What is Palmitoylethanolamide (PEA)?

Palmitoylethanolamide (PEA) is one of the oldest and most well researched natural products that balances inflammation and protects the immune system. But you may never have heard about it – even as its poised to become the next CBD. Why? Because this story contains a mystery – one that leads to another mystery.  

So how did scientists discover PEA? And how does it work with our endocannabinoid system (ECS) to influence inflammation? 

Our story begins during World War 2 – and indeed, geopolitics plays a significant role in this tale. Because of the war effort, it was a prosperous time for the new-ish field of public health. A healthy population of workers could help support the production of war materiel for the front. Two doctors named Coburn and Moore, working in New York City, found that if they gave dried eggs to the children of the tenements, it helped prevent rheumatic fever and other ills related to poor nutrition. They discovered egg yolks to be an anti-inflammatory food. 

Usually, when a plant is found to have unique health properties, scientists dig in to find the molecules responsible for the effect. And usually, these are proteins. Proteins are the workhorse 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 changes.  

Proteins may be the workhorses of the cell – but they’re very digital. Usually, they are either on or off. But lipids act in a more analog manner. Even minute changes in lipid levels are sensed by a cell, and it responds accordingly. Lipids have been described as a finely tuned system used by the cell to find homeostasis – or balance. 

Over the course of the Cold War ‘50s, a big breakthrough occurred  when a team led by Dr. Kuehl identified PEA as the active ingredient in egg yolks that caused the anti-inflammatory activity. He reported: “We have succeeded in isolating a crystalline anti-inflammatory factor from soybean lecithin and identifying it as N-(2-hydroxyethyl)-palmitamide. The compound also was isolated from a phospholipid fraction of egg yolk and from hexane-extracted peanut meal.

But scientists struggled to understand the mechanisms that caused this lipid to influence inflammation. During the ‘60s, some papers come out confirming the anti-inflammatory effects in animal models. And in an important turn of events, a team led by Dr. Udenfriend discovered that PEA occurs naturally – and at high levels – in a number of mammalian organs. So we realized that not only does PEA lessen inflammation - but our own bodies and brains also produce it as an internal regulator of inflammation. 

It wasn’t until the ‘70s that the first serious clinical trials emerged – and it happened behind the Iron Curtain. In Czechoslovakia, a nation that no longer exists, a pharmaceutical company named SPOFA (United Pharmaceutical Works) developed a PEA drug called Impulsin.  

To test PEA, they turned to the gigantic Skoda factory, a manufacturer of cars, tanks, and industrial equipment, that employed a huge workforce. SPOFA ran several clinical trials with the factory workers as well as the military and civilian populations. All in all, 2000 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 a key researcher, “No side effects were registered after several years of clinical testing of Impulsin in military and civilian communities.” 

It worked! It was proven in large trials. But then occurred, what is known in endocannabinoid circles, as the Silent Gap period.  

From the early 80’s, the work of SPOFA faded away, lost behind the Iron Curtain. Furthermore, scientists could not figure out the mechanism of action for PEA and so interest waned because no one knew how it work. PEA was labeled as an ‘unspecific immune enhancer’ and the scientific community lost interest. 

Until 1993, when our hero, Dr. Rita Levi-Montalcini entered the PEA stage. And here is where our geopolitics get too real. Earlier in her life, as a Jewish person in Mussolini’s Italy, Dr. Levi-Montalcini lost her laboratory. Forced to flee to Florence, she set up a workstation in the basement of the house where she landed. Here 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 her to discover nerve growth factor (NGF) – one of the most important neurochemical findings of the century - and whose discovery led to her sharing the Nobel Prize in 1986. 

How Does PEA Work?

In a famed 1993 paper, Dr. Levi-Montalcini and her team proposed that PEA works via its control of mast cells – an important type of white blood cell responsible for releasing histamine, a neurotransmitter involved in the inflammation response and most often associated with allergies. Mast cells also respond to the healing of wounds, the growth of new blood vessels, defense against pathogens, and the rallying of the immune response. For PEA’s relationship to mast cells, they called it the ALIA hypothesis. 

As this review of her work summarizes, “Autocoid or autacoid is a rather old-fashioned term for a regulating molecule, locally produced and locally exerting its actions... In this case 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 classic 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.” 

As often happens, a partial solution to how PEA works led to a rush of scientists following up on those clues to work out exactly how PEA modulates those mast cells. In 1998, a team in Naples was studying anandamide (AEA) – the first endogenous cannabinoid neurotransmitter discovered – and its 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 for their experiments. As Dr. Piomelli relates, they wanted another endocannabinoid-like molecule that wouldn’t have the same effects. So they chose PEA, mostly because they knew it didn’t bind to the CB1 or CB2 receptor thought to be behind the pain relieving effects. But as their paper 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 molecule known as oleamide (OEA) worked via the PPARα receptors. And 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. Activating these nuclear receptors altered genetic transcription and caused the cell to produce a host of new proteins with their own downstream effects. Dr. Piomelli worked with his student Dr. Jesse LoVerme to study PEA’s mechanism of action. By 2005, they found that the PPARα receptor mediated the anti-inflammation effects of PEA completely and by 2007, they determined that this relationship also mediated the anti-pain effects. It was a huge breakthrough. 

Their research confirmed that PEA occurs at high levels in many areas of the body – especially the skin – and that when PEA levels are low, the body can be helped by adding more PEA from outside sources. This used to be egg yolks and peanuts – but with products like CV Defense, now it’s easy to supplement your body’s PEA to improve health, balance inflammation, and boost immunity.  

It took the unraveling of decades of scientific mysteries led us to these exciting discoveries that are turning PEA into the next great dietary supplement poised to sweep the world. Try our CV Defense today to see what this wonderful fatty acid amide can do for you.