(+)- trans -Cannabidiol is a CB ₂ receptor agonist

( − ) -trans -Cannabidiol ((−)-CBD) is a principal phytocannabinoid from Cannabis sativa . (−)-CBD has complex pharmacology but is a relatively weak inhibitor of CB1 and CB2 receptor signalling. Cannabidiol has two chiral centres and thus four stereoisomers. (+)- trans -CBD ((+)-CBD) has a higher affinity than (−)-CBD at CB1 and CB2, but its pharmacodynamic effects at these receptors are incompletely described. We examined the activity of (+)-CBD at human CB1 and CB2 receptors using a fluorescence-based assay of membrane potential in AtT20 cells stably expressing CB1 or CB2 receptors. (+)-CBD produced a rapid, concentration-dependent hyperpolarization in CB2-expressing cells ( p EC50 6.63 ± 0.08) with a maximal effect ∼90% of the response to CP55940. The CB2 response was blocked by pertussis toxin pretreatment and competitively inhibited by the CB2 antagonist AM630 (Schild slope 1.1 ± 0.1). (+)-CBD was a low-efficacy, low-potency CB1 agonist and inhibited somatostatin-receptor effects at high concentrations (10-30 µM). It had no effect on the membrane potential of AtT20 wild-type cells. In silico modelling of ligand interactions with CB2 indicated that (+)-CBD but not (−)-CBD formed an H-bond with Ser285, a residue crucial for agonist activation of CB2. Our data suggests (+)-CBD acted as a CB2 agonist via the orthosteric binding site on the receptor. Synthetic CBD, including (+)-CBD, has previously been administered in clinical trials, presumably without consideration of its potential CB2 agonist activity. Given the relative safety of (−)-CBD in people, (+)-CBD may be a useful drug to explore CB2-sensitive disease states, should it prove similarly safe.