Vitamin B12

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Vitamin B12

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Vitamin B12, Cyanocobalamin, Cobalamin, B12

Common Names

  • Cyanocobalamin
  • Cobalamin

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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.

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 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.
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) has been reported following consumption of high doses of B6 and B12 for 2 weeks.
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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For Healthcare Professionals

Scientific Name
Cyanocobalamin
Clinical Summary

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.

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 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).

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 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.

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 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).

Dosage (OneMSK Only)
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:

  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

  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

  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.

  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.

  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.

  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.

  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]

  54. Araghi SO, Kiefte-de Jong JC, Van Dijk SC, et al. Folic Acid and Vitamin B12 Supplementation and the Risk of Cancer: Long-term Follow-up of the B Vitamins for the Prevention of Osteoporotic Fractures (B-PROOF) Trial. Cancer Epidemiol Biomarkers Prev. DOI:10.1158/1055-9965.EPI-17-1198. Epub February 2019.

  56. Rutjes AW, Denton DA, Di Nisio M, et al. Vitamin and mineral supplementation for maintaining cognitive function in cognitively healthy people in mid and late life. Cochrane Database Syst Rev. 2018 Dec 17;12:CD011906.

  59. Wang JY, Wu YH, Liu SJ, Lin YS, Lu PH. Vitamin B12 for herpetic neuralgia: A meta-analysis of randomised controlled trials. Complement Ther Med. 2018 Dec;41:277-282.

  61. Jenkins DJA, Spence JD, Giovannucci EL, et al. Supplemental Vitamins and Minerals for CVD Prevention and Treatment. J Am Coll Cardiol. 2018 Jun 5;71(22):2570-2584.
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