An open-label study looked at add-on cannabidiol in children and young adults with severe, intractable, childhood-onset treatment-resistant epilepsy.
Add-on cannabidiol, a derivative of cannabis, may reduce seizure frequency and have an adequate safety profile in children and young adults with treatment-resistant epilepsy, according to a study published online in Lancet Neurology.
“In our open-label study, add-on treatment with pure cannabidiol led to a clinically meaningful reduction in seizure frequency in many patients, and had an adequate safety profile in this patient population with highly treatment-resistant epilepsies,” wrote first author Orrin Devinsky, MD, of New York University Langone Medical Center, and colleagues.
“The efficacy of cannabidiol seems promising, with reductions of roughly a third in motor seizures and overall seizures in the efficacy analysis group,” they added.
Many US states have approved medical marijuana for the treatment of epilepsy, despite a dearth of quality evidence regarding its safety and efficacy. Using whole-plant extracts of cannabis may be especially problematic in children, whose developing brain may be particularly vulnerable to its psychoactive effects. In adolescents, potential toxic effects of tetrahydrocannabinol, one of the most extensively studied derivatives of cannabis, include cognitive impairment and psychiatric problems. Adverse effects of cannabis in younger children has not been studied. Past small trials of cannabidiol-the other most extensively studied derivative of cannabis - have suggested that it may have anticonvulsant properties, with few side effects.
The open-label trial took place from January 2014 to January 2015 at 11 epilepsy treatment centers in the US. It enrolled 214 participants aged 1-30 years with severe, intractable, childhood-onset treatment-resistant epilepsy. Participants received 99% pure oral cannabidiol at doses of 2-5 mg/kg per day, with dose increases as tolerated up to a maximum of 25 mg/kg or 50 mg/kg per day (depending on study site).
Parents or caregivers reported seizure frequency and type in diaries before and during the study. Tolerability was assessed every two weeks using standardized questionnaires.
The analysis focused on a safety group (162/214 participants) and an efficacy group (137/214 participants).
• Adverse events affected 79% of patients in the safety group, and commonly included:
♦ Somnolence: 25%
♦ Decreased appetite: 19%
♦ Diarrhea: 19%
♦ Fatigue: 13%
♦ Convulsion: 11%
• Serious adverse events: 30%
♦ One sudden death thought unrelated to cannabidiol
• Severe adverse events possibly related to cannabidiol: 20%
♦ The most common of which was status epilepticus: 6%
• Median percentage change in mean monthly frequency of motor seizures at 12 weeks (primary efficacy endpoint): -36·5%
The rate of serious adverse events was “higher than expected,” with half suspected to be related to cannabidiol, the authors pointed out.
“The absence of a control group with severe epilepsies, and the high burden of antiepileptic drugs, makes assessment of the rate of cannabidiol-related serious adverse events difficult,” they explained.
They also highlighted status epilepticus as the most common serious adverse event. Though animal studies have not shown cannibidiol to induce seizures, the cases of status epilepticus in this study could have been related to cannabidiol, they mentioned. Fluctuation of underlying epilepsy could also be to blame, the authors added.
The study included some of the most severely treatment-resistant patients at each clinic, many of whom had never experienced complete seizure control despite multiple medical and surgical therapies.
“In this study, the high rates of seizure reduction, and even seizure freedom for a few patients, suggest clinically meaningful efficacy… For many patients who achieved seizure freedom or a reduction in seizures of 90% or more, no previous antiepileptic drug regimen had been as efficacious during the preceding year,” the authors emphasized, “However, in view of the variable natural history of seizures in this cohort, without a control group, the results regarding safety and efficacy must be interpreted cautiously.”
The open-label nature of the trial means that results could have been inflated due to the placebo effect, which is especially pronounced in children and may have been exacerbated by social media attention on cannabis.
“Both safety and efficacy need to be assessed through blinded, randomised controlled studies using consistent study medication of known composition,” the authors stressed.
• An open-label study showed clinically meaningful reduction in seizure frequency and adequate safety profile with add-on cannabidiol in treatment resistant epilepsy in children and young adults
• Twenty percent of the study subjects experienced severe adverse events, possibly related to cannabidiol.
• A blinded, randomized controlled trial is needed to fully assess the safety and efficacy of cannabidiol.
The study was sponsored by GW Pharmaceuticals
Reference: Devinsky O, et al. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol. 2015 Dec 23.