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Vitamin B12 is an essential water-soluble vitamin that plays a role in neurological function and is important for DNA synthesis.
Cyanocobalamin (Vitamin B12) is most often used for
Last Updated:March 16, 2024
Vitamin B12 is one of the 8 B vitamins and is water soluble. It is found bound to protein, where it is used in several metabolic processes, and is important for one-carbon metabolism. One-carbon metabolism is a series of metabolic processes that are crucial for cellular function.[3][4] Vitamin B12 acts as a cofactor in these metabolic processes throughout the body, including the production of methionine, one of the amino acids that is integral for the production of the purines that make up DNA.[4]
Vitamin B12 is often used as an over-the-counter treatment for general fatigue and also might benefit people with myalgic encephalomyelitis (chronic fatigue syndrome) (ME/CFS) as a potential treatment. A B12 deficiency may even be a potential cause of the condition. A 2022 review found that some people with ME/CFS had a low B12 level in cerebrospinal fluid (CSF) samples but a normal level in blood samples. This could imply a low B12 supply in the brain, despite a normal level in the blood. Another study found that intranasal vitamin B12 improved symptoms of fatigue in two thirds of people with ME/CFS.[5] For general fatigue symptoms in otherwise healthy people, very little research has been done on this, so we are not sure if it is effective.[6]
Vitamin B12 may be beneficial for various types of neuropathy (nerve damage). Postherpetic neuralgia is a complication after the reactivation of a herpes virus (e.g., chicken pox) causes damage to the involved nerves, and vitamin B12 may improve the outcome of treatment when added to conventional treatment for this condition.[7] Similarly, a 2020 randomized control trial[8] found that supplementing with 1000 μg of vitamin B12 improved the symptoms of diabetic neuropathy. This could be because around 20% of people with diabetes are also deficient in B12.[9]
Vitamin B12 is crucial in the first trimester of pregnancy. A deficiency, as with a deficiency of folate (vitamin B9), can lead to neural tube defects. The neural tube develops in the third week of pregnancy, around day 20-28. It is ideal to start supplementation prior to pregnancy to ensure sufficient levels are present from day 1.[10]
Vitamin B12 supplements are sometimes used to improve cognitive symptoms in people with neurodegenerative disease. However, meta-analyses have not supported this use so far.[6][11][12]
A recent review suggests that vitamin B12 could be useful in viral infections, including SARS-CoV-2 (COVID-19). It seems that many people with viral infections may have low B12 levels, or levels on the low end of the normal range that could still result in symptoms. In these cases, providing a supplement could improve outcomes. However, this still needs to be studied further, and we can’t be sure it is helpful just yet.[1]
Vitamin B12 is considered to be a safe supplement. At the recommended dosages, toxicity is highly unlikely. Since it is a water soluble vitamin, the body will excrete any excess through the urine. As such, no upper limit of intake has been established yet.[13]
It seems that a high vitamin B12 level could increase the risk of certain cancers and decrease the risk of others. One study[14] found an association between elevated B12 levels and prostate cancer; however, it did not establish a causal relationship. A cohort study in 2017 found an increased lung cancer risk for men who smoked and took relatively high doses of vitamin B12. While this association doesn’t necessarily mean B12 caused the increased rate of lung cancer, it is certainly worth considering before supplementing in this population group.[15]
Conversely, another study found that a higher vitamin B12 intake was associated with a lower risk of colorectal cancer.[16]
In cardiovascular disease, the data also remains uncertain. A 2024 meta-analysis found that increased B12 levels were associated with an increase in cardiovascular disease mortality. However, this study looked at endogenous vitamin B12, not vitamin B12 intake, and this might indicate that B12 levels rise in the presence of cardiovascular disease.[17] Another study found that vitamin B12 had little impact on cardiovascular disease outcomes.[18] More studies will need to be done to assess supplemental vitamin B12 as a risk factor for cardiovascular disease.
Broadly speaking, vitamin B12 is important because it’s a necessary part of many chemical reactions in the body.
Vitamin B12 and folate work as cofactors in the synthesis of the amino acid methionine via the enzymes methionine synthase and L-malonyl-CoA mutase. A deficiency of vitamin B12 or of folate disrupts this process and leads to the production of abnormally large red blood cells, resulting in megaloblastic anemia.[19]
Vitamin B12 is also used by methyl-malonyl-CoA mutase to produce succinyl CoA. Interrupting this reaction leads to the neurological symptoms of B12 deficiency.[4]
B12 is also used in the production of the myelin sheaths that surround nerves and help with nerve signal transmission. If the sheath is damaged, the signals can become disrupted or abnormal, causing pain or loss of sensation. In vitamin B12 deficiency, peripheral neuropathy can occur, which is the result of damage to the myelin sheaths in the nerves of the hands and the feet.[19]
Vitamin B12 is part of one-carbon metabolism, the metabolic process that produces DNA in the body. It helps enzymes work in the production of the building blocks of DNA called purines and pyrimidines.[4]
The Recommended Daily Allowance (RDA) of vitamin B12 is 2.4 μg for adults without known health conditions. During pregnancy, the RDA increases to 2.6 μg.[1] For children 8 years and under, the RDA is 1.2 μg.[1] Supplementing with B12 is probably not helpful in people who are able to get enough of the vitamin through their diet and have no difficulty with absorption.
Supplements that are available over the counter contain 500–2000 μg of vitamin B12 per tablet. Long-term use is not recommended without monitoring of vitamin B12 levels.
For replenishing stores of vitamin B12, 1000 μg should be given by intramuscular injection three times per week for two weeks. This can then be done weekly for four weeks, then once monthly. In cases where absorption is not an issue, the maintenance dose can also be given orally.[2]
Recent evidence has linked B vitamins (specifically Vitamin B6 and vitamin-b12) to an increased risk of lung cancer in men, especially in smokers. Here, we analyze the study and interview the lead author, Dr. Theodore Brasky.
B vitamins are common ingredients of multivitamins, of course, but also of energy boosters, such as energy drinks. But while they are best known for their role in energy metabolism,[23] they may play a role in cancer biology through partaking in one-carbon metabolism[24] and thus in methylation reactions and DNA synthesis.
This hypothesis was substantiated in 2015 when a paper published by the New England Journal of Medicine caused a stir by reporting that nicotinamide (a form of vitamin B3 also known as niacinamide) could reduce the rate of new non-melanoma skin cancers.[25]
B vitamins had gained an “anti-cancer” reputation.
Yet it was just one study showing that one form of vitamin B3 could reduce the rate of one type of skin cancer; it didn’t preclude the possibility that some B vitamins could worsen at least some types of cancers.
To look for other possible connections between B vitamin supplementation and cancer, Dr. Theodore Brasky at The Ohio State University, in collaboration with colleagues at the Fred Hutchinson Cancer Research Center and at University of Taipei, performed a large observational study.[15] Since its publication in the Journal of Clinical Oncology, in 2017, this study has taken the supplement world by storm, for it linked the vitamins B6 and B12 each with a 30–40% increase in overall risk of lung cancer in men.
Let’s take a closer look at the study.
To look for possible connections between B vitamin supplementation and lung cancer, the researchers analyzed data from the 77,000 participants in the VITamins And Lifestyle (VITAL) prospective cohort study.[26] The study itself was designed to look for possible associations between cancer risk and vitamin, mineral, and non-vitamin/non-mineral supplementation.
The researchers chose to focus on the vitamins B6, B12, and B9, which play an important role in the one-carbon pathways and thus are most likely to affect carcinogenesis. The study participants, all residents of the State of Washington aged 50–76 at the beginning of the study, were classified into five groups based on their average daily dose of supplemental B vitamins over the previous 10 years. Statistical techniques were then used to adjust for confounding factors such as age, education, body size, and family history of lung cancer.
When the data were stratified by sex, B6 and B12 as individual supplements were each shown to increase lung cancer risk by 30–40% in men (but not in women).
The greatest risk was found among men with the highest average daily dose of B6 (>20 mg/day was associated with an 82% greater risk) and B12 (>55 mcg/day was associated with a 98% greater risk) over the ten years preceding the study.
When the data were stratified by smoking status, increased risk was associated with smoking. Smokers who had supplemented with high amounts of B6 had nearly three times the risk of developing lung cancer, and those having supplemented with high amounts of B12 had over three times the risk. The study found no association between supplementation and increased risk in either former smokers or recent smokers. As for never-smokers, the paper states they “were excluded from the smoking-stratified analysis because of the low number of participants with incident lung cancer in that group.”
The study showed that long-term supplementation with B6 or B12 increased lung-cancer risk in male current smokers, especially in those supplementing with high dosages of either vitamin.
One-carbon chemical groups lack stability, so they need to be attached to larger molecules in a process called one-carbon metabolism. The vitamins B6, B9,[27] and B12 play an important part in one-carbon metabolism, which in turn plays a crucial part in methylation reactions and nucleotide synthesis.
The nucleus of each of your cells contains your complete DNA. In your DNA is encoded the genetic blueprint for every protein in your body. How then do cells maintain a unique identity? By each reading only certain parts of your DNA, so that only the appropriate genes are turned on at the appropriate time.
For that purpose, sections of your DNA can be “marked” with methyl groups that prevent the expression of nearby genes. This type of epigenetic imprinting is critical to keeping cells normal, healthy, and well behaved. When the process becomes dysfunctional, the wrong genes can be turned on at the wrong times, potentially leading to uncontrolled cell growth — to cancer.
So how would high amounts of B6 or B12 increase cancer risk? We might find some clues in a recent study on DNA methylation,[28] which found that two years of supplementation with 400 mcg of B9 and 500 mcg of B12 changed DNA methylation. Thus, the increase in cancer risk seen in the Brasky study could be caused, in part, by changes in DNA methylation from long-term B vitamin supplementation.
Another curious finding from the Brasky study was that only men saw an increase in cancer risk from B6 or B12 supplementation. Women did not. We know androgens regulate some of the enzymes that participate in one-carbon metabolism,[29] which might explain the difference.
Androgens and the vitamins B6, B9, and B12 interact to play a role in DNA methylation. Since DNA methylation in part determines which genes are activated (or not) at any given time, this could explain the link between long-term B vitamin supplementation and cancer risk in men.
The Brasky study was not designed to show causation, but it did reveal a strong correlation between increased risk of lung cancer and long-term B6/B12 supplementation, especially in high doses and among smokers. There are several ways B vitamins may interact with cancer metabolism; more research is needed to determine the exact mechanisms at work. In the meantime, we are left with three takeaways:
Smoking, as you know, causes lung cancer. If you smoke, stop. If you are unable to stop, avoid supplementing with B vitamins for an extended period of time, especially if you are male. Long-term B vitamin supplementation seems to increase cancer risk in male smokers, possibly by potentiating carcinogenesis in precancerous cells in response to the carcinogens in cigarette smoke (which would explain why only current smokers, not former or recent smokers, seem affected).
The effect of B vitamins on non-smokers is still uncertain. In this study, sample sizes for never-smokers were too small to evaluate associations accurately.
Although observational studies cannot show causation, the associations between B vitamins and cancer risk found in this study raise an important point, which is that high-dose, long-term consumption of any supplement can potentially interact with your biochemistry in unexpected ways. Exceeding the recommended, tested doses of even the most healthful micronutrients may not be innocuous.
When this study was published, its finding that B vitamin supplements increased cancer risk in men generated a lot of press. But isn’t there some nuance to that finding, especially with regard to smoking habits? What ultimate take-home message can be extracted from the data?
The nuance is sort of centered around the general idea that once you start chopping up data, you lose precision. In epidemiology, our best estimates come from data reflecting the largest sample sizes. Our most cited finding was that long-term, high-dose supplementation of vitamin B6 and long-term, high-dose supplementation of vitamin B12 were each associated with about a doubling of lung-cancer risk in men. This is an entirely true representation of our results. However, when we drilled down further — and thus lost some precision — we found that this twofold increase in risk was an average across different groups of men, some with no increase in risk (men who had never smoked or had stopped smoking at the time the study began), and some with a threefold to fourfold increase in risk (men who smoked at the time the study began).
Here the scientist is left with two possibilities. Is the real finding (a) based on the larger sample size with more precise data? — men who use these supplements have twice the risk of lung cancer as do men who don’t use these supplements; or (b) based on the subgroups within men with less precise results? — men who currently smoke and who use these supplements have three to four times the risk of lung cancer as do men who currently smoke and don’t use these supplements. To me, the take-home message is the latter.
Supplementation dose, frequency, and duration are all important from a biological standpoint. How were those factors taken into account in the design of the study questionnaire? What were the pros and cons of the different ways of using those factors (and others) to identify meaningful associations with lung-cancer risk?
Put simply, we had a number of options. We could analyze separately a given supplement’s frequency of use (i.e., days per week), duration of use (i.e., number of years in the past 10 [our questionnaire only asked about the past 10 years of use]), and most common dose used, or we could combine those data.
Analyzing separately any single aspect removes the influence of the other two, which is, in my view, not ideal. Combining the data gives two additional options. We could determine a cumulative dose over the past 10 years or an average daily dose over the past 10 years. We chose the latter because it’s easier to understand and because it allowed us to compare risks with what might be expected for intakes at the level of a multivitamin taken daily for the same amount of time.
However, the disadvantage of this option — which, I contend, remains better than the alternatives — is that the 10-year, daily-dose calculation equates short-term, high-dose intakes with long-term, lower-dose intakes. The highest category of intake for supplemental B12, for instance, was >55 mcg/day. This is >55 mcg taken daily, on average, over 10 years. For some people, it may actually have been about that amount daily for 10 years, but for most it was shorter-term use at higher doses that averaged out to this level.
Therefore, >55 mcg is not meant to be interpreted as the actual dose that might confer risk. Indeed, most B12 supplements are sold at much, much higher doses. A standard pill from a bottle at the grocery store might contain between 500 and 2,000 mcg, with instructions that it should be taken daily. This is why the comparison to what might be consumed from a multivitamin (100% RDA) comes in handy.
Although the question “Does B vitamin supplementation increase cancer risk?” is straightforward, extracting a solid answer from a given study population is another matter. Epidemiologists like yourself are experts at identifying risk associations within large study populations. At the other end of the spectrum, basic scientists like myself tend to use defined experimental models to identify important cellular/molecular controls that drive disease processes. Could you comment on how epidemiological studies and basic science (i.e., bench research) fit in the big picture of biomedical science? Do you feel they complement each other?
A better scientist than I could probably comment on this with real nuance. I can only give my interpretation, which is, sadly, not based off any firsthand experience with bench science. I once pipetted something, but my assay didn’t run properly. C’est la vie. Looking broadly across disciplines, I can say that epidemiologists and “basic” scientists have a complementary relationship born out of necessity.
Epidemiologists cite rodent studies because in these experiments a lot of the variables can be controlled. The animals are very similar genetically, they’re all fed the same diet (unless it’s a nutrition study), handled the same way, etc. Moreover, we can perform some trials in animals that are considered unethical in humans — exposing rodents to tobacco smoke, for instance. We often see the results of these studies as hypothesis generating because, after all, the animal is a model for the human. People do not, in fact, have fur or tails, and we are much more genetically diverse than rodents purpose bred for disease models. In some instances, animal models are better approximations than others. Mice have estrous cycles rather than menstrual cycles, so some similarities for reproductive cancers are muddied by physiology here. Similarly, a mouse’s prostate gland is structured differently from a man’s; again, models. The idea is the same for work involving cells in petri dishes, although the contrast is starker. On the other hand, from what I’m told by my colleagues in these fields, epidemiologic research, which is predominantly done in an observational manner, is seen as hypothesis generating.
That we all work together towards the same goal is what’s important. Although we definitely give each other grief, epidemiologists appreciate basic scientists for their explanation of biologic mechanisms, and (I’m assuming) basic scientists appreciate epidemiologists for their findings in need of biologic explanation.
Full FAQ and database update
We fully updated this page and have several brand-new FAQs about this topic.