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
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."
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."
"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.