Excess folic acid and vitamin B12 deficiency
What it found
In people, high folate levels combined with low vitamin B12 were linked to worse cognitive test scores and higher blood markers of B12 deficiency.
The evidence is mostly from population studies and clinical observations, not controlled trials.
What they found
Studies in people
Cognitive scores and B12
In older adults with low B12, those who also had high serum folate had lower cognitive test scores than those with low B12 and normal folate. This pattern was seen in several population studies, though one study in the United Kingdom did not find it.
Blood markers of B12
People with low B12 and high folate had higher blood levels of homocysteine and methylmalonic acid, which are markers of B12 deficiency, compared to those with low B12 and normal folate.
Folic acid in patients
In patients with pernicious anemia or epilepsy, high-dose folic acid supplements caused significant reductions in serum B12. In some pernicious anemia patients, homocysteine and methylmalonic acid increased after folic acid and then decreased after switching to B12.
Active B12 in blood
In one study, B12-deficient people with high folate had about 50% lower levels of holotranscobalamin, the active form of B12 in blood, than those with normal folate. The authors suggest folic acid may cause this depletion, but the idea has not been tested.
Other findings
How folic acid might act
The authors propose two ways folic acid could lower active B12: by sending it to the bone marrow to make new blood cells, or by causing it to be lost in urine through effects on the kidney. These mechanisms are hypotheses, not proven.
What the authors conclude
“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.”
Also in their conclusions
- They say the evidence that excess folic acid worsens B12 deficiency is mostly correlative or from uncontrolled observations, and their hypothesis has not been tested.
- They advise clinicians to never rely solely on anemia to suspect B12 deficiency and to never treat B12-deficiency anemia with folic acid.
- They recommend increased vigilance for B12 deficiency in at-risk groups, including older adults, people with malabsorption, unexplained neurological symptoms, and those who follow vegan or vegetarian diets, especially if they also take folic acid supplements or are exposed to fortified foods.
How it was done
High-dose folic acid was once used to treat the anemia of vitamin B12 deficiency, but this masked the deficiency and may have worsened nerve damage. With folic acid now added to cereals and grains in many countries, the authors wanted to review whether excess folic acid could still be a problem for people with low vitamin B12.
The authors reviewed clinical and epidemiological studies that looked at the relationship between folic acid, folate levels, and vitamin B12 status in patients and in populations. They also summarized a hypothesis about how folic acid might deplete the active form of B12 in blood.
What it can’t tell you
- Most of the evidence comes from population studies and clinical observations, which can show links but cannot prove that folic acid causes B12 deficiency.
- The proposed mechanism for how folic acid might deplete active B12 has not been tested in experiments.
- The findings do not show whether lowering folic acid intake would prevent or reverse any B12-related problems.
Who paid
- Funding
- Funded by NIEHS NIH HHS; NIA NIH HHS; NIDDK NIH HHS (from the PubMed record).
- Conflicts
- Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: JWM is co-author of a patent titled “Assay for Vitamin B12 Absorption and Method of Making Labeled Vitamin B12” (Patent Number: 8,202,507) issued to The Regents of the University of California (Oakland, CA), JWM is an associate editor for the journal Nutrition Reviews .
- Authors work at
- Rutgers University, USA; The Hebrew University of Jerusalem, Israel; Tufts-USDA Human Nutrition Research Center on Aging, USA
The paper
- Title
- Excess Folic Acid and Vitamin B12 Deficiency: Clinical Implications?
- Type
- ReviewThe authors read earlier studies and describe what they found. It isn’t a new study.
- Evidence
- Studies in people
- Summarised from
- Full text
- Cite
- Miller JW, Smith A, Troen AM, Mason JB, Jacques PF, Selhub J (2024). Excess Folic Acid and Vitamin B12 Deficiency: Clinical Implications?. Food and nutrition bulletin. doi:10.1177/03795721241229503Free full textPubMed 38987872DOI
Summary written 26 Sep 2026. Check it against the paper before it changes what you eat. How we summarise papers · Report an error