Electronic versions



  • Ben Carter
    King's College London
  • Zohra Zenasni
    King's College London
  • Stuart J Moat
    Cardiff University
  • Peter R Hudson
    Cobalz Limited, Chester, United Kingdom
  • Ian T Russell
    Swansea University
  • Andrew McCaddon
    Glyndwr University
  • Rhiannon Whitaker
  • Joshua Pink
  • Seren Roberts
  • Clare Wilkinson
  • Dyfrig Hughes
  • Emma Betson
    Xi'an Jiaotong‐Liverpool University
  • Diana Carr
    Xi'an Jiaotong‐Liverpool University
  • Andrea Jorgenson
    Xi'an Jiaotong‐Liverpool University
  • Munir Pirmohamed
    Xi'an Jiaotong‐Liverpool University
  • Nevyn Williams
    Xi'an Jiaotong‐Liverpool University
  • Helen Lewis
    York University, Toronto
  • Keith Lloyd
    Swansea University
  • Yvonne Sylvesture
    Swansea University
  • Richard Tranter
    University of Otago

BACKGROUND: Individuals with low serum vitamin B-12 and high serum folate have higher plasma concentrations of methylmalonic acid (MMA). Whether folic acid (FA) causes an increase in MMA is not known.

OBJECTIVES: We aimed to determine the impact of FA supplementation on plasma MMA concentration in people with low or marginal serum vitamin B-12.

METHODS: We conducted a multicenter double-blind placebo-controlled randomized trial of oral FA (5 mg/d for 12 wk) in middle-aged patients treated with antidepressant medication participating in the FoLATED (Folate Augmentation of Treatment-Evaluation for Depression) trial. Participants defined as having "low" serum vitamin B-12 (vitamin B-12 ≥150 and <220 ng/L) or "marginal" serum vitamin B-12 (vitamin B-12 ≥ 220 and <280 ng/L) were included. The primary outcome of this substudy was MMA at week 12. A mixed-effects linear regression was fitted and reported using the adjusted mean difference (aMD).

RESULTS: A total of 177 participants were included (85 randomly assigned to placebo and 92 to FA); the mean ± SD age was 46.2 ± 11.8 y, and 112 (63.3%) were female. The MMA analysis included 135 participants and the aMD was -0.01 (95% CI: -0.06, 0.04; P = 0.71). Serum folate was measured on 166 participants and increased in the supplementation group; the aMD was 21.6 μg/L (95% CI: 8.13, 25.02 μg/L; P < 0.001). A total of 117 participants were assessed for RBC folate, which also increased in the supplementation group; the aMD was 461 μg/L (95% CI: 387, 535 μg/L; P < 0.001).

CONCLUSIONS: Supplementation of FA leads to an increase of serum and RBC folate, but does not change plasma MMA concentration in individuals with serum vitamin B-12 between 150 and 280 ng/L. We cannot exclude effects in older people or those with serum vitamin B-12 <150 ng/L. Previously reported associations may arise from effects of impaired vitamin B-12 status on folate metabolism.This trial was registered at www.isrctn.com as ISRCTN37558856.


  • Nutrition and Dietetics, Medicine (miscellaneous)
Original languageEnglish
Pages (from-to)3738-3745
Number of pages8
JournalJournal of Nutrition
Issue number12
Early online date11 Sept 2021
Publication statusPublished - Dec 2021

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