Mast Cell Activation And Histamine Triggers

There is a lot of talk in the Functional Medicine space about mast cell activation and histamine intolerance as these are often hard to diagnose and understand.

Many patients spend a lot of time and see a lot of doctors in search of answers for their hard-to-explain suffering. Often stemming from infections or toxin exposure, high levels of histamine contribute to a number of systemic symptoms that coincide with other health conditions. 

Today’s article will walk you through what you need to know about mast cells and then what root causes to consider as pieces to your own healing puzzle.

Specifically, you will learn… 

  • What mast cells are and why they matter
  • What goes wrong with mast cells
  • The difference between mast cell activation, mast cell activation syndrome and histamine intolerance 
  • Symptoms of high histamine
  • Root causes to consider
  • Action steps for healing

What Are Mast Cells and Why They Matter

Mast cells are immune cells found in all tissues of the body, with the highest levels in the gut and skin where your body interacts with the environment. 

The main job of mast cells is to determine if there is a threat, from an infection or toxin, and then to activate, producing a variety of chemicals that work to neutralize the threat or coordinate the immune system

When activated, mast cells release over 200 chemicals, depending on the situation. 

Examples include:

  • Inflammatory mediators, such as cytokines
  • Enzymes, such as proteases (that break down proteins)
  • Biogenic amines, such as histamine

Mast cells are involved in both the innate and adaptive immune response. The innate response is the body’s first line of defense against a pathogen or toxin and includes the inflammatory response.

The adaptative immune response is more specific and includes antibody production. For example, IgE antibodies, a type of antibody involved in allergic reactions, bind to mast cells. 

Other mast cell roles include:

  • Tissue repair
  • Wound healing
  • Angiogenesis (blood vessel growth)
  • Immune tolerance

Mast cells offer an important, and vital, function within the immune system. When mast cells work well, they contribute to a normal immune response. But mast cell activation may be overactive, as in the case of extreme swelling from a bug bite or anaphylaxis from a peanut allergy, as examples. 

One of the main reasons to explain these allergic symptoms is the release of histamine, a powerful immune messenger released from mast cells.

That’s why anti-histamine medications work to help control allergies and inflammation. While blocking histamine helps with symptom control, it doesn’t answer the question as to why histamine levels are high in the first place.

A Functional Medicine approach seeks to answer this question, rather than just band-aiding the symptoms .

Mast Cell Activation, Mast Cell Activation Syndrome And Histamine Intolerance 

Mast cell activation refers to the release of chemical mediators from mast cells, including histamine, which may initially cause transient symptoms. 

When the release of mast cell chemicals, including histamine, becomes chronic and contributes to systemic symptoms, it is known as Mast Cell Activation Syndrome, or MCAS.

MCAS is often diagnosed along with other diseases, such as autoimmune diseases or allergic disorders.

Both mast cell activation and MCAS cause high histamine levels. 

Histamine intolerance refers to a sensitivity to dietary histamine. However, in many cases, histamine intolerance may be a sign of MCAS. 

When histamine levels are high, in any of these situations, symptoms may include:

  • Itchy skin
  • Swelling or reddening of the skin
  • Rashes
  • Hives
  • Decreased memory or concentration
  • Headaches and/or migraines
  • Difficulty breathing
  • Swelling in the face or tongue
  • Rapid heart rate or heart palpitations
  • Dizziness or low blood pressure
  • Nausea, vomiting, diarrhea, constipation
  • Abdominal pain and cramping
  • Reflux/GERD
  • Food sensitivities
  • Food allergies, allergic reactions
  • Fatigue
  • Flushing
  • Mucus secretion
  • Nasal congestion
  • Wheezing

Root Causes Of Mast Cell Activation And High Histamine Levels

We’ve discussed mast cell activation and MCAS as reasons behind high histamine. There are also other factors that contribute to high histamine levels, and these can also be root causes involved in mast cell activation.

These include:

  • Genetic variations. DAO (diamine oxidase) is the enzyme that breaks down histamine in the gut. Some with a small change in the genetic code for this enzyme, called a SNP or single nucleotide polymorphism, may have a harder time breaking down histamine. A deficiency in DAO in the gut contributes to an intolerance to high histamine foods, such as fermented and aged food, and may lead to high histamine levels locally and throughout the body. There are also certain medications that suppress DAO production. Some medications that may reduce DAO production include ibuprofen, aspirin, indomethacin, diclofenac, clavulanic acid, cimetidine, verapamil.


Likewise, the HNMT, or histamine-n-methyltransferase, enzyme is essential for breaking down histamine within cells. Genetic variation may impact this breakdown. This enzyme also relies on methylation and genetics influence the body’s ability to methylate. Learn more about methylation here.  


  • Dysbiosis, or an imbalance in the microbiome. Much of the immune system resides in the gut and there are a lot of mast cells in the GI tract. GI pathogens, such as bacteria, viruses and fungi like candida trigger mast cell activation. In addition, certain bacteria produce histamine while others don’t, so an imbalance, even among beneficial bacteria, may lead to high histamine levels. 


  • Infections. It’s not just gut infections that lead to mast cell activation, viruses that cause the common cold, flu or even Covid activate mast cells. In these cases, we want the mast cell activation of a healthy immune system, but this can get out of balance for some. One recent study suggested a link between the hyperinflammatory cytokine storm associated with severe Covid infection, as well as long-covid, to a dysfunction in mast cells. 


  • Toxin exposure. Mold toxins, mycotoxins, can trigger mast cell activation. Many of the symptoms of high histamine overlap with symptoms of mold toxicity. Heavy metal exposure, such as aluminum and mercury, have been found to activate mast cells. In fact, this is one reason these metals are often used in vaccinations. Other chemicals and toxins that we’ve discussed on this blog may contribute as well. 


  • Nutrient deficiencies. Deficiencies in important immune nutrients, including vitamin D and zinc, may impair mast cell function and increase histamine levels. Deficiencies in folate, vitamin B12 and other methylation cofactors may impact the body’s ability to break down histamine, contributing to higher levels of histamine as well. 


How To Restore Mast Cell And Histamine Balance

By understanding the root causes for each individual, it’s easy to see how to address mast cell activation or histamine intolerance. It may be helpful to work with your Functional Medicine provider for guidance. 

Here are some key pieces for restoring balance and feeling better:

1. Balance the microbiome. Use stool testing, such as GI MAP, to identify pathogens and then follow a 5R protocol to eliminate pathogens and restore microbiome balance and digestive function. 

2. Consider your probiotic. If you have a hard time breaking down histamine in the gut, histamine-producing bacteria, such as lactobacillus, might not be your best choice. Non-histamine producing probiotics including soil-based options and bifido strains may be better tolerated. 

3. Improve histamine clearance. DAO enzymes can be taken as a supplement like a digestive enzyme along with meals to help reduce histamine in the GI tract. Supporting methylation with nutrition and lifestyle is also supportive. 

4. Avoid toxins and support detoxification. Since many toxins are mast cell triggers, removing them from the body allows the immune system response to calm down. This may look like having mercury fillings removed, for example, or detoxifying from mold exposure. There are many helpful tests for determining the specific toxins that may be contributing to mast cell and histamine symptoms, then target detoxification efforts accordingly. 

5. Support mast cells. Many nutrients and natural compounds found in herbs and food are supportive of balanced mast cell health. These include vitamin C, omega-3 fats, curcumin, glutathione, quercetin, nettles, green tea, resveratrol, milk thistle and more. 

It certainly doesn’t feel good when histamine is high, often triggered by infection or toxins. Symptoms of high histamine are clear messages from the body to dig deeper and restore balance to the microbiome and immune system.

Often some well-placed supplements, along with a gut healing and detoxification protocol, is a gentle and effective solution to acute or chronic symptoms associated with histamine intolerance or MCAS.

If this resonates with you, what is one step you can take today to move toward that balance?