Abstracts

Rationale: Epilepsy is a chronic disorder affecting ~1% of the world’s population. Moreover, ~30% of epilepsy patients experience drug-resistant seizures and many suffer intolerable or undesirable side effects. Therefore, an urgent clinical need for additional effective and tolerable treatment options remains. The most prevalent non-psychoactive phytocannabinoid is cannabidiol (CBD). Previous investigations have reported anticonvulsant effects of CBD in various preclinical animal models (Jones et al., 2010, 2012), and suggest it is a promising candidate for the control of seizures warranting systematic investigation. Here, the anticonvulsant and tolerability profile of plant-derived CBD (GW Pharmaceuticals) was investigated in the Anticonvulsant Screening Program (ASP) to verify and further characterize CBD’s effects in a battery of well-established rodent seizure models.Methods: The anticonvulsant profile of CBD in vivo was investigated in four different models of seizure: 6Hz “psychomotor” tests of therapy-resistant partial seizures and subcutaneous Metrazol seizure threshold test (scMET) of clonic forebrain seizures in mice, and maximal electroshock test (mES) of generalized tonic-clonic seizures in mice and rats. Additionally, CBD’s effect on minimal muscular and neurological impairment was assessed in mice using the rotarod test. Rats were examined in a battery of tests (gait and stance test, placing response test and righting reflex test) to determine any neurological deficits of CBD.Results: The ASP demonstrated that CBD exerted significant anticonvulsant effects in the 6Hz (32 mA) test (ED50 = 144 [102-194] mg/kg), 6 Hz (44 mA) test (ED50 = 173 [136-213] mg/kg), mES (ED50 = 80 [65-96] mg/kg) and scMET (ED50 = 120 [99-146] mg/kg) models in mice, and the mES model (ED50 = 53 [39-67] mg/kg) in rats. Moreover, CBD was well tolerated by both mouse (TD50 = 272 [241-303] mg/kg) and rat (TD50 = >500 mg/kg) in toxicity tests.Conclusions: These results demonstrate that CBD produces significant anticonvulsant effects in a number in vivo seizure models and is well-tolerated in both rodent species in the ASP. These data validate previous results from GW Pharmaceuticals’ preclinical program and 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. These studies were provided as a free service by the National Institute of Neurological Disorders and Stroke (NINDS) Anticonvulsant Screening Program (ASP), and were conducted at the University of Utah under NIH Contract No. HHSN271201100029C (H. Steve White, Ph.D., Principal Investigator). References: Jones, NA et al. Cannabidiol displays antiepileptiform and antiseizure properties in vitro and in vivo. The Journal of Pharmacology And Experimental Therapeutics. 2010; 332(2): 569-77. Jones, NA et al. Cannabidiol exerts anticonvulsant effects in animal models of temporal lobe and partial seizures. Seizure. 2012; 21(5): 344-352.