The Mighty Molecule: The Role of PEA in the Endocannabinoid System


PEA (N-palmitoylethanolamide): an endogenous fatty acid amide synthesized and metabolized by cells that bind to cell receptors. It influences a multitude of physiological functions and has potent effects for a healthy inflammatory response and helps to relieve minor discomfort.

Endocannabinoid System: A lipid communication network that has critical physiological functions and serves a vital purpose for our health and well-being through signaling processes, homeostasis and hormone regulation.

Lipids and the ECS

In 1929, scientists George Oswald Burr and his wife, Mildred Burr, discovered that omega 6 fatty acids were essential for health. This kicked off science’s interest into lipids, and by the 1960s a new age of lipid research had begun. Edward Dennis of University of California at San Diego wrote:

“Lipids are in many ways the most important of the biomolecules because they are the ultimate controllers and regulators of our bodily processes; they are key to signaling events in cells. Further, imbalances in lipids are implicated in many illnesses, such as heart disease, stroke, arthritis, diabetes and Alzheimer disease. If we are going to solve these diseases, we must know what the lipids are and what they do.”

The endocannabinoid system (ECS) is a lipid communication network with important physiological functions in all animal life. The complex biochemical array of pathways involved in the synthesis, release, transport, and degradation of endocannabinoids by the body is also known as the endocannabinoidome. This lipid signaling network is a key modulator of physiological functions in many of the other networks and signaling systems including; the nervous system, the endocrine network, the immune system, the gastrointestinal tract, and the reproductive system, as well as others.

Endocannabinoids, the products of the ECS, are directly released from membranes, which distinguishes them from other transmitter molecules, such as dopamine or hormones. Moreover, unlike the neurotransmitters or hormones, which are synthesized in one place but act globally in the body, the endocannabinoids are synthesized locally and act locally.

PEA – The Rising Star of the ECS

Classical endocannabinoids include anandamide (also termed AEA) and 2-acyl glycerol (2-AG). But other endocannabinoids were later discovered, and one, in particular, has been studied in considerable detail, N-palmitoylethanolamide or PEA. The origins of PEA started in 1939 when clinician and researcher Coburn was looking into how to prevent the incidence of rheumatic fever in poor children living in New York. He stumbled upon egg yolk as a key ingredient that supported the immune system. In 1957 scientists at Merck Sharp and Dome identified PEA as the molecule that provided this support. However, it wasn’t until 1993 that the mechanism of action of PEA was determined through the work of Rita Levi-Montalcini an Italian scientist who back in 1954 had discovered the nerve growth factor (NGF).

Levi-Montalcini’s discovery was that NGF activated specific immune cells called mast cells that further caused inflammation and allergic reactions. Almost forty years later, she discovered how a naturally produced fatty acid amide called PEA interacted with these mast cells, thereby supporting the inflammation response. Furthermore, Levi-Montalcini discovered that PEA was produced locally by cells under threat from noxious and injurious external triggers, like UV-A, various toxins, allergens, infectious agents as well as other inflammatory agents. The local production of PEA thereby supported the body against the threat. PEA was not only produced locally but also acted locally. It seemed like PEA was called into action whenever there was demand, when the body needed support not only against outside triggers but also when the body was under threat from within, for example against aging or whenever the immune system was overactive as in various autoimmune disorders, which occurs when the body stops recognizing friend from foe and starts acting against itself. Mast cells seem to be key components of the inflammatory response.

Levi-Montalcini succinctly pointed out the interaction between PEA and the mast cell:

“…Unregulated mast-cell activation constitutes a considerable risk to the health of the organism, and it is not unreasonable to expect that nature should have devised a means for the host to defend itself against such damage. It has recently been proposed that saturated N-acylethanolamine like palmitoylethanolamide (PEA), which accumulate in tissues following injury and which down modulate mast cell activation, exert a local, and anti-injury function via mast cells. Palmitoylethanolamide is orally active in reducing tissue inflammation and mast cells.”

Once the mechanism of action of PEA was identified, there was a flurry of research on PEA, and new and interesting health benefits were soon discovered. As early as 1980, it was learned that PEA had a tendency to accumulate in the damaged heart muscle due to ischemia or deprivation of oxygen, and this might be of physiological importance because of its properties that aid in a healthy inflammatory response. Researcher Denis Epps suggested that these fatty molecules played a supportive role and that their presence, “may signify a response of myocardial tissue to injury directed at minimizing damage and promoting survival”.

Recent studies have confirmed what Epps and his colleagues postulated. It has been shown in various animal disease models and human tissue analysis that PEA supports various tissues, including the colon, kidney and particularly the nervous tissue along with many other potential benefits.

Currently, there is a number of animal and human studies on the application of PEA in the following conditions:

  • Endometriosis
  • Benign prostatic hyperplasia (BPH)
  • Burning mouth syndrome
  • Inflammatory bowel disease and syndrome (IBD/IBS)
  • Depression
  • Autism
  • Transient brain injury
  • Arthritis
  • Pain originating from various types
  • Coronary heart disease
  • Chronic kidney disease
  • Atopic dermatitis and eczema
  • Vulvodynia
  • Cannabis dependence
  • Migraine
  • Infectious diseases

In conclusion, PEA is an endogenously, and locally produced health molecule, the sole function of which is to offer immediate support through down modulating disease processes and acting against noxious stimuli in various systems of the body. The medical potential of this fascinating and undervalued molecule that comes to the body’s rescue when the need arises is worthy of wider attention in the context of ongoing research into the endocannabinoid system.


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  2. Epps DE, Natarajan V, Schmid PC, Schmid HO (1980) Accumulation of N-acylethanolamine glycerophospholipids in infarcted myocardium. Biochim Biophys Acta 618: 420-430.
  3. Esposito E, Paterniti I, Mazzon E, Genovese T, Di Paola R, et al. (2011) Effects of palmitoylethanolamide on release of mast cell peptidases and neurotrophic factors after spinal cord injury. Brain Behav Immun 25: 1099-1112.
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  6. Gatti A, Lazzari M, Gianfelice V, Di Paolo A, Sabato E, et al. (2012) Palmitoylethanolamide in the treatment of chronic pain caused by different etiopathogenesis. Pain Med 13: 1121-1130.
  7. Keppel Hesselink, J (2013) Professor Rita Levi-Montalcini on Nerve Growth Factor, Mast Cells and Palmitoylethanolamide, an Endogenous Anti-Inflammatory and Analgesic . Compound Pain Relief 2013, 2:1-5

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