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

Background: The endocannabinoid system (ECS) is a key regulator of mood homeostasis, but its longitudinal dynamics during an acute manic episode until the clinical recovery in bipolar disorder (BD) and the specific influence of cannabis use remain poorly characterized. Methods: We conducted a longitudinal study of 23 patients with BD I followed from acute mania (T0) to clinical stabilization (T1). Plasma AEA and 2-AG were quantified via LC-MS/MS at T0 and T1. Patients were divided into cannabis users and non-cannabis users for further analyses. Linear mixed-effects models assessed the interaction between cannabis use and timepoint on endocannabinoid (eCB) trajectories. Results: Non-cannabis users exhibited a significant decline in both anandamide (AEA) and 2-arachidonoglycerol (2-AG) levels during the transition to euthymia (p < 0.05). In contrast, cannabis users showed a disrupted trajectory with no significant reduction in eCB tone despite clinical improvement (Cannabis x Timepoint interaction: AEA p = 0.016; 2-AG p = 0.029). In both groups of BD patients, eCB levels were not associated with sociodemographic factors and symptom severity measured by Young Mania Rating Scale (YMRS). Conclusions: Our findings suggest that circulating eCBs (AEA and 2-AG) may serve as a key state-transition biomarker from mania to clinical stabilization in BD. This intrinsic regulation could be disrupted by cannabis use, which might hinder recovery from manic episodes. Specifically addressing cannabis use and monitoring eCBs levels may play a crucial role to help returning to a biological balance and may support clinical stability in BD patients.