Cannabidivarin‐rich cannabis extracts are anticonvulsant in mouse and rat via a CB₁ receptor‐independent mechanism

Abstract

BACKGROUND AND PURPOSEEpilepsy 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 CB1 receptors. EXPERIMENTAL APPROACHThe anticonvulsant profiles of two CBDV BDSs (50-422 mg·kg −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 CB1 receptors was evaluated using displacement binding assays. KEY RESULTSCBDV BDSs exerted significant anticonvulsant effects in the pentylenetetrazole (≥100 mg·kg ). 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 Δ 9 -tetrahydrocannabinol and Δ 9 -tetrahydrocannabivarin content of CBDV BDS accounted for its greater affinity for CB1 cannabinoid receptors than purified CBDV. CONCLUSIONS AND IMPLICATIONSCBDV BDSs exerted significant anticonvulsant effects in three models of seizure that were not mediated by the CB1 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.

Cannabis in epilepsy: From clinical practice to basic research focusing on the possible role of cannabidivarin

“…In addition, our data did not allow us to exclude that it was not a single compound but the different molecules combined together to have the most effective antiepileptic action. This hypothesis is in accordance with recent in vivo studies testing enriched cannabis extracts, which showed not only that cannabis anticonvulsant properties are most likely independent from THC but also that CBD and CBDV may have an additive effect, as proved by isobolographic methods 14. Interactions between cannabinoids and the other antiepileptic drugs (AEDs)15 used by the patient (namely, LEV, topiramate, clobazam, clonazepam) could have also influenced the clinical outcome, either through pharmacodynamic mechanisms or reciprocal changes in pharmacokinetic properties.…”

Neuromotor tolerability and behavioural characterisation of cannabidiolic acid, a phytocannabinoid with therapeutic potential for anticipatory nausea

“…The battery of neuromotor tolerability tests used in this study has previously been utilised to assess other phytocannabinoids against drugs with known clinical neuromotor side effects (Hill et al 2012;Hill et al 2013). The benzodiazepine class of drugs, which are used clinically to attenuate AN, cause significant sedative side effects, decrease activity in the OFT (reviewed in Prut and Belzung 2003) and impair performance in the static beam (Stanley et al 2005) and forelimb grip strength assays (Meyer et al 1979;Ferguson and Paule 1996).…”

Characterisation of cannabinoid composition in a diverse Cannabis sativa L. germplasm collection

“…4). Selecting for chemotype III B CBDAS genotypes may prove especially beneficial for development of uniform plant lines for hemp fibre, seed, and pharmacological production, given the strong association between chemotype III and THC content \0.2 % DW (Pacifico et al 2008;, and growing interest in CBD(V)A and CBD(V) derivatives as pharmacological entities (De Petrocellis et al 2011;Gallily et al 2015;Hill et al 2013;Iseger and Bossong 2015). However, additional cannabinoid profiling is required in order to differentiate cannabinoid homologue compositions and to characterise CBD total :-THC total chemotype II variability accurately.…”