Histamine Intolerance, MCAD / MCAS and How Dietary Changes Help

INTRODUCTION: In the previous article about milk intolerance related to a novel beta casein protein found in commercial cow’s milk, I mentioned both histamine intolerance and Mast Cell Activation Disorder (MCAD) — which is also called MCAS (Mast Cell Activation Syndrome).  Quite a few people with these disorders reached out to me on social media, looking for articles I may have written about them and as I hadn’t yet, I decided to write this one.

Adverse reactions to food or components of food can be divided into food allergy and food intolerance.

A food allergy is an IgE antibody-mediated immune reaction and can range from mild skin itching or hives, to full-blown anaphylactic attack where a person is unable to breathe. Specific IgE-mediated antibodies can be assessed and quantified by a blood test for an allergen, or assessed via skin scratch test with a small amount of the allergen.

A food intolerance is a non-immune reaction to a food or food component that can result in a disturbance of enzymes of the gastrointestinal (GI) tract. Lactose intolerance is probably the best known food intolerance, where people have a disturbance of the enzyme lactase in the GI tract, which makes them unable to properly digest the sugar in milk.

Histamine intolerance, like tyramine intolerance is a food intolerance and while rarely life-threatening, it can makes people’s lives quite miserable.

What are Histamines

Most people know that term ‘antihistamine‘ as medications that people take when they have seasonal allergies, such as trees and grasses or ragweed (“hay fever”), but what are histamines?

Histamine is a chemical that performs many helpful functions in the body such as stimulating the production of stomach acid (via the H2 receptors), but in this context, the interest is in histamine’s role in the immune system.

As it is intended to, histamine is released in response to exposure to an allergen, in the body’s attempt to protect you against something that it perceives as a threat. If you have breathed in some pollen that you you are allergic to for example, a signal is sent to your mast cells to release histamine in the body.  These histamines result in inflammation; a condition which signals the immune system to respond. That response could make you sneeze or make your nose run in order to help get rid of the offending allergen — or in cases with people with IgE mediated allergies it can be a very serious reaction that causes your blood pressure to suddenly drop very low, and you find it very difficult to breathe (anaphylaxis).

In histamine intolerance or mast cell activation disorder, histamine is either not broken down properly so it builds up in the body or is released by the mast cells inappropriately, such as when there is no allergen present. In these people, histamine becomes like gluten to a celiac, or regular milk to someone with lactase deficiency — only worse.

Some foods are high in an amino acid called histidine; which converts to histamine during digestion (via a carboxylation reaction mediated L-histidine decarboxylase).

Foods high in histamine include aged and fermented foods such as cheese, yogurt, pickled foods such as kimchi or saurkraut, and smoked fish. Other foods include dried fruit, specific vegetables, some nuts, well as alcohol.

There are also foods that are histamine-liberators, such as chocolate, milk and tomatoes (just to name a few) that need to be considered to minimize the symptoms of histamine intolerance, as well as certain food additives [1].

Finally, foods high in histidine, which is converted to histamine upon digestion, aslo need to be factored in to the diet of someone with histamine intolerance or mast cell activation disorder.

People with mastocytosis, mast cell activation disorder (MCAD) or histamine intolerance react to foods high in histadine / histamine as well as to foods that liberate histamine from mast cells. While these are separate disorders, they all involve problems with histamine.

Mastocytosis is condition where there are too many mast cells. This can be limited to just the skin or can be systemic (all over the body) and occurs due to a mutation in a specific gene.

Mast Cell Activation Disorder (MCAD) – sometimes called Mast Cell Activation Syndrome (MCAS) is where the mast cells ‘degranulate’ (spill their contents, including histamine) at an inappropriate time.  That is, they release histamine when there is no allergen present.

Histamine Intolerance is where the rate of histamine accumulation in the body is greater than the rate at which histamine degrades. The analogy of histamine intolerance is that of an overflowing “bucket”.

Histamine Intolerance

Normally, histamine is stored in the mast cells, or is rapidly degraded by one of two enzymes; either by diamine oxidase (DAO) or histamine-N-methyltransferase (HNMT) upon release, so it doesn’t accumulate.  Disfunction in these enzymes can

DAO primarily functions in the small intestine, ascending colon (a section of the large intestine), as well as kidney [1]. The primary function of DAO is the elimination of excess histamine, as well as controlling the amount of histamine in the body, coming from the digestive tract [1].

HNMT is primarily functions at the level of the histamine receptors themselves, where it deactivates histamine. This enzyme is active in a wide range of body tissues; but greatest in the kidney and liver, followed by the spleen, colon (large intestine), reproductive organs (prostate, ovary), spinal cord cells and parts of the lungs (bronchi, trachea).

Histamine Receptors

There are 4 types of histamine receptors that bind histamine and cause mast cells to release histamine. The binding of histamine with these receptors result in different types of allergic reactions.

from [1] Baily N, Histamine Intolerance, Igennus Healthcare Nutrition, https://www.slideshare.net/igennus/managing-histamine-intolerance-80982438

H1 Receptors

H1 receptors are primarily involved in allergic rhinitis symptoms (sneezing, blowing ones nose), broncho-constriction such as what occurs in allergy-induced asthma, as well as systemic vasodilation (enlarging of the blood vessels)[2].

H2 Receptors

H2 receptors stimulate the stomach to release HCL acid, and inhibit the body from making antibodies, as well as activate the immune system response, including T-cell proliferation and the production of cytokines[2].

H3 Receptors

H3 receptors change neurotransmitter release in the central nervous system, including serotonin and norepinephrine (noradrenaline)[2].

H4 Receptors

H4 receptors are found mostly in bone marrow and white blood cells and are also expressed in the colon (large intestine), small intestine, spleen, tonsils and trachea (wind-pipe)[2].

Symptoms of Histamine Intolerance

People with histamine intolerance display a wide variety of symptoms, affecting different parts of the body.  Some people have many symptoms in different parts of the body, whereas others have a few symptoms clustered in specific parts.  Those with histamine intolerance may have chronic reactions and others may have them seemingly ‘randomly’.

That said, the most frequently observed symptoms are acute (sudden) or chronic (long term) gasto-intestinal GI symptoms [2] and can easily  be mistaken for ‘food poisoning’ (acute symptoms) or irritable bowel syndrome (chronic symptoms). That said, there are individuals with MCAD that have anaphylactic-type reactions. 

Gastro-intestinal symptoms often take place several hours after ingestion of the offending food or food component, because the food itself has to be digested (which takes time) for its histamine to be liberated and bind with the histamine receptors.

In other cases, the reaction is faster; especially when eating aged or leftover food or other foods with high histamine content. These foods may trigger abdominal cramps or diarrhea within 15-30 minutes[2].

Other non-GI related symptoms common with histamine intolerance and mast cell activation disorder (MCAD) are skin rashes, hives (with or without itchiness), facial and chest flushing (getting red and ‘hot’ feeling), faster or slower heartbeat (arrhythmia) or low blood pressure or extreme fatigue. Some people also experience mood changes, including inattentiveness or something described as a ‘brain fog’, as well as sleep disturbances [3,4].

Getting Diagnosed

Histamine intolerance and mast cell activation disorder are difficult to diagnose, firstly because people themselves don’t think wide range of symptoms are related, so they often don’t seek medical help. Another challenge is that the very fact that the symptoms are diverse may result in them be discounted by some physicians as being related to stress/anxiety or depression.

Mast cell activation disorder (MCAD) takes on average 14 years to be diagnosed [4] and often only occurs once the person finally gets a referral to an immunologist or allergist knowledgeable in the condition. I can assist in helping people get that referral, as well as provide support once they know they have either MCAD or histamine intolerance.

You may be interested in this article about similar condition called tyramine intolerance, especially if you suffer from migraine headaches.

More Info?

If you have been diagnosed with histamine-intolerance or mast cell activation disorder (MCAD) or suspect you may have one of these, I can help.

I can assess your symptoms to see if may meet the criteria for MCAD and if so, can put together the documentation required to obtain a referral to an experienced immunologist who can either rule out or make a diagnosis. If it seems you may have histamine intolerance or you have been diagnosed as such, I can provide you with the nutrition education in making the needed dietary changes in an effort to minimize your symptoms.

You can find out more about the packages and hourly consultations I offer by clicking here and if you would like additional information, please send me a note using the Contact Me form above and I will reply as soon as I can.

To your good health!


You can follow me on:

Twitter: https://twitter.com/lchfRD
Facebook: https://www.facebook.com/BetterByDesignNutrition/
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Copyright ©2019 BetterByDesign Nutrition Ltd.

LEGAL NOTICE: The contents of this blog, including text, images and cited statistics as well as all other material contained here (the ”content”) are for information purposes only.  The content is not intended to be a substitute for professional advice, medical diagnosis and/or treatment and is not suitable for self-administration without the knowledge of your physician and regular monitoring by your physician. Do not disregard medical advice and always consult your physician with any questions you may have regarding a medical condition or before implementing anything  you have read or heard in our content.


  1. Baily N, Histamine Intolerance, Igennus Healthcare Nutrition, https://www.slideshare.net/igennus/managing-histamine-intolerance-80982438
  2. Jernigan D, Histamine Intolerance Syndrome, Hansa Center for Optimal Health, Bimed Network, https://www.marioninstitute.org/histamine-intolerance-syndrome/
  3. Molderings GJ, Brettner S, Homann J et al, 2011, Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options, J of Hemat and Onc 4 (10)
  4. Hamilton MJ et al, 2011, Mast cell activation syndrome: A newly recognized disorder with systemic clinical manifestations. J of Allergy and Clin Immunology Vol 28 (1), p. 147-153


Milk Intolerance May be Caused by A1 Beta-Casein

Digestive issues that result from milk consumption are often attributed to lactose intolerance, but research indicates that it may be the result of an intolerance to a specific type of protein found in some types of cow’s milk; specifically A1 beta-casein.

Casein and whey are the two primary proteins found in milk, with casein accounting for ~ 80 % of the protein in milk. Approximately 30% of the protein in milk is beta-casein.

There are two variants of beta-casein; A1 and A2, however before cows were domesticated, they only produced milk that only contained the A2 form of beta-casein[1,2]. Older breeds of cows such as most Jerseys, Guernseys, Brown Swiss, Normandes, as well as most of the cows in Asia, Africa and southern Europe[2] produce milk with the A2 variant of beta-casein, as do goats, sheep, donkeys, yaks, camel and buffalo [2]. In addition, human milk contains A2 beta-casein.

It is thought that ~8,000 years ago, a single-gene mutation occurred in Holsteins which resulted in the production of the A1 beta-casein protein in this breed. This novel gene variant was passed on to other northern European breeds of cows, including Friesian, Ayrshire and British Shorthorn since Holsteins were bred with them to improve milk production[2]. 

Today’s Holstein breed is the most common dairy cow in the US, Canada, Australia and northern Europe and carries both A1 and A2 forms of beta casein in approximately equal amounts[2].

Milk intolerance may not always be due to lactose intolerance, but due to intolerance to milk containing A1 beta-casein.

Note: Primary lactose intolerance is a result of a lack of the enzyme lactase, which is genetic in origin. This is a permanent condition. Secondary lactose intolerance is temporary and the result of being sick with something that causes diarrhea which sloughs off the lactase from the wall of the intestine. Genuine lactose intolerance can be tested with a hydrogen breath test.

Research suggests that A1 beta-casein protein may be at the root of stomach pain and other gastrointestinal (GI) symptoms associated with consumption of milk from A1 cows and which closely resemble lactose intolerance. These symptoms are not present when consuming milk from cows that only produce A2 beta-casein. Food-derived peptides such as β-casomorphins and others are known to have different effects on the intestines, including the secretions of the stomach and pancreas, as well as gut motility [3]. Studies have found that a peptide called β-(beta) casomorphin (BCM-7) may be behind stomach pain and other symptoms associated with milk containing A1 beta-casein.

The Difference Between A1 and A2 Beta-Casein

If one thinks of proteins as chains of amino acids strung together like train-cars in a train, each one of the ‘cars’ represents a different amino acid.  In the older A2 beta-casein variant, the ‘car’ which occupies the 67th position is an amino acid called proline, but in the newer A1 beta-casein variant, the amino acid in the 67th position is histidine. When milk with A1 beta-casein is digested, the histidine bond breaks, resulting is a peptide made up of 7 amino acids, called β-(beta) casomorphin-7 (BCM-7).

β-(beta) casomorphin-7 (BCM-7) is a naturally occurring opioid peptide, with a structure similar to morphine and is known to bind to opioid receptors [3]. What effect does BCM-7 have on the body as a result of binding with these opioid receptors?

A 2015 review paper cites research demonstrating that milk containing A1 beta-casein increases GI transit time (the amount of time that it takes for food to go through the GI tract) which means in slows it down, and in animal studies, increases inflammatory markers significantly more than A2 beta-casein containing milk[5]. In a small, double-blinded, randomized crossover study from 2014 with 41 subjects, it was found that participants consuming A1 beta-casein cow’s milk had significantly softer stools, more bloating and more abdominal pain than those drinking A2 beta-casein milk [6]. In another unrelated double-blind, randomized, crossover trial from 2016 with 45 Chinese participants with self-reported intolerance to cow’s milk drank  250 mL of either A1/A2 or A2 milk following each of two meals over a 14-day period. When drinking the A1 beta-casein milk, there was an increase in transit time and in GI inflammation, and a worsening of digestive discomfort [7] as well as an increase in inflammatory markers such as IgG, IgE, and IgG1. These were significantly lower in those that drank A2 milk [7].

Addendum (July 22, 2019): *there has been some anecdotal evidence that people with arthritis do considerably better when they do not consume casein (see Arthritis Foundation website).

In a large scale 2017 randomized cross-over design follow-up study, 600 adult who reported lactose intolerance and digestive discomfort following milk consumption were assigned over a 7-day period to consume either 300 mL of conventional milk containing both A1 and A2 beta casein, or only A2 milk. Results indicated digestive symptoms were markedly reduced after consuming A2 milk versus conventional milk [8].

Healthcare professionals have often assumed (without giving people hydrogen breath tests to confirm it) that people with GI symptoms related to consuming dairy products have lactose intolerance, when it is possible that the symptoms could be related to intolerance of A1 beta-casein.

Concerning to those with histamine-intolerance, including those with Mast Cell Activation Disorder (MCAD) who need to lower their intake of histadine-containing foods and histamine-liberators [9] may unknowingly be adversely affected by milk commonly available in the US, Canada, Australia and northern Europe that contains A1 beta-casein, as when it is digested it produces betacasomorphin-7 (BCM-7), a potent histamine liberator. The most well-known Histamine Intolerance Food Compatibility List from the Swiss Histamine Intolerance Group (SIGHI) lists milk as producing a low reaction — perhaps because the milk available in Central Europe, as in southern Europe, contains A2 beta casein, and not A1 beta-casein as in North America, Australia and northern Europe [10]. Those with histamine-intolerance in the US and Canada, for example and other countries with A1 beta-casein in dairy need to be aware that the milk and the hard cheeses listed as being “well-tolerated, no symptoms expected at usual intake” does not apply to the milk and cheese available to them.

Final Thoughts…

While much research has yet to be done to determine the extent that A1 beta-casein proteins impact human health, those with suspected lactose intolerance who continue to have symptoms while consuming lactose-free milk and low-lactose products such as yogurt and hard cheese, should try eliminating milk produced at ordinary large-scale dairies that have milk containing both A1 and A2 beta-casein to see if their symptoms improve.  As a substitute, they could use goat milk or buffalo milk, or find small, local dairies that use “heritage herd” cows, such as specific species of Jerseys, Guernseys, Brown Swiss, and Normandes that only produce milk with A2 beta-casein.

Note: My tried and true recipe for making homemade goat or A2 yogurt in an oven or crock-pot using a temperature controller, as well as turning it into thick Greek yogurt is posted here.

Those with histamine-intolerance in the US, Canada and Australia might feel better avoiding milk, cheese, and yogurt from conventional dairies, as these contain A1 beta-casein, which are high histamine liberators. After a period of dairy avoidance to enable mast cells to calm, dairy products from “heritage herd” cows can then be trialed.

NOTE: Butter and full-fat (whipping) cream are entirely fat, and as such do not contain either A1 or A2 beta-casein proteins. These would be fine to consume regardless of which dairy they were from.

More Info?

If you have food allergies or food intolerances, including what you thought was lactose intolerance, or have been diagnosed with histamine-intolerance or Mast-Cell Activation Disorder (MCAD), I can help.

You can find out more about the packages and hourly consultations I offer under the Services tab or by clicking here. If you would like further information, please send me a note using the Contact Me form above and I will reply as soon as I can.

To your good health!


You can follow me on:

Twitter: https://twitter.com/lchfRD
Facebook: https://www.facebook.com/BetterByDesignNutrition/

Copyright ©2019 BetterByDesign Nutrition Ltd.

LEGAL NOTICE: The contents of this blog, including text, images and cited statistics as well as all other material contained here (the ”content”) are for information purposes only.  The content is not intended to be a substitute for professional advice, medical diagnosis and/or treatment and is not suitable for self-administration without the knowledge of your physician and regular monitoring by your physician. Do not disregard medical advice and always consult your physician with any questions you may have regarding a medical condition or before implementing anything  you have read or heard in our content.


  1. Ware M, Metropulos M, Medical News Today, A2 milk: What you need to know, July 25, 2017, https://www.medicalnewstoday.com/articles/318577.php
  2. Pasin G. A2 milk facts. California Dairy Research Foundation website. http://cdrf.org/2017/02/09/a2-milk-facts/. Published February 9, 2017.
  3.  European Food Safety Authority. Review of the potential health impact of β-casomorphins and related peptides. EFSA J. 2009;7(2):1-107.
  4. Kurek M, Przybilla B, Hermann K, A naturally occurring opioid peptide from cow’s milk, beta-casomorphine-7, is a direct histamine releaser in man, Int Arch Allergy Immunol. 1992;97(2):115-20.
  5. Pal S, Woodford K, Kukuljan S, Ho S. Milk intolerance, beta-casein and lactose. Nutrients. 2015;7(9):7285-7297.
  6.  Ho S, Woodford K, Kukuljan S, Pal S. Comparative effects of A1 versus A2 beta-casein on gastrointestinal measures: a blinded randomised cross-over pilot study. Eur J Clin Nutr. 2014;68(9):994-1000.
  7. Jianqin S, Leiming X, Lu X, Yelland GW, Ni J, Clarke AJ. Effects of milk containing only A2 beta casein versus milk containing both A1 and A2 beta casein proteins on gastrointestinal physiology, symptoms of discomfort, and cognitive behavior of people with self-reported intolerance to traditional cows’ milk. Nutr J. 2016;15:35
  8. He M, Sun J, Jiang ZQ et al, Effects of cow’s milk beta-casein variants on symptoms of milk intolerance in Chinese adults: a multicentre, randomised controlled study. Nutr J. 2017 Oct 25;16(1):72.
  9. Molderings GJ, Brettner S, Homann J, Afrin LB. Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. J Hematol Oncol. 2011;4:10. Published 2011 Mar 22. doi:10.1186/1756-8722-4-10
  10. Lamprecht H, Swiss Interest Group Histamine Intolerance (SIGHI), Histamine Intolerance Food Compatibility List, wwww.mastzellaktivierung.info & www.histaminintoleranz.ch

This article is based in part on material by Judith C. Thalheimer, RD, LDN, Is A2 Milk the Game-Changer for Dairy Intolerance?Today’s Dietitian, Vol. 19, No. 10, P. 26

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