Dr Joneja's Guides to Histamine Intolerance

Dr Janice Joneja, a world expert on histamine intolerance, has published two books on histamine intolerance:

A Beginner's Guide to Histamine Intolerance – read more about it here.

Buy the paperback from Amazon here; buy the e-book from Amazon here.

Histamine Intolerance: The Comprehensive Guide for Healthcare Professionals – read more about it here.

Buy the ebook from Amazon here.

You can buy all of Dr Joneja's books here in the UK or here in the US.

Histamine, stress, depression and chronic hives that get worse at night – is there a connection?
As part of our on-going histamine Q & A, Dr Janice Joneja was asked this question.


I am 18 years old and have had chronic hives since I was about 1 year old.  They have increased over time and are frequent in the night - and occasionally during the day.  They cover my whole body.  

I was given the standard grid prick test at age 4, and again at age 12.  Nothing major - light evidence of seasonal allergies and dog dander.   I was told by an immunology specialist that it could be an autoimmune condition and to treat it symptomatically.  I have been taking Zyrtec daily, often laced with Benadryl. 

I also have moderate OCD with bouts of depression and anxiety.  In the past year I have also acquired a low grade vaginal yeast infection that is not clearing with treatment.

 I have only recently learned about histamine intolerance and am feasting on what I can read. 

Can you please explain why do I break out mainly in the middle of the night-to-morning?  Does the resting state have an effect on histamine production / absorption?  Also, my therapist has suggested that I take an anti-anxiety pill to take the ‘edge’ off.  Could OCD, depression and anxiety fuel the histamine problem, or does histamine contribute to roller coaster anxiety and depression?  

I have an appointment with a new allergist in 1.5 weeks and would like to start the process off fresh.  I am afraid, however, that he might not look beyond the obvious indicators.  Can you please suggest the tests that I might expect him to perform?

Dr Joneja says:

You have provided some interesting pieces of information that may provide some answers as to the origin of your chronic urticaria (hives), your depression and anxiety, and even perhaps the reason why your yeast infection seems resistant to treatment.

As you will be aware from reading my numerous articles, histamine plays a key role in urticaria.  Histamine causes an increased permeability of small blood vessels, which allows fluid to move from the cells into tissues.  This causes the slight swelling and reddening typical of the urticarial lesions.  Hives are always itchy, which is one of the indicators that excess histamine is present.  An important question here is: what is the origin of your excess histamine?  Hives are frequently part of an allergic reaction as histamine is released whenever mast cells release their inflammatory mediators in the allergic response.  However, you indicate that allergy tests in the past were rather uninformative, so an allergic reaction may not be the main cause of your hives.

The immunologist you consulted may be correct in suggesting an autoimmune reaction, but until now it would appear that this has not been confirmed, neither has any specific autoimmune disease been diagnosed.
Obsessive-compulsive disorder (OCD) and anxiety are highly stressful reactions.  There are very close associations between stress and the immune system; these interactions are becoming more completely understood as research into the physiological processes is evolving.  A high level of stress initiates activation of two nervous system responses: 

  • The hypothalamic-pituitary adrenal axis response that is responsible for the “fight or flight’ reaction of the central nervous system involving the release of cortisol
  • The sympathetic nervous system that results in release of neurotransmitters such as epinephrine (adrenalin), noradrenalin and dopamine (catecholamines).

In both cases, mediators generated in these reactions initiate responses in the immune system, involving T-cells, cytokines and mast cells. (These responses are dealt with in much greater details in my books all of which you can buy here in the UK or here in the US.)

However, each of the processes can have different effects on the immune system:  cortisol tends to suppress the immune response, leading to an increased risk of infections as well as other physiological imbalances and additional triggers from the sympathetic nervous system can activate the immune response and lead to degranulation of mast cells and release of inflammatory mediators, including histamine.  Furthermore, the two processes can influence each other, setting up a kind of cyclical effect. Unfortunately, at present there is still much for us to learn about how all of these processes are expressed as reactions and symptoms in individuals.  It is often not possible to predict exactly how the immune system will respond to the different kinds of stress that as humans we are constantly experiencing.

So – a rather long and complex answer to your question, but I do hope that an understanding of the processes that may be going on your body will help you to feel more in control.

It is certainly possible that excess histamine is playing an important role in your symptoms, both as a trigger for your chronic hives, and also as a possible mediator of your OCD, anxiety and other nervous system reactions, as well as a possible consequence of them.  Understanding is the first stage – the next question, of course, is what can you do about it?

You indicate that you will be consulting an allergist shortly.  It would be informative if he or she orders blood tests for IgE-mediated allergy, and if positive, management strategies can be initiated to deal with them.  In addition, if the allergist is a clinical immunologist perhaps investigation of a possible underlying autoimmune process may be useful.  Unfortunately, in my experience, chronic hives is frequently labelled “idiopathic urticaria” (in other words, “cause unknown”) and no further investigations are carried out.

As for the OCD and anxiety:  there is not a lot that can be done at this stage in our knowledge to address the possible reactions that are taking place; however, I suggest that a trial on a histamine-restricted diet will definitely demonstrate whether excess histamine is involved in your adverse reactions and may provide some relief of all of your symptoms. (You will find detailed instructions on the histamine-restricted diet “foods allowed” and “foods to avoid” in Dealing with Food Allergies and the consumer handout of  “The Health Professional’s Guide to Food Allergies and Intolerances” . You can buy all of Dr Joneja's books here in the UK or here in the US.)

You ask why your symptoms occur most noticeably from the middle of the night to morning.  Two reasons: histamine from your diet will build up during the day and may “overflow your histamine bucket” (please see my histamine articles for a discussion of how histamine builds up beyond a person’s tolerance limit, which I liken to a bucket filling up with water).  Furthermore, there is a type of circadian rhythm associated with histamine release and breakdown within the body; we need histamine for several essential functions, so it will be constantly synthesised (produced by body cells) over the course of a 24 hour period.  Experiments with rats indicate that histamine release gradually increases in the second half of the light period (2.00 – 8.00 PM) and the average histamine release during the dark period (8.00 PM – 8.00) AM) is significantly higher than that during the light period. This clear circadian change in histamine release suggests that the histamine-producing process is related to the circadian rhythm .  Although it is not yet known exactly how this works in humans, in your case histamine is reaching its optimal production during the night, and so overwfhelms the enzymes that break it down (mainly diamine oxidase DAO) and symptoms of histamine excess develop.  In addition to a histamine-restricted diet it might be an interesting experiment to take a DAO supplement at bedtime to see whether that might increase your own DAO sufficiently to reduce your histamine level below your tolerance limit.  I have not seen any experiments to determine whether this might work, so if you decide to try it, I would be most interested in your results.  Please let me know.  DAO is a harmless supplement, so taking two or even three tablets would not be risky. (You can buy DAO supplements here in the UK or here in the US. )

Mochizuki T, Yamatodani A, Okakuta K, Horii A, Inagaki N, Wada H.  Circadian rhythm of histamine release from the hypothalamus of freely moving rats.  Physiology & Behavior Volume 51, Issue 2, February 1992, Pages 391–394

January 2016

Dr Joneja has gone on to discuss the physiological and immunological reactions to stress in more detail here.

If you found this article interesting you can find a number of other articles on histamine intolerance both by Dr Joneja and others here, reports on histamine research here and a Q & A section on histamine with Dr Joneja here.

For many, many other articles on every type of food allergy and intolerance click here; for coeliac disease and other food related conditions, go here.

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Dr Janice Joneja, Ph.D., RDDr. Janice Joneja is a researcher, educator, author, and clinical counsellor with over thirty years of experience in the area of biochemical and immunological reactions involved in food allergy and intolerances. Dr. Joneja holds a Ph.D. in medical microbiology and immunology and was a registered dietitian (RD) – now retired. 

She has been a member of the faculty at several Canadian universities, starting her career as an Assistant Professor in the Department of Microbiology, Faculty of Science, and in the Faculty of Dentistry, at the University of British Columbia, Vancouver. Since 2001 Dr. Joneja has been a faculty member in the School of Biomedical and Molecular Sciences, at the University of Surrey, in England, teaching in the M.Sc. course in Nutritional Medicine.  For 12 years she was head of the Allergy Nutrition Program at the Vancouver Hospital and Health Sciences Centre.

Dr. Joneja is the author of six books and a dietetic practice manual on food allergy, a textbook on Irritable Bowel Syndrome, and several distance education courses. Her most recent books include “The Health Professional’s Guide to Food Allergies and Intolerances”, “Dealing with Food Allergies”, and “Dealing with Food Allergies in Babies and Children”.  Dr. Joneja’s work has been published in peer-reviewed scientific and medical journals, as well as in popular magazines.  She is a respected lecturer at universities, colleges and hospitals internationally, and regularly appears on television and radio call-in shows as an expert in her field.

Dr. Joneja is President of Vickerstaff Health Services, Inc., a practice that provides counselling for people suffering from all aspects of adverse reactions to food, and resources for the professionals and care-givers who support them.

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