Health Care Professional Information

Scientific Name
Cyanocobalamin
Common Name

Cyanocobalamin, cobalamin

Clinical Summary

Vitamin B12 is part of the vitamin B-complex family and 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 the metabolism of homocysteine and synthesis of S-adenosylmethionine (SAMe), another compound that is essential to many biological processes.

Vitamin B12 is naturally synthesized by bacteria and abundant in diets that include meat and dairy products, although a deficiency can occur in those who have malabsorption syndromes (2), take medications for gastric disorders (3) (4) or for conditions associated with insulin resistance (5), or 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, and may increase the risk of cardiovascular diseases (8). Low serum B12 levels have been associated with increased bone turnover and fracture risk (9). Repletion of vitamin B12 may improve response in patients resistant to antidepressants (10).

When used as homocysteine-lowering therapy, vitamin B12, folate, and vitamin B6 may have some cardiovascular benefits after coronary interventions (11), but do not appear to reduce 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), and B12 supplementation as part of homocysteine-lowering therapy does not improve cognitive function (16) (17) (18) (19).

Clinical studies show that increased intake of vitamin B12 together with folate and vitamin B6 may lower the risk of breast (20) (21) (22) and cervical cancers (23), but has no effect on the risk of lung cancer (24). Findings from another study indicate that a combination of folate and vitamins B6 and B12 did not have an effect 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 supplementation with vitamin B12 and folic acid (26). Further studies are needed to confirm these findings in other populations.

Supplementation with vitamin B12 intramuscular injections and oral folic acid reduces toxicity of pemetrexed chemotherapy in patients with non-small cell lung cancer (27), and may also help to improve treatment efficacy (28) (29).

Food Sources
  • Meat
  • Poultry
  • Fish
  • Shellfish
  • Dairy
  • Fortified cereals
Purported Uses
  • B12 deficiency
  • Breast cancer
  • Cardiovascular disease
  • Cognitive function
  • Fatigue
  • Lung cancer
  • Pernicious anemia
  • Stroke
Mechanism of Action

Vitamin B12 is involved in the transfer of methyl groups and methylation reactions essential for the synthesis of phospholipids and neurotransmitters in the central nervous system. B12 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 two separate cellular compartments: methylcobalamin in the cytosol and adenosylcobalamin in the mitochondria (1). As a coenzyme in methyl transfer reactions, it converts homocysteine to methionine, and it also 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).

Pharmacokinetics

Absorption
The acidic stomach environment facilitates the release of B12 that is bound to food. Parietal cells of the stomach release intrinsic factor which binds to the vitamin in the duodenum. The vitamin B12/intrinsic factor complex assists B12 absorption in the terminal ileum. Evidence supports the existence of a second avenue of absorption that does not rely on intrinsic factor or an intact ileum. As much as 1% of a large oral dose of B12 is absorbed by this secondary mechanism (8). Drugs that reduce gastric intrinsic factor secretion can also reduce the absorption of B12. Patients with pernicious anemia are not able to produce intrinsic factor and therefore cannot absorb oral vitamin B12.

Distribution
Once absorbed, B12 is bound to transcobalamin II and is distributed throughout the body, with the largest amount taken up in the liver (8).

Metabolism/Excretion
Approximately 0.1% of body stores of B12 are lost per day with equal amounts excreted through the digestive and urinary tracts (31).

Contraindications

Vitamin B12 may increase the risk of in-stent restenosis in patients after coronary stenting (15).

Adverse Reactions

Case report
Rosacea fulminans: In a 17-year-old girl after consumption of high doses of vitamin B6 and vitamin B12 for 2 weeks (32).

Herb-Drug Interactions

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 a decrease in 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).

Literature Summary and Critique

Eussen SJ, et al. Effect of oral vitamin B-12 with or without folic acid on cognitive function in older people with mild vitamin B-12 deficiency: a randomized, placebo-controlled trial. Am J Clin Nutr. 2006;84:361-370.
In this study, 195 participants with mild B12 deficiency aged ≥70 years were assigned to receive 1000 mcg vitamin B12, 1000 mcg B12 plus 400 mcg folic acid, or placebo for 24 weeks. Cognitive function was assessed before and after treatment using a neuropsychological test battery including domains of attention, construction, sensomotor speed and memory. Memory function improved in the placebo group more so than in the group who only received B12 (P=.0036). Neither B12 supplementation alone or in combination with folic acid showed any improvement in cognitive function in test subjects after 24 weeks.

Zhang SM, et al. Plasma folate, vitamin B6, vitamin B12, homocysteine, and risk of breast cancer. J Natl Cancer Inst. 2003;95:373-380.
In this prospective nested case-control study within the Nurse's Health Study, 32,826 women had blood samples obtained in 1989 and 1990 and were followed through 1996 for the development of breast cancer. A total of 712 breast cancer patients and 712 matched controls were identified. Higher levels of plasma folate were associated with lower breast cancer risk especially in women with moderate alcohol consumption (≥15g/day) and in postmenopausal women. Premenopausal women with the highest plasma B12 levels also had lower breast cancer risk, although no significant effects of plasma B12 on breast cancer risk were found for postmenopausal women. The authors concluded that dietary folate and B6 may have a chemopreventive role in reducing the risk of breast cancer.

Dosage (Inside MSKCC Only)
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References
  1. Grober U, Kisters K, Schmidt J. Neuroenhancement with vitamin B12-underestimated neurological significance. Nutrients. Dec 2013;5(12):5031-5045. doi: 10.3390/nu5125031
  2. Hannibal L, DiBello PM, Jacobsen DW. Proteomics of vitamin B12 processing. Clin Chem Lab Med. Mar 1 2013;51(3):477-488. doi: 10.1515/cclm-2012-0568
  3. Lam JR, Schneider JL, Zhao W, et al. Proton pump inhibitor and histamine 2 receptor antagonist use and vitamin B12 deficiency. JAMA. Dec 11 2013;310(22):2435-2442. doi: 10.1001/jama.2013.280490
  4. Wilhelm SM, Rjater RG, Kale-Pradhan PB. Perils and pitfalls of long-term effects of proton pump inhibitors. Expert Rev Clin Pharmacol. Jul 2013;6(4):443-451. doi: 10.1586/17512433.2013.811206
  5. Buvat DR. Use of metformin is a cause of vitamin B12 deficiency. Am Fam Physician. Jan 15 2004;69(2):264; author reply 264, 266. doi:
  6. Pawlak R, Lester SE, Babatunde T. The prevalence of cobalamin deficiency among vegetarians assessed by serum vitamin B12: a review of literature. Eur J Clin Nutr. May 2014;68(5):541-548. doi: 10.1038/ejcn.2014.46
  7. Allen LH. How common is vitamin B-12 deficiency? Am J Clin Nutr. Feb 2009;89(2):693S-696S. doi: 10.3945/ajcn.2008.26947A
  8. Oh R, Brown DL. Vitamin B12 deficiency. Am Fam Physician. Mar 1 2003;67(5):979-986. doi:
  9. Dhonukshe-Rutten RA, Pluijm SM, de Groot LC, et al. Homocysteine and vitamin B12 status relate to bone turnover markers, broadband ultrasound attenuation, and fractures in healthy elderly people. J Bone Miner Res. Jun 2005;20(6):921-929. doi: 10.1359/JBMR.050202
  10. Kate N, Grover S, Agarwal M. Does B12 deficiency lead to lack of treatment response to conventional antidepressants? Psychiatry (Edgmont). Nov 2010;7(11):42-44. doi:
  11. Schnyder G, Roffi M, Flammer Y, et al. Effect of homocysteine-lowering therapy on restenosis after percutaneous coronary intervention for narrowings in small coronary arteries. Am J Cardiol. May 15 2003;91(10):1265-1269. doi:
  12. Desai CK, Huang J, Lokhandwala A, et al. The Role of Vitamin Supplementation in the Prevention of Cardiovascular Disease Events. Clin Cardiol. May 23 2014. doi: 10.1002/clc.22299
  13. Albert CM, Cook NR, Gaziano JM, et al. Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease: a randomized trial. JAMA. May 7 2008;299(17):2027-2036. doi: 10.1001/jama.299.17.2027
  14. Group VTS. B vitamins in patients with recent transient ischaemic attack or stroke in the VITAmins TO Prevent Stroke (VITATOPS) trial: a randomised, double-blind, parallel, placebo-controlled trial. Lancet Neurol. Sep 2010;9(9):855-865. doi: 10.1016/S1474-4422(10)70187-3
  15. Lange H, Suryapranata H, De Luca G, et al. Folate therapy and in-stent restenosis after coronary stenting. N Engl J Med. Jun 24 2004;350(26):2673-2681. doi: 10.1056/NEJMoa032845
  16. Eussen SJ, de Groot LC, Joosten LW, et al. Effect of oral vitamin B-12 with or without folic acid on cognitive function in older people with mild vitamin B-12 deficiency: a randomized, placebo-controlled trial. Am J Clin Nutr. Aug 2006;84(2):361-370. doi:
  17. Hvas AM, Juul S, Lauritzen L, et al. No effect of vitamin B-12 treatment on cognitive function and depression: a randomized placebo controlled study. J Affect Disord. Sep 2004;81(3):269-273. doi: 10.1016/S0165-0327(03)00169-1
  18. McMahon JA, Green TJ, Skeaff CM, et al. A controlled trial of homocysteine lowering and cognitive performance. N Engl J Med. Jun 29 2006;354(26):2764-2772. doi: 10.1056/NEJMoa054025
  19. Kang JH, Cook N, Manson J, et al. A trial of B vitamins and cognitive function among women at high risk of cardiovascular disease. Am J Clin Nutr. Dec 2008;88(6):1602-1610. doi: 10.3945/ajcn.2008.26404
  20. Lajous M, Lazcano-Ponce E, Hernandez-Avila M, et al. Folate, vitamin B(6), and vitamin B(12) intake and the risk of breast cancer among Mexican women. Cancer Epidemiol Biomarkers Prev. Mar 2006;15(3):443-448. doi: 10.1158/1055-9965.EPI-05-0532
  21. Shrubsole MJ, Jin F, Dai Q, et al. Dietary folate intake and breast cancer risk: results from the Shanghai Breast Cancer Study. Cancer Res. Oct 1 2001;61(19):7136-7141. doi:
  22. Zhang SM, Willett WC, Selhub J, et al. Plasma folate, vitamin B6, vitamin B12, homocysteine, and risk of breast cancer. J Natl Cancer Inst. Mar 5 2003;95(5):373-380. doi:
  23. Hernandez BY, McDuffie K, Wilkens LR, et al. Diet and premalignant lesions of the cervix: evidence of a protective role for folate, riboflavin, thiamin, and vitamin B12. Cancer Causes Control. Nov 2003;14(9):859-870. doi:
  24. Hartman TJ, Woodson K, Stolzenberg-Solomon R, et al. Association of the B-vitamins pyridoxal 5'-phosphate (B(6)), B(12), and folate with lung cancer risk in older men. Am J Epidemiol. Apr 1 2001;153(7):688-694. doi:
  25. Zhang SM, Cook NR, Albert CM, et al. Effect of combined folic acid, vitamin B6, and vitamin B12 on cancer risk in women: a randomized trial. JAMA. Nov 5 2008;300(17):2012-2021. doi: 10.1001/jama.2008.555
  26. Ebbing M, Bonaa KH, Nygard O, et al. Cancer incidence and mortality after treatment with folic acid and vitamin B12. JAMA. Nov 18 2009;302(19):2119-2126. doi: 10.1001/jama.2009.1622
  27. Ohe Y, Ichinose Y, Nakagawa K, et al. Efficacy and safety of two doses of pemetrexed supplemented with folic acid and vitamin B12 in previously treated patients with non-small cell lung cancer. Clin Cancer Res. Jul 1 2008;14(13):4206-4212. doi: 10.1158/1078-0432.CCR-07-5143
  28. Yang TY, Chang GC, Hsu SL, et al. Effect of folic acid and vitamin B12 on pemetrexed antifolate chemotherapy in nutrient lung cancer cells. Biomed Res Int. 2013;2013:389046. doi: 10.1155/2013/389046
  29. Scagliotti GV, Shin DM, Kindler HL, et al. Phase II study of pemetrexed with and without folic acid and vitamin B12 as front-line therapy in malignant pleural mesothelioma. J Clin Oncol. Apr 15 2003;21(8):1556-1561. doi: 10.1200/JCO.2003.06.122
  30. Kirsch SH, Herrmann W, Obeid R. Genetic defects in folate and cobalamin pathways affecting the brain. Clin Chem Lab Med. Jan 2013;51(1):139-155. doi: 10.1515/cclm-2012-0673
  31. Scott JM. Bioavailability of vitamin B12. Eur J Clin Nutr. Jan 1997;51 Suppl 1:S49-53. doi:
  32. Jansen T, Romiti R, Kreuter A, et al. Rosacea fulminans triggered by high-dose vitamins B6 and B12. J Eur Acad Dermatol Venereol. Sep 2001;15(5):484-485. doi:
  33. Rampersaud GC, Kauwell GP, Bailey LB. Folate: a key to optimizing health and reducing disease risk in the elderly. J Am Coll Nutr. Feb 2003;22(1):1-8. doi:
  34. McArthur JO, Tang H, Petocz P, et al. Biological variability and impact of oral contraceptives on vitamins B(6), B(12) and folate status in women of reproductive age. Nutrients. Sep 2013;5(9):3634-3645. doi: 10.3390/nu5093634
  35. Institute of Medicine. Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline. Available at: http://www.ncbi.nlm.nih.gov/books/NBK114310/. 1998 Accessed July 23, 2014.

Consumer Information

How It Works

Bottom Line: Vitamin B12, in combination with folate and vitamin B6, may reduce breast cancer risk.
Vitamin B12 is involved in 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. Drugs that reduce stomach acid secretion or production of intrinsic factor can reduce B12 absorption. Other drugs such as metformin or oral contraceptives may also decrease B12 absorption. High levels of folic acid intake may mask a B12 deficiency. Patients should discuss supplement use with their physicians.

Purported Uses
  • 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 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.
  • Breast cancer
    Some studies show a reduction in breast cancer risk with vitamin B12 when used in combination with folate and B6.
  • Cognitive function
    Neither B12 supplementation alone or in combination with folic acid showed any improvement in cognitive function in a clinical study.
  • Fatigue
    In those without a vitamin B12 deficiency, there is little indication in the medical literature that B12 supplementation can improve fatigue symptoms.
  • Stroke
    Two large-scales studies do not support this use.
  • Lung cancer
    Findings from one study suggest that B12 levels have no effect on the risk of lung cancer.
Research Evidence

Improving cognitive function
A randomized placebo-controlled clinical trial found that neither B12 supplementation alone or in combination with folate showed any improvement in cognitive function.

Breast cancer prevention

In a large study of nurses who were followed for a longer period of time, higher blood levels of folate were linked to lower breast cancer risk, especially in postmenopausal women and those with moderate alcohol consumption. Premenopausal women with the highest plasma B12 levels also had a lower breast cancer risk. The findings suggest that foods rich in folate and B6 may contribute to a reduction in risk of breast cancer.

Do Not Take If
  • You are undergoing a coronary stenting procedure: Vitamin B12 may increase the risk of narrowing blood vessels after coronary stenting.
Side Effects
  • A case of rosacea fulminans (a skin condition) following consumption of high doses of B-6 and B-12 for 2 weeks has been reported.
Special Point
  • Several classes of medications can decrease the body’s ability to absorb vitamin B12. These include: drugs to treat gastric disorders/reduce stomach acid, some diabetes medications, and oral contraceptives.
  • Taking large amounts of folic acid may mask B12 deficiency symptoms.
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