Why the Type of Folate You Take Matters

Inline_FolateWe have a problem. When discussing vitamin B9, common parlance is to use “folic acid” and “folate” interchangeably, as if the two are different terms for the same thing. Talk to most OB-GYNs about the type of vitamin B9 in your prenatal, and they’ll say the difference doesn’t matter. Look at the average nutrition label, and it’ll list folic acid rather than folate, even though it’s naturally occurring. They are not the same. The difference is meaningful. 

Our bodies don’t actually use “folic acid” or “folate”; they convert them into 5-methyltetrahydrofolate—the useable form of folate. Folic acid must go to the liver for conversion into 5-methyltetrahydrofolate, but there’s an issue here: The liver doesn’t always make enough of the enzyme necessary to convert folic acid into tetrahydrofolate.

Organic folates, like the ones found in food or supplemental 5-methyltetrahydrofolate, don’t have this problem. They’re easily converted into tetrahydrofolate at the gut level upon consumption. 

Okay, okay. So maybe just take a little more folic acid to make sure you produce enough tetrahydrofolate—right? Flood the pathways, brute-force conversion.

That same tactic used by millions of OB-GYNs to get their patients’ folate levels up to par may have unintended consequences. Unconverted folic acid can end up circulating throughout the body, where it has unwanted side effects. Let’s explore a few of them.

Immune Function

Natural killer cells are the immune system’s first line of defense against pathogens and immune insults. Their primary function is to kill—to promote cytoxicity, or cell death—and excessive folic acid in the blood may impair this. In one study, postmenopausal women with elevated blood levels of unmetabolized folic acid had lower natural killer cell cytotoxicity. A more recent study in Brazilian adults found the same thing: 5 mg of folic acid (an admittedly massive dose) given each day increased serum unmetabolized folic several-fold and lowered the cytotoxicity of natural killer cells. Natural killer cells that aren’t good at killing aren’t good at all.


As mentioned earlier, the presence of unmetabolized folic acid in circulation reduces the activity of natural killer cells, which in addition to defending against invading pathogens also stem the tide of unchecked inflammatory processes, including autoimmune destruction of the body’s own tissues.

A 2012 mouse study showed that administering NK cells halted the destruction of pancreatic beta cells and beat back the progression of autoimmune diabetes. If people are exposed to enough non-metabolized folic acid to depress NK cell function, that could partially explain the rise of type 1 diabetes.

Indeed, shortly after 159 countries began fortifying flour with folic acid, the diabetes rate skyrocketed, exceeding epidemiological forecasts


Folate is critical for fetal development, and supplementation with folic acid has been shown to reduce the incidence of neural tube defects. That’s synthetic folic acid, by the way. It’s clearly helpful, especially if you’re not eating folate-rich foods. But there may be an upper limit, particularly after the first month of pregnancy.

Unmetabolized folic acid, which is elevated in many pregnant women who supplement with it, competes with glutamate for binding on neural growth cones in fetuses. If the folic acid outcompetes glutamate, researchers hypothesize it could impair neural development. Some researchers even propose that excess unmetabolized folic acid from folic acid supplementation could increase the risk of autism.

But I heard that folic acid is more bioavailable than other forms of folate. If that’s true, isn’t folic acid better?

Not necessarily.

A recent study showed the “superiority” of folic acid compared to food-based folate and 5-methyltetrahydrofolate. Taking folic acid resulted in much greater serum levels of folic acid than either folate-rich foods or 5-methyltetrahydrofolate; they absorbed more. But were they using it? Or was a lot of that folate ending up in the bloodstream, unused and unmetabolized, where it’s been shown to cause the problems listed in the previous sections? A closer look reveals that while folic acid increased serum folate to a greater degree, the folate-rich foods and 5-methyltetrahydrofolate were better at increasing red blood cell folate levels.

There’s another variable to consider when choosing the type of folate you take: Genetics.

Certain genetic variants make conversion of both folic acid and food folate much harder. These are the infamous MTHFR mutations, which control production of an enzyme that plays a critical role in the folate conversion pathway. If you have an inhibitory mutation, your ability to complete the conversion of folic acid and folate into 5-methyltetrahydrofolate suffers.

Supplemental folic acid is just folic acid. It always has to travel the entire folate pathway for conversion into useable folate.  Food folate is different. A small portion of it is in the folic acid form requiring full conversion, but it also comes in different forms, some of which start out further along the conversion pathway. A significant portion of food folate is even 5-methyltetrahydrofolate itself, eliminating the need for conversion entirely.

You absorb more synthetic folic acid but may have trouble converting it into folate you can use.

You absorb less food folate but it’s easier to convert into useable folate.

Chris Masterjohn made an interesting point in a recent podcast, though: In the context of a vitamin B12 deficiency, synthetic folic acid may work better than food folate. If that’s the case for you, I’d recommend fixing the B12 deficiency.

While folic acid can certainly be helpful, especially in certain populations with certain health conditions, I err on the side of more “natural” (for lack of a better term) forms. For thousands of years, we’ve gotten our folate from foods. And some of the folate we find in foods comes in a form identical to supplemental 5-methyltetrahydrofolate. These are the forms to which we’ve adapted. They’re what our bodies expect. Folic acid clearly works at elevating folate levels, preventing neural tube defects, and preventing gross deficiencies, but it comes with potential side effects. I always like to err on the side of nature.

Why am I telling you this now? Personal experience. I recently just switched the vitamin B9 source in Master Formula from folic acid to 5-methyltetrahydrofolate. I did the research over time, saw that I could do better, and fixed it. I wasn’t providing the optimum B9 formulation in my supplement, a supplement that I myself take every day and have for years. Now I am.

That’s it for today, folks. If you have any questions about folate, folic acid, 5-methyltetrahydrofolate, chime in below!

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About the Author

Mark Sisson is the founder of Mark’s Daily Apple, godfather to the Primal food and lifestyle movement, and the New York Times bestselling author of The Keto Reset Diet. His latest book is Keto for Life, where he discusses how he combines the keto diet with a Primal lifestyle for optimal health and longevity. Mark is the author of numerous other books as well, including The Primal Blueprint, which was credited with turbocharging the growth of the primal/paleo movement back in 2009. After spending three decades researching and educating folks on why food is the key component to achieving and maintaining optimal wellness, Mark launched Primal Kitchen, a real-food company that creates Primal/paleo, keto, and Whole30-friendly kitchen staples.

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