Longitudinal changes in endocannabinoids and clinical course of adolescent non-suicidal self-injury.

Ferger M.; Brodesser S.; Kaess M.; Koenig J. · Translational psychiatry · 2026

**Background & Methods** This longitudinal cohort study examined 47 female adolescents with non-suicidal self-injury (NSSI) at baseline and after one year of treatment. Plasma endocannabinoid levels (anandamide and 2-arachidonoylglycerol) were measured and analyzed in association with NSSI symptom severity using the German Self-Injurious Thoughts and Behaviors Interview (SITBI-G). **Key Findings** • Anandamide (AEA) levels significantly decreased from baseline to follow-up over the one-year period, while 2-arachidonoylglycerol (2-AG) levels increased, indicating dynamic changes in the endocannabinoid system during treatment. • Despite overall clinical improvement in NSSI symptoms over the year, AEA levels continued to decline, suggesting a dissociation between endocannabinoid trajectories and symptom improvement. • Complex and partly inconsistent associations between circulating endocannabinoid levels and clinical symptoms were identified, limiting their utility as reliable biomarkers for monitoring treatment response or predicting symptom trajectories in adolescent NSSI. **Dosage & Administration** Not reported. **Safety & Adverse Effects** Not reported. **Evidence Quality** This study represents the first longitudinal investigation of endocannabinoids in adolescent NSSI, providing novel longitudinal data that extends prior cross-sectional findings. However, significant limitations reduce evidence quality: the sample size is modest (n=47), the population is restricted to females, limiting generalizability to male adolescents with NSSI. The one-year follow-up period may be insufficient to capture longer-term endocannabinoid dynamics. The study is observational without a control group, preventing causal inference about treatment effects on endocannabinoid levels. The counterintuitive finding that AEA decreased despite symptom improvement raises questions about the biological relevance of circulating endocannabinoid measurements and suggests that peripheral biomarkers may not accurately reflect central endocannabinoid system function. The lack of detail regarding treatment type, intensity, and adherence limits interpretation of whether clinical improvements relate to specific interventions. Overall, this represents preliminary evidence suggesting endocannabinoids are unlikely to serve as reliable clinical biomarkers for NSSI in adolescents, though further research with larger, more diverse cohorts and mechanistic investigations is warranted.

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