Scientific knowledge about marijuana has taken great strides
since 1988. Even in 1988, though, there was considerable doubt
to claims that marijuana caused brain damage, as claimed later
by administrators of the DEA.
In 1986 a comprehensive review of research on "The Chronic
Cerebral Effects of Cannabis Use" by Renee Wert and Michael
Raulin appeared in the International Journal of the Addictions.
Two papers examined neurological(59) and neuropsychological
(60) findings to date, and the authors found "no evidence
that marijuana produces gross structural impairment" and "little
evidence that it leads to functional impairment, although
subtle impairment cannot be ruled out."
In 1991 the Department of Health and Human Services (HHS)
published the Third Triennial Report to Congress on Drug Abuse
and Drug Abuse Research. (61) Their report reviewed research
published through 1988 and was written when it appeared likely
from the work of Howlett and Devane that a cannabinoid receptor
system may exist. There is no discussion of brain damage,
or the need for research to address the possibility. The focus
of research in 1988 was two-fold. First, the objective of
research was to discover the mechanism of action that marijuana
has in the brain. Second, the critical issue of marijuana's
dependence liability should be clarified by the discovery
of the mechanism of action.
The research priorities suggested by the discovery of
the cannabinoid receptor system have launched a new paradigm.
The pioneers of this research elaborate on the new paradigm
in the conclusion of a 1990 article on the cannabinoid receptor.
Their summation is entitled "A challenge to neuroscientists"
and is as follows:
"Clearly, a plethora of questions about the actions of
cannabinoid compounds in the CNS remain. Biochemical, anatomical
and neurophysiological studies of the effects of cannabis
compounds have been limited in the past due to the relatively
low potency of D9-THC, its high solubility in membrane lipids,
and its tendency to adhere to glass and plastic in in vitro
experiments (see Martin, 1986 and Pertwee, 1988]). The use
of high-affinity cannabinoid agonists such as desacetyllevonantradol
and CP-55,940 in these studies should allow rapid progress
in addressing the unique and important actions of cannabinoid
compounds in the CNS. Cannabinoid analgetics should be useful
in studying novel mechanisms of anti-nociceptive at the level
of the spinal cord as well as at higher levels in the CNS
involved in processing of the response to pain. The anatomical
and physiological properties of cannabinoceptive neurons in
the hippocampus and cortex must be re-evaluated with respect
to the role these neurons may play in cognition and memory.
Study of the interactions of cannabinoceptive neurons with
afferents to, efferents from, and interneurons within the
basal ganglia must be re-evaluated. Additionally, the function
of cannabinoid receptors in the cerebellum should be addressed.
Renewed scientific interest in cannabinoid compounds would
stimulate research within a broad range of neuroscience disciplines."(62)
A 1991 report to the CPDD by several of the principle
scientists responsible for the receptor breakthrough describes
the research problems currently before the scientific community:
"Much work is left to be done to unravel and utilize
our knowledge of cannabinoids and how they work. The tools
that allowed us to discover the receptor and pinpoint neuro-anatomical
distributions coupled with the design of new tools (e.g. affinity
ligands) will help us answer many other questions."
"There are at least four major areas where we look for
progress in the coming decades. The discovery of physiologically
relevant receptor subtypes will aid the ultimate goal of separating
the traditional activities of cannabinoids (specific agonists)
in search of therapeutically useful drugs. The discovery of
an antagonist will be a key event both as a research tool
and to combat cannabis overdose. Recent findings of agonists
and an antagonist in the aminoalkylindole (AAI) series gives
us a hope that this goal will be attained soon. The third
area ripe for new developments is the discovery of the endogenous
ligand. Three separate groups (Howlett, Childress, and Mechoulam)
are currently working on identifying the endogenous cannabinoid(s).
Finally, new areas will evolve from this research, e.g., the
discovery of peripheral cannabinoid receptors and new pain
In 1992 William Devane and colleagues identified a naturally
occurring chemical in a porcine brain that binds to cannabinoid
receptors. (64) In neurobiological terms, this substance is
likely to be an "endogenous ligand", and it appears to share
the pharmacological properties of D9-THC. Devane has named
this chemical Anandamide, after the Sanskrit word for bliss.
Martin summarizes the questions researchers began to face
in the mid 1990's:
"The future challenge is establishing the physiological
role for the endogenous cannabinoids. Is anandamide a neurotransmitter
or a neuromodulator? Does an entire cannabinoid family of
amide derivatives of fatty acids exist, each of which has
a distinct neurochemical role? If cannabinoids serve a normal
physiological role, then what are the consequences of an imbalance
in this system? Answers to these and related questions will
likely provide an entirely new perspective on the way we view
Considerable progress is being made in advancing cannabinoid
research. In 1994 Rinaldi-Carmona and her team found an orally
effective cannabinoid antagonist, SR141716A. (66) Along with
advances in understanding anandamide, the endogenous ligand,
the discovery of an antagonist will greatly accelerate development
of new drugs based on the cannabinoid receptor system.
Progress has been made in discovering how anandamide
is formed, (67) and verifying its actions on the cannabinoid
receptors.(68) The pharmacological activity of anandamide
has been tested and characterized, indicating distinct differences
between the pain killing properties of anandamide and cannabinoids.
(69) Low doses of anandamides inhibit the pharmacological
effects of D9-THC, perhaps on account of their partial agonist