Lack of historical evidence to support folic acid exacerbation of the neuropathy caused by vitamin B12 deficiency

Am J Clin Nutr. 2019 Sep 1;110(3):554-561. doi: 10.1093/ajcn/nqz089.


In 1998 a Tolerable Upper Intake Level (UL) for folic acid was established based on case reports from the 1940s suggesting that high-dosage folic acid intake, used to treat patients with pernicious anemia, had the potential to precipitate or speed-up the development of neurological problems. This UL has been employed in the decision-making process used by more than 80 countries to establish programs to fortify staple foods with folic acid to prevent neural tube birth defects. Some have claimed that this UL is flawed and has become an obstacle to the wider adoption of neural tube defect prevention programs and have called for re-evaluation of the scientific validity of this UL. Case reports cannot establish causality, but they can reveal patterns in the timing of the onset and treatment of patients with pernicious anemia. These patterns can be compared with secular trends of usual medical practice for the treatment of pernicious anemia and with the changes in usage of folic acid preparations, including recommended therapeutic dosage and precautions for its usage surrounding the synthesis of folic acid in 1945 and vitamin B12 in 1948. Folic acid package inserts, early editions of hematology textbooks, and international expert reports provide valuable historical information. The recommended therapeutic daily dosage for folic acid of 5-20 mg was unchanged from 1946 through to 1971. The likely cause of the neurological problems encountered is the development of vitamin B12 neuropathy when pernicious anemia was treated with high-dosage folic acid before vitamin B12 was widely available in the early 1950s. Thus, the historical record does not provide compelling evidence that folic acid can potentially cause neurologic complications among those with low vitamin B12 status and lends support for reconsidering the basis for the UL of folic acid.

Keywords: folate; folic acid; fortification; neural tube defects; neuropathy; pernicious anemia; public health; vitamin B12.

Publication types

  • Historical Article
  • Review

MeSH terms

  • Folic Acid / adverse effects*
  • History, 20th Century
  • Humans
  • Peripheral Nervous System Diseases / etiology*
  • Peripheral Nervous System Diseases / history
  • Vitamin B 12 / therapeutic use
  • Vitamin B 12 Deficiency / complications*


  • Folic Acid
  • Vitamin B 12