Mastering Nutrition With Chris Masterjohn, PhD Episode 46 Living With MTHFR
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Dr. Chris Masterjohn discussion on: Living With MTHFR

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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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.
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 Folate based 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.

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53 Comments

  1. I have tested positive for the MTHFR mutation. My report mentioned the mutation causes cardiovascular (3 of my 4 brother’s had heart attacks a d/or died of same in their 30’s). it specified psychiatric, as in “schitzophrenic-LIKE” illness (which my sister suffered from her 30’s until her death). But the zinger for me was “migraines”, which I’ve suffered from since puberty; and my “male” grandchildren ALL suffer from, beginning at age 6 or so.
    Thanks for allowing to add the migraine thing. It was a big ah ha moment for me. Actually ALL of it was. It fit us (the siblings and I) perfectly. Answered lots of mysteries.
    I forgot to mention that BOTH parents also died of heart related issues: Dad – atherosclerosis and Mother – misfiring (I forgot the medical term for that – sorry). My cholesterol number hovers around 300 without Crestor. Hope this helps someone.

  2. FYI. According to the manufacturer (I emailed them), the Micro Ingredients Sunflower Lecithin contains 8-9% phosphatidylcholine.

  3. What do you think of Nordic-Naturals-Omega-3-Phospholipids as a source for phosphatidylcholine, it claims 300mg on the label

  4. Does eating methionine drive up homocysteine? They are interconvertable. There is a study that uses a relative reduction of post-methionine load homocysteine level to show efficacy of supplemental betaine. The assumption was that homocysteine rises upon methionine load. What implications does this have on people who want to eat creatine in meat in order to free up methyl folate in order to decrease plasma homocysteine?

      1. Creatine is 1/3 methionine, arginine and glycine. The methionine would tend to indicate one should not take it. But there was that one studythat showed a drop in homocysteine with use, I don’t know.

  5. Hey there. I’m a little confused about the choline amounts. If you supplement with 900-1200 of alpha-GPC , since it’s only 40% choline by weight wouldn’t that only give you 360- 480 mg of choline? Also curious of your thoughts of CDP choline/citicoline and if there’s a benefit of getting your choline through lecithin/phosphatidylcholine over the other forms or a risk of getting too much lecithin etc.
    Any insight would be greatly appreciated! Unfortunatly I’m on such a limited diet so supplementing will be my preferred way of approaching this. I feel like this may be a game changer for me and I want to make sure I do it right.

    Thanks so much!

  6. Hi Chris,

    Amazing podcast man. I started at #1, five days ago, and I’m up to this one already. I’m curious, why are you suggesting collagen peptides over bone broth? Is bone broth a less dense source of glycine? Just curious b/c of your support for kettle and fire.

    Thanks,
    Kyle Dietrich

  7. Do you have any recommendations for those who cannot tolerate creatine monohydrate. I have tried taken it multiple times and every time it leads to GI issues. I have read that mixing it with hot water helps, but I have also heard that doesn’t do anything.

  8. What is science if it doesn’t serve real people? If it just confuses people even more and gives them no practical answers.

  9. Chris, you are awesome!
    Do you recommend organic acids and amino acids urine tests for someone with 8 MTFR polymorphisms, plus double A allele of rs5963409 in the OTC gene?
    C677T heterozygous. VDR Taq and MAO-A homozygous.
    Copper 140; D1.25 -94;D25-25; PTH 45; Homocysteine-9.5-11 and consistently elevated glucose (over 100). 115lb Female.
    5 years of Dysautonomia with no answers. Nothing makes any difference so far.
    Thank you

  10. Hi Chris,

    that was really great! Even as I now have looked into this topic for quite some time, it easily made a profound difference!
    Is there anything wrong with supplementing pure glycine?

    I’d really love an episode on arginine and it’s fates (NO, ADMA, ornithine, agmatine…)

  11. Hi Chris,

    Kudos on those highly interesting recent podcasts on the topic of both dopamine and living with MTHFR. I’ve listened to both of them with great interest.

    In the Living with MTHFR podcast, at some point you seemed to suggest that for those with an C677T +/- SNP, it might not be needed to do anything about it.

    Should it be assumed that having an C677T heterozygous SNP is unlikely to cause significant mood/attention related problems ?

  12. Chris,

    Thanks for the information, it is very useful. I have poor methylation status despite working on many fundamentals and I look forward to trying these recommendations. I am homozygous for C677T and am also homozygous for PEMT. Would you change any of the recommendations based on the PEMT snp?

    Thanks!

  13. Hey Chris,

    Excellent podcast as usual! I’ve shared it with my nutrition and naturopathic colleagues.

    I’m homozygous for C677T and COMT (lucky me), so I have found this podcast and previous ones very helpful.

    Bit of my experience re test results because I don’t think it fits the typical picture for MTHFR….I’ve always had stupidly high serum and RBC folate levels, without supplementing. A GP joked that I must be eating a lot of greens…um, I definitely wasn’t. So, I have no idea why my folate levels have always been so high when I have this polymorphism. FIGLU was also high whcih you mention is relevant to overall folate status and not specifically 5MTHF.

    I also do not have high homocysteine, if anything it is on the low side (under 6) which can present its own issues potentially. I have read it may be related to CBS (hetero for C699T).

    I’ve got some specific health issues that you talked about on the podcast and I’m so grateful you spend your time doing this. I have terrible issues with muscle strength, memory, and cognitive abilities (studying and writing is a huge effort for me) – classic CFS picture which I feel I have somewhat reversed with strategic health measures. So I’m re-starting the sunflower lecithin, creatine and going to add some pure glycine to the bovine collagen hydroylsate I already take. The marine collagen is way too pricey.

    I’m also going to sprout some black beans.

    thanks again Chris.

  14. I was looking at the Marine Collagen Peptides from Vital Proteins — it’s $49 for 24 servings at 3.7g glycine / serving. I can also pick up 500g pharma-grade L-Glycine for $23 (~135x 3.7g servings of glycine.)

    If I’m already getting enough protein in my diet from meats, eggs, vegetables, and the occasional whey protein, would it make sense to go straight for L-Glycine instead, or do these Marine Collagen Peptides offer other benefits (Hydroxyproline?) or might L-Glycine have some sort of extra risks (cancer metabolism?)

  15. Hi Chris. Thanks so much for the podcast and material, it’s fantastic.

    If you please, I’m having trouble verifying the math on eating 4-5 eggs per day to get 1200mg of choline. In your article Meeting the Choline Requirement you state that 100g of egg yolk contains 683mg of choline. Since a large egg yolk is around 17-18g, one would need 9-10 yolks to get around 1200mg. This matches what I’ve seen on nutritiondata (though I’m aware that there are other databases). What am I missing?

    Many thanks,

    1. That is a great question. Glycine and hydroxyproline metabolize to oxalate, so people with primary hyperoxaluria or recurring calcium oxalate stones ought to be careful.

    1. Hi James,

      In an effort to respond to everyone with a question, I cannot read external links or watch external videos.

      I don’t know what a “catalyzer” of an enzyme is. It makes no sense to me that anything can “catalyze” an enzyme.

      Chris

      1. In the video he uses the word “things that slow it down and things that speed it up”.
        It is part of the StrateGene analysis on the MTHFR and would be basically present in each report.
        I had a period when I believed taking massive amounts of DHA and ALA was beneficial(it maybe is) and can say I really felt my methylation work better – COMT in particular.

    1. I haven’t looked at that closely but if there are polymorphisms that decrease its activity that would have to be the case.

      1. I was curious about BHMT as well. Genetic Genie pulls up three BHMT SNPs. I’m “yellow” heterozygous for two of them, BHMT-02 and BHMT-04. I haven’t researched it, but I’m assuming those represent reduced activity. That’s on top of being heterozygous for both C677T and A1298C. I’ve upped my spinach intake, have long eaten two eggs a day, and I’ve been supplementing a little gelatin and glycine for awhile. I recently added some creatine and occasionally sunflower lecithin for additional choline. I think I’ve seen some health improvements from it, notably reduced headaches.

  16. Is there any reason that a homocysteine level below 6 would be undesirable? Could that be indicative of another issue, such as an increased demand for glutathione synthesis via the transsulfuration pathway, or would it simply just indicate an oversupply of methyl groups? According to the StrateGene report, it looks like reactive oxygen species increase the activity of CBS, but then again, so does elevated SAMe.

    1. Nick, I wasn’t trying to say it’s undesirable. I just see no basis for arguing it should be below six. The range I gave is approximately the median for young healthy people taking into account some gender effect. Low homocysteine could be low methionine/protein intake or upregulated CBS. Unlikely upregulated from SAMe because that is proportional to the increase in homocysteine that results from elevated SAMe.

  17. Great podcast! Thanks for your work.

    Question regarding cysteine – are you aware of any nutritional/supplement strategies to push cysteine towards glutathione production as opposed to taurine/sulfate?
    I’ve heard it suggested that a mutation in the CBS gene can cause it to be upregulated, leading to increased cysteine and therefore taurine/sulfate.

    Thanks!

  18. I think the problem with supplementing creatine is that it renders serum creatinine measurements useless, leaving doctors without a means to easily assess kidney function.

  19. Other potential drains on methylation are high doses of supplements and medications that require methylation to be activated or disposed of. One example is niacin, which is sometimes prescribed in high doses (1 – 3 grams) therapeutically to raise HDL-C. (though recent studies point to niacin being ineffective at preventing cardiovascular illness when combined with statins). But this much niacin does raise homocysteine: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1994037/
    Same homogeneity-raising effect is probably the case for high doses of niacinamide too.

  20. Another question – as it seems so many people have the MTHFR ‘mutation’ it must have some evolutionary advantage. What would be it?

    The hacks with creatine and choline sound legit in the context of what is presented in the podcast, but what natural foods have our ancestors with those variations eaten?
    It is claimed that no hunter-gatherer populations suffer(ed) from heart disease, so they either didn’t have elevated HCy or it didn’t cause any problems for reasons we don’t yet understand.

    1. There’s speculation that low activity MTHFR variants may improve DNA repair fidelity by shunting methyl groups [from conversion of homocysteine to methionine] toward thymidine synthesis from uridine, thus decreasing risk of misincorporation of uracil into DNA. This is the conjecture behind the finding that homozygous MTHFR 677TT confers a lower risk of colorectal cancer at higher folate levels. {and assumes that CRC results from DNA damage and misrepair.] https://academic.oup.com/aje/article/159/5/423/92121/Polymorphisms-in-Genes-Involved-in-Folate

      Hunter-gatherers did not consume a nutrient-poor, calorie-rich Standard American Diet (aka the Cafeteria Diet], nor were they as sedentary as the majority of Americans are today, or as stressed out, either. Living a low risk life style that includes nutrient dense foods, plenty of exercise and a natural environment–are likely more important for lowering cardiovascular risk than a single risk factor such as higher homocysteine levels.

    2. James,

      You need evidence of selective pressure to justify your first statement.

      That level of choline can be obtained in 4-5 egg yolks and that level of creatine from 1-2 pounds of meat.

    3. Hi James Bond,

      The MTHFR gene mutation is definitely not something to our advantages. It is caused by pesticides…the very dangerous, and very ubiquitous, glyphosate and glufosonate.

      Maureen

  21. Excellent information! I’ve got a few questions. What are your thoughts on Creatine HCl (which is advertised as being easier to absorb at lower dosages without as much water retention)? Does creatine need to be taken with a meal or around insulin secretion for ideal absorption, or is that just a myth? And, if SAMe supplementation is cautioned against, does this same warning apply to TMG?

    1. I don’t have personal experience with Creatine HCl, but I’ve read that it’s much more soluble than monohydrate. I think that the more soluble the better. However, if it’s very acidic then there’s potential for esophageal irritation unless taken with food or a buffer mixed in like sodium bicarbonate (but who knows what that would do, maybe precipitate out the creatine? This would take an experiment.) One thing about the higher acid is that creatine is more unstable so it’s important not to let it sit:
      “These researchers found that whereas creatine was relatively stable in solution at neutral pH (7.5 or 6.5), a lowering of pH resulted in an increased rate of degradation and after only 3 days of storage at 25°C creatine degraded significantly: 4% at pH 5.5; 12% at pH 4.5; and 21% at pH 3.5 ” [but is stable at pH below 2.5 such as in the stomach]. Quote from “Analysis of the efficacy, safety, and regulatory status of novel forms of creatine” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3080578/
      From same article: “One liter of water dissolves 6 g of creatine at 4°C, 14 g at 20°C, 34 g at 50°C, and 45 g at 60°C ”

      Today I dissolvef my small dose of creatine monohydrate (0.5 gram) in 1/2 glass of hot water (140° F – 60°C). Only a bit of white stuff floated on top but that was probably mag. stearate from capsule contents. My mast cells ( I have hyperactive mast cells – MCAS) did not react (no tinnitus) like the previous 2 times and headache free, so I’m very pleased. This means I can take another dose tonight and a larger dose tomorrow.

      I take most of my supplements mixed with food. But the creatine-water solution has too much volume, so I’ll probably sip it between bites.
      Taking creatine with food does not decrease, and may increase bioavailability depending on type of food: “… ingestion of creatine combined with BG [beta-glucan fiber] “facilitates its retention by slowing down its absorption rate and reducing its urinary excretion.” see “Kinetics of creatine ingested as a food ingredient” https://www.ncbi.nlm.nih.gov/pubmed/17851680

      For betaine supplementation, the only negative info I saw was effect on lipids. See this article: “Effect of Homocysteine-Lowering Nutrients on Blood Lipids: Results from Four Randomised, Placebo-Controlled Studies in Healthy Humans” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1140947/
      “Betaine supplementation (6 g/d) for 6 wk increased blood LDL cholesterol concentrations by 0.36 mmol/l (95% confidence interval: 0.25–0.46), and triacylglycerol concentrations by 0.14 mmol/l (0.04–0.23) relative to placebo.”
      This means my LDL-C of 98 mg/dl might increase to 112 mg/dl. But then again, 6 grams of betaine is a heck of a lot of betaine.
      On the other hand: “Phosphatidylcholine supplementation (lecithin) increased serum triacylglycerols, but did not affect serum cholesterol concentrations [at 2 weeks].”
      Currently I’m taking the Alpha GPC suggested by Chris.

    2. Ryan,

      Most of the research is on monohydrate. I don’t know about HCl. It’s very well absorbed but moreso retained with insulin. No the warning about SAMe does not apply to TMG.

  22. Creatine monohydrate can cause headache and stomach problems if not dissolved in water before consuming. (Just experienced this!) What helped me was to be well hydrated before taking the creatine and also to dissolve the creatine powder in very warm to hot water (wait until the water clears to drink). Some people drink large amounts of water to counteract the dehydrating effect of undissolved creatine monohydrate and have no problem, but some still have a headache. I’m thinking that some of these people are drinking so much water that they are diluting their serum sodium excessively (hyponatremia), which can cause brain swelling. When drinking water, avoid drinking too much at once and try to add electrolytes such as sodium chloride (salt), and potassium (KCl), though that does not allow indiscriminate water drinking either.

  23. Thank you Chris!
    You rock!
    Please, please address somewhere sometime VDR Taq++ with low D3 (25) and high D1.25 (90).
    What one is supposed to do? It seems like nobody knows.
    Thank you!!

    1. I second Ellie’s request, with VDR Bsm +/+ , but also low 25-OH D3 (18 ng/mL) and high 1,25 D (108 pg/dL).
      No supplemental D for over 2 years now. Post-viral ME/CFS patient.
      Thank you, Chris!

  24. Thank you for an in depth and informative podcast on MTHFR. Would there be any contraindications in your supplement recommendations in a person with both homozygous MTHFR and homozygous COMT?

  25. Another great podcast, Chris ! Please keep those coming !
    What’s your take on caffeine/coffe/MSM and methylation?

  26. Hi Chris, thank you so much for another highly interesting podcast. I am +/+ MTHFR A1298C and just found out I have a mild case of spina bifida occulta. I definetly have signs of glycine and creatine deficiency despite following what I consider a highly nutritious diet (plenty of folate and protein but likely low in glycine and choline). The problem is that supplemental glycine triggers me gout, and choline (both supplemental and in eggs) triggers hair loss. I need to find out how to take glycine and avoid gout… I must add that my issues include being underweight, post-menopausal, sarcopenia, Hashi’s. I work with two MDs but I have to continuously educate them about my issuues. Thanks in advance for any ideas.

  27. Hi Chris,

    The podcast is amazing as always! Thank you for sharing so much information!

    I hope you don’t mind a couple of quick questions:
    1. Are there any strong reasons to prefer collagen supplementation to direct supplementation with glycine? I like taking 3g of glycine (BulkSupplements brand) pre-bed – it’s very cheap, so I wonder if gets the job done.
    2. Are there any serious drawbacks/risks of supplementing with 400mcg of B9 and 600mcg of B12 except perhaps overpaying and excreting some the excessive amounts?
    The reason I ask is that I _really_ like my Basic Nutrients supplement by Thorne: at least based on what I know it has all the right forms of important nutrients and also the right amounts (high where might be needed and super conservative where there are potential downsides). It’s also super convenient just to take two pills a day and get all key vitamins. We can assume a healthy diet, sufficient amount of choline and creatine from food +5g of creatine supplement. If it matters: 1 mutation in A1298C and 0 mutations in C666T.

    3. Would really love to hear your thoughts on A66G and how it can affect all these variables!
    It’s the only methylation gene where I have two mutations but seems to be a lack of good material on it. It seems to increase the risk for late-onset Alzheimer’s which is particularly worrisome that I also have a 4/4 (yes, not just 4) APOE gene. Perhaps you might consider going in-depth series on APOE too – that would be very interesting!

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