Review on Exploring the Mechanisms by Which Cannabinoid Receptors Regulate Seizures

Abstract

Interest in cannabis-based products for treating refractory epilepsy has grown rapidly in recent years. Marijuana and other cannabis derivatives with high levels of -tetrahydrocannabinol (THC)—primarily used for recreational purposes—are generally unsuitable for this medical use due to THC’s association with numerous unwanted side effects. In contrast, cannabidiol (CBD) has demonstrated a more clearly defined anticonvulsant effect in animal studies and lacks the psychoactive effects and abuse potential associated with THC. This has led to increasing use of CBD-enriched extracts in managing seizure disorders, particularly in children. Although many reports have noted improvements in seizure control, as well as sleep and behavior, these findings are often difficult to interpret due to the uncontrolled nature of the observations. The evidence supporting the anti-seizure effects of cannabinoids reached  a significant milestone recently, with the completion of three high-quality, placebo-controlled trials testing a purified CBD product in patients with Dravet syndrome and Lennox-Gastaut syndrome. These studies showed that CBD was more effective than placebo in reducing the frequency of convulsive seizures (such as tonic-clonic, tonic, clonic, and atonic seizures) in patients with Dravet syndrome,    and drop seizures in those with Lennox-Gastaut syndrome. This marks the first time that class 1 evidence supports the use of CBD as an adjunct therapy to improve seizure control in specific epilepsy syndromes. However, it remains unclear whether the observed seizure reduction was due to CBD’s direct effects or was influenced by interactions with other medications—particularly the substantial increase in plasma levels of N-desmethylclobazam, the active metabolite of clobazam. To clarify   CBD’s true role, further analysis is needed—either by examining outcomes in patients not taking clobazam or by conducting new studies that control for this confounding interaction.