Cannabidivarin

Cannabidivarin, also known as cannabidivarol or CBDV, is a non-psychoactive cannabinoid found within DB14009. It is one of over 100 cannabinoids identified from the Cannabis plant that can modulate the physiological activity of cannabis, or marijuana ^A32584. Compared to its homolog, DB09061, CBDV is shortened by two methyl (CH2) groups on its side chain. Notably, both DB09061 and CBDV have demonstrated anticonvulsant activity in animal and human models and are demonstrating promising clinical trial results A33327, A31560, A33328, A33329. Other cannabinoids with some evidence of anti-epileptic activity include DB11755 (THCV) and ?9-tetrahydrocannabinolic acid.

While the primary components of cannabis, CBD and THC, have been shown to modulate many of their physiological effects through their binding to the cannabinoid-1 (CB1R) and cannabinoid-2 (CB2R) receptors, the investigational cannabinoids with anticonvulsant action mostly use mechanisms that do not involve these two endocannabinoid receptors.

The anti-epileptic activity of CBD and CBDV is thought to be modulated by their effects on transient receptor potential cation channel subfamily V member 1 (TRPV1), also known as the capsaicin receptor, which is a member of a large family of ion channels that are involved in the onset and progression of several types of epilepsy. CBD and CBDV have been shown to dose-dependently activate and then desensitize TRPV1 as well as TRPV2 and TRPA1 channels A31560, A33334, A32976. Desensitization of these ion channels is a potential mechanism by which these molecules cause a reduction of neuronal hyperexcitability that contributes to epileptic activity and seizures.

CBDV has also been shown to inhibit the activity of diacylglycerol (DAG) lipase-?, the primary enzyme responsible for the synthesis of the endocannabinoid, 2-arachidonoylglycerol (2-AG) A33296, A33347. The clinical implications of this are unclear however, as this interaction has not been shown to affect CBDV's anticonvulsant activity.

Cannabidivarin is being actively developed by GW Pharmaceuticals as the experimental compound GWP42006 as it has "shown the ability to treat seizures in pre-clinical models of epilepsy with significantly fewer side effects than currently approved anti-epileptic drugs" ^L2950. Unfortunately, as of February 2018, GW Pharmaceuticals announced that their Phase 2a placebo-controlled study of CBDV for focal seizure did not reach its primary endpoints. They will continue to study its use in epilepsy, however, and are expanding their investigations to include its potential use in Autism Spectrum Disorder, Rett syndrome and Fragile X among others ^L2949.

In October 2017 CBDV was given orphan designation by the European Medicines Agency for use in Rett Syndrome ^L2952 and again in February 2018 for treatment of Fragile X Syndrome ^L2951.