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Think of your brain as an ocean, an ecosystem inhabited by numerous species of fish-like neurotransmitters and their receptors, with currents of electricity connecting and delicately balancing all the different components. Inflammation is like a bloom of red algae, harming everything around it and upsetting the homeostasis of the environment.<\/p>\n
Enter our hero, Palmitoylethanolamide (PEA<\/span>) \u2013 a lipid messenger kindred to the endocannabinoid system and a close cousin of anandamide (AEA<\/span>), the famous endocannabinoid neurotransmitter. Sometimes referred to as \u201cthe endogenous version of CBD<\/span>,\u201d PEA<\/span> is a powerhouse against inflammation and pain. Like CBD<\/span>, PEA<\/span> increases the levels of endocannabinoids and strengthens the endocannabinoid system. And, again like CBD<\/span>, a constant theme in the scientific literature about PEA<\/span> is its incredibly strong safety profile.<\/p>\nIn our neural ocean metaphor, PEA<\/span> weighs in as the \u201cmost venerable of the leviathans,\u201d the grinning Right Whale, a stalwart fighter in our constant battle against inflammation and pain.<\/p>\nA Mystery<\/h2>\n The PEA<\/span> story begins with a mystery, which leads to another mystery \u2013 and ends with the next great wave of the cannabinoid revolution.<\/p>\nWe begin during World War 2 \u2013 and indeed, geopolitics plays a significant role in our tale. Because of the war effort, we find it a prosperous time for the new-ish field known as \u201cpublic health.\u201d A healthy population of workers was essential to support the production of war materiel. Two NYC<\/span> doctors named Coburn and Moore found that if they gave dried eggs to the poor children of the tenements, this helped to prevent rheumatic fever and other ills related to poor nutrition. They also discovered that egg yolks are an anti-inflammatory food.<\/p>\nUsually, when a plant or food is found to have unique health properties, scientists dig in to find the specific molecules responsible for the beneficial effect. And usually these are proteins because proteins are the workhorses of the cell. But in this case, as the researchers separated the various classes of molecules involved, they realized that it was the lipids \u2013 the fatty molecules \u2013 that caused the positive health effects.<\/p>\n
Proteins may be the workhorses, but they\u2019re more binary; usually they are either on or off. Lipids act in a more analog manner. Our cells are adept at sensing even minute changes in lipid levels and responding accordingly. While scientists used to think of lipids as just the foodstuff of cells, now we know them to be a finely tuned cellular system primed to find homeostasis and balance. But how do these fatty components of eggs work to maintain homeostasis?<\/p>\n
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Lipid Mechanisms<\/h2>\n The first big breakthrough occurred in the 1950s when a team led by Dr. F.A.<\/span> Kuehl identified the active anti-inflammatory ingredient in egg yolks to be palmitoylethanolamide. He also found the same molecule in soybeans and peanuts, two other anti-inflammatory foods.<\/p>\nBut scientists struggled to understand the mechanisms that caused this intriguing lipid to influence inflammation. During the 1960s, some papers in animal models were published confirming the anti-inflammatory effects of PEA<\/span>. And in an important turn of events, a team led by Dr. S. Udenfriend discovered that PEA<\/span> naturally occurs in a number of mammalian organs, and at high levels. So scientists realized that PEA<\/span> not only lessens inflammation \u2013 our own bodies and brains also produce it as an internal regulator of inflammation.<\/p>\nBut it wasn\u2019t until the 1970s that the first serious clinical trials emerged, and these happened in Czechoslovakia, a nation that no longer exists. The Czech pharmaceutical company SPOFA<\/span> (United Pharmaceutical Works) developed a PEA<\/span> drug called Impulsin. To test it, they turned to the gigantic Skoda factory, a manufacturer of cars, tanks, and industrial equipment, which employed a tremendous workforce. SPOFA<\/span> ran several clinical trials with the factory workers as well as with the military and civilian populations. Altogether, 2,000 adults and 400 children entered these trials.<\/p>\nAdministered in a double-blind manner (the gold-standard of modern medical trials), all of the results pointed in the same direction: PEA<\/span> was safe and possessed a clear efficacy in treating respiratory infections. It reduced the incidence of fever, headache, and sore throat. And furthermore, according to the Czech researchers, \u201cNo side effects <\/em>were registered after several years of clinical testing of Impulsin in military and civilian communities [emphasis added].\u201d<\/p>\n\nThe first big breakthrough occurred when PEA<\/span> was identified as the active anti-inflammatory ingredient in egg yolk. And our own brains also produce it.<\/p>\n<\/aside>\nPEA<\/span> worked! This was proven in large trials. But then ensued what is known in endocannabinoid circles as the Silent Gap period.<\/p>\nThrough the early 1980s, the work of SPOFA<\/span> faded away, lost behind the so-called Iron Curtain. Interest also waned because scientists could not explain PEA<\/span>\u2019s mechanism of action. No one could figure out how it actually worked. PEA<\/span> ended up being labeled an \u201cunspecific immune enhancer\u201d and the scientific community seemingly lost interest.<\/p>\nRescuing PEA<\/span> from Obscurity<\/h2>\nThat changed in 1993, when the human hero of our story, Dr. Rita Levi-Montalcini, entered the picture.<\/p>\n
Here is where geopolitics get too real. Earlier in her life, as a Jewish scientist in Mussolini\u2019s Italy, Dr. Levi-Montalcini lost her laboratory. Forced to flee to Florence, she set up a workstation in the basement of a house, and there she continued her work studying the early development of organisms \u2013 one of the most challenging problems in all of science. The work she performed in that basement led to her discovery of the brain\u2019s nerve growth factors (NGF<\/span>s), one of the most important neurochemical findings of the century \u2013 and resulted in her sharing the Nobel Prize in 1986.<\/p>\nSeven years later, while affiliated with the Institute of Neurobiology in Rome, Dr. Levi-Montalcini and her team published a famed paper in which they proposed that PEA<\/span> works via its control of mast cells \u2013 an important type of white blood cell responsible for releasing histamine. While most often associated with allergies, histamine is a both a hormone and a neurotransmitter involved in the inflammatory response. Mast cells respond to the healing of wounds, the growth of new blood vessels, the defense against pathogens, and the rallying of the immune response.<\/p>\nThey referred to PEA<\/span>\u2019s relationship to mast cells as \u201cthe ALIA<\/span> hypothesis.\u201d<\/p>\nA review of their work in the Journal of Pain and Relief<\/em> summarizes, \u201cAutocoid or autacoid is a rather old-fashioned term for a regulating molecule, locally produced and locally exerting its actions \u2026 PEA<\/span> is formed locally when inflammation or neurogenic pain occur, and increased PEA<\/span> concentrations are based on the body-own mechanisms to cope with pain and inflammation. This is called: on-demand synthesis.\u201d<\/p>\n\u201cAn ALIA<\/span>mide is an autocoid synthesized in response to injury or inflammation, and acting locally to counteract such pathology. Thus, PEA<\/span> is a classical example of an ALIA<\/span>mide. The mast cell soon after the breakthrough paper of Levi-Montalcini was indeed shown to be an important target for the anti-inflammatory activity of PEA<\/span>, and in the period 1993-2013 more than 30 papers were published on the impact of PEA<\/span> on the mast cell.\u201d<\/p>\nAs often happens with important research, a partial solution to the problem of how PEA<\/span> functions led to a rush of scientists following up on those clues to figure out exactly how PEA<\/span> modulates mast cells.<\/p>\nPEA<\/span> for Pain<\/h2>\nA key development in understanding PEA<\/span> happened serendipitously in 1998, when a team in Naples was studying anandamide (AEA<\/span>), the endogenous cannabinoid neurotransmitter that is structurally similar to PEA<\/span>. (Both lipid compounds are \u201cEA<\/span>s\u201d \u2013 N-acylethanolamines.) Specifically they were researching AEA<\/span>\u2019s ability to cause pain relief by blocking pain transmission in the spinal cord before it even reaches the brain.<\/p>\nFor their experiments, they decided that they needed a control molecule to act as a placebo. As Dr. Daniele Piomelli relates, they wanted another endocannabinoid-like molecule that wouldn\u2019t have the same effects. So they chose PEA<\/span>, mostly because they knew that it didn\u2019t bind to the CB1<\/span> or CB2<\/span> receptors thought to be causing the pain-relieving effects. But as their paper in Nature<\/em> pointed out, they were quite surprised to find out that PEA<\/span> had profound pain-relieving effects as well.<\/p>\nThis result intrigued them. If PEA<\/span> doesn\u2019t bind to the classic cannabinoid receptors CB1<\/span> and CB2<\/span>, then how does it do what it does?<\/p>\nThe researchers reasoned that a sister lipid molecule known as oleamide (OEA<\/span>) worked via the PPAR<\/span>\u03b1 (alpha) receptors. What\u2019s special about these PPAR<\/span>\u03b1 receptors is that they\u2019re nuclear receptors. They live not on the surface of the cell, but on the surface of its nucleus \u2013 the cellular control center that contains the DNA<\/span>. (In our neuronal ocean metaphor, the nucleus is City Hall and the PPAR<\/span> receptors are the bureaucrats who send out the orders.) Activating these nuclear receptors alters the transcription of genes and hence the production of new proteins. Each of these new proteins would have its own host of downstream effects. If you view the cell like a city, altering genetic transcription is like hiring a whole bunch of specialized workers to fix your problems, each with their own toolkit.<\/p>\nDr. Piomelli assigned his student Jesse LoVerme to study PEA<\/span>\u2019s mechanism of action. By 2005, they found that the PPAR<\/span>\u03b1 receptor mediated the anti-inflammatory effects of PEA<\/span>, and by 2007 they determined that this relationship also mediated PEA<\/span>\u2019s anti-pain effects. It was a huge breakthrough.<\/p>\n<\/div>\n
PEA<\/span> &<\/span> the Entourage Effect<\/h2>\nWith the mechanism unveiled and the positive clinical effects noted, PEA<\/span> research poured forth like a spring. In 2008, UK<\/span>-based scientists reported that the ability of anandamide to relax the arteries was strengthened by the presence of PEA<\/span> \u2013 a phenomenon described as an \u201centourage effect.\u201d Published in the British Journal of Pharmacology<\/em>, the study noted this effect occurred via the role of vanilloid receptors, which are part of a large, ancient family of Transient Receptor Potential ion channels (also known as TRP<\/span> or \u201ctrip\u201d receptors) that regulate core body temperature, inflammatory pain, and other basic visceral sensations, such as the burning sensation of hot foods like capsaicin.<\/p>\nAnandamide binds to the TRPV1<\/span> vanilloid receptor as does CBD<\/span>. The endocannabinoid system and the endovanilloid system are so intertwined that anandamide is often described as a vanilloid compound.<\/p>\nAlso in 2008, a study on PEA<\/span> and neuropathic pain found not only TRPV1<\/span> to be involved, but also the CB1<\/span> cannabinoid receptor and another nuclear receptor, PPAR<\/span>\u03b3 (gamma). And in a subsequent study of neuropathic pain, PEA<\/span> helped by improving the release of amino acids as well as restoring the functioning of glutamate, the brain\u2019s primary excitatory neurotransmitter (and the subject of a previous Project CBD<\/span> article in this series).\u00a0<\/p>\nIn mouse studies involving a wide range of disease models, PEA<\/span> was found to lower inflammation, lessen cell death, and prevent tissue injury \u2013 often via multiple biochemical pathways. It even helped four jumping horses return to competition after their injuries didn\u2019t respond to any other treatment.<\/p>\nScientists now believe that PEA<\/span> exists \u2013 at least at low levels \u2013 in every single mammalian cell.<\/p>\n<\/div>\n
Clinical Studies<\/h2>\n Clinical experiments have also yielded impressive results. In patients with migraines, lower back pain, burning mouth syndrome, spinal cord injuries or the neuropathy of shingles, PEA<\/span> decreased pain and worked well as an add-on to the standard treatments. PEA<\/span> also helped people with bladder problems, irritable bowels, glaucoma, osteoarthritis of the knee, and exercise recovery. (For an extensive list of conditions helped by PEA<\/span>, see The PEA<\/span> Health Files at the end of this article.)<\/p>\nIn 20 patients undergoing chemo, PEA<\/span> eased the pain and even showed \u201csignificant restoration of nerve function.\u201d In a patient with ALS<\/span>, PEA<\/span> improved their clinical picture \u2013 probably via the mast cells as well as the microglia (the guardian immune cells of the brain). In multiple sclerosis patients, PEA<\/span> combined well with the standard treatment to improve pain, lower inflammation, and raise quality of life. Observational studies of 600 patients with treatment-resistant chronic pain found PEA<\/span> to be effective and safe. In seven patients with chronic idiopathic axonal polyneuropathy (intense neuropathic pain from an unknown source), PEA<\/span> significantly reduced pain with no side effects, and it did the same for 70 kids with migraines.<\/p>\n\nPEA<\/span> is a powerhouse against inflammation and pain.<\/p>\n<\/aside>\nIn 24 women with endometriosis and chronic pelvic pain, PEA<\/span> combined with polydatin (a flavonoid often paired with PEA<\/span>) helped with their cramps, their pain during sex, and with their overall quality of life; similar results were later reported for 30 more patients. And in 30 diabetic patients, PEA<\/span> effectively reduced their neuropathic pain with no negative changes shown in their blood work or urine analysis. In two patients with autism, PEA<\/span> caused \u201crapid improvements in cognitive, behaviors, and sociability.\u201d In 58 patients with depression, 600 mg of PEA<\/span> twice a day in addition to citalopram significantly and rapidly improved symptoms. And it even works topically for humans with eczema; when, applied to the skin, PEA<\/span> caused less itching and better sleep with many of the patients stopping the use of corticosteroids.<\/p>\nWith respect to PEA<\/span>, throughout all of these studies, there\u2019s one assessment that comes up over and over again: \u201cWe also noted its safety due to the total absence of adverse effects.\u201d<\/p>\nPEA<\/span> as a Dietary Supplement<\/h2>\nDecades of unravelling a series of scientific mysteries have led to exciting discoveries that transformed PEA<\/span> from the stuff of egg yolk to the next great dietary supplement.<\/p>\nIn the ocean of our brain, the PEA<\/span> whale emerges to work its magic by orchestrating the lowering of inflammation and the reduction of pain across everywhere it roams. ClinicalTrials.gov lists 44 clinical trials for PEA<\/span> that are currently recruiting patients, in process, or completed. FSD<\/span> Pharma has PEA<\/span> in Phase 2 trials for use against an inflammatory disease of mast cell activation.<\/p>\nPEA<\/span> is already in widespread use around the world. In Italy and Spain, it\u2019s an approved nutraceutical. Lesvi, a European pharmaceutical company, combines PEA<\/span> with several plants as a nutraceutical for the brain. A Dutch firm produces a formulation called PeaPure. And the PEA<\/span> formulation known as Levagen+ from Gencor Pacific is touted to improve joint health, mood, sleep, immune system health, exercise recovery, and quality of life.<\/p>\nFortunately it\u2019s relatively easy to access food-derived PEA<\/span> as a legal health supplement in the US<\/span>. A number of reputable vendors market PEA<\/span> products, and one can order them online. Anecdotal accounts suggest that CBD<\/span> and PEA<\/span> amplify each other\u2019s anti-inflammatory effects, and combining the two compounds could prove to be a powerful healing option.<\/p>\nLex Pelger writes articles about psychoactives and the endocannabinoid system. His first book, <\/em>SUN<\/span>set, is available via Amazon. He publishes a weekly cannabinoid science newsletter Cannabinoids &<\/span> the People and conducts\u00a01-on-1 education sessions on using CBD<\/span>, PEA<\/span>, THC<\/span> &<\/span> CBDA<\/span> for serious health conditions. Copyright, Project CBD<\/span>. May not be reprinted without permission.<\/em><\/p>\nThe PEA<\/span> Health Files<\/h2>\n2013: A Kuhnian take on evolution of PEA<\/span> knowledge<\/strong>PPAR<\/span>-\u03b1 agonist and effective nutraceutical<\/p>\nThe best PEA<\/span> review papers:<\/strong><\/h3>\n\n2022: A review on the potential of using PEA<\/span> for antiseizure effects<\/strong>2021: From Gencor (producers of the PEA<\/span> product Levagen+, a paper reviewing the wonders of PEA<\/span><\/strong>2021: This review of female pelvic medicine and reconstructive surgery suggests PEA<\/span> as a treatment<\/strong>2021: This review looks at PEA<\/span> for autism and suggests that it may help via several different mechanisms<\/strong>2021: This review looks at the power of PEA<\/span> to protect the astrocytes (essential support cells of the brain) and fight Alzheimer\u2019s disease<\/strong>2021: This review suggests using PEA<\/span> for treating COVID<\/span> patients<\/strong>PEA<\/span>): A New Possible Adjuvant Treatment in COVID<\/span>-19 patients<\/li>\n2021: This review looks at how PEA<\/span> and oleoylethanolamide binds to GPR119<\/span> and GPR55<\/span> (receptors that may one day be known as CB3<\/span> and CB4<\/span>)<\/strong>GPR119<\/span> and GPR55<\/span> as Receptors for Fatty Acid Ethanolamides, Oleoylethanolamide and Palmitoylethanolamide<\/li>\n2021: A special issue of the International Journal of Molecular Sciences is dedicated to PEA<\/span><\/strong><\/li>\n2021: This mini-review examines why it makes sense to use PEA<\/span> to treat COVID<\/span> (includes one positive case study)<\/strong>PEA<\/span>) as natural neuroprotector against COVID<\/span>-19 inflammation<\/li>\n2020: A review of how PEA<\/span> moves through the body<\/strong>2020: A review of PEA<\/span> for pets<\/strong>ALIA<\/span>mides: Prohomeostatic Lipid Compounds for Animal Health and Wellbeing<\/li>\n2020: On using PEA<\/span> for pain (nice charts)<\/strong>ALIA<\/span>mides Update: Palmitoylethanolamide and Its Formulations on Management of Peripheral Neuropathic Pain<\/li>\n2020: PEA<\/span> + luteolin for neuroinflammation<\/strong>2019: A good review of PEA<\/span>\u2019s mechanisms of action<\/strong>2019: A review on PEA<\/span> for end of life care<\/strong>2019: A review on PEA<\/span> for Alzheimer\u2019s disease with a focus on neuroinflammation<\/strong>PEA<\/span>) as a Potential Therapeutic Agent in Alzheimer\u2019s Disease<\/li>\n2019: On combining PEA<\/span> with other antioxidant molecules found in your diet (nice diagrams)<\/strong>2019: A review of PEA<\/span> for asthma<\/strong>2018: A review of PEA<\/span> for depression<\/strong>PEA<\/span>) in Depression: Translational Evidence: Special Section on \u201cTranslational and Neuroscience Studies in Affective Disorders\u201d<\/li>\n