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What is it?


Vitamin B12 is an essential water-soluble nutrient that can be converted to the active coenzymes, methylcobalamin and adenosylcobalamin. It is also a cofactor for methionine synthase and l-methylmalonyl-CoA mutase, which synthesize methionine from homocysteine, and convert methylmalonyl coenzyme A to succinyl coenzyme A, respectively. It is crucial for the formation of DNA and red blood cells, and proper neurological function. (16)(18)(34)

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Main uses

Autoimmune conditions (Celiac’s disease)
B12 deficiency prevention
Homocysteine management
Neurological conditions
Neuropathy and pain-related conditions


2-5% bioavailability (1,000 μg hydroxocobalamin) compared to intramuscular administration but retention is 50% higher (29)(31)
10-20x higher plasma B12 with nasal hydroxocobalamin (750-1,500 μg) than oral administration (31)
2% bioavailability, 5% bioavailability (5,000 μg cyanocobalamin) in formulation with the addition of SNAC at compared to intravenous administration (6)
Equivalent retention between forms of varying doses of cyanocobalamin, methylcobalamin, & hydroxocobalamin (1, 5, & 25 μg) (1)
B12 increased more in hydroxocobalamin (500-1,000 μg) than cyanocobalamin via 33-44% higher relative retention (12)
Equal increase in serum cobalamin to the oral group (500 μg cyanocobalamin) (25)

Dosing & administration

Adverse effects

Adverse effects from B12 intake and supplementation are atypical. (16) Intravenous administration may produce reddening of the skin, pustular/papular rash, headaches, erythema at the injection site, decrease in lymphocyte percentage, nausea, pruritus, chest discomfort, dysphagia, and increased blood pressure in some volunteers. (30)



  • Oral absorption is low. Total B12 absorption increases with increasing doses, but relative absorption decreases (eg. absorption of 50% of 1 μg, 20% of 5 μg, 5% of 25 μg, and 1% 500 μg). Small amounts absorbed are often sufficient to meet the recommended daily allowance. 
  • B12 bound to proteins in food are uncoupled by stomach acid and pepsin to allow for binding to R proteins. B12 supplements are not bound to proteins and thus more available for R protein binding for gastric transport. 
  • Upon contact with pancreatic proteases, B12 is released from R proteins, and small amounts of free B12 in high concentrations can be absorbed through passive diffusion in the small intestine. In low concentrations, the majority of B12 binds to intrinsic factor allowing active transport in the mucosa of the ileum. (23)


  • B12 circulates through the blood after binding to transcobalamin I, II, or III. 
  • Most is bound to transcobalamin I but transcobalamin II is primarily responsible for deposition in most peripheral tissues. 
  • The liver stores 50% of circulating B12 and may hold 2-3 mg. (16)


  • Upon transport into peripheral tissue cells, lysosomes disassociate B12 from transcobalamin II. 
  • All B12 forms are then reduced in cytosol to the core form, cobalamin. 
  • Cobalamin is either methylated to the active cofactor, methylcobalamin, using 5-MTHF or SAMe, or it can enter the mitochondria to combine with adenosyl from ATP molecules to form the active cofactor, adenosylcobalamin. (23)
  • Methylcobalamin and vitamin B6 are used to reduce homocysteine and produce methionine, tetrahydrofolate, and subsequently, purines and pyrimidines used in RNA and DNA synthesis. (17)(19)(26)
  • Adenosylcobalamin is used by methylmalonyl CoA mutase to convert methylmalonyl CoA to Succinyl CoA, which enters the Krebs cycle. (23)


  • B12 is primarily excreted in stool, but can be excreted in urine if blood is saturated. (16)
  • Between 1.4-5.1 μg are lost each day in healthy and elderly individuals. (10)
  1. Adams, J. F., Ross, S. K., Mervyn, L., Boddy, K., & King, P. (1971). Absorption of cyanocobalamin, coenzyme B12, methylcobalamin, and hydroxocobalamin at different dose levels. Scandinavian Journal of Gastroenterology, 6(3), 249-252. ()
  2. Andrès, E., Zulfiqar, A. A., Serraj, K., Vogel, T., & Kaltenbach, G. (2018). Systematic review and pragmatic clinical approach to oral and nasal vitamin B12 (cobalamin) treatment in patients with vitamin B12 deficiency related to gastrointestinal disorders. Journal of Clinical Medicine, 7(10), 304. ()
  3. Bahadir, A., Reis, P. G., & Erduran, E. (2014). Oral vitamin B 12 treatment is effective for children with nutritional vitamin B 12 deficiency. Journal of Paediatrics and Child Health, 50(9), 721-725. ()
  4. Bertoglio, K., Jill James, S., Deprey, L., Brule, N., & Hendren, R. L. (2010). Pilot study of the effect of methyl B12 treatment on behavioral and biomarker measures in children with autism. The Journal of Alternative and Complementary Medicine, 16(5), 555-560. ()
  5. Bryan, J., Calvaresi, E., & Hughes, D. (2002). Short-term folate, vitamin B-12 or vitamin B-6 supplementation slightly affects memory performance but not mood in women of various ages. The Journal of Nutrition, 132(6), 1345-1356. ()
  6. Castelli, M. C., Wong, D. F., Friedman, K., & Riley, M. G. I. (2011). Pharmacokinetics of oral cyanocobalamin formulated with sodium N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC): An open-label, randomized, single-dose, parallel-group study in healthy male subjects. Clinical Therapeutics, 33(7), 934-945. ()
  7. Chan, C. Q. H., Low, L. L., & Lee, K. H. (2016). Oral vitamin B12 replacement for the treatment of pernicious anemia. Frontiers in Medicine, 3, 38. ()
  8. Deshmukh, U. S., Joglekar, C. V., Lubree, H. G., Ramdas, L. V., Bhat, D. S., Naik, S. S., ... & Jackson, A. A. (2010). Effect of physiological doses of oral vitamin B 12 on plasma homocysteine: A randomized, placebo-controlled, double-blind trial in India. European Journal of Clinical Nutrition, 64(5), 495-502. ()
  9. Devathasan, G., Teo, W. L., & Mylvaganam, A. (1986). Methylcobalamin (Methycobal) in chronic diabetic neuropathy: A double-blind clinical and electrophysiological study. Clinical Trials Journal, 23(2), 130-140. ()
  10. Doets, E. L., Szczecińska, A., Dhonukshe-Rutten, R. A., Cavelaars, A. E., van't Veer, P., Brzozowska, A., & de Groot, L. C. (2013). Systematic review on daily vitamin B12 losses and bioavailability for deriving recommendations on vitamin B12 intake with the factorial approach. Annals of Nutrition and Metabolism, 62(4), 311-322. ()
  11. Ellis, F. R., & Nasser, S. (1973). A pilot study of vitamin B 12 in the treatment of tiredness. British Journal of Nutrition, 30(2), 277-283. ()
  12. Glass, G. B. J., Skeggs, H. R., Lee, D. H., Jones, E. L., & Hardy, W. W. (1961). Hydroxocobalamin. I. Blood levels and urinary excretion of vitamin B12 in man after a single parenteral dose of aqueous hydroxocobalamin, aqueous cyanocobalamin and cyanocobalamin zinc-tannate complex. Blood, 18(5), 511-521. ()
  13. Hallert, C., Svensson, M., Tholstrup, J., & Hultberg, B. (2009). Clinical trial: B vitamins improve health in patients with coeliac disease living on a gluten‐free diet. Alimentary Pharmacology & Therapeutics, 29(8), 811-816. ()
  14. Hendren, R. L., James, S. J., Widjaja, F., Lawton, B., Rosenblatt, A., & Bent, S. (2016). Randomized, placebo-controlled trial of methyl B12 for children with autism. Journal of Child and Adolescent Psychopharmacology, 26(9), 774-783. ()
  15. Hoey, L., Strain, J. J., & McNulty, H. (2009). Studies of biomarker responses to intervention with vitamin B-12: A systematic review of randomized controlled trials. The American Journal of Clinical Nutrition, 89(6), 1981S-1996S. ()
  16. Institute of Medicine. (1998). Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. National Academies Press (US). Retrieved from ()
  17. Kirsch, S. H., Herrmann, W., Kruse, V., Eckert, R., Gräber, S., Geisel, J., & Obeid, R. (2015). One year B-vitamins increases serum and whole blood folate forms and lowers plasma homocysteine in older Germans. Clinical Chemistry and Laboratory Medicine (CCLM), 53(3), 445-452. ()
  18. Klee, G. C. (2000). Cobalamin and folate evaluation: Measurement of methylmalonic acid and homocysteine vs vitamin b12 and folate. Clinical Chemistry, 46(8), 1277-1283. ()
  19. Lea, R., Colson, N., Quinlan, S., Macmillan, J., & Griffiths, L. (2009). The effects of vitamin supplementation and MTHFR (C677T) genotype on homocysteine-lowering and migraine disability. Pharmacogenetics and Genomics, 19(6), 422-428. ()
  20. Mahawar, K. K., Reid, A., Graham, Y., Callejas-Diaz, L., Parmar, C., Carr, W. R., ... & Small, P. K. (2018). Oral vitamin B 12 supplementation after Roux-en-Y gastric bypass: A systematic review. Obesity Surgery, 28(7), 1916-1923. ()
  21. Obeid, R., Fedosov, S. N., & Nexo, E. (2015). Cobalamin coenzyme forms are not likely to be superior to cyano‐and hydroxyl‐cobalamin in prevention or treatment of cobalamin deficiency. Molecular Nutrition & Food Research, 59(7), 1364-1372. ()
  22. Obersby, D., Chappell, D., Tsiami, A. A., & Dunnett, A. (2015). Efficacy of methylcobalamin to normalise elevated homocysteine of vitamin B12 deficient vegetarians: A double blind placebo control study. Current Research in Nutrition and Food Science, 3(3), 187-196. ()
  23. Paul, C., & Brady, D. M. (2017). Comparative bioavailability and utilization of particular forms of B12 supplements with potential to mitigate B12-related genetic polymorphisms. Integrative Medicine: A Clinician's Journal, 16(1), 42. ()
  24. Paulin, F. V., Zagatto, A. M., Chiappa, G. R., & de Tarso Müller, P. (2017). Addition of vitamin B12 to exercise training improves cycle ergometer endurance in advanced COPD patients: A randomized and controlled study. Respiratory Medicine, 122, 23-29. ()
  25. Sharabi, A., Cohen, E., Sulkes, J., & Garty, M. (2003). Replacement therapy for vitamin B12 deficiency: comparison between the sublingual and oral route. British Journal of Clinical Pharmacology, 56(6), 635-638. ()
  26. Shipton, M. J., & Thachil, J. (2015). Vitamin B12 deficiency–A 21st century perspective. Clinical Medicine, 15(2), 145-150. ()
  27. Smelt, H. J., Pouwels, S., & Smulders, J. F. (2017). Different supplementation regimes to treat perioperative vitamin B12 deficiencies in bariatric surgery: A systematic review. Obesity Surgery, 27(1), 254-262. ()
  28. Strand, T. A., Taneja, S., Kumar, T., Manger, M. S., Refsum, H., Yajnik, C. S., & Bhandari, N. (2015). Vitamin B-12, folic acid, and growth in 6-to 30-month-old children: A randomized controlled trial. Pediatrics, 135(4), e918-e926. ()
  29. Tillemans, M. P., Donders, E. M., Verweij, S. L., Van der Hoeven, R. T., & Kalisvaart, K. J. (2014). Effect of administration route on the pharmacokinetics of cobalamin in elderly patients: A randomized controlled trial. Current Therapeutic Research, 76, 21-25. ()
  30. Uhl, W., Nolting, A., Golor, G., Ludwig Rost, K., & Kovar, A. (2006). Safety of hydroxocobalamin in healthy volunteers in a randomized, placebo-controlled study. Clinical Toxicology, 44(1), 17-28. ()
  31. Van Asselt, D. Z. B., Merkus, F. W. H. M., Russel, F. G. M., & Hoefnagels, W. H. L. (1998). Nasal absorption of hydroxocobalamin in healthy elderly adults. British Journal of Clinical Pharmacology, 45(1), 83-86. ()
  32. Volkov, I., Rudoy, I., Freud, T., Sardal, G., Naimer, S., Peleg, R., & Press, Y. (2009). Effectiveness of vitamin B12 in treating recurrent aphthous stomatitis: a randomized, double-blind, placebo-controlled trial. The Journal of the American Board of Family Medicine, 22(1), 9-16. ()
  33. Wade, D. T., Young, C. A., Chaudhuri, K. R., & Davidson, D. L. W. (2002). A randomised placebo controlled exploratory study of vitamin B-12, lofepramine, and L-phenylalanine (the “Cari Loder regime”) in the treatment of multiple sclerosis. Journal of Neurology, Neurosurgery & Psychiatry, 73(3), 246-249. ()
  34. Watanabe, F. (2007). Vitamin B12 sources and bioavailability. Experimental Biology and Medicine, 232(10), 1266-1274. ()
  35. Yaqub, B. A., Siddique, A., & Sulimani, R. (1992). Effects of methylcobalamin on diabetic neuropathy. Clinical Neurology and Neurosurgery, 94(2), 105-111. ()

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