MTHFR Methylfolate vs. Folic Acid Facts and Myths

By Samantha Gilbert, FNC, CHNP, CNC     Last updated on November 4th, 2021

Is it really true that folic acid is “bad” for you because it’s synthetic and your body must convert it to the metabolically active form of folate, L-methylfolate, before your body can use it? Or was this myth started to sell more expensive methylfolate supplements and inaccurate testing methods such as the MTHFR genetic test?

Proponents of methylfolate supplements often think that more is better, both in dose and duration. For many years now we have seen negative side effects from the use of all forms of folate and folic acid supplementation, and new reseach finally confirms what we’ve been sharing for decades: any form of folate or folic acid should not be taken long term without specific biochemical laboratory testing and evaluation due to the very negative side effects that could arise.

It is not only important to know who would benefit from taking folate, folic or folinic acid, or methylfolate and how much is beneficial, but also a need to understand which form is best for each individual.

What Is the Difference Between Folate, Folic Acid, and Methylfolate?

Also called Vitamin B-9, folate is naturally found in many foods including green leafy vegetables such as spinach and swiss chard, to beets and avocados. It helps us utilize proteins in our bodies, form new blood cells, and create new DNA. It is important for the prevention of neural tube defects in infants as well as heart disease. It is also needed to lower homocysteine, an amino acid that can be problematic when elevated.

In 1998, folic acid fortification of flour and cereal began in an effort to minimize neural tube birth defects. Doctors also began prescribing folic acid supplements, which are a way to take concentrated amounts of folate, to their pregnant patients. Unfortunatley, overprescribing became the norm (and continues to this day), which has lead to an increase in autism and mental health disorders in children such as ADHD, OCD, and depression and anxiety to name a few. Keep reading to learn why this is happening.

The Duality of All Forms of Folate and Folic Acid Activity

Much discussion surrounding methylfolate comes from genetic testing and the MTHFR paradigm, which is neither an accurate assessment nor an appropriate guide for true methylation disorders because the MTHFR test is only 30% expressive at best, which means 70% not expressive. Another misconception people have is that MTHFR is part of the primary pathway of methylation. MTHFR is a powerful methylating enzyme in a certain part of your system, but it’s part of a backup pathway, not the primary pathway.

Methyl groups control DNA by binding to a gene and telling it whether or not to express itself. I don’t know about you, but I’m not at all comfortable banking my health on something that might only be 30% expressive.

So what happens when you feed the backup pathway and not the primary pathway? Your backup is depleted and you plunge, and this is what we see happening all the time in people that take high doses of methylfolate. In fact, if you look at the Methylation Profile test by Doctor’s Data (which is what I use in my clinic) it specifically illustrates that MTHFR is part of the secondary or backup pathway, and it certainly does not play a prominent role in mental health.

MTHFR is a secondary pathway and only 30% expressive.
Doctor’s Data Methylation Profile Lab Test

Methylation status is determined by a tug of war, as we’ve said for a long time now, a tug of war between enzymes for undermethylation versus enzymes for overmethylation. The eight to 10 enzymes over here versus the 12 enzymes over here as groups, and whoever wins that tug of war determines your methylation status, not one enzyme. You may have a SNP (single-nucleotide polymorphism) but it doesn’t mean that that SNP is causing you any trouble (again, 70% NOT expressive). But people think it’s a genetic test, and it’s been hyped up by many doctors, so it must be fact, and it must have some relevance.

So Why Does Methylfolate Cause So Many Problems?

What many people fail to understand is the duality of all forms of folate and folic acid activity. One may take longer or faster to work, but they all end up doing the same thing over time, which can have a devastating effect on mental and physical health.

This is because in the cytoplasm (outside the nucleus of the cell), it’s a donor of methyl, so for an undermethylated individual (that doesn’t make enough methyl groups), the thinking is that MTHFR methylfolate is the appropriate course of treatment. In actuality, that’s not correct because in the nucleus, which is the command center of the cell, where we are trying to affect change, it steals 10 times more methyl than it donates. This can alter many cellular mechanisms including detoxification, enzymes, hormones, and neurotransmitters. This is because all forms of folic acid (including folinic, MTHFR methylfolate, and plant-based whole food sources such as spinach and avocados) steal methyl at the level of DNA.

This is why I don’t recommend vegan diets for undermethylated individuals.

Again, whatever form of folate or folic acid you take is going to work differently outside the nucleus of the cell where it actually donates some methyl into the system and this is one of the reasons MTHFR methylfolate has become so popular.

Yes, MTHFR Methylfolate Works Faster

The ready-made solution that so many clinicians use is “let’s just supplement with 5-methylfolate.” It certainly would be an open and shut case if biochemistry was as simple as this. But of course, things get more complicated, and this approach doesn’t usually work.

Loading up on 5-methylfolate, especially if given by itself will result in neurotransmitter changes, erring on the side of elevated glutamate, and shunted serotonin synthesis. It’s the reason so many people taking massive doses of methylfolate have such a high frequency towards adverse reactions and why so many people come to me with serious side effects from methylfolate supplementation.

Again, you need to address the entire pathway, not just one enzyme. So then the challenge with methylfolate, if given to an undermethylated person, is that the methyl piece acts and goes away and now you’re left with a demethylating agent. And as I shared previously, all forms of folate and folic acid donate some methyl outside the nucleus of the cell, but inside the nucleus, which is where our DNA lies and all our instructions are made, it steals 10 times what it donates in the cytoplasm.

Methylfolate is a nonfunctional creature. If you think about the methylation cycle, spinning millions of times in one second, do you know how often methylated folate actually works? One time. One time out of a million spins and it’s done for the day and this is why Dr. Walsh of the Walsh Research Institute calls it a suicidal nutrient. Methylfolate does not have the power most people think it does.

Folic Acid Supplements: Why Process Doesn’t Matter As Much

Most folks misunderstand the process involved in the metabolism of folic acid versus methylfolate. This is the key to understanding the difference between how folate gets into the cell, or the time it takes to do that, versus the end goal of having a physiological effect from taking the particular form of folate you have ingested.

Folic acid doesn’t have to be demethylated, but methylated folate does. Even though methylfolate gets into the system faster, it doesn’t actually begin to work faster than folic acid would because there is the extra step of demethylation before it can be utilized. It is only absorbed faster and still needs processing. Quicker absorption has to go through longer processing and can ultimately take longer to complete the utilization process.

It’s like the difference between taking a direct flight to a city and taking a connecting flight to the same city. There are more steps, more delays when you take a connecting flight that re-routes you through another city. One way takes longer. One way is more direct. Once something enters a cell there is a whole lot that goes on. Whether you take a direct route or a re-routed path makes little difference in the end. By the time it is all said and done these pieces are all moving in the same direction. The only difference we are talking about is the rate at which they are moving.

The Dangers of Methylfolate

Methylated folate is not a one size fits all folate supplement. For some, it can have adverse effects, and unless you are properly tested for your methylation status, you do not know whether it will be beneficial or detrimental to you.

What do you think happens to that methyl contained in methylated folate? That methyl is going to get absorbed into your body. I’ve already detailed what happens to an undermethylated individual taking methylfolate, but what if you give that methylfolate to a person who is overmethlyated? Well, it is like adding kerosene to put out a fire. You’ll make your methylation imbalance worse. Overmethylated patients should use folic acid that is not methylated. If you are overmethylated do not take methylated folate or any other product that is methylated.

But Folic Acid is Synthetic, and That’s Bad, Right?

Folic acid is synthetic, yes but this does not make it unhealthy. It works, and it works better than natural forms in most cases. Folic acid is used to fortify foods and is found in most dietary supplements, simply because it is more stable and bioavailable than natural folates. Historically, since the days of Carl Pfeiffer, the pioneer in orthomolecular medicine, we have traditionally used folic acid for our patients and it has shown to be extremely efficient and effective. The notion that folic acid is synthetic and is not effective is inaccurate.

Anytime you take something out of nature and take it into a lab it’s technically not natural anymore and has gone through processing and synthesizing to get it into pill form. This is the case for methylfolate, folate, folic and folinic acid.

Folinic acid is metabolically active, which means that folinic acid does not require enzymatic conversion before it can be utilized. Folinic acid can be found naturally in foods, but in order to benefit from folinic acid, it has to be prescribed in therapeutic doses for our patients. There are times when we may prefer the use of folinic acid to folic acid when we work with certain patient populations. Folinic acid has its best utility in autism, as we have seen over the years of research and clinical practice at Pfeiffer Treatment Center, now closed, the Walsh Research Institute, the Mensah Medical clinic, and here at the Eat for Life clinic.

Click here to listen to episode 3 of my podcast where Dr. Albert Mensah of Mensah Medical and I discuss how the body processes methylfolate and the myths surrounding MTHFR testing. In episode 14, we dive into the dangers of folic acid use and vegan diets for breast cancer patients.

We have seen clinically time and again that people who are truly undermethylated do not do well on methylfolate after two to three months. In fact, to the contrary, many people report worsening of symptoms. In summary, we have three decades of research and patient outcomes (a biochemical database of over 3 million chemical assays) that support all we’ve been discussing regarding the benefits of the different forms of folate and folic acid, and their appropriate usage as well as challenges.

Please remember everyone is unique so let’s not generalize regarding folic acid supplement use. There is only one you. Even if you are a twin, there is still only one epigenetic you.

Nutrition Counseling To Help You Thrive

In order to heal methylation disorders, I aim to identify and address the root biochemical causes and imbalances of your symptoms.

I offer a free 1:1 consultation to help you disconnect from the hype and the marketing jargon, and address the true source(s) of your discomfort. It’s time for your healing journey to truly begin.

References

Too Much Folate in Pregnant Women Increases Risk for Autism (Johns Hopkins Study)
Science Daily: Researchers found too much folic acid was just as detrimental as too little.
23 & Me article about MTHFR (with research links)
MTHFR ACMG Practice Guideline: lack of evidence for MTHFR polymorphism testing

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36 thoughts on “MTHFR Methylfolate vs. Folic Acid Facts and Myths”

    1. Folinic acid is metabolically active, which means that it does not require enzymatic conversion before it can be utilized. Methylfolate requires the extra step of de-methylation before it can be utilized.

      1. Im confused so confused. I hade a test done that said i had the mthr gene mutation. So what do I take ????

    1. Over 40 years of human research and clinical patient outcomes by Dr. Albert Mensah, MD, and William Walsh PhD, about the benefits of different forms of folic acid and their appropriate usage override what you’ve shared. I encourage you to read this post in its entirety, especially the section where synthetic folic acid is specifically addressed. Folic acid is extremely efficient and effective. The notion that folic acid is synthetic and is not effective is incorrect. Anytime you take something out of nature and take it into a lab, it is synthetic. Methylfolate is not a better form. In fact, as this post explains, it is not a good option for both over and undermethylated individuals.

  1. Hello Samantha,

    I am currently being treated by a practicioner who has been trained by Walsh so I will also bring up this question to her.

    I was tested being overmethylated and having (mild) pyroluria. I am on a regimen that includes methylfolate atm and I am not doing any better so far. I am feeling very tense a lot of times and certain supplements seem to make things worse.

    Now that I read your post, I am thinking of changing methylfolate for folic acid, but I am wondering if the dosage has to remain the same.

    Thanks for your answer.

    Best regards,

    Hans

    1. I’m overmethylated and use folinic acid. (I am also treated by Dr. Mensah.)
      I have an MFTHR snp and read about staying away from folic acid.

      1. As shared in this article that Dr. Mensah and I wrote together, folic acid isn’t bad and works quite well for patients that need it. Folinic is more metabolically active so we use it as well, again depending on the patient’s need and chemistry.

  2. Hi, I might want to recommend your recipes for our customers, but are your recipes for people with the biotype “undermethylation” all low-folate?
    One comment: According to Walsh, folate act as a serotonin reuptake promoter, driving serotonin activity even lower, and the benefits from improving methylation (if any) are overwhelmed by weakened serotonin neurotransmission for these persons. We have noticed mild depression from taking only 100-200 mcg of methylfolate for extended periods, so taking several hundreds or even thousands of mcg on a daily basis does not sound good. Still it is prescribed for many depressives with MTHFR. However I see some advantage of helping in the conversion of homocysteine to methionine, and other functions, but more is not better.
    https://www.vitacure.me/blogs/news/methylfolate-the-suicidal-nutrient-dont-believe-the-hype

  3. I am 8 weeks pregnant and an undermethylator. I had been avoiding folate for myself, but understand from Dr. Walsh’s writings that for the first trimester I should be taking methylfolate for the benefit of my developing baby, while continuing Sam-e and L-methionine for myself. I have been taking 400mcg of methylfolate and getting additional through foods. Do I need to revisit this? I have not been able to find a Walsh or Mensah trained practitioner in my area.

  4. So what about a doctor who prescribes high doses of folic acid to women, like myself, when they are pregnant very early on in the pregnancy to prevent birth defects, and then we have a child with severe ADHD, on the autism spectrum, etc. Could this have contributed to that? I have no clue what my methylation status was at the time or is now.

    1. Autism is an epigenetic disorder, meaning that one or both parents contributed mutations that created the condition. It is important to take folic acid in the beginning to protect your child, but not throughout pregnancy if you are undermethylated, as it can have negative effects. I encourage you both to get properly tested. Autism and ADHD are treatable, especially when caught early on.

      1. I am reading up on the these old posts. Can you please describe what specific tests you think the parents should have done?

  5. I am an under methylator (apparently down 40%.) I took folic acid prior to pregnancy and miscarried 3 times. This is one of the problems of taking folic acid for under methylation. Early 2017 I took a Genova test (Optimal Nutrition Evalutaion) which recommended I need 1200mcg of methylfolate. I have been doing this for 8 months now and feel great! Have also increased green leafy veg intake.

  6. Hi Samantha

    I’ve read your articles with great interest since reading Nutrient Power. I am going to be tested by a Walsh practitioner in Ireland (certified from WRI site so legitimate as I know many claim to be but are not) so I’m not looking for individual advice as I will get that in a few weeks once my tests are conducted and results come in. I just wondered generally about your opinion on the following

    Ive heard Walsh say bloods are only part of the picture and in the books many traits are listed for each biotype -specifically referring to depression chapter. I feel I have traits from both under and overmethylated lists so to me tests are the only way to truly tell.

    What I wondered is I had some tests on our national health service in the UK and have low folate at under 2.2 acceptable range seemed to be from 2.4- so lets say in theory I receive my Walsh tests back and and Im found to be an undermethylated person. Does this mean I should NOT attempt to increase my folates to an acceptable level as I know from reading the book undermethylaters should avoid folates.

    Secondly and this is just out of interest how often do you have clients who seem to have traits from many of the biotypes? As I get the impression this is part of the decision making process Ive even heard Mensah and Bowman say in webinars they suspect what tests results will be before they come back and are normally correct. Whereas to me the bloods will reveal the true picture and when they come back the traits become irrelevant scientifically speaking as they are just generalisations vs chemical proof.

    Thanks 🙂

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