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

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 in the treatment of psychotic disorders. Nonetheless, the effect of sustained PEA intake in CHR subjects has never been explored so far. 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 ultramicronized-PEA (um-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 um-PEA ability to reduce APS and psychic distress, um-PEA safety and tolerability, and the biological basis of um-PEA 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.