Role of palmitoylethanolamide (PEA) in depression: Translational evidence: Special Section on “Translational and Neuroscience Studies in Affective Disorders”. Section Editor, Maria Nobile MD, PhD. This Section of JAD focuses on the relevance of translational and neuroscience studies in providing a better understanding of the neural basis of affective disorders. The main aim is to briefly summaries relevant research findings in clinical neuroscience with particular regards to specific innovative topics in mood and anxiety disorders

Background: Antidepressants have a low rate of response paired with a delayed onset of action. Translational studies are thus seeking for novel targets for antidepressant drug development. Preclinical evidence has demonstrated that the endocannabinoid system plays an important role in mood and stress response, even if drugs targeting this system have not yet become available for clinical use. The dietary supplement N-Palmitoylethanolamide (PEA) is a fatty acid amide belonging to the endocannabinoid system with potential antidepressant properties. Methods: We performed a bibliographic search to review current knowledge on the potential antidepressant effects of PEA and its underlying mechanism of action. Results: PEA targets not only the peroxisome proliferator-activated receptor-alpha (PPAR-α), but also the endocannabinoid system, binding the G-protein-coupled receptor 55, a non-CB₁/CB₂ cannabinoid receptor, and also the CB₁/CB₂ receptors, although with a weak affinity. Preclinical studies have shown antidepressant activity of PEA in animal paradigms of depression and of depression associated with neuropathic pain and traumatic brain injury. In a translational perspective, PEA is increased in stress conditions, and a randomized, double-blind study in depressed patients indicated a fast-antidepressant action of PEA when associated with citalopram. Limitations: There are still limited preclinical and clinical studies investigating the effect of PEA upon the endocannabinoid system and its potential as antidepressant. Conclusions: PEA has potential antidepressant effects alone or in combinations with other classes of antidepressants. Future studies in depressed patients are needed to confirm the mood-modulating properties of PEA and its role as a biomarker of depression.