Histamine Intolerance: Methylation, the Gut, & Copper

By Samantha Gilbert, FNC, CHNP, CNC     Last updated on December 26th, 2021

If you think you may suffer from histamine intolerance or Mast Cell Activation Syndrome (MCAS), then this post is for you. To learn more about Mast Cell Activation Syndrome and Histamine Intolerance, check out my podcast episode 29 below with Dr. Beth O’Hara, the founder of MastCell 360. You can also find the Eat For Life podcast on Apple Podcasts, Spotify, Google Podcasts, or wherever you listen to podcasts!

What Are Histamines?

  • Protectors against infection and inflammation allowing white blood cells to engage pathogens in infected tissues.
  • Regulators of physiological functions in the gut, especially the release of gastric acid as part of the breakdown of proteins in the digestion of food.
  • Act as neurotransmitters, affecting sleep cycles and cognitive function.
  • Naturally occur in food and continue to rise the longer food sits, as well as during the process of fermentation.

Once formed, histamine is either stored or rapidly inactivated by its primary degradative enzymes, histamine-N-methyltransferase or diamine oxidase (DAO). In a healthy individual, if everything is functioning properly, the right amount of DAO will reside in the GI tract where nearly all histamine from food is metabolized (destroyed/eliminated by DAO).

What is a DAO Deficiency?

DAO is responsible for controlling histamine levels in blood fluids, not basophils and mast cells. Blood fluids are supposed to be very low in histamine. Mast cells are where most of the histamine in the body should reside.

An individual with DAO weakness may have normal whole blood histamine with very elevated plasma histamine and depressed DAO levels. Antihistamines and certain antidepressant medications can cripple DAO function and make symptoms worse.

Methylation and Histamine Intolerance

Mast cell disorders and methylation imbalances are both connected to histamine, but there are separate systems that control histamine. They are (a) blood basophils and tissue mast cells and (b) blood plasma.

Histamine elevations in plasma cause crippling skin and intestinal problems, while the histamine in basophils and mast cells correlate with mental problems (methylation imbalances).

Very elevated histamine in the blood signals blood basophil cells where additional methylation of histamine is needed (this is how we check methylation status). Keep in mind you can be over, under, or normally methylated, and still have an intolerance to histamine. Individuals with low DAO activity also tend to have high levels of histamine in serum and plasma, which affects the histamine/mast cell relationships.

A classic symptom of histamine intolerance in women is that they feel uncomfortable and miserable throughout life, but during pregnancy feel fabulous. This is because DAO can be at 500 times higher concentration during pregnancy.

The interesting tie that binds the mast cell/methylation relationship together is the undercurrent of severe oxidative stress, which is an imbalance between antioxidants and free radicals in the body.

I see a number of things that contribute to a significant amount of systemic oxidative stress in people with histamine intolerance: bacterial overgrowth in the GI tract, mold, viral infections, and copper/zinc imbalances. This also explains why mast cell disorders most commonly affect women, with the onset of serious symptoms beginning between the ages of 35 and 50 (but can occur much younger than that).

Copper Imbalance

When estrogen rises, so too does copper. The onslaught of hormonal events such as puberty, pregnancy, and menopause, as well as exogenous sources are also triggers for women. These sources include birth control, hormone replacement therapy (synthetic and natural sources), IUDs, vitamin and mineral supplements, food, and drinking water.

Copper lowers dopamine and increases norepinephrine in the brain leading to anxiety, depression, and in some cases, psychosis. With copper overload depression, 95% are female. Postpartum depression is especially interesting because, with each successive pregnancy, copper levels continue to rise rather than go back to normal after baby is born.

Copper and zinc work in tandem to control the overgrowth of fungal, yeast, bacteria, and parasitic infections. Without the proper ratio of copper and zinc, these types of infections can become chronic and difficult to eliminate. Copper/zinc imbalance also contributes to high levels of other toxic metals such as mercury, lead, cadmium, and arsenic.

What Does Histamine Do in the Gut?

An overgrowth of bacteria in the GI tract secretes histamine which also stimulates the immune system to release histamine as an immune response. This damages villi in the small intestine that are responsible for secreting DAO and absorbing nutrients from the food you eat. As I previously shared, when the DAO mechanism is impaired, histamine enters the bloodstream increasing its plasma concentration (where it should be low) and once located in the blood it spreads throughout the body.

This can lead to all kinds of nasty side effects such as migraines, digestive and skin problems, dizziness, irregular heartbeat, as well as a very high sensitivity to food, supplemental therapies, and environmental toxicants.

Many people turn to a low histamine diet along with DAO and other supplementation, such as quercetin, which can be helpful, but these remedies don’t get to the root cause of the issue.

Copper Metabolism and Regulation

The GI tract contains one of the most powerful antioxidants: metallothionein (MT), a family of cysteine-rich proteins.

If a person has an excess of copper in the GI tract, more MT is automatically expressed, which then binds to copper and prevents the amount of copper that can make it into the liver and bloodstream. That’s the primary way copper is regulated, meaning copper elevation is prevented.

When a person has chronically elevated copper levels, it means there is a genetic weakness to MT function. When copper gets into the bloodstream, it gets there by binding to proteins such as albumen when it leaves the intestinal membrane, then goes into the liver where most of the copper becomes bound to ceruloplasmin (a copper-binding protein that acts like a chaperone carrying copper throughout the body and delivering it where it’s needed). What’s also interesting is ceruloplasmin’s ability to destroy histamines (along with the copper-containing enzyme histaminase).

In a normal, healthy individual, copper is regulated throughout the bloodstream and bound to ceruloplasmin. If you wind up with too much copper in the liver, the excess is supposed to bind with ceruloplasmin and MT and go out through the bile duct.

A small percentage of free copper is normal, but if a person has a much higher level – higher than 30% – this is a definite indicator of high oxidative stress.

What Does Metallothionein Do?

  • Detoxifies mercury and other toxic heavy metals
  • Develops and improves functioning of the immune system
  • Delivers zinc to cells throughout the body
  • Prevents yeast overgrowth
  • Regulates stomach acid pH
  • Taste discrimination by the tongue
  • Protects enzymes that break down casein and gluten
  • Enhanced efficiency of the intestinal and blood-brain barriers
  • Reduces inflammation after injury or illness

Intolerance is an effect of massive oxidative stress and a lack of MT function, which in turn impacts gut microbiota. More research and intense study are needed. Dr. William Walsh of the Walsh Research Institute is currently looking at the factors that enhance genetic expression and utilization of DAO once it’s present in the body, which is the same line of research he did with MT.

If you know of someone who struggles with histamine intolerance or a mast cell disorder, please share this post. If you are struggling, please share your experience in the comments below. It is through sharing your story that we create community, eliminate guilt and shame, and bring about healing.


Oxford Journal. Effects of Histamine and Diamine Oxidase Activities on Pregnancy: A Critical Review.
Walsh, William J. (2012). Nutrient Power: Heal Your Biochemistry and Heal Your Brain. (190). New York, NY: Skyhorse.
Experimental Biology and Medicine. The Histaminase Activity of Ceruloplasmin.
American Journal of Clinical Nutrition. Histamine and Histamine Intolerance.
Pfeiffer, Carl C. (1975). Mental And Elemental Nutrients. New Canaan, CT: Keats Publishing.
Lontie, Rene. (1984). Copper Proteins and Copper Enzymes. Boca Raton, FL: CRC Press.


269 thoughts on “Histamine Intolerance: Methylation, the Gut, & Copper”

    1. This is dependant on your biochemistry, learned via proper testing. I do not recommend self-diagnosing/self-supplementation. Nutrients are very powerful.

      1. Angela Berry-Koch

        If one has Lyme – it is likely one has not been detoxing mercury well, and so starting at very low levels of zinc supplemetation is advised, like 15 to 30 mg only a few days a week to start, and building up. This is mostly to avoid detoxing mercury too fast. A binder needs to be used as well – like charcoal, clay, chlorella. blue green algae, etc. to avoid bouncing mercury through out the body. Some practitioners, such as Dr Klinghardt are saying with Lyme strive for zinc / copper balance and thus advise taking small amounts of copper with zinc to assist. However Dr Walsh seems to advise to supplement zinc well and high enough levels, especially where HPU (Pyrrole) is involved, which also is often the case with infection.

      2. Detoxifying mercury is but once piece of the puzzle when it comes to Lyme. Again, it’s important to look at the the overall oxidative stress component that is unique to the individual before making any kind of nutrient recommendations.

      3. Angela Berry-Koch

        Did not mean to imply to self medicate with vits– I am in total agreement to seek professional support before self treating with any nutrients/vitamins as they are often very potent (as with detoxing mercury with zinc). It is delicate. As a nutritionist in working with Lyme (both w my own family and other patients) – I have seen copper is not the evil we like to make it out to be. It is essential to all electrical impulses as a conductor (nerves). It just needs to be in the right amount in the right place in the body. So self medicating with zinc is indeed not advised. One needs professional guidance.
        In that regard, I highly recommend Dr Albert Mensah (sorry on Alberto, typo) – as he has been very helpful in explaining much of this to me and our family. It is whole blood histamine that is the measurement of methylation status – (available throught Direct labs via a doctor or ND), and this is an important distinction from regular histamine measurements, which your article explains can diverge. What I find fascinating is the fact that the different measures are indicative of different functional areas, as this must be very new research and makes complete sense.
        Thank you again for your time to write this out Sam.
        Angela (Msc)

      4. Angela Berry-Koch

        So right – chronic infections are very complex. I am beginning to look at lyme (bacteria), candida (fungal) and mold (micotoxin) infections as related for some people.

        There is evidence that they exchange DNA, (just as reportedly zika and dengue down here in Brazil. Worrying).

        When the hormones are really off balance and hard metals are occupying the role of minerals because the “bugs” are using minerals to create biofilm (one explanation), what is the order of tasks in your opinion?

        Do you lower the microbial load first and then work on re mineral and methylation support? Or visa versa? Dr Mensah answered this question once in a webmar and said one has to deal with infection first. Do you agree?

        Many thanks, Angela

  1. What are your thoughts on EDS and Chiari malformatoin? My story is long and complex but I have both the above dx and MCAD. Also listed on my multiple dx are POTS, small fiber neuropathy and iron deficiency anemia. Thank you.

    1. Hi Cynthia,
      EDS and Chiari malformation are not my areas of expertise, but everything else you’ve listed has a connection to copper.

      1. Hi Sami!
        4 years later and I stumbled upon this comment, I have the very same diagnoses as Cynthia. You said that everything she listed is connected to copper – so POTS is connected to it, too!? I’m currently trying to figure out the root causes.
        Do you offer consultation via Skype? I’m from Germany.
        Thank you.

  2. I found the information so very interesting, as usual I wish I could understand it all but it is the way my brain does NOT work properly anymore. I was diagnosed with RA, but she also mentioned how HIGH my histamine levels were and I must have severe allergies. I have knows for a long time I have lyme disease as I am on a refuge and all my animals have had it, my husband had it and I remember the distinct bulls eye rash but doctor didn’t believe me. I show myco pneumonia and so many other things but always HIGH histamine. how does one get tested for all this?
    thanks for the education, it is a constant battle putting the puzzle together to try and find healing.

  3. Hello, I am Marjon from Holland and I am a therapist in nutrition and hormone balances. Can you give me more details what kind of dieet these clients shout / must take?

      1. Do you have the name of a doctor in Orange County, CA that can help with Histamine Intolerance and the MTHFR Heterozygous gene mutations for both 1298 and 677?

  4. Do you know if there is a specific test available in NZ for methylation problems and to check copper/zinc status?

    1. We have 1 practitioner in NZ: Dr. Kate Armstrong, Colville Community Health Centre, 2299 Colville Rd, RD4, Coromandel, 3506, Phone: 07 866 6618. I can also work with you via Skype.

  5. Daughter has pyroluria and 61% unbound copper. Whole blood histamine indicates overmethylator. She’s homozygous DAO RS3741775. She takes antihistamines daily or else has extreme itching. I don’t understand the correlation as she is overmethylator. Should she be avoiding all antihistamines? She has taken Zyrtec daily for 3+ years at advice of family physician. Appt scheduled with Mensah in June but thinking there is something I can do in meantime.

    1. Hi Karen,
      I recommend waiting until you see Drs. Mensah and Bowman. Keep in mind you can be over, under, or normally methylated and still have an intolerance to histamine. They are completely different creatures. After you see them, I’ll be able to assist you with the dietary portion of your protocol.

  6. Wow. This is very helpful. I have been thinking for a while now that my daughter’s autism was due to a methylation imbalance (other articles I’ve read point out other symptoms related to this such as depression, alcoholism – both of which run rampant in my mother’s family predominantly). I don’t even know where to begin to help my daughter. Blood tests? Any advice, however brief would be most welcome.

    Thank you for your research and sharing this information!

  7. Just letting you know that if anybody wants Australian doctors trained by Dr Walsh our website has the full list – http://www.biobalance.org.au and that includes New Zealand doctors as well as some Asian doctors who have done the training.

    Great to get this information out there.

    Kind Regards,

    Judy Nicol

  8. Thanks for the really informative article summarizing a lot of research.

    Maybe I missed it, but how exactly do you asses your methylation status? What are symptoms of a methylation problem?

    Thank you.

    1. Hi Carol,
      You’re welcome, I’m glad it was beneficial to you. I use a whole blood histamine and/or SAM/SAH ratio test to check for methylation status. You can read more about methylation here.

  9. Hasanain Jafar

    Hi Sami
    since 2007 I suffer from chronic urticarial and angioedema, skin itching. I tried many doctors of allergy, and chronic taker of H1 and H2 anti histamine, ketotifien tab., anti stress supplements, probiotics, as well as diet of low histamine food. I have a little improvement but not much.
    I am living between Amman-Jordan and Paris.
    can you advice me what do you recommend me to do?

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