(+)-Trans-Cannabidiol Is an Agonist at Human CB₂ Receptors

(-)-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 signaling. 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 (pEC₅₀ 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). (+)-CBD had no effect on the membrane potential of AtT20 wild-type cells. In silico modeling 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.