The 1995 Marijuana Rescheduling Petition

Discovery of the Cannabinoid Receptor System

In 1988, Allyn Howlett and William Devane used radioimmunoassay techniques to characterize the existence of a cannabinoid receptor in a rat brain. (13) In 1990, Miles Herkenham and his team mapped the locations of a cannabinoid receptor system in several mammalian species, including man. (14)

Receptors are most dense in the basal ganglia, hippocampus, and cerebellum, and are sparse in the lower brainstem areas controlling heart and lung functions.

"High densities of receptors in the forebrain and cerebellum implicate roles for cannabinoids in cognition and movement." (15)

Billy Martin, in his 1986 review, acknowledged what many in the field suspected. Marijuana's effects might be produced by either membrane effects, or produced by a receptor system. A membrane-based mechanism was logical; like anesthesia marijuana's chemicals lodged in fatty cells. (16) Some factors pointed toward a receptor based mechanism, but no technology existed to research this. There are several comments in the literature indicating two directions for research to pursue, but only one road to follow. According to Herkenham's research findings, they all traveled in the wrong direction.

Contemporaneous with the localization of the cannabinoid receptor in the brain came was the publication by a paper by Thomas, Compton and Martin that characterized the relationship of the lipophilic (fat-loving) nature of cannabinoids with their behavioral potency."(17)

"The large number of cannabinoid compounds with which we have compared lipophilicity and pharmacological potency clearly indicates that a relationship does not exist between these two parameters. . . This lack of correlation between lipophilicity and CNS activity within the cannabinoids does not support a mechanism of action which involves only nonspecific membrane perturbation, but rather it suggest that the pharmacological effects of cannabinoids result from a more specific action . . .this lack of correlation does not entirely rule out the possibility that membrane partitioning cold contribute to some pharmacological effect of the cannabinoids."(18)

The location of cannabinoid receptors in the human brain correlate with the characteristic effects of marijuana. Of greater confirmation value, the receptor sites bind with cannabinoids and nothing else (at least none of the long list of drugs the researchers tried). (19) Characterization of the receptor allowed Matsuda and colleagues to identify a previously cloned receptor gene of unknown identity as the endogenous cannabinoid receptor. (20)

Lichtman and Martin found that converging lines of evidence indicating that cannabinoids produce antinociception (pain reduction) through multiple mechanisms at both the spinal and supraspinal levels of the Central Nervous System. (21) Further evidence indicates that discriminative stimulus and catalepsy are caused by two distinct mechanisms. (22)

A 1991 report to the CPDD verifies that the work of Howlett, Devane, Herkenham, and Matsuda as responsible for the discovery of the new research paradigm.


In 1992 Thomas, Wei, and Martin duplicated the localization of the cannabinoid receptor by Herkenham's team using a different autoradiographic assay. (24)

In 1993 Roger Pertwee published a minireview in the British review General Pharmacology on "The Evidence for the Existence of Cannabinoid Receptors." Pertwee reviewed the criteria necessary to establish the existence of a receptor, and reviewed the evidence establishing a structure-activity relationship of the cannabinoids, their stereoselectivity, potency, binding sites and other areas.


Also, Pertwee pounds another nail in the coffin of the cell membrane perturbation theory.



Zip Code:
Subscribe Unsubscribe