Prostaglandins and cannabis XIV. Tolerance to the stimulatory actions of cannabinoids on arachidonate metabolism.

The stimulation of prostaglandin E2 synthesis by delta 1-tetrahydrocannabinol in cultured cells is rapidly diminished by successive exposures to the drug at 24-hr intervals. Cannabidiol and cannabicyclol, two other constituents of cannabis, also displayed this in vitro tolerance effect. The phenomenon could, in addition, be observed by measuring the release of arachidonic acid from these cells, suggesting that the site of action of the cannabinoids is at one or more of the lipases that are believed to control prostaglandin synthesis under most conditions. Tolerance to cannabinoid action has been reported for a variety of in vivo parameters; thus, this in vitro system exhibits similar behavior and may, therefore, be a good model for studies on the molecular mechanisms involved in tetrahydrocannabinol action.