Assessment of the Anticonvulsant Effects and Tolerability Profile of Cannabidiol: GW Pharmaceuticals’ Preclinical Program (I6-5A)

Abstract

OBJECTIVE: The purpose of this study was to determine the preclinical anticonvulsant and tolerability profile of cannabidiol (CBD). BACKGROUND: Epilepsy is a chronic disorder affecting ~1[percnt] of the world’s population. ~30[percnt] of epilepsy patients experience pharmacologically intractable seizures and many suffer intolerable or undesirable side-effects. Therefore, there remains an urgent clinical need for additional effective and tolerable treatments. Here, the anticonvulsant effects and tolerability profile of plant derived CBD is described in a battery of in vitro and in vivo models. DESIGN/METHODS: The effect of CBD on status epilepticus-like epileptiform local field potentials (LFPs) induced by 4-aminopyridine application or Mg²⁺-free conditions in rat hippocampal brain slices was assessed by in vitro multi-electrode array recordings. Additionally, the anticonvulsant profile of CBD in vivo was investigated in five rodent models of seizure: maximal electroshock and audiogenic seizures in mice, and pentylenetetrazole, pilocarpine and penicillin-induced seizures in rats. The effects of CBD in combination with commonly used anti-epileptic drugs (AEDs) on rat seizures were also investigated. Finally, CBD’s tolerability profile in rats was investigated using the accelerating rotarod, static beam, grip strength and inclined screen assays. RESULTS: CBD significantly attenuated epileptiform LFPs in vitro. CBD exerted significant anticonvulsant effects in all in vivo models of seizure. Moreover, CBD was well-tolerated and devoid of any negative drug-drug interactions in the pentylenetetrazole and pilocarpine models of seizure when co-administrated with the AEDs: sodium valproate, phenobarbital and ethosuximide. In comparison to these AEDs, CBD did not produce any motor deficits or neurotoxicity in the tolerability assays. CONCLUSIONS: These results demonstrate promising anticonvulsant effects of CBD in a broad range of in vitro and in vivo seizure models and tolerability assays. This suggests that CBD may be a novel therapeutic candidate for a range of human epilepsies, with a potentially favorable tolerability profile, supporting further clinical investigation.

Disclosure: Dr. Jones holds stock and/or stock options in GW Pharmaceuticals. Dr. Hill has nothing to disclose. Dr. Hill has received personal compensation for activities with GW Pharmaceuticals as an employee. Dr. Peres has nothing to disclose. Dr. Hadid has nothing to disclose. Dr. Wright holds stock and/or stock options in GW Pharmaceuticals, Dr. Stephens has received research support from UCB Pharma and Pfizer Inc. Dr. Williams has received research support from GW Pharmaceuticals. Dr. Whalley has received research support from GW Pharmaceuticals.