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Vitamin B12

Nutrient Name: Vitamin B12.
Synonyms: Cobalamin, cyanocobalamin.
Chemistry and Forms: Adenosylcobalamin, cobalamin, cyanocobalamin, hydroxocobalamin, hydroxycyanocobalamin, methylcobalamin.

Summary Table
physiology and function

Physiology and Function

Vitamin B12is the generic term for the group of compounds, collectively known as cobalamins , that exhibit the biological activity of cyanocobalamin. Vitamin B12was isolated from liver extract in 1948 and was shown to control pernicious anemia; its structure was elucidated in 1955, and cobalamin was first synthesized in 1973. Cobalamin is the precursor to methylcobalamin and adenosylcobalamin, the bioactive cofactor forms of cobalamin. This water-soluble, crystalline substance derives its red color from the heavy metal cobalt molecule it contains. It is susceptible to degradation by dilute acid, alkali, light, and oxidizing or reducing agents; 30% is typically destroyed by cooking.

Vitamin B12from foods is released from the protein complex that it comes from via the action of hydrochloric acid and proteases. The absorption of cobalamin is highly dependent on intrinsic factor , a protein produced by the parietal cells, without which less than 1% of vitamin B12would be absorbed. The secreted intrinsic factor binds to the B12, enabling transfer of compound across the intestinal mucosa, and the resulting complex travels down to the ileum, where it is absorbed from the terminal aspect in the presence of calcium. Vitamin B12is normally actively transported into the blood via protein binding to transcobalamin II and carried to the liver, its major storage site for up to 3 years, and to the kidneys and adrenals. It is distributed throughout the body, where it is converted in tissues to active coenzymes, methylcobalamin and deoxyadenosylcobalamin, and plays a vital role in the metabolism of all cells, especially those of the gastrointestinal tract, bone marrow, and nervous tissue. Excretion is through the urine.

Vitamin B12acts as a coenzyme for various metabolic functions, including fat and carbohydrate metabolism and protein synthesis, and is used in cell replication and hematopoiesis. Its key functions include activation of folate to its active form (tetrahydrofolate, THF); conversion of homocysteine to methionine; fat and carbohydrate metabolism; synthesis of DNA and myelin; and antioxidant (maintains reduced glutathione).

Cobalamin is involved as a cofactor in the transfer of methyl groups in the synthesis of methionine and in folic acid metabolism. In particular, it is needed to remove the methyl group from methyltetrahydrofolate (MTHF) so that THF can be used for reducing RNA in the synthesis of DNA. Vitamin B12is necessary for the maturation of red blood cells (RBCs) as well. Thus, in the absence of B12, DNA is severely compromised, and RBCs grow without dividing, becoming megaloblasts, thus the term megaloblastic anemia, which occurs with deficiencies of either folate or B12.

Vitamin B12and folic acid work together to regulate homocysteine (Hcy) levels. Methyl-B12is used to transfer the methyl group onto Hcy to form methionine. Methionine is an essential sulfur-containing amino acid that is converted in the liver into S-adenosylmethionine (SAMe), considered the activated form of methionine. Methionine is important in methyl transfers and is necessary for the synthesis of myelin sheaths, among numerous other vital functions. Methionine synthase (5-MTHF–homocysteine S–methyltransferase) catalyzes the cobalamin-dependent methylation of Hcy, using 5-MTHF as the methyl donor. Defects in methionine synthase result in hyperhomocysteinemia and are implicated as the lesion in the cblG complementation group of disorders in cobalamin metabolism. Lower Hcy levels are associated with decreased risk of cardiovascular disease; high Hcy levels may also be associated with Alzheimer's disease, osteoporosis, and strokes. Methionine synthase reductase (MSR) is responsible for the reductive methylation and reactivation of methionine synthase with SAMe as a methyl donor. MSR is a member of the ferredoxin-NADP reductase family of electron transferases, containing the FMN, FAD, and NADPH binding sites necessary to maintain methionine synthase in its functional state. 1 SAMe plays an important role in detoxification processes, the synthesis of antioxidants, and the regulation of emotional states.

Vitamin B12is also involved in carbohydrate metabolism, plays a key role in nerve cell activity, and is required for the synthesis of myelin. Lactic acid and pyruvate production can increase from 50% to 100% during B12deficiency. Neurological problems often occur when there is a B12deficiency because the nervous system relies on carbohydrates as its main source of fuel.

nutrient in clinical practice

Known or Potential Therapeutic Uses

Vitamin B12deficiency is a common but underrecognized, yet easily treatable disorder in older adults. Although several causes exist, food-cobalamin malabsorption is considered the most common etiology. Therapeutic administration of vitamin B12is used primarily to prevent or treat a deficiency state or counter depletion. Although oral intake can serve some supportive function, intramuscular injection was considered the primary therapeutic mode of administration for many years. More recently, it has been shown that large oral doses (1-2 mg/day) are equally effective in treating even the severe B12deficiency associated with pernicious anemia. Concomitant folic acid therapy is also necessary in many circumstances.

Possible Uses

Acquired immunodeficiency syndrome and human immunodeficiency virus (AIDS/HIV) support, age-related cognitive decline (with vitamin B12deficiency), age-related hearing dysfunction, allergies, Alzheimer's disease, anemia (for thalassemia if deficient), anemia (if deficient), anemia of pregnancy, asthma, atherosclerosis, atopic dermatitis, Bell's palsy, bipolar disorder, bursitis, canker sores (for deficiency only), cardiac events and death (risk reduction after first stroke), chronic fatigue syndrome, contact dermatitis, Crohn's disease, cyanide poisoning (hydroxycobalamin form only), cystic fibrosis (with vitamin B12deficiency), depression (with vitamin B12deficiency), dermatitis herpetiformis (with vitamin B12deficiency), diabetes mellitus, diabetic neuropathies, diabetic retinopathy, Down's syndrome, heart attack, hepatitis, herpes zoster, hives, hypercholesterolemia, hyperhomocysteinemia, immune function, inherited cobalamin disorders, insomnia, low back pain, lung cancer (risk reduction), male infertility, methionine synthase reductase (MSR) deficiency (genetic), methionine synthase apoenzyme deficiency (genetic), methylmalonic aciduria (genetic), multiple sclerosis, neural tube defects (risk reduction), neuralgias, neuropathy, osteoporosis (with hyperhomocysteinemia), pain, pernicious anemia, phenylketonuria (with vitamin B12deficiency), presurgery and postsurgery support, postherpetic neuralgia, preclampsia, pregnancy support, restless leg syndrome, retinopathy (associated with childhood diabetes), schizophrenia, sciatica, seasonal affective disorder, seborrheic dermatitis, sickle cell anemia (with B12deficiency), stroke and second stroke (risk reduction), thyrotoxicosis, tinnitus, vitamin B12deficiency, vitiligo.

Deficiency Symptoms

Increased risk of vitamin B12deficiency is associated with deficiency of intrinsic factor and pernicious anemia; achlorhydria; atrophic gastritis; gastric carcinoma; gastrectomy, especially of the cardia or fundus; pregnancy and lactation; malnourished children; the elderly, especially those physically disabled and with urinary incontinence, tinnitus, or hearing loss; HIV-infected individuals; psychiatric disorders; liver disease or cancer; Helicobacter pylori infection; intestinal diseases, especially involving malabsorption, such as celiac disease, Crohn's disease, colitis, chronic diarrhea (e.g., in AIDS), pancreatic disease, and tapeworms; vegan diets, especially over an extended period; chronic heavy cigarette smoking and/or alcohol use; excessive or prolonged use of medications such as antibiotics, anticonvulsants, cholestyramine, colchicine, gentamicin, metformin, neomycin, and para-aminosalicylic acid (PAS); protracted intake of megadoses of vitamin C and copper.


  • Deficiency of methylmalonyl-CoA mutase, leading to methylsmalonic aciduria.
  • Elevated adenosylcobalamin, most likely due to a perturbation in cofactor binding.
  • Defects in methionine synthase result in hyperhomocysteinemia and are implicated as the lesion in the cblG complementation group of disorders in cobalamin metabolism.
  • Genetic mutations in the cobalamin-binding domain of methyltransferase.
  • Methionine synthase reductase (MSR) deficiency, such as mutation(s) in cblE complementation group.

Signs and Symptoms of B12Deficiency

Depression, irritability, agitation, bone loss, confusion and memory loss (especially in elderly), fatigue, psychosis, classic pernicious anemia due to lack of intrinsic factor, macrocytic anemia, decreased phagocyte and polymorphonucleocyte response, impaired lymphocyte response, poor blood clotting and easy bruising, progressive peripheral neuropathy, spinal degeneration, unstable gait, decreased coordination, paresthesias, loss of appetite, nausea, vomiting, glossitis, tongue and mouth irregularities, achlorhydria, dermatitis and skin sensitivity.

Complications associated with long-term depletion of this nutrient can take years to develop, and frank vitamin B12deficiency is considered rare. Years of deficiency are usually required before hematological and neurological signs and symptoms become evident. Vitamin B12deficiencies manifest primarily as anemia and neurological changes. Pernicious anemia is usually the first symptom of B12deficiency and results from either inadequate intake or inhibited absorption associated with reduced gastric secretion of intrinsic factor. Vitamin B12deficiency, and subsequent impairment of cell replication in atrophy and inflammation of mucus membranes in the mouth and throughout the digestive tract, not only results in reduced absorption of nutrients, gastric atrophy, anorexia, and weight loss, but also creates a gastric environment of increased susceptibility to imbalance and infection. Thus, numerous studies have observed a strong association between Helicobacter pylori and B12deficiency, even in the absence of gastric atrophy, 2-11with infection detected in 56% of individuals diagnosed with pernicious anemia in one trial. 12 Likewise, inhibited DNA synthesis associated with B12deficiency can lead to megaloblastic anemia and manifest as weakness, decreased ability to concentrate, and shortness of breath. Cobalamin-deficiency polyneuropathy is considered particularly difficult to diagnose, and deficiency for longer than 3 months can result in irreversible degenerative central nervous system (CNS) lesions. Low B12levels may also be associated with an increased risk of brain disorders, birth defects, colon cancer, and heart disease. Vitamin B12deficiency can mask signs of polycythemia vera.

In a clinical trial, Eussen et al. 13 found that the lowest dose of oral cyanocobalamin required to normalize mild vitamin B12deficiency is more than 200 times greater than the recommended dietary allowance (RDA).

Dietary Sources

Liver, meat, salt-water fish, oysters, milk, eggs, aged cheese such as Roquefort, fortified brewer's yeast. All foods of animal origin, especially organ meats, provide vitamin B12because it is produced by microbial synthesis in the digestive tract of animals. It does not occur in fruits, vegetables, grain, or legumes. A few foods of vegetable origin, specifically seaweed and microalgae (including nori, chlorella, and spirulina) and tempeh, can provide small but inconsistent amounts. 14,15

Nutrient Preparations Available

Hydroxycobalamin and cyanocobalamin are synthetic forms of vitamin B12. Methylcobalamin and 5-deoxyadenosylcobalamin are the two forms of vitamin B12that occur naturally in foods.

Hydroxycobalamin, cyanocobalamin, and adenosylcobalamin are the principal forms used in conventional clinical practice. Methylcobalamin is also used but is very expensive.

Absorption of large doses of B12in the form of oral supplements is relatively poor. Sublingual forms are available but may not offer significant absorption advantages. Intramuscular or deep subcutaneous injection, usually as hydroxycobalamin, is the most effective route of B12administration, especially for the elderly or those suffering from chronic depletion. However, some research indicates that oral doses may be as effective, even in the elderly. 13 Large doses (e.g., 1 mg), whether sublingual or oral, completely overcome the need for intrinsic factor.

Dosage Forms Available

Capsules, effervescent tablets, gels, injectable (prescription only), intranasal sprays, liposomal sprays, liquids, lozenges, powder, sublingual lozenges, tablets.

Dosage Range


Dietary: 1 to 3 µg daily.

Supplemental/Maintenance: 100 µg daily. Vegans (individuals who avoid all foods of animal origin) will generally benefit from a daily dose of 2 to 3 µg or more of vitamin B12. Individuals who include animal products in their regular diet usually do not need to supplement with B12. However, several studies show that B12absorption declines with increasing age and suggest that the elderly may generally benefit from regular supplementation with 10 to 25 µg per day of vitamin B12. 16-19

Pharmacological/Therapeutic: Pharmacological dosages in the scientific literature range from 100 to 3000 µg. For example, long-term supplementation might involve 30 µg/day for 5 to 10 days initially, followed by 100 to 200 µg per month. A daily dose of 250 µg is often used to treat deficiency, and daily doses as high as 2000 µg have been used in chronic renal insufficiency. Therapy for pernicious anemia usually involves vitamin B12injections, but oral administration of 1000 µg/day may be effective for some individuals. 20-25Some evidence indicates that individuals, particularly elderly, whose serum cobalamin concentration is less than 300 pg/mL should receive replacement parenteral therapy. Nonspecific neurological signs and symptoms, particularly in the elderly, including fatigue, appear to respond to B12supplementation, despite low-normal serum levels. Ralph Carmel, a hematologist, has researched and published extensively on this issue.

  • Gel, intranasal (Nascobal): 500 µg/0.1 mL (5 mL)
  • Injection: 100 µg/mL (1 mL, 10 mL, 30 mL); 1000 µg/mL (1 mL, 10 mL, 30 mL)
  • Tablet [OTC]: 50 µg, 100 µg, 250 µg, 500 µg, 1000 µg.

Dibencozide is a supplemental form of deoxyadenosylcobalamine that has been widely used by athletes and bodybuilders.

  • Toxic:   Few adverse effects and no reports of toxicity have been associated with B12therapy, even at unusually high oral doses such as 5000 µg/day.

Pediatric (<18 years)


  • Infants, birth to 6 months: 0.4 µg/day (AI, adequate intake)
  • Infants, 7 to 12 months: 0.5 µg/day (AI)
  • Children, 1 to 3 years: 0.9 µg/day (RDA)
  • Children, 4 to 8 years: 1.2 µg/day (RDA)
  • Children, 9 to 13 years: 1.8 µg/day (RDA)
  • Adolescents, 14 to 18 years: 2.4 µg/day (RDA)
  • Pharmacologic/Therapeutic:   1 to 5 mg given in single doses of 100 µg over 2 or more weeks, followed by 30 to 50 µg per month.

Laboratory Values

Elevated levels of urinary methylmalonic acid (MMA) is the most reliable sign of a need for increased intake of B12, regardless of the serum level of the vitamin.

Serum Vitamin B12

  • Normal range: 150 to 750 pg/mL; this represents 0.1% of total body content.
  • Levels less than 150 pmol/L indicate clear deficiency.
  • Serum levels may be normal even when anemia or neurological symptoms due to vitamin B12deficiency are present.

Urinary Methylmalonic Acid

  • Levels greater than 5 µg/mg creatinine indicate deficiency.
  • Urinary MMA is a more sensitive index of B12status than serum levels of the vitamin.

Hypersegmentation Index of Nuclei of Neutrophils

  • The ratio of neutrophils with five lobes or more to those with four lobes or less; values greater than 30% indicate deficiency.
  • Note:   These findings can also result from folate deficiency and are not reliable during pregnancy.
  • Note:   Antibiotics may interfere with microbiological assay for serum and erythrocyte vitamin B12(false low results).

Methotrexate, pyrimethamine, and most antibiotics invalidate folic acid and vitamin B12diagnostic microbiological blood assays.

safety profile


Vitamin B12is nontoxic in recommended dosages.

Nutrient Adverse Effects

No toxicities have been reported or suspected as being associated with vitamin B12in healthy adults, even at very high oral doses (>10 mg/day). However, no studies have specifically confirmed long-term safety in individuals with severe hepatic or renal disease.

General Adverse Effects

Adults: Infrequent diarrhea, urticaria, itching skin, peripheral vascular thrombosis. Megadoses of B12may cause or exacerbate acne symptoms. 26-28

Hydroxycobalamin is usually administered as an injectable. Some evidence indicates that the cyano part of cobalamin may be toxic to cells (related to cyanide) and rarely may provoke significant or even severe reactions. 29,30Most, but not all, injectable vitamin B12products contain preservatives; some may contain benzoyl alcohol. An intradermal test dose should be performed for hypersensitivity. Avoid use of preparations containing benzoyl alcohol in premature infants.

Reactions to intramuscular injections of cyanocobalamin:

  • Less than 10%: Weakness (1%-4%), anxiety, pain, nervousness, hypoesthesia, dizziness, paresthesia, abnormal gait, headache (2%-11%), sore throat, dyspnea, rhinitis, nausea and vomiting, dyspepsia, diarrhea, back pain, arthritis, myalgia, urticaria.
  • Less than 1%: Peripheral vascular thrombosis, urticaria, anaphylaxis, congestive heart failure (CHF), pulmonary edema.

Adverse Effects Among Specific Populations

Studies specifically confirming long-term safety in individuals with severe hepatic or renal disease are lacking.

Pregnancy and Nursing

No significant safety issues have been demonstrated regarding the use of vitamin B12by pregnant or lactating women. B12enters breast milk; compatible.

Infants and Children

No significant safety issues have been demonstrated regarding the use of vitamin B12by infants or children. Supplementation can be important for children on a vegetarian, especially vegan, diet.


Hypersensitivity to cyanocobalamin or any component of the formulation, cobalt; patients with hereditary optic neuropathy (Leber's disease).

Precautions and Warnings

Apparent vitamin B12deficiency should not be treated with vitamin B12alone until a definitive diagnosis has been established; that is, folate deficiency has been ruled out.

Treatment of vitamin B12–related megaloblastic anemia may result in severe hypokalemia, sometimes fatal, when anemia corrects, due to cellular potassium requirements. Because of the rapid DNA synthesis, with resulting rapid cell division in bone marrow, when a severe B12deficiency is corrected, it is prudent to supplement folate (1 mg/day) and ensure high dietary/supplemental (prescription) potassium intake. Conversely, because of vitamin B12's role in DNA synthesis, high doses of B12and folic acid should generally be avoided in oncology patients with known tumors.

interactions review

Strategic Considerations

Vitamin B12deficiency inhibits DNA synthesis, which systemically affects the growth, function and repair of all cells and tissues. Other than the expected epidemiological patterns among individuals exclusively under a long-term vegan diet, the elderly, malnourished, heavily medicated, and institutionalized populations are particularly at risk for developing deficiency or subclinical depletion patterns. Healthy gastric pH and gut ecology play a critical role in B12absorption and metabolism. Some reviewers have explored whether the association between Helicobacter pylori infection and coronary heart disease might be related to reduced cobalamin absorption and cobalamin status and, consequently, elevated homocysteine levels, but no conclusions have been ventured. 9 Scientific knowledge of the diverse roles and profound implications of enteric flora and healthy gut ecology has begun to emerge and is contributing to a fundamental reconceptualization of our understanding of assimilation and nutriture, immune function, neurotransmitter metabolism, and other core aspects of human physiology. 31-35

The primary commonly accepted drugs that deplete vitamin B12include AZT, cholestyramine, colchicine, and metformin. Histamine (H2) blockers and proton pump inhibitors impair B12absorption from food but do not appear to interfere significantly with B12absorption from supplemental sources. Medications that reduce folate absorption or interfere with its metabolism, such as methotrexate, oral contraceptives, and anticonvulsants, also contribute to B12depletion and decreased function. Generally, avoiding high doses of B12and folate with oncology patients is prudent, pending careful clinical study of the issue, because of vitamin B12's role in DNA synthesis and because large doses of B12/folate might stimulate tumor growth.

Vitamin B12deficiency is more common than suspected and can be difficult to recognize because of its often subtle and pervasive symptomatology at early and middle stages. Serum levels may be normal even when significant deficiency has been present for an extended period; urinary MMA provides a more sensitive assessment of B12status. There is some evidence that supplementation can improve symptoms of diabetic neuropathy and delay the progress of dementia related to vitamin B12deficiency. Health care providers are advised to elicit risk factors and discuss susceptibility, consequences, and preventive steps with patients at risk for B12deficiency or depletion. Hydroxycobalamin and adenosylcobalamin are the preferred forms of injectable B12; bioactive methylcobalamin tablets are the preferred sublingual form.

It appears that generous quantities of B12may be critical to effectiveness much more often than previously thought, especially in the elderly. Generally, nutritional education has framed B12dosing in single-digit micrograms, and folate dosing in hundreds of micrograms, because of the difference in quantity that prevent serious deficiency states. However, a pivotal clinical trial by Eussen et al. 13 showed that once deficient (by MMA levels), it takes 500 to 600 µg of oral vitamin B12, at minimum, to correct an established pattern of “mild” depletion. Moreover, it is advisable always to give equivalent amounts of B12with folate. The primary caution generally voiced against folic acid administration is the oft-repeated warning that vitamin B12deficiency, especially severe deficiencies such as those associated with pernicious anemia, might be masked. This caution, however, seems misplaced or at least uninformed, since almost all folic acid products on the market are formulated with vitamin B12, at the least, or a comprehensive range of synergistic nutrients, as in a multivitamin or B-complex formulation. All health care providers trained and experienced in nutritional therapeutics would routinely coadminister folic acid and vitamin B12as a matter of safety, synergy, and efficacy.

Homocysteine (Hcy) regulation appears as a recurrent theme in reviewing the strategic significance of drug interactions with dietary sources and supplemental forms of vitamin B12. The pervasive and destructive effects of elevated Hcy levels are well documented and widely known. Methionine synthase, the enzyme that metabolizes Hcy to methionine, uses 5-methyltetrahydrofolate and vitamin B12as cofactors. Folic acid may have antiatherogenic mechanisms independent of lowering Hcy levels. Apart from effects on the vascular system, plasma total homocysteine (tHcy) level (and low serum folate concentrations) is an independent risk factor for dementia, as well as low bone mineral density, particularly among women. 36-42

The evolving debate as to whether Hcy represents a causal or coincident factor in heart disease, stroke, and related conditions shifted to a new level with publication of the Vitamin Intervention for Stroke Prevention (VISP) trial. When the VISP trial's intention-to-treat analysis failed to show efficacy of combined-vitamin therapy for recurrent vascular events in patients with nondisabling stroke, Spence et al. 43 conducted an “efficacy analysis limited to patients most likely to benefit from the treatment, based on hypotheses arising from evidence developed since VISP was initiated.” They cited many reasons for the lack of observed efficacy, including “folate fortification of grain products, inclusion of the recommended daily intake for B12in the low-dose arm, treatment with parenteral B12in patients with low B12levels in both study arms, a dose of B12too low for patients with malabsorption, supplementation with nonstudy vitamins, and failure of patients with significant renal impairment to respond to vitamin therapy.” Consequently, they “excluded patients with low and very high B12levels at baseline (< 250 and > 637 pmol/L, representing the 25th and 95th percentiles), to exclude those likely to have B12malabsorption or to be taking B12supplements outside the study and patients with significant renal impairment.” On analyzing data for this subgroup of 2155 patients (37% female, mean age of 66±10.7 years), “there was a 21% reduction in the risk of events in the high-dose group compared with the low-dose group.” They also noted that “patients with a baseline B12level at the median or higher randomized to high-dose vitamin had the best overall outcome, and those with B12less than the median assigned to low-dose vitamin had the worst.” They concluded: “In the era of folate fortification, B12plays a key role in vitamin therapy for total homocysteine. Higher doses of B12, and other treatments to lower total homocysteine may be needed for some patients.” 43

Subsequently, the NORVIT and HOPE-2 trials supported the conclusions of a consistent body of scientific research demonstrating that these nutrients help lower Hcy levels, but failed to support the hypothesis that lowering Hcy levels alone will provide protection against a future cardiovascular event in high-risk patients with established cardiovascular disease. For example, in the Norwegian study of post–myocardial infarction (MI) patients randomized to a folate/B12/B6formulation or placebo, Bønaa et al. 44,45observed a pattern of increased risk of a second MI in the intervention group, despite a lowering of Hcy. Although relevant to certain patient populations, the findings from these trials suggest that such a study of secondary prevention (patients with previous MI) has limited applicability to primary prevention (individuals without previous vascular events) in healthy individuals and in those with elevated risk. Notably, the HOPE-2 study demonstrated a statistically significant, 25% reduction in nonfatal strokes. 46

Nevertheless, the current data are confounded because all patients were taking standard post-MI medications, such as beta blockers, angiotensin-converting enzyme (ACE) inhibitors, and aspirin, and investigators did not monitor drug levels to see if the B vitamins were depleted by the medications or, conversely, if the medications were impaired or levels lowered by the nutrients, as is possible if they induce the pregnane X receptor (PXR), as occurs, for example, with vitamin E. 47,48Such potentially significant variables, which were not assessed or factored in, might explain the unexpected “increased risk” associated with the B vitamins, which would actually be analogous to poor compliance with medication. Research into PXR is in preliminary stages, and a focus on its relevance to B vitamins may be warranted and could shed some light on these and other findings. More broadly, such findings do not detract from other potential benefits derived from lowering Hcy levels, or at least reversing processes associated with elevated Hcy.

The causes of hyperhomocysteinemia are broadly categorized as “inherited” and “acquired”; many involve vitamin B12(and folate) nutriture, metabolism, and function. The inherited causes include MTHFR deficiency or defect, methionine synthase defect, vitamin B12transport defect, vitamin B12coenzyme synthesis defect, and cystathionine beta-synthase deficiency. The acquired cause can be grouped as vitamin deficiencies, chronic diseases, and medication effects. Nutritional deficits of vitamin B12, folic acid, and vitamin B6can usually be remedied by ensuring adequate dietary sources and administering supplements providing these synergistic nutrients. As with folate, medications that adversely affect B12status and function constitute one of the primary risk factors for hyperhomocysteinemia. Fortunately, this last factor may be the most amenable to clinician intervention—with this monograph being a tool in providing safe and effective medical management by employing an evidence-based, integrative approach to health care delivery.

nutrient-drug interactions
Aminoglycoside Antibiotics
Anticonvulsant Medications, Including Phenobarbital, Phenytoin, and Valproic Acid
Bile Acid Sequestrants
Clofibrate and Related Fibrates
Histamine (H 2 ) Receptor Antagonists
Evidence: Cimetidine (Tagamet; Tagamet HB), famotidine (Pepcid RPD, Pepcid, Pepcid AC), ranitidine (Zantac). Similar properties but evidence lacking for extrapolation: Nizatidine (Axid, Axid AR), ranitidine bismuth citrate (Tritec).
END_Drug-Induced Nutrient Depletion, Supplementation Therapeutic, Not Requiring Professional Management

Probability: 3. Possible
Evidence Base: SYMBOL Consensus

Effect and Mechanism of Action

Histamine (H 2 ) receptor antagonists (H 2 RAs) decrease secretion of gastric acid and pepsin by gastric parietal cells. Gastric acid and pepsin are required for the cleavage of vitamin B 12 from animal protein-bound dietary sources. Thus, cimetidine, ranitidine, and related medications significantly impair liberation of dietary B 12 from its protein binder during digestion. Further, intrinsic factor (IF), also produced by gastric parietal cells, is required for vitamin B 12 absorption from the gastrointestinal (GI) tract. 117-119


Comparing the effect of cimetidine on the absorption of orally administered crystalline or food (egg yolk–bound) vitamin B 12 in 13 patients, Salom et al. 117 observed that whereas absorption of crystalline B 12 was normal and not significantly changed by cimetidine, the uptake of food-bound B 12 decreased by a mean of 53% in all patients. These authors further noted that their findings indicated that cimetidine-induced B 12 malabsorption would not be detected by the standard Schilling test. 117 Nevertheless, Walan and Strom 120 investigated the effect of continuous treatment with cimetidine (400 mg at night or twice daily) for 3 years and found no significant difference on plasma vitamin B 12 , as well as weight, hemoglobin, plasma iron, plasma folate, and albumin; a slight decrease of plasma calcium was observed. They concluded that moderate and inconstant reduction of acidity over 24 hours, typical of twice-daily administration of those H 2 antagonists available in 1985, was unlikely to result in metabolic consequences. Later, in a randomized controlled prospective study, Thorens et al. 121 investigated the incidence of gastric and duodenal bacterial overgrowth in 47 outpatients with peptic disease being treated with omeprazole or cimetidine. After a 4-week treatment regimen, they found higher basal gastric pH and a significantly higher level of bacterial overgrowth in patients receiving omeprazole than in those receiving cimetidine. However, even with this significant disruption of the digestive tract's environment, serum concentrations of vitamin B 12 , beta-carotene, and albumin were similar before and after treatment with both drugs. 121

Kirch et al. 122 reported that ranitidine (300 mg daily) distinctly reduced protein-bound cobalamin absorption from a mean of 7.66% before ranitidine administration to 0.84% during treatment with ranitidine.

Overall, a consensus emerged starting in the 1980s that H 2 RAs interfered with absorption of vitamin B 12 from food sources, more so than from supplemental sources, and that consistent long-term use in at-risk populations posed a significant potential for clinically significant nutrient depletion. Short-term or intermittent use has generally been considered to have an inconsequential effect on nutrient absorption. 123,124 In particular, Aymard et al. 123 noted that hematological adverse effects attributable to H 2 RAs are relatively uncommon, usually involving cimetidine, and that the inhibition of gastric secretion by the H 2 RAs may theoretically contribute to the occurrence of cobalamin (or iron) malabsorption and deficiency anemia with long-term use.

The interaction of H 2 RAs and other medications may also affect B 12 status. For example, metformin decreases absorption of vitamin B 12 and folic acid, and cimetidine decreases the elimination of metformin; therefore a reduced metformin dosage is usually recommended when these agents are combined. 125 The clinical implications of such multiple interactions have yet to be studied in any systematic manner in well-designed human trials, even though patients taking multiple pharmaceuticals may constitute the norm more than the exception among affected populations.


In a case report, Ruscin et al. 126 described vitamin B 12 deficiency in a 78-year-old nonvegetarian woman with symptomatic gastroesophageal reflux after long-term use (∼4.5 years) use of H 2 RAs, starting with cimetidine, and a proton-pump inhibitor. They noted a moderate decline in serum vitamin B 12 concentration, from an initial normal serum level of 413 pg/mL to a low-normal level of 256 pg/mL after almost 2 years. However, on the latter occasion, MMA and Hcy, clinically important biochemical markers of B 12 -dependent enzyme activity, were significantly elevated. These researchers then observed that MMA and Hcy concentrations decreased dramatically when oral replacement of vitamin B 12 (1000 µg daily) was instituted. This response not only confirmed vitamin B 12 deficiency, but also demonstrated that the woman was able to adequately absorb nonprotein-bound vitamin B 12 from the GI tract, suggesting that her deficiency was a result of food-cobalamin malabsorption, and that the accumulation of MMA and Hcy was not a consequence of renal dysfunction.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Although H 2 RAs have not conclusively been shown to decrease IF secretion, studies have demonstrated a significant reduction in protein-bound vitamin B 12 absorption secondary to decreased gastric acid and pepsin secretion in patients taking these drugs. Although this interaction probably lacks clinical importance during the short term, continuous use of these medications for more than 2 years could cause or contribute to vitamin B 12 deficiency, including anemia, especially in patients with a history of poor nutrition and other causes of inadequate stores of vitamin B 12 . Such impairment of vitamin B 12 absorption could be amplified for individuals also using antacids on a regular basis along with the H 2 RAs. Further research is warranted into the effect of these medications on the function of gastric acid and pepsin in the initial step of the B 12 absorption process and the clinical implications of any resulting impaired release of cobalamin from food protein.

Physicians prescribing H 2 RAs are advised to monitor cobalamin status, preferably using a sensitive test, such as urinary MMA, and to coadminister supplemental vitamin B 12 in individuals on H 2 RA and/or proton pump inhibitor (PPI) therapy for an extended period, especially when other risk factors for deficiency are present. In the event that supplementation is determined to be necessary, a typical adult dose of 10 to 25 µg per day would be appropriate, a level commonly found in a B-complex vitamin or in many multivitamins. Given the likely mechanism of action involved, patients taking H 2 RAs who are prone to or have developed a vitamin B 12 deficiency will generally respond to oral supplementation, which does not require stomach acid to be absorbed.

Metformin and Related Biguanides
Nitrous Oxide
Oral Contraceptives: Monophasic, Biphasic, and Triphasic Estrogen Preparations (Synthetic Estrogen and Progesterone Analogs)
Para-Aminosalicylic Acid
Proton Pump Inhibitors (PPIs)
Zidovudine (AZT) and Related Antiretroviral Agents, Reverse-Transcriptase Inhibitor (Nucleoside)
theoretical, speculative, and preliminary interactions research, including overstated interactions claims
Antibiotics, Particularly Cycloserine and Erythromycin
nutrient-nutrient interactions
Folic Acid
Potassium Chloride, Sustained/Controlled-Release Medications
Vitamin B 6
Vitamin C
Vitamin D
Citations and Reference Literature
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  • 38.Ramos MI, Allen LH, Mungas DM et al. Low folate status is associated with impaired cognitive function and dementia in the Sacramento Area Latino Study on Aging. Am J Clin Nutr 2005;82:1346-1352.View Abstract
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  • 43.Spence JD, Bang H, Chambless LE, Stampfer MJ. Vitamin Intervention for Stroke Prevention trial: an efficacy analysis. Stroke 2005;36:2404-2409.View Abstract
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  • 53.De Jager P, van Altena R. Hearing loss and nephrotoxicity in long-term aminoglycoside treatment in patients with tuberculosis. Int J Tuberc Lung Dis 2002;6:622-627.View Abstract
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  • 62.Lopez-Gonzalez MA, Delgado F, Lucas M. Aminoglycosides activate oxygen metabolites production in the cochlea of mature and developing rats. Hear Res 1999;136:165-168.View Abstract
  • 63.Takumida M, Anniko M, Shimizu A, Watanabe H. Neuroprotection of vestibular sensory cells from gentamicin ototoxicity obtained using nitric oxide synthase inhibitors, reactive oxygen species scavengers, brain-derived neurotrophic factors and calpain inhibitors. Acta Otolaryngol 2003;123:8-13.
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  • 65.Jin X, Sheng X. Methylcobalamin as antagonist to transient ototoxic action of gentamicin. Acta Otolaryngol 2001;121:351-354.View Abstract
  • 66.Shemesh Z, Attias J, Ornan M et al. Vitamin B12 deficiency in patients with chronic-tinnitus and noise-induced hearing loss. Am J Otolaryngol 1993;14:94-99.View Abstract
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  • 73.Morrell MJ. Folic acid and epilepsy. Epilepsy Currents 2002;2:31-34.View Abstract
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  • 87.Bjelland I, Tell GS, Vollset SE et al. Folate, vitamin B12, homocysteine, and the MTHFR 677C→T polymorphism in anxiety and depression: the Hordaland Homocysteine Study. Arch Gen Psychiatry 2003;60:618-626.View Abstract
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  • 92.Coronato A, Glass GB. Depression of the intestinal uptake of radio-vitamin B12 by cholestyramine. Proc Soc Exp Biol Med 1973;142:1341-1344.View Abstract
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