It makes sense that if your body has a difference in its ability to process folate, like the MTHFR variants, then you just flood the system so that even if the enzyme is moving slowly, you’ve still got enough. There is a problem with this logic – the form of folate that we usually see in supplements, foods, energy drinks, and everywhere else is FOLIC ACID and there is compelling evidence that it’s toxic.
First off, What is Folic Acid?
Folic acid is the first synthetic form of folate, which is a group of related compounds found in food that we group under the label Vitamin B9. There are many different forms of folate in foods, but most of them are unstable and degrade quickly and so can’t be used in vitamins or supplements.
Folic acid was first developed in 1948 – the first synthetic form of folate available and it was a revolution. Natural forms of folate, with the exception of folinic acid, are pretty unstable and certainly won’t keep if you add them to foods or vitamins. Folic acid has solved so many problems in undernourished populations and kept the rates of cleft palate, cleft lip and neural tube defects like spina bifida far lower than they would be without it, so it isn’t that it’s an entirely bad thing – when you have a choice between folate deficiency and not having that deficiency because of folic acid, then the choice is easy to make. It’s when you’re not in an undernourished situation that you have to be careful.
I’m Fuzzy – Why Would Folic Acid Be Toxic? They Add It To My Vitamins!
Vitamins and food additives must be shelf-stable, and naturally occurring folates aren’t. The crystalline form of folic acid was first synthesized in 1943 by Bob Stokstad at the American Cyanid Company (!!) What a name! And researched for use in human disease by 1945. It was shown to be useful in the same anemias and diseases of pregnancy for which folate was discovered to be useful by researcher Lucy Wills in 1931. Folic acid is not toxic in small doses and it can help correct a folate deficiency, but high doses are a problem.
Risks Associated With High-Doses of Folic Acid – Not Just For MTHFR Folks!!
Many of us have a chronically high intake of folic acid (not folate) because of the combination of fortified foods, energy drinks, and supplements. In the U.S. the recommended daily intake is 400 𝝁g, but actual consumption can be much higher due to fortified foods.
Folate has a dual effect on cancer, protecting against cancer initiation but facilitating progression and growth of preneoplastic cells and subclinical cancers, which are common in the population. Thus, a high folic acid intake may be harmful for some people.Smith AD, Kim YI, Refsum H. Is folic acid good for everyone?. Am J Clin Nutr. 2008;87(3):517-533. doi:10.1093/ajcn/87.3.517
- Cancer – this is a risk nobody wants to face. Many studies have shown a link between high-dose folic acid and cancer, especially, as with the above quote, in terms of promoting the growth of cancerous cells that are already in the body.
- Cognitive Decline – like cancer, this seems to be a double-edged sword. See the quote below.
- Diabetes and thyroid disease – two conflicting studies have shown associations between high folate status in pregnant mothers and metabolic syndrome or diabetes in the children. The results of each study are opposed to each other, and so inconclusive. (See this review article for more details).
- Hypersensitivity like childhood allergies, eczema, and asthma – this is thought to be through the mechanism of DNA methylation.
- Autism, twinning, heart disease, mortality (that’s death), immune issues, neurological issues, and fertility problems – these have all been shown in various small studies without larger research studies to back them up.
An observational study of data collected in the NHANES found that “In seniors with low vitamin B12 status, high serum folate was associated with anemia and cognitive impairment. When vitamin B12 status was normal, however, high serum folate was associated with protection against cognitive impairment.”Morris MS, Jacques PF, Rosenberg IH, Selhub J. Folate and vitamin B-12 status in relation to anemia, macrocytosis, and cognitive impairment in older Americans in the age of folic acid fortification. Am J Clin Nutr. 2007;85(1):193-200. doi:10.1093/ajcn/85.1.193
Another Problem is The Extra Unmetabolized Folic Acid Found Hanging Out In The Blood
What with all this food fortification, many people have more folic acid than their bodies can handle. Folic acid must be converted into something else to even begin to become useful, and it uses an enzyme (just like the MTHFR magic chair, only it converts a different valueless thing (folic acid) into something more valuable), called dihydrofolate reductase. We’ll call it DHF. DHF is a little bit slow, and can’t always keep up so we see folic acid hanging around in the blood stream, being harmful. Here’s a great study showing the link between fortified foods and unmetabolized folic acid.
The problem with this unmetabolized folic acid in the bloodstream is that it is associated with reduced Natural Killer Cell cytotoxicity. Your natural killer cells (NK) are your main patrol against cancer, so we want these guys to be as potent as possible – this is another potential explanation for the tendency of high folic acid levels to cause cancer.. Here’s a full research article from the Journal of Nutrition.
So, If Folic Acid is Toxic In Normals, What About MTHFR Folks?
Great question. With MTHFR issues, the folic acid situation becomes even dicier. This specific question hasn’t actually been studied in humans yet, and there are a lot of ethical considerations that would go into that (it’s frowned-upon to give humans potentially toxic doses of something for the sake of science.) There is a really great mouse study (we’re allowed to poison them) and the name mostly sums it up.
High folic acid consumption leads to pseudo-MTHFR deficiency, altered lipid metabolism, and liver injury in mice.
My work here is done.
Let me give you the run-down of key points from this study:
- Mice were fed either a normal diet or a high-folate diet (10x the normal level).
- Normally fed mice worked out normally so this is the last we’ll talk of them.
- Folic Acid-fed mice had abnormally weighty livers and spleens
- Folic Acid-fed livers were fatty in a pattern typical of Non-Alcoholic
- Fatty Liver Disease (often seen in MTHFR folks, BTW).
- Folic Acid-Fed mice showed signs and symptoms of megaloblastic anemia, worse in MTHFR+/+ mice (this is usually caused by folate deficiency)
- Folic Acid-Fed mice showed high white blood cell counts, which were even higher in these same mice with MTHFR issues.
- MTHFR activity is inhibited by high levels of folic acid in mice, even in genetically wild-type mice.
- The livers of Folic Acid-fed mice had reduced ability to methylate toxins as compared to the other mice.
- The amounts of SAMe (the product of the methylation pathway) and methyl-THF (active folate) were reduced in the Folic Acid-fed mice, especially in those with MTHFR issues.
- The expression of other genes involved in the methylation pathway was also altered in the Folic Acid-fed mice. (Mtr, Chdh, Pemt, and Mat1a)
We suggest that high folic acid consumption reduces MTHFR protein and activity levels, creating a pseudo-MTHFR deficiency. This deficiency results in hepatocyte degeneration, suggesting a 2-hit mechanism whereby mutant hepatocytes cannot accommodate the lipid disturbances and altered membrane integrity arising from changes in phospholipid/lipid metabolism. These preliminary findings may have clinical implications for individuals consuming high-dose folic acid supplements, particularly those who are MTHFR deficient.Christensen KE, Mikael LG, Leung KY, et al. High folic acid consumption leads to pseudo-MTHFR deficiency, altered lipid metabolism, and liver injury in mice. Am J Clin Nutr. 2015;101(3):646-658. doi:10.3945/ajcn.114.086603
So For MTHFR Folks, Folic Acid is… TOXIC.
Or at least, very, very bad. The bottom line is, don’t take it and avoid it in foods. We’ll cover foods in more detail because naturally occurring folate are great and should be eaten, but fortified foods – like breads, cereals, and grain products, should be avoided.