P.E.A: An Anti-Inflammatory And Analgesic Secret Weapon?
- sarah8648
- 1 day ago
- 8 min read
By Sarah Bersey BSc (hons) PG Dip
Interest in preventative dietary interventions for human and pet health continue, particularly for chronic problems (Bortoletto et al 2024, Pet Pain Relief 2025). Interest in PEA (Palmitoylethanolamide) has increased over the last decade or so. The review by Bortoletto et al (2024) summarises much of this work. However, this article seeks to bring together the uses for which PEA has shown promise.
The mechanism of action: PEA (Palmitoylethanolamide) is also known as: Hydroxyethylpalmitamide, Impulsin, N-(2-Hydroxyethyl) hexadecanamide, N-(2-Hydroxyethyl) palmitamide, Palmidrol, Palmitamide MEA, Palmitic Acid Monoethanolamide and Palmitoylethanolamine. It’s a naturally occurring substance in the bodies of humans and other mammals that is an N-(long-chain-acyl) ethanolamine (see above), an endocannabinoid and a N-(saturated fatty acyl) ethanolamine. It is functionally related to a hexadecanoic acid. (WebMD 2024, Huschtscha et al 2023, National Center for Biotechnology Information 2025). As an endogenous lipid mediator in the N‑acylethanolamine family, PEA’s principal actions include:
• Activation of peroxisome proliferator-activated receptor‑α (PPAR‑α), resulting in
anti-inflammatory and analgesic effects
• Modulation of mast cells, microglia, cannabinoid receptors (CB1/CB2), TRP channels, GPR119/GPR55, and NF‑κB pathways.
(National Center for Biotechnology Information 2025)
The therapeutic potential of PEA: it is listed by the National Center for Biotechnology Information (Pub Chem) as having a role as an anti-inflammatory drug, an analgesic, an antihypertensive agent, a neuroprotective agent and an anticonvulsant.
Synthesized on demand within the lipid bilayer of cells (D’Agostino et al 2012), it acts locally (Esposito et al 2013) and is found in all tissues including the brain (Esposito et al 2013, Scuderi et al 2014). The level of PEA production in the body, in common with other essential compounds such as CoEnzyme Q10, decreases with age (Volpi et al 2004).
Examples of PEA use, trials (RCTs are randomised clinical trials) and studies are shown below:
In Humans
1. Chronic pain (Neuropathic & inflammatory)
• A 2023 systematic review and meta‑analysis of 11 randomized controlled trials (n = 774) found that PEA significantly reduced pain versus placebo or active comparators (standardized mean difference ≈ 1.68; 95% CI 1.05–2.31, p = 0.00001). There were also improvements in quality of life and functional status, with no serious side effects reported.
• Additional systematic reviews confirm these analgesic benefits across conditions such as diabetic neuropathy, sciatica, and musculoskeletal pain. (Bortoletto et al 2024)
2. Pelvic pain & Endometriosis-related pain
• In multiple observational studies, women with endometriosis-related chronic pelvic pain received a supplement combining ultra‑micronized PEA with polydatin (typically 400 mg + 40 mg twice daily). Over 3 months, significant reductions in pelvic pain, dysmenorrhea, dyspareunia, and NSAID use were reported. Effects were comparable to celecoxib in some cases. (Bortoletto et al 2024, Petrosino et al 2020)
3. Joint pain & Osteoarthritis
• Trials in temporomandibular joint (TMJ) osteoarthritis showed PEA (around 300–600 mg/day) was more effective than ibuprofen in relieving pain and improving function.
• In a knee osteoarthritis trial, high-bioavailability PEA (300–600 mg/day) led to ~40–50% pain reduction (using WOMAC index) and lowered need for rescue medication. (Bortoletto et al 2024, Petrosino et al 2020)
4. Irritable Bowel Syndrome (IBS) and pediatric IBS
• A pediatric randomized controlled trial (ages 10–17) showed co‑micronized PEA/polydatin significantly increased complete remission rates in IBS (especially diarrhea‐predominant subtype) and reduced abdominal pain frequency and intensity. No adverse events were reported over 12 weeks.
• Observational evidence also suggests potential benefits in adult IBS pain symptoms. (Bortoletto et al 2024, Cruccu 2019)
5. Inflammatory biomarker modulation across conditions
• Controlled trials in conditions such as multiple sclerosis, diabetes, periodontitis, allergic rhinitis, arthritis, irritable bowel syndrome, and COVID‑19 showed PEA intake significantly reduced inflammatory markers including IL‑1β, IL‑6, IFN‑γ, IL‑8, histamine and D‑dimer. Effects on CRP and IL‑10 were mixed. (Bortoletto et al 2024, Petrosino et al 2020 )
6. Exercise recovery and muscle injury
• In a trial of healthy adults performing resistance training, PEA (liquid formulation, ~158 mg/day) resulted in lower myoglobin and lactate markers post-exercise—suggesting reduced muscle damage and potentially improved recovery. (Bortoletto et al 2024, Petrosino et al 2020)
7: Depression and Anxiety (Emerging Area)
May support mood regulation by modulating neuro-inflammation.
(Bortoletto et al 2024)
The therapeutic benefits established to date in humans can be summarised:
Considerations & Limitations from human studies:
Many human findings derive from small trials, open-label or pilot studies. Broad RCTs (randomized clinical trials) are still limited.
Formulation, dose, and duration vary across studies; standardized protocols remain to be established.
Although well tolerated, efficacy varies by indication; more high-powered,
placebo-controlled trials are needed.
As a fat-soluble compound, bioavailability of PEA may be limited unless enough lipids are available at dosing. Some manufacturers now produce a liposomal form of PEA to enhance uptake (Bortoletto et al 2024).
PEA therapeutic use in humans has therefore been demonstrated to be effective for a surprisingly wide range of complaints. Additionally, studies have shown that well-known fat-soluble anti-inflammatories such as boswellia and curcumin (found in turmeric) can act synergistically to enhance the overall effectiveness (Henrotin et al 2021). It is reported anecdotally that PEA also demonstrates this synergistic effect as the mechanisms of action are different between these compounds (Bortoletto et al 2024).
In Animals
Similarly, a concise summary of the therapeutic uses of palmitoylethanolamide (PEA) in animals (mainly dogs, cats, and horses), based on peer‑reviewed preclinical and veterinary clinical literature:
It can be seen that PEA, particularly in ultramicronized or co-micronized forms, shows promising anti-inflammatory, analgesic, anti-pruritic, neuroprotective and organ-protective properties in animal models and early veterinary trials. The strongest evidence is for canine and feline allergic skin disease, and chronic pain/osteoarthritis (Noli et al 2021), with emerging benefits in neuropathic pain (Pet Pain Relief 2025), ocular pressure modulation, and organ protection in small animals (Novoceuticals 2025). Further high-quality, placebo‑controlled veterinary clinical trials would help confirm these benefits. it is interesting to note that animal studies have lead to a recommendation that lipid-soluble PEA is fed with a source of fat such as vegetable oil or micronised linseed (Forageplus 2025). This could be a good adage for human consumers. Additionally, anecdotal results have shown that PEA could act synergistically with other fat-soluble anti-inflammatories such as the curcumin in turmeric to enhance the overall effectiveness (Henrotin et al 2021).
Considerations & Limitations from animal studies:
Most veterinary evidence comes from open-label or small animal number trials.
While results are positive, large randomized controlled trials in clinical veterinary settings are limited.
As a fat-soluble compound, bioavailability of PEA may be limited unless enough lipids are available at dosing. Some manufacturers now produce a liposomal form of PEA to enhance uptake (Bortoletto et al 2024).
So, on the face of it, PEA has potential to help human and animal patients with a variety of problems, including those associated with aging. Research and small trials have been carried out since the early 2000s, but currently the research base and associated licencing are not large enough to persuade physicians to routinely prescribe it for ailments that fall into these categories. However, it is increasingly being considered as an alternative to pharmaceutical treatments in situations where ani-inflammatory drugs are not advised (for example NSAID anti-inflammatories for hypertensive patients) (Mattace et al 2013) or where the undesirable side-effects of standard drugs (the gastro-intestinal effects of NSAIDS
for example) lead sufferers and prescribers to look for an alternative (WebMD 2004). In the current situation of increases in human neuro-divergence, it is extremely interesting to note the beneficial effects of PEA dosage noted by some researchers on autism spectrum characteristics (Colizzi et al 2021).
In conclusion, PEA is a multi‑target lipid mediator with good safety and accumulating evidence—especially for pain, inflammation, and neuroprotection. It has shown promising results in both humans and animals, but broader randomized trials are needed for definitive conclusions and wider clinical adoption. If of interest to sufferers of conditions mentioned, it is something that could be discussed with your healthcare provider as part of your pain and inflammation management regime.
Useful References
Bortoletto R, Comacchio C, Garzitto M, Piscitelli F, Balestrieri M, Colizzi M. Palmitoylethanolamide (2024) supplementation for human health: A state-of-the-art systematic review of Randomized Controlled Trials in patient populations. Brain Behav Immun Health. 43:100927 https://pmc.ncbi.nlm.nih.gov/articles/PMC11745966/
Colizzi M, Bortoletto R, Costa R, Zoccante L. (2021) Palmitoylethanolamide and Its Biobehavioral Correlates in Autism Spectrum Disorder: A Systematic Review of Human and Animal Evidence. Nutrients. 18;13(4):1346. [online] https://pmc.ncbi.nlm.nih.gov/articles/PMC8073263/
Cruccu G, Stefano GD, Marchettini P, Truini A. (2019) Micronized Palmitoylethanolamide: A Post Hoc Analysis of a Controlled Study in Patients with Low Back Pain - Sciatica. CNS Neurol Disord Drug Targets.18(6):491-495.[online] https://pubmed.ncbi.nlm.nih.gov/31269891/
D’Agostino G., Russo R., Avagliano C., Cristiano C., Meli R., Calignano A. (2012) Palmitoylethanolamide protects against the amyloid-β25-35-induced learning and memory impairment in mice, an experimental model of Alzheimer disease. Neuropsychopharmacology. 7:1784–1792 [online] https://pmc.ncbi.nlm.nih.gov/articles/PMC3358748/
Della Rocca G, Gamba D. (2021) Chronic Pain in Dogs and Cats: Is There Place for Dietary Intervention with Micro-Palmitoylethanolamide? Animals (Basel). 29;11(4):952.https://pubmed.ncbi.nlm.nih.gov/33805489/
Esposito E., Cuzzocre S. (2013) Palmitoylethanolamide in homeostatic and traumatic central nervous system injuries. CNS Neurol. Disord. Drug Targets 12:55–61 [online] https://pubmed.ncbi.nlm.nih.gov/23394520/
ForagePlus (2025) PEA For Horses [online] https://forageplus.co.uk/product/pea-for-horses/
Henrotin Y, Dierckxsens Y, Delisse G, Seidel L, Albert A. (2021) Curcuminoids and Boswellia serrata extracts combination decreases tendinopathy symptoms: findings from an open-label post-observational study. Curr Med Res Opin. 2021 Mar;37(3):423-430. [online] https://pubmed.ncbi.nlm.nih.gov/33287570/
Huschtscha Z, Fyfe JJ, Feros SA, Betik AC, Shaw CS, Main LC, Abbott G, Tan SY, Refalo MC, Gerhardy M, Grunwald E, May A, Silver J, Smith CM, White M, Hamilton DL.(2023) A randomised controlled trial assessing the potential of palmitoylethanolamide (PEA) to act as an adjuvant to resistance training in healthy adults: a study protocol. Trials. 24(1):245
Lang-Illievich K, Klivinyi C, Lasser C, Brenna CTA, Szilagyi IS, Bornemann-Cimenti H. (2023) Palmitoylethanolamide in the Treatment of Chronic Pain: A Systematic Review and Meta-Analysis of Double-Blind Randomized Controlled Trials. Nutrients.15(6):1350 [online] https://pubmed.ncbi.nlm.nih.gov/36986081/
Mattace Raso G, Simeoli R, Russo R, Santoro A, Pirozzi C, d'Emmanuele di Villa Bianca R, Mitidieri E, Paciello O, Pagano TB, Orefice NS, Meli R, Calignano A. (2013) N-Palmitoylethanolamide protects the kidney from hypertensive injury in spontaneously hypertensive rats via inhibition of oxidative stress. Pharmacol Res. 76:67-76
National Center for Biotechnology Information (2025). PubChem Compound Summary for CID 4671, Palmidrol [online] https://pubchem.ncbi.nlm.nih.gov/compound/Palmitoylethanolamide.
Noli C, Della Valle MF, Miolo A, Medori C, Schievano C; Skinalia (2015) Clinical Research Group. Efficacy of ultra-micronized palmitoylethanolamide in canine atopic dermatitis: an open-label multi-centre study. Vet Dermatol. 26(6):432-40, e101. https://pubmed.ncbi.nlm.nih.gov/26283633/
Novoceuticals (2025) Palmitoylethanolamide (PEA) for Pets: Natural Pain Relief for Dogs, Cats, and Horses [online] https://www.novoceuticals.com/blogs/articles/palmitoylethanolamide-pea-for-pets-natural-pain-relief-for-dogs-cats-and-horses
Petrosino S, Di Marzo V. (2017) The pharmacology of palmitoylethanolamide and first data on the therapeutic efficacy of some of its new formulations. Br J Pharmacol. 174(11):1349-1365. [online] https://pmc.ncbi.nlm.nih.gov/articles/PMC5429331/
Pet Pain Relief (2025) The Potential Of PEA [online] https://petpainrelief.co.uk/2025/02/16/the-potential-of-pea/
Petrosino S, Schiano Moriello A. (2020) Palmitoylethanolamide: A Nutritional Approach to Keep Neuroinflammation within Physiological Boundaries-A Systematic Review. Int J Mol Sci.15;21(24):9526. [online] https://pmc.ncbi.nlm.nih.gov/articles/PMC7765232/
Scuderi C., Stecca C., Valenza M., Ratano P., Bronzuoli M.R., Bartoli S., Steardo L., Pompili E., Fumagalli L., Campolongo P., et al. (2014) Palmitoylethanolamide controls reactive gliosis and exerts neuroprotective functions in a rat model of Alzheimer’s disease. Cell Death Dis. 11:e1419. [online] https://pubmed.ncbi.nlm.nih.gov/25210802/
Volpi E, Nazemi R, Fujita S. (2004) Muscle tissue changes with aging. Curr Opin Clin Nutr Metab Care. 7(4):405-10 [online] https://pmc.ncbi.nlm.nih.gov/articles/PMC2804956/#:~:text=Initial%20studies%20on%20a%20small,be%20discussed%20in%20this%20review.
WebMD (2024) Palmitoylethanolamide (Pea) - Uses, Side Effects, and More [online] https://www.webmd.com/vitamins/ai/ingredientmono-1596/palmitoylethanolamide-pea#overview
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