Evaluation of cannabimimetic effects of selected minor cannabinoids and Terpenoids in mice

The cannabis plant contains several cannabinoids, and many terpenoids that give cannabis its distinctive flavoring and aroma. Δ⁹-Tetrahydrocannabinol (Δ⁹-THC) is the plant's primary psychoactive constituent. Given the abuse liability of Δ⁹-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 Δ⁹-THC-like psychoactivity in mouse Δ⁹-THC drug discrimination and determine their binding affinities at CB₁ and CB₂ receptors.

Δ⁹-THC, cannabidiol (CBD), cannabinol (CBN), cannabichromene (CBC), cannabichromenevarin (CBCV), Δ⁸-tetrahydrocannabinol (Δ⁸-THC), (6aR,9R)-Δ¹⁰-tetrahydrocannabinol [(6aR,9R)-Δ¹⁰-THC], Δ⁹-tetrahydrocannabinol varin (THCV), β-caryophyllene (BC), and β-caryophyllene oxide (BCO) were examined.

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 Δ⁸-THC fully substituted for Δ⁹-THC, while CBN and (6aR,9R)-Δ¹⁰-THC partially substituted for Δ⁹-THC. THCV and BCO did not alter the discriminative stimulus effects of Δ⁹-THC.

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 [Δ⁹-THC, Δ⁸-THC, (6aR,9R)-Δ¹⁰-THC, and CBN] produced Δ⁹-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 Δ⁹-THC-like intoxication, is crucial.