Daniel Friedman, M.D., and Orrin Devinsky, M.D.

INTRO

Despite the availability of more than 20 different antiseizure drugs and the provision of appropriate medical therapy, 30% of people with epilepsy continue to have seizures.1,2 The approval of many new antiseizure drugs during the past two decades, including several with novel mechanisms  of action, has not substantially reduced the proportion of patients with medically refractory disease.

The safety and side-effect profile of antiseizure drugs has improved, but side effects related to the central nervous system are common and affect quality of life. Patients need new treatments that control seizures and have fewer side effects. This treatment gap has led patients and families to seek alternative treatments. Cannabis-based treatment for epilepsy has recently received prominent attention in the lay press and in social media, with reports of dramatic improvements in seizure control in children with severe epilepsy.
In response, many states have legalized cannabis for the treatment of epilepsy (and other medical conditions) in children and adults (for a list of medical marijuana laws according to state, see www.ncsl.org/research/health/state-medical-marijuana-laws .aspx). Cannabis has been used medicinally for millennia and was used in the treatment of epilepsy as early as 1800 b.c.e. in Sumeria. Victorian-era neurologists used Indian hemp to treat epilepsy and reported dramatic success.5,6 The use of cannabis therapy for the treatment of epilepsy diminished with the introduction of phenobarbital (1912) and phenytoin (1937) and the passage of the Marijuana Tax Act (1937). The discovery of an endogenous cannabinoid-signaling system in the
1990s7 rekindled interest in therapies derived from constituents of cannabis for nervous system disorders such as epilepsy (see ClinicalTrials.gov numbers, NCT02091375, NCT02224690, NCT02324673, NCT02318537, and NCT02318563).

This review addresses the current preclinical and clinical data that suggest that compounds found in cannabis have efficacy against seizures. The pharmacokinetic properties of cannabinoids and related safety and regulatory issues that may affect clinical use are also discussed, as are the distinct challenges of conducting rigorous clinical trials of these compounds. More than 545 distinct compounds have been isolated from cannabis species; the most abundant are the cannabinoids, a family of molecules that have a 21-carbon terpenophenolic skeleton and includes numerous metabolites.8 The best studied of these cannabinoids (termed “phytocannabinoids” if derived from the plant) are Δ9 -tetrahydrocannabinol (Δ9 -THC) and cannabidiol and their metabolites. (See Fig. 1 for the structure of Δ9 -THC, cannabidiol, and one other cannabinoid, cannabidivarin, as well as their targets in the central nervous system, and their actions.)
Most of the psychoactive effects of cannabis are mediated by Δ9 -THC. Many of the noncannabinoid molecules in cannabis plants may have biologic activity. This review focuses on cannabinoids, since other cannabis-derived compounds have been
less well studied.

From the Department of Neurology, New York University Langone School of Medicine, New York.