Vitamin B12#Absorption

Vitamin B₁₂ is a coordination complex of cobalt, which occupies the center of a corrin ligand and is further bound to a benzimidazole ligand and adenosyl group.{{cite book |doi=10.1007/3418_004|chapter=Biological Organometallic Chemistry of B12|title=Bioorganometallic Chemistry|series=Topics in Organometallic Chemistry|year=2006| vauthors = Butler P, Kräutler B |volume=17|pages=1–55|isbn=3-540-33047-X}} Several related species behave similarly to function as vitamins. This collection of compounds is sometimes referred to as "cobalamins". These chemical compounds have a similar molecular structure, each of which shows vitamin activity in a vitamin-deficient biological system. They are referred to as vitamers having vitamin activity as a coenzyme, meaning that its presence is required for some enzyme-catalyzed reactions.

• adenosylcobalamin
• cyanocobalamin, the adenosyl ligand in vitamin B₁₂ is replaced by cyanide.
• hydroxocobalamin, the adenosyl ligand in vitamin B₁₂ is replaced by hydroxide.
• methylcobalamin, the adenosyl ligand in vitamin B₁₂ is replaced by methyl.

Cyanocobalamin is a manufactured form of B₁₂. Bacterial fermentation creates AdoB₁₂ and MeB₁₂, which are converted to cyanocobalamin by the addition of potassium cyanide in the presence of sodium nitrite and heat. Once consumed, cyanocobalamin is converted to the biologically active AdoB₁₂ and MeB₁₂. The two bioactive forms of vitamin {{chem|B|12}} are methylcobalamin in cytosol and adenosylcobalamin in mitochondria.{{cite journal | vauthors = Moravcová M, Siatka T, Krčmová LK, Matoušová K, Mladěnka P | title = Biological properties of vitamin B₁₂ | journal = Nutrition Research Reviews | volume = 38 | issue = 1 | pages = 338–370 | date = June 2025 | pmid = 39376196 | doi = 10.1017/S0954422424000210 | doi-access = free }}

Cyanocobalamin is the most common form used in dietary supplements and food fortification because cyanide stabilizes the molecule against degradation. Methylcobalamin is also offered as a dietary supplement. There is no advantage to the use of adenosylcobalamin or methylcobalamin forms for the treatment of vitamin B₁₂ deficiency.{{cite journal | vauthors = Obeid R, Fedosov SN, Nexo E | title = Cobalamin coenzyme forms are not likely to be superior to cyano- and hydroxyl-cobalamin in prevention or treatment of cobalamin deficiency | journal = Molecular Nutrition & Food Research | volume = 59 | issue = 7 | pages = 1364–1372 | date = July 2015 | pmid = 25820384 | pmc = 4692085 | doi = 10.1002/mnfr.201500019 }}

Hydroxocobalamin can be injected intramuscularly to treat vitamin B₁₂ deficiency.{{cite journal |vauthors=Wang H, Li L, Qin LL, Song Y, Vidal-Alaball J, Liu TH |title=Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency |journal=The Cochrane Database of Systematic Reviews |volume=3 |issue=3 |pages=CD004655 |date=March 2018 |pmid=29543316 |pmc=6494183 |doi=10.1002/14651858.CD004655.pub3}} It can also be injected intravenously for the purpose of treating cyanide poisoning, as the hydroxyl group is displaced by cyanide, creating a non-toxic cyanocobalamin that is excreted in urine.{{cite web |title=Hydroxocobalamin (injection) |url=https://www.drugs.com/mtm/hydroxocobalamin-injection.html |publisher=Drugs.com |access-date=15 May 2025 |date=14 August 2023}}

Pseudovitamin B₁₂ refers to compounds that are corrinoids with a structure similar to the vitamin, but without vitamin activity.{{cite journal | vauthors = Watanabe F, Bito T | title = Determination of Cobalamin and Related Compounds in Foods | journal = Journal of AOAC International | volume = 101 | issue = 5 | pages = 1308–1313 | date = September 2018 | pmid = 29669618 | doi = 10.5740/jaoacint.18-0045 | s2cid = 4978703 }} Pseudovitamin B₁₂ is the majority corrinoid in spirulina, an algal dietary supplement sometimes erroneously claimed as having this vitamin activity.{{cite journal | vauthors = Watanabe F, Katsura H, Takenaka S, Fujita T, Abe K, Tamura Y, Nakatsuka T, Nakano Y | title = Pseudovitamin B(12) is the predominant cobamide of an algal health food, spirulina tablets | journal = Journal of Agricultural and Food Chemistry | volume = 47 | issue = 11 | pages = 4736–4741 | date = November 1999 | pmid = 10552882 | doi = 10.1021/jf990541b | bibcode = 1999JAFC...47.4736W }}

Antivitamin B₁₂ compounds (often synthetic B₁₂ analogues) not only have no vitamin action, but also actively interfere with the activity of true vitamin B₁₂. The design of these compounds mainly involves the replacement of the metal ion with rhodium, nickel, or zinc, or may have an inactive ligand attached, such as 4-ethylphenyl. These compounds have the potential for use in analyzing B₁₂ pathways or even attacking B₁₂-dependent pathogens.{{cite journal |vauthors = Kräutler B |title = Antivitamins B₁₂ - Some Inaugural Milestones |journal = Chemistry: A European Journal |volume = 26 |issue = 67 |pages = 15438–15445 |date = December 2020 |pmid = 32956545 |pmc = 7756841 |doi = 10.1002/chem.202003788 }}

{{Main|Vitamin B12 deficiency|l1=Vitamin B₁₂ deficiency}}

Vitamin B₁₂ deficiency can potentially cause severe and irreversible damage, especially to the brain and nervous system.{{cite journal | vauthors = van der Put NM, van Straaten HW, Trijbels FJ, Blom HJ | s2cid = 29053617 | title = Folate, homocysteine and neural tube defects: an overview | journal = Experimental Biology and Medicine | volume = 226 | issue = 4 | pages = 243–270 | date = April 2001 | pmid = 11368417 | doi = 10.1177/153537020122600402 }} Deficiency at levels only slightly lower than normal can cause a range of symptoms such as fatigue, feeling weak, lightheadedness, dizziness, breathlessness, headaches, mouth ulcers, upset stomach, decreased appetite, difficulty walking (staggering balance problems),{{cite web|url=https://www.health.harvard.edu/blog/vitamin-b12-deficiency-can-be-sneaky-harmful-201301105780|title=Vitamin B12 deficiency can be sneaky, harmful| vauthors = Skerrett PJ |date=February 2019|website=Harvard Health Blog|access-date=6 January 2020|archive-url=https://web.archive.org/web/20191029144521/https://www.health.harvard.edu/blog/vitamin-b12-deficiency-can-be-sneaky-harmful-201301105780|archive-date=29 October 2019|url-status=live}} muscle weakness, depression, poor memory, poor reflexes, confusion, pale skin and feeling abnormal sensations, especially in people over age 60.{{cite web|url=http://www.nhs.uk/Conditions/Anaemia-vitamin-B12-and-folate-deficiency/Pages/Symptoms.aspx|title=Vitamin B₁₂ or folate deficiency anaemia – Symptoms|publisher=National Health Service, England|date=23 May 2019|access-date=6 January 2020|archive-url=https://web.archive.org/web/20170812125551/http://www.nhs.uk/Conditions/Anaemia-vitamin-B12-and-folate-deficiency/Pages/Symptoms.aspx|archive-date=12 August 2017|url-status=live}} Vitamin B₁₂ deficiency can also cause symptoms of mania and psychosis.{{cite journal | vauthors = Masalha R, Chudakov B, Muhamad M, Rudoy I, Volkov I, Wirguin I | title = Cobalamin-responsive psychosis as the sole manifestation of vitamin B12 deficiency | journal = The Israel Medical Association Journal | volume = 3 | issue = 9 | pages = 701–703 | date = September 2001 | pmid = 11574992 | url = http://www.ima.org.il/IMAJ/ViewArticle.aspx?year=2001&month=09&page=702 }} Among other problems, weakened immunity, reduced fertility and interruption of blood circulation in women may occur.{{cite journal | vauthors = Bennett M | title = Vitamin B12 deficiency, infertility and recurrent fetal loss | journal = The Journal of Reproductive Medicine | volume = 46 | issue = 3 | pages = 209–212 | date = March 2001 | pmid = 11304860 }}

The main type of vitamin B12 deficiency anemia is pernicious anemia,{{cite web|title=What Is Pernicious Anemia?|url=https://www.nhlbi.nih.gov/health/health-topics/topics/prnanmia|website=NHLBI|access-date=14 March 2016|date=1 April 2011|url-status=live|archive-url=https://web.archive.org/web/20160314111724/https://www.nhlbi.nih.gov/health/health-topics/topics/prnanmia|archive-date=14 March 2016}} characterized by a triad of symptoms:

1. Anemia with bone marrow promegaloblastosis (megaloblastic anemia).{{cite book| vauthors = Bémeur C, Montgomery JA, Butterworth RF | chapter = Vitamins Deficiencies and Brain Function | pages = 103–124 (112) | veditors = Blass JP |title=Neurochemical Mechanisms in Disease | series = Advances in Neurobiology | year = 2011 | volume = 1 | doi = 10.1007/978-1-4419-7104-3_4 | isbn = 978-1-4419-7103-6 }} This is due to the inhibition of DNA synthesis (specifically purines and thymidine).{{medical citation needed|date=March 2025}}
2. Gastrointestinal symptoms: alteration in bowel motility, such as mild diarrhea or constipation, and loss of bladder or bowel control.{{cite journal|vauthors=Briani C, Dalla Torre C, Citton V, Manara R, Pompanin S, Binotto G, Adami F |date= November 2013|title=Cobalamin Deficiency: Clinical Picture and Radiological Findings|journal=Nutrients|volume=5|issue=11|pages=4521–4539|issn=2072-6643|doi=10.3390/nu5114521|pmid=24248213|pmc=3847746|doi-access= free}} These are thought to be due to defective DNA synthesis inhibiting replication in tissue sites with a high turnover of cells. This may also be due to the autoimmune attack on the parietal cells of the stomach in pernicious anemia. There is an association with gastric antral vascular ectasia (which can be referred to as watermelon stomach), and pernicious anemia.{{cite journal |title=Gastric Antral Vascular Ectasia (GAVE) Syndrome |vauthors=Amarapurka DN, Patel ND |url=http://japi.org/september2004/CR-756.pdf |journal=Journal of the Association of Physicians of India |volume=52 |date=September 2004 |page=757 |url-status=live |archive-url=https://web.archive.org/web/20160304064810/http://www.japi.org/september2004/CR-756.pdf |archive-date=4 March 2016 }}
3. Neurological symptoms: sensory or motor deficiencies (absent reflexes, diminished vibration or soft touch sensation) and subacute combined degeneration of the spinal cord.{{cite book| vauthors = Greenburg M |title=Handbook of Neurosurgery 7th Edition|year=2010|publisher=Thieme Publishers|location=New York|isbn=978-1-60406-326-4|pages=1187–1188}} Deficiency symptoms in children include developmental delay, regression, irritability, involuntary movements and hypotonia.{{cite book | vauthors = Lerner NB | chapter = Vitamin B12 Deficiency | veditors = Kliegman RM, Stanton B, St Geme J, Schor NF |title=Nelson Textbook of Pediatrics|isbn=978-1-4557-7566-8|pages=2319–2326|edition=20th|year=2016 | publisher = Elsevier Health Sciences }}

Vitamin B₁₂ deficiency is most commonly caused by malabsorption, but can also result from low intake, immune gastritis, low presence of binding proteins, or use of certain medications. Vegans—people who choose to not consume any animal-sourced foods—are at risk because plant-sourced foods do not contain the vitamin in sufficient amounts to prevent vitamin deficiency. Vegetarians—people who consume animal byproducts such as dairy products and eggs, but not the flesh of any animal—are also at risk. Vitamin B₁₂ deficiency has been observed in between 40% and 80% of the vegetarian population who do not also take a vitamin B₁₂ supplement or consume vitamin-fortified food.{{cite journal | vauthors = Pawlak R, Parrott SJ, Raj S, Cullum-Dugan D, Lucus D | title = How prevalent is vitamin B(12) deficiency among vegetarians? | journal = Nutrition Reviews | volume = 71 | issue = 2 | pages = 110–117 | date = February 2013 | pmid = 23356638 | doi = 10.1111/nure.12001 | doi-access = free }} In Hong Kong and India, vitamin B₁₂ deficiency has been found in roughly 80% of the vegan population. As with vegetarians, vegans can avoid this by consuming a dietary supplement or eating B₁₂ fortified food such as cereal, plant-based milks, and nutritional yeast as a regular part of their diet.{{cite journal | vauthors = Woo KS, Kwok TC, Celermajer DS | title = Vegan diet, subnormal vitamin B-12 status and cardiovascular health | journal = Nutrients | volume = 6 | issue = 8 | pages = 3259–3273 | date = August 2014 | pmid = 25195560 | pmc = 4145307 | doi = 10.3390/nu6083259 | doi-access = free }} The elderly are at increased risk because they tend to produce less stomach acid as they age, a condition known as achlorhydria, thereby increasing their probability of B₁₂ deficiency due to reduced absorption.

Nitrous oxide overdose or overuse converts the active monovalent form of vitamin B12 to the inactive bivalent form.{{cite journal |title=Nitrous oxide–induced vitamin B12 deficiency |date=2017 |pmc=5349816 |journal=Proceedings (Baylor University. Medical Center) |volume=30 |issue=2 |pages=171–172 |doi=10.1080/08998280.2017.11929571 |pmid=28405070 | vauthors = Stockton L, Simonsen C, Seago S }}

The U.S. Recommended Dietary Allowance (RDA) for pregnancy is {{value|2.6|u=micrograms per day (μg/d)}}, for lactation {{value|2.8|u=μg/day}}. Determination of these values was based on an RDA of {{value|2.4|u=μg/day}} for non-pregnant women, plus what will be transferred to the fetus during pregnancy and what will be delivered in breast milk.{{r|Obeid2017|p=972}} However, looking at the same scientific evidence, the European Food Safety Authority (EFSA) sets adequate intake (AI) at {{value|4.5|u=μg/day}} for pregnancy and {{value|5.0|u=μg/day}} for lactation.{{cite web| title = Overview on Dietary Reference Values for the EU population as derived by the EFSA Panel on Dietetic Products, Nutrition and Allergies| year = 2017| url = https://www.efsa.europa.eu/sites/default/files/assets/DRV_Summary_tables_jan_17.pdf| access-date = 28 August 2017| archive-url = https://web.archive.org/web/20200107010332/https://www.efsa.europa.eu/sites/default/files/assets/DRV_Summary_tables_jan_17.pdf| archive-date = 7 January 2020| url-status = live}} Low maternal vitamin B₁₂, defined as serum concentration less than 148 pmol/L, increases the risk of miscarriage, preterm birth and newborn low birth weight.{{cite journal |vauthors=Rogne T, Tielemans MJ, Chong MF, Yajnik CS, Krishnaveni GV, Poston L, et al. |title=Associations of Maternal Vitamin B12 Concentration in Pregnancy With the Risks of Preterm Birth and Low Birth Weight: A Systematic Review and Meta-Analysis of Individual Participant Data |journal=Am J Epidemiol |volume=185 |issue=3 |pages=212–223 |date=February 2017 |pmid=28108470 |pmc=5390862 |doi=10.1093/aje/kww212 }} During pregnancy the placenta concentrates B₁₂, so that newborn infants have a higher serum concentration than their mothers. As it is recently absorbed vitamin content that more effectively reaches the placenta, the vitamin consumed by the mother-to-be is more important than that contained in her liver tissue.{{cite journal |vauthors=Sebastiani G, Herranz Barbero A, Borrás-Novell C, Alsina Casanova M, Aldecoa-Bilbao V, Andreu-Fernández V, Pascual Tutusaus M, Ferrero Martínez S, Gómez Roig MD, García-Algar O |title=The Effects of Vegetarian and Vegan Diet during Pregnancy on the Health of Mothers and Offspring |journal=Nutrients |volume=11 |issue=3 |page= 557|date=March 2019 |pmid=30845641 |pmc=6470702 |doi=10.3390/nu11030557 |doi-access=free }}

Women who consume little animal-sourced food, or who are vegetarian or vegan, are at higher risk of becoming vitamin depleted during pregnancy than those who consume more animal products. This depletion can lead to anemia, and also an increased risk that their breastfed infants become vitamin deficient.{{cite journal | vauthors = Obeid R, Murphy M, Solé-Navais P, Yajnik C | title = Cobalamin Status from Pregnancy to Early Childhood: Lessons from Global Experience | journal = Advances in Nutrition | volume = 8 | issue = 6 | pages = 971–979 | date = November 2017 | pmid = 29141978 | pmc = 5683008 | doi = 10.3945/an.117.015628 }} Vitamin B₁₂ is not one of the supplements recommended by the World Health Organization for healthy women who are pregnant,{{cite journal | vauthors = Finkelstein JL, Fothergill A, Venkatramanan S, Layden AJ, Williams JL, Crider KS, Qi YP | title = Vitamin B12 supplementation during pregnancy for maternal and child health outcomes | journal = The Cochrane Database of Systematic Reviews | volume = 1 | issue = 1 | pages = CD013823 | date = January 2024 | pmid = 38189492 | pmc = 10772977 | doi = 10.1002/14651858.CD013823.pub2 | collaboration = Cochrane Pregnancy and Childbirth Group }} however, vitamin B₁₂ is often suggested during pregnancy in a multivitamin along with folic acid{{cite journal | vauthors = Wilson RD, O'Connor DL | title = Guideline No. 427: Folic Acid and Multivitamin Supplementation for Prevention of Folic Acid-Sensitive Congenital Anomalies | journal = Journal of Obstetrics and Gynaecology Canada | volume = 44 | issue = 6 | pages = 707–719.e1 | date = June 2022 | pmid = 35691683 | doi = 10.1016/j.jogc.2022.04.004 }}{{cite web |title=Nutrition During Pregnancy |url=https://www.acog.org/womens-health/faqs/nutrition-during-pregnancy |access-date=15 January 2024 |website=www.acog.org |language=en}} especially for pregnant mothers who follow a vegetarian or vegan diet.{{cite web |title=Pregnancy: Vegetarian Diet |url=https://myhealth.alberta.ca/Health/Pages/conditions.aspx?hwid=tn9108&lang=en-ca |access-date=15 January 2024 |website=myhealth.alberta.ca |language=en-US}}

Low vitamin concentrations in human milk occur in families with low socioeconomic status or low consumption of animal products.{{r|Obeid2017|pp=971,973}} Only a few countries, primarily in Africa, have mandatory food fortification programs for either wheat flour or maize flour; India has a voluntary fortification program. What the nursing mother consumes is more important than her liver tissue content, as it is recently absorbed vitamin that more effectively reaches breast milk.{{r|Obeid2017|p=973}} Breast milk B₁₂ decreases over months of nursing in both well-nourished and vitamin-deficient mothers.{{r|Obeid2017|pp=973–974}} Exclusive or near-exclusive breastfeeding beyond six months is a strong indicator of low serum vitamin status in nursing infants. This is especially true when the vitamin status is poor during the pregnancy and if the early-introduced foods fed to the still-breastfeeding infant are vegan.{{r|Obeid2017|pp=974–975}}

The risk of deficiency persists if the post-weaning diet is low in animal products.{{r|Obeid2017|pp=974–975}} Signs of low vitamin levels in infants and young children can include anemia, poor physical growth, and neurodevelopmental delays.{{r|Obeid2017|pp=975}} Children diagnosed with low serum B₁₂ can be treated with intramuscular injections, then transitioned to an oral dietary supplement.{{r|Obeid2017|pp=976}}

Various methods of gastric bypass or gastric restriction surgery are used to treat morbid obesity. Roux-en-Y gastric bypass surgery (RYGB) but not sleeve gastric bypass surgery or gastric banding, increases the risk of vitamin B₁₂ deficiency and requires preventive post-operative treatment with either injected or high-dose oral supplementation.{{cite journal |vauthors=Weng TC, Chang CH, Dong YH, Chang YC, Chuang LM |title=Anaemia and related nutrient deficiencies after Roux-en-Y gastric bypass surgery: a systematic review and meta-analysis |journal=BMJ Open |volume=5 |issue=7 |pages=e006964 |date=July 2015 |pmid=26185175 |pmc=4513480 |doi=10.1136/bmjopen-2014-006964 }}{{cite journal |vauthors=Majumder S, Soriano J, Louie Cruz A, Dasanu CA |title=Vitamin B12 deficiency in patients undergoing bariatric surgery: preventive strategies and key recommendations |journal=Surg Obes Relat Dis |volume=9 |issue=6 |pages=1013–1019 |date=2013 |pmid=24091055 |doi=10.1016/j.soard.2013.04.017 }}{{cite journal |vauthors=Mahawar KK, Reid A, Graham Y, Callejas-Diaz L, Parmar C, Carr WR, Jennings N, Singhal R, Small PK |s2cid=35209784 |title=Oral Vitamin B12 Supplementation After Roux-en-Y Gastric Bypass: a Systematic Review |journal=Obes Surg |volume=28 |issue=7 |pages=1916–1923 |date=July 2018 |pmid=29318504 |doi=10.1007/s11695-017-3102-y }} For post-operative oral supplementation, {{value|1000|u=μg/day}} may be needed to prevent vitamin deficiency.

According to one review: "At present, no 'gold standard' test exists for the diagnosis of vitamin B₁₂ deficiency and as a consequence the diagnosis requires consideration of both the clinical state of the patient and the results of investigations."{{cite journal |vauthors=Shipton MJ, Thachil J |title=Vitamin B12 deficiency – A 21st century perspective |journal=Clin Med (Lond) |volume=15 |issue=2 |pages=145–150 |date=April 2015 |pmid=25824066 |pmc=4953733 |doi=10.7861/clinmedicine.15-2-145 }} The vitamin deficiency is typically suspected when a routine complete blood count shows anemia with an elevated mean corpuscular volume (MCV). In addition, on the peripheral blood smear, macrocytes and hypersegmented polymorphonuclear leukocytes may be seen. Diagnosis is supported based on vitamin B₁₂ blood levels below 150–180 pmol/L (200–250 pg/mL) in adults.{{cite journal |vauthors=Devalia V, Hamilton MS, Molloy AM |title=Guidelines for the diagnosis and treatment of cobalamin and folate disorders |journal=Br. J. Haematol. |volume=166 |issue=4 |pages=496–513 |date=August 2014 |pmid=24942828 |doi=10.1111/bjh.12959 |s2cid=5772424 |doi-access=free }} However, serum values can be maintained while tissue B₁₂ stores are becoming depleted. Therefore, serum B₁₂ values above the cut-off point of deficiency do not necessarily confirm adequate B₁₂ status. For this reason, elevated serum homocysteine over 15 micromol/L and methylmalonic acid (MMA) over 0.271 micromol/L are considered better indicators of B₁₂ deficiency, rather than relying only on the concentration of B₁₂ in blood. However, elevated MMA is not conclusive, as it is seen in people with B₁₂ deficiency, but also in elderly people who have renal insufficiency,{{cite journal |vauthors=Lachner C, Steinle NI, Regenold WT |title=The neuropsychiatry of vitamin B12 deficiency in elderly patients |journal=J Neuropsychiatry Clin Neurosci |volume=24 |issue=1 |pages=5–15 |date=2012 |pmid=22450609 |doi=10.1176/appi.neuropsych.11020052 |s2cid=20350330 }} and elevated homocysteine is not conclusive, as it is also seen in people with folate deficiency.{{cite journal |vauthors=Moretti R, Caruso P |title=The Controversial Role of Homocysteine in Neurology: From Labs to Clinical Practice |journal=Int J Mol Sci |volume=20 |issue=1 |page= 231|date=January 2019 |pmid=30626145 |pmc=6337226 |doi=10.3390/ijms20010231 |doi-access=free }} In addition, elevated methylmalonic acid levels may also be related to metabolic disorders such as methylmalonic acidemia.{{cite web|title = Methylmalonic acidemia|url = http://ghr.nlm.nih.gov/condition/methylmalonic-acidemia|work = Genetics Home Reference |publisher=US National Library of Medicine |date = October 2015|access-date = 10 July 2022}} If nervous system damage is present and blood testing is inconclusive, a lumbar puncture may be carried out to measure cerebrospinal fluid B₁₂ levels.{{cite journal | vauthors = Devalia V | title = Diagnosing vitamin B-12 deficiency on the basis of serum B-12 assay | journal = BMJ | volume = 333 | issue = 7564 | pages = 385–386 | date = August 2006 | pmid = 16916826 | pmc = 1550477 | doi = 10.1136/bmj.333.7564.385 }}

Serum haptocorrin binds 80-90% of circulating B₁₂, rendering it unavailable for cellular delivery by transcobalamin II. This is conjectured to be a circulating storage function.{{cite journal |vauthors=McCorvie TJ, Ferreira D, Yue WW, Froese DS |title=The complex machinery of human cobalamin metabolism |journal=J Inherit Metab Dis |volume=46 |issue=3 |pages=406–20 |date=May 2023 |pmid=36680553 |doi=10.1002/jimd.12593 |url=}} Several serious, even life-threatening diseases cause elevated serum haptocorrin, measured as abnormally high serum vitamin B₁₂, while at the same time potentially manifesting as a symptomatic vitamin deficiency because of insufficient vitamin bound to transcobalamin II which transfers the vitamin to cells.{{cite journal |vauthors=Ermens AA, Vlasveld LT, Lindemans J |title=Significance of elevated cobalamin (vitamin B12) levels in blood |journal=Clin Biochem |volume=36 |issue=8 |pages=585–90 |date=November 2003 |pmid=14636871 |doi=10.1016/j.clinbiochem.2003.08.004 |url=}}

File:Hydroxocobalamin Injection.jpg

Severe vitamin B₁₂ deficiency is initially corrected with daily intramuscular injections of {{value|1000|u=μg}} of the vitamin, followed by maintenance via monthly injections of the same amount or daily oral dosing of {{value|1000|u=μg}}. The oral daily dose far exceeds the vitamin requirement because the normal transporter protein-mediated absorption is absent, leaving only very inefficient intestinal passive absorption.{{cite journal |vauthors=Elangovan R, Baruteau J |title=Inherited and acquired vitamin B12 deficiencies: Which administration route to choose for supplementation? |journal=Front Pharmacol |volume=13 |issue= |page=972468 |date=September 2022 |pmid=36249776 |pmc=9559827 |doi=10.3389/fphar.2022.972468 |doi-access=free |url=}}{{cite journal |vauthors=Andrès E, Zulfiqar AA, Serraj K, Vogel T, Kaltenbach G |title=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=J Clin Med |volume=7 |issue=10 |pages=304–17 |date=September 2018 |pmid=30261596 |pmc=6210286 |doi=10.3390/jcm7100304 |doi-access=free |url=}} Injection side effects include skin rash, itching, chills, fever, hot flushes, nausea and dizziness. There are not enough studies on whether pills are as effective in improving or eliminating symptoms as parenteral treatment.{{cite journal | vauthors = Wolffenbuttel BH, Wouters HJ, Heiner-Fokkema MR, van der Klauw MM | title = The Many Faces of Cobalamin (Vitamin B₁₂) Deficiency | journal = Mayo Clinic Proceedings. Innovations, Quality & Outcomes | volume = 3 | issue = 2 | pages = 200–214 | date = June 2019 | pmid = 31193945 | pmc = 6543499 | doi = 10.1016/j.mayocpiqo.2019.03.002 }}

For cyanide poisoning, a large amount of hydroxocobalamin may be given intravenously and sometimes in combination with sodium thiosulfate.{{cite journal | vauthors = Hall AH, Rumack BH | title = Hydroxycobalamin/sodium thiosulfate as a cyanide antidote | journal = The Journal of Emergency Medicine | volume = 5 | issue = 2 | pages = 115–121 | year = 1987 | pmid = 3295013 | doi = 10.1016/0736-4679(87)90074-6 }}{{cite journal | vauthors = MacLennan L, Moiemen N | title = Management of cyanide toxicity in patients with burns | journal = Burns | volume = 41 | issue = 1 | pages = 18–24 | date = February 2015 | pmid = 24994676 | doi = 10.1016/j.burns.2014.06.001 }} The mechanism of action is straightforward: the hydroxycobalamin hydroxide ligand is displaced by the toxic cyanide ion, and the resulting non-toxic cyanocobalamin is excreted in urine.{{cite journal | vauthors = Dart RC | title = Hydroxocobalamin for acute cyanide poisoning: new data from preclinical and clinical studies; new results from the prehospital emergency setting | journal = Clinical Toxicology | volume = 44 | issue = Suppl. 1 | pages = 1–3 | year = 2006 | pmid = 16990188 | doi = 10.1080/15563650600811607 | doi-access = free }}

Some research shows that most people in the United States and the United Kingdom consume sufficient vitamin B₁₂.{{cite book |vauthors=Stabler SP |title = Present Knowledge in Nutrition, Eleventh Edition |chapter = Vitamin B12 | veditors = Marriott BP, Birt DF, Stallings VA, Yates AA |publisher = Academic Press (Elsevier) |year=2020 |location = London|pages = 257–272 |isbn=978-0-323-66162-1 |quote=US survey data from the NHANES What We Eat in America 2013e16 cohort reported the median vitamin B12 consumption for all adult men of 5.1 mcg and women of 3.5 mcg.95b Using the Estimated Average Requirement (EAR) for adults for Vitamin B12 of 2 mcg,93 less than 3% of men and 8% of women in the United States had inadequate diets using this comparator. However, 11% of girls 14e18 years had intakes less than their EAR of 2.0 mcg.}} However, other research suggests that the proportion of people with low or marginal levels of vitamin B₁₂ is up to 40% in the Western world. Grain-based foods can be fortified by having the vitamin added to them. Vitamin B₁₂ supplements are available as single or multivitamin tablets. Pharmaceutical preparations of vitamin B₁₂ may be given by intramuscular injection. Since there are few non-animal sources of the vitamin, vegans are advised to consume a dietary supplement or fortified foods for B₁₂ intake, or risk serious health consequences. Children in some regions of developing countries are at particular risk due to increased requirements during growth coupled with diets low in animal-sourced foods.

The US National Academy of Medicine updated estimated average requirements (EARs) and recommended dietary allowances (RDAs) for vitamin B{{sub|12}} in 1998. The EAR for vitamin B{{sub|12}} for women and men ages 14 and up is 2.0{{nbsp}}μg/day; the RDA is {{value|2.4|u=μg/day}}. RDA is higher than EAR to identify amounts that will cover people with higher-than-average requirements. RDA for pregnancy equals 2.6{{nbsp}}μg/day. RDA for lactation equals {{value|2.8|u=μg/day}}. For infants up to 12 months, the adequate intake (AI) is 0.4–0.5{{nbsp}}μg/day. (AIs are established when there is insufficient information to determine EARs and RDAs.) For children ages 1–13 years, the RDA increases with age from 0.9 to 1.8{{nbsp}}μg/day. Because 10 to 30 percent of older people may be unable to effectively absorb vitamin B{{sub|12}} naturally occurring in foods, those older than 50 years should meet their RDA mainly by consuming foods fortified with vitamin B{{sub|12}} or a supplement containing vitamin B{{sub|12}}. As for safety, tolerable upper intake levels (known as ULs) are set for vitamins and minerals when evidence is sufficient. In the case of vitamin B{{sub|12}} there is no UL, as there is no human data for adverse effects from high doses. Collectively the EARs, RDAs, AIs, and ULs are referred to as dietary reference intakes (DRIs).{{cite book |last1 = Institute of Medicine |title = Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B₆, Folate, Vitamin B₁₂, Pantothenic Acid, Biotin, and Choline |chapter = Vitamin B₁₂ |publisher = The National Academies Press |year = 1998 |location = Washington, DC |pages = 306–356 |chapter-url = http://www.nap.edu/openbook.php?record_id=6015&page=306 | access-date = 7 February 2012 |isbn = 978-0-309-06554-2|author1-link = Institute of Medicine }}

The European Food Safety Authority (EFSA) refers to the collective set of information as "dietary reference values", with population reference intake (PRI) instead of RDA, and average requirement instead of EAR. AI and UL are defined by EFSA the same as in the United States. For women and men over age 18, the adequate intake (AI) is set at 4.0{{nbsp}}μg/day. AI for pregnancy is 4.5 μg/day, and for lactation 5.0{{nbsp}}μg/day. For children aged 1–14 years, the AIs increase with age from 1.5 to 3.5{{nbsp}}μg/day. These AIs are higher than the U.S. RDAs. The EFSA also reviewed the safety question and reached the same conclusion as in the United States—that there was not sufficient evidence to set a UL for vitamin B{{sub|12}}.{{cite web| title = Tolerable Upper Intake Levels For Vitamins And Minerals| publisher = European Food Safety Authority| year = 2006| url = http://www.efsa.europa.eu/sites/default/files/efsa_rep/blobserver_assets/ndatolerableuil.pdf| access-date = 12 March 2016| archive-url = https://web.archive.org/web/20191015155248/http://www.efsa.europa.eu/sites/default/files/efsa_rep/blobserver_assets/ndatolerableuil.pdf| archive-date = 15 October 2019| url-status = live}}

The Japan National Institute of Health and Nutrition set the RDA for people ages 12 and older at 2.4{{nbsp}}μg/day.[https://www.jstage.jst.go.jp/article/jnsv/59/Supplement/59_S67/_pdf "Dietary Reference Intakes for Japanese 2010: Water-Soluble Vitamins"] Journal of Nutritional Science and Vitaminology 2013(59):S67–S82. The World Health Organization also uses 2.4{{nbsp}}μg/day as the adult recommended nutrient intake for this vitamin.{{cite book | vauthors = ((World Health Organization)) | title = Vitamin and Mineral Requirements in Human Nutrition | url = https://archive.org/details/vitaminmineralre00orga | url-access = limited | edition = 2nd | publisher = World Health Organization | location = Geneva | year = 2005 | isbn = 978-92-4-154612-6 |pages = [https://archive.org/details/vitaminmineralre00orga/page/n297 279]–287| chapter = Chapter 14: Vitamin B12 | hdl = 10665/42716 | author-link = World Health Organization}}

For U.S. food and dietary supplement labeling purposes, the amount in a serving is expressed as a "percent of daily value" (%DV). For vitamin B{{sub|12}} labeling purposes, 100% of the daily value was 6.0{{nbsp}}μg, but on 27 May 2016, it was revised downward to 2.4{{nbsp}}μg (see Reference Daily Intake).{{cite web |url=https://www.gpo.gov/fdsys/pkg/FR-2016-05-27/pdf/2016-11867.pdf |work=Federal Register |date=27 May 2016 |title=Food Labeling: Revision of the Nutrition and Supplement Facts Labels |page=33982 |access-date=27 August 2017 |archive-url=https://web.archive.org/web/20160808164651/https://www.gpo.gov/fdsys/pkg/FR-2016-05-27/pdf/2016-11867.pdf |archive-date=8 August 2016 |url-status=live }}{{cite web | title=Daily Value Reference of the Dietary Supplement Label Database (DSLD) | website=Dietary Supplement Label Database (DSLD) | url=https://www.dsld.nlm.nih.gov/dsld/dailyvalue.jsp | access-date=16 May 2020 | archive-date=7 April 2020 | archive-url=https://web.archive.org/web/20200407073956/https://dsld.nlm.nih.gov/dsld/dailyvalue.jsp }} Compliance with the updated labeling regulations was required by 1 January 2020 for manufacturers with US$10 million or more in annual food sales, and by 1 January 2021 for manufacturers with lower volume food sales.{{cite web | title=Changes to the Nutrition Facts Label | website=U.S. Food and Drug Administration (FDA) | date=27 May 2016 | url=https://www.fda.gov/food/food-labeling-nutrition/changes-nutrition-facts-label | archive-url=https://web.archive.org/web/20190518044608/https://www.fda.gov/food/food-labeling-nutrition/changes-nutrition-facts-label | url-status=dead | archive-date=18 May 2019 | access-date=16 May 2020}} {{PD-notice}}{{cite web | title=Industry Resources on the Changes to the Nutrition Facts Label | website=U.S. Food and Drug Administration (FDA) | date=21 December 2018 | url=https://www.fda.gov/food/food-labeling-nutrition/industry-resources-changes-nutrition-facts-label | archive-url=https://web.archive.org/web/20190904175220/https://www.fda.gov/food/food-labeling-nutrition/industry-resources-changes-nutrition-facts-label | url-status=dead | archive-date=4 September 2019 | access-date=16 May 2020}} {{PD-notice}}

Vitamin B₁₂ is produced in nature by certain bacteria, and archaea.{{cite journal | vauthors = Fang H, Kang J, Zhang D | title = Microbial production of vitamin B12: a review and future perspectives | journal = Microbial Cell Factories | volume = 16 | issue = 1 | page = 15 | date = January 2017 | pmid = 28137297 | pmc = 5282855 | doi = 10.1186/s12934-017-0631-y | doi-access = free }}{{cite journal | vauthors = Moore SJ, Warren MJ | title = The anaerobic biosynthesis of vitamin B12 | journal = Biochemical Society Transactions | volume = 40 | issue = 3 | pages = 581–586 | date = June 2012 | pmid = 22616870 | doi = 10.1042/BST20120066 | s2cid = 26057998 | url = https://portlandpress.com/biochemsoctrans/article-pdf/40/3/581/483561/bst0400581.pdf }}{{cite book| vauthors = Graham RM, Deery E, Warren MJ | veditors = Warren MJ, Smith |editor2-link=Alison Gail Smith |title=Tetrapyrroles Birth, Life and Death|date=2009|publisher=Springer-Verlag|location=New York|isbn=978-0-387-78518-9|page=286|chapter=18: Vitamin B₁₂: Biosynthesis of the Corrin Ring |doi=10.1007/978-0-387-78518-9_18}} It is synthesized by some bacteria in the gut microbiota in humans and other animals, but it has long been thought that humans cannot absorb this as it is made in the colon, downstream from the small intestine, where the absorption of most nutrients occurs.{{cite journal | vauthors = Gille D, Schmid A | title = Vitamin B12 in meat and dairy products | journal = Nutrition Reviews | volume = 73 | issue = 2 | pages = 106–115 | date = February 2015 | pmid = 26024497 | doi = 10.1093/nutrit/nuu011 | doi-access = free }} Ruminants, such as cows and sheep, are foregut fermenters, meaning that plant food undergoes microbial fermentation in the rumen before entering the true stomach (abomasum), and thus they are absorbing vitamin B₁₂ produced by bacteria.

Other mammalian species (examples: rabbits, pikas, beaver, guinea pigs) consume high-fiber plants which pass through the gastrointestinal tract and undergo bacterial fermentation in the cecum and large intestine. In this hindgut fermentation, the material from the cecum is expelled as "cecotropes" and are re-ingested, a practice referred to as cecotrophy. Re-ingestion allows for absorption of nutrients made available by bacterial fermentation, and also of vitamins and other nutrients synthesized by the gut bacteria, including vitamin B₁₂.{{cite journal |vauthors=Stevens CE, Hume ID |s2cid=103191 |title=Contributions of microbes in vertebrate gastrointestinal tract to production and conservation of nutrients |journal=Physiol. Rev. |volume=78 |issue=2 |pages=393–427 |date=April 1998 |pmid=9562034 |doi=10.1152/physrev.1998.78.2.393 |doi-access=free }}

Non-ruminant, non-hindgut herbivores may have an enlarged forestomach and/or small intestine to provide a place for bacterial fermentation and B-vitamin production, including B₁₂. For gut bacteria to produce vitamin B₁₂, the animal must consume sufficient amounts of cobalt.{{cite book| vauthors = McDowell LR|title=Vitamins in Animal and Human Nutrition|date=2008|publisher=John Wiley & Sons|location=Hoboken|isbn=978-0-470-37668-3|pages=525, 539|edition=2nd|url=https://books.google.com/books?id=UR9MnQ806LsC&pg=PA525|access-date=17 January 2017|archive-url=https://web.archive.org/web/20170908174337/https://books.google.com/books?id=UR9MnQ806LsC&pg=PA525|archive-date=8 September 2017|url-status=live}} Soil that is deficient in cobalt may result in B₁₂ deficiency, and B₁₂ injections or cobalt supplementation may be required for livestock.{{cite web | vauthors = Erickson A |date=3 September 2019 |title=Cobalt deficiency in sheep and cattle |url=https://www.agric.wa.gov.au/livestock-biosecurity/cobalt-deficiency-sheep-and-cattle |url-status=live |archive-url=https://web.archive.org/web/20151111055217/https://www.agric.wa.gov.au/livestock-biosecurity/cobalt-deficiency-sheep-and-cattle |archive-date=11 November 2015 |access-date=18 April 2020 |website=Department of Primary Industries and Regional Development |publisher=Government of Western Australia |language=en}}

Animals store vitamin B₁₂ from their diets in their livers and muscles and some pass the vitamin into their eggs and milk. Meat, liver, eggs, and milk are therefore sources of the vitamin for other animals, including humans.{{cite news | vauthors = Rooke J |title=Do carnivores need Vitamin B₁₂ supplements?|url=http://baltimorepostexaminer.com/carnivores-need-vitamin-b12-supplements/2013/10/30|work=Baltimore Post Examiner|date=30 October 2013|access-date=17 January 2017|archive-url=https://web.archive.org/web/20170116144827/http://baltimorepostexaminer.com/carnivores-need-vitamin-b12-supplements/2013/10/30|archive-date=16 January 2017|url-status=live}} For humans, the bioavailability from eggs is less than 9%, compared to 40% to 60% from fish, fowl, and meat.{{cite journal | vauthors = Watanabe F | s2cid = 14732788 | title = Vitamin B12 sources and bioavailability | journal = Experimental Biology and Medicine | volume = 232 | issue = 10 | pages = 1266–1274 | date = November 2007 | pmid = 17959839 | doi = 10.3181/0703-MR-67 | doi-access= }} Insects are a source of B₁₂ for animals (including other insects and humans).{{cite news| vauthors = Dossey AT |title=Why Insects Should Be in Your Diet|url=http://www.the-scientist.com/?articles.view/articleNo/34172/title/Why-Insects-Should-Be-in-Your-Diet/|work=The Scientist|date=1 February 2013|access-date=18 April 2020|archive-url=https://web.archive.org/web/20171111204253/http://www.the-scientist.com/?articles.view%2FarticleNo%2F34172%2Ftitle%2FWhy-Insects-Should-Be-in-Your-Diet%2F|archive-date=11 November 2017|url-status=live}} Animal-derived food sources with a high concentration of vitamin B₁₂ include liver and other organ meats from lamb, veal, beef, and turkey; also shellfish and crab meat.{{cite web|url=http://nutritiondata.self.com/foods-000116000000000000000-w.html|title=Foods highest in Vitamin B₁₂ (based on levels per 100-gram serving)|work=Nutrition Data|publisher=Condé Nast, USDA National Nutrient Database, release SR-21|date=2014|access-date=16 February 2017|archive-url=https://web.archive.org/web/20191116172538/https://nutritiondata.self.com/foods-000116000000000000000-w.html|archive-date=16 November 2019|url-status=live}}{{cite web |url=https://ods.od.nih.gov/pubs/usdandb/VitaminB12-Content.pdf |title=Vitamin B-12 (μg) |date=27 October 2015 |website=USDA National Nutrient Database for Standard Reference Release 28 |access-date=6 January 2020 |archive-url=https://web.archive.org/web/20170126161608/https://ods.od.nih.gov/pubs/usdandb/VitaminB12-Content.pdf |archive-date=26 January 2017 |url-status=live }}

There is some evidence that bacterial fermentation of plant foods and symbiotic relationships between algae and bacteria can provide vitamin B₁₂. However, the Academy of Nutrition and Dietetics considers plant and algae sources "unreliable", stating that vegans should turn to fortified foods and supplements instead.{{cite journal | vauthors = Melina V, Craig W, Levin S | title = Position of the Academy of Nutrition and Dietetics: Vegetarian Diets | journal = Journal of the Academy of Nutrition and Dietetics | volume = 116 | issue = 12 | pages = 1970–1980 | date = December 2016 | pmid = 27886704 | doi = 10.1016/j.jand.2016.09.025 | quote = Fermented foods (such as tempeh), nori, spirulina, chlorella algae, and unfortified nutritional yeast cannot be relied upon as adequate or practical sources of B-12.39,40 Vegans must regularly consume reliable sources—meaning B-12 fortified foods or B-12 containing supplements—or they could become deficient, as shown in case studies of vegan infants, children, and adults. | s2cid = 4984228 }}

Natural plant and algae sources of vitamin B₁₂ include fermented plant foods such as tempeh{{cite journal | vauthors = Keuth S, Bisping B | title = Vitamin B12 production by Citrobacter freundii or Klebsiella pneumoniae during tempeh fermentation and proof of enterotoxin absence by PCR | journal = Applied and Environmental Microbiology | volume = 60 | issue = 5 | pages = 1495–1499 | date = May 1994 | pmid = 8017933 | pmc = 201508 | doi = 10.1128/AEM.60.5.1495-1499.1994 | bibcode = 1994ApEnM..60.1495K }}{{cite journal | vauthors = Mo H, Kariluoto S, Piironen V, Zhu Y, Sanders MG, Vincken JP, Wolkers-Rooijackers J, Nout MJ | title = Effect of soybean processing on content and bioaccessibility of folate, vitamin B12 and isoflavones in tofu and tempe | journal = Food Chemistry | volume = 141 | issue = 3 | pages = 2418–2425 | date = December 2013 | pmid = 23870976 | doi = 10.1016/j.foodchem.2013.05.017 | url = https://library.wur.nl/WebQuery/wurpubs/442636 | url-access = subscription }} and seaweed-derived foods such as nori and laverbread.{{cite journal | vauthors = Watanabe F, Yabuta Y, Bito T, Teng F | title = Vitamin B₁₂-containing plant food sources for vegetarians | journal = Nutrients | volume = 6 | issue = 5 | pages = 1861–1873 | date = May 2014 | pmid = 24803097 | pmc = 4042564 | doi = 10.3390/nu6051861 | doi-access = free }}{{cite journal | vauthors = Kwak CS, Lee MS, Lee HJ, Whang JY, Park SC | title = Dietary source of vitamin B(12) intake and vitamin B(12) status in female elderly Koreans aged 85 and older living in rural area | journal = Nutrition Research and Practice | volume = 4 | issue = 3 | pages = 229–234 | date = June 2010 | pmid = 20607069 | pmc = 2895704 | doi = 10.4162/nrp.2010.4.3.229 }}{{cite journal | vauthors = Kwak CS, Lee MS, Oh SI, Park SC | title = Discovery of novel sources of vitamin b(12) in traditional korean foods from nutritional surveys of centenarians | journal = Current Gerontology and Geriatrics Research | volume = 2010 | page = 374897 | year = 2010 | pmid = 21436999 | pmc = 3062981 | doi = 10.1155/2010/374897 | doi-access = free }} Methylcobalamin has been identified in Chlorella vulgaris.{{cite journal | vauthors = Kumudha A, Selvakumar S, Dilshad P, Vaidyanathan G, Thakur MS, Sarada R | title = Methylcobalamin – a form of vitamin B12 identified and characterised in Chlorella vulgaris | journal = Food Chemistry | volume = 170 | pages = 316–320 | date = March 2015 | pmid = 25306351 | doi = 10.1016/j.foodchem.2014.08.035 }} Since only bacteria and some archea possess the genes and enzymes necessary to synthesize vitamin B₁₂, plant and algae sources all obtain the vitamin secondarily from symbiosis with various species of bacteria,{{cite journal | vauthors = Smith AG | title=Plants need their vitamins too | journal=Current Opinion in Plant Biology | volume=10 | issue=3 | pages=266–275 | date=21 September 2019 | pmid=17434786 | doi=10.1016/j.pbi.2007.04.009 }} or in the case of fermented plant foods, from bacterial fermentation.

Foods for which vitamin B₁₂-fortified versions are available include breakfast cereals, plant-derived milk substitutes such as soy milk and oat milk, energy bars, and nutritional yeast. The fortification ingredient is cyanocobalamin. Microbial fermentation yields adenosylcobalamin, which is then converted to cyanocobalamin by the addition of potassium cyanide or thiocyanate in the presence of sodium nitrite and heat.{{cite journal|vauthors=Martins JH, Barg H, Warren MJ, Jahn D |s2cid=22232461 |title=Microbial production of vitamin B12 |journal=Appl Microbiol Biotechnol |volume=58 |issue=3 |pages=275–285 |date= March 2002 |pmid=11935176 |doi=10.1007/s00253-001-0902-7}}

As of 2019, nineteen countries require food fortification of wheat flour, maize flour, or rice with vitamin B₁₂. Most of these are in southeast Africa or Central America.{{cite web|url=https://fortificationdata.org/map-number-of-nutrients/|title=Map: Count of Nutrients In Fortification Standards|website=Global Fortification Data Exchange|access-date=15 April 2020|archive-url=https://web.archive.org/web/20190411123853/https://fortificationdata.org/map-number-of-nutrients/|archive-date=11 April 2019|url-status=live}}

Vegan advocacy organizations, among others, recommend that every vegan consume B₁₂ from either fortified foods or supplements.{{cite web|url=http://www.vrg.org/nutrition/b12.htm|title=Vitamin B₁₂ in the Vegan Diet|access-date=17 January 2008|author-link=Reed Mangels| vauthors = Mangels R |publisher=Vegetarian Resource Group|archive-url=https://web.archive.org/web/20121219075436/http://www.vrg.org//nutrition/b12.htm|archive-date=19 December 2012|url-status=live}}{{cite web |url=http://www.pcrm.org/health/diets/vegdiets/dont-vegetarians-have-trouble-getting-enough |title=Don't Vegetarians Have Trouble Getting Enough Vitamin B₁₂? |access-date=17 January 2008 |publisher=Physicians Committee for Responsible Medicine |archive-url=https://web.archive.org/web/20111008153836/http://www.pcrm.org/health/diets/vegdiets/dont-vegetarians-have-trouble-getting-enough |archive-date=8 October 2011 |url-status=live }}

File:Methylcobalamin tablets.jpg

Vitamin B₁₂ is included in multivitamin pills; in some countries grain-based foods, such as bread and pasta, are fortified with B₁₂. In the US, non-prescription products can be purchased providing up to 1,000{{nbsp}}μg each, and it is a common ingredient in energy drinks and energy shots, usually at many times the recommended dietary allowance of B₁₂. The vitamin can also be supplied on prescription and delivered via injection or other means.

When used in supplementation, all of the vitamin B12 vitamers have been argued to be beneficial, with there not being clear evidence that any are relatively more or less effective.{{cite journal | last1 = European Food Safety Authority | date = 25 September 2008 | title = 5′-deoxyadenosylcobalamin and methylcobalamin as sources for Vitamin B₁₂ added as a nutritional substance in food supplements: Scientific opinion of the Scientific Panel on Food Additives and Nutrient Sources added to food | journal = EFSA Journal | volume = 815 | issue = 10| pages = 1–21 | doi = 10.2903/j.efsa.2008.815 | author1-link = European Food Safety Authority | doi-access = free }}{{cite journal|date=28 March 2015|doi=10.1002/mnfr.201500019 |title=Cobalamin coenzyme forms are not likely to be superior to cyano- and hydroxyl-cobalamin in prevention or treatment of cobalamin deficiency |journal=Molecular Nutrition & Food Research |volume=59 |issue=7 |pages=1364–1372 |pmid=25820384 |pmc=4692085 | vauthors = Obeid R, Fedosov SN, Nexo E }}{{cite journal|doi=10.3390/jcm13082176|date=10 April 2024|doi-access=free |title=Diagnosis, Treatment and Long-Term Management of Vitamin B12 Deficiency in Adults: A Delphi Expert Consensus |journal=Journal of Clinical Medicine |volume=13 |issue=8 |page=2176 |pmid=38673453 | vauthors = Obeid R, Andrès E, Češka R, Hooshmand B, Guéant-Rodriguez R, Prada GI, Sławek J, Traykov L, Ta Van B, Várkonyi T, Reiners K |pmc=11050313 }}

The amount of cyanide in cyanocobalamin is generally not considered a health risk, since even in a 1,000{{nbsp}}μg dose, the 20{{nbsp}}μg of cyanide it contains is less than the daily consumption of cyanide from food.

Injection of hydroxycobalamin is often used if digestive absorption is impaired, but this course of action may not be necessary with high-dose oral supplements (such as 0.5–1.0{{nbsp}}mg or more),{{cite journal | vauthors = Lane LA, Rojas-Fernandez C | s2cid = 919401 | title = Treatment of vitamin b(12)-deficiency anemia: oral versus parenteral therapy | journal = The Annals of Pharmacotherapy | volume = 36 | issue = 7–8 | pages = 1268–1272 | date = July–August 2002 | pmid = 12086562 | doi = 10.1345/aph.1A122 }}{{cite journal | vauthors = Butler CC, Vidal-Alaball J, Cannings-John R, McCaddon A, Hood K, Papaioannou A, Mcdowell I, Goringe A | title = Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency: a systematic review of randomized controlled trials | journal = Family Practice | volume = 23 | issue = 3 | pages = 279–285 | date = June 2006 | pmid = 16585128 | doi = 10.1093/fampra/cml008| doi-access = free | citeseerx = 10.1.1.488.7931 }} because with large quantities of the vitamin taken orally, even the 1% to 5% of free crystalline B₁₂ that is absorbed along the entire intestine by passive diffusion may be sufficient to provide a necessary amount.{{cite journal |title=Cobalamins and Methylcobalamin: Coenzyme of Vitamin B12 |vauthors=Arslan SA, Arslan I, Tirnaksiz F |s2cid=1929961 |journal=FABAD J. Pharm. Sci. |volume=38 |issue=3 |pages=151–157 |date=March 2013 }}

A person with cobalamin C disease, a rare autosomal, recessive, inheritance disease which results in combined methylmalonic aciduria and homocystinuria),{{cite journal |vauthors=Wang C, Li D, Cai F, Zhang X, Xu X, Liu X, Zhang C, Wang D, Liu X, Lin S, Zhang Y, Shu J |title=Mutation spectrum of MMACHC in Chinese pediatric patients with cobalamin C disease: A case series and literature review |journal=Eur J Med Genet |volume=62 |issue=10 |pages=103713 |date=October 2019 |pmid=31279840 |doi=10.1016/j.ejmg.2019.103713 |url=}} can be treated with intravenous or intramuscular hydroxocobalamin.{{cite journal | vauthors = Thauvin-Robinet C, Roze E, Couvreur G, Horellou MH, Sedel F, Grabli D, Bruneteau G, Tonneti C, Masurel-Paulet A, Perennou D, Moreau T, Giroud M, de Baulny HO, Giraudier S, Faivre L | s2cid = 23493993 | title = The adolescent and adult form of cobalamin C disease: clinical and molecular spectrum | journal = Journal of Neurology, Neurosurgery, and Psychiatry | volume = 79 | issue = 6 | pages = 725–28 | date = June 2008 | pmid = 18245139 | doi = 10.1136/jnnp.2007.133025 }}

Conventional administration does not ensure specific distribution and controlled release of vitamin B₁₂. Moreover, therapeutic protocols involving injection require health care people and commuting of patients to the hospital thus increasing the cost of the treatment and impairing the lifestyle of patients. Targeted delivery of vitamin B₁₂ is a major focus of modern prescriptions. For example, conveying the vitamin to the bone marrow and nerve cells would help myelin recovery. Currently, several nanocarriers strategies are being developed for improving vitamin B₁₂ delivery to simplify administration, reduce costs, improve pharmacokinetics, and ameliorate the quality of patients' lives.{{cite journal | vauthors = Fidaleo M, Tacconi S, Sbarigia C, Passeri D, Rossi M, Tata AM, Dini L | title = Current Nanocarrier Strategies Improve Vitamin B12 Pharmacokinetics, Ameliorate Patients' Lives, and Reduce Costs | journal = Nanomaterials | volume = 11 | issue = 3 | page = 743 | date = March 2021 | pmid = 33809596 | pmc = 8001893 | doi = 10.3390/nano11030743 | doi-access = free }}

Gastric acid is needed to release vitamin B₁₂ from protein for absorption. Reduced secretion of gastric acid and pepsin, from the use of H₂ blocker or proton-pump inhibitor (PPI) drugs, can reduce the absorption of protein-bound (dietary) vitamin B₁₂, although not of supplemental vitamin B₁₂. H₂-receptor antagonist examples include cimetidine, famotidine, nizatidine, and ranitidine. PPIs examples include omeprazole, lansoprazole, rabeprazole, pantoprazole, and esomeprazole. Clinically significant vitamin B₁₂ deficiency and megaloblastic anemia are unlikely, unless these drug therapies are prolonged for two or more years, or if in addition, the person's dietary intake is below recommended levels. Symptomatic vitamin deficiency is more likely if the person is rendered achlorhydric (a complete absence of gastric acid secretion), which occurs more frequently with proton pump inhibitors than H₂ blockers.{{cite journal |vauthors=DeVault KR, Talley NJ |s2cid=25413839 |title=Insights into the future of gastric acid suppression |journal=Nat Rev Gastroenterol Hepatol |volume=6 |issue=9 |pages=524–532 |date=September 2009 |pmid=19713987 |doi=10.1038/nrgastro.2009.125 }}

Reduced serum levels of vitamin B₁₂ occur in up to 30% of people taking long-term anti-diabetic metformin.{{cite journal | vauthors = Ahmed MA |title=Metformin and Vitamin B12 Deficiency: Where Do We Stand? |journal=Journal of Pharmacy & Pharmaceutical Sciences |date=2016 |volume=19 |issue=3 |pages=382–398 |pmid=27806244 |doi=10.18433/J3PK7P |doi-access=free |hdl=2263/60716 |hdl-access=free }}{{cite journal | vauthors = Gilligan MA | title = Metformin and vitamin B12 deficiency | journal = Archives of Internal Medicine | volume = 162 | issue = 4 | pages = 484–485 | date = February 2002 | pmid = 11863489 | doi = 10.1001/archinte.162.4.484 | doi-broken-date = 10 January 2025 }} Deficiency does not develop if dietary intake of vitamin B₁₂ is adequate or prophylactic B₁₂ supplementation is given. If the deficiency is detected, metformin can be continued while the deficiency is corrected with B₁₂ supplements.{{cite web| vauthors =Copp S |title=What effect does metformin have on vitamin B₁₂ levels? |date=1 December 2007 |url=http://www.druginfozone.nhs.uk/Documents/103.1Metformin_final.doc?id=560841 |publisher=UK Medicines Information, NHS |archive-url=https://web.archive.org/web/20070927034337/http://www.druginfozone.nhs.uk/Documents/103.1Metformin_final.doc?id=560841 |archive-date=27 September 2007 }}

Certain medications can decrease the absorption of orally consumed vitamin B₁₂, including colchicine, extended-release potassium products, and antibiotics such as gentamicin, neomycin and tobramycin.{{cite web |url=https://www.webmd.com/drugs/2/drug-1010/cyanocobalamin-vitamin-b-12-oral/details |title=Vitamin B-12: Interactions |website= WebMD |access-date=21 April 2020}} Anti-seizure medications phenobarbital, pregabalin, primidone and topiramate are associated with lower than normal serum vitamin concentration. However, serum levels were higher in people prescribed valproate.{{cite journal |vauthors=Linnebank M, Moskau S, Semmler A, Widman G, Stoffel-Wagner B, Weller M, Elger CE |title=Antiepileptic drugs interact with folate and vitamin B12 serum levels |journal=Ann. Neurol. |volume=69 |issue=2 |pages=352–359 |date=February 2011 |pmid=21246600 |doi=10.1002/ana.22229 |s2cid=7282489 |url=https://www.zora.uzh.ch/id/eprint/43383/1/Main_r1_table_Annals_of_Neurology.pdf}} In addition, certain drugs may interfere with laboratory tests for the vitamin, such as amoxicillin, erythromycin, methotrexate and pyrimethamine.

File:B12 methylcobalamin.jpg

Vitamin B₁₂ is the most chemically complex of all the vitamins. The structure of B₁₂ is based on a corrin ring, which is similar to the porphyrin ring found in heme. The central metal ion is cobalt. As isolated as an air-stable solid and available commercially, cobalt in vitamin B₁₂ (cyanocobalamin and other vitamers) is present in its +3 oxidation state. Biochemically, the cobalt center can take part in both two-electron and one-electron reductive processes to access the "reduced" (B_12r, +2 oxidation state) and "super-reduced" (B_12s, +1 oxidation state) forms. The ability to shuttle between the +1, +2, and +3 oxidation states is responsible for the versatile chemistry of vitamin B₁₂, allowing it to serve as a donor of deoxyadenosyl radical (radical alkyl source) and as a methyl cation equivalent (electrophilic alkyl source).{{cite journal | vauthors = Giedyk M, Goliszewska K, Gryko D | title = Vitamin B12 catalysed reactions | journal = Chemical Society Reviews | volume = 44 | issue = 11 | pages = 3391–3404 | date = June 2015 | pmid = 25945462 | doi = 10.1039/C5CS00165J }}

File:Cobalamin-general-structure-color.png

Four of the six coordination sites are provided by the corrin ring and a fifth by a dimethylbenzimidazole group. The sixth coordination site, the reactive center, is variable, being a cyano group (–CN), a hydroxyl group (–OH), a methyl group (–CH₃) or a 5′-deoxyadenosyl group. Historically, the covalent carbon–cobalt bond is one of the first examples of carbon-metal bonds to be discovered in biology. The hydrogenases and, by necessity, enzymes associated with cobalt utilization, involve metal-carbon bonds.{{cite book|url=https://www.wiley.com/en-us/Bioorganometallics%3A+Biomolecules%2C+Labeling%2C+Medicine-p-9783527309900|title=Bioorganometallics: Biomolecules, Labeling, Medicine|publisher=Wiley-VCH|year=2006|isbn=978-3-527-30990-0|veditors=Jaouen G|location=Weinheim|pages=17–25}} Animals can convert cyanocobalamin and hydroxocobalamin to the bioactive forms adenosylcobalamin and methylcobalamin by enzymatically replacing the cyano or hydroxyl groups.

Several methods have been used to determine the vitamin B₁₂ content in foods including microbiological assays, chemiluminescence assays, polarographic, spectrophotometric, and high-performance liquid chromatography processes.{{cite web | vauthors = Lawrance P | title = Vitamin B12: A review of analytical methods for use in food. | date = March 2015 | url = https://www.gov.uk/government/publications/vitamin-b12-a-review-of-analytical-methods-for-use-in-food | publisher = LGC Limited }} The microbiological assay has been the most commonly used assay technique for foods, utilizing certain vitamin B₁₂-requiring microorganisms, such as Lactobacillus delbrueckii subsp. lactis ATCC7830. However, it is no longer the reference method due to the high measurement uncertainty of vitamin B₁₂.{{cite journal| vauthors = O'Leary F, Samman S |date= March 2010 |title=Vitamin B12 in Health and Disease|journal=Nutrients|language=en|volume=2|issue=3|pages=299–316|doi=10.3390/nu2030299|issn=2072-6643|pmc=3257642|pmid=22254022|doi-access= free }}

Furthermore, this assay requires overnight incubation and may give false results if any inactive vitamin B₁₂ analogues are present in the foods.{{cite book|title=Vitamin B12|date=12 July 2017|publisher=CRC Press|doi=10.1201/9781315119540|isbn=978-1-315-11954-0| veditors = Obeid R }} Currently, radioisotope dilution assay (RIDA) with labeled vitamin B₁₂ and hog IF (pigs) have been used to determine vitamin B₁₂ content in food. Previous reports have suggested that the RIDA method can detect higher concentrations of vitamin B₁₂ in foods compared to the microbiological assay method.

Vitamin B₁₂ functions as a coenzyme, meaning that its presence is required in some enzyme-catalyzed reactions.{{cite journal | vauthors = Banerjee R, Ragsdale SW | title = The many faces of vitamin B12: catalysis by cobalamin-dependent enzymes | journal = Annual Review of Biochemistry | volume = 72 | pages = 209–247 | date = July 2003 | pmid = 14527323 | doi = 10.1146/annurev.biochem.72.121801.161828 | s2cid = 37393683 | url = https://digitalcommons.unl.edu/biochemfacpub/460 | url-access = subscription }} Listed here are the three classes of enzymes that sometimes require B₁₂ to function (in animals):

1. Isomerases
2. : Rearrangements in which a hydrogen atom is directly transferred between two adjacent atoms with concomitant exchange of the second substituent, X, which may be a carbon atom with substituents, an oxygen atom of an alcohol, or an amine. These use the AdoB₁₂ (adenosylcobalamin) form of the vitamin.
3. Methyltransferases
4. : Methyl (–CH₃) group transfers between two molecules. These use the MeB₁₂ (methylcobalamin) form of the vitamin.
5. Dehalogenases
6. : Some species of anaerobic bacteria synthesize B₁₂-dependent dehalogenases, which have potential commercial applications for degrading chlorinated pollutants. The microorganisms may either be capable of de novo corrinoid biosynthesis or are dependent on exogenous vitamin B₁₂.{{cite journal |vauthors=Reinhold A, Westermann M, Seifert J, von Bergen M, Schubert T, Diekert G |title=Impact of vitamin B12 on formation of the tetrachloroethene reductive dehalogenase in Desulfitobacterium hafniense strain Y51 |journal=Appl. Environ. Microbiol. |volume=78 |issue=22 |pages=8025–8032 |date=November 2012 |pmid=22961902 |pmc=3485949 |doi=10.1128/AEM.02173-12 |bibcode=2012ApEnM..78.8025R }}{{cite journal |vauthors=Payne KA, Quezada CP, Fisher K, Dunstan MS, Collins FA, Sjuts H, Levy C, Hay S, Rigby SE, Leys D |title=Reductive dehalogenase structure suggests a mechanism for B12-dependent dehalogenation |journal=Nature |volume=517 |issue=7535 |pages=513–516 |date=January 2015 |pmid=25327251 |pmc=4968649 |doi=10.1038/nature13901 |bibcode=2015Natur.517..513P }}

In humans, two major coenzyme B₁₂-dependent enzyme families corresponding to the first two reaction types, are known. These are typified by the following two enzymes:

File:Propionate pathway.svg

Methylmalonyl coenzyme A mutase (MUT) is an isomerase enzyme that uses the AdoB₁₂ form and reaction type 1 to convert L-methylmalonyl-CoA to succinyl-CoA, an important step in the catabolic breakdown of some amino acids into succinyl-CoA, which then enters energy production via the citric acid cycle.{{cite journal |vauthors=Takahashi-Iñiguez T, García-Hernandez E, Arreguín-Espinosa R, Flores ME |title=Role of vitamin B12 on methylmalonyl-CoA mutase activity |journal=J Zhejiang Univ Sci B |volume=13 |issue=6 |pages=423–437 |date=June 2012 |pmid=22661206 |pmc=3370288 |doi=10.1631/jzus.B1100329 }} This functionality is lost in vitamin B₁₂ deficiency, and can be measured clinically as an increased serum methylmalonic acid (MMA) concentration. The MUT function is necessary for proper myelin synthesis.{{cite journal |vauthors=Calderón-Ospina CA, Nava-Mesa MO |title=B Vitamins in the nervous system: Current knowledge of the biochemical modes of action and synergies of thiamine, pyridoxine, and cobalamin |journal=CNS Neurosci Ther |volume=26 |issue=1 |pages=5–13 |date=January 2020 |pmid=31490017 |pmc=6930825 |doi=10.1111/cns.13207 }} Based on animal research, it is thought that the increased methylmalonyl-CoA hydrolyzes to form methylmalonate (methylmalonic acid), a neurotoxic dicarboxylic acid, causing neurological deterioration.{{cite journal | vauthors = Ballhausen D, Mittaz L, Boulat O, Bonafé L, Braissant O | s2cid = 34612963 | title = Evidence for catabolic pathway of propionate metabolism in CNS: expression pattern of methylmalonyl-CoA mutase and propionyl-CoA carboxylase alpha-subunit in developing and adult rat brain | journal = Neuroscience | volume = 164 | issue = 2 | pages = 578–587 | date = December 2009 | pmid = 19699272 | doi = 10.1016/j.neuroscience.2009.08.028 }}

File:Folate methionine cycle.svg

Methionine synthase, coded by MTR gene, is a methyltransferase enzyme which uses the MeB₁₂ and reaction type 2 to transfer a methyl group from 5-methyltetrahydrofolate to homocysteine, thereby generating tetrahydrofolate (THF) and methionine.{{cite journal | vauthors = Froese DS, Fowler B, Baumgartner MR | title = Vitamin B12, folate, and the methionine remethylation cycle-biochemistry, pathways, and regulation | journal = Journal of Inherited Metabolic Disease | volume = 42 | issue = 4 | pages = 673–685 | date = July 2019 | pmid = 30693532 | doi = 10.1002/jimd.12009 | doi-access = free | url = https://www.zora.uzh.ch/id/eprint/181018/1/Froese_et_al-2019-Journal_of_Inherited_Metabolic_Disease.pdf }} This functionality is lost in vitamin B₁₂ deficiency, resulting in an increased homocysteine level and the trapping of folate as 5-methyl-tetrahydrofolate, from which THF (the active form of folate) cannot be recovered. THF plays an important role in DNA synthesis, so reduced availability of THF results in ineffective production of cells with rapid turnover, in particular red blood cells, and also intestinal wall cells which are responsible for absorption. THF may be regenerated via MTR or may be obtained from fresh folate in the diet. Thus all of the DNA synthetic effects of B₁₂ deficiency, including the megaloblastic anemia of pernicious anemia, resolve if sufficient dietary folate is present. Thus the best-known "function" of B₁₂ (that which is involved with DNA synthesis, cell division, and anemia) is a facultative function that is mediated by B₁₂-conservation of an active form of folate which is needed for efficient DNA production. Other cobalamin-requiring methyltransferase enzymes are also known in bacteria, such as Me-H₄-MPT, coenzyme M methyltransferase.{{cite journal |vauthors=Marsh EN |title=Coenzyme B12 (cobalamin)-dependent enzymes |journal=Essays Biochem. |volume=34 |pages=139–154 |date=1999 |pmid=10730193 |doi=10.1042/bse0340139 }}

Vitamin B₁₂ is absorbed by a B₁₂-specific transport proteins or via passive diffusion. Transport-mediated absorption and tissue delivery is a complex process involving three transport proteins: haptocorrin (HC), intrinsic factor (IF) and transcobalamin II (TC2), and respective membrane receptor proteins. HC is present in saliva. As vitamin-containing food is digested by hydrochloric acid and pepsin secreted into the stomach, HC binds the vitamin and protects it from acidic degradation.{{cite journal |vauthors=Guéant JL, Guéant-Rodriguez RM, Alpers DH |title=Vitamin B12 absorption and malabsorption |journal=Vitam Horm |series=Vitamins and Hormones |volume=119 |issue= |pages=241–274 |date=2022 |pmid=35337622 |doi=10.1016/bs.vh.2022.01.016 |isbn=978-0-323-99223-7 |url=}} Upon leaving the stomach the hydrochloric acid of the chyme is neutralized in the duodenum by bicarbonate,{{Cite book | vauthors = Maton A, Hopkins J, McLaughlin CW, Johnson S, Warner MQ, LaHart D, Wright JD |title=Human Biology and Health |publisher=Prentice Hall |year=1993 |location=Englewood Cliffs, New Jersey, USA |isbn=978-0-13-981176-0 |url-access=registration |url=https://archive.org/details/humanbiologyheal00scho }} and pancreatic proteases release the vitamin from HC, making it available to be bound by IF, which is a protein secreted by gastric parietal cells in response to the presence of food in the stomach. IF delivers the vitamin to receptor proteins cubilin and amnionless, which together form the cubam receptor in the distal ileum. The receptor is specific to the IF-B₁₂ complex, and so will not bind to any vitamin content that is not bound to IF.

Investigations into the intestinal absorption of B₁₂ confirm that the upper limit of absorption per single oral dose is about 1.5{{nbsp}}μg, with 50% efficiency. In contrast, the passive diffusion process of B₁₂ absorption — normally a very small portion of total absorption of the vitamin from food consumption — may exceed the haptocorrin- and IF-mediated absorption when oral doses of B₁₂ are very large, with roughly 1% efficiency. Thus, dietary supplement B₁₂ supplementation at 500 to 1000{{nbsp}}μg per day allows pernicious anemia and certain other defects in B₁₂ absorption to be treated with daily oral megadoses of B₁₂ without any correction of the underlying absorption defects.

After the IF/B₁₂ complex binds to cubam the complex is disassociated and the free vitamin is transported into the portal circulation. The vitamin is then transferred to TC2, which serves as the circulating plasma transporter, hereditary defects in the production of TC2 and its receptor may produce functional deficiencies in B₁₂ and infantile megaloblastic anemia, and abnormal B₁₂ related biochemistry, even in some cases with normal blood B₁₂ levels. For the vitamin to serve inside cells, the TC2-B₁₂ complex must bind to a cell receptor protein and be endocytosed. TC2 is degraded within a lysosome, and free B₁₂ is released into the cytoplasm, where it is transformed into the bioactive coenzyme by cellular enzymes.{{cite journal |vauthors=Seetharam B, Li N |title=Transcobalamin II and its cell surface receptor |journal=Vitam Horm |series=Vitamins & Hormones |volume=59 |issue= |pages=337–66 |date=2000 |pmid=10714245 |doi=10.1016/s0083-6729(00)59012-8 |isbn=978-0-12-709859-3 |url=}}

Individuals with pernicious anemia do not have the ability to produce intrinsic factor. Individuals who lack intrinsic factor have no ability to absorb vitamin B₁₂.{{medical citation needed|date=June 2025}} The lack of intrinsic factor is most commonly due to autoimmune gastritis, which causes an autoimmune attack on the parietal cells that create it in the stomach.{{medical citation needed|date=June 2025}}

Antacid drugs that neutralize stomach acid, as well as acid-suppressing agents such as proton-pump inhibitors, can inhibit the absorption of vitamin B₁₂ by preventing its release from food in the stomach.{{cite journal | vauthors = Lam JR, Schneider JL, Zhao W, Corley DA | title = Proton pump inhibitor and histamine 2 receptor antagonist use and vitamin B12 deficiency | journal = JAMA | volume = 310 | issue = 22 | pages = 2435–42 | date = December 2013 | pmid = 24327038 | doi = 10.1001/jama.2013.280490 | doi-access = free }} Other causes of B₁₂ malabsorption include bariatric surgery, pancreatic insufficiency, obstructive jaundice, tropical sprue, celiac disease, inherited intrinsic factor deficiency, and radiation enteritis affecting the distal ileum. Age is also a contributing factor: elderly individuals are often achlorhydric due to reduced parietal cell function in the stomach, increasing their risk of vitamin B₁₂ deficiency.{{cite journal | vauthors = Baik HW, Russell RM | title = Vitamin B12 deficiency in the elderly | journal = Annual Review of Nutrition | volume = 19 | pages = 357–77 | year = 1999 | pmid = 10448529 | doi = 10.1146/annurev.nutr.19.1.357 }} The ability to absorb vitamin B₁₂ declines with age, particularly in individuals over 60.

How fast B₁₂ levels change depends on the balance between how much B₁₂ is obtained from the diet, how much is secreted and how much is absorbed. The total amount of vitamin B₁₂ stored in the body is about 2–5{{nbsp}}mg in adults. Around 50% of this is stored in the liver. Approximately 0.1% of this is lost per day by secretions into the gut, as not all these secretions are reabsorbed. Bile is the main form of B₁₂ excretion; most of the B₁₂ secreted in the bile is recycled via enterohepatic circulation. Excess B₁₂ beyond the blood's binding capacity is typically excreted in urine. Owing to the extremely efficient enterohepatic circulation of B₁₂, the liver can store 3 to 5 years' worth of vitamin B₁₂; therefore, nutritional deficiency of this vitamin is rare in adults in the absence of malabsorption disorders. In the absence of intrinsic factor or distal ileum receptors, only months to a year of vitamin B₁₂ are stored.{{cite news |title=Vitamin B12 Deficiency – Nutritional Disorders |url=https://www.msdmanuals.com/professional/nutritional-disorders/vitamin-deficiency,-dependency,-and-toxicity/vitamin-b12-deficiency |access-date=24 May 2022 |website=MSD Manual Professional Edition |language=en}}

Vitamin B₁₂ through its involvement in one-carbon metabolism plays a key role in cellular reprogramming and tissue regeneration and epigenetic regulation. Cellular reprogramming is the process by which somatic cells can be converted to a pluripotent state. Vitamin B₁₂ levels affect the histone modification H3K36me3, which suppresses illegitimate transcription outside of gene promoters. Mice undergoing in vivo reprogramming were found to become depleted in B₁₂ and show signs of methionine starvation while supplementing reprogramming mice and cells with B₁₂ increased reprogramming efficiency, indicating a cell-intrinsic effect.{{cite journal | vauthors = Kovatcheva M, Melendez E, Chondronasiou D, Pietrocola F, Bernad R, Caballe A, Junza A, Capellades J, Holguín-Horcajo A, Prats N, Durand S, Rovira M, Yanes O, Stephan-Otto Attolini C, Kroemer G, Serrano M | title = Vitamin B₁₂ is a limiting factor for induced cellular plasticity and tissue repair | journal = Nature Metabolism | date = November 2023 | volume = 5 | issue = 11 | pages = 1911–1930 | pmid = 37973897 | doi = 10.1038/s42255-023-00916-6 | doi-access = free | pmc = 10663163 }}{{cite journal | vauthors = Vílchez-Acosta A, Desdín-Micó G, Ocampo A | title = Vitamin B₁₂ emerges as key player during cellular reprogramming | journal = Nature Metabolism | date = November 2023 | volume = 5 | issue = 11 | pages = 1844–1845 | pmid = 37973898 | doi = 10.1038/s42255-023-00917-5 | s2cid = 265273574 }}

{{Main|Cobalamin biosynthesis}}

Vitamin B₁₂ is derived from a tetrapyrrolic structural framework created by the enzymes deaminase and cosynthetase which transform aminolevulinic acid via porphobilinogen and hydroxymethylbilane to uroporphyrinogen III. The latter is the first macrocyclic intermediate common to heme, chlorophyll, siroheme and B₁₂ itself.{{cite journal | vauthors = Battersby AR, Fookes CJ, Matcham GW, McDonald E | s2cid = 9070849 | title = Biosynthesis of the pigments of life: formation of the macrocycle | journal = Nature | volume = 285 | issue = 5759 | pages = 17–21 | date = May 1980 | pmid = 6769048 | doi = 10.1038/285017a0 | bibcode = 1980Natur.285...17B | doi-access = free }}{{cite journal | vauthors = Frank S, Brindley AA, Deery E, Heathcote P, Lawrence AD, Leech HK, Pickersgill RW, Warren MJ | title = Anaerobic synthesis of vitamin B12: characterization of the early steps in the pathway | journal = Biochemical Society Transactions | volume = 33 | issue = Pt 4 | pages = 811–814 | date = August 2005 | pmid = 16042604 | doi = 10.1042/BST0330811 | url = https://portlandpress.com/biochemsoctrans/article-pdf/33/4/811/539749/bst0330811.pdf }} Later steps, especially the incorporation of the additional methyl groups of its structure, were investigated using ¹³C methyl-labelled S-adenosyl methionine. It was not until a genetically engineered strain of Pseudomonas denitrificans was used, in which eight of the genes involved in the biosynthesis of the vitamin had been overexpressed, that the complete sequence of methylation and other steps could be determined, thus fully establishing all the intermediates in the pathway.{{cite journal |title = How Nature builds the pigments of life | vauthors = Battersby AR |s2cid = 83942303 |journal = Pure and Applied Chemistry |year = 1993 |volume = 65 |issue = 6 |pages = 1113–1122 |author-link = Alan Battersby |url = https://www.degruyter.com/downloadpdf/j/pac.1993.65.issue-6/pac199365061113/pac199365061113.pdf |doi = 10.1351/pac199365061113 |access-date = 20 February 2020 |archive-url = https://web.archive.org/web/20180724154121/https://www.degruyter.com/downloadpdf/j/pac.1993.65.issue-6/pac199365061113/pac199365061113.pdf |archive-date = 24 July 2018 |url-status = live }}{{cite book | vauthors = Battersby A |title=The 1702 chair of chemistry at Cambridge: transformation and change | veditors = Archer MD, Haley CD |editor-link=Mary Archer |chapter= Chapter 11: Discovering the wonder of how Nature builds its molecules |pages=xvi, 257–282 |publisher=Cambridge University Press |year=2005 |isbn=0-521-82873-2}}

Species from the following genera and the following individual species are known to synthesize B₁₂: Propionibacterium shermanii, Pseudomonas denitrificans, Streptomyces griseus, Acetobacterium, Aerobacter, Agrobacterium, Alcaligenes, Azotobacter, Bacillus, Clostridium, Corynebacterium, Flavobacterium, Lactobacillus, Micromonospora, Mycobacterium, Nocardia, Proteus,

Rhizobium, Salmonella, Serratia, Streptococcus and Xanthomonas.{{cite journal|vauthors=Perlman D|year=1959|title=Microbial synthesis of cobamides|journal=Advances in Applied Microbiology|volume=1|pages=87–122|doi=10.1016/S0065-2164(08)70476-3 |pmid=13854292}}{{cite journal|vauthors=Martens JH, Barg H, Warren MJ, Jahn D|s2cid=22232461|date=March 2002|title=Microbial production of vitamin B12|journal=Applied Microbiology and Biotechnology|volume=58|issue=3|pages=275–285|doi=10.1007/s00253-001-0902-7|pmid=11935176}}

Industrial production of B₁₂ is achieved through fermentation of selected microorganisms.{{cite journal |vauthors=Fang H, Kang J, Zhang D |title=Microbial production of vitamin B12: a review and future perspectives |journal=Microb. Cell Fact. |volume=16 |issue=1 |page=15 |date=January 2017 |pmid=28137297 |pmc=5282855 |doi=10.1186/s12934-017-0631-y |doi-access=free }} Streptomyces griseus, a bacterium once thought to be a fungus, was the commercial source of vitamin B₁₂ for many years.{{cite journal | vauthors = Linnell JC, Matthews DM | s2cid = 27191837 | title = Cobalamin metabolism and its clinical aspects | journal = Clinical Science | volume = 66 | issue = 2 | pages = 113–121 | date = February 1984 | pmid = 6420106 | doi = 10.1042/cs0660113 | url = https://portlandpress.com/clinsci/article-pdf/66/2/113/517226/cs0660113.pdf }} The species Pseudomonas denitrificans and Propionibacterium freudenreichii subsp. shermanii are more commonly used today. These are grown under special conditions to enhance yield. Rhone-Poulenc improved yield via genetic engineering P. denitrificans.{{cite journal |vauthors=Piwowarek K, Lipińska E, Hać-Szymańczuk E, Kieliszek M, Ścibisz I |title=Propionibacterium spp.-source of propionic acid, vitamin B12, and other metabolites important for the industry |journal=Appl. Microbiol. Biotechnol. |volume=102 |issue=2 |pages=515–538 |date=January 2018 |pmid=29167919 |pmc=5756557 |doi=10.1007/s00253-017-8616-7 }} Propionibacterium, the other commonly used bacteria, produce no exotoxins or endotoxins and are generally recognized as safe (have been granted GRAS status) by the Food and Drug Administration of the United States.{{cite journal|url=https://www.academia.edu/171654|vauthors=Riaz M, Ansari ZA, Iqbal F, Akram M|title=Microbial production of vitamin B₁₂ by methanol utilizing strain of Pseudomonas species|journal=Pakistan Journal of Biochemistry & Molecular Biology|year=2007|volume=40|pages=5–10}}{{Dead link|date=May 2022 |bot=InternetArchiveBot |fix-attempted=yes }}

The total world production of vitamin B₁₂ in 2008 was 35,000 kg (77,000 lb).{{cite news | vauthors = Zhang Y |date=26 January 2009|url=http://www.highbeam.com/doc/1G1-192899762.html|archive-url=https://web.archive.org/web/20130513111828/http://www.highbeam.com/doc/1G1-192899762.html|archive-date=13 May 2013|title=New round of price slashing in vitamin B₁₂ sector (Fine and Specialty)|website=China Chemical Reporter}}

{{Main|Vitamin B12 total synthesis|l1=Vitamin B₁₂ total synthesis}}

The complete laboratory synthesis of B₁₂ was achieved by Robert Burns Woodward{{cite journal|doi=10.1007/BF02837864 |title=Woodward's synthesis of vitamin B₁₂ |date=June 2003 | vauthors = Khan AG, Eswaran SV |s2cid=120110443 |journal=Resonance |volume=8 |pages=8–16|issue=6}} and Albert Eschenmoser in 1972.{{cite journal | vauthors = Eschenmoser A, Wintner CE | title = Natural product synthesis and vitamin B12 | journal = Science | volume = 196 | issue = 4297 | pages = 1410–1420 | date = June 1977 | pmid = 867037 | doi = 10.1126/science.867037 | bibcode = 1977Sci...196.1410E }}{{cite journal|doi=10.1002/1099-0690(200301)2003:1<30::AID-EJOC30>3.0.CO;2-I |title=Total Synthesis of Cobyric Acid: Historical Development and Recent Synthetic Innovations |year=2003 | vauthors = Riether D, Mulzer J |journal=European Journal of Organic Chemistry |volume=2003 |pages=30–45}} The work required the effort of 91 postdoctoral fellows (mostly at Harvard) and 12 PhD students (at ETH Zurich) from 19 nations. The synthesis constitutes a formal total synthesis, since the research groups only prepared the known intermediate cobyric acid, whose chemical conversion to vitamin B₁₂ was previously reported. This synthesis of vitamin B₁₂ is of no practical consequence due to its length, taking 72 chemical steps and giving an overall chemical yield well under 0.01%.{{cite web|url=https://www.synarchive.com/syn/71|title=Synthesis of Cyanocobalamin by Robert B. Woodward (1973)|website=www.synarchive.com|access-date=15 February 2018|archive-url=https://web.archive.org/web/20180216033904/https://www.synarchive.com/syn/71|archive-date=16 February 2018|url-status=live}} Although there have been sporadic synthetic efforts since 1972, the Eschenmoser–Woodward synthesis remains the only completed (formal) total synthesis.

{{Further|Vitamin#History}}

Between 1849 and 1887, Thomas Addison described a case of pernicious anemia, William Osler and William Gardner first described a case of neuropathy, Hayem described large red cells in the peripheral blood in this condition, which he called "giant blood corpuscles" (now called macrocytes), Paul Ehrlich identified megaloblasts in the bone marrow, and Ludwig Lichtheim described a case of myelopathy.{{cite book | vauthors = Greer JP |title=Wintrobe's Clinical Hematology Thirteenth Edition |place=Philadelphia, PA |publisher= Wolters Kluwer/Lippincott Williams & Wilkins |year=2014 |isbn=978-1-4511-7268-3}} Chapter 36: Megaloblastic anemias: disorders of impaired DNA synthesis by Ralph Carmel

During the 1920s, George Whipple discovered that ingesting large amounts of raw liver seemed to most rapidly cure the anemia of blood loss in dogs, and hypothesized that eating liver might treat pernicious anemia.{{cite web|url=https://www.nobelprize.org/nobel_prizes/medicine/laureates/1934/whipple-bio.html|title=George H. Whipple – Biographical|website=www.nobelprize.org|access-date=10 October 2017|archive-url=https://web.archive.org/web/20170913135825/https://www.nobelprize.org/nobel_prizes/medicine/laureates/1934/whipple-bio.html|archive-date=13 September 2017|url-status=live}} Edwin Cohn prepared a liver extract that was 50 to 100 times more potent in treating pernicious anemia than the natural liver products. William Castle demonstrated that gastric juice contained an "intrinsic factor" which when combined with meat ingestion resulted in absorption of the vitamin in this condition. In 1934, George Whipple shared the 1934 Nobel Prize in Physiology or Medicine with William P. Murphy and George Minot for discovery of an effective treatment for pernicious anemia using liver concentrate, later found to contain a large amount of vitamin B₁₂.{{cite web|title=The Nobel Prize in Physiology or Medicine 1934|url=https://www.nobelprize.org/prizes/medicine/1934/summary/|access-date=23 February 2023|website=NobelPrize.org|language=en-US}}

While working at the Bureau of Dairy Industry, U.S. Department of Agriculture, Mary Shaw Shorb was assigned work on the bacterial strain Lactobacillus lactis Dorner (LLD), which was used to make yogurt and other cultured dairy products. The culture medium for LLD required liver extract. Shorb knew that the same liver extract was used to treat pernicious anemia (her father-in-law had died from the disease), and concluded that LLD could be developed as an assay method to identify the active compound. While at the University of Maryland, she received a small grant from Merck, and in collaboration with Karl Folkers from that company, developed the LLD assay. This identified "LLD factor" as essential for the bacteria's growth.{{cite web|url=https://ansc.umd.edu/news/annual-events/shorb|title=Mary Shorb Lecture in Nutrition|access-date=3 March 2016|archive-url=https://web.archive.org/web/20160304085215/https://ansc.umd.edu/news/annual-events/shorb|archive-date=4 March 2016}} Shorb, Folker and Alexander R. Todd, at the University of Cambridge, used the LLD assay to extract the anti-pernicious anemia factor from liver extracts, purify it, and name it vitamin B₁₂.{{cite web | url = http://ansc.umd.edu/shorb/ | date = 10 May 2012 | vauthors = Shorb MS | title = Annual Lecture | publisher = Department of Animal & Avian Sciences, University of Maryland | access-date = 2 August 2014 | archive-url = https://archive.today/20121212131529/http://ansc.umd.edu/shorb/ | archive-date = 12 December 2012 | df = mdy-all }} In 1955, Todd helped elucidate the structure of the vitamin. The complete chemical structure of the molecule was determined by Dorothy Hodgkin based on crystallographic data and published in 1955{{cite journal|doi=10.1038/176325a0|pmid=13253565|title=Structure of Vitamin B12: The Crystal Structure of the Hexacarboxylic Acid derived from B12 and the Molecular Structure of the Vitamin|journal=Nature|volume=176|issue=4477|pages=325–28|year=1955|vauthors = Hodgkin DC, Pickworth J, Robertson JH, Trueblood KN, Prosen RJ, White JG |bibcode=1955Natur.176..325H|s2cid=4220926}} and 1956,{{cite journal|vauthors = Hodgkin DC, Kamper J, Mackay M, Pickworth J, Trueblood KN, White JG |s2cid=4210164|title=Structure of vitamin B12|journal=Nature|volume=178|issue=4524|pages=64–66|date=July 1956 |doi=10.1038/178064a0|pmid=13348621|bibcode=1956Natur.178...64H}} for which, and for other crystallographic analyses, she was awarded the Nobel Prize in Chemistry in 1964.{{cite journal | vauthors = Dodson G | title = Dorothy Mary Crowfoot Hodgkin, 12 May 1910 – 29 July 1994 | journal = Biographical Memoirs of Fellows of the Royal Society | volume = 48 | pages = 181–219 | date = December 2002 | pmid = 13678070 | doi = 10.1098/rsbm.2002.0011 | s2cid = 61764553 }} Hodgkin went on to decipher the structure of insulin.

George Whipple, George Minot and William Murphy were awarded the Nobel Prize in 1934 for their work on the vitamin. Three other Nobel laureates, Alexander R. Todd (1957), Dorothy Hodgkin (1964) and Robert Burns Woodward (1965) made important contributions to its study.{{cite web|url=https://www.nobelprize.org/prizes/themes/the-nobel-prize-and-the-discovery-of-vitamins/ | vauthors = Carpenter KJ |title=The Nobel Prize and the discovery of vitamins |website=nobelprize.org |access-date=19 November 2023 |archive-url=https://web.archive.org/web/20230820182152/https://www.nobelprize.org/prizes/themes/the-nobel-prize-and-the-discovery-of-vitamins/ |archive-date=20 August 2023 |url-status=live}}

{{Gallery

|title=Nobel laureates for discoveries relating to vitamin B₁₂

|width=180

|height=170

|align=center

|File:George Whipple nobel.jpg|George Whipple

|File:George Minot nobel.jpg|George Minot

|File:William P Murphy.jpg|William P. Murphy

|File:Alexander Todd Nobel.jpg|Alexander R. Todd

|File:Dorothy Hodgkin Nobel.jpg|Dorothy Hodgkin

|File:Robert_Woodward_Nobel.jpg|Robert Burns Woodward

}}

Industrial production of vitamin B₁₂ is achieved through fermentation of selected microorganisms. As noted above, the completely synthetic laboratory synthesis of B12 was achieved by Robert Burns Woodward and Albert Eschenmoser in 1972, though this process has no commercial potential, requiring more than 70 steps and having a yield well below 0.01%.

In the 1970s, John A. Myers, a physician residing in Baltimore, developed a program of injecting vitamins and minerals intravenously for various medical conditions. The formula included {{value|1000|u=μg}} of cyanocobalamin. This came to be known as the Myers' cocktail. After he died in 1984, other physicians and naturopaths took up prescribing "intravenous micronutrient therapy" with unsubstantiated health claims for treating fatigue, low energy, stress, anxiety, migraine, depression, immunocompromised, promoting weight loss, and more.{{cite journal |vauthors=Gaby AR |title=Intravenous nutrient therapy: the "Myers' cocktail" |journal=Altern Med Rev |volume=7 |issue=5 |pages=389–403 |date=October 2002 |pmid=12410623 }} However, other than a report on case studies there are no benefits confirmed in the scientific literature.{{cite web| vauthors = Gavura S |title=A closer look at vitamin injections|url=https://www.sciencebasedmedicine.org/a-closer-look-at-vitamin-injections/|website=Science-Based Medicine|access-date=10 January 2020|date=24 May 2013|archive-url=https://web.archive.org/web/20200111115726/https://sciencebasedmedicine.org/a-closer-look-at-vitamin-injections/|archive-date=11 January 2020|url-status=live}} Healthcare practitioners at clinics and spas prescribe versions of these intravenous combination products, but also intramuscular injections of just vitamin B₁₂. A Mayo Clinic review concluded that there is no solid evidence that vitamin B₁₂ injections provide an energy boost or aid weight loss.{{cite web |url=https://www.mayoclinic.org/healthy-lifestyle/weight-loss/expert-answers/vitamin-b12-injections/faq-20058145 |title=Are vitamin B-12 injections helpful for weight loss? | vauthors = Bauer BA |date=29 March 2018 |website=Mayo Clinic |access-date=11 January 2020 |archive-url=https://web.archive.org/web/20191127135506/https://www.mayoclinic.org/healthy-lifestyle/weight-loss/expert-answers/vitamin-b12-injections/faq-20058145 |archive-date=27 November 2019 |url-status=live }}

There is evidence that for elderly people, physicians often repeatedly prescribe and administer cyanocobalamin injections inappropriately, evidenced by the majority of subjects in one large study either having had normal serum concentrations or having not been tested before the injections.{{cite journal | vauthors = Silverstein WK, Lin Y, Dharma C, Croxford R, Earle CC, Cheung MC | title=Prevalence of Inappropriateness of Parenteral Vitamin B12 Administration in Ontario, Canada | journal=JAMA Internal Medicine | volume=179 | issue=10 | pages=1434–1436 | date=July 2019 | issn=2168-6106 | doi=10.1001/jamainternmed.2019.1859 | pmid=31305876 | pmc=6632124}}

• Adenosylcobalamin
• Cobalamin biosynthesis
• Cyanocobalamin
• Hydroxocobalamin
• Methylcobalamin
• Vitamins

• {{cite journal |vauthors=Gherasim C, Lofgren M, Banerjee R |title=Navigating the B(12) road: assimilation, delivery, and disorders of cobalamin |journal=J. Biol. Chem. |volume=288 |issue=19 |pages=13186–13193 |date=May 2013 |pmid=23539619 |pmc=3650358 |doi=10.1074/jbc.R113.458810 |doi-access=free }}

{{Reflist}}

• {{MeSH name|Cyanocobalamin}}

{{Vitamins}}

{{Tetrapyrroles}}

{{Portal bar | Medicine}}

{{Authority control}}

Category:B vitamins

Category:Cofactors

Category:Organocobalt compounds

Category:Cobalt(III) compounds

Category:Cobalt(II) compounds