Pharmacological interactions between delta 1-trans-tetrahydrocannabinol (THC), the primary active constituent of cannabis, and other cannabinoids, also commonly found in cannabis, will be examined in the rat. It is possible that cannabinoids such as cannabidiol, cannabinol, whose chemical structures are similar to that of THC, may influence the pharmacological activity of cannabis by altering the biological disposition of THC. THC/cannabinoid dose-response relationships will be studied using measures of operant schedule behavior, and body temperature, as indices of drug effect. The influence of the cannabinoids on the tissue distribution, metabolism and elimination of THC will be examined at doses of significant interaction. THC and its primary metabolite, 7-hydroxy-THC, are normally bound up to 99 percent by lipoprotein and albumin in blood. Therefore emphasis will also be placed on determining the effects of phenylbutazone and dicumarol, which are transported in the blood in a protein-bound form, on the plasma protein binding and disposition of THC and its metabolites. Blood plasma samples obtained from rats treated with C14-THC and an interacting drug will be subjected to ultracentrifugation and electrophoresis to permit a determination of the protein binding pattern of THC and its metabolites. Drugs causing an alteration of the plasma protein binding of THC and its metabolites, and hence tissue availability, could influence the pharmacological activity of THC. Behavioural experiments will be carried out to ascertain whether cross-tolerance develops between THC and ethanol. The disposition of the drugs involved will be examined to ascertain whether cross-tolerance is of 'metabolic' origin. In addition the influence of canabinoids on amphetamine disposition will be studied in an attempt to explain the potentiating effect of cannabis on amphetamine-induced activity in rats. BIBLIOGRAPHIC REFERENCES: Siemens, A.J. and Kalant, H. Metabolism of Delta 1-Tetrahydrocannabinol by the Rat in vivo and in vitro. Biochem. Pharmacol., 24: 755-763 (1975). Siemens, A.J., de Nie, J.C., Kalant, H. Effects of Psychoactive Drugs on the Metabolism of Delta 1-Tetrahydrocannabinol by the Rat in vitro and in vivo. Eur. J. Pharmacol., 31: 136-147 (1975).