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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.

Enter our hero, Palmitoylethanolamide (PEA) – a lipid messenger kindred to the endocannabinoid system and a close cousin of anandamide (AEA), the famous endocannabinoid neurotransmitter. Sometimes referred to as “the endogenous version of CBD,” PEA is a powerhouse against inflammation and pain. Like CBD, PEA increases the levels of endocannabinoids and strengthens the endocannabinoid system. And, again like CBD, a constant theme in the scientific literature about PEA is its incredibly strong safety profile.

In our neural ocean metaphor, PEA weighs in as the “most venerable of the leviathans,” the grinning Right Whale, a stalwart fighter in our constant battle against inflammation and pain.

A Mystery

The PEA story begins with a mystery, which leads to another mystery — and ends with the next great wave of the cannabinoid revolution.

We begin during World War 2 – 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 “public health.” A healthy population of workers was essential to support the production of war materiel. Two NYC 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.

Usually, 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 – the fatty molecules — that caused the positive health effects.

Proteins may be the workhorses, but they’re 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?

Lipid Mechanisms

The first big breakthrough occurred in the 1950s when a team led by Dr. F.A. 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.

But 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. And in an important turn of events, a team led by Dr. S. Udenfriend discovered that PEA naturally occurs in a number of mammalian organs, and at high levels. So scientists realized that PEA not only lessens inflammation — our own bodies and brains also produce it as an internal regulator of inflammation.

But it wasn’t 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 (United Pharmaceutical Works) developed a PEA 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 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.

Administered in a double-blind manner (the gold-standard of modern medical trials), all of the results pointed in the same direction: PEA 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, “No side effects were registered after several years of clinical testing of Impulsin in military and civilian communities [emphasis added].”

PEA worked! This was proven in large trials. But then ensued what is known in endocannabinoid circles as the Silent Gap period.

Through the early 1980s, the work of SPOFA faded away, lost behind the so-called Iron Curtain. Interest also waned because scientists could not explain PEA’s mechanism of action. No one could figure out how it actually worked. PEA ended up being labeled an “unspecific immune enhancer” and the scientific community seemingly lost interest.

Rescuing PEA from Obscurity

That changed in 1993, when the human hero of our story, Dr. Rita Levi-Montalcini, entered the picture.

Here is where geopolitics get too real. Earlier in her life, as a Jewish scientist in Mussolini’s 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 — one of the most challenging problems in all of science. The work she performed in that basement led to her discovery of the brain’s nerve growth factors (NGFs), one of the most important neurochemical findings of the century — and resulted in her sharing the Nobel Prize in 1986.

Seven 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 works via its control of mast cells – an important type of white blood cell responsible for releasing histamine. Histamine, while most often associated with allergies, 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.

They referred to PEA’s relationship to mast cells as “the ALIA hypothesis.”

A review of their work in the Journal of Pain and Relief summarizes, “Autocoid or autacoid is a rather old-fashioned term for a regulating molecule, locally produced and locally exerting its actions . . . . PEA is formed locally when inflammation or neurogenic pain occur, and increased PEA concentrations are based on the body-own mechanisms to cope with pain and inflammation. This is called: on-demand synthesis.”

“An ALIAmide is an autocoid synthesized in response to injury or inflammation, and acting locally to counteract such pathology. Thus, PEA is a classical example of an ALIAmide. 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, and in the period 1993-2013 more than 30 papers were published on the impact of PEA on the mast cell.”

PEA for Pain

As often happens with important research, a partial solution to the problem of how PEA functions led to a rush of scientists following up on those clues to figure out exactly how PEA modulates mast cells. A key development in understanding PEA happened serendipitously in 1998, when a team in Naples was studying anandamide (AEA), the endogenous cannabinoid neurotransmitter that is structurally similar to PEA. (Both lipid compounds are “EAs” — N-acylethanolamines.) Specifically they were researching AEA’s ability to cause pain relief by blocking pain transmission in the spinal cord before it even reaches the brain.

For 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’t have the same effects. So they chose PEA, mostly because they knew that it didn’t bind to the CB1 or CB2 receptors thought to be causing the pain-relieving effects. But as their paper in Nature pointed out, they were quite surprised to find out that PEA had profound pain-relieving effects as well.

This result intrigued them. If PEA doesn’t bind to the classic cannabinoid receptors CB1 and CB2, then how does it do what it does?

The researchers reasoned that a sister lipid molecule known as oleamide (OEA) worked via the PPARα (alpha) receptors. What’s special about these PPARα receptors is that they’re nuclear receptors. They live, not on the surface of the cell, but on the surface of its nucleus – the cellular control center that contains the DNA. (In our neuronal ocean metaphor, the nucleus is City Hall and the PPAR 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.

Dr. Piomelli assigned his student Jesse LoVerme to study PEA’s mechanism of action. By 2005, they found that the PPARα receptor mediated the anti-inflammatory effects of PEA, and by 2007 they determined that this relationship also mediated PEA’s anti-pain effects. It was a huge breakthrough.

PEA & the Entourage Effect

With the mechanism unveiled and the positive clinical effects noted, PEA research poured forth like a spring. In 2008, UK-based scientists reported that the ability of anandamide to relax the arteries was strengthened by the presence of PEA — a phenomenon described as an “entourage effect.” Published in the British Journal of Pharmacology, 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 or “trip” receptors) that regulate core body temperature, inflammatory pain, and other basic visceral sensations, such as the burning sensation of hot foods like capsaicin.

Anandamide binds to the TRPV1 vanilloid receptor as does CBD. The endocannabinoid system and the endovanilloid system are so intertwined that anandamide is often described as a vanilloid compound.

Also in 2008, a study on PEA and neuropathic pain found not only TRPV1 to be involved, but also the CB1 cannabinoid receptor and another nuclear receptor, PPARγ (gamma). And in a subsequent study of neuropathic pain, PEA helped by improving the release of amino acids as well as restoring the functioning of glutamate, the brain’s primary excitatory neurotransmitter (and the subject of a previous Project CBD article in this series). 

In mouse studies involving a wide range of disease models, PEA was found to lower inflammation, lessen cell death, and prevent tissue injury – often via multiple biochemical pathways. It even helped four jumping horses return to competition after their injuries didn’t respond to any other treatment.

Scientists now believe that PEA exists — at least at low levels — in every single mammalian cell.

Clinical Studies

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 decreased pain and worked well as an add-on to the standard treatments. PEA 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, see The PEA Health Files at the end of this article.)

In 20 patients undergoing chemo, PEA eased the pain and even showed “significant restoration of nerve function.” In a patient with ALS, PEA improved their clinical picture – probably via the mast cells as well as the microglia (the guardian immune cells of the brain). In multiple sclerosis patients, PEA combined well with the standard treatment to improve pain, lower inflammation, and raise the quality of life. Observational studies of 600 patients with treatment-resistant chronic pain found PEA to be effective and safe. In seven patients with chronic idiopathic axonal polyneuropathy (intense neuropathic pain from an unknown source), PEA significantly reduced pain with no side effects, and it did the same for 70 kids with migraines.

In 24 women with endometriosis and chronic pelvic pain, PEA combined with polydatin (a flavonoid often paired with PEA) 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 effectively reduced their neuropathic pain with no negative changes shown in their blood work or urine analysis. In two patients with autism, PEA caused “rapid improvements in cognitive, behaviors, and sociability.” In 58 patients with depression, 600 mg of PEA 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 caused less itching and better sleep with many of the patients stopping the use of corticosteroids.

With respect to PEA, throughout all of these studies, there’s one assessment that comes up over and over again: “We also noted its safety due to the total absence of adverse effects.”

PEA as a Dietary Supplement

Decades of unravelling a series of scientific mysteries have led to exciting discoveries that transformed PEA from the stuff of egg yolk to the next great dietary supplement.

In the ocean of our brain, the PEA 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 that are currently recruiting patients, in process, or completed. FSD Pharma has PEA in Phase 2 trials for use against an inflammatory disease of mast cell activation.

PEA is already in widespread use around the world. In Italy and Spain, it’s an approved nutraceutical. Lesvi, a European pharmaceutical company, combines PEA with several plants as a nutraceutical for the brain. A Dutch firm produces a formulation called PeaPure. And the PEA formulation known as Levagen+ from Gencor Pacific is touted to improve joint health, mood, sleep, immune system health, exercise recovery, and quality of life.

Fortunately it’s relatively easy to access food-derived PEA as a legal health supplement in the US. A number of reputable vendors market PEA products, and one can order them online. Anecdotal accounts suggest that CBD and PEA amplify each other’s anti-inflammatory effects, and combining the two compounds could prove to be a powerful healing option.

See other articles in the Get to Know a Neurotransmitter series.

Lex Pelger writes articles about psychoactives and the endocannabinoid system. He publishes a weekly cannabinoid science newsletter Cannabinoids & the People and conducts 1-on-1 education sessions on using CBD, PEA, THC & CBDA for serious health conditions. © Copyright, Project CBD. May not be reprinted without permission.

The PEA Health Files & Review Papers

A Timeline of PEA Research



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