Palmitoylethanolamide (PEA) is a naturally occurring molecule that has been shown to have anti-inflammatory, analgesic, and neuroprotective effects in the body and brain.
Key Facts:
- PEA is produced naturally in the body and is also found in many foods like egg yolks, coffee, and soy.
- It activates PPAR-alpha receptors which regulate inflammation, pain perception, and neuroprotection.
- PEA reduces pain and inflammation in many animal studies, even outperforming current pain medications.
- Clinical trials show PEA improves chronic pain in conditions like sciatica and knee osteoarthritis.
- PEA may protect the brain from damage in stroke, Parkinson’s disease, and other disorders.
- The compound is very safe and well-tolerated in humans with very minimal side effects.
Source: Int J Mol Sci. 2020
What is Palmitoylethanolamide and How is it Made in the Body?
Palmitoylethanolamide (PEA) is a lipid compound that consists of the fatty acid palmitic acid coupled to the molecule ethanolamine.
It belongs to a class of molecules called N-acylethanolamines (NAEs) that also includes the endocannabinoid anandamide.
PEA is synthesized naturally in the body from phospholipids in cell membranes.
An enzyme called N-acyltransferase (NAT) attaches a fatty acid to phosphatidylethanolamine, forming an N-acylphosphatidylethanolamine (NAPE).
Then an enzyme called NAPE-PLD cleaves off the NAPE to release PEA and other NAEs.
PEA is found at low levels throughout the body. It’s highest in the brain, spinal cord, skin, liver, and GI tract.
Foods like egg yolk, soy lecithin, and coffee beans also contain small amounts of PEA.
How Does PEA Get Absorbed and Broken Down in the Body?
Since PEA is a fat-soluble molecule, it can readily pass through cell membranes and enter tissues after being absorbed from food or supplements.
However, enzymes that break down PEA are also found throughout the body, so PEA gets rapidly metabolized.
The two main enzymes that metabolize PEA are fatty acid amide hydrolase (FAAH) and N-acylethanolamine acid amidase (NAAA).
FAAH is found predominantly in the liver and brain while NAAA is most abundant in immune cells like macrophages. Both enzymes break down PEA into palmitic acid and ethanolamine.
Micronized and ultra-micronized formulations of PEA have been developed to optimize absorption before the compound gets broken down.
However, there is still minimal data on exactly how well PEA gets absorbed or distributed to different tissues.
More research is needed to fully understand the pharmacokinetics of this compound after oral administration.
PEA’s effects in the body and brain likely depend on its ability to reach target tissues at sufficient concentrations.
PEA Activates PPAR-alpha Receptors to Reduce Inflammation and Pain
The major molecular target of PEA is the PPAR-alpha receptor.
PPAR-alpha is a transcription factor that regulates gene expression involved in metabolism and inflammation.
When activated by PEA, PPAR-alpha turns on genes that dampen inflammatory responses.
This reduces production of cytokines like TNF-alpha and results in broader anti-inflammatory and pain-relieving effects.
In fact, many of PEA’s benefits are lost in PPAR-alpha deficient mice, highlighting the importance of this receptor.
However, some anti-inflammatory effects remain even without PPAR-alpha, suggesting other targets like TRPV1, GPR55 or others may also be involved.
Additionally, PEA may inhibit the breakdown of natural endocannabinoids like anandamide, which could enhance endocannabinoid signaling.
But more research is needed to confirm this mechanism.
Overall, PEA mimics and enhances the effects of endocannabinoids in engaging cellular receptors that modulate pain and inflammation in both the peripheral and central nervous system.
PEA Improves Chronic Pain in Conditions Like Sciatica and Arthritis
A considerable amount of research shows that PEA provides pain relief in various animal models of nerve pain, arthritis, colitis and other inflammatory conditions.
Rats and mice given PEA have higher pain thresholds and reduced hypersensitivity from injured nerves.
Importantly, several human clinical trials also demonstrate PEA’s efficacy as a pain medication.
In a study of over 600 patients with chronic low back pain and sciatica, PEA supplementation substantially reduced pain scores compared to placebo.
Remarkably, just 1.7 patients needed to be treated with 600 mg PEA per day for one patient to achieve a 50% reduction in pain.
This makes PEA more effective than common analgesics like NSAIDs and gabapentinoids.
Other studies showed benefits of PEA treatment for osteoarthritis pain and itching/inflammation in eczema patients.
PEA may be particularly effective for chronic neuropathic and inflammatory pain conditions.
However, larger randomized controlled trials are still needed to fully confirm its efficacy.
PEA Protects the Brain from Injury and Neurodegeneration
In addition to reducing peripheral pain and inflammation, PEA also protects the brain and spinal cord from acute damage and chronic neurodegeneration.
In mice with stroke, PEA minimized brain injury and neurological deficits by suppressing inflammation and oxidative stress.
It also improved recovery in mice with spinal cord trauma by altering gene expression related to inflammation, neuronal survival, and nerve regeneration.
Furthermore, PEA prevented dopamine neuron loss and motor deficits in a mouse model of Parkinson’s disease.
It reduces neuroinflammation and oxidative damage in the brain from toxins that induce Parkinson-like pathology.
The neuroprotective effects of PEA make it a promising therapy not just for pain, but also for minimizing brain damage from stroke, trauma, and neurodegenerative diseases.
More research is underway to explore these applications.
PEA Has an Excellent Safety Profile in Humans
An important benefit of PEA is its outstanding safety and tolerability, even with long-term use at high doses.
No significant side effects or adverse events have been reported.
Minor gastrointestinal effects like nausea are occasionally seen with PEA treatment.
Chronic toxicity studies in animals also demonstrate an excellent safety profile and no organ damage with prolonged daily PEA administration.
This is likely due to PEA’s natural presence in the body and food.
PEA’s safety gives it a substantial advantage over current pain medications like NSAIDs and opiates, which have significant side effects and risks.
The optimal benefit-risk profile makes PEA an attractive alternative or adjunct treatment for many conditions.
However, more Phase III clinical trials are needed to fully confirm PEA’s safety and efficacy in humans.
Most evidence so far comes from smaller trials and animal research. But results so far are very promising for this natural compound.
The Future of Palmitoylethanolamide
In summary, palmitoylethanolamide (PEA) is emerging as a potentially powerful therapy for reducing inflammation and protecting neurons in both the peripheral and central nervous system.
Its effects are mediated in large part by activating PPAR-alpha receptors.
PEA performs remarkably well in animal research.
As more human trials are conducted, it may prove to be an excellent alternative or complement to current treatments for chronic pain, neurodegeneration, and other inflammatory conditions.
Its unparalleled safety also makes it ideal for long-term and preventative use.
However, key questions remain about how well PEA is absorbed and distributed to tissues and cells after oral intake.
Engineering optimal formulations could help enhance its delivery throughout the body.
Larger randomized controlled trials are also needed to fully confirm effectiveness in specific indications.
But the promise of PEA is clear. This natural lipid compound engages our own innate pathways for reducing inflammation and pain without significant side effects.
Unlocking the full potential of PEA could provide a safer, non-addictive solution to millions suffering from chronic pain, brain inflammation, and neurodegeneration worldwide.
References
- Study: The basal pharmacology of palmitoylethanolamide
- Authors: Linda Rankin & Christopher J. Fowler (2020)
