Histamine Intolerance Update

One of my most popular posts to date, based on the number of comments, emails, and links back to it, has been my post on Histamine Intolerance.

Histamine is a chemical which occurs naturally in certain foods. This is also one of the chemicals that is released in the body as part of an allergic reaction, causing the typical ‘itching, sneezing, wheezing, swelling’ allergy symptoms. We all have an enzyme (Diamine oxidase [DAO]) which breaks down any histamine that we absorb from a histamine-containing food, so when we eat a food which contains histamine it does not affect us. However some people have a low level of this enzyme, and when they eat too many histamine-rich foods, they may suffer ‘allergy-like’ symptoms such as headaches, rashes, itching, diarrhoea and vomiting or abdominal pain. This is called histamine intolerance. Some studies have also suggested links between histamine intolerance and urticaria, asthma, eczema and anxiety and panic attacks.

This diagram from that original post shows many of the systemic effects of high histamine levels, including;

  • Dizziness
  • Headache
  • Nausea/Vomiting
  • Circadian rhythm vigilance
  • Abdominal pain and cramps
  • Diarrhoea
  • Meteorism
  • Dysmenorrhoea
  • Airway constriction
  • Nasal obstruction and sneezing
  • Urticaria
  • Flushing
  • Pruritus
  • Anaphylaxis
  • Low blood pressure
  • Cardiac arrhythmia

Now all of these symptoms might seem familiar as they are the same or similar to many of the health complaints we see amongst those seeking help from a paleo-type diet.  You wouldn’t have to look too hard on the common sites that post paleo success stories to find many of these issues having been resolved amongst those who took the paleo leap.  So does that mean switching to a paleo-type diet fix histamine intolerance?  Not quite.  And that was part of the prompting for the original post.  Following a paleo diet, when you look at the list of foods which may trigger a large histamine release, may actually make things worse.

Reading of all the successes of those who adopt paleo only to be faced with your own lack of progress, can be very disheartening and may see people move away from what was otherwise a good strategy on the basis that “paleo didn’t work for them”.  Or, as I’ve mentioned previously, it can lead people to chase shadows, looking for what food *must* be contaminated with gluten, or think that toxins must be being released from their fat stores, to cause such a persistence in symptoms.

Since that original post, I have had many people share their stories and n=1 experiments with me.  This is one of the most recent ones I have received…

I have been formally diagnosed with histamine intolerance and I am being successfully treated for it now.

In my case there started with a histamine food link and was initially successfully managed through avoidance of histamine rich (i.e. fermented foods) but accelerated 4 years ago so now I need to stick a preservative free, colour free, low allergy diet which reduces my symptoms dramatically.

4 years ago I developed neurological issues including delirium and anxiety on prescription medication now known to release histamines and within 48 hours of removal was fine…

…My situation is managed through ensuring that drugs do not have a history of allergic reaction and if I react I use phenergan and they are removed and others found. I do not find other anti-histamines help.

I also think there is a hormonal component as my symptoms worsened when I went into menopause and I could not tolerate standard HRT. Treatment with compounded histamine free HRT has really helped although the histamine intolerance seems to make absorption of progesterone difficult.

There is a lot which can be done to relieve the symptoms and the challenge has been to find medical professionals who know about it. I am lucky to have a professor of immunology who has diagnosed me and vouched for the diagnosis with other professionals.

It has taken 4 years and it has been rough (especially the neurological component!) but I have seen dramatic changes to my health using traditional medicine.

That is my experience anyway…..and I hope it helps someone.

In my initial reading around this subject, I learned that the enzyme, Diamine Oxidase, is responsible for degrading histamine in the gut.  This enzyme is produced by the enterocytes of the gut mucosa.  But like all enzymes produced by, and transporters located in the gut mucosa, if there is any gut damage, then one might reasonably expect the capacity of enzymes, transporters, etc., to be diminished.  This is my belief with regard to those who have issues with FODMAP’s, fructose malabsorption, and the like.  I don’t see these as being the terminal issues, but rather a symptom of a bigger problem such as gut damage, inflammation, etc.  It’s my suspicion that histamine intolerance falls into the same category.

Supporting my notions above, I came across a paper looking at plasma histamine levels and chronic urticaria.  Whilst this paper focuses specifically on high plasma histamine levels and urticaria, when it comes to how those high plasma levels occurred, it is unlikely to make much of a difference with regard to any of the other effects that histamine might have.  This paper contains some statements of interest;

It has been suggested that pseudoallergic manifestations are not only the result of mast cell activation, but also a consequence of a defect in histamine metabolism. Histamine is metabolized by two pathways, oxidation and methylation. N-methyl transferase methylases histamine in the skin and is active in the liver. Diamine oxidase (DAO) normally degrades histamine, methyl histamine and diamine and it is confined to the small bowel mucosa. The loss of the protective role of mucosal DAO might allow an increased absorption of biological amines.

The researchers focus on the usefulness of a specific test for DAO activity and small intestine mucosa integrity – the plasma post-heparin diamine oxidase (PHD) test.  In this test, an intravenous dose of heparin should trigger the release of DAO from the small intestine mucosa into circulation.  As DAO is synthesised by mature and undamaged enterocytes (gut cells), if there is any gut damage, as might be seen with coeliac disease, then one might see a reduction in DAO release and therefore reduced activity.  This reduced capacity to degrade histamine may lead to large increases in plasma histamine levels (due to increased absorption of histamine from histamine-containing foods, and/or impaired metabolism of the body’s own histamine due to the effect of histamine-liberating foods), and all the downstream effects of this, as listed above.

Within this paper’s study, a group of 10 patients with urticaria were placed on a low antigenic, histamine-free diet for three weeks, followed by a 10-week challenge period reintroducing foods.  If any food reintroduced elicited symptoms, that food was re-eliminated.  When compared to a control group of patients without urticaria, plasma histamine levels were higher in those with urticaria, while post-heparin DAO activity was reduced or close to the lower limit of what is considered the normal range.

Interestingly, neither DAO activity nor intestinal permeability showed any significant improvement with the low histamine diet.  However, one must keep in mind that the diet used in this test is not one specifically designed to improve gut health.  That is, it isn’t one that necessarily excluded grains, vegetable oils, sugars, and soy from the diet.

The main findings from this study;

In the present study we found higher histamine plasma levels in CIU patients on free diet compared to controls. After an oligoantigenic and histamine-free diet, plasma histamine levels fell to the same levels of the control group. This finding suggests that histamine plasma levels are dependent on diet in patients with chronic idiopathic urticaria…

In our study, the disappearance or reduction of symptoms after the diet appeared to be correlated with lower histamine plasma levels.

A deficient degradation of histamine by the enzyme diamine oxidase has been hypothesized as a possible cause of an increased absorption of histamine. In our study, post-heparin DAO levels in CIU patients were slightly reduced compared to controls or in the lower part of the normal range. This observation may suggest a subclinical impairment of small bowel enterocyte function that can allow a higher absorption of histamine and higher histamine plasma levels.

However, no significant modification of post-heparin DAO was found after an effective oligoantigenic and histamine-free diet, while a significant clinical improvement was recorded. A possible explanation to this discrepancy is that the diet improved symptoms only by reducing histamine load to the small bowel but did not alter the functional status of intestinal mucosa. However, the reason for relatively low DAO levels remains unexplained and will need further studies to be clarified.

[We] can not establish whether clinical improvement was due to low levels of histamine or low levels of offending antigens in the diet. Furthermore, whether the low histamine plasma levels are caused by the reduced exogenous load or by a fall in mast cell histamine production remains unclear.

In conclusion, this study suggests that pseudo-allergic manifestations of CIU may be related to a subclinical functional impairment of the small bowel. This condition may result in a loss of the protective role of the intestinal mucosa against offending molecules in foods.

So, in this group at least, a condition related to high plasma histamine levels (urticaria) was significantly improved by following a low histamine diet.  And it would seem that most, if not all, of this improvement came from a fall in histamine intake and mast cell histamine liberation rather than any increase in enzyme capacity to degrade histamine.  Whilst in this group, intestinal permeability was normal, DAO capacity was low compared to controls, possibly signalling that intestinal function was impaired at a sub-clinical level.

A low histamine, non-paleo diet lead to improvements seemingly without any improvement in gut function.  Perhaps a paleo diet, aimed at improving gut function, in conjunction with a low histamine diet, might see additional improvements, and in particular, see improvements in those who adopt a paleo, but otherwise high histamine loading, diet and who do not necessarily get the improvements in their health issues that they had hoped for following a paleo diet alone.  And we simply cannot discount that there might be a subfraction of individuals with either genetics or other factors (extensive &/or refractory gut damage), that leaves DAO enzyme capacity permanently low.  In these people, they may require a life-long low histamine diet in order to minimise issues related to high histamine levels.

11 thoughts on “Histamine Intolerance Update

  1. Chris Kresser

    Hi Jamie,

    I’ve had a lot of success treating migraines with a diet low in histamine, tyramine and arginine. One recent patient had incapacitating headaches for 20+ years on a weekly basis that have largely disappeared after adopting this approach. Another n=1… actually, more like n=20.


    1. thatpaleoguy Post author

      Hi Chris

      Thanks for commenting here! As a fan of your approach I have referred people to you in the past when I haven’t been able to work with them myself. A low bioamine paleo diet does seem to be more successful for many than a straight paleo diet as is often first put into practice.



  2. Mr. Itchy

    Many, many thanks for this article, Jamie. I have had bizarre food allergies all my life. The primary symptom is intense, painful itching, triggered by changes in body temperature, after eating certain foods. This article is the first I’ve seen that adequately explains the problem.

    Aside from eating a paleo diet (avoiding grains, etc.) and consuming gelatin and bone broth, can you recommend any other steps to help heal the part of the intestine discussed in this article? I’ll be grateful for any suggestions you may have (even speculative ones).

    1. Anne

      Hi Mr. Itchy,

      My additional speculative/n=1 ideas for gut healing that have worked for me are eating ghee and taking L-glutamine supplements.

      Ghee is butter (preferably grass-fed) that’s been heated, skimmed, and poured through cheesecloth to remove the proteins and sugars. Ayurveda says it’s gut healing, which is why I started using it. From what I’ve read, butyrate is good for gut healing and butter is a decent source for it, so that might be part of the mechanism for it being helpful. It’s also yummy and a pleasure to cook with.

      I decided to try L-glutamine it after reading about an article where they found miRNA that interferes with glutamine synthetase expression and reduces L-glutamine availability to enterocytes in certain folks with IBS and impaired intestinal permeability. I found that my guts felt immediately better after I started taking a L-glutamine supplement.

      Hope this helps!

  3. JadPatrick

    “In a healthy person, after serotonin is released into the gut and initiates an intestinal reflex, it is whisked out of the bowel by a molecule known as the serotonin transporter, or SERT, found in the cells that line the gut wall.

    People with irritable bowel syndrome do not have enough SERT, so they wind up with too much serotonin floating around, causing diarrhea”. http://www.nytimes.com/2005/08/23/health/23gut.html?src=tp&smid=fb-share&pagewanted=1 this quote really stood out. Damage to intestinal lining seems to effect serotonin transporters as well as fructose receptors. Also in article interesting bit about childhood stress and gut permeability. The serotonin issue could also explain why FODMAPs which are not absorbed by anybody, cause so much distress for someone with fructose malabsorption even though they avoid excess fructose i.e. the gut is already inflamed and damaged. Does this make sense you think?

    1. thatpaleoguy Post author

      I think anything that can cause inflammation to the gut, alter the microbiome, etc., can reduce enzyme and transporter capacity, alter absorption, and so on. This is why I don’t think serotonin malabsorption, or fructose malabsorption, or low DAO activity, and so on, is the final diagnosis. They are just symptoms of an underlying inflammatory gut environment. This is why I believe Chris Kressers approach of remove dietary toxins, eat real food, and take specific steps to heal the gut, are the first steps everyone should be taking.

      1. JadPatrick

        Yeah thats what I was trying to get at, in a long winded way. That the inflam/damage etc comes first. Coupled with dysbiosis or sympathetic overactivity (chronic stress/trauma etc) and you have your recipe for all sorts of issues. After almost 3 months paleo (few cheats here and there, whatevs) I am finding my tolerance for things has improved markedly. Onion is still a big no no, but tonight went to a raw vegan restaurant (your welcome to eye roll) which had heaps of agave/onion etc in it, and seemed to be totally fine for once.
        I work in a health food store, and am scared of all the FM/IBS/Low FODMAP people coming in that seem to improve at first, but then get more and more sensitive in long run. I tend to believe in Dr Art Ayers of http://coolinginflammation.blogspot.com/ perspective that the microbiome of the gut is becoming so oversimplified from a processed food based diet that there isnt the variety of organisms down there to assist with enzymatic breakdown or to alter immune reactivity in the G.I.T. wall. p.s. really like your blog btw.

  4. Ruth @ Ruth's Real Food

    Thanks for the article, Jamie. Since I’ve been on a Paleo/WAP diet, I have experienced minor itchiness. I’d been wondering, since your last histamine post, if that was at the root of the problem.
    I was on Dr. Natasha Campbell McBride’s GAPS protocol for a couple of months. This is a gut healing protocal, so it gets to the root of the matter. I have to do a bit more testing, but it seems to have helped. I’ll have to see if I can now drink kombucha, because that made me itch more than anything else.
    Is GAPS the answer?

  5. Jennifer Reyna

    I developed a problem with histamine processing a few years ago (in addition to gluten and casein.) GAPS plus a low-histamine diet has greatly increased my capacity for high-histamine containing / releasing foods. Instead of fermented foods, I used VSL#3 and after a month or so began adding fermented foods in very slowly. Just today, I had tomatoes, chocolate and a fermented drink with few symptoms at all.

  6. Mel Curry

    Hi Jamie. I wondered if you have come across IgG food sensitivity testing known as Enzyme Immuno-Sorbent Assay (ELISA)? I wanted to know if it has any credibility, accuracy, usefulness etc or whether its just a bit of a gimmick? If the test is accurate does it also hold true (as for FODMAPs and histamine intolerance) that once gut healing has occured the sensitivities may disappear? Hope you can help.

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