Folate: A Critical Nutrient for a Healthy Balance

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Folate is a tricky nutrient. It is essential, which means your body can’t make it and you need to consume it, BUT there can be a big difference between how much you are consuming and how much your body is actually able to use. In honor of Folate Awareness Week, we would like to share a few ways to determine your folate status and seven very good reasons to take a methylfolate supplement. 

But first,

What is Folate?

Folate is the blanket term for all forms of the essential vitamin B-9. Activated folate, specifically, is necessary for the biochemical process called “methylation” where it works together with cofactors (including B-6, B-12, and magnesium) to modulate the transcription on DNA (affecting which of your genes get expressed). Healthy methylation is necessary for the production of neurotransmitters that affect mood and cognitive function, energy production, healthy cardiovascular and reproductive systems, and so much more.  

Folate is found naturally in leafy green and cruciferous veggies like kale, cabbage, broccoli, and bok choy. Unfortunately, it is not highly bioavailable, nor is it stable through food storage and preparation [1]. This means your body has a tough time accessing and absorbing this nutrient from food sources. For this reason, a synthetic form of the vitamin (folic acid) was developed and is technically much more bioavailable than natural folate found in food.

As we will delve into deeper later in this article, folate is critical for early fetal development, and as many pregnancies are unplanned, it is highly important that all women of childbearing age avoid folate deficiency. Therefore, many commonly consumed food items, such as rice and cereal grains, are fortified with folic acid. In fact, there are mandatory fortification laws regarding the folic acid enrichment of wheat flour in 53 different countries, including the US [1]. 

What’s the problem with Folic Acid?

For some people, there is no problem with folic acid. Some bodies are able to efficiently produce the necessary enzymes to convert synthetic folic acid into the activated form of folate actually used by cells for methylation and its associated biochemical processes. The problem is that not all bodies can do this. If your body cannot activate folic acid efficiently, it can lead to negative downstream consequences, symptoms of folate deficiency, and a buildup of unmetabolized folic acid in the circulation. 

Genetic Variation

In order to convert folic acid to its active form, known as methylfolate, a person’s cells must be able to make an enzyme called methylenetetrahydrofolate reductase (MTHFR enzyme) coded for by the MTHFR gene. Much of the global population, however, has inherited MTHFR gene mutations, which result in less-than-optimal MTHFR enzyme production. As with all genes, you get one copy from your mother and one copy from your father. Some people have a mutation in one or both copies of the MTHFR gene. There are two common MTHFR gene mutations: C677T and A1298C. The names represent where in the gene code a mutation has occurred, where one nucleotide is different from the fully functional gene. You can have either one or both.

C677T

This is the most common MTHFR gene mutation. 20-40% of white and Hispanic people in the United States have this mutation. It results in an MTHFR enzyme that can only work at 30-60% of its capacity [2]. 

A1298C

This mutation is found in 7-12% of white people and about 4% of Hispanic and Asian people. With this mutation, the enzyme can only work at 60% of its capacity [2].

There are other genes that can affect the way we metabolize and use folate, but these are by far the most common. Luckily, whether or not you have a genetic mutation (or two), supplementary L-methylfolate is available. By supplementing with L-methylfolate instead of folic acid, your body can use the active folate right away, as is, bypassing the conversion completely.

Mood Balance

Mood balance difficulties and fatigue are common symptoms of folate insufficiency. Because methylfolate and methylation are integral to the healthy production and metabolism of neurotransmitters, having an MTHFR variant, and therefore less circulating methylfolate, can lead to reduced neurotransmitter activity. MTHFR mutations are common in people who suffer from a chronically low mood [3].

An L-methylfolate supplement can be a superlative way to meet your active folate needs, supporting a balanced mood and sustainable energy.

Cardiovascular Health

Another serious risk of folate deficiency is hyperhomocysteinemia. Hyperhomocysteinemia is a buildup of homocysteine, which can be a result of inefficient methylation, which can be a result of low folate status (or low vitamin B-12). When homocysteine builds up in the circulation, there is an increased risk for a number of cardiovascular issues [4]. Researchers suggest that, for those with high homocysteine levels, increasing folate and thus decreasing homocysteine can significantly promote cardiovascular health and longevity [4].

If you have high homocysteine levels but are already taking a supplement with folic acid, you may be interested in having your genetics tested for an MTHFR mutation. Taking an L-methylfolate supplement (perhaps in combination with vitamin B-12) can also help to reduce homocysteine levels, regardless of your genetics.

Pregnancy

Since the 1960s, research has hypothesized a direct link between maternal folate levels and the neural development of her fetus. The neural tube is one of the first structures to form in an embryo and becomes the spinal cord and early brain. Folate is so critical during this step that deficiency can cause serious, and potentially fatal, developmental issues such as spina bifida and anencephaly [1].

Unfortunately, starting a prenatal vitamin with folate after pregnancy is determined is often too late, as this development happens so soon after conception. With so many pregnancies being unplanned (approximately 50% in the US [1]), it is highly important for all women of childbearing age to be wary of their folate and B-12 status, as both are independent risk factors for neural tube defects [1].

Since widespread cereal grain fortification began in the late 1990s, neural tube defects have seen a significant reduction. Because fortification practices use folic acid, and not activated methylfolate, there are likely many mothers who are still technically folate-deficient on a folic acid-sufficient diet due to genetic variation and enzyme inefficiency. Women of childbearing age can supplement with active methylfolate directly to avoid this potential problem.

Although indirect, there is also evidence to suggest that folate status may play a role in whether a pregnancy reaches full term or not. Observational studies have shown that a shorter duration of pregnancy can be associated with low serum folate or the absence of folate supplementation during pregnancy [5].

Unexplained infertility

Because methylfolate plays such an important role in the creation of healthy new cells, it has been hypothesized that some cases of unexplained infertility in both men and women are related to the folate pathway. Women with MTHFR genetic polymorphisms are more likely to experience fertility problems [6]. Higher folate intake has also been associated with higher rates of implantation, clinically-assisted pregnancy, and live birth [7]. The mechanisms behind this effect are not certain, but there are multiple possibilities.

In women, healthy folate levels in follicular fluid are associated with better quality oocytes (eggs) and a higher mature oocyte yield upon retrieval for assisted reproduction [7]. In men, a combination of zinc and folic acid supplementation leads to a 75% increase in sperm count and quality in subfertile men [8]. DNA synthesis is a key feature of spermatogenesis, so folate likely dictates, in part, how many healthy sperm cells a man’s body can make containing functional DNA. Of course, men and women with genetic polymorphisms affecting folic acid processing would benefit from supplementing with methylfolate to achieve healthy folate levels (rather than synthetic folic acid).

Menopause

Just because you won’t be conceiving a child after menopause, doesn’t mean you should forget about your folate levels. Folic acid has been shown to be effective in reducing the severity, duration, and frequency of hot flashes during menopause [9]. 

As estrogen activity declines during menopause, serotonin receptors in the brain become more active, stimulating changes in the temperature regulation center and autonomic responses such as sweating, followed by shivering and cooling of the body [9]. Any factor that increases serotonin levels, estrogen, or endorphins, and reduces norepinephrine should also decrease hot flashes. For example, some products prescribed to increase serotonin availability in the synaptic gaps, may provide hot flash relief.

As an essential cofactor in the biosynthesis of serotonin, folate can exhibit effects similar to some prescriptions products by interfering with serotonergic receptors. Folate can also reduce the secretion of norepinephrine considerably, and increase the activity of serotonin [9]. Of course, folic acid must be reduced and activated by the body before it can take effect. For those who cannot process folic acid effectively, L-methylfolate would be a more appropriate choice for supplementation.

Potential dangers of unmetabolized folic acid

For those who cannot process folic acid effectively, or even those who can but consume too much, there are potential dangers. Unmetabolized Folic Acid (UMFA) syndrome is suspected of causing immune dysfunction and other adverse pathological effects [10].

Unmetabolized folic acid is associated with a decrease in natural killer cell (NK) cytotoxicity [11]. As part of the nonspecific immune response system, NK cells are responsible, in part, for breaking down compromised cells [11]. Therefore, too much circulating folic acid could contribute to weakening the body’s immune response to both foreign and internal malignancies. The decrease in NK cytotoxicity associated with unmetabolized plasma folic acid was independent of total folate and active L-methylfolate concentrations, demonstrating no relationship between active methylfolate and immune weakening [11].

Another risk of overdosing folic acid can be the masking of B-12 deficiency. As B-12 is also required for methylation, B-12 deficiency can also cause similar, negative downstream effects. In one study of healthy adults over 60, it was shown that a combination of high folic acid and low B-12 increased the risk of cognitive decline [12]. This effect was only seen in participants taking folic acid, specifically, and was not observed before food fortification with folic acid was implemented [12].

A recent study documented a woman experiencing unexplained infertility, who was prescribed a high dose of folic acid. Although she was genetically tested to have two normal copies of the MTHFR gene, the high dose of folic acid appeared to cause symptoms of a methylfolate deficiency, with sky-high homocysteine levels [12]. Supplementing with L-methylfolate instead of folic acid helped this patient return to a healthy state [12]. This demonstrates yet again, that supplementing with active L-methylfolate is a superior choice to folic acid, across the board, regardless of one’s genetics.

Should you be concerned with your folate status?

While folate is an essential nutrient for all humans, if you are a woman of childbearing years, you should absolutely be concerned with your folate status. Unfortunately, determining your folate status is a bit more difficult than a simple blood test. If you are taking a high-quality daily multivitamin containing methylfolate (not folic acid) and not experiencing any symptoms of vitamin deficiency, you are likely doing just fine. 

If you are experiencing any symptoms of folate deficiency (including, but not limited to fatigue and a depressed mood), but are sure you are consuming plenty of folate, it is a great idea to have your genetics tested for variants in the folate processing-related genes. Your doctor can recommend a test that they may also be able to help you analyze. Alternatively, you could start taking a supplement containing activated L-methylfolate, and NOT folic acid. Be sure that methylfolate is complemented with vitamins B-6, B-12, and magnesium, as these nutrients are all important to the biochemical processes folate too participates in. 

References

1. Crider, Krista S., Lynn B. Bailey, and Robert J. Berry. “Folic acid food fortification—its history, effect, concerns, and future directions.” Nutrients 3.3 (2011): 370-384.
2. Moll S, Varga EA. Homocysteine and MTHFR Mutations. Circulation. 2015;132(1):e6-9.
3. Shelton RC, Sloan Manning J, Barrentine LW, Tipa EV. Assessing Effects of l-Methylfolate in Depression Management: Results of a Real-World Patient Experience Trial. Prim Care Companion CNS Disord. 2013;15(4):PCC.13m01520. doi:10.4088/PCC.13m01520
4. WebMD. “Folic Acid and your Heart”. WebMD Archives. Nov. 22, 2002. https://www.webmd.com/heart-disease/news/20021122/folic-acid-for-your-heart#:~:text=Researchers%20say%20a%20daily%20dose,in%20the%20blood%20called%20homocysteine.
5. Greenberg, James A., et al. “Folic acid supplementation and pregnancy: more than just neural tube defect prevention.” Reviews in Obstetrics and Gynecology 4.2 (2011): 52.
6. Altmäe, Signe, et al. “Variations in folate pathway genes are associated with unexplained female infertility.” Fertility and sterility 94.1 (2010): 130-137.
7. Gaskins, Audrey J., et al. “Dietary folate and reproductive success among women undergoing assisted reproduction.” Obstetrics and gynecology 124.4 (2014): 801.
8. Wong, Wai Yee, et al. “Effects of folic acid and zinc sulfate on male factor subfertility: a double-blind, randomized, placebo-controlled trial.” Fertility and sterility 77.3 (2002): 491-498.
9. Bani, Soheila, et al. “The effect of folic acid on menopausal hot flashes: a randomized clinical trial.” Journal of caring sciences 2.2 (2013): 131.
10. Servy, Edouard J., et al. “MTHFR isoform carriers. 5-MTHF (5-methyl tetrahydrofolate) vs folic acid: a key to pregnancy outcome: a case series.” Journal of assisted reproduction and genetics 35.8 (2018): 1431-1435.
11. Troen, Aron M., et al. “Unmetabolized folic acid in plasma is associated with reduced natural killer cell cytotoxicity among postmenopausal women.” The Journal of nutrition 136.1 (2006): 189-194.
12. Cornet, Dominique, et al. “High doses of folic acid induce a pseudo-methylenetetrahydrofolate syndrome.” SAGE open medical case reports 7 (2019): 2050313X19850435.