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Vitamins and Minerals (Oral Session 19)

(OR19-01-25) 5-methyltetrahydrofolate (5-MTHF) in Dietary Supplements (DS): Isomer Composition and Dosage Form Performance at the Initial Shelf-life

Tuesday, June 3, 2025
8:30 AM – 8:42 AM ET
Location: S220 E-G
Objectives: Adequate folate intake supports fetal development and prevents neural tube defects, adverse birth outcomes, and macrocytic hypochromic anemia. Synthetic folic acid is widely used in DS and is effective in meeting folate requirements. 5-MTHF, another bioactive form of folate, is increasingly being included in prenatal and other DS, although the stability and efficacy in products are unclear. The study evaluates 5-MTHF content, isomer composition and dosage form performance in DS over their shelf-life. We present findings for products early in shelf-life, within 2 months of purchase.

Methods: Fifty-three over-the-counter single vitamin and multi-vitamin mineral (MVM, prenatal, adult, child) DS and 10 prescription (Rx) prenatal MVMs labeled as containing 5-MTHF were tested.  Chiral separation techniques were used to determine D- and L-isomer ratios, and disintegration and dissolution testing was used to assess dosage form performance according to United States Pharmacopeia guidelines.

Results: Analyses showed all tested products contained 5-MTHF and no folic acid adulteration. The analytical content compared to labeled amounts for 5-MTHF varied from -18% to +99%. Two products fell >10% below, 12 were within ± 10%, 16 exceeded label claims by >10%, including 14 by > 30%. Two products contained > 1% D-isomer, despite the DS label claim that it contained only the L-isomer. One contained 50% D-isomer, effectively halving its active ingredient content. 11 out of 43 non-Rx products failed disintegration, and 17/43 failed initial dissolution tests. All 8 Rx prenatal softgels passed disintegration (rupture) but failed dissolution tests for both 5-MTHF and folic acid content.

Conclusions: Quality and performance issues exist with 5-MTHF in DS. The poor dosage form performance in disintegration and dissolution testing, especially for prenatal MVMs, raises concerns for bioavailability. Efficacy may be compromised by 5-MTHF content below label claims and the presence of the inactive D-isomer. Continued testing using more biorelevant models and evaluation are critical to assess the bioavailability and efficacy of 5-MTHF in DS over their entire shelf life.

Funding Sources: NIH Office of Dietary Supplement