In Vivo Characterization of Synthetic Cannabidiol Analogs for Seizure Suppression in Zebrafish

Epilepsy affects over 70 million people worldwide, nearly 20% of whom experience pharmacoresistant forms, particularly in pediatric populations. Cannabidiol (CBD) shows promise for the treatment of neurological disorders, including refractory epilepsy, but its low potency necessitates high dosing, leading to side effects that include drowsiness, gastric issues, and potential hepatotoxicity. Regulatory barriers, high cost, abuse liability, and the poor sustainability of hemp cultivation are further drawbacks to CBD use. In an effort to circumvent these issues, a series of structurally related, synthetic "pseudocannabinoids" have been evaluated for antiseizure activity. A high-throughput zebrafish model was employed using pentylenetetrazole (PTZ) and strobing light stimuli to induce seizures, with drug efficacy assessed by automated behavioral analysis and whole-brain imaging. Several of the tested analogs significantly suppressed PTZ-induced seizures, with some outperforming CBD. Imaging revealed corresponding reductions in neural hyperactivity. This study highlights both the promise of safer, more effective cannabinoids for seizure mitigation and the potential of phenotypic, target-agnostic zebrafish screening as a powerful tool for drug discovery.