Vitamin B12 and Health

Cardiovascular disease

Cardiovascular disease is the most common cause of death in industrialized countries, such as the United States, and is on the rise in developing countries. Risk factors for cardiovascular disease include elevated low-density lipoprotein (LDL) levels, high blood pressure, low high-density lipoprotein (HDL) levels, obesity, and diabetes [45].

Elevated homocysteine levels have also been identified as an independent risk factor for cardiovascular disease [46-48]. Homocysteine is a sulfur-containing amino acid derived from methionine that is normally present in blood. Elevated homocysteine levels are thought to promote thrombogenesis, impair endothelial vasomotor function, promote lipid peroxidation, and induce vascular smooth muscle proliferation [46,47,49]. Evidence from retrospective, cross-sectional, and prospective studies links elevated homocysteine levels with coronary heart disease and stroke [46,49-58].

Vitamin B12, folate, and vitamin B6 are involved in homocysteine metabolism. In the presence of insufficient vitamin B12, homocysteine levels can rise due to inadequate function of methionine synthase [6]. Results from several randomized controlled trials indicate that combinations of vitamin B12 and folic acid supplements with or without vitamin B6 decrease homocysteine levels in people with vascular disease or diabetes and in young adult women [59-67]. In another study, older men and women who took a multivitamin/multimineral supplement for 8 weeks experienced a significant decrease in homocysteine levels [68].

Evidence supports a role for folic acid and vitamin B12 supplements in lowering homocysteine levels, but results from several large prospective studies have not shown that these supplements decrease the risk of cardiovascular disease [48,62-67]. In the Women’s Antioxidant and Folic Acid Cardiovascular Study, women at high risk of cardiovascular disease who took daily supplements containing 1 mg vitamin B12, 2.5 mg folic acid, and 50 mg vitamin B6 for 7.3 years did not have a reduced risk of major cardiovascular events, despite lowered homocysteine levels [65]. The Heart Outcomes Prevention Evaluation (HOPE) 2 trial, which included 5,522 patients older than 54 years with vascular disease or diabetes, found that daily treatment with 2.5 mg folic acid, 50 mg vitamin B6, and 1 mg vitamin B12 for an average of 5 years reduced homocysteine levels and the risk of stroke but did not reduce the risk of major cardiovascular events [63]. In the Western Norway B Vitamin Intervention Trial, which included 3,096 patients undergoing coronary angiography, daily supplements of 0.4 mg vitamin B12 and 0.8 mg folic acid with or without 40 mg vitamin B6 for 1 year reduced homocysteine levels by 30% but did not affect total mortality or the risk of major cardiovascular events during 38 months of follow-up [66]. The Norwegian Vitamin (NORVIT) trial [62] and the Vitamin Intervention for Stroke Prevention trial had similar results [67].

The American Heart Association has concluded that the available evidence is inadequate to support a role for B vitamins in reducing cardiovascular risk [48].

Dementia and cognitive function

Researchers have long been interested in the potential connection between vitamin B12 deficiency and dementia [47,69]. A deficiency in vitamin B12 causes an accumulation of homocysteine in the blood [6] and might decrease levels of substances needed to metabolize neurotransmitters [70]. Observational studies show positive associations between elevated homocysteine levels and the incidence of both Alzheimer's disease and dementia [6,47,71]. Low vitamin B12 status has also been positively associated with cognitive decline [72].

Despite evidence that vitamin B12 lowers homocysteine levels and correlations between low vitamin B12 levels and cognitive decline, research has not shown that vitamin B12 has an independent effect on cognition [73-77]. In one randomized, double-blind, placebo-controlled trial, 195 subjects aged 70 years or older with no or moderate cognitive impairment received 1,000 mcg vitamin B12, 1,000 mcg vitamin B12 plus 400 mcg folic acid, or placebo for 24 weeks [73]. Treatment with vitamin B12 plus folic acid reduced homocysteine concentrations by 36%, but neither vitamin B12 treatment nor vitamin B12 plus folic acid treatment improved cognitive function.

Women at high risk of cardiovascular disease who participated in the Women’s Antioxidant and Folic Acid Cardiovascular Study were randomly assigned to receive daily supplements containing 1 mg vitamin B12, 2.5 mg folic acid and 50 mg vitamin B6, or placebo [76]. After a mean of 1.2 years, B-vitamin supplementation did not affect mean cognitive change from baseline compared with placebo. However, in a subset of women with low baseline dietary intake of B vitamins, supplementation significantly slowed the rate of cognitive decline. In a trial conducted by the Alzheimer's Disease Cooperative Study consortium that included individuals with mild-to-moderate Alzheimer's disease, daily supplements of 1 mg vitamin B12, 5 mg folic acid, and 25 mg vitamin B6 for 18 months did not slow cognitive decline compared with placebo [77]. Another study found similar results in 142 individuals at risk of dementia who received supplements of 2 mg folic acid and 1 mg vitamin B12 for 12 weeks [75].

The authors of two Cochrane reviews and a systematic review of randomized trials of the effects of B vitamins on cognitive function concluded that insufficient evidence is available to show whether vitamin B12 alone or in combination with vitamin B6 or folic acid has an effect on cognitive function or dementia [78-80]. Additional large clinical trials of vitamin B12 supplementation are needed to assess whether vitamin B12 has a direct effect on cognitive function and dementia [6].

Energy and endurance

Due to its role in energy metabolism, vitamin B12 is frequently promoted as an energy enhancer and an athletic performance and endurance booster. These claims are based on the fact that correcting the megaloblastic anemia caused by vitamin B12 deficiency should improve the associated symptoms of fatigue and weakness. However, vitamin B12 supplementation appears to have no beneficial effect on performance in the absence of a nutritional deficit [81].