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

Martinez-Sadurni L.; Toll A.; Olivares-Berjaga D.; Rodriguez N.; Martínez-Pinteño A.; Haro J.; Trabsa A.; Bergé D.; Sola V.; Mané A. · Psychiatry research · 2026

**Background & Methods** This prospective cohort study measured baseline plasma endocannabinoid concentrations (anandamide [AEA] and 2-arachidonoylglycerol [2-AG]) in 58 antipsychotic-naïve first-episode psychosis (FEP) patients and examined associations with clinical outcomes and cannabis use at one-year follow-up. Psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS), cannabis use was quantified via Standard Joint Units (THC consumption), and associations were analyzed using correlation and regression analyses adjusted for relevant covariates. **Key Findings** • Higher baseline plasma AEA concentrations were significantly associated with lower general psychopathology scores at one-year follow-up, suggesting a protective effect on overall symptom burden in early psychosis. • No significant associations were found between endocannabinoid concentrations and total PANSS scores or positive and negative symptom subscales specifically, indicating domain-specific rather than global effects. • Age emerged as the primary predictor of cannabis use at follow-up, while 2-AG showed a non-significant trend toward increased likelihood of cannabis use, with endocannabinoid concentrations demonstrating limited predictive value for substance use trajectories. **Dosage & Administration** Not reported. **Safety & Adverse Effects** Not reported. **Evidence Quality** This study is limited by its modest sample size (n=58), which may restrict generalizability and statistical power to detect meaningful associations. The cross-sectional baseline assessment of endocannabinoid concentrations limits causal inference regarding their prognostic value. The mechanism underlying AEA's association with general psychopathology—potentially involving stress- and anxiety-related symptom domains rather than core positive/negative symptoms—remains speculative and requires mechanistic investigation. The non-significant trend for 2-AG and cannabis use suggests underpowered analyses for this outcome. As an observational cohort study without randomized intervention, the evidence level is moderate (level 3). The authors appropriately acknowledge that further studies are needed to clarify endocannabinoid involvement in clinical outcomes and substance use trajectories during early psychosis phases, suggesting cautious interpretation pending larger, mechanistically-focused investigations.

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