Folate: Too Little, Too Much, or Just Right?

Reviewed and Updated January, 2021

I originally wrote this blog some years ago when we were discovering that folate was a double-edged sword. The topic of folic acid, folate, and methylation is just as important and controversial today as it was in 2012. Since writing this blog, even more studies have shown that some Americans are getting a lot of folic acid. Practically every American has folic acid circulating in blood that they cannot properly break down (called unmetabolized folic acid, UMFA).¹ Most of this is due to folic acid vitamins on top of folic-acid-fortified foods, such as flour and breakfast cereal. Many people don’t have enough of the enzyme that is needed to break down all of that folic acid, dihydrofolate reductase (DHFR).

Meanwhile, we have seen the interest in the MTHFR mutation skyrocket with the popularity of genetic testing, such as 23andMe, as well as the average consumer’s interest in the best folate or folic acid supplement to take. The MTHFR gene, which stands for methylenetetrahydrofolate reductase, may not work properly in up to 40% of White or Hispanic people in the United States.²

That’s why the form of folate that we take is very important. We want to take activated forms of B vitamins, not synthetic folic acid. In people who have the MTHFR gene mutation, they cannot use folic acid and therefore need the activated forms of folate. Ready-to-use forms of folate include 5-methylfolate (aka 5-MTHF, MTHF) and folinic acid.

We know that improving methylation (with activated B vitamins) seems to have a very significant benefit for some children with autism. And having the MTHFR mutation, or not enough folate and vitamin B12, can lead to difficulty getting pregnant, neural tube defects (birth defects), heart disease, cancer, and mood disorders. Very high doses of methylfolate (15 mg) may be effective for difficult-to-treat depression and these supplements are now available to consumers.

Photo by Dose Juice on Unsplash

Despite everything we know about how essential folate is for our health, and even with the correct form of folate, we could be getting sick from too much. That is especially the case with cancer. Dr. Kara Fitzgerald, ND and Ms. Romilly Hodges, MS, CNS have written an e-book called, Methylation Diet & Lifestyle. This book teaches you how to get plentiful methylation B vitamins from your food, without the risk of over-supplementation.

The sentiment in my original blog still rings true- we don’t want too little, or too much, folate. Just like the fairytale heroine Goldilocks, we want the amount that is just right. Figuring out what is “just right” for each person depends on diet, supplements, genetics, and your body’s unique needs, which can be revealed with functional tests. Easy-peasy, right? I discuss methylation testing in my next blog,”The Folate Tests You Need To Know About for Heart, Brain, and Reproductive Health.“

We are all familiar with the concerns about folate deficiency and we want to make sure everyone has enough folate to avoid neural tube defects, poor pregnancy outcomes, and cancer. Folic acid has been promoted by public health departments and it is a regular part of most people’s diets because of flour fortification. But now there are concerns about the effect of too much folic acid, or rather, too much unmetabolized folic acid.

But before we get too far, let’s review the terminology…Folic acid refers to the synthesized, oxidized compound that was discovered in the 1940’s. It is what you find in dietary supplements and food fortification. In the liver, folic acid is converted by the enzyme dihydrofolate reductase to the usable form, tetrahydrofolate. When this mechanism is overwhelmed or too slow, folic acid can build-up in the serum and this is referred to as unmetabolized folic acid (UMFA).

Folate refers to the water-soluble B-vitamin that we find naturally in whole foods. Folates found naturally in food include 5-methyltetrahydrofolate (5-MTHF), 10-formyltetrahydrofolate, and 5-formyltetrahydrofolate.

Figure courtesy of http://drsamsblog.blogspot.com/2015/05/acid-vs.html

Some studies have shown that folic acid intake is associated with cancer progression and growth (colorectal, breast, prostate).³  High UMFA might be responsible for these negative effects. As little as 300-400 mcg of folic acid can elevate serum UMFA, while consumption of naturally occurring folates does not increase UMFA.⁴  Therefore, some authors suggest that it is the synthetic form of the vitamin (folic acid) that causes problems and that natural folates (in food) are not problematic. However more research is needed to answer these questions.

While there is increasing concern about adverse health effects of excess folic acid intake and high UMFA, high 5-MTHF may not be desirable either. It could actually be that the cancer-promoting effect of folic acid is due to supraphysiologic levels of tetrahydrofolate (THF), the bioactive form of the vitamin. 5-MTHF could also increase THF. Therefore, either high 5-MTHF levels or high UMFA levels may be contraindicated in patients with cancer risk.

The bottom line is that when it comes to folic acid, too little or too much could lead to problems. It isn’t wise to give high doses of folic acid (or folate) to patients without evidence that they need it. Testing 5-MTHF can help a clinician determine if the patient requires no folate supplementation, a reduced or a maintenance dose of folate, or a high dose of folate. Serum UMFA will tell a clinician if the patient is having trouble metabolizing folic acid and needs to reduce folic acid vitamins and fortified foods.

Dangers of too little folate

• Neural tube defects
• Megaloblastic anemia
• Poor pregnancy outcomes
• Neuropsychiatric disorders
• Atherosclerosis (high homocysteine)
• Increased risk of cancers³

Dangers of too much folic acid

• Cancer progression and growth (colorectal, breast, prostate)³
• Pernicious anemia (masks the detection)
• Interferes with anti-folate⁵ medications
• Suppresses the immune system
• Contraindicated with cerebral folate deficiency

Studies suggest that too little folate causes disease and too much folic acid may also cause disease.^3-7 The old adage, “everything in moderation,” probably holds true, not just for folate but, for all nutrients. We can’t say all vitamins are good and we can’t say all vitamins are bad. There are many factors that determine if a vitamin is good or bad, and at what quantities, for a given individual.  Having to sort through all of these complexities for each patient reminds us of the wisdom of individualized medicine. Testing UMFA and 5-MTHF can help determine that a patient doesn’t have too little folate or too much folic acid, but the amount that is just right.

References

1. Pfeiffer CM, Sternberg MR, Fazili Z, et al. Unmetabolized folic acid is detected in nearly all serum samples from US children, adolescents, and adults. J Nutr. 2015;145(3):520-531.
2. Moll S, Varga EA. Homocysteine and MTHFR Mutations. Circulation. 2015;132(1):e6-9.
3. Kim YI. Folic acid fortification and supplementation–good for some but not so good for others. Nutr Rev. 2007;65(11):504-511.
4. Bailey RL, Mills JL, Yetley EA, et al. Unmetabolized serum folic acid and its relation to folic acid intake from diet and supplements in a nationally representative sample of adults aged > or =60 y in the United States. Am J Clin Nutr. 2010;92(2):383-389.
5. Kelly P, McPartlin J, Goggins M, Weir DG, Scott JM. Unmetabolized folic acid in serum: acute studies in subjects consuming fortified food and supplements. Am J Clin Nutr. 1997;65(6):1790-1795.
6. Powers HJ. Folic acid under scrutiny. Br J Nutr. 2007;98(4):665-666.
7. Solomons NW. Food fortification with folic acid: has the other shoe dropped? Nutr Rev. 2007;65(11):512-515.

Cass Nelson-Dooley, M.S.

Cass Nelson-Dooley, MS, is a researcher, author, educator, and laboratory consultant. She studied medicinal plants in the rain forests of Panama as a Fulbright Scholar and then launched a career in science and natural medicine. Early on, she studied ethnobotany, ethnopharmacology, and drug discovery at the University of Georgia and AptoTec, Inc. She joined innovators at Metametrix Clinical Laboratory as a medical education consultant helping clinicians use integrative and functional laboratory results in clinical practice. She owns Health First Consulting, LLC, a medical communications company with the mission to improve human health using the written word. Ms. Nelson-Dooley is an oral microbiome expert and author of Heal Your Oral Microbiome. She was a contributing author in Laboratory Evaluations for Integrative and Functional Medicine and Case Studies in Integrative and Functional Medicine. She has published case studies, book chapters, and journal articles about the oral microbiome, natural medicine, nutrition, laboratory testing, obesity, and osteoporosis.