Phase 1 trial maps CBD drug interactions with three common epilepsy medications
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.
Quick Facts
What This Study 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.
Key Numbers
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 They Did This
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.
Why This Research 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 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.
What This Study Doesn't 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.
Questions This Raises
- ?Should clobazam doses be routinely reduced when CBD is added?
- ?Do these pharmacokinetic interactions translate to meaningful clinical differences in seizure control?
Trust & Context
- Key Stat:
- 3.4-fold clobazam metabolite increase
- Evidence Grade:
- Strong: well-designed Phase 1 PK study from the Epidiolex manufacturer with bidirectional interaction data.
- Study Age:
- Published in 2019.
- Original Title:
- A Phase 1, Open-Label, Pharmacokinetic Trial to Investigate Possible Drug-Drug Interactions Between Clobazam, Stiripentol, or Valproate and Cannabidiol in Healthy Subjects.
- Published In:
- Clinical pharmacology in drug development, 8(8), 1009-1031 (2019)
- Authors:
- Morrison, Gilmour(2), Crockett, Julie(2), Blakey, Graham, Sommerville, Kenneth
- Database ID:
- RTHC-02195
Evidence Hierarchy
Participants are randomly assigned to treatment or placebo groups to test cause and effect.
What do these levels mean? →Frequently Asked Questions
Does CBD interact with clobazam?
Yes, CBD tripled blood levels of clobazam's active metabolite (N-desmethylclobazam), which may increase side effects like sedation. Clobazam dose reduction may be needed when adding CBD.
Is it safe to take CBD with valproate?
This study found no clinically relevant pharmacokinetic interaction between CBD and valproate, suggesting the combination is likely safe from an interaction standpoint.
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Cite This Study
https://rethinkthc.com/research/RTHC-02195APA
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
MLA
Morrison, Gilmour, et al. "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, 2019. https://doi.org/10.1002/cpdd.665
RethinkTHC
RethinkTHC Research Database. "A Phase 1, Open-Label, Pharmacokinetic Trial to Investigate ..." RTHC-02195. Retrieved from https://rethinkthc.com/research/morrison-2019-a-phase-1-openlabel
Access the Original Study
Study data sourced from PubMed, a service of the U.S. National Library of Medicine, National Institutes of Health.
This study breakdown was produced by the RethinkTHC research team. We analyze and report published research findings without making health recommendations. All interpretations are based solely on the published abstract and study data.