A hot product on the Internet, but should you consider L-methylfolate instead of plain old folic acid?

My favorite natural medicines website is the Natural Medicines Comprehensive Database. The NMCD has new information about L-methylfolate which is being heavily promoted, especially on the Internet, by some manufacturers as a more active form of folic acid. Are they telling the truth? Here’s the information from NMCD:

L-methylfolate is in many prenatal vitamins such as Optinate, Neevo DHA, Prenate Elite; and regular vitamin supplements including Optimized Folate, MegaFolinic, and others. It’s also being used in medical foods for memory loss or depression, in products such as CerefolinNAC and Deplin.

According to the NMCD, “folates” are a mixture of different forms of the vitamin that occur naturally in food. Most supplements contain folic acid, a synthetic form of the vitamin. In the body, all of these forms are converted to L-methylfolate before entering the bloodstream and being stored by the body.”

The Database reports, “It is true that L-methylfolate is slightly better absorbed than folic acid. You’ll hear claims that L-methylfolate is a better alternative than folic acid because many patients have reduced activity of an enzyme that metabolizes folic acid to L-methylfolate. “

However, “so far there’s no proof that this makes a clinical difference.”

For example, studies show that equivalent doses of folic acid and L-methylfolate raise folate levels in pregnant women equally well.

Also, there is also no proof that L-methylfolate is any better than folic acid for preventing neural tube defects.

The NMCD tells us physicians, “Explain to patients that L-methylfolate is just as safe as folic acid for supplementation, but there is no reliable evidence that it’s more efficacious.”

Also, keep in mind that doses in some products are very high. Deplin contains 7500 mcg and CerefolinNAC contains 5600 mcg. These amounts are much higher than the 1000 mcg/day that has been linked to a higher cancer risk in some patients.

The NMCD webstite cautions, “Clinical research shows that taking folic acid daily in doses of 800-1200 mcg for 3-10 years significantly increases the risk of developing cancer and adverse cardiovascular effects compared to placebo.” This has been reported in studies in 2004 and 2006 studies in the New England Journal of Medicine, a 2009 study in the Journal of the National Cancer Institute, and a 2009 study in the Journal of the American Medical Association.

Also, according to the NMCD, researchers have recommended that “Doses above 1000 mcg per day should be avoided if possible to prevent precipitation or exacerbation of neuropathy related to vitamin B12 deficiency. However, there is some evidence that doses of 5 mg per day orally for up to 4 months can be used safely if vitamin B12 levels are routinely measured.

So, the bottom line, from my perspective, is that it’s likely safer and as or more effective to just use old time folic acid.

7 thoughts on “A hot product on the Internet, but should you consider L-methylfolate instead of plain old folic acid?

  1. Tracy Johnson

    Dr. Walt,

    I enjoyed reading your article, “A hot product on the Internet, but should you consider L-methylfolate instead of plain old folic acid?” on May 3, 2010. I am the Medical Liaison Director for Pamlab, LLC, which markets medical foods that contain L-methylfolate. The information that you have provided in your article is valuable to the consumer and will certainly help them make an educated decision as to their nutrition.

    As a Medical Liaison, one of my goals is to provide physicians with accurate and up to date information on products marketed by Pamlab. I would like to respond to a few of your comments about L-methylfolate along with the supporting data.

    Your article mentions that “L-methylfolate is slightly better absorbed than folic acid”. The evidence suggests that L-methylfolate is considerably better absorbed than folic acid; however, it may depend upon the dose. Two studies from the British Journal of Pharmacology report that L-methylfolate is anywhere from two to seven times more bioavailable that folic acid1, 2.

    A separate study confirms your statement that L-methylfolate is slightly better absorbed than folic acid 39% to 31% respectively3.

    It seems the amount of folic acid that is used may be the reason for the differences in absorption/bioavailability.

    Recent evidence suggests that folic acid in doses of 200mcg or less can be fully metabolized by the body. However, when doses exceed 200mcg, unmetabolized folic acid starts to show up in the blood4.

    Unmetabolized folic acid has been linked to a reduction in the body’s natural defense to cancer, natural killer cells5. With L-methylfolate being the reduced form of folic acid, there is no unmetabolized L-methylfolate in the blood and it has not been linked to a reduction in natural killer cells5.

    You mention that 1000 mcg per day of L-methylfolate has been linked to a higher cancer risk in some patients. If you have a reference for this claim could you please share it?

    You are correct that studies have shown that synthetic folic acid has been associated with increased cancer risk. It is worth mentioning that these studies used folic acid in doses higher than 200mcg, usually 800-1000mcg, which resulted in unmetabolized folic acid in the blood. Based on the currently available literature, many experts have tied the link of synthetic folic acid (unmetabolized folic acid) to cancer concerns and not the natural forms of folate which include L-methylfolate.

    Lastly, you assert that for the patient with a defect of the enzyme that metabolizes folic acid to L-methylfolate, there is no clinical difference between L-methylfolate and folic acid. You say, “…there’s no proof that this makes a clinical difference. For example, studies show that equivalent doses of folic acid and L-methylfolate raise folate levels in pregnant women equally well. Based on the literature, this is a true statement that both forms of folate raise folate levels. However, L-methylfolate demonstrates a statistically significantly higher folate level than synthetic folic acid6. Also, there is no proof that L-methylfolate is any better than folic acid for preventing neural tube defects”.

    The American Journal of Clinical Nutrition, 2006 published an article showing that in women of child bearing age, L-methylfolate was more effective than folic acid at improving folate status over a 24 week period and significantly reduced risk of NTD better than folic acid6. With folate status being necessary for prevention of neural tube defects, this is a very important study.

    I thank you for the opportunity to respond to your article and I welcome any comments or questions you may have.

    Tracy Johnson
    Medical Liaison Director
    Pamlab, LLC

    1. Willems, et al, British Journal of Pharmacology, 2004
    2. Prinz-Langenohl, et al, British Journal of Pharmacology, 2009
    3. Wright, et al, British Journal of Nutrition, 2009
    4. Kelly, et al, American Journal of Clinical Nutrition, 1997
    5. Troen, et al, The Journal of Nutrition, 2006
    6. Lamers, et al, The American Journal of Clinical Nutrition, 2006

  2. Dr. Walt Post author

    Hello Tracy,

    Thanks for the note, and the updates. However, it’s not me saying this. If you read my post, it’s from the Doctors of Pharmacology at the Natural Medicines Database.

    On the face of it, they are unbiased, whereas I’m sure you’d admit to having a bias since your company sells the product, correct?

    Anyway, let me write the Editor of the NMCD and get the reference you’ve requested. I’ll also see if he has any other responses to your comments.

    Thanks again for writing.

  3. Dr. Walt Post author

    Tracy,

    You say, “You mention that 1000 mcg per day of L-methylfolate has been linked to a higher cancer risk in some patients. If you have a reference for this claim could you please share it?”

    Actually, neither I nor NMCD say this. What they say is this (and this is what is posted above):

    “The NMCD webstite cautions, ‘Clinical research shows that taking folic acid daily in doses of 800-1200 mcg for 3-10 years significantly increases the risk of developing cancer and adverse cardiovascular effects compared to placebo.’”

    They go on to say: “This has been reported in studies in 2004 and 2006 studies in the New England Journal of Medicine, a 2009 study in the Journal of the National Cancer Institute, and a 2009 study in the Journal of the American Medical Association.” The hyperlinks to the studies are in the original post.

    Hope this helps.

    Walt

  4. Tracy Johnson

    Dr. Walt,

    Thanks for pointing out the 1000 mcg per day of L-methylfolate statement. I got this from your post in the paragraph where you were mentioning the dose of Deplin and Cerefolin NAC. There was no distinction between folic acid and L-methylfolate. They are not the same thing. As it reads, one could assume that L-methylfolate was used in cancer studies. To my knowledge, it has not been used. I apologize if I mislead you or your readers to think otherwise.

    Also, allow me to address your statement about the Doctors of Pharmacology at the Natural Medicines Database being unbiased and my being biased because we market products that contain L-methylfolate. I can’t speak for the Doctors of Pharmacology at the Natural Medicines Database, but I am sure they are providing the information as they have it. My goal is the same today as it has always been and that is to provide the physician with the most accurate information at my disposal, even at the risk of loss of profit.

    Thank you for the opportunity to respond and share my thoughts.

    Tracy

  5. Dr. Walt Post author

    Tracy, thanks for the note and the correction. Were there more in the commercial world with your altruism. Hope we meet face-to-face some day.

    Walt

  6. Patricia

    Dr. Walt,

    I believe that you need to do more extensive research on what studies have shown about the use of methylfolate vs folic acid. One significant factor here is whether an individual has a difficulty metabolizing folic acid – due to genetic reasons or absorption issues. I have done a great deal of reading on the topic as I had two babies with Anencephaly in a row. Here are some questions for you to consider:

    1) Is there a difference between studies done with Methylfolate when treating specific conditions.
    2) Do some people have genetic reasons or absoption reasons for needing a pre-metabolized form of folate.
    3) What studies have been done with MethylF and neural tube defects?

    Look at studies done with testing of blood tests of folate levels at cellular level and plasma level.

    I’d be more than happy to put together a more detailed report for you (as I am a medical librarian.) I think as a result you might change your mind regarding this product. (By the way, after having supplemented my diet with methylfolate/b12/and other vit bs, I went on to have two healthy babies…)

    Patricia

  7. Walt Larimore

    Here’s a October 2011 update on this topic from the experts at Prescriber’s Letter:

    Reps are filling up sample closets, hoping prescribers will use Deplin to improve the efficacy of antidepressants.

    Deplin contains L-methylfolate … the active form of folic acid.

    The manufacturer can make medical claims for Deplin because it’s marketed as a medical food. Medical foods are a commonly misunderstood category of products. They’re not Rx drugs, not OTCs, not dietary supplements, and not homeopathics.

    Medical foods often have a package insert and say “Rx only” on their label … but they are NOT approved by FDA like traditional Rx drugs.

    There’s a link between folate deficiency and depression … possibly because folates are needed to make serotonin, norepinephrine, and dopamine. Some preliminary evidence also suggests that adding folate can increase antidepressant efficacy.

    Deplin claims to be more effective than folic acid because it’s already in the active form. But there’s NO PROOF that Deplin is more effective … and it costs more.

    Generic folic acid might be worth a try before going to other augmenting agents … antipsychotics, buspirone, thyroid, lithium, etc. Use at least 500 mcg/day of folic acid for augmentation. Keep doses under 800 mcg/day in the elderly due to concerns about cancer with higher folate doses in the elderly.

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