Many people know that vitamin B9 (known as folic acid or folate) is important for many things like prenatal care and prevention of birth defects, red blood cell formation, clearance of homocysteine, and brain function. Because of this high importance, cereals and grain products have been mandatorily fortified with folic acid in the United States since 1998. There is, however, a growing concern that the fortification of foods with “folic acid” may not always be helpful. It’s not that vitamin B9 is a bad thing. The concern is the form; folic acid is synthetic whereas folate is natural. Synthetic folic acid can actually build up in the body and become problematic. Natural folate is essential for health.

Natural Folate

The names folic acid and folate are often used interchangeably in conversation, but there are important differences that everyone should understand.

The natural form of vitamin B9 is called folate which is found in foods, especially dark green leafy vegetables like spinach. Other folate-rich foods are asparagus, broccoli, liver, and Brussels sprouts. Fruits, vegetables, nuts, beans, peas, seafood, eggs, dairy, meat and poultry also contain folate. Folate is the active form of vitamin B9. Its scientific name is 5-CH3H4PteGlu or 5-methyltetrahydrofolate which refers to the methylated or coenzyme form of folate or simply – 5-MTHF. Natural folate is also sometimes called folinic acid. Folate is metabolized in the digestive tract.

Synthetic Folic Acid

The synthetic form of vitamin B9 is called folic acid. This form is added to fortified foods, primarily cereals, flours, cornmeal, rice, and other grain products to help with prevention of neural tube defects. Synthetic folic acid is also found in many prenatal vitamins, multivitamins, B complexes, and prescription vitamins. It is not natural to the body.

The United States folate RDI is a minimum of 400 micrograms per day. Pregnancy RDI is 600 mcg and breastfeeding requires 500 mcg per day. The folic acid fortification policy amount requires 140 mcg of synthetic folic acid per 100 grams of grain product. Other countries like Canada, Chile, and Australia have similar requirements.

Synthetic folic acid is a monoglutamate form of folate and is known as pteroylmonoglutamic acid or PteGlu. This form requires an enzyme called DHFR to metabolize it in the liver before it is modified into the natural folate form. Folate from foods or supplemental forms of folate as 5-MTHF or folinic acid do not have to go through this step. Natural folate is easily absorbed and used by the body.

Folic Acid Metabolism is Impaired

Humans have a reduced ability to convert folic acid to folate compared to animals. If it is not converted or used, it builds up in the body and is known as oxidized folic acid or “unmetabolized folic acid”. Tests show that there is five-fold variation of the DHFR enzyme activity in individuals that can impair folic acid activation. This leaves a wide range of clinical effectiveness or significant lack of ability to metabolize folic acid.

It is estimated that an intake of just 266 - 400 micrograms (mcg) per day of folic acid in fortified foods and/or as synthetic folic acid supplement can lead to build-up of unmetabolized folic acid.

For those who have lower activity of this enzyme, unmetabolized folic acid builds up more readily. The concern is not too much folate, but rather the build-up of unmetabolized “folic acid”. This adversely affects several things, including methylation.

Unmetabolized Folic Acid Findings and Concerns

Methylation is a massive cellular process that requires folate and several other nutrients. It occurs trillions of times in every cell throughout the day. Build-up of unmetabolized folic acid adversely affects methylation. It is estimated that about 65 percent of the population has one MTHFR gene mutation and about 25 percent have two MTHFR gene mutations. When these genes are affected, the rate of methylation is lower and this ultimately impairs folate metabolism. In order to bypass these MTHFR gene mutations, natural folate or methylated folate is preferred rather than folic acid. Taking folic acid with methylation impairments will not help. It will be a greater stress on the body.

It is well known that taking folic acid or folate to the exclusion of other nutrients, it can mask or create other deficiencies. In particular, if one takes folic acid without vitamin B12, doing so can hide a vitamin B12 deficiency, create anemia and affect cognitive function, especially in the elderly.

Less than a decade after mandatory folic acid food fortification, reports started surfacing that raised concerns about unmetabolized folic acid. A 2006 publication evaluated postmenopausal women for unmetabolized folic acid levels in their blood. Of the participants, 78 percent of them had elevated levels of unmetabolized or oxidized folic acid.

It was also found that immune system changes occurred with suppression of natural killer (NK) cell functions. The NK cells lost their cytotoxic ability to attack damaged and harmful cells like virus and cancer cells. The higher the level of unmetabolized folic acid in the blood stream, the more dysfunctional and compromised the natural killer cells became.

Further insight has occurred in recent years with the build-up of unmetabolized folic acid. Too much folic acid may interfere with the use of natural folate as it may affect its transportation and receptor sites in the intestinal tract and kidneys. Other concerns due to high levels of unmetabolized folic acid include impaired DNA synthesis, methylation and repair processes, along with increased incidence of colorectal cancer and other cancers. Too much unmetabolized synthetic folic acid can block how some medications work in the body.

Prenatal Exposure of High Levels of Unmetabolized Folic Acid

Other studies have focused on prenatal exposure to folic acid. On one hand, folic acid has been helpful in low to moderate doses to help prevent birth defects that develop shortly after conception when cells are rapidly multiplying.

However, there is another side to the picture. Studies have found that pregnant women who had high levels of unmetabolized folic acid were more likely to have children develop insulin resistance and obesity. Other findings strongly question prolonged high intake of folic acid during pregnancy as it can affect gene expression.

In a 2011 study, scientists determined that high folic acid intake during pregnancy caused “dysregulation by greater than four-fold up or down to more than 1000 genes, including many imprinted genes” and may lead to neurodevelopmental defects such as autism. The amount of folic acid in the blood that adversely affected gene expression was lower than the FDA fortification guidelines.

More recent research published in 2017 also questions the impact of high levels of unmetabolized folic acid consumed throughout pregnancy and increased risk for autism spectrum disorder. Another 2017 study found that women who used 1000 mcg or higher of folic acid per day at the point of conception and continued long-term use of it, led to lower cognitive development in preschool aged children.

This is by no means a complete list of findings. Other concerns and controversies linked with unmetabolized folic acid versus folate populate the literature. These include cancers for adults and children, seizure disorders, ADHD, preterm delivery, and adverse effects on lymphocytes and white blood cells. Natural folate or methylfolate is the preferred form of vitamin B9 as it causes less stress in the body.

Why Do We Need Folate?

Since the fortification of foods with folic acid, there has certainly been measurable improvement in neural tube birth defects, congenital birth malformations, and some heart disease concerns. With the growing mountain of research, we see though that a build-up of unmetabolized synthetic folic acid stresses the body. Natural folate is essential for health as there is a daily need for it in the body.

Folate is necessary for cell replication and growth as it forms the building blocks of DNA (genetic information) and RNA (protein synthesis in all cells). Cell division, repair needs, and rapidly growing cells, such as the unborn, red blood cells, and immune cells all require adequate folate. Folate from foods or methylated folate supplements is required for methylation in order to maintain homeostasis inside of cells.

The synthesis of the neurotransmitters dopamine, serotonin, and norepinephrine requires folate. Methylated folate has been suggested as a valuable tool for mental health and mood challenges. Folate helps keep the brain from getting stuck in negative behavior and rumination. 

In addition, phosphatidylcholine levels in the brain depend upon folate in the brain. If there isn’t enough folate for the brain, then phosphatidylcholine levels are also depleted in the brain. Phosphatidylcholine is needed for the production of acetylcholine, the neurotransmitter essential for memory and autonomic nervous system function. Previous articles have discussed the intense need of adequate choline in the diet for the nervous system and gut health. Clearly, there is a significant inter-relationship between folate, acetylcholine function and the nervous system.

Your body needs folate for red blood cell formation, healthy mood, digestion, blood pressure, blood flow, oxygen utilization and breathing, energy production, growth, brain health, sleep, and physical strength. You need it to process the metabolite homocysteine, which can injure blood vessel linings and contribute to adverse cholesterol and heart health concerns if it builds up in the body. Your teeth and gums, eyes, nerves, skin, bones, reproductive organs, liver, gut, circulatory and immune systems need folate.

Numerous medications like antacids, aspirin and other pain relieving meds, cholesterol lowering, HRT, antibiotics, diuretics, diabetes meds, inhalers, steroids, antibiotics, inflammatory bowel disease meds and other medications deplete folate. Further information may be found in the article Common Medications That Rob the Body of Nutrients. Check with your pharmacist too if you don’t see your medication on the list.

Folate Supplements

It is best to supplement the active form of vitamin B9 or methylated form, which the body prefers. All Wellness Resources supplements with B9 contain the natural folate in the methylated form called Quatrefolic 5-MTHF. This folate is in Daily Energy Multiple Vitamin, Daily Prenatal Multi Vitamin, Super Mini-Multi, Blood Booster, and Super Coenzyme B-Complex. We also always combine the methylated folate with the coenzyme form of vitamin B12 so you don’t have to worry about creating an imbalance.

It is always best to take a multiple vitamin or a B complex to get all of the B vitamins and not further deplete other B vitamins. Once again, we find that natural forms of nutrients are what the body prefers. Synthetic ingredients just like synthetic chemicals in the environment create a challenge to the body. In the case of folic acid, it looks to me a little like “close, but no cigar”.