Derivatives from the cannabis plant, Cannabis sativa, have long been used as a treatment for many disorders, from anorexia to pain.1 Anecdotal reports suggest that cannabis extracts can reduce seizures.2, 3, 4 Cannabis contains more than 80 phytocannabinoids and, although little is known about the potential therapeutic effects of most of these molecules, two compounds—tetrahydrocannabiniol and cannabidiol—have garnered the most attention based on their abundance in the plant.
Tetrahydrocannabinol, the major psychoactive cannabinoid, has been shown to have both anticonvulsant and proconvulsant effects in animal studies of seizures.5 The potential medical use of whole-plant cannabis extracts, particularly in children with a developing brain, is limited by the psychoactive properties and the adverse effects associated with long-term tetrahydrocannabinol use. The potential adverse effects of tetrahydrocannabinol-containing drugs in adolescents include cognitive impairment and chronic psychiatric disturbances.6 The potential toxic effects of tetrahydrocannabinol and other cannabis constituents have not yet been studied in younger children (<12 years) who might be more vulnerable than adolescents to these and other potential adverse effects.
In the past few years, enormous interest has been generated by social and news media about the beneficial effects of non-purified medical marijuana, with high ratios of cannabidiol to tetrahydrocannabinol, in children with treatment-resistant epilepsies, especially Dravet syndrome.7, 8, 9 Preclinical evidence showing the anticonvulsant properties of cannabidiol in animals supports this focus on preparations with high cannabidiol content.5, 10 Furthermore, two of four previous trials in humans suggested modest benefits in seizure control11 and good tolerability, with patients experiencing mild or no side-effects. However, these trials were all too small (between nine and 15 patients) to adequately assess efficacy.
Research in context
Evidence before this study
Anecdotal evidence has long suggested that cannabis might have a role in control of epileptic seizures. We searched PubMed for English-language studies published between Nov 1, 1970, and Oct 15, 2015, with the search terms “cannabidiol and epilepsy” and “cannabis and epilepsy”. Our search identified several preclinical studies, from the 1980s to the past few years, of the effect of cannabidiol on electrical convulsant and chemoconvulsant models. Four small randomised studies of cannabidiol-based preparations showed an absence of serious side-effects, and two of these studies suggested some efficacy, but all studies were too small to provide definite answers. We additionally found two papers that used parental surveys of the effect of non-purified preparations of cannabis-based products for paediatric epilepsy.
Added value of this study
This multicentre study provides the first prospectively collected data of cannabidiol use in patients with epilepsy. Our findings provide the first estimates of safety, tolerability, and efficacy of this compound in children and young adults with treatment-resistant epilepsy.
Implications of all the available evidence
By comparison with previous studies, which could not obtain robust conclusions, our study is the first to provide evidence that cannabidiol might be an effective treatment option for children and young adults with intractable epilepsy. Randomised controlled trials are warranted to characterise the safety profile and true efficacy of this compound.
Insufficient preclinical and clinical data, in addition to anecdotal reports from the past few years, have intersected with a need for more effective therapies for treatment-resistant epilepsy, which has created a demand for access to cannabidiol-based treatments by patients and families. As such, many US states have approved the use of medical marijuana for children and adults with epilepsy. Unfortunately, few well designed and conducted safety or efficacy studies of cannabidiol have been done in humans. However, safety data are available for cannabidiol-containing compounds in adults with pain and multiple sclerosis-related spasticity.12 A pooled analysis of randomised trials of Sativex (GW Pharmaceuticals, London, UK), an oromucosal spray containing cannabidiol and tetrahydrocannabinol in a 1:1 ratio, showed no serious adverse events.13 Common mild or moderate adverse events included oral pain, dizziness, diarrhoea, nausea, oral mucosal disorder, bad taste, dry mouth, fatigue, heading, and somnolence.13 Because these compounds contain tetrahydrocannabinol, which is responsible for many of these effects, fewer adverse effects of cannabidiol alone are expected, and those that do occur (such as somnolence) are expected to be less severe. However this hypothesis remains undefined in a paediatric epilepsy population.
Given the scarcity of safety and efficacy data for cannabidiol use in children and young adults with severe epilepsy, and the intense interest from our patients' families in obtaining cannabis, we did this study to test whether cannabidiol as an add-on treatment to conventional anti-epileptic drugs would be safe, tolerated, and efficacious in children and young adults with highly treatment-resistant epilepsy.