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FROM MORIAH MEYER:

Chris,

Please read the journal article titled “ Low-Dose Creatine Supplementation Lowers Plasma Guanidinoacetate, but Not Plasma Homocysteine, in a Double-Blind, Randomized, Placebo-Controlled Trial”.

https://doi.org/10.3945/jn.115.216739

I am interested to see your thoughts on this statement detailing how creatine supplementation can ultimately inhibit MTHFR: “therefore, an increase in SAM from creatine supplementation would result in inhibition of MTHFR, decreased synthesis of 5-mTHF, alleviated inhibition of GNMT, and ultimately, decreased SAM, increased SAH, and increased homocysteine”.

Studies have also shown that supplementation of creatine results in significant decreases of glycine. (I apologize, I do not have the DOI for this but I am sure you can find a similar study). Might this be harmful for MTHFR individuals who have some reliance on the glycine-buffer system?

As someone with MTHFR supplementing creatine, the negative impact on my health that resulted prompted me to research more into it. I wonder if this is an appropriate recommendation. I understand the logic that since a large portion of methylation goes towards synthesizing creatine, supplementing it would free up methyl groups and ultimately ease the burden of the methylation cycle. However, I do not think it is as straightforward as this and may be a dangerous recommendation. “Unexpectedly, creatine supplementation (alone or in combination with l-arginine) was associated with an 11–20% increase in homocysteine concentration (p < 0.05), which was not attributable to worsened renal function, providing evidence against an effect of creatine on decreasing methylation demand.” https://doi.org/10.1177%2F1358863X08100834

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FROM KELLY:

Moriah,

It would probably be best to contact Chris on his facebook page, but thanks for posting the study. It seems like this can be countered by either adding TMG (a methyl-donor), or of course, stopping the creatine.

Interestingly however, this shows that creatine and/or arginine may be helpful for those whose homocysteine has become too low due to taking too many methyl supplements. Too LOW isn’t good either, as then the supply of cysteine drops as well, and as you probably know cysteine is needed for glutathione production.

And in those with protein-calorie malnutrition (or kwashiorkor), where one has the odd combination of muscle wasting along with edema, guanidinoacetate (or guanidineacetic acid) is (and serum creatinine) are LOW, and so arginine and glycine can help raise the both, and restore health for those suffering. Also B12 is has been found to be high in P-CM, folate low…suggesting taking methyl-B12 can make things worse unless one is getting enough protein, especially glycine and arginine.

https://academic.oup.com/ajcn/article-abstract/16/5/436/4787397?redirectedFrom=fulltext

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I think it is dubious to use homocysteine as a marker for methylation demand.

I agree with the logic of the biochemical sequence up to alleviated inhibition of GNMT.

However, this STARTED with "an increase in SAM."

The end.

You've increased SAM. Everything resulting from that reflects that methylation demand was in fact decreased. There is simply no more to it than that.

With that said, neither SAM nor homocysteine are the be-all-end-all of anything, so I am not saying that creatine couldn't have a negative health effect.

How was your health hurt by creatine?

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FROM RACHEL:

Thai you! I hope Chris responds.

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May 18, 2023Liked by Chris Masterjohn, PhD

I'm 42, and have an 81% decrease on my methylfolate score. I started this protocol a few weeks ago, and:

* my RHR is down to high 40s-mid 50s from the mid-60s;

* I haven't had a brain fog episode once -- very exciting to be able to do my business books whenever I have time, and not during a mysterious window of opportunity;

*HRV is is trending up;

*No more bouts of dyspnea;

*Energy and exercise tolerance has greatly improved;

*100% O2 sat for the first time in about two years. I live at altitude.

I feel like I have my life back. Thanks, Chris.

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Wow that’s awesome!

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Apr 24, 2023Liked by Chris Masterjohn, PhD

thanks!

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Apr 13, 2023Liked by Chris Masterjohn, PhD

Hi Chris.

I made a comment on youtube about not getting an email with pdf.

You wrote you will send my profile to substack tech support?

Thanks

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I just resent the email to you. If you don't see it, check spam, trash, etc. If needed, find instructions for whitelisting addresses for your email provider and whitelist everything from substack.

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Apr 13, 2023Liked by Chris Masterjohn, PhD

Got it.thx

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You’re welcome.

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I submitted your profile to Substack tech support.

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Apr 5, 2023Liked by Chris Masterjohn, PhD

Chris, great MTHFR pdf! Any chance that you can add Family Tree DNA to the choline calculator? I tried using citicoline the other day and got heart palpitations, ugh, trying to figure out how this happened.

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I would try uploading it and see what happens. I think it can read any raw data file that has the right information.

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This is great! Thanks Chris

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You're welcome!

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FROM JODY:

Thank you. This is a great page. I’m going to point a lot of people here. I found out about five years ago that I am homozygous C677T, it really explained a lot. As soon as I read a list of symptoms I knew I had it, as I had 90% of them, and the others had all been present in my family history over and over. I have strokes, non BRCA breast cancer, heart disease on one side of the family, and heart disease and prostate cancer on the other side. That day I found out about MTHFR genes for the first time, despite studying genetics at university in the 90s and going to numerous doctors over the preceding 15 years to try and explain my seemingly unrelated (and somewhat debilitating) symptoms. I ordered a gene test and high strength methylated B vitamins that very day. Within a week on the vitamins and avoiding folic acid, my numerous symptoms had vanished, some (like extreme tiredness) I’d had my entire life. I studied a lit online, and ended up treating myself, after one doctor after researching for 2 hours on the internet having never heard of it told me I had a mild form and I was oversupplementing. Both of these were incorrect, I have one of the most severe forms 25% of normal MTHFR function, and supplementing was making me feel human for the first time in my life. The blood tests were clearly reflecting the buildup of fake “vitamins” I was unable to metabolise. She was gobsmacked when I told her I had cured all my symptoms including moderate depression by just taking B vitamins in the proper (active, methylated) form. I had gone to her for support, thinking she would actually take me seriously, my first experience with a medical professional besides myself (a scientist) trying to explain MTHFR to them. My IVF doctor who’d been unwittingly poisoning me with high dose folic acid for several years, claimed the standard treatment protocol was high dose folic acid. I told her no I will be taking methylfolate from now on, and she then claimed it’s exactly the same, and handed me a prescription for 5mg folic acid as I left. I did not fill that prescription, having thrown out all the folic acid in the house previously.

Finally found the missing piece of the puzzle, I was able to get and stay pregnant after about a year of high dose B vitamins (Methylguard Plus to start with at full dose 5mg folate and 3mg B12). I’ve since worked out how to avoid side effects, I have heterozygous COMT also, and was quite nauseous and headachy to begin with. I take electrolytes and eat with food, and take 10mg niacin lozenges as needed. I should’ve started on a much lower dose, but I stayed on the high dose even after I found this out as I was finally MTHFR symptom free (apart from side effects) for the first time I can remember. I was practically leaping out of bed each morning, and my severe joint pains and peripheral neuropathy had disappeared. I later found a more comprehensive B Complex with all the B vitamins in their correct forms. I also put my nearly three year old on a chewable B12/B9/B6 by Jarrow and he’s a lot happier and back to sleeping all night again which he started at 10 weeks old when I was solely breastfeeding. He didn’t sleep well at all having to have some formula over his first year, it was impossible to get a folic acid free formula especially as he was born as our first lockdown began with its panic buying, but it’s hard anyway to find. He was born with a very minor sacral dimple, no other outward signs of his at least heterozygosity for C677T mutation. I don’t know about his other parent, as he was an anonymous clinic donor. I plan to get him tested, but I’m waiting as the best/cheapest way I found was basic Ancestry DNA on sale, and I don’t want to reveal his paternal ancestry too soon.

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Great job finding the solutions!

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FROM KRIS:

There is lot of good stuff here. But I am deeply puzzled by the emphasis on Choline by Chris. Because this reveals what I think is a great contradiction in Choline. Bear with me here:

Quick background – I have undermethylation and also suffer from OCD.

In couple of studies done on OCD people, it was found that their brains showed above average increase in Choline or had positive correlation to choline. Which means, if I am interpreting it correctly, that perhaps OCD sufferers should stay away from choline.

Here is the BIG KICKER – Usually people with OCD, especially my kind of OCD (Pure OCD/intrusive thoughts) also happen to be undermethylated, and vice versa.

I am wondering if I am interpreting anything wrong here given what seems to be a contradictory role of choline.

At the end, should I consider supplementing with or eating food rich in choline, given that I have both undermethylation and OCD? (And I suspect there are lot of people like me around)

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FROM JODY:

I wonder if it isn’t like folic acid pethaps? I learnt in my ex career as a medical scientist that folate is the salt of folic acid and the terms are interchangeable. I have since found out that that is not so, and a high blood test for “folate” does not mean that person is not folate deficient. I myself always tested at >45 for folate and in the 200s for B12, even when I was at my worst, suffering severe B12 and folate (and folic acid overload) symptoms. I guess that’s why I ended up having to diagnose myself in the end, by sending off for an “at home” MTHFR gene test, finally finding out I am homozygous C677T with around 25% of normal MTHFR activity. Apparently it’s very common to test high or normal for B12 and/or folate with severe MTHFR deficiency, as as well as the folate it’s also measuring all the folic acid and cyanocobalamin you couldn’t absorb so it’s stuck in your serum. So I’m wondering if choline is the same. There’s maybe a natural choline you can get from food or high quality supplements, and a synthetic choline that the medical fraternity swear by, that you get from only cheap and nasty supplements. That’s just my theory.

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The fact that there is more choline in their brains does not mean the choline caused the OCD.

I also think you need to distinguish between acetylcholine and betaine produced from the oxidation of choline to support methylation.

Nutrition and mental disorders must involve some art and some trial and error because the science is neglected. So, if you find choline makes your OCD worse, don't use it. But if you have low MTHFR status, choline will likely improve methylation, and methylation of dopamine should reduce mental rigidity.

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FROM KT:

When I supplement choline I get really, really pale stool – I presume from fat which has been exported from the liver, but then can’t be burnt off. It happens with choline bitartrate, alpha-GPC, betaine HCl and lecithin (though the latter makes me feel really good, at least in the short term). I then start having symptoms of mineral deficiencies etc.

I’ve tried adding carnitine, which doesn’t really help, and makes my hypothyroid symptoms worse. Lipase enzymes also don’t help. I also get paler stool from B12 (I take an adenosyl/methyl mix) and folate (folinic acid or 5MTHF) and fat-soluble vitamins. I’d love to know of any ideas of what might help. Creatine seems to be helping a bit but gives me symptoms of excessive levels of bile acids (which are really messing up my teeth) – which I think is probably due to increased B6 need. I suspect that low creatine may be causing low stomach acid which is causing poor fat digesiton.

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I'd consider whether your urine gets dark when your stool gets pale; if so, it could be an obstruction in bile flow. I'd get serum bilirubin measured. Talk to a doctor about an ultrasound or some such to look for obstruction. If bilirubin is low rather than high I'd consider niacin status and maybe a lactate/pyruvate ratio if niacin status is normal.

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FROM RACHEL_COLORADO

I cannot actually help, but maybe something I say will trigger a thought for you. I’ve noticed my stool was pale and I’ve worked in a different way for the past 9 months and it has gotten darker brown. When you say that maybe fat is exported from the liver, where do you suppose it goes? Surely, first into the blood, so how does it end up back in the stool? Well, maybe it goes into the bile, which isn’t what the bile is supposed to do? Maybe lecithin is trying to store the fat back into your liver and so it makes you feel good in short term but not long term? I used to take choline and lecithin but I am totally avoiding now as an additive, because my entire philosophy at this point is to strip down to just food and then VERY slowly add anything I think I need. The hyper supplementation is done, for me, at this point. I figured out that I did good with foods that are higher INsoluble fiber (but do have SOME soluble fiber)… different people are different, but in either way the whole goal is to sweep out the poo and wastes as quickly as possible. My main goal is 2 poops per day and get the consistency correct. If I eat too many nuts, stool is pale. If I add at least one apple, this seems to make the stool dark (good, get those dirty bile acids out). We need to start cleaning out our livers very slowly, but this will be, I think, starting on the foundation of pooping and binding those dirty bile acids and getting them out the door. Also, gut flora have a major impact on whether those bile acids get reabsorbed, and also whether they are converted into bad bile acids (secondary bile acids, and I don’t know if all secondary bile acids are bad, or just some). So, then, probiotics are important. And, I think which one you take should depend on which one you need. So, try to take just one strain at a time and see how you do on that one. I take Pure Encapsulations lactobacillus rhamnosus GG. Also look into taurine–I’m not taking this right now because as I said I stripped down to the basics and trying to pay closer attention to what affects me. Good luck

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FROM JONAH LAMONDA:

I have c677t homozygous gene

Should I take regular glycine or tmg or both?

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Glycine and TMG should be regarded as completely distinct from one another.

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FROM SARA BENTON:

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

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FROM RACHEL LAKEWOOD CO:

Chris,

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

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

I have been following this protocol with good results.

-adding dried beet powder and creatine powder to smoothies

-Adding additional beets or beet juice sometimes

-taking 2 scoops, about 4 Tbsp. collagen per day.

-B Complex to get the riboflavin (no folate or B12 in my current one). Added B6.

-6 capsules of liver per day

-cannot eat eggs right now. Taking one phosphatidyl choline supplement per day.

-cannot eat grains, legumes, or nuts right now. (autoimmune)

-do take mushroom powders regularly

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I would not worry about that, though it is possible, and if you have reasons based on your response to believe you are getting too much TMG, you can cut back on TMG itself to keep the betaine HCl wherever you need it for digestion.

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FROM MARCIA:

You need GLYCINE to make creatine. In fact it’s one of only three amino acids that makes creatine.

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FROM MARCIA:

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

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

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

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FROM SEBASTIAN:

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

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FROM GILES WESTWOOD:

I’d be interested in a mulitvitamin. Thorne covers some requirements with:- https://www.thorne.com/products/dp/multi-vitamin-elite

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No, not in the balance recommended here nor with the ability to personalize as needed.

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FROM CHRIS:

My daughter is SLC19a1 +/+,

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

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I would have her follow the protocol here.

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FROM GREG:

Chris, the ON creatine you recommend is no longer made with creapure. I would suggest recommending a different version.

Here is quote from customer service:

Hello-

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

Have a great day!

Consumer Affairs Rep 05269

Optimum Nutrition/ABB Performance

Thanks for your work Chris!

-Greg

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FROM RACHEL LAKEWOOD CO:

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

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FROM RACHEL LAKEWOOD CO:

I just looked this up and found the many brands that contain Creapure.

https://www.creapure.com/en/partners/nutrition-partners

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Yes, I agree with Rachel, select any brand using creapure.

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FROM TONY:

Hi Chris,

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

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I don't know but I really doubt it.

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