Effects of Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) on pentobarbital (PB)-induced sleeping time and on hepatic microsomal drug metabolizing enzyme systems were studied in male and female mice. 1) In all i.p. doses used (10, 50 and 100 mg/kg), Δ9-THC and CBD significantly prolonged PB-induced sleeping time in both sexes of mice. CBD was more active than Δ9-THC in this route of administration. 2) Δ9-THC prolonged PB-induced sleeping time by i.c.v. administration (5, 10 and 20 μg/mouse) in both sexes of mice. On the other hand, CBD did not show any significant prolongation by i.c.v. administration in male mice, although it prolonged the sleeping time in female mice by the same treatment. The result indicates that female mice are more sensitive to the sleep prolonging effect of the cannabinoids. 3) CBD showed an inhibitory effect on p-nitroanisole O-demethylase and aniline hydroxylase in vivo and in vitro. Δ9-THC also showed the inhibitory effect, but to lesser extents. 4) Kinetic analysis showed that CBD has lower K1 values for p-nitroanisole O-demethylase and aniline hydroxylase than Δ9-THC in both sexes of mice. The inhibitory effect of the cannabinoids was more remarkable in male than in female. 5) The in vivo inhibitory effect of the cannabinoids was paralleled to the reduction of cytochrome P-450 content in hepatic microsomes. It is concluded that CBD has greater inhibitory effect on hepatic microsomal drug metabolizing enzymes of male and female mice than Δ9-THC.
