Too much synthetic folic acid may interfere with absorption of bioactive folate, warns study

By Tim Cutcliffe contact

- Last updated on GMT

Credit: Gnosis S.p.A
Credit: Gnosis S.p.A

Related tags: Folic acid

Unmetabolised folic acid (UMFA) may reduce the uptake of the bioactive form of the vitamin, suggests recent research in the Journal of Cardiovascular Pharmacology.

Long-term exposure to folic acid reduced the uptake of 5-methyltetrahydrofolate (5-MTHF) in human umbilical vascular endothelial cells (HUVECs), found the research team from the Vrije Universiteit (VU) Medical Centre, Amsterdam.

Lower 5-MTHF may result in lower cellular folate status, which has a number of potential harmful consequences. These include disruption of methylation of DNA, RNA and proteins, as well as endothelial dysfunction, according to the researchers,

“The study provides the initial necessary proof-of-concept that UMFA, because it occurs in the plasma of subjects taking oral FA supplementation, interferes with endothelial cell uptake of the circulating bioactive folate 5-MTHF, and compromises intracellular folate pools,”​ wrote senior researcher Professor Yvo Smulders.

Fortification and UMFA

The use of synthetic folic acid to prevent birth defects has led to fortification in over 50 countries, resulting in fewer neural tube defects. UMFA may be present in the bloodstream of individuals in countries where mandatory fortification of food occurs or those taking folic acid supplementation, research has shown.  

The prevalence of UMFA was highlighted in a 2017 study​ of lactating Canadian mothers. In the study, UMFA was detected in 96% of the mothers’ breast milk, and was present even in many who did not supplement.

Mandatory FA fortification of a wide range of cereals has been in place since 1998 in Canada, while supplementation before and during pregnancy is also advocated by health authorities.

The study found that supplement users had 19% lower 5-MTHF breast-milk levels and 126% higher UMFA levels than non-users. Additionally, in women who supplemented with more than 400 micrograms/ day (ug/d), UMFA was proportionately higher than 5-MTHF.

The finding suggests that higher doses may exceed the physiologic capacity to metabolise FA, the researchers concluded. They also suggested that doses above 400 ug/d were unwarranted, especially in countries where food fortification occurred.

Commenting on the findings of the studies, Silvia Pisoni, marketing manager of the Gnosis SpA, supplier of Quatrefolic® 5-MTHF said: “Even more clinical investigations suggest reconsidering the role of folic acid supplementation for its potential unexpected effects.”

Reduced folate (5-MTHF)

5-MTHF, also known as reduced folate, is a widely available supplement which provides the vitamin in its metabolised, bioactive form and therefore avoids UMFA.  

“The best form of folate administration has been recognizing as the 5-MTHF, the metabolic active reduced form of folate, suitable for human body because it avoids any accumulation of UMFA in the blood. Quatrefolic® is the most bioavailable brand of 5-MTHF in the market, clinically tested for safety and efficacy,” ​Pisoni added.


Source:   Journal of Cardiovascular Pharmacology

Volume 70, issue 4, pp 271–275.  DOI:  10.1097/FJC.0000000000000514

“Folic Acid Impairs the Uptake of 5-Methyltetrahydrofolate in Human Umbilical Vascular Endothelial Cells”

Authors:   Desiree Smith, Yvo M. Smulders  et al

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