L-Methylfolate (5-MTHF): Your Must-Read Beginner’s Guide

L-Methylfolate (5-MTHF)- Your Must-Read Beginner’s Guide

Folate and folic acid are nutrients required for many critical functions in the body.

Unfortunately, many who have a genetic MTHFR mutation are unable to utilise these nutrients properly.

L-Methylfolate (5-MTHF) has emerged as a popular alternative, and has been used as a complementary medicine in several recent clinical trials.

This article covers what you need to know about it, but explained in human terms.

What is L-Methylfolate (5-MTHF)?

What is L-Methylfolate?L-methylfolate is the biologically active form of vitamin B9.

That means it is the form the human body can actually use in circulation.

It goes by several other common names including:

  • Methylfolate
  • L-Methylfolate calcium (refers to the calcium salt molecule it is attached to)
  • Metafolin and Deplin
  • 5-MTHF and L-5-MTHF (in this article 5-MTHF refers to L-5-MTHF)
  • Levomefolic acid
  • 5-methyltetrahydrofolate
  • (6S)-5-methyltetrahydrofolate and Quatrefolic.

The letters or numbers before the name refers to the 3D chemical structure of that compound.

In this case all you need to know is that L- and 6(S)- indicates biologically active L-Methylfolate (helpful). D- and 6(R)- indicate non-biologically active L-Methylfolate (not helpful).

Some products may only list Methylfolate or 5-MTHF, without specifying if which form it contains. If the label does not state L-Methylfolate, Metafolin or Quartrefolic then it may not be the biologically active form.

Summary: L-Methylfolate, also commonly known as 5-MTHF, is the active form of vitamin B9 the human body can actually use. L- and 6(S)- forms are biologically active, while D- and 6(R)- are not.

L-Methylfolate vs Folic Acid v Folate

The other forms of vitamin B9 you should know are folic acid and folate.

These are the forms we eat, although L-methylfolate is also found naturally in some high-folate food too.

Folate is often called the natural form of vitamin B9, but it actually refers to a family of different compound that occur naturally in some vegetables.

Folic acid is the supplemental or “synthetic” form of vitamin B9 and is typically the first line of treatment for folate deficiency and related health conditions, such as high homocysteine and Neural Tube Defects (1, 2).

In fact, it has been so beneficial for the general population that the addition (fortification) of folic acid to wheat flour is now mandatory in Australia, USA, Canada and several other countries (3).

But note that folic acid is also found naturally in foods, as it is just another compound of folate.

Any folic acid we ingest must be metabolised (converted) into Dihydrofolate (DHF), Tetrahydrofolate (THF), and then finally into L-methylfolate (5-MTHF) to be used in the body. Once in this form it can be transported into cells, tissues and even across the blood-brain barrier.

This is what they look like alongside each other… you can see they are almost identical:

folic acid, tetrahydrofolate and 5-MTHF structure

Image source.

But issues can arise during metabolism for those with an enzyme issue, such as an MTHFR mutation.

These individuals cannot complete the final metabolic step that converts folic acid to the active form L-methylfolate (5-MTHF) (4).

L-Methylfolate (5-MTHF) has emerged as a popular alternative to folic acid. This article covers what you need to know about it, but explained in human terms.

Note that the last step (the last black arrow) requires the MTHFR enzyme and Vitamin B2 to convert 5,10 methylene-THF to L-methylfolate.

This leaves folic acid supplements somewhat useless to you and potentially harmful in the long run (5).

Summary: Any folic acid or folate we ingest must be converted into its active form (L-methylfolate) to be useful. However this becomes a problem if you cannot do this conversion effectively, such as those with an MTHFR mutation.

Benefits of L-Methylfolate (5-MTHF)

Supplementing with L-methylfolate bypasses the entire folic acid metabolism cycle, which is good news if you have an MTHFR mutation.

Think of it like receiving a cooked meal instead of all the raw ingredients. An MTHFR mutation is equal to not having the pots and pans to cook with.

Studies show that L-Methyfolate supplementation is equally (if not more) effective than folic acid for increasing circulating folate in those with an MTHFR mutation. It is also highly effective at reducing homocysteine levels in healthy people (6, 7).

It is also better absorbed and interacts with fewer medications than folic acid (8).

Summary: Research shows it is just as effective as folic acid, if not better absorbed and tolerated.

L-Methylfolate During Pregnancy

L-Methylfolate During PregnancyActive folic acid is highly protective against Neural Tube Defects.

This is why all national and international health organisations advocate for folic acid supplementation before and during early pregnancy.

For those who do not metabolise folic acid well, supplementing L-Methylfolate is the clear alternative while pregnant. Especially if you have a homozygous C677T or A1298C mutation, which is thought to increase your folate requirements even more.

The link with miscarriage

Understanding why miscarriage occurs at all is still an active area of research.

Many large observational studies have found a link between MTHFR mutations and increased risk of miscarriage, at least for those of Asian decent (9, 10).

Not all studies found the link, and observational studies do not prove cause and effect, so we cannot say if it’s true for certain. Considering the important role of active folate in fetal growth and development, ensuring adequate L-Methyfolate intake should be your top priority.




Summary: Supplementing with L-Methylfolate while pregnant is the clear alternative for those who suspect an issue with metabolising folic acid.

Other L-Methylfolate Benefits

There are several other areas of health where it has been trialled or used successfully in treatment:

L-Methylfolate (5-MTHF) in depressionL-Methylfolate (5-MTHF) in depression

L-methylfolate is becoming widely recognised as an effective complementary medicine for patients with severe depression. That is, using it alongside pharmaceutical drugs (SSRI) to enhance the overall effectiveness of treatment (much like fish oil and depression).

Several randomised clinical trials have shown that 15 mg/day of L-methylfolate calcium is a safe, effective and well-tolerated treatment for patients with major depressive disorder who experience partial or no response to SSRIs (11, 12).

It appears to be particular effective in those with certain genetic variations (including MTHFR) and those with elevated inflammatory markers (13, 14).

L-Methyfolate (5-MTHF) in patients with diabetic neuropathy

Diabetic neuropathy is nerve disorder that develops over time in those with poorly managed type 1 or type 2 diabetes.

In a recent study, 544 patients with diabetic neuropathy were given Metanx (L-methylfolate-methylcobalamin-pyridoxal-5-phosphate) to trial for over a year. Based on self-reported surveys, overall pain rating decreased by 32% those previously treated with medications reported a 52% improvement in medication satisfaction (15).

Metanx is a combination vitamin B supplement, so this study did not test the effects of L-methylfolate on its own.

Summary: Early studies show L-Methylfolate supplementation may be beneficial in treating severe depression and diabetic neuropathy.

Important Considerations and Side-Effects of L-Methylfolate

Side-Effects of L-MethylfolateThere are several important factors to consider before starting L-methylfolate (5-MTHF).

  • Supplementing L-methylfolate bypasses the body’s natural checkpoints for preventing over-methylation. So we must be incredibly cautious with the dosage, as unnatural levels of folate is linked with several issues including cancer risk (16, 17, 18).
  • As with almost any supplement, this is not something you should take forever. Nor even everyday in most cases, but rather as a complementary medicine prescribed by your doctor. L-methylfolate also exists naturally in foods, so that should be your preferred source.
  • Your vitamin B levels – particularly vitamin B12 (cobalamin) – must be adequate before taking L-methylfolate. Otherwise homocysteine (not good) cannot be broken down and transformed, even with adequate folate. Think of L-methylfolate as the fire, and vitamin B12 as the firewood.
  • Minimise intake of folic acid. That means store-bought bread and anything else made with fortified wheat flour.
  • L-methylfolate (or any other form of vitamin B9 supplementation) can interact with numerous drugs and medications, so be sure to speak with your doctor first.
  • If you have been diagnosed with depression, you must first be screened for risk of bipolar disorder. Folate can enhance antidepressant effects of known antidepressant drugs, and is believed (although not clinically proven) to potentially trigger mixed/manic episodes in those with bipolar.

Potential side effects

As with any biologically active supplement or drug, certain people may experience unwanted side effects.

Unfortunately it is quite common with L-Methylfolate.

These are the most common symptoms and may appear after 2 weeks, 1 week, or even 1 day:

  • sore muscles and aches
  • acne or rash
  • insomnia and irritability
  • severe anxiety
  • nausea, headaches and migraines

If you experience this then you should speak with your doctor as soon as possible to reduce the dose or take a break. Persistent supplementation through symptoms can be dangerous.

There are also reported steps you can take to relieve some of the L-methylfolate side effects. This includes a small 10-50 mg dose of niacin, or a glutathione supplement (which I’m sceptical actually helps).

Additionally, the idea of taking more supplements to offset side effects of another is the same as taking more pharmaceutical drugs to offset the side effects of another drug.




Summary: There a very important factors to consider before taking L-methylfolate. Side-effects are also common and potentially dangerous if you do not address the problem immediately.

Recommended L-Methylfolate Dosage and Product

The FDA and European Food Standards Agency have approved L-methylfolate (5-MTHF) calcium supplements (16).

It can be obtained with or without prescription, but for non-prescribed supplements ensure the label specifies the amount of active L-methylfolate.

Prescription folate is available in 7 mg and 15 mg dosages which is very high. Unless recommended by your doctor, starting at less than 1 mg (1000 mcg) and then re-assessing is much more sensible if you are using because of an MTHFR mutation. 500 mcg (0.5 mg) or less appears to be the safest starting point.

If this is you, I recommend this supplement (disclosure: this is an affiliate link). The reason is because it contains 800 mcg of L-methylfolate (start with half) plus 1 milligram of vitamin B12 per pill.

It is also gluten, dairy and soy-free for those concerned, but always check with your doctor before taking any new supplements.

Again, there are a lot of risks associated with L-methylfolate supplementation, and it’s not recommended as a long-term solution.

You can get L-methylfolate from natural foods too.

[Last Updated: 23rd October 2016]

More on MTHFR and other genetic variations



L-Methylfolate (5-MTHF) has emerged as a popular alternative to folic acid supplementation. This article covers what you need to know about it, but explained in human terms.

Comments

  1. Pennie Farrell says:

    Because I have two mutations (MTHFR), my doctor recommended 15 mcg of L-Methylfolate. The side effects were a nightmare. I was anxious, irritable and cried for no reason. Tears would just be streaming down my face and I had no power over it. In addition, I could not sleep and was totally uncomfortable in my own skin. I would be sobbing to my poor husband and could think of no reason why. In addition, I felt mean and hostile. Finally, I did the research and found out that this product is nothing to play with. So, I am taking a week off. I plan to go back on it but follow the product you recommended.with B-12. I want to say how much I appreciate your article. You gave me far more information than my own doctor. Thanks again

    • Thanks for the feedback Pennie and kind words!
      Yes it seems your dose was too high, and/or your other vit b levels might be sub-optimal.
      Good luck, go very slow with it.

    • Hi Pennie

      Did this end up helping you? i.e. taking the b12 with methyl folate?

      I experienced the same symptoms you have with but had been taking high doses of p5p and a bit of folic acid in another concoction prescribed by a holistic doctor.

  2. I’m taking a prenatal containing 1mg of folate (500mcg as calcium folinate and 500mcg as L-5-methyltetrahydrofolaye from L-5-methyltetrahydrofoluc acid) and b12 (100mcg as adenosylcobalamin and 100mcg as methylcobalamin). Should be fine in terms of possible side-effects? Not been tested for MTHFR but pretty sure it runs in my family and my daughter is heterogenous though not sure for which mutation so just covering bases.

  3. Scott Salzman says:

    The Seeking Health supplement you recommend has 1 mg (1000 mcg), not 1 g of B12.

    And one of the other commenters said she was taking 15 mcg (really low dose), when I think she meant 15 mg (really big dose).

    Thanks for the helpful info. Ben Lynch @ mthfr.net has a great article on SLOWLY testing your tolerance for Methylfolate. And another couple of articles on Methylfolate side effects.

  4. My Doctor gave me this to help with Vitimin B absorption. It made me feel awful from the first of seven days I took it. I had a general sense of being unwell. I had extremely sore muscles making it hard to even walk upright and I am perfectly fit. It was weird. It felt like I was carrying someone on my upper back. I became easily out of breath when just moving around the house. I tried to exercise more, walking it off and using more asthma meds than normal but I never could find the right combo to start feeling better so I stopped taking it. I immediately felt back to my normal great self. I never had a change in my mood but feeling suddenly sick from a vitimin supplement that was supposed to help my body was frightening. L-Methofolate is not for me and I would caution anyone considering adding it to your regiment to improve your health. I vote F-!

    • This is a common side effect of too large a dose, and/or not taking with cofactor b-vitamins that work in tandem.
      But some people just do not do well with it, regardless of other factors, seems you are one of them!

    • Same symptoms. What do people do that can’t take Metho supplements yet need to get B’s absorbed in ones body?? Frustrated

  5. I’m homogenous c1298c and have a severe mercury poisoning after full mouth restoration last October 2015 and so many health problems my red blood cell count was so high doc tested for genetic mutation and low and behold. Problem is I can’t get stable. Between folate and b vitamins. I had such severe immune response with candida, lichen planus, dermidex outbreak, you name it after teeth issue and keep having folic acid side effects no matter my b vitamin etc. Eating very well no sugar very little carbs no processed foods.I got doen to 98lbs. Up to 105 now. I’m not sure my doctor knows what to do and I spend hours on the Internet searching for answers. Help

  6. Breanne says:

    Please help. I’m struggling with my diagnosis of MTHFR. I have two mutations, one from my mom, one from my dad. In addition to this I also found out I have PCOS. I have gained a ridiculous amount of weight over the last 6 months. My hematologist just told me she is pretty sure she won’t allow me to take birth Control, which is one of the only “treatments” for PCOS because of the fact that I have two mutations. Is this accruate? Would birth control put me at serious risk for stroke? Should I be more worried about the MTHFR. My doc didn’t seem as concerned with my mutations.

  7. Blenda Braswell says:

    What is the difference between methylfolate and L-methylfolate? Does it matter which I take to help with depression?

  8. Travis Marttila says:

    If Folic Acid and Dietary Folate are broken down the same way, should one also avoid Dietary Folate as much as possible?

  9. I’ve been taking a prescription for L-Methylfolate Calcium 15 mg per day for about 3 years. I was recently contacted an told my insurance would no longer cover this due to it not being FDA approved. The prescription is quite expensive. Does anyone know if the prescription is similar to some of the online vitamins for L-Methylfolate? Thanks

    • My insurance also denied the prescription, but I found a coupon through GoodRx.com. Good rx.com can direct you to a pharmacy in your area with the least expensive price. The savings were remarkable!

  10. Momma Megan says:

    My doctor prescribed 2 Folgard tablets per day because I have MTHFR. I know taking methylfolate is better so I’ve been taking 3mg daily. Is this an accurate conversation? I am also taking 800mg of folic acid that are in my prenatal vitamins as well. I also recently read to reduce the folate dose after 12 weeks? What is the recommendation for that?

  11. Can I take L-Methylfolate (5-MTHF) even if I don’t have the gene mutation but I am planning on getting pregnant or just folate? Is 800mg ok? Thanks!

  12. My daughter has bipolar disorder. She takes wellbutrin and lamotrigine for the bipolar. Her homocysteine is normal but her Vit B-12 in blood tests is always high, highest was 1600. She was tested for MTHFR mutation and it came back homozygous A1298C. She started taking the L-5-MTHF 5mg but after reading we decided to stop and figure out the right way to do it. Because she has the mutation does the high B-12 mean her body is not using it? For some reason they didn’t check folate. Should we check that also? We were going to try the product you suggested to restart and slowly increase. Is it okay to take the methyl B-12 if her B-12 in the blood is high? Also what is the precaution with bipolar disorder for taking these supplements?

    • Could be she is not using the B12.

      But there is risk with l-methyfolate and bipolar. Because it can greatly affect mood, up or down.

      You need to do this with your doctor.

      • Hello, I’m new here & that’s me exactly. High B-12, 1500 in my blood work yet, I’m a shaky, angry, irritable mess on Metnx, low dose or Deplin. Seems no health practitioners get it. I’m spinning as I get worse & my memory, cognitive function is suffering.

  13. I recently subscribed to your articles and am quite relieved to find one place to get this information. Thank you for this terrific service.

    I am heterogygous and my 14 yo daughter is homozygous for the C677T mutation and are currently taking psychiatrist-prescribed Deplin (L-Methylfolate), 15 mg/day for me and 7.5mg/day for her, as well as supplementing with B12. Both of us has suffered from depression and are currently stable with the Deplin and SSRIs.

    After reading your article, I am concerned that the Deplin doses we are taking may be too high. How would we know? Also, I was a bit confused by your statement that “as with any supplement, this is not something you should take forever.” If we don’t have the enzymes to break down folate//folic acid to its usable form, isn’t that a permanent condition requiring permanent supplementation?

    • Deplin is a high dose, but the side effects are severe. So if it was too high you would know about it.
      Your psychiatrist knows best in any case.
      I recommend extra low to people taking l-methylfolate on their own.
      You are right, I’m referring to any one particular supplement or drug, and anyone particular dosage. I will re-phrase

  14. Suzi mclean says:

    I have a toxic level of b6…?
    I do not use a supplement..
    Being tested for the mthfr mutation ..waiting for results..
    Pain, muscle cramps, tremor, bilat. foot pain,

    What am I supposed to eat?!?!

  15. Mimi Cox ND says:

    Folic acid is the synthetic form of B9, and is not absorbable for those that have the MTHFR polymorphism. It is artificial and inactive. It will NOT have any good effects for these people. If someone who is positive for the MTHFR gene mutation were to take this artificial form of folate, once it adheres to our receptors it actually stops enzyme production. Please stop reporting about folic acid that it is ok. It is important individuals who have this mutation eliminate anything with folic acid in it.

    • Dulce Andrade says:

      are you stating this artil is wrong and people should not take L-Methylfolate.
      I have MTHFR (dual mutation) and Dr has me on prescribe Folic Acid.
      was considering switching to L-Methylfolate.

      • You have a genetic mutation called MTHFR where your body cannot breakdown anything synthetic. You should not be taking ANY form of synthetic vitamin. Synthetic vitamins are: Riboflavin, Niacin, D-Biotin, Folic Acid, Cyanocobalamin. To clarify, Folic Acid is synthetic. L-Methyfolate is not synthetic and therefore you can take this form of folate and your body will be able to use it.

  16. I only just heard there is a difference between folic acid and folate. i have been taking at least 1.8mg of folic acid for years as recommended by my arthritis doctor because he has me on Methetrexate. should I switch ti folate? The dose is supposed to lessen hair loss.

  17. My doc currently has me on 5-MTHF Optimizer w/ AstraGin and BioPerine for optimal absorpiton… i take 2 a day (8mg)… I have a hard time swallowing pills and wanted to switch to Superior Source Methylfolate microlingual tablets… each is 1000 mcg… would that do the same and/or be okay? the doc tells me i need the broken down folic acid as my body doesn’t break it down… thanks for any help.

  18. Ana Rodriguez says:

    I find your site to be so thorough and informative that I feel compelled to assist in making it even more complete and informed.
    B-12 is, as you put it, The Firewood. Therefore your site could stand to have much more information on this vital and important nutrient.
    http://dramyneuzil.com/what-is-the-best-b12-for-mthfr-mutants/
    Thanks for all you do!!!
    Ana

  19. Susan Price says:

    I am going on a cruise next month and I am very concerned about what to eat. Any suggestions on how to survive a 7 day cruise when I have so many dietary restrictions due to MTHFR. I’m aLSO a congestive heart failure patient and I require a low sodium diet. Thank you ahead of time for any light you can shed on this for me.

  20. Great article, learned a ton! Would you mind attaching your sources please? Thanks!

  21. I am homozygous A1298C. I began titrating your B12 sublingual tablet – 1/4 for four days, then 1/2 tablet for a week. I immediately noticed a lift in energy and spirit. My urine was noticeably potent but is now normal. After 8 days on the 1/2 tablet my headaches and fatigue returned so yesterday I added another 1/4 at lunch time. Today I feel lousy with a continued headache that may well need migraine medication (injectable Imitrex) to stop. I don’t seem to have any other other symptoms listed like irritability, anxiety, insomnia – although I have not slept as soundly the last three nights.

    Do I increase to a whole tablet or just stop for a period? I am basically gluten and dairy free and have not eaten processed foods in years.

    I was feeling so good at the beginning and thought I had a new lease on life!

    Hope you can suggest where I go from here. I have a new order for the Optimal Multivitamin and more B12 sublingual tablets backordered – wonder if I should cancel it.

    Thank you for any ideas.

  22. MARY JONES says:

    Douglas Laboratories B-Complex with Metafolin® and Intrinsic Factor — 60 Vegetarian Capsule
    Is this a good product to take for this?
    Thank you

  23. i am supposed to be starting methotrexate treatment for rheumatoid arthritis. my rheum has me on 5 mg’s of folic acid daily (as you need to take it with mtx),
    i would rather take the l-methylfolate. unfortunately deplin isn’t available out in Canada, so I’d have to do this with the supplemental form. any recommendations for equivalent dose?

    thank you!

    -Charlie Sacks.

  24. In September of last year I was prescribed Cetefolin NAC by my integrative M.D. I was not tested for the MTHFR mutation. At that time I was also taking Lexapro. Within about two weeks I had a severe panic attack. My doctor advised me to go off of the Lexapro. For the next four months I felt great even though I was going through a very stressful time in my life. About one month ago I started to experience what I think is a tension headache. I get pressure mainly in the back of my head and sometimes between my temples. In addition, I’ve had several panic attacks too. When I went to the emergency room they did take a CAT scan and that came back negative. Since then I went back to my chiropractor to see if this was originating from a neck issue. I also went to an ENT and I’m having a CAT scan of my sinuses performed tomorrow. I even have an appointment with my eye doctor because I really haven’t been wearing my glasses and I do squint a lot. When I called my doctor about a week ago he told me to stop taking the Cerefolin for a week. It’s been six days since I’ve been off of it but I’m still experiencing similar symptoms. I decided as of yesterday to go back on the Lexapro. Based on all the research I’ve been doing my best guess is that I am over methylated. Is it possible that my ymptoms are being caused by this? If so, would it take longer than six days for the symptoms to go away?

  25. I did the genetic test with 23 and me and found I had a problem with MTHF. I took the supplement but ended up breathless, fatigue, muscle pain etc… all the side effects that can bring your functioning to a halt. However, I found that if I took Coq10 and Glutathione as well, I handle the 5-MTHF supplement perfectly and now I feel great all the time.

  26. Questions:
    1. Does the time of day make a difference when taking the pills? Ex: Does taking the pills at night instead of the morning increase the risk for insomnia?
    2. If you are taking a SSRI in the morning should you take the supplements at the same time or in the evening to lessen the stress on the body processing everything at once?
    Thanks
    Mike

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