Palmitoylethanolamide is hot. It is a body-own compound which seems quite interesting for a number of clinical reasons, and most importantly for its analgesic properties in neuropathic pain. But how does it work? 

The search for the palmitoylethanolamide receptor was the title of a publication in Life Sciences, written by pharmacologists from the Department of Experimental Pharmacology, University of Naples, and the Department of Pharmacology, University of California, Irvine, USA.

The paper is very much worthwhile to read. ^[1]

The discovery of the endogenous cannabinoid receptor-agonists, the ethanolamides (FAEs), originated from clinical finding in the early 1940s. At that time it was found that supplementing the diets of starving children with dried chicken egg yolk prevented recurrences of rheumatic fever, despite ongoing streptococcal infections. 

In this early time Coburn and colleagues isolated lipid fractions from egg yolk as well as from peanut oil and soybean lecithin These lipids exerted anti-allergic effects in an animal model and in 1957 PEA (N-(2-hydroxyethyl)hexadecanamide, N-palmitoylethanolamine), was isolated as the compound responsible for these anti-inflammatory properties. PEA was first identificatied in mammalian tissues in 1964.^[2]

Early clinical studies with PEA

In the 70s first clinical studies are conducted using PEA, and PEA was evaluated under the trade name of Impulsin by a Czech pharmaceutical company called SPOFA.^[3] In those early trials it was claimed that PEA could reduce the severity and duration of flu symptoms in school children and soldiers. In that period PEA was used in the former Czechoslovakia for the treatment of acute respiratory diseases. ^{[4][5][6][7][8]}

Two field trials were conducted at that time to test the efficacy of Impulsin in reducing the incidence and severity of respiratory tract infections. It was found that repeated daily intake of Impulsin 30 mg per kg helped to prevent virus infections of the respiratory tract. Prophylactic treatment with Impulsin was claimed to diminished the number of episodes of fever, headache and sore throat. The administration of Impulsin had no effect on the mean duration of disability and fever.^[9]

However, at that time it was totally unknown how PEA interacted with the body, and the receptor for its action remained a mystery for many years. Only after the discovery of a related fatty acid amide, anandamide (arachidonoylethanolamide), the endogenous agonist for cannabinoid receptors,  a new surge of studies exploring the biological functions of PEA started.

Biological activity of PEA

PEA is produced by the enzyme fatty acid amide hydrolase (FAAH) which is an integral membrane protein. This enzyme plays a key role for the catabolism of the fatty acid amide (FAA) family of endogenous signaling lipids. These FAAs function in general as agonists of the cannabinoid receptors CB1 and CB2. They and are also referred to as ‘endovanilloids’ because of their affinity to the vanilloid receptors. The endogenous FAAs have been shown to modulate these receptors and have a wide variety of biological actions. However, we will see that for PEA many of these activities are independent of the affinity to the cannabinoid receptors. 

PEA has been evaluated in a variety of animal models and many different biological actions have been identified, and we do not mention all, but just a few:^[10][11][12]

1. analgesic properties 
2. anti-convulsive actions,
3. neuroprotection,
4. food intake behaviour modification,
5. gastrointestinal motility
6. cancer cell proliferation
7. protection of the vascular endothelium
8. inhibiting mast cell degranulation 
9. inhibiting pulmonary inflammation 
10. reducing nitric oxide production by macrophages 
11. reducing neutrophil influx  

PEA synthesis

Classical neurotransmitters and hormones are stored in and released from intracellular secretory vesicles. PEA production and release does not follow this principle, the production of FAA's occurs through on-demand synthesis within the lipid bilayer.

The first step is the transfer of a fatty acid from membrane-phospholipids to phosphatidylethanolamine (PE), catalyzed by calcium and N-acyltransferase (NAT), producing the precursor N-acyl phosphatidylethanolamine (NAPE). Next occurs the cleavage of the membrane-bound NAPE to release PEA, this reaction is mediated by a NAPE-specific phospholipase D.

PEA binding: the receptor story

Now, due to the structural similarities between our endogenous cannabinoid anandamide and PEA first is was suggested that PEA would share the same receptors as anandamide, the cannabinoid receptors. Although first experiments seemed to substantiate that idea, it is now clear that PEA does not bind to cannabinoid receptors. So the search for the receptor of PEA continued. It were the experiments related to the PPAR-α receptors and their ligands, important modulators of the inflammatory process, which created some new insight in PEA's putative mechanism of action. Some years now it is clear that PEA directly activates PPAR-α, and that this mechanism of action explains its anti-inflammatory action. Meanwhile, we know that even the analgsic properties of PEA are mediated via the same mechanism, probably amongst others.^[13][11] Evidence now suggests that endocannabinoids are natural activators of PPAR-α.^[15]

The processes leading to this inhibition are starting with ligation of PPAR-α by PEA, and the induction of a heterodimerization with ligated retinoic acid receptors (RXR). This in its turn leads to the formation of an activated receptor complex, which translocates to the nucleus to bind a PPAR-α response element (PPRE) and in this way reduce inflammation.

PEA and the other endogenous acylethanolamines, oleoylethanolamide are now known to regulate feeding and body weight, stimulate fat utilization and have neuroprotective effects mediated through this mechanism of action via PPAR-α. There are also other endocannabinoids that activate the same route via PPAR-α, including anandamide, virodhamine and noladin ether.^[16]

The above data are based on the fine review of LoVerme J, La Rana G, Russo R, Calignano A, and Piomelli D.^[1]

September 2010, prof. dr. Jan M. Keppel Hesselink, MD, PhD

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