(+)‐Trans‐Cannabidiol Is an Agonist at Human CB 2 Receptors

ABSTRACT (−)‐ trans ‐Cannabidiol ((−)‐CBD) is a principal phytocannabinoid from Cannabis sativa . (−)‐CBD has complex pharmacology but is a relatively weak inhibitor of CB 1 and CB 2 receptor signaling. Cannabidiol has two chiral centres and thus four stereoisomers. (+)‐ trans ‐CBD ((+)‐CBD) has a higher affinity than (−)‐CBD at CB 1 and CB 2 , but its pharmacodynamic effects at these receptors are incompletely described. We examined the activity of (+)‐CBD at human CB 1 and CB 2 receptors using a fluorescence‐based assay of membrane potential in AtT20 cells stably expressing CB 1 or CB 2 receptors. (+)‐CBD produced a rapid, concentration‐dependent hyperpolarization in CB 2 ‐expressing cells ( p EC 50 6.63 ± 0.08) with a maximal effect 90% of the response to CP55940. The CB 2 response was blocked by pertussis toxin pretreatment and competitively inhibited by the CB 2 antagonist AM630 (Schild slope 1.1 ± 0.1). (+)‐CBD was a low‐efficacy, low‐potency CB 1 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 CB 2 indicated that (+)‐CBD but not (−)‐CBD formed an H‐bond with Ser285, a residue crucial for agonist activation of CB 2 . Our data suggests (+)‐CBD acted as a CB 2 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 CB 2 agonist activity. Given the relative safety of (−)‐CBD in people, (+)‐CBD may be a useful drug to explore CB 2 ‐sensitive disease states.