The <i>Cannabis sativa </i>plant contains more than 120 cannabinoids. Comparatively little is known about the vast majority of plant-derived cannabinoids beyond Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD). Pre-clinical research regarding the cannabinoids has largely focused on the type 1 and 2 cannabinoid receptors (CB1R, CB2R), which remain the most-characterized cannabinoid receptors. Δ9-THC treatment is associated with pain-relieving, appetite-inducing, and anxiolytic effects; whereas CBD has recently been approved for the treatment of refractory epilepsies. In our group, we have been studying the pharmacology of 10 cannabinoids and 6 terpenes present in cannabis at lower amounts than Δ9-THC or CBD. These compounds have been assessed alone and in combination with one another for their (1) affinity to CB1R and CB2R, (2) modulation of intracellular signalling cascades, and (3) effects on pain, anxiety, and movement in mice. We have also begun exploring the role of these cannabinoids in anti-convulsant effects in clinical trials. Our findings demonstrate many less-abundant plant cannabinoids are partial agonists of CB1R and/or CB2R but that terpenes have little-to-no impact on cannabinoid pharmacology at these receptors. Among the cannabinoid tested, Δ9-THC appears to be unique in its engagement of β-arrestin2, which may explain its intoxicating properties and undesirable side effects. CBC and cannabichromene appear unique in their potential anticonvulsant activity. These initial data represent a first step toward understanding the complex pharmacology of cannabis and may improve our harms reduction approach to cannabis as well as the development of novel cannabinoid-based therapeutics.

Novel pharmacology of plant cannabinoids from Cannabis sativa in vitro, in vivo, and in clinic

ACS Spring Meeting 2021

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