Low Histamine, Gene SNPs, and MTHFR

Low histamine is generally not recognized as a problem within the medical community or even in the media, but histamine is emerging as a target in research for conditions like cancer, cardiac protection, and alzheimer’s so I think in the next decade or so, we will begin to see some talk about low histamine and not just high histamine. Histamine is there for a reason and present in different levels in different humans, so it is equally likely that there are problems from low levels just like there are from high levels.

Histamine is involved in so many things beyond the allergies we usually attribute to it.

Histamine is involved in:

  • Allergic reactions – this is the part everyone knows about.
  • Immune response
  • Opening blood vessels (or vasodilation)
  • Neurotransmission
  • Signaling within your stomach

Histamine levels depend on two factors.

  1. How much histamine is being produced – this depends on your gut microbiome, how easily your mast cells degranulate, 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 histmine-specific enzymes called DAO and HNMT.

Histamine has an incredibly diverse range of effects including:

  • Promoting wakefulness, or stopping you from sleeping all the time.
  • Constricting airways
  • Increasing stomach acid secretion
  • Modulating pain signals
  • Itch perception

Histamine interconnects with MTHFR in a couple of ways. Histamine breakdown is dependent on healthy methylation just like other monoamine neurotransmitters. Also, the HNMT enzyme needs a methyl group from SAMe in order to function. That means if you have an overactive methylation cycle, then you break down histamine more quickly than average and you are more likely to have a low histamine picture.

Keep in mind that low histamine states are one of the characteristics of the “overmethylation” basic state – these are the folks I like to call the Black Sheep. Of course, far more than just your MTHFR status goes into your histamine levels but it is still really useful for us MTHFR folks to know which side of the basic state picture we fall on. I believe this simply because the general patterns between over- and under-methylators, especially as it pertains to probable drug and supplement tolerances, are surprisingly accurate..

Gene SNPs That Affect Histamine

  1. MTHFR and other genes in the methylation pathway – including MTR and MTRR. Also, even if these gene SNPs are “wild type” (or “normal”), this can look impaired if your folate status is low, your folic acid intake is too high, or your riboflavin levels are too low.
  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.

Low Histamine Symptoms Include

  • Seasonal allergies that present as general symptoms for a season but aren’t the typical allergy picture. This could include a seasonal headache, body pain, muscle tightness, brain fog, and more long-term, non-specific symptoms. If your allergies don’t look like hay fever, but repeat seasonally and don’t feel any better with antihistamines, you might fall into this category.
  • Fatigue, lack of alertness, and difficulty feeling awake in the morning. Keep in mind there are a number of other factors involved here like the MAOA or COMT gene SNP which may lower dopamine, epinephrine and norepinephrine and that will also feel like fatigue and lack of alertness in the morning.
  • Digestive symptoms including low stomach acid and reflux related to low stomach acid, cramping, and bloating
  • High blood pressure
  • Alzheimer’s disease – this is not actually a symptom of low histamine, but an interesting association has been found specifically with low brain levels of histamine and the progression of Alzheimer’s. Raising brain levels of histamine is being explored as a new treatment strategy.
  • Increased heart damage in heart attack – new research is showing that histamine levels rise sharply in the first moments of a heart attack, and that if they don’t rise appropriately then the level of damage the heart sustains is likely to be worse.

Managing Low Histamine Naturally

Low histamine isn’t typically regarded as a problem by the medical community, but balancing histamine levels can make you feel better on a day to day basis, especially if you struggle with lack of alertness, high blood pressure for no clear reason, or low stomach acid and digestive power. If you find, like I do, that you generally feel better with high-histamine foods like aged cheeses, smoked meats, bone broth, and leftovers, then your histamine might be on the lower end of normal.

  • Eat a higher histamine diet – some foods are extremely high in histamine including alcohol, fermented foods, processed or smoked meats, aged cheeses, and shellfish. Adding those into your diet can help to boost histamine levels
  • Embrace the leftovers – food that sits for a while, like leftovers, accumulates histamine while it sits so if you generally have a low histamine picture then leftovers are great for you. Batch cook your favorite foods and enjoy for a few days.
  • Exercise exercise has been shown to boost histamine levels, which is part of your body’s mechanism to increase blood flow to muscles and to decrease pain perception. If you tend to have low histamine symptoms, exercise can be a great way to boost your numbers.
  • Boost your folate levels if you can tolerate it – histamine increases with increasing folate, and so boosting your folate levels can help to boost a flagging histamine. Just don’t flip over into a too-high histamine picture.

Thank you so much for listening today, and be sure to check out courses.tohealthwiththat.com for the Free MTHFR Basics class and to sign up so you’re the first to know about beta testing opportunities with the MTHFR for life class at 1/4 of the usual price.

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S2E27: What is Really Going On With MTHFR Basic State?

Basic state is something that we’ve talked about before, but I want to dive a little bit deeper into why I feel it’s important when other fantastic practitioners, like Dr. Ben Lynch, aren’t really into it. Honestly, there is no right answer here.  So let’s look a little more closely.

The idea of over and under-methylators came originally from the research of Dr. Walsh from the Walsh Research Institute.The main thrust of his research was that mental and emotional disorders often stem from an imbalance or deficiency of nutrients in the brain. 

This research was not based on genetics and had nothing whatsoever to do with the MTHFR polymorphism, or any polymorphisms in the histamine pathway. It was based on Dr. Walsh’s clinical observations over years of working with vast numbers of patients. The terms “overmethylator” and “undermethylator” were his own and based on what he theorized was happening. The names, in my opinion, are a bit misleading because we don’t actually know what is happening with the genetics or if the DNA is really overmethylated or undermethylated. Hopefully, that research will happen eventually, but it certainly hasn’t happened yet.

The reason I like using basic states as a guidepost, is because it’s an easy way, especially in the beginning of your MTHFR journey, to guess how you might respond to certain supplements and drugs for mental health.  This can be hugely helpful because we all have a tendency to dive into the deep end with this, and believe me – taking a big dose of methylfolate if your body isn’t ready for it can scare you off of taking methylfolate for a very long time. 

Also, since the basic state is based on observable personality traits, allergies, and measurable signs and symptoms, we’re not looking at just one gene. We’re looking at how the totality of a person’s genes plays out in real life, because how they look on paper isn’t always how they act and how they act is what really matters at the end of the day.

Also, this is something that can be determined without any genetic testing, without any specialized help from practitioners and without the need for any fancy interventions at all. That makes it extremely valuable because for every one  person who thinks they have an MTHFR polymorphism who is working with a knowledgeable practitioner, there is another hundred who are doing this on their own.

For that, basic state is invaluable. Also, I love the fact that it’s based on what is called phenotype, or genetic expression, not genotype, or genes as they’re written. What that means, is that elements like personality traits or high or low histamine, represent the way all of your genes come together to express, which is by far more valuable information clinically than the actual gene polymorphisms themselves. 

There are so many genes involved in each pathway – when you look at actual gene expression, or phenotype, you’re seeing the way all the genes come together, which is more relevant than just the status of one gene or another. Also, all of your genes express or don’t express depending on a variety of factors including lifestyle, nutritional status, other health factors and even your mother’s health status while you were in utero. It’s far more complicated than just this or that gene, but looking at who you are as a person and how your personality expresses is actually a great way to sum up this information.

Knowing your basic state can give you some well informed starting places in terms of how you will respond to supplements, pharmaceutical drugs, and even the types of doses you might expect to be optimal. It isn’t 100% accurate, but it gives you a better idea of starting places than you would otherwise have. Still always start low and go slow, but knowing your basic state can speed up the process of discovery. 

The MTHFR Basic State Mirror Image

When you’re trying to determine your own basic state, it’s most helpful to think of them as flip-sides of the same coin with opposite traits on either side.  Your basic state will come down to how many traits you have from each side.

For instance, the traits of overachievement and perfectionism show a subtle but important difference. Both under and over-methylators express these traits, but undermethylators tend to be perfectionistic and overachieve in all areas, where overmethylators hyperfocus on the areas that are important to them and let the rest slide.

There is a very important difference in allergic response as well. High histamine type allergies and sensitivities are like classic hay-fever, where you open a window and the pollen instantly makes your eyes stream and starts the sneezing.  That is an undermethylation, high-histamine type reaction. Overmethylators, on the other hand, show more chronic allergies and sensitivities – the low-grade headache, neck tension, entire season with a blocked nose that doesn’t particularly change whether you’re indoors or out. That is a low-histamine sensitivity pattern. Also, overmethylators tend more toward chemical and food sensitivities, where undermethylators tend more toward histamine intolerance in foods.

High, for everythingAchievement and DriveHigh for the thing that matters to them, low for other things
Typically follows rules and social norms wellRules and guidanceFollows rules that make sense to them, disregards others. Follows the beat of their own drum.
Typically pushes for achievement in everything they doAchievementPushes for achievement in the things that matter to them, but not interested in other things
High histamine and seasonal allergiesHistamineLow or normal histamine with chronic allergies/sensitivities
Typically lowerPain ToleranceTypically higher
Often intolerant to histamine in foods, but less often to foods themselves.Food reactionsTypically has sensitivities to specific foods and chemicals
High fluidity (saliva, tears, etc…)FluidityLow fluidity (saliva, tears, etc…)
The MTHFR Basic State Mirror Image

At the end of the day, trying to decipher the big picture by looking at each particular gene SNP can lead to a really messy situation in which you can end up taking supplements that look good on paper, but aren’t actually addressing the issues you have in real life.  This is far less likely to happen if you’re working with a good practitioner, but sadly I’ve seen some practitioners fall victim to this mentality as well. Even worse, you can end up taking one supplement for each gene SNP and getting completely overwhelmed by a cumbersome protocol that costs a lot of money and time, but doesn’t get you anywhere.

If you’re looking for a MTHFR basic state refresher, you can follow this link to learn more about the idea in general. Here’s a link to dive deeper into the undermethylator picture and here’s one for overmethylators.

Thank you so much for listening today, and if you haven’t done so already, check out the show notes at tohealthwiththat.com. There are resources, downloads, links to research, and best of all an email list where you can sign up to be sure you’re the first to hear about exciting new courses, free resources, and other great things.

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Overmethylation – an MTHFR Basic State

Overmethylation, as we have discussed, is the least common state according to the research of Dr. Carl Pfeiffer in his book Nutrition and Mental Illness, An Orthomolecular Approach To Balancing Body Chemistry. Ovmethylation isn’t caused by just one thing – it’s a tendency based on your genes, lifestyle, stressors, diet, and environment. Interestingly – you can be an overmethylator without having an MTHFR mutation at all. Overmethylation also flows on a spectrum, from very mild symptoms to far more severe ones.

If you’re not sure if you’re an undermethylator, methylation neutral, or an overmethylator then visit this post for a comparative chart. As with everything else, even the most severely overmethylated person will have some traits and not others – this is all very individual. The biggest constants are artistic or creative tendencies, empathy and/or social activism, and anxiety.

Overmethylators Are Blessed With Many Positive Traits.

  • Creative
  • Highly artistic or musical
  • Highly empathic and sensitive
  • March to the beat of their own drum
  • Passionate and self-sacrificing
  • High pain threshold

Some of These Traits Have a Darker Side:

  • Obsessive or manic focus on what is important to them (social cause, activism, artistic project)
  • Ruminating – hard to shut brain off
  • Sleep disorders
  • Anxiety
  • A tendency toward self-enhancement (extreme plastic surgery, implants of all types), tattoos, piercings

Overmethylation Can Lead to Physical and Medical Issues

  • Food and chemical sensitivities – this picture is dominated by low histamine which then translates to alternate immune pathway sensitivities.
  • Pain – head, neck, and general body pain.
  • Low Histamine
  • Anxiety or panic
  • Sleep disorders – especially with physical or mental restlessness.
  • Depression – depression – especially with an anxiety component
  • Hyperactivity, ADHD – in combo with restlessness and anxiety

At The Extreme End of Pathology Overmethylators Can Be Prone To:

  • Schizophrenia
  • Panic attacks
  • Self-mutilation or self-harm
  • Major Depression
  • Bipolar Disorder
  • Psychosis including post-partum psychosis

Nutritional Tendencies In Overmethylation

  • Great Reactions to B Vitamins – most overmethylators are low in B vitamins generally, but especially folate and B12 and typically do well with higher than average dosages.
  • Often high copper levels, which can be balanced by increasing zinc
  • Often low histamine
  • Often low B3 and B6
  • Often intolerant to estrogen therapies including birth control and HRT
  • Serotonin, dopamine and norepinephrine may be elevated

Medication and Supplement Reactions in Overmethylation

This represents what is typical for the group, but drug and nutrient reactions can be very personal, so this is a general guideline and not a certainty. This information is both from Dr. Pfeiffer’s book (see above), this article, and my own experience with clients.

Typically Good ReactionTypically Bad Reaction
BenzodiazepinesSSRI Antidepressants
Lithium (Rx) or Lithium OrotateAntihistamines
High-folate foodsEstrogen – birth control pills, hormone replacement therapy
Folate, Folinic Acid, 5-LMTHFSAMe
B3, B6Copper
ZincTryptophan, phenylalanine
Antioxidants – C, E, A, NAC, etc…St John’s Wort
MagnesiumDMG, TMG (methyl donors)
Omega-3 fatty acids

You can read more about overmethylation here.

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Overmethylator or Undermethylator… What Is Your Basic State?

Different Opinions of Methylation

There are several different versions of this conversation floating out there on the web, and this is a point that matters very much in terms of finding the right MTHFR solutions for you.

Typically, people with MTHFR mutations have one of three basic states – overmethylation, undermethylation, and neutral methylation. Knowing your basic state can help you to track your progress on your MTHFR journey, and know when you’re headed in the right direction.

Which way do you lean on the methylation spectrum?

Undermethylation, according to the Walsch Research Institute, is the most common human state at around 45% of the population. Neutral methylation makes up another 40% of the population and Overmethylation constitutes the remaining 15% of the population, solidly holding the black-sheep positions in most families. Most people will have symptoms and personality traits on both sides of the spectrum, but you might notice more of a trend in one direction or the other.

Overmethylation (15%)Undermethylation (45%)
Marches to the beat of their own drumTypically  mentally healthy, but overly driven
Depression – mixed neurotransmitter issuesDepression (low serotonin)
Paranoia or anxietyPerfectionism (this can also look like anxiety)
Head and neck painObsessive or compulsive tendencies
Highly creative and often gifted artists or musiciansRitualistic behavior
Low motivation or hyper-motivated but only in what is interesting to them (not globally).High motivation
Self-mutilation or heavy on the tattoos, piercings, and other body enhancementsAddictive personality
Food or chemical sensitivitiesSeasonal/inhalant allergies
Sleep often disorderedStrong-willed
Diminished tears or saliva (low fluidity)Excessive tears or saliva (high fluidity)
Highly empathic and sensitiveFrequent headaches
Pacing or constant movementPoor concentration/mental endurance
High pain thresholdLow tolerance for pain
Ruminating – mind has a hard time shutting offSelf-motivated
Tend toward more hair (head and body)Tend toward sparser hair (head and body)
Often reacts badly to SSRI medications – better with benzodiazepinesOften good reaction to SSRI medications
Often reacts badly to antihistaminesOften good reaction to antihistamines
Often reacts badly to estrogen therapy (or birth control pills)Can have delusions or thought disorders
Passionate and self-sacrificingHistory of high accomplishment
Do you lean toward one of these?

This is One Place Where I Don’t Agree With Ben Lynch

Some people, with the notable MTHFR expert Ben Lynch being one of them (if I’m interpreting his work correctly – feel free to correct me if I’m wrong, Ben!) seem to use the term “overmethylated” as synonymous with either “over-supplemented” or “pushing methylation pathways too hard.” (I”m getting this idea from this post on MTHFR.net).

Others, like myself and Dr. Walsh of the Walsh Research Institute, use the term more to describe a person’s basic natural tendency based on their genes and also the ways their genes are influenced by the environment (epigenetics). Of course someone in this view who is overmethylated can also over supplement, but their basic state, personality traits, and natural tendencies are still those of an overmethylator. Truly, how often do you see the overachiever (undermethylator) of the family turn into the black sheep (overmethylator) because of a supplement, and then stop it and turn back into the overachiever?

Can you tell your basic state just by comparing yourself to these two pictures?

Using Your Basic State As A Guide

Understanding and using both your basic state and your symptom profile can help you to understand when you’re moving toward health and more balance, or in the opposite direction toward imbalance and disease. I like to think of it as pushing my own pathology.

This is a great way to help you understand when you’re on track because some of these symptoms are easy to track and might change before more serious physical issues shift. For example, it’s easy to tell if you’re having a good or bad day for ruminating, when your concentration is clearer or when you’re not quite as perfectionist as you usually are. These are easy for most people to rate on a symptom tracker, but might not be things they would have put onto the symptom tracker if they didn’t know their basic state. More long-term issues like inflammation or blood pressure respond more slowly. This can be a very immediate tool to help you assess your symptoms today.

Whether you’re an overmethylator or an undermethylator, balancing your basic state can only help.

So, Will I Suddenly Have A Different Personality?

Absolutely not. The passionate artist or activist is still going to be a passionate artist or activist, but they will be more balanced and more able to keep themselves healthy while being a passionate activist. Likewise, the highly competitive overachiever will still be a highly competitive overachiever, but they’ll take better care of themselves, take breaks for sleep, not push themselves so far into damage in order to overachieve. Balancing your methylation doesn’t change who you are. It unlocks the best of you.

Thanks so much for tuning in and if you can, give me a shout and let me know if you’re an overmethylator, undermethylator, or a neutral methylator.

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