3D model (JSmol)
|Abbreviations||Palmitamide MEA|
CompTox Dashboard (EPA)
|Molar mass||299.499 g·mol−1|
|Density||910 mg mL−1|
|Melting point||93 to 98 °C (199 to 208 °F; 366 to 371 K)|
|Flash point||323.9 °C (615.0 °F; 597.0 K)|
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
|what is ?)(|
Palmitoylethanolamide (PEA) is an endogenous fatty acid amide, belonging to the class of nuclear factor agonists. PEA has been demonstrated to bind to a receptor in the cell-nucleus (a nuclear receptor) and exerts a great variety of biological functions related to chronic pain and inflammation. The main target is thought to be the peroxisome proliferator-activated receptor alpha (PPAR-α). PEA also has affinity to cannabinoid-like G-coupled receptors GPR55 and GPR119. PEA cannot strictly be considered a classic endocannabinoid because it lacks affinity for the cannabinoid receptors CB1 and CB2. However, the presence of PEA (and other structurally related N-acylethanolamines) has been known to enhance anandamide activity by an "entourage effect".
Several papers have demonstrated that an imbalance of the endocannabinoid system (ECS) and alterations in the levels of PEA occur in acute and chronic inflammation. For instance, during β-amyloid-induced neuroinflammation the deregulation of cannabinoid receptors and their endogenous ligands accompanies the development and progression of disease.
Palmitoylethanolamide was discovered in 1957. Indications for its use as an anti-inflammatory and analgesic date from before 1980. In that year, researchers described what they called "N-(2-hydroxyethyl)-palmitamide" as a natural anti-inflammatory agent. They stated: " 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."
In 1975 Czech physicians described the results of a clinical trial using it for joint pain,. The analgesic action of 3 grams of aspirin during the day was compared to PEA 1.8 gram/day. Both drugs were reported to enhance joint movements and decrease pain. In 1970 the drug manufacturer Spofa introduced "Impulsin" tablets of 500 mg PEA for the treatment and prophylaxis of flu and respiratory infections in Czechoslovakia; the company Almirall introduced "Palmidrol", as either tablets or as a suspension, in Spain in 1976 for the same indications.
In the 1990s, the relation between anandamide and PEA was described; the expression of mast cell receptors sensitive to the two molecules was first demonstrated by the research group of Nobel prize winner Rita Levi-Montalcini. 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. One group demonstrated that PEA could alleviate, in a dose-dependent manner, pain behaviors elicited in mice-pain models, and could downregulate hyperactive mast cells. PEA and related compounds such as anandamide also seem to have synergistic effects in models of pain and analgesia.
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.
In the mouse forced swimming test, palmitoylethanolamide was comparable to fluoxetine for depression. An Italian study published in 2011 found that PEA reduced the raised intraocular pressure of glaucoma. 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. 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. In models of stroke and other CNS trauma, PEA exerted neuroprotective properties.
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. As cannabinoids, such as THC, have been proven to be effective in neuropathic pain states. 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. 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. 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. PEA, as well as its analogue adelmidrol (di-amide derivative of azelaic acid), can both down-regulate mast cells. 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. 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.
PEA seems to be produced in human as well as in animals as a biological response and a repair mechanism in chronic inflammation and chronic pain. 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. 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. Chronic pelvic pain in patients seem to respond favourably to a treatment with PEA.
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. It was the group of the Nobel prize laureate Rita Levi-Montalcini who in 1993 first presented evidence that lipid amides of the N-acylethanolamine type (such as PEA) are potential prototypes of naturally occurring molecules capable of modulating mast cell activation; her group coined the acronym ALIA in that paper. 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. 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. Microglia plays a key role in the winding up phenomena and central sensitization.
PEA has been explored in humans; spanning various clinical trials in a variety of pain states, for inflammatory and pain syndromes. Its positive influence in atopic eczema for instance seems to originate from PPAR alpha activation. PEA is available for human use as a dietary supplement.
In a 2012 review, all clinical trials to date were summarized. 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. Since 2012 a number of new trials have been published, among which studies in glaucoma. 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).
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. In a blind pilot trial in 25 patients affected by temporomandibular joint's (TMJ) osteoarthritis or synovitis pain, patients were randomly to PEA or ibuprofen 600 mg three times a day for two weeks. Pain decrease after two weeks of treatment was significantly higher in PEA treated patients than in patients receiving the NSAID (p=0.0001) Masticatory function also improves more on PEA compared to the NSAID. In 2012, 20 patients suffering from thalidomide and bortezomib induced neuropathy were reported to have improved nerve functions and less pain after a two months treatment with PEA 600 mg daily. 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. 30 patients suffering from neuropathic pain, which were refractory to treatment with analgesics, included pregabalin, were responding well in 45 days, with a decrease of painscores > 50% when pregabalin was tapered in again, up to 600 mg/day in combination with PEA, without signs of drug-drug interaction. In 2013 a review was published on the clinical efficacy and safety of PEA in flu, based on a 6 double blind placebo controlled RCT's. This review underscores the anti-inflammatory action of PEA. These effects are also the explanation of PEA's retinoprotectant effects.
Significant increases in fatty acid amides including PEA, with arachidonoylethanolamide, and oleoylethanolamide were noted in 2019 of a Scottish woman with a previously undocumented variant of congenital insensitivity to pain. This was found to be caused by a combination of fatty acid amide hydrolase(FAAH) hypomorphic SNP, 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.
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. To date, no drug interactions have been reported in the literature, nor any clinically relevant or dose-limiting side effects.
- "palmidrol - Compound Summary". PubChem Compound. USA: National Center for Biotechnology Information. 25 March 2005. Identification. Retrieved 26 June 2012.
- O'Sullivan, S. E. (2007). "Cannabinoids go nuclear: evidence for activation of peroxisome proliferator-activated receptors". British Journal of Pharmacology. 152 (5): 576–582. doi:10.1038/sj.bjp.0707423. PMC 2190029. PMID 17704824.
- Lo Verme, J.; Fu, J.; Astarita, G.; La Rana, G.; Russo, R.; Calignano, A.; Piomelli, D. (2005). "The nuclear receptor peroxisome proliferator-activated receptor-alpha mediates the anti-inflammatory actions of palmitoylethanolamide". Molecular Pharmacology. 67 (1): 15–19. doi:10.1124/mol.104.006353. PMID 15465922.
- Godlewski, G.; Offertáler, L.; Wagner, J. A.; Kunos, G. (2009). "Receptors for acylethanolamides—GPR55 and GPR119". Prostaglandins & Other Lipid Mediators. 89 (3–4): 105–297. doi:10.1016/j.prostaglandins.2009.07.001. PMC 2751869. PMID 19615459.
- O'Sullivan, S. E.; Kendall, D. A. (2010). "Cannabinoid activation of peroxisome proliferator-activated receptors: Potential for modulation of inflammatory disease". Immunobiology. 215 (8): 611–616. doi:10.1016/j.imbio.2009.09.007. PMID 19833407.
- Jonsson, K. O.; Vandevoorde, S. V.; Lambert, D. M.; Tiger, G.; Fowler, C. J. (2001). "Effects of homologues and analogues of palmitoylethanolamide upon the inactivation of the endocannabinoid anandamide". British Journal of Pharmacology. 133 (8): 1263–1275. doi:10.1038/sj.bjp.0704199. PMC 1621151. PMID 11498512.
- Ho, W. S.; Barrett, D. A.; Randall, M. D. (2008). "'Entourage' effects of N-palmitoylethanolamide and N-oleoylethanolamide on vasorelaxation to anandamide occur through TRPV1 receptors". British Journal of Pharmacology. 155 (6): 837–846. doi:10.1038/bjp.2008.324. PMC 2597234. PMID 18695637.
- De Filippis, D.; d’Amico, A.; Cipriano, M.; Petrosino, S.; Orlando, P.; Di Marzo, V.; Iuvone, T.; Iuvone, T. (2010). "Levels of endocannabinoids and palmitoylethanolamide and their pharmacological manipulation in chronic granulomatous inflammation in rats". Pharmacological Research. 61 (4): 321–328. doi:10.1016/j.phrs.2009.11.005. PMID 19931394.
- d'Agostino, G.; Russo, R.; Avagliano, C.; Cristiano, C.; Meli, R.; Calignano, A. (2012). "Palmitoylethanolamide Protects Against the Amyloid-β25-35-Induced Learning and Memory Impairment in Mice, an Experimental Model of Alzheimer Disease". Neuropsychopharmacology. 37 (7): 1784–1792. doi:10.1038/npp.2012.25. PMC 3358748. PMID 22414817.
- Calignano a, L. R. G. (2001). "Antinociceptive activity of the endogenous fatty acid amide, palmitylethanolamide". Eur J Pharmacol. 419 (2–3): 191–198. doi:10.1016/S0014-2999(01)00988-8. PMID 11426841.
- Koch, M.; Kreutz, S.; Böttger, C.; Benz, A.; Maronde, E.; Ghadban, C.; Korf, H. W.; Dehghani, F. (2010). "Palmitoylethanolamide Protects Dentate Gyrus Granule Cells via Peroxisome Proliferator-Activated Receptor-Alpha". Neurotoxicity Research. 19 (2): 330–340. doi:10.1007/s12640-010-9166-2. PMID 20221904.
- Lambert DM, Vandevoorde S, Diependaele G, Govaerts SJ, Robert AR (2001). "Anticonvulsant activity of N-palmitoylethanolamide, a putative endocannabinoid, in mice". Epilepsia. 42 (3): 321–7. doi:10.1046/j.1528-1157.2001.41499.x. PMID 11442148.
- Masek, K.; Perlík, F. (1975). "Letter: Slow encephalopathies, inflammatory responses, and arachis oil". Lancet. 2 (7934): 558. doi:10.1016/s0140-6736(75)90939-3. PMID 51386.
- Facci, L.; Dal Toso, R.; Romanello, S.; Buriani, A.; Skaper, S. D.; Leon, A. (1995). "Mast cells express a peripheral cannabinoid receptor with differential sensitivity to anandamide and palmitoylethanolamide". PNAS. 92 (8): 3376–3380. doi:10.1073/pnas.92.8.3376. PMC 42169. PMID 7724569.
- Walker, J. M.; Krey, J. F.; Chu, C. J.; Huang, S. M. (2002). "Endocannabinoids and related fatty acid derivatives in pain modulation". Chemistry and Physics of Lipids. 121 (1–2): 159–172. doi:10.1016/s0009-3084(02)00152-4. PMID 12505698.
- Lambert, D. M.; Vandevoorde, S.; Jonsson, K. O.; Fowler, C. J. (2002). "The palmitoylethanolamide family: A new class of anti-inflammatory agents?". Current Medicinal Chemistry. 9 (6): 663–674. doi:10.2174/0929867023370707. PMID 11945130.
- Mazzari, S.; Canella, R.; Petrelli, L.; Marcolongo, G.; Leon, A. (1996). "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): 227–236. doi:10.1016/0014-2999(96)00015-5. PMID 8739213.
- Piomelli, D.; Calignano, A.; Rana, G. L.; Giuffrida, A. (1998). "Control of pain initiation by endogenous cannabinoids". Nature. 394 (6690): 277–281. doi:10.1038/28393. PMID 9685157.
- Loría, F.; Petrosino, S.; Mestre, L.; Spagnolo, A.; Correa, F.; Hernangómez, M.; Guaza, C.; Di Marzo, V.; Docagne, F. (2008). "Study of the regulation of the endocannabinoid system in a virus model of multiple sclerosis reveals a therapeutic effect of palmitoylethanolamide". European Journal of Neuroscience. 28 (4): 633–641. doi:10.1111/j.1460-9568.2008.06377.x. hdl:10261/73342. PMID 18657182.
- Costa, B.; Comelli, F.; Bettoni, I.; Colleoni, M.; Giagnoni, G. (2008). "The endogenous fatty acid amide, palmitoylethanolamide, has anti-allodynic and anti-hyperalgesic effects in a murine model of neuropathic pain: Involvement of CB1, TRPV1 and PPARγ receptors and neurotrophic factors". Pain. 139 (3): 541–550. doi:10.1016/j.pain.2008.06.003. PMID 18602217.
- Yu, H. L.; Deng, X. Q.; Li, Y. J.; Li, Y. C.; Quan, Z. S.; Sun, X. Y. (2011). "N-palmitoylethanolamide, an endocannabinoid, exhibits antidepressant effects in the forced swim test and the tail suspension test in mice". Pharmacological Reports : PR. 63 (3): 834–839. doi:10.1016/s1734-1140(11)70596-5. PMID 21857095.
- Gagliano, C.; Ortisi, E.; Pulvirenti, L.; Reibaldi, M.; Scollo, D.; Amato, R.; Avitabile, T.; Longo, A. (2011). "Ocular Hypotensive Effect of Oral Palmitoyl-ethanolamide: A Clinical Trial". Investigative Ophthalmology & Visual Science. 52 (9): 6096–6100. doi:10.1167/iovs.10-7057. PMID 21705689.
- Esposito, E.; Paterniti, I.; Mazzon, E.; Genovese, T.; Di Paola, R.; Galuppo, M.; Cuzzocrea, S. (2011). "Effects of palmitoylethanolamide on release of mast cell peptidases and neurotrophic factors after spinal cord injury". Brain, Behavior, and Immunity. 25 (6): 1099–1112. doi:10.1016/j.bbi.2011.02.006. PMID 21354467.
- Scuderi, C.; Esposito, G.; Blasio, A.; Valenza, M.; Arietti, P.; Steardo Jr, L.; Carnuccio, R.; De Filippis, D.; Petrosino, S.; Iuvone, T.; Di Marzo, V. D.; Steardo, L. (2011). "Palmitoylethanolamide counteracts reactive astrogliosis induced by beta-amyloid peptide". Journal of Cellular and Molecular Medicine. 15 (12): 2664–2674. doi:10.1111/j.1582-4934.2011.01267.x. PMC 4373435. PMID 21255263.
- Hansen, H. S. (2010). "Palmitoylethanolamide and other anandamide congeners. Proposed role in the diseased brain". Experimental Neurology. 224 (1): 48–55. doi:10.1016/j.expneurol.2010.03.022. PMID 20353771.
- Garcia-Ovejero, D.; Arevalo-Martin, A.; Petrosino, S.; Docagne, F.; Hagen, C.; Bisogno, T.; Watanabe, M.; Guaza, C.; Di Marzo, V.; Molina-Holgado, E. (2009). "The endocannabinoid system is modulated in response to spinal cord injury in rats". Neurobiology of Disease. 33 (1): 57–71. doi:10.1016/j.nbd.2008.09.015. hdl:10261/73343. PMID 18930143.
- Schomacher, M.; Müller, H. D.; Sommer, C.; Schwab, S.; Schäbitz, W. R. D. (2008). "Endocannabinoids mediate neuroprotection after transient focal cerebral ischemia". Brain Research. 1240: 213–220. doi:10.1016/j.brainres.2008.09.019. PMID 18823959.
- Sasso, O.; Russo, R.; Vitiello, S.; Raso, G.; d'Agostino, G.; Iacono, A.; Rana, G.; Vallée, M.; Cuzzocrea, S.; Piazza, P. V.; Meli, R.; Calignano, A. (2011). "Implication of allopregnanolone in the antinociceptive effect of N-palmitoylethanolamide in acute or persistent pain". Pain. 153 (1): 33–41. doi:10.1016/j.pain.2011.08.010. PMID 21890273.
- Ware, M. A.; Wang, T.; Shapiro, S.; Robinson, A.; Ducruet, T.; Huynh, T.; Gamsa, A.; Bennett, G. J.; Collet, J. -P. (2010). "Smoked cannabis for chronic neuropathic pain: A randomized controlled trial". Canadian Medical Association Journal. 182 (14): E694–E701. doi:10.1503/cmaj.091414. PMC 2950205. PMID 20805210.
- Skaper, S. D.; Buriani, A.; Dal Toso, R.; Petrelli, L.; Romanello, S.; Facci, L.; Leon, A. (1996). "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): 3984–3989. doi:10.1073/pnas.93.9.3984. PMC 39472. PMID 8633002.
- Raso GM, Esposito E, Vitiello S, Iacono A, Santoro A, D'Agostino G, et al. (July 2011). "Palmitoylethanolamide stimulation induces allopregnanolone synthesis in C6 Cells and primary astrocytes: involvement of peroxisome-proliferator activated receptor-α". J. Neuroendocrinol. 23 (7): 591–600. doi:10.1111/j.1365-2826.2011.02152.x. PMID 21554431.
- De Filippis, D.; Luongo, L.; Cipriano, M.; Palazzo, E.; Cinelli, M. P.; De Novellis, V.; Maione, S.; Iuvone, T. (2011). "Palmitoylethanolamide reduces granuloma-induced hyperalgesia by modulation of mast cell activation in rats". Molecular Pain. 7: 1744–8069–7–3. doi:10.1186/1744-8069-7-3. PMC 3034677. PMID 21219627.
- Cerrato, S.; Brazis, P.; Della Valle, M. F.; Miolo, A.; Puigdemont, A. (2010). "Effects of palmitoylethanolamide on immunologically induced histamine, PGD2 and TNFα release from canine skin mast cells". Veterinary Immunology and Immunopathology. 133 (1): 9–15. doi:10.1016/j.vetimm.2009.06.011. PMID 19625089.
- De Filippis, D.; d’Amico, A.; Cinelli, M. P.; Esposito, G.; Di Marzo, V.; Iuvone, T. (2009). "Adelmidrol, a palmitoylethanolamide analogue, reduces chronic inflammation in a carrageenin-granuloma model in rats". Journal of Cellular and Molecular Medicine. 13 (6): 1086–1095. doi:10.1111/j.1582-4934.2008.00353.x. PMC 4496105. PMID 18429935.
- Di Paola, R.; Impellizzeri, D.; Mondello, P.; Velardi, E.; Aloisi, C.; Cappellani, A.; Esposito, E.; Cuzzocrea, S. (2012). "Palmitoylethanolamide Reduces Early Renal Dysfunction and Injury Caused by Experimental Ischemia and Reperfusion in Mice". Shock. 38 (4): 356–66. doi:10.1097/SHK.0b013e318267bbb9. PMID 22772472.
- Darmani, N. A.; Izzo, A. A.; Degenhardt, B.; Valenti, M.; Scaglione, G.; Capasso, R.; Sorrentini, I.; Di Marzo, V. (2005). "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): 1154–1163. doi:10.1016/j.neuropharm.2005.01.001. PMID 15910891.
- Jaggar, S. I.; Hasnie, F. S.; Sellaturay, S.; Rice, A. S. (1998). "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): 189–199. doi:10.1016/S0304-3959(98)00041-4. PMID 9696473.
- Farquhar-Smith, W. P.; Rice, A. S. (2001). "Administration of endocannabinoids prevents a referred hyperalgesia associated with inflammation of the urinary bladder". Anesthesiology. 94 (3): 507–513, discussion 513. doi:10.1097/00000542-200103000-00023. PMID 11374613.
- Calabrò, R. S.; Gervasi, G.; Marino, S.; Mondo, P. N.; Bramanti, P. (2010). "Misdiagnosed Chronic Pelvic Pain: Pudendal Neuralgia Responding to a Novel Use of Palmitoylethanolamide". Pain Medicine. 11 (5): 781–784. doi:10.1111/j.1526-4637.2010.00823.x. PMID 20345619.
- Indraccolo, U.; Barbieri, F. (2010). "Effect of palmitoylethanolamide–polydatin combination on chronic pelvic pain associated with endometriosis: Preliminary observations". European Journal of Obstetrics & Gynecology and Reproductive Biology. 150 (1): 76–79. doi:10.1016/j.ejogrb.2010.01.008. PMID 20176435.
- Buznikov, G. A.; Nikitina, L. A.; Bezuglov, V. V.; Francisco, M. E. Y.; Boysen, G.; Obispo-Peak, I. N.; Peterson, R. E.; Weiss, E. R.; Schuel, H.; Temple, B. R. S.; Morrow, A. L.; Lauder, J. M. (2010). "A Putative 'Pre-Nervous' Endocannabinoid System in Early Echinoderm Development". Developmental Neuroscience. 32 (1): 1–18. doi:10.1159/000235758. PMC 2866581. PMID 19907129.
- Aloe, L.; Leon, A.; Levi-Montalcini, R. (1993). "A proposed autacoid mechanism controlling mastocyte behaviour". Agents and Actions. 39 Spec No: C145–C147. PMID 7505999.
- Xanthos, D. N.; Gaderer, S.; Drdla, R.; Nuro, E.; Abramova, A.; Ellmeier, W.; Sandkühler, J. R. (2011). "Central nervous system mast cells in peripheral inflammatory nociception". Molecular Pain. 7: 1744–8069–7–42. doi:10.1186/1744-8069-7-42. PMC 3123586. PMID 21639869.
- Donvito, G; Bettoni, I; Comelli, F; Colombo, A; Costa, B (2015). "Palmitoylethanolamide relieves pain and preserves pancreatic islet cells in a murine model of diabetes". CNS & Neurological Disorders Drug Targets. 14 (4): 452–62. PMID 25921749.
- Nakagawa, T.; Kaneko, S. (2010). "Spinal astrocytes as therapeutic targets for pathological pain". Journal of Pharmacological Sciences. 114 (4): 347–353. doi:10.1254/jphs.10r04cp. PMID 21081837.
- Guasti, L.; Richardson, D.; Jhaveri, M.; Eldeeb, K.; Barrett, D.; Elphick, M. R.; Alexander, S. P.; Kendall, D.; Michael, G. J.; Chapman, V. (2009). "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. doi:10.1186/1744-8069-5-35. PMC 2719614. PMID 19570201.
- Eberlein, B.; Eicke, C.; Reinhardt, H. -W.; Ring, J. (2007). "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. doi:10.1111/j.1468-3083.2007.02351.x. PMID 18181976.
- Conigliaro, R.; Drago, V.; Foster, P. S.; Schievano, C.; Di Marzo, V. (2011). "Use of palmitoylethanolamide in the entrapment neuropathy of the median in the wrist". Minerva Medica. 102 (2): 141–147. PMID 21483401.
- Phan, N. Q.; Siepmann, D.; Gralow, I.; Ständer, S. (2009). "Adjuvant topical therapy with a cannabinoid receptor agonist in facial postherpetic neuralgia". Journal der Deutschen Dermatologischen Gesellschaft. 8 (2): 88–91. doi:10.1111/j.1610-0387.2009.07213.x. PMID 19744255.
- Cerrato, S.; Brazis, P.; Valle, M. F. D.; Miolo, A.; Petrosino, S.; Marzo, V. D.; Puigdemont, A. (2011). "Effects of palmitoylethanolamide on the cutaneous allergic inflammatory response in Ascaris hypersensitive Beagle dogs". The Veterinary Journal. 191 (3): 377–82. doi:10.1016/j.tvjl.2011.04.002. PMID 21601500.
- Hatano, Y.; et al. (2010). "Murine atopic dermatitis responds to peroxisome proliferator-activated receptor α, β/δ(but not γ), and liver-X-receptor activators". Journal of Allergy and Clinical Immunology. 125 (1): 160–169.e1–169. doi:10.1016/j.jaci.2009.06.049. PMC 2859962. PMID 19818482.
- Jan M. Keppel Hesselink (2012). "New Targets in Pain, Non-Neuronal Cells, and the Role of Palmitoylethanolamide" (PDF). The Open Pain Journal. 5: 12–23. doi:10.2174/1876386301205010012.
- Costagliola, C; Romano, M. R.; Dell'Omo, R; Russo, A; Mastropasqua, R; Semeraro, F (2014). "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. doi:10.1089/jmf.2013.0165. PMID 24827384.
- Pescosolido, N; Librando, A; Puzzono, M; Nebbioso, M (2011). "Palmitoylethanolamide effects on intraocular pressure after Nd:YAG laser iridotomy: An experimental clinical study". Journal of Ocular Pharmacology and Therapeutics. 27 (6): 629–35. doi:10.1089/jop.2010.0191. PMID 21830944.
- Koltyn, K. F.; Brellenthin, A. G.; Cook, D. B.; Sehgal, N; Hillard, C (2014). "Mechanisms of exercise-induced hypoalgesia". The Journal of Pain. 15 (12): 1294–1304. doi:10.1016/j.jpain.2014.09.006. PMC 4302052. PMID 25261342.
- Petrosino, S.; Iuvone, T.; Di Marzo, V. (2010). "N-palmitoyl-ethanolamine: Biochemistry and new therapeutic opportunities". Biochimie. 92 (6): 724–727. doi:10.1016/j.biochi.2010.01.006. PMID 20096327.
- Keppel Hesselink JM, Kopsky DJ (2013). "Treatment of chronic regional pain syndrome type 1 with palmitoylethanolamide and topical ketamine cream: Modulation of nonneuronal cells". Journal of Pain Research. 6: 239–245. doi:10.2147/JPR.S42417. PMC 3643547. PMID 23658493.
- Palmitoylethanolamide Vs NSAID In The Treatment Of TMJD Pain Archived 2012-07-19 at Archive.today
- Truini, A.; et al. (2012). "Palmitoylethanolamide Restores Myelinated-Fibre Function in Patients with Chemotherapy-Induced Painful Neuropathy". CNS & Neurological Disorders Drug Targets. 10 (8): 916–20. doi:10.2174/187152711799219307. PMID 22229320.
- Desio P. (2010). "Pregabalin and Palmitoylethanolamide in the treatment of neuropathic pain". Pathos. 17 (4): 9–14.
- Keppel Hesselink JM, de Boer T, Witkamp RF (2013). "Palmitoylethanolamide: A Natural Body-Own Anti-Inflammatory Agent, Effective and Safe against Influenza and Common Cold". International Journal of Inflammation. 2013: 1–8. doi:10.1155/2013/151028. PMC 3771453. PMID 24066256.
- Habib AM, Okorokov A, 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 (2019). "Microdeletion in a pseudogene identified in a patient with high anandamide concentrations and pain insensitivity". British Journal of Anaesthesia. 123: 249–253. doi:10.1016/j.bja.2019.02.019. PMID 30929760.
- Tsuboi, K.; Takezaki, N.; Ueda, N. (2007). "The N-Acylethanolamine-Hydrolyzing Acid Amidase (NAAA)". Chemistry & Biodiversity. 4 (8): 1914–25. doi:10.1002/cbdv.200790159. PMID 17712833.