The Endocannabinoid Activity Remodulation for psychosis Liability in Youth (EARLY) Study: An Open-Label Feasibility Trial of Palmitoylethanolamide Oral Supplementation in Clinical High-Risk State for Psychosis

Abstract Background To date, no psychotropic medication has shown to effectively halt progression to psychosis among individuals at Clinical High-Risk for psychosis (CHR), fueling the search for novel therapeutic agents. Recent evidence supports Palmitoylethanolamide (PEA) signaling as a potential psychosis biomarker, also indicating a therapeutic role for its supplementation. Nonetheless, the effect of sustained PEA intake in CHR subjects has never been explored so far. Methods We will assess the feasibility of enrolling 20 CHR young adults presenting with attenuated psychotic symptoms (APS) in a 12-week, open-label, investigator-initiated, proof-of-concept, single-arm trial of PEA 600 mg/day. Once completed the 12-week phase, participants will be proposed to enter a 24-week extension phase of the study. We will examine PEA ability to reduce APS and psychic distress, PEA safety and tolerability, and the biological basis of PEA effect in terms of modulation of inflammatory response, endocannabinoid (eCB) system, and microbiome. Discussion Our trial aims to address an unmet clinical need in CHR subjects, providing an initial solid basis for the development of future studies evaluating the efficacy and tolerability of PEA supplementation in this group of patients. Trial registration Clinicaltrials.gov, NCT06037993 (https://classic.clinicaltrials.gov/ct2/show/NCT06037993). Registered on 21 September 2023. Retrospectively registered.