Psilocybin as a Serotonergic Therapy in Epilepsy: Narrative Review of Therapeutic Potentials and Seizure Risks

Background: Psilocybin has shown promise in neuropsychiatric disorders but presents a paradoxical relationship with seizures and epilepsy. Methods: A narrative review was conducted up to November 23, 2025. We conducted structured literature searches across PubMed/MEDLINE, Scopus, Web of Science. and Google Scholar using MeSH terms and keywords to identify studies on psilocybin, magic mushrooms, or psilocin related to seizures or epilepsy. We also covered our research on serotonergic modulation and epilepsy. We selected a set of core studies directly addressing the research question and additional publications providing mechanistic and contextual evidence for the narrative synthesis. The Risk of Bias of the studies was assessed according to their type. Results: Experimental models demonstrate that psilocybin’s action on 5-HT2A receptors may confer anticonvulsant effects, reducing seizure severity in certain contexts. Preclinical findings support serotonergic modulation as a therapeutic strategy, notably in Dravet syndrome models. However, observational studies report seizures associated with recreational psilocybin use, raising concerns about its pro-convulsant potential, particularly outside controlled environments. Our risk of bias assessment of this evidence revealed significant methodological limitations, urging a cautious interpretation. Nevertheless, clinical trials in neuropsychiatric populations have not shown increased seizure risks under medical supervision. Conclusions: Psilocybin holds potential as a novel adjunctive therapy for epilepsy through selective serotonergic modulation, although conflicting data emphasize the caution with which psilocybin should be implemented clinically, especially in high doses. Animal studies and clinical trials in the future should verify the efficacy and safety of psilocybin in the treatment of epilepsy.