Histamine Intolerance: Methylation, the Gut, & Copper

By Samantha Gilbert, FNC, CHNP, CNC     Last updated on May 23rd, 2022

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. Working with a “Functional Medicine” doctor right now.
    I have low serotonin, high histamine, all of my sex hormones
    are very high;including DHEAS, Testosterone, progesterone,
    Symptoms of depression started with postpartum depression,
    with the help of anti-depressants for 12 years, until the last 4 years.
    It stopped working.
    Doctor working on adrenals and detoxing liver to move estrogens
    If this doesn’t help me, where begin with all of the testing for
    copper overload and methylation?
    Thank you

    1. Hi Carrie,
      Based on what you’ve shared, I highly encourage you to look at copper. Keep in mind that adrenal fatigue is just another word for oxidative stress and that adrenal stress index tests are not reliable.

      1. Hi , in desperation of help , my gp is treating me for under-methylation with high vit B , zinc compounded capsules and cream to detox , also glutathione spray under the tongue to support liver detox , have lost 2 kilos in weight now 41.5 kgs , migraines , anxiety , nausea , profuse sweating and balanc s all over the place , I’m 57 yrs old and have had under-methylation since very young , introverted , anxiety motion sickness since I can remember now I’m being treated I feel worse than I have for a long time , please help with any ideas or suggestions , getting to me and my family for being silly and accepting this treatment , I don’t know what to do , assurance or anything that might help me I’m desperate for help before I get to depressed , thank you

      2. Hi Robyn,
        I’m really sorry you’re struggling. Is your GP being mentored by Dr. Mensah? Were you properly tested?

      3. How do you get these tests done when you have an uncooperative GP? I am on subsidized health plan and can’t afford $thousands. My doctor doesn’t believe in integrative medicine, and refused to do the tests recommended by the IMD I paid for out of pocket ($900 for one consult). I’ve had to figure this whole mess out on my own, and the closest I’ve got to any answer and relief for the vicious asthma and allergies that have wrecked my life is histamine intolerance and low histamine diet. I’d like to think I will someday know what the heck went wrong with me and fix it enough to have a life again, but how when no doctors care enough to dig deeper than the surface, anyone that does is $$$$$ I don’t have, and there is so much more to this problem?!

      4. Did you start the supplements slowly, and GRADUALLY titrate up? Too much too fast can make symptoms worse at first causing agitation, anxiety… Also did he test your copper? You could be decoppering perhaps from the zinc and this can cause horrible symptoms of done too fast…. Not sure where you are located but I have a son who is a severe undermythelator; he has been with Mensah for over 7 years ( he is now 13), I find dr Mensah and Dr bowman to be the authority over everyone… At the very least if you are far away you could be tested via direct healthcare access and then do a phone consult with dr Mensah to see if something is being missed. My guess is that it is. It’s worth the money and time to do this. You should be able to achieve positive results with treating your undermythelation…

      5. hi Robyn,
        what happens when we take supplements is we begin to change our biochemistry. When you feel worse taking them it is because your body is struggling with trying to detox what is being removed. It is important to support your liver during this time. If you are still struggling feel free to contact me

      6. Im trying to detox what i believe is mold toxicity that caused mass cell syn and gave me histamine intolerance. Not sure what is the process but i have supplements from activated charcole , the methl guard , betine, grape fruit extract, low his probiotics. How do i use this to heal i took some of them and felt horrible.

      7. Hi Sami I’d like to know if it’s possible to have high mast cell activation or high histamine intolerance even when your histamines measure normal in the blood? Mine do, but since I had toxic exposure 8 years ago I have reacted as though I have severe histamine issues. It was methyl bromide poisoning. 1st reaction was extreme sneezing and mucus – had never had hayfever before. Then many normal foods I ate, and supplements I took (eg a multivitamin) made my hair fall out. I could no longer tolerate probiotics or most herbs or spices. Many many things. It has not improved in all this time. I can eat meat no problem. Taking colloidal copper seems to help, I can take that. So is it possible to have normal blood levels and still have this issue? Thank you for an excellent article.

    2. Nathalie Ramos

      Good day

      I have been diagnosed with adrenal fatigue and Fibromylgia. Years id stomach discomfort, extreme anxiety and heart palps that have landed me .in ER. chest pains
      Painful neck and shoulders. These are my worst stmptoms.
      Seen so many doctors
      Wish I had relief.

      1. Your symptoms sound like mine, which turned out to be actually Lyme disease, a bacterial infection I acquired from a known tick bite in my foot. Antibiotics helped my symptoms, also turmeric takes down the pain. You can discuss at www lymenet org in the Medical Questions section, also get Lyme doctor referrals in the Seeking a Doctor section.

      2. Dear dr need orientation,

        Histamine intolerance affecting sleeping (tiny groaning when breathing out enough to wake me and just in the moment of falling asleep the tiny sound is done again and so start the cycle).
        Copper ok, Zn right in the lower limit, histamine blood ok, vitamin D (21, under the lower limit), homeocysteine 11.4, the other parameters ok.
        Glutamine, jelly, collagen, too bad for me. Also oxalates rich foods.
        One dosage of methyl-b12 is enough to give me sleeping problems. Alcohol, stress or exercise are also a trigger. Have tried a ton of supplements. Some relief when taking Lact Rhamnosus GG but afterwards no more progress. Bad with Mg glycinate, bad with quercetine. Character typical of an overmethylator (although homeocysteine tends to be close to the upper limit). 53 years old, male.

        Any advice regarding the direction to take or try?
        Thanks a lot for your kind help!

  2. I know I have a problem with histamine and I’ve been taking quercithin I was going to do the sprouted pea shoots or take DAO supplement,Ihave MTHFRmutation plus Lyme so it gets a little complicated. I am also considering something that looks promising ,I will let you know if it works. I am doing a consultation with Dr. Mensa hnext week so I’ll have more information. Thank you

    Warm regards


  3. Amazing how it all fits together. My daughter struggled with histamine and mental health issues until her doctor put all of the pieces together. We are now following Dr. Walsh’s nutrient therapy and she is a happy and healthy kid again. Such a blessing.

    1. Hi Abbey,
      I’m so happy your daughter is doing well! Thanks for sharing your story and keep up the great work of being an amazing mom!

    2. Abby- I would love to chat about your daughter. Going through this with my 18 year old spending $1000’s out of pocket since most docs don’t get it and want to give a pill that doesn’t work. Who is Dr Walsh?? Thank you!

      1. I’ve read alot about Dr Walsh. Just by googling his name also put his name into search area on You Tube.

    1. Hi Karen,
      Absolutely! Especially since Gilbert’s Syndrome is a byproduct of an inherited gene mutation.

      1. How does the interaction of Gilberts syndrome display. Am trying to see if I’m on the right track with the symptoms that are being displayed. Thanks

      2. I would like to know too as I have Gilbert’s and have just been diagnosed with Gilbert’s possible methylation problems.

  4. So if antihistamines interfere with the dao activity, does that mean H1 and H2 blockers are not good to help with the itch and swelling associated with histamine release? Is it better to treat the hives and angioedema swells with H2 rather than H1 blockers or do they both interfere with dao activity? DAO supplementation alone does NOT control my symptoms I have tried to wein from antihistamines with assistance from DAO and I have not been successful?

    1. Hi Lisa,
      Although H1 and H2 blockers work differently, the end result is the same, so yes, both interfere. I recommend testing for copper/zinc and methylation status, along with a low histamine diet that is appropriate for your biotype.

  5. right now I’m attending the Australasian Mastocytosis Society Annual Conference in Sydney Australia, so this article is of real interest. Dr Theoharides is going to talk about Histamine tomorrow at the conference. Thanks for sharing this article, very informative.

  6. This is so fascinating, although difficult to fully understand/comprehend. I stumbled across my compound heterozgous MTHFR status by randomly looking at blood work from 2 yrs. ago. So tired of feeling like garbage every day. I’m getting ready to visit a doctor who specializes in methylation pathways, as it is so confusing to try to sort out myself. Foods and supplements can help or hurt you, and it’s hard to understand what to take and how much, and when to back off. I remember getting a biomeridian scan years ago which showed elevated copper, but you don’t really know what everything means at the time. I also have liver/gallbladder struggles and have been having major histamine reactions (hugely swollen eyes) for the first time in my life. It’s overwhelming to figure it out, and of course I want my 4 children tested to see what their issues would be. Thanks for this article!! Will be sharing it with others.

    1. Hi Jodi,
      Thank you for sharing your story, and I’m glad my article was of benefit to you. I do recommend functional testing to check copper/zinc and methylation status.

  7. I am wondering if this article explains my severe insomnia, that I inherited from my mom and she did her mother as well as her siblings. I also have auto-immune issues, gastro-paresis, thyroid disease, auto-immune issues that cause nearly chronic joint pain, brain fog, etc.. just wish I could figure out how to fix it.. been to so many sleep clinics that no one will even take on my case anymore.

    1. There’s a possibility that you might have Lyme disease, which causes insomnia and other symptoms you’re describing. Check it out in discussions in the Medical Question section at www lymenet org, also Lyme doctor referrals there in the Seeking a Doctor section.

  8. I also have severe reactions to gluten,casein, and so many other foods that never hurt me before, am B6, B12 and Vitamin D deficient, and anemic. 23andme testing helped me with this.. b/c doctors kept testing me for individual vitamins b/c of insomnia, but no matter how much I took, it kept coming up as deficient.. knowing genetically which kinds work for my body has helped this slightly. Insomnia is still terrible though.. w/o medication.. and have tried over 27 of them.. over past ten years, I only get about four hours of sleep every four nights.. the other three in between, nothing. I could keep a job down before and drive, but now the last ditch effort meds are failing and I”m scared!

    1. Hi Faith,
      Thank you for sharing your story. I know exactly how you feel. It is scary, but I also know there is hope. I recommend functional testing to check copper/zinc and methylation status.

    2. Faith, I strongly urge you to work directly with Dr. Mensah or Dr. Bowman of Mensah Medical. From my understanding they go beyond the limitations of what 23&Me can show – to get to the root of your issues. I also used to suffer from insomnia (for years) as well as gluten intolerance; candida issues; brain fog; adhd symptoms…
      After testing (order the metabolic panel from Direct Healthcare Access) that showed undermythelation; pyroluria and low zinc – Dr. Mensah wrote an individualized nutrient protocol…every issue that I suffered with has improved greatly – especially my sleep!
      I am aware of other doctors who study methylation and these issues but after a lot of research and a son who has shown HUGE improvement with bipolar/mood/hyperactivity issues after working directly with Dr. Bowman – I would never go anywhere else.
      These two doctors, are the best in the world, in my opinion. And they can be accessed through DHA and a phone consult to begin with, if necessary. Making no excuse not to access their clinic.
      I would not wait, they will help you with your multiple issues.

      1. Amen! I couldn’t agree more. I will add that being an actual patient is a very different and more comprehensive experience than just consultation so I always encourage that.

      2. Yes!! Being an actual patient allows the greatest amount of intervention of Dr Mensah and Dr Bowman. For our son at age 7, and he was at rock bottom with a full blown mood disorder – we were at our wits end. We had tried everything and nothing had worked. As a full patient, Dr Bowman worked very carefully with us every step of the way. He is now 12 and in full recovery as a normal, healthy, happy boy! What Mensah Medical does requires extreme targeted precision – Walsh says rifle shot precision- I could not agree more! It’s worth the time, effort and money – it has been a complete miracle for us and honestly, I would go to the ends of the earth for both Dr Mensah and Bowman. They gave us our son back and gave him a brand new healthy life!

      3. I’m so very happy for you and your family Michele! Likewise, my life has completely changed for the better as a result of their guidance. They are wonderful human beings and I love them very much.

      4. Thanks for your comment. I suffer the same. I know this is an old thread, so probably no-one will see this. But if there’s any way you can share what type of protocol worked, and what was your status/symptoms that would be so useful! I am on agimarx@gmail.com – or just here 🙂 Thanks

    3. Faith, thanks for your comment. I know this is an old thread, so probably no-one will see this.

      I suffer the same, especially the insomnia and then also severe anxiety. If there’s any way you can share what type of protocol worked, that would be so useful! I am on agimarx@gmail.com – or just here Thanks

Leave a Comment

Your email address will not be published.

Schedule a Free One-on-One Consultation

If you’re ready to start your healing journey, schedule your free one-on-one consultation to discuss your current mental and/or physical health challenges, history, and desired health goals. Take the first step on your healing journey today.

Scroll to Top