Towards Understanding the Phenytoin-like Antiepileptic Effect of Cannabidiol and Related Phytocannabinoid Metabolites: Insights from Molecular Modeling

Cannabidiol (CBD), a nonpsychotropic constituent of Cannabis sativa , has recently been approved by the US FDA for the treatment of certain forms of pediatric epilepsy. The mechanism by which CBD exerts its antiepileptic effects, however, is not known. Herein we describe the results of molecular modeling studies comparing the stereoelectronic properties of phenytoin (PHT) with those of CBD and its carboxylic acid metabolite, as well as of 7-hydroxycannabidivarin. Also, the cyclohexenecarboxylic acid core of 7-COOH-CBD perfectly mimics the unsaturated bioactive metabolite of the commonly used antiepileptic valproic acid was also noted. We propose that C–7 oxidized phytocannabinoid metabolites are involved in the phenytoin-like anticonvulsant effects of the parent phytocannabinoid drugs.