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

Burtchaell P.; Santiago M.; Wang C.; Hagdoost M.; Clay E.; Mohnot D.; Connor M. · Pharmacology research & perspectives · 2026

**Background & Methods** This review examined the pharmacodynamic activity of (+)-trans-cannabidiol ((+)-CBD), a stereoisomer of the principal cannabis phytocannabinoid (-)-CBD, at human CB1 and CB2 receptors. Researchers utilized a fluorescence-based membrane potential assay in AtT20 cells stably expressing either CB1 or CB2 receptors, supplemented by in silico modeling of ligand-receptor interactions to elucidate binding mechanisms. **Key Findings** • (+)-CBD acts as a partial agonist at human CB2 receptors, producing concentration-dependent hyperpolarization (pEC50 6.63 ± 0.08) with maximal effects reaching 90% of the CP55940 response. This CB2 activity was blocked by pertussis toxin pretreatment and competitively inhibited by the CB2 antagonist AM630 (Schild slope 1.1 ± 0.1), confirming G-protein coupled receptor signaling via the orthosteric binding site. • (+)-CBD demonstrated low-efficacy, low-potency agonist activity at CB1 receptors and inhibited somatostatin receptor signaling at high concentrations (10-30 μM), while showing no effect on wild-type AtT20 cells. • Molecular modeling revealed that (+)-CBD, but not (-)-CBD, forms a critical hydrogen bond with Ser285, a residue essential for CB2 agonist activation, explaining the stereoisomer's differential pharmacological profile. **Dosage & Administration** Not reported. The study focused on in vitro receptor pharmacology at varying concentrations (10-30 μM range tested for somatostatin inhibition); clinical dose equivalents were not established. **Safety & Adverse Effects** Not reported. The authors note that synthetic (+)-CBD has been administered in previous clinical trials without documented consideration of its CB2 agonist activity. The relative safety profile of the naturally occurring (-)-CBD in humans is referenced as a basis for potential therapeutic exploration of (+)-CBD, but specific adverse event data were not presented. **Evidence Quality** This is a mechanistic in vitro study with significant limitations. Results derive from a single cell line model and lack in vivo validation or human clinical data. The in silico modeling supports but does not definitively prove the proposed binding mechanism. As a review article examining preliminary pharmacological characterization, this work provides foundational evidence for (+)-CBD's CB2 agonism but represents early-stage research requiring substantial additional validation before clinical application.

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