ABSTRACT Objective Endocannabinoids are involved in biological processes relevant to mood regulation, and altered circulating levels have been reported in bipolar disorder (BD). However, serum endocannabinoid levels have not previously been examined across mania and remission within the same patients and compared with healthy controls. This study evaluated serum palmitoylethanolamide (PEA), oleoylethanolamide (OEA), 2-arachidonoylglycerol (2-AG), anandamide (AEA), and C-reactive protein (CRP) levels in patients with BD during manic episodes and remission and in healthy controls. Methods Fifty-one patients diagnosed with BD, manic episode, according to DSM-5-TR criteria, and 49 healthy controls were included. After discharge, 32 patients who attended outpatient follow-up visits were re-evaluated during remission. Serum PEA, OEA, 2-AG, AEA, and CRP levels were measured in all participants. Patients with BD were additionally assessed using the Young Mania Rating Scale, Hamilton Depression Rating Scale, and Positive and Negative Syndrome Scale. Results Serum PEA and OEA levels were significantly lower during manic episodes than in healthy controls. During remission, serum PEA and OEA levels did not differ significantly from those of healthy controls. In within-patient comparisons between manic episodes and remission, only serum PEA levels were significantly lower during manic episodes. Conclusion This is the first study to assess serum endocannabinoid levels in patients with BD during both manic episodes and remission, together with healthy controls. PEA and OEA levels were significantly lower during mania and returned to values comparable to healthy controls during remission. These findings suggest that endocannabinoid-related mechanisms may have potential as future biomarkers and therapeutic targets in mood regulation.
