Key Takeaways (expand)
- Vitamin B12, or cobalamin, has the biggest and most complex chemical structure out of any vitamin.
- Although a number of compounds are technically cobalamins, only two forms are used by the human body: methylcobalamin, and 5-deoxyadenosylcobalamin.
- Vitamin B12 serves as a cofactor for the enzymes methionine synthase (which requires B12 in the form of methylcobalamin), and L-methylmalonyl-coenzyme A mutase (which requires B12 in the form of 5-deoxyadenosylcobalamin).
- Vitamin B12 is a cofactor for methionine synthase, giving it a critical role in the creation of methionine from homocysteine.
- Like other B vitamins, vitamin B12 is involved in energy metabolism; its specific role is in synthesizing an important intermediate called succinyl CoA, which allows some branched-chain amino acids and fatty acids to enter the cycle.
- Vitamin B12 is also needed for hemoglobin synthesis and red blood cell production, as well as for the metabolism of folate
- Although vitamin B12 is able to lower levels of homocysteine (a cardiovascular risk factor), studies haven’t found a notable protective effect of this vitamin on actual heart disease risk or stroke.
- Some research has linked low vitamin B12 levels to a greater risk of cancer, as well as chromosome breakage (a cancer risk marker); this may be due to vitamin B12’s role in folate metabolism, with folate being needed for preventing the DNA damage associated with cancer.
- Vitamin B12 plays a role in synthesizing neurotransmitters and preserving the myelin sheath surrounding neurons, giving it a role in maintaining neurological health.
- Vitamin B12 may be protective against dementia and Alzheimer’s disease, possibly through its effects on homocysteine (with elevated levels being linked to higher risk of these conditions, as well as to lower cognitive function scores in the elderly); Alzheimer’s patients also have disproportionately high rates of vitamin B12 deficiency.
- Patients with depression tend to have higher rates of B12 deficiency, and studies have linked low levels of vitamin B12 with greater risk of depression during pregnancy.
- Vitamin B12 deficiency can occur due to long-term insufficient intake (including from unsupplemented vegan or vegetarian diets) or from conditions that inhibit absorption (such as celiac disease, Crohn’s disease, or pernicious anemia—where the body lacks a protein called intrinsic factor that’s needed to bind and absorb vitamin B12 in the small intestine).
- When it occurs, vitamin B12 deficiency can produce neurologic symptoms (sometimes permanent) like numbness and tingling in the feet and hands, difficulty walking, memory loss, and dementia, as well as gastrointestinal symptoms like appetite loss, diarrhea, loss of bladder control, and constipation.
- Vitamin B12 is manufactured exclusively by microorganisms, so the best sources of vitamin B12 are animal foods that concentrate bacterially produced B12 in their cells (particularly fish, shellfish, organ meat, beef, eggs, poultry, and dairy products); some fermented soy products like tempeh also contain vitamin B12.
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Vitamin B12, also called cobalamin, is a water-soluble nutrient with the biggest and most complex chemical structure out of any vitamin! It’s the only vitamin to contain a metal ion (cobalt), a fact that lent itself to the vitamin’s name (cobalamin being a combination of the words cobalt and vitamin). It took over 100 years for the deficiency effects of this nutrient to be discovered and fully understood, with chemists first officially isolating vitamin B12 in 1948. And, research on its role in disease prevention is still ongoing today!
Although a number of compounds are technically cobalamins, the human body only uses two forms: methylcobalamin, and 5-deoxyadenosylcobalamin. (Many nutritional supplements contain vitamin B12 in the form of cyanocobalamin, but our bodies readily convert this into the two forms we can use.)
Like other B vitamins, vitamin B12 is involved in energy metabolism and red blood cell production, but it also plays a major role in DNA synthesis, nervous system health, and the metabolism of another B vitamin: folate.
Because vitamin B12 is manufactured exclusively by microorganisms, the best sources of vitamin B12 are animal foods that concentrate bacterially produced B12 in their cells—such as fish (especially sardines, salmon, tuna, and cod), shellfish such as shrimp and scallops, organ meat, beef, eggs, poultry, and dairy products. Some fermented soy products like tempeh also contain vitamin B12. Although non-fermented plant foods don’t contain vitamin B12, fortified products such as nutritional yeast, breakfast cereals, and plant-based meat and dairy substitutes (like plant milks) can also supply vitamin B12.
The Biological Roles of Vitamin B12
Vitamin B12 serves as a cofactor for two enzymes: methionine synthase (which requires B12 in the form of methylcobalamin), and L-methylmalonyl-coenzyme A mutase (which requires B12 in the form of 5-deoxyadenosylcobalamin). As a methionine synthase cofactor, vitamin B12 helps create the amino acid methionine from homocysteine; methionine is then used to synthesize an important methyl group donor called S-adenosylmethoinine (SAM), which is needed for methylation reactions involving DNA, RNA, proteins, and more. When methionine synthase isn’t functioning sufficiently, it can lead to excess homocysteine accumulation (potentially increasing cardiovascular disease risk), as well as aberrant DNA and protein methylation (leading to altered gene expression and chromatin structure, characteristic of cancer cells).
Meanwhile, in the form of a L-methylmalonyl-coenzyme A mutase cofactor, vitamin B12 helps catalyze the conversion of L-methylmalonyl-coenzyme A to succinyl-coenzyme A (succinyl-CoA). In turn, succinyl-CoA is needed for lipid metabolism, protein metabolism, hemoglobin synthesis.
As a result of these enzyme functions, vitamin B12 is also vital for maintaining cardiovascular, brain, and nervous system health. And, along with folate, vitamin B12 is important for metabolizing homocysteine, an amino acid that’s been linked to cardiovascular disease risk when its levels in the blood are elevated.
Like other B vitamins, it also plays an important role in energy metabolism—particularly the second stage of cellular respiration, called the Krebs cycle or citric acid cycle. The Krebs cycle is an incredibly important series of chemical reactions that all aerobic organisms use to generate energy, through an eight-step process taking place in a cell’s mitochondria. During this cycle, acetate (in the form of acetyl CoA) derived from carbohydrates, fat, or protein undergoes a series of redox, dehydration, hydration, and decarboxylation reactions to produce adenosine triphosphate (ATP), the energy currency for all cells—as well as the waste product carbon dioxide, and reduced forms of NADH and FADH2 (which can then be converted into yet more ATP in the last step of the Krebs cycle: oxidative phosphorylation in the electron transport chain). This is complex biochemistry, but the important part here is that there are a whole lot of chemical reactions required to produce energy for our cells, and B vitamins are essential for that process!
Vitamin B12’s specific role in the Krebs cycle is in synthesizing an important intermediate, succinyl CoA, which is catalyzed from methylmalonyl CoA via the B12-dependent enzyme methylmalonyl-coenzyme A mutase. In turn, succinyl CoA allows some branched chain amino acids (valine and isoleucine), propionate, and odd-chain fatty acids to enter the cycle.
Vitamin B12 in Health and Disease
Vitamin B12 plays a potential role in protecting against some diseases, although in most cases, the current evidence is too mixed (or unavailable!) to be able to say anything conclusive. Research suggests vitamin B12 could be protective against dementia, Alzheimer’s disease, and depression, possibly via its effects on homocysteine levels and neurotransmitter production. However, trials in humans have generally used a mixture of B vitamins rather than vitamin B12 in isolation when studying these conditions, making the individual health effects of vitamin B12 unclear. It’s also shown interesting links with cancer, with low vitamin B12 rates potentially impairing folate metabolism and leading to a reduced ability for the body to repair DNA damage (a cancer risk factor).
Vitamin B12 and Cardiovascular Disease
Vitamin B12’s homocysteine-lowering abilities (confirmed both mechanistically and in controlled trials) gives us reason to believe this vitamin could benefit cardiovascular health. But, studies have failed to find a protective effect of vitamin B12 supplementation on heart disease risk, and only combinations of B vitamins (rather than vitamin B12 alone) have demonstrated a protective effect for stroke—making it unclear how much of a role vitamin B12 itself plays.
Vitamin B12 and Cancer
Some (but not all!) observational studies have also shown that low vitamin B12 status is associated with a greater risk of cancer, as well as cancer risk markers like chromosome breakage. Because vitamin B12 is needed for folate metabolism, a shortage of vitamin B12 can keep folate trapped in an inactive form, ultimately impairing DNA synthesis and methylation (both of which are needed to prevent the DNA damage associated with cancer).
Some observational studies have found that women in the lowest quintile of serum vitamin B12 had a more-than-doubled risk of developing breast cancer compared to women in the four higher quintiles, suggesting a threshold effect (meaning low levels increase risk, but there might not be an additive protective effect of higher levels). One study found a similar trend for vitamin B12 intake, with women ingesting the least B12 having a significantly higher risk of breast cancer than those ingesting the most B12 (this trend was particularly dramatic among postmenopausal women).
But, not all studies have supported these associations, and more research is needed to get a clearer picture—especially well-designed studies that can control for factors that influence breast cancer risk, like alcohol intake, ethnicity, and menopausal status.
Vitamin B12 and Pregnancy
As with folate, low vitamin B12 status during pregnancy has been linked with a higher risk of neural tube defects. But, while folate supplementation has been clearly shown to help reduce this risk, the jury is still out about whether vitamin B12 supplementation can do the same; studies haven’t documented the effects of vitamin B12 supplementation for neural tube prevention purposes.
Vitamin B12 and Neurodegenerative Disease
Due to its role in preserving the myelin sheath that surrounds neurons, as well as in synthesizing neurotransmitters, vitamin B12 is involved in maintaining neurological health. This includes a potential protective effect for conditions like dementia and Alzheimer’s disease.
In fact, Alzheimer’s patients have frequently been shown to be vitamin B12 deficient, and vitamin B12 deficiency could very plausibly contribute to a number of features of dementia (including excess homocysteine and methylmalonic acid accumulation). In observational studies, high homocysteine levels (again, a potential consequence of vitamin B12 deficiency) lead to a significantly higher risk of developing dementia or Alzheimer’s disease over time (for example, compared to people with lower levels, those with plasma homocysteine exceeding 14 μmol/L had over twice the risk of getting Alzheimer’s disease over the span of a decade). Elevated homocysteine has also been linked with significantly lower cognitive function scores in the elderly—though it’s hard to say how much vitamin B12 itself is involved in that trend. And, studies using highly sensitive biomarkers of vitamin B12 status (including methylmalonic acid and holo-transcobalamin, a vitamin B12 carrier) have generally shown that low vitamin B12 status correlates with more rapid cognitive decline and greater risk of Alzheimer’s disease.
That being said, actual trials showing benefit for B-vitamin supplementation on cognitive decline have generally used multiple B vitamins, not vitamin B12 alone—making it hard to distill the effects of vitamin B12 versus other nutrients like folate and vitamin B6, which also play a neuroprotective role.
Vitamin B12 and Depression
Lastly, vitamin B12 has a compelling relationship with depression. Across studies, a disproportionate number of patients suffering from depression have been shown to have low levels of vitamin B12—possibly due to vitamin B12 deficiency inhibiting the methylation reactions orchestrated by S-adenosylmethionine (SAM), in turn impacting affecting depression-linked neurotransmitters. (Indeed, some studies have shown that supplementing with SAM is able to improve symptoms of depression!) Observational research has even linked low levels of vitamin B12 with greater risk of depression during pregnancy, even after controlling for potential confounders.
However, as with dementia and cognitive decline, trials testing the effects of vitamin B12 on depression have also included other B vitamins (especially folate and vitamin B6), so more research is needed to understand the effects of vitamin B12 specifically.
Health Effects of Vitamin B12 Deficiency
Because the body has a very high storage capacity for vitamin B12 and a slow daily turnover, true vitamin B12 deficiency is relatively uncommon. But, it can develop from long-term insufficient intake (such as from unsupplemented vegetarian or vegan diets) or, more often, from conditions that inhibit absorption. For example, vitamin B12 deficiency can result from an autoimmune malabsorption syndrome called pernicious anemia, in which the body lacks a protein called intrinsic factor (IF) that’s needed to bind and absorb vitamin B12 in the small intestine. This disorder involves a long-term destruction of cells that line the stomach, and requires treatment with vitamin B12 injections (since the body lacks the protein necessary to obtain vitamin B12 from digestion). Another disorder, food-bound vitamin B12 malabsorption, inhibits the absorption of vitamin B12 that’s bound to food or protein—usually as a result of chronic stomach inflammation, which damages stomach glands and reduces gastric acid production (in turn limiting the amount of vitamin B12 that can be freed from the proteins in food). But, in this case, individuals can still absorb vitamin B12 in its free (unbound) form, and can be treated with vitamin B12 supplements. Both of these conditions tend to be more common in older people (generally over the age of 60), due to digestive dysfunctions associated with age. In addition, infection with the H. pylori bacteria, which leads to stomach inflammation (and sometimes progresses to peptic ulcer disease, gastric cancer, or atrophic gastritis), causes reduced vitamin B12 levels in the blood; treating the infection has been shown to subsequently improve vitamin B12 status.
Additional causes of vitamin B12 deficiency include health conditions affecting nutrient absorption (such as celiac disease, Crohn’s disease, and tropical sprue), surgical resectioning of the stomach or small intestine, pancreatic insufficiency, alcoholism (which leads to reduced intestinal absorption of vitamin B12), and long-term use of drugs that reduce stomach acid. And, several rare inherited conditions can affect vitamin B12 metabolism, such as Imerslund-Gräsbeck syndrome (which causes B12 malabsorption) and hereditary intrinsic factor deficiency (also known as congenital pernicious anemia).
Certain medications can interfere with vitamin B12 absorption. These include proton-pump inhibitors (like omeprazole or lansoprazole), histamine-2 receptor antagonists often used for treating peptic ulcers (like cimetidine, famotidine, and ranitidine), and metformin (a common diabetes drug).
Even before physical symptoms of vitamin B12 deficiency manifest, deficiency can show up in tests as high blood levels of homocysteine or methylmalonic acid. Left untreated, vitamin B12 deficiency can lead to a number of damaging health effects. These include neurologic symptoms (sometimes permanent) like numbness and tingling in the feet and hands, difficulty walking, absent reflexes, disorientation, memory loss, nerve damage, and dementia, as well as gastrointestinal symptoms like appetite loss (and subsequent weight loss), sore tongue, diarrhea, loss of bladder control, and constipation. These gastrointestinal symptoms are believed to be caused by defective DNA synthesis, which inhibits replication in tissues that have high cell turnover, such as in the GI tract. In children, vitamin B12 deficiency can have symptoms including regression, low muscle tone and strength, involuntary movements, irritability, and developmental delay.
Both severe folate deficiency and vitamin B12 deficiency can lead to megaloblastic anemia—a form of anemia where the bone marrow produces big, underdeveloped red blood cells due to impaired DNA synthesis and reduced nuclear division. As the anemia progresses, it leads to impaired oxygen carrying capacity within the blood, causing symptoms such as fatigue, pale mucus membranes and palms, weakness, and shortness of breath. Because both folate and vitamin B12 deficiency can cause megaloblastic anemia, and the symptoms in both cases are identical, it’s important to correct the condition with the right nutrient: improperly treating B12-induced anemia with high doses of folate can perpetuate the vitamin B12 deficiency, potentially leading to irreversible brain damage.
How Much Vitamin B12 Do We Need?
The recommended dietary allowance (RDA) for vitamin B12 is 2.4 micrograms per day for adults (2.6 micrograms when pregnant and 2.8 micrograms daily when breastfeeding); after the age of 50, adults are advised to obtain some vitamin B12 from supplements or fortified foods, due to the increased risk of food-bound B12 malabsorption. Individuals following strict vegetarian diets, or who otherwise consume diets low in animal products, should regularly consume fortified food sources of vitamin B12 or supplements (although no official recommendations exist here, 25 to 100 micrograms daily of sublingual vitamin B12, or 1000 to 2500 micrograms several times per week, is common).
Individuals with pernicious anemia should seek medical advice from their healthcare provider, since neither food sources nor oral supplements will deliver enough vitamin B12 to meet the body’s needs. Due to vitamin B12’s low toxicity, no tolerable upper intake level has been set. In fact, oral doses as high as 2000 micrograms daily have been used without any significant side effects!
Although vitamin B12 has extremely low toxicity, it’s worth noting that high-dose vitamin B12 supplements—particularly in the form of intramuscular injections—can sometimes cause side effects, including headache, nausea, vomiting, mild diarrhea, itching, skin rash, tiredness, weakness, or tingling in the hands and feet. Vitamin B12 in the form of dietary supplements, including B12-containing multivitamins, are unlikely to produce any noticeable side effects, largely because it’s a water-soluble vitamin and only a fraction of it gets absorbed orally.
Best Food Sources of Vitamin B12
The following foods have high concentrations of vitamin B12, containing at least 50% of the recommended dietary allowance per serving, making them our best food sources of this valuable B-vitamin!
Good Food Sources of Vitamin B12
The following foods are also excellent or good sources of vitamin B12, containing at least 10% (and up to 50%) of the daily value per serving.
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