Cannabidiol displays unexpectedly high potency as an antagonist of CB 1 and CB 2 receptor agonists in vitro

Background and purpose: A nonpsychoactive constituent of the cannabis plant, cannabidiol has been demonstrated to have low affinity for both cannabinoid CB ₁ and CB ₂ receptors. We have shown previously that cannabidiol can enhance electrically evoked contractions of the mouse vas deferens, suggestive of inverse agonism. We have also shown that cannabidiol can antagonize cannabinoid receptor agonists in this tissue with a greater potency than we would expect from its poor affinity for cannabinoid receptors. This study aimed to investigate whether these properties of cannabidiol extend to CB ₁ receptors expressed in mouse brain and to human CB ₂ receptors that have been transfected into CHO cells. Experimental approach: The [ ³⁵S]GTPγS binding assay was used to determine both the efficacy of cannabidiol and the ability of cannabidiol to antagonize cannabinoid receptor agonists (CP55940 and R-(+)-WIN55212) at the mouse CB ₁ and the human CB ₂ receptor. Key results: This paper reports firstly that cannabidiol displays inverse agonism at the human CB ₂ receptor. Secondly, we demonstrate that cannabidiol is a high potency antagonist of cannabinoid receptor agonists in mouse brain and in membranes from CHO cells transfected with human CB ₂ receptors. Conclusions and implications: This study has provided the first evidence that cannabidiol can display CB ₂ receptor inverse agonism, an action that appears to be responsible for its antagonism of CP55940 at the human CB ₂ receptor. The ability of cannabidiol to behave as a CB ₂ receptor inverse agonist may contribute to its documented anti-inflammatory properties.