B12 (Methylcobalamin)

Origin and structure

B12 is not a peptide. Vitamin B12, or cobalamin, is a large vitamin built around a single cobalt atom held in a ring structure called a corrin, with a nucleotide 'tail' below the ring and one group on top. That upper group names the form: cyanide in cyanocobalamin, a hydroxyl group in hydroxocobalamin, a methyl group in methylcobalamin (international name mecobalamin) and a deoxyadenosyl group in adenosylcobalamin. Methylcobalamin and adenosylcobalamin are the two forms the body's enzymes work with; cyanocobalamin and hydroxocobalamin are the forms in the licensed medicines.

People get vitamin B12 from animal foods or supplements; a diet without any animal products supplies none. Active absorption depends on intrinsic factor, a protein made by the stomach lining that carries the vitamin to the last part of the small intestine. Apart from that route, about 1% of an oral dose passes the gut wall by passive diffusion, which is why very high oral doses can work even without intrinsic factor. The body stores about 2,000 to 3,000 µg, most of it in the liver, which is considered enough for three to four years, so a deficiency usually develops slowly.

The vitamin was found by working back from pernicious anaemia, an autoimmune disease in which the stomach stops making intrinsic factor. It was once fatal, until doctors found that patients recovered on large amounts of liver, a discovery that earned a Nobel Prize; chemists later isolated the active factor from liver and solved its structure by X-ray crystallography.

How it works

Vitamin B12 is a cofactor for two enzymes. In the cytosol, methylcobalamin lets methionine synthase move a methyl group from folate to homocysteine, making methionine; this step also keeps folate in the form needed to build DNA, which is why a shortage hits fast-dividing cells such as those of the bone marrow. In the mitochondria, adenosylcobalamin lets methylmalonyl-CoA mutase process certain fatty acids and amino acids. In a deficiency, homocysteine and methylmalonic acid build up, the bone marrow makes too few, oversized red blood cells (megaloblastic anaemia), and nerves in the spinal cord and limbs can be damaged.

Folic acid can correct the anaemia of a B12 deficiency without stopping the nerve damage, and according to the US label a deficiency left for more than three months can cause permanent damage to the spinal cord. The labels ask for the nature and cause of an anaemia to be established before B12 is given.

The form that is taken matters less than its name suggests. Inside the cell a processing protein, MMACHC, first strips the upper group from whichever form arrives: it removes the cyanide from cyanocobalamin and, using glutathione, the methyl or adenosyl group from methylcobalamin and adenosylcobalamin. The cell then rebuilds both active forms from the same intermediate, so methylcobalamin is not handed on intact to the enzyme that uses it.

Is B12 approved?

Yes, as a medicine for vitamin B12 deficiency, but in other forms than methylcobalamin. B12 medicines in the Netherlands and the US contain hydroxocobalamin or cyanocobalamin; neither the EMA nor the FDA has authorised a medicine with methylcobalamin, and none is on the Dutch medicines register. Methylcobalamin is sold legally as a food supplement.

Research-grade methylcobalamin is none of these products. It has no marketing authorisation, is not made under a medicines licence and may not be used in people. The approvals below describe the licensed products only.

• Netherlands: B12 injections are prescription-only medicines for B12 deficiency with megaloblastic (pernicious) anaemia, with or without nerve damage, for example after stomach surgery, with atrophic stomach lining or after bowel resection for Crohn's disease. The oldest, Hydrocobamine (1,000 µg hydroxocobalamin in a 2 ml ampoule), has been registered since 1966; other hydroxocobalamin injections and a cyanocobalamin injection are also on the register. Cyanocobalamin tablets of 1 mg are sold without prescription and are not reimbursed.
• Dutch guideline: the Farmacotherapeutisch Kompas makes oral cyanocobalamin the first choice for anaemia from B12 deficiency, at the dose of the GP guideline on anaemia (NHG-Standaard Anemie, 2024): 1 mg once a day. According to the Kompas this also works when absorption is impaired by inflammatory bowel disease, gastrointestinal surgery, metformin or proton-pump inhibitors, because the dose is high enough to be absorbed without intrinsic factor. Hydroxocobalamin injections are kept for an insufficient effect, intolerance or severe anaemia.
• EU food law: Regulation (EC) No 1170/2009 lists four forms of vitamin B12 that may be used in food supplements: cyanocobalamin, hydroxocobalamin, 5'-deoxyadenosylcobalamin and methylcobalamin.
• US: cyanocobalamin injection is an FDA-approved prescription medicine for B12 deficiency caused by malabsorption, including pernicious anaemia. No FDA-approved medicine contains methylcobalamin. It is in category 1 of the substances nominated for pharmacy compounding (list updated 14 May 2026), which means the FDA does not intend to act against pharmacies that compound with it under the conditions of its interim policy while it evaluates the substance.
• Japan: high-dose mecobalamin (Rozebalamin, 25 mg for injection into a muscle) was approved in September 2024 for slowing the progression of functional impairment in ALS.

What the research shows

That B12 corrects a deficiency is the basis of its approval. Beyond that, the evidence is thinner than the popularity of B12 injections suggests, and most of it concerns other forms than methylcobalamin:

• Tablets or injections (Cochrane review, 2018): three randomised trials with 153 participants compared oral and intramuscular B12 for deficiency over three to four months. With 1,000 µg a day by mouth, blood B12 rose about as much as with injections; in the trial with 2,000 µg a day it rose more, by 680 pg/mL. The evidence was rated low quality, and no trial measured symptoms or quality of life.
• Energy, memory and mood (meta-analysis, Nutrients 2021): across 16 randomised trials with 6,276 people without a B12 deficiency or advanced neurological disease, B12 alone or with folic acid had no effect on any area of cognitive function and no overall effect on depressive symptoms. Unexplained tiredness had been studied in only one trial, too few for any analysis, so the popular use of B12 injections for energy in people who are not deficient has no solid trial support.
• Neuropathy (meta-analysis, 2020): methylcobalamin is widely used in Asia for nerve damage. Fifteen randomised trials with 1,707 people with neuropathy from diabetes or shingles were pooled, and 11 of the 15 were rated at high risk of bias. Methylcobalamin alone scored better than comparison treatments on a global effectiveness rating (risk ratio 1.17; 95% CI 1.03 to 1.33), but it did not improve pain or neuropathic symptom scores, and nerve conduction improved only when it was combined with other treatments.
• ALS: an earlier phase II/III trial of high-dose methylcobalamin missed its primary endpoint. The investigator-led JETALS trial at 25 Japanese centres then enrolled people within a year of symptom onset whose functional score had dropped by 1 or 2 points over a 12-week run-in: 130 were randomised to 50 mg methylcobalamin or placebo, injected into a muscle twice a week for 16 weeks. The score on the ALS functional rating scale (ALSFRS-R) fell by 2.66 points on methylcobalamin against 4.63 on placebo (difference 1.97 points; 95% CI 0.44 to 3.50), with similar rates of adverse events. Japan approved the treatment on the basis of this trial. The dose is 50 times a standard 1 mg injection, and the result says nothing about ordinary doses.

Methylcobalamin, cyanocobalamin or hydroxocobalamin?

Supplement marketing often presents methylcobalamin as the active or natural form that the body can use straight away. The biochemistry gives little reason to expect a large difference: cells strip every form down to the same intermediate before rebuilding both active forms, and cyanocobalamin is converted into both active forms in the body. The trials behind the licensed treatments used cyanocobalamin or hydroxocobalamin, and evidence that methylcobalamin corrects a deficiency better is lacking.

What does differ is how long a form stays in the body. Hydroxocobalamin binds more strongly to plasma proteins than cyanocobalamin, stays longer and is excreted more slowly, which suits injections spaced weeks apart: the Dutch label gives a maintenance injection every two months. Much of a large injection is still lost. About 90% of a 100 µg hydroxocobalamin injection is retained, but only about 30% of a 1,000 µg injection; the rest leaves in the urine. Given into a vein, almost all of a cyanocobalamin dose is lost in the urine, which is why the US label advises against that route.

B12 solutions are sensitive to light: both the Dutch hydroxocobalamin label and the US cyanocobalamin label require storage protected from light.

Side effects and warnings

At the doses used for deficiency, B12 is well tolerated, and an overdose of this water-soluble vitamin is not known to cause poisoning: once the tissues are saturated, the excess leaves in the urine. The Dutch label lists acne and acne-like skin rash as common (1 to 10% of users), reactions at the injection site without a known frequency and, very rarely, allergic reactions caused by the cobalt, such as eczema or rash, up to anaphylactic shock. The US label adds that anaphylactic shock and death have been reported after injected B12, and lists itching, a passing rash, mild short-lived diarrhoea and a feeling of swelling of the whole body.

Two warnings concern the start of treatment for severe deficiency. When severe megaloblastic anaemia is treated intensively, potassium can drop, and the US label warns that hypokalaemia and sudden death may occur; it asks for potassium to be watched closely in the first 48 hours. It also lists fluid on the lungs and heart failure early in treatment, and blood clots in peripheral vessels. People with early Leber's disease, a hereditary disorder of the optic nerve, developed severe and rapid optic atrophy when treated with cyanocobalamin.

Because B12 corrects the blood picture, giving it before a diagnosis can hide the cause of an anaemia. Because blood B12 levels always rise during injections, the Dutch label calls measuring them during injection treatment pointless. Metformin lowers the absorption of B12.

Frequently asked questions

Is vitamin B12 legal in the Netherlands?

Yes. Oral B12, including methylcobalamin, is sold freely as a food supplement, and EU law lists methylcobalamin among the permitted forms. B12 injections are medicines: in the Netherlands they contain hydroxocobalamin or cyanocobalamin and are available on prescription only, while 1 mg cyanocobalamin tablets are sold without prescription. No methylcobalamin medicine is on the Dutch register. Research-grade methylcobalamin is not a medicine and may not be used in people.

Do B12 injections give you more energy?

Only when tiredness comes from a deficiency. In 16 randomised trials with 6,276 people who were not deficient, B12 did not improve memory, thinking or mood, and unexplained tiredness had been studied in only one trial, too few to draw a conclusion. In a real deficiency, injections or high-dose tablets correct the anaemia; the Farmacotherapeutisch Kompas expects haemoglobin to rise by at least 10% after four weeks of supplementation.

Are B12 tablets as good as injections?

For raising blood levels, high-dose tablets did about as well as injections in the small trials available: in a Cochrane review of three randomised trials with 153 participants, 1,000 µg a day by mouth raised blood B12 about as much as injections, although the evidence is of low quality. The Dutch GP guideline therefore starts with a 1 mg tablet a day, also when absorption is impaired, and keeps hydroxocobalamin injections for an insufficient effect, intolerance or severe anaemia. With clear nerve damage, the Dutch label gives injections once or twice a week.

Is methylcobalamin better than cyanocobalamin?

There is no good evidence that it is. Cells strip every form of B12 down to the same intermediate and rebuild both active forms from it, so methylcobalamin is not delivered intact to the enzyme that uses it, and the licensed treatments and the trials behind them use cyanocobalamin or hydroxocobalamin. Methylcobalamin's own distinct result comes from very high doses in ALS: 50 mg twice a week in the Japanese JETALS trial, 50 times a standard injection.

Who is at risk of a B12 deficiency?

The labels and the Dutch Kompas name people with pernicious anaemia, people who have had stomach or bowel surgery, people with Crohn's disease or other bowel disorders that impair absorption, users of metformin or proton-pump inhibitors, and people on a diet without any animal products. Because the body holds a store of 2,000 to 3,000 µg, a deficiency can take years to appear.

Is B12 banned in sport?

No. Vitamin B12 is not on the WADA Prohibited List for 2026, and as an approved medicine it does not fall under the S0 class for non-approved substances either. The method can matter: under rule M2.2, intravenous infusions or injections of more than 100 mL within 12 hours are prohibited unless they are legitimately received during hospital treatment, surgical procedures or clinical diagnostic investigations. An injection into a muscle is not an intravenous infusion.

Storage and handling

Store according to product-label instructions and batch handling notes. Lyophilized research peptides are commonly kept dry, protected from light, and handled with clean laboratory technique.

References

Checked against these sources on 28 October 2026.

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