Vitamin B12

What it is

Vitamin B12 is a water-soluble vitamin found naturally in some foods, added to others, and sold as a supplement and as a prescription medicine. It occurs naturally in foods of animal origin; plant foods do not naturally contain it, though fortified cereals and nutritional yeasts do.

What the research says

The clearest evidence concerns people who are deficient or at risk: long-term metformin use and long-term acid-suppressing drugs (PPIs and H2 blockers) are associated with lower B12 status, and older adults with atrophic gastritis absorb less. For treating deficiency, a Cochrane review found low-quality evidence that high-dose oral B12 normalises blood levels about as well as injections. In people without deficiency, a 2021 meta-analysis of 16 trials found no evidence that B12 improves cognition or depressive symptoms, and there were too few trials to analyse fatigue. A trial of high-dose B vitamins including 1 mg B12 in people with diabetic kidney disease reported worse outcomes.

Evidence grade: Well established.

What goes wrong

In the Diabetes Prevention Program Outcomes Study, long-term metformin use was associated with biochemical B12 deficiency and anemia. (Source 1)

• Cohort study, Moderate certainty.
• Size: 2,155 randomised (1,082 placebo, 1,073 metformin); B12 measured in 857/858 at 5 years and 756/764 at 13 years.
• Who: US adults with prediabetes and overweight or obesity.
• How long: About 13 years.
• Result: Low B12 (<=203 pg/mL) 4.3% vs 2.3% at 5 years (P=.02); low or borderline-low B12 (<=298 pg/mL) 20.3% vs 15.6% at 13 years (P=.02); OR per year of metformin use 1.13 (95% CI 1.06-1.20)
• Funding: not stated in the fetched text.

Long-term use of metformin in DPPOS was associated with biochemical B12 deficiency and anemia.

In a large case-control study, previous and current use of acid-suppressing drugs was associated with B12 deficiency. (Source 2)

• Case-control study, Low certainty.
• Size: 25,956 cases with B12 deficiency and 184,199 controls.
• Who: Kaiser Permanente Northern California members.
• How long: 2 or more years' drug supply.
• Result: 2+ years PPIs OR 1.65 (95% CI 1.58-1.73); 2+ years H2RAs OR 1.25 (95% CI 1.17-1.34)
• Funding: not stated.

Previous and current gastric acid inhibitor use was significantly associated with the presence of vitamin B12 deficiency.

In a trial of people with diabetic kidney disease, reported in an American Family Physician summary, equal numbers progressed to dialysis on high-dose B vitamins (folic acid 2.5 mg, B6 25 mg, B12 1 mg daily) and placebo, but the B-vitamin group had higher rates of heart attack, stroke, revascularisation and death; no single one of these differences was statistically significant, only their combined rate (P = .04). (Source 3)

• Randomized trial, Moderate certainty.
• Size: 238 randomised.
• Who: Adults with diabetes and known renal disease (stages 4-5 excluded)
• How long: Follow-up every six months for up to 36 months.
• Result: Greater fall in GFR with B vitamins (16.5 vs 10.7 mL/min; P = .02); equal progression to dialysis; higher combined rate of secondary outcomes (P = .04), with no individual event statistically significant.
• Funding: not stated in the fetched summary.

Limit of this finding: This trial is known here only through a journal summary (American Family Physician, 2011), not the original JAMA 2010 paper. The summary says 238 patients were randomised but also says enrolment stopped after 252 patients, without explaining the difference, and it prints the placebo group's kidney-function figure in different units (per m2) from the treatment group's (per 1.73 m2), which looks like a typing slip. The direction of the result is not affected, but exact numbers should be checked against the original paper.

Equal numbers of patients progressed to dialysis in each group, but patients in the B-vitamin group had higher rates of myocardial infarction, stroke, revascularization, and all-cause mortality. None of the individual events reached statistical significance, but the overall rate of secondary outcomes was statistically significant (P = .04).

What the evidence supports

In adults with B12 deficiency, oral and intramuscular B12 had similar effects on normalising serum B12 levels, with low-quality evidence. (Source 4)

• Systematic review, Low certainty.
• Size: 153 participants across 3 RCTs.
• Who: Adults with vitamin B12 deficiency.
• How long: 3 to 4 months.
• Result: Similar normalisation of serum B12 with 1000-2000 mcg/day oral versus IM; oral costs less; very low-quality evidence that oral is as safe as IM.
• Funding: not stated.

Low quality evidence shows oral and IM vitamin B12 having similar effects in terms of normalising serum vitamin B12 levels, but oral treatment costs less.

What the evidence does not support

In people without advanced neurological disorders or overt B12 deficiency, the meta-analysis found no evidence that B12 alone or B-complex supplementation affected any area of cognitive function. (Source 5)

• Meta-analysis, Moderate certainty.
• Size: 6,276 participants across 16 RCTs.
• Who: Adults without advanced neurological disorders or overt B12 deficiency.
• How long: Varied by trial.
• Result: No effect of B12 alone or B complex on any cognitive subdomain; no overall effect on depression.
• Funding: not stated.

Regarding cognitive function outcomes, we found no evidence for an effect of B12 alone or B complex supplementation on any subdomain of cognitive function outcomes.

The same meta-analysis concluded B12 is likely ineffective for cognitive function and depressive symptoms in this population. (Source 6)

• Meta-analysis, Moderate certainty.
• Size: 16 RCTs, 6,276 participants.
• Who: Adults without advanced neurological disorders.
• How long: Varied.
• Result: Pooled estimates not significant.
• Funding: not stated.

Vitamin B12 supplementation is likely ineffective for improving cognitive function and depressive symptoms in patients without advanced neurological disorders.

Evidence on B12 for idiopathic (unexplained) fatigue in people without overt deficiency is too thin to analyse: only one trial reported it. (Source 7)

• Meta-analysis, Very low certainty.
• Size: 1 trial.
• Who: Adults with idiopathic fatigue, without overt B12 deficiency.
• How long: not stated.
• Result: No pooled analysis possible.
• Funding: not stated.

Further, only one study reported effects on idiopathic fatigue, and therefore, no analysis was possible.

NIH ODS position: B12 supplements do not appear to improve athletic performance or endurance in people with sufficient B12 status. (Source 8)

• Official position, Certainty not rated.
• Size: not applicable.
• Who: General population.
• How long: not applicable.
• Result: not applicable.
• Funding: Government.

Vitamin B12 supplementation does not appear to improve athletic performance or endurance in people who have sufficient vitamin B12 status.

Where the evidence is mixed

The trials behind the oral-versus-injection comparison were few, small and short. (Source 9)

• Systematic review, Low certainty.
• Size: 153 participants (74 oral, 79 IM)
• Who: Adults with vitamin B12 deficiency.
• How long: 3 to 4 months.
• Result: Three RCTs; review rated serum B12 evidence low because of imprecision.
• Funding: not stated.

The trials randomised 153 participants (74 participants to oral vitamin B12 and 79 participants to IM vitamin B12).

Where the research disagrees

Whether people taking metformin should have routine B12 testing

• Aroda et al., Diabetes Prevention Program Research Group (2016), Secondary analysis of a randomised trial cohort: Routine testing of vitamin B12 levels in metformin-treated patients should be considered. (Source 1)
• Lam et al., JAMA (2013), on acid-suppressing drugs, Case-control study: These findings should be considered when balancing the risks and benefits of using these medications. (Source 2)

How much

• Reference intake: RDA 2.4 mcg/day for adults 19 and older (US Food and Nutrition Board, Institute of Medicine, 1998); 2.6 mcg in pregnancy and 2.8 mcg in lactation. (Source 10)
• Upper limit: No UL set by the US Food and Nutrition Board (1998), because of B12's low potential for toxicity. (Source 11)
• Studied: Oral cyanocobalamin 1000 to 2000 mcg/day versus intramuscular injection for 3 to 4 months in adults with deficiency. (Source 9)
• Studied: Daily tablet of folic acid 2.5 mg, vitamin B6 25 mg and vitamin B12 1 mg, versus placebo, for up to 36 months in 238 adults with diabetes and kidney disease. (Source 12)

A common belief, and what the research shows

The belief: B12 supplements boost energy and brain function in anyone.

What the research shows: In people without overt deficiency, a meta-analysis found 'no evidence for an effect of B12 alone or B complex supplementation on any subdomain of cognitive function outcomes', and noted 'only one study reported effects on idiopathic fatigue, and therefore, no analysis was possible.'

Questions and answers

What is it?

Vitamin B12 (cobalamin) is a water-soluble vitamin. It occurs naturally in some foods, is added to others, and is sold both as a supplement and as a prescription medicine. (Source 13)

What does it do in the body?

US reference intakes for adults were set at the amount of B12 needed to maintain healthy blood (hematological) status and normal serum B12 levels. (Source 10)

Is it good or bad for you?

In people without advanced neurological disorders, a 2021 meta-analysis concluded that B12 supplements are likely ineffective for improving cognitive function and depressive symptoms. (Source 6)

How do you get more of it?

Through food, supplements or injections. For people with deficiency, a Cochrane review found low-quality evidence that oral B12 normalised blood levels about as well as intramuscular injections, at lower cost. (Source 4)

If it is harmful, what reduces it?

Does not apply. US authorities set no upper limit for B12 because of its low potential for toxicity. (Source 11)

Why might someone be low in it or missing it?

Poor absorption is one reason: atrophic gastritis, an autoimmune condition affecting 2% of the general population but 8% to 9% of adults 65 and older, reduces intrinsic factor and stomach acid and so reduces B12 absorption. (Source 14)

Which whole foods contain it or feed it?

Fish, meat, poultry, eggs and dairy products contain B12 naturally. Plant foods do not, but fortified breakfast cereals and fortified nutritional yeasts do. (Source 15)

What happens if you do not have it?

B12 deficiency can cause megaloblastic anemia and neurological damage. Large amounts of folate can correct the anemia but not the neurological damage. (Source 16)

How can you test for it?

B12 status is usually tested with a serum or plasma B12 level; the cutoff for deficiency varies by method and laboratory, but most laboratories treat values below 200 or 250 pg/mL as low. Serum methylmalonic acid (MMA) is described as the most sensitive marker, and a level above 0.271 micromol/L suggests deficiency. (Source 17)

References

1. The Journal of Clinical Endocrinology & Metabolism. Long-term Metformin Use and Vitamin B12 Deficiency in the Diabetes Prevention Program Outcomes Study. 2016. PMID 26900641, DOI 10.1210/jc.2015-3754. Read the source
2. JAMA. Proton Pump Inhibitor and Histamine 2 Receptor Antagonist Use and Vitamin B12 Deficiency. 2013. PMID 24327038, DOI 10.1001/jama.2013.280490. Read the source
3. American Family Physician. High Doses of B Vitamins May Worsen Diabetic Nephropathy (POEM summary of House AA et al., JAMA 2010;303(16):1603-1609). 2011. Read the source
4. Cochrane Database of Systematic Reviews. Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency. 2018. PMID 29543316, DOI 10.1002/14651858.CD004655.pub3. Read the source
5. Nutrients. Effects of Vitamin B12 Supplementation on Cognitive Function, Depressive Symptoms, and Fatigue: A Systematic Review, Meta-Analysis, and Meta-Regression. 2021. PMID 33809274, DOI 10.3390/nu13030923. Read the source
6. Nutrients. Effects of Vitamin B12 Supplementation on Cognitive Function, Depressive Symptoms, and Fatigue: A Systematic Review, Meta-Analysis, and Meta-Regression. 2021. PMID 33809274, DOI 10.3390/nu13030923. Read the source
7. Nutrients. Effects of Vitamin B12 Supplementation on Cognitive Function, Depressive Symptoms, and Fatigue: A Systematic Review, Meta-Analysis, and Meta-Regression. 2021. PMID 33809274, DOI 10.3390/nu13030923. Read the source
8. NIH Office of Dietary Supplements. Vitamin B12 - Fact Sheet for Health Professionals. n.d. (fetched 2026-09-21). Read the source
9. Cochrane Database of Systematic Reviews. Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency. 2018. PMID 29543316, DOI 10.1002/14651858.CD004655.pub3. Read the source
10. NIH Office of Dietary Supplements. Vitamin B12 - Fact Sheet for Health Professionals. n.d. (fetched 2026-09-21). Read the source
11. NIH Office of Dietary Supplements. Vitamin B12 - Fact Sheet for Health Professionals. n.d. (fetched 2026-09-21). Read the source
12. American Family Physician. High Doses of B Vitamins May Worsen Diabetic Nephropathy (POEM summary of House AA et al., JAMA 2010;303(16):1603-1609). 2011. Read the source
13. NIH Office of Dietary Supplements. Vitamin B12 - Fact Sheet for Health Professionals. n.d. (fetched 2026-09-21). Read the source
14. NIH Office of Dietary Supplements. Vitamin B12 - Fact Sheet for Health Professionals. n.d. (fetched 2026-09-21). Read the source
15. NIH Office of Dietary Supplements. Vitamin B12 - Fact Sheet for Health Professionals. n.d. (fetched 2026-09-21). Read the source
16. NIH Office of Dietary Supplements. Folate - Fact Sheet for Health Professionals. n.d. (fetched 2026-09-21). Read the source
17. NIH Office of Dietary Supplements. Vitamin B12 - Fact Sheet for Health Professionals. n.d. (fetched 2026-09-21). Read the source