What is PEA?
PEA (palmitoylethanolamide) is a fatty acid amide molecule which can be found in plant, human, and animal tissues. When the body experiences pain or inflammation, levels of endogenous PEA increase. 
The nutraceutical PEA was discovered by a chain of many scientists and researchers, each capitulating on each other’s observations and research and eventually fostering its successful molecular identification and isolation. Its long and interesting history begins with a scientist in 1957 who, after studying Strep-A rheumatic fever in underprivileged children, noticed that the children fed supplemental dried egg yolk fared better and did not develop rheumatic fever, despite infection with Strep-A. Later, it was isolated from the dried egg yolk and is now a known constituent contained in soy lecithin. Since the 1970s, PEA has been studied for its immune-modulating properties which have been applied towards studying its effects on the common cold and the influenza virus. More recently, it has been studied for its effects on pain and inflammation. 
Two American bacteriologists, Coburn and Moore, spearheaded the study of PEA starting in 1939. They studied children from an American population which had been exposed repeatedly to group-A streptococcal infections and had suffered repeated bouts of rheumatic fever. Coburn noted that these children were impoverished and malnourished and designed a field study to determine if extra nutrition could mitigate the effects of rheumatic fever.
The children were divided into three groups. One group was fed their normal diets; one group was fed whole food sources of nutrition and were given two eggs, meat, a quart of milk, butter, and fish oil (halibut-liver oil) daily; and the third group continued their normal diet but were given an addition of dried powdered egg yolk, equivalent to six eggs per day.
Coburn noted that the children who continued their normal, nutritionally inadequate diet experienced a higher recurrence of rheumatic fever (11 children became sick). The children who were fed the enriched, whole food source diet only had 3 recurrences, and the group fed dried egg yolk only had 1 recurrence of rheumatic fever.
The children fed dried egg yolk tested positive for Strep-A in their blood, but they did not have any recurrence of rheumatic fever. This correlation led Coburn and Moore to investigate what compounds were in the dried egg yolk which could have these effects.
In 1954, Coburn and his colleagues isolated and identified a phospholipid fraction in egg yolk which exerted antiallergic properties. Though still in the stage of animal research, the phospholipid fraction was purified in 1956 by scientists Long and Martin. This purified fraction biochemically resembled compounds isolated earlier from peanuts in 1950. This compound appeared to be related to a compound known at that time as “vegetable lecithin.”
Together, these two isolated compounds would come together to form PEA. In 1957, scientist Kuehl Jr. and his colleagues were able to isolate the anti-inflammatory factor in crystalline form from a vegetable lecithin derived from soy (soy lecithin). Kuehl identified it as N-(2-hydroxyethyl)-palmitamide. Pursuing the earlier studies into egg yolk and its anti-inflammatory properties, Kuehl found the same compound in a phospholipid fraction within the egg yolk and also in peanut meal. This successfully identified the active compound in egg yolk which had first been empirically noted by Coburn and Moore.
Kuehl went on to hydrolyze the N-(2-hydroxyethyl)-palmitamide into two smaller substances: palmitic acid and ethanolamine. This hydrolyzed compound was then referred to as PEA. Kuehl substantiated that the molecule of PEA itself was the active molecule accountable for the anti-inflammatory effects seen by Coburn and Moore.
Coburn and Moore went on to conduct three more field studies in children supplemented with egg-yolk powder, and their research accrued traction in the scientific community. PEA’s anti-inflammatory effects became well-known, and PEA was recognized in the muscle, liver, and brain tissue of the guinea pig and rat during animal research. Later, it was discovered that PEA is endogenously produced within the human body and could be detected in blood plasma samples.
Interest in PEA reached a turning point by the 1970s, when the consensus on PEA had gone beyond its effects on inflammation and were now being noted for its effects on the immune system and immunological processes. Within the last 50 years, over three hundred scholarly papers have mentioned PEA and its pharmacological properties.
PEA studies were then directed towards the influenza virus, the common cold, and other respiratory viruses and respiratory inflammations from 1971-1980. This focus included over six clinical trials where PEA was found to be an effective and safe treatment. As the late twentieth-century progressed into the 1990s, PEA was tested in the animal model for broader applications, researching its role in pain relief. 
PEA’s role in pain relief and inflammation was made famous by the work of Professor Rita Levi-Montalcini who won a Nobel Prize in 1993 for her discovery that PEA moderated overactive mast cells. Since the connection between mast cells, inflammation, and pain was made by Levi-Montalcini, PEA’s effects for neuropathic pain (both central and peripheral) has been studied. 
How does PEA work?
- Inhibiting Pro-Inflammatory Molecules
PEA works directly to reduce inflammation by inhibiting inflammatory cytokines. Cytokines are proteins that function as intracellular messengers. Specifically, PEA inhibits the secretion of a cytokine called tumor necrosis factor alpha (TNF alpha). Perhaps the biggest effect on inflammation which PEA exerts is over interleukins, a type of cytokine that is a protein which helps cells communicate. Like TNF alpha, interleukins are secreted during the inflammation process, and they are part of the immunological system. 
PEA is synthesized in the body from one of the most common fatty acids, palmitic acid. Palmitic acid is produced through the synthesis of fatty acids and is also found in dietary sources such as dairy, butter, meats, palm tree oil, and cheeses. There are several routes in the body PEA can take to be synthesized, but most pathways are through their precursors, NAPEs (N-acylphosphatidylethanolamines) or NAEs (N-acylethanolamine).
Despite one of the pathways for synthesis involving dietary fatty acids, PEA is not affected by varying levels of dietary fatty acid intake, with the exception of the small intestine. Within the small intestine, dietary fatty intake counterintuitively reduces the amounts of PEA and their precursors NAE. Therefore, consuming dietary fatty acids in an attempt to stimulate more production of endogenous PEA will not be an effective strategy. 
- PEA and the Endocannabinoid System
PEA indirectly activates the endocannabinoid system within the body. The ECS (endocannabinoid system) contains fat based neurotransmitters and proteins that bind with cannabinoid receptors in the brain and peripheral nervous system. The current understanding of the ECS is that it is involved in processes such as pain-sensation, immune system activity, fertility, pre/post-natal development, mood, and memory.
PEA is believed to activate endocannabinoid receptors similar to CB2, rather than have a direct, particular affinity for the receptors CB1 and CB2. PEA’s effects occur through an entourage effect. 
Safety and Side Effects of PEA
Speak with your doctor if it sounds like PEA might be a good fit for you before beginning any supplementation.
Despite most of the studies only tracking consumption of PEA over short periods of time (usually a two-week period), there have been several clinical trials conducted in humans for which no side effects were noted. Most of the evidence for PEA’s safety in both rodents and humans shows very few adverse effects even at high doses (around 1200 mg of micronized PEA daily). 
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