The Difference Between Folic acid, Dietary Folates, and So-Called “Natural Food” Folate

Why It Matters Before and During Pregnancy

Multiple medical professional societies recommend against testing for MTHFR variations (also called polymorphisms, which are minor spelling changes in the genetic code). These societies have no incentive to recommend against MTHFR testing—there is no “Big Anti-MTHFR.” They recommend against the testing because it isn’t backed by research. And there has already been a lot of research. I have previously explained the data about MTHFR variations and reproductive outcomes here and the data about estrogen here.

MTHFR variations do not cause blood clots, they don’t cause infertility, and they are not a cause of recurrent miscarriages. There may be a link between neural tube defects (a birth defect involving the brain and spinal cord) for some women with two copies of the C677T polymorphism, but the magnitude of the effect is low. The most important factor in determining risk of neural tube defects is whether a woman with these polymorphisms has adequate intake of folic acid.

Despite the recommendations against testing for MTHFR mutations, it happens a lot. In response to my previous posts on MTHFR, my Instagram and Twitter feeds were filled with women who have been tested and who have been given medical recommendations based on the results of a test that should never have been ordered. Some were on blood thinners for years. Many have been led to believe they should be taking something styled as “natural food” folate in prenatal vitamins. They have been told this is “safer” or “more effective at preventing miscarriages” or “easier on the liver” than the recommended folic acid. 

Sadly, there is a lot of misinformation and unverified claims. 

A Primer on Folates

There are several different kinds of folate (or vitamin B9), and often the terms are used interchangeably. Understandably, this can be confusing, so it’s worth investing a little time to sort them all out. Folate can be a generic term that refers to the natural folates in food, but it can also be the synthetic folates (meaning those made in a lab) found in supplements. 

Food or dietary folates (for those who want to know, they are polyglutamate derivatives) are absorbed by the intestine, and through a sequence of chemical reactions, are converted to L-methyltetrahydrofolate or L-5-methylTHF, which is the active form of folate in the body. We’ll call this plasma folate for simplicity. The process of converting dietary folate to plasma folate happens in the intestine and the enzyme produced by the MTHFR gene is involved in the last step. Dietary folates are not that stable and are easily broken down by heat during cooking, so getting enough from an unfortified diet can be hard. 

Folic acid is a synthetic form of folate, meaning it is made in a lab. It is more easily absorbed than dietary folates, and just like dietary folates, folic acid is converted to L-5-methylTHF or plasma folate in the bowel, and the last step involved also uses the enzyme MTHFR. Folic acid may also be converted into plasma folate in the liver and possibly elsewhere. Folic acid is also more easily absorbed from food than dietary folates and is not destroyed by heat. This is why it is used to supplement food. Folic acid is the only form of folate that has been shown to reduce the risk of neural tube defects, a serious birth defect that involves the brain and spine.

There is also a synthetic version of 5-methyltetrahydrofolate; we’ll call this synthetic 5-methylTHF. It is now popping up on the internet as an alternative to folic acid in prenatal vitamins in spite of the fact that it hasn’t been tested for this purpose and there is a perfectly good proven alternative, folic acid. 

Synthetic 5-methylTHF is either a calcium or a glucosamine salt of 5-methylTHF. It is absorbed by the intestine and enters the blood as plasma folate. Unlike dietary folates and folic acid, synthetic 5-methylTHF does not need the enzyme MTHFR to become plasma folate. Some people call this “natural food folate,” but that term is inaccurate as it is not the folate found in food. As I noted above, like folic acid, it is also synthetic. It is also sometimes styled as methylated folate. 

The calcium form of 5-methylTHF is less stable than the glucosamine form and the stability of non-prescription synthetic methylTHF has not been tested. Meaning, if you buy a bottle the synthetic 5-methyTHF could be degraded (basically, you could be getting less drug than you think). We don’t know as it has not been tested. This is an important consideration, as this could affect the amount of folate that makes it into the bloodstream.  

What Is the Deal with Folate and Pregnancy?

Neural tube defects—birth defects of the brain and spine—are associated with folate deficiency. This connection has been known for years. Eventually, this led to recommending supplementation with folic acid before pregnancy (preconceptually) and during pregnancy. The recommended dose is 400-800 mcg (micrograms) a day. This is based on more than 30 years of research. So we have a lot of long-term data showing folic acid is safe and effective.

Taking folic acid before and during pregnancy is a recommendation of the US Preventative Services and Task Force and is endorsed by all of these medical professional societies:

Many pregnancies in the United States are unplanned. As a result, many people are not taking a folic acid supplement when they conceive, so a decision was made in 1998 to fortify certain foods in the United States with folic acid. The rate of neural tube defects fell 35%. We now have over 20 years of data on folic acid fortification, and it appears to be safe. 

Wait, if Food Is Supplemented with Folic Acid, Why Take a Prenatal Vitamin with Folic Acid?

Even with fortified foods, most women don’t get the recommended intake of folate from their diet needed to help prevent neural tube defects. Hence, prenatal vitamins are still recommended. The combination of fortified foods and a prenatal vitamin that contains folic acid and other B vitamins can prevent 90% of neural tube defects.

“Natural Food” or Synthetic 5-methylTHF vs. Folic Acid

Synthetic 5-methylTHF is not ground-up vegetables or chicken liver. It is made in a lab, but whether something is made in a lab or not doesn’t actually matter. What matters is if the product is safe and it can do what it claims. 

People who promote synthetic 5-methylTHF claim that people with MTHFR variations can’t “use” folic acid as well; their claim appears to rest on the fact that the final step in converting folic acid into plasma folate involves the enzyme made by the MTHFR gene. People who make this claim are also ignoring the research. Even people with two copies of the C677T polymorphism can process folic acid as well as those without these variations. This has been studied

I’ve also seen claims that the liver has to “work harder” to convert folic acid to plasma folate. That is simply not true. 

Other concerns about folic acid have been raised related to vitamin B12 deficiency. It’s true that folic acid can mask early signs of vitamin B12 deficiency and vitamin B12 deficiency can be devastating. Theoretically, synthetic 5-MethylTHF may be less likely to do this, but data proving this has not been presented in a peer-reviewed publications—meaning we don’t yet know. There is no evidence that folic acid masking vitamin B-12 deficiency is a problem among women of reproductive age in the United States. (Vitamin B12 deficiency is much more common with old age). Also, prenatal vitamins typically contain vitamin B12, and it is absorbed well from the intestine, making a deficiency highly unlikely. 

Preventing Neural Tube Defects

While both synthetic 5-methylTHF and folic acid raise the levels of plasma folate, only folic acid has been studied for prevention of neural tube defects. This is an important point—we don’t know if synthetic 5-methylTHF can reduce neural tube defects or not, and the assumption should not be that it is as effective as folic acid. We just don’t know. Maybe folic acid has another mechanism in preventing neural tube defects apart from raising levels of plasma folate that we haven’t yet discovered? 

What we do know is folic acid reduces neural tube defects.

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Who Benefits from Sales of Synthetic 5-methylTHF?

The people who sell it are benefiting big time. For example, Ritual sells a prenatal vitamin with the synthetic 5-methylTHF that they call “methylated folate” for $35 a month ($105 for 3 months), and their advertising insinuates it can reduce neural tube defects, when in reality, it is untested. Their advertising makes false claims amount MTHFR polymorphisms and folate.

The naturopath Jolene Brighten sells a prenatal vitamin with synthetic 5-methylMHT for $57.89 for one month’s supply (or $173.67 for 3 months.) 

So right now synthetic 5-methylTHF is a way to sell more expensive prenatal vitamins that are untested for prevention of neural tube defects in place of  fully tested and less expensive folic acid. Nature Made prenatal vitamins with folic acid are $20.99 for three months supply at Target. That is 8x cheaper than Brighten’s prenatal vitamin with the unproven alternative. Eight times!

Promoting synthetic 5-methylTHF also makes a provider sound like they “know” something more than other doctors or helps them position themselves as some kind of “expert.” It provides the illusion of being more caring. People with infertility, recurrent miscarriages, and those who have had a pregnancy with a neural tube defect are desperate, and the desire to do something concrete is real. Taking synthetic-5methylTHF feels concrete. After all, it is heavily promoted as special and beneficial. It is easy to see how people can be swayed. 

Why are there no studies looking at synthetic 5-methylTHF and neural tube defects? Don’t consumers using the product deserve to know if it’s effective or not? Shouldn’t the justification for paying so much more be more than a hypothesis? Good questions.

Here are the facts. The MTHFR variation is not associated with infertility, recurrent pregnancy loss, stillbirth, or blood clots, so no special supplement beyond a standard prenatal vitamin with folic acid is needed. This has been studied. It is possible that some people with two copies of the C677T polymorphism are at a slightly increased risk of neural tube defects, but the effect of that is minor compared to the effect of adequate folic acid. The best thing to prevent neural tube defects is folic acid.

If someone wants to take the untested synthetic 5-methylTHF in their prenatal vitamin that is their choice, but they should make that choice from an informed decision and understand that folic acid has been shown to raise plasma folate levels for people with and without MTHFR variations, and only folic acid has been shown to reduce the risk of neural tube defects.

With synthetic 5-methylTHF people are getting an unstudied form of folate and taking the word people who are profiting from the sale that it is better for their pregnancy based on no evidence.