Adjunctive Cannabidiol for Drug-Resistant Epilepsy: A Systematic Review and Meta-Analysis of Randomized Trials Across Syndromes, Formulations, and Dose Ranges

Background: Cannabidiol (CBD) has emerged as a promising adjunctive therapy for drug-resistant epilepsy, yet clinical findings remain heterogeneous across trials. This meta-analysis aimed to evaluate the efficacy, safety, and formulation-dependent performance of CBD in patients with treatment-resistant epilepsies. Methods: A systematic review and meta-analysis were conducted in accordance with PRISMA 2020 guidelines, including randomized, double-blind, placebo-controlled trials of adjunctive CBD in drug-resistant epilepsy. Literature was sourced from PubMed/MEDLINE, Scopus, and the Cochrane Central Register of Controlled Trials (CENTRAL). Data were synthesized using random-effects models to estimate pooled risk ratios (RRs) with 95% confidence intervals (CIs) for seizure reduction and adverse events. Subgroup analyses explored the influence of epilepsy syndrome, CBD dose, and formulation type. Results: Seven randomized controlled trials involving 1154 participants met inclusion criteria. Adjunctive CBD significantly reduced seizure frequency compared with placebo (pooled RR = 0.72, 95% CI 0.71– 0.73; p < 0.0001). The effect was consistent across Dravet syndrome, Lennox–Gastaut syndrome, and tuberous sclerosis complex, with optimal efficacy observed at 20 mg/kg per day of highly purified oral CBD. Liposomal CBD produced modest benefit, whereas transdermal formulations showed no short-term efficacy. Adverse events were predominantly mild and comparable to placebo, although elevations in hepatic enzymes and somnolence occurred more frequently in patients receiving concomitant valproate or clobazam. Conclusion: Adjunctive oral CBD provides a reproducible and clinically meaningful reduction in seizures in drug-resistant epilepsy, with an acceptable safety profile. Oral CBD at 20 mg/kg per day represents the current benchmark for efficacy, while alternative formulations require further evaluation. Future research should address long-term outcomes, optimal dosing strategies, and formulation refinement to improve tolerability and accessibility in diverse epileptic populations.