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|Major Studies of Drugs and Drug Policy|
|Marihuana, A Signal of Misunderstanding - Table of Contents|
The Report of the National Commission on Marihuana and Drug Abuse
Acute Effects of Marihuana
(Delta 9 THC)
There is no conclusive evidence that short-term marihuana use alone directly results in any physical damage to man. A few scattered fatalities associated with marihuana use are occasionally reported. Most are from 19th century Indian experiences with large oral doses of charas (Deakin, 1880; Bouquet, 1951; Ewens, 1904, Walton, 1938; Indian Hemp Drugs, 1893). Brill et al. (1970) and Smith (1968) have noted that there have not been any reliable reports of human fatalities attributable purely to marihuana, although very high doses have been administered by users.
A frequently cited recent report from Belgium by Heyndrickx et al. (1970) describes an essentially negative pathological and toxicological study of a 23-year-old man found dead in the presence of marihuana, and hashish. A cannabinoid was detected in his urine. However, this finding in no way inculpates marihuana as the responsible agent. There are many possible causes of sudden death which are not toxins and do not produce observable pathology; e.g. anaphylactic reactions, insulin shock, cardiac arhythmias, etc.
A case report (Nahas, 1971) of an attempted suicide by smoking hashish, recently in France is even more anecdotal. An individual was reported to have smoked consecutively ten pipes of hashish containing approximately 200 mg of Delta 9 THC each before losing consciousness. But recovery occurred after supportive treatment.
Another case report (Hughes et al., 1970) relates severe diabetic coma with ketoacidosis after the ingestion of huge amounts of marihuana by a mental patient. However, it appears that the pronounced vomiting secondary to the marihuana ingestion caused a severe electrolyte imbalance and alkalosis. Possibly a vulnerable glucose-regulating system responded to the severe stress inappropriately. Retrospectively, there was no history of diabetes noted previously but this was not confirmed or ruled out by lab tests prior to the episode.
Several case reports (Henderson and Pugsley, 1968 King and Cowen, 1970; King et al., 1970; Lundberg et al., 1971; Gary and Keylon, 1970) noted acute severe, physiological disturbances and acute collapse (shock, chills and fever) subsequent to intravenous injection of suspensions of marihuana. These symptoms may have been due to an allergic reaction to injected foreign plant material, to a bacteremia and/or to the injection of insoluble particles which are filtered by the organs. The symptoms may be considered a complication of the mode of use, rather than results of the drug.
Although a median lethal dose has not been established in man (Brill et al., 1970), one has been found in laboratory animals. Earlier reports (Lowe, 1946; Joachimoglu, 1965) used materials of uncertain potency and composition. Recent studies utilized carefully quantified materials. One group, Phillips et al. (1971), utilizing THC extracted from marihuana, demonstrated the following LD50 (the dose that causes death in 50% of the animals) in units of mg/kg of Delta 9 THC from mice,/rats: oral 481.9/666, intraperitoneal 454-9/ 372.9, intravenous 28.6/42.47.
Thompson et al. (1971) under contract to the National Institute of Mental Health have recently carried out extensive studies in rats, dogs and monkeys in order to define the range of toxicity of the drug. The group used synthetic Delta 9 and A' THC and a crude marihuana extract (CME) of carefully define composition. Delta 9 THC was more potent than Al THC. CME was less potent than a similar quantity of A' THC.
Acute toxicity was studied using intravenous, intraperitoneal and oral routes of administration in rats. An LD50 similar to that reported by Phillips et al. (1971) was found by the intravenous route (20 mg/kg of THC) and intraperitoneal route (400 mg/kg) but higher values were noted with oral administration (1140 mg/kg). Interestingly, the LD50 for males was 1400 mg/kg while for females it was 700 mg/kg by the oral route. The minimal lethal dose orally was between 225 and 450 mg/kg.
An LD50 was not attainable in monkeys and dogs by the oral route. Enormous dose levels (over 3000 mg/kg of Delta 9 THC) were administered without lethality to most animals. A dose of about 1000 mg/kg THC was the lowest dose which caused death in any animals The completeness of intestinal absorption of THC at these high doses is unknown. Behavioral changes in the survivors included sedation, huddled posture, muscle tremors, hypersensitivity to sound and hypermobility.
The cause of death in the rats and mice subsequent to oral THC was profound central nervous system depression leading to dyspnea, prostration, weight loss, loss of Fighting reflex, ataxia, and severe fall in body temperature which led to cessation of respiration from 10 to 46 hours after single dose oral administration. No consistent pathological changes were observed in any organs. The cause of death when it rarely occurred in the higher species did not appear to be related to the same mechanism as in the rats.
Using intravenous administration, the acute one dose LD50 for Delta 9 THC was 100 mg/kg in dogs and 15.6 to 62.5 mg/kg in monkeys depending on concentration of the solution. The minimal lethal intravenous dose for dogs, also depending upon concentration, was 25 to 99 mg/kg and for monkeys 3.9 to 15.5 mg/kg.
In contrast to the delayed death observed in rats after oral administration, lethality in rats, dogs and monkeys after intravenous injection occurred within minutes after injection. When sublethal amounts were injected, central nervous system depression with concomitant behavioral changes similar to those observed after oral doses were observed. However, their onset was more rapid and the intensity of effect more severe with anaesthesia, and convulsions noted after injection. The monkeys and dogs that survived the intravenous injection of THC recovered completely within five to nine days.
The only consistent pathological changes were noted in the animals which succumbed. Pulmonary changes including hemorrhage, edema, emphysema and generalized congestion were found and death resulted from respiratory arrest and subsequent cardiac failure. The investigators presumed one mechanism possibly accounting for these findings was due to the concentration of the THC solution and its insolubility in water. Presumably, when these highly concentrated solutions mixed with the blood, the THC precipitated out of solution. The precipitated foreign material then formed aggregates (or emboli) that were filtered out in the lung capillaries causing a physical blockage of pulmonary blood flow.
Subsequently, intravenous studies were repeated using Delta 9 THC emulsified in a sesame oil-Tween 80-saline vehicle at 15 mg/ml or 40 mg/ml. The emulsions were administered at a uniform rate of 2 ml/15 sec. Doses administered were 1, 4, 16, 64, 92,128, 192 and 256 mg/kg. All monkeys injected with 92 mg/kg or less survived and completely recovered from all effects with two to four days. All monkeys injected with 128 mg/kg or more succumbed within 30 minutes for all but one (180 minutes).
Histopathological changes found in the lungs of the deceased monkeys were like those described after the, previous intravenous experiment. All the monkeys that died exhibited severe respiratory depression and bradycardia within five minutes after the injection. Respiratory arrest and subsequent cardiac failure occurred within minutes. Behavioral changes preceding death were salivation, prostration, coma and tremors.
Behavioral and physiological changes described clinically in the surviving monkeys followed a consistent developmental sequence and were roughly dose related in severity and duration. Onset was 15 minutes following injection and duration was up to 48 hours. Huddled posture and lethargy were the most persistent changes. Constipation, anorexia and weight loss were noted. Hypothermia, bradycardia and decreased respiratory rate generally were maximal two to six hours post injection. Tremors with motion but not at rest were believed to be caused by peripheral muscle inadequacy.
In summary, enormous doses of Delta 9 THC, All THC and concentrated marihuana extract ingested by mouth were unable to produce death or organ pathology in large mammals but did produce fatalities in smaller rodents due to profound central nervous system depression.
The non-fatal consumption of 3000 mg/kg A THC by the dog and monkey would be comparable to a 154-pound human eating approximately 46 pounds (21 kilograms) of 1%-marihuana or 10 pounds of 5% hashish at one time. In addition, 92 mg/kg THC intravenously produced no fatalities in monkeys. These doses would be comparable to a 154-pound human smoking at one time almost three pounds (1.28 kg) of 1%-marihuana or 250,000 times the usual smoked dose and over a million times the minimal effective dose assuming 50% destruction of the THC by smoking.
Thus, evidence from animal studies and human case reports appears to indicate that the
ratio of lethal dose to effective dose is quite large. This ratio is much more favorable
than that of many other common psychoactive agents including alcohol and barbiturates
(Phillips et al. 1971, Brill et al. 1970).
Schaffer Library of Drug Policy
Major Studies of Drug and Drug Policy
Marihuana, A Signal of Misunderstanding - The Report of the US National Commission on Marihuana and Drug Abuse
Licit and Illicit Drugs
Short History of the Marijuana Laws
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Congressional Transcripts of the Hearings for the Marihuana Tax Act of 1937
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