Folate, Folic Acid, L-methylfolate and You

I’ve talked about this particular supplement a few times and wanted to review it again seeing as how we just discussed B-12. B-9 is the number for folate. Unfortunately we won’t get to talk about B-4. Sorry Star Trek fans.

Folate is a term for for naturally occurring folate, as well as folic acid, the synthetic vitamin. This is unfortunate because there are some difference that we will see.


Folate is necessary for single carbon transfers in DNA and RNA synthesis. Without it those molecules are unable to properly be formed. The methylation of deoxyuridylate to thymidylate in the formation of DNA is required for cell division, something that folate mediates. This most commonly shows up as megaloblastic anemia, or folate deficiency anemia. It is also necessary for conversion of homocysteine to methionine.

In the gut, folate is hydrolyzed and then actively transported across into the blood. Before entering the bloodstream, it is converted to either the methyl or formyl forms of tetrahydrafolate (THF). In the plasma the most common form is 5-methyl-THF.

Folic acid, the synthetic version of real folate, can be measured in the blood, but doesn’t indicate that it actually has activity. Folic acid must enter the liver to be metabolized by dihydrofolate reductase, an enzyme to convert it to allow it to enter into the pathway that fully converts it into 5MTHFR or l-methylfolate (biologically active folate). This conversion does happen to some extent, however the amount of people who take full advantage of this conversion is limited.

Around  60% of the population are intermediate metabolizers of folate or heterozygous for genetic polymorphism of the MTHFR enzyme, whereas up to 25% of certain populations are homozygous for these genetic variations. [1] In varying degrees, these polymorphisms impair the conversion of folate to its active form, l-methylfolate. In essence, just because you take folic acid doesn’t mean you’ll convert every micro-gram into something usable. Some people are unable to convert any folate of any kind in l-methylfolate. These people must supplement.


One possible hazard with too much folic acid is the development of cancer. As one news report tells, in Chile colon cancer rose for both males and females after fortification of the food supply with folic acid became mandatory [2] and in the United States, a similar increase was seen in the late 90’s and into 2000’s when supplementation became mandatory here. [3] It has also been linked with lung and prostate cancers.

Scientist think that when a person has precancerous cells, folic acid may act like gas on a fire and allow the cells to become full blown cancer cells.[3] Excess blood folic acid is also associated with natural killer cell cytotoxicity [4]. This is the power with which natural killer cells can take out renegade cells and keep things like infections at bay. The interesting thing about this study is that women who had a folate poor diet and supplemented had increased activity in natural killer cells. Those who ate a folate rich diet and supplemented with folic acid had the reduced activity. Too much folate is not always good….no surprise there.

What to Do?

There are lots of things a person can do to get adequate folate. Eating organ meats like liver is a good start. Greens are another great form. Folic acid isn’t the best because it’s folic acid and we just learned that isn’t a form that is ideal, in fact it’s probably bad for you in some cases.

There are also a ton of supplements that you can buy and they aren’t all the same. Lets examine these. This information comes from:   This is a site dedicated to teaching people that have MTHFR genetic disorder.

  • 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

That’s a bunch of terms. They aren’t all the same either.

L-5-MTHF = L-5-Methyltetrahydrofolate = 6(S)-L-MTHF = 6(S)-L-Methyltetrahydrofolate

These are good.

L-Methylfolate Calcium = Metafolin = Levomefolic Acid

These are good

D-5-MTHF = D-5-Methyltetrahydrofolate = 6(R)-L-MTHF = 6(R)-L-Methyltetrahydrofolate

These ARE NOT good

The difference between 6(S) and 6(R) is they have different properties. They look similar to each other but don’t necessarily do the same thing. It’s kind of like the Star Wars original movies and the prequels. They both give you a dose of Star Wars, but in very different ways. The prequels of course causing cancer while the originals cure depression.

Yup, taking folic acid is like only getting the prequels, it just doesn't cut it.

Yup, taking folic acid is like only getting the prequels, it just doesn’t cut it.

So what to look for:

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

Take a look at this product from Thorne:

The website states that it is 5-MTHF. You have to look at the ingredient list to see “L-5-Methyltetrahydrofolate” So by looking at that you can conclude that it is indeed an “L-5” form and should be active.

Another page:

This shows “L-methylfolate, Metafolin” which again would be ok.

Yet another site:

shows the active ingredient as “ 5-Methyltetrahydrofolate”. By this alone you don’t know if it is active or not active. This would require you to talk with the manufacturer to find out what they use specifically. If they don’t know or just repeat back what the label says, think about looking elsewhere. 

If you receive a prescription from your doctor for the following:

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

you can be sure that these are the active forms. They are also ridiculously expensive but are higher doses so depending on where you buy it might end up being the same. I have talked to 2 patients that use Deplin and they’ve said it makes all the difference. One said she was finally able to get pregnant and have a child because of the Deplin. She said no amount of folic acid would do it.

It’s worth noting that there are drug interactions with folate in the body.



  • Antacids, H2 blockers, proton pump inhibitors (these pesky things again)
  • Bile acid sequestrants (Cholestyramine)
  • Carbamazepine
  • Nonsteroidal anti-inflammatory drugs (NSAIDs) ie ibuprofen or naproxen
  • Sulfasalazine
  • Triamterene
  • Methotrexate

If you take any of these drugs or any others you’re not sure ok, talk with your pharmacist. If they don’t know and won’t look, leave a message in the comments.

Folate is vitally important for people to function properly, just like any of the other B vitamins and since you can’t make it yourself you have to ingest it in some form. For people with depression I’ve heard them say Deplin (prescription only) works better than their antidepressants. Having an adequate amount of folate is definitely important.





1.Greenberg, James A., et al. “Folic acid supplementation and pregnancy: more than just neural tube defect prevention.” Reviews in obstetrics and gynecology4.2 (2011): 52.

2.Hirsch, Sandra, et al. “Colon cancer in Chile before and after the start of the flour fortification program with folic acid.” European journal of gastroenterology & hepatology 21.4 (2009): 346-349.


4.Troen, Aron M., et al. “Unmetabolized folic acid in plasma is associated with reduced natural killer cell cytotoxicity among postmenopausal women.” The Journal of nutrition 136.1 (2006): 189-194.


2 thoughts on “Folate, Folic Acid, L-methylfolate and You

    • Hi Lisa! 500mcg would be a good start with the guidance of your doctor. That’s 10x less than the 5mg dose of folic acid but you don’t know how much is actually getting converted and with methotrexate and board it will be hard to judge at first with the response. That’s why I suggest doing it with a competent healthcare provider.

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