Effects of palmitoylethanolamide in clinical high-risk for psychosis: A nonrandomized open-label trial

Clinical high-risk (CHR) for psychosis state still lacks effective and safe treatments. Recent evidence supports the anti-neuroinflammatory properties of fatty acid palmitoylethanolamide (PEA) dietary supplementation across the psychosis spectrum. Sixteen subjects at CHR for psychosis with attenuated psychotic symptoms (APS) enrolled in a 12-week, open-label, nonrandomized, single-arm clinical trial of ultramicronized-PEA (um-PEA, 600 mg/day). Biobehavioral assessments were conducted at baseline, 4 weeks, and 12 weeks, particularly using the Comprehensive Assessment of At-Risk Mental States (CAARMS) and quantifying changes in peripheral neuroimmune biomarkers. Linear mixed-effects models showed significant reductions in CAARMS total APS (Δ_12-weeks = -3.8 units, -30.0 %) and Unusual Thought Content (UTC; Δ_12-weeks = -2.0, -52.5 %). No treatment-emergent side effects were reported. In exploratory analyses including neuroimmune biomarkers as covariates and potential moderators, lower baseline Interleukin (IL)-1β was associated with greater improvement in UTC, while time-varying IL-10/IL-6 ratio, Interferon (IFN)-γ, and IL-6 were linked to changes in CAARMS total APS and UTC.A reduction in APS was observed in subjects at CHR for psychosis receiving PEA supplementation, possibly through immune-inflammatory modulation, warranting further research into its therapeutic potential for this condition.

ClinicalTrials.gov Identifier NCT06037993.