Palmitoylethanolamide
Palmitoylethanolamide (PEA) is an endogenous fatty acid amide produced naturally in the body as part of the endocannabinoid system. It is structurally related to anandamide (the 'bliss' endocannabinoid) but binds different receptors. PEA is found in trace amounts in egg yolks, peanuts, and soybeans, but achieving therapeutic doses requires supplementation.
Starting dose. 300-600mg — Micronized PEA 2x daily
Can be taken with or without food. Split dosing (2-3x daily) maintains steadier therapeutic levels. Effects develop over 2-4 weeks - not for acute pain. Loading dose (1,200mg/day for 2 weeks) then maintenance (600mg/day) is a common protocol.
Start here. Every protocol below is ordered lowest-first. Begin at the smallest effective dose, hold about a week to assess tolerance, and step up only if needed.
PEA's primary mechanism is activation of PPAR-alpha (peroxisome proliferator-activated receptor alpha), a nuclear receptor that regulates anti-inflammatory and pain-modulating gene expression. PPAR-alpha activation downregulates NF-kB signaling, reducing pro-inflammatory cytokine production (TNF-alpha, IL-6, IL-1).
Mast cell stabilization: PEA is one of the most effective natural mast cell stabilizers known. Mast cells release histamine, tryptase, and inflammatory mediators when activated - particularly relevant in allergic, inflammatory, and chronic pain conditions. PEA reduces mast cell degranulation and prevents excessive mast cell-mediated inflammation.
Endocannabinoid 'entourage effect': PEA is not a cannabinoid receptor agonist but enhances the activity of anandamide (the endogenous CB1 agonist) by inhibiting its breakdown enzyme FAAH. This indirectly increases endocannabinoid tone, contributing to analgesia and mood support.
TRPV1 receptor: PEA modulates TRPV1 (the capsaicin receptor) which is involved in pain transduction, particularly in inflammatory and neuropathic pain.
Microglial modulation: PEA reduces microglial activation in the CNS, decreasing neuroinflammation. This is particularly relevant for chronic pain that has 'centralized' (central sensitization) where peripheral pain has caused CNS inflammatory changes.
Glial cell function: PEA modulates glial-neuronal communication, important in chronic pain pathophysiology.
Weeks 1-2: Subtle anti-inflammatory effects.
Each reference below was re-fetched from its PubMed record, and the quoted sentence was confirmed to appear in that abstract and to support the claim it sits under. Follow any of them to read the source.
PEA has anti-inflammatory and analgesic properties and is very well tolerated in humans.
PEA has anti-inflammatory and analgesic properties and is very well tolerated in humans.
The Basal Pharmacology of Palmitoylethanolamide.
Evidence scope. Pharmacology review; broad human tolerability statement without confirming the card's exact micronized regimen.
Claims we could not support
No abstract we checked supports these for this molecule at this route. That is not the same as saying they are false — it marks where the evidence is missing.
Dose/route: 300-600mg micronized PEA 2x daily via Oral, 2-3x daily, with or without food. No checked live PubMed abstract supported this complete molecule/formulation/route/dose/frequency combination.
Mechanism: PEA's primary mechanism is activation of PPAR-alpha (peroxisome proliferator-activated receptor alpha), a nuclear receptor that regulates anti-inflammatory and pain-modulating gene expression. PPAR-alpha activation downr. No checked live abstract supported this full mechanistic claim at the card's formulation/route without extrapolation.
Exact-regimen safety: Generally extremely well-tolerated - one of the safest pain interventions. The verified safety row does not establish incidence or severity at every element of the card's exact regimen.
Two different questions: what is documented about running these together, and what is documented about drawing them into the same syringe. A good pharmacological partner can still have to be pinned separately.
Check any specific pair in the Stack & Interaction Checker, which answers both questions separately. Absence of a documented conflict is not evidence of safety.
Plasma (rapid clearance), but tissue effects persist longer due to PPAR-alpha gene expression changes.
Oral.
Plasma clearance 4-6 hours. Anti-inflammatory and analgesic effects build over weeks of consistent dosing.
Standard PEA: poor (~3-10%). Micronized: 5-10x better (~30-50%). Ultra-micronized: highest absorption.
Acute effects per dose: 6-12 hours. Chronic anti-inflammatory and analgesic effects build over 2-8 weeks of consistent dosing.
Hydrolyzed by FAAH and NAAA enzymes to palmitic acid and ethanolamine. No drug interactions of significance.
Storage. Store at room temperature (20-25C) in a cool, dry place. Protect from light and moisture. Capsules shelf-stable 2+ years.
Approved as 'food for special medical purposes' (FSMP) in EU for chronic pain. Classified as a dietary supplement in the US - no prescription required. Wider availability and acceptance in Europe than US.
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