The short version
- Among 141 consecutive patients with neuropsychiatric abnormalities from cobalamin deficiency, 28% had no anaemia and no macrocytosis, so a normal full blood count does not exclude B12 deficiency.
- Only 22 of those 40 patients had a serum B12 below 75 pmol/L, which is why methylmalonic acid and homocysteine are used when the serum level sits in the grey band.
- Metformin at 850mg three times daily for 4.3 years lowered vitamin B12 by a mean of 19% and raised the absolute risk of deficiency by 7.2 percentage points in a randomised placebo-controlled trial of 390 people.
- Two or more years of proton pump inhibitor use was associated with an odds ratio of 1.65 for vitamin B12 deficiency in a case-control study of 25,956 cases and 184,199 controls.
- A Cochrane review of three trials in 153 people found oral B12 at 1,000 to 2,000 micrograms a day comparable to intramuscular injection for normalising serum levels, on low-quality evidence.
Ask most people how you spot low B12 and they will say anaemia. That answer has been out of date since 1988.
Lindenbaum and colleagues reported 141 consecutive patients with neuropsychiatric abnormalities caused by cobalamin deficiency in the New England Journal of Medicine. Forty of them — 28% — had no anaemia and no macrocytosis. The haematocrit was normal in 34, the mean cell volume was normal in 25, and both were normal in 19.
What those patients did have was paraesthesia, sensory loss, ataxia, dementia and psychiatric disturbance, alongside markedly raised serum methylmalonic acid and homocysteine. Except for one patient who died in the first week of treatment, every one of them improved on cobalamin therapy: 39 of 39.
The serum B12 numbers in that cohort are the part worth staring at. Only 22 of the 40 had a level below 75 pmol/L. Sixteen sat between 75 and 150, and two were above 150. A single serum B12 in the low-normal range is not a clean all-clear.
Who is more likely to be low
Two groups stand out because the cause is a medication rather than a diet.
Metformin. In a randomised placebo-controlled trial of 390 people with type 2 diabetes taking insulin, 850mg of metformin three times daily for 4.3 years lowered vitamin B12 by a mean of 19% (95% CI −24% to −14%, p<0.001). The absolute risk of deficiency below 150 pmol/L was 7.2 percentage points higher than placebo, a number needed to harm of 13.8 over 4.3 years. The authors recommend that regular measurement during long-term metformin treatment be strongly considered.
Acid suppression. A case-control study inside Kaiser Permanente compared 25,956 people with incident B12 deficiency against 184,199 without. Two or more years of proton pump inhibitors carried an odds ratio of 1.65 (95% CI 1.58–1.73); two or more years of H2 blockers, 1.25. Doses above 1.5 PPI pills a day sat at 1.95. This is an association in observational data, not a randomised finding, and the sensible response is a test rather than stopping a medication you were prescribed for a reason.
Beyond those two: anyone eating little or no animal food, anyone with coeliac or Crohn's disease, anyone post gastric surgery, and anyone with pernicious anaemia, which is an autoimmune failure of absorption rather than a dietary problem at all.
What to ask for
Serum B12 is the starting test and it is imperfect, which is why methylmalonic acid and homocysteine exist. In the Lindenbaum cohort both were markedly elevated and both fell by more than 50% after treatment in 31 of 31 patients tested. If your serum B12 sits in the grey band and your symptoms fit, those are the follow-up tests to ask about by name.
One sequencing point that costs people months: start supplementing before you test and you will make the result uninterpretable. Test first.
Tablets versus injections, and where a multivitamin sits
The received wisdom is that real deficiency needs injections. A Cochrane review of three randomised trials in 153 participants found low-quality evidence that oral and intramuscular B12 had similar effects on normalising serum B12 levels, with two trials using 1,000 µg a day orally and one using 2,000 µg showing a mean difference of 680 pg/mL in favour of oral. Oral treatment also cost less. The review is explicit that the evidence base is small and that no trial reported on clinical signs and symptoms.
Note the dose in those trials. A thousand micrograms a day is a therapeutic regimen prescribed and monitored by a clinician. The B12 in a general multivitamin is a fraction of that, and it is doing a different job: covering a dietary shortfall in someone who absorbs B12 normally. That is a genuinely useful job if you eat little animal food. It is not a substitute for investigating malabsorption, and topping up serum B12 while leaving the underlying cause unexamined is the failure mode we would most like you to avoid.
What we would actually say
If you are on long-term metformin or long-term acid suppression, ask for a B12 level at your next appointment. If you have numbness, pins and needles, unsteadiness or memory change alongside tiredness, do not treat that as an afternoon energy dip and do not treat it with a supplement — those are neurological symptoms and they need a clinician now, because the neurological recovery in that 1988 cohort came from prompt treatment.
And if your tiredness has no neurological component at all, B12 is one item on a short list. Your thyroid and your iron status are the others worth ruling out before anything gets bought.
Good questions
Can my B12 be low if my blood count is normal?
Yes, and this is the single most important thing to know about it. In the landmark 1988 series, 28% of patients with neurological damage from B12 deficiency had neither anaemia nor a raised mean cell volume. If your symptoms fit and your full blood count came back clean, ask specifically for a B12 level rather than treating the blood count as an answer.
What does B12 deficiency actually feel like?
Often neurological before it is haematological: pins and needles, numbness, unsteadiness on your feet, memory or mood change, alongside fatigue. Those symptoms warrant a clinician rather than a supplement, because the recovery in the published series followed prompt treatment. Tiredness alone is a much weaker signal and has a long list of other causes.
I take metformin — should I be watching my B12?
It measurably lowers B12 over years. In a randomised trial running 4.3 years, metformin cut mean B12 by 19% and increased the absolute risk of deficiency by 7.2 percentage points, with a number needed to harm of about 14. The response is monitoring, not stopping a medication that is managing your blood glucose.
Will a multivitamin fix a B12 deficiency?
No, and it is worth being precise about why. A multivitamin's B12 covers a dietary shortfall in someone who absorbs it normally. Diagnosed deficiency was treated in trials with 1,000 to 2,000 micrograms a day, or by injection, under supervision. If absorption is the problem, a multivitamin can nudge a serum number without addressing the cause.
Do I need injections or will tablets do?
Cochrane found high-dose oral B12 comparable to intramuscular injection for normalising serum levels across three small trials, and cheaper. The evidence was rated low quality and no trial measured symptom outcomes, so this is a conversation with your prescriber rather than a decision to make alone, particularly with pernicious anaemia.
Should I start taking B12 before I get tested?
No. Supplementing before the blood draw makes the result uninterpretable and can delay a diagnosis by months. Test first, then supplement based on what the number says. This is the one place where a few days of patience is worth more than a few days of tablets.
Sources
- Lindenbaum J, Healton EB, Savage DG, Brust JC, Garrett TJ, et al. Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. N Engl J Med, 1988. View study
- de Jager J, Kooy A, Lehert P, Wulffèle MG, van der Kolk J, et al. Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. BMJ, 2010. View study
- Lam JR, Schneider JL, Zhao W, Corley DA. Proton pump inhibitor and histamine 2 receptor antagonist use and vitamin B12 deficiency. JAMA, 2013. View study
- Wang H, Li L, Qin LL, Song Y, Vidal-Alaball J, Liu TH. Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency. Cochrane Database Syst Rev, 2018. View study
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