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Palmitoylethanolamide | Known for Its Pain Reducing Qualities


PEA, which is short for palmitoylethanolamide, is a  natural substance found in the body that has been shown to potentially provide effective treatment for chronic and neuropathic pain. It was discovered in 1957 by scientists extracting it from soybean lecithin, which they referred to at the time as N-(2-hydroxyethyl)-palmitamide. Let’s take a closer look at this amazing natural molecule.

What is Palmitoylethanolamide?

PEA is an endogenous fatty acid amide, and a member of the N-acetyl-ethanolamine family. Fatty acid amides, as the name suggests, are formed by a combination of a fatty acid and an amine. They are widely distributed in the body, and play an important role in biochemical signaling. PEA itself can commonly be found in foods, including eggs and milk. In addition, being an endogenous compound, PEA is found all over the human body; including the brain and spinal cord. Interestingly, pain hypersensitivity that follows sciatic nerve constriction in is associated with a significant decrease in the level of endogenous PEA in spinal cord and in brain areas directly or indirectly involved in nociception. This indicates that PEA is vital to the body’s pain response.

In studies,  Palmitoylethanolamide has been shown to bind to the peroxisome proliferator-activated receptor (PPAR-α) in the nucleus of cells. This receptor is responsible for regulating the gene networks connected to the control of inflammation and pain. Palmitoylethanolamide also has affinity for the cannabinoid-like receptors GPR55 and GPR119. However, PEA does not have affinity for the classic cannabinoid receptors CB1 and CB2. As such, it does not possess the psychoactivity seen in classic cannabinoids. PEA also inhibits the release of mast cell mediators, such as histamine and TNF-alpha. In addition, PEA also has been shown to down-regulate mast cell expression, making it a very interesting compound for those with mast cell disorders.

Palmitoylethanolamide also has the ability to reduce the expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). Elevated levels of COX-2 are found during periods of inflammation, and NSAID painkillers, like ibuprofen, naproxen, and aspirin, work by inhibiting COX-2. PEA prevents IkB-alpha degradation and p65 NF-kappaB nuclear translocation, due to its PPAR-alpha agonism. In 2012, it was shown that PEA can also reduce reperfusion injury, and the negative impact of shock on various systems, such as renal dysfunction, ischemic injury, and inflammation. Clinical trials have found that the compound’s action performs numerous biological functions related to chronic pain, neuropathic pain, and inflammation.

Palmitoylethanolamide and Endocannabinoids

While PEA is not technically an endocannabinoid, it often gets grouped into the family; particularly with anandamide, because PEA operates via similar metabolic and synthetic pathways. Endocannabinoids are chemical compounds that activate many of the same receptors as THC, which is the active component in marijuana. Both humans and animals naturally synthesize endocannabinoids, which play a crucial 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. Endocannabinoids may help certain chronic immune and neurologic conditions, including chronic pain and nausea.

The two novel cannabinoid receptors that palmitoylethanolamide binds to, GPR55 and GPR119, are G protein-coupled receptors found in the human body and brain. GPR55 is activated by both the marijuana cannabinoids Δ 9-THC and cannabidiol, along with anandamide. The GPR55 receptor was only discovered in 1999, and many have started referring to it as 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 it also leads to increased binding of anandamide to the CB1 and CB2 receptors. This is because it competes for the GPR55 receptor, leaving more anandamide available for binding to the other cannabinoid receptors.

The GPR119 receptor is another G protein-coupled receptor expressed mostly in the pancreas and gastrointestinal tract. Activation of the GPR119 receptor have been shown to cause a reduction in food intake and reduction in body weight in rats. It has also been shown to regulate insulin and incretin secretion, making it a possible target for the treatment of obesity and diabetes.

PEA may be a more feasible solution over endocannabinoids and other similar compounds, as it does not come with many of the negative effects. PEA is an endogenous modulator and, as mentioned, it’s already present in many of the foods you already consume. As a result, there have been no reports of serious side effects or negative interactions with drugs or other supplements. In addition, its novel binding sites make it a unique possible solution for those with chronic pain and mast cell disorders that do not currently have many effective treatments.

The Effects of PEA

PEA offers numerous potential benefits for your personal health. It is most well known as a  suppressant for pain and inflammation. Clinical trials suggest that it may be helpful in various  forms of peripheral neuropathy, including:

  • Carpal tunnel syndrome
  • Sciatic pain
  • Neuropathy induced by chemotherapy
  • Diabetic neuropathy
  • Pain caused by stroke and multiple sclerosis
  • Lower back pain
  • Osteoarthritis
  • Postherpetic neuralgia
  • Vaginal pain
  • Chronic pelvic pain
  • Failed back surgery syndrome
  • Dental pain
  • Fibromyalgia syndrome

PEA anti-inflammatory effects have been shown to extend to eye cells, potentially offering assistance to those suffering glaucoma, diabetic nerve damage, and other eye diseases. Palmitoylethanolamide has been shown to protect the sensitive light-monitoring retinal cells from neurodegeneration as well as high intraocular pressures. In one human study, PEA was effective at reducing the progression of visual field damage in patients with normal-tension glaucoma.

Some studies with mice also show that PEA may help with irritable bowel syndrome. It was shown to help normalize intestinal motility, by down-regulating the expression of TRPV1, also known as the capsaicin receptor or vanilloid receptor 1. PEA also increased anandamide levels, possibly allowing for higher activation of the CB1 receptors.

PEA may also benefit the heart. Studies with mice using PEA found less injury to heart tissue, decreased cell death, and lower levels of inflammatory cytokines following an induced heart attack. In rat studies, those rats treated with PEA for at least five weeks had lower blood pressure than control rats. It has been shown that mast cells seem to proliferate in cardiovascular diseases, and that mast cell mediators contribute to coronary vasoconstriction, arrhythmias, leukocyte recruitment, and tissue injury and repair. PEA’s down-regulation of mast cell expression could positively affect the outcome of those suffering from heart diseases.

PEA can also potentially protect the brain. Stroke patients who were given PEA demonstrated improved recovery outcomes, including cognitive skills and overall brain status. Mice who were given PEA showed higher neuron regeneration after spinal cord injury. Studies with mice also showed that PEA preserved brain cells and decreased pro-inflammatory enzymes, suggesting that the compound may protect against brain inflammation and brain cell death. In addition, PEA taken within one hour after severe brain trauma significantly reduces the severity of damage, and improved the locomotor performance post-trauma.

Palmitoyalethanolamide is truly an amazing natural compound, with a variety of potential benefits and positive mechanisms in the body and brain. Research about this compound continues to expand on its new benefits and effects. If you are considering adding PEA to your stack, Nootropics Depot offers the compound in both powder form, for self-measuring and customized dosage, and an easy to take capsule form .


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