CBD and epilepsy: promise tempered by safety and evidence gaps

Epilepsy affects approximately 50 million people worldwide, with nearly 30% of patients exhibiting drug-resistant seizures despite treatment with multiple antiepileptic drugs (AEDs). In this context, cannabidiol (CBD) has emerged as a promising therapeutic candidate. This review examines the mechanistic basis of CBD's antiepileptic effects, focusing on its modulation of neurotransmitter systems, ion channels, and neuroinflammatory pathways, alongside its relevance in current clinical practice. By integrating mechanistic neuropharmacology with a critical appraisal of clinical trial data, this review identifies key translational gaps that may limit the optimization of CBD-based therapeutic strategies. The pharmacokinetic profile of CBD varies across routes of administration and is associated with clinically significant drug-drug interactions, particularly via inhibition of CYP2C19 and CYP3A4, thereby influencing the plasma levels and safety of concomitant AEDs. While emerging evidence supports the efficacy of CBD in certain refractory epilepsies, comprehensive and standardized evaluations across broader epilepsy subtypes remain limited. Safety concerns, including long-term outcomes and interaction profiles, necessitate careful patient monitoring and dose individualization. Furthermore, the evolving regulatory landscape and increasing consumer-driven use underscore the need for robust evidence generation, interdisciplinary collaboration, and standardized clinical protocols. Overall, this review aims to delineate the therapeutic potential of CBD in epilepsy management, positioning it as a valuable adjunct in the antiepileptic armamentarium. Notably, it uniquely integrates a critical mechanistic comparison of GPR55 and TRPV1 pathways-including conflicting evidence-with a structured critique of clinical trials and explicit evidence-level grading to support clinical recommendations.