Abstract: The FDA has historically relied on the synthetic folic acid form of folate to address a public health concern regarding neural tube defects and folate deficiency. However, the latest research shows that excess folic acid can circulate unmetabolized in our bodies, leading to problematic side effects. In order to avoid these unmetabolized products and effectively improve folate levels, supplementing with methyl folate forms is a great solution. There are plenty of dietary sources of folate, which ideally provide us with sufficient vitamins and minerals. However, dietary folate amounts are more susceptible to loss from various processing and absorption factors. 

Folic Acid, Get Your Folic Acid! No? 

Imprecise use of the term "folic acid" (FA) has caused confusion surrounding the various forms of vitamin b9, or folate. There are differences between folate vitamin forms; there are various tetrahydrofolates obtained from natural foods and a chemically synthesized form used for food fortification and nutritional supplements. The latter form is folic acid. 

Folic acid is a chemical compound absent from human tissues and whole foods. It is not a vitamin but a provitamin that must be converted to tetrahydrofolate to be useful to human cells. The active compounds in the human body are tetrahydrofolates - methyltetrahydrofolic acid (5-MTHF) is the predominant form in the blood and many foods. 

Since 1996, the FDA has mandated that grains, flours, and breads be fortified with synthetic folic acid in the United States to address a public health concern regarding folate deficiencies in women leading to neural tube defects. The fortification amounts are not high, as FDA regulators agree that small fortification amounts often yield much larger than anticipated protective results. "Enriched" cereals have 0.14 mg/serving of folic acid. In a lot of ways, fortification has shown to be beneficial over the years. However, in recent years, studies have shown folic acid in food fortification and nutritional supplements to be underutilized in the body. Human tissues lack the ability to convert synthetic folic acid into tetrahydrofolates, especially in high doses. The low activity of the DHFR enzyme in the liver suggests that increasing the dose of folic acid may, at some point, with individual variation, no longer produce further increases in the active folate pool. It's not that folic acid doesn't help improve folate status and correct overall folate deficiencies; it's that dosing needs to be exactly right to avoid unmetabolized particles that could potentially be dangerous. Deficiencies can be corrected in an even better way. And that better way is a more efficient and natural supplement form of folate, methyl folate, or tetrahydrofolates.

Multiple research studies have detected unmetabolized folic acid in plasma several hours after consuming more than 200 μg of folic acid. The presence of circulating unmetabolized folic acid in the body may be detrimental. Although folate deficiency has been linked to cancer susceptibility, recent evidence suggests that high intake (>1 mg/day) of folic acid may exacerbate some preexisting cancers or progression of precancerous lesions. Furthermore, unmetabolized folic acid has also been hypothesized to cause the masking of B12 deficiency and aggravate the neurological damage associated with prolonged B12 deficiency. If supplementation is done with methyl folate, the natural bioavailable form, unmetabolized and potentially problematic, synthetic particles are not found in circulation.

A Little History Lesson On The Topic 

Soon after its discovery in the late 1920s, folic acid came to the attention of clinical researcher Sydney Farber. He hypothesized that using folic acid supplements might help children with leukemia by fortifying tumor suppressive physiological responses. Instead, it greatly enhanced lymphocyte proliferation, an immune response associated with cancer growth. By looking at folate antagonists, Faber initiated the field of cancer chemotherapy. 

The potential for enhancing certain types of cancer continues to be a concern for individuals with elevated serum folic acid. Rapidly growing cells acquire folic acid faster than resting cells, adding to the potential for causing altered cell responses. Human cells acquire folic acid, which may persist in the unmetabolized form because of the liver's poor activity of the DHFR enzyme and causing interference with the functions of tetrahydrofolates.  

A Further Breakdown of The Two Supplemental Forms 

The forms used in folate supplementation are evolving. Before 2015, it was very rare to see prenatal supplements utilizing the methyl folate form. However, methyl folates are currently present in over a third of offerings. Because they are a newer form, the more natural supplemental form was not tested directly in clinical trials for preventing neural tube defects. They are also not mentioned in the current public health recommendations by the CDC. So technically, methyl folates (L-5-MTHF) are not proven effective in preventing neural tube defects; however, based on what we know, that conclusion is very likely. 

• The body must convert folic acid into active forms of folate such as (L-5-MTHF) or other methyl folates to function in the body. 
• Both natural methyl folates and synthetic folic acid forms of the vitamin prevent folate-deficiency anemia and maintain blood folate concentrations. 
• Both natural methyl folates and synthetic folic acid forms of the vitamin cause similar decreases in homocysteine and produce similar serum and RBC folate concentrations. 
• The bioavailability of methyl folates is similar to folic acid; however, increased serum folate from methyl folates is independent of MTHFR status, a common genetic variant influencing the body's ability to process folate. Serum folate levels from methyl folates do not depend on this gene's efficiency. 
• Greater increases in serum folate levels have been observed using methyl folates relative to folic acid in women who were folate deficient. 
• Methyl folate may not mask the signs of vitamin B12 deficiency. High intakes of folic acid have been reported to temporarily correct the anemia associated with vitamin B12 deficiency, possibly hindering early diagnosis and allowing associated neurological damage to progress.

With all this in mind, even though a specific clinical study has not been conducted, it is apparent that methyl folates work similarly, and even slightly better than folic acid, in improving serum folate levels and consequently combating neural tube defects. 

Folate Found in Food 

Obtaining adequate vitamins and minerals from food is always ideal - however, it is not always possible. 

Folate is found in many foods, including legumes, leafy greens, citrus, broccoli, sprouts, sea vegetables, and fermented dairy products. Many commercial fermented dairy products contain significant folate levels, especially if the cows are grass-fed. Fermented yogurt has, on average, 100 μg/L of folate, while milk contains 20 μg/L. Dried herbs are also an excellent food source of folate, particularly in the colder months. Spearmint, rosemary, basil, parsley, and chervil contain folate. Lastly, peanuts and sunflower seeds are also great sources. 

However, absorption rates and amounts of dietary folate are more variable and susceptible to influences than supplemental forms. Dietary folate needs to be hydrolyzed by an enzyme in the small intestine before it can be absorbed. This enzyme can be influenced by yeast, beans, and acidic pH levels. Supplemental forms of folate do not require extensive digestion before absorption. 

Lastly, dietary folate is often lost during cooking due to thermal degradation and leaching into cooking water. Boiling significantly reduces folate levels in food. Food processing, such as canning, destroys 50% to 95% of dietary folate. Alcohol intake, as well as zinc deficiency, impedes folate absorption.  

Resources:

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3. Kohlstadt I, ed. Advancing Medicine with Food and Nutrients. Second edition. CRC Press, Taylor & Francis Group; 2013.
4. Perspective: Time to Resolve Confusion on Folate Amounts, Units, and Forms in Prenatal Supplements | Advances in Nutrition | Oxford Academic. Accessed July 13, 2022. https://academic.oup.com/advances/article/11/4/753/5781886
5. The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake. doi:10.1073/pnas.0902072106
6. CDC. MTHFR Gene and Folic Acid. Centers for Disease Control and Prevention. Published June 15, 2022. Accessed July 13, 2022. https://www.cdc.gov/ncbddd/folicacid/mthfr-gene-and-folic-acid.html