What it is
Vitamin B12 is a large, red molecule. At its center is one atom of cobalt, a metal. The body cannot make B12. Only certain bacteria can. People get it from animal foods.
Cells need B12 for two jobs. It helps make DNA in new blood cells. It also keeps nerves healthy. Without enough B12, people can get anemia (too few healthy red blood cells). In this kind of anemia, the red blood cells are too big. People can also get nerve damage, and it may become permanent.
“Vitamin B12” is a family name for several forms. Cyanocobalamin is a stable, man-made form. It is in the approved shots and in many supplements. Methylcobalamin and adenosylcobalamin are the two forms the body actually uses. Hydroxocobalamin is another natural form. It is also the active ingredient in an approved antidote for cyanide poisoning.
Cobalamins share a corrin ring coordinating a central cobalt ion, with a 5,6-dimethylbenzimidazole nucleotide as the lower axial ligand; the upper ligand defines the form (cyano, methyl, hydroxo or 5′-deoxyadenosyl). Cyanocobalamin (C63H88CoN14O14P, 1355.4 g/mol) is converted inside cells to the two coenzymes. Methylcobalamin is the cofactor for cytosolic methionine synthase, which methylates homocysteine to methionine while regenerating tetrahydrofolate from 5-methyltetrahydrofolate; deficiency traps folate and impairs DNA synthesis, producing megaloblastic anemia. Adenosylcobalamin is the cofactor for mitochondrial methylmalonyl-CoA mutase, so deficiency raises methylmalonic acid.
Food B12 is released by digestion, bound to intrinsic factor secreted by the stomach, and absorbed in the terminal ileum; the Nascobal label notes that about 1% of a large oral dose is absorbed by passive diffusion. In plasma it is carried by transcobalamin, and the liver is the main store. After intramuscular cyanocobalamin, plasma levels peak within an hour, and 50–98% of a 100 or 1,000 mcg dose appears in the urine within 48 hours, according to the injection label.
Who made it and when
The story starts with pernicious anemia. This blood disease killed people in the early 1900s. George Whipple fed liver to dogs that had lost blood. Their blood recovered faster. In 1926, George Minot and William Murphy reported that a diet rich in liver kept patients with pernicious anemia alive. The three men shared the 1934 Nobel Prize in Physiology or Medicine.
Finding the helpful substance in liver took two more decades. In 1948, chemists at Merck in the US found it. So did E. Lester Smith at Glaxo in the UK, working on his own. They pulled it out as red crystals. Dorothy Hodgkin’s team at Oxford then worked out its 3D shape using X-rays. They published it in 1956. This work was cited when she won the 1964 Nobel Prize in Chemistry.
The 1934 Nobel Prize went to Whipple, Minot and Murphy “for their discoveries concerning liver therapy in cases of anaemia”. Rickes, Brink, Koniuszy, Wood and Folkers (Merck) reported crystalline vitamin B12 in Science in April 1948; Smith (Glaxo) reported purification of the anti-pernicious-anemia factor from liver in Nature the same month, and the presence of cobalt that July. Hodgkin, Kamper, Mackay, Pickworth, Trueblood and White published the structure in Nature in 1956. A total chemical synthesis by the Woodward and Eschenmoser groups followed in the early 1970s; commercial production relies on bacterial fermentation.
The earliest dated single-ingredient cyanocobalamin injection application in Drugs@FDA is NDA 007012, approved 1949-09-15; the current reference listed drug is American Regent’s ANDA 080737. Nascobal nasal gel was approved in 1996 and Nascobal nasal spray on 2005-01-31; both are now discontinued, while generic cyanocobalamin nasal sprays remain listed. Cyanokit (hydroxocobalamin 5 g for IV infusion) was approved on 2006-12-15. In Japan, Eisai’s methylcobalamin injection Rozebalamin was approved in September 2024 to slow functional decline in ALS; it has no US approval.
What the data say
For true B12 deficiency (not enough B12 in the body), the evidence is old and steady. Shots fix the anemia. The shot’s label says people with pernicious anemia will need B12 shots for life. Later research asked if shots are always needed. A 1998 US trial looked at 38 people low in B12. A large daily dose by mouth (2 mg) fixed blood counts and nerve symptoms as well as shots did. Two newer reviews pooled studies of B12 by mouth, under the tongue and by shot (one covered 16 studies with 6,098 people). All routes raised blood B12, and the reviews found no clear difference between them. One of the reviews was paid for by a B12 maker.
Very high doses of methylcobalamin have been tested in ALS, a disease of the nerves. A Japanese trial of 373 patients did not meet its main goals. A later trial looked at 130 patients who were recently diagnosed. They got 50 mg shots twice a week. Over 16 weeks, they lost function more slowly. A 2026 follow-on study gave the 50 mg shots to 144 people with advanced ALS for up to a year. Side effects linked to the drug were rare (3.5%), and none made anyone stop. Some of the authors work for the drug’s maker. These trials were about B12 deficiency and ALS. They did not test B12 shots in people whose B12 levels are already normal.
The injection label states that patients with pernicious anemia will require parenteral B12 for the rest of their lives, and that deficiency allowed to progress for longer than 3 months may produce permanent degenerative lesions of the spinal cord. Kuzminski et al. (Blood 1998) randomized 38 newly diagnosed patients to cyanocobalamin 1 mg intramuscularly on nine occasions over 90 days or 2 mg orally daily for 120 days. Among 33 evaluable patients, hematologic and neurologic correction was indistinguishable; at 4 months mean serum cobalamin was 1,005 vs 325 pg/mL and methylmalonic acid 169 vs 265 nmol/L (oral vs intramuscular). Pooled data point the same way: Mazur et al. (Front Pharmacol 2025; 16 studies, 6,098 participants) found a pooled serum cobalamin rise of 402.6 pg/mL (95% CI 293.6–511.5) and a homocysteine fall of 4.83 µmol/L, with no significant difference between oral, sublingual and intramuscular routes (p = 0.270). Debone et al. (EClinicalMedicine 2026; 13 studies including 7 RCTs, searches to 2026-07-13; funded by Myralis, a manufacturer) found that all routes raised serum B12 and that oral dosing gave comparable or superior biochemical responses to intramuscular injection in several studies, while rating every included RCT at “some concerns” for bias.
In ALS, Eisai’s phase 2/3 study (NCT00444613; n=373; 25 or 50 mg intramuscularly twice weekly) did not meet either primary endpoint (minimum p = 0.087), although post hoc analysis favored patients enrolled within 12 months of onset. JETALS (NCT03548311; n=130) enrolled that population and reported a least-squares mean ALSFRS-R difference of 1.97 points at week 16 (−2.66 vs −4.63; 95% CI 0.44–3.50; P = .01), with similar adverse-event incidence in both arms (Oki et al., JAMA Neurol 2022). In the open-label extension of E0302 (Kaji et al., J Neurol Sci 2026; 144 patients with advanced ALS; methylcobalamin 50 mg intramuscularly twice weekly for up to 52 weeks; Eisai-employed co-authors), adverse drug reactions occurred in 3.5% (proteinuria 2.1%), none led to discontinuation or death, and 52-week survival was 85.7%. Evidence for methylcobalamin outside deficiency and ALS is limited.
Regulatory picture
There are three separate points here.
Approval: Cyanocobalamin shots have been FDA approved for decades. They treat B12 deficiency caused by the body not absorbing B12 well. This includes pernicious anemia. A prescription nasal spray called Nascobal was approved in 2005. Its maker stopped selling it in 2024, but generic versions are still around. Hydroxocobalamin is approved as a regular shot. It is also approved as Cyanokit, an antidote for cyanide poisoning. No methylcobalamin product is FDA approved.
Compounding (pharmacies mixing their own versions): Pharmacies may not make near-copies of approved cyanocobalamin products while those are available. In the US, methylcobalamin shots are made by compounding pharmacies. The FDA keeps a list of bulk ingredients that pharmacies may use. For that list, it marks methylcobalamin as “under evaluation” (Category 1). This means no final decision has been made. In 2021, an FDA advisory group voted 9 to 5 to add it to the list. But the vote does not have to be followed, and the FDA has not acted on it.
Supply: Hydroxocobalamin shots were still listed as in short supply in October 2026. Cyanocobalamin and methylcobalamin were not on the shortage list.
Recalls: In July 2026 American Regent recalled some batches of cyanocobalamin injection. Bits of hair, glass or a chemical were found in vials. No one was reported harmed. In 2026 two compounding pharmacies also recalled weight-loss shots (semaglutide or tirzepatide) mixed with B12. The FDA’s reports say their sterility could not be assured.
Approval: the cyanocobalamin injection label covers B12 deficiency due to malabsorption, including Addisonian (pernicious) anemia, GI pathology or surgery, fish tapeworm infestation, pancreatic or bowel malignancy and folic acid deficiency, plus the Schilling test. The Nascobal label is limited to adults: maintenance in pernicious anemia in remission without nervous system involvement, other deficiency not due to pernicious anemia, and prevention when requirements exceed normal. After FDA’s 2025-04-09 Federal Register determination that Nascobal was not withdrawn for safety or effectiveness, FDA may keep approving generics that reference it.
Compounding: cyanocobalamin is a component of approved drugs and has a USP monograph, so 503A compounding from bulk is lawful except for essentially copies of a commercially available product (section 503A(b)(1)(D)). Cyanocobalamin injection was not on FDA’s shortage list when checked, so this article records compounding as restricted. Methylcobalamin sits in 503A Category 1 (list updated 2026-05-14) and is not on the bulks list in 21 CFR 216.23; under FDA’s interim policy the agency does not intend to act against its use while under evaluation, if other conditions are met. The Pharmacy Compounding Advisory Committee reviewed methylcobalamin on 2021-06-09 and voted 9–5 in favour of inclusion; the vote is non-binding, and FDA rulemaking would be required to add it to the list, which had not happened as of the 2026-05-14 update.
Supply: FDA’s shortage database lists Hydroxocobalamin Injection as “Currently in Shortage” (first posted 11/04/2024); Teva’s 30 mL multi-dose vial (NDC 0591-2888-30) is “Unavailable” with recovery estimated for mid-November 2026 (reverified 10/15/2026), and Cyanokit (NDC 50633-310-11) is “Limited Availability” (10/19/2026). Cyanocobalamin and methylcobalamin have no shortage entry.
Recalls: American Regent, Inc. (Shirley, New York) initiated a Class II recall on 2026-07-24 (report 2026-08-26) of Cyanocobalamin Injection USP 1,000 mcg/mL, covering 10 mL multi-dose vials (NDC 0517-0032-01 and -25, lot 25082, expiring 2027-03-31, 26,450 vials; D-0793-2026) and 1 mL vials (NDC 0517-0031-01 and -25, lots 24297 and 24364; D-0792-2026), for “Presence of Particulate Matter: Product contaminated with particulate matter identified as hair, glass and/or paraformaldehyde”, as part of a 12-product event; the California Board of Pharmacy’s 2026-08-04 notice describes a retail-level recall with possible phlebitis, capillary occlusion, thromboembolism or immunologic response and no adverse events reported. Compounded B12 blends were also recalled in 2026 for lack of assurance of sterility: Carolina Infusion, LLC’s semaglutide/cyanocobalamin and tirzepatide/cyanocobalamin prefilled syringes (initiated 2026-09-10; formulation using bacteriostatic water and processing equipment cited; D-0019-2027, D-0026-2027 to D-0030-2027) and Payless Compounders LLC / Northwest Compounders’ semaglutide-glycine-cyanocobalamin 2.5 mg/5 mg injectable (2026-03-06; D-0471-2026).
