Feature Summary

Palmitoylethanolamide (PEA) is an endogenously produced lipid that mediates the resolution of neuroinflammation and clinically reduces pain from a variety of sources.^1,2,3 PEA is a type of fatty acid ethanolamine produced in microglia and mast cells, where it downregulates the activation of both cell types; levels of PEA are increased in brain areas involved in nociception, and appear to modulate protective responses to both inflammation and pain.⁴ Its effects are mediated via direct activation of PPAR-a and GPR55 receptors, and potentially by indirect activation of CB1 and CB2 receptors and the TRPV1 channel (i.e., the capsaicin receptor).^5,6

In clinical trials, PEA has been shown to reduce pain levels from a variety of chronic conditions (of at least 6 months duration) where pain was not controlled by standard therapies, demonstrating effectiveness both alone and when combined with standard treatments.⁷ PEA has been shown to be efficacious for pain resulting from nerve compression syndromes, including sciatica and carpal tunnel syndrome.⁸ Randomized trials have also shown benefit for pain control for specific conditions, including TMJ,⁹ as well as for depressive symptoms in major depressive disorder when used in conjunction with antidepressants.¹⁰ In addition, PEA has been shown to improve endothelial function and reduce intraocular pressure among patients with ocular hypertension.^11,12

1. Skaper, S.D., Facci, L., Barbierato, M., et al. (2015). N-Palmitoylethanolamine and neuroinflammation: a novel therapeutic strategy of resolution. Molecular Neurobiology, 52(2),1034–1042. PMID: 26055231
2. Artukoglu, B.B., Beyer, C., Zuloff-Shani, A., et al. (2017). Efficacy of palmitoylethanolamide for pain: a meta-analysis. Pain Physician, 20(5), 353–362. PMID: 28727699
3. Paladini, A., Fusco, M., Cenacchi, T., et al. (2016). Palmitoylethanolamide, a special food for medical purposes, in the treatment of chronic pain: a pooled data meta-analysis. Pain Physician, 19(2), 11–24. PMID: 26815246
4. Skaper, S.D., Facci, L., et al. (2012). Mast cell-glia axis in neuroinflammation and therapeutic potential of the anandamide congener palmitoylethanolamide. Philosophical Transactions of the Royal Society of London Series B, Biological Sciences, 367(1607), 3312–3325. PMID: 23108549
5. Rinne, P., Guillamat-Prats, R., Rami, M., et al. (2018). Palmitoylethanolamide promotes a proresolving macrophage phenotype and attenuates atherosclerotic plaque formation. Arteriosclerosis, Thrombosis, and Vascular Biology, 38(11), 2562–2575. PMID: 30354245
6. Petrosino, S.& Di Marzo, V. (2017). The pharmacology of palmitoylethanolamide and first data on the therapeutic efficacy of some of its new formulations. British Journal of Pharmacology, 174(11), 1349–1365. PMID: 27539936
7. Gatti, A., Lazzari, M., et al. (2012). Palmitoylethanolamide in the treatment of chronic pain caused by different etiopathogenesis. Pain Medicine, 13(9), 1121–1130. PMID: 22845893
8. Keppel Hesselink, J.M. & Kopsky, D.J. (2015). Palmitoylethanolamide, a neutraceutical, in nerve compression syndromes: efficacy and safety in sciatic pain and carpal tunnel syndrome. Journal of Pain Research, 8, 729–734. PMID: 26604814
9. Marini, I., Bartolucci, M.L., et al. (2012). Palmitoylethanolamide versus a nonsteroidal anti-inflammatory drug in the treatment of temporomandibular joint inflammatory pain. Journal of Orofacial Pain, 26(2), 99–104. PMID: 22558609
10. Ghazizadeh-Hashemi, M., Ghajar, A., et al. (2018). Palmitoylethanolamide as adjunctive therapy in major depressive disorder: A double-blind, randomized and placebo-controlled trial. Journal of Affective Disorders, 232, 127–133. PMID: 29486338
11. Strobbe, E., Cellini, M., & Campos, E.C. (2013). Effectiveness of palmitoylethanolamide on endothelial dysfunction in ocular hypertensive patients: a randomized, placebo-controlled cross-over study. Investigative Ophthalmology & Vision Science, 54(2), 968–973. PMID: 23307959
12. Gagliano, C., Ortisi, E., Pulvirenti, L., et al. (2011). Ocular hypotensive effect of oral palmitoyl-ethanolamide: a clinical trial. Investigative Ophthalmology & Vision Science, 52(9), 6096–6100. PMID: 21705689
13. Nestmann, E.R. (2016). Safety of micronized palmitoylethanolamide (microPEA): lack of toxicity and genotoxic potential. Food Science Nutrition, 5(2), 292–309. PMID: 28265364