Palmitoylethanolamide Explained

Palmitoylethanolamide (PEA) is an endogenous fatty acid amide, and lipid modulator.[1]

A main target of PEA is proposed to be the peroxisome proliferator-activated receptor alpha (PPAR-α).[2] [3] PEA also has affinity to cannabinoid-like G-coupled receptors GPR55 and GPR119.[4] PEA cannot strictly be considered a classic endocannabinoid because it lacks affinity for the cannabinoid receptors CB1 and CB2.[5]

Early and recent studies

In 1975, Czech physicians described the results of a clinical trial 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.[6] 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. In Spain, the company Almirall introduced Palmidrol in tablet and suspension forms in 1976, for the same indications.

In the mid-1990s, the relationship between anandamide and PEA was described;[7] the expression of mast cell receptors sensitive to the two molecules was demonstrated by Levi-Montalcini and coworkers. 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.[8] [9]

Primary reports also have provided evidence that PEA downregulates hyperactive mast cells in a dose-dependent manner,[10] and that it alleviates pain elicited in mouse models. PEA and related compounds such as anandamide also seem to have synergistic effects in models of pain and analgesia.[11]

Animal models

In a variety of animal models, PEA seems to have some promise; researchers have been able to demonstrate relevant clinical efficacy in a variety of disorders, from multiple sclerosis to neuropathic pain.[12] [13]

In the mouse forced swimming test, palmitoylethanolamide was comparable to fluoxetine for depression.[14] An Italian study published in 2011 found that PEA reduced the raised intraocular pressure of glaucoma.[15] 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.[16] 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.[17] In models of stroke and other CNS trauma, PEA exerted neuroprotective properties.[18] [19] [20] [21]

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.[22] 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.[23] [24] 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.[25] The mechanism of action of PEA as an analgesic and anti-inflammatory molecule is probably based on different aspects. PEA inhibits the release of both preformed and newly synthesised mast cell mediators, such as histamine and TNF-alpha.[26] PEA, as well as its analogue adelmidrol (di-amide derivative of azelaic acid), can both down-regulate mast cells.[27] 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. Studies have shown that PEA activates PPAR-alpha and TRPV1 receptors that control inflammation and the sensation of pain. 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.[28]

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.[29] 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.[30] 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.[31] Chronic pelvic pain in patients seem to respond favourably to a treatment with PEA.[32] [33]

Activity in non-neuronal cells

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

PEA's mechanism of action sometimes is described as Autacoid Local Injury Antagonism (acronym ALIA), 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.[34] 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.[35] 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.[36] Microglia plays a key role in the winding up phenomenon and central sensitization.[37] [38]

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.[39] [40] [41] [42] Daily doses range from 300 to 1200 mg per day.[43] 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).[44] Positive influences have also been observed in dermal applications, specifically atopic eczema, which may be linked to PPAR alpha activation.[39] [45]

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 to originate mainly from PPAR alpha activation.[39] Since 2012 a number of new trials have been published, among which studies in glaucoma.[46] [47] PEA also seems to be one of the factors responsible for the decrease in pain sensitivity during and after sport, comparable to the endogenous opiates (endorphines).[48]

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.[49] [50] In a blind trial reported in a conference proceeding, patients affected by pain from synovitis or TMJ osteoarthritis (N=25, in total) 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.[51] [52] 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.[53] 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)[54] —whose symptoms spanned eight pain categories ("burning", "osteoarticular", "piercing", etc.[55]) 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).[56]

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, addressing PEA's proposed anti-inflammatory and retinoprotectant effects.[57]

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.[58] [59]

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.[60] 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.[61]

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.[62]

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.[63] A 2016 pooled meta-analysis involving twelve studies found that no serious ADRs were registered and/or reported.[64] 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

Further reading

Notes and References

  1. Petrosino S, Di Marzo V . 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 . 27539936 . 5429331 . 10.1111/bph.13580.
  2. O'Sullivan SE . Cannabinoids go nuclear: evidence for activation of peroxisome proliferator-activated receptors . British Journal of Pharmacology . 152 . 5 . 576–82 . November 2007 . 17704824 . 2190029 . 10.1038/sj.bjp.0707423 .
  3. Lo Verme J, Fu J, Astarita G, La Rana G, Russo R, Calignano A, Piomelli D . The nuclear receptor peroxisome proliferator-activated receptor-alpha mediates the anti-inflammatory actions of palmitoylethanolamide . Molecular Pharmacology . 67 . 1 . 15–9 . January 2005 . 15465922 . 10.1124/mol.104.006353 . 12671741 .
  4. Godlewski G, Offertáler L, Wagner JA, Kunos G . Receptors for acylethanolamides-GPR55 and GPR119 . Prostaglandins & Other Lipid Mediators . 89 . 3–4 . 105–11 . September 2009 . 19615459 . 2751869 . 10.1016/j.prostaglandins.2009.07.001 .
  5. O'Sullivan SE, Kendall DA . Cannabinoid activation of peroxisome proliferator-activated receptors: potential for modulation of inflammatory disease . Immunobiology . 215 . 8 . 611–6 . August 2010 . 19833407 . 10.1016/j.imbio.2009.09.007 .
  6. Masek K, Perlík F . Letter: Slow encephalopathies, inflammatory responses, and arachis oil . Lancet . 2 . 7934 . 558 . September 1975 . 51386 . 10.1016/s0140-6736(75)90939-3 . 54360899 .
  7. 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 . Proceedings of the National Academy of Sciences of the United States of America . 92 . 8 . 3376–80 . April 1995 . 7724569 . 42169 . 10.1073/pnas.92.8.3376 . 1995PNAS...92.3376F . free .
  8. Walker JM, Krey JF, Chu CJ, Huang SM . Endocannabinoids and related fatty acid derivatives in pain modulation . Chemistry and Physics of Lipids . 121 . 1–2 . 159–72 . December 2002 . 12505698 . 10.1016/S0009-3084(02)00152-4 .
  9. Lambert DM, Vandevoorde S, Jonsson KO, Fowler CJ . The palmitoylethanolamide family: a new class of anti-inflammatory agents? . Current Medicinal Chemistry . 9 . 6 . 663–74 . March 2002 . 11945130 . 10.2174/0929867023370707 .
  10. Mazzari S, Canella R, Petrelli L, Marcolongo G, Leon A . 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 . 8739213 . 10.1016/0014-2999(96)00015-5 .
  11. Calignano A, La Rana G, Giuffrida A, Piomelli D . Control of pain initiation by endogenous cannabinoids . Nature . 394 . 6690 . 277–81 . July 1998 . 9685157 . 10.1038/28393 . 4418082 . 1998Natur.394..277C .
  12. Loría F, Petrosino S, Mestre L, Spagnolo A, Correa F, Hernangómez M, Guaza C, Di Marzo V, Docagne F . 6 . 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 . 18657182 . 10.1111/j.1460-9568.2008.06377.x . free . 11299981 . 10261/73342 .
  13. Costa B, Comelli F, Bettoni I, Colleoni M, Giagnoni G . The endogenous fatty acid amide, palmitoylethanolamide, has anti-allodynic and anti-hyperalgesic effects in a murine model of neuropathic pain: involvement of CB(1), TRPV1 and PPARgamma receptors and neurotrophic factors . Pain . 139 . 3 . 541–550 . October 2008 . 18602217 . 10.1016/j.pain.2008.06.003 . 7954018 .
  14. Yu HL, Deng XQ, Li YJ, Li YC, Quan ZS, Sun XY . N-palmitoylethanolamide, an endocannabinoid, exhibits antidepressant effects in the forced swim test and the tail suspension test in mice . Pharmacological Reports . 63 . 3 . 834–9 . 2011 . 21857095 . 10.1016/s1734-1140(11)70596-5 .
  15. Gagliano C, Ortisi E, Pulvirenti L, Reibaldi M, Scollo D, Amato R, Avitabile T, Longo A . 6 . Ocular hypotensive effect of oral palmitoyl-ethanolamide: a clinical trial . Investigative Ophthalmology & Visual Science . 52 . 9 . 6096–100 . August 2011 . 21705689 . 10.1167/iovs.10-7057 .
  16. Esposito E, Paterniti I, Mazzon E, Genovese T, Di Paola R, Galuppo M, Cuzzocrea S . Effects of palmitoylethanolamide on release of mast cell peptidases and neurotrophic factors after spinal cord injury . Brain, Behavior, and Immunity . 25 . 6 . 1099–112 . August 2011 . 21354467 . 10.1016/j.bbi.2011.02.006 . 11062539 .
  17. Scuderi C, Esposito G, Blasio A, Valenza M, Arietti P, Steardo L, Carnuccio R, De Filippis D, Petrosino S, Iuvone T, Di Marzo V, Steardo L . 6 . Palmitoylethanolamide counteracts reactive astrogliosis induced by β-amyloid peptide . Journal of Cellular and Molecular Medicine . 15 . 12 . 2664–74 . December 2011 . 21255263 . 4373435 . 10.1111/j.1582-4934.2011.01267.x .
  18. Hansen HS . Palmitoylethanolamide and other anandamide congeners. Proposed role in the diseased brain . Experimental Neurology . 224 . 1 . 48–55 . July 2010 . 20353771 . 10.1016/j.expneurol.2010.03.022 . 2069111 .
  19. Garcia-Ovejero D, Arevalo-Martin A, Petrosino S, Docagne F, Hagen C, Bisogno T, Watanabe M, Guaza C, Di Marzo V, Molina-Holgado E . 6 . The endocannabinoid system is modulated in response to spinal cord injury in rats . Neurobiology of Disease . 33 . 1 . 57–71 . January 2009 . 18930143 . 10.1016/j.nbd.2008.09.015 . free . 269334 . 10261/73343 .
  20. Schomacher M, Müller HD, Sommer C, Schwab S, Schäbitz WR . Endocannabinoids mediate neuroprotection after transient focal cerebral ischemia . Brain Research . 1240 . 213–20 . November 2008 . 18823959 . 10.1016/j.brainres.2008.09.019 . 26957176 .
  21. Sasso O, Russo R, Vitiello S, Raso GM, D'Agostino G, Iacono A, La Rana G, Vallée M, Cuzzocrea S, Piazza PV, Meli R, Calignano A . 6 . Implication of allopregnanolone in the antinociceptive effect of N-palmitoylethanolamide in acute or persistent pain . Pain . 153 . 1 . 33–41 . January 2012 . 21890273 . 10.1016/j.pain.2011.08.010 . 24365083 .
  22. Ware MA, Wang T, Shapiro S, Robinson A, Ducruet T, Huynh T, Gamsa A, Bennett GJ, Collet JP . 6 . Smoked cannabis for chronic neuropathic pain: a randomized controlled trial . CMAJ . 182 . 14 . E694-701 . October 2010 . 20805210 . 2950205 . 10.1503/cmaj.091414 .
  23. 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 . Proceedings of the National Academy of Sciences of the United States of America . 93 . 9 . 3984–9 . April 1996 . 8633002 . 39472 . 10.1073/pnas.93.9.3984 . 1996PNAS...93.3984S . free .
  24. Raso GM, Esposito E, Vitiello S, Iacono A, Santoro A, D'Agostino G, Sasso O, Russo R, Piazza PV, Calignano A, Meli R . 6 . Palmitoylethanolamide stimulation induces allopregnanolone synthesis in C6 Cells and primary astrocytes: involvement of peroxisome-proliferator activated receptor-α . Journal of Neuroendocrinology . 23 . 7 . 591–600 . July 2011 . 21554431 . 10.1111/j.1365-2826.2011.02152.x . 25234676 .
  25. De Filippis D, Luongo L, Cipriano M, Palazzo E, Cinelli MP, de Novellis V, Maione S, Iuvone T . 6 . Palmitoylethanolamide reduces granuloma-induced hyperalgesia by modulation of mast cell activation in rats . Molecular Pain . 7 . 1744-8069-7-3 . January 2011 . 21219627 . 3034677 . 10.1186/1744-8069-7-3 . free .
  26. Cerrato S, Brazis P, della Valle MF, Miolo A, Puigdemont A . 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 . 19625089 . 10.1016/j.vetimm.2009.06.011 .
  27. De Filippis D, D'Amico A, Cinelli MP, Esposito G, Di Marzo V, Iuvone T . 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 . 18429935 . 4496105 . 10.1111/j.1582-4934.2008.00353.x .
  28. Di Paola R, Impellizzeri D, Mondello P, Velardi E, Aloisi C, Cappellani A, Esposito E, Cuzzocrea S . 6 . Palmitoylethanolamide reduces early renal dysfunction and injury caused by experimental ischemia and reperfusion in mice . Shock . 38 . 4 . 356–66 . October 2012 . 22772472 . 10.1097/SHK.0b013e318267bbb9 . 35074720 . free .
  29. Darmani NA, Izzo AA, Degenhardt B, Valenti M, Scaglione G, Capasso R, Sorrentini I, Di Marzo V . 6 . 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 . 15910891 . 10.1016/j.neuropharm.2005.01.001 . 14828175 .
  30. Jaggar SI, Hasnie FS, Sellaturay S, Rice AS . 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 . 9696473 . 10.1016/S0304-3959(98)00041-4 . 6250848 .
  31. Farquhar-Smith WP, Rice AS . Administration of endocannabinoids prevents a referred hyperalgesia associated with inflammation of the urinary bladder . Anesthesiology . 94 . 3 . 507–13; discussion 6A . March 2001 . 11374613 . 10.1097/00000542-200103000-00023 . 1282800 . free .
  32. Calabrò RS, Gervasi G, Marino S, Mondo PN, Bramanti P . Misdiagnosed chronic pelvic pain: pudendal neuralgia responding to a novel use of palmitoylethanolamide . Pain Medicine . 11 . 5 . 781–4 . May 2010 . 20345619 . 10.1111/j.1526-4637.2010.00823.x . free .
  33. Indraccolo U, Barbieri F . 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 . 20176435 . 10.1016/j.ejogrb.2010.01.008 .
  34. Aloe L, Leon A, Levi-Montalcini R . A proposed autacoid mechanism controlling mastocyte behaviour . Agents and Actions . 39 . C145–C147 . 1993 . 7505999 . 10.1007/BF01972748 . 20577242 .
  35. Xanthos DN, Gaderer S, Drdla R, Nuro E, Abramova A, Ellmeier W, Sandkühler J . Central nervous system mast cells in peripheral inflammatory nociception . Molecular Pain . 7 . 1744-8069-7-42 . June 2011 . 21639869 . 3123586 . 10.1186/1744-8069-7-42 . free .
  36. Donvito G, Bettoni I, Comelli F, Colombo A, Costa B . Palmitoylethanolamide relieves pain and preserves pancreatic islet cells in a murine model of diabetes . CNS & Neurological Disorders Drug Targets . 14 . 4 . 452–62 . 2015 . 25921749 . 10.2174/1871527314666150429111537 .
  37. Nakagawa T, Kaneko S . Spinal astrocytes as therapeutic targets for pathological pain . Journal of Pharmacological Sciences . 114 . 4 . 347–53 . 2010 . 21081837 . 10.1254/jphs.10r04cp . free .
  38. Guasti L, Richardson D, Jhaveri M, Eldeeb K, Barrett D, Elphick MR, Alexander SP, Kendall D, Michael GJ, Chapman V . 6 . 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 . 19570201 . 2719614 . 10.1186/1744-8069-5-35 . free .
  39. Eberlein B, Eicke C, Reinhardt HW, Ring J . 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 . 18181976 . 10.1111/j.1468-3083.2007.02351.x . 22183787 .
  40. 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 Medica . 102 . 2 . 141–7 . April 2011 . 21483401 .
  41. Phan NQ, Siepmann D, Gralow I, Ständer S . Adjuvant topical therapy with a cannabinoid receptor agonist in facial postherpetic neuralgia . Journal der Deutschen Dermatologischen Gesellschaft . 8 . 2 . 88–91 . February 2010 . 19744255 . 10.1111/j.1610-0387.2009.07213.x . 36048790 .
  42. Cerrato S, Brazis P, Della Valle MF, Miolo A, Petrosino S, Di Marzo V, Puigdemont A . Effects of palmitoylethanolamide on the cutaneous allergic inflammatory response in Ascaris hypersensitive Beagle dogs . Veterinary Journal . 191 . 3 . 377–82 . March 2012 . 21601500 . 10.1016/j.tvjl.2011.04.002 .
  43. Rankin L, Fowler CJ . The Basal Pharmacology of Palmitoylethanolamide . International Journal of Molecular Sciences . 21 . 21 . 7942 . October 2020 . 33114698 . 7662788 . 10.3390/ijms21217942 . free .
  44. Artukoglu BB, Beyer C, Zuloff-Shani A, Brener E, Bloch MH . Efficacy of Palmitoylethanolamide for Pain: A Meta-Analysis . Pain Physician . 20 . 5 . 353–362 . July 2017 . 28727699 .
  45. Hatano Y, Man MQ, Uchida Y, Crumrine D, Mauro TM, Feingold KR, Elias PM, Holleran WM . 6 . 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 . 19818482 . 2859962 . 10.1016/j.jaci.2009.06.049 .
  46. Costagliola C, Romano MR, dell'Omo R, Russo A, Mastropasqua R, Semeraro F . 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 . 24827384 . 10.1089/jmf.2013.0165 .
  47. Pescosolido N, Librando A, Puzzono M, Nebbioso M . 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 . 21830944 . 10.1089/jop.2010.0191 .
  48. Koltyn KF, Brellenthin AG, Cook DB, Sehgal N, Hillard C . Mechanisms of exercise-induced hypoalgesia . The Journal of Pain . 15 . 12 . 1294–1304 . December 2014 . 25261342 . 4302052 . 10.1016/j.jpain.2014.09.006 .
  49. Petrosino S, Iuvone T, Di Marzo V . N-palmitoyl-ethanolamine: Biochemistry and new therapeutic opportunities . Biochimie . 92 . 6 . 724–7 . June 2010 . 20096327 . 10.1016/j.biochi.2010.01.006 .
  50. Keppel Hesselink JM, Kopsky DJ . 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 . 23658493 . 3643547 . 10.2147/JPR.S42417 . free .
  51. Web site: Paper: Palmitoylethanolamide Vs NSAID in the Treatment of TMJD Pain (IADR General Session (July 14-17, 2010)) . 2011-10-25 . https://archive.today/20120719064940/http://iadr.confex.com/iadr/2010barce/webprogramcd/Paper137174.html . 2012-07-19 . dead .
  52. Web site: Paper: Palmitoylethanolamide Vs NSAID In The Treatment Of TMJD Pain (IADR General Session (July 14-17, 2010)) . https://archive.today/20120719064940/http://iadr.confex.com/iadr/2010barce/webprogramcd/Paper137174.html . dead . 2012-07-19 . Archive.is . 2020-02-27.
  53. Truini A, Biasiotta A, Di Stefano G, La Cesa S, Leone C, Cartoni C, Federico V, Petrucci MT, Cruccu G . 6 . Palmitoylethanolamide restores myelinated-fibre function in patients with chemotherapy-induced painful neuropathy . CNS & Neurological Disorders Drug Targets . 10 . 8 . 916–20 . December 2011 . 22229320 . 10.2174/187152711799219307 .
  54. In the article, these appear as "neuropatia diabetica periferica... o a nevralgia post herpetica". See Desio, op. cit.
  55. These terms were "urente", "osteoarticolare", "lancinante", etc. See Table 1 in Desio, op. cit.
  56. Desio, P. . 29 November 2010 . Associazione tra pregabalin e palmitoiletanolamide (PEA) per il trattamento del dolore neuropatico . Combination of pregabalin and palmitoylethanolamide (PEA) for neuropathic pain treatment . . 2385-0744 . 17 . 4 . it, en . 9–14 . Milano, IT . Società italiana dei clinici del dolore/PubliEditing . 26 February 2020 .
  57. 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 . 151028 . 2013 . 24066256 . 3771453 . 10.1155/2013/151028 . free .
  58. Habib AM, Okorokov AL, Hill MN, Bras JT, Lee MC, Li S, Gossage SJ, van Drimmelen M, Morena M, Houlden H, Ramirez JD, Bennett DL, Srivastava D, Cox JJ . 6 . 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 . 30929760 . 6676009 . 10.1016/j.bja.2019.02.019 .
  59. 2019 . Mikaeili H, Yeung C, Habib AM, Wood JN, Okorokov AL, Cox JJ . CRISPR interference at the FAAH-OUT genomic region reduces FAAH expression . 10.1101/633396.
  60. Gigante A, Aquili A, Farinelli L, Caraffa A, Ronconi G, Enrica Gallenga C, Tetè G, Kritas SK, Conti P . 6 . Sodium chromo-glycate and palmitoylethanolamide: A possible strategy to treat mast cell-induced lung inflammation in COVID-19 . Medical Hypotheses . 143 . 109856 . October 2020 . 32460208 . 7236677 . 10.1016/j.mehy.2020.109856 . free .
  61. News: Ralston S . 9 June 2020. HUGE.CN: FSD Pharma is conducting Phase 1 clinical trial of FSD-201 for inflammation and has FDA approval for a Phase 2a clinical trial design for the treatment of COVID-19 patients. Yahoo Finance.
  62. Tsuboi K, Takezaki N, Ueda N . The N-acylethanolamine-hydrolyzing acid amidase (NAAA) . Chemistry & Biodiversity . 4 . 8 . 1914–25 . August 2007 . 17712833 . 10.1002/cbdv.200790159 . 32163665 .
  63. Gabrielsson L, Mattsson S, Fowler CJ . Palmitoylethanolamide for the treatment of pain: pharmacokinetics, safety and efficacy . British Journal of Clinical Pharmacology . 82 . 4 . 932–42 . October 2016 . 27220803 . 5094513 . 10.1111/bcp.13020 .
  64. Paladini A, Fusco M, Cenacchi T, Schievano C, Piroli A, Varrassi G . 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 . 10.36076/ppj/2016.19.11 . 26815246 . free .

This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Palmitoylethanolamide".

Except where otherwise indicated, Everything.Explained.Today is © Copyright 2009-2024, A B Cryer, All Rights Reserved. Cookie policy.