Endocannabinoid Activity Remodulation for Psychosis Liability in Youth

NCT06037993 | Unknown

• 1 other identifier: IRB-DAME 93/2023
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 2

Brief Summary

Clinical High-Risk (CHR) for Psychosis is characterized by the occurrence of unusual stressful experiences (attenuated psychotic symptoms, APS), anxious symptoms, psychological distress, and substantial impairment of the subject's daily functioning. It is estimated to be associated with up to 30-35% risk of evolution to frank psychotic disorder within 2-2.5 years. To date, no psychotherapeutic or pharmacological approaches have shown therapeutic evidence in this group of patients. The aim of this study is to provide a response to an unmet clinical need in this framework of psychic vulnerability by initiating oral therapy with palmitoylethanolamide (PEA), a nutraceutical/food supplement with proven anti-inflammatory and neuroprotective properties. Indeed, many conditions of psychological distress are thought to be underpinned by systemic inflammatory and/or neuroinflammatory processes, on which PEA has shown remarkable efficacy, including through modulation of the immune response and the interaction between the endocannabinoid system and the gut-microbiota-brain axis. The trial we are proposing is a 12-week open-label phase 2 study involving the daily intake of PEA 600 mg, at a dosage of 1 tablet/day. This study will be conducted at the Unit of Psychiatry of Santa Maria della Misericordia Udine University Hospital. Through this study, we wish to evaluate: the ability of PEA to alleviate APS, anxiety, and psychic distress in CHR-APS individuals; the safety and tolerability of sustained intake of PEA in CHR-APS individuals; and the biological basis of PEA functioning. The study involves taking PEA orally once daily (600 mg daily) at the same time as a meal during the initial 12-week phase. Upon completion of the initial phase, subjects will be offered to enter an extension phase of the trial of an additional 24 weeks to assess treatment stability, with the possibility of titration of PEA to 1200 mg daily based on observed clinical compensation. Each participant will be on PEA treatment for up to 36 weeks. During the course of the study, periodic clinical re-evaluations will be conducted at our Day-Hospital setting. The trial will unfold through one screening visit, one baseline visit, and two follow-up visits (FUP, 4 weeks and 12 weeks apart). The patient will be administered standardized interviews by a qualified investigating physician; clinical objective examination, collection of blood and urine samples for standard hematochemical investigations, collection of blood and stool samples for analysis of some biological markers of interest, monitoring of adherence to therapy intake, side effects, and adverse effects will also be performed during the follow-up visits. The nutraceutical PEA will be dispensed by the clinical investigators at each follow-up visit.

Conditions

Clinical High Risk for Psychosis; Ultra High Risk for Psychosis; Attenuated Psychotic Symptoms

Keywords

At-Risk Mental State; Schizophrenia; Endocannabinoid System; Gut-Brain Axis; Palmitoylethanolamide; Nutraceuticals; Prevention; Early Intervention

Outcome Measures

Primary Outcomes (1)

• Severity of attenuated psychotic symptoms (APS)

  Comprehensive Assessment of At-Risk Mental State (CAARMS)

  12 weeks for the initial phase, further 24 weeks for the extension phase

Secondary Outcomes (5)

• Distress associated with psychotic symptoms

  12 weeks for the initial phase, further 24 weeks for the extension phase

• Severity of anxiety symptoms

  12 weeks for the initial phase, further 24 weeks for the extension phase

• Level of impaired global functioning

  12 weeks for the initial phase, further 24 weeks for the extension phase

• Clinical remission, defined as no longer meeting the APS criteria

  12 weeks for the initial phase, further 24 weeks for the extension phase

• Total CAARMS score

  12 weeks for the initial phase, further 24 weeks for the extension phase

Other Outcomes (1)

• Safety endpoints: Incidence of adverse effects during the study period

  12 weeks for initial phase, further 24 weeks for the extension phase

Study Arms (1)

PEA arm

EXPERIMENTAL

Palmitoylethanolamide (PEA)-treated patients

Dietary Supplement: Ultra-micronized Palmitoylethanolamide (PEA)

Interventions

Ultra-micronized Palmitoylethanolamide (PEA) DIETARY_SUPPLEMENT

Palmitoylethanolamide (PEA) is an N-acylethanolamine (AE), produced "on demand" by different cell types as a response to actual or potential damage, proven to down-regulate central and peripheral activity of mast cells and non-neuronal cells (e.g., astrocytes, microglia) and to exert protective functions against glutamate neuro-toxicity, accounting for its naturally-occurring anti-inflammatory, analgesic, and anticonvulsant properties. Due to the shared pharmacodynamic properties, PEA is considered as the endogenous equivalent of Cannabidiol (CBD). A growing body of literature has confirmed the role of PEA in most neurobiological mechanisms underpinning several neuropsychiatric conditions both in clinical and preclinical settings. The effect of PEA over neuroinflammation and glutamate signaling may represent a promising biobehavioral mechanism underlying the clinical utility of its oral supplementation in CHR state.

PEA arm

Eligibility Criteria

• Age: 18 Years - 35 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Individuals diagnosed with CHR-APS, as defined using CAARMS criteria;
• Aged 18-35 years;
• To be able to understand and communicate in Italian;
• To be able to give informed consent.

You may not qualify if:

• Lifetime history of a psychotic or manic episode lasting 7 days or longer;
• Active suicidal ideation indicating significant current risk or history of serious suicide attempt in the opinion of the PI, as evaluated at the screening stage;
• Lifetime neurological disorders (e.g., epilepsy, except febrile convulsions) or severe intercurrent physical illness;
• Current treatment with psychotropic medication, with the exception of Selective Serotonin Reuptake Inhibitor (SSRI) stable monotherapy (at least 8 months);
• Lifetime treatment with antipsychotic medication for more than 7 days;
• IQ \< 70;
• Female patients who are pregnant, lactating or not using an acceptable effective form contraception if they are at risk of falling pregnant;
• Taking part in another pharmacological trial.

Sponsors & Collaborators

• University of Udine: lead
• National Research Council (CNR), Institute of Biomolecular Chemistry (ICB), Italy: collaborator

Study Sites (2)

Unit of Psychiatry, University Hospital of Udine

Udine, UD, 33100, Italy

RECRUITING

Unit of Psychiatry, University Hospital of Udine

Udine, 33100, Italy

RECRUITING

Related Publications (1)

• Bortoletto R, Garzitto M, Basaldella M, Scipioni C, Sepulcri O, Fabris M, Curcio F, Balestrieri M, Colizzi M. Effects of palmitoylethanolamide in clinical high-risk for psychosis: A nonrandomized open-label trial. Brain Behav Immun Health. 2025 Nov 22;50:101141. doi: 10.1016/j.bbih.2025.101141. eCollection 2025 Dec.

  PMID: 41378189 DERIVED

Related Links

• Questioning the role of palmitoylethanolamide in psychosis: a systematic review of clinical and preclinical evidence
• Therapeutic effect of palmitoylethanolamide in cognitive decline: A systematic review and preliminary meta-analysis of preclinical and clinical evidence
• Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia
• Childhood trauma and being at-risk for psychosis are associated with higher peripheral endocannabinoids

MeSH Terms

Conditions

Schizophrenia

Condition Hierarchy (Ancestors)

Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders

Study Officials

• Marco Colizzi, MD, PhD

  University of Udine

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Marco Colizzi, MD, PhD

CONTACT

+390432559155; marco.colizzi@uniud.it

Riccardo Bortoletto, MD

CONTACT

+393484739255; bortoletto.riccardo@spes.uniud.it

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: We will evaluate the study viability through an internal pilot that will assess the ability of the study to identify, consent, and follow up CHR patients experiencing APS in the study. We propose a 12-week, open-label, investigator-initiated proof of concept study (Phase-2 Pilot Study) of PEA (600 mg/day) for the treatment of APS in CHR patients. We plan to enrol 20 CHR young adults. Those completing the 12-week initial phase, will be proposed to enter a 24-week extension phase to evaluate the clinical stability of treatment, with the possibility of PEA titration to 1200 mg/day based on clinical improvement obtained so far.

Study Record Dates

• First Submitted: September 7, 2023
• First Posted: September 14, 2023
• Study Start: November 1, 2022
• Primary Completion: November 1, 2024
• Study Completion: November 1, 2025
• Last Updated: September 21, 2023

Record last verified: 2023-09

Locations

IT (2)