Vitamin B12

Purported Benefits, Side Effects & More
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Vitamin B12

Purported Benefits, Side Effects & More
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Vitamin B12

Common Names

  • Cyanocobalamin
  • Cobalamin

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For Patients & Caregivers

Tell your healthcare providers about any dietary supplements you’re taking, such as herbs, vitamins, minerals, and natural or home remedies. This will help them manage your care and keep you safe.

What is it?

Vitamin B12 is found in many foods. For those who may not get enough, a healthcare provider can identify and appropriately treat deficiencies.

Vitamin B12 is involved in the synthesis of phospholipids, neurotransmitters, DNA, and the metabolism of fatty acids and amino acids. 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. However, findings are mixed on whether long-term supplementation with this combination improves fracture risk or medical conditions even when it lowers homocysteine levels. Data on whether this supplement combination can lower cancer risk are also mixed.

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. Also, high folic acid intake may mask a B12 deficiency, so it's important for patients to discuss any supplement use with their physicians.

What are the potential uses and benefits?
  • 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.
  • Cancer prevention

    Studies are mixed on whether vitamin B12 in combination with folate and B6 can reduce cancer risk, and it may increase risk of lung or colorectal cancers. Additional studies are needed to determine how vitamin B12 levels may affect cancer risk.
  • Fatigue

    In those without a vitamin B12 deficiency, there is little indication in the medical literature that B12 supplementation can improve fatigue symptoms.
What are the side effects?
  • Acute skin irritation: Reported with high doses of B6 and B12 for 2 weeks.
What else do I need to know?

Do Not Take if:

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

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 malabsorption syndromes (2) or those who 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, such combined supplementation did not reduce depression risk among middle-age and older women 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 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). Long-term B12 and folic acid supplementation also had no effect on arterial stiffness and atherosclerosis in elderly patients with hyperhomocysteinemia (42), and a meta-analysis suggests that evidence for cardiovascular preventive benefits with B-vitamins is lacking (61).

In other studies, B12 did not improve cognitive function (16) (17) (18) (19) (45) (47) (56), but may positively affect gait and physical performance in the elderly (48), or reduce analgesic use in patients with postherpetic neuralgia (59).

Studies of B vitamin supplementation for cancer prevention are also mixed (20) (21) (22) (23) (25), and long-term supplementation may actually increase risk for lung or colorectal cancers (53) (54).

Preliminary data suggest B12 supplementation may help reduce pain and improve quality of life in patients with aromatase inhibitor-associated musculoskeletal symptoms (62). However, individual B12 or iron supplement use during chemotherapy may be significantly associated with poorer outcomes (63). Additional studies are needed to elucidate these findings.

Food Sources
  • Meat
  • Poultry
  • Fish
  • Shellfish
  • Dairy
  • Fortified cereals
Purported Uses and Benefits
  • Anemia
  • B12 deficiency
  • Cancer
  • Cardiovascular disease
  • Cognition
  • Fatigue
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 reports
Rosacea fulminans: In a 17-year-old girl after consumption of high doses of vitamins B6 and 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 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.
  2. Hannibal L, DiBello PM, Jacobsen DW. Proteomics of vitamin B12 processing. Clin Chem Lab Med. Mar 1 2013;51(3):477-488.
  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.
  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.
  5. Buvat DR. Use of metformin is a cause of vitamin B12 deficiency. Am Fam Physician. Jan 15 2004;69(2):264.
  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.
  7. Allen LH. How common is vitamin B-12 deficiency? Am J Clin Nutr. Feb 2009;89(2):693S-696S.
  8. Oh R, Brown DL. Vitamin B12 deficiency. Am Fam Physician. Mar 1 2003;67(5):979-986.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
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  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  31. Scott JM. Bioavailability of vitamin B12. Eur J Clin Nutr. Jan 1997;51 Suppl 1:S49-53.
  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.
  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.
  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.
  35. Institute of Medicine. Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline. Washington (DC): National Academies Press (US). 1998, National Academy of Sciences.
  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.
  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 Oct 20;35(30):3440-3448.
  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. 2019 Feb;28(2):275-282.
  55. Harada Y, Komori I, Morinaga K, Shimizu T. Microangiopathic haemolytic anaemia with thrombocytopenia induced by vitamin B12 deficiency long term after gastrectomy. BMJ Case Rep. 2018 Sep 19;2018.
  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.
  57. Thomas S, Thomas T, Bosch RJ, et al. Effect of Maternal Vitamin B12 Supplementation on Cognitive Outcomes in South Indian Children: A Randomized Controlled Clinical Trial. Matern Child Health J. 2019 Feb;23(2):155-163.
  58. Nozari E, Ghavamzadeh S, Razazian N. The Effect of Vitamin B12 and Folic Acid Supplementation on Serum Homocysteine, Anemia Status and Quality of Life of Patients with Multiple Sclerosis. Clin Nutr Res. 2019 Jan 25;8(1):36-45.
  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.
  60. Sil A, Kumar H, Mondal RD, et al. A randomized, open labeled study comparing the serum levels of cobalamin after three doses of 500 mcg vs. a single dose methylcobalamin of 1500 mcg in patients with peripheral neuropathy. Korean J Pain. 2018 Jul;31(3):183-190.
  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.
  62. Campbell A, Heydarian R, Ochoa C, Dwivedi AK, Nahleh ZA. Single arm phase II study of oral vitamin B12 for the treatment of musculoskeletal symptoms associated with aromatase inhibitors in women with early stage breast cancer. Breast J. 2018 May;24(3):260-268.
  63. Ambrosone CB, Zirpoli GR, Hutson AD, et al. Dietary Supplement Use During Chemotherapy and Survival Outcomes of Patients With Breast Cancer Enrolled in a Cooperative Group Clinical Trial (SWOG S0221). J Clin Oncol. Mar 10 2020;38(8):804-814.
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