Vitamin B12 (Cobalamin)

What Vitamin B12 Does

Vitamin B12 is the cofactor for two enzymes. Methionine synthase uses it to move a methyl group from 5-methyl-folate onto homocysteine, regenerating methionine — the step that keeps homocysteine low and folate in circulation. Methylmalonyl-CoA mutase uses it to process certain fatty acids and amino acids; when B12 runs short, methylmalonic acid (MMA) builds up. That is why MMA is the most specific blood marker of deficiency, and why homocysteine rises with it.

Deficiency causes a megaloblastic anaemia and, more importantly, damage to nerves and the spinal cord that may not fully reverse. Folate can correct the anaemia but not the nerve damage — the reason B12 must be checked before anyone takes folate in any form. How B12 fits the wider methylation picture is covered in Homocysteine: What Your Level Means and How to Lower It.

Who Is Short of It

• Older adults. About 6% of people over 60 in the US and UK are deficient and around 20% are marginal, mainly because stomach acid and intrinsic factor decline with age. In 2,403 older people, 6% had definite and 16% probable metabolic deficiency by MMA.
• Vegans. A meta-analysis of 17 studies found lower serum B12 and higher homocysteine in vegans than omnivores; deficiency is most common in those who do not supplement.
• Metformin users. In a 4.3-year randomised trial, metformin lowered B12 by 19% and raised the absolute risk of deficiency by 7.2 percentage points — one extra case for every 14 people treated. In the Diabetes Prevention Program, each year of metformin use raised the odds of deficiency by 13%.
• Long-term acid suppression. In a case-control study of 25,956 deficient patients, two or more years of PPI use carried 65% higher odds, and H2 blockers 25%.

Testing

Serum B12 alone is a poor test: in older adults it produced more false positives than true positives. Holotranscobalamin (the active fraction) performed better, and MMA is the standard second-line test for borderline results — roughly 150–300 pmol/L. Homocysteine rises in deficiency too, but is not specific.

Oral Works — Even for Deficiency

The belief that deficiency needs injections does not survive the trials. A Cochrane review found that 1 mg oral daily produced serum B12 comparable to intramuscular injections, and 2 mg oral daily produced higher levels. In a randomised trial, 2 mg oral daily for four months gave higher serum B12 (1,005 vs 325 pg/mL) and lower MMA than injections, with indistinguishable haematological and neurological recovery. A dose-finding trial in older adults with mild deficiency found that about 650–1,000 mcg daily was needed for 80–90% of the maximal MMA reduction — more than 200 times the dietary requirement, because only a small fraction is absorbed passively without intrinsic factor.

Severe deficiency with neurological signs is still a medical situation; injections give faster certainty and a clinician should be involved.

Cyanocobalamin vs Methylcobalamin

Methylcobalamin and adenosylcobalamin are marketed as "active" forms. In the cell, every form — including cyanocobalamin — is stripped back to the same core and rebuilt into both coenzymes by the same processing protein. A mechanistic review concluded that the coenzyme forms are unlikely to be superior to cyano- or hydroxocobalamin. Cyanocobalamin is the form used in most of the trials above. Buy on price and dose.

Safety

No toxicity has been identified at any oral dose, and neither the US nor the EU has set an upper limit. The genuine safety issue is the reverse: high-dose folate given to someone with undiagnosed B12 deficiency. Nitrous oxide — anaesthetic or recreational — inactivates B12 and has precipitated spinal cord degeneration in people with low stores; most such cases had an underlying absorption problem.

Where It Fits

B12 is Layer 1 of the Methylation Support Protocol: correct it first, then decide whether folate is needed. The Neuroprotection protocol monitors homocysteine annually and hands its correction to B12 and folate — this is that correction.

Related Research

• Homocysteine: What Your Level Means and How to Lower It
• MTHFR Variants: What the Evidence Actually Supports
• The Methylation Support Protocol: Test, Then Target
• Methylfolate