Cannabidiol in patients with treatment-resistant epilepsy

Researchers from the Comprehensive Epilepsy Center at New York University have published an open-label trial assessing the safety, tolerability, and efficacy of cannabidiol (CBD), a compound of marijuana devoid of psychoactive properties in children and adults with severe, highly treatment-resistant epilepsy.

Between January 2014 and January 2015, they enrolled 214 patients from 11 epilepsy centers across the United States. Participants ranged in age from 1 to 30 years, and all had intractable epilepsy. Of the original participants, 162 had at least 12 weeks of follow-up after the first dose of CBD and were included in the safety and tolerability analysis, and 137 were included in the efficacy analysis. The dose of oral CBD ranged from 2 to 5 mg/kg/day, with dose titration to tolerance, or a maximum dose of 25 or 50 mg/kg/day, depending on the trial site. Seizures were recorded by parents or caregivers in diaries and reviewed by study teams at each visit.

The median reduction in total seizures was 34.6%, with the greatest reduction occurring in patients with focal and atonic seizures, followed by tonic and tonic-clonic seizures. Two patients were completely seizure free over the entire 12 weeks. Adverse events included drowsiness, decreased appetite, diarrhea, fatigue, and convulsions. Most adverse events were mild to moderate and transient, though 20 patients had serious adverse events, most commonly status epilepticus.

On the basis of these results, the researchers have progressed to a randomized controlled trial of CBD for intractable epilepsy.

http://www.medscape.com/medline/abstract/26724101

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Devinsky O; Marsh E; Friedman D; Thiele E; Laux L; Sullivan J; Miller I; Flamini R; Wilfong A; Filloux F; Wong M; Tilton N; Bruno P; Bluvstein J; Hedlund J; Kamens R; Maclean J; Nangia S; Singhal NS; Wilson CA; Patel A; Cilio MR.  Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol.  2016; 15(3):270-8 (ISSN: 1474-4465)

BACKGROUND: Almost a third of patients with epilepsy have a treatment-resistant form, which is associated with severe morbidity and increased mortality. Cannabis-based treatments for epilepsy have generated much interest, but scientific data are scarce. We aimed to establish whether addition of cannabidiol to existing anti-epileptic regimens would be safe, tolerated, and efficacious in children and young adults with treatment-resistant epilepsy.

METHODS: In this open-label trial, patients (aged 1-30 years) with severe, intractable, childhood-onset, treatment-resistant epilepsy, who were receiving stable doses of antiepileptic drugs before study entry, were enrolled in an expanded-access programme at 11 epilepsy centres across the USA. Patients were given oral cannabidiol at 2-5 mg/kg per day, up-titrated until intolerance or to a maximum dose of 25 mg/kg or 50 mg/kg per day (dependent on study site). The primary objective was to establish the safety and tolerability of cannabidiol and the primary efficacy endpoint was median percentage change in the mean monthly frequency of motor seizures at 12 weeks. The efficacy analysis was by modified intention to treat. Comparisons of the percentage change in frequency of motor seizures were done with a Mann-Whitney U test.

RESULTS: Between Jan 15, 2014, and Jan 15, 2015, 214 patients were enrolled; 162 (76%) patients who had at least 12 weeks of follow-up after the first dose of cannabidiol were included in the safety and tolerability analysis, and 137 (64%) patients were included in the efficacy analysis. In the safety group, 33 (20%) patients had Dravet syndrome and 31 (19%) patients had Lennox-Gastaut syndrome. The remaining patients had intractable epilepsies of different causes and type. Adverse events were reported in 128 (79%) of the 162 patients within the safety group. Adverse events reported in more than 10% of patients were somnolence (n=41 [25%]), decreased appetite (n=31 [19%]), diarrhoea (n=31 [19%]), fatigue (n=21 [13%]), and convulsion (n=18 [11%]). Five (3%) patients discontinued treatment because of an adverse event. Serious adverse events were reported in 48 (30%) patients, including one death-a sudden unexpected death in epilepsy regarded as unrelated to study drug. 20 (12%) patients had severe adverse events possibly related to cannabidiol use, the most common of which was status epilepticus (n=9 [6%]). The median monthly frequency of motor seizures was 30·0 (IQR 11·0-96·0) at baseline and 15·8 (5·6-57·6) over the 12 week treatment period. The median reduction in monthly motor seizures was 36·5% (IQR 0-64·7). 

INTERPRETATION: Our findings suggest that cannabidiol might reduce seizure frequency and might have an adequate safety profile in children and young adults with highly treatment-resistant epilepsy. Randomised controlled trials are warranted to characterise the safety profile and true efficacy of this compound.