Knowledge gaps in understanding the metabolic and clinical effects of excess folates/folic acid: a summary, and perspectives, from an NIH workshop

Authors: MARUVADA, PADMA - National Institutes Of Health (NIH); STOVER, PATRICK - Texas A&M University; MASON, JOEL - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; BAILEY, REGAN - Purdue University; DAVIS, CINDY - National Institutes Of Health (NIH); FIELD, MARTHA - Cornell University; FINNELL, RALPH - Baylor College Of Medicine; GARZA, CUTBERTO - Cornell University; GREEN, RALPH - University Of California; GUEANT, JEAN-LOUIS - University Of Lorraine; JACQUES, PAUL - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; Klurfeld, David; LAMERS, YVONNE - University Of British Columbia; MACFARLANE, AMANDA - Health Canada; MILLER, JOSHUA - Rutgers University; MOLLOY, ANNE - Trinity College Dublin; O'CONNOR, DEBORAH - University Of Toronto; PFEIFFER, CHRISTINE - Centers For Disease Control And Prevention (CDC) - United States; POTISCHMAN, NANCY - National Institutes Of Health (NIH); RODRICKS, JOSEPH - Ramboll; ROSENBERG, IRWIN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; ROSS, SHARON - National Institutes Of Health (NIH); SHANE, BARRY - University Of California; SELHUB, JACOB - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; STABLER, SALLY - University Of Colorado; TRASLER, JACQUETTA - McGill University - Canada; YAMINI, SEDIGHEH - Us Food & Drug Administration (FDA); ZAPPALA, GIOVANNA - National Institutes Of Health (NIH)

Submitted to: The American Journal of Clinical Nutrition
Publication Type: Review Article
Publication Acceptance Date: 8/20/2020
Publication Date: 10/6/2020
Citation: Maruvada, P., Stover, P.J., Mason, J.B., Bailey, R.L., Davis, C.D., Field, M., Finnell, R.H., Garza, C., Green, R., Gueant, J., Jacques, P.F., Klurfeld, D.M., Lamers, Y., MacFarlane, A.J., Miller, J.W., Molloy, A.M., O'Connor, D.L., Pfeiffer, C.M., Potischman, N.A., Rodricks, J.V., Rosenberg, I.H., Ross, S.A., Shane, B., Selhub, J., Stabler, S.P., Trasler, J., Yamini, S., Zappala, G. 2020. Knowledge gaps in understanding the metabolic and clinical effects of excess folates/folic acid: a summary, and perspectives, from an NIH workshop. American Journal of Clinical Nutrition. 112(5):1390-1403. https://doi.org/10.1093/ajcn/nqaa259.
DOI: https://doi.org/10.1093/ajcn/nqaa259

Interpretive Summary: Folate is an essential vitamin, the natural forms of which are chemically-reduced. The form that is used in supplements and to fortify foods, however, is a fully oxidized derivative, folic acid. Certain segments of the adult and child population within the U.S. exceed the safe upper limit of folic acid established by the U.S. Institute of Medicine, raising concerns about potential adverse effects on health associated with excess intake of either total dietary folate or, more specifically, folic acid. However, existing knowledge about these purported adverse health effects is inadequate since the veracity of these adverse effects is in question as is the dose-response relationships and their biological basis. In August of 2019, a one-and-a-half day workshop was convened by the NIH at which experts in the field arrived at an outline of what gaps in knowledge exist and what research priorities should be pursued in the coming decade in order to clarify these gaps. This paper summarizes the outcomes of this workshop.

Technical Abstract: Folate, an essential nutrient found naturally in foods in a reduced form, is present in dietary supplements and fortified foods in an oxidized synthetic form (folic acid). Maintaining adequate folate status is critical to prevent diseases due to folate inadequacy (e.g., cancer, birth defects, anemia). The effects of excess folic acid intake and/or elevated folate status are controversial. The original concern focused on exacerbation of clinical effects of vitamin B12 deficiency and its role in neurocognitive health. More recently, animal and observational studies suggest potential adverse effects on cancer risk, birth outcomes, and other diseases. Observations indicating adverse effects from excess folic acid intake, elevated folate status, and unmetabolized folic acid (UMFA) remain inconclusive; the data do not provide the evidence needed to affect public health recommendations. Moreover, strong biological and mechanistic premises connecting elevated folic acid intake, UMFA, and/or high folate status to adverse health outcomes are lacking. However, the body of evidence on potential adverse health outcomes indicates the need for comprehensive research to clarify these issues and bridge knowledge gaps. Three key research questions encompass the additional research needed to establish whether high folic acid or total folate intake contributes to disease risk: (1) Does UMFA affect biological pathways leading to adverse health effects? (2) Does elevated folate status resulting from any form of folate intake affect vitamin B12 function and its roles in sustaining health? (3) Does elevated folate intake, regardless of form, affect biological pathways leading to adverse health effects other than those linked to vitamin B12 function? This paper summarizes the proceedings of an August 2019 National Institutes of Health expert workshop focused on addressing these research areas.