Cannabidivarin-rich cannabis extracts are anticonvulsant in mouse and rat via a CB sub(1) receptor-independent mechanism

Background and Purpose Epilepsy is the most prevalent neurological disease and is characterized by recurrent seizures. Here, we investigate (i) the anticonvulsant profiles of cannabis-derived botanical drug substances (BDSs) rich in cannabidivarin (CBDV) and containing cannabidiol (CBD) in acute in vivo seizure models and (ii) the binding of CBDV BDSs and their components at cannabinoid CB sub(1) receptors. Experimental Approach The anticonvulsant profiles of two CBDV BDSs (50-422mg.kg super(-1)) were evaluated in three animal models of acute seizure. Purified CBDV and CBD were also evaluated in an isobolographic study to evaluate potential pharmacological interactions. CBDV BDS effects on motor function were also investigated using static beam and grip strength assays. Binding of CBDV BDSs to cannabinoid CB sub(1) receptors was evaluated using displacement binding assays. Key Results CBDV BDSs exerted significant anticonvulsant effects in the pentylenetetrazole ( greater than or equal to 100mg.kg super(-1)) and audiogenic seizure models ( greater than or equal to 87mg.kg super(-1)), and suppressed pilocarpine-induced convulsions ( greater than or equal to 100mg.kg super(-1)). The isobolographic study revealed that the anticonvulsant effects of purified CBDV and CBD were linearly additive when co-administered. Some motor effects of CBDV BDSs were observed on static beam performance; no effects on grip strength were found. The Delta super(9)-tetrahydrocannabinol and Delta super(9)-tetrahydrocannabivarin content of CBDV BDS accounted for its greater affinity for CB sub(1) cannabinoid receptors than purified CBDV. Conclusions and Implications CBDV BDSs exerted significant anticonvulsant effects in three models of seizure that were not mediated by the CB sub(1) cannabinoid receptor and were of comparable efficacy with purified CBDV. These findings strongly support the further clinical development of CBDV BDSs for the treatment of epilepsy.