Palmitoylethanolamide: A Guide To Its Pain Management Benefits And Beyond

Palmitoylethanolamide: A Guide To Its Pain Management Benefits And Beyond


Often abbreviated as PEA, Palmitoylethanolamide is a natural substance found in the body that may support pain management. Palmitoylethanolamide (PEA) was discovered in 1957 and it was referred to as N-(2-hydroxyethyl)-palmitamide at the time. Let’s take a closer look at this intriguing natural molecule.


PEA is an endogenous fatty acid amide, and a member of the N-acetyl-ethanolamine family. Fatty acid amides are created from a combination of a fatty acid and an amine. Fatty acid amides are widely circulated in the body, and have a key role in biochemical signalling. Although PEA is an endogenous compound found throughout the human body, Palmitoylethanolamide can be found in foods too. The most common Palmitoylethanolamide food sources are milk and eggs. However, Palmitoylethanolamide is only present in these foods at trace amounts and does not promote significant PEA benefits.

Interestingly enough, hypersensitivity to pain is associated with a large decrease in PEA levels in the brain and spinal cord, areas directly and indirectly involved in helping the nervous system from potentially harmful stimuli. This seems to indicate that PEA may be vital in bodily responses to pain. PEA research discovered that Palmitoylethanolamide binds to the peroxisome proliferator-activated receptor (PPAR-α) in the nucleus of cells. This particular receptor is responsible for regulating gene networks linked to pain control.

Another element that makes Palmitoylethanolamide unique is that it also has an affinity for cannabinoid-like receptors GPR55 and GPR119. Yet, PEA has no affinity for the classic cannabinoid receptors CB1 and CB2, so PEA does not carry the psychoactivity typically seen in classic cannabinoids.

Palmitoylethanolamide may also help regulate the expression of cyclooxygenase-2 (COX-2) as well as inducible nitric oxide synthase (iNOS). Research has found that COX-2 levels are elevated during periods of pain and inflammation. Interestingly, the expression of these proinflammatory molecules was also discovered in cases of neuroinflammation. The impact on inflammation, specifically Palmitoylethanolamide interactions with COX-2 and iNOS suggest that PEA may also support cognitive function. Findings also suggest that PEA may help regulate IkB-alpha degradation and p65 NF-kappaB nuclear translocation, due to its PPAR-alpha agonism. Studies have indicated that Palmitoylethanolamide’s action performs several biological functions that may help support pain management.


Although it isn’t technically an endocannabinoid, PEA often gets bundled into the cannabinoid family; particularly with anandamide, since PEA operates through similar synthetic and metabolic pathways. Endocannabinoids are compounds that naturally exist in our bodies, which interact with cannabinoid receptors. Both humans and animals naturally synthesize endocannabinoids that play a key role in bioregulation. They are mainly involved in cell signaling; producing same cell (autocrine) and cell-to-cell (paracrine) actions rather than full systemic effects.

The two notable cannabinoid receptors that PEA binds to are known as GPR55 and GPR119. These are G protein-coupled receptors found throughout the human body and brain. The GPR55 receptor is activated by endogenous cannabinoids such as anandamide (AEA). The GPR55 receptor was first discovered in 1999, and many started calling it the CB3 receptor.

Since both PEA and anandamide bind to the GPR55 receptor, supplementing PEA not only leads to the effects modulated by direct binding to the GPR55 receptor, but also leads to increased binding of anandamide to the CB1 and CB2 receptors. This happens since PEA competes for the GPR55 receptor with AEA. thus allowing more anandamide to become available to bind to the other cannabinoid receptors. The GPR119 receptor is another G protein-coupled receptor expressed mostly in the pancreas and gastrointestinal tract. GPR119 receptor activation has been shown to cause a reduction in food intake and reduction in body weight in rats.

PEA is an endogenous modulator and, as mentioned, it’s already present in many of the foods you already consume, albeit in trace amounts. In addition, its novel binding sites make it a unique possible solution for those looking for a supplement that may help promote balanced inflammation levels.


Although it is most well known for its ability to support pain management, here’s a list of other potential Palmitoylethanolamide benefits:

May Help Support Pain Management

May Help Promote Cognitive Function

May Help Support Balanced Inflammation Levels

May Help Promote Cardiovascular Function

May Help Support Immune Function

As can be seen above, Palmitoylethanolamide benefits are quite diverse! Better yet, Palmitoylethanolamide has been incredibly well studied over the last few decades, giving us unrivaled insight into the effect of these unique compounds.

As we mentioned above, PEA is most well known for its effects on pain, however, research has also found that a Palmitoylethanolamide supplement may help support cardiovascular function. Rodent research has found that Palmitoylethanolamide promoted cellular function and overall cell proliferation, particularly around heart tissue. These findings also revealed lower cytokine levels.

The unique effects profile of Palmitoylethanolamide however does not stop at pain management and cardiovascular support, because believe it or not, there is even evidence that indicates Palmitoylethanolamide benefits brain health! It appears to do this through the role it plays with neuroinflammation and its interaction with PPAR-α receptor. By balancing neuroinflammation, and through its effects on PPAR-α receptors, a Palmitoylethanolamide supplement may exert a positive effect on cognitive function. This pro-cognitive effects may even extend into promoting feelings of well being!

Palmitoylethanolamide Immune System Effects

PEA has even been shown to help support immune function, which is why we included it in our highly comprehensive Immune Defense formula.

In fact, one of the original uses of Palmitoylethanolamide was to minimize sick time. Several trials during the 1970s were conducted to evaluate PEA’s effects on our immune system. Interestingly enough, results determined that the use of PEA significantly supported immune system function.

Studies found that Palmitoylethanolamide may also help stabilize mast cells, which play a role in allergies. Palmitoylethanolamide has also demonstrated some ability to strengthen the immune system and also been shown to help speed up recovery from sickness.

Palmitoylethanolamide is a remarkable compound with several potential benefits and positive mechanisms within the body and brain. Ongoing PEA research aims to discover additional Palmitoylethanolamide benefits. If you’re thinking about adding PEA to your nootropic regimen, offers PEA as both a powder for customized dosing and as an easy to take 400mg capsule.


Unlike some other supplements, Palmitoylethanolamide takes a few weeks to build up in our bodies, so certain effects may not be noticeable right away. The effects that are the most time-dependent with PEA are it’s pain support effects. However, don’t let this discourage you, as a lot of people have great success with PEA after giving it 2-4 weeks to build up in their bodies. This means that taking PEA consistently is the only way to ensure that your body is maximizing the potential Palmitoylethanolamide benefits.


PEA has a versatile range of benefits and goes great with a lot of our other products. Here are 3 of our recommended PEA stacks!

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