The diverse CB₁and CB₂receptor 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 -Δ 9 -tetrahydrocannabinol (Δ 9 -THC), (−)-cannabidiol (CBD) and (−)- trans -Δ 9 -tetrahydrocannabivarin (Δ 9 -THCV), interact with cannabinoid CB 1 and CB 2 receptors. Δ 9 -THC, the main psychotropic constituent of cannabis, is a CB 1 and CB 2 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 CB 1 /CB 2 receptor agonists in CB 1 - and CB 2 -expressing cells or tissues, the manner with which it interacts with CB 2 receptors providing a possible explanation for its ability to inhibit evoked immune cell migration. Δ 9 -THCV behaves as a potent CB 2 receptor partial agonist in vitro . In contrast, it antagonizes cannabinoid receptor agonists in CB 1 -expressing tissues. This it does with relatively high potency and in a manner that is both tissue and ligand dependent. Δ 9 -THCV also interacts with CB 1 receptors when administered in vivo , behaving either as a CB 1 antagonist or, at higher doses, as a CB 1 receptor agonist. Brief mention is also made in this review, first of the production by Δ 9 -THC of pharmacodynamic tolerance, second of current knowledge about the extent to which Δ 9 -THC, CBD and Δ 9 -THCV interact with pharmacological targets other than CB 1 or CB 2 receptors, and third of actual and potential therapeutic applications for each of these cannabinoids.