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 mechanisms."(63)

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 cannabinoids."(65)

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 effects. (70)