Endocannabinoid plasma concentrations and their relationship with clinical outcome and cannabis use in antipsychotic-naïve first episode psychosis.

Disturbances in the endocannabinoid system (ECS) have been reported in psychosis, with evidence suggesting consistent alterations in N-arachidonoylethanolamine (anandamide; AEA) and inconclusive findings for 2-arachidonoylglycerol (2-AG). Lower AEA concentrations have been associated with greater symptom severity, while the relationship between ECS and cannabis use remains unclear. However, the prognostic value of peripheral endocannabinoid concentrations for clinical outcomes and cannabis use in first-episode psychosis (FEP) remains largely unknown. This study examined whether baseline plasma endocannabinoid concentrations are associated with clinical outcomes and cannabis use at one-year follow-up in antipsychotic-naïve patients with FEP. Plasma AEA and 2-AG concentrations were measured in 58 antipsychotic-naïve patients. Psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS), and cannabis use was evaluated using Standard Joint Units to estimate THC consumption. Associations were examined using correlation and regression analyses adjusted for relevant covariates. Higher baseline AEA concentrations were associated with lower general psychopathology scores at follow-up. No significant associations were observed between endocannabinoid concentrations and total PANSS scores or positive and negative symptom subscales. Age emerged as a significant predictor of cannabis use at follow-up, while 2-AG showed a non-significant trend toward a higher likelihood of use. These findings suggest that higher baseline plasma AEA concentrations may be associated with a more favourable course of general psychopathology in early psychosis, potentially reflecting ECS involvement in stress- and anxiety-related symptom domains. Further studies are warranted to clarify the role of endocannabinoids in clinical outcomes and substance use trajectories in early phases of psychosis.