Folic Acid Safety, Interactions, and Effects on Other Outcomes
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FAQ Topic Areas
- General Information About NTDs, Folic Acid, and Folate
- Folic Acid Safety, Interactions, and Effects on Other Outcomes
- Folic Acid and Its Link to Other Health Outcomes
- Folic Acid Fortification and Supplementation
- Neural Tube Defects Surveillance
- References
- At this time, folic acid taken at or up to the recommended amount of 400 micrograms per day (mcg/day) has not been shown to be harmful. Additional information continues to be assessed as it becomes available.
- The benefits of taking folic acid are well established. Folic acid has been shown to be effective in preventing neural tube defects in randomized control trials and food fortification programs 2-6.
- Folic acid also prevents a type of anemia called megaloblastic anemia.
- Some vitamins (such as vitamin D and vitamin A) can collect in fat tissues in the body, so they can be toxic if someone consumes too much. Folic acid does not collect in fat, but instead dissolves in water. This means that any amount of folic acid that is not used by the body (also called “unmetabolized folic acid”) goes through the kidneys, into the urine, and out of the body.
- The term, tolerable upper intake level (UL), is defined by the Institute of Medicine (IOM) as “the highest level of daily nutrient intake that is likely to pose no risk of adverse health effects to almost all individuals in the general population” 15.
- In 1998, the IOM set the UL at 1,000 micrograms per day (mcg/day) of folic acid (coming from foods fortified with folic acid and from vitamin supplements).
- Although the UL is used more broadly, it is only intended to prevent people who don’t know that they have a deficiency of vitamin B12 from consuming too much folic acid.
- When taking supplements, more is not better. Women who can get pregnant (whether planning to or not) need just 400 mcg/day of folic acid, and they can get this amount from vitamins or fortified foods. This is in addition to eating foods rich in folate. But, your doctor might ask you to take more for certain reasons.
- People with a severe deficiency of another B vitamin – vitamin B12 – can develop a type of anemia called pernicious anemia, and eventually they might have nervous system damage. If people with vitamin B12 deficiency receive high doses of folic acid, the folic acid supplementation can correct the anemia; however, the nervous system damage can still occur because these people are still deficient in vitamin B12 15. This effect was seen among some patients who were given very high dosages [more than 5,000 micrograms per day (mcg/day)] of folic acid for many months 15. Based on these data, the Institute of Medicine specified a dose of 5,000 mcg/day of folic acid as the Lowest Observed Adverse Effect Level (LOAEL). The tolerable upper intake level (UL) for folic acid was established at 1,000 mcg/day (one-fifth of the LOAEL) to prevent individuals from taking so much folic acid that they reach the LOAEL risk level of 5,000 mcg/day 15.
- New laboratory tests can readily measure a person’s vitamin B12 status. This means that vitamin B12 deficiency can be detected and diagnosed quite easily. It also means that not being able to identify the anemia caused by vitamin B12 deficiency, as described in early case reports, is unlikely to remain an issue. A recent population-based study examined anemia among people with vitamin B12 deficiency before and after folic acid fortification and found that folic acid did not delay the identification of vitamin B12 deficiency after fortification began 16.
- The Institute of Medicine has not established a separate tolerable upper intake level (UL) for women of reproductive age. It states that, in general, vitamin B12 deficiency among U.S. women of reproductive age is rare, and they are unlikely to have any adverse effects from consuming supplemental folic acid at or above the UL 15.
- When the Institute of Medicine (IOM) set the tolerable upper intake level (UL) for folic acid, there were no data on any potential adverse effects for children consuming very high amounts of folic acid, nor are there any currently. Because of this, the IOM used data from adults and proposed ULs for children based on body weight. Because there is no clinical evidence that the consumption of high amounts of folic acid among children has caused any adverse effects, the age-specific ULs (based on body weight) might not be meaningful. Another reason that ULs for children might not be meaningful is that vitamin B12 deficiency is very rare among U.S. children 17.
- Undiagnosed and untreated vitamin B12 deficiency can cause cognitive impairment. Many forms of dementia – such as Parkinson disease or Alzheimer disease – are made worse when vitamin B12 levels are low, regardless of a person’s folate status 18. Once a diagnosis of vitamin B12 deficiency is established, standard medical practice is to treat such individuals with vitamin B12.
- Some studies have suggested that a higher concentration of blood folate might be related to cognitive impairment among older adults (older than 59 years of age) who have low vitamin B12 levels 19-21, while other studies have failed to confirm these findings 22-24.
- In studies of older adults with cognitive impairment and low vitamin B12 levels who consumed higher amounts of folic acid, these adults typically took multivitamin supplements that contained both folic acid and vitamin B12. Because these multivitamins contained sufficient amounts of vitamin B12 to correct vitamin B12 deficiency under normal circumstances, these older adults were probably not able to absorb vitamin B12 from their intestines 25. Therefore, these adults likely developed cognitive impairment because they had pernicious anemia from their low vitamin B12 status, and not because they consumed vitamin supplements containing folic acid.
- All women can benefit from getting 400 micrograms per day (mcg/day) of folic acid, especially before and during early pregnancy.
- MTHFR (methyltetrahydrofolate reductase) is an enzyme that plays a role in how all people process folate. A common genetic variant of the MTHFR enzyme (also known as the MTHFR TT or CT genotypes) determines how rapidly some people can process folate. Even though women with the MTHFR TT or CT genotypes process folate more slowly, they can increase their blood folate concentrations enough to help prevent neural tube defects—some serious birth defects of the brain and spine—by consuming the recommended 400 mcg/day of folic acid 11.
- Research studies have shown that among populations in which more people have the MTHFR TT or CT genotypes, getting 400 mcg/day of folic acid before and during early pregnancy can reduce by 85% the risk of having a baby with a neural tube defect 5.
- Many studies have shown that consuming folic acid increases blood folate concentrations 26. For example, a research study among a population at high risk for neural tube defects showed that, after consuming 400 mcg/day of folic acid for three months, average blood folate concentrations increased to levels that would prevent neural tube defects among women with all MTHFR genotypes, including the MTFHR TT genotype 9.
- Unmetabolized folic acid is any amount of folic acid that is found in the blood because it has not been converted into other forms of folate or removed from the body through urination.
- Folic acid is absorbed by the intestines into the bloodstream, and then converted to other forms of folate by the liver. The liver is capable of processing only a certain amount of folic acid at one time. Unused folic acid in the blood goes to the kidneys and leaves the body in urine 27.
- Studies dating back to the late 1990s have shown that people taking a single dose of folic acid of more than 200 micrograms (mcg) can have some unmetabolized folic acid circulating in their blood 28, 29.
- Research also has shown that individuals consuming folic acid from fortified foods, ready-to-eat cereals, or vitamin supplements, or any combination thereof, have varying amounts of unmetabolized folic acid in their blood 28, 30-32. Since the beginning of mandatory folic acid fortification, most people have had some unmetabolized folic acid circulating in their blood 32.
- Although some people have been concerned about unmetabolized folic acid in the blood, no confirmed health risks have been found 20, 33, 34.
- A recent review found no evidence of harmful effects of unmetabolized folic acid in the blood of infants 35.
Page last reviewed: June 17, 2022