L-Methylfolate, Methylfolate, 5-MTHF, L-5-MTHF. What is the Difference!?

Those with MTHFR mutations scan labels, read websites or listen to their doctors rattle of conflicting terms for a nutrient they really need.

Understanding which form of methylfolate is best must be clear.

Why all the confusion?

Because there are so many different terms used for methylfolate.

By the end, you will understand everything you need to know about methylfolate.

More significantly – you will understand how to pick the right form of methylfolate.

Terms often used for methylfolate are:

  • Methylfolate
  • L-MTHF
  • L-Methylfolate
  • L-Methylfolate Calcium
  • D-Methylfolate
  • D-5-Methylfolate
  • Levomefolic Acid
  • Metafolin
  • 5-MTHF
  • 5-Methylfolate
  • 5-Methyltetrahydrofolate
  • L-5-MTHF
  • L-5-Methyltetrahydrofolate
  • 6(S)-5-MTHF
  • 6(S)-5-Methyltetrahydrofolate
  • 6(R)-5-MTHF
  • 6(R)-5-methyltetrahydrofolate
  • Quatrefolic

Are these forms of methylfolate all the same?

Are any of these forms of methylfolate the same?
Yes. The same forms are grouped together here. These forms are synonymous with each other:

  1. L-5-MTHF = L-5-Methyltetrahydrofolate = 6(S)-L-MTHF = 6(S)-L-Methyltetrahydrofolate
    • Good forms which are well absorbed
  2. L-Methylfolate Calcium = Metafolin = Levomefolic Acid
    • Good forms which are all well absorbed
  3. D-5-MTHF = D-5-Methyltetrahydrofolate = 6(R)-L-MTHF = 6(R)-L-Methyltetrahydrofolate
    • Avoid these (learn why soon…)

Then what are the other forms of methylfolate?

The other forms of methylfolate may or may not be 99% pure biologically active methylfolate.

  • 5-MTHF
  • 5-Methylfolate
  • 5-Methyltetrahydrofolate

How come these may or may not be 99% pure biologically active methylfolate?
These forms do not specify the L form (or 6(S) form) of methylfolate; therefore, you do not know what you are ingesting.

The forms of methylfolate not specifying L or 6(S) likely contain more than 1% of the D form of methylfolate.

What is the difference between D and L forms of Methylfolate?
In organic chemistry, one learns compounds may have the exact same molecular formula and sequence of bonded atoms but differ three dimensionally. These compounds are known as steroisomers.[1]

There are two common forms of sterioisomers:

  1. Enantiomers:
    • mirror images of each other, such as our hands.
    • same physical properties
    • may have different biological effects
  2. Diastereoisomers:
    • not mirror images of each other
    • rarely have same physical properties
    • have different biological effects

Methylfolate has stereoisomers in the form of diastereoisomers.

The forms of methylfolate that are biologically active are:

  • L forms
  • 6(S) forms
  • L-5 forms
  • Metafolin
  • L-Methylfolate Calcium
  • Levomefolic Acid
  • Quatrefolic

The forms of methylfolate that are NOT biologically active are:

  • D forms
  • 6(R) forms

The forms of methylfolate that may or may not be biologically active are the:

  • forms which do not specify L, 6(S) or trademarked name of Metafolin
  • 5-MTHF
  • 5-methylfolate
  • 5-methyltetrahydrofolate

From the package insert of Metanx, a prescription drug using biologically active Metafolin[2]:
“L-methylfolate or 6(S)-5-methyltetrahydrofolate [6(S)-5-MTHF], is the primary biologically active diastereoisomer of folate and the primary form of folate in circulation. It is also the form which is transported across membranes into peripheral tissues, particularly across the blood brain barrier. In the cell, 6(S)-5-MTHF is used in the methylation of homocysteine to form methionine and tetrahydrofolate (THF). THF is the immediate acceptor of one carbon units for the synthesis of thymidine-DNA, purines (RNA and DNA) and methionine. About 70% of food folate and cellular folate is comprised of 6(S)-5-MTHF. Folic acid, the synthetic form of folate, must undergo enzymatic reduction by methylenetetrahydrofolate reductase (MTHFR) to become biologically active. Genetic mutations of MTHFR result in a cell’s inability to convert folic acid to 6(S)-5-MTHF.

Metafolin® (L-methylfolate calcium) is a substantially diastereoisomerically pure source of L-methylfolate containing not more than 1% D-methylfolate which results in not more than 0.03 milligrams of D-methylfolate in Metanx®

D-methylfolate or 6(R)-5-methyltetrahydrofolate [6(R)-5-MTHF] is the other diastereoisomer of folate. Studies administering doses of 2.5 mg per day or higher resulted in plasma protein binding of D-methylfolate higher than L-methylfolate causing a significantly higher renal clearance of L-methylfolate when compared to D-methylfolate. Further, D-methylfolate is found to be stored in tissues in the body, mainly in the liver. D-methylfolate is not metabolized by the body and has been hypothesized to inhibit regulatory enzymes related to folate and homocysteine metabolism and reduces the bioavailability of L-methylfolate.”

Example of why all this is important to know
A supplement company has a supplement called, “5-MTHF”

Let’s say this supplement states it contains 10 mg of 5-MTHF.

One assumes this contains 10 mg of biologically active L-methylfolate.

Don’t assume.

The likelihood of it containing 99% of the biologically active form of L-methylfolate is slim to none.


Prescription drugs such as Deplin contain 99% active L-methylfolate as Metafolin. Deplin provides two potencies of L-methylfolate: 7.5 mg and a 15 mg

This much L-methylfolate is VERY potent and must be prescribed by a physician.

Merck does not allow any supplement company to provide more than 1 mg of their L-methylfolate in a stand-alone supplement. If L-methylfolate, as Metafolin, is included in a formula along with other nutrients, then a maximum of 800 mcg is allowed.

What amount of this 10 gram 5-MTHF supplement actually contains the biologically active L-methylfolate?
It is not known without requesting a lab report.

The likelihood of it containing a significant amount of the inactive D form of methylfolate is high.

Remember, the D form of methylfolate is undesirable and actually may reduce the bioavailability of L-methylfolate.

What to do?
Two things:

  1. Request a prescription from their physician to obtain drugs containing Metafolin.
  2. Look for supplements specifying the amount of active L-methylfolate.

Drugs containing Metafolin are:

  • Metanx
  • Deplin
  • Cerefolin
  • CerefolinNAC
  • Neevo
  • NeevoDHA

Supplements with Methylfolate
One must carefully evaluate supplements specifying the use of Metafolin, Quatrefolic or the L form.

If the supplement does not specify on the label that it uses Metafolin, Quartrefolic or the L form of methylfolate, then it is not recommended to use without first inquiring directly to the manufacturer. A manufacturer may have named their product as 5-MTHF and use the pure L form of methylfolate; however, one must inquire to be certain.

Quatrefolic: What is this?
This is a new form of methylfolate that uses glucosamine instead of calcium to bind the L-methylfolate. Quatrefolic is also a quality form of L-methylfolate.

Key Points about Methylfolate:

  1. Not all methylfolate is the same
  2. The D form of methylfolate actually is undesired and should be avoided
  3. The L form of methylfolate is the desired form
  4. There are many names for the same thing. Understand them.


Supplements using the pure form of L-Methylfolate

Seeking Health uses purely the L-methylfolate as Metafolin.





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41 Responses to “L-Methylfolate, Methylfolate, 5-MTHF, L-5-MTHF. What is the Difference!?”

  1. Laura April 26, 2012 at 6:40 pm # Reply

    Thank you for the work you’re doing to help those of us with MTHFR and repeated miscarriages! I’ve been taking Garden of Life’s Raw One for Women multivitamin. It lists “Folate” 800 mcg. Would that be an acceptable form? We have a call out to Garden of Life, but haven’t heard back yet. I just found out that I’m pregnant, and trying to wade through the information to figure out what to do as far as a prenatal and B vitamins. I am hetro for C677t. I’ve had four miscarriages. Three second-trimester, and one at nine weeks. I have 6 healthy children, but my last three pregnancies were miscarried, and this is the only possible cause that was found. I also have hashimotos. I have upped my synthroid dose and am now on heparin. I’m planning on ordering the sublingual B12 w/ Methylfolate.

    • Laura April 29, 2012 at 6:03 pm # Reply

      Dear Dr. Lynch,

      I am hetero for MTHFR, C677T allele. I have a 13 yr old son who is diagnosed with ADHD, Autism/Aspergers ( very high functioning), severe asthma, allergies, autoantibodies to folate ( Dr. Edward Quadros test), hypothyroid, immune dysfunction, mitochondrial dysfunction complexes 1 & 3, and has been identified recently by his neurologist as having significant problems with methylation.

      He is currently on 25mg of Leucovorin daily. Within 3 months his binocular vision defects resolved. This year in school ( after nearly a year on leucovorin, his reading comprehension has improved greatly to grade level ( truely amazing). He takes many supplements – too many to list here – all prescribed by his DAN! Doctor and his neurologist. I put him on an oral IgG supplement due to chronic illnesses enabled by Low IgG and low neutrophils ( not low enough to qualify for IVIG). He has also demonstrated low IgM. Since starting the oral IgG last sumer, his health has been much better. He also gets B12 (methylcolbalamin shots every 3 days.

      I am considering having him tested for MTHFR mutations. Is the Leucovorin the best form of folate for him?

      My own health issues are endometriosis, hypothyoid, premature ovarian failure, chronic hives, keratoconus and other collagen related problems.

      Thanks in advance!

      • Melissa June 11, 2012 at 6:09 pm # Reply

        Don’t know if this is appropriate posting etiquette or how we could get in touch and still maintain everyone’s privacy, but please, if it’s possible, could you tell me who your DAN doc/Neurologist is? They sound amazing, and good Neurologists, especially, seem notoriously difficult to come by–especially ones that may understand the whole cerebral folate metabolism issues, methylation polymorhisms, etc. I have a son who has, for the most part, recovered from autism, but continue to do research for him and my myriad, lifelong, vague health issues. In doing so I have recently put some GIANT puzzle pieces together regarding my extended family’s health history and really want to work with someone knowledgable. I will continue to dig in to this (amazing–a Godsend) website, hopefully contact Dr. Ben, but your post struck a chord and I thought I’d reach out, mom-to-mom. Also, dying to find out how to get Dr. quadros’ test…can’t seem to find it? Who did you find to do it? Please help! Thanks in advance…

        • Dr Ben June 11, 2012 at 7:01 pm # Reply

          Melissa –

          I will be making Dr Quadro’s test available soon on my website. It is an important test to evaluate.

          Asking for doctor referrals from each other is perfectly fine – and encouraged – please post directly in the comments ;)

          • Des October 7, 2012 at 4:21 pm #

            Just an IMPORTANT FYI: many of the Brands you listed such as NEEVO, contain Soy Lecithin (MSG) and Titanium Dioxide… Toxic when ingested on a daily basis…

        • Laura June 11, 2012 at 9:32 pm # Reply

          Dr. Richard Frye is my son’s Neurologist. He is at Arkansas Childrens Hospital. Just moved and not seeing patients yet. Well worth the time for any parent of an autistic child.

          Dr. Bryan Jepson was my son’ s DAN Dr. Unfortunately, he is no longer seeing patients. He has an excellent book called ” Changing The Course of Autism”, though.
          Feel free to email me @ lauc174@aol.com

          • Sherrie Line-Coil November 14, 2012 at 11:56 pm #

            my Neurologist in Davis, California is Eric Hassid, M.D. of Institute of Restorative Health a functional Neurology, Anti-Aging and Regenerative Medicine clinic.
            He tested me and I am compound heterozygous for the mutations.
            Am now taking 5-MTHF and having IV treatments.

            It is a releif to have some answers and a road less traveled to take my journey

  2. Jennifer July 27, 2012 at 6:02 pm # Reply

    Hi Dr. Ben,

    First of all, I’d like to say thank you for all of your responses to my questions and everyone else’s – you are providing us with so much good information!

    I have a question regarding the Prenatal Pro multivitamin made by Designs for Health. I saw it mentioned on another post as a potentially good option. In looking at their ingredient list, I see its folate is a blend called NatureFolate (a trademark blend). Then I saw on another post that you said naturefolate is not an adequate type of folate for MTHFR. Are these two terms referring to the same entity? If they are the same, do you feel the Prenatal Pro is not a good option?

    Thanks so much,

  3. prasad August 6, 2012 at 12:19 pm # Reply

    what is profalactic use of l-5,methyltetrahydrofolate?

  4. Jennifer August 13, 2012 at 9:48 pm # Reply

    Hi Dr. Ben,

    In my quest to find a good prenatal vitamin, I made an inquiry to Designs for Health, after seeing it listed on one of your posts. I asked specifically what type of methylfolate they used (they call their folate blend “NatureFolate”, which I thought I had read somewhere on here that it was not a good type). This is the response I received from them:

    “I asked our product development manager to help answer your question.

    His replied with the following information: “NatureFolate is a blend of the natural S-form of both 5-Methyl and 5-Formyl tetrahydofolate. The amounts of each is proprietary information. ”

    Would you consider this to be an acceptable form of methylfolate for a heterozygous C677T person like myself?

    Thank you for your advice,

    • Pat December 31, 2013 at 7:22 pm # Reply

      Jennifer, did you every get a response to this question? I am interested to know this also.

  5. Latoria September 1, 2012 at 2:02 pm # Reply

    I was online researching 5-MTHF and came across this page. I have a 5 year old son who was diagnosed with autism at age 2. For the past 3 months, we have been slowly introducing supplements recommended by his DAN specialist. Following testing we found that my son would benefit from: Calcium citrate, DPP IV digestive enzyme, Super Nu Thera liquid multivitamin, VSL #3 morning and ProBio Gold at dinner, Speak (which contains vitamin E, omega 3, GLA, and vitamin K), L-Glutamine, Alpha-Ketoglutaric acid, Ester C; antifungals goldenseal and grapefruit seed extract (which we rotate every four weeks), Uva Ursi for 2 week periods and switch to Oregon grape extract for six weeks, and rotate the Biofilm strippers Interfase and Nattokinase every four weeks. We have yet to introduce, Acetyl L-Carnitine, L-MethylFolate, 5-HTP, Lipoceutical Glutathione, N-acetyl-L-cysteine, and Transfer Factor Sensitive/Multi-Immune…which brings me to my research today. Of these new supplements, I will be introducing one today and would appreciate any input you viewers can offer. This site has helped me understand the differences in Folate supplements, but I question if my son has a good brand. My son takes a brand containing 1,000 mcg Folate (as Metafolin L-5-methyltetrahydrofolate). I would appreciate any advice/info you could provide Dr. Ben.

  6. Ann September 21, 2012 at 4:01 pm # Reply

    I have a 5-MTHF product that is 10mg derived from 5-methyltetrahydrofolate 20mg. I just asked the manufacturer about the 6S vs 6R composition, and here is their reply:

    “10 mg (6S)-5-MTHF and 10 mg (6R)-5-MTHF. As stated on the label, we use 20 mg total racemic (50/50) 5-MTHF to yield 10 mg (6S)-5-MTHF. ”

    Thanks Dr Lynch for your post. This product is going in the trash.

    • Marie December 21, 2012 at 7:23 pm # Reply

      Ann, is the product you mention by Metabolic Maintenance? I have several bottles with the same ingredients.

      Dr. Ben, is it okay to give this folic acid to someone who does not have the MTHFR gene mutation, or is it better not to use it at all?

      Also, I have a product by Jigsaw called Activated B w/SRT. It’s an activated B complex with Quatrefolic 5MTHF in 200 mcg. Do you know anything about this supplement? I’m wondering if it’s safe to take.

  7. Meg January 6, 2013 at 2:36 am # Reply


    Thanks so much for writing this.

    I am 30 yrs old and have MTHFR and Leiden Factor 5. Is it acceptable to take the New Chapter Prenatal (it has folate) plus one of the seeking health’s L-methylfolates?

    Also does a thyroid issue have anything to do with MTHFR?

    Thanks so much

  8. Sharon March 11, 2013 at 1:09 am # Reply

    I have a homozygous MTHR 667t defect – my naturopath has me on Thorne Laboratories 5-MTHF – the active ingredient is not listed as an L or a D methyltetrahydrofolate. Do you know if this brand has the most bio available forms that you suggest in your writings?
    Thank you

  9. Bec April 11, 2013 at 11:35 pm # Reply

    Folate (as Quatrefolic® [6S]-5-methyltetrahydrofolic acid equivalent to 1.6 mg of [6S]-5- methyltetrahydrofolic acid

    Not sure if i can post specific brands but i found this one with the above stated ingredients and am wondering if ‘folinic acid’ is okay to take for MTHFR homozygous.

    • Fruitbat December 13, 2013 at 8:12 am # Reply

      How much Quatrefolic is equivalent to 1.6 mg of [6S]-5- methyltetrahydrofolic acid?

  10. jslim180 April 19, 2013 at 8:38 pm # Reply

    I’m taking 4,500 mg of Cysteine HCL per day. The protocol also calls for 400 mcg of Folate per day. I would like to use L-5-MTHF instead. How do I figure out how much I need take?

  11. Karen July 20, 2013 at 2:46 pm # Reply

    Hi Dr. Lynch,

    Is folate in a multivitamin as broccoli the same as folate in a b-complex as Metafolin, L-5-MTHF? There is a multivitamin with 4,000mcg of folate as broccoli and a b-complex with 400mcg of folate as Metafolin, L-5MTHF. Though the dosage for the multivitamin is much higher, is it a safer bet to start with since the source of folate is natural foods? Please advise, thank you.


    • Dr Ben July 21, 2013 at 12:19 am # Reply

      Hi Karen –

      I’d call the supplement manufacturer and ask.

      My bet is it is most likely a form of THF or folinic acid and not methylfolate.

      I like to know exactly which forms of folate one is getting. Food forms may be great but I prefer knowing what I and my clients are supplementing with exactly.

      Then eating folate rich foods on your own is great.

  12. Zach August 1, 2013 at 2:08 am # Reply

    Hi Dr. Ben.

    First off, thank you for all the work that you do. Clearly it’s highly valuable to all those struggling with these issues.

    Just a couple of quick questions. I’ve taken 5-MTHF as a way to augment my current SNRI (Pristiq) and to be honest I felt quite good. I was taking 1mg per day in the morning. ON the 3rd day I had some mild insomnia and muscle aches in the shoulders/upper back. 4th day, I actually pulled something in my upper back, which seemed to be due to muscle weakness. I’ve read about taking niacin to combat the side effects of the 5-mthf, but should I continue with the 5-mthf regimen and just include niacin daily? Should the niacin be taken at a certain time or just as needed?

  13. Ryan August 22, 2013 at 1:14 am # Reply

    Is (6S)-5-methyltetrahydrofolate good? My supplement includes 800 mcg a day. I’m a double heterozygote.

    • Dr Lynch August 22, 2013 at 8:25 am # Reply

      Hello Ryan – yes absolutely. It is a great form of methylfolate which I also use.

      • Ryan August 22, 2013 at 9:21 am # Reply

        Is 800 mcg enough? I haven’t yet been able to see a doctor, but until then, what can I do? I’m taking the Country Life Coenzyme B-Complex, but I don’t know how to tell if it’s working.

  14. Jaime Michaels August 28, 2013 at 5:07 pm # Reply

    Hi Dr. Lynch, I am really confused about the B Complex Seeking Health sells. It lists for folate: 5-methyltetrahydrofolate which is a questionable form you don’t recommend. Why do you support this product? And why don’t they use the metafolin form? Also I read that Quatrefolic is much better absorbed than Metafolin – what do you think? Thanks for all your incredible information!

    • Dr Lynch August 29, 2013 at 12:44 am # Reply

      Hi Jaime –

      The B Complex provided by Seeking Health offers the 5-methyltetrahydrofolate as Metafolin which is L-5-MTHF.

      Quatrefolic is a bit better absorbed from what I am finding as well. We have switched out from Metafolin to Quatrefolic in our:
      - Prenatal
      - Active B12 with L-5-MTHF
      - HomocysteX Plus

      We will continue to move from Metafolin to Quatrefolic.

      The differences are minimal overall. I have other reasons from switching from Metafolin to Quatrefolic and it does not relate to absorption or quality. Just a personal preference.

      • Rachel February 25, 2014 at 4:45 pm # Reply

        Hi Dr. Lynch,

        Could you please elaborate further on why you are switching from Metafolin to Quatrefolic, even if it is just personal preference.

        I have switched back and forth between the two forms myself. I don’t know if it is placebo effect that Metafolin seems to work slightly better for me.

        Also, I have spent hours researching which of the two forms is better, and it is frustrating not to find a clear answer other than that Quatrefolic is the newer, next generation.

        Thank you for your response!

        • Dr Lynch February 25, 2014 at 8:09 pm # Reply

          Rachel –

          The switch was for a few reasons:
          - better absorption (slightly)
          - prefer the non-calcium bound methylfolate

          Both are very good forms of methylfolate – I think the differences are very slight.

          The difference you feel may be that Quatrefolic is actually stronger than Metafolin – try taking less Quatrefolic compared to Metafolin – don’t take the equal amount. See if that helps. You may be taking too much methylfolate when taking Quatrefolic compared to Metafolin – due to improved absorption.

  15. Cariker C September 25, 2013 at 3:15 pm # Reply

    Thank you so much for this detailed and clear information :)

  16. Fruitbat December 13, 2013 at 8:39 am # Reply

    Can you give any advice on the relative available folate in the different acceptable supplement forms?

    I ask because of wondering about the situation of switching from L-5-MTHF (Metafolin) to Quatrefolic. I have read contradictory advice elsewhere about adjusting the dosage of Quatrefolic both up and down relative to the Metafolin. Would be great to know your thoughts on this.

    Many thanks

  17. Gary December 29, 2013 at 3:03 pm # Reply

    Dr. Lynch,

    Do you know if there is a connection between folacin and histamine? I started using the Solgar Metafolin which seems to restore libido when everything else has failed. All my hormone labs look normal, and I’m wondering if I could be histapenic…

  18. Carie February 18, 2014 at 9:19 pm # Reply

    Hi, Dr. Lynch!
    Thanks for all your info from your research.
    My multi for women over 40 is listed as Folate(500 mcg as Calcium Folinate and 500 mcg as L-Methyltetrahydrofolate from L-5-Methyltetrahydrofolinic Acid, Glucosamine salt) 1 mg.
    I heard your webinar with Dr Christianson that hypothyroid patients are very likely to have the MTHFR mutation. I have been avoiding synthetic folic acid as a result.
    Would this Calcium Folinate be “safe”. Thanks.

    • Dr Lynch February 18, 2014 at 9:49 pm # Reply

      Hello Carie –

      Yes – calcium folinate can be very useful as it supports DNA base production. Methylfolate supports SAMe production and homocysteine recycling.

      Since the Methionine synthase enzyme is so picky, it is best, in my opinion, to support people with folinic acid a bit as well.

      If you are feeling good and your doctor agrees, then should be good to go.

  19. Alex February 22, 2014 at 5:16 am # Reply

    Hi Dr. Lynch. Thank you for all you do. The information on your website has helped me identify that I have a MTHFR mutation and I’ve been working with my primary care physician and taking a quality methylfolate supplement.

    In this article, you mention “steroisomers” and how we need a certain type of methylfolate to make sure we get the right form. I’m wondering if there are other vitamins/mineral supplements that could also have non-active, undesirable forms.

    I take a variety of supplements, and am curious if there are inactive forms of other nutrients – B12/methylcobalamin, B6/P5P, etc.

    Thank you!

  20. Simon March 16, 2014 at 4:22 pm # Reply

    Dear Dr. Ben,

    I was wondering about the potency bioavailability of L-methylfolate as Metafolin , or whats used in Deplin vs Quatrefolic . If Quatrefolic is just as potent (or more) as you suggest, mg. vs mg. why is Quatrefolic alot less expensive?




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