Chemistry of the cannabinoids
Biological activity of cannabis
Pharmacokinetics
Author: Stig AGURELL, J. Lars G. NILSSON
Pages: 35 to 37
Creation Date: 1972/01/01
The last two years has been a period when a considerable amount of basic knowledge concerning cannabis has been collected in laboratories all around the world. Most of these new, but largely unpublished, data were presented and discussed during a Symposium held in Stockholm (26-28 October 1971), under the sponsorship of Apotekarsocieteten, the Swedish Academy of Pharmaceutical Sciences. There were 40 papers covering the chemistry, biological activity and pharmacokinetics of the cannabinoids read before 100 participants from 16 countries.
The President of the Symposium was Dr. Leo Hollister, Veterans Administration Hospital, Palo Alto, California. In his opening lecture he gave the human pharmacological background to the subsequent presentations. The clinical effects of cannabis, he said, are dose related, ranging from mild and brief states of intoxication to long-lasting hallucinogenic experiences. The initial clinical state is one of euphoria and stimulation, but later the subjects report a drowsy, sleepy state. Dr. Hollister also pointed out that the question of tolerance and sensitization to the effect of cannabis in man is not settled, although this has been studied both in his laboratory and by other groups.
Cannabis research at the Division of Narcotic Drugs, United Nations, Geneva, was presented by Dr. Olav J. Braenden. The most important function of the UN Laboratory is to coordinate, on the international level, cannabis research to avoid unnecessary duplication of effort. Reference cannabis samples for comparative studies are also provided.
On the national level, a similar but more detailed programme is carried out by the National Institute of Mental Health, Bethesda, Maryland. This was presented to the Symposium by Dr. Monique C. Braude. NIMH has at present 57 grants and 16 contracts dealing exclusively with cannabis research. They cover a wide variety of pre-clinical and clinical studies, ranging from chemical, analytical and pre-clinical pharmacological studies, to clinical studies of physiologic, behavioural and social effects of the cannabinoids. Of particular interest are two studies now going on in Greece and Jamaica, which deal with the long-term effects of cannabis smoking.
The emphasis has been to elucidate the effects of the compounds responsible for the psychoactive effects of cannabis in man, to quantify the constituents or their metabolites in biological fluids, to determine their toxicity and side effects and to correlate these data with the social effects of the drug.
The three main cannabinoids present in cannabis preparations are tetrahydrocannabinol (THC), cannabinol (CBN) and cannabidiol (CBD). Altogether, approximately 30 different cannabinoids have today been identified in cannabis. The synthesis of many of these compounds and their metabolites have been carried out by Dr. Raphael Mechoulam, Hebrew University, Jerusalem. Among other compounds, he presented a synthesis of the recently discovered active metabolite 6-β-hydroxy-Δ 1-THC. The presence of a number of active metabolites, Dr. Mechoulam said, makes the understanding of the pharmacological effects of cannabis in man difficult. The different effects that various people encounter may depend on the ratio between THC and its metabolites at the receptor sites. The presence of the metabolites in body fluids may also be the basis for the identification of cannabis users.
The structure-activity relationships for the tetrahydro-cannabinoids has also been studied by Dr. Mechoulam and Dr. Edery of the Tel-Aviv University Medical School. The benzopyran structure seems to be necessary for activity, since an open analogue is inactive. Other essential structural fragments of THC is the phenolic hydroxyl group and the alkyl side chain. The position of the double band in the terpenoid ring is also important. It is known that Δ1 and Δ 1( 6) are equally potent while Δ3-THC is less active, and Δ5-THC is inactive. Dr. Mechoulam also reported that (+)-Δ1-THC and (+)-Δ 1( 6) THC are inactive, while the corresponding naturally occurring ( - )-forms have activity.
In several papers, the synthesis of the different cannabinoid metabolites were reported. Dr. J. L. G. Nilsson, Stockholm, and Dr. T. Petrzilka of the Zürich Technical High School, both described new synthetic routes to 7-hydroxy-Δ 1( 6)-THC. Dr. R. K. Razdan of the Sheehan Institute for Research at Cambridge, Mass., reported on some water-soluble derivatives of THC that could be used in pharmacological experiments. These compounds where the phenolic hydroxyl group was esterified with hydrophilic acid residues chain-formed micelles and were rapidly hydrolyzed in vivo to THC.
Three papers reported on the morphology and the constituents of Cannabis sativa. Using scanning electron microscopy, Dr. Fairbairn of London University could show some very detailed pictures of the plant leaves. He also reported that the vegetative leaves as well as the glandular hairs, contain cannabinoids. This may be of importance to workers on biosynthesis as well as to the legislators.
The natural occurrence of several cannabinoids with shorter side chains (propyl or methyl instead of n-amyl) was studied by Dr. Merkus, of the R.C. Hospital at Sittard in the Netherlands, and by Dr. Vree of the University of Nijmegen, in the Netherlands. Dr. Vree showed that by recording the mass spectra of the cannabinoids at different but low electron voltages and plotting certain peak heights against the electron voltages, curves characteristic for each type (CBD, THC, CBN) of cannabinoid were obtained. This technique was then used to identify minor constituents in the plant.
The second day of the Symposium was devoted to the biological activity of the cannabinoids. Dr. Sidney Cohen, UCLA, Los Angeles, California talked first about what he called the "changing concepts of cannabis pharmacology". A number of widely held ideas about the pharmacology of cannabis must be abandoned in the light of recent findings. These include its classification as a sedative, the absence of tolerance and withdrawal effects, the notion of reversed tolerance, its ability to dilate the pupils, to produce hypoglycemia and the development of conjunctival infections.
Prolonged heavy use of cannabis may lead to an "amotivational syndrome" where the users lose interest in themselves and in the surrounding world. We still need to know more about this effect and also about the carcinogenic and teratogenic potentials of cannabis. The widely held idea that cannabis leads to the use of harder narcotics like heroin was also discussed by Cohen. He pointed out that this was a serious risk for the heavy users, while "social users" who took cannabis only occasionally normally did not start using heroin.
The behavioural effects of cannabis had been studied by several groups. Dr. E.A. Carlini from Sao Paulo Medical School, Brazil, could demonstrate that rats under stress, such as cold, starvation or morphine abstinence showed a pronounced aggressive behaviour when given cannabis extracts. Other groups reported results indicating that cannabis has a pronounced influence on the behaviour of animals and man.
A general review of the pharmacology of Cannabis was presented by Dr. Paton of Oxford University. The pharmacology is largely determined by the lipophilicity of the cannabinoids, he said. This physical property brings the cannabinoids into analogy with the anaesthetics and in this way a considerable number of its actions can be interpreted: certain neurophysiological and behavioural effects; respiratory depression; hypothermia and analgesia.
The role of the cannabinoids on the brain amines was discussed by several speakers. The over-all picture obtained from the experiments described is still not clear, although THC seems to affect both levels and turnover of the mono-amines in the brain.
An investigation of the stimulation of the metabolic transformation of THC in pigs was reported by Dr. J. Schou of Copenhagen University. The results indicated a metabolic adaptation of the pigs. After prolonged administration of THC, the disappearance rate of THC increases and also the appearance rate for metabolites in plasma was enhanced. Similar results were reported for humans by Dr. L. Lemberger of Lilly Laboratory for Clinical Research, Indianapolis, Indiana. He also showed that when the activity of cannabis is maximal, the amount of THC present in the plasma is very low, indicating the presence of active metabolites.
The metabolic conversions of the various cannabinoids were reported by several groups. Dr. S. Agurell, Stockholm, reported that the Δ 1( 6)-THC metabolite 7-hydroxy-Δ 1( 6-THC is pharmacologically very active and further converted in the rabbit to a carboxylic acid. This acid had also been isolated by Dr. S. Burstein of the Worchester Foundation for Experimental Biology Mass., who could show that it had a carboxyl group in the 7-position and also an additional hydroxyl group in the side chain.
The metabolism of cannabidiol was studied by Dr. I. M. Nilsson of the Faculty of Pharmacy, Stockholm. She presented three new monohydroxylated metabolites of CBD with a hydroxyl group at position 7, 10, and in the benzylic position of the side chain, respectively.
Dr. Gill of Oxford University, had also studied the metabolism of THC. He could show that CBD increased the amount of 7-hydroxy-THC in the plasma, and thus acted as a synergist. It is thus apparent that cannabis contains both the active THC and a synergist CBD.
Recently, radioactively labelled THC with high specific activity has become available. This material has been used by three groups to study its distribution using autoradiography.
Dr. McIsaac, of the Texas Research Institute of Mental Sciences at Houston, Texas, reported on the behavioural correlates of brain distribution of THC using rhesus monkeys. Dr. J. E. Indanpaan-Heikkila of the National Board of Health, Helsinki, Finland, had investigated the placental transfer and the variation in distribution of THC in mice after different routes of administration. Finally, Dr. Ryrfeldt AB Astra, Sodertalje, Sweden, had studied the whole body distribution in mice after intravenous administration.
Radioactive THC had also been used to study its binding to the plasma proteins. Dr. H. Klausner of the Vanderbilt School of Medicine, Nashville, Tennessee, and Dr. M. Widman of the Stockholm Faculty of Pharmacy both reported that THC is extensively bound to lipoproteins in plasma. Dr. Widman could also demonstrate that the metabolite 7-hydroxy-THC under the same conditions largely is bound to serum albumin.
In summary, it can be stated that the Symposium revealed that a large amount of knowledge has been accumulated on the chemistry of Cannabis and the synthesis of cannabinoid compounds and their metabolites. There remains some uncertainty as to how much THC is absorbed by smoking, to give the biological " high ". In metabolism studies it has been shown that the three compounds, however, are further converted to still others, and so far unknown metabolites, before elimination. The metabolic pattern is thus, very complex and requires much further work particularly since some metabolites are very active compounds. Quite a few other pharmacokinetic parameters are known. A number of limited clinical studies in humans, using orally administered THC or THC absorbed by smoking, have been carried out.
Thus, THC and cannabis of known potency, can now be used with confidence in large scale clinical trials. During the next few years the present clinical knowledge will be supplemented with a large amount of clinical data which undoubtedly will shed some new light on two basic questions " How dangerous is cannabis "? and " What should we do about it? ".
The abstracts of the papers presented at this Symposium will be published in Acta Pharmaceutica Suecica, No. 6, 1971. These abstracts describe most of the results presented at the Symposium.
