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Vitamin B12 supplements are effective in increasing serum B12 levels and improving vitamin B12 status, especially in populations at risk of deficiency such as vegans, vegetarians, older adults, and those with absorption issues. They can be administered orally, intramuscularly, or sublingually, with evidence showing no significant difference in efficacy between these routes. Supplementation with vitamin B12 also lowers blood homocysteine levels, which are associated with cardiovascular risk, but the evidence does not conclusively show a reduction in cardiovascular disease or dementia risk through supplementation alone. High doses of oral vitamin B12 can be effective for deficiency treatment, and supplementation is generally safe.

### Evidence on Absorption and Forms of Supplementation
Vitamin B12 supplements commonly come in forms such as cyanocobalamin, methylcobalamin, hydroxycobalamin, and adenosylcobalamin, which convert metabolically into active forms in the body. Oral, intramuscular (IM), and sublingual (SL) routes are effective for increasing serum B12 levels, with IM often ranked slightly higher but without clinically significant differences between routes. Sublingual and oral supplements appear equally effective for absorption, making oral supplementation a well-tolerated, cost-effective option ((46)) ((47)) ((48)) ((49)) ((201)).

Oral absorption of vitamin B12 is limited by intrinsic factor-mediated uptake, which saturates at doses of about 1–2 micrograms, though passive absorption allows about 1% of large doses (e.g., 500–1,000 mcg) to be absorbed without intrinsic factor ((48)) ((169)).

### Populations at Risk and Benefits of Supplementation
Populations at heightened risk of deficiency include:
- Older adults with reduced absorption due to atrophic gastritis,
- Vegans and vegetarians lacking dietary B12 sources,
- Individuals with pernicious anemia and gastrointestinal disorders,
- People on medications such as metformin and proton pump inhibitors that reduce absorption.

Supplementation in these groups improves serum B12 status and reduces deficiency-related biochemical markers ((63)) ((64)) ((65)) ((66)) ((67)).

### Effect on Biomarkers and Clinical Outcomes
Vitamin B12 supplementation significantly lowers homocysteine levels, a marker linked to cardiovascular risk. Meta-analyses of randomized controlled trials (RCTs) show reductions in homocysteine by approximately 3.8 to 4.2 μmol/L with B12 supplements, especially at doses above 500 mcg daily and intervention duration of 12 weeks or longer ((217)) ((218)) ((219)) ((220)) ((221)). However, despite lowering homocysteine, supplementation has not demonstrated a significant reduction in coronary heart disease or major adverse cardiovascular events but may reduce stroke risk modestly (by about 12-14%) when combined with other B vitamins like folic acid and B6 ((276)) ((278)) ((279)).

### Cognitive Function and Neurological Health
While vitamin B12 deficiency is associated with neurological symptoms and cognitive decline, evidence from RCTs indicates that supplementation in patients without advanced neurological disease does not improve cognitive function or prevent dementia significantly ((227)) ((273)). Some meta-analyses suggest modest improvements in cognitive test scores after six months of combined B12 and folic acid supplementation in Alzheimer’s patients, but effects on daily functioning are lacking ((280)).

For infants and children, adequate maternal and infant B12 status is crucial for neural development, but direct evidence on supplementation improving cognition during childhood is limited ((242)).

### Deficiency Treatment and Safety
Treatment of deficiency traditionally involves intramuscular injections but high-dose oral supplementation (1,000–2,000 mcg) is similarly effective in normalizing serum B12 levels ((62)) ((234)) ((274)). Vitamin B12 supplementation is generally safe even at high doses, with no established upper intake limit due to low toxicity potential ((101)) ((133)). Common mild side effects at high doses include nausea and tingling sensations ((134)) ((135)) ((136)) ((137)).

### Summary
- Vitamin B12 supplements effectively improve serum B12 biomarkers and reduce deficiency risk, particularly in vulnerable populations ((214)) ((243)).
- Oral, intramuscular, and sublingual supplementation routes are comparably effective ((201)).
- They significantly reduce homocysteine but do not consistently decrease cardiovascular events except for a stroke risk reduction when combined with other B vitamins ((217)) ((276)).
- Evidence does not strongly support cognitive benefits from supplementation in non-deficient individuals ((273)).
- High-dose oral supplementation is a safe, effective treatment for B12 deficiency ((62)).

Thus, vitamin B12 supplementation is beneficial primarily for correcting and preventing deficiency and associated biochemical abnormalities, with mixed evidence on preventing broader diseases like cardiovascular and cognitive disorders.

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what evidence is there about b-12 vitamin supplements?