CBD had little effect on clobazam itself but tripled its active metabolite levels, slightly increased stiripentol exposure, and had no clinically relevant effect on valproate.
Epileptologists, clinical pharmacologists, and patients on CBD plus AEDs.
3.4-fold clobazam metabolite increase
What the researchers found
CBD increased N-desmethylclobazam (active clobazam metabolite) 3.4-fold for both Cmax and AUC. Stiripentol exposure increased modestly (Cmax 1.3-fold, AUC 1.6-fold). No clinically relevant effect on valproate. Clobazam increased 7-OH-CBD levels 1.5-1.7-fold. Stiripentol slightly decreased CBD metabolite levels. CBD was moderately well tolerated with all three AEDs.
Why it matters
These three AEDs are among the most commonly co-prescribed with CBD for Lennox-Gastaut and Dravet syndromes. Knowing that CBD triples the active clobazam metabolite is clinically actionable: clobazam doses may need reduction when adding CBD.
The numbers in context
N-desmethylclobazam: Cmax and AUC 3.4-fold increase. Clobazam: 1.2-fold increase. Stiripentol: Cmax 1.3-fold, AUC 1.6-fold. Valproate: no relevant change. 7-OH-CBD with clobazam: Cmax 1.7-fold, AUC 1.5-fold.
How the study worked
Phase 1, open-label, fixed-sequence drug-drug interaction study in healthy volunteers, examining bidirectional pharmacokinetic interactions between pharmaceutical CBD (Epidiolex) and clobazam, stiripentol, and valproate at steady state.
What this study cannot tell us
Healthy volunteers, not epilepsy patients. Single-dose escalation design. Cannot assess whether interactions change with chronic dosing or in patients with hepatic impairment.
How to read the evidence
Strong: well-designed Phase 1 PK study from the Epidiolex manufacturer with bidirectional interaction data.
When this study was published
Published in 2019.
The bigger picture
The somnolence commonly attributed to CBD in epilepsy may partly be caused by the 3.4-fold increase in the active clobazam metabolite. Understanding these interactions allows dose adjustments that could improve tolerability.
Questions still open
- Should clobazam doses be routinely reduced when CBD is added? Do these pharmacokinetic interactions translate to meaningful clinical differences in seizure control?
Common questions
Does CBD interact with clobazam?
Is it safe to take CBD with valproate?
Read the original research
A Phase 1, Open-Label, Pharmacokinetic Trial to Investigate Possible Drug-Drug Interactions Between Clobazam, Stiripentol, or Valproate and Cannabidiol in Healthy Subjects.
Clinical pharmacology in drug development, 8(8), 1009-1031
Citation
Morrison, Gilmour; Crockett, Julie; Blakey, Graham; Sommerville, Kenneth. (2019). A Phase 1, Open-Label, Pharmacokinetic Trial to Investigate Possible Drug-Drug Interactions Between Clobazam, Stiripentol, or Valproate and Cannabidiol in Healthy Subjects.. Clinical pharmacology in drug development, 8(8), 1009-1031. https://doi.org/10.1002/cpdd.665
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