Vitamin B12: what it's for and when it's lacking

Vitamin B12, or cobalamin, is the only vitamin that has a metal atom, cobalt, at the centre of its molecule. The human body can use it but cannot produce it: only bacteria and archaea synthesise it, and we receive it from foods of animal origin or from a supplement. In the cell, it works in two places: in the cytoplasm, where as methylcobalamin it helps methionine synthase to keep methylation reactions moving, on which DNA synthesis depends, and in the mitochondria, where as adenosylcobalamin it converts methylmalonyl-CoA into succinyl-CoA, an entry point into the Krebs cycle [1]. This guide follows the vitamin along its entire journey, from the foods in which it is found to the orodispersible tablet with which we have chosen to bring it into circulation.

What vitamin B12 is for: energy, nerves, blood

The first job of vitamin B12 is to help cells make energy. In the mitochondria, it keeps the reaction that feeds what remains from the breakdown of certain fats and amino acids into the Krebs cycle moving: from there, the cell obtains ATP, the currency with which it pays for everything it does. When the vitamin is scarce, that pathway slows down, and tiredness is the first signal to arrive [1].

The second job concerns the nerves. The methylation reactions that B12 supports also serve to build and maintain myelin, the sheath that surrounds nerve fibres and makes the signal travel fast. The sensitivity of hands and feet, memory, concentration, and mood balance depend on it: the tingling and brain fog in those with low B12 originate right there [1].

The third job is the blood. The bone marrow produces billions of red blood cells every day, and to divide at that rate, the cells must synthesise DNA without interruption: B12, together with folates, is a cog in that chain. When it is lacking, the red blood cells leave the marrow large and in insufficient numbers [1].

Then there are two less visible but equally tangible functions. B12 keeps the level of homocysteine low, an intermediate amino acid that methionine synthase converts back into methionine: with little of the vitamin, homocysteine accumulates in the blood, and it is one of the values that a doctor measures when they suspect a deficiency [1]. And the immune system also depends on it, because white blood cells are among the fastest-dividing cells.

Eight of these functions have an official wording: for vitamin B12, Regulation (EU) 432/2012 authorises claims on normal energy-yielding metabolism, on the reduction of tiredness and fatigue, on the normal functioning of the nervous system, on normal psychological function, on normal red blood cell formation, on the process of cell division, on normal homocysteine metabolism and on the normal function of the immune system. These are the sentences that can be written on a label, and they cover almost entirely what biochemistry tells us.

Where to find vitamin B12: foods and the forms that count

Vitamin B12 is produced by microorganisms and accumulates along the food chain in animal tissues. In food composition databases (the CREA Tables and, where the data is missing, the USDA database) the highest values, per 100 g, are in beef liver (about 60 µg), in clams and other molluscs (from ten to several tens of micrograms), in mackerel and sardines (around 9 µg); followed by beef (1-3 µg), mature cheeses (1-3 µg), egg (about 1 µg) and milk (about 0.5 µg). With a requirement of a few micrograms per day, a varied omnivorous diet covers the intake without difficulty: the problem, as we will see, is almost always with absorption.

The plant kingdom is an almost complete exception. Fruit, vegetables, cereals and pulses do not contain vitamin B12, and many products sold as plant-based sources—spirulina first and foremost—actually contain cobalamin analogues that the human body cannot use; among algae, only dried nori (the alga for maki) contains real vitamin B12 in appreciable quantities [2]. That leaves fortified foods, such as some breakfast cereals and fortified plant-based drinks. In the Framingham study, of almost three thousand adults, those who used supplements had low vitamin B12 levels much less often than those who did not (8% versus 20%) [3]: a clue, already twenty-five years ago, that the form in which the vitamin arrives counts as much as the quantity.

How vitamin B12 is absorbed and why it can be lacking even in those who eat meat

Vitamin B12's journey from the plate to the blood is the longest and most complex of all vitamins, and it is the key to understanding who may be deficient. In food, cobalamin is bound to proteins: stomach acidity and pepsin are needed to release it. Once free, it binds to a protein in the saliva and stomach, haptocorrin, which protects it during the acidic passage; in the duodenum, it is passed to the intrinsic factor, a glycoprotein produced by the parietal cells of the stomach, and the vitamin-intrinsic factor complex travels to the last section of the small intestine, the terminal ileum, where a specific receptor recognises it and brings it inside [1]. Each link in this chain is a point where the journey can be interrupted.

The first case is the most intuitive: the vitamin does not arrive. Those who follow a vegan or vegetarian diet without fortified sources or supplements see their stores diminish over time, and Pawlak's review of eighteen studies documents this at every age, with higher frequencies in vegans; the authors' recommendation is a regular intake through supplements [4].

The second case concerns those who eat meat and fish every day. With age, the stomach produces less acid and less pepsin, and the vitamin remains attached to food proteins: in Andrès's review, this "food-cobalamin malabsorption" explains over 60% of cases of deficiency in the elderly, and the deficiency affects more than one in five elderly people; pernicious anaemia, in which the intrinsic factor is lacking, explains another 15-20% and is a diagnosis for a doctor to make [5]. As Carmel points out, the deficiency that matters almost always arises when intrinsic factor-mediated absorption fails, rather than from a poor diet, and it takes years to manifest [6].

The third case relates to some long-term therapies. Metformin, the most commonly used drug for type 2 diabetes, reduces the absorption of vitamin B12: in a randomised placebo-controlled trial of 390 people followed for more than four years, B12 dropped by 19% in the treated group, with a seven-percentage-point higher risk of deficiency, and the authors advise periodic measurement of the vitamin during therapy [7]; the thirteen-year follow-up of the Diabetes Prevention Program confirms that the risk increases with years of treatment [8]. Drugs that reduce gastric acidity act on the first link of the chain: in an analysis of almost 26,000 people diagnosed with deficiency, two or more years of proton pump inhibitors were associated with a 65% increased risk, and H2 antagonists with a 25% increased risk [9]. Those on these long-term therapies are therefore more exposed to low vitamin B12 levels, and supplementary intake makes sense in these cases — all the more so since, as we will see, no authority has set a tolerable upper intake level for B12 — to be agreed with the doctor overseeing the therapy, who should also be asked to check levels.

However, there is a backup route, and it is this that makes oral supplementation possible even when the intrinsic factor is missing: a small fraction of any dose, about 1%, crosses the mucosa by simple passive diffusion. This was demonstrated in 1968 by Berlin's Swedish group, who treated patients lacking intrinsic factor with high oral doses [10].

How vitamin B12 is absorbed

1. 1 Foodsfish, meat, cheese, eggs
2. 2 Gastric acidityB12 separates from food
3. 3 Intrinsic factor
4. 4 Ileumreceptor-mediated absorption

mouth → bloodstream: Passive route: about 1% of a high dose

Vitamin B12 deficiency: signs that warrant a test, not self-diagnosis

Vitamin B12 deficiency develops slowly, because the liver keeps a store that lasts for years, and it manifests with signs that mean little on their own: unrelenting tiredness, tingling in the hands and feet, difficulty concentrating, pallor, and sometimes a red, sore tongue. These are the same signs of dozens of other conditions, and for this very reason they should be read as a reason to talk to a doctor and not as a DIY diagnosis. A doctor can request a measurement of vitamin B12 in the blood and, when confirmation is needed, of homocysteine and methylmalonic acid, the two metabolites that accumulate when the vitamin is truly lacking in the cells [1]. If the deficiency is confirmed, the doctor manages it: studies show that high oral doses work as well as injections — in 38 patients with deficiency, 2 mg per day by mouth corrected the blood and nervous system abnormalities just as 1 mg intramuscular injections did [11] — but the choice of dose and long-term monitoring remain the doctor's responsibility.

Vitamin B12 requirements: why labels read 1000 mcg and 40,000% NRV

You need very little vitamin B12. The LARN (Dietary Reference Values) from the Italian Society of Human Nutrition indicate a recommended intake for adults of 2.4 µg per day (2.6 during pregnancy, 2.8 during breastfeeding); EFSA, in its 2015 opinion on dietary reference values, sets an adequate intake of 4 µg per day. The nutrient reference value (NRV) that appears on European labels, established by Regulation (EU) 1169/2011, is 2.5 µg. This explains the number that strikes anyone reading a package: a 1000 µg tablet declares 40,000% of the NRV, because 1000 divided by 2.5 is 400. We explain how to read that percentage in how to read a supplement label.

The biological reason for such a high dose lies in the pathway described above. The intrinsic factor system transports a maximum of a couple of micrograms at a time and then becomes saturated; the rest passes through by passive diffusion, about 1% [10]. Of 1000 µg, therefore, around ten enter via that route: enough to cover a day's needs, even in those with a poorly functioning stomach or a lack of intrinsic factor. This is the logic behind the doses used in human studies, from 500 µg to 2 mg per day [11][12][13]. And 1000 µg per day is also the maximum intake that the Ministry of Health permits for vitamin B12 in food supplements (table 'Daily intakes of vitamins and minerals permitted in food supplements', May 2017 revision): our Sublingual Vitamin B12 is formulated exactly at that ceiling, one tablet per day, to cover requirements even when the gastric pathway has low yield. For vitamin B12, it must be said, no authority has set a tolerable upper intake level: it is water-soluble and the amount that the body does not retain is eliminated in the urine.

Why the label says 40,000%

1. 2.5 µgreference value (NRV)
2. 1000 µgthe dose in one tablet (40,000% NRV)
3. about 1% absorbed passively ≈ 10 µg

Methylcobalamin or cyanocobalamin: what really changes

Vitamin B12 exists in several forms, which differ in the chemical group attached to the cobalt atom. Methylcobalamin and adenosylcobalamin are the two coenzymatic forms, the ones the cell actually uses in its reactions, and are the forms found in foods and tissues; hydroxocobalamin is the form that circulates in the blood and is used for injections; cyanocobalamin is a synthetic, stable and inexpensive form, in which a cyanide group is attached to the cobalt — in amounts that are completely irrelevant for safety — which the body must detach before it can be used. A 2017 review, also signed by an author with ties to the supplement industry, summarises the difference as follows: methyl-, adenosyl- and hydroxocobalamin are bioidentical, identical to the forms in human physiology and in food, whereas cyanocobalamin appears only in trace amounts in tissues [14].

In our Sublingual Vitamin B12, we chose methylcobalamin for this reason: it is the coenzymatic form that is ready for use, the same one that methionine synthase uses in the cytoplasm, and it arrives without the step of removing the cyanide group. It is a 'clean' choice in the sense that we give to this word throughout our catalogue, the same logic by which we prefer L-leucine to magnesium stearate and bamboo silica to silicon dioxide: the substance that already exists in nature, in the form the body knows. Once inside the cell, every form of vitamin B12 is reduced to a basic cobalamin and from there reconverted into the two coenzymes [15]: the comparison between the forms comes down to the starting molecule and the steps it saves, and methylcobalamin already starts at the destination. We describe how the chemical form of an active ingredient generally affects the amount that reaches the circulation in bioavailability of supplements.

Forms of vitamin B12

Cobalamin (structure with Co)

• Methylcobalaminin food and tissues
• Adenosylcobalaminin mitochondria
• Hydroxocobalamin
• Cyanocobalaminsynthetic

Inside the cell, all forms become base cobalamin

Sublingual vitamin B12: how the 1000 mcg orodispersible tablet works

A sublingual, or orodispersible, tablet is left to dissolve under the tongue: no water, nothing to swallow. Its strength lies in where it dissolves. The floor of the mouth is one of the most vascularised areas of the body: under the tongue, the mucosa is thin and the capillaries run close to the surface, so the portion of the vitamin that passes through it enters the bloodstream directly, without going through the stomach. For a vitamin whose weak point is precisely the gastric route — the acidity needed to release it, the intrinsic factor that can decline with age — starting from the mouth means partially bypassing the weak link in the chain. The rest of the dose travels down with saliva and follows the usual route, where with 1000 µg the portion for passive diffusion is still absorbed. It is a convenient form for those who struggle to swallow tablets, including those with a less efficient stomach, and for anyone who wants a vitamin that can be taken anywhere, at any time, with or without food, as we discussed in supplements morning or evening. Why an orodispersible form is chosen for certain active ingredients and not for others is explained in capsules or tablets.

Human studies confirm that the orodispersible route works. In 30 people with low vitamin B12 levels, 500 µg per day for four weeks tripled blood values for both the sublingual and swallowed routes, with no difference between the two [12]. A group from the University of Milan followed 40 vegans and vegetarians with a marginal deficiency for twelve weeks, using two sublingual vitamin B12 regimens, 350 µg per week or 2000 µg in a single weekly dose: both returned the vitamin and its markers to normal levels [16]. In people taking metformin, 1 mg per day of sublingual methylcobalamin for three months raised levels more than a single injection [13]. And a 2024 network meta-analysis of thirteen studies and over four thousand patients concludes that the oral, sublingual and intramuscular routes raise vitamin B12 without significant differences [17]. The tablet that dissolves in the mouth is therefore the route that brings everything together: it does its job as well as an injection, bypasses the stomach when the stomach is underperforming, and requires neither water nor needles. For this vitamin it is, in our opinion, the best form — and it is the one we have chosen.

Our Sublingual Vitamin B12 provides 1000 mcg of methylcobalamin per tablet, to be taken once a day by letting it dissolve under the tongue; the 60-tablet pack lasts for 60 days. It has a wild berry flavour and is sugar-free, sweetened with stevia (steviol glycosides) along with mannitol and xylitol, two polyols that give body to the tablet and allow it to dissolve in the mouth. The other ingredients follow our 'clean label' policy: microcrystalline cellulose as a bulking agent, L-leucine as a flow agent and bamboo extract titrated in silica as an anti-caking agent, which we discuss in excipients in supplements. The bottle is made of amber glass. We have chosen the same orodispersible form for our Sublingual Melatonin 1 mg, to be dissolved under the tongue shortly before bedtime.

How to take vitamin B12: comparing the routes in studies

Frequently asked questions

What is vitamin B12 mainly for?

It is needed to produce energy in cells, to keep the nervous system healthy and to form red blood cells; it also keeps homocysteine levels low and supports the body's defences. The authorised health claims in Europe cover these functions: energy-yielding metabolism, reduction of tiredness and fatigue, nervous system, psychological function, red blood cells, cell division, homocysteine and the immune system. In the cell, it is the cofactor for two enzymes, methionine synthase and methylmalonyl-CoA mutase [1].

Where is vitamin B12 found?

Only in foods of animal origin: liver, fish and shellfish, meat, eggs, milk and cheese. Fruit, vegetables, cereals and legumes do not contain it; among algae, only dried nori has a usable amount, while spirulina contains inactive analogues [2]. Fortified foods and supplements are the sources for those who follow a plant-based diet.

Can meat-eaters have low vitamin B12?

Yes. With age, the stomach produces less acid and the vitamin remains bound to food proteins: in the elderly, this malabsorption accounts for over 60% of deficiency cases, which affects more than one in five people over a certain age [5]. Some long-term therapies also reduce absorption.

What are the signs of a vitamin B12 deficiency?

Persistent fatigue, tingling in the hands and feet, difficulty concentrating, paleness. These are signs common to many other conditions and should be seen as a reason to talk to your doctor, who can order a test for vitamin B12 levels and, if necessary, for homocysteine and methylmalonic acid [1]. The diagnosis and management of a confirmed deficiency are their responsibility.

Why is the vitamin B12 in supplements at 40,000% of the NRV?

Because the reference value is 2.5 µg, and a 1000 µg tablet exceeds this by 400 times. The dose is high because the system that absorbs the vitamin becomes saturated after a few micrograms, and the rest is absorbed by passive diffusion, about 1% [10]: of 1000 µg, a day's requirement is thus absorbed. In Italy, 1000 µg is also the maximum permitted amount in food supplements, and our tablet is formulated at that limit.

Methylcobalamin or cyanocobalamin: what is the difference?

Methylcobalamin is one of the two coenzymatic forms of vitamin B12, present in foods and tissues and ready for use; cyanocobalamin is a synthetic form, which is stable and inexpensive, that the body must first strip of its cyanide group and then convert [14][15]. In our Vitamina B12 Sublinguale, we have chosen methylcobalamin because it is the bioidentical and ready-to-use form: a "clean" choice, consistent with our entire catalogue.

How do you take sublingual vitamin B12?

As indicated on our tablet's label: "Take 1 tablet a day, letting it dissolve under the tongue." Without water, without chewing or swallowing, at any time of day and regardless of meals.

Do people who take metformin or gastroprotectors absorb less vitamin B12?

Yes, studies show this: metformin taken for years reduces vitamin B12 levels [7][8], and two or more years of proton pump inhibitors or H2-receptor antagonists are associated with a higher risk of deficiency [9]. A supplementary intake makes sense in these cases, to be agreed upon with the doctor overseeing the therapy; in those taking metformin, 1 mg per day of sublingual methylcobalamin restored levels in three months [13].

Further reading

• How to read a supplement label: a practical six-step guide
• Bioavailability of supplements: what it really depends on
• Capsules or tablets: how the form of a supplement is chosen

Regulatory references and sources

Regulatory references

• Commission Regulation (EU) No 432/2012 — list of permitted health claims (vitamin B12).
• Regulation (EU) No 1169/2011, Annex XIII, Part A — nutrient reference values (vitamin B12: 2.5 µg).
• Regulation (EC) No 1924/2006 — nutrition and health claims.
• Legislative Decree 21 May 2004, No 169 — food supplements.
• Ministry of Health, ‘Daily intakes of vitamins and minerals permitted in food supplements’, May 2017 revision (vitamin B12: 1000 mcg).
• SINU, LARN — Reference Intake Levels of Nutrients and energy for the Italian population, IV revision (2014).
• EFSA NDA Panel, Scientific Opinion on Dietary Reference Values for cobalamin (vitamin B12). EFSA Journal 2015;13(7):4150.
• CREA, Food composition tables — alimentinutrizione.it; USDA FoodData Central for values not reported in the Italian tables.

Studies

1. Green R, Allen LH, Bjørke-Monsen AL, et al. Vitamin B12 deficiency. Nat Rev Dis Primers. 2017;3:17040. PMID 28660890. DOI 10.1038/nrdp.2017.40
2. Watanabe F, Yabuta Y, Bito T, Teng F. Vitamin B12-containing plant food sources for vegetarians. Nutrients. 2014;6(5):1861-73. PMID 24803097. DOI 10.3390/nu6051861
3. Tucker KL, Rich S, Rosenberg I, et al. Plasma vitamin B-12 concentrations relate to intake source in the Framingham Offspring study. Am J Clin Nutr. 2000;71(2):514-22. PMID 10648266. DOI 10.1093/ajcn/71.2.514
4. Pawlak R, Parrott SJ, Raj S, Cullum-Dugan D, Lucus D. How prevalent is vitamin B12 deficiency among vegetarians? Nutr Rev. 2013;71(2):110-7. PMID 23356638. DOI 10.1111/nure.12001
5. Andrès E, Loukili NH, Noel E, et al. Vitamin B12 (cobalamin) deficiency in elderly patients. CMAJ. 2004;171(3):251-9. PMID 15289425. DOI 10.1503/cmaj.1031155
6. Carmel R. How I treat cobalamin (vitamin B12) deficiency. Blood. 2008;112(6):2214-21. PMID 18606874. DOI 10.1182/blood-2008-03-040253
7. de Jager J, Kooy A, Lehert P, 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;340:c2181. PMID 20488910. DOI 10.1136/bmj.c2181
8. Aroda VR, Edelstein SL, Goldberg RB, et al. Long-term metformin use and vitamin B12 deficiency in the Diabetes Prevention Program Outcomes Study. J Clin Endocrinol Metab. 2016;101(4):1754-61. PMID 26900641. DOI 10.1210/jc.2015-3754
9. Lam JR, Schneider JL, Zhao W, Corley DA. Proton pump inhibitor and histamine 2 receptor antagonist use and vitamin B12 deficiency. JAMA. 2013;310(22):2435-42. PMID 24327038. DOI 10.1001/jama.2013.280490
10. Berlin H, Berlin R, Brante G. Oral treatment of pernicious anemia with high doses of vitamin B12 without intrinsic factor. Acta Med Scand. 1968;184(4):247-58. PMID 5751528. DOI 10.1111/j.0954-6820.1968.tb02452.x
11. Kuzminski AM, Del Giacco EJ, Allen RH, Stabler SP, Lindenbaum J. Effective treatment of cobalamin deficiency with oral cobalamin. Blood. 1998;92(4):1191-8. PMID 9694707
12. Sharabi A, Cohen E, Sulkes J, Garty M. Replacement therapy for vitamin B12 deficiency: comparison between the sublingual and oral route. Br J Clin Pharmacol. 2003;56(6):635-8. PMID 14616423. DOI 10.1046/j.1365-2125.2003.01907.x
13. Parry-Strong A, Langdana F, Haeusler S, Weatherall M, Krebs J. Sublingual vitamin B12 compared to intramuscular injection in patients with type 2 diabetes treated with metformin: a randomised trial. N Z Med J. 2016;129(1436):67-75. PMID 27355231
14. Paul C, Brady DM. Comparative bioavailability and utilization of particular forms of B12 supplements with potential to mitigate B12-related genetic polymorphisms. Integr Med (Encinitas). 2017;16(1):42-9. PMID 28223907 (PMC5312744)
15. Obeid R, Fedosov SN, Nexo E. Cobalamin coenzyme forms are not likely to be superior to cyano- and hydroxyl-cobalamin in prevention or treatment of cobalamin deficiency. Mol Nutr Food Res. 2015;59(7):1364-72. PMID 25820384. DOI 10.1002/mnfr.201500019
16. Del Bo' C, Riso P, Gardana C, Brusamolino A, Battezzati A, Ciappellano S. Effect of two different sublingual dosages of vitamin B12 on cobalamin nutritional status in vegans and vegetarians with a marginal deficiency: a randomized controlled trial. Clin Nutr. 2019;38(2):575-83. PMID 29499976. DOI 10.1016/j.clnu.2018.02.008
17. Abdelwahab OA, Abdelaziz A, Diab S, et al. Efficacy of different routes of vitamin B12 supplementation for the treatment of patients with vitamin B12 deficiency: a systematic review and network meta-analysis. Ir J Med Sci. 2024;193(3):1621-39. PMID 38231320. DOI 10.1007/s11845-023-03602-4