The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ9-tetrahydrocannabinol, cannabidiol and Δ9-tetrahydrocannabivarin

Cannabis sativa is the source of a unique set of compounds known collectively as plant cannabinoids or phytocannabinoids. This review focuses on the manner with which three of these compounds, (−)-trans-Δ⁹-tetrahydrocannabinol (Δ⁹-THC), (−)-cannabidiol (CBD) and (−)-trans-Δ⁹-tetrahydrocannabivarin (Δ⁹-THCV), interact with cannabinoid CB₁ and CB₂ receptors. Δ⁹-THC, the main psychotropic constituent of cannabis, is a CB₁ and CB₂ receptor partial agonist and in line with classical pharmacology, the responses it elicits appear to be strongly influenced both by the expression level and signalling efficiency of cannabinoid receptors and by ongoing endogenous cannabinoid release. CBD displays unexpectedly high potency as an antagonist of CB₁/CB₂ receptor agonists in CB₁– and CB₂-expressing cells or tissues, the manner with which it interacts with CB₂ receptors providing a possible explanation for its ability to inhibit evoked immune cell migration. Δ⁹-THCV behaves as a potent CB₂ receptor partial agonist in vitro. In contrast, it antagonizes cannabinoid receptor agonists in CB₁-expressing tissues. This it does with relatively high potency and in a manner that is both tissue and ligand dependent. Δ⁹-THCV also interacts with CB₁ receptors when administered in vivo, behaving either as a CB₁ antagonist or, at higher doses, as a CB₁ receptor agonist. Brief mention is also made in this review, first of the production by Δ⁹-THC of pharmacodynamic tolerance, second of current knowledge about the extent to which Δ⁹-THC, CBD and Δ⁹-THCV interact with pharmacological targets other than CB₁ or CB₂ receptors, and third of actual and potential therapeutic applications for each of these cannabinoids.