P 3: PSYCHOACTIVITY OF CANNABINOIDS & INTERACT W/ DELTA-9-TETRAHYDROCANNABINOL

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cannabis sativa L. is the one the oldest plants known in medicine and also the source of marijuana, the most widely used illicit drug in the world. To date, a total of almost 500 natural constituents have been isolated and/or identified from Cannabis sativa L. The most widely studied has been delta-9-tetrahydrocannabinol (A9-THC), which is now recognized as the main biologically active component in the Cannabis plant. A9-THC is the primary psychoactive component in marijuana. It has also been approved by the Food and Drug Administration for the control of nausea and vomiting associated with chemotherapy, and more recently, for appetite stimulation of AIDS patients suffering from the wasting syndrome. The drug also shows other biological activities which lend itself to therapeutic applications for the treatment of glaucoma, migraines, spasticity, anxiety, and pain. The mechanism of action of A9-THC involves an interaction with the endogenous cannabinoid system. In recent years, this system has become the focus of many drug development efforts to develop compounds that provide therapeutic benefit, with a reduced abuse liability compared to A9-THC. Given that then; are hundreds of natural constituents of Cannabis, we hypothesize that many of the poorly characterized constituents in Cannabis also exhibit biological activity through the endogenous cannabinoid system. We anticipate that some of them will possess A9-THC-like activities, others will enhance the activity of A9-THC, and others will be natural antagonists of A9-THC. A multidisciplinary approach will be used in this project to isolate and analyze natural constituents of Cannabis that have never been studied before for biological activity. The specific aims of the project are to: 1) Isolate and structurally analyze different Cannabis compounds, especially cannabitriols group and non-cannabinoid phenolics, whose biological activity is unknown, 2) Confirm that the mechanism of action of the isolated compounds involves an interaction with the endogenous cannabinoid system, 3) Study the psychoactivtty of the isolated compounds and compare it with that of A9-THC, and 4) Study the interaction of A9-THC with the individual isolated compounds and determine their contribution to the overall biological activities of Cannabis. It is anticipated that the results of this project will provide important new information regarding the constituents of Cannabis that contribute to its abuse liability and medicinal properties.