Chemistry:Palmitoylethanolamide

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Palmitoylethanolamide
Skeletal formula of palmitoylethanolamide
Names
Preferred IUPAC name
N-(2-Hydroxyethyl)hexadecanamide[1]
Other names
  • Hydroxyethylpalmitamide
  • Palmidrol
  • N-Palmitoylethanolamine
  • Palmitylethanolamide
Identifiers
3D model (JSmol)
Abbreviations PEA
ChEMBL
ChemSpider
EC Number
  • 208-867-9
KEGG
MeSH palmidrol
UNII
Properties
C18H37NO2
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
Hazards
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).
☒N verify (what is ☑Y☒N ?)
Infobox references

Palmitoylethanolamide (PEA) is an endogenous fatty acid amide, and lipid modulator [2] 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,[3] through which it exerts a variety of biological effects, some related to chronic inflammation and pain.[2]

A main target of PEA is proposed to be the peroxisome proliferator-activated receptor alpha (PPAR-α).[3][4] PEA also has affinity to cannabinoid-like G-coupled receptors GPR55 and GPR119.[5] PEA cannot strictly be considered a classic endocannabinoid because it lacks affinity for the cannabinoid receptors CB1 and CB2.[6] However, primary research supports the conclusion that the presence of PEA (or other structurally related N-acylethanolamines) enhances anandamide activity by an "entourage effect".[7][8][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.[9][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.[10][non-primary source needed]

In some primary research studies,[non-primary source needed] PEA has been shown to have anti-inflammatory,[4] anti-nociceptive,[11] neuroprotective,[12] and anticonvulsant properties.[13]

Early and recent studies

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.[14] 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;[15][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.[16][17]

Primary reports also have provided evidence that PEA downregulates hyperactive mast cells in a dose-dependent manner,[18] and that it alleviates pain elicited in mouse models.[11][verification needed] PEA and related compounds such as anandamide also seem to have synergistic effects in models of pain and analgesia.[19]

Animal models

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.[20][21]

In the mouse forced swimming test, palmitoylethanolamide was comparable to fluoxetine for depression.[22] An Italian study published in 2011 found that PEA reduced the raised intraocular pressure of glaucoma.[23] 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.[24] 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.[25][verification needed] In models of stroke and other CNS trauma, PEA exerted neuroprotective properties.[12][26][27][28][29]

Animal models of chronic pain and inflammation

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, because cannabinoids, such as THC, have been proven to be effective in neuropathic pain states.[30] 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.[31][32] 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.[33] 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.[34] PEA, as well as its analogue adelmidrol (di-amide derivative of azelaic acid), can both down-regulate mast cells.[35] 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] Studies have shown that PEA activates activates PPAR-alpha and TRPV1 receptors that control inflammation and the sensation of pain.[36] 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 mast cells 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 bladder syndrome.[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

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),[15] 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 phenomenon and central sensitization.[46][47]

Clinical relevance

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][49][50][51] Daily doses range from 300 to 1200 mg per day.[52] In a 2017 systematic meta-analysis involving 10 studies including data from 786 patients receiving PEA for pain-related indications and 512 controls, PEA was found to be associated with pain reduction significantly greater than observed in controls (P < 0.001).[53] Positive influences have also been observed in dermal applications, specifically atopic eczema, which may be linked to PPAR alpha activation.[48][54][verification needed]

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][54][verification needed] Since 2012 a number of new trials have been published, among which studies in glaucoma.[55][56] 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).[57][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 pain states.[38][42][49][50][58][59] 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.[60][61][better source needed] In 2012, 20 patients with thalidomide and bortezomib induced neuropathy were reported to have improved nerve functions and less pain after a two-month treatment with PEA.[62] 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 with 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)[63]—whose symptoms spanned eight pain categories ("burning", "osteoarticular", "piercing", etc.[64]) 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 pain scores (without drug-drug interactions).[verification needed][65]

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.[66]

In 2019, significant increases in fatty acid amides including PEA, arachidonoylethanolamide, and oleoylethanolamide were noted 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.[67][68]

In 2020, PEA has been suggested as a drug that may prove beneficial for the treatment of lung inflammation caused by SARS-CoV-2 infection.[69] A pharmaceutical company called FSD Pharma have entered PEA into a Phase 1 clinical trial under the name FSD-201, and has approval from the FDA for progressing to Phase 2a for this indication.[70]

Metabolism

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.[71]

Safety

PEA is generally considered safe, and without adverse drug reactions (ADRs) or drug interactions. A 2016 study assessing safety claims in sixteen clinical trials, six case reports/pilot studies and a meta‐analysis of PEA as an analgesic, concluded that for treatment periods up to 49 days, clinical data argued against serious ADRs at an incidence of 1/200 or greater.[72] A 2016 pooled meta-analysis involving twelve studies found that no serious ADRs were registered and/or reported.[73] No data on interactions with PEA have been reported. Based on its mechanism, PEA may be considered likely to interact with other PPAR-α agonists used to treat high triglycerides; this remains unconfirmed.

See also

References

  1. ↑ NCBI-PubChem Staff (25 March 2005). "Compound Summary: Palmitoylethanolamide" (database entry). PubChem.NCBI.NLM.NIH.gov. Bethesda, MD: US NLM-National Center for Biotechnology Information (NCBI). https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=4671&loc=ec_rcs#x291. 
  2. ↑ 2.0 2.1 "The pharmacology of palmitoylethanolamide and first data on the therapeutic efficacy of some of its new formulations". British Journal of Pharmacology 174 (11): 1349–1365. 2017. doi:10.1111/bph.13580. PMID 27539936. 
  3. ↑ 3.0 3.1 "Cannabinoids go nuclear: evidence for activation of peroxisome proliferator-activated receptors". British Journal of Pharmacology 152 (5): 576–82. November 2007. doi:10.1038/sj.bjp.0707423. PMID 17704824. 
  4. ↑ 4.0 4.1 "The nuclear receptor peroxisome proliferator-activated receptor-alpha mediates the anti-inflammatory actions of palmitoylethanolamide". Molecular Pharmacology 67 (1): 15–9. January 2005. doi:10.1124/mol.104.006353. PMID 15465922. https://escholarship.org/uc/item/9nf911g2. 
  5. ↑ "Receptors for acylethanolamides-GPR55 and GPR119". Prostaglandins & Other Lipid Mediators 89 (3–4): 105–11. September 2009. doi:10.1016/j.prostaglandins.2009.07.001. PMID 19615459. 
  6. ↑ "Cannabinoid activation of peroxisome proliferator-activated receptors: potential for modulation of inflammatory disease". Immunobiology 215 (8): 611–6. August 2010. doi:10.1016/j.imbio.2009.09.007. PMID 19833407. 
  7. ↑ "Effects of homologues and analogues of palmitoylethanolamide upon the inactivation of the endocannabinoid anandamide". British Journal of Pharmacology 133 (8): 1263–75. August 2001. doi:10.1038/sj.bjp.0704199. PMID 11498512. 
  8. ↑ "'Entourage' effects of N-palmitoylethanolamide and N-oleoylethanolamide on vasorelaxation to anandamide occur through TRPV1 receptors". British Journal of Pharmacology 155 (6): 837–46. November 2008. doi:10.1038/bjp.2008.324. PMID 18695637. 
  9. ↑ "Levels of endocannabinoids and palmitoylethanolamide and their pharmacological manipulation in chronic granulomatous inflammation in rats". Pharmacological Research 61 (4): 321–8. April 2010. doi:10.1016/j.phrs.2009.11.005. PMID 19931394. 
  10. ↑ "Palmitoylethanolamide protects against the amyloid-β25-35-induced learning and memory impairment in mice, an experimental model of Alzheimer disease". Neuropsychopharmacology 37 (7): 1784–92. June 2012. doi:10.1038/npp.2012.25. PMID 22414817. 
  11. ↑ 11.0 11.1 "Antinociceptive activity of the endogenous fatty acid amide, palmitylethanolamide". European Journal of Pharmacology 419 (2–3): 191–8. May 2001. doi:10.1016/S0014-2999(01)00988-8. PMID 11426841. https://escholarship.org/uc/item/9js9j6f1. 
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  14. ↑ "Letter: Slow encephalopathies, inflammatory responses, and arachis oil". Lancet 2 (7934): 558. September 1975. doi:10.1016/s0140-6736(75)90939-3. PMID 51386. 
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  18. ↑ "N-(2-hydroxyethyl)hexadecanamide is orally active in reducing edema formation and inflammatory hyperalgesia by down-modulating mast cell activation". European Journal of Pharmacology 300 (3): 227–36. April 1996. doi:10.1016/0014-2999(96)00015-5. PMID 8739213. 
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  20. ↑ "Study of the regulation of the endocannabinoid system in a virus model of multiple sclerosis reveals a therapeutic effect of palmitoylethanolamide". The European Journal of Neuroscience 28 (4): 633–41. August 2008. doi:10.1111/j.1460-9568.2008.06377.x. PMID 18657182. 
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  30. ↑ "Smoked cannabis for chronic neuropathic pain: a randomized controlled trial". CMAJ 182 (14): E694-701. October 2010. doi:10.1503/cmaj.091414. PMID 20805210. 
  31. ↑ "The ALIAmide palmitoylethanolamide and cannabinoids, but not anandamide, are protective in a delayed postglutamate paradigm of excitotoxic death in cerebellar granule neurons". Proceedings of the National Academy of Sciences of the United States of America 93 (9): 3984–9. April 1996. doi:10.1073/pnas.93.9.3984. PMID 8633002. Bibcode: 1996PNAS...93.3984S. 
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  34. ↑ "Effects of palmitoylethanolamide on immunologically induced histamine, PGD2 and TNFalpha release from canine skin mast cells". Veterinary Immunology and Immunopathology 133 (1): 9–15. January 2010. doi:10.1016/j.vetimm.2009.06.011. PMID 19625089. 
  35. ↑ "Adelmidrol, a palmitoylethanolamide analogue, reduces chronic inflammation in a carrageenin-granuloma model in rats". Journal of Cellular and Molecular Medicine 13 (6): 1086–95. June 2009. doi:10.1111/j.1582-4934.2008.00353.x. PMID 18429935. 
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  38. ↑ 38.0 38.1 "Involvement of the cannabimimetic compound, N-palmitoyl-ethanolamine, in inflammatory and neuropathic conditions: review of the available pre-clinical data, and first human studies". Neuropharmacology 48 (8): 1154–63. June 2005. doi:10.1016/j.neuropharm.2005.01.001. PMID 15910891. 
  39. ↑ "The anti-hyperalgesic actions of the cannabinoid anandamide and the putative CB2 receptor agonist palmitoylethanolamide in visceral and somatic inflammatory pain". Pain 76 (1–2): 189–99. May 1998. doi:10.1016/S0304-3959(98)00041-4. PMID 9696473. 
  40. ↑ "Administration of endocannabinoids prevents a referred hyperalgesia associated with inflammation of the urinary bladder". Anesthesiology 94 (3): 507–13; discussion 6A. March 2001. doi:10.1097/00000542-200103000-00023. PMID 11374613. 
  41. ↑ "Misdiagnosed chronic pelvic pain: pudendal neuralgia responding to a novel use of palmitoylethanolamide". Pain Medicine 11 (5): 781–4. May 2010. doi:10.1111/j.1526-4637.2010.00823.x. PMID 20345619. 
  42. ↑ 42.0 42.1 42.2 "Effect of palmitoylethanolamide-polydatin combination on chronic pelvic pain associated with endometriosis: preliminary observations". European Journal of Obstetrics, Gynecology, and Reproductive Biology 150 (1): 76–9. May 2010. doi:10.1016/j.ejogrb.2010.01.008. PMID 20176435. 
  43. ↑ "A proposed autacoid mechanism controlling mastocyte behaviour". Agents and Actions 39: C145–C147. 1993. doi:10.1007/BF01972748. PMID 7505999. 
  44. ↑ "Central nervous system mast cells in peripheral inflammatory nociception". Molecular Pain 7: 1744-8069-7-42. June 2011. doi:10.1186/1744-8069-7-42. PMID 21639869. 
  45. ↑ "Palmitoylethanolamide relieves pain and preserves pancreatic islet cells in a murine model of diabetes". CNS & Neurological Disorders Drug Targets 14 (4): 452–62. 2015. doi:10.2174/1871527314666150429111537. PMID 25921749. 
  46. ↑ "Spinal astrocytes as therapeutic targets for pathological pain". Journal of Pharmacological Sciences 114 (4): 347–53. 2010. doi:10.1254/jphs.10r04cp. PMID 21081837. 
  47. ↑ "Minocycline treatment inhibits microglial activation and alters spinal levels of endocannabinoids in a rat model of neuropathic pain". Molecular Pain 5: 1744-8069-5-35. July 2009. doi:10.1186/1744-8069-5-35. PMID 19570201. 
  48. ↑ 48.0 48.1 48.2 "Adjuvant treatment of atopic eczema: assessment of an emollient containing N-palmitoylethanolamine (ATOPA study)". Journal of the European Academy of Dermatology and Venereology 22 (1): 73–82. January 2008. doi:10.1111/j.1468-3083.2007.02351.x. PMID 18181976. 
  49. ↑ 49.0 49.1 "Use of palmitoylethanolamide in the entrapment neuropathy of the median in the wrist". Minerva Medica 102 (2): 141–7. April 2011. PMID 21483401. 
  50. ↑ 50.0 50.1 "Adjuvant topical therapy with a cannabinoid receptor agonist in facial postherpetic neuralgia". Journal der Deutschen Dermatologischen Gesellschaft 8 (2): 88–91. February 2010. doi:10.1111/j.1610-0387.2009.07213.x. PMID 19744255. 
  51. ↑ "Effects of palmitoylethanolamide on the cutaneous allergic inflammatory response in Ascaris hypersensitive Beagle dogs". Veterinary Journal 191 (3): 377–82. March 2012. doi:10.1016/j.tvjl.2011.04.002. PMID 21601500. 
  52. ↑ "The Basal Pharmacology of Palmitoylethanolamide". International Journal of Molecular Sciences 21 (21): 7942. October 2020. doi:10.3390/ijms21217942. PMID 33114698. 
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  54. ↑ 54.0 54.1 "Murine atopic dermatitis responds to peroxisome proliferator-activated receptors alpha and beta/delta (but not gamma) and liver X receptor activators". The Journal of Allergy and Clinical Immunology 125 (1): 160–9.e1–5. January 2010. doi:10.1016/j.jaci.2009.06.049. PMID 19818482. 
  55. ↑ "Effect of palmitoylethanolamide on visual field damage progression in normal tension glaucoma patients: results of an open-label six-month follow-up". Journal of Medicinal Food 17 (9): 949–54. September 2014. doi:10.1089/jmf.2013.0165. PMID 24827384. 
  56. ↑ "Palmitoylethanolamide effects on intraocular pressure after Nd:YAG laser iridotomy: an experimental clinical study". Journal of Ocular Pharmacology and Therapeutics 27 (6): 629–35. December 2011. doi:10.1089/jop.2010.0191. PMID 21830944. 
  57. ↑ "Mechanisms of exercise-induced hypoalgesia". The Journal of Pain 15 (12): 1294–1304. December 2014. doi:10.1016/j.jpain.2014.09.006. PMID 25261342. 
  58. ↑ "N-palmitoyl-ethanolamine: Biochemistry and new therapeutic opportunities". Biochimie 92 (6): 724–7. June 2010. doi:10.1016/j.biochi.2010.01.006. PMID 20096327. 
  59. ↑ "Treatment of chronic regional pain syndrome type 1 with palmitoylethanolamide and topical ketamine cream: modulation of nonneuronal cells". Journal of Pain Research 6: 239–45. 2013. doi:10.2147/JPR.S42417. PMID 23658493. 
  60. ↑ "Paper: Palmitoylethanolamide Vs NSAID in the Treatment of TMJD Pain (IADR General Session (July 14-17, 2010))". http://iadr.confex.com/iadr/2010barce/webprogramcd/Paper137174.html. 
  61. ↑ "Paper: Palmitoylethanolamide Vs NSAID In The Treatment Of TMJD Pain (IADR General Session (July 14-17, 2010))". Archive.is. http://iadr.confex.com/iadr/2010barce/webprogramcd/Paper137174.html. 
  62. ↑ "Palmitoylethanolamide restores myelinated-fibre function in patients with chemotherapy-induced painful neuropathy". CNS & Neurological Disorders Drug Targets 10 (8): 916–20. December 2011. doi:10.2174/187152711799219307. PMID 22229320. 
  63. ↑ In the article, these appear as "neuropatia diabetica periferica... o a nevralgia post herpetica". See Desio, op. cit.
  64. ↑ These terms were "urente", "osteoarticolare", "lancinante", etc. See Table 1 in Desio, op. cit.
  65. ↑ Desio, P. (29 November 2010). "Associazione tra pregabalin e palmitoiletanolamide (PEA) per il trattamento del dolore neuropatico" (in it, en). Pathos (Milano, IT: Società italiana dei clinici del dolore/PubliEditing) 17 (4): 9–14. ISSN 2385-0744. https://www.pathos-journal.com/page_69.html. Retrieved 26 February 2020. 
  66. ↑ "Palmitoylethanolamide: A Natural Body-Own Anti-Inflammatory Agent, Effective and Safe against Influenza and Common Cold". International Journal of Inflammation 2013: 151028. 2013. doi:10.1155/2013/151028. PMID 24066256. 
  67. ↑ "Microdeletion in a FAAH pseudogene identified in a patient with high anandamide concentrations and pain insensitivity". British Journal of Anaesthesia 123 (2): e249–e253. August 2019. doi:10.1016/j.bja.2019.02.019. PMID 30929760. 
  68. ↑ Mikaeili H, Yeung C, Habib AM, Wood JN, Okorokov AL, Cox JJ (2019). "CRISPR interference at the FAAH-OUT genomic region reduces FAAH expression". bioRxiv 10.1101/633396.
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  71. ↑ "The N-acylethanolamine-hydrolyzing acid amidase (NAAA)". Chemistry & Biodiversity 4 (8): 1914–25. August 2007. doi:10.1002/cbdv.200790159. PMID 17712833. 
  72. ↑ "Palmitoylethanolamide for the treatment of pain: pharmacokinetics, safety and efficacy". British Journal of Clinical Pharmacology 82 (4): 932–42. October 2016. doi:10.1111/bcp.13020. PMID 27220803. 
  73. ↑ "Palmitoylethanolamide, a Special Food for Medical Purposes, in the Treatment of Chronic Pain: A Pooled Data Meta-analysis". Pain Physician 19 (2): 11–24. February 2016. doi:10.36076/ppj/2016.19.11. PMID 26815246. 

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