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

To date, no psychotropic medication has been shown to effectively halt progression to psychosis among individuals at Clinical HighRisk of 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 in the treatment of psychotic disorders. Nonetheless, the effect of sustained PEA intake in CHR subjects has not explored so far. We will assess the feasibility of enrolling 20 CHR young adults presenting with attenuated psychotic symptoms (APSs) in a 12-week, open-label, investigator-initiated, proof-of-concept, single-arm trial of ultramicronized-PEA (um-PEA) at a dose of 600 mg/day. Once having completed the 12-week phase, participants will be asked to enter a 24-week extension phase of the study. We will examine um-PEA’s ability to reduce APSs and psychic distress, um-PEA’s safety and tolerability, and the biological basis of um-PEA’s effect in terms of modulation of inflammatory response, endocannabinoid (eCB) signaling, and microbiome composition. 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.