Evaluation of Cannabimimetic Effects of Selected Minor Cannabinoids and Terpenoids in Mice.

Background: The cannabis plant contains several cannabinoids, and many terpenoids that give cannabis its distinctive flavoring and aroma. A9-Tetrahydrocannabinol (A9-THC) is the plant's primary psychoactive constituent. Given the abuse liability of A9-THC, assessment of the psychoactive effects of minor cannabinoids and other plant constituents is important, especially for compounds that may be used medicinally. This study sought to evaluate select minor cannabinoids and terpenes for A9-THC-like psychoactivity in mouse A9-THC drug discrimination and determine their binding affinities at CB1 and CB2 receptors. Methods: A9-THC, cannabidiol (CBD), cannabinol (CBN), cannabichromene (CBC), cannabichromenevarin (CBCV), A8-tetrahydrocannabinol (A8-THC), (6aR,9R)-A10-tetrahydrocannabinol [(6aR,9R)-A10-THC], A9-tetrahydrocannabinol varin (THCV), p-caryophyllene (BC), and p-caryophyllene oxide (BCO) were examined. Results: All minor cannabinoids showed measurable cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptor binding, with CBC, CBCV, and CBD, showing the weakest CB1 receptor binding affinity. BC and BCO exhibited negligible affinity for both CB1 and CB2 receptors. In drug discrimination, only A8-THC fully substituted for A9THC, while CBN and (6aR,9R)-A10-THC partially substituted for A9-THC. THCV and BCO did not alter the discriminative stimulus effects of A9-THC. Conclusion: In summary, only some of myriad cannabinoids and other chemicals found in the cannabis plant bind potently to the identified cannabinoid receptors. Further, only four of the compounds tested herein [A9-THC, A8THC, (6aR,9R)-A10-THC, and CBN] produced A9-THC-like discriminative stimulus effects, suggesting they may possess cannabimimetic subjective effects. Given that the medicinal properties of phytocannabinoids and terpenoids are being investigated scientifically, delineation of their potential adverse effects, including their ability to produce A9-THC-like intoxication, is crucial.