(Many people haven’t connected histamine with fibromyalgia or chronic fatigue syndrome but it’s been a suspected player for over twenty years. The first study suggesting overactive mast cells were pumping high levels of histamine into FM patients bodies goes back to 1990.  Greatly increased levels of mast cells in the skin of every FM patient tested in a 2010 Spanish FM findingand then a small but successful  NIH funded mast cell blocking FM study featuring ketiotifen suggested the theory might have legs. One patient in the trial remarked that she was pain free for the first time in years.

 Meanwhile, Tufts University professor Theorharis Theorharides proposed stress induced mast cell release could be causing ME/CFS and other disorders and got a rare NIH grant to try and prove it. He noted that two helpful drugs, amytriptyline and doxepin elixir, just happen to have histamine reducing properties as well.  He’s gone on to develop a series of histamine blocking nutraceuticals

histamine receptors

Theorharides calls mast cell receptors the “grand maestro’s of the central nervous system”

We also know that mast cell activation can cause postural orthostatic tachycardia syndrome (POTS). Biaggioni described a process by which mast cell activation (MCA) caused orthostatic intolerance, particularly in patients who experienced ‘flushing’, (POTS).  In a small 2005 study . In fact Biaggioni found he could produce histamine associated episodes of flushing, shortness of breath, headache, lightheadedness, excessive urination, and gastrointestinal symptoms (including vomiting) simply by having some of his POTS patients exercise or stand for extended periods of time. 

Dr. Klimas has called the mast cell theory one of the more intriguing and promising immunological theories to come along. It’s hard not to come to the conclusion that histamine and mast cells play a significant role in at least a subset of patients with FM, ME/CFS and POTS. Learn more about the research and possible treatments in 

Now fibromyalgia patient Darden looks at histamine from a different direction – our diet and gut -and relates the effects an anti-histamine approach have had for her. )

A Histamine Overview

Histamine is a potent signaling molecule or biogenic amine made from the amino acid histidine. It is naturally found in plants and animals. Histamine helps regulate many bodily functions including digestion, sleep, sexual function, and blood pressure, and in the brain it functions as a neurotransmitter, carrying chemical messages between nerve cells.

Under normal circumstances small amounts of histamine help to facilitate health and balance in many systems of the body. In  response to foreign pathogens, wounds and allergies, however, large quantities of histamine are released in our bodies by mast cells and basophils – two types of white blood cells that reside in blood and tissues respectively.  People with allergies often take antihistamine medications to provide relief of symptoms associated with this inflammatory response.

Histamine exerts its effects by binding to four different receptor sites on cells. Each site is able to produce different symptoms by impacting different tissues and organ systems. (See diagram below).

Because antihistamine drugs block histamine from binding only to its H1 receptors –  they are not effective at countering all histamine-related symptoms.

Histamine and Diet

Histamine is found in a variety of foods. When ingested it is broken down by an enzyme called diamine oxidase of DAO found in the lining of the small intestine and the upper end of the large intestine. In the central nervous system, histamine is broken down primarily by histamine N-methyltransferase (HMT).

Reduced DAO activity in some people’s intestines can result in high histamine levels and a condition called Histamine Intolerance. These excess amounts of histamine can cause a wide variety of symptoms including low blood pressure, headache, sleep disturbances, diarrhea, heart rhythm problems, acid reflex, hypertension, vertigo, anxiety, flushing, runny nose, asthma, hives, flushing, itchy skin, painful or irregular periods and fatigue.

DAO is produced in very high concentrations by the placenta during pregnancy, and as a result women with Histamine Intolerance often report a remission of symptoms when they are pregnant. That’s an intriguing finding, of course, given reports of similar symptom remissions in some women with ME/CFS.

An association between estrogen and DAO levels, resulting in a decline in DAO levels and a worsening of the symptoms of histamine intolerance in perimenopausal and menopausal women also exists.

Histamine Intolerance

Histamine Intolerance is often misdiagnosed as food allergies, eczema or Candida. It is, however, an IgG, as opposed to the IgE mediated response that occurs in allergies.

The symptoms caused by histamine intolerance are dose-related; the amount of histamine present causes symptoms only when they’re above a certain threshold. (This is another important difference between histamine intolerance and allergies.)


Diet can be a major source of histamine. The histamine content of foods is not clear, though.

The idea of histamine intolerance was initially conceived in Germany in the 1980’s. A Canadian Immunology PHD and dietician named Dr. Janice Joneja has also done a lot of research on this condition.

Reduced DAO levels can be caused by gastrointestinal conditions including small intestinal bacterial overgrowth (SIBO), Crohn’s disease, gluten intolerance, ulcerative colitis and inflammatory bowel disease. Alcohol and many medications can interfere with DAO activity and some evidence suggests low levels of DAO and HMT can be inherited.

Histamine Producing Foods

Dunwoody Labs is currently the only laboratory that tests for DAO levels. The accuracy of their test has not been thoroughly validated, however, and is based on studies performed on rats. Most experts agree that if one avoids foods that are high in histamine for a couple of weeks and the symptoms clear up, then it is likely that one has histamine intolerance.

Histamine levels are only known for some foods, however. Unfortunately, some  lists of histamine releasing foods on the Internet are based on subjective reactions instead of objective scientific information. In general we know that alcohol (red wine has particularly high levels of histamine), fermented foods, black tea, cured meats, aged cheese, and ripe fruit and tomatoes, and many medications are high in histamine. (Histamine is a byproduct of fermentation when bacteria or yeast are added to foods or when foods ages, ripens or spoils.)

The foods that individuals react to vary and sometimes a person can become increasingly intolerant to more and more foods. Along with avoiding foods high in histamine, taking a supplement that contains DAO obtained from pigs 15 minutes before each meal can be helpful. An Austrian company called Sciotech Diagnostic Laboratories (www.sciotec.at/en) is the only producer of DAO micropellets. They market a product called DAOsin in Europe and they sell micropellets to a few American companies that produce their own DAO supplements. Those companies include Swanson (DAOsin), Seeking Health (Histamine Block), and Xymogen (HistDAO). Not all people with Histamine Intolerance benefit from taking these supplements, however.

My Story

My particular food and drug sensitivities began at the onset of my health condition forty years ago. I suffered from chronic tension headaches, which I eventually resolved by doing EMG biofeedback training on the muscles in my neck and eliminating alcohol, caffeine (I drank black tea), drugs and sweets.

Over the years, though, I became increasingly sensitive to more and more foods and wound up eliminating citrus and dried fruits, soy sauce, aged cheese, cured and smoked meat and fish, and tomatoes.

sleep - fibromyalgia

Darden noticed that some foods left her fatigued and experiencing muscle tension and heat – sensations and unable to sleep well

My reactions to these foods began within several minutes of consuming them and lasted 24 hours. During that time I experienced elevated muscle tension, felt uneasy, and had very disturbed sleep often associated with a feeling of  heat.

I have never discovered an antidote to this reaction and simply have to ride it out; It often leaves me exhausted afterwards and I may need several days to fully recover.

Although there are some things that I can never consume without a reaction there are many that I can tolerate occasionally as my threshold is variable. I did not have these reactions when I was pregnant and my condition worsened as I approached menopause and has stayed about the same since that time.

My food and drug reactions do not correspond to any allergy testing whatsoever. In the early 90’s I underwent a year of electrodermal allergy treatments at the Tahoma Clinic, then several years later I did a year of Nambudripad’s Allergy Elimination Techniques (NAET) treatments, and more recently I tried Advanced Allergy Therapeutics. I experienced no improvement in my condition with these therapies. Last spring I discovered that I have Small Intestinal Bacterial Overgrowth (SIBO) and began treatments that have improved my digestion and overall health.

I wrote a post about this last fall and received two independent responses from persons that have SIBO and also Histamine Intolerance, a condition I had never heard of. Looking into this subject I quickly realized that the foods and drugs I react to are high in histamine and that I have inadvertently been on a low histamine diet for years as a way of managing it.

My naturopathic physician ordered a test to measure my DAO levels from Dunwoody Labs, the results of which are still pending as the lab is revamping its procedures. I had a phone consultation with Wendy Busse, (www.HistamineReducingDiet.com) a Canadian nutritionist who worked closely with Dr. Janice Joneja.

In terms of my particular reactions, Busse said that every person is unique however the fact that I am without symptoms when I adhere to my diet and that I did not have symptoms when I was pregnant is pretty strong evidence that I have Histamine Intolerance. She was skeptical about the validity of the test performed by Dunwoody Labs, however, because histamine levels in the blood fluctuate a lot.

Two months ago I started taking 2-4 HIST DAO capsules 15 minutes before each meal. HIST DAO is manufactured by Xymogen (www.xymogen.com) and contains DAO micropellets and a small amount of ascorbic acid (vitamin C), which is an antihistamine. The instructions on the bottle are somewhat misleading: “Take 1-2 capsules no more than 15 minutes before the consumption of histmaine-rich foods, or take as directed by your health practitioner.”

Busse says that according to ScioTech, the DAO micropellets are only active when taken 15-30 minutes before eating. Taking these supplements has not allowed me to expand my diet but it seems like when I have a reaction it is less severe and I have not become sensitive to additional foods.

My health has been on a gradual trajectory of improvement for the past seven years due and adding DAO supplements seems to have contributed to this trend. Since taking HIST DAO I’ve experienced better sleep, energy and muscle function. As an experiment I discontinued taking them for 5 days and I did not feel as well.

It appears that Histamine Intolerance and Small Intestine Bacterial Overgrowth (SIBO) are overlapping conditions. This makes sense because DAO is produced in the lining of the small intestine, which is also the location of the bacterial overgrowth.

is histamine the elephant?

Cognition, gut and sleep problems and fatigue could all be associated with increased histamine.

A number of studies show an increase in the activity of mast cells in persons with fibromyalgia and chronic fatigue syndrome. I think that histamine intolerance may play a role in sleep disturbances in persons with CFS & FMS because histamine is known to modulate sleep and histamine releasing neurons produce a wakefulness firing pattern.

The research on histamine intolerance and its connection with other health conditions is, however, preliminary at best.  It’s possible, though, that it is a key player for many persons with CFS and FMS.  An experimental trial on a low histamine diet and then taking DAO supplements before meals is a reasonable approach as it may yield improvements in one’s health.

ScanHistamine Resources


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