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Are cannabidiol and Δ 9 ‐tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review
Author(s) -
McPartland John M,
Duncan Marnie,
Di Marzo Vincenzo,
Pertwee Roger G
Publication year - 2015
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.12944
Subject(s) - rimonabant , cannabidiol , cannabinoid receptor , cannabinoid , endocannabinoid system , pharmacology , receptor , in vivo , inverse agonist , agonist , cannabinoid receptor agonists , partial agonist , chemistry , cannabinoid receptor antagonist , neuroscience , biology , cannabis , medicine , biochemistry , microbiology and biotechnology , psychiatry
Based upon evidence that the therapeutic properties of C annabis preparations are not solely dependent upon the presence of Δ 9 ‐tetrahydrocannabinol ( THC ), pharmacological studies have been recently carried out with other plant cannabinoids (phytocannabinoids), particularly cannabidiol ( CBD ) and Δ 9 ‐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 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 CB 1 receptors: CBD is a very low‐affinity CB 1 ligand that can nevertheless affect CB 1 receptor activity in vivo in an indirect manner, while THCV is a high‐affinity CB 1 receptor ligand and potent antagonist in vitro and yet only occasionally produces effects in vivo resulting from CB 1 receptor antagonism. THCV has also high affinity for CB 2 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.