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