Medical cannabis has received widespread attention in recent decades for its potential in the treatment of intractable, or treatment-resistant, forms of epilepsy. Lennox-Gastaut and Dravet Syndrome have been of particular interest, as an increasing amount of both clinical and anecdotal evidence demonstrates that cannabidiol (CBD) from the plant can help to reduce seizures in patients of these forms of epilepsy.

Epidiolex, a CBD isolate oil, is approved by the National Institute for Health and Care Excellence (NICE) for this purpose alongside clobazam, a licensed epilepsy medication. CBD works to both enhance anti-seizure potential and increase the concentration of active metabolites of clobazam in blood plasma. In a recent article, researchers aimed to establish whether CBD can decrease seizure frequency independent of common epilepsy medication, Clobazam.

CBD as an Adjunct Therapy

The review, published in Epilepsia, assessed the results from four pivotal randomised placebo-controlled trials. The results of these trials were considered when the USA’s Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approved CBD as an adjunct therapy for epilepsy. The addition of CBD led to an improved reduction in seizures in comparison to placebo in Lennox-Gastaut and Dravet syndrome patients with treatment-resistant epilepsy.

Drug-Drug Interactions of CBD and Clobazam

In these trials, around 47%-51% of Lennox-Gastaut syndrome patients and 68% of Dravet syndrome patients were also treated with clobazam. CBD is an inhibitor of the cytochrome P450 (CYP) enzymes CYP3A4 and CYP2C19, which are involved in the metabolism of clobazam and its major active metabolite norclobazam. Norclobazam is predicted to have around one fifth the anti-convulsant potency of its parent drug clobazam, however, CBD increases norclobazam concentration by an average of between 3-5 times that of clobazam.

In one study of 13 mostly paediatric patients, the addition of 20-25mg/kg/d dose of CBD was associated with an average of a 5-fold increase in norclobazam plasma concentration. In another study of adult patients, a norclobazam plasma increase of 3.4-fold was seen following the addition of CBD. This raised the question of whether CBD could be an effective treatment option, independent of its drug-drug interactions with existing epilepsy medications.

Anti-Seizure Potential of Cannabidiol

CBD has not been found to significantly affect plasma concentrations of other anti-seizure medications. Therefore, the researchers reviewed data from Lennox-Gastaut and Dravet syndrome patients on alternative anti-epileptic drugs. The studies included in this review demonstrated that patients who received CBD alongside clobazam experienced, on average, a higher anti-seizure effect. However, CBD improved seizure frequency in patients both on and off Clobazam when compared to the placebo group.

After reviewing all available data from the aforementioned patient trials, the researchers concluded that significant reductions in seizures tended to be experienced when CBD was administered alongside clobazam. However, CBD still demonstrated potential efficacy in reducing seizures in Lennox-Gastaut and Dravet syndrome on its own or with other anti-epilepsy medications.

This review also noted the issue of clobazam related side effects. Patients who were not currently taking clobazam had often used the medication in the past and discontinued treatment, presumably due to lack of effect or intolerable side effects. The combination of clobazam and CBD has been seen to increase the risk of adverse effects such as respiratory hypersecretions, in addition to its effects in seizure reduction.

However, there are notable limitations of this review, such as relatively small sample sizes, a lack of randomisation, as well as a questionable rationale for the pooling of data from different seizure types and syndromes. This review cautiously supports the anti-seizure potential of CBD, independent of its drug-drug interactions with clobazam. However, well-designed clinical trials are needed to understand this potential more clearly.