What it is
Vitamin B12 is a large, red molecule built around a single atom of cobalt. The body cannot make it; only certain bacteria can, and people get it from animal foods. Cells need it for two chemical jobs: making DNA in newly forming blood cells, and keeping nerves healthy. Without enough B12, people develop an anemia with oversized red blood cells and can suffer nerve damage that may become permanent.
“Vitamin B12” is a family name. Cyanocobalamin is the stable, manufactured form found in the approved injections and in many supplements. Methylcobalamin and adenosylcobalamin are the two forms the body actually works with. Hydroxocobalamin is another natural form, and it is also the active ingredient of 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 begins with pernicious anemia, a disease that was fatal in the early 1900s. George Whipple found that liver in the diet speeded blood recovery in dogs made anemic by bleeding. In 1926 George Minot and William Murphy reported that a liver-rich diet kept patients with pernicious anemia alive. The three shared the 1934 Nobel Prize in Physiology or Medicine.
Finding the active factor in liver took two more decades. In 1948 chemists at Merck in the US and, separately, E. Lester Smith at Glaxo in the UK isolated it as red crystals. Dorothy Hodgkin’s team at Oxford worked out its three-dimensional shape by X-ray crystallography and published the structure in 1956, work cited in her 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 genuine B12 deficiency the evidence is old and consistent: injections correct the anemia, and the injection label states that people with pernicious anemia will need B12 injections for life. Later research asked whether injections are always required. In a 1998 US trial of 38 deficient patients, a large daily oral dose (2 mg) corrected blood counts and nerve symptoms as well as injections did.
Very high doses of methylcobalamin have been studied in the nerve disease ALS. A Japanese trial of 373 patients missed its main goals, but a follow-up trial in 130 recently diagnosed patients reported slower loss of function over 16 weeks with 50 mg injections twice a week. The trials described here concern deficiency and ALS; they do not test B12 injections 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).
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). Evidence for methylcobalamin outside deficiency and ALS is limited.
Regulatory picture
Three separate facts. Approval: cyanocobalamin injection has been FDA approved for decades for B12 deficiency caused by poor absorption, including pernicious anemia. A prescription nasal spray, Nascobal, was approved in 2005; its maker stopped selling it in 2024, but generic versions remain. Hydroxocobalamin is approved both as an ordinary injection and, as Cyanokit, as a cyanide antidote. No methylcobalamin product is FDA approved.
Compounding: pharmacies may not make near-copies of approved cyanocobalamin products while those are available. Methylcobalamin injections in the US are compounded; the FDA lists methylcobalamin as “under evaluation” (Category 1) for its bulk-ingredient list, which means no final decision has been made. An FDA advisory committee voted 9 to 5 in 2021 to recommend adding it to the list, but the vote is not binding and the FDA has not acted on it. Supply: hydroxocobalamin injection was listed as in shortage when this was written.
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.
