Side Effects of Folic Acid

Side Effects of Folic Acid – Overview

Vitamin B9 is essential for the body’s DNA and RNA formation, healthy blood cell production, and protein metabolism. (1) It is also vital for the healthy development of the fetus and the prevention of neural tube defects (serious birth defects of the brain and spinal cord). For this reason, in the first three months, pregnant women are recommended to take folic acid in addition to a diet containing vitamin B9. (1, 2)

Although the body’s needs for vitamin B9 are well-known, there is an ongoing discussion on the possible side effects of folic acid. Some associate folic acid with the cognitive development of babies or the risk of cancer. Moreover, in some articles, you may read about folate, folic acid, or vitamin B9, but you are unsure if these terms have the same meaning.

Keep reading this article to learn about the differences between folic acid and folate. In addition, this article addresses possible side effects, the latest discussion of additional risks, and advice on the safe intake of folic acid.

Folic Acid vs Folate – Are They the Same?

Side Effects of Folic Acid

Side Effects of Folic Acid – Is There Any Difference from Folate?

Folic acid and folate are usually used interchangeably and as another term for vitamin B9. Yet, there is a difference that impacts the usage in the body.

Folate is vitamin B9 available in natural food (vegetables, fruits, seafood, or eggs) and is used as an umbrella term for different types of folates:

  • dihydrofolate (DHF);
  • tetrahydrofolate (THF);
  • 5-methyltetrahydrofolate (5-MTHF);
  • 5, 10-methylenetetrahydrofolate (5, 10-MTHF). (3)

Folic acid is a synthetic form of vitamin B9 available as a supplement, and food producers use it for food fortification. After absorption in the intestines, folic acid goes through the bloodstream to the liver, which converts it into 5-MTHF, a form usable for the body. (3, 4)

The liver has a limited daily capacity for conversion. Unused folic acid goes to the kidneys, with urine thrown away. The amount of folic acid in the blood not eliminated by urine or converted into 5-MTHF is called unmetabolized folic acid. (4)

When and How is Folic Acid Used?

In normal individuals with a balanced diet, daily intake of folate with food should be sufficient. However, in people with anemia, young people, and pregnant women, vitamin B9 might be deficient, so doctors can prescribe or recommend supplements.

Other conditions that may need increased vitamin B9 intake are alcoholism, continuous diarrhea, prolonged fever, hemodialysis, liver disease, and others. (1, 5)

Recommended daily folic acid intakes depend on the age and are up to 400mcg. The daily dose for pregnant and breast-feeding females can vary from 400-800mcg/day. For newborns to three-year-old children, it is recommended 25-100mcg/day. (5)

Folic Acid Side Effects; Any Reason to Worry About?

When taken in recommended therapeutic doses of 400 mcg/day, folic acid didn’t show to be harmful. (4) Folic acid is a water-soluble substance that doesn’t deposit in the lipid part of the body. If taken in higher doses that the liver cannot metabolize, high concentrations of folic acid can be present in the blood. (6, 7)

Some people are hypersensitive and experience itching, skin rash or redness, or trouble breathing. When people take high doses (higher than 1mg daily), they can rarely experience side effects, which include nausea, appetite loss, bad taste in the mouth, bloating, confusion, or sleep pattern disturbance. (8)

In the past decade, there has been a dramatic increase in folic acid intake and concentration due to mandatory folic acid food fortification and supplement consumption. Folic acid is available in different sources such as multivitamins (400mcg), breakfast cereals (≤400mcg per serving), fortified food products (100-200mcg/day), and health drinks or bars (≤400mcg). Consequently, the daily intake can easily exceed the Tolerable Upper Intake Level of 1000 mcg/day. (9)

Additionally, folic acid is 85% absorbed from supplements or fortified food and is higher than 50% folate absorption from food. (1, 6) This is important for the daily intake recommendation, but it also can be a reason for increased concentration in the body.

Folic Acid During Pregnancy

In its article “Folic Acid Safety, Interactions, and Effects on Other Outcomes,” the CDC published that confirmed risk has not been found due to UMFA in studies conducted till 2010. (4)

Yet, some recent studies suggest that high doses of folic acid supplements in pregnant women might negatively impact cognitive development in children. Doses of folic acid >1.000mcg/day used by pregnant women was associated with a lower level of cognitive development in children aged 4-5 years, a Spanish study from 2017 showed. (10)

A deficit of attention function in children aged 4-5 years was identified in another study and was associated with folic acid taken at doses higher than recommended, results showed. (11)

Folic acid use, longer than the recommended period from conception to early pregnancy, might affect the children’s attention and working memory at ages 7-9. (12) A high dosage of FA (≥ 1000 µg/day) in the periconceptional period may be associated with an increased risk of a small for gestational age according to weight at birth. (13)

Therefore, Valera-Gran Desiree and the team in their study will conclude: “…the use of folic acid supplements in doses ≥1000 mcg/day during pregnancy should be monitored and prevented as much as possible unless medically prescribed.” (10)

High Amount Supplements and Vitamin B12 Deficiency

The Office of Dietary Supplements by the National Institutes of Health suggests that taking large amounts of folate supplements might hide vitamin B12 deficiency, which can result in permanent brain, spinal cord, and nerve damage. (7) Vitamin B12 (cobalamin) is essential for DNA and red blood cell formation and is a crucial player in brain and nerve cell development. (14)

With age, vitamin B12 becomes deficient because the body produces less stomach acid needed to extract this vitamin from food, explains Dr. Meir Stampfer, a professor of epidemiology and nutrition at the Harvard T.H. Chan School of Public Health. (15)

Vitamin B12 deficiency can cause megaloblastic anemia (presence of abnormal nucleated red blood cells), neuropathies, and other conditions. While anemia is reversible, neuropathies are not; therefore, B12 deficiency must be diagnosed on time and treated. (1, 7)

Higher doses of folic acid intake may mask a vitamin B12 deficiency, which the UK Scientific Advisory Committee on Nutrition from 2017 addressed in its report. The US National Toxicology Program report emphasizes that there is an uncertainty in the present literature and that:

“…additional work is critical to fully evaluating the known public health benefits of folic acid, as well as the potential—but still unevaluated—risks that may exist.” (16)

Folic Acid High Doses and Cancer

Numerous studies have shown the dual role of folic acid and cancer. Many support the positive effect of folic acid on cancer. For example, the results of the meta‐analysis of studies completed by 2010 indicated that:

there was no significant effect of folic acid supplementation (with a median dose of 2.0 mg/day folic acid) on the incidence of cancer of the large intestine, prostate, lung, breast, or any other specific site.” (17)

In a study published in 2023, results showed that folic acid supplementation is beneficial for preventing and reversing precancerous gastric conditions. (18)

On the other hand, high doses of folic acid might increase the risk of colorectal cancer. (7) Another study in mice, published in the British Journal of Cancer in 2017, concluded that “dietary folic acid markedly promotes early tumor growth in PyMT breast cancer mouse model.” (19)

Beth Kitchin, the Assistant Professor at the University of Alabama at Birmingham, would say:

Getting the right amount of folic acid may be important for cancer prevention… Too much folic acid may be related to a slightly increased risk of cancer.” (20)

Folate, Folic Acid, and Diet

Vitamin B9 or folate is present in many foods, so people can naturally consume it when eating:

  • Beef liver;
  • Beans and peas;
  • Nuts such as walnuts;
  • Fruits – orange and orange juice;
  • Vegetables – asparagus, sprouts, dark green leaves such as spinach, mustard greens, etc. (21)

Some food such as bread, pasta, rice, cornmeal, breakfast cereals, and others is fortified with folic acid following the FDA requirement from 1998 to ensure daily intake as required and decrease the number of newborns with neural tube defects. (7)

The unit measure for folate is mcg dietary folate equivalents (DFE). The daily value (DV) is the amount you need to consume and depends on your age.

You may find the amount of folate presented in mcg DFE and in DV% on the food product label. If folic acid is added to the product, it will be listed on the label with the quantity in mcg.

Products that contain up to 5% DV of folate per serving are low in folate. If the percentage is 20% or higher, the product is high in folate. (21)

Conclusion

Vitamin B9 or folate is available in various vegetables and seafood and can be consumed in sufficient amounts daily. In combination with fortified food richened with folic acid, there is no need for additional supplement consumption unless recommended by a doctor.

Folic acid supplements are safe if used in recommended doses and duration. When there is a deficiency or increased need in our body, treatment with folic acid is necessary if a regular diet cannot achieve DV.

Currently, available clinical evidence has opened scientific discussion on the possible risks of high doses of folic acid. We can expect more accurate data and clear recommendations in the future.

Till then, we shouldn’t use folic acid or other supplements on our own that might bring a risk to our health. So before taking a folic acid supplement or multivitamin product, consult a doctor.

A healthy diet, rich in fruits and vegetables, is beneficial for sufficient vitamin B9 and other nutrients necessary for a healthy body. Practice balanced food and take supplements only when necessary.

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Current Version
December 12, 2022
Written By
Biljana Srbinovska, MPharm

References

1.Folate (Folic Acid) – Vitamin B9, Harvard T.H.Chan, School of Public Health, https://www.hsph.harvard.edu/nutritionsource/folic-acid/

2. Folic Acid Recommendations, Centers for Disease Control and Prevention, June 28, 2022, https://www.cdc.gov/ncbddd/folicacid/recommendations.html#:~:text=All%20women%20of%20reproductive%20age,and%20spine%20(spina%20bifida)

3. General Information About Neural Tube Defects, Folic Acid, and Folate, Centers for Disease Control and Prevention, July 13, 2022, https://www.cdc.gov/ncbddd/folicacid/faqs/faqs-general-info.html#:~:text=The%20terms%20%E2%80%9Cfolic%20acid%E2%80%9D%20and,(5%2DMTHF)%201

4. Folic Acid Safety, Interactions, and Effects on Other Outcomes, Centers for Disease Control and Prevention, June 17, 2022,

https://www.cdc.gov/ncbddd/folicacid/faqs/faqs-safety.html

5. Folic Acid (Oral Route, Injection Route), Mayo Clinic, November 1, 2022, https://www.mayoclinic.org/drugs-supplements/folic-acid-oral-route-injection-route/side-effects/drg-20063897?p=1

6. Folate, Fact Sheet for Health Professionals, National Institutes of Health, November 30, 2022,

https://ods.od.nih.gov/factsheets/Folate-HealthProfessional/

7. Folate, Fact Sheet for Consumers, National Institutes of Health, November 1, 2022, https://ods.od.nih.gov/factsheets/Folate-Consumer/

8. Folate (folic acid), Mayo Clinic, February 22, 2021, https://www.mayoclinic.org/drugs-supplements-folate/art-20364625

9. Young-In Kim, Folate and cancer: a tale of Dr. Jekyll and Mr. Hyde?, The American Journal of Clinical Nutrition, Volume 107, Issue 2, February 2018, Pages 139–142, https://doi.org/10.1093/ajcn/nqx076

https://academic.oup.com/ajcn/article/107/2/139/4911454?login=false

10. Valera-Gran D, Navarrete-Muñoz EM, et al. Effect of maternal high dosages of folic acid supplements on neurocognitive development in children at 4-5 y of age: the prospective birth cohort Infancia y Medio Ambiente (INMA) study. Am J Clin Nutr. 2017 Sep;106(3):878-887. doi: 10.3945/ajcn.117.152769. Epub 2017 Jul 19. PMID: 28724645.

https://pubmed.ncbi.nlm.nih.gov/28724645/

11. Compañ Gabucio LM, García de la Hera M, et al. The Use of Lower or Higher Than Recommended Doses of Folic Acid Supplements during Pregnancy Is Associated with Child Attentional Dysfunction at 4-5 Years of Age in the INMA Project. Nutrients. 2021 Jan 23;13(2):327. doi: 10.3390/nu13020327. PMID: 33498619; PMCID: PMC7912326.

https://pubmed.ncbi.nlm.nih.gov/33498619/

12. Compañ-Gabucio LM, et al. Association between the Use of Folic Acid Supplements during Pregnancy and Children’s Cognitive Function at 7-9 Years of Age in the INMA Cohort Study. Int J Environ Res Public Health. 2022 Sep 25;19(19):12123. doi: 10.3390/ijerph191912123. PMID: 36231425; PMCID: PMC9566194.

https://pubmed.ncbi.nlm.nih.gov/36231425/

13. Navarrete-Muñoz EM, et al. High doses of folic acid in the periconceptional period and risk of low weight for gestational age at birth in a population based cohort study. Eur J Nutr. 2019 Feb;58(1):241-251. doi: 10.1007/s00394-017-1588-7. Epub 2017 Nov 27. PMID: 29181588.

https://pubmed.ncbi.nlm.nih.gov/29181588/

14. Vitamin B12, Harvard T.H.Chan, School of Public Health, https://www.hsph.harvard.edu/nutritionsource/vitamin-b12/

15. Should you take a vitamin B12 supplement?, Harvard Medical School, August 15,2022, https://www.health.harvard.edu/staying-healthy/should-you-take-a-vitamin-b12-supplement

16. Martha S. Field and Patrick J. Stover, Safety of folic acid, Ann N Y Acad Sci. 2018 Feb; 1414(1): 59–71. Published online 2017 Nov 20. doi: 10.1111/nyas.13499 PMCID: PMC5849489NIHMSID: NIHMS906174PMID: 29155442 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5849489/

17. Vollset, S.E. , Clarke R., Lewington S., et al 2013. Effects of folic acid supplementation on overall and site‐specific cancer incidence during the randomized trials: meta‐analyses of data on 50,000 individuals. Lancet 381: 1029–1036.

18. Lei J, Ren F, Li W, Guo X, Liu Q, Gao H, Pang Y, He Y, Guo J, Zeng J. Use of folic acid supplementation to halt and even reverse the progression of gastric precancerous conditions: a meta-analysis. BMC Gastroenterol. 2022 Aug 2;22(1):370. doi: 10.1186/s12876-022-02390-y. PMID: 35918654; PMCID: PMC9344768.

https://pubmed.ncbi.nlm.nih.gov/35918654/

19. Hansen, M., Jensen, S., Füchtbauer, EM. et al. High folic acid diet enhances tumour growth in PyMT-induced breast cancer. Br J Cancer 116, 752–761 (2017). https://doi.org/10.1038/bjc.2017.11

https://www.nature.com/articles/bjc201711

20. Beth Kitchin MS RD, Assistant Professor at UAB Department of Nutrition Sciences https://www.uab.edu/shp/nutritiontrends/nutrition-know-how/consumer-concerns/folic-acid-and-cancer#:~:text=Folic%20acid%20plays%20a%20role,cells%20to%20grow%20more%20easily.

21. Folate and Folic Acid on the Nutrition and Supplement Facts Labels, Food and Drug Administration, February 25, 2022, https://www.fda.gov/food/new-nutrition-facts-label/folate-and-folic-acid-nutrition-and-supplement-facts-labels

 

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