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Acute Effects of Marihuana

 

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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

(Delta 9 THC)

LETHALITY

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).


 














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