Conversion of calcium‐l‐methylfolate and (6S)‐5‐methyltetrahydrofolic acid glucosamine salt into dietary folate equivalents

Abstract

Following a request from the European Commission, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver a scientific opinion on the conversion of calcium‐l‐methylfolate and (6S)‐5‐methyltetrahydrofolic acid glucosamine salt (collectively called 5‐MTHF hereafter) into dietary folate equivalents (DFE). Following a systematic review, the conclusions of the opinion are based on one intervention study in adults for intakes < 400 μg/day and three intervention studies in adults for intakes ≥ 400 μg/day. At intakes below 400 μg/day, folic acid (FA) is assumed to be linearly related to responses of biomarkers of intake and status and is an appropriate comparator for deriving a DFE conversion factor for 5‐MTHF. It is proposed to use the same factor as for folic acid for conversion of 5‐MTHF into DFE for intakes < 400 μg/day. As such intake levels are unlikely to be exceeded through fortified food consumption, the conversion factor of 1.7 relative to natural food folate (NF) could be applied to 5‐MTHF added to foods and to food supplements providing < 400 μg/day. At 400 μg/day, 5‐MTHF was found to be more bioavailable than folic acid and a conversion factor of 2 is proposed for this intake level and for higher intakes. The derived DFE equations are DFE = NF + 1.7 × FA + 1.7 × 5‐MTHF for fortified foods and food supplements providing intakes < 400 μg/day; and DFE = NF + 1.7 × FA + 2.0 × 5‐MTHF for food supplements providing intakes ≥ 400 μg/day. Although this assessment applies to calcium‐L‐methylfolate and 5‐MTHF glucosamine salt, it is considered that the influence of the cation on bioavailability is likely to be within the margin of error of the proposed DFE equations. Therefore, the proposed equations can also be applied to 5‐MTHF associated with other cations.

Safety of monosodium salt of l‐5‐methyltetrahydrofolic acid as a novel food pursuant to Regulation (EU) 2015/2283 and the bioavailability of folate from this source in the context of Directive 2002/46/EC, Regulation (EU) No 609/2013 and Regulation (EC) No 1925/2006

“…Consistent with the different kinetic behaviour of 5-MTHF salts and folic acid (EFSA NDA Panel, 2022;Wright et al, 2003), lower AUC 0-8h and C max , and longer T max were observed upon administration of the equimolar dose of folic acid. The Panel, however, notes that acute studies are not suitable to quantify the relative bioavailability of 5-MTHF salts and folic acid; rather longer-term measures of biomarkers of folate status (e.g.…”

“…The Panel, however, notes that acute studies are not suitable to quantify the relative bioavailability of 5‐MTHF salts and folic acid; rather longer‐term measures of biomarkers of folate status (e.g. measures of RBC folate concentrations and plasma total folate in repeated‐dose study) are required (EFSA NDA Panel, 2022 ).…”

“…In addition, EFSA was recently asked to assess the bioavailability of various forms of folate added to food and establish the conversion factor to express their amount into DFE (EFSA NDA Panel, 2022 ). The derived DFE equations were: DFE = natural food folate + 1.7 × folic acid (FA) + 1.7 × 5‐MTHF for fortified foods and food supplements providing intakes < 400 μg/day; DFE = natural food folate + 1.7 × FA + 2.0 × 5‐MTHF for food supplements providing intakes ≥ 400 μg/day.…”

Supplementation with (6S)-5-methyltetrahydrofolic acid appears as effective as folic acid in maintaining maternal folate status while reducing unmetabolised folic acid in maternal plasma: a randomised trial of pregnant women in Canada

“…North American supplement manufacturers are permitted to use the folic acid factor of 1·7 to convert µg (6 S )-5-MTHF to DFE (11,17) . Appropriateness of this is unclear, given potential differences in bioavailability as observed in non-pregnant populations (86) ; however, findings of the current trial suggest that bioavailability of folate forms during pregnancy may differ from non-pregnant individuals, in that a greater effect of (6 S )- 5 -MTHF on folate status was not observed at a 0·6 mg dose. Ca salt of (6 S )-5-MTHF (Metafolin®) is stable in its crystalline form for use in supplements (87,88) .…”

“…Overall, we hypothesise that the 95 % CI would tighten following assessment in a larger sample size, suggesting a similar effect of both forms at a 0·6 mg dose, given that overall there was a high degree of variability in folate estimates, 95 % CIs were wide and crossed 0, and a stronger response to folic acid contradicts the body of evidence on dose–response of folic acid v . (6 S )-5-MTHF (86) . Both biochemical (e.g.…”