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

Eur J Clin Nutr. 2016 May;70(5):537-40. doi: 10.1038/ejcn.2015.231. Epub 2016 Feb 10.


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.

Publication types

  • Review

MeSH terms

  • Adult
  • Cognition / drug effects
  • Dietary Supplements / adverse effects*
  • Dietary Supplements / standards
  • Folic Acid / administration & dosage
  • Folic Acid / adverse effects*
  • Folic Acid / standards
  • Humans
  • Nervous System Diseases / chemically induced*
  • No-Observed-Adverse-Effect Level
  • Vitamin B 12 Deficiency / drug therapy*
  • Vitamin B Complex / administration & dosage
  • Vitamin B Complex / adverse effects*
  • Vitamin B Complex / standards


  • Vitamin B Complex
  • Folic Acid