Palmitoylethanolamide (PEA) is an endogenously produced fatty acid amide, with significant anti-inflammatory, analgesic and neuroprotective properties.¹ It is an analogue of the endocannabinoid anandamide and thereby helps to mitigate pain and inflammation via the endocannabinoid system.² PEA has been shown to act directly and on several molecular targets modifying pain and inflammation.³ Research suggests that PEA works via three major mechanisms:

1. Antagonism of local inflammation, via mast cell and microglial cell inhibition.⁴
2. Inhibition of inflammatory cascades, via nuclear peroxisome proliferator-activated receptors (PPAR) inhibition.⁵
3. Enhancing the anti-inflammatory and analgesic effects of other endogenous substances.⁶

Clinical Indications

Research into PEA has expanded over the past few decades, highlighting it potential as a therapeutic agent in a range of painful, inflammatory, and neurocognitive conditions, including:

Musculoskeletal conditions

Osteoarthritis,^7,8 sciatica/lumbosciatalgia,⁹ low back pain,¹⁰ temporomandibular joint pain,¹¹ and carpal tunnel syndrome¹²

Neuropathic pain

Traumatic neuropathy,¹³ shingles pain (postherpetic neuralgia),¹⁴ diabetic neuropathic pain⁸ and burning mouth syndrome.⁸

Nervous system disorders

Depression,¹⁵ Parkinson’s disease,¹⁶ multiple sclerosis,⁸ adjunct support for autism,¹⁷ adjunct support for psychosis,¹⁸ and cognitive decline.¹⁹

Other pain states

Chronic pelvic pain,⁸ upper respiratory tract infections and Influenza virus,²⁰ migraine,²¹ and dental surgery.⁹

The Importance of Quality and Bioavailability

While PEA is naturally produced in the body, the supplemental form is derived from plant fatty acid amides. As such, not all PEA compounds are of the same quality and bioavailability, with some simply being finely milled, or PEA which is micronised (mPEA), or ultra-micronised (um-PEA). The next generation of bioavailability concerns novel delivery system technology, including that of the hydrogel FenuMAT™. FenuMAT™ enhances the solubility, stability and bioavailability of bioactive nutrients and phytochemicals by utilising the unique chemical structure of the soluble dietary fibre galactomannan, derived from Fenugreek. Galactomannan serves as a physical hydrogel matrix for the sustained delivery of bioactives,²² resulting in better absorption in the intestinal tract.²³

In a double-blind, two-way crossover study, 12 individuals were randomised to receive a single 500 mg dose of a PEA formulated with or without FenuMAT™ (unpublished data). The formulated PEA contained 194.7 mg of PEA, whereas the other contained 490 mg of PEA. Plasma concentration of PEA revealed a markedly higher peak concentration, a longer time to reach this peak concentration (i.e. slower release for better absorption), a longer half-life (i.e. sustained therapeutic effect), and an increased plasma PEA concentration by 5.41 times for the FenuMAT™ PEA formulation as compared to the standard PEA formulation (see Figure 1). This indicates that the use of FenuMAT™ technology successfully improves the bioavailability of oral PEA.²³

Figure 1: Changes in plasma uptake of PEA with and without FenuMAT™ technology²³

Abbreviations: PEA, Palmitoylethanolamide; UF PEA, unformulated PEA; F PEA, formulated PEA; Cmax, maximum concentration; Tmax, time to maximum concentration; T ½, half-life.

Dose and Safety

The effective dosage range for PEA has been established as between 10 and 30 mg/kg bodyweight/day.²⁰ Clinical trial data suggests a loading dose of 600 – 1,200 mg/day for 3 to 4 weeks followed by a maintenance dose of 300 – 600 mg/day may be most effective.^5,24

PEA has been proven to be safe in adults in a dose-range up to 50-100 mg/kg bodyweight, with no clinically relevant or dose-limiting side effects.²⁵ PEA has been given alongside opiate medications in clinical studies, demonstrating good efficacy and tolerability.^26,27

Conclusion

PEA is a promising, well tolerated supplement with significant applications in pain management, inflammation and neuroprotection. Clinicians should consider PEA as part of a holistic approach to patient care, particularly in cases where conventional treatments provide inadequate relief.

References

¹ Petrosino S, Schiano Moriello A, Verde R, Allarà M, Imperatore R, Ligresti A, et al. Palmitoylethanolamide counteracts substance P-induced mast cell activation in vitro by stimulating diacylglycerol lipase activity. J Neuroinflammation. 2019 Dec;16(1):274. DOI:10.1186/s12974-019-1671-5

² Passavanti MB, Alfieri A, Pace MC, Pota V, Sansone P, Piccinno G, et al. Clinical applications of palmitoylethanolamide in pain management: Protocol for a scoping review. Syst Rev. 2019 Dec;8:1-4.

³ Kytikova O, Novgorodtseva T, Antonyuk M, Denisenko Y, Gvozdenko T. Molecular targets of fatty acid ethanolamides in asthma. Medicina. 2019 Apr 1;55(4):87.

⁴ Petrosino S, Di Marzo V. The pharmacology of palmitoylethanolamide and first data on the therapeutic efficacy of some of its new formulations. British J Pharmacology. 2017 Jun;174(11):1349-65. DOI:10.1111/bph.13580

⁵ Skaper SD, Facci L, Fusco M, della Valle MF, Zusso M, Costa B, et al. Palmitoylethanolamide, a naturally occurring disease-modifying agent in neuropathic pain. Inflammopharmacol. 2014 Apr;22(2):79-94. DOI:10.1007/s10787-013-0191-7

⁶ Skaper SD, Facci L, Giusti P. Mast cells, glia and neuroinflammation: partners in crime?. Immunology. 2014 Mar;141(3):314-27. DOI:10.1111/imm.12170

⁷ 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. Inflammopharmacol. 2019 Jun;27(3):475-85. DOI:10.1007/s10787-019-00582-9

⁸ 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 Mar 10;15(6):1350. DOI:10.3390/nu15061350

⁹ Artukoglu BB, Beyer C, Zuloff-Shani A, Brener E, Bloch MH. Efficacy of Palmitoylethanolamide for Pain: A Meta-Analysis. Pain Physician. 2017 Jul;20(5):353-62.

¹⁰ Passavanti MB, Fiore M, Sansone P, Aurilio C, Pota V, Barbarisi M, et al. The beneficial use of ultramicronized palmitoylethanolamide as add-on therapy to Tapentadol in the treatment of low back pain: a pilot study comparing prospective and retrospective observational arms. BMC Anesthesiol. 2017 Dec;17(1):171. DOI:10.1186/s12871-017-0461-9

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¹² Conigliaro R, Drago V, Foster PS, Schievano C, Di Marzo V. Use of palmitoylethanolamide in the entrapment neuropathy of the median in the wrist. Minerva Med. 2011 Apr;102(2):141-7.

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¹⁴ Gatti A, Lazzari M, Gianfelice V, Di Paolo A, Sabato E, Sabato AF. Palmitoylethanolamide in the Treatment of Chronic Pain Caused by Different Etiopathogenesis. Pain Med. 2012 Sep;13(9):1121-30. DOI:10.1111/j.1526-4637.2012.01432.x

¹⁵ Ghazizadeh-Hashemi M, Ghajar A, Shalbafan M, Ghazizadeh-Hashemi F, Afarideh M, Malekpour F, et al. Palmitoylethanolamide as adjunctive therapy in major depressive disorder: A double-blind, randomized and placebo-controlled trial. Journal of Affective Disorders. 2018 May;232:127-33. DOI:10.1016/j.jad.2018.02.057

¹⁶ Brotini S, Schievano C, Guidi L. Ultra-micronized palmitoylethanolamide: An efficacious adjuvant therapy for Parkinson’s disease. CNSNDDT. 2017 Aug 23;16(6):705-13. DOI:10.2174/1871527316666170321124949

¹⁷ Khalaj M, Saghazadeh A, Shirazi E, Shalbafan M, Alavi K, Shooshtari MH, et al. Palmitoylethanolamide as adjunctive therapy for autism: Efficacy and safety results from a randomized controlled trial. Journal of Psychiatric Research. 2018 Aug;103:104-11. DOI:10.1016/j.jpsychires.2018.04.022

¹⁸ Bortoletto R, Piscitelli F, Candolo A, Bhattacharyya S, Balestrieri M, Colizzi M. Questioning the role of palmitoylethanolamide in psychosis: a systematic review of clinical and preclinical evidence. Front Psychiatry. 2023 Jul 18;14:1231710. DOI:10.3389/fpsyt.2023.1231710

¹⁹ Colizzi M, Bortoletto R, Colli C, Bonomo E, Pagliaro D, Maso E, et al. Therapeutic effect of palmitoylethanolamide in cognitive decline: A systematic review and preliminary meta-analysis of preclinical and clinical evidence. Front Psychiatry. 2022 Oct 28;13:1038122. DOI:10.3389/fpsyt.2022.1038122

²⁰ Keppel Hesselink JM, de Boer T, Witkamp RF. Palmitoylethanolamide: A Natural Body-Own Anti-Inflammatory Agent, Effective and Safe against Influenza and Common Cold. International Journal of Inflammation. 2013;2013:1-8. DOI:10.1155/2013/151028

²¹ Dalla Volta G. Ultramicronized palmitoylethanolamide reduces frequency and pain intensity in migraine. A pilot study. IJNBD. 2016;3(2):1-5. DOI:10.15436/2377-1348.16.019

²² Kumar D, Jacob D, PS S, Maliakkal A, NM J, Kuttan R, et al. Enhanced bioavailability and relative distribution of free (unconjugated) curcuminoids following the oral administration of a food-grade formulation with fenugreek dietary fibre: A randomised double-blind crossover study. Journal of Functional Foods. 2016 Apr;22:578-87. DOI:10.1016/j.jff.2016.01.039

²³ Akay Natural Ingredients. Human pharmacokinetic study report of FenuMAT-palmitoylethanolamide (PEA 40%). [Unpublished data].

²⁴ Gabrielsson L, Mattsson S, Fowler CJ. Palmitoylethanolamide for the treatment of pain: pharmacokinetics, safety and efficacy. Brit J Clinical Pharma. 2016 Oct;82(4):932-42. DOI:10.1111/bcp.13020

²⁵ Keppel Hesselink JM. Chronic pain and the use of palmitoylethanolamide. Austin J Neurol Disord Epilepsy. 2018; 5(2):1042.

²⁶ Varrassi G, Fusco M, Skaper SD, Battelli D, Zis P, Coaccioli S, et al. A Pharmacological Rationale to Reduce the Incidence of Opioid Induced Tolerance and Hyperalgesia: A Review. Pain Ther. 2018 Jun;7(1):59-75. DOI:10.1007/s40122-018-0094-9

²⁷ Di Cesare Mannelli L, Corti F, Micheli L, Zanardelli M, Ghelardini C. Delay of Morphine Tolerance by Palmitoylethanolamide. BioMed Research International. 2015;2015:1-12. DOI:10.1155/2015/894732