were differences in mood and behaviour between the THC and
prochlorperazine trials, with patients reporting greater impairment of
concentration and less social interaction after receiving THC. There
were also more side effects from THC than prochlorperazine, with
sedation, sleepiness and mental clouding being the most common. There
was no difference in the frequency of panic attacks between the two
drugs. Despite these differences in side effects there was a small
patient preference in favour of THC as an anti-emetic, with 41 per
cent experiencing less nausea on THC, 31 per cent experiencing less
nausea on prochlorperazine, and 29 per cent reporting no difference in
effectiveness. The effectiveness of THC was not related to age or
prior experience with marijuana, but it was related to the experience
of side effects, with patients experiencing them reporting less
nausea.
Given the wide variety of patients who have been studied in terms of
age and type of cancer, the wide variety of chemotherapeutic agents
that have been used to treat their cancers, and the variety of
different anti-emetics with which THC has been compared, the fact that
findings of these studies are generally positive for THC is more
impressive than the apparent differences in outcome. The positive
results from the controlled trials also seem to be borne out by
clinical experience with cannabinoids in managing cancer patients. A
recent survey of a large sample of American oncologists, for example,
found that 44 per cent of oncologists had recommended marijuana to at
least one cancer patient, and 64 per cent of these physicians reported
that it was successful controlling nausea in at least half of their
patients. Overall, just under half of the oncologists in the sample
(44 per cent) believed that cannabinoids could be safely used in the
treatment of nausea caused by chemotherapy and radiotherapy (Dobin and
Kleiman, 1991). A similar proportion (48 per cent) reported that they
would prescribe marijuana for their patients if it was legal.
The general conclusion on the available literature is that THC is
superior to placebo, and equivalent in effectiveness to other
widely-used anti-emetic drugs, in its capacity to reduce the nausea
and vomiting caused by some chemotherapy regimens in some cancer
patients. There are a number of issues that remain to be resolved in
deciding upon the clinical role of cannabinoids as anti-emetic agents
in cancer chemotherapy. These issues include: the types of nausea
against which it may be most effective, and hence the types of
patients for which they are most appropriately prescribed; the degree
of patient tolerance of the psychotropic side effects of THC and other
cannabinoids; the potential seriousness of possible THC induced
immunosuppression in patients who are already immunologically
compromised; the most effective dosing schedules for THC as an
anti-emetic; the potential use of THC in combination with other
anti-emetic drugs; and the extent to which the motivation for the use
of THC may have been reduced by the availability of newer anti-emetic
drugs that are more effective than prochlorperazine (the main
anti-emetic drug in the 1980s).
8.2.2 Which patients?
Which patients with what types of nausea are the most suitable for
treatment with cannabinoids as anti-emetics? Patients with various
forms of cancer have been the most extensively investigated patient
group, but the numbers of different types of cancer have been too
small to allow convincing analyses of differences in patient response.
The same point can be made about types of chemotherapy regimens; they
have varied widely in these studies, and have often not been reported,
but there has been no systematic analysis of the effectiveness of
cannabinoids in controlling emesis produced by different agents. It is
uncertain to what extent the cannabinoids may be effective against
nausea from other causes. The mechanisms that produce nausea are not
well understood but there are believed to be one or more protective
mechanisms located in the brain stem that can be triggered by a
variety of emetic agents. This raises the possibility that
cannabinoids may be therapeutically useful against nausea from a
variety of causes.
8.2.3 Side effects
The psychoactive effects of cannabis which are prized by recreational
users - euphoria, relaxation, drowsiness - are not always welcomed by
older patients, most of whom are cannabis-naive. In some studies a
substantial minority of such patients have discontinued the use of THC
because of the unwelcome dysphoria and somnolence (Levitt et al,
1986). This has not been a universal experience, so further research
is required to discover to what extent this has been the result of
unnecessarily large doses, or poor patient preparation for these
effects, and failure to adequately manage them by reassurance. What
does seem to be the case is that the experience of some psychological
effects of THC, including the "high", is necessary for the occurrence
of a clinically significant anti-emetic effect. This fact has led to
the search, so far unsuccessful, for cannabinoid derivatives of THC
which possess its anti-emetic properties but not its psychoactive
ones. The recent discovery of the cannabinoid ligand and receptor, and
receptor subtypes (see pp7-8) has encouraged researchers to believe
that this may be an achievable goal (Iversen, 1993).
A potentially more serious side effect of therapeutic THC is its
possible immunosuppressive effect. Any such effect would limit its use
as an anti-emetic in the treatment of cancer, since cancer patients
experience immune suppression as a side effect of their treatment.
There are several reasons why this may be less serious an issue that
it seems at first glance. First, there are doubts about the existence
of any immunosuppressive effect of cannabinoids (see Section 6.2 on
the immune system, pp62-68), and the effect is small in those studies
which report one. Second, the clinical significance of any such
effects is doubtful in the use of THC in cancer chemotherapy. Such use
would be intermittent, and relatively short-term, and the possible
gain in increased life expectancy from being able to complete a course
of cancer chemotherapy is such that most patients would be prepared to
take the risk, in the same way that they chose to undergo the highly
toxic chemotherapy in the first place.
8.2.4 Unresolved clinical issues
If THC has a place in the management of nausea from cancer treatment
(Poster et al, 1981), and perhaps other causes, a number of clinical
issues remain to be resolved (Levitt, 1986). Foremost among these is
the best way in which to administer the drug. Should it be given well
in advance of treatment at low doses to ensure a stable blood level,
or should it be given in larger doses shortly before chemotherapy or
radiotherapy? This issue has not been systematically studied (Levitt,
1986).
An additional question is whether there is any clinical benefit to be
derived from combining THC with existing anti-emetic agents. There is
suggestive evidence that there might be, since the mechanisms of
action, while not well understood, appear to be different, raising the
possibility that there may be positive synergistic effects from the
combination of THC and other anti-emetics. One single-blind study of
the combination of dronabinol and prochlorperazine, for example,
suggested that the combination of these drugs may have a superior
anti-nausea effect to either drug used alone (Plasse et al, 1991).
Clearly, more research is warranted on this issue, especially as it
may enable cannabinoids to be used as anti-emetics at lower doses with
fewer unwanted psychotropic effects.
It seems surprising that the desirability of undertaking research on
dosing and combined use of cannabinoids was highlighted by Poster et
al in 1981 and by the Institute of Medicine in 1982. Yet very little
research has been done, and THC has not been routinely incorporated
into the management of nausea caused by cancer chemotherapy. One of
the likely reasons has been the American controversy about the
rescheduling of marijuana under the Controlled Substances Act, which
some argue has discouraged clinical research on cannabinoids (see
below). Another reason has been that the motivation for further
research on the anti-emetic properties of THC has been removed by the
recent development of newer anti-emetic drugs which are superior to
prochlorperazine (Iversen, 1993), the "gold standard" drug when the
major controlled trials were conducted on cannabis in the 1970s and
1980s. In the absence of trials comparing THC with these newer drugs,
its comparative efficacy is unknown, although given its approximate
equivalence to prochlorperazine it is likely to be inferior to the
newer drugs.
8.3 Cannabinoids as anti-glaucoma agents
Glaucoma is the leading cause of blindness in the United States,
affecting two million people and producing 300,000 new cases each year
(Adler and Geller, 1986). It is a condition "which is generally
characterised by an increase in intraocular pressure ... that
progressively impairs vision and may lead to absolute blindness"
(Adler and Geller, 1986, p54). Although its causes are not understood,
it is believed to involve an obstruction to the outflow of the aqueous
humour in the eye leading to a gradual increase in intraocular
pressure (IOP) which, if untreated, may damage the optic nerve,
resulting in blindness. Its incidence increases over the age of 35,
especially among individuals who are myopic (i.e. short-sighted).
Although various drugs are available which reduce IOP, all possess
unwanted side-effects and patients may become tolerant to their
therapeutic effects.
The effects of cannabis in reducing IOP were discovered
serendipitously by researchers and patients in the early and middle
1970s. Hepler and his colleagues (1971, 1976) observed a substantial
decrease in IOP while researching the effects of cannabis intoxication
on pupil dilation. They demonstrated that both cannabis and oral THC
produced substantial reductions in IOP in both normal volunteers and
patients with glaucoma (Hepler and Petrus, 1976; Hepler et al, 1976).
Subsequent research identified THC as the agent responsible for
producing this effect (Adler and Geller, 1986).
Around the same time, patients with glaucoma who had used cannabis
recreationally also discovered its therapeutic effects. One such
patient, Robert Randall, used cannabis daily to control his glaucoma.
When arrested for possession and cultivation of cannabis, he
successfully used the defence of "medical necessity" arguing, with the
support of his physicians, that he would go blind if he stopped his
cannabis use. He subsequently was given legal access to cannabis for
medical purposes (Randall Affidavit, in Randall, 1988).
Although there have been a number of case reports of the successful
use of cannabis in the management of glaucoma (e.g. Grinspoon and
Bakalar, 1993; Randall, 1990), there have not been any controlled
clinical studies of its effectiveness and safety in the long-term
management of glaucoma. Informed clinical opinion has been that THC is
an effective anti-glaucoma agent when used acutely, but there are
doubts about its effectiveness with chronic use because of the
development of tolerance to its effects on IOP (Jones et al, 1981).
Ophthalmologists who are opposed to the clinical use of THC point to a
number of major disadvantages. First, because THC is not
water-soluble, it cannot, unlike other anti-glaucoma agents, be
applied topically to the eye to ensure that enough is absorbed to
produce a clinically significant reduction in IOP. Second, as a
consequence, THC must be absorbed systemically in order to produce a
therapeutic effect on IOP, which means that patients must experience
the psychoactive effects of THC in order to derive its therapeutic
benefits against glaucoma. Third, because glaucoma is a chronic
condition, THC or cannabis would need to be taken in substantial doses
on a daily basis over long periods of time, if not for the remainder
of adult life. There has been an understandable concern about the
health risks of chronic daily cannabis use (e.g. Hepler, 1990;
American Academy of Ophthalmology, 1990).
The position adopted by the American Academy of Ophthalmology has been
to insist that cannabis has no accepted medical use in the management
of glaucoma, and cannot have such medical use until a large controlled
trial has been conducted into its safety and effectiveness in daily
chronic use. There has been no evidence that the Academy has any
interest in, or has given any encouragement to, the conduct of such a
trial. Consequently, its position is that THC and other cannabinoids
should not be used be in the management of glaucoma.
A contrary position has been taken by Randall, who has argued that
patients should be allowed to make the choice between the uncertain
health risks of chronic cannabis use and the more certain risks to
sight of poorly controlled glaucoma:
"People with life- and sense-threatening diseases are routinely
confronted by stark choices ... [between] the devastating consequences
of a debilitating, progressive disease ... [and] often highly damaging
biological and mental consequences of the toxic chemicals required to
check the progression of disease. .. Viewed in this medical context,
marihuana is more benign and far less damaging that the synthetic
toxins routinely prescribed by physicians" (cited in Grinspoon and
Bakalar, 1993, p153)
8.4 Cannabinoids and neurological disorders
8.4.1 Anti-convulsant
Historically one of the commonest medical uses of cannabis
preparations has been as an anti-convulsant. O'Shaughnessy (1842), for
example, recommended the use of cannabis to control seizures in
epilepsy, tetanus and rabies (Nahas, 1984). Animal studies have
provided some support for this use in showing that THC has dual
effects on convulsions, i.e. they can produce convulsions in
susceptible animals, and suppress the maximum severity of convulsions
from a variety of causes, while cannabidiol (CBD) appears to be a
potent anti-convulsant (Chesher and Jackson, 1974; Consroe and Snider,
1986; Institute of Medicine, 1982).
Despite this animal evidence, there is very limited evidence on the
therapeutic effects of cannabinoids in humans with epilepsy. There are
a small number of case studies of individuals with epilepsy in which
the recreational use of cannabis appeared to enhance the
anti-convulsant effects of more traditional anti-convulsant medication
(e.g. Consroe et al, 1975; Grinspoon and Bakalar, 1993). There is a
single randomised placebo controlled study of the administration of
CBD in 15 patients with epilepsy that was not well controlled by
conventional anti-convulsants. Four of the eight patients who received
CBD in addition to their usual anti-convulsant drugs were free of
seizures throughout the study period, and three were improved. By
contrast, only one out of seven patients in the placebo condition
showed any clinical improvement (Cunha et al, 1980). Despite this
suggestive evidence of efficacy in epilepsy, CBD has not been widely
used in clinical management. Perhaps this is not surprising given the
absence of evidence of its efficacy, the existence of other effective
anti-convulsant drugs, and concerns about the safety of chronic use in
the management of a chronic disease. It is perhaps more surprising
that there has been no further research on the anti-convulsant
properties of CBD, especially as it has no psychoactive side effects
(Nahas, 1984).
8.4.2 Anti-spasmodic
Cannabinoids have been used in an empirical way in the management of
some patients with movement disorders, a variety of syndromes that
have in common a deficit in non-pyramidal motor control function,
which is expressed in usually one or more of the non-epileptic,
abnormal involuntary movements, such as those found in Parkinson's
disease, Huntington's disease, multiple sclerosis, and spasticity.
Although a number of drugs may be of benefit in the management of
these conditions, they are not always effective, and may produce
troublesome side-effects (Consroe and Snider, 1986).
There has been some animal evidence which indicates that THC and its
analogues produce a broad spectrum of neurological effects, which
include alterations in motor function, and changes in muscle tone and
reflexes. The acute motor effects in normal humans - ataxia,
tremulousness and subjective weakness - also suggest a potential for
therapeutic effects in some movement disorders (Consroe and Snider,
1986).
The evidence that cannabinoids have therapeutic effects in patients
with movement disorders is largely anecdotal. Grinspoon and Bakalar
(1993), for example, present four case histories of individuals with
multiple sclerosis whose condition improved while they smoked
marijuana, and deteriorated after they stopped smoking. Meinck et al
(1989) report a case history of a young man with multiple sclerosis
with severe limb and gait ataxia who complained of erectile impotence.
After smoking marijuana his gait improved sufficiently to be able to
walk unaided, and he was able to achieve and sustain an erection. When
cannabis was withdrawn under medical supervision, the patient's motor
function deteriorated to the point where he was unable to walk without
assistance.
There has been one controlled study by Clifford (1983) who examined
the effects of THC on tremor in eight patients (four male and four
female) with advanced multiple sclerosis who had ataxia and tremor.
Five patients reported subjective benefit from THC and there was
objective evidence of benefit in two of these cases. Single-blind
placebo challenge in these cases produced evidence that their clinical
condition deteriorated when given placebo and improved with the
reinstatement of THC.
Grinspoon and Bakalar (1993) described several case histories of
individuals with paraplegia and quadriplegia who reported that
cannabis use helped to reduce muscle spasm. The experiences of these
individuals were supported by similar reports obtained from a survey
of 43 individuals with spinal cord injuries, 22 of whom reported that
they used cannabis to control their muscle spasm.
The only controlled trial of a cannabinoid in a movement disorder has
been an evaluation of the effects of CBD on severity of chorea in
patients with advanced Huntington's disease (Consroe et al, 1991).
This study was prompted by the authors' observation that CBD had
improved the condition of an individual with Huntington's disease
(Sandyck et al, 1988). In this study 19 Huntington's patients were
enrolled in a double-blind controlled trial in which they received six
weeks administration of CBD or placebo in a cross-over design. The
outcome was the severity of chorea, as assessed by blind clinical
ratings, patient self-report, and a variety of measures of motor
function. Although the study had sufficient statistical power to
detect a relatively small clinical benefit, there was no evidence of
improvement in chorea on any of the clinical, self-report or motor
measures. In the light of Consroe et al's failure to replicate the
earlier favourable single case, further controlled trials are
warranted before any of the cannabinoids can be routinely used in
treating movement disorders.
8.5 Cannabinoids as anti-asthmatic agents
Smoked cannabis, and to a lesser extent oral THC, have an acute
bronchodilatory effect in both normal persons and persons with asthma
(Tashkin et al, 1975; Tashkin et al, 1976). Tashkin et al (1975), for
example, compared the bronchodilator effect of smoked cannabis with
that of a standard clinical dose of the bronchodilator isoproterenol
in relieving experimentally induced asthma in asthmatic patients. They
found that smoking a 2 per cent-THC cannabis cigarette produced a
bronchodilator nearly equivalent to that of a clinical dose of
isoproterenol.
Despite this early suggestion of a therapeutic effect in asthma,
cannabinoids have not been used therapeutically, nor have they been
extensively investigated as anti-asthmatic agents other than by
Tashkin and his colleagues (Tashkin, 1993). A major obstacle to
therapeutic use has been the route of administration. Oral THC
produces a smaller bronchodilator effect after a substantial delay,
and when used as an inhalant produces irritation and reflex
bronchoconstriction. Hence, smoking marijuana has been the most
dependable way of delivering a clinically effective dose of THC. There
is an understandable concern among clinical researchers that smoking
is an unsuitable mode of administering any drug, and an especially
inappropriate way to administer a drug to patients with asthma,
because it would inevitably involve the delivery of other noxious
chemicals that would nullify its therapeutic value in the short term,
and carry an increased risk of other respiratory disease and possibly
cancer in the long term (Tashkin, 1993). The unwanted psychotropic
effects from marijuana smoking have also been a barrier to its use as
an anti-asthmatic drug. Some investigators (e.g. Graham, 1986) have
nonetheless argued that the suitability of THC as a spray should be
further investigated because of the possible hazards of the chronic
use of the more widely-used beta-blocker antagonists. The recent
discovery of the cannabinoid receptor and ligand may prompt a
re-examination of this question.
8.6 Cannabinoids as analgesics
There is some animal evidence that THC has an analgesic effect which
operates via a different mechanism from that of the opioid drugs
(Segal, 1986). There is a small amount of human experimental studies
which have reported mixed evidence of an analgesic effect (Nahas,
1984). There has been little clinical evidence beyond historical use
for various forms of chronic pain, including migraine, dysmenorrhoea,
and neuralgia, and the small number of case histories of its use in
chronic pain, dysmenorrhoea, labour pain, and migraine reported by
Grinspoon and Bakalar (1993).
Only one double-blind controlled cross-over study has been reported.
This study compared the analgesic effect of THC and codeine in
patients with cancer pain (Noyes et al, 1975). The findings suggested
that 20mg of THC was of equivalent analgesic effect to 120mg of
codeine. However, neither drug produced substantial analgesia in these
patients, and the majority of patients found the psychotropic effects
of 20mg of THC sufficiently aversive that they discontinued its use.
Clearly, much more basic pharmacological and animal investigation is
required before cannabinoids or their derivatives have any clinical
use as analgesics. Nevertheless, such investigations may be worth
pursuing because of the dependence potential of the more potent opioid
analgesics, and the likelihood that any cannabinoid mediated analgesic
effect operates by a different mechanism to that of the opioids.
8.7 Other possible therapeutic uses
A variety of other therapeutic uses have been suggested, although few
have been investigated in any depth. In the late 1940s, for example,
there were some investigations of the therapeutic uses of the
euphoriant properties of cannabis, as a possible anti-depressant agent
in the form of synhexil, a synthetic cannabis analogue. The results in
one uncontrolled study were positive, but these were not replicated in
later studies using lower doses (Nahas, 1984; Grinspoon and Bakalar,
1993). None of these suggestions have been further investigated,
probably because of the potential for THC to produce dysphoric and
other unwanted psychotropic side effects.
8.8 Cannabis and AIDS
One of the areas of greatest contemporary interest in the therapeutic
uses of cannabinoids and cannabis has been their possible roles as an
anti-nausea agent, an appetite stimulant and an analgesic in patients
with AIDS (Randall, 1989). The development of this interest seems to
have replicated the earlier discovery of the anti-emetic effects of
cannabis in young cancer patients in the 1970s. AIDS patients often
experience nausea and weight loss, either while receiving cytotoxic
drugs to suppress HIV, or as a direct effect of the AIDS spectrum
diseases. Many patients have been recreational cannabis users, and so
have reported that the smoking of marijuana produces a diminution in
their nausea, an increased appetite, reduced pain, and general
improvements in well being. AIDS advocacy groups have accordingly
argued that marijuana should be made legally available to AIDS
patients (e.g. Randall, 1991).
So far the bulk of evidence for these therapeutic claims has been
provided by case reports (see Randall, 1989). There has been one small
uncontrolled study of 10 symptomatic AIDS patients which suggested
that dronabinol (synthetic THC) may be effective in reducing nausea
and stimulating appetite (Plasse et al, 1991). The evidence of its
anti-emetic properties in cancer patients seems to support its
potential application in AIDS treatment, and is deserving of further
investigation.
A potential concern with the use of cannabinoids in HIV positive
individuals and AIDS patients is the possible immunosuppressive
effects of cannabinoids. Although, as argued above, this effect is
likely to be small and of limited concern when used intermittently in
cancer patients, it is of potentially greater significance in AIDS
patients, since cannabis would be used regularly by patients with a
major immune system disorder. Even a small impairment in immunity may
have major consequences for HIV and AIDS affected individuals. Recent
epidemiological evidence does something to allay this concern. A large
prospective cohort study of HIV/AIDS in homosexual and bisexual men
recently failed to find any relationship between cannabis use, or any
other psychoactive drug use, and the rate at which HIV positive men
developed clinical AIDS (Kaslow et al, 1989). Nonetheless, the issue
of immunosuppression needs to be explicitly investigated in any
research which is undertaken into the therapeutic uses of cannabinoids
in the treatment of AIDS.
8.9 The limitations of anecdotal evidence
Much of the case for the therapeutic uses of cannabinoids as other
than anti-emetic agents depends upon anecdotal evidence from case
histories. Such evidence has justifiably come to be distrusted as
evidence of therapeutic effectiveness in clinical medicine, especially
in the case of chronic conditions which have a fluctuating course of
remission and exacerbation. In such diseases, it is difficult to
exclude alternative explanations of any apparent relationship between
the use of a drug (e.g. THC) and an improvement in a patient's
condition. Among the alternative explanations that are most difficult
to exclude in a single case or even a succession of single cases is
simple coincidence: that is, there may be no relationship between the
use of the drug and improvement; the apparent relationship between the
two may have arisen because the use of the drug preceded an
improvement in the patient's condition that would have occurred in its
absence. This is especially likely to occur in a chronic condition
with a fluctuating course. In addition, the well-known placebo effect
which is observed in many conditions may explain the apparent benefits
of a drug or other treatment. It is for these reasons that this review
has relied upon evidence from controlled clinical trials in appraising
the therapeutic uses of cannabinoids.
Grinspoon and Bakalar (1993) have attempted to defend anecdotal
evidence of therapeutic efficacy of cannabinoids. They argue that a
double standard has been used in the appraisal of the safety and
efficacy of cannabinoids: anecdotal evidence of harm has been readily
accepted while anecdotal evidence of benefit has been discounted.
Although at first glance "double standards" may seem to describe the
behaviour of the regulatory authorities, it is defensible to use
different standards of proof when evaluating the benefits and the
costs of therapeutic drugs. It is reasonable to err on the side of
caution by requiring stronger evidence of benefit from putatively
therapeutic drugs in order to ensure that the possible risks incurred
by their therapeutic use do not outweigh their benefits. Moreover,
this behaviour is not peculiar to the therapeutic appraisal of
cannabinoids; it is standard practice in the therapeutic appraisal of
all drugs. Medical practitioners are encouraged to report cases
histories of possible adverse effects of prescribed drugs. Such
reports are treated as a noisy but necessary way of detecting rare but
serious side effects of drugs that have not been detected in clinical
trials or animal studies.
8.10 The politics of therapeutic cannabinoid use
A puzzle in the field of cannabinoid therapeutics is that despite the
positive appraisal of the therapeutic potential of cannabinoids as
anti-emetics and anti-glaucoma agents, they have not been widely used.
Nor has the detailed type of clinical pharmacological research been
undertaken on optimal methods of clinical use in those areas where the
cannabinoids do have therapeutic potential (e.g. as anti-emetics).
Part of the reason for this is that research on the therapeutic use of
these compounds has become a casualty of the debate in the United
States about the legal status of cannabis. This emerges from an
inspection of the arguments recently advanced for and against an
application to the United States Drug Enforcement Agency to change the
status of marijuana under the Controlled Substances Act, 1970 from a
schedule I drug which has no accepted medical use to a schedule II
drug which has an accepted medical use (see Randall, 1988, 1989,
1990).
The proponents of rescheduling (National Organisation for the Reform
of Marijuana Laws, Alliance for Cannabis Therapeutics, and Cannabis
Corporation of America) have argued that marijuana should be available
for medical use, as smoking is the most effective mode of delivering
THC for some therapeutic purposes. The opponents of rescheduling (Drug
Enforcement Agency, International Chiefs of Police, The National
Federation of Parents for a Drug Free Youth) have countered that
marijuana has no therapeutic use, since its few uses are better met,
either by other more effective drugs which do not have the
psychoactive effects of THC, or by the oral delivery of synthetic
cannabinoids. They have been supported by medical researchers and
practitioners who argue for the therapeutic superiority of
pharmaceutically pure drugs which can be given in defined doses (e.g.
Levitt, 1986; Mechoulam, 1988; Nahas, 1984).
Medical researchers who have supported the rescheduling of marijuana
(e.g. Grinspoon and Bakalar, 1993; Merritt, 1988; Mikuriya, 1990;
Morgan, 1990; Weil, 1988) have argued that smoked cannabis is superior
to oral synthetic cannabinoids in effectiveness and has a lower risk
of producing unwanted psychoactive side-effects. Apart from the
unsuitability of oral medication for patients who are vomiting, their
main arguments in favour of smoking as a route of THC administration
are similar to the reasons recreational users often give for
preferring smoking to the oral use of cannabis. The greater
bioavailability of THC via smoking produces a more dependable
therapeutic effect, which is more easily controlled because users have
a greater ability to titrate their dose, and hence, to maximise the
desired effects while minimising the unpleasant effects. An additional
argument sometimes used is that there may be other cannabinoids
present in the crude plant product which modulate the undesired side
effects, including the unpleasant dysphoric effects of THC (Grinspoon
and Bakalar, 1993). There is also suggestive evidence that smoked
cannabis is as effective as oral THC, and may be preferred by patients
because of the greater control they have over dose (Chang et al,
1979).
Opponents of marijuana rescheduling argue that the undesirable
psychoactive side effects of THC disqualify it from widespread medical
use, whatever the route of administration. Most also believe that
smoking is a medically unacceptable route of administration of THC
because it is unsuitable for very young and very old patients, there
is a risk of infection with micro-organisms which may contaminate the
plant material, and there is the danger that chronic smoke inhalation
may produce or exacerbate bronchitis, and expose the user to
carcinogens (e.g. Levitt, 1986; Mechoulam, 1988; Nahas, 1984).
The proponents of rescheduling respond that none of these are
compelling reasons for rejecting smoked marijuana for therapeutic
purposes until more potent and specific therapeutic cannabinoids have
been identified and synthesised. Smoking, they point out, would not be
a compulsory method of administration; only an option for those
patients who preferred it, as would the use of cannabinoids if
patients did not like their psychoactive effects. The contamination of
micro-organisms reported with blackmarket cannabis can be overcome,
they argue, by standardising dose and using an anti-microbial
treatment, as has been done by National Institute on Drug Abuse (NIDA)
in preparing cannabis cigarettes for research (Randall, 1988). The
risks of bronchitis and respiratory tract cancers, it is argued, are
small with the intermittent and time-limited smoking of cannabis that
would occur in the course of cancer chemotherapy. In any case,
proponents of rescheduling argue, it is probably a risk that many
patients with a life-threatening illness may be prepared to run, as
shown by their preparedness to take highly toxic and carcinogenic
anti-cancer agents.
Weil (1988) has argued that some opponents have used double standards
in appraising the risks of marijuana smoking. According to Weil, the
most common psychoactive effects of marijuana (euphoria, somnolence
and dysphoria) are minor, non-life-threatening and self-limiting
effects that can be easily managed, and are of much less severity than
the side effects of many other widely-used therapeutic drugs. Medical
witnesses for the government, he claims, "do not contrast marijuana's
supposed adverse effects with the known adverse effects of drugs
routinely prescribed for the treatment of conditions like cancer,
glaucoma and multiple sclerosis. Instead, ... [they] compare marijuana
to some abstract, unobtainable standard of perfection" (p437).
Merritt (1988) has made a similar point in criticising the arguments
raised against the therapeutic use of marijuana to manage glaucoma: "
... each drug family used in glaucoma therapy is capable of producing
a lethal response, even when properly prescribed and used .. [p470]
[but] these drugs are all deemed "safe" for use in glaucoma therapy ..
because their adverse consequences are considered less threatening to
the patient than blindness" (p472). Yet marijuana is excluded from
therapeutic use because of a possible risk of cancer from long-term
daily smoking. "I cannot see", observes Merritt, "how an alleged case
of marijuana-induced lung cancer which results in death is
significantly different in result from an acute adverse reaction to a
myotic drug which results in respiratory failure, except, of course,
that the patient with cancer is likely to outlive the patient who is
unable to draw in a breath of air" (p474).
Although the debate about the rescheduling of marijuana has been
ostensibly about the safety and efficacy of marijuana use, it has been
driven by the debate about the legal status of recreational marijuana
use. For example, some of the groups advocating the therapeutic use of
cannabis have also been proponents of cannabis legalisation (e.g.
NORML), thereby fuelling the fears of opponents of cannabis use that
success in the campaign for marihuana rescheduling will be the thin
edge of a wedge to legalise cannabis. Other proponents of legalisation
(e.g. Grinspoon and Bakalar, 1993) have turned this reasoning around,
by arguing for the legalisation of cannabis as a way of making
cannabis available for therapeutic purposes.
On the other side of the argument are those opponents of marijuana use
who fear that the admission that marijuana, or any of its
constituents, may have a therapeutic use will send the "wrong message"
to youth. This has led to the denial that cannabinoids have any
therapeutic effects, and to attempts to stifle all scientific inquiry
into any such effects. For example, Mr Bernstein representing the
National Federation of Parents for a Drug Free Youth had the following
to say in his summing up against Rescheduling marijuana before Judge
Young (1989):
"If marijuana were to be rescheduled to Schedule II, what kind of
message are we sending to a nation that is engaged in a battle for
it's very survival because of epidemic drug abuse? ... will not the
message be that marijuana is good for cancer, good for glaucoma, good
for spasticity and a host of other illnesses? Now to all of this who
are the most vulnerable? The answer is, of course, our young people.
Their reaction will be that if it is good for all of these things, it
can't be bad for me. We then have another youngster trying marijuana,
the gateway drug and probably starting down the road that leads to
nowhere but destruction" (in Randall, 1989, p395).
It is unfortunate that a connection has been forged between the
debates about the legal status of cannabis as a recreational drug and
the use of cannabinoids for therapeutic use. Any such connection is
spurious, since there is a world of difference between the use of
controlled doses of a purified drug under medical supervision and the
recreational use of crude preparations of a drug. In a rational world,
clinical decisions about whether to use pure cannabinoid drugs should
not be abrogated because crude forms of the drug may be abused by
those who use it recreationally. As a community we do not allow this
type of thinking to deny us the use of opiates for analgesia. Nor
should it be used to deny access to any therapeutic uses of
cannabinoids derivatives that may be revealed by pharmacological
research.
8.11 Conclusions
The following provisional conclusions can be drawn on the available
evidence. First, there is good evidence for the therapeutic potential
of THC as an anti-emetic agent. Although uncertainty exists about the
most optimal method of dosing and the advantages and disadvantages of
different routes of administration, there is sufficient evidence to
justify it being made available in pure synthetic form to cancer
patients. In the light of the recent development of more effective
anti-emetic agents, it remains to be seen how widely used the
cannabinoids will be. Second, there is reasonable evidence for the
potential efficacy of THC in the treatment of glaucoma, especially in
cases which have proved resistant to existing anti-glaucoma agents.
Further research is clearly required, but this should not prevent its
use under medical supervision in poorly controlled cases, provided
patients make informed decisions about its use in the light of
information about the possible health risks of long-term use. Third,
there is sufficient suggestive evidence of the potential usefulness of
various cannabinoids as analgesic, anti-asthmatic, anti-spasmodic, and
anti-convulsant agents to warrant further basic pharmacological and
experimental investigation, and perhaps clinical research into their
effectiveness.
Despite the basic and clinical research work which was undertaken in
late 1970s and early 1980s, the cannabinoids have not been widely used
therapeutically, nor have further investigations been conducted along
the lines suggested in the positive evaluations made by the Institute
of Medicine (1982). This seems largely attributable to the fact that
clinical research on the therapeutic use of cannabinoids has been
discouraged by regulation and a lack of funding in the United States,
where most cannabis research has been conducted. The discouragement of
therapeutic research, in turn, derives from the fact that THC, the
most therapeutically effective cannabinoid, has the psychoactive
effects sought by recreational users. In opposing the therapeutic uses
of cannabinoids, some researchers have used double standards in
appraising efficacy and safety, setting unreasonably high standards in
assessing the evidence on the comparative therapeutic safety and
efficacy of cannabinoids and existing agents. The application of the
same demanding standards to existing agents for the candidate
diseases, and more generally, to existing psychoactive drugs that are
widely used in medical practice, would denude the pharmacopoeia. The
recent discovery of the cannabinoid receptor may help to overcome some
of the resistance to research into the therapeutic uses of
cannabinoids, by holding out the prospect that the psychoactive
effects of the cannabinoids can be disengaged from their other
therapeutically desirable effects.
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9. An overall appraisal of the health and psychological effects of
cannabis
9.1 Summary
The following is a summary of the major adverse health and
psychological effects of acute and chronic cannabis use, grouped
according to the degree of confidence in the view that the
relationship between cannabis use and the adverse effect is a causal
one.
9.1.1 Acute effects
The major acute psychological and health effects of cannabis
intoxication are:
• anxiety, dysphoria, panic and paranoia, especially in naive
users;
• cognitive impairment, especially of attention and memory for the
duration of intoxication;
• psychomotor impairment, and probably an increased risk of
accidental injury or death if an intoxicated person attempts to drive
a motor vehicle or operate machinery;
• an increased risk of experiencing psychotic symptoms among those
who are vulnerable because of a personal or family history of
psychosis; and
• an increased risk of low birth weight babies if cannabis is used
during pregnancy.
9.1.2 Chronic effects
The major health and psychological effects of chronic cannabis use,
especially daily use over many years, remain uncertain. On the
available evidence, the major probable adverse effects appear to be:
• respiratory diseases associated with smoking as the method of
administration, such as chronic bronchitis, and the occurrence of
histopathological changes that are precursors to the development of
malignancy;
• development of a cannabis dependence syndrome, characterised by
an inability to abstain from or to control cannabis use; and
• subtle forms of cognitive impairment, most particularly of
attention and memory, which persist while the user remains chronically
intoxicated, and may or may not be reversible after prolonged
abstinence from cannabis.
The following are the major possible adverse effects of chronic, heavy
cannabis use which remain to be confirmed by controlled research:
• an increased risk of developing cancers of the aerodigestive
tract, i.e. oral cavity, pharynx, and oesophagus;
• an increased risk of leukemia among offspring exposed in utero;
and
• a decline in occupational performance marked by underachievement
in adults in occupations requiring high level cognitive skills, and
impaired educational attainment in adolescents.
• birth defects occurring among children of women who used cannabis
during their pregnancies.
9.1.3 High risk groups
A number of groups can be identified as being at increased risk of
experiencing some of these adverse effects.
Adolescents
• Adolescents with a history of poor school performance may have
their educational achievement further limited by the cognitive
impairments produced by chronic intoxication with cannabis.
• Adolescents who initiate cannabis use in the early teens are at
higher risk of progressing to heavy cannabis use and other illicit
drug use, and to the development of dependence on cannabis.
Women of childbearing age
• Pregnant women who continue to smoke cannabis are probably at
increased risk of giving birth to low birth weight babies, and perhaps
of shortening their period of gestation.
• Women of childbearing age who continue to smoke cannabis at the
time of conception or while pregnant possibly increase the risk of
their children being born with birth defects.
Persons with pre-existing diseases
Persons with a number of pre-existing diseases who smoke cannabis are
probably at an increased risk of precipitating or exacerbating
symptoms of their diseases. These include:
• individuals with cardiovascular diseases, such as coronary artery
disease, cerebrovascular disease and hypertension;
• individuals with respiratory diseases, such as asthma,
bronchitis, and emphysema;
• individuals with schizophrenia, who are at increased risk of
precipitating or of exacerbating schizophrenic symptoms; and
• individuals who are or have been dependent upon alcohol and other
drugs, who are probably at an increased risk of developing dependence
on cannabis.
9.1.4 A caveat
As has been stressed throughout this document, there is uncertainty
surrounding many of these summary statements about the adverse health
effects of acute, and especially chronic, cannabis use. To varying
degrees, these statements depend upon inferences from animal research,
laboratory studies, and clinical observations about the probable ill
effects. In some cases, the inferences depend upon arguments from what
is known about the adverse health effects of other drugs, such as
tobacco and alcohol. In very few cases are there sufficient studies
which provide the detailed evidence that epidemiologists would require
to make informed judgments about the health effects of cannabis; the
interpretation of what epidemiological evidence is available is
complicated by difficulties in quantifying degree of exposure to
cannabis, and in excluding alternative explanations (including other
drug use) of associations observed between cannabis use and adverse
health outcomes. These interpretative problems are especially obvious
in the case of many of the alleged psychological outcomes of cannabis
use in adolescence, since many of these putative "consequences" (e.g.
poor school performance, deviant behaviour) also antedate the use of
cannabis. Nevertheless, these statements provide the best available
basis for making societal decisions about what policies ought to be
adopted towards cannabis use.
9.2 Two special concerns
Two issues which have hitherto been ignored require brief discussion.
These are the possible health implications of: the storage of THC in
body tissue; and any increases in the average potency of cannabis
products (as indexed by THC content) that may have occurred in recent
decades.
9.2.1 Storage of THC
There is good evidence that with repeated dosing of cannabis at
frequent intervals, THC can accumulate in fatty tissues in the human
body where it may remain for considerable periods of time (see above
pp34-35). Attitudes towards this fact are strongly coloured by the
perceiver's views about cannabis use: those who are opposed to its use
usually regard this as a cause for major concern; proponents of
cannabis use largely ignore it. There is no evidence to make a
confident judgment one way or the other. The storage of cannabinoids
would be serious cause for concern if THC were a highly toxic
substance which remained physiologically active while stored in body
fat. The evidence that THC is a highly toxic substance is weak,
although it does have a bewildering variety of biological effects
(Martin, 1986). Its degree of activity while stored has not been
investigated. One potential health implication of THC storage is that
the release of stored cannabinoids into blood may produce unexpected
symptoms of cannabis intoxication. The release of stored THC has been
suggested as an explanation of "flashback experiences" (e.g. Negrete,
1988; Thomas, 1993). Such experiences have been rarely reported by
cannabis users (e.g. Edwards, 1983), and even in these cases
interpretation of their significance is complicated by the fact that
those who have reported such experiences have typically used other
hallucinogenic drugs. Whatever the uncertainties about health
implications of THC storage, all potential users of cannabis should be
aware that it occurs.
9.2.2 Increases in the potency of cannabis
Cohen (1986) has been credited (Mikuriya and Aldrich, 1988) with
initiating the recent claim that the existing medical literature on
the health effects of cannabis underestimates its adverse effects
because it was based upon research conducted on less potent forms of
marijuana (O.5 per cent to 1.0 per cent THC) than those that became
available in the USA in the past decade (3.5 per cent THC in
1985-1986). This claim has been repeated often in the popular and
scientific media, and supported by anecdotal evidence that samples
containing up to 40 per cent THC have been seized by the police. An
alleged "ten-fold" increase in potency has contributed to recent
concerns about the health effects of cannabis, because of the
assumption that increases in average potency necessarily mean
substantial increases in the health risks of cannabis use. In
Australia this concern has been recently raised by the discovery of
hydroponically cultivated clones of cannabis plants that produce high
levels of THC, and by reports of the importation of high THC producing
strains of cannabis from New Guinea.
There are a number of points to be made about this issue. First, the
evidence for an increase in potency is not as clear as Cohen (1986)
claimed, or as it seems from the data reported by ElSohy and ElSohy
(1989). The inference that these data demonstrate that potency has
increased depends upon the assumption that the samples analysed are
representative of cannabis consumed. Mikuriya and Aldrich (1988), for
example, have contested this assumption. They cite the results of
chemical analyses conducted on cannabis samples in California during
the middle 1970s in which the average potency was well within the
ranges reported in samples seized by the US Drug Enforcement Agency in
the middle 1980s. They also argue that the analyses of the DEA samples
from the middle 1970s underestimated THC potency because the samples
were not properly stored, allowing their average THC content to be
degraded.
Second, even if we allow that there probably has been a small increase
in the THC potency of cannabis products in the USA, there is at
present no evidence of a similar increase in Australia. There is good
evidence from police samples analysed in New Zealand over the past
decade that average potency has not increased there (Bedford, 1993).
Press reports of increased potency have often been misleading in that
they have been based upon individual samples of highly concentrated
cannabis extracts, such as hash oil, which have never had a major
share of the cannabis market.
Third, the use of average potency can be also be potentially
misleading, since the average ignores differences between cannabis
users in preferences for cannabis products of varying potency. There
probably has always been a market for more potent products among the
heavier, and hence, more THC-tolerant, cannabis users. Marijuana
probably remains the majority preference of cannabis users, although
this is an issue worthy of investigation.
Fourth, it is not obvious that more potent forms of cannabis
inevitably have more adverse effects on users' health than less potent
forms. Indeed, it is conceivable that increased potency may have
little or no adverse effect if users are able to titrate their dose to
achieve the desired state of intoxication, as some have argued they do
(e.g. Kleiman, 1992; Mikuyira and Aldrich, 1988). If users were able
to titrate their dose, the use of more potent cannabis products would
reduce the amount of cannabis material that was smoked, which would
marginally reduce the risks of developing respiratory diseases.
Fifth, even if users do not titrate their dose of THC, (or if they do
so inefficiently), any increase in the average dose received would not
inevitably have an adverse impact on users' health. The effect would
depend upon the type of health effect in question, and the relative
experience of users. Higher average doses may produce an increase in
the risk of minor adverse psychological effects of acute use,
especially among naive users. This could be a desirable outcome if it
discouraged further experimentation with the drug. Among experienced
cannabis users, an increased average dose may increase the risks of
accidents among those who drive while intoxicated, especially if
combined with alcohol. Higher average doses may also increase the risk
of regular users developing dependence.
All considered then, it is far from established that the average THC
potency of cannabis products has substantially increased over recent
decades. If potency has increased, it is even less certain that the
average health risks of cannabis use have materially changed as a
consequence, since users may titrate their dose to achieve the desired
effects. Even if the users are inefficient in titrating their dose of
THC, it is far from certain that the probability of adverse health
effects will be thereby increased. Nevertheless, given these concerns
about THC potency, it would be preferable to conduct research on the
issue rather than to rely upon inferences about the likely effects of
increased cannabis potency. Studies of the ability of experienced
users to titrate their dose of THC would contribute to an evaluation
of this issue, as would the inclusion in sample surveys of questions
about the form and perceived potency of cannabis products used.
9.3 A comparative appraisal of health risks: alcohol, tobacco and
cannabis use
The probable and possible adverse health and psychological effects of
cannabis need to be placed in comparative perspective to be fully
appreciated. A useful standard for such a comparison is what is known
about the health effects of alcohol and tobacco, two other widely used
psychoactive drugs. Cannabis shares with tobacco, smoking as the usual
route of administration, and resembles alcohol in being used for its
intoxicating and euphoriant effects.
Considerable care must be exercised in making such comparisons.
Firstly, the quantitative risks of tobacco and alcohol use are much
better known than the health risks of cannabis, since alcohol and
tobacco have been consumed by substantial proportions of the
population, and there have been 40 years of scientific studies of the
health consequences of their use. Cannabis, by contrast, has been much
less widely used, and for a shorter period, in Western society; it has
been primarily used by healthy young adults, and there have been few
studies of its adverse health effects.
Secondly, the prevalence of use of alcohol and tobacco is much higher
than that of cannabis. For example, the proportions of the Australian
population who are at least weekly users of alcohol, tobacco and
cannabis are: 61 per cent, 29 per cent, (Department of Health, Housing
and Community Services, 1992), and 11 per cent (Donnelly and Hall,
1994) respectively. Any overall comparison of the health consequences
of the three drug types that was based upon existing patterns of use
would unfairly disadvantage alcohol and tobacco. Any attempt to adjust
for the differences in prevalence (e.g. by estimating the health
effects if the prevalence of cannabis use was the same as those for
alcohol and tobacco) would involve making controversial assumptions,
so no such attempt has been made.
The very different prevalence of use of alcohol, tobacco and cannabis,
and the fact that we know a great deal more about the adverse effects
of alcohol and tobacco use, precludes any quantitative comparison of
the current health consequences of these drugs. Nevertheless, a
qualitative comparison of the probable health risks of cannabis with
the known health risks of alcohol and tobacco serves the useful
purpose of reminding us of the risks we currently tolerate with our
favourite psychoactive drugs.
In undertaking this qualitative comparison, we have avoided the
necessity to comprehensively review the vast literatures on the health
effects of alcohol and tobacco by using the following authorities as
the principal sources of evidence for our assertions about their
health risks: Anderson et al (1993); Holman et al's (1988) compendium
of the health effects of alcohol and tobacco; the Institute of
Medicine (1987); the International Agency for Research into Cancer
(1990); Roselle et al (1993); and the Royal College of Physicians
(1987).
9.3.1 Acute effects
Alcohol. The major risks of acute cannabis use are similar to the
acute risks of alcohol intoxication in a number of respects. First,
both drugs produce psychomotor and cognitive impairment, especially of
memory and planning. The impairment produced by alcohol increases
risks of various kinds of accident, and the likelihood of engaging in
risky behaviour, such as dangerous driving, and unsafe sexual
practices. It remains to be determined whether cannabis intoxication
produces similar increases in accidental injury and death, although on
balance it probably does.
Second, there is good evidence that substantial doses of alcohol taken
during the first trimester of pregnancy can produce a foetal alcohol
syndrome. There is suggestive but far from conclusive evidence that
cannabis used during pregnancy may have similar adverse effects.
Third, there is a major health risk of acute alcohol use that is not
shared with cannabis. In large doses alcohol can cause death by
asphyxiation, alcohol poisoning, cardiomyopathy and cardiac infarct.
There are no recorded cases of fatalities attributable to cannabis,
and the extrapolated lethal dose from animal studies cannot be
achieved by recreational users.
Tobacco. The major acute health risks that cannabis shares with
tobacco are the irritant effects of smoke upon the respiratory system,
and the stimulating effects of both THC and nicotine on the
cardiovascular system, both of which can be detrimental to persons
with cardiovascular disease.
9.3.2 Chronic effects
Alcohol. There are a number of risks of heavy chronic alcohol use,
some of which may be shared by chronic cannabis use. First, heavy use
of either drug increases the risk of developing a dependence syndrome
in which users experience difficulty in stopping or controlling their
use. There is strong evidence of such a syndrome in the case of
alcohol and reasonable evidence in the case of cannabis. A major
difference between the two is that it is uncertain whether a
withdrawal syndrome reliably occurs after dependent cannabis users
abruptly stop their cannabis use, whereas the abrupt cessation of
alcohol use in severely dependent drinkers produces a well defined
withdrawal syndrome which can be potentially fatal.
Second, there is reasonable clinical evidence that the chronic heavy
use of alcohol can produce psychotic symptoms and psychoses in some
individuals. There is suggestive evidence that chronic heavy cannabis
use may produce a toxic psychosis, precipitate psychotic illnesses in
predisposed individuals, and exacerbate psychotic symptoms in
individuals with schizophrenia.
Third, there is good evidence that chronic heavy alcohol use can
indirectly cause brain injury - the Wernicke-Korsakov syndrome - with
symptoms of severe memory defect and an impaired ability to plan and
organise. With continued heavy drinking, and in the absence of vitamin
supplementation, this injury may produce severe irreversible cognitive
impairment. There is good reason for concluding that chronic cannabis
use does not produce cognitive impairment of comparable severity.
There is suggestive evidence that chronic cannabis use may produce
subtle defects in cognitive functioning, that may or may not be
reversible after abstinence.
Fourth, there is reasonable evidence that chronic heavy alcohol use
produces impaired occupational performance in adults, and lowered
educational achievements in adolescents. There is suggestive evidence
that chronic heavy cannabis use produces similar, albeit more subtle
impairments in occupational and educational performance of adults.
Fifth, there is good evidence that chronic, heavy alcohol use
increases the risk of premature mortality from accidents, suicide and
violence. There is no comparable evidence for chronic cannabis use,
although it is likely that dependent cannabis users who frequently
drive while intoxicated with cannabis increase their risk of
accidental injury or death.
Sixth, alcohol use has been accepted as a contributory cause of cancer
of the oropharangeal organs in men and women. There is suggestive
evidence that chronic cannabis smoking may also be a contributory
cause of cancers of the aerodigestive tract.
Tobacco. The major adverse health effects shared by chronic cannabis
and tobacco smokers are chronic respiratory diseases, such as chronic
bronchitis, and probably, cancers of the aerodigestive tract (i.e. the
mouth, tongue, throat, oesophagus, lungs). The increased risk of
cancer in the aerodigestive tract is a consequence of the shared route
of administration by smoking. It is possible that chronic cannabis
smoking also shares the cardiotoxic properties of tobacco smoking,
although this possibility remains to be investigated.
It should be stressed that this section only describes the adverse
health effects of alcohol and tobacco for which there is some evidence
that chronic heavy cannabis use may also cause. It does not,
therefore, provide an exhaustive inventory of all the adverse health
effects of either chronic alcohol or tobacco use. Among the major
additional adverse health effects of chronic heavy alcohol use which
are not shared by cannabis are: liver cirrhosis, peripheral
neuropathy, and gastritis.
9.4 Implications for harm reduction
The simplest health advice to anyone who wishes to avoid the probable
acute and chronic adverse health effects of cannabis is to abstain
from using the drug. This advice is especially apt for persons with
any of the diseases (e.g. cardiovascular) or conditions (e.g.
pregnancy) which would make them more vulnerable to the adverse
effects of cannabis.
Current cannabis users should be aware of the following risks of using
the drug. First, the risk of being involved in a motor vehicle
accident is likely to be increased when cannabis users drive while
intoxicated by cannabis. The combination of alcohol and cannabis
intoxication will substantially increase this risk. Second, the
chronic smoking of cannabis poses significant risks to the respiratory
system, apart from any specific effects of THC. Third, the respiratory
risks of cannabis smoking are amplified if deep inhalation and
breath-holding are used to maximise the absorption of THC in the
lungs. This technique greatly increases the delivery and retention of
particulate matter and tar. Fourth, daily or near daily use of
cannabis is to be avoided, as it has a high risk of producing
dependence.
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