Abstract
BackgroundIndividuals 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. ObjectivesWe aimed to determine the impact of FA supplementation on plasma MMA concentration in people with low or marginal serum vitamin B-12. MethodsWe 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). ResultsA 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). ConclusionsSupplementation 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.
Highlights
The interaction between vitamin B-12 and folate has important public health implications
A total of 117 participants were assessed for RBC folate, which increased in the supplementation group; the adjusted mean difference (aMD) was 461 μg/L
Primary outcome analysis There was no difference in the between-group plasma methylmalonic acid (MMA) concentration; the aMD was −0.01
Summary
The interaction between vitamin B-12 and folate has important public health implications. The combination of mandatory fortification and self-supplementation has exposed a significant proportion of these populations to concentrations of FA above the upper intake level [5]. This has led to various concerns regarding the potential toxicity of such exposure. Individuals with low serum vitamin B-12 and high serum folate have higher plasma concentrations of methylmalonic acid (MMA). 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.
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