CBD Can Reduce Seizures Independent of Clobazam, Study Says
Add-on CBD can effectively reduce seizure frequency in patients with Lennox-Gastaut syndrome and Dravet syndrome, irrespective of concurrent clobazam usage, new research claims.
Published in Acta Neurologica Scandinavica and led by neurologists from the Stichting Epilepsie Instellingen Nederland (SEIN), the new research details the results of four randomized, controlled trials examining the efficacy and safety of CBD as an anti-seizure medication.
The results of previous clinical studies on CBD and epilepsy have been called into question on the grounds that a significant proportion of participants in these trials were also taking clobazam – a common antiepileptic drug that is known to interact with CBD in a way that increases the active metabolites of both drugs in the body.
The data from this new study appear to support the idea that while CBD can amplify clobazam’s effectiveness, the cannabinoid may also have an anti-seizure effect in its own right.
Seizures reduced in phase 3 trials for two rare epilepsies
In total, the four trials included more than 700 patients with either Lennox-Gastaut syndrome (LGS) or Dravet syndrome (DS).
For patients with these types of epilepsies it is common to be on multiple antiepileptic drugs (AEDs) at once as there is no single effective treatment option available for either syndrome. Across the whole study, participants were on a median of three concomitant AEDs. Approximately 50 percent of the patients with LGS took clobazam as one of their AEDS, and 64 percent of the patients with DS did the same.
The researchers observed that the CBD treatment – being the purified oral CBD solution Epidiolex, given at doses of either 10 or 20 milligrams per kilogram per day (mg/kg/day) – effectively reduced primary seizure frequency when compared to a placebo in the patients taking clobazam, and also in the general study population.
Similarly, CBD was also able to reduce the total seizure frequency, increase the number of seizure-free days, and returned positive impressions of change from the patients and their caregivers across all patient demographics irrespective of clobazam use.
While most patients across the four trials received the higher of the two dosage options, the researchers also noticed that there appeared to be no consistent dose response in the effectiveness of the CBD treatment. As a result, the researchers recommend 10 mg/kg/day as an ideal maintenance dose for patients prescribed add-on CBD, with the possibility that this could be gradually increased up to a maximum of 20 mg/kg/day based on individual experience.
CBD works independently of clobazam
In 2018, Epidiolex (known as Epidyolex in Europe) became the first cannabis-based medicine approved by the US Food and Drug Administration (FDA), and the first drug in general to be officially approved for the treatment of Dravet syndrome. The FDA used evidence from three randomized, double-blind, placebo-controlled clinical trials to support its approval.
In the years since, these trials have been highly scrutinized. One 2019 study published in the British Journal of Clinical Pharmacology argued that the reduction of seizures in these three FDA-cited trials may have actually been down to concomitant clobazam use, not CBD.
“I went back to [two of the three cited] papers… and I thought, ‘let’s have a look.’ How many of those patients were actually using clobazam?” Geert Jan Groeneveld, the lead author of the study, told Analytical Cannabis shortly after publication.
“And I was awestruck,” he continued. “I was flabbergasted when I saw that 50 percent in one study and 60 percent in the other study were actually using this other drug, clobazam.”
“I'm not saying that I know for a fact that cannabidiol does not have any anti-epileptic effects. What I am saying is, I can explain the effects that you've observed through elevated blood levels of clobazam.”
The authors of this new research acknowledge these concerns directly in their paper.
“Some have previously questioned whether CBD has an antiseizure effect independent of clobazam, or whether its efficacy is due to a bidirectional drug-drug interaction with clobazam leading to increased levels of active metabolites of both drugs,” they write.
They explain that while previous trials have established that clobazam and CBD do interact in a way that can increase their active metabolites, other preclinical studies also support the idea of CBD having its own independent antiseizure effect.
One study in particular, using a mouse model of epilepsy, found that using small sub-anticonvulsive doses of CBD with clobazam did nothing to better control the seizures. It was only once larger doses of CBD were used that seizure frequency was reduced any further. In their present research, the researchers point to the improvements seen in both the sub-group using clobazam and the rest of the general population as additional evidence to support the idea of CBD’s independent effects.
“Add-on CBD was effective in reducing seizures in patients with LGS and DS, both in the overall trial populations and in conjunction with clobazam,” the authors concluded.
Using add-on CBD in practice
The researchers also sought to determine the safety of using add-on CBD, finding its effects to be well tolerable with the exception of drowsiness, which is already a common side-effect of clobazam use.
In some cases patients taking CBD were found to have elevated liver enzyme levels, but a greater proportion of these patients were taking concomitant valproate medication than clobazam. Again, this is a known risk for this medication. Still, the researchers strongly recommend reducing or discontinuing CBD and/or concomitant clobazam or valproate should these enzyme levels increase significantly at any point during treatment.
Study restrictions, such as the infeasibility of assessing the impact of individual clobazam levels, made it harder for the researchers to properly establish if these adverse events could be mitigated by adjusting other medications. Still, they hope that their analysis of these trials “will aid clinicians in making informed decisions regarding the efficacy and safety of CBD when prescribed in conjunction with clobazam.”