Drug–drug interaction between clobazam and cannabidiol in children with refractory epilepsy
Open accessAbstract
Summary: Objective: Under an expanded access investigational new drug ( IND ) trial, cannabidiol ( CBD ) is being studied as a possible adjuvant treatment of refractory epilepsy in children. Of the 25 subjects in the trial, 13 were being treated with clobazam ( CLB ). Because CLB and CBD are both metabolized in the cytochrome P450 ( CYP ) pathway, we predicted a drug–drug interaction, which we evaluate in this article. Methods: Thirteen subjects with refractory epilepsy concomitantly taking CLB and CBD under IND 119876 were included in this study. Demographic information was collected for each subject including age, sex, and etiology of seizures, as well as concomitant antiepileptic drugs (AEDs). CLB , N ‐desmethylclobazam (norclobazam; nCLB ), and CBD levels were measured over the course of CBD treatment. CLB doses were recorded at baseline and at weeks 4 and 8 of CBD treatment. Side effects were monitored. Results: We report elevated CLB and n CLB levels in these subjects. The mean (± standard deviation [SD]) increase in CLB levels was 60 ± 80% (95% confidence interval ( CI ) [−2–91%] at 4 weeks); the mean increase in nCLB levels was 500 ± 300% (95% CI [+90–610%] at 4 weeks). Nine of 13 subjects had a >50% decrease in seizures, corresponding to a responder rate of 70%. The increased CLB and nCLB levels and decreases in seizure frequency occurred even though, over the course of CBD treatment, CLB doses were reduced for 10 (77%) of the 13 subjects. Side effects were reported in 10 (77%) of the 13 subjects, but were alleviated with CLB dose reduction. Significance: Monitoring of CLB and n CLB levels is necessary for clinical care of patients concomitantly on CLB and CBD . Nonetheless, CBD is a safe and effective treatment of refractory epilepsy in patients receiving CLB treatment.
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Significantly elevated levels of the antiepileptic clobazam and its metabolite, n-desmethylclobazam, have been observed when co-administered with very high doses of CBD, likely due to co-metabolism through CYP2C19 and CYP3A4.
“Significantly elevated levels of the antiepileptic clobazam and its metabolite, n-desmethylclobazam, have been observed when co-administered with very high doses of CBD, likely due to co-metabolism through CYP2C19 and CYP3A4.110”
From Clinical Practice Guidelines for Cannabis and Cannabinoid-Based Medicines in the Management of Chronic Pain and Co-Occurring Conditions (2024) · cites this paper as [110]
The Results report a statistically significant increase in N-desmethylclobazam during CBD treatment, but say the increase in clobazam itself was not statistically significant. The Clinical protocol specifies CBD doses of 20–25 mg/kg/day at measurement; the paper does not characterize them as “very high.” The Discussion proposes inhibition of CYP2C19 and CYP3A4 as an explanation for N-desmethylclobazam accumulation. Page numbers were not supplied in our copy. (LLM, conf=0.93)
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- Authors
- Geffrey, A. L., Pollack, S. F., Bruno, P. L., & Thiele, E. A.
- Affiliations
- Massachusetts General Hospital (US)
- Corresponding author
- Thiele, Elizabeth A.
- Venue
- Epilepsia
- Publisher
- Wiley
- Published
- 2015-06-26
- Volume
- 56
- Issue
- 8
- Pages
- 1246-1251
- ISSN
- 0013-9580 (ISSN-L)
- 1528-1167
- OpenAlex
- W1873975405
- Cited by
- 496
- References
- 23
- Citations by year
- 2026: 22 · 2025: 21 · 2024: 35 · 2023: 40 · 2022: 51 · 2021: 42 · 2020: 93 · 2019: 68 · 2018: 55 · 2017: 31 · 2016: 31 · 2015: 7
- FWCI
- 33.51
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Epilepsia (publishedVersion)
- PubMed (publishedVersion)
- Funders
- The Pediatric Epilepsy Program at Massachusetts General Hospital
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmacological Effects and Toxicity Studies
- Keywords
- clobazam, cannabidiol, drug-drug interactions, drug-resistant epilepsy, pediatric epilepsy, cytochrome P450 metabolism, dose reduction, seizure reduction, drug safety
- MeSH terms
- Clobazam, Adolescent, Benzodiazepines, Cannabidiol, Child, Child, Preschool, Cytochrome P-450 Enzyme System, Drug Interactions, Epilepsy, Female, Humans, Male, Young Adult
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