Mast cells sit directly against the small nerve endings in the skin

This is not a theory about what causes anything. It is where the cells are.

Ultrastructural imaging places mast cells in direct anatomical contact with unmyelinated nerve fibres in skin and other peripheral tissue.¹ Skin mast cells located beside sensory nerve endings release histamine, tryptase and nerve growth factor into that space.¹

The fibres they sit against are the small unmyelinated C fibres and thinly myelinated A-delta fibres. Those are the fibres that carry burning, tingling, heat and touch.

When a mast cell degranulates, it does not empty into open space. It empties onto whatever is next to it.

What the mast cell releases acts on the nerve directly

Each of the major mast cell mediators has a documented receptor on sensory neurons and a documented effect on how those neurons fire.

TRPV1 is the receptor capsaicin acts on. It is, functionally, the channel that reports burning.

A nerve sitting beside an activated mast cell is not a nerve that has been damaged and left alone. It is a nerve being acted on, continuously, by the cell next to it.

It has been measured in people with MCAS, by biopsy

In 2021, a team at Brigham and Women's Hospital published in the Annals of Allergy, Asthma & Immunology. Patients with a confirmed diagnosis of idiopathic mast cell activation syndrome or hereditary alpha tryptasemia, who had neurologic symptoms, were given standardised autonomic testing and skin biopsies to look for small fibre neuropathy.³

Small fibre neuropathy is damage to exactly the fibres described in section one. It is diagnosed from a punch biopsy of the skin, by counting nerve fibres under a microscope. It is not a questionnaire and it is not self-reported.

The same study also found reduced cerebral blood flow in these patients.³

The senior author, Mariana Castells, is among the most published clinicians working in mast cell disease. The journal is the official journal of the American College of Allergy, Asthma and Immunology.

Four out of five people with MCAS have documented damage to the nerve fibres that mast cells sit against.

The body makes its own molecule to shut mast cells down

Palmitoylethanolamide is produced on demand from a cell membrane precursor, locally, at the site of injury or inflammation, to restrain immune cell responses.⁴ Its levels rise in inflamed tissue, and particularly in skin.⁴

Rita Levi-Montalcini, who won the Nobel Prize in Physiology or Medicine in 1986, is the reason this class of molecules has a name. She described their action as Autacoid Local Injury Antagonism ‚Äî ALIA ‚Äî and PEA is the parent compound of the family.⁴

PEA is considered the most important of the ALIAmides specifically because of its ability to negatively modulate mast cell activation.⁴ The class is named after what it does to those cells.

Where it acts

PEA's primary receptor is PPAR-alpha, a nuclear receptor. Through it, PEA modulates pro-inflammatory cytokine synthesis, mast cell degranulation, microglial activation and oxidative stress.⁵

In 1995, work published in the Proceedings of the National Academy of Sciences showed that mast cells express a peripheral cannabinoid receptor, and that PEA downmodulates mast cell activation through it. Anandamide, which binds the same receptor, does not ‚Äî and in fact antagonises PEA's effect.⁶

Nobody had to aim this molecule at mast cells. That is where it was found.

Given PEA, mast cells beside nerve fibres stop degranulating

The most directly relevant animal work is a rat granuloma model published in Molecular Pain. In the inflamed tissue, mast cells were degranulated and closely localised near nerve fibres — the same arrangement described in section one.

PEA significantly reduced mast cell degranulation, reduced nerve fibre formation, and reduced the hyperalgesia that went with it.⁷

On skin mast cells specifically

In isolated skin mast cells challenged immunologically, PEA reduced the release of histamine, prostaglandin D2 and TNF-alpha.⁸ Those are three of the four mediators in the table in section two.

On the substance P pathway

Substance P is one of the neuropeptides that triggers mast cell degranulation, and it is released by the sensory nerves themselves. PEA counteracts substance P-induced mast cell activation by stimulating diacylglycerol lipase, raising 2-AG, and acting through the CB2 receptor.⁹

PEA pre-treatment also prevented mast cell degranulation in cultured mast cells, measured by both beta-hexosaminidase release and direct histamine quantification.⁹

The loop runs both directions: the nerve triggers the mast cell, and the mast cell sensitises the nerve. PEA acts on the cell side of it.

In humans, PEA lowered circulating histamine and inflammatory markers

In a double-blind, placebo-controlled trial, participants with seasonal allergic rhinitis took PEA or placebo daily for two weeks, with blood drawn at baseline and at the end.¹⁰

The PEA group showed a significant decrease from baseline in histamine, IL-4, IL-8, IL-10 and TNF-alpha. The placebo group showed a reduction in IL-4 only.¹⁰

Two of those — histamine and TNF-alpha — are mast cell mediators that appear in the section two table, acting directly on sensory nerve endings.

On pain, in controlled trials

A number needed to treat of 1.7 means that in that trial, for roughly every two people given 600 mg who would not have responded to placebo, one reached the pain endpoint.

600 mg is the dose that produced those results. It is the dose in this bottle.

Particle size decides how much of it is absorbed

PEA is lipophilic and dissolves poorly in water. For a compound like that, the rate at which it dissolves in the gut is the step that limits how much gets into the body at all ‚Äî and dissolution rate is governed by particle size.¹⁵

Micronised and ultramicronised PEA showed superior oral efficacy compared with non-micronised PEA in a controlled animal model of inflammatory pain.¹⁶

Two bottles can both say 600 mg and not deliver the same amount of anything.

PEA is cleared by a single enzyme, and that enzyme can be slowed

Fatty acid amide hydrolase ‚Äî FAAH ‚Äî is the enzyme that hydrolyses PEA. It is the route by which PEA is broken down and stops working.¹⁷

When FAAH is inhibited, PEA is no longer hydrolysed at the same rate, and remains available to act at PPAR-alpha and TRPV1.¹⁷

Several naturally occurring flavonoids inhibit FAAH. In direct comparison, the order of potency runs genistein and kaempferol, then apigenin and quercetin, then luteolin.¹⁸

Quercetin and luteolin are in this formula for that reason and no other. They are not what acts on the mast cell. They are what keeps the PEA present long enough to do it.

A dose that is cleared before it has finished working is a dose that was never really given.

Fifty years of people taking it, at doses well above this one

In 1970 the Czechoslovak pharmaceutical manufacturer Spofa introduced PEA as a tablet under the name Impulsin. Between 1972 and 1977, while it was an approved drug there, six placebo-controlled trials were run in a total of 3,627 people.¹⁹

Those trials studied respiratory infection, not pain. What they establish here is different and simpler: how many people have taken this compound, at what dose, and what happened to them. Subjects took 30 mg per kilogram of body weight. Relevant side effects were not seen at oral doses up to 1,800 mg per day.¹⁹

The modern record is consistent with it. Across more than twenty clinical trials in approximately two thousand patients, at doses from 300 to 1,200 mg daily and durations from 15 to 180 days, no serious side effects have been reported.²⁰

Two capsules a day is 600 mg. The 1970s trials ran at three times that without incident.

1. Cutaneous neuroimmune interactions in peripheral neuropathic pain states. Frontiers in Immunology, 2021. frontiersin.org · See also: Significance of conversation between mast cells and nerves. PMC2877069
2. Involvement of mast cells in the pathophysiology of pain. Frontiers in Cellular Neuroscience, 2021. frontiersin.org · Mast cells: versatile gatekeepers of pain. PMC4171343
3. Novak P, Giannetti MP, Weller E, Hamilton M, Castells MC. Mast cell disorders are associated with decreased cerebral blood flow and small fiber neuropathy. Annals of Allergy, Asthma & Immunology, 2021. PMID 34648976. pubmed.ncbi.nlm.nih.gov/34648976 · ScienceDirect
4. Palmitoylethanolamide and related ALIAmides: state of the art. PMC9496254 · New insights in mast cell modulation by palmitoylethanolamide. researchgate.net
5. Mechanisms and clinical applications of palmitoylethanolamide (PEA) in the treatment of neuropathic pain. Inflammopharmacology, 2024. springer.com
6. Facci L, et al. Mast cells express a peripheral cannabinoid receptor with differential sensitivity to anandamide and palmitoylethanolamide. PNAS, 1995;92(8):3376. pnas.org
7. De Filippis D, Luongo L, Cipriano M, et al. Palmitoylethanolamide reduces granuloma-induced hyperalgesia by modulation of mast cell activation in rats. Molecular Pain, 2011;7:3. PMC3034677
8. Effects of palmitoylethanolamide on immunologically induced histamine, PGD2 and TNF-alpha release from skin mast cells. ScienceDirect
9. Palmitoylethanolamide counteracts substance P-induced mast cell activation in vitro by stimulating diacylglycerol lipase activity. Journal of Neuroinflammation, 2019. PMC6933707
10. The effect of palmitoylethanolamide supplementation on symptoms of allergic rhinitis: a double-blind placebo-controlled trial. Nutrients, 2023;15(23):4940. PMC10707829
11. Guida G, et al. Palmitoylethanolamide in chronic neuropathic pain due to compressive lumbosciatalgia: multicentre clinical study, 636 patients. See also the post-hoc analysis: Micronized palmitoylethanolamide: a post hoc analysis of a controlled study in patients with low back pain – sciatica. PMC7132032
12. Efficacy of ultramicronized palmitoylethanolamide in burning mouth syndrome-affected patients: a randomized double-blind controlled trial. Clinical Oral Investigations. springer.com
13. A randomized controlled trial assessing the safety and efficacy of palmitoylethanolamide for treating diabetic-related peripheral neuropathic pain. PMC9700575
14. Palmitoylethanolamide in the treatment of chronic pain: a systematic review and meta-analysis of double-blind randomized controlled trials. Nutrients, 2023;15(6):1350. PMC10053226
15. Particle size profiles of native, micronised and ultramicronised PEA, and the effect of dissolution rate on oral bioavailability. Review
16. Micronized/ultramicronized palmitoylethanolamide displays superior oral efficacy compared to nonmicronized palmitoylethanolamide in a rat model of inflammatory pain. PMID 25164769. pubmed.ncbi.nlm.nih.gov/25164769
17. Fatty acid amide hydrolase catalyses the hydrolysis of anandamide, palmitoylethanolamide and oleoylethanolamide; inhibition preserves signalling at TRPV1 and PPAR-alpha. PMC3477273
18. Inhibition of fatty acid amide hydrolase by kaempferol and related naturally occurring flavonoids. Potency order: genistein, kaempferol > apigenin ≈ quercetin > luteolin. researchgate.net
19. Prophylactic efficacy of N-2-hydroxyethyl palmitamide (Impulsin) in acute respiratory tract infections. European Journal of Clinical Pharmacology. springer.com · Evolution in pharmacologic thinking around the natural analgesic palmitoylethanolamide. PMC3744360
20. Palmitoylethanolamide supplementation for human health: a state-of-the-art systematic review of randomized controlled trials in patient populations. PMC11745966