Review | Published:

The adverse effects of an excessive folic acid intake

European Journal of Clinical Nutrition volume 71, pages 159163 (2017) | Download Citation

Abstract

Folate is a vital component of a healthy diet, being essential for numerous bodily functions. Deficiency of folate is common, with studies suggesting prevalence of deficiencyas high as 85.5% as was shown in women between the ages of 16 and 49, living in the UK. Causes of folate deficiency range from diet and lifestyle, to pathological and pharmacological processes. Because of the well-known role of folate in prevention of neural tube defects, numerous countries have implemented strategies to increase folate intake, with programs such as mandatory grain fortification. As a result, the intake of folate in these countries is often higher than the recommended dietary allowance for many groups of people. Although folate is believed to be non-toxic, the potential adverse effects of excessive intake of folic acid (synthetic form of folate) have not been highlighted well by authorities to people taking supplements; despite this, many studies have addressed this issue. However, the results of these studies provide discrepant results, leading to confusion as to whether mandatory folic acid fortification should be introduced in other countries. The purpose of this review was to provide a summary of evidence related to high folic acid ingestion and to look at the unwanted effects it may have on the certain groups within the general population.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    , . Vitamin B12—folate interrelations. Clin Haematol 1976; 5: 697–745.

  2. 2.

    The British Dietetic Association (BDA) Food Fact Sheet Folic Acid. Avaliable at: (accessed on 30 July 2016).

  3. 3.

    , , , , , et al. Long term trends in prevalence of neural tube defects in Europe: population based study. BMJ 2015; 351: h5949.

  4. 4.

    , . Folate, folic acid and 5-methyltetrahydrofolate are not the same thing. Xenobiotica 2014; 44: 480–488.

  5. 5.

    . Is folic acid the ultimate functional food component for disease prevention? BMJ 2004; 328: 211–214.

  6. 6.

    , , . Folic acid fortification and public health: report on threshold doses above which unmetabolised folic acid appear in serum. BMC Public Health 2007; 7: 41.

  7. 7.

    , , , , . Unmetabolized folic acid in serum: acute studies in subjects consuming fortified food and supplements. Am J Clin Nutr 1997; 65: 1790–1795.

  8. 8.

    . Folic acid under scrutiny. Br J Nutr 2007; 98: 665–666.

  9. 9.

    , , , , , et al. Unmetabolized folic acid is detected in nearly all serum samples from US children, adolescents, and adults. J Nutr 2015; 145: 520–531.

  10. 10.

    , , , , , et al. Estimation of trends in serum and RBC folate in the U.S. population from pre- to postfortification using assay-adjusted data from the NHANES 1988-2010. J Nutr 2012; 142: 886–893.

  11. 11.

    Institute of Medicine (US). Standing Committee on the Scientific Evaluation of Dietary Reference Intakes and its Panel on Folate, Other B Vitamins, and Choline1998, Available at accessed on 20 July 2016.

  12. 12.

    B vitamin supplementAvailable at: (accessed on 30 November 2015).

  13. 13.

    , , , , , et al. Hyperhomocysteinaemia and B vitamin intakes in patients with a history of cardiovascular disease). 10th international conference 7/07/15-11/07/15 Page 51 University of Lorraine One Carbon Metabolism, Vitamins B and Homocysteine Conference 2015: Nancy, France.

  14. 14.

    , , , , , et al. Erythrocyte folate and 5-methyltetrahydrofolate levels decline during 6 months of oral anticoagulation with warfarin. Blood Coagul Fibrinolysis 2009; 20: 297–302.

  15. 15.

    . Folic acid supplementation: too much of a good thing? J Neurol Neurosurg Psychiatry 2009; 80: 468.

  16. 16.

    , . Potential toxic side effects of folic acid. J Natl Cancer Inst 1985; 74: 263.

  17. 17.

    Food and Drug Administration. Food standards: amendment of standards of identity for enriched grain products to require addition of folic acid. Federal Register 1996; 61: 8781–8789.

  18. 18.

    , , , , , et al. Trends in the postfortification prevalence of spina bifida and anencephaly in the United States. Birth Defects Res A Clin Mol Teratol 2008; 82: 527–532.

  19. 19.

    , , , , , et al. Global birth prevalence of spina bifida by folic acid fortification status: a systematic review and meta-analysis. Am J Public Health 2016; 106: e24–e34.

  20. 20.

    , , , , , et al. Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA 2007; 297: 2351–2359.

  21. 21.

    , , , , , et al. A temporal association between folic acid fortification and an increase in colorectal cancer rates may be illuminating important biological principles: a hypothesis. Cancer Epidemiol Biomarkers Prev 2007; 16: 1325–1329.

  22. 22.

    , , . Folic acid metabolism in human subjects revisited: potential implications for proposed mandatory folic acid fortification in the UK. Br J Nutr 2007; 98: 667–675.

  23. 23.

    SACNFolate status of women in the United Kingdom and the risk of congenital neural tube defects (NTD) (2015). Available at: (accessed on 20 February 2016)..

  24. 24.

    , , , , , et al. National Diet and Nutrition Survey rolling Programme (NDNS RP) supplementary report: blood folate results for the UK as a whole, Scotland and Northern Ireland (years 1 to 4 combined) and Wales (years 2 to 5 combined). Public Health England, London 2015.

  25. 25.

    , , et al. Optimal serum and red blood cell folate concentrations in women of reproductive age for prevention of neural tube defects: World Health Organization guidelines. MMWR Morb Mortal Wkly Rep 2015; 64: 421–423.

  26. 26.

    , , , . Decision on folic acid fortification in Europe must consider both risks and benefits. BMJ 2016; 352: i734.

  27. 27.

    , , , , . Not all cases of neural-tube defect can be prevented by increasing the intake of folic acid. Br J Nutr 2009; 102: 173–180.

  28. 28.

    , , , , , et al. Mapping low intake of micronutrients across Europe. Br J Nutr 2013; 110: 755–773.

  29. 29.

    , , . Influence of maternal vitamin B12 and folate on growth and insulin resistance in the offspring. Nestle Nutr Inst Workshop Ser2013; 74: 145–154.

  30. 30.

    , , , , , et al. High dose folic acid supplementation of rats alters synaptic transmission and seizure susceptibility in offspring. Sci Rep 2013; 3: 1465.

  31. 31.

    , , , , , et al. High folic acid consumption leads to pseudo-MTHFR deficiency, altered lipid metabolism, and liver injury in mice. Am J Clin Nutr 2015; 101: 646–658.

  32. 32.

    , . Folate status: effects on pathways of colorectal carcinogenesis. J Nutr 2002; 132: 2413S–2418S.

  33. 33.

    , , , , , et al. Unmetabolized folic acid in plasma is associated with reduced natural killer cell cytotoxicity among postmenopausal women. J Nutr 2006; 136: 189–194.

  34. 34.

    , . Folate and cancer—timing is everything. JAMA 2007; 297: 2408–2409.

  35. 35.

    , , , , , et al. Colon cancer in Chile before and after the start of the flour fortification program with folic acid. Eur J Gastroenterol Hepatol 2009; 21: 436–439.

  36. 36.

    , , , , , . High levels of folate from supplements and fortification are not associated with increased risk of colorectal cancer. Gastroenterology 2011; 141: 98–105.

  37. 37.

    , , , , . Aspirin and folic acid for the prevention of recurrent colorectal adenomas. Gastroenterology 2008; 134: 29–38.

  38. 38.

    , , , , , et al. Folic acid and risk of prostate cancer: results from a randomized clinical trial. J Natl Cancer Inst 2009; 101: 432–435.

  39. 39.

    , , , , , et al. Effects of folic acid supplementation on overall and site-specific cancer incidence during the randomised trials: meta-analyses of data on 50000 individuals. Lancet 2013; 381: 1029–1036.

  40. 40.

    , , , . Safe use of high intakes of folic acid: research challenges and paths forward. Nutr Rev 2016; 74: 469–474.

  41. 41.

    , , , , , et al. Total folate and folic acid intake from foods and dietary supplements in the United States: 2003-2006. Am J Clin Nutr 2010; 91: 231–237.

  42. 42.

    , , . Divergence between dietary folate intake and concentrations in the serum and red blood cells of aging males in the United States. Clin Nutr 2016; 35: 928–934.

  43. 43.

    . Folic acid: an update on scientific developments European Union Publications Office January 2009. EFSA Meeting summary report. Available at accessed on 17 June 2016.

  44. 44.

    World Health Organization, Food and Agricultural Organization of the United Nations, World Health Organization, Food and Agricultural Organization of the United Nations, World Health Organization, Food and Agricultural Organization of the United NationsVitamin and Mineral Requirements in Human Nutrition. FAO: Rome, Italy, 2004, pp 53–62.

  45. 45.

    , , , , . Association between maternal folate concentrations during pregnancy and insulin resistance in Indian children. Diabetologia 2014; 57: 110–121.

  46. 46.

    , , , , , et al. Excess perigestational folic acid exposure induces metabolic dysfunction in post-natal life. J Endocrinol 2015; 224: 245–259.

  47. 47.

    , . Adiponectin in diabetes mellitus. Curr Med Chem 2012; 19: 5451–5458.

  48. 48.

    , . The obesity epidemic is a worldwide phenomenon. Nutr Rev 1998; 56: 106–114.

  49. 49.

    , , et al. Dihydrofolate reductase 19-bp deletion polymorphism modifies the association of folate status with memory in a cross-sectional multi-ethnic study of adults. Am J Clin Nutr 2015; 102: 1279–1288.

  50. 50.

    , , , , , et al. Fruit and vegetable intake during pregnancy and risk for development of sporadic retinoblastoma. Cancer Epidemiol Biomarkers Prev 2005; 14: 1433–1440.

  51. 51.

    , . Excessive folic acid intake and relation to adverse health outcome. Biochimie 2016; 126: 71–78.

  52. 52.

    , , , . Plasma and red cell reference intervals of 5-methyltetrahydrofolate of healthy adults in whom biochemical functional deficiencies of folate and vitamin B 12 had been excluded. Adv Hematol 2014; 2014: 465623.

  53. 53.

    , , , . Folate-vitamin B-12 interaction in relation to cognitive impairment, anemia, and biochemical indicators of vitamin B-12 deficiency. Am J Clin Nutr 2009; 89: 702S–706SS.

  54. 54.

    , , , , , . High folate and low vitamin B-12 intakes during pregnancy are associated with small-for-gestational age infants in South Indian women: a prospective observational cohort study. Am J Clin Nutr 2013; 98: 1450–1458.

  55. 55.

    . Maternal nutrition, fetal nutrition, and disease in later life. Nutrition 1997; 13: 807–813.

  56. 56.

    , , , . Increase in seizure frequency following folic acid. Ir Med J 1979; 72: 241–242.

  57. 57.

    , . Seizures following reduction in phenytoin level after orally administered folic acid. Neurology 2005; 64: 1982.

  58. 58.

    , , , , , et al. Preliminary evidence shows that folic acid fortification of the food supply is associated with higher methotrexate dosing in patients with rheumatoid arthritis. J Am Coll Nutr 2007; 26: 453–455.

  59. 59.

    , , , . Effect of folate oversupplementation on folate uptake by human intestinal and renal epithelial cells. Am J Clin Nutr 2007; 86: 159–166.

Download references

Acknowledgements

We thank Mrs Renata Gorska (The Nutristasis Unit, Viapath) for preparation of the figure. We also thank the reviewers for their helpful comments. All of the information in this review is of original research and has not been published or submitted for publication to other journals.

Author information

Affiliations

  1. Faculty of Life Sciences & Medicine, Kings College London, Strand, London, UK

    • K R Patel
    •  & A Sobczyńska-Malefora
  2. Nutristasis Unit, Viapath, St. Thomas’ Hospital, London, UK

    • A Sobczyńska-Malefora

Authors

  1. Search for K R Patel in:

  2. Search for A Sobczyńska-Malefora in:

Competing interests

The authors declare no conflict of interest.

Corresponding author

Correspondence to K R Patel.

About this article

Publication history

Received

Revised

Accepted

Published

DOI

https://doi.org/10.1038/ejcn.2016.194

Further reading