S2E9: MTHFR Questions

I love it when listeners leave me questions so here is this month’s roundup!

I don’t have a doctor that advises me about MTHFR. A mental health provider suspected the mutation because of years of resistant depression. She did a swab to test genetics for specific medication absorption which included MTHFR testing.we found that I have compound heterozygous mutations. I’ve been on high dose methyl folate and B12 for a few years and wonder if I should be getting regular tests for levels etc. where should I go? I have researched the topic myself online but it’s very confusing and there seems to be no general consensus. Can you help me? Thank you,

– Jamie L

This is a great question, Jamie because so many MTHFR folks are out there doing it on their own. Unfortunately, online and between practitioners, there is absolutely no consensus on the best way to do this, so really it comes down to finding the right way for you.

I notice you mention methylfolate and B12 and that is great, but make sure you’re taking the other B vitamins as well because they are all necessary for this to work – especially riboflavin. Also, if you’ve been taking high doses of methylfolate without other Bs, then cut your dose down before you start them because the dose might be too high once you get the other pieces of the puzzle in there.

In terms of testing, the things we want to look at specifically for MTHFR are folate, B12, and homocysteine. Testing every couple of years is fine. Testing folate is complicated because unmetabolized folic acid can be mixed into your total so the test isn’t so valuable except to show us trends (like it’s getting higher or it’s getting lower). B12 testing is straightforward as is homocysteine testing and if you aren’t familiar with homocysteine, check out Season 1, Episode 40: Homocysteine by The Numbers.

Outside of testing, the biggest determinant of whether or not you’re on track is your symptoms. How are you actually doing? If you’re not where you want to be, then maybe it’s time to work with a practitioner who has knowledge about MTHFR and can help you on your path.

Hi! I have an 8 year old boy. He was diagnosed ADHD at the age of 6. We started him on methylphenidates at age 7. We have tried nearly all of them and none of them agreed with him. We had gene testing done earlier this year and MTHFR came back as “Low to Intermediate activity”. Majority of the ADHD medications came back with lower odds of response. What do I do with this information? We have family history of bipolar and anxiety disorders. The adhd medications really brought out a lot of anxiety in my child. He is very competitive. He is obsessive. My son has a terrible issue with skin rashes that started when he was 4. We had skin patch testing done. He’s allergic to hydrocortisone, formaldehyde, fragrance. Once we took gluten out of his diet as well his rashes were more under control. Every time I listen to your podcasts I think some of my son’s issues point back to his MTHFR. Do I take this to his pediatrician? Do I work with his psychiatrist? Do I see a functional medical doctor? What do we do next?

– Mindy J.

ADHD on top of MTHFR is very common and it’s a difficult situation because the medications that help so many other kiddos just don’t work here. I DO think that addressing the MTHFR is the next best step. I would talk with both his psychiatrist and his pediatrician and see if either of them is comfortable fielding this issue in a way other than prescribing massive doses of folic acid, because that won’t be helpful.

If they aren’t familiar enough with MTHFR, then find a practitioner who is. It’s always best to work with someone local, but if you can’t find someone then I do still work with people one-on-one. Check the Amy + Health Coaching link at the top of the page on tohealthwiththat.com

This is why MTHFR folks need other Bs. It isn’t just about folate.

Hi! I am compound heterozygous so I of course have the C/T and A/C copies. I am hoping to start trying to get pregnant soon and I want to know what vitamins I should be taking that will work with the copies that I have. I am on 5mg of l-methylfolafe right now but no B vitamins. I tried a b complex and it made me very mean and hateful so I have been scared to try anything else. I want to have the best chance at a healthy pregnancy, thank you!

– Breonna H.

Congratulations on future baby-making, Breonna. That is such an exciting time. I’m so glad you brought this up because it’s really common for people to start 5-LMTHF before other B vitamins or B12 and then have weird reactions to other Bs when they start.

It is absolutely crucial that you do start other B vitamins. I think the reason why the B complex made you mean and hateful before was that with the other B vitamins there, suddenly your dose of 5-LMTHF was way too high so it was actually that causing the mood and attitude changes and not the Bs.

Basically what is happening in this situation is that your MTHFR enzyme is still really limited because it needs other B vitamins to work – riboflavin is a direct cofactor and without riboflavin, it just won’t go. So your dietary intake of riboflavin was maxing out the amount of 5-LMTHF that you can use.

So you do need to add a B complex back in there, but before you do, drop your 5-LMTHF down to 1mg for a couple of weeks and then add the B-complex. Also, check the B12 in the B complex because some people have a weird reaction to methyl-B12 too. Here’s a post on all the different forms of B12.

When you do give this a try, let me know how it all goes!

How do my folate levels drop after starting Metanx and multivitamin with active folate?

– Human

This is another great question, and I’m actually guessing a bit because I don’t know where your folate levels were before you started. I can say that what I see often in clients is that they come in with super high folate on lab tests, but functional folate deficiencies. Once we eliminate the folic acid and get them started on active folate then blood levels are technically getting lower because we’re clearing out the unmetabolized folic acid that hangs around in there cluttering up the works. Or at least that’s what we hope to do. Even as folate levels look like they’re dropping, the person is symptomatically improving.

I see that happen a lot, but if that doesn’t sound like what is going on for you, reach out again and give me a bit more detail so I can answer more thoroughly. Just remember that serum folate measures everything in the serum – usually that includes natural folate, 5-LMTHF that has been made by your body, whatever folate you’re taking, PLUS any unmetabolized folic acid that is still kicking around. It isn’t a great test on in terms of value on its own, but what we can do is exactly what you’re doing, which is compare numbers over time. But typically we want this to drop a bit as the unmetabolized folic acid (or UMFA) is leaving your system.

I *love* listener questions and I’d love to answer yours. If you happen to have a question, let me know. There is a video-ask for questions on the home page of tohealthwiththat.com. I’ll try to do an answer podcast every month or two just depending on how many questions come in. I also love meeting you guys in Genetic Rockstars, it’s an MTHFR community away from the craziness of social media with lots of inside information, polls, tips, and generally other MTHFR folks who are talking about their experiences. Please join us at community.tohealthwiththat.com.

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S2E2: Getting the Folic Acid Out of Your Diet.

I know it’s poor planning on my part to start this season off with the hardest part of this whole process, but sadly this is the only good way to start. If you skip this step, you can create mountains of problems for future you. Keeping folic acid in sounds good to so many people, but folic acid actually blocks the other, more useful forms of folate from being utilized. I talked a lot about the technical details in this post. This basically makes all the work you’re thinking about doing to add in natural food sources of folate or to take expensive 5-LMTHF supplements, worthless. All the money you spend on those things becomes wasted as well.

Let’s start with a bang.

Folic acid also hangs out in your bloodstream as unmetabolized folic acid, or UMFA which contributes to many health problems for MTHFR folks and non-MTHFR folks alike, including increased risk of many forms of cancer.

This is step one, and ignoring it is far, far easier than actually doing it, but you’ll regret it in the long run. Honestly, it won’t even serve you in the short term because eliminating folic acid from your diet can show you a lot about how you react to folates in general. It’s a huge part of this journey and skipping it isn’t a great option. I know it’s hard but stay with me.

Folate is vital to our functioning as humans and especially to the healthy making of babies, which is a pretty big deal. Folate deficiency during pregnancy leads to major preventable complications like cleft palate, spina bifida, anencephaly, heart defects, low birth weight, and stillbirth. Because it’s so important, many governments around the world have adopted programs to fortify commonly eaten foods with the synthetic form of folate, which is our nemesis, folic acid.

This public health measure has had a tremendous impact on the rate of these birth defects, which is wonderful. It just doesn’t take into account people with the MTHFR mutation, or a culture that generally over-eats and over-supplements the way we are prone to in North America.

As a caveat to public health in general, even for MTHFR folks some folate in the worst form, folic acid, is better than none at all. This measure makes sense for society. The problems start to happen when either there is too much folic acid, which is now very common, or when there are too many compromised copies of the MTHFR gene.

So this week, if you want to follow along with this MTHFR adventure, you are ditching all of the folate fortified foods and starting with a folic-acid-free diet. Nothing else should change. Just get the folic acid out of there. This includes supplements as well so if your multivitamin, B-complex, energy-booster, or meal-replacement has folic acid in it or says “folate” on the label, then it’s out. If you’re dropping supplements, try not to add anything back in right now unless it’s absolutely necessary – we’ll look for particular things in the weeks to come and there’s no sense rushing out to buy something you might be changing shortly.

In the US, there are two foods that are fortified with folic acid. Those are wheat and corn, which are pretty much the backbone of every American meal out there. This means your bread, pasta, tortillas, corn chips, baked goods, even the doughnuts have to go. Here’s a bit more about what to eat and what not to eat for MTHFR folks.

This is the moment when people’s eyes bulge menacingly and a tic starts in one of their eyelids. Typically, spittle flies out of their mouths when they say, “But, but, then what do I eat?”

Have no fear. There is actual food left, but you might have to look around a bit. First off, you can still have wheat products as long as they are certified organic. In order to earn organic certification, they have to be unadulterated. In terms of bread, finding an organic option, or a sprouted whole-grain option is probably the best one.

For pasta, there are not so many organic options, but lots of gluten-free options that are not fortified – look for any pasta that claims to be gluten-free, or rice pasta that is made of rice and therefore not fortified.

For the baked goods, you’re going to be in a bit of trouble. There are some gluten-free options but they’re pretty limited if you’re used to the smorgasbord of wheat-based options. Sorry about that. Even baking at home has to be different because wheat flour is mostly enriched. Some whole wheat flour is safe, but some still has added folate so read your labels.

I can see that tic under your eye intensifying, so let me just reassure you that there is also every meat, veggie, fruit, and nut option under the sun. It is really just your major sources of carbs that are taking a hit. I know, that reassurance is entirely too thin for anybody’s liking.

This is the hardest part of the whole thing, so stick with me – it’s all so much simpler from here. Just keep using the symptom tracker that you started last week to see if you notice anything from the folate elimination. People are often surprised to find that something as mundane as bread can be causing them so much mental and physical pain.

It’s a bit last-minute, but I’m just offering a course starting September 15th called Methylfolate masterclass to answer the #1 question I get, which is, “How do I know when I’m taking the right dose of 5-LMTHF?” If you’re interested you can find out more at tohealthwiththat.com but register now because the cart closes at 11:59 pm Monday the 13th.

Thanks so much for listening today and if any of you are brave enough to come back next week, we’ll lighten it all up with talk about some amazing high-folate foods that you can add in to your diet to give your body good sources of natural folate. It will be great! To everyone who didn’t throw their device out the window when I started talking about not eating wheat, thanks for hanging in there!

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I Have MTHFR, How Do I Start 5-LMTHF?

Once you’ve adjusted your diet, you have a new baseline. This is your new normal and it may be great, it may just be getting there (but not great yet). Make sure you give yourself about a month on your new diet — with MTHFR it’s way better to go slow and give your body time to adjust to things properly before you jump into something new. This is when you should start to think about supplementing.

Three rules to successfully start 5-LMTHF supplements:

  1. Always start low – use the lowest dose you can find. You can always add more, but once you’ve taken it, it’s hard to get it back out. Start with a low dose.
  2. Always go slow – give your body time to get used to the low dose before you increase. At least a week, but two if you know you’re particularly sensitive.  It is really common for someone to be able to take something for three days and then start to have symptoms because the dose is actually a bit too high and they’re pushing too hard.  Make changes slowly and be as willing to decrease the dose as you are to increase the dose. There is no right dose for everybody, only the right dose for you.
  3. Change only one thing at a time – I see it happen all the time that people get excited about a new health journey, add five supplements from internet research, then have some kind of symptom and have absolutely no idea where it came from or what is causing it, so they end up dropping all of those supplements.  This isn’t the best way forward. If you make small changes with only one supplement at a time, you can avoid this problem and you’ll always know exactly how you respond to something.  That doesn’t mean that adding another supplement might not change the dose you need of something else, but at least it helps you to know where to look.
Be like the snail when you start 5-LMTHF

Start 5-LMTHF:

If you’ve already:

  • Taken folic acid out of your diet
  • Added in natural folate
  • Started a multivitamin or B complex without folate or B12 

And you’re tolerating these changes well, then you’re at the point where you might consider adding some extra 5-LMTHF. 

Start with the lowest dose you can find and if you can only find high doses, cut them (if they’re tablets) or take the powder out of capsules and divide it. If you typically react strongly to things you take, which is common for in MTHFR issues, then start even lower than you think you need to.

The Three Possible Reactions to 5-LMTHF

  1. Miracle! – It starts out as a miracle (although it might feel weird the first couple of days because your body is adjusting), it keeps being a miracle and everyone is happy.
  2. Bait and switch – It starts out amazing and you love this thing. A couple of weeks later you find yourself either spackling minuscule cracks in your ceiling at midnight because you have too much energy and can’t sleep (overdose), or hating everything and everyone because you feel toxic (too much, too fast).
  3. 5-LMTHF is the devil – If it always feels bad, there is a good chance you will either never tolerate it, or only tolerate tiny doses later on in the process.

It is normal to feel a little strange for the first few days. Remember, 5-LMTHF is the only form of folate that bypasses the MTHFR enzyme and that means it can feel a bit odd the first time you take it. That enzyme has been dysfunctional, to some degree, your whole life and your body is going to need a minute to adjust. For me, the only way I could describe it was that my brain felt “different.” This is a useless description, I know, but there wasn’t really anything I could put my finger on, it was just … “different.”

5-LMTHF has the potential to change your neurotransmitters, your cellular energy, your antioxidant balance, and lots of other things very quickly, so it can feel a little odd. Your body has probably never experienced this before.

Outside of a normal adjustment reaction, it is also possible to have a bad reaction. The most common ones I see are anxiety or restlessness, edginess, depression, or difficulty sleeping. 

Remember, 5-LMTHF is the only form of folate that bypasses the MTHFR enzyme, and that means it can feel a bit odd the first time you take it.

amy neuzil Tohealthwiththat.com

Any big uncomfortable symptom should be considered a bad reaction and if that happens, stop the 5-LMTHF and wait until the symptom clears before you try it again. If the symptom was really bad then try again at a much lower dose. Even if you can tolerate natural folate in food, you might not handle 5-LMTHF well. 

If you have an adjustment reaction, but it clears in a few days and you’re tolerating the dose of 5-LMTHF that you’re taking, that’s great news! Stay at this dose for a couple of weeks and then try increasing it by a little bit. Dosing is very individual with MTHFR and there isn’t any way to give you a target dose, but there is a right dose for you out there somewhere.  It’s just a matter of slowly working your way up until you find it. 

What If I Can’t Tolerate 5-LMTHF?

This is a surprisingly common issue. If you just can’t take any 5-LMTHF at all, try a tiny dose of folinic acid instead. Folinic acid is metabolized differently than 5-LMTHF, but it’s a natural form (like the natural folate in foods) and is often easier to tolerate for MTHFR folks, even though it still needs the MTHFR enzyme to be activated.  If you need a refresher on folinic acid or the different forms of folate, check out this post. Here is a diagram of the methylation cycle showing where the different types of folate come in.

Folinic acid still goes through the MTHFR enzyme, but it bypasses the DHFR (slow) enzyme and the DHFR (fast) enzymes. For many MTHFR folks, it gives them the benefits of natural folate but is easy to supplement as a pill form (which natural folate isn’t because it isn’t shelf-stable) and it metabolizes more slowly than 5-LMTHF, which means that most people have fewer side effects. 

Once you’ve taken folinic acid for a while you might be able to tolerate a small dose of 5-LMTHF because some of the accumulated problems from a functional folate deficiency have been worked out, so your body might be better able to handle it. Again, start low, go slow and change only one thing at a time. You might still find you can’t take 5-LMTHF, but this whole journey evolves so just because something was true when you began the journey doesn’t mean it will be true three months in, three years in, or three decades in. Remember, MTHFR is for life.

Next week we’ll talk about dosing strategies because for many of us, taking the same dose every day isn’t a great idea. After that, we’ll dive deeper into what to expect when you first start taking 5-LMTHF, what to do if symptoms arise, and how to manage any reactions you might be having.

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What To Eat For MTHFR Mutants

We’ve been talking a lot about natural folate and its food sources vs. synthetic folic acid (which is toxic in high doses.). So in theory, we’ve got it. But in reality, what does this actually look like? Let’s dive in right now.

How Much Folate Are We Talking? Do I Have To Bathe In The Stuff?

Not at all. Although MTHFR folks might need to adjust based on their own responses, generally we’re aiming for the same targets as everyone else. The units are in “dietary folate equivalents” because absorption of folate and folic acid are different. Natural folate is about 50% absorbed and folic acid about 85%. If you want to geek out on it:

1 mcg DFE = 1 mcg natural folate = 0.6 mcg artificial folic acid.

According to Harvard University School of Public Health, daily folate needs are:

  • Adults: 400 mcg
  • Pregnant women: 600 mcg
  • Lactating women: 500 mcg
  • People who regularly drink alcohol: 600 mcg (because alcohol impairs absorption).
  • Children – from 65 mcg up to 400 mcg at 14 years old.
Assuming 1 whole avocado and 1 cup of fresh-squeezed orange juice (juice from about three oranges) this breakfast has approximately 300 mcg of natural folate. BOOM. Photo by Ba Tik from pexels.

Food Sources of Natural Folate

Naturally occurring folate is present in lots of the foods you might already eat, and also in some that might be new to you. Here are the 10 foods highest in natural folate according to USDA nutrition data:

FoodFolate per 100g (3.5 oz)Folate per cupRelated foods?
Edamame311 mcg482mcgPeas, soybean sprouts
Lentils (cooked)181 mcg358 mcgRoman beans, black-eyed peas, pinto beans, chickpeas, black beans
Asparagus
(cooked)
149 mcg268 mcgArtichokes, beets, okra
Spinach146 mcg263mcgTurnip greens, pak choi, collard greens
Broccoli
(cooked)
108 mcg168 mcgBrussels sprouts, kale, cabbage, cauliflower
Marmite (yeast extract)100 mcg per 8 g servingUnhelpfully, the makers of Marmite have listed the folate as “folic acid” because the terms are used interchangeably. It is actually natural folate.
Avocados81 mcg163 mcg
Mangos43 mcg71 mcgGuavas, pomegranate, papaya, kiwi, durian
Romaine lettuce136 mcg64 mcgEndive, butterhead lettuce, garden cress
Sweet corn42 mcg61 mcg
Oranges54 mcg30 mcgStrawberries, cantaloupe, blackberries, honeydew, pineapple
So many yummy choices…

With MTHFR Mutation, If You Can Eat Your 400 mcg and Avoid Folic Acid, You’ve Pretty Much Nailed It.

Of course, there are lots of times when it isn’t quite so simple, but this is a nice easy benchmark to strive for. So – What to eat for MTHFR? Lots of beans, veg, and fruit. No problem. The much harder part is what not to eat.

Don’t make getting your natural folate harder than it has to be! Photo by alleksana from Pexels

With MTHFR mutation, if you can eat your 400 mcg of natural folate and avoid folic acid, you’ve pretty much nailed it.

– Amy Neuzil

What Not To Eat For MTHFR Folks

There is a small list of fortified foods that have added synthetic folic acid that should be avoided (also, all vitamins and supplements with folic acid). The list is short but impactful. Here it is:

  • Enriched wheat flour
  • Enriched corn flour

There – That wasn’t so hard, was it? Except it turns out it is hard because here are all the foods that are made with those two things.

  • Bread
  • Cereal
  • Pasta
  • Crackers
  • Cookies
  • Corn chips
  • Tortillas
  • Baked goods
  • Baking mixes for cakes, cookies, brownies and whatnot.

This is very much where the wheels fall off the cart because, in the West, most people don’t really know how to eat without hefty doses of bread, pasta, crackers, and cereal. It is just how we are used to eating.

What to eat for MTHFR? Yeah. It’s not doughnuts. Lovely photo by Sharon McCutcheon from Pexels

What to Eat for MTHFR – Substitutions

With every substitution, be sure to read the label. If folic acid is listed in the ingredients (or fortified or enriched flour), then it’s a no-go. Also, remember that if you’re just buying flour and making it yourself (go you!), then you still have to make sure you get un-enriched flour – usually, this is gluten-free, organic, or specialty.

Fortified FoodMTHFR-Safe Substitution (usually. Read your labels.)
BreadOrganic bread, 100% rye bread, gluten-free bread, sprouted bread, rice cakes
CerealOrganic cereals (sometimes), oatmeal (sometimes – usually not the instant ones),
PastaRice noodles, gluten-free noodles, organic pasta (don’t forget, rice and potatoes are still on the menu!)
CrackersRice crackers, rice cakes, Some rye crackers, most organic crackers
CookiesGluten-free cookies, organic cookies.
Corn chipsOrganic corn chips, bean chips,
TortillasOrganic tortillas or sprouted tortillas.
Baking flourOrganic flour, brown rice flour, gluten-free baking mix, wheat alternative flours like buckwheat or sorghum.
You’ve got options!

This Sounds Like a Big Change

It is a big change from the typical Western diet, but it’s a very doable change – especially now when there are so many products designed for people with gluten sensitivities or people looking for organics. Still, it takes some commitment, especially at first, while you’re getting used to your new normal.

Why Do This?

The payoff from this one change can be really significant. Many people report better energy, more stability in moods, reduced brain fog, increased attention, and even better hormone balance. Also, if you’re trying to get pregnant, this sets you up for a healthier pregnancy. That still doesn’t make it easy, but it does make it worth it.

This is The Foundation For a Healthy Life With MTHFR Issues

Many of us MTHFR folks can reduce or resolve any MTHFR related issues just by following this diet. There are a few exceptions.

  1. MTHFR folks with very low serotonin – sometimes these folks can’t tolerate any folate intake and have to avoid folate-rich foods along with fortified foods (although cutting out the fortified foods will make a huge positive difference). We’ll talk about this in detail next week.
  2. Some overmethylators – MTHFR folks with symptoms usually fall into one of two categories. Overmethylators or undermethylators. Undermethylators are more common and usually need higher doses of folate to manage symptoms. Overmethylators are less common and sometimes need very low doses of folate to manage their symptoms. I happen to be an overmethylator but I still eat a very high-folate diet and occasionally supplement so it’s very individual. We will talk more about over- and under- methylators in September.

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This Vitamin Could Be Hurting You

It makes sense that if your body has a difference in its ability to process folate, like the MTHFR variants, then you just flood the system so that even if the enzyme is moving slowly, you’ve still got enough. There is a problem with this logic – the form of folate that we usually see in supplements, foods, energy drinks, and everywhere else is FOLIC ACID and there is compelling evidence that it’s toxic.

First off, What is Folic Acid?

Folic acid is the first synthetic form of folate, which is a group of related compounds found in food that we group under the label Vitamin B9. There are many different forms of folate in foods, but most of them are unstable and degrade quickly and so can’t be used in vitamins or supplements.

Folic acid was first developed in 1948 – the first synthetic form of folate available and it was a revolution. Natural forms of folate, with the exception of folinic acid, are pretty unstable and certainly won’t keep if you add them to foods or vitamins. Folic acid has solved so many problems in undernourished populations and kept the rates of cleft palate, cleft lip and neural tube defects like spina bifida far lower than they would be without it, so it isn’t that it’s an entirely bad thing – when you have a choice between folate deficiency and not having that deficiency because of folic acid, then the choice is easy to make. It’s when you’re not in an undernourished situation that you have to be careful.

At high doses, folic acid is toxic.

I’m Fuzzy – Why Would Folic Acid Be Toxic? They Add It To My Vitamins!

Vitamins and food additives must be shelf-stable, and naturally occurring folates aren’t. The crystalline form of folic acid was first synthesized in 1943 by Bob Stokstad at the American Cyanid Company (!!) What a name! And researched for use in human disease by 1945. It was shown to be useful in the same anemias and diseases of pregnancy for which folate was discovered to be useful by researcher Lucy Wills in 1931. Folic acid is not toxic in small doses and it can help correct a folate deficiency, but high doses are a problem.

Risks Associated With High-Doses of Folic Acid – Not Just For MTHFR Folks!!

Many of us have a chronically high intake of folic acid (not folate) because of the combination of fortified foods, energy drinks, and supplements. In the U.S. the recommended daily intake is 400 𝝁g, but actual consumption can be much higher due to fortified foods.

 Folate has a dual effect on cancer, protecting against cancer initiation but facilitating progression and growth of preneoplastic cells and subclinical cancers, which are common in the population. Thus, a high folic acid intake may be harmful for some people.

Smith AD, Kim YI, Refsum H. Is folic acid good for everyone?. Am J Clin Nutr. 2008;87(3):517-533. doi:10.1093/ajcn/87.3.517
  • Cancer – this is a risk nobody wants to face. Many studies have shown a link between high-dose folic acid and cancer, especially, as with the above quote, in terms of promoting the growth of cancerous cells that are already in the body.
  • Cognitive Decline – like cancer, this seems to be a double-edged sword. See the quote below.
  • Diabetes and thyroid disease – two conflicting studies have shown associations between high folate status in pregnant mothers and metabolic syndrome or diabetes in the children. The results of each study are opposed to each other, and so inconclusive. (See this review article for more details).
  • Hypersensitivity like childhood allergies, eczema, and asthma – this is thought to be through the mechanism of DNA methylation.
  • Autism, twinning, heart disease, mortality (that’s death), immune issues, neurological issues, and fertility problems – these have all been shown in various small studies without larger research studies to back them up.

An observational study of data collected in the NHANES found that “In seniors with low vitamin B12 status, high serum folate was associated with anemia and cognitive impairment. When vitamin B12 status was normal, however, high serum folate was associated with protection against cognitive impairment.”

Morris MS, Jacques PF, Rosenberg IH, Selhub J. Folate and vitamin B-12 status in relation to anemia, macrocytosis, and cognitive impairment in older Americans in the age of folic acid fortification. Am J Clin Nutr. 2007;85(1):193-200. doi:10.1093/ajcn/85.1.193

Another Problem is The Extra Unmetabolized Folic Acid Found Hanging Out In The Blood

What with all this food fortification, many people have more folic acid than their bodies can handle. Folic acid must be converted into something else to even begin to become useful, and it uses an enzyme (just like the MTHFR magic chair, only it converts a different valueless thing (folic acid) into something more valuable), called dihydrofolate reductase. We’ll call it DHF. DHF is a little bit slow, and can’t always keep up so we see folic acid hanging around in the blood stream, being harmful. Here’s a great study showing the link between fortified foods and unmetabolized folic acid.

The problem with this unmetabolized folic acid in the bloodstream is that it is associated with reduced Natural Killer Cell cytotoxicity. Your natural killer cells (NK) are your main patrol against cancer, so we want these guys to be as potent as possible – this is another potential explanation for the tendency of high folic acid levels to cause cancer.. Here’s a full research article from the Journal of Nutrition.

So, If Folic Acid is Toxic In Normals, What About MTHFR Folks?

Great question. With MTHFR issues, the folic acid situation becomes even dicier. This specific question hasn’t actually been studied in humans yet, and there are a lot of ethical considerations that would go into that (it’s frowned-upon to give humans potentially toxic doses of something for the sake of science.) There is a really great mouse study (we’re allowed to poison them) and the name mostly sums it up.

High folic acid consumption leads to pseudo-MTHFR deficiency, altered lipid metabolism, and liver injury in mice.

My work here is done.

Let me give you the run-down of key points from this study:

  • Mice were fed either a normal diet or a high-folate diet (10x the normal level).
  • Normally fed mice worked out normally so this is the last we’ll talk of them.
  • Folic Acid-fed mice had abnormally weighty livers and spleens
  • Folic Acid-fed livers were fatty in a pattern typical of Non-Alcoholic
  • Fatty Liver Disease (often seen in MTHFR folks, BTW).
  • Folic Acid-Fed mice showed signs and symptoms of megaloblastic anemia, worse in MTHFR+/+ mice (this is usually caused by folate deficiency)
  • Folic Acid-Fed mice showed high white blood cell counts, which were even higher in these same mice with MTHFR issues.
  • MTHFR activity is inhibited by high levels of folic acid in mice, even in genetically wild-type mice.
  • The livers of Folic Acid-fed mice had reduced ability to methylate toxins as compared to the other mice.
  • The amounts of SAMe (the product of the methylation pathway) and methyl-THF (active folate) were reduced in the Folic Acid-fed mice, especially in those with MTHFR issues.
  • The expression of other genes involved in the methylation pathway was also altered in the Folic Acid-fed mice. (Mtr, Chdh, Pemt, and Mat1a)

We suggest that high folic acid consumption reduces MTHFR protein and activity levels, creating a pseudo-MTHFR deficiency. This deficiency results in hepatocyte degeneration, suggesting a 2-hit mechanism whereby mutant hepatocytes cannot accommodate the lipid disturbances and altered membrane integrity arising from changes in phospholipid/lipid metabolism. These preliminary findings may have clinical implications for individuals consuming high-dose folic acid supplements, particularly those who are MTHFR deficient.

Christensen KE, Mikael LG, Leung KY, et al. High folic acid consumption leads to pseudo-MTHFR deficiency, altered lipid metabolism, and liver injury in mice. Am J Clin Nutr. 2015;101(3):646-658. doi:10.3945/ajcn.114.086603

So For MTHFR Folks, Folic Acid is… TOXIC.

Or at least, very, very bad. The bottom line is, don’t take it and avoid it in foods. We’ll cover foods in more detail because naturally occurring folate are great and should be eaten, but fortified foods – like breads, cereals, and grain products, should be avoided.

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