Questioning the role of palmitoylethanolamide in psychosis: a systematic review of clinical and preclinical evidence

Introduction The endocannabinoid (eCB) system disruption has been suggested to underpin the development of psychosis, fueling search for novel, better-tolerated antipsychotic agents that target eCB system. Among these, palmitoylethanolamide (PEA), an N-acylethanolamine (AE) with neuroprotective, anti-inflammatory, and analgesic properties, drawn attention its potential. Methods This Preferred Reporting Items Systematic Reviews Meta-Analyses (PRISMA) 2020-compliant systematic review aimed at reappraising all clinical preclinical studies investigating biobehavioral role PEA in psychosis. Results Overall, 13 were eligible data extraction (11 human, 2 animal). Observational tone psychosis patients converged on evidence increased plasma (6 human) central nervous (CNS; 1 levels, as a potential early compensatory response illness severity, seems be lost longer-term human), opening possibility exogenously supplementing it sustain control disorder. Consistently, oral supplementation reduced negative psychotic manic symptoms among patients, no serious adverse events (3 human). No changes emerged either model (2 animal) studied. Discussion Evidence supports signaling biomarker, also indicating therapeutic registration https://doi.org/10.17605/OSF.IO/AFMTK .