INVESTIGATOR: Daniele Piomelli, Pharm.D., Ph.D.
STUDY LOCATION: University of California, Irvine
PROJECT TITLE: Effects of Cannabis Therapy on Endogenous Cannabinoids
PROJECT TYPE: Pre-Clinical Study
This study assessed the effect of acute and chronic treatment of rats with the cannabinoid agonist, WIN-55212-2, on the levels of anandamide in blood and brain tissue. No change was observed in plasma anandamide concentration after either acute or chronic treatment. Likewise, there was no significant change in anandamide levels in three brain regions: cerebellum, nucleus accumbens, and brainstem. Chronic, but not acute, treatment with WIN-55212-2 caused a marked increase in anandamide levels in the brain hippocampus, a region that is crucially involved in learning and memory.
In order to compare the actions of cannabinoids with those of other abused substances, the effects of acute administration of amphetamine and alcohol on brain anandamide levels in the rat were measured. It was found that amphetamine (2 mg/kg ip) significantly increases anandamide levels in the nucleus accumbens, but not in the hippocampus and cerebellum. Furthermore, it was found that acute alcohol administration (4 g/kg ip) decreased anandamide levels in the hippocampus, cerebellum, and nucleus accumbens. These finding suggest that the endogenous cannabinoid system may respond in selective ways to different drugs of abuse.
These experiments contributed preliminary data to work that was later published in the journal Neuropsychopharmacology.
Despite a long history of use in traditional medicine, the therapeutic value of the cannabis remains uncertain. The active principle in cannabis, D9-tetrahydrocannabinol (D9-THC), exerts its effects by activating high-affinity receptors present on the surface of brain and immune cells. These receptors are called cannabinoid receptors and are normally engaged by a group of natural fat-derived substances called endocannabinoids. The endocannabinoids are a novel group of neurotransmitters that may contribute in important ways to movement, cognition, pain and other physiological processes. We have learned much on these molecules in recent years, but still don't know how they may be affected by treatment with cannabis and D9-THC. Yet, elucidating such interactions would be important to evaluate the consequences of medical treatment with these and other cannabinoid agents. Here, we propose to test the hypothesis that long-term cannabis and D9-THC administration interfere with activity of the endocannabinoid system. The first aim of the proposed research is to determine whether cannabis and D9-THC affect circulating levels of endocannabinoid compounds in humans. Initial analyses have shown that such measurements are feasible by using a technique known as high-performance liquid chromatography/mass spectrometry (HPLC/MS). The proposed studies will determine circulating endocannabinoid levels in persons treated with marijuana, D9-THC (dronabinol) or placebo. The plasma samples will be kindly provided by Dr. D. Abrams (at U.C. San Francisco) who is currently funded by the CMCR to investigate the effects of cannabinoid therapy in HIV patients. The second aim of the proposed research is to determine whether cannabis and D9-THC affect endocannabinoid formation and/or inactivation in rodents. We will examine the effects of acute and chronic D9-THC administration on (1) endocannabinoid levels in rat plasma and brain tissue; and (2) activities of endocannabinoid-metabolizing enzymes in rat brain tissue. The main purpose of these experiments, which will be conducted in collaboration with Dr. F. Rodríguez de Fonseca (at the Carlos Haya Hospital in Málaga, Spain), is to complement our human studies by providing mechanistic insight on how cannabinoid drugs affect the endocannabinoid system. Brain neurotransmitter systems are highly plastic and regulate their activity when they are challenged with exogenous drugs. We hypothesize that treatment with cannabis or D9-THC may produce compensatory changes in the activity of the endocannabinoid system. Such changes might in turn influence in important ways the therapeutic outcome of cannabinoid therapy and participate in withdrawal phenomena after drug cessation.