For Patients & Caregivers
How It Works
Vitamin B12, in combination with folate and vitamin B6, may reduce the risk for some cancers.
Vitamin B12 is involved in the synthesis of phospholipids, neurotransmitters, DNA, and the metabolism of fatty acids and amino acids in cells. It is found in meat, fish, dairy products, and fortified cereals. A number of studies have evaluated B12, folic acid, and B6 as part of homocysteine-lowering therapy. This is because elevated homocysteine levels can be a marker for various conditions including heart disease, depression, cognitive disorders, and risk of fracture incidence. However, findings are mixed on whether long-term supplementation with this combination improves fracture risk or medical conditions even when it lowers homocysteine levels.
Some large studies suggest this supplement combination may lower the risks for cervical cancer, but not lung or invasive cancers, and results are mixed for breast cancer. Another study found an increased cancer incidence when evaluating only B12 taken with folic acid, although results suggested these effects were related to folic acid. Further studies are needed to confirm these findings.
Since vitamin B12 is found in many foods, deficiency is more common in the elderly, strict vegetarians, or those who take oral contraceptives, or medications for gastric disorders or insulin resistance. High levels of folic acid intake may mask a B12 deficiency. Patients should discuss supplement use with their physicians.
- B12 deficiency Diagnosed deficiencies can be effectively treated with B12 therapy if dietary changes alone are not enough.
- Pernicious anemia The injectable form of B12 is used as a prescription drug to treat pernicious anemia.
- Cardiovascular disease When combined with folate and B6, vitamin B12 can reduce homocysteine levels, which may offer benefit for cardiovascular disorders, although results from studies are mixed.
- Breast cancer Studies are mixed on whether vitamin B12 in combination with folate and B6 can reduce breast cancer risk.
- Lung cancer Some studies suggest that long-term use of vitamin B12 may increase the risk of lung cancer.
- Fatigue In those without a vitamin B12 deficiency, there is little indication in the medical literature that B12 supplementation can improve fatigue symptoms.
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For Healthcare Professionals
Vitamin B12, part of the vitamin B-complex family, refers to the group of compounds that consists of cyanocobalamin, hydroxycobalamin, and related substances (1). It is essential for normal nerve function, DNA synthesis, hematopoiesis, fatty acid metabolism, and amino acid synthesis in the mitochondria. It also plays an important role in homocysteine metabolism. Vitamin B12 is abundant in diets that include meat and dairy products, although deficiency can occur in those with mal-absorption syndromes (2), take medications for gastric disorders (3) (4), for conditions associated with insulin resistance (5), or in those who follow a strict vegetarian diet (6). B12 deficiency is also more common among the elderly (7). Lack of B12 can lead to a wide variety of hematologic, neurologic, and psychiatric disorders, may increase the risk of cardiovascular disease (8), and cause pseudo-thrombotic microangiopathy following gastrectomy (55). Vitamin B12 is often included in vitamin products used to reduce homocysteine, which is associated with cardiovascular diseases.
High dietary intakes of B vitamins including B12 have been associated with a decreased risk for cataracts (36). However, combined supplementation with B12, B6, and folic acid may increase the risk of cataract extraction (37).
Although low serum B12 levels have been associated with increased bone turnover and fracture risk (9), long-term B12 and folic acid supplementation did not improve bone mineral density (38), or reduce osteoporotic fracture incidence in elderly individuals with elevated plasma homocysteine levels (39).
Repletion of vitamin B12 may improve response in patients resistant to antidepressants (10); and in older adults with major depression, long-term supplementation with a combination of B12, B6, and folic acid enhanced antidepressant treatment efficacy (40). However, among middle-age and older women, such combined supplementation did not reduce depression risk compared with placebo, despite significant reductions in homocysteine levels (41).
Homocysteine-lowering therapy may have some cardiovascular benefits following coronary interventions (11), but does not appear to lower the risk of further cardiovascular events including stroke (12) (13) (14). In addition, increased risk of in-stent restenosis with such treatment has been reported in patients after coronary stenting (15). In a large Dutch study known as the B-PROOF trial, 2 years of B12 and folic acid supplementation in hyper-homocysteinemic elderly patients also had no effect on arterial stiffness and atherosclerosis (42). However, in a long-term field study of individuals residing in India at high altitude, B12 and folic acid supplementation reduced the incidence of thrombosis (43). And, conclusions of a meta analysis indicate moderate to low evidence for preventive benefits of folic acid and B-vitamins for stroke (61).
In other studies, B12 as part of homocysteine-lowering therapy or B12 repletion therapy (45), did not improve cognitive function (16) (17) (18) (19) (56), even though low-normal B12 concentrations are associated with poorer memory performance (46). This was further echoed in secondary data from the B-PROOF study which showed improving homocysteine levels does not improve cognitive outcomes (47), although the intervention may positively affect gait and physical performance in the elderly (48). Additional data show an association between maternal B12 supplementation during pregnancy with higher expressive language scores in children (57).
And, combination of folic acid and vitamin B12 supplements decreased serum homocysteine levels and improved anemia in patients with multiple sclerosis (58); vitamin B12 improved the quality of life patients with postherpetic neuralgia, and may help reduce analgesic use (59); as well as methylcobalamin, an analogue of vitamin B12, was reported useful in increasing vitamin B12 levels in patients with peripheral neuropathy (60).
Increased intake of B12, folate and B6 may lower the risk of breast (20) (21) (22) and cervical (23) cancers, but not lung cancer (24). In fact, long-term use of vitamin B12 supplement is associated with increased risk of lung cancer, especially in male smokers (53). Another large study did not find an effect with this combination on overall risk of invasive cancer or breast cancer (25). However, data from a Norwegian study suggest higher cancer incidence and mortality in patients with ischemic heart disease following B12 and folic acid supplementation (26), although these effects appear to be mediated by folic acid. The combination may also increase the risk of colorectal cancer (54). But supplementation may help reduce pain and improve quality of life in patients with musculoskeletal symptoms associated with aromatase inhibitor use (62). Dietary intake of folate and B12 during pregnancy has been associated with a lower risk for acute lymphoblastic leukemia in children (49). Further studies are needed to confirm these findings.
Intramuscular B12 injections and oral folic acid reduce toxicity of pemetrexed chemotherapy in patients with non-small cell lung cancer (27), and may also help to improve treatment efficacy (28) (29), but oral administration of vitamin B12 did not have similar effects (50). A large Danish population study identified a correlation between high plasma B12 levels and elevated risk of hematological, smoking-related, and alcohol-related cancers (51); and cancer patients with elevated B12 levels had higher mortality than those with normal values (52). However, such increases are probably due to changes in cobalamin metabolism caused by cancer. It does not suggest that B12 supplementation can cause cancer.
Mechanism of Action
Vitamin B12 is involved in the transfer of methyl groups, and in methylation reactions essential for the synthesis of phospholipids and neurotransmitters in the central nervous system. It is also required for synthesis of nucleic acid, notably DNA, the metabolism of fatty acids and amino acids in the mitochondria, and in delivering SAMe, the universal methyl donor (16) (30). In humans, two enzymatic reactions dependent on B12 are produced and activated in separate cellular compartments: methylcobalamin in the cytosol and adenosylcobalamin in the mitochondria (1). As a coenzyme in methyl transfer reactions, B12 converts homocysteine to methionine, and participates in L-methylmalonyl-coenzyme A (CoA) conversion to succinyl-CoA (8). In the first enzyme reaction, methylcobalamin is used to recycle the folate cofactor 5-methyltetrahydrofolate to tetrahydrofolate thereby allowing the folate cofactor to participate in a cycle involving the biosynthesis of purines and pyrimidines. During this reaction, homocysteine is converted to methionine yielding the methyl groups required for methylation that is essential in biosynthesis (31).
When used with pemetrexed, B12/folic acid therapy further increases sub-G1 populations in human adenocarcinoma and large-cell carcinoma cell lines, independent of p53 status (28).
Rosacea fulminans: In a 17-year-old girl after consumption of high doses of vitamins B6 and B12 for 2 weeks (32).
Higher cancer incidence and mortality occurred in patients with ischemic heart disease following supplementation with vitamin B12 and folic acid (26), although these effects appeared to be mediated by folic acid.
Proton pump inhibitors or histamine type 2 (H2)-receptor antagonists: Medications to treat gastric disorders that interfere with or suppress gastric acid and intrinsic factor production can lead to decreased vitamin B12 absorption (3) (4).
Biguanides (metformin): Medications used to treat type 2 diabetes, metabolic syndrome, nonalcoholic fatty liver disease, and polycystic ovary syndrome can lead to decreased vitamin B12 absorption (5).
Folic acid: Ingesting amounts greater than the Tolerable Upper Intake Level may mask vitamin B12 deficiency symptoms (33).
Oral contraceptives: May lower serum vitamin B12 concentrations (34).