Cannabidiol for the Treatment of Epilepsy

Cannabidiol (CBD) is a phytocannabinoid found in the Cannabis plant. Written records of trained medical doctors prescribing Cannabis in the Anglophone world exist from the 19th century, especially as regards treatment-resistant epilepsy. Although the psychoactive component of Cannabis, tetrahydrocannabinol (THC), was first investigated as a treatment for seizures, the isolation and testing of cannabidiol (CBD) led to preclinical studies that indicated a stronger and more reliable anti-seizure effect for the latter, as well as fewer side effects. The first pharmaceutical-grade product containing purified CBD (Epidiolex) was approved by the U.S. Food and Drug Administration (FDA) in 2018 for the treatment of seizures associated with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) in children 2 years of age or older. However, investigation of CBD as a treatment for other epilepsy syndromes, including focal epilepsy associated with tuberous sclerosis complex (TSC), is ongoing. Although the biosynthesis, pharmacokinetics and hepatic metabolism of CBD are thoroughly characterized, the exact mechanism of action of CBD in reducing seizures in DS and LGS remains unclear. Some likely mediators include an agonistic effect on transient receptor potential cation channel subfamily V member 1 (TRPV1) channels, inhibition of adenosine reuptake and antagonism of G-protein coupled receptor 55 (GPR55). Four pivotal randomized placebo-controlled clinical trials that led to the approval of CBD all showed strong seizure frequency reduction with side effect profiles that regulators considered acceptable. The most common adverse effects reported in the literature include sedation, fatigue, weight loss and gastrointestinal disturbances. The most common serious adverse effect was elevated bilirubin and serum transaminases, more commonly when CBD was co-administered with valproate. There is also a well-documented interaction of CBD with clobazam through inhibition of CYP2C19, leading to increased plasma concentration of the active metabolite N-desmethylclobazam. On the basis of these results, and subject to ongoing pharmacovigilance studies, CBD is a promising new medication for the add-on management of treatment-resistant DS and LGS. Its utility as a standalone drug and its efficacy in comparison with other antiseizure agents AEDs remains to be investigated.