Vitamin B12

What it is

Vitamin B12 (cobalamin) is a water-soluble vitamin needed for DNA synthesis, methylation, red blood cell formation, the myelin sheath around nerves, and folate metabolism [1]. The main forms used in supplements are cyanocobalamin, hydroxocobalamin and methylcobalamin, taken as tablets, under the tongue, as a nasal spray or by injection, in doses from about 100 to 3000 µg [2]. B12 occurs naturally in animal foods: about 2.6 µg per 85 g of cooked salmon, about 1.3 µg per cup of milk and about 0.5 µg per large egg [2]. Fortified cereals and meat substitutes are the only reliable plant sources, providing about 0.5 to 1.8 µg per 100 g [2]. In the United States the recommended intake is 2.4 µg a day for adults, 2.6 µg in pregnancy and 2.8 µg during breastfeeding [2]. Absorption through the pathway that uses intrinsic factor, a protein made by the stomach, saturates at roughly 1 to 2 µg per dose; larger oral doses rely on a small passive-diffusion component instead [2]. B12 deficiency affects roughly 2% to 3% of adults in the United States and is more common with older age, malabsorption, vegan diets and certain medicines; testing usually starts with serum B12, where a level below 180 pg/mL is considered diagnostic and borderline values between 180 and 350 pg/mL are checked with methylmalonic acid [3]. In populations with little access to animal foods or fortified products, reported deficiency rates reach up to 69% [2].

How it might work

Vitamin B12 acts as a cofactor for two enzymes: methionine synthase, which converts homocysteine into methionine, and methylmalonyl-CoA mutase, which helps process methylmalonic acid [2]. When B12 is low these reactions slow and blood homocysteine and methylmalonic acid rise, which is why they are used as markers of deficiency [2]. Through methylation and DNA synthesis, B12 also supports red blood cell production and keeps nerves insulated [1]. Because high homocysteine has been linked to blood vessel and brain damage, researchers proposed that lowering it with B vitamins might protect the heart and the brain, but in large trials lowering the marker has not translated into fewer heart attacks or deaths [4].

What the research says

Treating deficiency: a 2018 Cochrane review found three randomised trials comparing oral with injected B12 in 153 adults with deficiency; at 1000 µg a day, tablets produced no clinically relevant difference in blood B12 levels compared with injections, and one trial of 2000 µg a day favoured the tablet [5]. The review rated the evidence low quality and noted that oral treatment cost less; no trial reported on symptoms [5]. A 2026 Cochrane review of 16 trials in 4083 children found that oral B12 alone reduced deficiency (about 56 fewer cases per 1000 children) and raised total B12 by about 69 pmol/L, with little to no effect on growth, cognition or development [1]. In 984 pregnant women across five trials, supplementation reduced maternal B12 deficiency, though the evidence was rated very uncertain [6]. In 800 pregnant Nepali women, 50 µg a day improved B12 status but did not improve infant growth or neurodevelopment [7].

Metformin and plant-based diets: in metformin-treated type 2 diabetes, a systematic review of seven trials (506 participants) found that B12 supplementation raised blood levels in every study that measured them, while effects on neuropathy symptoms were unclear [8]. That matters because metformin users had about twice the risk of B12 deficiency as non-users, with levels about 64 pmol/L lower [9]. Among 151 Czech vegans, those who did not take B12 supplements were 4.4 times more likely to have low cobalamin than those who did, and supplementing vegans had levels similar to non-vegans [10]. A meta-analysis, which pools results from separate studies, of 19 studies in adult vegans found lower serum B12 and higher homocysteine than in omnivores, with supplement users doing better on every B12 marker [11]. In a Norwegian study of 205 vegans and vegetarians, status was adequate overall but 14% still had serum B12 below 221 pmol/L, and regular supplement use predicted higher levels [12].

Energy and tiredness: in a randomised trial of 95 people with IBS or IBD who had fatigue but normal B12 levels (at least 150 pmol/L), 1000 µg of B12 a day for eight weeks did not reduce subjective fatigue compared with placebo and did not improve mood or quality of life [13]. A meta-analysis of 16 trials (6276 participants) in people without advanced neurological disease or overt deficiency found no effect of B12 on any cognitive measure or on depression, and only one trial reported fatigue, so it could not be pooled [14]. A 2026 review of supplementation in people without confirmed deficiency likewise found no consistent benefit for fatigue or well-being [2].

Memory and thinking: the same 16-trial meta-analysis found no effect of B12 alone or B-complex vitamins on any cognitive subdomain [14], and a meta-analysis restricted to cognitively healthy adults found no overall effect of oral B vitamins on global cognition [15]. In a 12-month trial of 201 older people with moderate B12 deficiency but no anaemia or symptoms, supplementation raised blood B12 by 177% without improving nerve conduction, cognitive tests or neurological examination [16]. In the other direction, a 2025 meta-analysis of 17 trials in adults over 60 reported a very small improvement in global cognitive scores after excluding outlying and single-blind studies (Hedges' g 0.110) [17], and a meta-analysis of 95 studies found a small edge for B vitamins on Mini-Mental State Examination scores (0.14 points) but no link between higher B12 intake and lower dementia risk [18]. Two combined-vitamin trials reported positive findings: in 900 older adults with psychological distress, 400 µg folic acid plus 100 µg B12 daily improved memory scores at 24 months (effect sizes 0.15 to 0.18) [19], and in the VITACOG trial, 168 people with mild cognitive impairment who completed MRI scans had slower brain shrinkage on folic acid, B12 and B6 together (0.76% versus 1.08% per year), with the largest effect in those with homocysteine above 13 µmol/L [20].

Heart disease and stroke: a 2017 Cochrane review of 15 trials with 71,422 participants taking B vitamins to lower homocysteine found no difference in heart attacks, deaths or serious adverse events, while strokes were slightly less common with treatment (4.3% versus 5.1%); the authors calculate that about 143 people would need treating for 5.4 years to prevent one stroke [4]. A later analysis of individual patient data found the stroke difference appeared only in people with normal kidney function (relative risk 0.78), not in those with impaired function (1.04) [21], and a 2026 review concluded the effect was probably driven by folic acid rather than B12 [2].

Doses used in studies

Deficiency trials used 1000 to 2000 µg of oral B12 a day for three to four months [5], or 1 mg a day for 12 months in older adults with moderate deficiency [16]. Cochrane reviews of children used 0.9 to 150 µg a day for 28 days to 31 months [1]. Pregnancy trials used 5 to 250 µg a day [6]; the 800-woman Nepal trial used 50 µg a day until six months after birth [7]. Fatigue and cognition trials used 1000 µg a day for 8 weeks in IBS or IBD [13], 400 µg folic acid plus 100 µg B12 daily for 2 years in the Beyond Ageing trial [19], and 0.5 mg B12 with 0.8 mg folic acid and 20 mg B6 daily for 2 years in VITACOG [20]. Ultra-high-dose studies in ALS injected 50 mg of methylcobalamin twice weekly for up to a year [22]. Across the literature, oral regimens range from 0.02 to 1 mg a day and injections from 1 to 5 mg a week, over roughly 4 weeks to 7 years [2]. Because absorption through the intrinsic-factor pathway is limited, older people with poor absorption may respond poorly to daily oral doses below 500 µg [23].

Safety and interactions

Side effects: B12 is generally well tolerated, including at the high doses used in studies, and no tolerable upper intake level has been established [2]. In the Cochrane review of 15 B-vitamin trials, serious adverse events were similar between treatment and comparator groups (relative risk 1.07, 95% CI 1.00 to 1.14) [4]. Even methylcobalamin injections of 50 mg twice weekly for up to a year in 144 people with ALS caused adverse drug reactions in 3.5% of patients, none serious or leading to discontinuation [22], and a 373-patient ALS trial found similarly low rates of treatment-related side effects [24]. Rare reactions that have been reported include acne-like rashes, rosacea flares and allergic reactions ranging to anaphylaxis after high-dose injections [2]. One Norwegian trial in patients with heart disease found more cancer diagnoses with folic acid plus B12 than with placebo (10.0% versus 8.4%), driven mainly by lung cancer, but the B12 contribution cannot be separated from folic acid, other trials have not repeated the finding, and genetic studies have not supported a causal link [25][2].

Interactions: metformin lowers B12, with users having about double the risk of deficiency and levels about 64 pmol/L lower in pooled studies [9], and a fall of about 57 pmol/L over 6 weeks to 3 months in four early trials [26]; supplementation raises levels back up [8]. Long-term acid-reducing medicines show a similar pattern: in a study of about 210,000 people, those dispensed at least two years of proton pump inhibitors had 65% higher odds of B12 deficiency and H2 blockers 25% higher odds [27], and a meta-analysis found a hazard ratio of 1.83 for long-term acid-lowering drugs [28]. In a study of 3299 older adults, atrophic gastritis (a shrunken, low-acid stomach) was linked to more deficiency than PPI use, and higher-dose PPIs (30 mg a day or more) lowered holotranscobalamin [29]; a review notes the PPI evidence is not fully consistent and longer studies are needed [30].

Pregnancy and breastfeeding: pregnancy trials found no clear difference in preterm birth or low birthweight, but the evidence was rated low to very low certainty [6]. Supplementation with 50 to 250 µg a day during pregnancy and breastfeeding raises B12 in breast milk while it is taken [31]. No children's trial of B12 supplementation reported adverse-effect data [1].

Kidney, liver and other conditions: in stroke-prevention trials, high-dose cyanocobalamin-containing regimens did not benefit people with impaired kidney function, unlike those with normal function [21]. High blood B12 measurements are often seen in liver disease, kidney disease or other underlying conditions rather than being caused by supplements [2]. No data were found on interactions with bleeding disorders.

Caveats and open questions

B12 deficiency definitions vary: serum cut-offs, methylmalonic acid and holotranscobalamin can give different answers in the same person, which makes prevalence numbers hard to compare across studies [2]. The strongest evidence on energy and cognition comes from selected groups (older adults, people with fatigue or cognitive complaints) rather than healthy volunteers, and meta-analyses disagree on whether B vitamins offer a very small cognitive benefit [14][17]. The small stroke reduction seen with B vitamins appears to come mainly from folic acid and did not appear in people with impaired kidney function [2][21]. The cancer signal seen with folic acid plus B12 in Norway remains unresolved, and observational links between high B12 levels and disease most likely reflect the underlying illness rather than the vitamin [25][2]. Ongoing trials are comparing methylcobalamin with cyanocobalamin for B12 status (NCT05785585), testing B12 for physical and mental performance (NCT06639789), and pairing B vitamins with omega-3 for brain atrophy markers in people at risk of dementia (NCT07312435).