What is PEA?
PEA (palmitoylethanolamide) is a fatty acid amide molecule which has been shown to have anti-inflammatory properties, especially relating to neuropathic pain, and modulate immune system responses. It can be found in plant, human, and animal tissues. When the body experiences pain or inflammation, levels of endogenous PEA increase. 
The nutraceutical PEA was discovered by a chain of many scientists and researchers, each capitulating on each other’s observations and research and eventually fostering its successful molecular identification and isolation. Its long and interesting history begins with a scientist in 1957 who, after studying Strep-A rheumatic fever in underprivileged children, noticed that the children fed supplemental dried egg yolk fared better and did not develop rheumatic fever, despite infection with Strep-A. Later, it was isolated from the dried egg yolk and is now a known constituent contained in soy lecithin. Since the 1970s, PEA has been studied for its immune-modulating properties which have been applied towards studying its effects on the common cold and the influenza virus. More recently, it has been studied for its effects on pain and inflammation. 
Two American bacteriologists, Coburn and Moore, spearheaded the study of PEA starting in 1939. They studied children from an American population which had been exposed repeatedly to group-A streptococcal infections and had suffered repeated bouts of rheumatic fever. Coburn noted that these children were impoverished and malnourished and designed a field study to determine if extra nutrition could mitigate the effects of rheumatic fever.
The children were divided into three groups. One group was fed their normal diets; one group was fed whole food sources of nutrition and were given two eggs, meat, a quart of milk, butter, and fish oil (halibut-liver oil) daily; and the third group continued their normal diet but were given an addition of dried powdered egg yolk, equivalent to six eggs per day.
Coburn noted that the children who continued their normal, nutritionally inadequate diet experienced a higher recurrence of rheumatic fever (11 children became sick). The children who were fed the enriched, whole food source diet only had 3 recurrences, and the group fed dried egg yolk only had 1 recurrence of rheumatic fever.
The children fed dried egg yolk tested positive for Strep-A in their blood, but they did not have any recurrence of rheumatic fever. This correlation led Coburn and Moore to investigate what compounds were in the dried egg yolk which could have these effects.
In 1954, Coburn and his colleagues isolated and identified a phospholipid fraction in egg yolk which exerted antiallergic properties. Though still in the stage of animal research, the phospholipid fraction was purified in 1956 by scientists Long and Martin. This purified fraction biochemically resembled compounds isolated earlier from peanuts in 1950. This compound appeared to be related to a compound known at that time as “vegetable lecithin.”
Together, these two isolated compounds would come together to form PEA. In 1957, scientist Kuehl Jr. and his colleagues were able to isolate the anti-inflammatory factor in crystalline form from a vegetable lecithin derived from soy (soy lecithin). Kuehl identified it as N-(2-hydroxyethyl)-palmitamide. Pursuing the earlier studies into egg yolk and its anti-inflammatory properties, Kuehl found the same compound in a phospholipid fraction within the egg yolk and also in peanut meal. This successfully identified the active compound in egg yolk which had first been empirically noted by Coburn and Moore.
Kuehl went on to hydrolyze the N-(2-hydroxyethyl)-palmitamide into two smaller substances: palmitic acid and ethanolamine. This hydrolyzed compound was then referred to as PEA. Kuehl substantiated that the molecule of PEA itself was the active molecule accountable for the anti-inflammatory effects seen by Coburn and Moore.
Coburn and Moore went on to conduct three more field studies in children supplemented with egg-yolk powder, and their research accrued traction in the scientific community. PEA’s anti-inflammatory effects became well-known, and PEA was recognized in the muscle, liver, and brain tissue of the guinea pig and rat during animal research. Later, it was discovered that PEA is endogenously produced within the human body and could be detected in blood plasma samples.
Interest in PEA reached a turning point by the 1970s, when the consensus on PEA had gone beyond its effects on inflammation and were now being noted for its effects on the immune system and immunological processes. Within the last 50 years, over three hundred scholarly papers have mentioned PEA and its pharmacological properties.
PEA studies were then directed towards the influenza virus, the common cold, and other respiratory viruses and respiratory inflammations from 1971-1980. This focus included over six clinical trials where PEA was found to be an effective and safe treatment. As the late twentieth-century progressed into the 1990s, PEA was tested in the animal model for broader applications, researching its role in pain relief. 
PEA’s role in pain relief and inflammation was made famous by the work of Professor Rita Levi-Montalcini who won a Nobel Prize in 1993 for her discovery that PEA moderated overactive mast cells. Since the connection between mast cells, inflammation, and pain was made by Levi-Montalcini, PEA’s effects for neuropathic pain (both central and peripheral), osteoarthritic pain, multiple sclerosis, traumatic brain injury, Alzheimer’s disease, and other conditions resulting in pain has since been studied. 
How does PEA work?
Inhibiting Pro-Inflammatory Molecules
PEA works directly to reduce inflammation by inhibiting inflammatory cytokines. Cytokines are proteins that function as intracellular messengers. Specifically, PEA inhibits the secretion of a cytokine called tumor necrosis factor alpha (TNF alpha). Perhaps the biggest effect on inflammation which PEA exerts is over interleukins, a type of cytokine that is a protein which helps cells communicate. Like TNF alpha, interleukins are secreted during the inflammation process, and they are part of the immunological system. 
PEA is synthesized in the body from one of the most common fatty acids, palmitic acid. Palmitic acid is produced through the synthesis of fatty acids and is also found in dietary sources such as dairy, butter, meats, palm tree oil, and cheeses. There are several routes in the body PEA can take to be synthesized, but most pathways are through their precursors, NAPEs (N-acylphosphatidylethanolamines) or NAEs (N-acylethanolamine).
Despite one of the pathways for synthesis involving dietary fatty acids, PEA is not affected by varying levels of dietary fatty acid intake, with the exception of the small intestine. Within the small intestine, dietary fatty intake counterintuitively reduces the amounts of PEA and their precursors NAE. Therefore, consuming dietary fatty acids in an attempt to stimulate more production of endogenous PEA will not be an effective strategy. 
PEA and the Endocannabinoid System
PEA indirectly activates the endocannabinoid system within the body. The ECS (endocannabinoid system) contains fat based neurotransmitters and proteins that bind with cannabinoid receptors in the brain and peripheral nervous system. The current understanding of the ECS is that it is involved in processes such as pain-sensation, immune system activity, fertility, pre/post-natal development, mood, and memory.
PEA is believed to activate endocannabinoid receptors similar to CB2, rather than have a direct, particular affinity for the receptors CB1 and CB2. PEA’s effects occur through an entourage effect. 
Benefits of PEA
PEA has been studied in several clinical trials, and there is quite a large amount of clinical trials and studies that have confirmed it can relieve pain.
—Reduced lower back pain and sciatic pain 
A double-blind, placebo-controlled study from 2015 confirmed pain reduction in the pain related to nerve compression syndromes, such as sciatic pain and carpal tunnel syndrome. PEA successfully achieved a 50% reduction in pain 1.5-3 weeks after beginning treatment. 
PEA seemed to bolster the effect of pharmaceutical analgesics, such as oxycodone, in patients with sciatic and back pain, vertebral stenosis, and hernia when previous treatment with analgesics alone did not offer pain relief. 
—Reduced arthritis, back pain after surgery (failed back surgery syndrome) 
—Reduced pain from fibromyalgia 
An observational study added PEA to a combination of the medications pregabalin and duloxetine (medications used to relieve nerve pain). The introduction of PEA to this combination significantly improved pain symptoms better than the other two pharmaceutical medications on their own. 
—Reduced pain from endometriosis 
A study from 2013 in women with severe pelvic pain from endometriosis took PEA supplements, along with polydatin (a form of resveratrol), for 90 days and experienced a decrease in pelvic pain and a decrease of the need to use NSAIDs (nonsteroidal anti-inflammatory drugs). 
In a randomized, double-blind, and placebo-controlled study from 2016,
PEA (an ultramicronized form) was combined with the subcutaneous injection of the autoimmune medication Interferon in patients with Multiple Sclerosis. The study noted that the patients’ pain level improved, and they saw less inflammation at the injection site. 
Brain Recovery after Injury or Disease
In humans, one of the studies found that supplementing PEA with the antioxidant flavonoid luteolin improved cognitive function after a stroke.
In this 2016 study, the combination of PEA and luteolin improved daily and cognitive function and pain in stroke patients after 30 days of treatment. 
PEA has been studied in several trials with mice for reducing damage from neurodegenerative diseases such as Parkinson’s or damage from spinal cord injuries. 
In a double-blind, randomized, placebo-controlled study in 2018, PEA was added to existing pharmacological therapy for adults with major depressive disorder (MDD). The combination of PEA and the medication citalopram improved depressive symptoms better than citalopram alone. 
Several studies from the 1970s showed PEA to be effective at reducing the incidence of serological infection and severity of symptoms from the virus that causes the common cold and the influenza virus. 
Safety and Side Effects of PEA
Despite most of the studies only tracking consumption of PEA over short periods of time (usually a two-week period), there have been several clinical trials conducted in humans for which no side effects were noted. Most of the evidence for PEA’s safety in both rodents and humans shows very few adverse effects even at high doses (around 1200 mg of micronized PEA daily). 
Where to Buy
PEA is available by itself, or in combination with other supplements. PEA + Luteolin is also available if you're specifically looking for the benefits that combination may provide.
PEA (only) Capsules:
PEA + Luteolin Capsules:
- Hesselink, J. M. Keppel, et al. “Palmitoylethanolamide: A Natural Body-Own Anti-Inflammatory Agent, Effective and Safe against Influenza and Common Cold.” International Journal of Inflammation, vol. 2013, no. 151028, 27 Aug. 2013, doi:https://doi.org/10.1155/2013/151028. https://www.hindawi.com/journals/iji/2013/151028/
- Hesselink JMK (2013) Professor Rita Levi-Montalcini on Nerve Growth Factor, Mast Cells and Palmitoylethanolamide, an Endogenous Anti-Inflammatory and Analgesic Compound. J Pain Relief 2:114. doi: 10.4172/2167-0846.1000114. https://www.omicsonline.org/open-access/professor-rita-levi-montalcini-on-nerve-growth-factor-mast-cells-and-palmitoylethanolamide-an-endogenous-anti-inflammatory-and-analgesic-compound-2167-0846.1000114.php?aid=12372
- “Interleukin.” Encylopaedia Brittanica, https://www.britannica.com/science/interleukin.
- “Cytokine.” Encylopaedia Brittanica, https://www.britannica.com/science/cytokine
- Guida, F et al. “Palmitoylethanolamide induces microglia changes associated with increased migration and phagocytic activity: involvement of the CB2 receptor.” Scientific reportsvol. 7,1 375. 23 Mar. 2017, doi:10.1038/s41598-017-00342-1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5428303/
- “Endocannabinoid System.” Wikipedia, https://en.wikipedia.org/wiki/Endocannabinoid_system.
- Bouaziz, Jerome, et al. “The Clinical Significance of Endocannabinoids in Endometriosis Pain Management.” Cannabis and Cannabinoid Research, vol. 2, no. 1, 1 Apr. 2017, doi:https://doi.org/10.1089/can.2016.0035. https://www.liebertpub.com/doi/full/10.1089/can.2016.0035
- Davis, MP, et al. “The Potential Benefits of Palmitoylethanolamide in Palliation: A Qualitative Systematic Review.” Am J Hosp Palliat Care, vol. 36, no. 12, Dec. 2019, pp. 1134–1154., doi:10.1177/1049909119850807. https://www.ncbi.nlm.nih.gov/pubmed/31113223
- Hesselink, JM Keppel, and DJ Kopsky. “Palmitoylethanolamide, a Neutraceutical, in Nerve Compression Syndromes: Efficacy and Safety in Sciatic Pain and Carpal Tunnel Syndrome.” J Pain Res., vol. 8, 23 Oct. 2015, pp. 729–734., doi:10.2147/JPR.S93106. https://www.ncbi.nlm.nih.gov/pubmed/26604814
- Keppel Hesselink, Jan M, and David J Kopsky. “Palmitoylethanolamide, a neutraceutical, in nerve compression syndromes: efficacy and safety in sciatic pain and carpal tunnel syndrome.” Journal of pain researchvol. 8 729-34. 23 Oct. 2015, doi:10.2147/JPR.S93106. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631430/
- Del Giorno, R, et al. “Palmitoylethanolamide in Fibromyalgia: Results from Prospective and Retrospective Observational Studies.” Pain Ther, vol. 4, no. 2, Dec. 2015, doi:10.1007/s40122-015-0038-6.
- Lo Monte, G, et al. “[Administration of Micronized Palmitoylethanolamide (PEA)-Transpolydatin in the Treatment of Chronic Pelvic Pain in Women Affected by Endometriosis: Preliminary Results].” Minerva Ginecol, vol. 65, no. 4, Aug. 2013, pp. 453–63., https://www.ncbi.nlm.nih.gov/pubmed/24051945.
- Orefice, Nicola S et al. “Oral Palmitoylethanolamide Treatment Is Associated with Reduced Cutaneous Adverse Effects of Interferon-β1a and Circulating Proinflammatory Cytokines in Relapsing-Remitting Multiple Sclerosis.” Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeuticsvol. 13,2 (2016): 428-38. doi:10.1007/s13311-016-0420-z. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4824021/
- Siracusa, R, et al. “The Association of Palmitoylethanolamide with Luteolin Decreases Neuroinflammation and Stimulates Autophagy in Parkinson's Disease Model.” CNS Neurol Disord Drug Targets, vol. 14, no. 10, 2015, pp. 1350–65., https://www.ncbi.nlm.nih.gov/pubmed/26295827.
- Avagliano, C, et al. “Palmitoylethanolamide Protects Mice against 6-OHDA-Induced Neurotoxicity and Endoplasmic Reticulum Stress: In Vivo and in Vitro Evidence.” Pharmacol Res., vol. 113, no. A, Nov. 2016, doi:10.1016/j.phrs.2016.09.004.
- Crupi, R, et al. “Co-Ultramicronized Palmitoylethanolamide/Luteolin Promotes Neuronal Regeneration after Spinal Cord Injury.” Front Pharmacol, vol. 7, no. 47, 8 Mar. 2016, doi:10.3389/fphar.2016.00047.
- Caltagirone, C, et al. “Co-Ultramicronized Palmitoylethanolamide/Luteolin in the Treatment of Cerebral Ischemia: from Rodent to Man.” Transl Stroke Res., vol. 7, no. 1, Feb. 2016, pp. 54–69., doi:10.1007/s12975-015-0440-8.
- Ghazizadeh-Hashemi, Maryam, et al. “Palmitoylethanolamide as Adjunctive Therapy in Major Depressive Disorder: A Double-Blind, Randomized and Placebo-Controlled Trial.” Journal of Affective Disorders, vol. 232, May 2018, pp. 127–133., doi:https://doi.org/10.1016/j.jad.2018.02.057.
- Keppel Hesselink, Jan M et al. “Palmitoylethanolamide, a Natural Retinoprotectant: Its Putative Relevance for the Treatment of Glaucoma and Diabetic Retinopathy.” Journal of ophthalmologyvol. 2015 (2015): 430596. doi:10.1155/2015/430596. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4667059/
- Costagliola, C, et al. “Effect of Palmitoylethanolamide on Visual Field Damage Progression in Normal Tension Glaucoma Patients: Results of an Open-Label Six-Month Follow-up.” J Med Food, vol. 17, no. 9, Sept. 2014, doi:10.1089/jmf.2013.0165. https://www.ncbi.nlm.nih.gov/pubmed/24827384
- Pescosolido, N, et al. “Palmitoylethanolamide Effects on Intraocular Pressure after Nd:YAG Laser Iridotomy: an Experimental Clinical Study.” J Ocul Pharmacol Ther, vol. 27, no. 6, Dec. 2011, pp. 629–35., doi:10.1089/jop.2010.019. https://www.ncbi.nlm.nih.gov/pubmed/21830944
- Nestmann, Earle R. “Safety of micronized palmitoylethanolamide (microPEA): lack of toxicity and genotoxic potential.” Food science & nutritionvol. 5,2 292-309. 15 Jun. 2016, doi:10.1002/fsn3.392. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5332261/