High Histamine and MTHFR, and gene SNPs

Histamine and MTHFR are bound together for so many reasons. Histamine levels are affected by methylation, and histamine breakdown is methylation-dependent. Another big reason is that just like MTHFR, histamine has its fingers in so much more than just allergies.

Histamine is involved in:

• Allergic reactions - this is the part everyone knows about.

• Immune response

• Opening blood vessels (or vasodilation)

• It's a neurotransmitter (!)

• Signaling within your stomach

Histamine levels in your body depend on two factors.

1. How much histamine is being produced or entering your system - this depends on your gut microbiome, the amount of histamine-rich foods and drinks you consume, how easily your mast cells degranulate, your allergies, and the action of your basophils, which are one of your white blood cells.

2. How much histamine is being broken down - this depends on MTHFR, and two histamine-specific enzymes called DAO and HNMT.

Histamine is mostly produced by your mast cells, which are immune cells that protect sites vulnerable to injury, such as the mucous membranes in your nose and mouth, your internal body surfaces, and the insides of your blood vessels. Also, in your basophils, which are white blood cells in your immune system that respond to allergens. It is also scattered throughout your body tissues and has an incredibly diverse range of effects, including:

• Promoting wakefulness (otherwise known as stopping a good night's sleep)

• Constricting airways

• Increasing stomach acid secretion

• Modulating pain signals

• Itch perception

High Histamine and MTHFR

Histamine is related to MTHFR for a couple of other reasons as well. Histamine breakdown is dependent on healthy methylation, just like the breakdown of other monoamine neurotransmitters. The HNMT enzyme, which is involved in one of the main breakdown pathways, requires a methyl group from SAMe to function. That means if you have a sluggish MTHFR, it is much harder to break down histamine, and you are more likely to have a high-histamine picture.

Keep in mind that high histamine states are one of the characteristics of the "undermethylation" (legacy term) basic state - these are the folks I like to call the Achievers and the Athletes. Of course, much more than just your MTHFR status goes into high histamine - there are several gene SNPs that can affect it, including SNPs in the DAO and HNMT genes. These are the two major histamine breakdown pathways, so these genes influence histamine levels far more than MTHFR does.

A woman with histamine-related allergies.

Gene SNPs and Other Factors That Affect Histamine

1. MTHFR and other genes in the methylation pathway - especially MTR (or MTRR, which affects MTR's ability to function.

2. DAO - DAO is one of the major breakdown pathways of histamine and gene SNPs can cause problems.

3. HNMT - HNMT is the other major breakdown pathway and it needs a SAMe (from the methylation cycle) in order to function.

4. Riboflavin deficiency - Because MTHFR is dependent on riboflavin, or vitamin B2, low riboflavin levels can look like compromised methylation, even in a person without the MTHFR gene. Folate levels, vitamin B12 levels, and magnesium levels are also involved here.

High Histamine Symptoms Include

• Seasonal allergies that present as hayfever-type allergies - sneezing, watery eyes, runny nose, itching, hives, itchy nose, sudden symptoms.

• Headaches and migraines

• Shortness of breath

• Dizziness

• Heart palpitations

• Hives, rash, skin itching for no apparent reason, or because of anything and everything that happens, and low pain tolerance

• Digestive symptoms, including cramping, diarrhea, and bloating

• Wakefulness, insomnia, anxiety

• Drop in blood pressure, dizziness on change of position, or irregular heartbeat.

• Facial flushing with exercise or activity

Managing High Histamine Naturally

High histamine can be seasonal, or it can be constant in the case of something called Histamine Intolerance. Either way, here are some steps you can take toward managing high histamine levels.

• Eat a low histamine diet - Some foods are extremely high in histamine, including alcohol, fermented foods, processed or smoked meats, aged cheeses, and shellfish. Avoid these and focus on fresh, unprocessed foods. See a more complete list below.

• Ditch the leftovers - Food that sits for a while, like leftovers, accumulates histamine, so if you generally have a high histamine picture, leftovers may not be your friend. Make enough food for one sitting and cook fresh each time.

• Vitamin C - Vitamin C helps to prevent mast cell degranulation, which is the histamine-release event. In my own clinical experience, it is quite often a larger-than-average dose of vitamin C, and a buffered vitamin C product like Ester-C can be most effective.

• Calcium - Calcium helps lower histamine levels in brain tissues and has a complex relationship with histamine in mast cells - stimulating histamine release in some circumstances and regulating it in others. Some people seem to experience a clear, direct improvement in their symptoms with calcium supplementation, while others don't notice any change.

• Watch your folate levels - Histamine increases with increasing folate, and often people with folic acid toxicity have problems with high histamine levels. Also, people who are supplementing with too much folate in any form - even the good ones like 5-LMTHF - can experience high histamine symptoms.

• DAO enzyme - DAO, remember, is one of your main histamine breakdown pathways and a DAO supplement can help tremendously, especially if you experience a lot of histamine release directly related to foods. Still eat a low-histamine diet if possible, but supplement with a DAO enzyme to help your body calm down.

• Try Quercetin - Quercetin is well known and well researched to inhibit histamine production and to reduce pro-inflammatory mediators. For allergies it should be taken in a higher dose. Around 400 mg twice daily, away from food, is the most common.

• Herbal teas - Stinging nettle and butterbur are both well known for their calming, histamine-reducing properties.

High Histamine Foods

One of the best way to deal with high histamine is to make changes in your diet. While some foods and vitamins for histamine intolerance can help moderate excessive levels in the body, certain foods contain high levels of histamine and can trigger inflammatory reactions.

Foods that may increase histamine levels are:

• Fermented foods like sauerkraut, yogurt, kimchi, vinegar

• Processed or smoked meats

• Alcohol

• Leftovers

• Slow-cooked bone broth

• Dried fruits

• Shellfish

• Aged cheese

• Avocado

• Dairy products

• Eggplant

• Spinach

• Tomatoes and other veggies in this family like eggplants

• Beans

• Pickles

• Chocolate

• Frozen, salted, or canned fish

If your histamine has been high for a while, managing your levels takes time and patience. The longer you maintain good histamine practices, the less reactive your mast cells will become and the easier your histamine levels will be to manage.

References:

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Culhuac EB, Bello M. Evaluation of Urtica dioica Phytochemicals against Therapeutic Targets of Allergic Rhinitis Using Computational Studies. Molecules. 2024 Apr 12;29(8):1765. doi: 10.3390/molecules29081765. PMID: 38675586; PMCID: PMC11052477.

Lorenz W, Thon K, Barth H, Neugebauer E, Reimann HJ, Kusche J. Metabolism and function of gastric histamine in health and disease. J Clin Gastroenterol. 1983;5 Suppl 1:37-56. doi: 10.1097/00004836-198312001-00005. PMID: 6197437.

Casacchia M, Squitieri G, Agnoli A. SAMe and histamine. Monogr Gesamtgeb Psychiatr Psychiatry Ser. 1978;18:55-69. doi: 10.1007/978-3-642-88516-7_6. PMID: 692538.

McClain JL, Morales-Soto W, Gonzales J, Parmar V, Demireva EY, Gulbransen BD. Sexually Dimorphic Effects of Histamine Degradation by Enteric Glial Histamine N-Methyltransferase (HNMT) on Visceral Hypersensitivity. Biomolecules. 2023 Nov 14;13(11):1651. doi: 10.3390/biom13111651. PMID: 38002333; PMCID: PMC10669271.