Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome

Ms. Atkinson brings her 7-year-old son Tommy to your office today. Tommy has suffered for many years from polymorphic seizures, including many episodes of refractory convulsions. Despite taking maximally tolerated doses of levetiracetam, phenytoin, and topiramate, Tommy continues to experience generalized tonic-clonic seizures at least three times per week. Ms. Atkinson has heard from other moms that cannabis can be used as a treatment for seizures and wants to know: Is there any research to show it could be effective?

Cannabinoids have been reported to be beneficial in patients with conditions ranging from chronic pain to multiple sclerosis. Preliminary preclinical evidence and small clinical studies suggest potential efficacy of cannabinoids for the treatment of epilepsy. However, until now, no randomized studies have been conducted to test this hypothesis.

In this week’s issue of NEJM, investigators report the results of a multinational, randomized, double-blind trial comparing oral solution of cannabidiol, one specific cannabinoid, or placebo in 120 patients (age range, 2–18 years) with Dravet syndrome, a rare genetic form of encephalopathic epilepsy caused by a sodium channel gene mutation. All study participants experienced seizures that were not controlled by aggressive antiepileptic regimens, with a median of 13 convulsive seizures per month at baseline. The primary endpoint was the percentage change from baseline in convulsive-seizure frequency during the 14-week treatment period.

The median number of convulsions in the cannabidiol group decreased from 12.4 at baseline to 5.9 during the treatment period and from 14.9 to 14.1 in the placebo group (adjusted mean difference, 22.8%, P=0.01). No statistically significant differences between groups were reported in the percentage of patients who experienced ≥50% reduction in convulsive-seizure frequency, the frequency of nonconvulsive seizures, or the percentage of patients who were seizure-free. Caregivers of patients in the cannabidiol group were more likely than caregivers of patients in the placebo group to report improvement in the child’s overall condition. Similar adverse events including vomiting, fatigue, pyrexia, decreased appetite, and lethargy, were reported in 93% of patients in the cannabidiol group and 75% of patients in the placebo group. Serious adverse events, including status epilepticus and elevated liver aminotransferase levels, were reported in 10 patients in the cannabidiol group and 3 patients in the placebo group.

In an accompanying editorial, Dr. Samuel Berkovic from the University of Melbourne notes, “This trial represents the beginning of solid evidence for the use of cannabinoids in epilepsy.” But he cautions, “Much more research is needed to understand the basic science, benefits, and risks of cannabinoids in epilepsy.” NEJM Deputy Editor Allan Ropper adds, “These are provocative data, but we do not know if they are more widely applicable to children with other types of epilepsy.”

What can you tell Ms. Atkinson? First, the cannabidiol used in the study is a different component of the cannabis plant than tetrahydrocannabinol (THC) that produces the euphoric effect of smoked or ingested cannabis. Second, because the trial was conducted only in patients with Dravet syndrome, the results may not be generalizable to Tommy’s seizure condition; a study is currently underway in patients with another disorder associated with treatment-resistant epilepsy (Lennox-Gastaut syndrome). Further, the frequency of seizures was reported subjectively by caregivers, who could have guessed which treatment the child received on the basis of side effects. Finally, the authors acknowledge that this study was preliminary and further studies are needed to understand the potential efficacy in other patient groups and contexts. You conclude that the use of cannabinoids for treatment of seizure disorders is still far from being ready for prime time, but these results are an important step towards demonstrating potential efficacy.

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Rebecca is a 2016-2017 NEJM Editorial Fellow and a hospitalist at Massachusetts General Hospital. She graduated from Columbia University College of Physicians and Surgeons in 2013 and completed internal medicine residency at Massachusetts General Hospital in 2016. Her interests include medical education, quality improvement, patient safety, health care delivery innovation, and teaching value in health care.