Epilepsy is one of the most common chronic disorders of the brain, with an estimated 70 million people affected worldwide. While a large proportion of patients can ultimately reach sustained remission – characterised by the absence of seizures – around a third of patients will continue to experience seizures. There are a number of treatment-resistant epilepsies – each of which can have a significant impact on cognitive and behavioural function and quality of life. Therefore, there remains an urgent need for the development of new therapies to manage these conditions.
In recent years, cannabis has gained increasing attention for its potential in reducing seizure frequency and severity in a number of epileptic conditions. The drug has been recorded as an anti-seizure medication for thousands of years, however, prohibition means that there is still limited clinical research on the subject. Nonetheless, the promising results that have been recorded have led to the approval of a highly purified formulation of cannabidiol (CBD) in a number of countries, including the UK, for the treatment of two forms of treatment-resistant epilepsy: Dravet syndrome and Lennox-Gastaut syndrome.
A recent review aimed to assess the potential of this cannabis-based formulation as a treatment in patients with other epileptic conditions. The researchers aimed to use the existing evidence to suggest implications for clinical practice and future research.
Identifying Relevant Studies
The researchers identified a total of 570 relevant studies up until October 2020. Clinical trials, cohorts, case-control, cross-sectional, clinical series, and case reports were included for review while self-reported surveys, reviews, meta-analyses, editorials, commentaries, and expert opinions were excluded.
Participants in included studies also had to have a diagnosis of epilepsy and have received plant-derived, highly purified (> 98%) CBD in a sesame oil-based oral solution (Epidiolex/Epidyolex®) for the treatment of seizures. Studies that recruited patients with only Lennox-Gastaut syndrome or Dravet syndrome were also excluded from the review. Of the 570 relevant studies identified, 57 studies were retrieved for detailed assessment and 42 were eventually included for the review.
Outcomes of the Included Studies
Across the trials, purified CBD was administered as an adjunctive treatment at doses up to 50mg/kg/day. Most studies aimed to assess the efficacy and safety of CBD treatment, and study endpoints included seizure frequency reduction, seizure response rate, seizure freedom, change in seizure severity, treatment discontinuation, and occurrence of adverse events.
However, 8 of the included studies primarily aimed to describe pharmacokinetic analyses or drug-drug interactions between CBD and antiseizure or non-antiseizure medications. Seven of the studies included cognitive and/or quality of life measures, and three primarily focused on assessing functional brain function.
Results of the Included Studies
Following the assessment of the included studies, the authors of this review noted that response to treatment with a highly purified, plant-derived CBD oil-based solution can be seen in patients across a wide range of epilepsy disorders and etiologies.
Tuberous sclerosis complex (TSC)
The highest quality evidence was identified for tuberous sclerosis complex. In one randomised, double-blind, placebo-controlled trial, CBD was seen to produce a significant percent reduction in tuberous sclerosis complex-associated focal and generalised seizure frequency. In addition, CBD was associated with a reduction in total seizure frequency, including focal sensory and epileptic spasms in comparison to placebo. Furthermore, the administration of purified CBD as an adjunctive therapy resulted in electrographic and clinical response in patients with TSC with refractory epileptic spasms enrolled in an open-label study. Subjective improvements in cognitive and behavioural domains were also identified.
Other Epileptic Conditions
A number of open-label drug trials included in this review provided class III evidence for the efficacy of CBD in patients with CDKL5 deficiency disorder and Aicardi, Doose, and Dup15q syndromes, which cause epileptic encephalopathies. Overall, add-on treatment with pure CBD was associated with a significant reduction in baseline monthly seizure frequency at week 12 which was sustained between week 12 and week 48.
Long-term response to treatment was further reported over 2-4 years in patients with medically refractory epilepsy including CDKL5 epileptic encephalopathy and epilepsy with myoclonic absences. Patients enrolled in these studies were among the most treatment-resistant patients at each centre and had syndromes characterised by a poor outcome, with a high incidence of status epilepticus, use of rescue medication, and sudden unexpected death in epilepsy. In this scenario, the rates of seizure response and even seizure freedom for a few cases are suggestive of clinically relevant CBD efficacy.
The researchers also noted a significant decrease in seizure frequency (85-90%) with CBD add-on therapy in patients with SYNGAP1 developmental and epileptic encephalopathy, accompanied by an improvement of background electroencephalogram activity and interictal anomalies. Appreciable reductions in seizure frequency in a subset of patients with Sturge–Weber syndrome, focal cortical dysplasia, lissencephaly, brain tumour-related epilepsy, and frontal and temporal lobe epilepsy of unknown aetiology were also identified.
Safety, Tolerability, and Adverse Events
Overall, the studies included in this review demonstrated that CBD had a favourable tolerability profile across different epileptic conditions which “substantially overlapped that reported in patients with Lennox-Gastaut Syndrome and Dravet Syndrome enrolled in randomised controlled trials.”
The most common adverse events reported across the included study were somnolence, gastrointestinal symptoms, decreased appetite, and weight loss. The incidence of somnolence was generally higher in patients concomitantly taking Clobazam. Gastrointestinal symptoms were generally reported to be mild to moderate in severity. The researchers note that the sesame-oil based drug vehicle and the effects of CBD on the gut microbiome may contribute to diarrhoea.
Lack of appetite and weight loss observed in some patients were believed to be directly related to CBD as they occurred independently from diarrhoea. Clinically significant weight loss emerged typically only after about 6 months of treatment.
Following the assessment of the current evidence for the potential of purified CBD in patients with various epileptic conditions, the researchers concluded that “CBD may have antiseizure properties in a broad range of epilepsy syndromes and aetiologies, and open-label studies suggested the effectiveness of purified CBD in the treatment of children and adults presenting with other epilepsy syndromes and seizure types than those addressed by regulatory trials”.
However, the authors also note that these results cannot be directly transferred to other cannabis-derived products and non-purified forms of medical cannabis and cannabinoids.
To date, there are no drugs specifically approved for the conditions assessed in this review, and existing therapies can determine or exacerbate cognitive, behavioural, and motor disorders. Finally, the researchers conclude that the existing evidence about pharmaceutical-grade CBD provides preliminary support for additional research. It is recommended that traditional randomised, controlled trials, and novel trial designs be considered.