Reduced efficacy and risk of seizure aggravation when cannabidiol is used without clobazam

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Cannabidiol oral solution (Epidiolex) was recently approved in the United States for the treatment of seizures associated with Dravet syndrome. It is typically used as an adjunct with other medication(s). This paper highlights the observation that the effect of cannabidiol is significantly increased when used in conjunction with clobazam (a.k.a. “Onfi”), and it raises the question of whether cannabidiol has antiseizure activity alone.

Clobazam, like most drugs, is metabolized over time by the body – initially to a compound called norclobazam, which is then broken down by an enzyme called CYP2C19. Norclobazam has nearly as much anti-seizure activity as the parent. It is known that cannabidiol is an inhibitor of CYP2C19 , and when used with clobazam has been shown to cause a 2.5 to 3-fold increase in plasma concentrations of norclobazam. So the author asks whether cannabidiol has antiseizure activity alone or whether its effects might be entirely due to this elevation in norclobazam levels. He notes an open-label trial of cannabidiol where only 27% of patients not taking clobazam experienced a reduction in seizures whereas 51% of those who did take clobazam were responders. He also notes that a recent analysis of open-label uncontrolled studies has provided an interpretation that cannabidiol does reduce seizure frequency even in the absence of clobazam. Ultimately he argues that to rigorously address the issue, controlled trials are required.

Rogawski, M.A. Reduced efficacy and risk of seizure aggravation when cannabidiol is used without clobazam. Epilepsy & Behavior in press (2019) preprint available online. doi: 10.1016/j.yebeh.2019.106506.
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