Migra Well

PEA Science: An Overview of Palmitoylethanolamide in Pain and Beyond

Palmitoylethanolamide (PEA) is an endocannabinoid-like lipid mediator that has been gaining increasing attention in the management of pain and inflammation. First isolated in the 1950s as an anti-viral agent, PEA was later recognized for its potent analgesic and anti-inflammatory properties. Today, it is available in Europe as a “Food for Special Medical Purposes” and more recently as a dietary supplement across the globe. Research now positions PEA as a safe and promising adjunctive therapy for chronic pain and related conditions.

Poster Presented at Painweek September 4, 2025 Las Vegas, Nevada

PEA Mechanisms of Action

How PEA Works

PEA is unique in that it does not bind directly to classical cannabinoid receptors like THC or CBD. Instead, it acts through several overlapping mechanisms:
• Indirect Cannabinoid Modulation (Entourage Effect): Reduces breakdown of anandamide, enhancing CB1 and CB2 activity.
• PPAR-α Activation: Suppresses pro-inflammatory cytokines (TNF-α, IL-1β).
• TRPV1 Desensitization: Reduces neurogenic inflammation and peripheral sensitization.
• Mast Cell & Glial Cell Stabilization: Decreases neuroinflammation and central sensitization.

Evidence Across Clinical Conditions

Migraine
Several clinical trials have demonstrated benefit for migraine. A 2024 double-blind RCT (Briskey et al.) showed that Levagen+ (a highly bioavailable PEA formulation) significantly reduced pain duration and medication use in otherwise healthy migraine patients. A 2025 trial (Piccolo et al.) reported that a fixed combination of PEA and melatonin was effective in preventive therapy. Pediatric use has also been explored: Papetti et al. (2020) found PEA well tolerated in children with migraine.

Neuropathy
Neuropathic pain is where PEA has been most extensively studied. A 2022 RCT (Pickering et al.) showed significant improvement in diabetic peripheral neuropathy. A 2024 multicenter trial (Didangelos et al.) combining PEA with alpha-lipoic acid, vitamins, and minerals further improved neuropathic outcomes. In chronic inflammatory demyelinating polyneuropathy (CIDP), Cocito et al. (2024) found ultramicronized PEA effective. Chemotherapy-induced peripheral neuropathy (CIPN) has shown mixed results: a 2024 phase II pilot (Davis et al.) suggested some efficacy.

Fibromyalgia
Fibromyalgia management has benefited from combination approaches. Salaffi et al. (2023) reported that PEA plus acetyl-L-carnitine potentiated the effects of duloxetine and pregabalin. A 2024 pilot study (Terribili et al.) using PEA with melatonin improved pain, sleep, and disability scores, highlighting PEA’s synergistic potential.

Musculoskeletal Pain & Arthritis
In musculoskeletal conditions, Steels et al. (2019) conducted a double-blind placebo-controlled trial showing PEA improved pain and stiffness in knee osteoarthritis. Meta-analyses also support its role: Lang-Illievich et al. (2023) and Schweiger et al. (2024) systematically reviewed RCTs and concluded that micronized and ultramicronized PEA significantly reduce pain intensity.

Summary of Benefit Across Pain Conditions

In a systematic review & meta-analysis of umPEA in chronic pain, Schweiger V et al. (2024) noted a significant decrease in pain level (VAS) representing a 35% reduction in pain intensity the first month of treatment with an addition 35.4% reduction in month two. 

Pain reduction with PEA

Dosing Recommendations

Across clinical studies, the most commonly used dosage is between 600 and 1200 mg per day.  Micronized and ultramicronized formulations (mPEA, umPEA) show enhanced bioavailability and may achieve greater clinical benefit at lower doses.
In practice:

Standard dose: 600–1200 mg/day
Formulation: Micronized or ultramicronized preferred
Adjunctive use: May be combined with melatonin, alpha-lipoic acid, or carnitine
Add-on benefit: When utilized in conjunction with prescription medications including gapapentin  duloxetine
Safety: Well tolerated across adult and pediatric populations, with no major safety concerns even in long-term use.

Conclusions

Palmitoylethanolamide (PEA) represents a unique, multi-targeted compound that bridges gaps in pain management. By modulating endocannabinoid tone, calming glial and mast cell activity, and reducing neuroinflammation, PEA addresses core mechanisms of chronic pain that traditional drugs often leave untouched. Clinical evidence supports its benefit in migraine, neuropathy, fibromyalgia, and musculoskeletal pain. While more research is needed to optimize formulations, dosing strategies, and co-administration protocols, PEA already stands as a safe, well-tolerated, and effective adjunctive therapy.

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References

  1. Clayton P, Hill M, Bogoda N, Subah S, Venkatesh R. Palmitoylethanolamide: A Natural Compound for Health Management. Int J Mol Sci. 2021;22(10):5305. Published 2021 May 18. doi:10.3390/ijms22105305
  2. Keppel Hesselink JM, de Boer T, Witkamp RF. Palmitoylethanolamide: A Natural Body-Own Anti-Inflammatory Agent, Effective and Safe against Influenza and Common Cold. Int J Inflam. 2013;2013:151028. doi:10.1155/2013/151028
  3. Kuehl FA, Jacob TA, Ganley OH, Ormond RE, Meisinger MAP (1957) The identification of N-(2-hydroxyethyl)-palmitide as a naturally occurring anti-inflammatory agent. J Am Chem Soc 79: 5577-5578.
  4. Briskey D, Skinner R, Smith C, Rao A. Effectiveness of Palmitoylethanolamide (Levagen+) Compared to a Placebo for Reducing Pain, Duration, and Medication Use during Migraines in Otherwise Healthy Participants-A Double-Blind Randomised Controlled Study. Pharmaceuticals (Basel). 2024;17(2):145. Published 2024 Jan 23. doi:10.3390/ph17020145
  5. Piccolo V, Marzocchi A, Maisto M, Summa V, Tenore GC, Amoresano A. Fixed combination of palmitoylethanolamide and melatonin in preventive therapy of migraine: results from a randomized clinical trial. Front Nutr. 2025;12:1560654. Published 2025 Apr 10. doi:10.3389/fnut.2025.1560654
  6. Papetti L, Sforza G, Tullo G, et al. Tolerability of Palmitoylethanolamide in a Pediatric Population Suffering from Migraine: A Pilot Study. Pain Res Manag. 2020;2020:3938640. Published 2020 Apr 24. doi:10.1155/2020/3938640
  7. Pickering E, Steels EL, Steadman KJ, Rao A, Vitetta L. A randomized controlled trial assessing the safety and efficacy of palmitoylethanolamide for treating diabetic-related peripheral neuropathic pain. Inflammopharmacology. 2022;30(6):2063-2077. doi:10.1007/s10787-022-01033-8
  8. Didangelos T, Karlafti E, Kotzakioulafi E, et al. Efficacy and Safety of the Combination of Palmitoylethanolamide, Superoxide Dismutase, Alpha Lipoic Acid, Vitamins B12, B1, B6, E, Mg, Zn and Nicotinamide for 6 Months in People with Diabetic Neuropathy. Nutrients. 2024;16(18):3045. Published 2024 Sep 10. doi:10.3390/nu16183045
  9. Cocito D, Peci E, Torrieri MC, Clerico M. Ultramicronized Palmitoylethanolamide in the Management of Neuropathic Pain Related to Chronic Inflammatory Demyelinating Polyneuropathy: A Proof-of-Concept Study. J Clin Med. 2024;13(10):2787. Published 2024 May 9. doi:10.3390/jcm13102787
  10. Davis MP, Ulrich A, Segal R, et al. Treatment of Established Chemotherapy-Induced Neuropathy with N-Palmitoylethanolamide: A Randomized, Double-Blind Phase II Pilot Study. Cancers (Basel). 2024;16(24):4244. Published 2024 Dec 20. doi:10.3390/cancers16244244
  11. Terribili R, Vallifuoco G, Bardelli M, Frediani B, Gentileschi S. A Fixed Combination of Palmitoylethanolamide and Melatonin (PEATONIDE) for the Management of Pain, Sleep, and Disability in Patients with Fibromyalgia: A Pilot Study. Nutrients. 2024; 16(16):2785. https://doi.org/10.3390/nu16162785
  12. Salaffi F, Farah S, Sarzi-Puttini P, Di Carlo M. Palmitoylethanolamide and acetyl-L-carnitine act synergistically with duloxetine and pregabalin in fibromyalgia: results of a randomised controlled study. Clin Exp Rheumatol. 2023;41(6):1323-1331. doi:10.55563/clinexprheumatol/pmdzcq
  13. Steels E, Venkatesh R, Steels E, Vitetta G, Vitetta L. A double-blind randomized placebo controlled study assessing safety, tolerability and efficacy of palmitoylethanolamide for symptoms of knee osteoarthritis. Inflammopharmacology. 2019;27(3):475-485. doi:10.1007/s10787-019-00582-9
  14. Lang-Illievich K, Klivinyi C, Lasser C, Brenna CTA, Szilagyi IS, Bornemann-Cimenti H. Palmitoylethanolamide in the Treatment of Chronic Pain: A Systematic Review and Meta-Analysis of Double-Blind Randomized Controlled Trials. Nutrients. 2023; 15(6):1350. https://doi.org/10.3390/nu15061350
  15. Schweiger, V., Schievano, C., Martini, A., Polati, L., Del Balzo, G., Simari, S., Milan, B., Finco, G., Varrassi, G., & Polati, E. (2024). Extended Treatment with Micron-Size Oral Palmitoylethanolamide (PEA) in Chronic Pain: A Systematic Review and Meta-Analysis. Nutrients, 16(11), 1653. https://doi.org/10.3390/nu16111653