

The Protective Power of PEA and the Immune System

By Dr. Michael Murray

In this article:

One of the most exciting nutritional compounds emerging in the 21st century is palmitoylethanolamide (PEA). Already used by over 1 million people all over the world as a dietary supplement, this fatty substance belongs to the family of biologically active lipids that are produced by the body that help in regulating cellular functions. PEA was identified over 60 years ago as an active biological factor when it was isolated from extracts from the brain, liver, and muscle of rat and guinea pig. It was later found to be a nutritional factor contained in chicken egg yolk, olive oil, safflower and soy lecithin, peanut meal, and several other foods. PEA has been used as a dietary supplement to boost the body’s supply of this valuable compound.

How Does PEA Work in the Human Body?

PEA is naturally made in the human body where it functions in concert with the endocannabinoid system or ECS.1 The ECS serves as a master conductor, sending chemical messages and triggering biological actions throughout the body that are critical to health and wellbeing. The outcome of this delicate balancing act is to create homeostasis, that internal drive within every cell and our entire system to maintain balance and promote health within its internal environment, even when faced with external changes.

PEA itself is referred to as a “pro-resolving lipid signaling molecule.” What this term means is that PEA acts through impacting central control mechanisms within our cells where it has an ability to resolve factors that lead to cellular stress and inflammation. This extremely beneficial effect has been demonstrated in over 600 scientific investigations including use as a dietary supplement in over 20 double-blind human clinical trials.2 

PEA is not acting as a drug to treat health conditions per se. Instead, taking PEA as a preformed dietary supplement is simply a strategy to ensure that there are adequate levels within the cells throughout the body, especially during what appears to be times of increased need. Similar situations exist with other “conditionally essential nutrients” like coenzyme Q10alpha-lipoic acidcarnitine, and many other compounds that are required for normal bodily processes. Some conditions cause the body to not make sufficient levels of these compounds or cause an increased demand for them.

PEA exerts what is referred to as a cytoprotective effect. This means it protects cells from damage. It exerts this effect not only through central cell functions but also on the fatty matrix of cell membranes. In a landmark study in 1973 mice, fed PEA demonstrated structural and functional changes in the cell membranes of liver cells as well as the membranes of cellular mitochondria, the energy-producing compartments of the cells.3 Once incorporated into cell membranes PEA was better able to protect the cells and mitochondria from damage. This study led to intense investigations by other researchers showing that when cells are damaged or lacking sufficient oxygen supplies, the body tries to offset this damage by making more PEA so that it can be incorporated into cell membranes for protection and better function. This basic effect of PEA has been overshadowed because of its role as a “pro-resolving lipid signaling molecule,” but it is still very important to its overall benefits to cellular function.4 

How Does PEA Affect Immune Health?

The actions of PEA on all immune cells in the body are central to all aspects of cellular function through the effect on receptors known as peroxisome proliferator-activated receptors (PPARs). These compounds are a group of nuclear receptor proteins that function in regulating the expression of the cell’s genetic codes. In other words, PPARs act as the “software” that tell our cell’s “hardware or computer,” our DNA, what to do in terms of expressing the genetic code to make chemicals that the cell will use to regulate its function. PPARs play a critical role in all cellular functions including metabolism and energy production. In the brain, PPARs influence mental function and mood. Its effect on supporting the function of the immune system is critical to balancing the response to an infection or inflammation.2,4

PEA has been studied for its ability to support immune health and respiratory tract function in five double-blind, placebo-controlled clinical trials between 1971 and 1975.5 What appears to have happened was that after this time the areas of research on PEA shifted from supporting the body during processes of infection to a focus on PEA’s role during inflammation. However, these processes share many common underlying physiological features. Sometimes they reflect two sides of the same coin. For example, PEA has shown some amazing effects in supporting brain health through acting on the immune cells that are responsible for clearing cellular debris from the brain leading to reduced inflammation and improved brain cell function.6 The same is true on its effects on macrophages, the large tissue-based white blood cells that engulf and destroy microorganisms and particulate matter.7

The first human clinical study on PEA and immune health involved a total of 444 employees of the Skoda car factory in Czechoslovakia. The dosage of PEA in the study was 600 mg three times daily (total daily dose of 1800 mg PEA) for 12 days. These volunteers were evaluated if they experienced any symptom suggestive of respiratory tract challenges such as sore throat, nasal stuffiness or discharge, or productive or dry cough, as well as associated symptoms such as fever, joint pain, malaise, and fatigue. The results showed that subjects receiving PEA had a lower number of episodes of symptoms compared with the placebo group. PEA had less effect on respiratory tract symptoms such as nasal stuffiness, discharge, and cough, but associated symptoms such as fever and pain were significantly reduced by 45.5% in the PEA group compared with the placebo group.8 

In the second study of PEA on immune health, 899 healthy volunteers between 18 and 20 years of age from an army unit were given either PEA or a placebo for 9 weeks. Soldiers were selected as they are housed close together and more susceptible to outbreaks of an immune challenge. The dosage schedule was 600 mg PEA three times daily for the first 3 weeks, after which a continuation phase started based on a single dose of 600 mg once daily for 6 weeks. Results showed the total number of sick days was significantly reduced in the PEA group, 40% lower at week 6 and 32% lower at week 8 compared to placebo.9 

In order to verify the conclusions, 3 more trials in soldiers were conducted during 1973-1975. All three trials showed significant support to the immune system as confirmed by clinical assessment as well as through blood measurements in these soldiers. All these clinical trials concluded that PEA has clear health benefits without any reported side effects.8 

What is a Cytokine Storm?

During an infection the immune system responds by increasing the production of many signaling compounds known as cytokines. In some particularly virulent infections, the immune system overproduces these compounds to produce what is referred to as a “cytokine storm.” This excessive immune response can lead to serious consequences. A cytokine storm represents an immune system that is out of control and one that starts attacking and killing everything in sight, including our healthy human cells. 

Viruses are sneaky in that in order for them to survive they need to find shelter in human cells to reproduce. Outside infected cells, viruses are easier targets for our immune system to neutralize. Inside human cells, the immune system relies on special forces in the form of white blood cells known as cytotoxic T cells and natural killer (NK) cells. These special forces are brought in through cytokines released by other white blood cells. Cytotoxic T cells and NK cells roam the body and seek to kill infected cells who are chemically calling out to be killed by releasing their own signals. That is how things are supposed to work, but in a cytokine storm, the immune system is so overstimulated by the overload of cytokines that it starts destroying everything it comes in contact with. The immune cells cannot differentiate between an infected and a healthy cell. This leads to massive inflammation and tissue destruction that can, in turn, lead to pneumonia, organ failure, and often death.

Can PEA Promote Balance in the Immune Response?

As described above, PEA works to protect cells from damage and affects the central control mechanisms within cells, including those that produce cytokines, T, and NK cells. PEA is widely known for its ability to support normal balance in the inflammatory response of the immune system. This balancing action is related not only to its effects on PPARs but also on the manufacture and secretion of cytokines and other compounds associated with inflammation. Its ability to dampen or modulate the effects of cytokines may be helpful in maintaining the function of the immune system during times it is being challenged.10,11

Recommended Dosage of PEA

Most recent studies have used a PEA dosage of 300 to 600 mg twice daily. The dosage used in some of the early studies was up to 600 mg three times a day. In all studies, no side effects or drug interactions occurred. PEA is completely safe and nontoxic.


  1. Tsuboi K, Uyama T, Okamoto Y, Ueda N. Endocannabinoids and related N-acylethanolamines: biological activities and metabolism. Inflamm Regen. 2018 Oct 1;38:28. 
  2. Petrosino S, Di Marzo V. The pharmacology of palmitoylethanolamide and first data on the therapeutic efficacy of some of its new formulations. Br J Pharmacol. 2017 Jun;174(11):1349-1365.
  3. Obermajerova H, Masek K, Seifert J, Buchar E, Havlik L. Structural and functional changes in liver mitochondria of mice fed palmitoylethanolamide (PEA) Biochem Pharmacol. 1973;22:2529–2536.
  4. Hesselink JM. Evolution in pharmacologic thinking around the natural analgesic palmitoylethanolamide: from nonspecific resistance to PPAR-α agonist and effective nutraceutical. J Pain Res. 2013 Aug 8;6:625-34. 
  5. Hesselink JM, Boer T, Witkamp RF. Palmitoylethanolamide: A Natural Body-Own Anti-Inflammatory Agent, Effective and Safe against Influenza and Common Cold. Int J Inflam. 2013; 2013: 151028.
  6. Skaper SD, Facci L, Giusti P. Glia and mast cells as targets for palmitoylethanolamide, an anti-inflammatory and neuroprotective lipid mediator. Mol Neurobiol. 2013 Oct;48(2):340-52.
  7. Pontis S, Ribeiro A, Sasso O, Piomelli D. Macrophage-derived lipid agonists of PPAR-α as intrinsic controllers of inflammation. Crit Rev Biochem Mol Biol. 2016;51(1):7-14.
  8. Masek K, Perlik F, Klima J, Kahlich R. Prophylactic efficacy of N 2 hydroxyethyl palmitamide (Impulsin) in acute respiratory tract infections. European Journal of Clinical Pharmacology. 1974;7(6):415–419. 
  9. Kahlich R, Klima J, Cihla F, et al. Studies on prophylactic efficacy of N-2-hydroxyethyl palmitamide (Impulsin) in acute respiratory infections. Serologically controlled field trials. Journal of Hygiene Epidemiology Microbiology and Immunology. 1979;23(1):11–24. 
  10. Berdyshev EV, Boichot E, Germain N, Allain N, Anger JP, Lagente V. Influence of fatty acid ethanolamides and delta9-tetrahydrocannabinol on cytokine and arachidonate release by mononuclear cells. Eur J Pharmacol. 1997 Jul 9;330(2-3):231-40.
  11. Orefice NS, Alhouayek M, Carotenuto A, 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. 2016 Apr;13(2):428-38.

Related Articles

View All


Saffron: Nature’s Best Answer to Boosting Mood


The Different Forms and Benefits of Vitamin E

