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A RANDOMIZED, PLACEBO-CONTROLLED TRIAL OF THE FATTY ACID AMIDE HYDROLASE INHIBITOR PALMITOYLETHANOLAMIDE IN BIPOLAR DEPRESSION

Rodrigo Machado-Vieira — Alan C. Courtes2, Ana C. Ruiz3, Abdul Hasseb3, Lokesh Shahani4, Jair Soares5, Scott D. Lane6 1McGovern Medical School, University of Texas Science Center in Houston, 2Louis A. Faillace, McGovern Medical School at UTHealth Houston, 3University of Texas, UTHealth Houston, 4Louis Faillace, McGovern Medical School, University of Texas Health Center, 5University of Texas School of Medicine at Houston, 6The University of Texas Health Science Center at Houston Rodrigo Machado-Vieira, McGovern Medical School, University of Texas Science Center in Houston

2026 ASCP Annual Meeting

There is growing interest in the endocannabinoid system (ECS) as an alternative signaling pathway involved in mood disorders. In response to stressors such as mood episodes, the breakdown of endocannabinoids by the Fatty Acid Amide Hydrolase (FAAH), a degrading enzyme located in the somatodendritic compartments of neurons, reduces endocannabinoid levels and increases HPA stress and inflammation. Higher FAAH breakdown has been described in subjects with depression, PTSD, and suicide ideation. Thus, FAAH inhibition may also represent a unique, valuable target in the therapeutics of Bipolar Depression. Palmitoylethanolamide (PEA) is an FAAH inhibitor, a member of the extended endocannabinoid family. PEA significantly increases the levels of key endocannabinoids (ECs), such as anandamide (AEA), and, through the so-called entourage effect, indirectly activates CB1 receptors. PEA also has shown potent anti-inflammatory and antioxidant effects in humans. Lower PEA levels were observed in depression, inversely associated with depressed mood, diminished interest/pleasure, and psychomotor retardation. In Depression, the first clinical trial examining the antidepressant effects of PEA (600 mg twice daily for six weeks, double-blind, placebo-controlled design) showed a significant improvement in depression scores compared to placebo. The PEA group showed a rapid onset and significantly greater improvements in depressive symptoms score from week 2 compared to the placebo group. The objective of this 6-week, double-blind, placebo-controlled study is to evaluate the antidepressant efficacy of the PEA in Bipolar Depression and the association between antidepressant response with endogenous cannabinoids and cytokines (PEA, AEA, 2-AG, OEA; TNF, IL2, 4, 6, 10, 12). Outpatients with BD in a depressive episode will be followed up for six weeks, with baseline, week 2, 4, and endpoint (post-treatment) assessments. Two groups will be randomized: treatment as usual (TAU, mood stabilizer) plus placebo (n=25) versus TAU plus PEA (600mg/day bid) (n=25). Overall, PEA showed a significant improvement of depressive symptoms in 6 weeks, but not statistically different from placebo. Further studies are warranted.