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My Recommendations for MTHFR Mutations

If you are looking for information on methylation and the MTHFR gene, this is where to start.

If you do not know what methylation is, and would like to understand the basics, click open the introduction below:

Click here for an introduction to methylation.

An Introduction to Methylation

Methylation is profoundly important to our physical, mental, and emotional health. To properly discuss it, we should first define it.

You and I, and everything that lives upon the face of the earth, are made primarily of organic molecules, which are strings of carbon atoms that are bound mostly to hydrogen, but are sometimes bound to other atoms, such as nitrogen, oxygen, and sulfur. A single carbon atom that attaches to such a molecule at one point and is otherwise bound only to hydrogen is known as a “methyl group.” Methylation is the transfer of these methyl groups and is also known as one-carbon metabolism.

Most of your methylation is used to synthesize two molecules: creatine and phosphatidylcholine.

Creatine is best known for boosting muscular strength. Bodybuilders take it as a supplement to build muscle and many kinds of athletes take it to boost their power and performance. Less well known, creatine helps you make the stomach acid you need to digest your food, provides the energy you need to absorb the nutrients in your food, powers sperm as they swim up the vaginal canal, fuels the regeneration of healthy skin, and helps you see and hear.

Phosphatidylcholine is a critical constituent of your cell membranes throughout your body, but is especially important to helping you remove fat from your liver. Without enough of it, we are more vulnerable to fatty liver disease, which afflicts an estimated 70 million Americans. It also serves as a precursor for acetylcholine. Acetylcholine is a neurotransmitter with many roles. In the brain, it supports cognitive performance during tasks that require sustained attention. In your muscles, it's what stimulates contraction and lets you push, pull, lift, throw, and move in whatever other way pleases you.

Methylation has many other roles as well. It helps get rid of histamine, best known for its contribution to allergic reactions. In the brain, it acts to make you mentally more flexible, and helps prevent you from ruminating on negative thought patterns that may contribute to anxiety and depression. In the liver, it contributes to detoxification of foreign chemicals and heavy metals. Our cells are constantly altering the expression of our genes according to the demands of our environment, and methylation is one of the key tools they use to do it.

There is such a thing as too much methylation. For example, too much methylation in the brain can make you so mentally flexible that you become too easily distracted and have difficulty focusing. It may also make you drowsy or interfere with your ability to break established habits. Too much methylation also seems to shorten lifespan.

So, we need to have proper balance. To achieve that balance, we use the amino acid glycine as a buffer of excess methyl groups. If we get a lot of methyl groups but not much glycine, we run the risk of running low in glycine, and this can hurt our detoxification system, destabilize our blood sugar, interfere with our sleep, weaken our bones, and make our skin age faster.

The best way to balance this system is to get plenty of everything, things that supply methyl groups on one hand and glycine as a buffer of the excess on the other.

These are the key nutritional players in the methylation system:

  • Methionine is an amino acid found in all proteins, but which is especially rich in animal products. After being activated using ATP, the fundamental energy currency of the cell, methionine becomes the universal methyl donor.
  • Once activated methionine donates its methyl group, it becomes homocysteine. Homocysteine needs to be recycled back to methionine so methylation can continue, and homocysteine itself is thought to be harmful by contributing to cardiovascular disease.
  • Vitamin B12 and folate (vitamin B9) recycle homocysteine back to methionine. They take the methyl group from the metabolism of amino acids that we get from dietary protein.
  • Alternatively, betaine (trimethylglycine, TMG), which is mainly derived from choline, recycles homocysteine back to methionine.
  • Several other B vitamins, mainly thiamin (vitaminB1), riboflavin (vitamin B2), niacin (vitamin B3), and pyridoxine (vitamin B6), support B12 and folate in recycling methionine, even though they themselves are not methyl donors.
  • Glycine is our buffer for excess methyl groups.
  • A number of minerals are needed to support the enzymes involved in this system: ironphosphorus, sulfur, magnesium, potassium, zinc, and possibly cobaltVitamin A is also needed to produce the enzyme involved in using glycine as a methyl buffer.


For recommendations on how to obtain sufficient methylation-supporting nutrients in your diet, click open the next section, “How to Eat to Nourish Your Methylation.”

Click here for how to eat to nourish your methylation.

How to Eat to Nourish Your Methylation System

While there are a handful of nutrients that are notable for their specific contributions to the methylation system, the system operates within a framework that depends on most of the B vitamins and many of the essential minerals. It makes sense, then, to layer methylation-specific advice on top of some general rules of thumb that are always good to follow to make sure you obtain all your vitamins and minerals.

For someone with no allergies or other reasons to restrict food groups, the following general principles help ensure that you’re meeting all your nutritional needs:

  • Diversify your protein among meat, fish, shellfish or other invertebrates, eggs, and dairy. Get a half gram to a gram of protein per pound of bodyweight (if overweight, reduce this to your ideal bodyweight), which for a 150-pound person would be 75-150 grams of protein. Most people have plenty of wiggle room within this range, but if you are trying to lose body fat, gain muscle, or meet athletic goals, you should aim for the higher side of the range (and in some cases higher).
  • Make an effort to eat “nose to tail” by utilizing parts of the animals we’ve been neglecting in our society. For example, try eating liver once a week and using bones to make broths, gravies, and sauces or eating the edible bones found in canned fish.
  • Get about 1000 milligrams of calcium per day, which is easiest to get from several daily servings of dairy or edible bones, such as the ones found in canned fish.
  • Diversify your carbohydrates among legumes, whole grains, starchy tubers, and fruits. 
  • Eat a large volume (several cups per day) of vegetables, diversifying them across colors with an emphasis on red, orange, yellow, and green. Always include dark green vegetables in the daily mix.
  • Include foods or supplements that aid in digestion at every meal. Examples include ginger, lacto-fermented vegetables, kombucha, raw apple cider vinegar, Swedish bitters, and digestive enzyme supplements. The reasoning behind this one is simple: all those nutrient in your food are only useful if you digest your food well, breaking it down fully and absorbing everything it has to offer.

If you follow these recommendations, you will meet your needs for many methylation-related nutrients almost automatically. For example, the protein will supply your needs for methionine and for the amino acids that folate and B12 use to recycle homocysteine. The diversity of unrefined plant foods will ensure you get enough magnesium and potassium. The general diversity of whole foods of all kinds will ensure you get enough of most of the B vitamins involved in energy metabolism that indirectly support the methylation pathway.

Nevertheless, we can add some methylation-specific recommendations:

    • Folate. 2-3 servings of liver, legumes, or leafy greens provide the daily requirement for folate. A serving is 100 grams or three to four ounces. For the liver, it can be measured before cooking but for the legumes and greens it should be measured after cooking. This is especially important for veggies, because most leafy veggies shrink a lot during cooking and you should actually eat twice this amount if you are eating them raw.

Out of these foods, folate is most stable in liver, even in the freezer, but you can only eat one or two servings of liver per week without overdosing on other nutrients. Folate is also very stable in dried legumes, making these the easiest way to get a lot of folate. In vegetables, folate is very unstable, even in the freezer. In fact, frozen vegetables should not be trusted at all as a source of folate. For fresh veggies, it is best to purchase them from a farmers market where you can have more trust in how fresh they are, and to use them up within 3-5 days.

If you rinse or wash your veggies, do so before you cut, dice, or shred them. Otherwise, they will lose a lot of folate in the rinsing water. Cooking degrades folate, and causes loss of folate in cooking water. Here, as in storage, folate is very stable in liver and least stable in veggies. If you cook all your folate-rich foods and throw out the cooking water, you should increase the number of servings from 2-3 to 3-5. It is best to cook gently (for example, steaming), and to consume the cooking water whenever there are not downsides to doing so (for example, you could stew vegetables in a soup where the folate runs into the broth and you consume the broth, but if you are cooking beans you might hurt your digestion if you consume the cooking water).

Although the data are too limited to make definite recommendations, eggs from pasture-raised chickens might be a very potent source of folate, and sprouting your legumes or buying them sprouted may cut the amount you need to eat by 75 percent.

If you expect to have difficulty meeting these targets, I would take Jarrow Methylfolate on each day where you are unable to meet the folate requirement from food. (If you join the CMJ Masterpass, you will have access to a storefront where you have a permanent 35% discount on this and all other available Jarrow products. Use the code MTHFR for 10% off the Masterpass membership fee.)

  • Vitamin B12. Vitamin B12 is found almost exclusively in animal products. You can only absorb enough of it every four to five hours to last you one day. You can stock up on it to use later by consuming enough for one day at multiple meals, but the one-day's-worth-per-meal rule puts a limit on how much you can stock up on. For example, if you get a day's worth at 122 meals per year, you could stack all of these meals into four months as long as you spaced them apart by 4-5 hours, and you could eat a diet devoid of B12 for the other eight months, and you'd be fine. But you can't eat a month's worth of B12 in one day and be fine for the month, because you wouldn't absorb most of it. This is important because some foods, such as liver, oysters, and clams, contain many days worth of B12 in a single serving. You can take advantage of them by eating small amounts at many meals, but you can't take full advantage by eating large amounts in one meal.Here are five ways to get a day's worth of B12:
    • 4-8 grams of liver.
    • 8 grams of oysters or clams.
    • 12 ounces of meat, poultry, or fish.
    • 3 eight-ounce glasses of milk or 12 ounces of cheese.
    • For the vegans: substitute green or purple laver (nori) for oysters and clams; or substitute black trumpet, chanterelle, or shiitake mushrooms for the meat.

    Although B12 deficiency can be caused by poor dietary intake, especially in vegans and vegetarians, many people are deficient due to poor absorption. Pernicious anemia is an autoimmune disease that impairs B12 absorption, and it affects 0.1% of the general population and about 2% of the elderly. Chronic gastritis associated with H. pylori also impairs B12 absorption, even if it doesn't cause any symptoms typically associated with gastritis, and it may be bad enough to cause B12 deficiency in 10-15% of the elderly. In these cases, B12 supplements or injections are needed.

    If you expect, on average, to fall short of consuming a third of a day's worth of B12 at most of your meals, or a day's worth of B12 at a third of your meals, I recommend taking one capsule per day of Pure Encapsulations Adenosyl/Hydroxy B12. (If you join the CMJ Masterpass, you will have access to a storefront where you have a permanent 35% discount on this and all other available Pure Encapsulations products. Use the code MTHFR to save 10% off the Masterpass membership fee.)

  • Choline and Betaine. It is betaine, not choline, that directly supports methylation. However, while you can obtain betaine in the diet, most people consume more choline than betaine, and we convert choline into betaine as needed. Since they are interchangeable with respect to methylation, I recommend thinking of a general “choline requirement” that can be partly met by betaine. Since choline does some things that betaine cannot — making acetylcholine as a neurotransmitter or phosphatidylcholine to support cell membranes and prevent fatty liver disease — I recommend getting up to half of the choline requirement from betaine but getting at least half from choline itself.A simple way to think of the choline requirement is as “egg yolk equivalents.” You want to consume 2-3 egg yolk's worth of choline per day, but you can mix and match different foods to do it.Each of these foods is equivalent to one egg yolk:
    • An egg yolk itself, or a whole egg.
    • 50 grams of liver (you can use this as one egg yolk equivalent up to four times per week).
    • 200 grams of nuts or cruciferous vegetables. (I would not consume more than 200 grams per day of either of these categories because of some anti-nutrients they contain.)
    • One tablespoon of lecithin. I recommend this one.
    • Two 300-mg capsules of Jarrow alpha-GPC. I recommend using this if you have symptoms of low acetylcholine, such as muscular weakness, difficulty performing well at tasks that require sustained attention, or, in the elderly, any form of dementia. (If you join the CMJ Masterpass, you will have access to a storefront where you have a permanent 35% discount on this and all other available Jarrow products. Use the code MTHFR to save 10% off the Masterpass membership fee.)

    You can obtain one egg yolk's worth of choline as betaine from the following foods, and you can use these options to supply up to half of your choline requirement:

    • 25 grams of wheat germ.
    • 100 grams of cooked or canned beets.
    • 200 grams of raw beets.
    • 100 grams of cooked spinach.

    Additionally, one 500-mg capsule of trimethylglycine (TMG) counts as two egg yolk equivalents in betaine. If you join the CMJ Masterpass, you will have access to a storefront where you have a permanent 35% discount on this and all other available Jarrow products. Use the code MTHFR to save 10% off the Masterpass membership fee.)

    Overall, you want to consume 2-3 foods per day from among those in either list. At least half of this, meaning at least 1-2 foods per day, should come from the first list. Choosing foods from the second list is optional. Two capsules of the alpha-GPC counts as one food from the first list, while one capsule of the TMG counts as two foods from the second list.

  • Glycine. If you eat a largely plant-based, moderate-protein diet and make an effort to consume skin or bones whenever you eat animal products, you probably get enough glycine. However, most of us eat a lot of methionine-rich animal flesh without eating enough glycine-rich skin and bones to match it. I recommend the following rule of thumb. For a protein intake of 0.5 grams protein per pound of bodyweight, consume one gram of supplemental gelatin or collagen for every ten grams of animal protein, but ignore your plant protein. As you go above 0.5 grams protein per pound of bodyweight, consume one gram of supplemental gelatin or collagen for every 10 grams of plant protein and for every 5 grams of animal protein. For example, if you weigh 150 pounds and consume 150 grams of animal protein, add 7.5 grams of collagen for the first 75 grams of protein and 15 grams of collagen for the next 75 grams, bringing the total to 22.5 grams of collagen. Instead of gelatin or collagen, you can use bone broth, as long as you know the amount of protein per serving. 10 grams of bone broth protein is equivalent to 10 grams of collagen. The collagen brands I trust most are Great Lakes and Vital Proteins. For bone broth, Kettle and Fire and Kitchen Basics both have 10 grams of protein per serving.

Click open the next link for my protocol for adapting your diet and supplements to the common genetic variations in the methylation pathway, most notably MTHFR:

Click here for my MTHFR protcol.

 

The MTHFR Protocol

MTHFR is an enzyme that uses folate (vitamin B9) to support the process of methylation. It's the last in a series of enzymes that construct a methyl group on the folate molecule to make methylfolate. That methyl group is then used, with the help of vitamin B12, to recycle homocysteine to methionine.

There are variations in the MTHFR gene. Common genetic variations are known as polymorphisms. Specific variants in polymorphic genes are known as alleles. The two common polymorphisms in the MTHFR gene are known as the C677T allele and the A1298C allele. You have two alleles for every genetic polymorphism, one from your mother and one from your father. If you have the same allele from both parents you are homozygous for that allele, and if you have different alleles from each parent you are heterozygous for each allele of that polymorphism. Your own combination of alleles is your genotype.

There's a good chance you have an MTHFR polymorphism. In some populations, the percentage of people who do not have either at least one C677T allele or one A1298C allele is only 15%!

Most of the research is on the homozygous C677T allele because it's the strongest variant. But actually the two alleles and their combinations simply cause a graded decrease in the activity of the MTHFR enzyme. One A1298C allele decreases its activity by 17%. One C677T decreases it 33%. Two A198C decrease it by 39%. One of each decreases it 53%. Two C677T decrease it by 75%.

So, two things are clear. First, having at least one of these is so common that this should just be viewed as a variation in metabolism that requires different dietary emphasis, not any kind of disorder or defect. Second, the degree to which you need to follow my recommendations below increases in proportion to the level of decrease in your enzymatic activity. And even your genes are operating in the context of a complex physiology. The numbers above are averages. So you don't need to follow everything, but testing with my blood test recommendations and testing against your symptoms and sense of well being should help you decide how strictly you should follow them.

How to Know If You Have an MTHFR Polymorphism, or Other Closely Related Polymorphisms

My Genetic Choline Calculator is a free tool you can use to turn your raw data file from Ancestry or 23andMe into a precise recommendation of how much choline you should aim to get from food, and it includes a calculation of how much your production of methylfolate is compromised by your genetics.

If you want something more expansive than this, I recommend StrateGene. You can save 25% off the price of Strategene by joining the CMJ Masterpass. You can use the code MTHFR for a lifetime discount of 10% off the Masterpass membership fee.

A Dietary Strategy for Low Methylfolate Production

This protocol adapts an otherwise nutrient-replete diet to a genotype favoring low methylfolate production. It is important, therefore, to follow the general recommendations in the How to Eat to Nourish Your Methylation System section, altered only as described below.
The principle nutritional effects of low methylfolate production are these:
  • The low activity of the MTHFR enzyme is a result of its lower ability to use riboflavin, and an extra 1.6 milligrams of riboflavin per day helps bring the activity back up closer to normal. It isn't clear whether enough riboflavin will make the enzyme work just as well as in someone with the genes for high MTHFR activity, but it might. Therefore, getting enough riboflavin should be central, but we should still work on the assumption that your methylfolate production is lower than it could be.
  • Because you are less good at making methylfolate, you use choline as an alternative methyl donor more often.
  • Methylfolate is the off-switch for the glycine buffer system, so low levels of methylfolate make you methylate glycine more often, even when you shouldn't. This makes you waste methyl groups and can deplete your glycine levels.

This strategy is not based on compensating for low methylfolate production with high doses of methylfolate supplements. In fact, there's no way on earth you can compensate for low methylfolate in this way. The reason is that every folate molecule you consume gets methyl groups added to it 18,000 times a day. It is not safe or wise to take supplements providing 18,000 times the normal amount of methylfolate.

The strategy, then, is based instead on these principles:

  • We aim to get 3 milligrams of riboflavin per day. This provides the 1.6 extra milligrams that have been shown to increase MTHFR activity and adds it to the RDA. Note, however, that endurance exercise, weight loss, high-fat diets, and sunlight exposure will all increase your riboflavin requirement further, and you may need as much as 5 milligrams if many of these apply to you.
  • We double the normal choline intake, to ensure an adequate supply of methyl groups and to conserve methylfolate.
  • We supplement with creatine, to cut the demand for methyl groups in half and thereby conserve methylfolate even further.
  • We supply a normal or slightly higher amount of methylfolate, but make sure it is spread out evenly across the day, ensuring that there is always some methylfolate around, no matter how bad you are at producing it.
  • By constantly supplying methylfolate and by conserving it as much as possible, we hope to suppress the unnecessary use of the glycine buffer system. Nevertheless, our success on this point will only be partial, so we add extra glycine to compensate for what we are losing.
Here are the five points of the strategy.
1) Get 3 milligrams of riboflavin per day. On one or two days a week, eat four ounces of liver, ideally from beef, bison, or lamb. On the other days, consume one “liver equivalent,” mixed and matched from the following foods. These foods supply 1/2 of a liver equivalent: kidney, heart, and almonds. These foods provide 1/6 of a liver equivalent: red meat, cheese, eggs, salmon, mushrooms, seaweed, sesame, wheat germ, and wheat bran. On days that you cannot meet the food requirement for a liver equivalent, take a low-dose riboflavin supplement or B complex providing 3-5 milligrams of riboflavin. For example, you could use a half a dropper of this liquid riboflavin supplement.
2) Get enough folate, and evenly spread it out across the day. Follow the Folate section of How to Eat to Nourish Your Methylation System, but make sure to spread it out evenly across your meals. As a backup, take one 400-mcg capsule of methylfolate (such as Jarrow Methyl Folate) at each meal in which you are unable to consume the recommended amounts of folate-rich foods. (If you join the CMJ Masterpass, you will have access to a storefront where you have a permanent 35% discount on this and all other available Jarrow products.) If trying to fully optimize the system, instead of taking a 400-mcg folate supplement at a meal, take one drop of Holistic Health 5-MTHF Drops at the two-hour time point after each meal, before bed, and, if you don't eat breakfast for an hour after waking, upon waking, to yield a total intake of 5-8 drops.
3) Supplement with 3-5 grams of creatine per day. Although you could get 3 grams of creatine from 1-2 pounds of muscle meat or fish (but not organ meats, eggs, dairy, or plant proteins), the high level of methionine-rich protein would worsen your tendency toward glycine depletion. Therefore, I recommend using a supplement. Specifically, I recommend Optimum Nutrition Micronized Creatine Powder for use at home and  Optimized Nutrition creatine caps for use while traveling.

4) Consume 4-5 egg yolks worth of choline per day, at least half as choline and up to half as betaine. Use the same food and supplement equivalents listed in the Choline and Betaine section of How to Eat to Nourish Your Methylation System, but consume 4-5 foods or supplements from the two lists combined rather than 2-3, and make sure that at least 2-3 come from the first list instead of 1-2.

5) Boost your glycine intake. Unfortunately there are no studies documenting how much more glycine needs to be taken to match low methylfolate production. However, I suggest the following rule of thumb: Supplement with one gram of gelatin or collagen for every five grams of protein in your diet. Instead of gelatin or collagen, you can use bone broth, as long as you know the amount of protein per serving. 10 grams of bone broth protein is equivalent to 10 grams of collagen. The collagen brands I trust most are Great Lakes and Vital Proteins. For bone broth, Kettle and Fire and Kitchen Basics both have 10 grams of protein per serving. (If you join the CMJ Masterpass, you will have access to a storefront where you have a permanent 35% discount on Vital Proteins products, and will also have access to Kettle and Fire at 30% off. Use the code MTHFR to get a lifetime discount of 10% off the membership price.)

Final Caution: Be careful with Excess Protein and SAMe Supplements. Low methylfolate levels make you more likely to use the glycine buffer system when you don't need to. The methionine in dietary protein will aggravate this effect. SAMe is the activated form of methionine and is sold as a supplement. SAMe supplements will aggravate glycine wasting just like excess protein does. I recommend limiting protein to 1 gram per pound of bodyweight unless you are doing testing to ensure your glycine levels remain adequate at higher protein intakes. Similarly, I would avoid SAMe supplements unless you have a very good reason to use them (for example, you have tried SAMe for a health issue and found it to work very well) and unless you are monitoring your glycine levels with lab testing. (See the section below on lab testing).

 

Click open the section below if you are interested in lab testing related to methylation:

Click here for lab tests related to methylation.

 

Lab Testing Related to Methylation

I recommend running 23andMe data through my free Genetic Choline Calculator. This will give you your MTHFR status and estimate the combined effect of several other genes on your total capacity to produce methylfolate. StrateGene is not free but much more expansive. You can save 25% off the price of Strategene by joining the CMJ Masterpass. You can use the code MTHFR for a lifetime discount of 10% off the Masterpass membership fee.
These are the blood tests that would best help you assess your methylation status:
1) Homocysteine. Available from LabCorp, Quest, and the Genova ION panel, aim to keep your numbers between 6 and 9, rather than the larger range on the report.
2) Plasma or serum folate and RBC folate. Available from Quest or LabCorp, aim to be in the normal range as listed. Plasma or serum folate represents mainly methylfolate, while RBC folate represents total folate. Getting both can help distinguish between problems related to low folate levels in general and those related to low methylfolate levels specifically.
3) Plasma methionine, glycine, and sarcosine. Available on a LapCorp amino acids profile, a Quest amino acids profile, a Genova ION +40 panel, or a NutrEval, methionine and glycine should be toward the middle of the range rather than the bottom and sarcosine is best being as low as you can get it.
Testing Nutritional Status: The Ultimate Cheat Sheet contains eight pages of instructions for using lab testing related to methylation. Four other tests related to folate and B12 are covered, and they are put in the context of assessing signs and symptoms related to methylation and dietary intakes of the related nutrients. It also covers testing for the B vitamins indirectly involved in methylation (thiamin, riboflavin, niacin, and pyridoxine) and for the minerals (iron, phosphorus, sulfur, magnesium, potassium, zinc) that support the enzymes of this pathway. To purchase it, use this link and copy and paste the discount code METHYLATION5 to get $5 off.

 

The rest of this page compiles all the resources I have made related to methylation. If you feel confident that you have the basics, choose any of the links below to continue learning.

Searchable Databases Related to Methylation

Balancing Methionine and Glycine in Foods: The Database

Consuming Creatine in Foods and Supplements

Podcast Episodes Related to Methylation

Living With MTHFR

Methylate Your Way to Mental Health With Dopamine

Why You Need Glycine: A Panel Discussion

Creatine: Far More Than a Performance Enhancer

Why You Should Manage Your Riboflavin Status and How to Do It

Niacin, Part 1: What It Is and Why You Need It

Nutrition in Neuroscience (Parts 2 and 4 are most relevant to methylation): Part 1, Part 2, Part 3, Part 4

Chris Masterjohn Lite Episodes Related to Methylation

What EVERYONE Should Be Doing About Methylation

How to Get Enough Folate

Folate: You Can Freeze Your Liver But Not Your Veggies

Supercharge Your Folate With Pastured Egg Yolks and Sprouted Legumes

Getting Enough B12: Vegans, Omnivores, and Everyone In Between

How to Know If You Need to Care About Your MTHFR

What to Do About MTHFR

This is the Blood Work You Should Get for MTHFR

Does Methylfolate Make You Angry or Depressed?

DON'T Use Niacin to Buffer Excess Methyl Groups

Why I Don't Believe in “Undermethylators” and “Overmethylators”

DON'T Use Histamine To Assess Methylation Status

Your MTRR Genes and Vitamin B12

What to Do About Your COMT Genes

5 Ways to Eat Enough Liver

Sometimes Synthetic Folic Acid Is Better Than Natural Food Folate

5 Ways to Help With Glutamate Sensitivity and Glutamate Dominance

Get Better Sleep With Glycine

Collagen Before Your Workout For Tendon Health

Glycine With a Meal for Blood Sugar

Oxalates — Should You Be Concerned About Collagen?

Blog Posts Related to Methylation

Your “MTHFR” Is Just a Riboflavin Deficiency!

Alex Leaf: Supplement riboflavin to fix the MTHFR polymorphism

The Sweet Truth About Liver and Egg Yolks — Choline Matters More to Fatty Liver Than Sugar, Alcohol, or Fat

Does Choline Deficiency Contribute to Fatty Liver in Humans?

Meeting the Choline Requirement — Eggs, Organs, and the Wheat Paradox

Off-Site Articles Related to Methylation

Beyond Good and Evil: Synergy and Context with Dietary Nutrients

When SAMe Helps, Consider Magnesium and Your Metabolic Rate

Should We Avoid Animal Protein to Optimize Methylation?

Guides Related to Methylation

Testing Nutritional Status: The Ultimate Cheat Sheet contains a comprehensive approach to assessing and managing your status for all of the essential vitamins, minerals, and fatty acids. It outlines three different approaches depending on whether time or money are your most limiting resources. It includes guidance for dietary analysis, lab testing, and analyzing your signs and symptoms.

It is called a “cheat sheet” because, although it is 78 pages long, the first five pages give you complete instructions and hold your hand through a step-by-step process to read only those other sections of the guide as are most important for your particular situation. When you identify an issue with a nutrient, it leads you to the section for that nutrient, where you are given signs and symptoms of deficiencies and toxicities, dietary patterns and other risk factors that would cause a problem with that nutrient, and a way to fix the issue and monitor how effective your fix is. Eight pages are devoted to methylation-related nutrients, and many more pages are devoted to the B vitamins and minerals that indirectly support methylation.

To purchase it, use this link and copy and paste the discount code METHYLATION5 to get $5 off.

For Even More

Try searching the site for “methyl,” “methylation,” or any of the specific nutrients discussed on this page. Try doing the same on Google and adding “masterjohn” to turn up things I have written on this site or elsewhere.

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If you need help implementing the methylation strategies discussed on this page, I offer personal health and wellness consulting, in which I serve as your data analyst and strategist, not as a health care provider or coach. Click here to learn more about my services.

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38 Comments

  1. Hello Chris, I’m heterozygous A1298C. My b12 and folate are low. B12 is 258 and Folate is 7.9. Back in 2017, I had great number s b12 was 660 and folate 20. I wasn’t supplementing at all and I haven’t changed my eating habits much. I’m assuming stress kicked my gene into the “on” position. I struggle taking any and all supplements but especially anything methylated. I am homozygous for the COMT gene and suspect this is the reason I can’t take methyl supplements. Any advice?

  2. Chris,
    I have decided to take Betaine HCL + Pepsin in order to better digest my proteins. I saw your comment that it does contain trimethylglycine, so this counts toward our glycine requirements. QUESTION: If I’m taking more Betaine HCL now, will that possibly throw things off by getting TOO MUCH glycine or betaine? Because I was already doing this protocol and I don’t know if I’ll end up getting too much in total of choline/betaine/glycine. At what point is doing all of the things in earnest “too much”??

    I do know that glycine and phosphatidyl choline as supplement greatly helped me.

    I have been following this protocol with good results.
    -adding dried beet powder and creatine powder to smoothies
    -Adding additional beets or beet juice sometimes
    -taking 2 scoops, about 4 Tbsp. collagen per day.
    -B Complex to get the riboflavin (no folate or B12 in my current one). Added B6.
    -6 capsules of liver per day
    -cannot eat eggs right now. Taking one phosphatidyl choline supplement per day.
    -cannot eat grains, legumes, or nuts right now. (autoimmune)
    -do take mushroom powders regularly

    1. Check out the talk he mentions above, “Why You Need Glycine: A Panel Review”.

      One of the guests mentions humans need a MINIMUM of 10 grams/day, so I’d suggest you’re not getting enough. And there’s no way I am…I think that podcast may have saved my life.

      Also, beets are VERY high in salicylates. Glycine is the main way salicylates are processed, which Chris also talks about in the podcast. Nuts and other vegetables can also have high levels…

  3. Is there a product that combines these supplements together that you could recommend so I don’t have to take a handful of vitamins on top of the handfuls I already take?

  4. My daughter is SLC19a1 +/+,
    MTHFD1 +/+, MTHFR c677T +/+, VDR taq +/-. She takes pyridostigmine which is an acetylcholinesterase inhibitor to control dizziness from having POTS. She still suffers from fatigue. Which supplements should she take based on her genetics to help with this?

  5. Chris, the ON creatine you recommend is no longer made with creapure. I would suggest recommending a different version.
    Here is quote from customer service:

    Hello-
    Thanks for choosing ON! We have decided to stop using Creapure in the product. It was a company decision to move in a different direction from branded creapure to non-branded. By moving to non-branded we are able to secure multiple suppliers of creatine, which gives us a robust supply chain. It also guarantees that we always have enough creatine as an ingredient so that we can continue to produce our micronized creatine products. We use high quality micronized creatine that has been approved through our high Quality standards and specifications. Our creatine is made of 100% Pure Creatine Monohydrate.
    Have a great day!
    Consumer Affairs Rep 05269
    Optimum Nutrition/ABB Performance

    Thanks for your work Chris!
    -Greg

    1. I am following CM’s recommendations also, and taking ON creatine. Would like to see a response to this comment by Greg October 29, 2019 at 11:36 am

  6. Hi Chris,

    I have started taking spinach powder in a protein shake daily because of my mthfr etc issues with folate. Do you know if this process retains the folate? ( as it’s pointless doing it if not. )

  7. ”if you get a day’s worth at 122 meals per year, you could stack all of these meals into four months as long as you spaced them apart by 4-5 hours, and you could eat a diet devoid of B12 for the other eight months”

    Wouldn’t you need a day’s worth of B12 at *365* meals for a year? Which might be stacked into 122 days or so? (Seems like an editing error of some sort, or maybe I just misunderstand it. :))

  8. @Dr. Masterjohn ~ A search on your site for “Metallothionein” (MT) doesn’t have any results. I would like to know more about this: Is there anything besides taking zinc that can boost my MT? I read this article:
    https://eatfor.life/histamine-mast-cell-disorder-or-methylation-imbalance/
    And would love to have your feedback on the entire concept–do you think it merits a deep dive on a Mastering Nutrition episode? I know a lot of people end up here wanting to find missing puzzle pieces to controlling histamine. I have some kind of histamine intolerance and as a layperson I am trying to understand the “mechanics” and the real root cause.

  9. Hi Chris, I have extreme adrenal fatigue and bad liver function, so my methylation is off. I also have histamine issues (with MCAS) and extreme food allergies which force me to only eat a very limited vegan diet (I cannot digest animal protein, like meat, and eggs are also a no go).
    I have started with animal organ meat capsules, which have a lot of the B-vitamins, en the groups that are required for methylation.
    Now I cannot handle that much of those capsules, so was wondering if you would suggest dosing with extra B-vitamins to support my adrenals and liver?
    I’ve also just started with vitamin B6 which seems super helpful.

    Best,
    Claire

  10. Can we take l histidine to cure overmethylation or histapenia? Also tell me what form of glycine is better, l glycine or magnesium glycinate?

  11. Hi Chris,
    I suffer with “bipolar 1 rapid cycle” and insomnia from pyroluria/copper toxicity/ and what would be labeled “undermethylator”. Any advice on where to go for info or to get help or any advice? Glycine, zinc picolinate, p5p, Magnesium citrate, l theanine and sunflower lecithan are what I take that helps control mania intensity and insomnia some. Staying away from gluten and dairy also helps and stopped all hallucinations I used to have. I still have to add in benedryl for sleep and I often only sleep 4-5 days a night when I’m good and often time it’s not restful or uninterrupted, the sleep part just drives me nuts. Thanks for all you do!

    1. I have histamine intolerance, but have it under control now. Since you take benadryl for sleep that would seem to me (I’m not a doctor!) that if you need to get rid of histamine, that could help. I can tell you how to deal with histamine, at least in so far as I now have mine under control. One resource is Alison Vickery blog. To lower the amount of histamine in your food a) no fermented foods or beverages, watch out for cheese, yogurt, dairy, and egg whites, avoid leftover foods, avocado, tomato paste, chocolate, seafood, alcohol, watch out for honey and bottled sauces (that’s the simple version) b) take buffered vitamin C with each meal or about 3-4 capsules per day, spread out. c) take a DAO pill – Seeking Health – with each meal. d) Quercetin d) add fresh green herbs. If you have a histamine flare or symptoms, drive down histamine with a smoothie made out of a big handful of curly parsley, water and frozen peaches (for flavor and texture).
      Take the Theanine at night. Vitamin D+K at night. If you are taking any calcium, move it to the A.M. Theanine and B6 at night. Phosphatidyl serine at night. Look into Ashwagandha, 5htp (and as it relates to melatonin). Maybe take melatonin at night. Also read book(s) by Joan Mathews Larson–although she may be getting outdated, maybe you’ll also glean something from it. Finally, I take 2 capsules of Oregon’s Wild Harvest brand “Muscle Relax” containing Valerian root, Skullcap tops and Hops–I took it for my muscles but it usually helps me sleep deeper.

    2. P.S. I don’t know if this is relevant to you about the BiPolar. But, it seems tit should be relevant to everyone. I use the original formula of Concentrace (not the Volts formula) to remineralize my drinking water after filtering. I like it that it has a bit of natural lithium in it. It seems to me that we probably have a need for it and most aren’t getting it. If anyone reading this page has an opinion on dietary Lithium, I’d be glad to hear it.

    3. Gosh, one more thing. I would take up a self-study or maybe labs to help you look at your blood sugar stability. I think this is a big thing for mood disorders.

      I hope Dr. Masterjohn has some other good ideas for you!

  12. I purchased your Testing Nutritional Status Cheat Sheet and it’s very helpful, but I am not able to figure this one small part out:

    I have high homocysteine and I am not sure of the cause.

    I fit this profile: High homocysteine, moderately high methionine, low cysteine, normal MMA, normal folate.

    Homocysteine : 15.3 umol/L (<11.4) HIGH
    MCV: 94 fL (80-100)
    RBC: 4.50 Million/uL (4.20-5.80)
    B12 Serum: 355 pg/mL (200-1100)
    Methylmalonate: 0.2 mcg/mg (5.4)
    Folate, RBC: 559 ng/mL (>280)
    Copper: 87 mcg/DL (70-175)
    Methionine : 34 umol/L (14-48)
    Cystine: 2 umol/L (0.8-27.5)
    Lipid Peroxides: 1.72 nmol/L (<=2.60)
    Isocitrate: 37 mcg/mg (39-143) LOW

    Had full amino acid / Genova ION test, and all B vitamin & amino acid levels were within range.

    I am compound homozygous BHMT-02, BHMT-04, BHMT-08, CBS A360A, VDR Bsm.

    I am heterozygous for COMT V158M, COMT H62H, MTHFR 03 P39P, MTHFR A1298C, MTRR R415T

  13. “You can obtain one egg yolk’s worth of choline as betaine ” -This wording is confusing to me. Help, anyone!

    1. The body converts choline into betaine for use in the methylation pathway. If you supply betaine directly, this reduces your need for choline. Same would apply in regards to creatine. (roughly half of methylation is used to synthesize creatine).

      Chris’ recommendation for choline intake assumes minimal betaine and creatine intake. If you eat a significant amount of betaine or creatine, you can reduce your choline intake. However, you still need choline for other things in the body besides to supply methyl groups to the methylation pathway. So he’s giving you permission to replace one egg yolk’s worth of choline by betaine but you still need to eat your egg yolks or cruciferous vegetables to get the rest of the choline your body needs

  14. Hello! Is it harmful for someone with a COMT mutation to take metformin, since metformin disrupts folate absorption in the intestine. Some Metformin users have higher homocysteine level

  15. Hello,

    I was wondering if you have any information on how MTHFR affects the ability to process GABA, and how potassium might play a role in that. I am compound heterozygous, and supplements that increase GABA tend to give me anxiety including GABA, theanine, magnesium, and progesterone. Any information on how exactly MTHFR/GABA/potassium interact would be super appreciated!

    Thank you!

  16. Hi, I recently found that I have homozygous c677t mutations and have been struggling since I became pregnant with my son (he’s a little over 3 now) with fatigue, brain fog, anxiety, depression, memory issues.. the list goes on. My son has also had health problems, including a speech delay, sensory issues, high, cyclical fevers, and the only remarkable (and consistent) thing that his doctors and specialists have found are high inflammatory markers in his bloodwork. Our story is a long one, but I guess my question is related to supplementing and the likelihood that he could have some of the same difficulties that I do. We’ve made a number of diet changes (it hasn’t been easy with his aversions to many foods), removed lots of processed foods etc., but until recently, hadn’t seen significant improvement. After researching my results (my doctor doesn’t know much about these mutations or what to do about them), I started introducing jarrow methyl b12 + methyl folate (with b6 as p5p) and as quickly as the second day, I noticed a HUGE increase in clarity, energy, even clearer skin. I know that there are other things that are required, like magnesium, etc. and as my methylation process is reduced to about 30% or so of what’s normal, I have to be more careful about what I try. Also, who can I see to have my son tested? I have already changed his multi vitamin to one that has methyl folate instead of folic acid but with his continuing difficulties and issues eating healthy foods, I feel that it’s imperative to begin a regimen ASAP. Any advice?

    And thank you for sharing some great info!

    1. I’d run 23andMe and StrateGene for testing. Yes, it makes sense that you and he would have similar issues.

    2. Hi, my son also had cyclical fevers starting when he was a baby (he’s 23 now) very picky eater. Has both of the MTHR gene mutations. We only found this out recently.
      I would have him at the Dr’s constantly for the fevers. They always would tell me it’s viral, but no one else in the family would be sick. Years later I finally come across information about his cyclical fevers and it being a genetic problem. One of the Dr’s who specializes in this happens to be in Boston (we live in Massachusetts) so off we went and yes he has the genetic gene for this. Eventually they usually outgrow the condition. Which my son did a couple of years ago. So frustrating for so many years. My son has also been diagnosed with bi -polar. He tried to commit suicide when he was 17. He thinks about suicide every day, self mediacates with pot. Currently I’m giving him methyl factors with folate, a small amount of magnesium Malate, Iadoral, selenium, niacin, Vit D and K. He does better when he takes the supplements but it’s like pulling teeth. Good luck with your son. I hope you get him better quickly and not have to go through years of hell. The fact that you’ve already learned about these things is great!

  17. Chris, is this methylation you talk about here the same thing that they’re addressing when they use “hypomethylating agents” (like azacitidine or lenalidomide) to treat MDS (myelodysplastic syndromes) or is it something completely different and unrelated?

    Thank you.
    Jo

  18. Hi Chris,

    I am heterozygous for A1298C and suffer from ADD/brain fog, particularly in the afternoons when my brain seems to hit a wall and I can’t function at all; extreme cognitive fatigue.

    I recently discovered that supplementing with active Bs + creatine gives my brain energy throughout the afternoons and ameliorates a great deal of my symptoms, however I’ve also discovered that creatine also destroys my sleep quality/maintenance.

    Is there something else I can substitute for the creatine, or any other recommendations you might have?

    Thanks,
    James

    1. My suspicion is the anti-sleep effect of creatine is from altering methyl group balance and will go away within six weeks of consistent supplementation. No, nothing else can fulfill the role of creatine here, though no one *must* take it, barring some rare genetic defects.

  19. Thanks yet again for these resources Chris! Just watched your seminar with Kresser on the ADAPT group, very helpful.

  20. Great read.

    I’m wondering why you equate 600mg of supplemental choline with 1 egg yolk. A quick google search shows that one egg yolk has ~100mg of choline.

    Is there a reason for this discrepancy?

    1. A large egg yolk has about 130 mg. I might have made a mistake in the math and will look at it later, but the 600 mg alpha-GPC only provides 240 mg choline. There’s still a discrepancy and I’ll see what I did when I have some time. It seems like I should have one egg yolk equaling one capsule.

  21. Calories are entirely invented, made up , fictitious. They are not somehow central to food. You could use calories, inverse fermions for calculations for the Hiroshima explosion. There is no such thing in Nature. Energy is not…. anything….Energy (only a number) and its units cannot and do not act. Carbon atoms are what count

    1. Thx for sharing Miki. That resource does indeed make a compelling case that one should not count on dried nori or mushrooms as a source of vitamin B12.

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