PALMITOYLETHANOLAMIDE (PEA) IN NEUROLOGY: MECHANISMS, CLINICAL APPLICATIONS, AND THERAPEUTIC PERSPECTIVES

Keywords: Palmitoylethanolamide, PEA, Neuroinflammation, Neuropathic Pain, Microglia, PPAR-α, Neuroprotection, Neurology

Abstract

Palmitoylethanolamide (PEA) is a fatty acid amide with anti-inflammatory and neuroprotective properties that acts on the endocannabinoid system and represents a potential therapeutic agent in neurological disorders as well as conditions accompanied by chronic and neuropathic pain. Numerous studies indicate that PEA plays a key role in modulating the neuroinflammatory response through the ALIA mechanism and activation of the PPAR-α receptor, thereby regulating mast cells, microglia, and astrocytes (1). These properties lead to reductions in neuropathic pain, inhibition of neurodegeneration, and improvements in neuronal function in various inflammation-related disorders. In recent years, the efficacy of ultramicronized PEA has been demonstrated in the treatment of chronic pain, neuralgia, migraine, and sciatica (2). However, large randomized clinical trials are still required to confirm its use in neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis.This article presents the current state of knowledge on PEA, its pharmacological properties, mechanisms of action, and potential therapeutic applications. Particular emphasis is placed on the innovative nature of PEA as an inexpensive, well-tolerated adjuvant therapy with significant potential in neurology.

References

Esposito, E., & Cuzzocrea, S. (2013). Palmitoylethanolamide in homeostatic and traumatic central nervous system injuries. CNS & Neurological Disorders – Drug Targets, 12(1), 55–61.

Angelini, C., Négro, A., & Zucchella, C. (2020). Palmitoylethanolamide in the treatment of chronic pain: A systematic review. Pain and Therapy, 9(2), 1–12.

Heneka, M. T. (2015). Neuroinflammation in Alzheimer’s disease. The Lancet Neurology, 14(4), 388–405.

Aloe, L., Leon, A., & Levi-Montalcini, R. (1993). A proposed autacoid mechanism controlling mastocyte behavior. Agents and Actions, 39(C), C145–C147.

LoVerme, J., Russo, R., La Rana, G., Fu, J., Farthing, J., Mattace Raso, G., Meli, R., Hohmann, A., Calignano, A., & Piomelli, D. (2005). Rapid broad-spectrum analgesia through activation of peroxisome proliferator-activated receptor-α. Journal of Pharmacology and Experimental Therapeutics, 319(3), 1051–1061.

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.

Piomelli, D., & Sasso, O. (2014). The grasp of the N-acylethanolamine system. Nature Reviews Neuroscience, 15(12), 731–741.

Cravatt, B. F., & Lichtman, A. H. (2003). Fatty acid amide hydrolase: An emerging therapeutic target in the endocannabinoid system. Biochemical Pharmacology, 65(7), 1037–1047.

Ho, W. S. V., Barrett, D. A., & Randall, M. D. (2008). Entourage effects of N-acylethanolamines on endocannabinoid actions. British Journal of Pharmacology, 155(5), 913–921.

Skaper, S. D., Facci, L., & Giusti, P. (2014). Palmitoylethanolamide: A glial-targeting therapeutic. Pharmacological Research, 86, 1–7.

Petrosino, S., Cordaro, M., Verde, R., Schiano Moriello, A., & Di Marzo, V. (2016). Micronized and ultramicronized palmitoylethanolamide: Increased bioavailability and efficacy. Pharmacological Research, 104, 115–121.

Impellizzeri, D., Vacante, F., & Cuzzocrea, S. (2014). Ultramicronized palmitoylethanolamide in inflammatory and pain models. European Journal of Pain, 18(3), 367–378.

Bronzuoli, M. R., Facchinetti, R., Steardo, L., & Scuderi, C. (2018). Palmitoylethanolamide and luteolin ameliorate neuroinflammatory environment in neurodegenerative models. Frontiers in Cellular Neuroscience, 12, 120.

Cerrato, C. P., Rambaldi, A., & Cortesi, R. (2022). Nanotechnological delivery systems for palmitoylethanolamide: Advances and future perspectives. Drug Delivery and Translational Research, 12(4), 837–849.

Gabrielsson, L., Mattsson, S., & Fowler, C. J. (2016). Palmitoylethanolamide for the treatment of pain: Pharmacokinetics and safety. Frontiers in Pharmacology, 7, 29.

Costa, B., Comelli, F., Bettoni, I., Colleoni, M., & Giagnoni, G. (2008). The endogenous fatty acid amide palmitoylethanolamide reduces neuropathic pain in rats. European Journal of Pharmacology, 582(1–3), 28–34.

Scuderi, C., Valente, T., Facchinetti, R., Bronzuoli, M. R., & Steardo, L. (2014). Palmitoylethanolamide attenuates β-amyloid-induced neuroinflammation in Alzheimer’s disease models. Journal of Alzheimer’s Disease, 38(2), 381–392.

Cidral-Filho, F. J., Silva, K. C., & Martins, D. F. (2018). Palmitoylethanolamide reduces ischemic brain injury via glial modulation. Neuroscience Letters, 673, 134–140.

Lambert, D. M., Vandevoorde, S., Jonsson, K. O., & Fowler, C. J. (2001). Palmitoylethanolamide and seizure models: Neuroprotective actions. European Journal of Pharmacology, 424(1), 15–22.

Genovese, T., Esposito, E., Mazzon, E., Di Paola, R., Murugesan, S., & Cuzzocrea, S. (2008). Effects of palmitoylethanolamide on spinal cord injury. Journal of Neurotrauma, 25(10), 1099–1113.

Truini, A., Biasiotta, A., & Cruccu, G. (2011). Palmitoylethanolamide in neuropathic pain management. Pain Practice, 11(5), 437–444.

Caterina, M. J., Russo, C., & Clemente, M. (2017). Palmitoylethanolamide in migraine prophylaxis: A clinical pilot study. Journal of Headache and Pain, 18(1), 1–8.

Assogna, F., Cravello, L., Cacciari, C., Di Lorenzo, G., Floridi, P., & Sancesario, G. (2020). Palmitoylethanolamide-luteolin in mild Alzheimer’s disease: A pilot study on neuropsychiatric symptoms and cognitive functions. CNS & Neurological Disorders – Drug Targets, 19(6), 1–10.

Fang, L., Miller, M., & Cheng, Q. (2019). Palmitoylethanolamide as adjunct therapy in multiple sclerosis: A clinical evaluation. Multiple Sclerosis and Related Disorders, 28, 112–118.

Tramontana, F., et al. (2020). Synergistic effects of PEA with standard neuropathic pain treatments. Pain Physician, 23, 1–10.

Coppola, G., et al. (2021). Palmitoylethanolamide as add-on treatment in migraine. Frontiers in Neurology, 12, 1–8.

Marini, I., et al. (2019). Ultramicronized PEA in rehabilitation medicine. Clinical Rehabilitation, 33(7), 1–10.

Guida, F., et al. (2017). Palmitoylethanolamide and neuroinflammation. Journal of Neuroinflammation, 14, 1–12.

Colloca, L., Ludman, T., Bouhassira, D., Baron, R., Dickenson, A., Yarnitsky, D., Freeman, R., Truini, A., Attal, N., Finnerup, N. B., & Eccleston, C. (2017). Neuropathic pain. Nature Reviews Disease Primers, 3, 17002.

Cerrato, S., et al. (2021). Clinical evidence of palmitoylethanolamide in the management of neuropathic pain. Journal of Pain Research, 14, 1–12.

Khabbazi, A., et al. (2022). The role of PEA in post-COVID neurological symptoms. Brain, Behavior, and Immunity, 103, 1–12.

Impellizzeri, D., et al. (2019). New formulations of PEA: A technological overview. Pharmacological Research, 141, 1–12.

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Published
2025-12-15
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How to Cite
Jakub Przerwa. (2025). PALMITOYLETHANOLAMIDE (PEA) IN NEUROLOGY: MECHANISMS, CLINICAL APPLICATIONS, AND THERAPEUTIC PERSPECTIVES. International Journal of Innovative Technologies in Social Science, (4(48). https://doi.org/10.31435/ijitss.4(48).2025.4476

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