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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83 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?

    • Megan December 1, 2014 at 1:18 am # Reply

      I also have a supplement with these exact ingredients. Did you find an answer to this question?

      • Michael_Dowdy December 29, 2014 at 8:48 pm # Reply

        Hello Megan. I’ve looked for the answer. To me the much more serious question is; “Can the body produce 5-D MTHF when it sees the wrong molecule?” 5MTHF has both but exactly what happens to the wrong one which is in 5MTHF still seems to be not fully known or understood. 5-D MTHF is going to have different properties than 5-LMTHF and toxicity is something I think is likely. Thalidomide is an example of what can go wrong when there’s a chiral problem. http://www.chirality.org/homepage.htm

  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.

      • Josh August 1, 2014 at 5:55 pm # Reply

        Dr. Lynch,

        I first want to commend and thank you for providing resources about MTHFR and the hard work and effort you are putting into the effort to spread awareness.

        I do have one follow-up question based on this post.

        The supplement (a Thorne product) that I am taking to help my own health issues has L-5-Methyltetrahydrofolate from L-5-Methyltetrahydrofolic Acid, Glucosamine Salt. Is this the same thing as the Quatrefolic you discussed in your post?

        If not, is this form of folate still effective (bio-available) for helping with MTHFR issues?

        Thank you so much!

        Best regards,

  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?



  21. Chris April 26, 2014 at 10:03 pm # Reply

    Dr. Lynch,

    I’m heterozygous A1298C. The person who diagnosed me and ordered the lab testing is a very well read nurse practitioner and she has a compound diagnosis herself. She wants me to go on Deplin and B12 (methylcobalamin form). I found an affordable and good formulation of methylcobalamin that I like. Unfortunately as you know, Deplin is VERY expensive, I still can’t figure why it is so expensive other than Merk took out a patent on it and there is only one “authorized” generic that is cheaper but still expensive. I asked her about several other products that appear to be legitimate to me and are much more affordable. She went to a conference of sorts for medical professionals and afterwards said, “There are no products that can be taken in place of Deplin or the generic L-Methyfolate Calcium made by Breckenridge… Now I have a hard time swallowing that and I have my doubts about that statement.

    I have looked at your guidelines above as well as in your introductory video at the home page of mthfr.net. I have tirelessly looked for other products with methylfolate and they are also expensive (like Deplin), illegitimate forms of methylfolate, or aren’t the dose my NP wants me on.

    I have found several products (see links below) called MethylPro. The methylfolate seems to meet your guidelines and criteria for the good form. They get their methylfolate from Gnosis S.p.A. They have both Quatrefolic and Extrafolate-S (both registered trademarks). I’m looking at the 10 mg dose. It looks like it’s based in Sisters, Oregon.


    My questions to you are:
    1. Are these legitimate forms of methylfolate?
    2. Knowing I already take B12, which MethylPro product, assuming these are legitimate, would you recommend (Extrafolate-S, Quatrefolic, Quatrefolic+cofactors)?

    If you would like there is helpful narrative about their products and a section on how it compares to Deplin: http://www.methylpro.com/more_info

    On another note, I guess Gnosis in the past had a labeling problem with the Extrafolate-S (see http://www.gnosis-bio.com/pdf/Corrective%20advertising%20letter%20for%20Extrafolate%20&%20Extrafolate-S.pdf) however, it appears they have corrected this under court order.

    I really appreciate any guidance you can offer on this matter to me. I also appreciate the wealth of information you have here and that it is free to all so that they may better their health.

  22. Chris May 3, 2014 at 8:46 pm # Reply

    I forgot to mention I’m currently on Gabapentin, Doxepin, and methylcobalamin.

  23. Val May 15, 2014 at 7:21 pm # Reply

    Hello Dr. Lynch,
    My understanding is that {6S} L-5 MTHF is processed from folic acid. It is a synthetic
    form of folate and that Formaldehyde is used in the distillation process to obtain this form of folate. Could you please clarify all of this!!! Of course my concern is in the possibility of ingesting any formaldehyde residue.

    Many Thanks,

  24. Sucramdw May 20, 2014 at 2:24 am # Reply

    So what does it mean for this whole foods Woman’s multi to have real Folate as 100% Organic?? http://www.herbalprovider.com/Wholefood-Womens-Multi-Organic

    Thank You!!

  25. Michelle May 21, 2014 at 2:03 am # Reply

    Seeking Health Kids Optimal Multivitamin lists Folate as 5-methyltetrahydrofolate. It doesn’t specify D or L and doesn’t mention Metafolin. You put that type on your questionable list.

  26. Dale June 12, 2014 at 9:56 pm # Reply

    What do you think about the use of Rheumate?

  27. rex August 1, 2014 at 7:40 pm # Reply

    I was hoping that you would have references to your statements about the biological activity and effectiveness of the various forms of folic acid so that I can share this info my wife’s physician. So I went onto PubMed.com and typed “folic acid and l-5-methyltetrahydrofolate ” in the search section. There are many studies showing that L-5MTHF supplements are effective. Some say that it is better or at least the same as a general form of folic acid supplementation. Obviously, L5MTHF would be far superior for those who have issues with folic acid. here are 3 articles that I found regarding L5MTHF effectiveness:

    1: Pietrzik K, Bailey L, Shane B. Folic acid and L-5-methyltetrahydrofolate:
    comparison of clinical pharmacokinetics and pharmacodynamics. Clin Pharmacokinet.
    2010 Aug;49(8):535-48. doi: 10.2165/11532990-000000000-00000. Review. PubMed
    PMID: 20608755.

    2: Akoglu B, Schrott M, Bolouri H, Jaffari A, Kutschera E, Caspary WF, Faust D.
    The folic acid metabolite L-5-methyltetrahydrofolate effectively reduces total
    serum homocysteine level in orthotopic liver transplant recipients: a
    double-blind placebo-controlled study. Eur J Clin Nutr. 2008 Jun;62(6):796-801.
    Epub 2007 May 23. PubMed PMID: 17522618.

    3: Venn BJ, Green TJ, Moser R, Mann JI. Comparison of the effect of low-dose
    supplementation with L-5-methyltetrahydrofolate or folic acid on plasma
    homocysteine: a randomized placebo-controlled study. Am J Clin Nutr. 2003
    Mar;77(3):658-62. PubMed PMID: 12600857.

  28. Catherine August 11, 2014 at 1:16 pm # Reply

    Hi, Dr. Lynch. Thank you so much for explaining about the different forms of folate. If the generic equivalent of Deplin 15 mg (L-Methylfolate Calcium manufactured by Virtus) states it has less than 1% of D-methylfolate, is this safe to take for someone who is compound heterozygous MTHFR? I had planned to take 1/4 of the tablet daily along with methyl b-12. Having just learned about the harmful effects of D-methylfolate on your website, I am not sure what to do. This stuff cost a lot of money, but should I throw it in the trash? Can you please advise? Thank you so much!!

  29. Adrian August 20, 2014 at 2:11 pm # Reply

    My question is does anyone notice a recurring theme here with the companies manufacturing these supplements? Very few that I have found have actually been worth much.

    I suffer from mild depression and have had very bad experiences with anti depressants. They actually make the depression worse. I have a great doctor though who tested my genes and found several traits that predispose me to depression and not responding to serotonin reuptake inhibitors. He said that I was lacking certain chemicals that helped me to absorb folic acid. He told me that it was necessary to have the proper amount of folic acid in order for my body to create serotonin, dopamine and other chemicals that helped ones moods and depression. He put me right on L-Methylfolate Calcium and said that he wanted to give it a try. Within a few weeks, I was feeling a bit better. Within a few months I was happier in general than I have ever been. Great! I was able to get excited about fun things that were coming up and remain stable even in bad times.

    My girlfriend suffers from similar symptoms of light depression. Her doctor puts her on Anti depressants and she gets worse just like I did. She can see what the Deplin has done for me. She goes to her doctor to ask about L-Methylfolate and he tells her that she is crazy. He ups her dosage of anti-depressant and she gets even worse. I discuss this with my doctor who unfortunately does not accept my girlfriends insurance. He cant believe that her doctor wont just try the Deplin. The more I have read up on this though, the more I have found that there are LOTS of doctors out there who refuse to try L-Methylfolate. Why is this? People are being forced to find alternatives on the internet and other places that are nowhere near as effective as the prescription. These companies are getting rich and doing no good for their patients.

    Why are doctors so afraid to leave the confines of conventional Anti-depressants and try something that is mostly natural? We aren’t hippies trying to be All Natural just for the heck of it. This vitamin really does some good. Especially when you can get the purest form possible. I just don’t know why so many are so against helping us obtain that.

    My doctor is retiring soon and I have been left to find a new doctor. A lot of these new doctors would put me on just about any chemical that I want, but the second that I mention the Deplin they have all told me “No, Just take B-12″ or ” you can buy supplements online that has folate in it” HUH!?!?!?!

    I am asking you for a simple thing here. L-Methylfolate Calcium. How about some OXYCODONE Doc? “Sure thing Adrian, but I’m not writing a prescription for L-Methylfolate” Whats wrong with this picture?

  30. Natasha August 20, 2014 at 2:47 pm # Reply

    Hi Dr, so here goes…long story short…I have suffered from sensorial neuropathy and anxiety since my plastic surgery procedure 5 months ago. I have been tested for everything imaginable and nothing to explain the neuropathy so my Neuro had me take Metanx. When I started researching the drug medication after experiencing itching, dizziness, and irritability I started reading about MTHFR. I had my PCP test me for it and found out I’m homozygous C677t. I tried to quit the Metanx and experiment with Country Life Coenzyme B Complex (anxiety, itchiness), Garden of Life Kind Organic Women’s Once a Day (instant Niacin-like reaction of red and itchy flush), Real Food Organics Prenatal Daily (anxiet, itchiness), Seeking Health Optimal Multivitamin Chewable (dizziness, depression, anxiety). Even taking supplements for my neuropathy such as acetyl l carnitine backfired by giving me dizziness and anxiety for 2-3 days. I have been juicing for about 2 months and noticed that adding the spinach makes me itchy! Therefore I am now down to just taking my Vitamin D and Omega 3 supplements and juicing. None of my doctors are knowledgable enough about my MTHFR to help me. Someone suggested that an added ingredient in the Metanx is causing the itching and being off of it so long with my MTHFR issue is not addressing the neuropathy. I have noticed feeling more neuropathy lately. Could you recommend a doctor for me to see in the Miami Rea that can help me get on track?

  31. Deb August 23, 2014 at 1:39 am # Reply

    I am looking for foods that have the active form of folate, my husband has one of the MTHFR defects and my daughter has both.mLooking for natural food source to supplement their diets. I live on a farm and if I can plant berries that have this will grow my own… But need to know if ALL berries have the active form… I have been told blackberries and raspberries do, just not sure about strawberries and blueberries. or any other types of berries. Any help would be appreciated.

    • Dr Lynch August 26, 2014 at 6:45 am # Reply

      Folate comes from the root ‘folar’ I believe which means leaves. Eat anything green and that will provide you a lot of folates – especially if they are uncooked.

      • Mara September 7, 2014 at 6:37 pm # Reply

        Would organic folate be tolerated as well as the good forms of folate for someone with MTHFR and COMT? Or could it still cause overmethylation. I’ve been taking an organic whole food multivitamin (Kind Organics), which say their folate (800mcg) is from organic lemon, but I’ve been feeling a bit off.

      • Deb September 10, 2014 at 2:57 pm # Reply

        Dr Lynch, can you explain something to me?
        Husband has : c677t mutation is heterozygous a1298c was negative
        Daughter has: c677t mutation is heterozygous a1298c is heterozygous
        I was told I have no mutations…
        I would have expected to have at least 1298c…

  32. Samantha McRorie September 8, 2014 at 2:40 am # Reply

    I use a Thorne Multi – B product – easiest for me to get in Canada as I can get it from my naturopath and I don’t have to pay shipping.

    I have 2 of their multi-B’s right now. On one label it says: Folate (L-5-Methyltetrahydrofolic acid) – which I do not see on your list. Yes it has the L and the 5 but why would it say folic acid at the end?

    The other product says Folic Acid (5-Methyltetrahydrofolate). So this one doesn’t have the L. I am very confused by all of this and want to be sure I am using the correct folate since I am heterozygous for C677T.

    Do you have any advice on this?

    • Dr Lynch September 9, 2014 at 6:10 pm # Reply

      You need to have the L form or the 6S form. If they are not stating this, it may be racemic meaning that there are two forms in there of methylfolate. One of those forms is absorbed and used by your body and the other one is not.

      • Deb September 11, 2014 at 3:36 pm # Reply

        Husband and daughter had blood drawn, sent of to Clinical Pathology Labs, Inc. whom the Dr office uses. Mine was done by cheek swab. It was done by a company, DNASTAT Pharmacogenomic Testing Services.

        Would you expect mother to have one or these defects if child has both and father only has one?

  33. Mara September 11, 2014 at 4:52 pm # Reply

    Would organic folate be tolerated as well as the good forms of folate for someone with MTHFR and COMT? Or could it still cause overmethylation. I’ve been taking an organic whole food multivitamin (Kind Organics), which say their folate (800mcg) is from organic lemon, but I’ve been feeling a bit off.

  34. ing November 13, 2014 at 6:47 pm # Reply

    I just wanted to add my experience with different brands
    I tried three. Only one worked for me.
    Jarrow Quatrefolic had no effect at all.
    Solgar metafolin worked for some aspects of my health but caused irritability.
    Thorne 5-Mthf Extrafolate-S (uses Gnosis S.p.A.’s L-5-Methyltetrahydrofolate) works beautifully with added benefits on mood and sleep.

    Can you tell me why you say all active forms work the same when clearly all these different active forms work differently for me?

    Can you comment on Extrafolate-S, Im concerned over some things Ive read about it.

    thanks much

    • Dr Lynch November 14, 2014 at 7:31 am # Reply

      Good points.

      They should work the same but clearly they do not with you.

      It also depends on the quality of the manufacturer – how do they handle the raw material, how do the encapsulate it, store it, how fresh, how seal it, delivery system?

      My company, http://www.SeekingHealth.com is switching to all Gnosis Quatrefolic and most of our products currently use that.

      I am not sure about Extrafolate-S but my first thought is that they use calcium salt vs glucosamine salt – like Metafolin. Also it may be racemic – I am not sure of the percentage of each isomer.

      • ing November 15, 2014 at 9:19 pm # Reply

        Thank you Dr Lynch for your response.

        I have done more research and seems Gnosis extrafolate-s is not recemic – from their website:
        “extrafolate-S® is the calcium salt of (6S)-5-methyltetrahydrofolate, and is suitable as a food ingredient.
        they also make “extrafolate – the calcium salt of (6R,S)-5-methyltetrahydrofolic acid.”

        I have found that the quatrefolic form of methylfolate gives me many of the negative symptoms listed as “side effects” on your website. For me personally -irritiblity, anxiety, racing heart, aching muscles, weak muscles, back pain) whereas extrafolate-s gives me only excellent results with added benefits on sleep and mood.

        I have found many people online commenting that this has been their experience as well with quatrefolic and would ask you to consider selling a supplement that contains extrafolate-s as an alternative to those who can not tolerate quatrefolic.

        Had I tried quatrefolic first I would not have believed that methylfolate therapy was for me and based on the negative reactions would not have continued supplementation nor would I have tried a different form of methylfolate because most websites claim all active form of methylfolate work the same.

        Thankfully my first try with a methylfolate supplement was with a brand that uses extrapolate-s and I had no side effects and could tell right away that it was indeed working for my symptoms.

        I fear many people who may be intolerant like I was may try quatrefolic first since it is what you and many other websites are endorsing based on the fact that it is the latest/fourth generation form of methylfolate and may give up based on negative symptoms, and not consider another form/brand of methylfolate.

        I feel like methylfolate in the form of extrafolate-s has given me back my life and I would hate for someone like myself to miss out only to not have found the right form of methylfolate that works for their personal chemisty.

        I would love to know what you think about my personal experience and would love for an article to be writen for those like me.

        Thank you very much for your response and consideration!

        • ing November 18, 2014 at 8:30 pm # Reply

          metafolin (solgar brand) was causing negative symptoms not quatrefolic.
          However quatrefolic (Jarrow) has no beneficial effect for me unlike like extrapolate-s.
          Sorry for the mix up.

          • Jeff November 20, 2014 at 7:31 pm #

            Hi “ing”,
            Since you’ve tried various forms of active methylfolate I’m wondering if you have ever taken multiple forms of active methylfolate simultaneously on a daily basis?

            Do you know if the effectiveness of the folate is adversely affected or are there any safety concerns you’d have with taking multiple forms of methylfolate ?

            I’m planning on taking these two supplements when they arrive:
            L-5-MTHF 1000 from the “Seeking Health” company.
            and B-Complex #12 from “Thorne Research”.

            There is 200 mcg. of L-5-Methyltetrahydrofolic Acid, Glucosamine Salt and
            200 mcg. of Calcium Folinate in each of the B-Complex capsules by Thorne Research.
            1,000 mcg. of Quatrefolic(6S)-5-methyltetrahydrofolate, glucosamine salt contained in the Seeking Health L-5 MTHF capsules.
            Thank you very much!

      • Jeff November 20, 2014 at 3:39 am # Reply

        I’m so glad to have found this excellent site. My physician suspected that I may have MTHFR mutations and ordered the blood lab test. I just received my test results back which show that I have both the C677T & A1298C mutations.

        I’m sure there’s a lot of factors that affect this question, but I’m wondering what is a good general starting dose of 5-MTHF for someone like me with both mutations?

        I ordered L-5-MTHF 1000 from your “Seeking Health” company.
        I also ordered B-Complex #12 from “Thorne Research”.
        I need to know if these three different forms of folate are safe to take together?

        There is 200 mcg. of L-5-Methyltetrahydrofolic Acid, Glucosamine Salt and 200 mcg. of Calcium Folinate in each of my B-Complex capsules by Thorne Research.
        I then plan on taking your L-5-MTHF 1000 from “Seeking Health” which contains 1,000 mcg. of Folate from Quatrefolic(6S)-5-methyltetrahydrofolate, glucosamine salt in the Seeking Health L-5 MTHF capsules.

        My doctor wants to prescribe me a large 15mg starting dose of folate, but after reading a little of the wealth of information on this site it sounds like this may be way too much with a high probability of causing adverse side effects.

        I’d sure appreciate your input on the recommended starting dose and to the effectiveness and safety of taking the multiple forms of folate I listed.

        Thanks in advance for your input, I appreciate it very much!

  35. Bridget November 14, 2014 at 9:30 pm # Reply

    Dr. Lynch, can you explain the difference between just plain folate and methylfolate? (I understand the difference between folate and folic acid.) I am taking an organic, raw vegan vitamin formula that lists “folate” as one of the ingredients. But I am also taking a supplement that says “(6S-5)-5-Methyltetrahydrolic Acid.” A fiend says I shouldn’t take the vitamin with the folate because it could interfere with metabolizing the methylfolate. Thank you for your reply.

  36. Pamela November 27, 2014 at 2:18 am # Reply

    Dr. Lynch,
    Thank u for your remarkable information. My MD actually recommended it since I was diagnosed with heterozygous A1298c/A1298c. We discussed the methylation Plus that she recommends. But when I asked for a prescription instead, she said there wasny one available in a dose small enough. She mentioned 300 or 400mcg. I guess I’m wondering if you may know of one that she might not. She also mention the methylation plus will take care of my B 2, 6, &9 deficiencies all at once instead of having to take separate pills . I have very good prescription insurance. & would rathe go that route if possible due to finances. Will this be a lifelong requirement or would/could it resolve with the candida irradication ?
    Thank you

  37. Judit B. January 1, 2015 at 10:31 pm # Reply

    Dear Dr. Lynch!

    I am MTHFR C677T homozygotes.I have polyneuropathia with a very late stage of chronic lyme disease ( + other lots of symptoms). I have been very ill for many years.I have done a Nutrahacker health info from my 23andme test. I am Hungarian and really can’ t imagine who could help me. I am 27 years old.
    I would like to ask you what kind of folate should I take if Nutrahacker “reports”me to avoid folinic acid and methyl donors! (methyl B12 too). I also have three kind of COMT gene and rs6922269, rs1801133, rs1805087, rs1802059, rs1801394 , rs7946, rs7925545, rs234706.
    A huge problem is nerve pain.I have tried taking Turmeric (300mg-600mg), but the pain increased insupportably so I have finished taking it.

    I just want you to help me a little bit.

    Thank you very much in advance: Judit B.

  38. Sherry Goeke January 8, 2015 at 3:11 pm # Reply

    Dr Lynch,
    What about “folate” in whole food based vitamins, and more specifically Garden of Life raw vitamins?
    I have been unable to tolerate medium chain triglycerides in “Seeking Health” products.
    Thank you for your response.

    • Dr Lynch January 9, 2015 at 9:06 am # Reply

      Sherry – if they don’t specify which form of folate it is, then I wouldn’t trust it. Medium chain triglycerides are derived from coconut oil – and the amount is very very small. Are you sure that’s the problem?

  39. suzan January 14, 2015 at 7:01 am # Reply

    Hi! Thank you for this article it is very helpful! I have been diagnosed with mthfr homozygous c677.. I am finding it hard to find methylfolate, can I supplement with folate ( pill not just naturally) and if yes what is the dosage? For folate or methylfolate. Would really appreciate some insight! Where i am from it seems lime they dont really consider mthfr as a problem! I have experienced already 2 miscarriages so i want to get it right this time. Thanks in advance.

  40. sowmya January 20, 2015 at 8:04 pm # Reply

    Dear Dr.Ben Lynch
    Could you explain to me when does one use L5 MTHF or its various forms mentioned, versus Leucovorin? I understand that lack of 5mtf causes Cerebal Folate deficiency , but they supplement it with Leucovorin, I am trying to understand, what matters where? Thank you

    • Dr Lynch January 21, 2015 at 10:49 pm # Reply

      I’m not sure why they use folinic acid vs MTHF in those studies.


      As far as I know, folinic acid is needed to produce DNA bases and MTHF is needed for methylation – the general overview anyhow – they do other things as well – but those are the two major ones.

      Neurotransmitters need methylation to be formed and eliminated – the major ones –

      I need to research further if folinic acid plays a role specifically – as folinic acid – in neurotransmission. At this point, I am not aware of that but I could be just ignorant on the matter.

      • Sowmya January 22, 2015 at 8:31 am # Reply

        Dear Dr.Lynch
        I got the answer from some of the moms who are working towards healing children with autism like me, from what I understood, Leucovorin would be converted to L5MTHF however if you have mutations etc, then the conversion would be affected or slowed down..here is what someone answered, I am sharing it incase someone else would be interested to know..Leucovorin does not contain methyl groups and thus, this form does not participate directly in the methyl cycle. However, it is a valuable player in generating pyramidines and it can be transformed into 5-MTHF. Of course, this is best accomplished if a child does not have an MTHFr polymorphism in which that enzyme is less efficient. The MTHF reductase will still transform Leucovorin into 5-MTHF, albeit somewhat slower. This can be especially hindered by homozygous polymorphism in that particular gene.

        Folinic acid (INN) or leucovorin (USAN), generally administered as calcium or sodium folinate (or leucovorin calcium/sodium),……..Folinic acid is a 5-formyl derivative of tetrahydrofolic acid. It is readily converted to other reduced folic acid derivatives (e.g., tetrahydrofolate), and, thus, has vitamin activity that is equivalent to that of folic acid. However, since it does not require the action of dihydrofolate reductase for its conversion, its function as a vitamin is unaffected by inhibition of this enzyme by drugs such as methotrexate.
        Folinic acid, therefore, allows for some purine/pyrimidine synthesis to occur in the presence of dihydrofolate reductase inhibition, so that some normal DNA replication and RNA transcription processes can proceed.

        Deplin is a trade name for 5-MTHF. Folapro is also the same thing, but in a low OTC dose, i.e., 800 mcg/tab. Deplin is the prescription version of this and my understanding of this is that it is much higher …in milligrams rather than micrograms. This is does have methyl groups attached. It is the only form that partakes directly in the Met cycle. This one can overcome the MTHF reductase blockade if it is present.
        thank you for all the inputs, it really brings in so much knowledge and so much hope that if there are solutions to problems and we can some way help our children to lead a normal life!
        Best Wishes
        Sowmya Fesenbeck

  41. Zach March 15, 2015 at 5:08 pm # Reply

    Dr. Lynch,
    After countless hours of educating myself about L-5-Methyfolate and B12 (Methyl, Hydroxy), I want to personally thank you for your dedication to helping others. It gives hope to those of us who have suffered with chronic depression & anxiety over the years without any success to typical SSRI treatments. I wish more doctors and mental health professionals were aware of this as an alternative treatment when antidepressants simply do not work in some people, such as myself. There is hope in feeling “normal” again.


    • Dr Lynch March 21, 2015 at 5:01 am # Reply

      Hi Zach –

      My pleasure! I am pleased to here that this information is helping you.

      Do listen/watch this as well – may provide some more useful info – http://www.seekinghealth.org/gift

      Keep getting better!


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