The 1995 Marijuana Rescheduling Petition

Structure Activity Relationship and Toxicity

The chemistry of the cannabinoids has been known for some time. The chemistry of marijuana (59) and its biogenesis (60) has been published by Rapheal Mechoulam, a co-discoverer of THC. In the early 1980's researchers made great strides in associating changes in the chemical structure of cannabinoids with related changes in the observed effects, and in correlating this structure-activity relationship with various testing paradigms.

The structure-activity relationships of cannabinoids discovered by researchers were discussed and reviewed by Raz Razdan in 1986. Here is an extensive description of the pharmacological profile of marijuana.

"The gross effects produced in man or animals cannot be classified pharmacologically as being primarily due to a stimulant, sedative, tranquilizer, or a hallucinogen, although they share some properties with each of these. In general, the effects produced by this drug are dose dependent. Thus in small doses, it produces subjective effects more typical of a hallucinogen and subjective effects more typical of a hallucinogen and somewhat resembling those of a small dose of lysergic acid diethylamide (LSD). However, unlike the latter, it produces sedative effects, with no significant sympathomimetic actions, and there is no cross-over tolerance to LSD. In addition, it is not a narcotic, and compared to many drugs such as the opiates, barbiturates, etc. it does not produce physical dependence. Interestingly, the user may be in a high state of intoxication, but to an observer, he may appear to be in a near normal state. Mild states of intoxication are generally undetected, and the mood may vary from being happy and gregarious to quiet and introspective. With high doses, notable signs are minimal, but the most reproducible signs include an increase in pulse rate and bloodshot eyes. Dryness of the mouth and throat and an increased appetite are common. In some cases, there may also be slurring of the speech. With moderate dosages, the user can perform simple physical and mental tasks, but the performance of more complicated physical and psychological tasks may be impaired. The most common subjective effect appears to be time distortion with other effects varying from pleasant relaxation to acute anxiety, loss of contact with reality, hallucinations, and panic. These latter effects are generally associated with large dosages. As with other psychoactive drugs, the effects vary greatly and are mostly dictated by the psychological makeup of the individual and the setting under which the drug is used."(61)

Razdan concludes that:

"the concept of drug development from THC's and cannabinoids is based on very sound foundations, since unlike morphine, D9-THC has a remarkable low toxicity in animals and humans. In addition, it has practically no respiratory-depressant activity, none or very low physical dependence liability, and, finally, a unique pharmacological profile compared to other psychoactive drugs." (62)

William Dewey also summarizes the pharmacological effects of cannabinoids as having two striking characteristics. One of them is the multiplicity of effects described above by Razdan. The other is the low toxicity of the chemical family.

"Throughout this review, I have indicated that the minimal effective dose of D9-THC for a particular pharmacological effect in animals was higher than that usually consumed by man. Yet, in almost all cases, it was much lower than the dose which produced toxic effects in the same species, The two characteristics of the animal pharmacology of cannabinoids carry over to humans. For instance, each of the cannabinoids tested in man causes many side effects at active doses and lethal effects of overdose by humans are nonexistent or rare. Toxicity following chronic use may be a different issue." (63)

The reason it may be a different issue is that at this time, the mid 1980's, no one knew what was marijuana's mechanism of action on the human brain. The popular research paradigm was that cannabinoid effects on the central nervous system were produced by a cell membrane perturbation effect." (64) A review of the biochemical research on possible mechanisms of action for cannabinoids was also included in the 1986 edition of Pharmacological Reviews by Billy Martin. Martin concluded his review of the "Cellular Effects of Cannabinoids" with this concerned and widely quoted observation:

"While the cannabinoids do not appear to be highly toxic, it is disconcerting that they seem to exert some alteration in almost every biological system that has been studied." (65)

"Martin's article is prefaced with a discussion of the problems caused by the solvents used to create THC solutions for biochemical research on its effect on cells. Razdan also notes that these solvents "are not without pharmacological activity." (66) As discussion of the discovery of marijuana's mechanism of action in Section 3 below will explain, these problems resulted in the invalidation of may of the findings produced by the biochemical studies Martin reviewed in this 1986 article. Martin's article is cited frequently in 1990's cannabinoid research, not though for the alterations hypothesized above, but for his warnings and descriptions of the ultimately fatal flaws in this research paradigm.

Martin and co-authors realized in 1988 that a major change in research paradigms was looming on the horizon.

"Two general mechanisms of action have been proposed for the cannabinoids. The first is that they act through a specific receptor as do the opiods and many other drugs. . . A second mechanism of action that has been proposed for the cannabinoids is that they alter the fluidity or ordering of biological membranes. This possibility was first investigated because of the highly lipophilic nature of most cannabinoids and their preferential association with biological membranes." (67) (emphasis added)

Allyn Howlett, one of the co-authors of that statement, had made a breakthrough with a model neural system. One of her graduate students, William Devane, made a related breakthrough developing a radioimmunoassay that would allow researchers to conduct binding studies with a potent, experimental cannabinoid. The initial evidence that a cannabinoid receptor system existed was discussed in Martin and Howlett's presentation to the 49th annual meeting of the CPDD in 1988. The work of Howlett's team, especially due to the contributions of Devane, led to a major breakthrough in scientific knowledge about the effects of marijuana and their neural mechanism of action. This breakthrough will be discussed in Section 3 of this petition, which will also review the ramifications of this discovery on understanding the pharmacology of marijuana.


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