Palmitoylethanolamide (PEA) for neuropathic pain

Palmitoylethanolamide: in 2012 more than 300 entries in pubmed for this interesting molecule as it works for pain! The internationalization of PEA started at the Third International Congress on Neuropathic Pain, Athens, Greece, May 27 – 30, 2010.

87846823-Romastudio-Dreamstime-INP-Instituut-voor-Neuropathische-Pijn Palmitoylethanolamide (PEA)A. Biasiotta, S. et al presented a poster which demonstrated a clinical relevant and electro physiological measurable effect from this rather unknown compound classified as medical food, Palmitoylethanolamide. The compound is available as diet food for medical purposes.

This is very interesting for doctors as well as patients, as PEA is an endogenous fatty acid without any troublesome side effects and easy to use to reduce pain, even together with other drugs.

Lipids like N-Palmitoylethanolamine can act as signaling molecules, activating intracellular and membrane-associated receptors to regulate physiological functions.

The signaling lipid PEA is known to activate intracellular, nuclear and membrane-associated receptors and regulate many physiological functions related to the inflammatory cascade, and thus is of high interest in the treatment of neuropathic, or gliopathic pain.

PEA: an lipid signaling ligand. This approach is, as said, fascinating, as Palmitoylethanolamide may potentiate endocannabinoids activity, but not as an endocannabinoid, but as a lipid signaling ligand.[1] 

Palmitoylethanolamide (PEA) is an endogenous fatty acid amide analogue of the endocannabinoid anandamide.[2][3] This makes the use of this non-psychomimetic drug as novel analgesic for the treatment of neuropathic pain fascinating.

PEA belongs to the class of N-Acylethanolamides (NAEs) (amides of ethanolamine with long-chain fatty acids) and these are defined as endogenously generated lipid-signaling molecules. These lipids are widely distributed in a variety of plant, invertebrate, and mammalian tissues. The molecular formulation is C14H38O2NCL.[4] 

1968 the first paper on PEA

Bio active lipids such as PEA, an anandamide analogue, were described for the first time in 1957 when it was discovered that PEA, isolated from soybeans, peanuts, and egg yolk, has anti inflammatory properties. 1965, the group of Bachur et al found that these bio active lipids also existed in mammalian tissues, especially in the brain.[4] Already in the sixties it was found that PEA has anti-inflammatory effects.[6]

IN 1968 the first paper on PEA is indexed in Pubmed [7] and (since) than more than 300 entries can be found! In the 90s the relation between anandamide and PEA was described, and the expression on mast cells of receptors sensitive for those 2 molecules was demonstrated.[8] In the same period more data supported its neuroprotective effects.[9] Recent data even show that Palmitoylethanolamide can be used in the treatment of atopic dermatitis.[10]

It was due to the work of professor Rita Levi-Montalcini, Nobel Prize laureat in Medicine 1986, that PEA was taken up in development.

Meanwhile, it is a fact that anandamide (AEA) and PEA regulate directly or indirectly many of the same patho physiological processes, including pain perception, inflammation, convulsions and neuro protection. There are a number of biological effects of endocannabinoids which can be enhanced by related endogenous fatty acid derivatives which are devoid of some of these primary effects.  

In the past, the finding that the CB2 receptor antagonist, SR144528 inhibits some analgesic responses to PEA in vivo implicates that PEA might either directly activates an unidentified CB2-like receptor or acts indirectly by potentiation of endocannabinoid actions. The last mechanism of action is called the entourage effect.

Entourage effect 

This principle of enhance mend was termed ‘the entourage effect’ and was first described by the group Ben-Shabat et al. in 1998. In their experiments they characterized the potentiation of cannabinoid receptor-mediated responses to 2-arachidonoylglycerol by other endogenous fatty acids in a mouse model.

They found entourage properties of these fatty acids, and since their work various compounds have been shown to enhance cannabinoid effects via this principle: oleamide, various N-acyl and N-acyl ethanolamines such as Palmitoylethanolamide (PEA), PEA.

These fatty acids seem to be co-synthesized and co-released with the endocannabinoids such as anandamide. Anandamide and PEA both are present in the spinal cord, but the concentration of PEA is most probably 10 times higher.

The entourage effect of PEA most probably is due to interactions with a special cannabinoid receptor, the TRPV1 receptors, and this was showed by the group of De Petrocellis et al.[11]

It has also been suggested that PEA enhances the effects of endocannabinoids by acting as a competitive inhibitor of the enzymatic degradation of endocannabinoids. Furthermore, it is well-known that anandamide can inhibit a number of different ion channels and PEA has comparable properties and can also inhibit some potassium channels. Interestingly in isolated mitochondria PEA can dose dependently decrease generation of reactive oxygen species and thus PEA might protect mitochondria against oxidative stress.

PEA and related fatty acids in the brain have a variety of important biological effects: increase ceramide levels, inhibit of mast cell activation,  stabilize of mitochondrial function, and inhibition of degradation of anandamide that, as an endocannabinoid, can have neuroprotective effects on its own.


The anti-inflammatory effect of PEA is partly linked to its modulation of mast cells degranulation, as has been shown via histological analysis and by the inhibition of the release of several pro-inflammatory enzymes such as iNOS, chymase and metalloproteinase MMP-9), as well as mediators such as nitric oxide and TNF-α.  

We will now discuss the poster on PEA presented in Athens.[12]

PEA in neuropathic pain 

In the introduction they referred to the fact that recent studies suggest that inflammation and mast cell activity play a crucial role in the pathophysiology of neuropathic pain. Palmitoylethanolamide is a supplement which, based on in vivo findings, seems to inhibit mast cell activity. The researchers assessed the efficacy and safety of Palmitoylethanolamide in painful neuropathy. 30 drug naïve patients with painful neuropathy were included and treated with 600 mg Palmitoylethanolamide/day.

They clinically investigated sensory disturbances and pain using the 11-point Lickert numerical rating scale in 20 patients before and after treatment with Palmitoylethanolamide. Furthermore they investigated non-nociceptive fibre function by nerve conduction study and nociceptive fibre function by laser evoked potentials.

Both neuropathic pain and positive sensory symptoms significantly improved after treatment (P < 0.01), and clear trends in amplitude changes of sural and ulnar sensory nerve action potential and foot and hand LEPs were documented (P < 0.06). Their preliminary findings suggest that Palmitoylethanolamide may improve nerve function and reduce neuropathic pain.

In the above picture the structure of PEA is given, in the picture below that of anandamide. The resemblance of both structures is clear.

In pudendal neuropathic pain Palmitoylethanolamide reduced the pain scores in a clinical relevant way.[13] In another paper the positive effects on pelvic pain were reported.[14] Animal studies are also supportive for the use of this supplement in the treatment of neuropathic pain.[15]

PEA pharmacokinetic

PEA can be measured in plasma. Recently Pfizer developed and published a method. The liquid chromatography tandem mass spectrometry (LCMSMS) method has been developed for the simultaneous quantification in human plasma of the endocannabinoid anandamide (AEA) and three other related ethanolamides, linoleoyl ethanolamide (LEA), oleoyl ethanolamide (OEA), and Palmitoylethanolamide PEA with lower limit of quantitation was 0.05 ng/mL for AEA and LEA, 0.5 ng/mL for OEA and 1.0 ng/mL for PEA.  [16]  This seems relevant when we further want to test PEA as a therapy for neuropathic pain.

Meanwhile there are plasma levels measured for PEA in human subjects and indeed the compound is detectable, and reaches levels comparable to effective levels based on preclinical models.

December 2010:

No new analgesics in 50 years
Pregabalin not effective in HIV neuropathy
Fractalkine CX3CR1 and neuropathic pain


[1] Gaczynska M, Chwialkowski M, Olejniczak W, Wojczuk S, Bartosz G. | Scanning tunneling microscopy of human erythrocyte membranes. | Biochem Biophys Res Commun. | 1991 Dec 16;181(2):600-3.

[2] Re G, Barbero R, Miolo A, Di Marzo V. | Palmitoylethanolamide, endocannabinoids and related cannabimimetic compounds in protection against tissue inflammation and pain: potential use in companion animals. | Vet J. | 2007 Jan;173(1):21-30. Epub 2005 Dec 1.

[3] Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, Gibson D, Mandelbaum A, Etinger A, Mechoulam R. | Isolation and structure of a brain constituent that binds to the cannabinoid receptor. | Science. | 1992 Dec 18;258(5090):1946-9.



[6] GANLEY OH, GRAESSLE OE, ROBINSON HJ. | Anti-inflammatory activity on compounds obtained from egg yolk, peanut oil, and soybean lecithin. | J Lab Clin Med. | 1958 May;51(5):709-14.

[7] Benvenuti F, Lattanzi F, De Gori A, Tarli P. | [Activity of some derivatives of palmitoylethanolamide on carragenine-induced edema in the rat paw]. | Boll Soc Ital Biol Sper. | 1968 May 15;44(9):809-13.

[8] Facci L, Dal Toso R, Romanello S, Buriani A, Skaper SD, Leon A. | Mast cells express a peripheral cannabinoid receptor with differential sensitivity to anandamide and palmitoylethanolamide. | Proc Natl Acad Sci U S A. | 1995 Apr 11;92(8):3376-80.

[9] Skaper SD, Buriani A, Dal Toso R, Petrelli L, Romanello S, Facci L, Leon A. | The ALIAmide palmitoylethanolamide and cannabinoids, but not anandamide, are protective in a delayed postglutamate paradigm of excitotoxic death in cerebellar granule neurons. | Proc Natl Acad Sci U S A. | 1996 Apr 30;93(9):3984-9.

[10] Kircik L. | A nonsteroidal lamellar matrix cream containing palmitoylethanolamide for the treatment of atopic dermatitis. | J Drugs Dermatol. | 2010 Apr;9(4):334-8.

[11] Di Marzo V, Bisogno T, De Petrocellis L, Melck D, Martin BR. | Cannabimimetic fatty acid derivatives: the anandamide family and other endocannabinoids. | Curr Med Chem. | 1999 Aug;6(8):721-44.

[12] Biasiotta A., La Cesa S., Leone C., Di Stefano G., Truini A., Cruccu G. | Efficacy of Palmitoylethanolamide in patients with painful neuropathy. A clinical and neuro physiological open study. Preliminary results. | European Journal of Pain Supplements | 2010, 4(1):77.

[13] Calabrò RS, Gervasi G, Marino S, Mondo PN, Bramanti P. | Misdiagnosed chronic pelvic pain: pudendal neuralgia responding to a novel use of palmitoylethanolamide. | Pain Med. | 2010 May;11(5):781-4. Epub 2010 Mar 22.

[14] Indraccolo U, Barbieri F. | Effect of palmitoylethanolamide-polydatin combination on chronic pelvic pain associated with endometriosis: preliminary observations. | Eur J Obstet Gynecol Reprod Biol. | 2010 May;150(1):76-9. Epub 2010 Feb 21.

[15] D'Agostino G, La Rana G, Russo R, Sasso O, Iacono A, Esposito E, Mattace Raso G, Cuzzocrea S, Loverme J, Piomelli D, Meli R, Calignano A. | Central administration of palmitoylethanolamide reduces hyperalgesia in mice via inhibition of NF-kappaB nuclear signalling in dorsal root ganglia. | Eur J Pharmacol. | 2009 Jun 24;613(1-3):54-9. Epub 2009 Apr 20.

[16] Palandra J, Prusakiewicz J, Ozer JS, Zhang Y, Heath TG. | Endogenous ethanolamide analysis in human plasma using HPLC tandem MS with electrospray ionization. | J Chromatogr B Analyt Technol Biomed Life Sci. | 2009 Jul 15;877(22):2052-60. Epub 2009 May 28.

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