In vitro, the cannabinoids delta 9-tetrahydrocannabinol (delta 9-THC), 11-OH-delta 9-THC, cannabidiol and cannabinol all increased adenylate cyclase activity in mouse cerebral cortical homogenates. Levonantradol, a synthetic cannabinoid analog, also increased adenylate cyclase activity while its optical isomer dextronantradol did not. The increases in enzyme activity produced by the active compounds were biphasic with significant increases at 10 microM and/or 30 microM concentrations with return to control levels at 100 microM. The increases did not occur in the absence of added GTP nor did delta 9-THC have any effect on fluoride-stimulation of adenylate cyclase activity. The prostaglandin synthetase inhibitors acetyl salicylic acid and indomethacin and the phospholipase A2 inhibitor quinacrine all abolished the increase in adenylate cyclase activity produced by delta 9-THC, suggesting the involvement of prostaglandins in this cannabinoid action.