Metabolism of 14C-tetrahydrocannabinol (14C-THC) by rat liver microsomal preparations in vitro was studied in the absence and presence of other psychoative drugs. Disappearance of 14C-THC, and changes in metabolite patterns as shown by thin layer chromatography, were studied. SKF 525-A, pentobarbital, phenobarbital and amphetamine all produced an apparently non-competitive inhibition of THC metabolism. The inhibition produced by meprobamate was at least partly competitive. Morphine and mescaline had no evident effect. SKF 525-A and the barbiturates markedly decreased the concentrations of all the major THC metabolites found in the incubation media. In contrast, none of the drugs tested in vivo, with the exception of SKF 525-A, had any effect on the biliary 14C-excretion or metabolite pattern, or on final tissue levels of 14C, when administered in doses comparable to those used for studies of interaction with THC in vivo. SKF 525-A, however, did markedly decrease the excretion of total 14C and alter the pattern of THC metabolities in the bile, and increased the final tissue 14C levels. It is concluded that in vivo interactions between THC and other psychoactive drugs are probably not explainable primarily on the basis of altered THC metabolism.