Cannabidiol (CBD) has emerged as a promising anti-epileptic drug in otherwise treatment-resistant genetic epileptic disorders. However, the clinical trials have been limited by their use of CBD only as an add-on therapy, their lack of assessment of CBD on comorbid phenotypes, and their lack of insight into CBD’s therapeutic mechanism. To address these limitations, we tested CBD’s effects on behavior and physiology in our genetic mouse model of Dravet Syndrome (DS). DS is a severe childhood epileptic disorder characterized by treatment resistant epilepsy, as well as cognitive and social deficits consistent with autism. Our DS mice recapitulate these core behavioral phenotypes and are thus a powerful precision medicine tool to test the efficacy of CBD as a monotherapy in DS. We find that acute CBD administration reduced the thermally-induced seizures that model febrile seizures in the early stage of DS. Twice-daily CBD administration also reduced the frequency of spontaneous seizures that characterize the later stages of DS.
These anti-epileptic effects were associated with an enhancement in GABAergic signaling in the dentate gyrus of the hippocampus, which is mediated by CBD antagonism of GPR55 signaling. Furthermore, we find that CBD rescued social interaction deficits and abnormal social responses in our DS mice. Together, our data suggest that CBD is an effective monotherapy against epileptic seizures and autism in DS. Our results also reveal that GPR55 signaling is an important target for CBD’s therapeutic benefits.