Toxicology and pharmacology of cannabis sativa with special reference to Δ 9-THC

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Toxicity of cannabis and Δ 9-THC
Metabolism and distribution
Pharmacology
Summary
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Author: Gabriel G. NAHAS
Pages: 11 to 27
Creation Date: 1972/01/01

Toxicology and pharmacology of cannabis sativa with special reference to Δ 9 -THC *

M.D. Ph.D. Gabriel G. NAHAS Professor of Anaesthesiology, College of Physicians and Surgeons of Columbia University, New York

Classical texts describing the pharmacological and toxicological actions of cannabis and its derivatives are difficult to interpret and even misleading. Indeed, the experimenters had no way to assess the nature of the preparations which they used since they did not have at their disposal any pure reference compounds of a known potency. Consequently, the reports of toxicologic and pharmacologic effects of crude extracts or synthetic derivatives of cannabis published before 1968 lack precision and uniformity and preclude any quantitative correlation between physiological effects and chemical composition.

The recent availability of Δ ⁹- and Δ ⁸-THC has allowed pharmacologists and toxicologists to establish dose-response curves relating physiopathological effects to dose administered. These quantitative experiments do replicate to a great extent the qualitative results obtained with cannabis extracts.

However, one cannot draw a complete parallel between the pharmacological or other effects produced by Δ ⁹-THC and those engendered by cannabis extracts. Cannabis extracts contain in addition to Δ-9 and Δ ⁸-THC many other cannabinoids and chemical compounds, such as esters and alkaloids, the effects of which will have to be evaluated separately and in combination. Furthermore, pharmacological and toxicological studies are performed on animals with compounds administered intravenously, by mouth or intraperitoneally. Results observed in such studies cannot be strictly compared with those produced by smoking cannabis extracts. Indeed, smoking will release plant constituents such as tars, carbon monoxide, acids, aldehydes and particulate irritant substances. In addition to the Δ ⁹-THC content of smoke, therefore, all of these by-products of smoking should also be considered in toxicity studies, especially chronic ones.

Furthermore, because of the insolubility of pure cannabinoid compounds in water, their intravenous administration in animals requires the addition of solvents such as tween, alcohol, ethylene glycol, which have to be taken into account.

* This paper will form part of a book to be published by the author later this year.

This insolubility makes it very difficult to study Δ ⁹-THC in isolated tissue preparations suspended or incubated in the standard electrolyte solutions (such as Krebs Ringer) and obtain dose response curves.

Toxicity of cannabis and Δ 9 -THC

Acute toxicity

The acute oral toxicity of the cannabis derivatives used as intoxicants (marihuana, kif, hashish) is low.

O'Shaughnessy and Moreau de Tours administered large amounts of hashish extracts to mice, rabbits and rats without producing any lethal effects. Moreau de Tours observed in some pigeons and two rabbits given very strong doses of pure extract to swallow, a "slight excitement followed by an apparent somnolence of short duration".

According to Loewe, the LD ₅₀ (lethality in 50% of animals administered the toxic) of cannabis extracts administered to mice, orally, subcutaneously, and intravenously were 21.6, 11.0, and 0.18 gm/kg respectively. Joachimoglu reported an LD ₅₀ of 1.5 gm/kg for natural hashish extract administered intraperitoneally. The figures reported by Patton for this same animal are within the same range.

However, the acute toxicity of Δ ⁹-THC, especially when administered intravenously is much greater. It was only recently established in rodents (see table below). The intravenous LD ₅₀ in rats and mice is in the vicinity of 30 and 40 mg/kg respectively with death occurring in 15 minutes. The LD ₆₀ by intraperitoneal and oral route requires a 10 to 20 times greater dosage, with death occurring 10 to 36 hours later. These results indicate that Δ ⁹-THC is poorly absorbed by the gut, or through the peritoneal route. In addition, by these two routes they might be more rapidly metabolized in the liver. Toxic signs preceding death in both species were ataxia, hyperexcitability, depression, loss of righting reflex and dyspnea progressing to respiratory arrest. Diarrhea in mice, with in addition, tremor and lacrimation in rats were observed after intraperitoneal or intragastric administration. Immediate post mortem examination showed œdema and congestion of the lungs in all animals. All toxic signs disappeared within 24 hours in the surviving animals. By oral route, LD ₅₀ is greater in female than in male rats. There is also evidence of variation in toxicity between rat species. With the same compound Scheckel and coll. observed a 50% mortality in the squirrel monkey after a dosage varying from 36 to 64 mg/kg administered intraperitoneally.

Acute Toxicity of Δ 9 -Tetrahydrocannabinol in rats and mice a

Administration was intravenous (iv), intraperitoneal (ip), and intragastric (ig)

	Route of adm	No. of animals/group	Observation time (days)	LD50 (mg/kg)
Rats	iv	6	7	29
				(27-30) b
	ip	6	7	373
				(305-454)
	ig	6	7	666
				(604-734)
Mice	iv	6	7	43
				(37-49)
	ip	10	7	455
				(419-493)
	ig	10	7	482
				(451-515)

a Vehicle: 10% Tween 80.

b Confidence interval 95%

In man it is unlikely that Δ ⁹-THC plasma concentrations elevated enough to produce such acute toxic effects, could be reached after ingestion of cannabis preparations. Cannabinoids are poorly and irregularly absorbed by the gut. Only two cases of fatalities due to ingestion of very large amounts of charas are recorded in the Indian literature.

As no serious impairment of vital functions has ever been reported in the United States following inhalation or ingestion of cannabis preparations, (which have in general low-1% or less-content in Δ ⁹-THC) it has been commonly stated that cannabis is an inocuous drug, safer than alcohol or cigarettes.

Such a contention should be made with caution in view of two recent case reports documenting cases of severe acute cannabis intoxication.

The first case is "a toxicological study of a fatal intoxication in man due to cannabis smoking" reported by Heyndrickx et al. (Dr. Heyndrickx is Professor of Toxicology and Dean of the Medical Faculty of the University of Ghent). This fatality due to cannabis is somewhat better documented than those reported in the Indian literature at the end of the last century. A 23-year-old student was found dead in his room, which contained large amounts of cannabis herb and resin and a water pipe, but no drugs. From the autopsy there was no evidence of natural or violent cause of death. Classical toxicological analysis of the specimens (blood, urine, kidney, liver, stomach) was negative for barbiturates and weak acids, neutral poisons, alkaline poisons, weak amines, benzodiazepine compounds, phenotiazines; for morphine, mephenon, palfium, and other related narcotics, for alcohol and carbon monoxide. The only toxic substance identified (by thin layer chromatography) was cannabinol in the urine of the deceased. The same cannabinol was identified chromatographically from the cannabis herb and resin and combustion residues from the pipe, which were found in the room of the dead man (at the exclusion of any other toxic substances). Though the evidence herein presented is still presumptive, it does indicate that Δ ⁹-THC might be a lethal compound in man as well as animal when present in high enough concentration in the blood stream and that such concentrations can be reached by inhalation of strong cannabis preparations because of the rapid absorption of Δ ⁹-THC by the lung. The report by Heyndrickx was corroborated by the observation of Gourves et al. who reported the case of a coma of four days' duration due to cannabis intoxication in a 20-year-old French soldier. After recovery, the patient acknowledged having smoked nine to ten pipes of a mixture of tobacco and hashish with the intent of committing suicide, claiming that this method had been used by others. He admitted each pipe contained 15 to 20 gm of smoking mixture. Assuming (1) that the subject had smoked 180 gm; (2) 5% Δ ⁹-THC content for a potent hashish preparation; (3) a half-and-half mixture of tobacco and cannabis; (4) 50% absorption of the drug by the lungs, the lethal intravenous dose of Δ ⁹-THC in a 70 kg. man would be of the order of 2,000 mg. or 30 mg/kg. LD50 (I.V.) in rats is 28.6 mg/kg.

These reports indicate that potent cannabis preparations may be used in the drug subculture of western Europe for suicidal purpose. Furthermore, several cases of accidental deaths occurring in children who had smoked hashish from a water pipe have also been reported in Egypt. The lack of more reports of severe cases of cannabis intoxication from countries where this drug is abused, might be misleading. Severe cannabis intoxication with potent material occurs mainly in the developing countries where health facilities are seriously lacking. The causes of the many cases of coma or sudden death go often unrecorded. Hospitals are inadequate, under-staffed and rarely have emergency rooms. Even in western countries, the statistics in an emergency ward or poison centre have a number of cases which are reported as of "undetermined etiology ".

However, the acute somatic toxicity of cannabis extract is low when compared with that of other simple chemical substances which are rapidly absorbed in their pure form in the gastrointestinal tract. These substances which are readily available would be used preferentially by those who are driven to commit suicide.

It should also be remembered that the lack of:

Severe physical untoward effects of a psychotropic drug is poorly correlated with its psychotoxicity and its ability to disintegrate mental function, a condition which secondarily may cause bodily harm to self and others.

Subacute toxicity

Studies have been performed on rats and monkeys which were administered by mouth for 90 to 104 days 50 to 500 mg/kg/day of either Δ ⁹-THC or Δ ⁸-THC. Other animals were given 150 to 1,500 mg/kg/day of crude marihuana extract. A biphasic pattern of toxicity was observed in rats treated with all three substances. An initial period of five to ten days of generalized depression was first observed, similar to that occurring after a single dose. Tolerance to these depressant effects developed gradually and coincided with the appearance of hyperactivity. The animals progressively displayed increased grooming, tremors, orientation movements, 1ocomotor activity, and aggressiveness. When kept in cages together they inflicted severe mutilating wounds on each other. After three to four weeks of treatment, clonic and tonic convulsions were observed. Such behavioural aberrations have not been observed in animals given much ethanol, or other psychoactive drugs which display some of the acute effects of Δ ⁹-THC.

After three months of such treatment with the higher doses the animals succumbed. Pathological changes were present in bone marrow, spleen, adrenal cortex and semi-niferous tubules. In monkeys, initial depression to which tolerance developed was also observed. Hyperactivity in the primates was only observed with the higher dosage used (250 mg/kg/day). The daily dosage used in these experiments is far out of proportion with the heaviest chronic human consumption of cannabis extracts. These studies, however, are of interest because they point out the primary and cumulative neurotoxicity of the psychoactive fractions of cannabis extracts. This cumulative toxicity may be related to the storage of the cannabinoids in the fat depots of the body from which they are slowly eliminated. It would appear that very large amounts of Δ ⁹-THC are required to saturate the storage capacity of the tissues. It cannot be excluded that this storage capacity might also be reached in man over prolonged periods of chronic cannabis consumption.

Chronic toxicity

Systematic studies of the chronic toxicity of these components are not yet available in animal or man. Chronic toxicity studies in animals are difficult to perform with a drug which might have to be used by man for several decades before any sign of toxicity will become apparent. Man's life span outlasts that of all laboratory animals. Furthermore, his reaction to drugs especially psychotropic ones is quite different.

Among the vital organs affected by cannabis one must consider the brain which is the primary target, the liver and the lungs where the active ingredients are metabolized, and the heart, which rapidly accelerates its rate in response to the drug.

Damage to the brain?

The effect of chronic use of cannabis in the most important organ of the human economy, our brain, has not yet been assessed. One of the main reasons is that with our present methods, it is not possible to establish histological damage produced in the central nervous system by psychotropic drugs.

These substances exert their action through molecular biochemical mechanisms which do not distort gross cell architecture. For instance, it has not been possible to establish any significant brain damage after chronic administration of opium or morphine-like drugs after more than 50 years of study of opiates in animals and man.

Moreau de Tours in 1846 recognized this fundamental fact when he says "undeniably in mental illness or hashish intoxication changes exist in the organ charged with intellectual function but these changes are not what one would generally wish them to be. In the structural form that one imagines them to have, they always escape the search of investigators. We must not look for certain peculiar, abnormal arrangements of various parts of the brain in which the texture of the brain will be found to be changed, but we must look for an alteration of its sensitivity, namely in the irregular, increased, decreased or distorted action of its special properties upon which depends the performance of mental functions."

Moreau de Tours' opinion was ignored by his contemporaries. It is widely accepted today by the neuro-physiologists and neurochemists who believe that functional change in the brain is accompanied by one of the biochemical changes such as the turnover rate of neuro-hormones which regulate all of our thought processes. One cannot exclude that the repetitive impairment of these processes by frequent cannabis intoxication in the adolescent years, might after a few years induce permanent changes in patterns of thinking or of behaviour. Such permanent changes would have to be related with permanent organic alterations.

Why we should carefully evaluate a study from which reports evidence of cerebral atrophy young men who smoked marihuana daily for years. They had also taken amphetamines and the regular smoking of cannabis was the main at their intoxication. These subjects presented of their cerebral ventricles measured after phalography. Similar enlargements which of brain atrophy, are observed in people older, Parkinson's Disease, or subjects such who have presented multiple head trauma. aints of the cannabis users which were studied, headaches, memory loss for recent events, personality and temperament, decreased thought and decreased desires to work". symptoms, indicative of a basic impairment ction, which have been reported by chronic users from all over the world for many decades, be related to an organic brain lesion. It should a mind, that it also took several decades to relate al impairment of the thought processes and of former boxers to the brain atrophy which years after multiple head traumatisms suffered ophy is a major non-specific organic altera- ainly must be preceded by other more subtle molecular changes. The mechanics by which be brought about by chronic cannabis intoxi- be clarified.

The lung ble damage to the lung should be next in the habitual smoker of cannabis prepararts from areas where potent preparations are as India, Egypt and Morocco, indicate that smoking of the drug produces bronchial irrita- catarrhal laryngitis and asthma. symptoms have also been observed in 22 of American soldiers, 19 to 23 years old, who hashish for periods ranging from 6 to. The material used was not assayed for the patients smoked 100 grams or more a this corresponds to 3-4 one gram cigarettes a patients presented primarily bronchitis with wheezes and rales, one exhibited audible wheezing identical to asthma. Chest X-rays increased bronchiovascular markings. Sputum yielded normal flora, and pulmonary function adicated mild obstructive pulmonary defect. did not improve the symptoms but isopro-. The patients were dyspneic and frequently to the point they could not function in "a working capacity" and four required hospital. Only a decrease of hashish consumption relieved ems and improved pulmonary function. Twelve had recurrent rhinopharangitis and five others complained of related symptoms. They presented uvular œdema which according to the authors of the report, is a common symptom observed after the smoking of large amounts of hashish, and a more reliable clinical symptom than injection of conjunctival vessels.

These ailments of the upper respiratory and bronchial tracts could not be causally related to any specific component of hashish, which besides Δ ⁹-THC, contains many other substances. Those which might act as allergen remain to be identified.

But steroids and triterpens which are readily converted into carcinogenic agents have been isolated from cannabis sativa. And it has already been reported that tar yield from marihuana smoke condensate is as carcinogenic to the mouse skin as smoke from the tobacco of commercial cigarettes.

Alveolar macrophages sampled from four non-smokers and eight marihuana smokers in the United States, presented significant structural and functional differences. The 19 subjects were 21 to 28 years of age. An equal number of male and females were studied. The marihuana smokers had smoked a total of 1,000 to 9,300 marihuana cigarettes over a period of 2 to 8 years, and 3 of them also used hashish. There was a smaller percentage of macrophages in the fluid recovered from the lungs of cannabis smokers, than was recovered from non-smokers. In marihuana smokers, macrophages, a primary pulmonary defense against inhaled organisms and particles, were replaced by other cell types. This reduction contrasts with the greater volume and number of macrophages recovered by similar methods from tobacco smokers than non-smokers. There were also unstructural differences in macrophages from marihuana smokers which were confined to cytoplasmic inclusions. Their phagocytic ability was not impaired. A higher percentage of macrophages from smokers adhered to glass indicating a difference in net negative surface change. The significance of these changes is not clear, but they are indicative of subtle unphysiological alterations which cannabis extracts may produce at the cellular level. It would therefore appear that chronic daily smoking of cannabis preparations is associated with damage to the lung, and subtle cellular alterations which are not unlike those related to heavy smoking of tobacco.

Damage to the cardio-vascular system

Significant tachycardia related to the dose administered is consistently observed during acute cannabis intoxication. The mechanism of this action is not clear and its persistence among chronic heavy users remains to be systematically studied. In the meantime, in view of the high incidence of acute cardiac accidents in the United States, the use of cannabis derivatives by middle aged men who wish to escape the stress of daily life, might present some hazard.

Chopra and Chopra report in India that conjunctivitis was present in 72% of the chronic cannabis users they examined. It consists of an active congestion in the transverse ciliary vessels accompanied by a yellow discoloration of the conjunctiva due to deposits of yellow pigment around the vessels. Similar symptoms have not been reported from other areas of chronic cannabis intoxication of the Middle East. The most serious vascular complications, allegedly associated with the smoking of cannabis extracts has been described by Sterne and Ducastaing. These authors observed 9 cases of progressive obliterative arteritis of the lower extremities developing in young Moroccan males who were heavy smokers of cannabis extracts (they smoked 10 to 15 pipes a day). Evolution of the disease, which closely paralleled cannabis intoxication, was lethal in one to three years in spite of repeated limb amputations. According to Sterne and Ducastaing, cannabis-induced juvenile arteritis is a frequent disease among North African Moslems, and contrasts with their otherwise low incidence of arteriosclerosis (15 times less than the local European population). It is possible that the large amount of carbon monoxide absorbed under such conditions might also be a contributing factor of this condition which has not been reported elsewhere.

Damage to the liver and gastrointestinal tract

The liver in spite of its well known resilience might be affected by cannabis extracts, especially after ingestion of this material. A case of cirrhosis in a heavy use was observed by Kew and associates. This observation led them to study 12 subjects who smoked cannabis extracts but who had not taken intravenous drugs or used alcohol to excess. Eight showed "mild liver dysfunction", and biopsy in three showed "striking parenchymatosis degeneration". However, no laboratory evidence of liver disease was found in 31 heavy smokers of hashish studied by Tennant.

The occurrence of diarrhea, abdominal cramps and gastroenteritis has been reported in India, Egypt, and Morocco among chronic users of cannabis preparations whether ingested or smoked.

Chronic diarrhea and abdominal cramps associated with heavy smoking of hashish were reported in three young American soldiers. Weight loss was also a predominant finding in these patients.

It would appear that many of the chronic toxic effects associated with the habitual (daily) usage of cannabis preparations and described in the Middle Eastern countries, are now starting to be observed in Western man.

One could expect that as more potent cannabis preparations become available in the United States, toxic manifestations which have been described, will become more frequent.

Interaction of cannabis with other drugs

Δ ⁹-THC potentiates in the dog the cardiovascular action of norepinepherine and epinepherine; in rodents it acts synergistically with amphetamines and caffein in stimulating exploratory locomotor activity. It also potentiates significantly the action of ethanol in experimental animals and in man. The Δ ⁹-THC also potentiates the depressant action of barbiturates. All of these drugs along with antihistamines, tranquillizers, phenothiazines, benzodiazepines, imipramines, butyrophenones, are frequently used in the western countries. The resulting interactions of Δ ⁹-THC and other cannabinoids with these drugs must be carefully appraised. Indeed, it has been established that in the U.S.A., the consumers of cannabis do not abstain from smoking cigarettes, or drinking wine and alcohol. Moreover, the young users of cannabis are also prone to experiment with other drugs such as LSD, amphetamines, barbiturates and to escalate to opiate derivatives.

It is probable that all of these drug interactions would adversely affect physiological and mental functions of man.

Teratogenicity

Experimental evidence concerning the teratogenic effect of cannabis derivatives is not conclusive. Intraperitoneal injections to pregnant rats of 4 mg/kg of cannabis resin from day one to day six of gestation produced a significant incidence of congenital malformations in the offspring. Similar observations were made on fœtal hamsters and rabbits after maternal administration of large and multiple doses of resin (100-400 mg/kg). In contrast with these results, others have reported that administration of large amounts of Δ ⁹-THC (10 to 200 mg/kg) in pregnant rats, hamsters, rabbits and dogs did not result in abnormal offspring. But a high incidence of neonatal deaths and some fœtal abnormalities were reported by the same authors, after administration of large doses of "marihuana extract distillate", MED, a concentrated extract of cannabis. These results indicate that the teratogenic effect of cannabis derivatives is not related to Δ ⁹-THC but to another constituent of the plant. The lack of gross teratogenic effect of Δ ⁹-THC is not due to a lack of passage of this agent through the placental barrier, as demonstrated in studies with labelled compounds. The Δ ⁹-THC and its metabolites could therefore also exert their pharmacological effects on the fœtus. But chromosome breakage, reported in man after LSD usage, has not been observed in preliminary studies of cannabis users.

In countries where chronic cannabis intoxication has prevailed for centuries, it is only the male population which has indulged in the use or abuse of cannabis derivatives, usually of high potency. As a result, man was not exposed to the effects of cannabis derivatives during his early intrauterine development. Such a situation would not prevail in Western countries where men and women share the same pursuits, including the use of cannabis.

Tolerance, dependence

It is now well established that tolerance to Δ ⁹-THC develops rapidly in all the animal species tested with this drug; birds, rats, dogs and monkeys, will require within 5 to 15 days increased dosage for continued alteration of basic physiological or acquired learned responses. In addition to tolerance, Δ ⁹-THC may induce in primates some symptoms of physical dependence and withdrawal reactions. These are rather mild, when compared with those developing after chronic ethanol or barbiturate intoxication. But tolerance to Δ ⁹-THC is very marked, develops rapidly, and the animal may become quite refractory to the drug until toxicity ensues.

McMillan et al. have reported that pigeons displayed a marked tolerance to the behavioural effects of Δ ⁹-THC. The effective dose (1.8 mg/kg) which completely eliminated a learned food presentation schedule could be subsequently and gradually increased over a one-month period to 180 mg/kg. Non-tolerant birds succumbed when given the higher dose. Black et al. report the development in seven weeks of similar tolerance to Δ ⁹-THC in pigeons on scheduled controlled behaviour and given a weekly i.m. injection of Δ ⁹-THC (10 mg/kg) and other cannabis derivatives. They conclude that tolerance and cross tolerance can occur among these cannabis derivatives (Δ ⁹-and Δ ⁸-THC) and that the tolerance is of pharmacological origin. Tolerance to the depressant effect of daily injections of Δ ⁹-THC (125 mg/kg) on the locomotor activity of the rat was also observed by the eleventh day.

Tolerance and physical dependence to Δ ⁹-THC was very clearly demonstrated by Deneau in six rhesus monkeys trained for intravenous self-administration of Δ ⁹-THC. No monkey initiated self-administration over a three-week period. Automatic injections were delivered at doses increasing from 0.4 to 1.6 mg/kg. Drug effects were ptosis, blank staring, scratching and docility. Tolerance developed within a few days of each increase of dosage. When injections were stopped all monkeys showed abstinence symptoms and two of the six animals initiated and maintained self-administration of THC. The abstinence symptoms appeared at 12 hours and lasted 5 days; they were yawning, anorexia, pilo erection, irritability, scratching, biting and licking fingers, pulling hair, tremors, twitches, shaking, photophobia, and apparent hallucinations.

If the psychoactive substance derived from Δ ⁹-THC is an intermediary metabolite resulting from enzymatic induction, as suggested by some, tolerance to cannabis would have a biochemical basis. The maximum turnover of this enzyme would be, in this case, the biochemical limiting factor controlling the development of tolerance with chronic usage of cannabis. This tolerance is similar to the one which develops to other hallucinogens like LSD and amphetamines. The nature of the tolerance which animals develop to Δ ⁹-THC is not clear. It may be due in part to a change in drug metabolism, a more rapid disposition or elimination of the toxic. This hypothesis would be substantiated by the observation that mice, pretreated with phenobarbitol which increases microsomal drug metabolism, will double their tolerance to a lethal dose of Δ ⁹-THC; by contrast, SK 525-A, a compound which inhibits microsomal metabolism, will potentiate considerably in the same animal THC-induced mortality. The very high tolerance developing in animals treated with Δ ⁹-THC would indicate that in addition to metabolic tolerance, this drug might also induce tissue or functional tolerance in the target organ. Cross tolerance has been found between Δ ⁸-THC and Δ ⁹-THC and between Δ ⁹-THC and synhexyl and between the dimethylheptyl analogue and Δ ⁹-THC. But there is no cross tolerance between Δ ⁹-THC and LSD or mescaline. Since cross tolerance has been established for the two latter drugs, it would appear that tolerance to cannabis must involve a different mechanism from that of mescaline or LSD. Cross tolerance between Δ-THC, and ethanol and between Δ ⁹-THC and barbiturates has been suggested by some.

Metabolism and distribution

The availability of tagged Δ ⁸- or Δ ⁹-THC have only recently permitted the study of the distribution of these compounds and of their metabolites in different tissues and organs, as well as their elimination from the body.

These studies were performed on rats, mice, rabbits, and monkeys with ¹⁴C or trititium labelled Δ ⁸- or Δ ⁹-THC intravenously administered. In spite of the high lipid solubility, Δ ⁹-THC and their metabolites did not preferentially accumulate in neural tissue. The pattern of distribution and elimination of Δ ⁹-THC and of its metabolites indicates that these compounds are preferentially stored in organs of absorption and metabolism (liver, lung, spleen) in those most affected by the drug (brain, heart) as well as in the organs and products of elimination (liver - bile, kidney - urine).

Schematic outline of the metabolism of Δ 9 -THC


Δ ⁹-THC
	Lung
Enzymatic induction		Metabolic tolerance
	Liver
Active metabolites (2-8 hrs)	Brain	Functional tissue tolerance
	Gall bladder	Bile

	Intestine **	Excretion
	Spleen
Inactive metabolites *	Adrenal
(8 days)	Fat
	Kidney	Excretion
	Gonads
	Brain
	Muscle

*Listed in order of decreasing concentration in various tissues.

**Note entero-hepatic circulation.

The radioactivity of whole body homogenates of rats given i.v. 4 mg/kg of ¹⁴C-THC declined experimentally, with a half-life of 16 hours. Fifteen minutes after the injection there was an accumulation of radioactivity (Δ ⁹-THC and metabolites) in tissues with tissue-to-plasma ratios of brain, 2.7; lung, 55.2; liver, 12.1; fat, 5.5; muscle, 3.0; kidney, 6.5; heart, 6.7; intestine, 3.5. Seventy-five per cent of the radioactivity administered is excreted in urine and feces within 120 hours, with 90% of this in the feces, mostly in the form of metabolites. The relative distribution of radioactivity in the rabbit three days after intravenous administration of tritiated Δ ⁹- THC is shown above. High concentrations are found in the organs of excretion, bile, gall bladder, kidney and liver. High activity is also present in the spleen, adrenal glands and fat. After 3 days comparatively little activity remains in the lung and brain. Elimination of the metabolites of Δ ⁹-THC occurs primarily in the urine, unlike the rat where fecal excretion predominates. In both animals the total period of elimination is similar, exceeding a week. Fractionization of protein of rat and human plasma by ultracentrifugation after addition of Δ ⁹-THC indicated that 90% of this compound was bound to protein, mostly to the lipoprotein. The rapid distribution of Δ ⁹-THC from plasma into tissues can be explained by its intracellular binding. In the isolated perfused liver, Δ ⁹-THC was localized in the nuclei and the microsomes. Subsequent studies of the metabolism of 3H and ¹⁴C Δ ⁸-THC or Δ ⁹-THC in lung and liver homogenates showed the rapid production of metabolites which are specific to these two tissues. The metabolite produced by the liver is II hydroxy Δ ⁸- or Δ ⁹-THC. It was shown that nonspecific enzymes (oxidases) in the microsomal fraction of the cell are induced rapidly, in vivo and in vitro, to form this metabolite. It is known that these same liver enzymes can be induced to higher rates of activity (initial methylation or hydroxylation steps) by repeated usage of many other drugs which include barbiturates, antidepressants, tranquillizers, analgesics, and anticoagulants. Chronic administration of these drugs produce a metabolic tolerance due to an induction of an increased activity of these enzymes. -

The Δ ⁹-THC will interact with these drugs and alter their therapeutic action through metabolic competition. It was shown that THC (10-4 M) inhibits in the liver microsomal oxidation of aminopyrine by 50%, of hexobarbital by 58%, conjugation of estradiol by 25% and of paranitrophenol by 18% - conversely it will enhance the reduction of paranitrobenzoic acid by 33 %.

Pretreatment of mice with phenobarbital, which enhances microsomal-induced drug metabolism, will decrease by 50% the acute lethal toxicity of Δ ⁹-THC.

It has also been shown that Δ ⁹-THC is metabolized in the lung where it produces two metabolites distinct from the 11 hydroxy compound produced in the liver. The enzymes which metabolize Δ ⁹-THC in the lung can be induced by methylcholantrene. This carcinogenetic agent therefore will enhance the pharmacologic effects of Δ ⁹-THC in the rat. However, methylcholantrene will not change the metabolism of Δ ⁹-THC in the liver.

The production of psychoactive metabolites of Δ ⁹-THC by enzyme induction in liver and lung, could account for the delayed appearance in many subjects of their first recorded manifestations of cannabis intoxication. Very few effects are felt when the drug is taken or smoked for the first time. They only appear after the second or third intake. If this is the case one would have to develop metabolic tolerance to Δ ⁹-THC before experiencing fully all of its effects, and initially it would appear that the same dosage as taken the first time is accompanied by greater effects. This phenomenon has been called "reverse tolerance". However, pharmacologically this tolerance should be of brief duration. Indeed, tissue or functional tolerance also develops to the drug and increments in Δ ⁹-THC will be required to maintain the same effects.

Distribution of Δ ⁹-THC and its metabolites was studied in the brain of squirrel monkeys after intravenous administration of 2-30 mg/kg of tritiated Δ ⁹-THC. The dose-response relationship noted with these increasing dosages was similar to that observed in man. Low doses have a euphoric, quieting effect, with disruption of perception; medium doses produced stimulation, excitation and uncoordination and hallucination. Higher dosages were accompanied by severe psychomotor incapacitation. A correlation was established between the distribution of Δ ⁹-THC at different times in certain areas of the brain and concomitant behaviour alterations. Fifteen minutes after administration of the drug, 79% of the radioactivity present in the brain was due to Δ ⁹-THC and the behavioural aberrations in the animals were maximal. This value declined to 50% at 4 hours and at the same time the abnormal behavioural patterns subsided. Many of the behavioural effects were related not only to the distribution of Δ ⁹-THC in the brain but also to changes in their distribution pattern at different times: within 15 minutes after administration, the frontal cortex which is the site of the higher functions of mentation, contained elevated concentrations of Δ ⁹-THC. A similar distribution is observed with ¹⁴C-ethanol. Another similarity between Δ ⁹-THC and ethanol is their marked accumulation in cerebellum and dental nuclei which may be related to the motor uncoordination produced by both substances. Fifteen minutes after Δ ⁹-THC administration, lateral and medial geniculate nuclei had high concen- tration of the drug. These structures, which have connexions with the visual pathways, contained elevated Δ ⁹-THC concentrations when visual perception appeared most distorted, and when the behaviour of the animals suggested that they were hallucinating. High concentrations of the drug were also seen in the amygdala, hippocampus, superior and inferior colliculi. The amygdala accumulation of Δ ⁹-THC (and/or metabolites) may be related to its reported anxiolytic and euphoric effect in man. It has been shown that antidepressant drugs used in man do accumulate in the amygdala. The authors conclude "The extremely high concentration of Δ ⁹-THC in the frontal cortex together with the hippocampal accumulation, makes it tempting to suggest that the interactions between these two areas play an important part in associating stimuli into a temporal context. It is well known that one of the chief effects of marihuana is distortion of time perception. Thus the typical disruption effect of Δ ⁹-THC could well be attributed to its unique distribution in the central nervous system."

Studies in man which will be subsequently discussed have corroborated the metabolic pattern observed in animals. It is now well established that the metabolites of cannaboinoids and Δ ⁹-THC linger in the body for a long period after their administration, from 4 to 8 days according to species. This prolonged retention is attributed to the fat solubility and protein binding of these compounds and to their recycling through the enterohepatic system, which delays considerably their fecal excretion. A large portion of the metabolites are excreted into the bile and then into the small intestine from where they are reabsorbed. The metabolic products of cannabis derivatives which tend to accumulate in the body, do not contribute to their initial psychotoxic effect. But the effects due to their prolonged storage in lung, liver, kidney, intestine, and brain requires careful evaluation. The completion of such studies, especially in man, will require many years.

Pharmacology

The psychoactive component of cannabis has many pharmacologic properties, centrally acting, autonomic, cardiovascular, which are common to stimulants, sedatives, tranquillizers, narcotics, analgesics and hallucinogens. However, the chemistry and pharmacology as well as the mechanism of action of the Δ ⁹-THC are quite different from those of barbiturates, amphetamines, opiates, ethyl alcohol or other hallucinogens.

Pharmacologists use in their experimental preparations much larger dosages of drugs than those used clinically for therapeutic purposes. This experimental attitude stems for the necessity of obtaining a maximal physiological or biochemical response which can be readily measured with methods which are still quite crude. The Δ ⁹-THC, like any other drug studied phar- macologically, has been, therefore, used on experimental animals in dosages much higher than those which will produce in man a psychotoxic effect. These experimental studies are mostly aimed at understanding the possible mechanism of action of these drugs. The Δ ⁹-THC, like cannabis extracts, acts primarily on the central nervous system and behaviour of experimental animals. Its second target organ is the richly innervated conductive system of the heart.

Effects on the central nervous system

The neurophysiological and neurohormonal mechanisms of brain function are poorly understood. In the brain, billions of nerve cells are constantly emitting myriads of coded signals which are transmitted through what resembles an intricate network of conductors, relays and amplifiers. Transmission of the signals from one neuron to the other is mediated by neurohormones, norepinephrine, 5 hydroxytryptamine and acetylcholine, which are stored in the synaptic vesiculae. The storage of past signals and their retrieval which characterizes memory involves the DNA and RNA of the neuron. The over-all electrical activity of the brain can be recorded with the electroencephalogram, which results in patterns typical of gross brain activity such as wakefulness, sleep, or arousal. But there are no easy methods to measure the turnover rate of the neurohormonal transmitters which modulate the electrical activity of the brain.

In animals, cannabis derivatives and Δ ⁹-THC will alter the over-all electrical activity of the brain as measured by the electroencephalogram and polysynaptic reflex activity. These compounds will also change the delicate balance of neurohormones which characterizes the normally functioning brain; finally, the ratio of RNA to DNA which appears to be related to a proper functioning of immediate memory is also impaired by Δ ⁹-THC.

Effects of Δ 9-THC on polysynaptic reflexes and EEG

The Δ ⁹-THC and some of its synthetic derivatives inhibit in cats and dogs polysynaptic reflexes such as the flexion linguo mandibular one and those involving the trigeminal system. As the tibialis nerve is unaffected, this effect is attributed to a specific central depressant action of THC localized in the forebrain area: facilitation of reflexes induced by stimulation of this area is blocked by THC. Like barbiturates, THC inhibits behavioural and EEG response to stimulation of the reticular activating system. However, THC also acts differently than barbiturates, in as much as it also enhances a late phase of the evoked pattern in the polysensory cortex, displaying an ambivalent pattern of action, depressing total activity and enhancing sensory input signals. This effect of THC in animals might correlate with the increased sensory awareness produced in man by this intoxicant. Accumulation of Δ ⁹-THC in the structures of the brain connected with the visual and auditory pathways do correlate with increased visual and auditory sensitivity reported by man. The ambivalent action of THC is also apparent by its ability to enhance in mice the stimulation induced by amphetamine and caffeine.

Administration of Δ ⁹-THC-or Δ ⁸-THC or of cannabis extracts alter consistently electroencephalographic and electrocorticographic (ECoG) patterns in rats, cats and rabbits. In the rat, marihuana extract distillate, 20 mg/kg given per os, or 2.5 to 10 mg/kg of Δ ⁸- or Δ ⁹-THC I.P. will significantly decrease the integrated EEG voltage and produce also, superimposed on this low voltage, high voltage "spindle like activity", suggesting increased excitability of neurons. Tolerance develops to the depressant activity and after ten days of treatment the integrated voltage was no longer significantly lowered. But tolerance does not develop to the high voltage spindle like activity. The association of a reduction in the voltage EEG output with polyspike discharges is unique to this hallucinogenic agent. Such a pattern correlates with a central nervous system arousal during which the rats appear sedated. Similar spike and wave patterns were also observed in cats treated by intra-peritoneal administration or after inhalation of marihuana extract (with known Δ ⁹-THC content). Slow waves with spikes were recorded after ten days and associated with progressive behavioural depression and withdrawal. Changes in EEG persisted for 22 days after the three-week treatment with the highest doses (16 mg/kg/day, I.P.). Synchronization of the EEG changes by cannabis derivatives could be in part related to the inhibition of the reticular arousal system produced by these substances.

Effects of Δ 9-THC on metabolism of brain neurotransmitters

Attempts have been made to correlate these functional changes in brain activity and in behaviour of rodents to alterations in the metabolism of brain neurotransmitters

With large pharmacological doses administered to rats and mice (5-10 mg/kg, I.P. or 3 mg/kg, I.V.), some authors have reported an increase in brain 5 HT while norepinephrine concentration and turnover rate had a tendency to be reduced. These results are of interest since it has been shown that a rise in brain 5 HT with a slight decrease of norepinephrine is associated with the behavioural effect of hallucinogenic drugs. As Δ ⁹-THC does not inhibit monoamine oxidase, its inhibitory effect on the turnover rate of 5HT has been attributed to a direct effect on the permeability of the vesicular membrane of the neuron.

Other authors have reported that smaller dosages of Δ ⁹-THC (5 mg intraperitoneally, or 1 mg/kg, I.V.) which produced marked behavioural effects, did not alter the dynamics of the cerebral serotonergic system. However, after repeated daily exposure of rats to the smoke of a cigarette containing Δ ⁹-THC (10 mg) Ho et al. have reported significant changes in neurohormone metabolism in rats. While there were no changes in hydroxytryptamine and norepinephrine brain concentrations, there was a marked decrease in their metabolites, 5-hydroxyindoleacetic acid and normetanephrine. The decreases in the metabolites under the effects of Δ ⁹-THC were interpreted as being due to a facilitation of their transport from the brain. Other studies with tritiated tyrosine, showed that Δ ⁹-THC significantly enhanced the turnover of brain norepinephrine, a pattern which could account for the stimulating effect of the drug. This increase of norepinephrine turnover in the brain would be related according to Bein, to an activation of tyrosine hydroxylase by Δ ⁹-THC.

It has been reported that another very important brain neurotransmitter, acetylcholine, also is increased by chronic administration of large doses of Δ ⁸-THC or Δ ⁹-THC to rats and monkeys.

Rises in brain 5HT and acetylcholine have been previously correlated with sleep and sedation (decreased activity) and a decrease or increase in catecholamine levels have accounted for decreased or increased locomotor activity. But it is probably the combined effect of the changes in all three neurotransmitters which determines the ultimate neurophysiological and behavioural effects. At present the interrelationship between the turnover and metabolism of the basic neurotransmitters we have mentioned, is not known during normal brain activity of sleep, wakefulness or arousal. A biochemical interpretation of the alterations in brain activity produced by the cannabinoids lies, therefore, in the far distant future. It might be very complex because of the multiple and contradictory effects of Δ ⁹-THC on the brain function and behaviour.

Changes in the ratio of DNA to RNA concentration in the brain of rats and monkeys administered chronically large amounts of Δ ⁹-THC have also been reported. These nucleic acids are involved in the storage of immediate memory which is known to be impaired during cannabis intoxication.

It has also been reported that Δ ⁹-THC has in rats and mice anticonvulsant and analgesic effects. The anticonvulsant action of Δ ⁹-THC in mice required relatively high dosages to prevent electroconvulsive shock (effective dose 50 was 54 mg/kg intraperitoneally). This compound, like diphenylhydantoin, did not prevent seizure induced by strychnine or pentylenetetrazol.

The analgesia produced in rats by Δ ⁹-THC also required high dosage (effective dose 50 was 10 mg/kg subcutaneously administered). In cats the analgesic dose was 1 mg/kg and it enhanced the excitory effect of morphine, while reducing motor activity. The dosage of Δ ⁹-THC required to obtain anticonvulsant or analgesic action will also produce other central nervous effects which should limit its clinical usefulness. Therefore, synthetic derivatives of Δ ⁹-THC free of untoward side effects will have to be developed for possible therapeutic applications.

Behavioural effects

The effects of cannabis derivatives on the central nervous system are accompanied by marked behavioural changes in animals. The changes are related to the species studied, to the dosage used, the mode of administration, and the experimental setting. The over-all picture is a mixture of depressant and stimulatory effects which are in keeping with the pharmacological action of cannabis derivatives on the central nervous system. Rats, given Δ ⁹-THC intraperitoneally, display increased or decreased spontaneous locomotor activity. A dose of 2 mg/kg produces initial excitation followed by depression. A single dose of 10 to 20 mg/kg will produce depression of activity, the rats appearing ataxic and flaccid with some of them, however, reacting aggressively to external stimuli. This dose disrupts learned behaviour such as conditioned avoidance response, not reactions to unconditioned stimuli. Continuous administration of such elevated dosages will produce tolerance and marked increase in locomotor activity and aggressive behaviour. It would also appear that intragastric administration is more effective in producing reproducible effects than intraperitoneal administration and requires lesser dosage: the minimal dose of Δ ⁸-THC to produce behavioural effects in mice and rats is 0.1 mg/kg with the maximal effect occurring 2 hours after administration. Repeated administration of Δ ⁹-THC in the peritoneum produces chronic diffuse chemical peritonitis.

Effects of cannabis derivatives on social behaviour of animals will vary according to dosage and frequency of administration. A single administration tends to decrease aggressive behaviour in rats and mice, which show less group aggregation and disruption of social hierarchies. Repetitive administration of large dosages of Δ ⁹-THC will enhance aggressive and fighting behaviour of rats. This increased aggressiveness had already been reported in starved rats given intraperitoneally cannabis extracts.

Administration of Δ ⁹-THC to rats (4 mg. intraperitoneally or 2-32 mg. intra-gastrically) for 30 days significantly decreased their food intake and weight gain. During that same period of time the animals developed tolerance to other behavioural effects of Δ ⁹-THC. The weight loss suffered during Δ ⁹-THC administration persisted during 30 days following the end of this treatment, while food intake was restored to control levels. It would seem that in rats while tolerance to many of the bahavioural effects of Δ ⁹-THC develops rapidly, the anoretic action of this agent is maintained.

A dog displays a typical ataxia when treated with marihuana extracts or Δ ⁹-THC (0.5 to 1 mg/kg). These motor deficiencies are accompanied with dysbarism, retching and vomiting, and do limit the usefulness of the dog in behavioural studies of this drug.

Behavioural tests such as operant schedules of the aversion or reward type have been used to assess the psychopharmacologic action of the constituents of cannabis.

Schedule controlled behaviour was studied in pigeons using key-pecking rates with a multiple fixed-ratio response, fixed interval (5 min) schedule of food presentation. Effects of Δ ⁹-THC and of two of its synthetic derivatives were measured two hours after intramuscular injections, which were performed once weekly for seven weeks. A marked decrease in rate of responding under both schedules, and tolerance developed, with cross tolerance among the different cannabinoids used. A similar tolerance to Δ ⁹- and Δ ⁸-THC developed in pigeons trained to peck keys for food, under a multiple fixed, ratio, fixed interval. The birds did not peck keys for four hours after the injection. As tolerance developed, normal rate of pecking gradually returned after 5 to 8 daily injections. Subsequent progressive one-hundred-fold increase in dosage did not change pecking rate when administration of the drug was 3 times a week. Cross tolerance with Δ ⁸-THC was also observed.

The effects of synthetic tetrahydrocannabinols on patterns of operant behaviour induced in rats by different schedules were difficult to interpret. Drug effects varied greatly with the type of schedule used and appeared according to the test situation, to depress or stimulate learned behaviour.

Behavioural effects of Δ ⁹- and Δ ⁸-THC administered intraperitoneally were studied in rhesus and squirrel monkeys with operant conditioning techniques. Continuous avoidance behaviour was induced by both compounds and complex behaviour involving memory and visual discrimination was markedly disrupted by these agents. Monkeys receiving 32 to 64 mg/kg of racemic Δ ⁹-THC exhibited initial excitation, such as hand tremors, unusual limb positions, panic-like states, and apparent hallucinations. These symptoms, which lasted for 3 hours, were followed by depression. Nine of 14 animals died after receiving the higher dosage. The ambivalent effect of Δ ⁹-THC was apparent in this study. A dose of 4 to 8 mg/kg reduced the response rate by 50% in a continuance avoidance schedule while 16-24 mg/kg increased response by 200%. The social dominance hierarchy was not changed by the drug but expressions of demeanour were changed, and the monkeys were less aggressive. In general these substances caused stimulation, depression, apparent hallucinations and the loss of motivation or ability to perform complex tasks.

Studies in chimpanzees given oral doses of 0.2 to 4.0 mg/kg of Δ ⁹-THC showed that this compound can have both stimulating and depressing effects on reinforcement schedule-controlled operant behaviour. A significant facilitation of differential reinforcement of low rate responding was obtained with an oral dose of 0.4 mg/kg Δ ⁹-THC, which is an effective oral dose in man.

All of these studies indicate that Δ ⁹-THC, the major psychoactive compound of cannabis, acutely or subacutely administered, produce in all animals species studied marked and complex aberrations of spontaneous and of conditioned behaviour. The possible additional toxic effects of the other cannabinoids and alkaloids present in cannabis remained to be appraised as they became available for experimental studies.

Autonomic and cardiovascular effects

In dogs, Δ ⁹-THC, (1-3 mg/kg, intravenously administered) produces a decrease in systolic, diastolic and mean arterial blood pressure, heart rate, cardiac output and total peripheral resistance. The pressor response to catecholamines is also potentiated. In the rat, 1 mg/kg intragastrically produces hypertension while 7 and 20 mg/kg produce hypotension. Both dose schedules induced bradycardia. Control heart rate was restored by vagotomy or atropinization of the animals. Bradycardia is also produced by Δ ⁹-THC in cats, dogs and monkeys.

The decrease in blood pressure might be a peripheral inhibiting effect of the cannabinoids on smooth muscle contraction. The Δ ⁹-THC or cannabis extracts inhibit the acetylcholine or oxytocin-induced contractions of uterine muscle strip. These compounds also inhibits the contraction of ileum and aortic strip. The cardiovascular effects produced by Δ ⁹-THC in laboratory animal are difficult to correlate with those produced in man where tachycardia is observed, while blood pressure tends to increase except in cases of massive intoxication where hypotension occurs.

Endocrine effects

Cannabis extracts appear to alter carbohydrate metabolism in rabbits by increasing glycogenolysis and blood sugar levels. These effects have not been reported in man, except for an increase in glucose tolerance test as measured by standard clinical tests.

The Δ ⁹-THC (4-16 mg/kg) produces in the rat a two-to three-fold increase in plasma corticosterone mediated through the pituitary. The same dose produced an inhibition of antidiuretic hormone with a two-fold increase of urine output. Large doses of Δ ⁹-THC (10 mg/kg) or cannabis extract reduce thyroidal uptake of radio-iodine in the rat.

Cannabis extract or Δ ⁹-THC will produce hypothermia in mice, rats, cats, dogs and monkeys (4 to 10 mg/kg intraperitoneally). A similar hypothermia has only been reported in man following massive intoxication.

Therapeutic claims reconsidered

The many therapeutic applications claimed for cannabis preparations, from the treatment of tetanus to that of cholera, belongs to the history of medicine. They have been briefly reviewed in the historical part of this monograph. Only one therapeutic property has really been proven: the antibiotic activity against Gram positive bacteria which is due to the non-psychoactive, cannabinol fraction of the plant. All other therapeutic claims have not been substantiated. This is especially true for Δ ⁸- and Δ ⁹-THC. The experimental results obtained with these two most important psychoactive ingredients of cannabis, as well as with crude marihuana extract, containing known amounts of the ingredients, have been unconclusive. These compounds will not rekindle the therapeutic potential of cannabis for the treatment of many common diseases ailments affecting the central nervous system.

There are many unfavourable features inherent in the use of these psychoactive compounds as routine therapeutic agents in modern medicine. Their lack of water solubility precludes administration for rapid effect; their slow and uneven absorption in the gastrointestinal tract results in a delayed effect of 2 to 3 hours. Their absorption by smoking is more rapid but short lived, and this unusual method of drug administration might not be acceptable to all patients; their uneven mode of action is accompanied by periods of waning and waxing. They have a prolonged half life and their metabolites accumulate in tissues for one week before being eliminated; there is rapid development of tolerance to their action, making a prolonged uninterruppted course of therapy hazardous.

All of these features would make it difficult to prescribe Δ ⁸- or Δ ⁹-THC in a quantitative way even if they had a unique specific therapeutic property. But this is not the case. All of the alleged therapeutic indications of Δ ⁹- or Δ ⁸-THC are met today by drugs which are more specific, more potent, easier to prescribe, administer, and control, which have a mechanism of action better understood and which are free of psychotomimetic effects.

Good substitutes for the hypnotic, sedative, analgesic, tranquillizing, anticonvulsant and relaxant drugs now available should have a rapid onset and a duration of action; they should not give rise to rapid tolerance, should not be habit forming or psychotomimetic.

The alleged hypertensive effect of Δ ⁹-THC has never been clearly demonstrated in all animal species. Doses of 10 to 20 mg/kg do not change systematically blood pressure of normal or spontaneous hypertensive rats (personal observation). A psychotomimetic dose of Δ ⁹-THC does not always produce in man clear hypotensive effects while it induces a marked acceleration of heart rate; which is not desirable in the treatment of hypertension.

It was also suggested that cannabis derivatives might be useful in the treatment of withdrawal symptoms to alcohol, barbiturates or opiates. It has been established that the effects of cannabis on psychomotor performance are potentiated by alcohol, but the mechanism of action of these two substances is quite different. A great degree of tolerance develops to both drugs with the development of tolerance to Δ ⁹-THC being much more rapid. One report by Thompson and Proctor, claimed that pyrohexyl treatment with a cannabis synthetic derivative (15 mg, 3 to 4 times daily) alleviated in 80% of the cases treated (59 out of 70) withdrawal symptoms from ethenol intoxication. However, subsequent treatment with pyrohexyl beyond five days was not continued, and the "cured" patients after overcoming their withdrawal symptoms remained abstinent without any form of substitutive therapy. Treatment, by the same authors, of withdrawal symptoms from morphine were less successful. It is evident that Δ ⁹-THC cannot compete with methadone in the treatment of withdrawal symptoms from opiate intoxication.

Moreau de Tours was the first to assume that the "feeling of gaiety and joy" produced by cannabis intoxication would be most valuable to treat "the fixed ideas of the depressives". He treated several such cases of deep depression with increasing dosages of hashish, but with little result. Moreau de Tours also tried hashish in the treatment of schizophrenia with disappointing results. He continued his trials on less sick "manic" patients, and reports that seven of them were cured.

One hundred years after, a similar lack of effectiveness of cannabis derivatives on the depressive state, was observed by Thompson, who treated 20 cases of depression with pyrohexyl. By contrast, Stockings claimed a successful use of synhexyl (15 to 90 mg orally) another synthetic cannabis derivative, in the treatment of "50 depressive patients" which included a large heterogeneous group with what the author calls "Thalamic dysfunction". He states that 30 out of 50 improved, but this study, with no control subjects, no objective measurements is impossible to interpret. In any event, though an effective sedative drug might help common types of depression with anxiety. They cannot replace the tricyclic antidepressants which are the agents of choice, in the treatment of the severe depressions which Moreau de Tours wished to influence favourably.

Cannabis was prescribed in Hindu medicine not only to stimulate the appetite, as reported by Snyder, but also to deaden the need for food or beverage by concentration of the mind toward the eternal. According to Chopra, the chronic user of ganja is thin and emaciated. The contemporary grapevine also mentions the powerful stimulus for appetite that marihuana produces in the user. Cannabis is also supposed to increase the quality of food. All of these claims might be true in the context of the social setting where they developed. After a lively party ending late at night, and where only tobacco has been smoked, everyone seems to have a ravenous appetite. That is why in Paris, some bistros stay open all night. It would be difficult to substantiate the claim that cannabis increases the appetite and might be a good drug to use in anorexia nervosa. On the basis of well controlled pharmacological studies on animals the appetite was observed. Rats given Δ ⁹-THC decreased their food intake significantly; furthermore, the weight loss suffered persisted 30 days following the end of the treatment. The possibility that Δ ⁹-THC be used in the treatment of obesity, was not suggested by the authors of this study.

Others have claimed that cannabis derivatives could be useful in the treatment of migraine or facial neuralgia and as a sexual stimulant. There is little pharmacological basis for these first indications. Δ ⁹-THC has weak analgesic activity, while the basic difficulty of formulating dosage, foreseeing the extent and reactions to its use, remain important obstacles. The aphrodisiac properties of cannabis derivatives are reported throughout its long history. Many in the Orient still absorb cannabis for the amorous prowess it is supposed to foster. Many youth claim that indeed their sexual performance and enjoyment is enhanced by the use of marihuana. The subjective impression of the slowing of time might indeed confer to the performer a very unusual gratification if his orgastic experience is extended from 30 seconds to 30 minutes. However, the experimenter should be informed that this alleged effect of cannabis is not dose dependent and only occurs with low dosage. Theophile Gauthier, a wild young French romantic, stated after taking a good dose of hashish "the hashish user would not lift a finger for the most beautiful maiden in Venice". Young French romantics of the nineteenth century like their ancestors, did not seem to need any special drug to increase their dashing amorous prowesses. This tradition has prevailed in France until recently. Moderate doses of cannabis might act like ethanol. "It provokes and unprovokes: it provokes the desire, but it takes away the performance." The chronic use of cannabis according to Chopra and Benabud leads to a sad condition where a lack of desire is coupled with an inability to perform.

The only truly demonstrated therapeutic applicable property of cannabis is the antibacterial effect of cannabidiol. This effect has been demonstrated in vitro and pharmaceutical preparations such as ointments for topical application against staphylococcal infections have been proposed. Cannabidiol does not appear to have any particular advantage over the large number of powerful antibiotic substances but it might be a substance worthy to be studied further in bacteriology and microbiology.

The most biologically active molecules isolated from cannabis sativa have not held their therapeutic promises. The curative properties were attributed to this magic plant, first by the Indian and Arabic folklore, and then by the pre-scientific nineteenth century era of western medicine. Δ ⁹-THC is quite unlike digitoxin or reserpine, two biologically active molecules extracted from the foxglove leaf or from Rawolfia serpentina. Δ ⁹-THC does not meet any of the modern pharmacological standards of safety, specificity, and effectiveness required for a new drug to replace those presently in use. The analogues and homologues of Δ ⁹-THC which have now been synthesized in large numbers might display the therapeutic properties which have been sought in vain for the psychoactive substances isolated from cannabis sativa.

Summary

Δ ⁹-THC which appears to be the major psychoactive substance of cannabis presents the following pharmacological properties:

It is insoluble in water and body fluids.
It has a very high fat solubility and binds to plasma and cellular proteins.
It is poorly and irregularly absorbed from the gastrointestinal tract.
It induces enzymes in lung and liver (nonspecific oxydoses).
It has a prolonged half life (greater than 24 hours).
Its metabolites accumulate in the brain and other tissues and are eliminated over a week in urine and feces.
It rapidly induces tolerance in all animal species.
It primarily affects the central nervous system where it alters the turnover rate of the major neurotransmitters-norepinephrine, 5 hydroxytryptamine and acetylcholine.
Its acute or chronic administration produces multiple behavioural aberrations in learned and evoked response.
It produces ambivalent action in the central nervous system with stimulatory sensory effects combined or followed by depressant ones.
It interacts with other centrally acting drugs such as amphetamines, ethanol, barbiturates.
It does not present any specific pharmacological property which could justify its use as a therapeutic agent more effective than any presently in use.

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