Skeletal formula of palmitoylethanolamide
IUPAC name
Other names
3D model (JSmol)
Abbreviations PEA
ECHA InfoCard 100.008.062
EC Number
  • 208-867-9
MeSH palmidrol
Molar mass 299.499 g·mol−1
Appearance White crystals
Density 910 mg mL−1
Melting point 93 to 98 °C (199 to 208 °F; 366 to 371 K)
log P 5.796
Flash point 323.9 °C (615.0 °F; 597.0 K)
Related compounds
Related compounds
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references

Palmitoylethanolamide (PEA) is an endogenous fatty acid amide, belonging to the class of nuclear factor agonists.[not verified in body] PEA has been studied in in vitro and in vivo systems using exogenously added or dosed compound; there is evidence that it binds to a nuclear receptor,[2] through which it exerts a variety of biological effects, some related to chronic inflammation and pain.[3][4]

A main target of PEA is proposed to be the peroxisome proliferator-activated receptor alpha (PPAR-α).[2][5] PEA also has affinity to cannabinoid-like G-coupled receptors GPR55 and GPR119.[6] PEA cannot strictly be considered a classic endocannabinoid because it lacks affinity for the cannabinoid receptors CB1 and CB2.[7] However, primary research supports the conclusion that the presence of PEA (or other structurally related N-acylethanolamines) enhances anandamide activity by an "entourage effect".[8][9][non-primary source needed]

Some primary research reports support the conclusion that PEA levels are altered and that the endocannabinoid system (ECS) is "imbalanced" in acute and chronic inflammation.[10][non-primary source needed] A primary research article, for instance, has reported that the deregulation of cannabinoid receptors and their endogenous ligands accompanies the development and progression of β-amyloid-induced neuroinflammation.[11][non-primary source needed]

In some primary research studies,[non-primary source needed] PEA has been shown to have anti-inflammatory,[5] anti-nociceptive,[12] neuroprotective,[13] and anticonvulsant properties.[14]

Early studies[edit]

Palmitoylethanolamide was discovered in 1957.[citation needed] Indications for its use as an anti-inflammatory and analgesic date from before 1980.[citation needed] In that year, researchers described what they called "N-(2-hydroxyethyl)-palmitamide" as a natural anti-inflammatory agent, stating, "We have succeeded in isolating a crystalline anti-inflammatory factor from soybean lecithin and identifying it as (S)-(2-hydroxyethyl)-palmitamide. The compound also was isolated from a phospholipid fraction of egg yolk and from hexane-extracted peanut meal."[This quote needs a citation]

In 1975, Czech physicians described the results of a clinical trial[clarification needed] looking at joint pain, where the analgesic action of aspirin versus PEA were tested; both drugs were reported to enhance joint movements and decrease pain.[15] In 1970 the drug manufacturer Spofa in Czechoslovakia introduced Impulsin, a tablet dose of PEA, for the treatment and prophylaxis of influenza and other respiratory infections.[citation needed] In Spain, the company Almirall introduced Palmidrol in tablet and suspension forms in 1976, for the same indications.[citation needed]

In the mid 1990s, the relationship between anandamide and PEA was described;[16][non-primary source needed] the expression of mast cell receptors sensitive to the two molecules was demonstrated by Levi-Montalcini and coworkers.[according to whom?][non-primary source needed] During this period, more insight into the functions of endogenous fatty acid derivatives emerged, and compounds such as oleamide, palmitoylethanolamide, 2-lineoylglycerol and 2-palmitoylglycerol were explored for their capacity to modulate pain sensitivity and inflammation via what at that time was thought to be the endocannabinoid signalling pathway.[17][18]

Primary reports also have provided evidence that PEA downregulates hyperactive mast cells in a dose-dependent manner,[19] and that it might[editorializing] likewise alleviate pain behaviors elicited in mice-pain models.[12][verification needed] PEA and related compounds such as anandamide also seem to have synergistic effects in models of pain and analgesia.[20]

Animal models[edit]

In a variety of animal models, PEA seems to have some promise;[editorializing][citation needed] researchers have been able to demonstrate relevant clinical efficacy in a variety of disorders, from multiple sclerosis to neuropathic pain.[21][22]

In the mouse forced swimming test, palmitoylethanolamide was comparable to fluoxetine for depression.[23] An Italian study published in 2011 found that PEA reduced the raised intraocular pressure of glaucoma.[24] In a spinal trauma model, PEA reduced the resulting neurological deficit via the reduction of mast cell infiltration and activation. PEA in this model also reduced the activation of microglia and astrocytes.[25] Its activity as an inhibitor of inflammation counteracts reactive astrogliosis induced by beta-amyloid peptide, in a model relevant for neurodegeneration, probably via the PPAR-α mechanism of action.[26][verification needed] In models of stroke and other CNS trauma, PEA exerted neuroprotective properties.[13][27][28][29][30]

Animal models of chronic pain and inflammation[edit]

Chronic pain and neuropathic pain are indications for which there is high unmet need in the clinic. PEA has been tested in a variety of animal models for chronic and neuropathic pain. As cannabinoids, such as THC, have been proven to be effective in neuropathic pain states.[31] The analgesic and antihyperalgesic effects of PEA in two models of acute and persistent pain seemed to be explained at least partly via the de novo neurosteroid synthesis.[32][33] In chronic granulomatous pain and inflammation model, PEA could prevent nerve formation and sprouting, mechanical allodynia, and PEA inhibited dorsal root ganglia activation, which is a hallmark for winding up in neuropathic pain.[34] The mechanism of action of PEA as an analgesic and anti-inflammatory molecule is probably based on different aspects.[editorializing][citation needed] PEA inhibits the release of both preformed and newly synthesised mast cell mediators, such as histamine and TNF-alpha.[35] PEA, as well as its analogue adelmidrol (di-amide derivative of azelaic acid), can both down-regulate mast cells.[36] PEA reduces the expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) and prevents IkB-alpha degradation and p65 NF-kappaB nuclear translocation, the latter related to PEA as an endogenous PPAR-alpha agonist. In 2012 it became clear that PEA can also reduce reperfusion injury and the negative impact of shock on various outcome parameters, such as renal dysfunction, ischemic injury and inflammation, most probably via the PPAR-alpha pathway.[editorializing][citation needed] Among the reperfusion and inflammation markers measured PEA could reduce the increase in creatinine, γGT, AST, nuclear translocation of NF-κBp65; kidney MPO activity and MDA levels, nitrotyrosine, PAR and adhesion molecules expression, the infiltration and activation of mastcells and apoptosis.[37]

The biological responses to PEA dosing in animal models and in humans are being investigated vis-à-vis its involvement in a repair mechanism relevant to patient conditions of chronic inflammation and chronic pain.[38][verification needed] In a model of visceral pain (inflammation of the urinary bladder) PEA was able to attenuate the viscero-visceral hyper-reflexia induced by inflammation of the urinary bladder, one of the reasons why PEA is currently explored in the painful bladdersyndrome.[39] In a different model for bladder pain, the turpentine-induced urinary bladder inflammation in the rat, PEA also attenuated a referred hyperalgesia in a dose-dependent way.[40] Chronic pelvic pain in patients seem to respond favourably to a treatment with PEA.[41][42]

Activity in non-neuronal cells[edit]

PEA, as an N-acylethanolamine, has physico-chemical properties comparable to anandamide,[clarification needed] and, while it is not strictly an endocannabinoid, it is often studied in conjunction with anandamide because of their overlapping synthetic and metabolic pathways.[non-primary source needed] N-acylethanolamines such as PEA often act as signaling molecules, activating receptors and regulating a variety of physiological functions.[non-primary source needed] PEA is known to activate intracellular, nuclear and membrane-associated receptors,[non-primary source needed] and to regulate many physiological functions related to the inflammatory cascade and chronic pain states.[non-primary source needed] Endocannabinoid lipids like PEA are widely distributed in nature, in a variety of plant, invertebrate, and mammalian tissues.[non-primary source needed]

PEA's mechanism of action sometimes is described as Autacoid Local Injury Antagonism (acronym ALIA),[16] and PEA under this nomenclature is an ALIAmide. Levi-Montalcini and coworkers presented evidence in 1993 that lipid amides of the N-acylethanolamine type, such as PEA, are potential prototypes of naturally occurring molecules capable of modulating mast cell activation, and her group used the acronym ALIA in that report.[non-primary source needed][43] An autocoid is a regulating molecule, locally produced. An ALIAmide is an autocoid synthesized on-demand in response to injury, and acts locally to counteract such pathology. soon after the breakthrough paper of Levi-Montalcini, The mast cell appeared to be an important target for the anti-inflammatory activity of PEA. Since 1993, at least 25 papers have been published on the various effects of PEA on mast cells. These cells are often found in proximity to sensory nerve endings, and their degranulation can enhance the nociceptive signal, the reason why peripheral mast cells are considered to be pro-inflammatory and pro-nociceptive.[44] PEA's activity is currently seen as a new inroad in the treatment of neuropathic pain and related disorders based on overactivation of glia and glia-related cells, such as in diabetes and glaucoma.[45] Microglia plays a key role in the winding up phenomena and central sensitization.[46][47]

Clinical relevance[edit]

Effects of oral dosing of PEA has been explored in humans, and include clinical trials for a variety of pain states, for inflammatory and pain syndromes.[42][48][48][49][50][51] An observed positive influence in atopic eczema, for instance, seems[editorializing] to originate from PPAR alpha activation.[48][52][verification needed]

In a 2012 review, all clinical trials to date were summarized.[3] In a 2015 analysis of a double blind placebo controlled study of PEA in sciatic pain, the Numbers Needed to Treat was 1.5. Its positive influence in chronic pain, and inflammatory states such as atopic eczema, seems[editorializing] to originate mainly from PPAR alpha activation.[48][52][verification needed] Since 2012 a number of new trials have been published, among which studies in glaucoma.[53][54] PEA also seems[editorializing] to be one of the factors responsible for the decrease in pain sensitivity during and after sport, comparable to the endogenous opiates (endorphines).[55][verification needed]

From a clinical perspective the most important and promising indications for PEA are linked to neuropathic and chronic pain states, such as diabetic neuropathic pain, sciatic pain, CRPS, pelvic pain and entrapment neuropathic painstates.[38][42][49][50][56][57] In a blind trial reported in a conference proceeding, patients affected by pain from synovitis or TMJ osteoarthritis (N=25, in total[clarification needed]) were randomly assigned to PEA or ibuprofen groups for two weeks; the decrease in pain reported after two weeks was significantly higher for the PEA-treated group, likewise for improved masticatory function.[58][59][better source needed] In 2012, 20 patients suffering from thalidomide and bortezomib induced neuropathy were reported to have improved nerve functions and less pain after a two-month treatment with PEA.[60] The authors pointed out that although a placebo effect might play a role in the reported pain relief, the changes in neurophysiological measures clearly indicated that PEA exerted a positive action on the myelinated fibre groups. Sixteen men and fourteen women suffering from two major types of neuropathic pain refractory to analgesic treatment—peripheral diabetic neuropathy (4 men, 7 women) or post-herpetic neuralgia (12 men, 7 women)[61]—whose symptoms spanned eight pain categories ("burning", "osteoarticular", "piercing", etc.[62]) who were under prior treatment with pregabalin were transferred to PEA, after which pregabalin treatment was gradually reintroduced; all were responding well after 45 days, and presented significant decreases in painscores (without drug-drug interactions).[verification needed][63]

In 2013, a metareview was published on the clinical efficacy and safety of PEA in the treatment of the common cold and influenza, based on reports from six double-blind, placebo, randomized controlled trials,[verification needed] addressing PEA's proposed anti-inflammatory and retinoprotectant effects.[4]

Significant increases in fatty acid amides including PEA, arachidonoylethanolamide, and oleoylethanolamide were noted in 2019 in a Scottish woman with a previously undocumented variant of congenital insensitivity to pain. This was found to be a result of a combination of a hypomorphic single nucleotide polymorphism of fatty acid amide hydrolase (FAAH), alongside a mutation of the pseudogene, FAAH-OUT. The pseudogene was previously considered to be non-coding DNA, FAAH-OUT was found to be capable of modulating the expression of FAAH, making it a possible future target for novel analgesia/anxiolytic drug development.[64] [65]


PEA is metabolized by the cellular enzymes fatty acid amide hydrolase (FAAH) and N-acylethanolamine acid amide hydrolase (NAAA), the latter of which has more specificity toward PEA over other fatty acid amides.[66]

Review bibliography[edit]


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See also[edit]