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!

I don’t often highlight the latest deals on the blog here, but this just fits the topic too readily. For those who are interested, when you buy Primal Master Formula today, you’ll receive an email with a $20 discount code for your next purchase of $50+ at the Primal Blueprint store.

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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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27 thoughts on “Why the Type of Folate You Take Matters”

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  1. Great article. I struggled with unexplained infertility for years, until I learned I’m compound heterozygous for both the MTHFR mutations. I started taking 5-methyltetrahydrofolate, desiccated liver(high in folate), and a low dose aspirin to combat the extra clotting that tends to accompany one of those mutations. Wouldn’t you know, after only two months, I’m now pregnant for the first time in my life!

    1. BAM!!!! Brianna, CONGRATULATIONS!!!!

      MY story is almost identical. 10 years of throwing everything we could at it, diagnosed with “unexplained infertility”

      After taking a 23 and Me test, and finding I was homozygous for MTHFR. I switched to prenatal vitamins with folate and a daily baby aspirin. Discovered I was “accidentally” pregnant 2 months later, at 39. My sweet boy is now three, and we just had twin girls in December.

      I’ve been convinced that the folate is what did it, but every doctor I had insisted it was just a freak coincidence. So it’s great to see it worked for you too.

  2. Hi Mark. Would you care to also comment on potential increase cancer risks connected to folic acid? Particularly breast and prostate.

  3. Finally. Thank you so much.

    The inclusion of folic acid was a barrier for me in making the purchase of your, and most, formulas. I admit, finding a formula using folate is tough in and of itself. Then several different kinds of “natural” folate are use …some list the “real” source and others use a form that starts as folic acid that they turn into a form of folate via a lab.

    I’m also mindful of the study about excessive folic acid intake due to it being in many fortified foods and how it appears it may contribute to our higher rates of cancer.

  4. Just because I have tried multiple types of methylfolate I was wandering if you are using the amorphous salt version (Thorne) or one of the crystalline versions (like Pamlabs medications or methyl-life)

  5. Great example of why its best to get our nutrients from whole foods…and when we chose to supplement we need to be super picky. Thanks for letting us know about the update/upgrade in Primal Master Formula. I don’t take a multi every day, but when I do chose to supplement that’s the one I go with.

  6. Mark, this article was great and really got me looking at your Primal Master Formula. Is there a way to get a sample instead of 360 count? I have a difficult time taking certain supplements that cause upset stomach and or gas/bloating.

    I have a decent supplement stack going now, that I tolerate well, but your product has quite a number of things that I don’t normally take that could be beneficial.

    Great stuff as always!

    1. twilliams, thanks for your note. One of my team members here will get in touch with you this afternoon about your request. Best, M

  7. After finding out that I have serious methylation flaws, my doc recommended Thorne and suddenly everything changed. I take methylated versions of my vitamins and also switched to a primal/modified keto diet and the improvements are so significant I couldn’t list them all here! 37 lb weight loss, thyroid improvement, off all RA meds… personalized nutrition is awesome. I’m graduating from college at 55 in May and hope to move in the direction of helping others with regaining their health as well.

    1. Hi, I am hypothyroid and have RA. Can you tell me more about Thorne?

  8. Don’t forget the importance of choline to conserve folate stores. Some MTHFR mutants end up on megadoses of methylfolate and/or folinic acid, but the need for this would go down if they remembered to take phosphatydl choline, or to increase their consumption of foods like liver.

    I believe that when we stopped eating liver regularly as a society, as well as cut back on egg yolks (also high in choline) due to misplaced cholesterol fears, and then we went ahead and fortified our flours, the methylation crapstorm hit the fan.

  9. So glad to hear about the switch in the Master Formula! That was just about the only thing keeping me from using it myself.

  10. A timely article, thanks Mark. Both my one year old son and I suffer from a hereditary blood disorder called spherocytosis. One feature of this condition is a much higher turn over of red blood cells due to them being mis-shapen (spherical) and therefore structurally fragile. These cells also carry less oxygen around the body.

    The doctors have recently advised us both to start taking “folic acid” to assist with red cell production. I incorrectly assumed FA came in only one format. I now know this is not the case and will be seeking out the more effective 5-methyltetrahydrofolate as a supplement for us both in future. Hopefully I can find it in liquid form as it’s easier to hide in kids food! Thanks for your great work as always.

    1. Alchornea cordifolia is a herb wihich is tradionally used for sickle-cell disease with great success in Africa . I think sickle-cell desease and spherocytosis are closely related. It’s highly protective for red blood cells and very safe to use. Look it up and do your research! I would highly recommend it for your condition! All the best for you and your child!

      1. Jack, thanks for the tip. I wasn’t aware of that herb but will definitely look into it. Sounds very promising. Cheers.

  11. I just wish the Primal Master Formula was more affordable. Once your health has gone far south, it can be pretty hard to climb back up without a good financial standing. We really are entering an age where the healthiest people are the ones who can financially afford it.

  12. I take a B complex, the label just lists folate. So I really should be looking for a B complex that lists 5-methyltetrahydrofolate instead?

  13. Very interesting, I have macrocytic cells and am on B12 injections, I splurged on 5 methylfolate as a co-factor for the absorption of B12, but am now going to go get some cheap folic acid as that might be just what I need! TY

  14. Thanks for addressing this topic! As a MTHFR C677T homozygous mutant, the issue of folate supplementation is a big deal to me as is avoiding synthetic forms of folate in enriched foods. I do not tolerate methylfolate supplementation even in very small doses, which is not uncommon (vicious mood alterations and complete inability to sleep-an important bit of info for anyone trying active folate supplements) so my folate all comes through food. That can be done quite successfully with a little dedication. Since it is estimated that 20-30% of the population has some form of MTHFR mutation, I think this is really critical info to discuss. I hope it becomes more mainstream for the sake of everyone’s health.

    1. My bad, that should say “synthetic forms of folic acid” in the post above, not “synthetic forms of folate.”

  15. A year and a half ago I’d written into customer service to pose the issues of folic acid in the Master’s Formula (I have the MTFHR mutation) and pointed out the irony that Primal Damage Control used folate. The response the rep passed on from Mark kind of surprised me, “Folic acid is a perfectly fine form to supplement, especially when you are not consuming fortified grains anymore.”

    I’m happy to see Mark has researched the variables further and, as a result, has reformulated MF, which I’m sure isn’t a cheap process since it also includes reprinting the labels. Primal Blueprint products are stellar and attention to improvements like this are why we trust the brand.

  16. Anybody get overstimulated taking methylated B vitamins? I’m compound heterozygous for MTHFR and thought I should take methylated vitamins. The result was that I could not sleep at night.

    Now, I focus on food-based forms of folate. Just discovered liver pate. I eat it on celery or with pork rinds. : ) I also eat quite a bit of cooked spinach.

  17. I’ve been taking folic acid without any problems. How should I get checked if it’s the right one for me? If I don’t have MTHFR is it still relevant?

  18. A number of yrs. ago, I discovered that my level of homocysteine (C4H9NO2S) was quite high With my cardiac history, I tried titrating suggested supplements, B-12, B-6 & Folate w/little success, I came across info suggesting that a small % of the population had problems metabolizing folate. I switched to L-Methyl-Folate, and sure enough, I significantly lowered my ?C4H9NO2S level. Within the last yr., I read about the association of C4H9NO2S w/depression. It was a eureka moment, as I realized that my chronic depression ameliorated beginning when I reduced my ?C4H9NO2S level. So. after many years on a variety of anti-depressants,I gave up Prozac to the dismay of my psychiatrist. I gave him up too.