MTHFR is an enzyme that allows folate (vitamin B9) to support the cellular process of methylation, which is important for the synthesis of creatine and phosphatidylcholine, the regulation of gene expression, neurotransmitter metabolism, and dozens of other processes. There are two common polymorphisms that decrease its activity, A1298C and C677T, with C677T having the stronger effect. Genetic decreases in MTHFR activity are associated with cardiovascular disease, neurologic and psychiatric disorders, pregnancy complications and birth defects, and cancer.

While discussions of these polymorphism tend to focus on supplementing with methyl-folate, this should only be a small piece of the puzzle, and may be unnecessary in the context of a diet rich in natural food folate. The bigger pieces of the puzzle are restoring choline, creatine, and glycine.

In this episode, I describe how the methylation system works, how it’s regulated, and how it’s altered with MTHFR variations. I then use this to develop a detailed dietary strategy and an evaluative strategy to make sure the dietary strategy is working.

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This episode is brought to you by Ample Meal. Ample is a meal-in-a-bottle that takes a total of two minutes to prepare, consume, and clean up. It provides a balance of fat, protein, and carbohydrate, plus all the vitamins and minerals you need in a single meal, all from a blend of natural ingredients. The protein is from whey and collagen. The fat is from coconut oil and macadamia nut oil. The carbohydrates, vitamins, and minerals come exclusively from food sources like sweet potatoes, bananas, cocoa powder, wheat and barley grass, and chlorella. I use Ample on Mondays when I have 12 hours of appointments with breaks no longer than 15 minutes. It keeps my brain going while I power through the long day, never letting food prep make me late for an appointment. Head to amplemeal.com and enter the promo code “MASTERJOHN” at checkout for a 15% discount off your first order.

This episode is brought to you by US Wellness Meats. I use their liverwurst as a convenient way to make a sustainable habit of eating a diversity of organ meats. They also have a milder braunschweiger and an even milder head cheese that gives you similar benefits, as well as a wide array of other meat products, all from animals raised on pasture. Head to grasslandbeef.com and enter promo code “Chris” at checkout to get a 15% discount on any order that is at least 7 pounds and is at least $75 after applying the discount but under 40 pounds (it can be 39.99 lbs, but not 40). You can use this discount code not once, but twice!

Ways You Can Use the Podcast Notes

Read the show notes.
Read how to know if you have an MTHFR mutation.
Read the dietary strategy.
Read the recommended lab tests.
Check out other related episodes.
View the related research.
Read the transcript.
Leave a comment.

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Show Notes for “Living With MTHFR”

00:35 Cliff Notes

12:15 Introduction of Living with MTHFR

13:05 Bird’s eye view of methylation & MTHFR

14:25 How to know if you have MTHFR

17:00 Prevalence (these are really common)

20:30 This is not a genetic disease: this is a variation in metabolism

21:10 Health Associations

23:00 Mechanisms of what MTHFR does

31:35 Methylation system as a whole (methyltransferases)

36:50 How the system is regulated

56:05 Two Addenda: COMT and Agouti Mouse Study

01:00:10 Mechanistic impact of polymorphisms (% down in enzyme activity)

01:04:45 It’s not all about 5-methyl folate

01:05:35 You can restore normal flux

01:08:45 Compensate with choline

01:13:26 Creatine

01:15:30 Glycine Buffer

01:16:42 Why upping Methionine and SAMe is bad idea

01:19:00 Dietary Strategy – Basic Objectives

01:22:15 Folate

01:26:35 Protein

01:27:50 Creatine

01:33:05  Glycine

01:35:45 Reiterate problem with methionine/and SAMe in context of meat for creatine 900-1200 mg choline 

01:41:40 The evaluative strategy

01:42:00 StrateGene Report

01:43:55 Homocysteine, methionine and glycine

01:46:36 HDRI methylation panel

01:47:35 Folate in plasma and FIGLU

01:49:40 Other tests of interest

How to Know If You Have an MTHFR Mutation

I recommend getting 23andMe Health and Ancestry and then running your raw data through StrateGene.

A Dietary Strategy for MTHFR Polymorphisms

1) Get the RDA for folate from non-fortified whole foods.

  • For adults and children 14 years and older, the RDA is 400 micrograms, except that it is 600 for pregnant and lactating women, regardless of age.
  • For children, the RDA increases from 65 micrograms in the first six months, to 80 in the second six months, 150 for 1-3-year-olds, 200 for 4-8-year-olds, and 300 for 9-13-year-olds.
  • Feel free to use (as an adult, not for children), 400 or 600 micrograms per day of a methyl-folate supplement, providing you are adding it to a folate-rich diet rather than using it to replace food folate. I recommend Jarrow Methyl Folatebased on cost, dose, and the fact that it is otherwise the same high-quality product as sold by other manufacturers in more expensive, higher-dose supplements.

2) Consume at least the RDA for protein.

  • The RDA for protein is 0.36 grams per pound bodyweight.
  • Most people need more than this for other reasons, such as optimizing body composition, preventing loss of lean mass during weight loss, reaching satiety to manage energy intake, or reaching athletic goals. You may need one gram per pound body weight or more, depending on your goals, but the RDA is adequate to support the methylation pathway.

3) Get 3 grams of creatine per day.

  • 1-2 pounds of muscle meat or fish (but not organ meats, eggs, dairy, or plant proteins) will supply on average 3 grams of creatine.
  • Large volumes of muscle protein may be undesirable for someone with an MTHFR mutation because it could exacerbate the loss of glycine.
  • Alternatively, you can supplement with 3 grams of creatine (or 5, if you wish, the standard maintenance dose for athletes). I’m currently using Optimum Nutrition Micronized Creatine Powder.

4) Consume 900-1200 mg/d choline.

  • This can be obtained by eating 4-5 egg yolks per day.
  • You can substitute 100 grams of liver for two egg yolks.
  • You can meet this choline amount by eating a very large volume of low-carbohydrate plant foods. See Meeting the Choline Requirement for more details.
  • You can supplement with phosphatidylcholine, but be careful of the labeling. Usually the supplement lists the phosphatidylcholine, and not the choline yield. A 420 mg capsule of phosphatidylcholine only provides 55 mg of choline, which means you’d have to take 22 capsules per day to get 1200 mg. On the basis of quality, soy-free status, and good feedback from others about the taste, I recommend Micro Ingredients Sunflower Lecithin. Although the choline content is not guaranteed, on the basis of this paper I recommend consuming four to five tablespoons per day to reach the recommended choline yield.
  • If you find that memory loss, poor cognitive function, or weakness are your primary symptoms of concern, consider using alpha-GPC for your choline at the same dose. This form is more effective at converting to acetylcholine, a neurotransmitter involved in neuromuscular function.

5) Boost your glycine intake.

  • At a minimum, use the skin and bones of the animals you eat. For example, eat chicken with the skin instead of without. Use the bones to make bone broth. If you eat canned fish, get the fish with edible bones.
  • Consider supplementing with glycine. I recommend using between 1/2 serving and 3 servings of Vital Proteins Marine Collagen, on the basis that it has a much higher glycine content than beef hide products made by the same company or others with a similar devotion to quality and cleanness of source.

6) Be careful with SAMe. SAMe supplements support methylation, but MTHFR mutations increase the use of glycine to buffer SAMe levels, even when you don’t have enough. While I do not make a blanket recommendation against supplementing with SAMe, I caution against its use in this context because it could aggravate the loss of glycine. If you use it, be careful, and consider monitoring your glycine levels (see recommended lab tests below).

Lab Tests Recommended for MTHFR Polymorphisms

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. Available from Quest or LabCorp, aim to be in the normal range as listed. Avoid RBC folate unless you also corroborate it with plasma or serum.

3) Plasma methionine, glycine, and sarcosine.  Available on a LapCorp amino acids profile, a Quest amino acids profile, a Genova ION 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.

4) The HDRI methylation panel. Aim to keep 5-CH3-THF in the normal range. If it is specifically low while other folate forms are normal, this suggests your MTHFR mutation is impacting your methylation pathway negatively. The “extended” panel has methionine and homocysteine, but not glycine or sarcosine.

5) Other tests of interest. Serum creatine from Quest or LabCorp might be a good way of testing whether your MTHFR mutation is affecting your creatine synthesis if you are not supplementing. Aim to be in the normal range. The combination of creatine, creatinine, and guanidinoacetate (the direct precursor to creatine) from the same urine sample can be used to test problems with creatine synthesis. Unfortunately, these are only offered from labs looking for a genetic disorder, such as Mayo Clinic, Greenwood Genetics Center, and Baylor Genetics, and I’m not sure if they are easy to order for someone with no suspicion of a metabolic disorder or whether the reference ranges would be relevant for looking at the impact of an MTHFR mutation.

Update: Quest now offers this combination as “Creatine Biosynthesis Disorders Panel, Urine.”

Posts and Episodes Related to “Living With MTHFR”

You Asked Me Anything About Methylation, Facebook Live, 06/25/16 | Mastering Nutrition Episode 17

Methylate Your Way to Mental Health With Dopamine | Mastering Nutrition Episode 43

Meeting the Choline Requirement — Eggs, Organs, and the Wheat Paradox | December, 2010 blog post

How to Get Enough Folate | Chris Masterjohn Lite

Folate: You Can Freeze Your Liver But Not Your Veggies | Chris Masterjohn Lite

Supercharge Your Folate With Pastured Egg Yolks and Sprouted Legumes | Chris Masterjohn Lite

Carbs and Sports Performance | Masterclass With Masterjohn Energy Metabolism Lesson 17

This discusses the role of creatine in energy metabolism.

Should We Avoid Animal Protein to Optimize Methylation? | May, 2015 blog post

Beyond Good and Evil: Synergy and Context With Dietary Nutrients | The first section of this December 2012 article on methionine, B vitamins, and glycine is very relevant.

Research Related to “Living With MTHFR”

Liew and Gupta. Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism: epidemiology, metabolism and the associated diseases. 2015.

Chao et al. Correlation between methyltetrahydrofolate reductase (MTHFR) polymorphisms and isolated patent ductus arteriosus in Taiwan. 2014.

van der Put, et al. A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? 1998.

Reed et al. Mathematical analysis of the regulation of competing methyltransferases. 2015.

Reed et al. A mathematical model gives insights into nutritional and genetic aspects of folate-mediated one-carbon metabolism. 2006.

Mudd et al. Methyl balance and transmethylation fluxes in humans. 2007.

Gregory and Quinlivan. In vivo kinetics of folate metabolism. 2002.

Bertolo and McBreairty. The nutritional burden of methylation reactions. 2013.

Wolff et al. Maternal epigenetics and methyl supplements affect agouti gene expression in Avy/a mice. 1998.

Brosnan and Brosnan. The role of dietary creatine. 2016.

Brosnan, et al. The metabolic burden of creatine synthesis. 2011.

Kalhan. Whole body creatine and protein kinetics in healthy men and women: effects of creatine and amino acid supplementation. 2016.

Ipsiroglu et al. Changes of tissue creatine concentrations upon oral supplementation of creatine-monohydrate in various animal species. 2001.

Population reference values for plasma total homocysteine concentrations in US adults after the fortification of cereals with folic acid

Petr et al. Effect of the MTHFR 677C/T polymorphism on homocysteinemia in response to creatine supplementation: a case study. 2013.

Shin et al. Choline intake exceeding current dietary recommendations preserves markers of cellular methylation in a genetic subgroup of folate-compromised men. 2010.

Yan et al. MTHFR C677T genotype influences the isotopic enrichment of one-carbon metabolites in folate-compromised men consuming d9-choline. 2011.

Ganz. Genetic impairments in folate enzymes increase dependence on dietary choline for phosphatidylcholine production at the expense of betaine synthesis. 2016.

Transcript of Episode 46

This transcript was generously provided by Nick Waring.

This is Dr. Chris Masterjohn of chrismasterjohnphd.com, and you’re listening to Episode 46 of Mastering Nutrition, where we’re talking about living with MTHFR.

This is Mastering Nutrition with Chris Masterjohn. Take control of your health, master the science, and apply it like a pro. Are you ready?

00:35 Cliff Notes

If you’re on the run, here are the cliff notes. MTHFR is an enzyme that participates in a process called methylation using the B vitamin folate. Methylation is critically important to mental health, to preventing neurological disorders, to energy metabolism, to cognitive performance, learning, memory, muscular athletic performance, cancer risk. All kinds of things are affected by methylation, so it’s critically important.

But having an MTHFR mutation—which is not a disease, it is a common variation in metabolism. Having that variation does not mean that you don’t have enough methylfolate for methylation and that what you should do is replace the methylfolate with a high-dose methylfolate supplement. Actually, the primary shifts in your metabolism are going to be that you use more choline and therefore need more choline, because choline can do the same thing that folate is doing, and when folate can’t do its job as effectively, choline steps in to a greater degree than normal.

Second thing that happens is not having enough methylfolate actually means, for reasons that are described later in the podcast, that you will be more likely to waste glycine by adding methyl groups to the glycine and possibly peeing them out in your urine. That means that simply adding more methyl groups into the mix isn’t always better, because it might just make you lose more glycine, and you actually have to be careful to replete the glycine.

The third effect is that if anything declines, it’s going to be your creatine synthesis first. Yes, your mental health could be affected. In extreme cases your gene expression might be regulated differently. But what’s almost certainly gonna happen is you’re gonna synthesize less creatine. You need to replace that creatine with more creatine from your diet and supplemental creatine might actually be the best way to conserve your folate. In fact, I describe in the podcast why supplementing with creatine might be your best strategy to stop wasting glycine in your urine.

I give a multi-point dietary strategy that’s focused around getting the RDA for folate primarily as food folate, but if you supplement, getting 400-600 micrograms and no more of methylfolate; getting enough protein, which if you have any ambitions around body composition, athletic performance, weight loss, means for those reasons, you’re gonna be eating above the RDA for protein, and even the RDA for protein supplies enough methionine for this system, but you may need to eat 1-2 pounds of meat to get the 3 grams of creatine you should be getting. That might not be the best idea because the extra methionine might exacerbate the wasting of glycine. Supplementing with creatine may conserve glycine. Either way, you need more glycine. At a minimum, skin and bones of the animals you eat. At a maximum, 3 servings of Vital Proteins Marine Collagen. And you need 900-1200 milligrams of choline per day to normalize your choline metabolism if you have MTHFR mutations, and that means eating 4-5 egg yolks, substituting 1 serving of liver occasionally for 2 of those egg yolks, or eating a very large volume of low-carbohydrate vegetables or other low-carbohydrate plant foods.

I also recommend an evaluative strategy that focuses on genetic analysis with StrateGene; measuring homocysteine, methionine, glycine, and sarcosine in your blood; possibly adding the HDRI methylation panel; some usefulness for plasma or serum folate; and some possible additions to that that are harder to get and harder to interpret but may be interesting for self-experimentation oriented folks or clinicians.

Alright, if you want the deets, if you want the nuance, you want the sophistication, then after these words from my sponsors, we get into the full episode.

This episode is brought to you by Ample Meal

Ample is incredible. It’s a meal-in-a-bottle that takes a total of two minutes to prepare, consume, and clean up. Two minutes. I’m not kidding. Now, I know what you’re thinking. Anything that quick just has to be made of synthetic ingredients you’d have a hard time pronouncing and wouldn’t want to put in your body. But it’s not. Ample is made entirely from natural ingredients and designed to provide an optimal balance between protein, fat, and carbohydrate, as well as all the vitamins and minerals that you’d need in a single meal.

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Here is a great example where Ample is perfect for me. In order to carve out time for creative focus, like the kind of focus that I need to make this podcast, I block-schedule all of my consultations on Mondays. That means I’m often working a 12-hour day on Monday with no longer than a 15-minute break in between sessions, and I have a need for constant brain power so I can truly help the people I’ve committed to helping. I just can’t spend time preparing meals on Mondays. Even if I prepare meals in advance that I can reheat, I don’t even have time to eat the meals or wash the dishes. Ample is the answer to my Monday problem.

It comes in two versions: 400 calorie and 600 calorie. The 600 calorie version gives me 37 grams of protein from a mix of whey and collagen, which promotes satiety and flips my brain on.

Its fat comes from coconut oil and macadamia nut oil. I like these oils because they’re low in polyunsaturated fatty acids, or PUFAs, oils that promote aging and are usually loaded into the processed foods that most people eat when they need something on the go. The coconut oil provides some medium-chain fats to keep my energy levels up too.

The carbs, the vitamins, the minerals all come exclusively from food sources, like sweet potatoes, bananas, cocoa powder, wheat and barley grass, and chlorella. It’s full of natural prebiotic fibers and probiotics to promote a healthy microbiome, and the gentle sweetness comes from a mix of honey, monk fruit, and stevia.

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As a listener to the Mastering Nutrition podcast, I’ve also worked out a special deal for you. If you use the discount code “Masterjohn” you’ll get 15% off your first order of Ample. To get your discount, go to amplemeal.com—that’s amplemeal.com—and use the code “Masterjohn” at checkout.

This episode is brought to you by US Wellness Meats.

I discovered this company at Paleofx this spring and I fell in love with them as soon as I tried their liverwurst.

For years, I’ve known that I feel best when I eat a diversity of organ meats like liver and heart. I have a clearer mind, feel more energetic, and my energy is much more stable between meals, but it’s so hard and so time consuming to make a sustainable habit out of preparing and cooking organ meats.

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12:15 Introduction of Living with MTHFR

Welcome back, everybody. In Episode 46 of Mastering Nutrition, we’re talking about living with MTHFR. MTHFR is an enzyme that is involved in the metabolism of folate, which is also known as vitamin B9, or in its synthetic form, which is added to supplements and fortified foods, also known as folic acid. And folate plays a number of roles, but MTHFR is an enzyme that enables it to play a specific role in a cellular process called methylation. We’ll get into much more detail about what methylation is soon, but suffice it to say for now, as we introduce the topic, that methylation is important for dozens of different cellular processes.

13:05 Bird’s eye view of methylation & MTHFR

And the chief among those are the synthesis of creatine, which is incredibly important for energy metabolism; the synthesis of phosphatidylcholine, which is a phospholipid that is an important constituent of our cell membranes and can also act as a precursor to the neurotransmitter acetylcholine, which, among its many roles, is important for memory, cognitive performance, and our ability to contract our muscles.

Methylation is also very important for the regulation of gene expression and in that way can contribute to the regulation of many, many, many genes. Virtually all of our genes have some degree of control through methylation. It also plays an incredibly important role in regulating dopamine, something that I explored in great detail in Episode 43 in discussing how methylation is important to regulating the balance between mental stability and mental flexibility, or fluidity. If you want more on that, go to Episode 43 at chrismasterjohnphd.com/43.

14:25 How to know if you have MTHFR

Now, the title of this episode is “Living with MTHFR.” Well, we are all living with MTHFR. It’s an essential enzyme. But when someone says, “I have MTHFR,” what they mean is that they have a mutation that decreases the enzyme’s activity, and that means that they have a potential problem with MTHFR because their MTHFR enzyme is less effective.

There are at least 14 very, very rare mutations that just obliterate MTHFR activity, and these are rare, severe disorders. But most of the time, what we’re talking about are two common mutations, or polymorphisms, that decrease the activity partially. These are the C677T mutation and the A1298C mutation. Out of the two of these, the C677T mutation more strongly decreases the activity of the enzyme. Consequentially, most of the research has focused on C677T and left A1298C behind. But they’re essentially similar in their effects, and A1298C is just a weaker effect than C677T.

You inherit your genes from your mother and your father, and so we all have two copies of the MTHFR gene. That allows us to either have zero mutations, in which case we would be wild type, or we would have the ancestral allele—the allele is a variant of a gene—or we could be homozygous for one of the mutations, which means that we got the same mutation from our mother and our father, or we could be heterozygous for the mutation, which means we got the mutation from our mother but not our father or from our father but not our mother, or we could be compound heterozygous. That would mean that we were heterozygous for one and the other. For example, we could have C677T inherited from our mother and A1298C from our father or vice versa. And so this allows a diversity of genotypes that each have their own average effect on how low they make the the enzyme activity.

17:00 Prevalence (these are really common)

Now, these mutations are actually really common. One way to look at this would be with data from the HapMap project, which is a project that looks at genetic variation in different ethnic populations.

If we look at the HapMap project for C677T, we see that the proportion of people who do not have the mutation is highest among Nigerians at 78%. That still leaves 22% of Nigerians who have it. Among people with European ancestry, this falls to 59%, but that means 41% have it. Among Japanese, 40% do not have the mutation at all. That means 60% have it. The number of people who do not have the mutation at all drops even lower to 29% among Taiwanese or 27% among Chinese, meaning over two-thirds of those populations have at least one T allele, meaning they’re at least heterozygous for the C677T mutation.

For A1298C, the numbers make it look similarly common. So 78% of Nigerians again don’t have any A1298C mutations, but that leaves 22% who do. Sixty-seven percent of Japanese and 64% of Chinese don’t have the mutation. That leaves about one-third of those populations who do. Forty-two percent of Europeans don’t have the mutation. That leaves 58% who do. Twenty-eight percent of Taiwanese don’t have the mutation. That leaves over two-thirds of that population who do.

Now on the other hand, when you look at homozygotes, they’re not the largest pool. So that pool is largest among the Chinese for C667T at 29%, but it’s only 7% among Europeans. Most of the people who have at least one mutation are heterozygous.

So I want to now look at some data from a Dutch study—and I’ll post these papers in the show notes—but in the Dutch study, they split the population according to who had C677T and/or A1298C. And when we look at it this way, only 15% of the population didn’t have one or the other. That means that 85% of the population had at least one or the other. Forty-nine percent had at least one C677T mutation, 54% had at least one A1298C mutation, and 38% were either compound heterozygous or homozygous for one or the other mutation. And it’s those homozygous or compound heterozygous genotypes that produce the strongest reduction in enzymatic activity.

20:30 This is not a genetic disease: this is a variation in metabolism

So I think it should be clear from reviewing the frequencies of these mutations that this is not a genetic disease. This is a variation in metabolism. With that said, we can appreciate the potential implications of having this variation by looking at some of the diseases that it’s associated with. And unfortunately, we just don’t know anywhere near as much about A1298C as we do C677T. It’s the stronger mutation, so it’s the more studied one.

21:10 Health Associations

But if we look at the diseases that these are associated with, there’s an enormous wealth of data looking at cardiovascular disease; psoriasis; infertility; pregnancy loss and pre-eclampsia; birth defects, like Down syndrome and spina bifida; the risk of all psychiatric diseases combined; and specific neurological or psychiatric diseases, such as Parkinson’s, Alzheimer’s, migraines, and schizophrenia; diabetes; a variety of cancers.

There’s an enormous wealth of data around this that doesn’t all agree. There are meta-analyses of the many studies. There are conflicts in the data. That’s not very surprising, because MTHFR is an enzyme in the metabolic pathways of folate. This is the exact sort of thing where you would expect to see a huge effect of diet on the manifestation of that genetic polymorphism because it’s not a defect in a gene that results in a specific disease. It is a variation in your ability to support the process of methylation, which underlies dozens of other process with a nutrient, folate. So of course your nutritional status is going to impact the associations between the genes and these various diseases.

23:00 Mechanisms of what MTHFR does

So although MTHFR is not a disease, we can look at what it does and how this system functions to try to understand how you should modify your nutrition in order to leverage your strengths and compensate for your weaknesses in the methylation pathway. So, here’s what MTHFR does.

It catalyzes the last step in the construction of a methyl group on the molecule of folate. A methyl group is a chemistry term that simply refers to a single carbon atom. And because of that, the whole methylation pathway is often referred to as one-carbon metabolism.

With that said, it’s not just a carbon atom. It’s a carbon atom that is saturated with hydrogens. And in most of the molecules that make up our entire biology, we have hydrocarbons where there’s a carbon chain and almost every position in that carbon chain has hydrogens in place, unless there’s something else there that plays a specific role. Carbon has the ability to bind to four other things. So if one carbon is joined to the rest of the molecule, it would be bound to another carbon of that molecule with one of the binding sites. And if it’s a methyl group, the other three binding sites of that carbon are saturated with hydrogens. So a methyl group is -CH3.

That methyl group is constructed in several steps. The carbon and its first hydrogen come either from serine or from glycine, which are two amino acids. Then there are successive steps where the second and third hydrogens are added along with electrons that act as the glue to hold them together to the molecule. And those two hydrogens and two electrons come from glucose in the pentose phosphate pathway and are carried by NADPH, which is an energy carrier derived from niacin, or vitamin B3.

MTHFR is adding that third hydrogen. And so it is the final step in constructing the methyl group. Once you’ve constructed that methyl group, you have made 5-methyltetrahydrofolate, or 5-methyl-THF. And for the purposes of simplicity, I’m just going to refer to this from now on as methylfolate.

So once folate has the methyl group, it then passes it to vitamin B12. And then vitamin B12 passes it to homocysteine. Homocysteine then becomes methionine, and methionine, with the help of magnesium and ATP, gets activated to S-Adenosylmethionine. S-Adenosylmethionine is sometimes abbreviated AdoMet. It’s sometimes abbreviated SAM, and it’s sometimes abbreviated SAMe. People who are in the supplement world tend to call it SAMe, and so I’ll use that for the rest of this podcast.

You can buy SAMe as a supplement. You can eat methionine in the diet. In fact, we all eat methionine in the diet. So we don’t necessarily have to start with homocysteine. We could just eat the methionine from protein. Or we could take the SAMe as a supplement.

Either way, what then happens is that methyl group gets donated to one of dozens of different methyl acceptors using specific enzymes called methyltransferases. And in mammals, there are over 150 identified methyltransferases. I don’t know what the exact number is in humans. It’s probably smaller than that. And some of these methyltransferases could be adding the methyl groups to a wide variety of acceptors. For example, we regulate gene expression with DNA methyltransferase, but the DNA methyltransferase, or DNMT, can methylate many, many genes. So that one enzyme is doing a whole host of things.

On the other hand, quantitatively about 40-45% of methylation is used to make creatine, and another 40-45% is used to make phosphatidylcholine, and the DNA methylation and all the other dozens of methyl acceptors constitute some bit of this last 10 or 15, maybe 20% of methylation. So if you have a genetic polymorphism that decreases your ability to make methylfolate, then you’re decreasing the ability to methylate vitamin B12, you’re decreasing the ability to pass that methyl group on to homocysteine to make methionine, and to engage in all those methylation reactions.

It doesn’t have to be a polymorphism. The same thing would happen if you were deficient in folate. And in fact, there are many nutrients that are needed to make that methyl group besides simply having the folate and simply having high MTHFR activity. Just in MTHFR itself, the MTHFR is using NADPH, and that comes from niacin, or vitamin B3. Part of the MTHFR molecule is riboflavin, or vitamin B2. Even just to get up to the precursor of methylfolate, the substrate for MTHFR—which by the way, it’s full name is 5,10-methylenetetrahydrofolate reductase.

So to get 5,10-methylenetetrahydrofolate, which is what MTHFR is making the methylfolate from, we need vitamin B6. We need that because it’s important for the interconversion of glycine and serine, and depending on which pathway we’re using, one of those two is going to be donating the carbon. It’s dependent on ATP and magnesium for the energy to invest in constructing the precursors. And it’s dependent on thiamin, or vitamin B1, because thiamin is critical to the pentose phosphate pathway, which is where niacin in the form of NADPH takes the hydrogen ions and electrons from the glucose molecule so that it can bring them over to the folate molecule so MTHFR can construct the methyl group of methylfolate.

For the purposes of this discussion, which is gonna focus around how do you nutritionally handle MTHFR, I’m going to assume nutritional adequacy in all of these things. So you could be magnesium-deficient. That would change the equation. You could be hypothyroid, and your ATP production could be crashed. That changes the equation. You could be thiamin-deficient. That would change the equation. This discussion is going to assume that all these other things are adequate and is gonna ask the question what then should we do differently if we have a polymorphism in MTHFR.

31:35 Methylation system as a whole (methyltransferases)

And to really understand the practical take-home points of what to do requires us to understand the biochemistry of this system in more detail. Don’t worry, it doesn’t require us to understand it in complete detail. But it requires us to understand it in more detail than we’ve done so far. So let’s take a deeper look at that system.

In addition to using MTHFR for methylfolate, we have a second system, where we use something called betaine. Betaine can be eaten in the diet in spinach, wheat, and beets. Some may crucify me for that statement because I included wheat. But don’t kill the messenger. Spinach, wheat, and beets are major sources of betaine. It’s also called trimethylglycine and can be obtained as a supplement.

In our bodies, we primarily get betaine from choline because we have an enzyme called choline dehydrogenase that oxidizes choline to form betaine. Betaine then with an enzyme betaine-homocysteine methyltransferase, or BHMT, will convert homocysteine to methionine. Once you have methionine, then everything is happening the same as we said before.

So MTHFR is generating methylfolate so that the enzyme methionine synthase can take the methyl group from folate, pass it along to B12, and pass it along to homocysteine to generate methionine. Choline and betaine are supporting BHMT, a totally different enzyme that completely bypasses MTHFR and does the same thing.

When we have an excess of methyl groups coming in, we have a buffer system to get rid of the extra. That buffer is the amino acid glycine. Glycine soaks up methyl groups from SAMe and, itself, becomes sarcosine. In doing so, it acts just as any other methyl acceptor would. And because it took a methyl group from SAMe, it generates homocysteine. More specifically, it generates S-Adenosylhomocysteine, or SAH, and then the adenosyl group that came from ATP with the help of magnesium is then hydrolyzed off to generate homocysteine.

So the glycine buffer system is not doing anything to buffer the accumulation of homocysteine. What it’s doing is it’s buffering the excess of methyl groups so that you don’t methylate things that you’re not supposed to. That sarcosine can go into the mitochondrion—all this stuff is happening in the cytosol, the main fluid of the cell. That sarcosine can go into the mitochondrion, and it can regenerate glycine. However, it can also spill out of the cell, and it can spill into the urine. So although you’re not getting a one-to-one loss of glycine every time you use this buffer system, you’re losing some of the glycine. I don’t know how much, but you’re losing some of the glycine as sarcosine that is essentially peed out into your urine.

That buffer system is catalyzed by the enzyme glycine N-methyltransferase, or GNMT. When you have this excess of methyl groups and you’ve used GNMT and now you have homocysteine, you now wind up with an excess of homocysteine. So what you do with it is you use the enzyme cystathionine beta-synthase to make cystathionine. And you do that with the help of serine, which you can consume in the diet or you can interconvert from glycine.

And once you have cystathionine, you cleave it using cystathionine gamma-lyase to alpha-ketobutyrate and to cysteine. Cysteine is an amino acid whose principle use in this case would be to make glutathione, the master antioxidant of the cell, a key detoxifier, an incredibly important protector against asthma, a regulator of many, many hundreds of proteins, something I’ve talked about a lot in the past. And if you’ve met your needs for glutathione, the cysteine spills over into taurine and sulfate. Taurine and sulfate both play essential roles in the body, but they can also be viewed as waste products, so if you have a lot of this stuff, the taurine and sulfate is eventually gonna get spilled over into the urine and leave the body.

36:50 How the system is regulated

So that’s the basics of the system. We also need to talk about how the system is regulated. And it’s regulated primarily by a tiny handful of players that will activate or inhibit the enzymes. These players are S-Adenosylmethionine, or SAMe, S-Adenosylhomocysteine, or SAH, and methylfolate. In other words, all this regulation is happening through regulation by the metabolites in the pathway itself that provide really rapid real-time feedback about the flux of things through that pathway.

When S-Adenosylmethionine, or SAMe, accumulates beyond the amount that you need, it does three primary things. One is that it activates the enzyme cystathionine beta-synthase, or CBS. That primes the homocysteine that’s generated from that SAMe to be funneled out of the methylation pathway into the production of cysteine, and that’s called the transsulfuration pathway.

The second thing it does is it inhibits its own production. Well, what are the enzymes that produce SAMe? The two enzymes that it’s going to inhibit are MTHFR and BHMT. Why? Because MTHFR is generating the methylfolate that then donates the methyl group through methionine synthase with the help of vitamin B12 to convert homocysteine into methionine. And BHMT does the same exact thing but uses betaine mostly which came from choline. And so in that way, when you have too much SAMe, the SAMe level goes back down because you get rid of the excess in transsulfuration to form cysteine and you stop the accumulation of methyl groups into that pathway.

But here’s the real kicker that has huge implications for how we should see MTHFR. The accumulation of methylfolate is a reflection of the SAMe level because if there’s too much SAMe, SAMe shuts down MTHFR and thereby shuts down the accumulation of methylfolate. So when you have too much SAMe, you get less methylfolate.

Why is that important? Because methylfolate is the off switch for the glycine buffer system. GNMT, the enzyme that uses glycine to mop up extra methyl groups and make sarcosine, is maximally active when there is no methylfolate bound to it. When one molecule of methylfolate binds to GNMT, it decreases its activity by 50%. When two molecules of methylfolate bind to GNMT, it decreases its activity to 0%. So one molecule of methylfolate is a half off switch. Two molecules are a total off switch.

So you can imagine that there’s a pool of methylfolate and there’s a pool of GNMT, and through random interactions simply by moving around, there’s some probability that they will run into each other that increases the more methylfolate there is. And if that probability increases, you go through several stages where when there’s low methylfolate concentrations, you’re unlikely to have any of the GNMT bound, but then as you increase, you’re likely for some of the GNMT to be bound by one methylfolate molecule. And then as you get even more methylfolate, that probability increases further, and eventually, you start to get a meaningful probability that two GNMT molecules will be bound by methylfolate. And then as the methylfolate concentration increases even further, eventually you get a lot of GNMT that’s bound by two methylfolate molecules.

And so you get this linear shutdown of the glycine buffer system in proportion to accumulating methylfolate. Why? Because the accumulation of methylfolate is the signature of not having enough SAMe. Because if you don’t have enough SAMe, you don’t have SAMe shutting down MTHFR, so you do get lots of methylfolate production and you do shut down the glycine buffer system because you don’t want it active when you don’t have enough SAMe.

If you have too much SAMe, then you shut down MTHFR. Methylfolate levels decline. The inhibition of GNMT declines. GNMT becomes very active. The glycine buffer system is then activated, and that extra SAMe gets its methyl groups added to glycine to make sarcosine meanwhile generating homocysteine, with the homocysteine being shunted down the transsulfuration pathway because the SAMe itself has activated CBS.

The reason that this is so massively important to understand when thinking about MTHFR is that in MTHFR, your problem is that you can’t get enough methylfolate. That methylfolate is the off switch for the glycine buffer system. So you may think that you just—because you have MTHFR mutations, you may think that you just don’t have enough methylation. But then you add in methyl groups. Say you take a SAMe supplement. Then what you do is you just waste more glycine because you don’t have the methylfolate as the off switch for the glycine buffer system. You just add more SAMe, you’re just gonna add it all to glycine and pee it out as sarcosine.

Meanwhile, it wasn’t that big of a deal that you didn’t have enough methylfolate for methylation, because you can use your choline and betaine for that purpose. So your real problem is you need to figure out a way to shut down the glycine buffering system because you’re probably running low in glycine.

In addition to the methylfolate as an off switch and the effects of SAMe itself on CBS, MTHFR, and BHMT, there is also an inhibition by S-Adenosylhomocysteine, the product of the methylation reactions, on virtually all of the methyltransferases. That does two things. First of all, it inhibits its own production, and so that mitigates the accumulation of homocysteine that you would have if you had too many methyl groups coming in.

It also helps stabilize the activities of enzymes to changes in the pool of SAMe, because when an enzyme, a methyltransferase uses SAMe, it generates SAH, or S-Adenosylhomocysteine. And so if there’s way too much SAMe coming in and that enzyme winds up generating lots of homocysteine, that homocysteine acts as a negative feedback loop on that enzyme, and so that can make an enzyme not erratically change the amount of methylation when the level of SAMe is going up and down, because more SAMe allows you to engage in that methylation reaction more, but then you generate more S-Adenosylhomocysteine in the process that then feeds back to ramp that level of that enzyme activity back down to normal.

Now, with these basics of the regulation in common, we can also say that there are different levels of priority over what will be methylated because of the relative affinities of the methyltransferases and how much of those enzymes there are and the relative degree to which they’re inhibited by S-Adenosylhomocysteine.

So, almost all of the methyltransferases have really high affinity for SAMe. What that means is that even at really low SAMe concentrations, they’ll continue to have more or less the same activity. DNA methyltransferase, the regulator of gene expression falls into that category. In most cases, MTHFR or a deficiency of methyl groups coming in because of a folate deficiency or a B12 deficiency, in most cases, the DNA methylation rate is gonna remain relatively stable because the enzymes have such a high affinity for SAMe that they’re saturated at relatively low concentrations of SAMe well below what’s usually present in the cell. So you have to be really deficient to have a major impact on DNA methylation. And if there’s an abundance of SAMe, you just saturate that enzyme.

What that means is that you control DNA methylation not mainly through controlling the supply of methyl groups but mainly by controlling, number one, how much DNA methyltransferase you have, and then number two, what are you doing to regulate the structure of that genetic information at the level of the DNA? Is it unwinding? Is it winding up? Are there things coming along to help the methylation process or not? You’re regulating the expression of specific genes in very specific ways by controlling all of those things, not by, oh, I just ate a steak and now I have lots of SAMe coming in from the methionine and now I’m gonna methylate twice as much DNA. That doesn’t happen.

It’s the enzymes with really low affinity that are theoretically most vulnerable to fluxes in the methionine pool or the SAMe pool. And these are GNMT, glycine N-methyltransferase, the glycine buffer system; guanidinoacetic acid, or guanidinoacetate methyltransferase, which is the enzyme that synthesizes creatine. Creatine is—this is the final step in creatine synthesis. When you synthesize creatine, you take arginine and glycine, two amino acids, and you make guanidinoacetate. And then you methylate the guanidinoacetate to get creatine. Creatine is then super important for energy metabolism, especially in skeletal muscle, quite a bit in the brain, and to some degree basically everywhere.

And then the third enzyme that has low affinity is PEMT, phosphatidylethanolamine methyltransferase. And PEMT is synthesizing phosphatidylcholine from phosphatidylethanolamine, another phospholipid. Based on the fact that these three enzymes have low affinity for S-Adenosylmethionine, you would predict that these are the three enzymes that are highly variable with the flux of methyl groups, in other words, that are highly sensitive to how many methyl groups you have, because you have to have a lot of methyl groups in order for them to be active. That’s what we mean by low affinity.

However, PEMT is an exception here. And that’s because PEMT is extremely strongly inhibited by S-Adenosylhomocysteine. When you produce phosphatidylcholine from phosphatidylethanolamine, you have to methylate phosphatidylethanolamine three times, and you generate three molecules of homocysteine for every molecule of phosphatidylcholine you make.

That right there shows you why you can’t synthesize choline in that pathway to support your methylation system. Imagine you take the phosphatidylcholine, then you break it down to choline, then you make betaine out of it. And then betaine comes over and donates one methyl group. And so you consumed three methyl groups for every one that you donated. You made three homocysteine for every one that you recycled. That’s not the purpose of PEMT, clearly.

Now, perhaps PEMT is so strongly inhibited by S-Adenosylhomocysteine because it generates so much S-Adenosylhomocysteine. My suspicion is that it is playing a more fundamental physiological role that’s not really supposed to change. One thing we know is that PEMT generally accounts for about 30% of how much phosphatidylcholine you’re making. The other pathway is called the CDP-choline pathway, and that’s where you take choline from the diet or from the breakdown of acetylcholine or phosphatidylcholine. You take free choline and you synthesize phosphatidylcholine without the use of methylation. That’s 70% of phosphatidylcholine synthesis.

Phosphatidylethanolamine methyltransferase, PEMT, makes phosphatidylcholine molecules that are highly enriched in DHA. And the phosphatidylcholine molecules that are derived from the CDP-choline pathway are not highly enriched in DHA. So I suspect that PEMT is designed to stay pretty much constant because it’s a means of getting DHA-enriched phosphatidylcholine phospholipids. In other words, it’s a means of getting DHA into the cell membrane. So actually, you would think that you would synthesize less choline in that pathway when you ate a lot of choline, and that’s not true. PEMT just stays very stable no matter what happens.

So what that means is that out of these three, there are two methyltransferases that are very sensitive to the methionine or SAMe flux. And that’s guanidinoacetate methyltransferase, creatine synthesis, and glycine N-methyltransferase, the glycine buffer system.

Out of these two, GNMT, the glycine buffer system, is exquisitely sensitive to the SAMe flux because not only does it have low affinity for S-Adenosylmethionine and thus become more active when you get SAMe into the higher ranges, but you augment that with this powerful regulation by the methylfolate levels that act as the off switch that correlate inversely with the SAMe pool.

So GNMT is the thing that is going to be really low when you have normal physiologically low levels of SAMe and be really high when you have normal physiologically high levels of SAMe. So if you have moderate changes because of, for example MTHFR, you’re gonna hit GNMT hard. You’re gonna really affect the glycine buffer system.

GAMT, guanidinoacetate methyltransferase, creatine synthesis, is not going to be as sensitive as GNMT, because you don’t have this incredible augmentation of the low affinity with the regulation by methylfolate, but you still have this low affinity for S-Adenosylmethionine that makes it so that when you have relatively low levels of SAMe, you don’t get a lot of creatine synthesis, and when you have relatively high levels, you get a lot of creatine synthesis.

My suspicion is that this is largely designed around the idea that you do need creatine in your muscles, but you store creatine in your muscles, or in your brain, or elsewhere in your tissues as well. But 90% of the creatine in the body is in your skeletal muscle. And you need to have it there, but you don’t need to be always making it.

By contrast, you have many cellular processes that are the routine minute-to-minute, second-to-second, hour-to-hour regulatory processes—DNA methylation, all these other things—that you do need to have fine-tuned. And so creatine synthesis says, “Hey, like it’s been four hours since your last steak? I don’t need to be that active right now. DNA methylation, you take over for a bit.” Then when you get the steak, you say, “Aha, now we have the excess pool of methyl groups, let’s saturate our creatine synthesis as much as we can,” and then whatever is left over gets buffered, gets added to glycine, generates homocysteine that goes through transsulfuration.

So the huge things that you want to be thinking about with MTHFR, the two really, really, really big things are the glycine buffer system and creatine synthesis.

56:05 Two Addenda: COMT and Agouti Mouse Study

Now, there are two addenda that I think are worth talking about here. So first of all, in Episode 43 I talked a lot about COMT, catechol O-methyltransferase, which is metabolizing many things, but chief among them, dopamine. If you look at the affinity of COMT for SAMe, it’s intermediate between DNMT and GNMT. In other words, DNA methyltransferase, DNA methylation, regulation of gene expression, is extremely insensitive to the SAMe pool. The glycine buffer system is extremely sensitive to the SAMe pool. COMT is intermediate.

If you have tiny fluctuations in the methyl flux, I don’t think you’re gonna have a big impact on COMT. But I think if you have a big decline in your MTHFR activity genetically or you have folate deficiency or you have a B12 deficiency or a choline deficiency, you have any of these things that are having pretty big impacts nutritionally or genetically, then that will play out for COMT. And thus, the basis for all of Episode 43.

The second addenda point I want to make is about the famous Agouti mouse study. This study got a lot of press and was very widely circulated in the nutritional world. It came out in 1998, and what they did was there are mice with the pseudoagouti gene, which are lean and healthy and longer-lived than their siblings. And there’s a difference in coat color where their siblings are yellow, but they’re also obese, hyperinsulinemic, more susceptible to cancer, shorter-lived. And the mice with the pseudoagouti gene develop black modeling in their coat and also health effects.

And so this famous paper showed that you could dietarily impact the DNA methylation of that gene and push the mice in the direction of the pseudoagouti phenotype and then have this inherited through other generations because of the DNA methylation effect of those methyl groups. And that seems to contradict what I was saying before, that DNA methylation is not very sensitive to the methyl group supply.

Well, it’s all about whether you’re acting within the homeostatic system or you’re providing pharmacological doses that push you out of the homeostatic system. In that study, they gave the mice 9 times the amount of choline that they need, 9 times the amount of folic acid that they need, 60 times the vitamin B12 that they need, 3.1 times as much methionine, and 4.7 times as much zinc.

So yes, if you’re very deficient, you’ll get serious DNA methylation consequences, and if you provoke massive shifts out of the homeostatic system with pharmacological doses of the nutrients, you will impact DNA methylation. But if you’re operating in the range of a 50% decrease or a doubling of the increase of the methyl groups coming in, you are unlikely to get more than a minor impact on DNA methylation.

01:00:10 Mechanistic impact of polymorphisms (% down in enzyme activity)

So now let’s turn our attention to how polymorphisms in the MTHFR gene would impact this system, and that will allow us to consider what we should do about it. So let’s start off by looking at what is the change in activity of MTHFR that you get when you have these polymorphisms.

If you’re heterozygous for A1298C and you don’t have any C677T mutation, you have a 17% decrease in MTHFR activity. If you’re homozygous, you have a 39% decrease. Granted, these are averages taken from a study, and it’s 17% give or take, 39% give or take. But it gives you a general idea of the magnitude of the effect.

The C677T mutation is stronger than the A1298C mutation. For heterozygous, you have a 33% decrease instead of a 17% decrease. For homozygous, you have a 75% decrease instead of a 39% decrease. So to be homozygous for A1298C is only slightly worse than to be heterozygous for C677T. If you are compound heterozygous, meaning you have one A1298C mutation and one C677T mutation, you have a 53%, on average, give or take, decrease of MTHFR activity. You cut it a little bit more than in half.

So these are pretty big effects on enzyme activity, and they’re driven by the enzyme starting to degrade at temperatures that are close to body temperature. And so the enzyme is produced, but it just isn’t very stable at body temperature, and the enzyme activity decreases.

So there are two points to draw here. Number one, most of the research has focused on homozygotes for C677T because this 75% average decrease in enzyme activity produces the strongest effect. And people point out that, hey, homocysteine levels are higher in C677T homozygotes but not in the others. Some people come back and say, “Yeah, but if you’re compound heterozygous, you see the increase in homocysteine.” Well, that’s one thing.

But another way to look at this is this is a continuum. There’s no categorical difference between someone who’s homozygous for C677T and someone who’s heterozygous for A1298C. The effect is 4-5 times greater, but it’s not categorical. It’s continuous. And then you have to consider, well, the average homocysteine might not be different in one group versus another, but that doesn’t mean that one of those people doesn’t have higher homocysteine, or some of those people. And it doesn’t mean that those people if put on a really good diet versus a really bad diet aren’t gonna see that effect come to life.

So I would look at this as, you want to bias your diet towards what will capitalize on your strengths and compensate for your weaknesses around MTHFR if you have any of these mutations. And you want to be stricter about it. You want to be more careful about watching your blood levels and your symptoms the more you go towards the C677T homozygous phenotype.

So if you’re A1298C heterozygous, you probably don’t need to be worried about it that much, but you should probably check your homocysteine and a few other things, probably eat towards the way that I’m gonna describe here. Versus, if you’re C677T homozygous, you need to really keep your eye on it, and you probably need to be pretty careful about how you design your diet in order to make sure that you’re maximizing your ability to work with what you got.

01:04:45 It’s not all about 5-methyl folate

So, before we get into the dietary strategy itself, let’s talk about why this is not, not, not, not, not, not, not, not all about getting methylfolate. Here are five reasons it’s not all about methylfolate.

Reason number one. You can’t restore the normal flux of methylfolate through this pathway no matter how much methylfolate you eat. Let’s think through a few facts. The RDA for folate is 400-600 micrograms depending on your sex and life stage, and that assumes that you’re going to absorb 200-300 micrograms of food folate.

01:05:35 You can restore normal flux

If you calculate the flux of methyl groups through this pathway, we can do a little back-of-the-envelope calculation, not incredibly precise but pretty right on in terms of magnitude, that each molecule of folate you consume is recycled 18,000 times per day. If you consume a molecule of methylfolate, the methyl group on that folate is available once, and then it has to be recycled 17,999 times. Where does that recycling come from? The carbons come from serine or glycine, but the part that MTHFR is catalyzing, the part that’s defective in someone with an MTHFR mutation, they’re coming from glucose, from the pentose phosphate pathway.

One glucose molecule, if you’re burning it for energy, supplies enough NADPH to recycle one molecule of folate one time. You can operate the pentose phosphate pathway as a closed circuit if you’re not burning the glucose for energy, and you lose one carbon each time you go through it, but you keep interconverting the sugars and just run round and round and round and round and round. If you are operating it that way because you’re not burning glucose for energy, 1 glucose molecule can recycle 6 molecules of folate, or recycle 1 molecule of folate 6 times.

So you’re gonna need 3,000-6,000 molecules of glucose for every molecule of folate to get your daily methyl flux out of it. That’s a trivial amount of glucose. We’re talking 30-180 milligrams, and you consume grams of glucose per day. Utterly trivial.

But if you wanted to make up for that process by adding individual methyl groups from individual molecules of methylfolate that you got out of a capsule, in order to make up for that process, you would have to consume an incomprehensible amount of folate: 4.5 grams of folate. You would have to consume 18,000 times the RDA of folate.

I have no idea what happens to folate when you consume 18,000 times the RDA for it. I just don’t know. My guess is a lot of it winds up in your poop. But I do know that I would never advise anyone to eat 4.5 grams of folate and that if anyone thinks that by eating super high doses of folate, like several milligrams, that they’re getting anywhere near inching their way towards making up for the normal flux of methyl groups through that pathway, that’s delusional.

01:08:45 Compensate with choline

Reason number two that this is not all about 5-methylfolate, and this reason is about choline. So normally, you get your methyl groups when you’re recycling homocysteine to methionine about 50% from folate and 50% from betaine and choline. If you deprive someone of methionine and choline and all the other sources of incoming methyl groups, you can push that up to 100% derivation of methyl groups from folate. You can likewise push it down if your MTHFR activity declines, and you ramp up the use of betaine.

So your real problem here is not so much that you don’t have methylfolate. That is a problem when it comes to the off switch on the glycine buffering system, which we’ll talk about shortly, but in terms of having methylfolate, it is not the case that you can’t methylate if you have less methylfolate. That’s not the case at all, because you can get those methyl groups from betaine in the exact same process of regenerating homocysteine to methionine, but derived not from folate, not from B12, instead from choline or dietary betaine or supplemental trimethylglycine.

In people with MTHFR variations, what happens is that the use of betaine is increased. Now, exactly what happens to the choline depends on what study you look at, and it’s not that well-characterized. But it is clear that you use more of the betaine pathway.

There’s a study in women that showed that when they have MTHFR polymorphisms, they are using the betaine pathway more. But surprisingly and counterintuitively, they are also taking choline and they’re shuttling it in through the CDP-choline pathway to make phosphatidylcholine.

The reason that this is counterintuitive is that you would think that if they’re depending more on betaine, they would be trying to free choline for the choline dehydrogenase reaction to make more betaine, and they’re essentially doing the opposite. I don’t know why that is, but my suspicion is that it’s probably a way to protect the choline supply to make sure you don’t run deficient in the phosphatidylcholine that you need for your cell membranes.

One of the reasons that—or one of the pieces of evidence that would support that is that when those women are given double the RDA for choline, that choline partitioning normalizes, so it gets rid of the shuttling of choline into phosphatidylcholine synthesis. And that seems consistent with the idea that the cell is saying, “Ah, I’m relaxed now. I’m relieved. I’m not worried that I’m gonna run out of phosphatidylcholine.”

And the reason that that seems really significant to me is if you’re trying to minimize your free choline so that it doesn’t all get used for those reactions, you could potentially run deficient in acetylcholine, and that would affect your learning and your memory and your cognitive performance and your muscular function. It’s a speculative concern, but it’s a real one.

There’s another study in Mexican-American men showing that the choline dehydrogenase reaction is increased and that they are oxidizing more choline to betaine. That suggests a different type of choline partitioning, but it suggests that when you have the MTHFR polymorphism, you’re depleting yourself of choline.

Whichever study you look at, it implies that there’s a major increase in your need for choline when you have the MTHFR polymorphism. And in fact, there was a study showing that there’s DNA damage in people with the MTHFR polymorphisms that is abolished when you double the RDA for choline.

01:13:26 Creatine

Reason number three is about creatine. Remember that when we talked about the system, we said that there are three enzymes that have low affinities for S-Adenosylmethionine that we would expect to be very sensitive to the SAMe pool. But we ruled out PEMT because its inhibition by SAH makes it very stable. The two that were left over were GNMT, the glycine buffer system, which we’ll get to next, and GAMT, creatine synthesis.

Out of the essential reactions, the synthetic reactions—remember glycine is just a buffer system to get rid of extra methyl groups—out of the essential synthetic, or regulatory, reactions, the only one that is highly sensitive to the SAMe pool is creatine synthesis. And creatine synthesis constitutes 40-45% of the demand for methyl flux through this pathway. PEMT is another 40-45%, but it is very stable. So the only thing that’s sensitive to the SAMe flux and constitutes a huge chunk of it is creatine synthesis.

So that means two things. Number one is if you have MTHFR polymorphisms, you’re probably kind of bad at synthesizing creatine, and you need to eat more in the diet. That’ll factor into our dietary strategy. The other thing is you could probably consume your entire essential need for creatine in your diet or with supplements, and you could probably thereby cut your demand for methylation in half. If you suck at methylation, why wouldn’t you want to cut the amount you need in half?

01:15:30 Glycine Buffer

Reason number four is the glycine buffer system. 5-methylfolate is the off switch for the glycine buffer system. That means that if you have more SAMe coming in, rather than getting more methylation out of it if maybe that’s what you need or want, you waste more of it and you waste your glycine because you’re not shutting off the glycine buffer system when you’re supposed to.

And so that means two things. Number one is you probably run low in glycine. Number two is part of your dietary strategy should be to conserve methylfolate so that the methylfolate you do get doesn’t need to be utilized as much, and that might be your only hope for shutting off the glycine buffer system. So that will factor into the dietary strategy.

01:16:42 Why upping Methionine and SAMe is bad idea

Reason number five is a bonus reason. It doesn’t really fit into the category of five reasons that this is not all about methylfolate. I wanted five reasons because if I gave you four, I thought that would be an ugly number, and I felt that I needed five. Nevertheless, this is a good segue.

So, reason number five that it’s not all about methylfolate is why it’s also all not about methionine and SAMe. And reason number five is why it’s a bad idea to correct your MTHFR by adding SAMe into the system, at least if you’re not paying close attention to these other factors. And that is that—what we just said. If you’re missing 5-methylfolate and your glycine buffer system is on when it should be off, adding SAMe as a supplement or eating three times as much methionine so you don’t need as much recycling from folate could aggravate your glycine loss.

So yes, maybe it’s better to have the methyl groups, but it’s coming at the expense of potentially wasting glycine. And my suspicion is that the more you waste the glycine, the more sarcosine you generate, the less likely you are to shuttle the sarcosine back into the mitochondrion and regenerate glycine from it, because if you overwhelm that system, my suspicion is that’s when you cross some threshold where you’re mostly spilling it into your urine.

So adding SAMe might mainly be a—and by the way, what methyltransferase got that SAMe? Glycine N-methyltransferase. So did you get more COMT activity out of it? Did you get more creatine synthesis out of it? Did you get more DNA methylation? Probably not. Maybe a little. But mainly you spent lots of money on a SAMe supplement that mostly wound up in your pee because you’re not controlling your glycine buffer system. So, let’s then move onto a dietary strategy.

01:19:00 Dietary Strategy – Basic Objectives

My basic overall objectives with a dietary strategy are as follows. Number one, we want to conserve methylfolate. We can’t generate a lot of it, so it would be better not to spend what we don’t need to. I don’t know how well we can do this, but to whatever extent we can keep methylfolate present as an off switch for the glycine buffer system, we want to try to do that.

Number two, we want to compensate for the use of choline by supplying enough choline that we both can compensate for MTHFR by getting the same methylation flux through the alternative pathway and not run low in choline so we have all the choline we need for acetylcholine and we have all the choline we need for phosphatidylcholine.

Objective number three is to make sure we compensate for creatine synthesis. And objective number three ties back into objective number one because I believe that supplying creatine is not only the way that you compensate for whatever decrease in creatine synthesis that you have, but that if you go over and above that, you can actually shut down half of your need for this system. And I believe that doing that is probably the best chance you have to conserve your methylfolate so that you can get its power as an off switch for the glycine buffer system.

The fourth objective is to maintain adequate glycine levels. We want glycine there as the methyl buffer when it’s supposed to be there, but our real problem with MTHFR is that we’re aberrantly methylating the glycine and possibly losing a lot of it. We don’t want to lose glycine, because glycine does other things that are great. Glycine helps regulate inflammation. Glycine might help you sleep better. Glycine is needed for your tissue repair, especially your connective tissues. It’s especially good for your skin and your bones. It’s even conceivable that if you deplete your glycine enough, you’re not gonna be able to use the glycine buffer system anymore, because you don’t have enough glycine to do it.

And you may think that because you’re MTHFR, that means you’re a low methylator. But that’s not true if you’re MTHFR and the combination of those genes with your nutrition has made you really depleted in glycine so that you lose the capacity of that buffer system, then maybe you’re overmethylating. So it’s not so simple as undermethylation and overmethylation. You may, in some cases, become a seesaw of undermethylation, overmethylation. So, let’s get into specifics of the dietary strategy, and we’ll start with folate.

01:22:15 Folate

I would look at food first for your folate. I think you want to focus on methylfolate. You want to get about the RDA. I think you could push your total intake up to double the RDA, and it would be fairly safe, but I see no reason to go any higher than that. So I think you could add a 400-600 micrograms per day supplement as methylfolate. I don’t think it’s necessary in most cases, and I don’t think it should replace food. I think you should start with food as your baseline and as your foundation.

For food, you want to focus on the three L’s: liver, legumes, and leafy greens. Really, it’s greens that are important, not leafy, but then we’d have two L’s and one G, so I say the three L’s. And to be honest, the best thing to do would be to use something like Cronometer or another nutrition tracker to actually track what you’re eating at least for a little while and see if you’re hitting the RDA for folate and which foods are helping you do that.

But to generalize, you could break legumes and greens into foods that are really good and foods that are good. So, the really good ones are ones where you could get away with one to two servings a day, and those are kidney beans, chickpeas, lima beans, soybeans, mung beans, black beans, and pinto beans. For greens, it’s leeks, spinach, and broccoli. I’m sure I’m leaving out some, but generally most other things are gonna fall into the category of wanting two to three servings a day instead of one to two.

There are some data that if you sprout legumes for four days, you get a massive peak in folate that would imply that you could get away with eating a half a serving of legumes. But there’s too much potential to have variation in where the peak folate is. In the one study that I’ve seen, it’s four days of sprouting. I tried contacting some manufacturers of sprouted legumes, and they wouldn’t tell me how long they sprout their legumes for. If you do it at home, I don’t know if your mileage would vary.

So I would still, I would opt for sprouted or germinated legumes whenever you can, but I would still try to hit one to two to three servings. Liver falls into the one to two category, so you could have one serving of the better legumes or greens and one serving of liver, for example.

You have to be careful about freezing vegetables. Folate degrades very rapidly in the freezer. Washing vegetables, if you wash them, you should wash them while they’re whole. If you grate them, for example, the more surface area there is when you wash them, the more folate runs out in the water.

If you’re soaking legumes, you want to judge this by whether you’re trying to get rid of something toxic in the legumes. If that’s the case with a lectin that’s dangerous, for example, then you want to throw that water out. But if you’re just looking at nutrient content, you do lose some folate into the water that can be recovered. So depending on what you’re soaking, if it’s something like lentils, for example, I would prefer to soak it in the water and use the water if possible.

In the freezer, liver is actually incredibly stable, unlike vegetables. And for legumes, I’m not sure of the stability over time, but I believe because they’re stored dried, it’s probably very stable. There is some data suggesting that egg yolks are an incredible source of folate if the chickens eat grass, but I’m not 100% sure how well we can trust that data, particularly on a quantitative level. So I would say, eat grass-fed egg yolks, but still try to get the one to two or two to three servings of the three L’s. If you add a folate supplement, add methylfolate. I would not add more than 400-600 micrograms per day.

01:26:35 Protein

And now, the protein strategy. Remember, protein is supplying things like methionine, glycine, and serine, supporting this system. The RDA for protein is 0.8 grams per kilogram body weight. For most people, or for the average person of healthy body weight, that’s 50-60 grams or so. If you eat that, you will get sufficient methionine to meet your needs.

Most people need more than that to help with body composition, particularly if they have any aesthetic or athletic goals, athletic performance, satiety to help with weight loss. So I think a lot of people, especially if they have aesthetic or athletic goals or are trying to lose weight, a lot of people would benefit from a gram of protein per pound body weight. If you’re very high body fat percentage, you might want to recalculate that based on lean mass or estimated lean mass. But you don’t need those high levels to get methionine to support methylation.

01:27:50 Creatine

So, let’s move onto the creatine strategy. Synthesis of creatine is proportional to what you need, and what you need is proportional to your lean body mass. The average male who’s 70 kilograms is gonna synthesize about 1.3-1.6 grams of creatine a day. That’s based on tracing the creatine synthesis on a creatine-free diet. But if you look at what the creatine loss is, you might round that up to 2.4 grams per day, because when you look at creatine loss in the urine, it seems like that’s how much you would need. In general, that’s gonna be half for females what it is for males, but that’s largely an artifact of lower lean body mass in females.

So, what I would do is I would take those numbers and assume that they’re for someone who weighs 70 kilograms, which is 154 pounds, or if you want to round that off, 150 pounds. And so if you want to adjust it to your body weight if your body weight is substantially different from that, you can take those numbers, if you think in kilograms, divide them by 70 and then multiply them by your weight in kilograms. If you think in pounds like I do, divide that by 154 and then multiply it by your weight in pounds.

Let’s just go with the average numbers though. Let’s say that you need as much as 2.4 grams of creatine. If you add creatine in your diet, you’re not only simply gonna suppress your creatine synthesis. In fact, athletes regularly supplement with creatine in order to boost the creatine levels of their tissues. Across animal studies, it looks like you can increase your total body pool of creatine about 30%, and at a constant dose, this takes about 4-8 weeks.

In humans, the way creatine is usually supplemented, often you have a loading phase, where you try to get that over with quickly by taking 20 grams a day for 4-5 days. So if you calculate what you’re likely to need if you increase your body pool by 30%, then I think it’s probably the case that if you wanted to maximally saturate your tissues with creatine and use what’s left over in your daily intake to suppress your endogenous synthesis, you’re going to need a little bit more than 3 grams per day. Notably, that is what hunter-gatherers are estimated to have consumed, 2-4 grams per day when they—hunter-gather groups, from animal flesh.

If you wanted to eat that amount of creatine, you would want to eat 1-2 pounds of meat, not including liver. And when I say meat, I mean animal flesh. This does include fish and does not really include eggs and dairy, which are much lower in creatine. If you eat 1-2 pounds of meat or fish, then on average, you are going to get 3 grams of creatine in your diet. That is more meat than you need to meet your protein and methionine needs, and you could argue that a downside of that strategy is that you’re supplying extra methionine when you have the risk of wasting it in the glycine buffering system.

If you wanted to eat a lower-meat diet, you could supplement with 3 grams of creatine per day. And I see no reason to use anything other than creatine monohydrate, which is what’s used for athletic performance. Now, I don’t know whether this approach would maximally shut down your creatine synthesis.

There was a study lasting five days that showed that 20 grams per day of creatine decreased creatine synthesis by about 30%. My suspicion is that over the long term, it would shut down creatine synthesis by much more than that. Twenty grams per day for five days is the standard loading phase of creatine for athletic performance, where the goal is not to shut down creatine synthesis, it’s to drive up the creatine content of your tissues.

So my suspicion is that once the creatine content of the tissues is maximized, then the main effect of the creatine is to shut down endogenous creatine synthesis, in which case if you maximally cut it down, maximally shut it off, you would decrease your methylation demand by about 40-45%, which is the single most powerful thing that you could do that I can possibly think of to conserve your methylfolate.

01:33:05  Glycine

For glycine, the baseline strategy is to eat the skin and bones of the animal products you consume, whether it’s the edible bones of fish or it’s using bone broth, et cetera. I think you could experiment based on how you feel or based on your blood levels of glycine with more than that through supplementation.

At the moment, the supplement that I would recommend is Vital Proteins Marine Collagen. A lot of collagens are derived—including Vital Proteins Beef Collagen—are derived from beef hide instead of the bones. And the hide is not as high in glycine as the bones are. Consequentially, the available beef gelatins—I don’t know if this is true for dirt-cheap gelatin powder, but it’s true for the grass-fed, organic, et cetera available beef gelatins. If they’re derived from hides, they’re not as high in glycine. The Vital Proteins Marine Collagen is much higher in glycine than their beef hide collagen. You get about 3.7 grams of glycine per serving.

I think it’s reasonable to hit 10 grams of glycine per day, not as a goal but as an upper boundary to what’s reasonable to play around with based on your symptoms and your blood levels. Ten grams a day glycine has been estimated as what we fall short of for supporting our collagen turnover in our skin. That was estimated mathematically. I don’t know of any studies showing that 10 grams a day of glycine make your skin better, but that’s one basis. There are also inborn metabolic errors, genetic metabolic diseases of energy metabolism that are treated with glycine, and the high-dose glycine that they use is somewhere around 7-10 grams, maybe higher in some studies.

But altogether, if I want to guess at where a reasonable upper boundary for glycine is to play around with, I would say it’s 10 grams. And that would be 3 servings, or 6 scoops, of the Vital Proteins Marine Collagen. I’m not saying, go out and take 6 scoops. I’m just saying, on one end of the boundary is a diet that includes the skin and bones of the animals you eat, and on the other end is supplementing with 1, or even a half, 2, or up to 3 servings of Vital Proteins Marine Collagen.

01:35:45 Reiterate problem with methionine/and SAMe in context of meat for creatine 900-1200 mg choline 

Here is a good point to reiterate another part of the strategy, which is, the reason that we’re supplementing glycine is because we want to replete the glycine that’s lost in this aberrant glycine buffering system. If we add methionine or SAMe here, we could aggravate the loss of glycine, and that’s a notable downside of trying to eat 1-2 pounds of animal flesh to get creatine that potentially argues in favor of a lower meat diet and creatine supplementation.

The final leg of the dietary strategy is around choline. I would recommend someone with an MTHFR mutation eat 900-1200 milligrams per day of choline. That’s based on a small handful of studies that show that somewhere around this is what you need to normalize the metabolism of choline that’s altered in people with MTHFR and what you need to minimize certain endpoints such as DNA damage in people with MTHFR mutations.

If you want to get that much choline, you could get it from food in 4-5 egg yolks per day, or you could substitute one serving of liver for 2 of those egg yolks. You could also eat a very large volume of low-carbohydrate plant foods. This is not about carbohydrate. It’s about the fact that most plant foods that are low in carbohydrate tend to be the ones that are high in choline. No plant food is anywhere near as high in choline as egg yolks or liver. But if you eat a very large volume of low-carbohydrate plant foods, they’ll add up, and they could contribute to that.

It’s too complicated to delineate exactly what plants you would eat in the podcast, but you could use a nutrient tracker, or you could check out my blog post on meeting the choline requirement. I believe that comes up if you Google “meeting the choline requirement.” It would certainly come up if you Google “meeting the choline requirement Masterjohn.” And I will post it in the show notes at chrismasterjohnphd.com/46.

As an alternative to diet, or on top of diet, you could supplement with choline. If you do that, I would recommend by default you use phosphatidylcholine, which is what is found in lecithin. If you feel that you’re doing it for cognitive enhancement, you could use a similar dose of alpha-GPC, alpha-glycerophosphocholine. And this is much more effective at boosting acetylcholine. So for the cognitive boost or for if your muscles are weak or anything that looks like it could be an acetylcholine deficiency, you might want to try alpha-GPC at those doses.

But if that’s not the case, the default would be phosphatidylcholine or lecithin, and that’s because that’s the form of choline that is least likely to generate TMAO, or trimethylamine oxide, in the gut. Now, I’ve argued in the past why I’m not convinced that TMAO causes heart disease, as has been argued very forcefully in the press, and I think anyone who says that it does needs to deal with the fact that you’re gonna get a lot more of that when you eat fish than when you eat choline. However, it has been shown that food choline generates some degree of TMAO. There’s questions around it. So if you’re gonna take 1200 milligrams of a choline supplement, I would use the form that generates the least TMAO just to be on the safe side, because why take choline bitartrate when there’s no advantage and there’s some theoretical, possible risk?

So that’s the dietary strategy. To sum up, we have get the RDA for folate, preferably as food, possibly adding 400-600 micrograms of methylfolate, not a different kind, and no more than that. We have protein. Get the RDA for protein, 50-60 grams. You probably want more protein than that for other goals. Get creatine. Three grams of creatine a day as a supplement. You’d probably need to eat 1-2 pounds of meat per day to get that, but that might give you too much methionine and put a tax on your glycine buffer system. For glycine, at a minimum, eat the skin and the bones of the animals that you eat and use up to, not definitely, but up to 3 servings of Vital Proteins Marine Collagen. Be careful about supplementing with SAMe. Not saying don’t do it. But be careful. And 900-1200 milligrams of choline per day.

01:41:40 The evaluative strategy

Then we want an evaluative strategy because I’m not saying that everyone should go out and do exactly these things. I’m saying that to the degree that you have compromised MTHFR activity, meaning in the proportion to which you approach the 75% reduction of someone with homozygous C677T, to that proportion, you are likely to need to approach this dietary strategy to some degree. You might not need to be that strict about it. Maybe you don’t even need to do it at all, especially if you’re heterozygous A1298C. And maybe you need more than that because, again, these estimates of reduction in enzyme activity are averages that are gonna vary from person to person and are gonna operate within a much more nuanced and sophisticated physiology inside your cells, and we don’t really know everything that’s going on there.

So, here’s what I would do for the evaluative strategy. First of all, there are many ways to know what your methylation genes are like.

01:42:00 StrateGene Report

My overwhelmingly preferred way, my strategy, my preferred strategy, is StrateGene. And this is Ben Lynch’s product. You get your 23andMe data, you run it through. In a matter of minutes with 45 dollars paid to StrateGene, you get your StrateGene report.

The reason I like it is because I think it has a good balance of information and interpretive help. I don’t believe that someone with no background would get a whole lot out of it, but I believe that someone with a reasonable background in nutrition and metabolism would get a lot of it. I think they’d get a lot more out of that report than all the other ones that I’ve seen. Not in terms of the quantity of genes discussed but in terms of the holistic approach to give you the data and help you interpret it.

And I think that someone who’s interested in their metabolism could get help from someone who knows it well. And let’s say you got this report, and you had a consultation with someone who helped you interpret it. The help that you get in that report would then become really helpful to you, because after someone’s explained it to you, you can go back and understand what it means when you read through the descriptions in the metabolic pathways and everything. So I would get StrateGene not only to know your MTHFR status but to characterize the other genes in this pathway.

For example, let’s say you have a 50% decrease in folate transport into your cells. Well, suddenly that 75% decrease in MTHFR activity looks potentially way worse, and you’d be much more vulnerable to a moderate-folate diet, for example. So, StrateGene to more fully characterize the genes that can impact this pathway.

01:43:55 Homocysteine, methionine and glycine

Homocysteine levels. You should be able to ask your doctor for homocysteine levels. You might even get them without asking, because it’s fairly routine. You can get homocysteine from LabCorp, from Quest, and it’s on the Genova ION Panel.

I think homocysteine is the one measurement where I would comment on why the numbers you should shoot for are different than the wider reference range that they would give you in the lab. And I think you want to shoot for numbers between 6 and 9. And I say this on the basis that if you look across males and females, and there’s some differences, that tight range seems to be consistent with the median of young and healthy people.

As you increase, you’re gonna get higher levels with age, but as you do, you get closer and closer to, for example, cardiovascular disease. And just having the MTHFR mutation can double your levels of homocysteine. So you at a minimum want to try to get back to your age-appropriate homocysteine level. And I’ll post a paper that has it broken down by age and sex, et cetera, in the show notes at chrismasterjohnphd.com/46. But I think you probably want to shoot to get it down in the 6-9 range.

Now, as we go further from here, it becomes more difficult to get some of these tests. I would want to look at methionine and glycine and sarcosine. If you get a LabCorp amino acids panel, a Quest amino acids panel, a Genova ION Panel, or a NutrEval, you will get methionine, glycine, and sarcosine.

The risk with MTHFR is that your methionine would run low because you’re not recycling homocysteine as effectively. The risk would also be that your glycine levels run low because you are using the glycine buffer system too much and you’re not repleting the glycine. If that’s true, your sarcosine levels will run high. I don’t have any basis to use anything different than their reference ranges. I think you probably want to be somewhere in the middle of those reference ranges because they’re not diagnostic. They’re based on the averages that you see in the population. So I don’t have any basis to say anything other than shoot to be in the middle of the range.

01:46:36 HDRI methylation panel

The HDRI methylation panel. If you get the extended panel, it includes methionine and cysteine, but it does not include glycine or sarcosine. If you get the regular panel, the main objective that you’re looking for is you don’t want rock-bottom 5-methylfolate levels. If you see really low methylfolate levels and really high or normal levels of all the other folate metabolites, that would suggest that you are not conserving your methylfolate, and that means maybe more creatine to try to conserve it better or maybe more input with methylfolate supplementation.

It is with moderate confidence that I recommend the HDRI methylation panel. I think it would be better to not rely on them exclusively. And so if you have, for example, homocysteine measurements elsewhere to corroborate what you’re looking at, I think that is helpful.

01:47:35 Folate in plasma and FIGLU

You can look at plasma and serum folate. They will be lower in someone with MTHFR, particularly if you’re not nutritionally compensating for it correctly. And actually, circulating folate is mostly 5-methylfolate, and that might be why they’re good. If you get RBC folate, I would get it with serum folate so that you can compare the two. The diversity of folate forms is gonna be greater inside a red blood cell, and it’s not as clear to me if your methylfolate deficiency would show up as low red blood cell folate.

I would not use FIGLU. FIGLU stands for formiminoglutamate. It is a product of the catabolism of the amino acid histidine, and it is converted to glutamate with the help of folate. And so when you’re folate-deficient, you get more FIGLU in your urine. However, the form of folate that does this is not methylfolate. So it’s gonna rise when you’re deficient in total folate or when you’re deficient in some other enzymatic activity. It’s not gonna rise as a result of a deficiency specifically of methylfolate.

Similarly, I would not use markers of macrocytic megaloblastic anemia. In folate deficiency, you see elevated mean corpuscular volume, or MCV, on your complete blood count, or CBC. If your MCV is elevated, it’s a sign of macrocytic megaloblastic anemia that occurs in folate deficiency. But that does not occur because of a deficiency of methylfolate. MTHFR mutations do not cause macrocytic megaloblastic anemia, so that marker is also not useful for looking at your methylfolate status.

So the basics are StrateGene, homocysteine, methionine, glycine, and sarcosine, and maybe the HDRI methylation panel plus plasma or serum folate.

01:49:40 Other tests of interest

We could go on to things that I think are interesting to talk about but are either harder to get or less clear about how to interpret. You can get serum creatine from Quest or LabCorp. If your creatine levels run low, then that could reflect lower creatine levels because of the reasons we talked about earlier, because of lower creatine synthesis. I don’t know exactly, quantitatively how does the MTHFR affect that and is the reference range useful.

It would also be interesting to look at, from the same batch of urine, guanidinoacetate, the immediate precursor to creatine, creatine, and creatinine. When the three are measured together, it can be used to diagnose metabolic disorders in creatine synthesis. It would be interesting, if you have a lot of money or you’re a healthcare practitioner trying to run correlations or do some research, it would be interesting to see if these are impacted to a lesser degree in people with MTHFR.

With that said, you can get it from the Mayo Clinic, the Greenwood Genetics Center, Baylor Genetics. Just Google “urinary guanidinoacetate” and you will see that it’s going to be done in specialized laboratories for the genetic disorder. I’m not sure how easy or possible it is to get these tests if you’re not trying to diagnose one of these metabolic disorders.

Update: Quest now offers this as “Creatine Biosynthesis Disorders Panel, Urine.”

And there you have it. So, MTHFR is not a disorder. It’s a very common variation in metabolism. It makes you less able to use folate, which pushes you towards using choline instead. So it increases your choline requirement. It possibly makes you less good at synthesizing creatine.

If that’s true, you need more dietary creatine. Extra dietary creatine could be helpful in conserving your methylfolate. So eat normal amounts of methylfolate from food, adequate other nutrients. Extra creatine could help you conserve that methylfolate. The reason that’s helpful is it can suppress—conserving that folate can suppress your wasting of glycine. Adding extra glycine can help compensate for the wasting of glycine, and these are the big things that are changing in MTHFR.

It’s not all about methylfolate. It’s not mostly about methylfolate in terms of practical strategies. Methylfolate is an important but small piece of that puzzle. Choline, creatine, and glycine are huge chunks of that puzzle that are often deeply underappreciated. That is, until now.

Alright, I hope you found this useful. Signing off, this is Chris Masterjohn of chrismasterjohnphd.com. You’ve been listening to Mastering Nutrition Episode 46 about living with MTHFR. The show notes are found at chrismasterjohnphd.com/46. And I will see you in the next episode.

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Now, this isn’t just about high-quality, grass-fed meat products that can up your nutritional game, and save you time in the morning. It’s also about saving money. And that’s because I worked out a special deal for you. As a member of my audience you can go to grasslandbeef.com, order whatever you want as long as your total order is at least seven pounds and at least $75 after applying the discount, and as long as it’s under 40 pounds, you can enter the promo code “Chris” at checkout.  Putting my name in the box earns you 15% off your order, and since you can order up to 39.9999 pounds of meat at that discount, you can potentially save a lot of money. If you’re on the fence or not ready for a big order, don’t worry. You can use the promo code “Chris” not once but twice. So order the minimum your first time and if you love this stuff as much as I do, you can order the max the second time around and get the same level of discount. Or, just max out your order both times and get just shy of 80 pounds of meat at the discounted price. Either way, head over to grasslandbeef.com and make sure you enter “Chris” at checkout to get the discount.

This episode is brought to you by Ample Meal

Ample is incredible. It’s a meal-in-a-bottle that takes a total of two minutes to prepare, consume, and clean up. Two minutes. I’m not kidding. Now, I know what you’re thinking. Anything that quick just has to be made of synthetic ingredients you’d have a hard time pronouncing and wouldn’t want to put in your body. But it’s not. Ample is made entirely from natural ingredients and designed to provide an optimal balance between protein, fat, and carbohydrate, as well as all the vitamins and minerals that you’d need in a single meal.

There’s no question that it’s always best to sit down and take your time eating a home-cooked from fresh ingredients. But let’s face it. Oftentimes, we just don’t have time for that. If you live a busy life like I do, and your goal is to get things done, you need quality fuel you can get into your system quickly.

Here is a great example where Ample is perfect for me. In order to carve out time for creative focus, like the kind of focus that I need to make this podcast, I block-schedule all of my consultations on Mondays. That means I’m often working a 12-hour day on Monday with no longer than a 15-minute break in between sessions, and I have a need for constant brain power so I can truly help the people I’ve committed to helping. I just can’t spend time preparing meals on Mondays. Even if I prepare meals in advance that I can reheat, I don’t even have time to eat the meals or wash the dishes. Ample is the answer to my Monday problem.

It comes in two versions: 400 calorie and 600 calorie. The 600 calorie version gives me 37 grams of protein from a mix of whey and collagen, which promotes satiety and flips my brain on.

Its fat comes from coconut oil and macadamia nut oil. I like these oils because they’re low in polyunsaturated fatty acids, or PUFAs, oils that promote aging and are usually loaded into the processed foods that most people eat when they need something on the go. The coconut oil provides some medium-chain fats to keep my energy levels up too.

The carbs, the vitamins, the minerals all come exclusively from food sources, like sweet potatoes, bananas, cocoa powder, wheat and barley grass, and chlorella. It’s full of natural prebiotic fibers and probiotics to promote a healthy microbiome, and the gentle sweetness comes from a mix of honey, monk fruit, and stevia.

I just mix it with water, drink it, rinse out the bottle, and boom. Two minutes in, and I’m fully fueled and ready to face the next phase of the day.

I first came across Ample when I met its founder and CEO Connor Young at Paleofx last year. Connor inspired me with his vision for Ample, which I anticipate as being much more than a meal-in-a-bottle in the near future. I’ve become an official adviser to Ample, and I’ll be helping Ample design scientific research that will lead both to an ever-improving Ample Meal and, I hope, meaningful contributions to our understanding of how to use nutrition to help people be healthier and happier and perform better at the challenges that they care most about.

As a listener to the Mastering Nutrition podcast, I’ve also worked out a special deal for you. If you use the discount code “Masterjohn” you’ll get 15% off your first order of Ample. To get your discount, go to amplemeal.com—that’s amplemeal.com—and use the code “Masterjohn” at checkout.

Well, I’m glad you made it this far, and I’m glad you love the show. If you want to see more of this, please help support the show by rating it and reviewing it. It makes a huge difference in improving the visibility of the show, the success of the show, and my ability to keep on doing it.

If you want more of my content, check out Masterclass with Masterjohn Energy Metabolism on YouTube and Facebook. Comes out twice a week. We’re now going into our more than 30th lesson on the system of energy metabolism. Chris Masterjohn Lite has been on hiatus, but don’t worry, it’s coming back soon.

And you can always find me on YouTube, Facebook, Instagram, Snapchat, and Twitter, and I do have a newsletter that I am starting to ramp up to weekly. So you can get on my email newsletter at chrismasterjohnphd.com/newsletter. However you find me, I look forward to seeing you soon, and I’ll certainly see you in the next episode.

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