Fallacies of clinical studies on folic acid hazards in subjects with a low vitamin B₁₂ status

Abstract

A 2016 plea for revision of the 1 mg/day upper level of folic acid intake prompted us to comprehensively review the 1945–2017 literature on folic acid hazards in subjects with low cyanocobalamin. The concept of folic acid treatment ‘masking’ the anemia in undiagnosed cyanocobalamin deficiency, thereby delaying the diagnosis of neuropathy, does not account for the dissociation between the deficiency’s hematologic and neurologic manifestations. Possible risks of this concept were addressed by 1963–1971 FDA rulings, classifying all folic acid preparations as prescription-only drugs, delivering ≤1 mg daily. The neuropathy in folic acid trials for ‘pernicious anemia’ is due to the singular use of folic acid–neuropathy improved or disappeared with replacement of folic acid by liver extract or cyanocobalamin. The hypothesis that cognitive impairment in ‘subclinical’ cyanocobalamin deficiency is folate-mediated is untenable. Of 6 papers specifically investigating this, none could prove that increased cognitive impairment was related to high folate intake. This review fully supports the safety of the 1 mg/day upper level for folic acid intake.

Keywords:

• Neural tube defects
• spina bifida
• folic acid fortification
• vitamin B₁₂ deficiency
• pernicious anemia
• subclinical cobalamine deficiency
• cognitive impairment
• upper level of intake for folic acid

Acknowledgments

The authors want to thank Professor Andreas Stang, Institute of Medical Informatics, Biometry and Epidemiology, University Hospital Essen, Germany, for his support with this epidemiological endeavor, right from the beginning. Special thanks are due to Susan Makris, United States Environmental Protection Agency, Washington, DC, U.S.A., for drawing attention to a monograph of the National Toxicology Program, “Identifying Research Needs for Assessing Safe Use of High Intakes of Folic Acid” (2015), including an expertly researched list of study summaries on vitamin B₁₂ and cognition. The authors also want to thank Roger Bayston, FRCPath, School of Medicine, University of Nottingham, U.K., as well as Asher Ornoy, Child Development and Rehabilitation, Ministry of Health, Israel, and Dick Lindhout, Professor emeritus of Medical Genetics, University Medical Center, Utrecht, The Netherlands, for their constructive comments on earlier versions of this paper. Last but not least, the authors are grateful for the thoughtful amendments suggested by the first anonymous reviewer, as well as for the kind comments of the second anonymous reviewer.

Declaration of interest

The work of all authors on this manuscript was done as part of their regular affiliations – beyond these affiliations, no financial support was received for the research, authorship, and/or publication of this manuscript. The findings and conclusions in this manuscript are solely those of the authors, and, over the last 5 years, none of them have engaged in any legal, regulatory or advocacy activities related to the contents of this paper.