Skip to main content
Evidence-Based Supplement Research
Evidence-Based Supplement Research
Pillser
Search
Sign UpLog In

Excess Folic Acid and Vitamin B12 Deficiency: Clinical Implications?

  • 2024-06
  • Food and nutrition bulletin 45(1_suppl)
    • Joshua W Miller
    • Andre Smith
    • Aron M Troen
    • Joel B Mason
    • Paul F Jacques
    • Jacob Selhub

Study Design

Type
Review

Background

In the 1940s to 1950s, high-dose folic acid supplements (>5 mg/d) were used clinically to reverse the megaloblastic anemia of vitamin B12 deficiency caused by pernicious anemia. However, this treatment strategy masked the underlying B12 deficiency and possibly exacerbated its neuropathological progression. The issue of masking and exacerbating B12 deficiency has recently been rekindled with the institution of folic acid fortification and the wide-spread use of folic acid supplements.

Objectives

The objectives of this review are to describe clinical and epidemiological evidence that excess folic acid exacerbates B12 deficiency, to summarize a hypothesis to explain this phenomenon, and to provide guidance for clinicians.

Results

Cognitive function test scores are lower and blood homocysteine and methylmalonic acid concentrations are higher in people with low B12 and elevated folate than in those with low B12 and nonelevated folate. High-dose folic acid supplementation in patients with pernicious anemia or epilepsy cause significant reductions in serum B12. It is hypothesized that high-dose folic acid supplements cause depletion of serum holotranscobalamin and thus exacerbate B12 deficiency.

Conclusion

The evidence for excess folic acid exacerbating B12 deficiency is primarily correlative or from uncontrolled clinical observations, and the hypothesis to explain the phenomenon has not yet been tested. Nonetheless, the evidence is sufficiently compelling to warrant increased vigilance for identifying B12 deficiency in at risk individuals, including older adults and others with low B12 intake or conditions that are associated with B12 malabsorption, who also ingest excessive folic acid or are prescribed folic acid in high doses.

Research Insights

  • Vitamin B9→Increased Blood Homocysteine Level

    Cognitive function test scores are lower and blood homocysteine and methylmalonic acid concentrations are higher in people with low B12 and elevated folate than in those with low B12 and nonelevated folate.

    Effect
    Harmful
    Effect size
    Moderate
    Dose
    >5 mg/d
  • Vitamin B9→Increased Free Fatty Acid Levels

    Cognitive function test scores are lower and blood homocysteine and methylmalonic acid concentrations are higher in people with low B12 and elevated folate than in those with low B12 and nonelevated folate.

    Effect
    Harmful
    Effect size
    Moderate
    Dose
    >5 mg/d
  • Vitamin B9→Reduced Cognitive Function Test Score

    Cognitive function test scores are lower and blood homocysteine and methylmalonic acid concentrations are higher in people with low B12 and elevated folate than in those with low B12 and nonelevated folate.

    Effect
    Harmful
    Effect size
    Moderate
    Dose
    >5 mg/d
  • Vitamin B9→Reduced Vitamin B12 Level

    High-dose folic acid supplementation in patients with pernicious anemia or epilepsy cause significant reductions in serum B12.

    Effect
    Harmful
    Effect size
    Moderate
    Dose
    High-dose (≥5 mg/d)
Back to top