The Common Mechanism of Action of All Cannabinoid Drugs

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The use of highly potent, stereoselective synthetic cannabinoid analogs made the discovery and characterization of the endogenous cannabinoid receptor system between 1988 and 1993 possible. As discussed throughout the petition above, all recent advances in understanding about the effects of marijuana have been based on the discovery of the common mechanism of action for cannabinoids, including D9-THC, which provide the pharmacological basis for the effects of marijuana.

A review of the conclusions of Herkenham’s team’s findings on tolerance reiterates this important point:

“The magnitude of the present effect, like the striking behavioral tolerance, may stem in part that, unlike other psychoactive agonist drugs, cannabinoids can be administered in very high doses. It is ironic that the magnitude of both tolerance (complete disappearance of the inhibitory motor effect) and receptor down-regulation (78)% loss . . .) is so large, whereas cannabinoid dependence and withdrawal phenomena are minimal. This supports the claim(35) that tolerance and dependence are independently mediated in the brain.”(36)

WIN 55,212 is another experimental cannabinoid which produces the same effects as D9-THC and CP-55,940, however there are some differences in the effects of each of the three. A 1994 study demonstrated cross-tolerance between these three cannabinoids.(37) The authors hypothesize that D9-THC and WIN-55,212 are partial agonists whereas CP 55,940 is a complete agonist, explaining some of the minor differences between these cannabinoids. Cross tolerance among certain psychoactive cannabinoids has been well documented.(38)

Valid assertions about the relative abuse potential and relative dependence liability of marijuana can now be made by scientists on the basis of the known existence of a cannabinoid receptor system in the human body. Valid assertions about the relative abuse potential and relative dependence liability of all cannabinoids can be made on the same scientific basis.

The psychoactive qualities of marijuana are produced by one constituent chemical, D9-THC. Conclusive evidence exists that marijuana does not have a dependence liability greater than that of D9-THC alone, and that no other cannabinoid has psychoactive properties. Conclusive evidence exists that the pharmacological properties of individual natural cannabinoids have less pharmacological action than either marijuana or D9-THC alone, and that their dependence liabilities (if any) and potential for abuse is less than that of marijuana and D9-THC.

Experimental cannabinoids may have greater potencies, and may present qualities which warrant stricter controls than necessary for natural cannabinoids or synthetic copies of naturally occurring cannabinoids, such as synthetic THC.

There is no scientific basis for an assertion that marijuana had a greater dependence liability than D9-THC. There is no scientific basis for an assertion that any cannabinoid compound has a greater dependence liability than D9-THC. Consequently, there is no basis for distinguishing between the scheduling of marijuana, cannabinoids, and D9-THC on the basis of dependence liability or potential for abuse.

As discussed in sections 1 and 7 above, neither marijuana, cannabinoids, or D9-THC have sufficient potential for abuse for inclusion in schedule I or II of the Controlled Substances Act.

On the basis of the chemical similarities between marijuana, cannabinoids, and specifically D9-THC, their common endogenous receptor system, the lack of self-administration of cannabinoids in animals, the lack of cannabinoid receptor activity in dopamine producing areas of the brain, and the additional scientific and medical evidence discussed above, this petition calls for the repeal of the administrative rules placing marijuana and cannabinoids in schedule I and placing D9-THC in schedule II.