Abstract
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. Funding GW Pharmaceuticals, Epilepsy Therapy Project of the Epilepsy Foundation, Finding A Cure for Epilepsy and Seizures.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 270-278 |
| Number of pages | 9 |
| Journal | The Lancet Neurology |
| Volume | 15 |
| Issue number | 3 |
| DOIs | |
| State | Published - 2016 |
Funding
OD has received funding support from the National Institute of Neurological Disorders and Stroke (NINDS) and the Centers for Disease Control and Prevention (CDC). EM has received personal fees from Stanley Brothers Social Enterprise, and grants from NINDS and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), outside the submitted work. ET received support from GW Pharmaceuticals during the conduct of the study. LL has received supported, in part, from the National Institutes of Health (NIH) National Center for Advancing Translational Sciences (grant number 8UL1TR000150). The content presented here is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. JS has received personal fees from Epilepsy Study Consortium, outside the submitted work. MW received support from GW Pharmaceuticals during the conduct of the study. PB received research funding from GW Pharmaceuticals for the neuropsychological testing component of this trial. JM has received personal fees from Cyberonics, outside the submitted work. SN has received grants from GW Research, outside the submitted work. AP reports grants from Pediatric Epilepsy Research Foundation, grants and personal fees from Cyberonics, grants from GW Pharmaceuticals, personal fees from GW Pharmaceuticals, personal fees from Health Logix, outside the submitted work. DF received non-financial support from GW Pharmaceuticals during the conduct of the study, and salary support to New York University from the Epilepsy Study Consortium, personal fees from Cyberonics, grants from UCB Pharmaceuticals, the Epilepsy Foundation, NINDS, and the CDC, and personal fees from Oxford University Press, outside the submitted work. MRC received a grant from the Epilepsy Therapy Project of the Epilepsy Foundation, and administrative support from GW Pharmaceuticals, during the conduct of the study. IM, RF, AW, FF, NT. JB, JH, RK, NSS, CAW declare no competing interests. This study was not registered on ClinicalTrials.gov . The expanded access programme was supported by grants from GW Pharmaceuticals and the Epilepsy Therapy Project of the Epilepsy Foundation. GW Pharmaceuticals provided cannabidiol free of charge, administrative support across all sites, and provided some sites with funds to undertake the study. No funds were provided for salary support.
ASJC Scopus subject areas
- Clinical Neurology
