Abstracts

Rationale: Epilepsy is a chronic disorder affecting ~1% of the world's population. Moreover, ~30% 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 treatment options. The most prevalent non-psychoactive phytocannabinoid is cannabidiol (CBD). Anecdotal experience and emerging data suggest that CBD is a promising candidate for the control of seizures and warrants systematic investigation. Here, the anticonvulsant effects and tolerability profile of plant derived CBD (GW Pharmaceuticals) in a battery of in vitro and in vivo models is described. Methods: The effect of CBD on epileptiform local field potentials (LFPs) induced in rat hippocampal brain slices by 4-aminopyridine (4-AP) application or Mg²⁺-free conditions was assessed by in vitro multi-electrode array recordings. Additionally, the anticonvulsant profile of CBD in vivo was investigated in five different rodent models of seizure: maximal electroshock (mES) and audiogenic seizures in mice, and pentylenetetrazole (PTZ), 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: GW Pharmaceuticals' preclinical program demonstrated that CBD significantly attenuated status epilepticus-like epileptiform LFPs induced by 4-AP or Mg²⁺-free conditions. In vivo, CBD exerted significant anticonvulsant effects in the mES, audiogenic, PTZ, pilocarpine and penicillin models of seizure. Moreover, CBD was well-tolerated and devoid of any negative drug-drug interactions in the PTZ and pilocarpine models of seizure when co-administrated with clinically used AEDs, sodium valproate (VPA), phenobarbital (PB) and ethosuximide (ESM). In comparison to VPA, PB and ESM, CBD did not produce any motor deficits or neurotoxicity in the preclinical tolerability assays. Conclusions: In conclusion, these results demonstrate anticonvulsant effects of CBD in a broad range of in vitro and in vivo seizure models and tolerability assays. These data suggest that CBD may be a novel therapeutic candidate for a diverse range of human epilepsies, with a potentially favorable tolerability profile and support further clinical investigation.