Evidence for Endocannabinoid-Like Compound Supplementation for Human Health: Palmitoylethanolamide as a Potential Treatment in Clinical High-Risk for Psychosis

This doctoral project investigated the biobehavioral potential of palmitoylethanolamide (PEA), an endocannabinoid-like lipid mediator, as a safe and mechanistically grounded intervention for early states of mental health vulnerability. The role of PEA as a homeostatic regulator of immune–glial activity and glutamatergic signaling is generating growing interest in its therapeutic applications across neuropsychiatric conditions characterized by inflammation-driven dysregulation. The research adopted a translational approach integrating systematic reviews and proof-of-concept studies. The first systematic review synthesized evidence from randomized controlled trials on PEA supplementation across clinical populations, highlighting consistent efficacy in pain management and emerging benefits for neuropsychiatric symptoms, while underscoring methodological heterogeneity and lack of mechanistic insight. The second systematic review focused on the biobehavioral role of PEA in psychosis across different stages of illness and clinical phenotypes. Building on this foundation, an open-label, single-arm proof-of-concept trial was conducted in individuals at clinical high-risk (CHR) for psychosis to assess the feasibility, tolerability, and biobehavioral correlates of ultramicronized PEA supplementation (600 mg/day, 12 weeks). Significant improvements were observed in attenuated psychotic symptoms and functional outcomes, with no treatment-emergent adverse effects. Exploratory analyses identified peripheral neuroimmune biomarkers as potential predictors of treatment responsiveness, suggesting that PEA may act as a homeostatic modulator in this population, most effective in individuals with reactive or pro-inflammatory biological profiles. Overall, this project provides preliminary evidence supporting PEA as a biologically informed and well-tolerated intervention for early and therapy-orphan mental health conditions, including the CHR state for psychosis. By integrating clinical and biological data, it contributes to the advancement of personalized, mechanism-based strategies within the framework of precision psychiatry.