Mast Cell Activation Syndrome Resource Page

The following is a mast cell summary put together for and from my own research. It is not meant to be medical advice, but rather an aggregation of resources and my own ‘self-experimentation’ results. I’m sharing it here as many have asked what I learned and how I’ve tamped down on huge reactions since going into anaphylaxis during my last round of blood patching.

For reference, prior to starting the regimen below, I had 24/7 searing and burning pain in my skin, adrenaline dumps at night that kept me up until 5am with heart racing, shaking with cold and low blood pressure, hives, heart racing, gastro-intestinal distress, and many instances of anaphylaxis following certain foods or smells.

Since using the protocol I’ve listed out below, those have all disappeared, save for occasional reactions to new foods or smells. The skin burning disappearing was especially a relief, as is my newfound ability to sleep.

These issues arose following diagnostics for a CSF leak, and worsened as treatment occurred. Following severe anaphylaxis to fibrin glue patching in early 2018, my mast cells have been most upset, and I have been working on managing it since.

I update this page often, and welcome corrections or additional research – please use the contact page on the menu bar above to send me an email. 

NOTE: For those with mast cell dysfunction concerned about COVID-19 and the reports that inflammatory immune conditions may worsen cytokine storms and consequently the outcomes for the virus, please see this release from MCAS expert Dr. Laurence Afrin. All the more reason to practice social distancing now, and urge others to do so preemptively to help flatten the curve of this pandemic.

Mast Cell Activation Syndrome: Table of Contents

1. Basics of Mast Cell Dysfunction
2. Symptoms and Triggers of Mast Cell Dysfunction
3. Treating Mast Cell Activation Naturally
4. Treating Mast Cell Activation Pharmaceutically
5. Mast Cells and Pain
6. Mast Cells and Inflammation
7. Mast Cells and Celiac Disease
8. Mast Cells and Ehlers Danlos Syndrome (EDS)
9. Mast Cells and Jet Lag
10. Unconventional Treatments for Mast Cell Dysfunction
11. Books to Read

BUT FIRST, WHAT ARE MAST CELLS?

Mast cells are immune system cells that live in the bone marrow and in body tissues, internal and external, such as the gastrointestinal tract, the lining of the airway, and the skin. Everyone has mast cells in their body, and they play many complex and critical roles in keeping us healthy. The positive roles that they play include protecting us from infection, and helping our body by participating in the inflammatory process. However, mast cells are also involved in allergic reactions, from the tiny swelling that appears after a mosquito bite to a life threatening, full-blown anaphylaxis.

-The Mastocytosis Society of the United States (TMS)

Mast cells are “sentinels” of the immune system, a type of white blood cell that helps control the immune processes in the body. When they get “angry,” a process known as degranulation, they dump up to 200 different signalling chemicals – called mediators – into the blood stream. That degranulation response is part of the body’s natural defence when it senses invaders. But mast cell activation syndromes result when that normal defence response goes off the rails, meaning the mast cells mount a defence for innocuous things that would not otherwise be a threat.

Mast cells exist in organs and tissue throughout the body, and mediate allergic, immune, and inflammatory reactions.

They also increase anxiety, via their mediator release, huge inflammatory response to that release, and high levels of histamine in the body. A recent Psychology Today article even called for examining patients for mast cell dysfunction when they present with anxiety, depression, or brain fog. Furthermore, a 2017 case study entitled “Mast cell activation disorder masquerading as a nervous breakdown”, notes that a patient who presented with severe psychiatric symptoms was actually found to have MCAS, and his neuro-psych symptoms dissipated once the mast cells were stabilized. That same paper states that “although rare, some patients can present with minor neurocognitive disturbances as well as frank psychotic behaviors.”

Anecdotally, several mast cell patients I’ve spoken with have said their anxiety levels plummeted once the mast cells were stabilized, including several who had a “feeling of doom” that accompanied extreme anxiety.

 

Mast cells and pain

Mast cells and pain. Source: EMBRN

1. BASICS OF MAST CELL DYSFUNCTION

Mast cell activation syndrome should not be confused with mastocytosis, or histamine intolerance.

The former is usually a lifelong issue that gets worse with trauma, triggers, diseases, etc. The latter can occur at childhood or adulthood, and often with a sudden onset.

Histamine intolerance can be a subset of mast cell diseases, or potentially a standalone issue with a specific root cause. Mast cell diseases are transcend histamine alone, as you can see in the section about meditators below – histamine is one of 200 meditators that dump into the bloodstream when mast cells degranulate. If your issue is histamine intolerance and not a mast cell issue, see Dr. Joneja’s PDF primer about it here.

All mast cell diseases are caused by the proliferation and accumulation of trained/altered mast cells or the inappropriate release of mast cell mediators, creating symptoms in multiple organ systems, but mastocytosis is often confirmed with a bone marrow biopsy (looking for a KIT mutation).

The way I describe it to friends and family: MCAS involves inappropriate mast cell degranulation (angry mast cells) and mastocytosis involves extra mast cells that proliferate from the bone marrow and they may also be angry – sometimes a double whammy.

The Mastocytosis Society has a chart for the different types of systemic mastocytosis, and this chart does not even include other varients such as Cutaneous Mastocytosis, Mast Cell Leukemia or the rare Mast Cell Sarcoma, nor does it include the newer Hereditary Alpha Tryptasemia.

Varients of Systemic Mastocytosis from TMS

The three major forms of mast cell diseases are mastocytosis, mast cell activation syndrome (MCAS), and Hereditary Alpha tryptasemia (HAT). Mast cell diseases can cause tremendous suffering and disability due to symptomatology from daily mast cell mediator release, and/or symptoms arising from infiltration and accumulation of mast cells in major organ systems. Although systemic mastocytosis is a rare disease, those suffering with MCAS have recently been increasingly recognized and diagnosed. As a result, patients with MCAS appear to represent a growing proportion of the mast cell disease patient population. It is important to note that the process of mast cell activation can occur in anyone, even without a mast cell disease, as well as in patients with both mastocytosis and MCAS.
– The Mastocytosis Society, Overview page

A. Good overview posts about MCAS:

  • This thorough symptom list, Clinical Manifestations of Mast Cell Activation Syndrome By Organ Systems, by Dr. Lawrence Afrin and Dr. Tania Dempsey.
  • Jill Carnahan’s overview of mast cell activation, When Histamine Goes Haywire, here.
  • Hoffman Center: MCAS, When The Immune System Runs Rampant, here. Their MCAS questionnaire here.
  • This PDF from the Mastocytosis Society, that differentiates between mastocytosis, cutaneous masto issues, and mast cell activation syndrome. (Link is to PDF in my Dropbox where you can download to your computer)
  • The video below “Living With Mast Cell Activation Syndrome” from Dr. Maitland, presented at the Ehlers Danlos Global Learning Conference in 2018.

B. Technical explanation of mast cells / mediators in the body: There’s a lot of science discussing the association between mast cells and nerves in most tissues, including studies that suggest the mast cells are constantly providing information to the nervous system. Mast cells are also widely distributed in both connective tissue and mucosal surfaces, and interact with their environment locally in very different ways. They’ve got a load of different functions, too – they’re thought to play a major role in resistance to infection, and are involved in inflammation and the tissue repair that follows initial inflammation during an injury. They also are involved in hair follicles! And that’s just the tip of the iceberg.

Mast cells are capable of the synthesis of a large number of pro- and anti-inflammatory mediators, including cytokines, growth factors and products of arachidonic acid metabolism. Pre-stored mediators, such as histamine, serine proteases, proteoglycans, sulphatases, and tumour necrosis factor (TNF), are released within minutes after degranulation of the cell.”
Full study/explanation of mediators in Significance of Conversation between Mast Cells and Nerves.

Mast cells increase their numbers in specific site in the body by proliferation, increased recruitment, increased survival, and increased rate of maturation from its progenitors. Mast cells are implicated in brain injuries, neuropsychiatric disorders, stress, neuroinflammation, and neurodegeneration. Source: Mast Cell Activation in Brain Injury, Stress, and Post-traumatic Stress Disorder and Alzheimer’s Disease Pathogenesis.

C. Additional publications: Good resources page from Dr. Theoharides, the “Mast cell master” behind Neuroprotek supplements. Great starting point for mast cell questions/studies. Page is here.

2. SYMPTOMS AND TRIGGERS OF MAST CELL ACTIVATION DISORDERS

mast cell activation symptoms and effects in the body
A. Symptoms: Because mast cells exist in so much of the body’s tissues and systems, when they degranulate a large range of symptoms throughout the body may occur.

  • Flushing of the face, neck, and chest Itching, +/- rash
  • Hives, skin rashes – see TMS’ “visual guide to skin lesions” for more, here.
  • Atopic dermatitis and eczema (see here, and here.)
  • Angioedema (swelling)
  • Nasal itching and congestion
  • Wheezing and shortness of breath
  • Throat itching and swelling
  • Headaches
  • Brain fog and cognitive dysfunction, accompanied with anxiety or depression
  • Diarrhea, nausea, vomiting, abdominal pain, bloating, gastroesophageal reflux disease (GERD)
  • Bone/muscle pain, osteosclerosis, osteopenia, osteoporosis
  • Light-headedness, syncope/fainting
  • Rapid heart rate, chest pain
  • Low blood pressure, high blood pressure at the start of a reaction
  • of a reaction, blood pressure instability
  • Uterine cramps or bleeding
  • Tinnitus / ear ringing
  • Dermatographism (can write on your skin leaving a red welt where you traced something with fingernail or blunt object – more here.)
  • Edema (fluid accumulation in different parts of body)
  • Decreased wound healing
  • Interstitial cystitis
  • Deterioration in dentin and teeth
  • Often liver enzymes that are wonky (High bilirubin, elevated liver enzymes, and high cholesterol)
  • Brain fog
  • Coagulation issues and blood disorders (Clots, deep vein thrombosis, easy bruising, heavy periods, nosebleeds and/or cuts that won’t seal up easily)

Mast cell mediator that is degranulated, plus possible effects:

Histamine: Flushing, itching, diarrhea, hypotension, panic attacks/anxiety
Leukotrienes: Shortness of breath
Prostaglandins: Flushing, bone pain, brain fog, cramping
Tryptase: Osteoporosis, skin lesions
Interleukins: Fatigue, weight loss, enlarged lymph nodes
Heparin: Osteoporosis, problems with clotting/ bleeding
Tumor Necrosis Factor-α: Fatigue, headaches, body aches

B. Triggers: Triggers for mast cell degranulation are across the map, from food to activity to environmental exposure and trauma. It’s difficult to imagine just how such disparate and seemingly innocuous things (vibration?!) can degranulate mast cells, but here we are.

The list below is cobbled together from the The Mastocytosis Society, the Canadian Mastocytosis Society, and blogs:

  • Exercise Heat, cold or sudden temperature changes
  • Sun/sunlight
  • Fatigue
  • Stress
    • Emotional (trauma, loss, abandonment)
    • Physical (including pain, accidents, and medical procedures. For medical procedures, see this 2019 PDF guide to bring to hospital with you that discusses mast cell disorders, plus stages of anaphylaxis and triggers.)
    • Environmental (weather changes, pollution, pollen, pet dander, mold, gas leaks)
  • Food or beverages higher in histamine. See diet lists below under TREATING MCAS for more details. A big problem for people trying to get well is that many of the “no” list for histamine is actually recommended heavily for autoimmune diets – eg. fermented foods/natural probiotics, spinach, etc which will all make MCAS symptoms worse.
    • Yeast
    • Alcohol
    • Dairy (especially fermented dairy like kefir, blue cheeses, or aged dairy like Parmesan cheese)
    • Gluten
    • Fermented foods (especially sauerkraut, kombucha, miso, kimchi, fish sauce, and soy sauce – anything that gives food a wonderful umami taste, basically)
    • Cured and smoked meats and fish
    • Shellfish
    • Citrus fruits
    • Vinegars
    • Leftovers (I can tolerate dinner food the next day at lunch but that’s it. Usually, I will just freeze it right away and defrost to eat, so it stops the aging/histamine degradation process.
    • Berries, especially strawberries
    • Spinach
    • Chocolate other than pure dark chocolate
    • Tomatoes
    • Some food additives (see here for more)
  • A surprising amount of medications (most opioids, NSAIDs, antibiotics and some local anesthetics – a longer list is here)
  • Contrast dyes used in MRIs, CTs etc
  • Mechanical irritation (rubbing/chafing)
  • Friction
  • Vibration
  • Natural odours (strong natural scents like essential oils, environmental smells)
  • Chemical odours (cleaning products, for example)
  • Perfume
  • Infections (viral, bacterial or fungal infections can make MCAS worse and should be addressed carefully with help of your doctor.)
  • Venom (bees, wasps, spiders, snakes, etc.)
  • Diesel fuel (smell)
  • For some, sunlight (!!)

3. TREATING MAST CELL ACTIVATION NATURALLY **

** This is just what has worked for me so far and is not medical advice. I do not have access to stronger stabilizers like compounded ketotifen or sodium cromolyn, and per doctor’s advice am holding off on H2 blockers because as a celiac I am already prone to low stomach acid. Mast cell doctors (see the overview links above) do say to embark on a full H1/H2 blockade, every 12 hours.

Studies supporting why I take each of these products are below.

 A. PRODUCT LINKS FOR PRODUCTS I’VE TESTED AND I USE / STUFF MENTIONED IN THE STUDIES:

  • DAO Umbrellux: A DAO enzyme made from porcine sources, taken 15 minutes prior to meals.
  • Vitamin C Nutribiotic Ascorbic Acid Powder (non-gmo, pharmaceutical grade)
  • Vitamin C Nutribiotic Sodium Ascorbate (non-gmo, pharmaceutical grade). There is some evidence that sodium ascorbate also helps the extracellular matrix, so I include that in my supplements / total Vitamin C count.
  • Camu Camu, organic and freeze dried. My preferred vehicle for vitamin C.
  • Non-GMO MicroIngredients Quercetin from Sephora Japonica buds If you prefer capsules, Jarrow Formulas Quercetin, Cardiovascular Support, 500 mg
  • Zeolite: Functional doctors believe that zeolate can help clear histamine from the body. Zeolite is also used as a binder for metals for some.
  • NasalChrom: Useful for seasonal-type allergies, food reactions that include nose running/itching in face. Sodium cromlyn is a mast cell stabilizer.
  • Zatidor eye drops: These are ketotifen fumerate, potent mast cell stabilizer – if you can’t access pills or compounded ketotifen, eye drops may help with oral symptoms considerably.
  • PEACure: Palmitoylethanolamide, pure and from a reputable source.
  • Magnesium LThreonate is the type of magnesium I use. Doublewood’s brand has caused no reactions, and is available in USA and Canada.
  • Jarrow Formulas Curcumin 95, Provides Antioxidant Support, 500 mg, (don’t buy with black pepper extract – mast cell degranulator!)
  • Luteolin plus Rutin powder (NOTE- not Lutein! Must be luteolin. Another option for luteolin, rutin, and quercetin is Neuroprotek –  this is Dr. Theoharides supplement from his Algonot company, and profits fund further studies)
  • Mirica® – Pea (Palmitoylethanolamide) and Luteolin – Natural Pain Relief – Made with OptiPEA® from The Netherlands
  • Amazing Herbs Premium Black Seed Oil, Organic and Cold Pressed.
  • PROBIOTICS:
  • Vital Nutrients Vitamin E 400 (with Mixed Tocopherols) (NOT soy free) OR, Healthy Origins Tocomin SupraBio (Tocotrienols) 50 mg –  if like me you don’t just want one of the tocopherol but rather tocotrienols too. (Soy free. 1 in AM and 1 in PM)

** Note that the links above for Amazon are affiliate links, as with the others on Legal Nomads (see the footer for more), where I get a 4% commission on some purchases.

B. My current protocol: 

  • H1s twice a day, 10am and 10pm (Zyrtec)
  • MicroIngredients pure powdered Quercetin – 1 scoop 500mg, 2x a day
  • PEA (PeaCure brand), 1x AM, 1x with lunch
  • Vitamin C 1-3g per day (camu-camu is what I use most)
  • Luteolin/Rutin powder
  • DAO, 1x with lunch and 1x with dinner
  • Magnesium L-Threonate – 2 capsules in late afternoon
  • 1 Vitamin E with lunch and 1 with dinner

As needed things:

  • Zeolite spray if I have a particularly bad day – 6x sprays. Was sceptical but it seems to really cut my reactions down. Study below.
  • Zatidor eye drops if eyes are burning / itching
  • NasalCrom nose spray if sinus congestion / sneezing too much after food

C. Reducing Histamine and Stabilizing the Mast Cells Naturally

A note on eliminating triggers. This is not only environmental (I had to switch shampoos and soaps and much more to all-natural products as my skin would burn when I used ‘normal’ ones), but also eating a lower histamine diet to ensure lower circulating levels of histamine in the body. 
Note that for many vibration is a trigger, so car rides, electric toothbrushes, and more can degranulate. For me personally, any concentrated oils are an issue. I used a serum on my hands every night before bed and had huge histamine issues/adrenaline dump at midnight until I realized that it was the serum – it had mint oil in it, which for me is now a trigger. That’s how sensitive things are for some, even when least expected.

  • Some medications are also degranulators or histamine liberators. See this list from the Canadian Mastocytosis Society here.
  • NOTE: how food is processed / ingested can affect your reaction, so you may react one day but not another. The way that a food is processed can change how much of an IgE reaction a person has to it.
  • NOTE ABOUT IgG / IgE REACTIONS: There’s often confusion about testing for food allergies or allergies using IgG and IgE testing. They are related to the functioning of mast cells, but not an accurate test for mast cell activation. Mast cells have receptors for both IgE or IgG on them, and both types of antibodies can result in higher histamine levels or higher levels of other meditators, as well as triggering degranulation itself. IgG reactions the calmer of the two, though they are still capable of producing anaphylaxis-like symptoms. These antibodies are common not only for pathogens we are affected by, but also food issues when we have issues with GI permeability (leaky gut and more). IgE reactions, in contrast, are usually sharp and immediate — like when we are stung by something we are allergic to. It’s a fast-paced degranulation response by the sentinels of the immune system to try and protect from something significant. While not part of MCAS testing per se, they can be useful. It’s important to use IgG antigen testing if you are testing IgG, and then phase out those foods for several months to see if that makes a big difference, then try to reintroduce with nutritionist support.

DIET

  • Low Histamine- Swiss Sighi lists
    • Elimination diet recommendations here.
    • Food lists for histamine: long PDF of graded histamine levels in foods/additives, etc here.
  • Low Histamine – Alison Vickery:
    • DIET PDF from Allison Vickery. She uses a functional approach that combines naturopathic and allopathic medicine, and cites her sources fully. In my case, with no doctors here yet – still trying to find a GP – I’ve found with all of the MCAS documents hers is the most accurate for food for me. I can’t tolerate any pulses/many of the vegetables that other lists recommend.
    • You can find her mast cell posts here.
  • Beyond low histamine: some people with Ehlers Danlos variations or auto-immune issues such as Crohns or colitis also have trouble digesting foods beyond the low histamine varieties. See this page about those additional restrictions, including a low histamine diet suggestion list for people who need to mindful of other categoris.
    • These categories include lectins, oxalates, salicylates, sulfur, and FODMAPs, which – depending on the body – can affect MCAS as well.
    • Lectins are proteins found in some plants, and preliminary research suggests that they may activate mast cells also. For a low-lectin diet list, see here.
    • Oxalates are found in Vitamin C, which is an issue as high-dose vitamin C is helpful for mast cell stabilization, and for collagen synthesis.
  • Speaking of FODMAPS: a low FODMAP diet can also reduce circulating histamine.

STUDIES RE: SUPPLEMENTS ABOVE

  • Brain “fog,” inflammation and obesity: key aspects of neuropsychiatric disorders improved by luteolin. (Study – Brain “fog,” inflammation and obesity: key aspects of neuropsychiatric disorders improved by luteolin). The same study also notes that luteolin protects against histamine release from mast cells
  • Palmitoylethanolamide  (works on the endocannabanoid system)
    • “The ability of PEA to control MC degranulation, via a CB1 ⁄ CB2 independent mechanism, has paved the way for its therapeutic use in both animals and humans. The PEA-mediated stabilisation of MCs has proven to be useful in the treatment of atopic and irritative dermatitis. In conclusion, we can hypothesise that cannabinomimetic compounds, including PEA and its congeners, act to control MC activation and degranulation early during the inflammatory response, thus leading to a swift resolution and preventing the development of chronic inflammatory disease.” (Study)
    • Palmitoylethanolamide is a potent mast cell stabilizer and pain reliever (Glia and mast cells as targets for palmitoylethanolamide, an anti-inflammatory and neuroprotective lipid mediator – study)
    • For those with other issues a potent neuroinflammation reducer too, acting synergistically within the endocannabenoid system. Overview /meta analysis, and neuroinflammation study: N-Palmitoylethanolamine and Neuroinflammation: a Novel Therapeutic Strategy of Resolution.
    • And luteolin PLUS Palmitoylethanolamide = even more stabilization. Study: PEA and luteolin synergistically reduce mast cell-mediated toxicity and elicit neuroprotection in cell-based models of brain ischemia. (This is the Mirica product above)
  • Binders, including zeolite, mentioned as a help for mopping up histamine here, and a specific post about how zeolite binds histamines here. See also Study – Histamine-binding capacities of different natural zeolites: a comparative study.
  • Rosae multiflora fructus extract stops mast cell release of histamine (rat study – Rosae Multiflorae Fructus Hot Water Extract Inhibits a Murine Allergic Asthma Via the Suppression of Th2 Cytokine Production and Histamine Release from Mast Cells – Study
  • Quercetin
    • Blocks histamine release due to chemotherapy drug. Study – Quercetin ameliorates paclitaxel-induced neuropathic pain by stabilizing mast cells, and subsequently blocking PKCε-dependent activation of TRPV1.
    • Quercetin also generally works for a wide range of allergies. Quercetin and Its Anti-Allergic Immune Response – study.
    • Quercetin works better than sodium cromlyn for stabilizing mast cells in certain conditions. Study: Quercetin Is More Effective than Cromolyn in Blocking Human Mast Cell Cytokine Release and Inhibits Contact Dermatitis and Photosensitivity in Humans.
  • Cannabinoid receptor agonists suppress mast cell release of histamine Study – Selective Cannabinoid Receptor-1 Agonists Regulate Mast Cell Activation in an Oxazolone-Induced Atopic Dermatitis Model. Also in the study “Cannabinomimetic Control of Mast Cell Mediator Release: New Perspective in Chronic Inflammation,”
  • Curcumin (tumeric) also acts as an antihistamine, and has been found to decrease mediator release by mast cells, when activated:
    • Anti-inflammatory effect of curcumin on mast cell-mediated allergic responses in ovalbumin-induced allergic rhinitis mouse (study)
    • Lipopolysaccharide (LPS) exposure differently affects allergic asthma exacerbations and its amelioration by intranasal curcumin in mice. (study)
    • Curcumin Ingestion Inhibits Mastocytosis and Suppresses Intestinal Anaphylaxis in a Murine Model of Food Allergy. (study)
    • Inhibitory eff ects of curcumin on passive cutaneous anaphylactoid response and compound 48/80-induced mast cell activation (study)
  • Vitamin C: Helps stabilize mast cells
    • Alison Vickery’s post about how Vitamin C can help increase DAO in the body, which then mops up histamine from food.
    • Article: The relationship between Vitamin C, Mast Cells and Inflammation:
      In the light of these studies, we found that vitamin C relieves most of the symptoms of diseases that involve activation of MCs and we can conclude that further research on the role of vitamin C and MCs is needed.”
    • Article: Vitamin C Revisited: “In critically ill patients, future research should focus on the use of short-term high-dose intravenous vitamin C as a resuscitation drug, to intervene as early as possible in the oxidant cascade in order to optimize macrocirculation and microcirculation and limit cellular injury.”
  • Nigella sativa (black cumin seed) blocks mast cell degranulation in rats (A study – “Effects of Nigella sativa seeds and certain species of fungi extracts on number and activation of dural mast cells in rats.”)
  • Probiotics that may help:
    • Lactobacillus G/G: study
    • Not a great site, but lists probiotics that trigger histamine release vs. those that are safe: here.
  • Vitamin E has been found to decrease mast cell degranulation in some studies. (study)

D. SUMMARY OF TREATMENT SECTION:

4. TREATING MAST CELLS PHARMACEUTICALLY

Generally:  H1/H2 “blockade”, taken every 12 hours. Plus mast cell stabilizers and occasionally pain medication.

  • H1 blockers (Suggested to leave Benadryl for emergencies) – eg. Zyrtec, Xyzal, Claritin, Allegra, hydroxyzine, doxepin, loratadine, fexofenadine.
  • H2 blockers Pepcid, Zantac, Tagamet, famotidine
  • Leukitriene inhibitors: Montelukast/Singulair
  • Prescription mast cell stabilizers:
    • Cromolyn sodium
    • Ketotifen (oral, compounded and by prescription. Zatidor eye drops are ketotifen as well, but fumarate form)

See the study Pharmacological treatment options for mast cell activation disease, as well as the suggestions in the Hoffman article from the overview section, here.

Further, the Mastocytosis Society has a list of pharmaceutical treatments that are common in mast cell disorders here.

5. MAST CELLS AND PAIN

too much histamine due to mast cell dysfunction

[Image source]

A. Generally (and tables with treatment options)

(Source: “A Practical Guide for Treatment of Pain in Patients with Systemic Mast Cell Activation Disease”)

Throughout the entire pain communication network, mast cells are the gatekeepers of pain. Mast cells can communicate with neurons, glia cells, microglia, and vascular endothelial cells through mediators. They influence brain functions directly through histamine. Pain alone can thus increase mast cell degranulation. Mast cells and the nervous system influence each other’s responses through mediators and cytokines. In the periphery mediators can stimulate receptors, resulting in pain. This stimulates mast cell activation creating a feedback loop, resulting in neurogenic inflammation. Mast cells can recruit other immune cells, which release more mediators, boosting inflammation.

Extreme mast cell activation causes inappropriate mediator release and reactivity, causing an enormous range of reactions in all tissues and systems. Classical analgesics, most narcotics and nonsteroidal anti-inflammatory drugs (NSAIDS), can trigger MCAD and thus can be ineffective. (See chart 1 “TABLE 4” below)

Pain in Mast Cell Activation Disorders

Source: study.

Pain perception in mast cell dysfunction should be treated by addressing the mast cell mediator-related causes. But pain is also one of the biggest mast cell triggers – so lowering pain levels is important. Mast cell stabilizers, avoiding inflammatory foods, meditation: these have all helped and may help before stronger drug therapy if that’s what you prefer — especially since neuropathic pain is so hard to treat. (Personally, I went from 24/7 burning pain all over my body to none, unless I consume/am around something that angers mast cells.)

Neuropathic pain poorly (if at all) responsive to classical drug management in the case of mast cell activation, as shown in the table below. Moreoever, some of those drugs may worsen the severity of symptoms by further increasing mast cell activity.

Drug management of MCAS/MCAD

Source: study.

B. Mast cells and fibromyalgia / pain: 2019 study – Concludes that mast cells are key players of neuroendocrine and painful disorders, including fibromyalgia, and that inhibiting mast cells would be a useful tool in treating fibromyalgia.

 Natural molecules could include the flavonoids, luteolin and tetramethoxyluteolin, alone or in combination with other substances selected to reduce stress Other natural molecules could include palmitoylethanolamide, which apparently inhibits neuro-inflammation and reduces pain.” Source: “Mast Cells, Neuroinflammation and Pain in Fibromyalgia Syndrome

6. HOW DO MAST CELLS INCREASE INFLAMMATION?

(This is why low inflammation + low histamine diets are useful)

  • Dr Theoharides believes CRH stimulates the mast cells in the hypothalamus (and elsewhere) to produce something called vascular endothelial growth factor (VEGF), which then increases the permeability of the blood-brain barrier (BBB). That leaky BBB then allows more immune cell (e.g. mast cell) and perhaps pathogen infiltration into the brain and bingo, you have inflammation. Source: Could the Brain’s Mast Cells Be Causing Chronic Fatigue Syndrome (ME/CFS)?.
  • Mast cells and neuroinflammation: Mast cells are both sensors and effectors communicating between the nervous, vascular, and immune systems. In the brain, they live in the “brain side” of the blood-brain-barrier, and there they interact with astrocytes, microglia, and blood vessels via their mediators and chemicals. They are first responders in the body, catalyzing reactions, amplifying responses in the body, and also recruiting OTHER immune responses once they’re activated. When dysregulated, this contributes to neuroinflammation. See also the next study.

    “Mast cells both promote deleterious outcomes in brain function and contribute to normative behavioral functioning, particularly cognition and emotion. Mast cells may play a key role in treating systemic inflammation or blockade of signaling pathways from the periphery to the brain.”
    Source: Mast Cells and Neuroinflammation“.

  • An enhanced interaction between mast cells and nerves can lead to neurogenic inflammation. Inflammatory models have shown a significant increase in the number of mast cells, resulting in the increased release of inflammatory mediators on degranulation.

    “Inflammatory mast cell mediators may modulate sensory nerves through the activation of receptors on nerve terminals. […] Thus, mast cell activation can result in an increase in the excitability of sensory nerves and the production and secretion of neuropeptides.”
    Source: Significance of Conversation between Mast Cells and Nerves

  • Mast cells play a crucial role in the peripheral inflammation as well as in neuroinflammation due to brain injuries, stress, depression, and PTSD. Therefore, mast cells activation in brain injury, stress, and PTSD may accelerate the pathogenesis of neuroinflammatory and neurodegenerative diseases including Alzheimer’s disease. Mast cells in brain injuries, stress, and PTSD may promote the pathogenesis of Alzheimer’s disease. “We suggest that inhibition of mast cells activation and brain cells associated inflammatory pathways in the brain injuries, stress, and PTSD can be explored as a new therapeutic target to delay or prevent the pathogenesis and severity of Alzheimer’s disease.” Source: Mast Cell Activation in Brain Injury, Stress, and Post-traumatic Stress Disorder and Alzheimer’s Disease Pathogenesis
  • Another study from April 2019 called Mast Cells in Neurodegenerative Disease notes that neuroinflammation is well-established now as a primary pathological component of diseases such as multiple sclerosis, and is gaining acceptance as an underlying component of most, if not all, neurodegenerative diseases. Before, studies focused on the glial cells of the central nervous system, but now researches are looking at mast cells as well, since mast cells affect both their microenvironment and neighbouring cells including T cells, astrocytes, microglia, and neurons. And they can also disrupt and change the permeability of the blood brain barrier, which “has the potential for dramatically altering the neuroinflammatory state,” per the study.
  • Mast cell disorders: From infancy to maturity: “Mast cells are also establishing a new‐found importance in severe asthma, and in remodeling of blood vessels in cancer and atherosclerotic vascular disease. Furthermore, recent evidence suggests that mast cells sense changes in oxygen tension, particularly in neonates, and that subsequent degranulation may contribute to common lung, eye, and brain diseases of prematurity classically associated with hypoxic insults.” This article is a review of mast cell disorders and chronic inflammatory conditions that involve mast cell dysfunction.

7. MAST CELLS AND CELIAC DISEASE

  • Mast cells associated with onset of celiac [study].
  • Intestinal mast cell involvement with celiac disease [study].
  • Dr Tania Dempsey on the comorbidity of celiac, MCAS, here. 

8. EHLERS DANLOS SYNDROME (EDS) AND MCAS

“Several investigators have noted a possible link between EDS and MCAD, primarily patients with the hypermobility type of EDS.” – this study examines whether the fact that mast cells live in connective tissue, combined with the “wonky” connective tissue of EDSers means that mast cell activation is more common because of the changes in structure of connective tissue in primarily hEDS patients. Full study hereby Doctor Maitland and Doctor Afrin.

After being recruited to connective tissues, mast cells go through more change when they are influenced by surrounding cells. And many mast cells live in our connective tissues. This study looks into how dysregulation of the mast cells occurs in connective tissue disorders.

9. MAST CELLS AND JET LAG

The circadian clock modulates a multitude of human conditions including asthma and allergy although the cellular mechanisms regulating the clock are still under investigation. Mast cells, which serve as key effector cells in allergic disease were shown to be under control of the SCN and to have a circadian expression and release of their mediators in response to activation.

For more see my long article about jet lag, mast cells, and immune cellswhich includes a thorough jet lag protocol to minimize the circadian rhythm disruption when you travel.

10. UNCONVENTIONAL TREATMENTS

  • Breathing: pranayama, Butyeko:
    • Treatment of mast cells with carbon dioxide suppresses degranulation via a novel mechanism involving repression of increased intracellular calcium levels. [Study breathing increases Co2]
    • Evidence-Based Role of Hypercapnia and Exhalation Phase in Vagus Nerve Stimulation: Insights into Hypercapnic Yoga Breathing Exercises [Study article – “Research has shown that vagal stimulation helps you not only in controlling the health of your organs and tissues, but it also determines the growth of your stem cells which, in turn, help body in repairing and replacing damaged cells”]
  • Meditation:
    • A comparison of mindfulness-based stress reduction and an active control in modulation of neurogenic inflammation [study]
    • Meditation and vacation effects have an impact on disease-associated molecular phenotypes [study]
  • Self-hypnosis
  • Removing triggers (emotionally and physically)
  • EMDR / trauma therapy or somatic experiencing therapy
  • Intermittent fasting. Not recommended to try multi-day water fasts, as histamine levels start rising again with too much fasting. However, restricting eating to an 8-hour or 6-hour window does seem to benefit. More on types of IF here.

11. FURTHER READING

The two most helpful books I’ve read about mast cells are:

  • Mast Cells United: A Holistic Approach to Mast Cell Activation Syndrome, by Amber Walker The title notes that it’s a holistic approach, and I suppose this simply shows how non-holistic other approaches are because the treatment she uses includes antihistamines, ketotifen, cromlyn and other medication that are not simply holistic/flavonoids. But from worldwide travels to essentially being completely bedbound and incapacitated indefinitely, she has put together a remarkably thorough book. She’s in the medical field, though not a doctor, so the perspective as patient is also invaluable.
    • See this study article for the tryptase requirement, one Afrin, Castells, and other doctors disagree with as being too strict/exclusionary. Afrin’s measures for useful diagnostic markers are heparin, prostaglandin D2, histamine and chromogranin A.
    • And also see this response from Drs Afrin and Dempsey, about why tryptase shouldn’t be a gold start of diagnostics for MCAS, below:

Is an elevated tryptase level a reliable marker of mast cell activation syndrome?

In our combined clinical experience now across many thousands of MCAS patients, we (Dr. Dempsey and Dr. Afrin) have not seen a rise in tryptase to be a reliable marker of mast cell activation.  Again, a persistently elevated tryptase may be a reliable marker of an increased number of mast cells in a person, and a clear, brief spike in the tryptase level over some lower, stable baseline level of tryptase probably represents a brief flare of mast cell activation, but such a spike it is not a reliable marker of mast cell activation.  In fact, it appears that mast cells can become activated via so many different routes, releasing so many different mediators under different circumstances, that it is difficult to imagine how a spike (by any amount) in just one mast cell mediator could be a truly reliable marker of mast cell activation detectable in most activation events in most people.  We have even seen many patients whose tryptase levels have gone *down* during events of flagrant mast cell activation, such as anaphylaxis.  And we have seen that in patients whose symptoms are suggestive of mast cell activation, it almost always is the case that elevated levels of mast-cell-specific mediators other than tryptase can be found in the blood and/or urine.

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