Adverse Events of Cannabidiol Use in Patients With Epilepsy

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TL;DR

This systematic review and meta-analysis of 9 RCTs found that cannabidiol (CBD) use in epilepsy patients was associated with significantly higher risks of adverse events compared to placebo, including a 1.12-fold increase in any-grade AEs and a 3.39-fold increase in severe-grade AEs. The most common AEs in the CBD group were somnolence (22.0%), decreased appetite (19.5%), and pyrexia (15.3%), with notably elevated risks for diarrhea, somnolence, decreased appetite, and ALT/AST elevation. These findings indicate that while CBD is an approved adjunctive therapy for severe epilepsies, clinicians should monitor patients closely for these specific adverse effects.

Full summary

4,173 CHARS

**Background:** Epilepsy affects approximately 7.6 per 1000 population globally, with about one-third of cases remaining refractory to standard treatments. Cannabidiol (CBD), a non-intoxicating cannabinoid, has been approved as adjunctive therapy for Dravet syndrome and Lennox-Gastaut syndrome. While prior work examined CBD efficacy and safety across indications, no systematic review had specifically focused on adverse events (AEs) associated with CBD use in epilepsy patients. This study aimed to evaluate the frequency and risk of AEs in patients with epilepsy using CBD.

**Methods:** A systematic review and meta-analysis was conducted following PRISMA guidelines. PubMed, Scopus, Web of Science, and Google Scholar were searched from database inception to August 4, 2022. The search strategy used keywords: (cannabidiol OR epidiolex) AND (epilepsy OR seizures). Included studies were RCTs investigating at least one AE associated with CBD use in epilepsy patients, with no age restriction. Two reviewers independently screened, extracted data, and assessed quality using the Cochrane RoB2 tool. Meta-analysis was performed using Stata 17.0 with random-effects (DerSimonian and Laird) or fixed-effects models depending on heterogeneity (I² < 40% for fixed-effects). Continuity correction of 0.5 was applied when zero events occurred in one arm.

**Key Results:** From 3280 initial records, 9 RCTs met eligibility criteria (published 2017-2022), involving patients with Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis-associated epilepsy. Daily oral CBD doses ranged from 5-50 mg/kg over 3-16 weeks; one study used transdermal gel. Three trials had low risk of bias, three had some concerns, and three had high risk of bias. In the CBD group, the most common any-grade AEs were somnolence (22.0%), decreased appetite (19.5%), and pyrexia (15.3%). In controls, upper respiratory tract infection (11.8%), diarrhea (10.9%), and pyrexia (10.2%) predominated. The overall percentage of any-grade AEs was 9.7% in the CBD group vs 4.0% in controls. The pooled risk ratio (RR) for any-grade AEs was 1.12 (95% CI, 1.02-1.23; I²=58.9%). For severe-grade AEs (5 studies), RR was 3.39 (95% CI, 1.42-8.09; I²=3.5%). Significantly elevated risks were found for diarrhea (RR, 1.93; 95% CI, 1.44-2.58; I²=0.0%), somnolence (RR, 2.29; 95% CI, 1.61-3.25; I²=0.0%), decreased appetite (RR, 2.13; 95% CI, 1.48-3.06; I²=10.2%), and ALT/AST elevation (RR, 12.29; 95% CI, 4.22-35.80; I²=0.0%). Serious AEs (8 studies) had an RR of 2.67 (95% CI, 1.83-3.88; I²=8.9%). AEs leading to discontinuation (8 studies) had an RR of 3.95 (95% CI, 1.86-8.37; I²=0.0%), and AEs leading to dose reduction (3 studies) had an RR of 9.87 (95% CI, 5.34-14.40; I²=0.0%). Among moderate-grade AEs, decreased appetite (RR, 3.25; 95% CI, 1.20-8.83) and somnolence (RR, 3.62; 95% CI, 1.45-9.04) were significantly higher with CBD. Subgroup analysis by study quality showed pooled RRs for any-grade AEs of 1.05 (95% CI, 0.96-1.16) in low-risk studies, 1.15 (95% CI, 0.95-1.39) in high-risk studies, and 1.35 (95% CI, 0.95-1.92) in studies with some concerns.

**Clinical Implications:** CBD use in epilepsy is associated with a significantly increased risk of several AEs, particularly somnolence, diarrhea, decreased appetite, and transaminase elevation. The risk of somnolence appears potentiated by concomitant clobazam use due to drug-drug interactions (CBD inhibits CYP2C19, increasing N-desmethyl clobazam exposure 2-3 fold). While CBD is a relatively safe option compared to other cannabinoids (serious AEs in 4.5% vs dronabinol 5.4% and nabilone 6.3%), clinicians should monitor liver function, appetite, and sedation, especially at higher doses and with concurrent clobazam. Limitations include substantial heterogeneity in study populations, CBD dosages, and routes of administration; inability to assess publication bias due to fewer than 10 studies; and exclusion of AEs reported in fewer than 3 studies. Future research should investigate dose-dependent AE profiles and interactions with specific antiepileptic drugs to optimize safe dosing for treatment-resistant epilepsy patients.