CHAPTER 4 TOXIC EFFECTS OF CANNABIS AND CANNABINOIDS:
REVIEW OF THE EVIDENCE
4.1 The prohibition of the recreational use of
cannabis, and some of the doubts about medical use, are based on the presumption that
cannabis is harmful to individual and public health. We have tested the strength of that
presumption, and this Chapter records what we have found. New research on this subject is
constantly coming forward, so this cannot be said to be the last word on it. Although
cannabis is not in the premier league of dangerous substances, new research tends to
suggest that it may be more hazardous to health than might have been thought only a few
years ago (Edwards QQ 21, 27).
4.2 In assessing the adverse effects associated
with cannabis use, we have been assisted by a number of detailed recent reviews, including
the recent WHO report Cannabis: a health perspective and research agenda
(WHO/MSA/PSA/97.4); the Australian National Drug Strategy report The health and
psychological consequences of cannabis use (1994) and other documents[9] submitted by Professor Wayne Hall, Executive Director of
the Australian National Drug and Alcohol Research Centre in Sydney, and his colleagues;
and the recent reviews noted above commissioned by the Department of Health. The evidence
submitted to us by the Royal Society and the Royal College of Psychiatrists is also
particularly relevant.
Acute (short-term) effects of cannabis
4.3 The acute toxicity of cannabis and the
cannabinoids is very low; no-one has ever died as a direct and immediate consequence of
recreational or medical use (DH QQ 219223). Official statistics record two deaths
involving cannabis (and no other drug) in 1993, two in 1994 and one in 1995
(HC WA 533, 21 January 1998); but these were due to inhalation of vomit.
Animal studies have shown a very large separation (by a factor of more than 10,000)
between pharmacologically effective and lethal doses.
4.4 One minor toxic side-effect of taking cannabis
which merits attention is the short-term effect on the heart and vascular system. This can
lead to significant increases in heart rate and a lowering of the blood pressure (Pertwee
Q 299). For this reason patients with a history of angina or other cardiovascular disease
could be at risk and should probably be excluded from any clinical trials of
cannabis-based medicines.
4.5 The most familiar short-term effect of cannabis
is to give a "high" — a state of euphoric intoxication. This is, of course,
precisely the effect sought by the recreational user, analogous to the effect of alcohol
and sought for similar reasons. We have been told, however, that people who use cannabis
for medical purposes regard it as an unwelcome side-effect (Hodges Q 97).
4.6 Intoxication with cannabis leads to a slight
impairment of psychomotor and cognitive function, which is important for those driving a
vehicle, flying an aircraft or operating machinery (DH Q 197). The Department of Health
rate this as "the major concern from a public health perspective" raised by
recreational use (p 46), and Professor Hall considers it the most serious
possible short-term consequence of cannabis use, both for the user and for the public
(p 222).
4.7 There is some disagreement about how long such
impairments persist after taking cannabis: most assume that they last for only a few hours
(e.g. Kendall p 266); but Professor Heather Ashton of the University of
Newcastle-upon-Tyne, principal author of the BMA report, suggested that subtle cognitive
impairments could persist for 24 or even 48 hours or more (Q 72), whereas the
DETR say "probably .... 24 hours at most" (Press Notice 94/Transport, 11
February 1998). On the other hand the impairment in driving skills does not appear to be
severe, even immediately after taking cannabis, when subjects are tested in a driving
simulator. This may be because people intoxicated by cannabis appear to compensate for
their impairment by taking fewer risks and driving more slowly, whereas alcohol tends to
encourage people to take greater risks and drive more aggressively (POST note 113; cp DH
p 240).
4.8 Analysis of blood samples from road traffic
fatalities in 1996-97 (the results of the first 15 months of a three year DETR
study—Press Notice 94/Transport, 11 February 1998) showed that 8 per
cent of the victims were positive for cannabis, including 10 per cent of the victims who
were driving. However, it is not clear what figures would have been obtained from a random
sample of road users not involved in accidents (DH Q 211); and some of those who
tested positive may have taken the cannabis as much as 30 days before, so that the
effects would have worn off long since (DH p 240). The interpretation of traffic
accident data is further confounded by the fact that 22 per cent of the drivers found
to be cannabispositive also had evidence of alcohol intake; proportions of
alcoholpositives among cannabispositive drivers as high as 75 per cent have been
reported in other countries in similar studies. Professor Hall considers cannabis's
contribution to danger on the roads to be very small; in his view the major effect of
cannabis use on driving may be in amplifying the impairments caused by alcohol (cp Keen
Q 42). According to a survey of 1,333 regular cannabis users by the Independent Drug
Monitoring Unit (IDMU) in 1994, users who drove reported a level of accidents no higher
than the general population; those with the highest accident rates were more likely to be
heavier poly-drug users.
4.9 It is difficult to see how cannabis
intoxication could be monitored, if its use were permitted. There could be no equivalent
of the breathalyser for alcohol, since small amounts of cannabis continue to be released
from fat into the blood long after any short-term impairment has worn off (see paragraph
3.5 above).
4.10 A single dose of cannabis for an inexperienced
user, or an overdose for an habitual user, can sometimes induce a variety of intensely
unpleasant psychic effects including anxiety, panic, paranoia and feelings of impending
doom (BMA p 9, RCPsych p 282). These adverse reactions are sometimes referred to
as a "whitey" as the subject may become unusually pallid (Montgomery
Q 577). These effects usually persist for only a few hours.
4.11 In some instances cannabis use may lead to a
longer-lasting toxic psychosis involving delusions and hallucinations that can be
misdiagnosed as schizophrenic illness (Strang Q 239, van der Laan Q 512). This is
transient and clears up within a few days on termination of drug use; but the habitual
user risks developing a more persistent psychosis, and potentially serious consequences
(such as action under the Mental Health Acts and complications resulting from the
administration of powerful neuroleptic drugs) may follow if an erroneous diagnosis of
schizophrenia is made. It is also well established that cannabis can exacerbate the
symptoms of those already suffering from schizophrenic illness (Q 239) and may worsen
the course of the illness; but there is little evidence that cannabis use can precipitate
schizophrenia or other mental illness in those not already predisposed to it (RCPsych
p 283).
4.12 These relatively rare adverse psychological
effects of cannabis are not considered to represent a serious limitation on the potential
medical use of the drug (Strang Q 244), save that patients suffering from
schizophrenic illness or other psychoses should be excluded. However they do constitute an
issue for public health. According to the Department of Health, cannabis contributes to
the extra cost of acute psychiatric services imposed by drug misuse, though this cannot be
separately costed (p 46; cp RCPsych p 282). The Royal College of Psychiatrists
(p 284) believe that the proportion of users who experience acute adverse mental
effects is "significant".
Chronic (long-term) toxicity
4.13 Cannabis can have untoward long-term effects
on cognitive performance, i.e. the performance of the brain, particularly in heavy users.
These have been reviewed for us by the Royal College of Psychiatrists and the Royal
Society. While users may show little or no impairment in simple tests of short-term
memory, they show significant impairments in tasks that require more complex manipulation
of learned material (so-called "executive" brain functions) (Edwards Q 21).
There is some evidence that some impairment in complex cognitive function may persist even
after cannabis use is discontinued[10]; but
such residual deficits if present are small, and their presence controversial (van
Amsterdam Q 494, Hall Q 741). Dr Jan van Amsterdam of the Netherlands
National Institute of Public Health and the Environment, who has reviewed the literature
on long-term cognitive effects of prolonged heavy use and kindly came to Westminster to
tell us his findings, pointed out the practical difficulties of assessing possible
residual effects (Q 487). These include the impossibility of obtaining predrug baseline
values (i.e. measures of the cognitive functioning of the subject before their first use
of cannabis), the difficulty of estimating the drug dose taken, the need for a lengthy
"washout" period after termination of use to allow for the slow elimination of
residual cannabis from the body, and the possibility of confusing long-term deficits with
withdrawal effects. He felt that many of the published reports on this subject had not
taken adequate account of these problems.
4.14 The occurrence of an "amotivational
syndrome" in long-term heavy cannabis users, with loss of energy and the will to
work, has been postulated. However it is now generally discounted (van Amsterdam
Q 503); it is thought to represent nothing more than ongoing intoxication in frequent
users of the drug (RCPsych p 283).
4.15 Animal experiments have shown that
cannabinoids cause alterations in both male and female sexual hormones; but there is no
evidence that cannabis adversely affects human fertility, or that it causes chromosomal or
genetic damage (WHO report ch.7). The consumption of cannabis by pregnant women may,
however, lead to significantly shorter gestation and lower birth-weight babies in mothers
smoking cannabis six or more times a week (WHO report ch.8; DH p 47). These effects
may be due to the inhalation of carbon monoxide in cannabis smoke, which lowers the
ability of the blood to carry oxygen to the foetus, rather to any direct effect of
cannabinoids. If so, they are comparable with the effects of smoking tobacco.
4.16 The NHS National Teratology [i.e. foetal
abnormality] Information Service advise, "There are a few case reports of
malformations following marijuana use in pregnancy. However, there is no conclusive
evidence to suggest either an increase in the overall malformation rate or any specific
pattern of malformations". Nevertheless, they warn: "We would not recommend the
legalisation of cannabis because of the potential fetotoxicity that may occur if it is
used in pregnancy" (p 280).
4.17 Most of our witnesses regard the consequences
of smoking cannabis as the most important long-term risk associated with cannabis use[11]. Cannabis smoke contains all of the toxic
chemicals present in tobacco smoke (apart from nicotine), with greater concentrations of
carcinogenic benzanthracenes and benzpyrenes It has been estimated (BMA p 11) that
smoking a cannabis cigarette (containing only herbal cannabis) results in approximately a
fivefold greater increase in carboxyhaemoglobin concentration[12], a threefold greater increase in the amount of tar inhaled, and a
retention in the respiratory tract of one third more tar, than smoking a tobacco
cigarette. Cannabis resin, the most commonly used form of cannabis in the United Kingdom,
is often smoked mixed with tobacco, thus adding the well-documented risks of exposure to
tobacco smoke, while complicating the picture for the researcher.
4.18 Regular cannabis smokers suffer from an
increased incidence of respiratory disorders, including cough, bronchitis and asthma.
Microscopic examination of the cells lining the airways of cannabis smokers has revealed
the presence of an inflammatory response and some evidence for what may be pre-cancerous
changes. There is as yet no epidemiological evidence for an increased risk of lung cancer
(DH p 46, Q 205); but, by analogy with tobacco smoking, such a link may take
25-30 years or more before it becomes evident, and the widespread use of smoked
cannabis in Western societies dates only from the 1970s. There are some reports of an
increased incidence of cancers of the mouth and throat in young cannabis users[13], but so far these involve only small numbers and
no cause and effect relationship has been established. Nevertheless, Professor Hall
considers it a "pretty reasonable bet" that heavy users incur a risk of cancer
(Q 741); and the risk is considered by some of our witnesses to be sufficiently serious to
rule out any approval of long-term medical use of smoked cannabis, and to justify the
present prohibition on recreational use.
Tolerance to cannabis
4.19 Tolerance is the phenomenon whereby a regular
user of a drug requires more each time to achieve the same effect. It is not an adverse
effect in itself; but it may make medical use more difficult, and recreational use more
damaging as the user's demand for the drug increases.
4.20 Dr Pertwee told us that both animal and
human data show that tolerance can develop on repeated administration of high doses of
cannabinoids; tolerance may develop more readily to some effects in animals (e.g. lowering
of body temperature) than to others (Q 304). However Clare Hodges[14], a sufferer from MS, said that she had not experienced tolerance to
the palliative effects of low doses of cannabis, and had been taking the same dose (9g of
herbal cannabis per week, costing about £30 per week, usually smoked) for six years;
neither had other medical users reported tolerance in their experience (QQ 117-119;
cp LMMSG p 269).
4.21 Whether tolerance develops may therefore
depend on how much drug is consumed, and how often. Neil Montgomery, a research
journalist currently studying cannabis users through the Department of Social Anthropology
at the University of Edinburgh, said that his observations of heavy cannabis users (using
more than 28g of cannabis resin per week) suggested that they needed as much as eight
times higher doses to achieve the same psychoactive effects as regular users consuming
smaller doses of the drug (Q 570). Clear evidence of tolerance has also been reported
in volunteers given large doses of THC under laboratory conditions (Pertwee Q 304).
4.22 This conforms with the evidence of Professor
Wall, who compared the experience with morphine and related opiate pain-relieving agents
during the past 20-30 years, pioneered by Dame Cicely Saunders and the Hospice
movement. This has shown that tolerance (and addiction—see below) are not major
problems in the medical use of these drugs, although in recreational use they may pose
severe problems (Q 120).
Dependence on cannabis
4.23 The repeated use of cannabis or cannabinoids
does not result in severe physical withdrawal symptoms when the drug is withdrawn; so many
have argued that these drugs are not capable of inducing dependence. Dr Pertwee, and
Dr David Kendall of the University of Nottingham (p 267), however, described new
evidence from animal studies showing marked signs of withdrawal in animals treated
repeatedly with large doses of cannabinoids and then challenged with a newly developed
cannabinoid CB1 receptor antagonist (see Box 1) called SR141716A. This has provided the
first real evidence for physical dependence and withdrawal symptoms in animals
(QQ 308-310).
4.24 The BMA report says that withdrawal symptoms
from cannabis in man are mild and shortlived; but in the light of the newer definitions
of dependence noted in Box 2 this evidence is inconclusive. Professor Ashton indicated
that she felt cannabis to be potentially addictive, and compared the withdrawal
symptoms—tremor, restlessness and insomnia—to those experienced by users of
alcohol, sleeping pills or tranquillisers. She had talked to students with quite severe
cannabis withdrawal problems (Q 73).
BOX 2: DEFINITIONS OF DEPENDENCE |
|
| The consumption of any psychoactive drug, legal or illegal, can be
thought of as comprising three stages: use, abuse, and addiction. Each stage is marked by
higher levels of drug use and increasingly serious consequences. |
| Abuse and addiction have been defined and redefined by various
organisations over the years. The most influential current system of diagnosis is that
published by the American Psychiatric Association (DSM-IV, 1994). This uses the term substance
dependence instead of addiction, and defines this as a cluster of symptoms indicating
that the individual continues to use the substance despite significant substance-related
problems. The symptoms may include tolerance (the need to take larger and larger
doses of the substance to achieve the desired effect), and physical dependence (an
altered physical state induced by the substance which produces physical withdrawal
symptoms, such as nausea, vomiting, seizures and headache, when substance use is
terminated); but neither of these is necessary or sufficient for the diagnosis of
substance dependence. Using DSM-IV, dependence can be defined in some instances entirely
in terms of psychological dependence; this differs from earlier thinking on these
concepts, which tended to equate addiction with physical dependence. |
|
| The DSM-IV system also defines substance abuse as a less severe
diagnosis, involving a pattern of repeated drug use with adverse consequences but falling
short of the criteria for substance dependence. |
|
4.25 Professor Griffith Edwards, a member of the
Advisory Council on the Misuse of Drugs[15]
(Q 27), said that, using internationally agreed criteria (DSM-IV—see
Box 2), there seemed no doubt that some regular cannabis users become dependent, and
that they suffer withdrawal symptoms on terminating drug use. According to the WHO report,
cannabis dependence is characterised by a loss of control over drug use, cognitive and
motivational impairments that interfere with work performance, lowered self-esteem and
often depression. Professor Hall wrote, "By popular repute, cannabis is not a
drug of dependence because it does not have a clearly defined withdrawal syndrome. There
is, however, little doubt that some users who want to stop or cut down their cannabis use
find it very difficult to do so, and continue to use cannabis despite the adverse effects
that it has on their lives." In oral evidence he added that users who sought
treatment for cannabis dependence had typically taken large amounts of cannabis every day
for perhaps 15 years or more (Q 745).
4.26 The Institute for the Study of Drug Dependence
likewise conclude that, while physical dependence is rare, "Regular users can come to
feel a psychological need for the drug or may rely on it as a "social
lubricant": it is not unknown for people to use cannabis so frequently that they are
almost constantly under the influence" (p 263).
4.27 One measure of the significance of cannabis
dependence is the proportion of users who become dependent. Since cannabis dependence is
poorly defined, and the total number of users is unknown, this figure is elusive. Data
from a recent study of 200 regular users in Australia[16]
suggest that more than 50 per cent of such users may be classified as dependent,
although many of these do not consider themselves as dependent. This corresponds with the
finding of an American study of 1991, cited by the WHO report, that "about half of
those who use cannabis daily will become dependent". According to Professor Hall,
"Epidemiological studies suggest that cannabis dependence in the sense of impaired
control over use is the most common form of drug dependence after tobacco and alcohol,
affecting as many as one in ten of those who ever use the drug" (p 221).
4.28 Neil Montgomery estimates that
approximately 5 per cent of regular cannabis users are heavy users, consuming as much
as 28g of cannabis resin per week. "These are people who have become dependent on
cannabis; they are psychologically addicted to the almost constant consumption of
cannabis...Becoming stoned and remaining stoned throughout the day is their prime
directive" (Q 554).
4.29 Another measure of the extent of cannabis
dependence is the number of people who seek treatment for it. Department of Health figures
(1996) show that in 6 per cent of all contacts with regional drug clinics cannabis
was the main drug of misuse (Q 27). A similar figure, that cannabis users constitute
7 per cent of all new admissions to drug treatment centres in Australia, was reported
recently. Dr Philip Robson[17], who runs a
Regional Drug Dependence Unit in Oxford, said that 4.9 per cent of those admitted to
his unit cited cannabis as their main drug (Q 462). However he did not regard
cannabis as an important drug of addiction: "The drug falls well below the threshold
of what would be expected for a dependencyproducing drug which has clinical
significance...I do not meet people who are prepared to knock over old ladies in the
street or burglarise houses or commit other crimes to obtain cannabis". Professor
Robbins estimated that at least 2 per cent of regular cannabis users (whom he defined
as those using cannabis more than once a week) in the USA are dependent, on the basis of
an estimate of 5m users and an official figure of 100,000 on specific treatment for
cannabis dependency syndrome (Q 623).
4.30 It has been suggested that US figures may be
inflated by people on compulsory treatment, for instance after testing positive at work,
who may not in fact be dependent. According to Professor Hall, however, "In Australia
... drug testing is uncommon and there is no cannabis treatment industry. Yet treatment
services...have seen an increase in the number of persons seeking help for cannabis"
(p 221). He even suggests that the figures may be kept down by the widespread belief
that it is not possible to be dependent on cannabis (Q 748).
4.31 Giving up cannabis is widely believed to be
relatively easy: according to the Department of Health, "studies report that of those
who had ever been daily users only 15 per cent persisted with daily use in their late
twenties" (p 45). Most epidemiological studies in Britain and the United States have
shown that the illicit use of cannabis mainly involves people in their late teens and
twenties, with relatively few users over the age of 30.
4.32 It has been assumed that young cannabis users
give up the habit when they enter their thirties; IDMU (p 236), however, suggest that
this pattern may be changing. The British Crime Survey (1996) shows that although the
prevalence of cannabis use falls after the age of 30, the greatest proportional increases
in the period 1991-1996 were in older age groups, with incidence of past use doubling in
the 40-44 age group (from 15 per cent to 30 per cent) and trebling in the 45-59 age group
(from 3 per cent to 10 per cent). IDMU conclude that the current relatively low levels of
cannabis use in the over-30 age group may reflect a generational and cultural divide,
rather than substantial numbers of users giving up.
4.33 It is therefore clear that cannabis causes
psychological dependence in some users, and may cause physical dependence in a few. The
Department of Health sum up the position thus (p 45, cp Edwards Q 28): "Cannabis
is a weakly addictive drug but does induce dependence in a significant minority of regular
cannabis users."
9 Including Hall W, Room R and Bondy S, A comparison of
the health effects of alcohol, cannabis, tobacco and opiates, in Kallant H, Corrigal
W, Hall W and Smart R eds The Health Effects of Cannabis, Addiction Research
Foundation, Toronto, 1998; and articles awaiting publication in Addiction (Respiratory
risks of cannabis smoking, 1998, 93, 1461), Drug and Alcohol Review, and the Lancet
Seminar series (14 November 1998). Back
10 N Solowij, Cannabis and Cognitive Functioning,
Cambridge University Press, 1998. Back
11 See in particular DH p 46; papers kindly supplied by
Professor Donald Tashkin, University of California Los Angeles School of Medicine, and
Professor Hall; and Appendix 3, paragraph 8. Back
12 Carboxy-haemoglobin is formed by the action of carbon
monoxide on haemoglobin in the blood. It interferes with the transport of oxygen around
the body. Back
13 E.g. Taylor FM III, Marijuana as a potential
respiratory carcinogen: a retrospective analysis of a community hospital population,
South. Med. J. 1988, 81, 1213. Back
14 Miss Hodges is the founder-Director of the UK Alliance for
Cannabis Therapeutics (ACT). "Clare Hodges" is a nom de guerre. Back
15 Professor Edwards is Professor Emeritus of Addiction
Behaviour at the Institute of Psychiatry, University of London; past Chairman of the
National Addiction Centre; and editor-in-chief of the journal Addiction. The ACMD
is established under the Misuse of Drugs Act 1971, to advise the Government. Back
16 By Dr Wendy Swift, Australian National Drug and Alcohol
Research Centre. Back
17 Consultant psychiatrist, Warneford Hospital; senior
clinical lecturer, University of Oxford; author of one of the reviews for the Department
of Health referred to in paragraph 1.4. Back
|
