CBD Benefit Within a Clobazam Subgroup Did Not Prove a Superior Combination

CBD reduced seizures among trial participants already taking clobazam, but this does not prove that the combination outperforms CBD without clobazam. CBD treatment was randomized; pre-existing clobazam use was not.

An original reanalysis of four trials

The report reanalyzed four randomized trials involving Lennox–Gastaut or Dravet syndrome. Participants received highly purified oral CBD at 10 or 20 mg/kg/day, or placebo, during fourteen weeks of treatment. The pooled efficacy populations included 396 participants with Lennox–Gastaut syndrome and 318 with Dravet syndrome.

Approximately 49% of the Lennox–Gastaut group and 64% of the Dravet group were taking clobazam. The primary seizure endpoint differed by syndrome: drop seizures for Lennox–Gastaut and convulsive seizures for Dravet. Those outcomes should not be combined into an undifferentiated claim about all seizures.

Within-subgroup efficacy was demonstrated

For Lennox–Gastaut participants taking clobazam, the pooled CBD-versus-placebo treatment ratio for drop-seizure frequency was 0.56, with a 95% confidence interval of 0.47–0.67. The overall Lennox–Gastaut ratio was 0.70, with a confidence interval of 0.62–0.80. Both comparisons favored CBD.

Those ratios describe modeled relative seizure-frequency effects against placebo in the specified analyses. They are not percentages of patients cured, seizure-freedom rates or a direct randomized comparison of combination therapy against CBD without clobazam.

Why the apparently larger subgroup effect needs caution

People taking clobazam could differ from those not taking it in disease characteristics, treatment history and previous response. Some off-clobazam patients may have tried and stopped it. Trials were not designed around the subgroup comparison, and clobazam doses could be adjusted for adverse effects.

The reanalysis also did not fully account for the many other concomitant treatments. It supports CBD efficacy within the studied subgroup while leaving the optimal-combination question less certain. These are further analyses of existing trial participants, not four additional independent experiments beyond the original trials. Seizure endpoints also do not validate driving ability or generalize to unstandardized retail cannabis products.

Related: CBD, clobazam and its active metabolite.

Primary research

Cannabidiol in conjunction with clobazam: analysis of four randomized controlled trials. DOI: 10.1111/ane.13351.