Mechanism and effects of the skeletal muscle Nav1.4 inhibition by cannabidiol

Cannabis sativa contains active constituents called phytocannabinoids. Whereas some phytocannabinoids are psychotropic, others are not. The primary non-psychotropic phytocannabinoid is cannabidiol (CBD), which is proposed to be therapeutic against many conditions, including muscle spasms. Mechanisms have been proposed for the action of CBD on different systems, involving multiple targets, including the voltage-gated sodium channel (Nav) family, which are heavily implicated in many of the conditions for which CBD has been reported to relieve. Pathogenic variants of the skeletal muscle sodium channel, Nav1.4, cause contractility complications, including myotonia and periodic paralyses. Here, we show that CBD reduces skeletal muscle contraction. Because skeletal muscle contraction is related to Nav1.4, we investigated the full modulatory mechanism and effects of CBD on Nav1.4. We found that CBD alters membrane elasticity and penetrates into the Nav pore through fenestrations. Finally, we suggest that CBD may alleviate myotonia via direct and indirect effects on Nav1.4.