Histamine is a powerful molecule. When it is activated, it has numerous physiological effects through its various histamine receptors. Understanding the various roles that histamine occupies, confers new insights into the implications for dietary, immunological, gastro-intestinal, cardiovascular, endocrinological, neurological, and inflammatory mechanisms.
4 histamine receptors have been identified, and each exert different effects. Histamine is released by immune cells such as basophils and MAST cells where it exerts its effects as a vasodilator, and as such increases capillary permeability. Histamine acting as an immune modulator enables various types of white blood cells to migrate more readily to target tissues. The immunological effects of histamine can be felt through the binding of histamine to the H-1 and H-4 receptors. These symptoms may include itching, allergy, wheezing, asthma, and bronchial constriction.
Importantly, the H-2 histamine receptor when activated will exert effects on cytokine activation, proliferation of T-cells, and the inhibition of the antibody response. In other words, H-2 histamine receptor activation will incite the cell mediated inflammatory response. Additionally, the H-2 receptor stimulates gastric acid secretion, and has a modulatory effect on the sinus rhythm (increases heart rate) and on smooth muscle relaxation. A little known function of histamine is the induction of cyclic AMP (cAMP) (2). When cyclic AMP is increased, it acts to increase another protein known as protein kinase A (PKA). In muscle cardiac cells, the hyperstimulation of cAMP has been found in myocardial infarction. At least one study has found a significant correlation between elevated plasma histamine and myocardial infarction risk (3).
The H-2 receptor induces the activation of numerous immunologic cytokines. Some of these include:
- IL-1 (5)
- IL-6 (4)
- IL-8 (4)
- IL-18 (1)
- Interferon gamma (1)
Cytokines may be inflammatory or anti-inflammatory. While functioning as important signaling molecules, the over-expression of certain inflammatory cytokines is an accelerant of various disease and immunological, inflammatory processes.
Histamine & Neurotransmitters
The histamine H-3 receptor acts in the central nervous system as an excitatory neurotransmitter, where it inhibits serotonin, acetylcholine, and norepinephrine. And it is this histamine H-3 receptor, which may be implicated in depression, anxiety disorders, cognition disorders, OCD, and so called adrenal fatigue.
Because HNMT is a methyltransferase, it is believed that whole blood histamine testing would serve as one viable marker of functional methylation activity in the body. Since the great majority of methylation activity involves methyltransferases (such as HNMT), this theory seems plausible. Because histamine exerts an inhibitory effect on serotonin, histamine activity in the central nervous system should be investigated as a possible cause of some types of clinical depression. In these regards, the urinary organic acid levels of 5-HIAA (primary serotonin metabolite) could be compared to a test result for whole blood histamine, and/or DAO enzyme levels to investigate such a connection.
Acetylcholine acts both as an excitatory and inhibitory neurotransmitter. In the central nervous system, the G-coupled M2 muscarinic acetylcholine receptors exert an inhibitory effect. Specifically they reduce the contractile forces of the atrial flow and decrease heart rate. The action of these receptors decreases cyclic AMP (cAMP). Histamine has been shown to inhibit acetylcholine as well as increase cAMP.
Histamine Metabolism, Yeast & Acetaldehyde
Histamine is metabolized via 2 enzymes DAO (diamine oxidase) and HNMT (Histamine N-methyltransferase). A key point to understand is that HNMT only metabolizes histamine inside of cells, whereas DAO metabolizes extracellular histamine. Both DAO and HNMT metabolize histamine into acetaldehyde. Acetaldehydes are then metabolized into acetic acid via the enzyme ALDH2. Another molecule is converted into acetaldehyde: yeasts such as candida. Many individuals reporting symptoms of drunkenness (without drinking alcohol), feeling of being hungover (without drinking alcohol), chemical sensitivity and concomitant histamine/yeast-type itching/sneezing symptoms may have acute acetaldehyde toxicity.
DAO converts extracellular histamine into acetaldehyde. The great majority of DAO is concentrated in the GI tract, where it degrades histamine in the intestines into acetaldehyde. In theory, someone with down-regulated DAO activity (due to heritable genetics, intestinal dysbiosis, among other factors) could experience a higher tendency towards acetaldehyde-toxicity symptoms such as those mentioned above. Additionally, individuals with reduced DAO activity may experience a greater sensitivity to histamine-containing foods (wine, cheese, fermented vegetables, cashews, chocolate, bananas, avocado, to name a few).
Histamine Modulation – Nutraceuticals, Botanicals & Supplementation
Vitamin C has been shown to reduce histamine activity in studies (6, 7, 8). An in-vivo study found a 38% reduction in plasma histamine following ascorbate supplementation (6). Interestingly, elevated histamine has been shown to inhibit norepinephrine, and norepinephrine can be increased with Vitamin C (13). A 2014 study on seasickness found that Vitamin C increased DAO enzyme activity, and this seems to be consistent around a 4X 500mg dosage. (14).
Various botanical compounds have shown an ability to inhibit histamine activities. This list includes:
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- Black cumin seed oil (9) on the H-1 histamine receptor
- Scutilleria baicalensis (Chinese skullcap) (12) – Metabolites of scutilleria have shown to reduce histamine activity in rodents.
- Albizia lebbeck (10) – Albizia inhibits the H-1 histamine receptor, and may inhibit various TH-2 mediated cytokine pathways. Albizia may also induce GABAnergic and serotonergic actions (11)
- Feverfew (15) – Shown to inhibit MAST cell histamine in rats. Feverfew is also robustly effective at reducing migraine, especially if taken for several weeks consistently.
- Quercitin – Numerous studies going back 35 years have found quercitin to inhibit MAST cell release of histamine
- Standard Process Antronex – is a reputable anti-histamine derived from bovine liver fat extract. Although the mechanism is unclear, a significant body of anecdotal evidence confirms this product’s efficacy
- DAO enzyme products – Clinically speaking, the various DAO enzyme products do not seem to be effective at reducing histamine symptoms in most people
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Enjoyed the article. I will be back to this site. I am also surprised though that you don’t find better results with DAO. I have a child with migraine and food allergies and food intolerances. the true food allergies were gotten under control with allergy shots, because it was birch pollen cross reactive tree fruit allergies. However, the food intolerances which generated migraine kept expanding. Gluten, dairy, eggs, but then eventually every kind of meat/fish/protein. it was crazy, and when we got to eggplant and avocado causing headaches I finally figured out it was histamine. She was colicky as an infant, as was I. I have gotten headaches all my life, bad ones, from red wine, but only from alcohol. DAO before meals stopped the migraines, she is still on Topamax, but they were breaking through the Topamax on a daily basis, even with a vegan diet, before the DAO. It was awful. Now we’re adding protein back to her diet and she is OK with it. We use Seeking Health brand 10,000 degrading units per capsule, and minimal 2 caps per meal. I felt FANTASTIC with both pregnancies, now I know it was really high DAO! Awaiting our 23andme data, I know for sure certain things it will say! Want to work on gut health which I think is a contributing factor too.
Great post, Michael! I am surprised to hear you say that DAO enzyme supplements seem to be largely ineffective for people as I have had really good results with Xymogen HistDAO. I think it depends on the timing of the use of this product (they say about 20min before a meal to deliver the enzyme to digestive tract prior to eating). Although, I have noticed that it still provides relief of symptoms if taken during the meal. Also depends on quantity of capsules, sometimes 2 or more is needed. I believe it’s a relatively new product and users are still experimenting with it, any other practitioners have comments on this?
Also, are you familiar with methionine supplementation and its ability to lower histamine?