Vitamin
Replacing it works fast in people who are short of it, by tablet as well as by injection. In people who are not short, the trials find nothing to replace.
Cobalamin; vitamin B-12; B12. Supplement and medicinal forms: cyanocobalamin (the synthetic form used in most fortification and most tablets), methylcobalamin (also written mecobalamin), hydroxocobalamin, adenosylcobalamin (5'-deoxyadenosylcobalamin). Methylcobalamin and adenosylcobalamin are also the two cofactor forms the body makes inside the cell, whichever form is swallowed. Historically called the anti-pernicious-anaemia factor or extrinsic factor.
Dietary requirement: 2.4 micrograms per day for non-pregnant adults, 2.6 micrograms per day in pregnancy (US Institute of Medicine Recommended Dietary Allowance, as cited by Dror and Allen 2012). Treating diagnosed deficiency, by mouth: 1000 to 2000 micrograms per day. Trials that corrected deficiency used 2 mg per day (Kuzminski 1998), 1 mg per day for eight weeks then 1 mg per week (Sanz-Cuesta 2020), and 1000 micrograms per day including in pernicious anaemia (Lacombe 2024). Treating diagnosed deficiency, by injection: 1 mg intramuscularly on a loading schedule of alternate days for two weeks, then weekly to week eight, then monthly (Sanz-Cuesta 2020). The treatment doses are hundreds of times the dietary requirement because absorption is saturable: only about 5 percent of a large oral dose is taken up (Dror and Allen 2012). The rest of the tablet is not doing anything.
None established. No tolerable upper intake level has been set for vitamin B12, for the general population or for pregnancy, because there is not enough evidence of adverse effects to derive one (US Institute of Medicine Food and Nutrition Board framework, as reported by Dror and Allen 2012). That is an absence of demonstrated harm rather than a demonstration of safety at any dose. Two observational signals sit against a clean bill of health and disagree with each other: a cohort of 77,118 adults found roughly doubled lung cancer risk in men taking more than 55 micrograms per day from standalone supplements, while the same group's later cohort of 159,232 women found nothing. A 2022 review judging causality concluded the evidence does not support high B12 causing cancer, and that raised blood B12 is more plausibly a consequence of illness than a cause.
Repletion of a diagnosed deficiency is fast. About 88 percent of pernicious anaemia patients on 1000 micrograms of oral B12 daily were no longer deficient after one month (Lacombe 2024), and over 90 percent of deficient adults aged 65 and over had normal blood levels by eight weeks on either tablets or injections (Sanz-Cuesta 2020). Correction of blood-count and neurological abnormalities was described as prompt on both routes (Kuzminski 1998). In people who are not deficient there is no onset to describe, because there is no measured effect to time.
Standard oral supplement tablets — commonly 1000 micrograms per tablet, the dose used in the deficiency-treatment trials (Lacombe 2024, Kwok 2017). High-dose oral cyanocobalamin — 2 mg per day, the dose shown to match injections in cobalamin deficiency (Kuzminski 1998). Intramuscular injection ampoules — 1 mg per dose, given on a loading-then-maintenance schedule (Sanz-Cuesta 2020). Sublingual tablets and sprays — pooled with oral and intramuscular in a 16-study meta-analysis and not distinguishable from either on blood levels (Mazur 2025). B12-fortified foods — regular consumption (five or more portions a week) improved B12 biomarkers in older adults, but did not correct deficits in those with atrophic gastritis (Porter 2021).
Being tired means you are low on B12, and a B12 supplement or a B12 shot will give you your energy back.
In people who are genuinely deficient, replacing B12 works and works quickly, by tablet as well as by injection. In people whose B12 is already normal, it does not. A meta-analysis of 16 randomised trials in 6,276 people without overt deficiency found no effect on any cognitive measure and none on depression. It could not even test fatigue, because only one of the 16 trials had bothered to measure it. The one randomised trial that did test fatigue head-on gave 1000 micrograms daily to tired patients with normal B12 and found fatigue improved by the same amount on placebo.
The tiredness B12 fixes and the tiredness most people buy B12 for are rarely the same tiredness. The question worth asking is not whether B12 raises energy but whether you are one of the people who is actually short of it, and the answer to that turns on a blood test most people have never had.
Deficiency is judged on four markers, not one: the blood level, the share bound for delivery into cells, and two that build up when cells cannot use what is there.
This is a snapshot of one Irish and Northern Irish cohort recruited between 2008 and 2012, not a picture of what happens over time. Anyone already taking a B12 supplement was excluded, which sharpens the dietary signal but leaves out most real supplement users.
Over 4.3 years against placebo, metformin cut B12 by 19 percent and left 7.2 percentage points more people deficient. Because people were randomised, it is the drug doing it.
Everyone in the trial was on insulin for type 2 diabetes, so the absolute numbers may not carry to metformin alone. Deficiency was called on the blood level alone, not on markers of whether cells were short. The homocysteine rise that would prove a functional cost fell short of significance.
At five years, low or borderline B12 was twice as common on metformin as on placebo, 19.1 percent against 9.5, and each extra year raised the odds 13 percent.
B12 was measured only at years 5 and 13, so nothing is known about the years between. Frank deficiency at 13 years, 7.4 percent against 5.4, did not reach significance. The neuropathy link is an observation within the group, not a demonstration that the low B12 caused it.
Oral treatment works at 1 to 2 milligrams a day, far above an ordinary supplement. At that dose, over 90 percent of both the tablet and injection groups had normal levels by week eight.
These trials counted blood levels, not whether anyone felt better. The Cochrane review behind the comparison had three eligible trials and 153 people, and graded its own certainty low. By one year the oral group had slipped slightly behind the injected one on the stricter analysis.
Pooling 17 studies, vegan adults had significantly less B12 in the blood than omnivores and significantly more homocysteine, which builds up when cells cannot get B12.
The two most specific markers, methylmalonic acid and holotranscobalamin, pointed the same way but missed significance at p=0.06 and p=0.09, so the case rests on homocysteine, which folate and kidney function also move. The comparisons are observational, so other diet-linked differences remain live.
Over 27 months, 271 older adults with diabetes and borderline-low B12 took 1000 micrograms a day. The shortage markers fell; dementia ratings and test scores did not move.
All of them were older outpatients with diabetes, many on metformin, so this is not a general older-adult sample. Forty-four percent already had questionable dementia at the start, which may put some of the decline beyond reach. Borderline-low is not outright deficiency.
Eating five or more portions of B12-fortified food a week went with better markers across 3,299 older adults. In the 15 percent whose stomach lining had thinned, it was not enough.
This is an association measured at a single point in time, so it cannot show that the fortified food did the lifting. The thinned stomach lining was inferred from a blood ratio rather than confirmed by biopsy, so the group is drawn approximately.
About 6 percent of over-60s are outright deficient and roughly 20 percent sit in the marginal band. The usual cause at that age is not a meat-free diet but food-bound malabsorption.
The survey figures were reviewed in 2009 and predate current fortification and supplement habits. The 148 pmol/L line between deficient and marginal is itself contested, and moving it moves both percentages. The review was written to argue for fortifying flour, a stated policy position.
B12 deficiency shows up first as anaemia, which is what sends someone to a doctor. Folic acid corrects that anaemia on its own while the neurological damage carries on.
The clinical cases that established this used folic acid above 5mg a day in the 1940s and 1950s, roughly ten times a modern supplement and far above what fortified flour delivers, so it does not transfer straight to a 400 microgram tablet. The authors of the review say themselves that the modern evidence is correlative or from uncontrolled observation, and that their proposed mechanism has not been tested. They are also the group that proposed it.
The sixteen trials pooled 6,276 people who were not deficient and found nothing on memory, attention or depression. Fatigue was meant to be the third outcome, and there was nothing to pool.
Everyone studied already had normal B12, so this says nothing about people who are actually short of it. Several of the pooled trials gave B12 inside a B complex alongside folate, so the B12-only signal rests on fewer studies. The fatigue gap is an absence of trials, not a pooled null.
In 95 people with disabling tiredness and normal B12 levels, eight weeks of 1000 micrograms a day and a placebo each improved fatigue by about eight points.
Both arms improved by roughly eight points, a large placebo response that leaves little room to detect a small real benefit. The bar for normal B12 was set at 150 pmol/L, low enough that some participants may have been functionally short despite passing it.
Cyanocobalamin at 1 to 2 milligrams a day cleared deficiency, and a separate trial of methylcobalamin saw the same markers fall. No trial gave the two forms to the same people.
None of these trials set out to compare the forms, so this is an absence of evidence that one beats the other, not evidence they are the same. They enrolled different patients on different schedules, which is what a real comparison would have to hold constant.
In 77,118 adults, men taking over 55 micrograms a day from a standalone supplement for a decade had roughly twice the lung cancer risk of non-users. Women showed nothing.
It appeared only for standalone high-dose supplements, not for the same vitamins inside a multivitamin, which is hard to explain if the vitamin is doing it. Intake was reported once, at the start. The review clearing B12 includes authors with declared ties to manufacturers.
Whether high-dose B12 supplements raise lung cancer risk is unresolved. One cohort saw about double the risk in men, none in women, a split nobody has explained, and the risk ran higher in smokers, so something besides B12 may explain it.
About 5 percent of a large oral dose is absorbed, and no tolerable upper intake has been set, for the general population or for pregnancy. Harm has not been demonstrated.
Both figures are background citations inside a review about pregnancy trials rather than results its authors produced, so they carry the weight of a textbook footnote and not of a measurement. The review dates from 2012 and predates the later cohort reports on high blood B12 and cancer.
In pernicious anaemia the body stops making the protein that carries B12 across the gut wall. Twenty-six patients swallowed 1000 micrograms a day, and after a month 23 were no longer deficient.
Twenty-six people, one hospital, and no group given injections to compare against. Three of them did not respond. The dose works by seeping across the gut wall rather than through the missing transporter, so a run of missed days costs more than it would with a monthly injection.
Whether a swallowed B12 dose is enough when the gut cannot absorb it normally is still open. The support is 26 patients with no comparison group and three small trials rated low certainty: promising, not yet properly tested.
Across 25 observational studies, people on proton pump inhibitors had 42 percent higher odds of B12 deficiency, but most of the studies found no difference in blood B12.
Every included study was observational, and people on long-term acid blockers differ from those who are not in ways that also affect B12. Heterogeneity was high, with just over half the variation between studies not attributable to chance. The review was not registered in advance.
About a third of American seniors had folic acid circulating unconverted. Among those whose B12 was low, its presence went with lower cognitive test scores.
This is a single snapshot in time, so it cannot say which came first. The finding sits inside a subgroup defined by poor B12 status, well under the 1858 people surveyed, which is where chance findings live, and the authors describe some of their own results as unexpected and internally inconsistent. In the people whose B12 was normal, more of the natural circulating folate went with better scores, not worse.
No findings tagged to that goal.
What the evidence says about combining Vitamin B12 with each of these. The marker is how well established the interaction is; a caution is about the hazard, which is a different question.
8 open questions
Search runs entirely in your browser. Nothing you type is sent anywhere.