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What is the safe upper intake level of folic acid for the nervous system? Implications for folic acid fortification policies

European Journal of Clinical Nutrition volume 70, pages 537–540 (2016)Cite this article

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Abstract

Between 1945 and 1959 it was convincingly documented that folic acid can precipitate or aggravate the neurological and haematological consequences of vitamin B12 deficiency by increasing the demand for vitamin B12. Since then there has been much misunderstanding of the issues, mainly by advocates of folic acid fortification who have been inclined to minimise or even dismiss the risks by misinterpreting the evidence as only a ‘masking’ of the anaemia of pernicious anaemia. Recent studies in the era of fortification are rediscovering the risks to the nervous system, especially cognitive function, of excess folate in the presence of vitamin B12 deficiency. I have reviewed the Reports of four Expert Advisory Committees in Europe and the USA, which suggest that the safe upper tolerable limit (UL) for folic acid is 1 mg in adults. These reports are unsound and there is already evidence of neurological harm from long-term exposure to doses of folic acid between 0.5 and 1 mg in the presence of vitamin B12 deficiency. There is an urgent need to review the safe UL for folic acid and to consider the addition of vitamin B12 to folic acid fortification policies.

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References

  1. Israëls MCG, Wilkinson JF . Risk of neurological complications in pernicious anaemia treated with folic acid. BMJ 1949; ii: 1072–1075.

    Article  Google Scholar 

  2. Schwartz SO, Kaplan SR, Armstrong BE . The long-term evaluation of folic acid in the treatment of pernicious anaemia. J Lab Clin Med 1950; 35: 894–898.

    CAS  PubMed  Google Scholar 

  3. Will JJ, Mueller JF, Brodine C, Kiely CE, Friedman B, Hawkins VR et al. Folic acid and vitamin B12 in pernicious anaemia. Studies on patients treated with these substances over a 10 year period. J Lab Clin Med 1959; 53: 22–38.

    CAS  PubMed  Google Scholar 

  4. Shorvon SD, Carney MWP, Chanarin I, Reynolds EH . The neuropsychiatry of megaloblastic anaemia. BMJ 1980; 281: 1036–1038.

    Article  CAS  Google Scholar 

  5. Reynolds EH . Neurological aspects of folate and vitamin B12 metabolism. In: Hoffbrand AV (ed). Clinics in Haematology, vol 5. Saunders: London, UK, 1976, pp 661–696.

    Google Scholar 

  6. Reynolds EH . Vitamin B12, folic acid and the nervous system. Lancet Neurol 2006; 5: 949–960.

    Article  CAS  Google Scholar 

  7. Smithells RW, Sheppard S, Schorah CJ, Seller MJ, Nevin NC, Harris R et al. Apparent prevention of neural tube defects by periconceptional vitamin supplementation. Arch Dis Child 1981; 56: 911–918.

    Article  CAS  Google Scholar 

  8. MRC Vitamin Study Group. Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet 1991; 338: 131–137.

    Article  Google Scholar 

  9. Mitchell LE, Adzick NS, Melchionne J, Pasquariello PS, Sutton LN, Whitehead AS et al. Spina bifida. Lancet 2004; 364: 1885–1895.

    Article  Google Scholar 

  10. Dickinson CJ . Does folic acid harm people with vitamin B12 deficiency? QJM 1995; 88: 357–364.

    CAS  PubMed  Google Scholar 

  11. Wald MJ, Bower C . Folic acid and the prevention of neural tube defects. BMJ 1995; 310: 1019–1020.

    Article  CAS  Google Scholar 

  12. Oakley GP . Delaying folic acid fortification of flour. BMJ 2002; 324: 1348–1349.

    Article  Google Scholar 

  13. Committee on Medical Aspects of Food and Nutrition Policy (COMA) Folic Acid and the Prevention of Disease. The Stationery Office: London, UK, 2000.

  14. Hall BE, Watkins CH . Experience with pteroylglutamic (synthetic folic) acid in the treatment of pernicious anaemia. J Lab Clin Med 1947; 32: 622–634.

    CAS  PubMed  Google Scholar 

  15. Bethell FH, Sturgis CC . The relation of therapy in pernicious anaemia to changes in the nervous system. Early and late results in a series of cases observed for periods of not less than 10 years, and early results of treatment with folic acid. Blood 1948; 3: 57–67.

    CAS  PubMed  Google Scholar 

  16. Lear AA, Castle WB . Supplemental folic acid therapy in pernicious anaemia: the effect on erythropoiesis and serum vitamin B12 concentrations in selected cases. J Lab Clin Med 1956; 47: 88–97.

    CAS  PubMed  Google Scholar 

  17. Bok J, Faber JG, de Vries JA, Stenfert Kroese WF, Nieweg HO . The effect of pteroylglutamic acid administration on the serum vitamin B12 concentration in pernicious anaemia in relapse. J Lab Clin Med 1958; 51: 667–671.

    CAS  PubMed  Google Scholar 

  18. Baldwin JN, Dalessio DJ . Folic acid therapy and spinal-cord degeneration in pernicious anaemia. N Engl J Med 1961; 264: 1339–1342.

    Article  CAS  Google Scholar 

  19. Chanarin I . The Megaloblastic Anaemias. Blackwell Scientific: Oxford, UK, 1969.

    Google Scholar 

  20. Agamanolis DP, Chester EM, Victor M, Kark JA, Hines JD, Harris JW . Neuropathology of experimental vitamin B12 deficiency in monkeys. Neurology 1976; 26: 905–914.

    Article  CAS  Google Scholar 

  21. Van der Westhuvzen J, Fernandes-Costa F, Metz J . Cobalamin inactivation by nitrous oxide produces severe neurological impairment in fruit bats: protection by methionine and aggravation by folates. Life Sci 1982; 31: 2001–2010.

    Article  Google Scholar 

  22. Waters AH, Mollin DL . Studies on the folic acid activity of human serum. J Clin Pathol 1961; 14: 335–344.

    Article  CAS  Google Scholar 

  23. Reynolds EH . Interrelationships between the neurology of folate and vitamin B12 metabolism. In: Botez MI, Reynolds EH (eds), Folic Acid in Neurology, Psychiatry and Internal Medicine. Raven Press: New York, NY, USA, 1979, pp 501–515.

    Google Scholar 

  24. Herbert V . Staging vitamin B12 (cobalamin) status in vegetarians. Am J Clin Nutr 1994; 59 (Suppl), 1213s–1222s.

    Article  CAS  Google Scholar 

  25. Morris MC, Evans DA, Bienias JL, Tangney CC, Herbert LE, Scherr PA et al. Dietary folate and vitamin B12 intake and cognitive decline among community-dwelling older persons. Arch Neurol 2005; 62: 641–645.

    Article  Google Scholar 

  26. Morris MS, Jacques PF, Rosenberg IH, Selhub J . Folate and vitamin B12 status in relation to anaemia, macrocytosis, and cognitive impairment in older Americans in the age of folic acid fortification. Am J Clin Nutr 2007; 85: 193–200.

    Article  CAS  Google Scholar 

  27. Morris MS, Selhub J, Jacques PF . Vitamin B12 and folate status in relation to decline in scores on the mini-mental state examination in the Framingham Heart Study. J Am Geriatr Soc 2012; 60: 1457–1464.

    Article  Google Scholar 

  28. Moore E, Ames D, Mander A, Carne R, Brodaty H, Woodward M et al. Among vitamin B12 deficient older people, high folate levels are associated with worse cognitive function: combined data from three cohorts. J Alzheimer’s Dis 2014; 39: 661–668.

    Article  CAS  Google Scholar 

  29. Selhub J, Morris MS, Jacques PF . In vitamin B12 deficiency, higher serum folate is associated with increased total homocysteine and methylmalonic acid concentrations. Proc Natl Acad Sci USA 2007; 104: 19995–20000.

    Article  CAS  Google Scholar 

  30. Selhub J, Morris MS, Jacques PF, Rosenberg IH . Folate-vitamin B12 interaction in relation to cognitive impairment, anaemia, and biochemical indicators of vitamin B12 deficiency. Am J Clin Nutr 2009; 89 (Suppl), 702s–706s.

    Article  CAS  Google Scholar 

  31. Miller JW, Garrod MG, Allen LH, Haan MN, Green R . Metabolic evidence of vitamin B-12 deficiency, including high homocysteine and methylmalonic acid and low holotranscobalamin is more pronounced in older adults with elevated plasma folate. Am J Clin Nutr 2009; 90: 1586–1592.

    Article  CAS  Google Scholar 

  32. Food and Drug Administration. Food labelling: health claims and label statements; folate and neural tube defects. Federal Register 1993; 58: 53254–53270.

    Google Scholar 

  33. Institute of Medicine Dietary Reference Intakes for Thiamine, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin and Choline. National Academy Press: : Washington, DC, USA, 1998, pp 196–305.

  34. European Food Safety Authority, Scientific Committee on Food Tolerable Upper Intake Levels for Vitamins and Minerals. EFSA: Parma, Italy, 2000.

  35. UK Expert Group on Vitamins and Minerals 2003 Safe Upper Levels for Vitamins and Minerals. Food Standards Agency: London, UK, 2003.

  36. Savage DG, Lindenbaum J . Neurological complications of acquired cobalamin deficiency: clinical aspects. Bailliere’s Clin Haematol 1995; 8: 657–678.

    Article  CAS  Google Scholar 

  37. Reynolds EH, Gallagher BB, Mattson RH, Bowers M, Johnson AL . Relationship between serum and cerebrospinal fluid folate. Nature 1972; 240: 155–157.

    Article  CAS  Google Scholar 

  38. Hommes OR, Obbens EAMT, Wijfels CCB . Epileptogenic activity of sodium-folate and the blood brain barrier in the rat. J Neurol Sci 1973; 19: 63–71.

    Article  CAS  Google Scholar 

  39. Spector R, Lorenzo AV . Folate transport in the central nervous system. Am J Physiol 1975; 229: 777–782.

    Article  CAS  Google Scholar 

  40. EFSA Panel on Dietetic Products, Nutrition and Allergies. Scientific opinion on dietary reference values for folate. EFSA J 2014; 12: 3893–3895.

    Google Scholar 

  41. Crider KS, Bailey LB, Berry RJ . Folic acid food fortification; it’s history, effect, concerns, and future directions. Nutrients 2011; 3: 370–384.

    Article  Google Scholar 

  42. Yang Q, Cogswell ME, Hamner HC, Carriguiry A, Bailey LB, Pfeiffer CM et al. Folic acid source, usual intake, and folate and vitamin B12 status in US adults: National Health and Nutrition Examination Survey (NHANES) 2003-2006. Am J Clin Nutr 2010; 91: 64–72.

    Article  CAS  Google Scholar 

  43. Crider KS, Devine O, Hao L, Dowling NF, Li S, Molloy AM et al. Population red blood cell folate concentrations for prevention of neural tube defects: Bayesian model. BMJ 2014; 349: g4554.

    Article  Google Scholar 

  44. Clarke R, Bennett D . Folate and prevention of neural tube defects. BMJ 2014; 349: g4810.

    Article  Google Scholar 

  45. Toole JF, Malinow MR, Chambless LE, Spence JD, Pettigrew LC, Hoard VJ et al. Lowering homocysteine in patients with ischaemic stroke to prevent recurrent stroke, myocardial infarction, and death: the vitamin intervention for stroke prevention (VISP) randomised controlled trial. JAMA 2004; 291: 565–575.

    Article  CAS  Google Scholar 

  46. The Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med 2006; 354: 1567–1577.

    Article  Google Scholar 

  47. Molloy AM, Kirke PN, Troendle JF, Burke H, Sutton M, Brody LC et al. Maternal vitamin B12 status and risk of neural tube defects in a population with high neural tube defect prevalence and no folic acid fortification. Pediatrics 2009; 123: 917–923.

    Article  Google Scholar 

  48. ZP Wang XX Shang, ZT Zhao . Low maternal vitamin B12 is a risk for neural tube defects: a meta analysis. J Matern Fetal Neonat Med 2012; 25: 389–394.

    Article  Google Scholar 

Download references

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  1. Department of Clinical Neurosciences, King’s College, London, UK

    E H Reynolds

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Correspondence to E H Reynolds.

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Reynolds, E. What is the safe upper intake level of folic acid for the nervous system? Implications for folic acid fortification policies. Eur J Clin Nutr 70, 537–540 (2016). https://doi.org/10.1038/ejcn.2015.231

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