Plasma endocannabinoid levels in bipolar disorder: Differences between manic and euthymic states and the impact of cannabis use.

Ochandiano I.; Powlowski P.; Andreu H.; Olivier L.; Cabeza G.; Gimenez-Palomo A.; Guitart M.; Garrabou G.; Escelsior A.; Bioque M. et al. · Journal of affective disorders · 2026

**Background & Methods** This longitudinal study followed 23 patients with bipolar I disorder from acute manic episodes (T0) to clinical stabilization (T1), with plasma endocannabinoid levels (anandamide [AEA] and 2-arachidonoglycerol [2-AG]) measured via LC-MS/MS at both timepoints. Patients were stratified by cannabis use status, and linear mixed-effects models evaluated the interaction between cannabis use and disease state on endocannabinoid trajectories. **Key Findings** - Non-cannabis users demonstrated significant decline in both AEA and 2-AG levels during transition from acute mania to euthymia (p < 0.05), suggesting endocannabinoid downregulation may be a biological marker of mood stabilization in bipolar disorder. - Cannabis users exhibited disrupted endocannabinoid trajectories with no significant reduction in AEA or 2-AG despite clinical improvement (Cannabis × Timepoint interaction: AEA p = 0.016; 2-AG p = 0.029), indicating cannabis use may interfere with normal mood-regulating endocannabinoid homeostasis. - Endocannabinoid levels showed no significant association with sociodemographic factors or symptom severity measured by Young Mania Rating Scale (YMRS) in either group, suggesting eCB changes reflect state-specific biological recovery rather than symptom intensity. **Dosage & Administration** Not reported. Cannabis use was assessed categorically (user vs. non-user status) without quantification of frequency, dose, or cannabinoid composition. **Safety & Adverse Effects** Not reported. The study did not evaluate adverse effects or safety outcomes in either cannabis users or non-cannabis users with bipolar disorder. **Evidence Quality** This study represents preliminary longitudinal evidence but has notable limitations reducing generalizability. The small sample size (n = 23) limits statistical power and clinical applicability. The study lacks detail on cannabis use characteristics (frequency, duration, potency), concurrent medications, or psychosocial interventions that could confound results. Absence of healthy control comparison groups prevents determination of whether observed eCB patterns are bipolar disorder-specific. The mechanism by which cannabis disrupts normal eCB regulation requires further investigation. While the state-transition biomarker hypothesis is novel, findings require replication in larger, prospective cohorts with standardized cannabis exposure assessment before clinical implementation for patient monitoring or treatment guidance.