Are cannabidiol and Δ9‐tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review

JM McPartland, M Duncan, V Di Marzo… - British journal of …, 2015 - Wiley Online Library
JM McPartland, M Duncan, V Di Marzo, RG Pertwee
British journal of pharmacology, 2015Wiley Online Library
Based upon evidence that the therapeutic properties of C annabis preparations are not
solely dependent upon the presence of Δ9‐tetrahydrocannabinol (THC), pharmacological
studies have been recently carried out with other plant cannabinoids (phytocannabinoids),
particularly cannabidiol (CBD) and Δ9‐tetrahydrocannabivarin (THCV). Results from some
of these studies have fostered the view that CBD and THCV modulate the effects of THC via
direct blockade of cannabinoid CB 1 receptors, thus behaving like first‐generation CB 1 …
Based upon evidence that the therapeutic properties of Cannabis preparations are not solely dependent upon the presence of Δ9‐tetrahydrocannabinol (THC), pharmacological studies have been recently carried out with other plant cannabinoids (phytocannabinoids), particularly cannabidiol (CBD) and Δ9‐tetrahydrocannabivarin (THCV). Results from some of these studies have fostered the view that CBD and THCV modulate the effects of THC via direct blockade of cannabinoid CB1 receptors, thus behaving like first‐generation CB1 receptor inverse agonists, such as rimonabant. Here, we review in vitro and ex vivo mechanistic studies of CBD and THCV, and synthesize data from these studies in a meta‐analysis. Synthesized data regarding mechanisms are then used to interpret results from recent pre‐clinical animal studies and clinical trials. The evidence indicates that CBD and THCV are not rimonabant‐like in their action and thus appear very unlikely to produce unwanted CNS effects. They exhibit markedly disparate pharmacological profiles particularly at CB1 receptors: CBD is a very low‐affinity CB1 ligand that can nevertheless affect CB1 receptor activity in vivo in an indirect manner, while THCV is a high‐affinity CB1 receptor ligand and potent antagonist in vitro and yet only occasionally produces effects in vivo resulting from CB1 receptor antagonism. THCV has also high affinity for CB2 receptors and signals as a partial agonist, differing from both CBD and rimonabant. These cannabinoids illustrate how in vitro mechanistic studies do not always predict in vivo pharmacology and underlie the necessity of testing compounds in vivo before drawing any conclusion on their functional activity at a given target.
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