Meta-analysis of four phase 3 RCTs found add-on CBD reduced seizures by about 30% in both LGS and Dravet syndrome, with greater reductions (37-44%) in patients also taking clobazam, though somnolence was more common in the combination.
Epileptologists, neurologists prescribing CBD, parents of children with severe epilepsy
37-44% seizure reduction with CBD+clobazam vs. ~30% with CBD overall
What the researchers found
CBD reduced primary seizure frequency versus placebo in LGS (treatment ratio 0.70) and Dravet syndrome (0.71) in the overall population. Effects were larger in patients on clobazam (LGS: 0.56; DS: 0.63). CBD improved 50% responder rates, total seizure frequency, seizure-free days, and global impression of change. Somnolence and sedation were more common with CBD plus clobazam. Elevated transaminases occurred mainly in patients on concomitant valproate.
Why it matters
This meta-analysis directly addresses the critical question of whether CBD's seizure reduction is partly driven by its interaction with clobazam, showing CBD is effective in both clobazam users and the overall population, but more so in the combination.
The numbers in context
714 total patients (396 LGS, 318 DS); overall seizure reduction: LGS 0.70, DS 0.71; with clobazam: LGS 0.56, DS 0.63; higher somnolence/sedation with CBD+clobazam; elevated transaminases mainly with concomitant valproate
How the study worked
Subgroup analysis of patients on clobazam and meta-analysis by syndrome across four randomized, placebo-controlled phase 3 trials of pharmaceutical-grade CBD (Epidiolex/Epidyolex; 10 or 20 mg/kg/day for 14 weeks). 396 LGS patients (49% on clobazam) and 318 DS patients (64% on clobazam).
What this study cannot tell us
Post-hoc subgroup analysis, not pre-specified in original trials. Cannot fully separate CBD's direct effects from clobazam interaction effects. 14-week treatment period may not reflect long-term outcomes. Industry-sponsored trials.
How to read the evidence
Meta-analysis of four high-quality phase 3 RCTs providing strong evidence, though the clobazam subgroup analysis was post-hoc.
When this study was published
Published in 2021.
The bigger picture
The enhanced effect with clobazam is clinically important: it means the combination may be more effective than either alone, but clinicians need to manage the increased sedation and monitor liver enzymes, especially with valproate co-administration.
Questions still open
- Should CBD be preferentially combined with clobazam for maximum seizure reduction? Would adjusting clobazam doses when adding CBD maintain efficacy while reducing sedation?
Common questions
Is CBD more effective with clobazam?
What side effects should be monitored?
Read the original research
Cannabidiol in conjunction with clobazam: analysis of four randomized controlled trials.
Acta neurologica Scandinavica, 143(2), 154-163
Citation
Gunning, Boudewijn; Mazurkiewicz-Bełdzińska, Maria; Chin, Richard F M; Bhathal, Hari; Nortvedt, Charlotte; Dunayevich, Eduardo; Checketts, Daniel. (2021). Cannabidiol in conjunction with clobazam: analysis of four randomized controlled trials.. Acta neurologica Scandinavica, 143(2), 154-163. https://doi.org/10.1111/ane.13351
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