Grant: Project Grant

Public and scientific interest in marijuana (or cannabis)-derived products for treatment resistant epilepsy has increased exponentially in recent years. Specifically, cannabidiol (CBD) has been used by a growing number of patients in mostly unregulated ways due to immediate accessibility of commercial artisanal forms. Recent clinical studies indicate that pharmaceutical grade CBD is effective in pediatric patients with treatment-resistant epilepsy (i.e., those with Dravet and Lennox-Gastaut syndromes), but how this compound works remains a mystery. Given the mounting use of CBD and other cannabinoids, it is vitally important to understand the mechanisms of action, as this knowledge is necessary for uncovering new medications with greater clinical efficacy and improved tolerability. Recently, we have identified a novel target inside brain mitochondria (the specialized structures that generate energy molecules) that is affected directly by CBD. Specifically, we found that CBD blocks a chloride channel on the inner membrane of mitochondria, and that this action affects the metabolic function of mitochondria as well as the neuron itself. The overall goal of our research project is to study the effects of CBD on the mitochondrial chloride channel, and to determine whether this action contributes to seizure control in two animal models of epilepsy (one that models Dravet syndrome). Further, we will examine the effects of CBD on various aspects of cellular metabolism and mitochondrial function, and in validated tests of cognition (learning/memory) and behavior. Importantly, these experiments are designed to establish safe and effective dose and concentration ranges for CBD. Our team possesses the necessary expertise in molecular neuropharmacology to successfully implement the proposed studies. With the explosive growth of cannabis and cannabinoid use, especially in Canada, the research described herein is both timely and clinically relevant.