7-Oxo-Δ⁸-tetrahydrocannabinol as an active metabolite of Δ⁸-tetrahydrocannabinol

Pharmacological effects of Δ⁸-tetrahydrocannabinol (THC) metabolites, 7α-hydroxy-Δ⁸-THC (7α-OH-Δ⁸-THC), 7β-OH-Δ⁸-THC and 7-oxo-Δ⁸-THC, were examined in mice using catalepsy, hypothermia and pentobarbital-induced sleep prolongation as indices. Each cannabinoid was injected to mice intravenously, and two doses of 5 and 10 mg/kg were used for assessments of hypothermia and barbiturates synergism. In cataleptogenic effect assessed using various doses, ED₅₀ values of 7-oxo-Δ⁸-THC and 7α-OH-Δ⁸-THC were 3.2 and 7.5 mg/kg, respectively. The value of 7-oxo-Δ⁸-THC was comparable to that of Δ⁸-THC (3.3 mg/kg). In 7β-OH-Δ⁸-THC-treated groups, 25% of mice showed cataleptogenic effect at a dose of 13.8 mg/kg. In hypothermia, 7-oxo-Δ⁸-THC was most effective among three cannabinoids, and 7α-OH-Δ⁸-THC was the next. Pentobarbital (40 mg/kg, intraperitoneally)-induced sleep prolonging effect was also ranked in the following order, 7-oxo-Δ⁸-THC > 7α-OH-Δ⁸-THC > 7β-OH-Δ⁸-THC. The activity 7-oxo-Δ⁸-THC 7-oxo-Δ⁸-THc is comparable to that of Δ⁸-THC in all the pharmacological indices assessed. These results demonstrate that oxication at 7-position is one of the metabolically activating pathway of Δ⁸-THC.