Psilocybin as serotonergic therapy in epilepsy: Narrative review of potentials and limitations

Psilocybin shows potential in neuropsychiatric disorders but has a complex relationship with epilepsy and seizures. We reviewed literature up to November 2025 to identify studies relevant to psilocybin's effects on seizures and epilepsy, including our research on serotonergic modulation. Core studies addressing the research question and supplementary mechanistic evidence were included for synthesis. Risk of bias (RoB) was assessed by study type; independent reviewers achieved strong agreement (unweighted Cohen's κ = 0.80, SE = 0.185; 99% CI 0.006-0.011; per cent agreement = 88.9%). Experimental models suggest psilocybin, through 5-hydroxytryptamine receptor 2A (5-T2A) activation, may confer antiseizure effects. Preclinical data support serotonergic modulation as a promising strategy. RoB assessment highlighted methodological challenges, suggesting cautious interpretation. Clinical evidence in neuropsychiatric populations shows no increased seizure risk under medical supervision. Psilocybin could serve as an adjunctive therapy via selective serotonergic modulation. However, conflicting evidence and concerns at high doses urge caution. Future animal studies and clinical trials must confirm psilocybin's safety and efficacy in the treatment of epilepsy.