Vitamin B12

Vitamin B12, Cyanocobalamin, Cobalamin, B12

Common Names

  • Cyanocobalamin
  • Cobalamin

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For Patients & Caregivers

Vitamin B12, in combination with folate and vitamin B6, may reduce the risk for some cancers, but not others.

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, a 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.
  • Cognitive function
    Studies do not show benefit with B12 supplementation alone or in combination with folic acid for cognitive functioning.
  • 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.

  • You are undergoing a coronary stenting procedure: Vitamin B12 may increase the risk of narrowing blood vessels after coronary stenting.

  • A case of rosacea fulminans (a skin condition) following consumption of high doses of B6 and B12 for 2 weeks has been reported.
  • 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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For Healthcare Professionals

Cyanocobalamin

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 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). 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, combination supplementation with B12, B6, and folic acid may actually 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, this combination homocysteine-lowering supplementation over 7 years’ average treatment duration did not result in reduced depression risk compared with placebo, despite significant homocysteine level reductions (41).

Homocystene-lowering therapy may have some cardiovascular benefits after coronary interventions (11), but does not appear to reduce 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 hyperhomocysteinemic elderly patients also had no effect on arterial stiffness and atherosclerosis (42). In a long-term field study of individuals residing in India at high altitude however, B12 and folic acid supplementation reduced thrombosis incidence (43). A large study of B12, folic acid, and B6 supplementation to prevent recurrent ischemic stroke among a large Chinese population is underway (44).

B12 as part of homocysteine-lowering therapy or B12 repletion therapy (45) does not improve cognitive function (16) (17) (18) (19), even though low-normal B12 concentrations are associated with poorer memory performance (46). This was further echoed in secondary data from the aforementioned B-PROOF study which showed improving homocysteine levels does not improve cognitive outcomes (47), although the intervention may positvely affect gait and physical performance in the elderly (48).

Increased intake of B12, folate and B6 may lower the risks for 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 appeared to be mediated by folic acid. Dietary intake of folate and B12 during pregnancy is 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 reduces toxicity of pemetrexed chemotherapy in patients with non-small cell lung cancer (27), and may also help to improve treatment efficacy (28) (29), whereas oral administration of vitamin B12 for this purpose does not (50).

A large Danish population study identified high plasma B12 levels as related to elevated risks for hematological, smoking-related, and alcohol-related cancers (51) and that cancer patients with elevated B12 levels had higher mortality than those with normal values (52). However, such elevations are probably are due to changes in cobalamin metabolism caused by the cancer. It does not suggest that B12 supplementation can cause cancer.

  • Meat
  • Poultry
  • Fish
  • Shellfish
  • Dairy
  • Fortified cereals
  • B12 deficiency
  • Breast cancer
  • Cardiovascular disease
  • Cognitive function
  • Fatigue
  • Lung cancer
  • Pernicious anemia
  • Stroke

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).

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

Case report
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).

  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.

  36. Glaser TS, Doss LE, Shih G, et al. The Association of Dietary Lutein plus Zeaxanthin and B Vitamins with Cataracts in the Age-Related Eye Disease Study: AREDS Report No. 37. Ophthalmology. Jul 2015;122(7):1471-1479.

  37. Christen WG, Glynn RJ, Chew EY, et al. Folic Acid, Vitamin B6, and Vitamin B12 in Combination and Age-Related Cataract in a Randomized Trial of Women. Ophthalmic Epidemiol. 2016;23(1):32-39.

  38. Enneman AW, Swart KM, van Wijngaarden JP, et al. Effect of Vitamin B12 and Folic Acid Supplementation on Bone Mineral Density and Quantitative Ultrasound Parameters in Older People with an Elevated Plasma Homocysteine Level: B-PROOF, a Randomized Controlled Trial. Calcif Tissue Int. May 2015;96(5):401-409.

  39. van Wijngaarden JP, Swart KM, Enneman AW, et al. Effect of daily vitamin B-12 and folic acid supplementation on fracture incidence in elderly individuals with an elevated plasma homocysteine concentration: B-PROOF, a randomized controlled trial. Am J Clin Nutr. Dec 2014;100(6):1578-1586.

  40. Almeida OP, Ford AH, Hirani V, et al. B vitamins to enhance treatment response to antidepressants in middle-aged and older adults: results from the B-VITAGE randomised, double-blind, placebo-controlled trial. Br J Psychiatry. Dec 2014;205(6):450-457.

  41. Okereke OI, Cook NR, Albert CM, et al. Effect of long-term supplementation with folic acid and B vitamins on risk of depression in older women. Br J Psychiatry. Apr 2015;206(4):324-331.

  42. van Dijk SC, Enneman AW, Swart KM, et al. Effects of 2-year vitamin B12 and folic acid supplementation in hyperhomocysteinemic elderly on arterial stiffness and cardiovascular outcomes within the B-PROOF trial. J Hypertens. Sep 2015;33(9):1897-1906; discussion 1906.

  43. Kotwal J, Kotwal A, Bhalla S, et al. Effectiveness of homocysteine lowering vitamins in prevention of thrombotic tendency at high altitude area: A randomized field trial. Thromb Res. Oct 2015;136(4):758-762.

  44. Liu X, Shi M, Xia F, et al. The China Stroke Secondary Prevention Trial (CSSPT) protocol: a double-blinded, randomized, controlled trial of combined folic acid and B vitamins for secondary prevention of stroke. Int J Stroke. Feb 2015;10(2):264-268.

  45. Dangour AD, Allen E, Clarke R, et al. Effects of vitamin B-12 supplementation on neurologic and cognitive function in older people: a randomized controlled trial. Am J Clin Nutr. Sep 2015;102(3):639-647.

  46. Kobe T, Witte AV, Schnelle A, et al. Vitamin B-12 concentration, memory performance, and hippocampal structure in patients with mild cognitive impairment. Am J Clin Nutr. Apr 2016;103(4):1045-1054.

  47. van der Zwaluw NL, Dhonukshe-Rutten RA, van Wijngaarden JP, et al. Results of 2-year vitamin B treatment on cognitive performance: secondary data from an RCT. Neurology. Dec 2 2014;83(23):2158-2166.

  48. Swart KM, Ham AC, van Wijngaarden JP, et al. A Randomized Controlled Trial to Examine the Effect of 2-Year Vitamin B12 and Folic Acid Supplementation on Physical Performance, Strength, and Falling: Additional Findings from the B-PROOF Study. Calcif Tissue Int. Jan 2016;98(1):18-27.

  49. Bailey HD, Miller M, Langridge A, et al. Maternal dietary intake of folate and vitamins B6 and B12 during pregnancy and the risk of childhood acute lymphoblastic leukemia. Nutr Cancer. 2012;64(7):1122-1130.

  50. Takagi Y, Hosomi Y, Nagamata M, et al. Phase II study of oral vitamin B12 supplementation as an alternative to intramuscular injection for patients with non-small cell lung cancer undergoing pemetrexed therapy. Cancer Chemother Pharmacol. Mar 2016;77(3):559-564.

  51. Arendt JF, Pedersen L, Nexo E, et al. Elevated plasma vitamin B12 levels as a marker for cancer: a population-based cohort study. J Natl Cancer Inst. Dec 4 2013;105(23):1799-1805.

  52. Arendt JF, Farkas DK, Pedersen L, et al. Elevated plasma vitamin B12 levels and cancer prognosis: A population-based cohort study. Cancer Epidemiol. Feb 2016;40:158-165.

  53. Brasky TM, White E, Chen CL. Long-Term, Supplemental, One-Carbon Metabolism-Related Vitamin B Use in Relation to Lung Cancer Risk in the Vitamins and Lifestyle (VITAL) Cohort. J Clin Oncol. 2017 Aug 22:JCO2017727735. doi: 10.1200/JCO.2017.72.7735. [Epub ahead of print]

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