PEA (Palmitoylethanolamide)
An endogenous fatty acid amide produced naturally in the body in response to pain and inflammation. PEA activates PPAR-alpha receptors and indirectly enhances endocannabinoid signaling without binding to cannabinoid receptors. It has strong evidence for neuropathic pain, neuroinflammation, and neuroprotection. Unlike anti-inflammatory drugs, it resolves inflammation rather than merely suppressing it.
Dosage
Standard: 300-1200 mg daily in 2-3 divided doses. Start at 600 mg daily. Micronized or ultra-micronized (um-PEA) forms have much better absorption. For chronic pain: 600 mg twice daily. For neuroinflammation: 400-600 mg twice daily. Effects build over 2-4 weeks.
Dosages shown are for research reference only. Always consult a qualified healthcare provider.
Half-Life
1-2 hours (rapidly metabolized). Micronized forms have improved bioavailability
Administration
Oral (capsules, powder). Micronized (m-PEA) or ultra-micronized (um-PEA) forms preferred for bioavailability.
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Mechanism of Action
PEA activates PPAR-alpha (peroxisome proliferator-activated receptor alpha), a nuclear receptor that heterodimerizes with RXR and downregulates pro-inflammatory gene expression (NF-kB target genes, COX-2, iNOS, TNF-alpha). It has an 'entourage effect' on the endocannabinoid system — it inhibits the degradation of anandamide by fatty acid amide hydrolase (FAAH) through allosteric modulation or substrate competition, and upregulates CB2 receptor expression on immune cells. This provides anti-inflammatory and analgesic effects without directly activating CB1/CB2. PEA also activates GPR55 and GPR119. It inhibits mast cell degranulation (reducing histamine, tryptase, and cytokine release) and reduces microglial activation in the brain (inhibiting Iba1 expression and pro-inflammatory cytokine production). PEA may also modulate TRPV1.
Regulatory Status
Dietary supplement or food for special medical purposes (varies by country). Available OTC. Prescription in some European countries.
Risks & Safety
Common
Very well-tolerated — rare side effects. Mild GI discomfort.
Serious
None documented. Over 30 clinical trials confirm excellent safety profile.
Rare
Skin rash.
Compare PEA (Palmitoylethanolamide) With
Research Papers
10Published: July 25, 2023
AI Summary
Those findings indicate potential treatment options for obesity. Conclusion: We noticed the profound decline of endocannabinoids concentrations in subjects with increased 18F-FDG PET/MR uptake in BAT.
Published: October 23, 2024
AI Summary
Therefore, in the search for compounds with a protective and regenerative effect on keratinocyte phospholipids, the effectiveness of two antioxidant compounds has been tested: a stable derivative of ascorbic acid, 3-O-ethyl ascorbic acid (EAA) and cannabigerol (CBG), both of which are primarily located in the membrane structures of keratinocytes...
Published: May 1, 2017
AI Summary
Consumption of food for pleasure was reported to be associated with increased circulating levels of both the orexigenic peptide ghrelin and some specific endocannabinoids in normal-weight subjects and patients with morbid obesity.
Published: May 14, 2007
AI Summary
In vivo studies revealed that AEA decreases were associated with a remarkable inhibition of the release of both anandamide and glutamate in the nucleus accumbens. These results suggest that receptor-mediated release of acylethanolamide is inhibited by the acute administration of ethanol, and that this effect is not derived from increased fatty a...
Published: March 27, 2016
AI Summary
In addition, elevated plasma DHEA levels in response to DHA intake tended to be associated with lower plasma OEA levels and an increased gynoid fat mass. In summary, data suggest that the metabolic and physiological responses to dietary FA may be influenced via circulating FAE.
Published: June 27, 2023
AI Summary
Fibromyalgia (FM) is characterised by a form of debilitating pain that is unresponsive to standard analgesics. The aim of this study was to evaluate the efficacy of supplementing ongoing pregabalin (PGB) and duloxetine (DLX) treatment with palmitoylethanolamide (PEA) and acetyl-L-carnitine (ALC) for
Published: August 30, 2021
AI Summary
Acetyl-L-Carnitine (ALC) has also been shown to be an effective and safe treatment in painful peripheral neuropathy. In the last years the synergistic effect between PEA and ALC has been demonstrated.
Published: August 26, 2025
AI Summary
The treatment of peripheral neuropathies includes medications targeting the nociceptive component, whereas the neuropathic component is managed with agents such as gabapentinoids or antidepressants, though their prolonged use is limited by significant side effects.
Published: February 16, 2021
AI Summary
All these parameters were decreased in a significantly manner by oral administration of a compound constituted by a mixture of um-PEA and LAC in relation 1:1 (5 mg/kg), but not with the association of single compounds administered one after the other.
Published: June 24, 2024
AI Summary
There is a growing evidence suggesting the association of vitamin D deficiency (VDD) and cognitive impairment. In VDD mice we found cognitive malfunctioning associated with reduced neuroplasticity, indicated by impaired long term potentiation, and neuroinflammation at the hippocampal level.
Frequently Asked Questions
What is PEA (Palmitoylethanolamide) used for?
An endogenous fatty acid amide produced naturally in the body in response to pain and inflammation. PEA activates PPAR-alpha receptors and indirectly enhances endocannabinoid signaling without binding to cannabinoid receptors. It has strong evidence for neuropathic pain, neuroinflammation, and neuroprotection. Unlike anti-inflammatory drugs, it resolves inflammation rather than merely suppressing it.
What are the side effects of PEA (Palmitoylethanolamide)?
Common: Very well-tolerated — rare side effects. Mild GI discomfort. Serious: None documented. Over 30 clinical trials confirm excellent safety profile. Rare: Skin rash.
How is PEA (Palmitoylethanolamide) administered?
PEA (Palmitoylethanolamide) is administered via oral (capsules, powder). micronized (m-pea) or ultra-micronized (um-pea) forms preferred for bioavailability..
What is the half-life of PEA (Palmitoylethanolamide)?
The half-life of PEA (Palmitoylethanolamide) is 1-2 hours (rapidly metabolized). Micronized forms have improved bioavailability.
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