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

Abstract

SummaryCannabidivarin (CBDV) and cannabidiol (CBD) have recently emerged among cannabinoids for their potential antiepileptic properties, as shown in several animal models. We report the case of a patient affected by symptomatic partial epilepsy who used cannabis as self‐medication after the failure of countless pharmacological/surgical treatments. Clinical and video electroencephalogram (EEG) evaluations were periodically performed, and the serum levels of CBDV, CBD, and Δ9‐tetrahydrocannabinol were repeatedly measured. After cannabis administration, a dramatic clinical improvement, in terms of both decrease in seizure frequency and recovery of cognitive functions, was observed, which might parallel high CBDV plasma concentrations. To widen the spectrum of CBDV possible mechanisms of action, electrophysiological methods were applied to investigate whether it could exert some effects on γ‐aminobutyric acid (GABA)A receptors. Our experiments showed that, in human hippocampal tissues of four patients affected by drug‐resistant temporal lobe epilepsy (TLE) transplanted in Xenopus oocytes, there is decrease of current rundown (i.e., reduction of use‐dependent GABAA current) after prolonged exposure to CBDV. This result has been confirmed using a single case of Rasmussen encephalitis (RE). Our patient's electroclinical improvement supports the hypothesis that cannabis could actually represent an effective, well‐tolerated antiepileptic drug. Moreover, the experimental data suggest that CBDV may greatly contribute to cannabis anticonvulsant effect through its possible GABAergic action.

Modulation of GABAergic dysfunction due to SCN1A mutation linked to Hippocampal Sclerosis

“…This current rundown was mitigated by pretreatment of 2 hours with endogenous factors, as BDNF, or exogenous agents, as the cannabis derivative cannabidivarine (CBDV, Fig. 2D; Table S3) showing again a strong similarity with data previously published for MTLE patients 5,11 …”

Phytocannabinoids in Neurological Diseases: Could They Restore a Physiological GABAergic Transmission?

“…However, these results do not fully explain the CBDV strong anti-convulsant efficacy shown in the preclinical models of epilepsy. Notably, in a recent paper [35] it has been shown that CBDV could act, as for CBD, on GABA A Rs modulating its function. In fact, CBDV was able to significantly recover the GABAergic "run-down" phenomenon [65] in a TRPV-independent manner, probably linked to intracellular processes of phosphorylation/dephosphorylation on GABA A Rs [35].…”

Erythropoietin Increases GABAA Currents in Human Cortex from TLE Patients

“…We then investigated the possible mechanism of action of EPO on GABAergic transmission, using staurosporine, a kinase blocker that binds to many kinases with a very low selectivity (Rüegg and Burgess, 1989). Our results clearly showed that EPO effect is indeed linked to a phosphorylation, but likely not due to the isoforms of PKC that are blocked by GF (PKC α, β1,δ, ζ) (Morano et al, 2016). Further experiments will better elucidate this point.…”