Cannabidiol May Reduce Seizures in Children and Young Adults with Treatment-Resistant Epilepsy

Reference – Lancet Neurol 2015 Dec 23 early online (level 3 [lacking direct] evidence)

  • Anecdotal reports suggest medical marijuana or marijuana-derived compounds might benefit patients with intractable epilepsy, though evidence from clinical studies supporting this claim is extremely limited.
  • A recent uncontrolled trial including 214 children and young adults with treatment-resistant, intractable epilepsy reported a median 36.5% reduction in motor seizures and 34.6% reduction in total seizures after 12 weeks of cannabidiol treatment.
  • Cannabidiol was well tolerated, with most patients reporting only mild-to-moderate, transient adverse events including somnolence, decreased appetite, diarrhea, fatigue, and convulsion.

Up to one third of patients with epilepsy are resistant to medical therapy and are at an increased risk of injury, poor quality of life, and premature death (Lancet 2015 Mar 7;385(9971):884, N Engl J Med 2011 Sep 8;365(10):919).  Anecdotal evidence suggests cannabidiol, 1 of the 2 main cannabinoids found in marijuana, might reduce seizures in drug-resistant patients (Epilepsy Behav 2013 Dec;29(3):574, Lancet 2015 Oct 24;386(10004):1615).  This limited evidence has generated great interest in the potential use of this compound as an add-on therapy to antiepileptic drugs, particularly in rare pediatric epilepsies such as Dravet syndrome, Lennox-Gastaut syndrome, and Doose syndrome.  In response, many states have approved medical marijuana (or cannabidiol extracts) specifically for children and adults with intractable epilepsy.  However, the efficacy and safety of using cannabinoids for treating patients with epilepsy, especially children, remains unknown.  To further examine this issue, a recent study evaluated oral cannabidiol in 214 children and young adults aged 1-30 years (mean age 11 years) with treatment-resistant, intractable, childhood onset epilepsy.  All patients had ≥ 4 countable seizures with a motor component in a 4-week period and were receiving stable treatment for at least 4 weeks before enrollment.  Cannabidiol dosing began at 2-5 mg/kg/day and was titrated up weekly until it was no longer tolerated or the maximum dose (25 mg/kg/day or 50 mg/kg/day depending on study site) was achieved.

Only 64% of patients were assessed in the efficacy analysis, which included patients with ≥ 12 weeks follow-up, but excluded patients who had no motor seizures during a 4-week pretreatment baseline period.  The most common epilepsy syndromes in this group were Dravet syndrome (23%) and Lennox-Gastaut syndrome (22%).  The mean cannabidiol dose was 22.7 mg/kg at 12 weeks and 30% of patients were eventually titrated to the maximum 50 mg/kg daily dose.  At the 12-week follow-up, the median number of monthly motor seizures had decreased from 30 at baseline to 15.8, with a median 36.5% decrease in monthly motor seizures.  During weeks 8-12 of treatment, 11% of patients were free from motor seizures and 7% were free from all seizures.  Efficacy of cannabidiol appears to be influenced by seizure type, with the greatest reduction seen in patients with focal seizures (55% reduction) or atonic seizures (54.3% reduction).  Overall, cannabidiol reduced total seizures by 34.6%.

Twenty-five additional patients (12%), most of whom had been excluded for lack of motor seizures during the baseline period, were included in the safety analysis.  Adverse events were reported in 79% of patients, though most were mild-to-moderate and transient.  The most commonly reported adverse events were somnolence, decreased appetite, diarrhea, fatigue, and convulsion.  Only 12% of patients reported serious adverse events that were possibly related to treatment, most frequently status epilepticus.

The results of this study are promising, showing a large reduction in seizures in children and young adults with treatment-resistant epilepsy with minimal adverse effects.  With 137 patients included in the efficacy analysis and 162 patients included in the safety analysis, this is the largest study to date on the effects of cannabidiol in this population.  Even though this drug is not yet available, this study still informs the discussion about the potential benefit of marijuana in this group of patients.  There are a number of potential sources of bias to consider, however.  There was no control group to truly determine efficacy or assess the potential for a placebo effect.  This is especially important in epilepsy where there is a natural variation in seizure frequency.  In addition, the 12-week follow-up period only allows for the assessment of immediate treatment effect, but long-term efficacy and safety remain unknown.  Finally, 24% of patients were excluded from all analyses because they did not have 12 weeks of follow-up.  Overall, the results of this study suggest that cannabidiol may help reduce seizures for severe, drug-resistant epilepsy, but randomized controlled trials are clearly needed.

For more information, see the Medical uses of cannabinoids and Epilepsy in children topics in DynaMed Plus. DynaMed users click here and here.

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