Cannabichromene is a Cannabinoid CB₂ receptor agonist

Background and Purpose: Cannabichromene (CBC) is one of the most abundant phytocannabinoids in Cannabis spp. It has modest antinociceptive and anti-inflammatory effects and potentiates some effects of Δ⁹-tetrahydrocannabinol in vivo. How CBC exerts these effects is poorly defined and there is little information about its efficacy at cannabinoid receptors. We sought to determine the functional activity of CBC at cannabinoid CB₁ and CB₂ receptors. Experimental Approach: AtT20 cells stably expressing haemagglutinin-tagged human CB₁ and CB₂ receptors were used. Assays of cellular membrane potential and loss of cell surface receptors were performed. Key Results: CBC activated CB₂ but not CB₁ receptors to produce hyperpolarization of AtT20 cells. This activation was inhibited by a CB₂ receptor antagonist AM630, and sensitive to Pertussis toxin. Application of CBC reduced activation of CB₂, but not CB₁, receptors by subsequent co-application of CP55,940, an efficacious CB₁ and CB₂ receptor agonist. Continuous CBC application induced loss of cell surface CB₂ receptors and desensitization of the CB₂ receptor-induced hyperpolarization. Conclusions and Implications: CBC is a selective CB₂ receptor agonist displaying higher efficacy than tetrahydrocannabinol in hyperpolarizing AtT20 cells. CBC can also recruit CB₂ receptor regulatory mechanisms. CBC may contribute to the potential therapeutic effectiveness of some cannabis preparations, potentially through CB₂ receptor-mediated modulation of inflammation.