The Clinical High-Risk (CHR) for psychosis state has been first described over two decades ago and represents the phase preceding the potential development of full-blown psychosis [1]. Recent meta-analyses of risk of transitioning to psychosis at 2 years among CHR individuals show rates of approximately 16–19%, while risk factors accumulation (risk enrichment) results in increasing rates of up to 35% at 10 years [2,3]. Compared to the outdated “prodrome” concept, the CHR paradigm provides a less deterministic understanding of schizophrenia (SCZ), thus highlighting the importance of detection, assessment, and early intervention on milder symptoms preceding psychosis onset to halt disease progression [4,5,6]. However, to date, no psychotherapeutic or psychopharmacological interventions have shown to effectively prevent progression to psychosis among CHR subjects [3,7], nor to relieve them from attenuated psychotic symptoms (APS) [8], negative symptoms [9], or impaired global functioning [10]. Compelling evidence of the endocannabinoid (eCB) system early disruption in the neurophysiological pathway leading to schizophrenia onset has fostered the search for novel medications (e.g., cannabidiol, CBD) targeting the eCB system for both psychosis patients and CHR individuals [11,12,13,14,15,16].

To this extent, growing research is focusing on the role of the eCB-like compound Palmitoylethanolamide (PEA) as a potential therapeutic agent in the context of several neuropsychiatric conditions [17,18,19]. PEA is a naturally occurring N-Acylethanolamine (AE), proven to modulate the central and peripheral neuroimmune systems and to exert protective functions against glutamate neurotoxicity [20,21,22]. It directly activates the Peroxisome Proliferator Activated Receptor-α (PPAR-α) and G protein-coupled receptor 55 (GPR55), allosterically modulates the Transient Receptor Potential Vanilloid 1 (TRPV1), and indirectly interacts with type 1- (CB1) and type 2- (CB2) cannabinoid receptors [23], sharing similar pharmacodynamic properties with the phytocannabinoid CBD [24]. We recently conducted a systematic review aimed at investigating the biobehavioral role of PEA in psychotic disorders [25]. Overall, evidence from clinical studies included in our reappraisal converges on the involvement of PEA in different psychotic phenotypes. A robust strain of research indicates an endogenous attempt of PEA to restore homodynamic balance under disease conditions in CHR individuals [26], non-affective psychosis patients [27,28,29,30], and affective psychosis patients [28,31] at different stages of illness. Specifically, PEA blood tone would increase in the initial phases of a psychotic disorder, while subsiding concomitantly to disease progression. Consistently, PEA levels in the central nervous system (CNS) were found to be elevated in the early stages of SCZ [32], before declining as the disease progresses [33]. Limited but promising evidence was also obtained from interventional studies assessing the potential of PEA therapeutic supplementation in SCZ patients [34], bipolar disorder patients with manic symptoms [35], and Parkinson’s disease patients with psychotic symptoms [36]. PEA showed a selective efficacy on negative psychotic (e.g., alogia) [34] and acute manic [35] symptoms, while not significantly ameliorating positive psychotic symptoms (e.g., delusions) [34,35,36]. To the best of our knowledge, to date there is no evidence of the effect of PEA treatment in the clinical stages preceding the onset of psychosis as well as to prevent the risk of disease progression.

We propose a feasibility study of sustained ultramicronized-PEA (um-PEA) supplementation in CHR individuals to address the lack of a first-line treatment for this group of subjects, focusing on study recruitment and patient acceptability.