Micronutrient Information Center

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The Linus Pauling Institute's Micronutrient Information Center is a source for scientifically accurate information regarding the roles of vitamins, minerals, phytochemicals (plant chemicals that may affect health), and other dietary factors, including some food and beverages, in preventing disease and promoting health. All of the nutrients and dietary factors included in the Micronutrient Information Center may be obtained from the diet, and many are also available as dietary supplements. 


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The Linus Pauling Institute's Micronutrient Information Center (MIC) is a source for scientifically accurate information on the functions and health effects of all micronutrients (vitamins and nutritionally essential minerals); other nutrients like choline and essential fatty acids; dietary factors, including many phytochemicals (non-nutritive plant chemicals that may affect health); and some food and beverages, including tea, coffee, and alcohol. All of the nutrients and dietary factors included in the MIC may be obtained from the diet, and many are also available as dietary supplements; dietary and supplemental sources are discussed in each article.

Human research is emphasized in the MIC, although cell culture or animal studies may be mentioned when human studies are lacking. Most MIC articles have summaries at the beginning and include the following subsections: Function or Biological Activities, Metabolism and Bioavailability, Deficiency, The RDA or AI (for males and females of various age groups), Disease Prevention, Disease Treatment, Sources (food and supplements), and Safety (toxicity and drug or nutrient interactions). For the micronutrients (vitamins and essential minerals), the Linus Pauling Institute provides a daily intake recommendation.

For each article, Ph.D. nutrition scientists critically review and synthesize basic, clinical, and epidemiological studies in the peer-reviewed literature and provide references throughout. Each article is then additionally reviewed by an expert in the field; the names of the authors and reviewers are listed at the bottom of each article. This multiple review process minimizes bias and presents objective information.

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The term vitamin is derived from the words vital and amine, because vitamins are required for life and were originally thought to be amines. Although not all vitamins are amines, they are organic compounds required by humans in small amounts from the diet. An organic compound is considered a vitamin if a lack of that compound in the diet results in overt symptoms of deficiency.

The information from the Linus Pauling Institute's Micronutrient Information Center on vitamins and minerals is now available in a book titled, An Evidence-based Approach to Vitamins and Minerals: Health Benefits and Intake Recommendations. The book can be purchased from the Linus Pauling Institute or Thieme Medical Publishers.

Select a vitamin from the list for more information.


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  • Water-soluble biotin is an essential cofactor to enzymes in intermediary metabolism and a key regulator of gene expression. (More information)
  • Both parenteral nutrition devoid of biotin and prolonged consumption of raw egg white have been associated with symptoms of frank biotin deficiency, including hair loss, dermatitis, skin rash, ataxia, seizures, and other neurologic dysfunctions. (More information)
  • Biotinidase deficiency is a rare hereditary disorder that impairs biotin absorption and recycling, resulting in secondary biotin deficiency. (More information)
  • The recommended adequate intake (AI) of biotin is set at 30 micrograms (μg)/day in adults. Biotin requirements are likely increased during pregnancy and breast-feeding. (More information)
  • Animal studies have shown that biotin sufficiency is essential for normal fetal development. Yet, it is not known if marginal biotin deficiency during pregnancy increases the risk for congenital anomalies in humans. (More information)
  • Biotin is used in the treatment of biotin-thiamin responsive basal ganglia disease, an inherited disorder of thiamin transport. (More information)
  • Recent randomized controlled trials have not found high-dose biotin supplementation to be beneficial in the treatment of multiple sclerosis. Yet, results of animal studies and meta-analyses of human clinical trials are promising. (More information)
  • Definitive evidence that establishes whether biotin supplementation improves glucose and lipid homeostasis in individuals with type 2 diabetes mellitus is currently lacking, but suggestive observations have been published. (More information)
  • Biotin cannot be synthesized by mammalian cells and must be obtained from exogenous sources. Biotin is widely found in food, and good dietary sources include egg yolk, liver, whole-grain cereal, and some vegetables. (More information)
  • Long-term anticonvulsant (anti-seizure) therapy may increase the dietary requirement for biotin because anticonvulsants can interfere with the intestinal absorption and renal re-absorption of biotin and likely also increase degradation of biotin to inactive metabolites. (More information)
  • Use of high-dose biotin supplements can result in aberrant results of laboratory tests that utilize the very high affinity biotin-streptavidin (avidin) interaction. (More information)

Biotin is a water-soluble vitamin that is generally classified as a B-complex vitamin. After its initial discovery in 1927, 40 years of additional research was required to unequivocally establish biotin as a vitamin (1). Biotin is required by all organisms but can be synthesized by some strains of bacteria, yeast, mold, algae, and some plant species (2).



Biotin functions as a covalently bound cofactor required for the biological activity of the five known mammalian biotin-dependent carboxylases (see below). Such non-protein cofactors are termed “prosthetic groups” and are common in water-soluble vitamins. The covalent attachment of biotin to the apocarboxylase (i.e., the carboxylase protein without the biotin prosthetic group and is catalytically inactive) is catalyzed by the enzyme, holocarboxylase synthetase (HCS). The term “biotinylation” refers to the covalent addition of biotin to any molecule, including the apocarboxylases and histones. HCS catalyzes the post-translational biotinylation of the epsilon amino group of a lysine residue at the active site of each apocarboxylase, converting the inactive apocarboxylase into a fully active holocarboxylase (Figure 1a). Particular lysine residues within the N-terminal tail of specific histone that help package DNA in eukaryotic nuclei can also be biotinylated (3). Biotinidase is the enzyme that catalyzes the release of biotin from biotinylated histones and from the peptide products of holocarboxylase breakdown (Figure 1b).

Figure 1a. Biotin Figure 1a. Biotinylation of Carboxylases. Holocarboxylase synthetase catalyzes the transfer of biotin to a specific lysine residue at the active site of apocarboxylase, converting the enzyme to a fully active holocarboxylase. Five mammalian carboxylases are known to require biotin for their biological activity: acetyl-CoA carboxylases 1 and 2, pyruvate-CoA carboxylase, propionyl-CoA carboxylase, and methylcrotonyl-CoA carboxylase.

Biotin Figure 1b. Biotin Recycling. The biotinylation of apocarboxylase is catalyzed by holocarboxylase synthetase, while the enzyme biotinidase catalyzes the removal of biotin from the peptide products of carboxylase breakdown.

Enzyme cofactor

Five mammalian carboxylases catalyze essential metabolic reactions:

• Both acetyl-Coenzyme A (CoA) carboxylase 1 (ACC1) and acetyl-CoA carboxylase 2 (ACC2) catalyze the conversion of acetyl-CoA to malonyl-CoA using bicarbonate and ATP; however, the two enzymes have different roles in metabolism and different intracellular locations. ACC1 is located in the cytosol, and the malonyl CoA generated by ACC1 is a rate-limiting substrate for the synthesis of fatty acids (Figure 2). ACC1 is found in all tissues and is particularly active in lipogenic tissues (i.e., liver, white adipose tissue, and mammary gland), heart, and pancreatic islets. ACC2 is located on the outer mitochondrial membrane, and the malonyl CoA generated via ACC2 inhibits CPT1, an enzyme that regulates malonyl-CoA entry into the inner mitochondria, thereby regulating fatty acid oxidation (Figure 3). ACC2 is especially abundant in skeletal muscle and heart (4).

Biotin Figure 2. Pyruvate Carboxylase and Acetyl-CoA Carboxylase 1. Biotin-containing pyruvate carboxylase supplies the citric acid cycle with oxaloacetate by catalyzing the conversion of pyruvate to oxaloacetate using bicarbonate and ATP. In the liver, oxaloacetate can be used as a precursor for gluconeogenesis. It is first converted to phosphoenolpyruvate (PEP) by PEP carboxykinase and then to glucose via the reverse pathway of glycolysis. In the citric acid cycle, oxaloacetate can also be condensed with acetyl-CoA to produce citrate, which can be exported from the mitochondria. In the liver, adipose tissue, and skeletal muscle, citrate is cleaved to oxaloacetate and acetyl-CoA in the cytosol. Acetyl-CoA is converted to malonyl-CoA by another biotin-containing enzyme, acetyl-CoA carboxylase 1. Malonyl-CoA is then used by fatty acid synthase 1 to generate long-chain fatty acids. CoA, coenzyme A.

Pyruvate carboxylase is a critical enzyme in gluconeogenesis (the formation of glucose from sources other than carbohydrates, such as pyruvate, lactate, glycerol, and the glucogenic amino acids). Pyruvate carboxylase catalyzes the ATP-dependent incorporation of bicarbonate into pyruvate, producing oxaloacetate; hence, pyruvate carboxylase is anaplerotic for the citric acid cycle (Figure 3). Oxaloacetate can then be converted to phosphoenolpyruvate and eventually to glucose.

Biotin Figure 3. Acetyl-CoA Carboxylase 1 and Acetyl-CoA Carboxylase 2. In the cytosol of liver cells, fatty acids are converted to acyl-CoA, and glucose undergoes glycolysis that produces pyruvate. Acyl-CoA is shuttled into the mitochondria via CPT1-mediated transport and undergoes β-oxidation that generates acetyl-CoA. In addition, pyruvate is converted to acetyl-CoA in the mitochondria, and acetyl-CoA is condensed with oxaloacetate to form citrate. The latter can be exported to the cytosol and cleaved to oxaloacetate and acetyl-CoA. Acetyl-CoA is used to generate malonyl-CoA in a reaction catalyzed by biotin-containing acetyl-CoA carboxylase 1 (ACC1) in the presence of ATP and bicarbonate. Malonyl-CoA is an essential substrate for the biosynthesis of fatty acids and subsequent triglycerides, phospholipids, and lipoproteins. Malonyl-CoA is also a regulator of fatty acid β-oxidation. Indeed, malonyl-CoA generated from acetyl-CoA by another biotin-containing enzyme, acetyl-CoA carboxylase 2 (ACC2), localized at the outer mitochondrial membrane, has been shown to downregulate fatty acid β-oxidation in the mitochondria by inhibiting CPT1. ACC1, acetyl-coenzyme A carboxylase 1; ACC2, acetyl-coenzyme A carboxylase 2; CoA, coenzyme A; CPT1, carnitine/palmitoyl-transferase 1.

Methylcrotonyl-CoA carboxylase catalyzes an essential step in the catabolism of leucine, an essential branched-chain amino acid. This enzyme catalyzes the production of 3-methylglutaconyl-CoA from methylcrotonyl-CoA (Figure 4a).

Propionyl-CoA carboxylase produces D-malonylmalonyl-CoA from propionyl-CoA, a by-product in the β-oxidation of fatty acids with an odd number of carbon atoms (Figure 4a). The conversion of propionyl-CoA to D-malonylmalonyl-CoA is also required in the catabolic pathways of two branched-chain amino acids (isoleucine and valine) and the side chain of cholesterol (Figure 4a) and of the amino acids methionine and threonine (Figure 4b).

Biotin Figure 4a. Biotin-containing Carboxylases in the Metabolism of BCAAs, Odd-chain Fatty Acids, and Cholesterol. Two biotin-containing enzymes, namely propionyl-CoA carboxylase and methylcrotonyl-CoA carboxylase, are required in the metabolism of branched chain amino acids (leucine, valine, and isoleucine), the oxidation of odd-chain fatty acids, and the degradation of cholesterol side chain. The metabolic pathways generate acetyl-CoA and succinyl-CoA, which then enter the citric acid cycle. BCAAs, branched chain amino acids; CoA, coenzyme A.

Biotin Figure 4b. Biotin-containing Propionyl-CoA Carboxylase in the Metabolism of Methionine and Threonine. Propionyl-CoA carboxylase converts propionyl-CoA to D-malonylmalonyl-CoA in the metabolism of methionine and threonine. CoA, coenzyme A; SAH, S-adenosylhomocysteine; SAM, S-adenosylmethionine.

Regulation of chromatin structure and gene expression

In eukaryotic nuclei, DNA is packaged into compact structures to form nucleosomes — fundamental units of chromatin. Each nucleosome is composed of 147 base pairs of DNA wrapped around eight histones (paired histones: H2A, H2B, H3, and H4). The H1 linker histone is located at the outer surface of each nucleosome and serves as an anchor to fix the DNA around the histone core. The compact packaging of chromatin must be relaxed for DNA replication and transcription. Chemical modifications of DNA and histones affect the folding of chromatin, increasing or reducing DNA accessibility to factors involved in replication and transcription. DNA methylation and a number of chemical modifications within the N-terminal tail of core histones modify their electric charge and structure, thereby changing chromatin conformation and transcriptional activity of genes.

The modifications of histone tails ("marks"), including acetylation, methylation, phosphorylation, ubiquitination, SUMOylation, ADP-ribosylation, carbonylation, deimination, hydroxylation, and biotinylation, have various regulatory functions. Several sites of biotinylation have been identified in histones H2A, H3, and H4 (5). Amongst them, histone H4 biotinylation at lysine (K) 12 (noted H4K12bio) appears to be enriched in heterochromatin, a tightly condensed chromatin associated with repeat regions in (peri)centromeres and telomeres. H4 biotinylation appears to be enriched in transposable elements known as long terminal repeats (3). These biotinylation marks also co-localize with well-known gene repression marks like methylated lysine 9 in histone H3 (H3K9me) in transcriptionally competent chromatin (6). For example, H4K12bio can be found at the promoter of the gene SLC5A6 that codes for the transporter mediating biotin uptake into cells, the human sodium-dependent multivitamin transporter (hSMVT). When biotin is abundant, HCS can biotinylate histones H4 in the SLC5A6 promoter, which down regulates hSMVT synthesis and reduces biotin uptake. Conversely, in biotin-deficient cells, biotinylation marks in the SLC5A6 promoter are removed increasing gene expression and enabling the synthesis of hSMVT and uptake of biotin (7).


Although clinically overt biotin deficiency is very rare, the human requirement for dietary biotin has been demonstrated in three different situations: prolonged intravenous feeding (parenteral) without biotin supplementation, infants fed an elemental formula devoid of biotin, and consumption of raw egg white for a prolonged period (many weeks to years) (8). Raw egg white contains avidin; this antimicrobial protein binds biotin with an affinity and specificity that is almost unique as a reversible binding. Because native avidin is resistant to mammalian and microbial digestion, avidin prevents biotin absorption. Cooking egg white denatures avidin, rendering it susceptible to digestion and therefore unable to block the absorption of dietary biotin (5).

Signs and symptoms of biotin deficiency

Signs of overt biotin deficiency include hair loss (alopecia) and a scaly red rash around the eyes, nose, mouth, and genital area. Neurologic symptoms in adults have included depression, lethargy, hallucinations, numbness and tingling of the extremities, ataxia, and seizures. The characteristic facial rash, together with unusual facial fat distribution, has been termed the "biotin deficient facies" by some investigators (1). Individuals with hereditary disorders of biotin metabolism (see Inborn metabolic disorders) that result in functional biotin deficiency often have similar physical findings, impaired immune system function, and increased susceptibility to bacterial and fungal infections (9, 10).

Risk factors for biotin deficiency

Aside from prolonged consumption of raw egg white or total intravenous nutritional support lacking biotin, other conditions may increase the risk of biotin depletion. Smoking has been associated with increased biotin catabolism (11). The rapidly dividing cells of the developing fetus require biotin for synthesis of essential carboxylases and for histone biotinylation; hence, the maternal biotin requirement is likely increased during pregnancy. Research suggests that a substantial number of women develop marginal or subclinical biotin deficiency during normal pregnancy (see also Disease Prevention) (8, 12, 13). Moreover, certain types of liver disease may decrease biotinidase activity and theoretically increase the requirement for biotin. For example, a study of 62 children with chronic liver disease and 27 healthy controls found serum biotinidase activity to be abnormally low in those with severely impaired liver function due to cirrhosis (14). However, this study did not provide evidence of biotin deficiency. Additionally, anticonvulsant medications used to prevent seizures in individuals with epilepsy increase the risk of biotin depletion (for more information on biotin and anticonvulsants, see Drug interactions).

Inborn metabolic disorders

Biotinidase deficiency

Biotinidase deficiency is an autosomal recessive inherited disorder that is often detected upon newborn screening for metabolic disorders, although late-onset forms have been recently described (15-17). Biotinidase deficiency leads to secondary biotin deficiency in several ways. Intestinal absorption is decreased because deficient biotinidase impairs release of biotin from dietary protein (18). Further, recycling of intracellular biotin bound to carboxylases and histones is also impaired, and urinary loss of biocytin (N-biotinyl-lysine) and biotin is increased (see Figure 1 above) (5). Biotinidase deficiency responds to supplemental biotin. Oral supplementation with as much as 5 to 20 milligrams (mg) of biotin daily is sometimes required (19, 20), although smaller doses may be sufficient, especially later in childhood (reviewed in 20, 21). Prognosis is characteristically good when biotin therapy is introduced in infancy or early childhood and reliably continued for life (10).

Holocarboxylase synthetase deficiency

Holocarboxylase synthetase deficiency results in decreased formation of all holocarboxylases at physiological blood biotin concentrations; thus, high-dose biotin supplementation (10-80 mg of biotin daily) is required (10). Holocarboxylase synthetase deficiency responds to supplementation with pharmacologic doses of biotin in some cases but not others. The prognosis of holocarboxylase synthetase is usually, but not always, good if biotin therapy is introduced early (even antenatally) and continued for life (10, 22)

Biotin transport deficiency

There has been one case report of a child with biotin transport deficiency who responded to high-dose biotin supplementation (23). Of note, the presence of a defective human sodium-dependent multivitamin transporter (hSMVT) was ruled out as a cause of biotin transport deficiency.

Markers of biotin status

Four measures of marginal biotin deficiency have been validated as indicators of biotin status: and (1) reduced levels of holo-methylcrotonyl-CoA carboxylase and holo-propionyl-CoA carboxylase in lymphocytes, the most reliable indicators of biotin status (24); (2) reduced propionyl-CoA carboxylase activity in peripheral blood lymphocytes (5); (3) high urinary excretion of an organic acid, 3-hydroxyisovaleric acid, and its derivative, 3-hydroxyisovaleryl carnitine, both of which reflect decreased activity of biotin-dependent methylcrotonyl-CoA carboxylase; (4) reduced urinary excretion of biotin and some of its catabolites. These markers have been only validated in men and nonpregnant women, and they may not accurately reflect biotin status in pregnant or breast-feeding women (12, 25).

The Adequate Intake (AI)

Sufficient scientific evidence is lacking to estimate the dietary requirement for biotin; thus, no Recommended Dietary Allowance (RDA) for biotin has been established. Instead, the Food and Nutrition Board of the National Academy of Medicine set recommendations for an Adequate Intake (AI; Table 1). The AI for adults (30 μg/day) was extrapolated from the AI for infants exclusively fed human milk and probably overestimates the dietary requirement for biotin for most adults. Dietary intakes of generally healthy adults have been estimated to be 40 to 60 micrograms (μg) of biotin daily (1). The requirement for biotin in pregnancy may be increased (26).

Table 1. Adequate Intake (AI) for Biotin
Life Stage Age Males (μg/day) Females (μg/day)
Infants 0-6 months 5 5
Infants 7-12 months 6 6
Children 1-3 years 8 8
Children 4-8 years 12 12
Children 9-13 years 20 20
Adolescents 14-18 years 25 25
Adults 19 years and older 30 30
Pregnancy all ages - 30
Breast-feeding all ages - 35

Disease Prevention

Congenital anomalies

Current research indicates that at least one-third of women develop marginal biotin deficiency during pregnancy (8). Small observational studies in pregnant women have reported an abnormally high urinary excretion of 3-hydroxyisovaleric acid in both early and late pregnancy, suggesting decreased activity of biotin-dependent methylcrotonyl-CoA carboxylase (27, 28). In a randomized, single-blinded intervention study in 26 pregnant women, supplementation with 300 μg/day of biotin for two weeks limited the excretion of 3-hydroxyisovaleric acid compared to placebo, confirming that increased 3-hydroxyisovaleric acid excretion indeed reflected marginal biotin deficiency in pregnancy (29). A small cross-sectional study in 22 pregnant women reported an incidence of low lymphocyte propionyl-CoA carboxylase activity greater than 80% (13). Although these levels of biotin deficiency are not associated with overt signs of deficiency in pregnant women, such observations are sources of concern because subclinical biotin deficiency has been shown to cause cleft palate and limb hypoplasia in several animal species (reviewed in 13). In addition, biotin depletion has been found to suppress the expression of biotin-dependent carboxylases, remove biotin marks from histones, and decrease the proliferation in human embryonic palatal mesenchymal cells in culture (30). Impaired carboxylase activity may result in alterations in lipid metabolism, which have been linked to cleft palate and skeletal abnormalities in animals. Further, biotin deficiency leading to reduced histone biotinylation at specific genomic loci may increase genomic instability and result in chromosome anomalies and fetal malformations (13).

Analogous to pregnant women who are advised to consume supplemental folic acid prior to and during pregnancy to prevent neural tube defects (see Folate), it would also be prudent to ensure adequate biotin intake throughout pregnancy. The current AI for pregnant women is 30 μg/day of biotin, and no toxicity has ever been reported at this level of intake (see Safety).

Disease Treatment

Biotin-thiamin-responsive basal ganglia disease

Biotin-thiamin-responsive basal ganglia disease (also called biotin-responsive basal ganglia disease, thiamin transporter-2 deficiency, and thiamin metabolism dysfunction syndrome-2) is caused by an autosomal recessive mutation in the SLC19A3 gene that codes for thiamin transporter-2 (THTR-2). The disease usually presents around 3 to 10 years of age (31), but an early infantile form of the disease exists with onset as early as one month of age (32). Clinical features include subacute encephalopathy (confusion, drowsiness, altered level of consciousness), ataxia, and seizures.

A retrospective study of 18 affected individuals from the same family or the same tribe in Saudi Arabia showed that biotin monotherapy (5-10 mg/kg/day) efficiently abolished the clinical manifestations of the disease, although one-third of the patients suffered from recurrent acute crises. Often associated with poor outcomes, acute crises were not observed after thiamin supplementation started (300-400 mg/day) and during a five-year follow-up period, early diagnosis and immediate treatment with biotin and thiamin led to positive outcomes (33). Although the specific mechanism for therapeutic effects of biotin in biotin-thiamin-responsive basal ganglia disease remains unknown, lifelong high-dose supplementation with a combination of biotin and thiamin is the recommended treatment (31). Early diagnosis and treatment is important to ensure a better prognosis (32, 34).

Multiple sclerosis

Multiple sclerosis (MS) is an autoimmune disease characterized by progressive damage to the myelin sheath surrounding nerve fibers (axons) and neuronal loss in the brain and spinal cord of affected individuals in anatomic locations that vary widely among affected individuals producing variable signs and symptoms. The progression of neurologic disabilities in MS patients is often assessed by the Expanded Disability Status Scale (EDSS) with scores from 1 to 10, from minimal signs of motor dysfunction (score of 1) to death by MS (score of 10). ATP deficiency due to mitochondrial dysfunction and increased oxidative stress may be partly responsible for the progressive degeneration of neurons in MS (35). Given its role in energy production by intermediary metabolism and fatty acid oxidation and in fatty acid synthesis (required for myelin formation) (see Function), high-dose biotin supplementation it has been hypothesized that to exert beneficial effects that would limit or reverse MS-associated functional impairments (35).

The mechanism of action of high-dose biotin has been investigated in a genetic mouse model of chronic axon injury caused by oxidative damage and bioenergetic failure. High-dose biotin restored redox homeostasis, mitochondria biogenesis, and ATP levels, and reversed axonal death and locomotor impairment. Dysregulation of the transcriptional program for lipid synthesis and degradation in the spinal cord was also normalized, possibly as the result of hyperactivation of a nutrient/energy/redox sensor that controls protein synthesis restoring lipid homeostasis.

A nonrandomized, uncontrolled pilot study in 23 patients with progressive MS found high doses of biotin (100-600 mg/day) to be associated with sustained clinical improvements in five (out of five) patients with progressive visual loss and 16 (out of 18) patients with partial paralysis of the limbs after a mean three months following treatment onset (36). Additionally, a multicenter, randomized, placebo-controlled trial in 154 subjects with progressive MS reported that 13 out of 103 patients supplemented with high-dose, pharmaceutical-grade biotin (300 mg/day) for 12 months achieved MS-related disability reversal — assessed by improved EDSS or 25-foot walk time (37). In comparison, none of the 51 patients randomized to the placebo group showed significant clinical improvements (37). However, when this regimen of high-dose biotin supplementation was examined in a larger, international cohort of patients with progressive MS (326 patients receiving biotin and 316 patients receiving placebo), no benefits on EDSS or walk time were seen after 12 months (38). Moreover, a randomized, double-blind, placebo-controlled trial in 93 MS patients with chronic visual loss found that 300 mg/day of pharmaceutical-grade biotin for six months did not improve visual acuity, but an interesting trend favoring the biotin group was observed in the subgroup of patients with progressive optic neuritis (39). Moreover, a meta-analysis of three randomized controlled trials (2 on disability; 3 on adverse effects), involving 889 individuals diagnosed with MS (the preponderance of participants [830] had progressive MS while only 59 had remitting relapsing MS) was conducted (40). Pooling results of two trials found no benefit of high-dose biotin on MS-related disability, but there was significant heterogeneity between the trials. When the subgroup progressive MS was analyzed separately, a moderate certainty of evidence suggested a potential benefit in favor of high-dose biotin for the 25-foot minute walk time (40). On balance, studies remain inconclusive but promising.

Diabetes mellitus

Overt biotin deficiency has been shown to impair glucose utilization in mice (41) and cause fatal hypoglycemia in chickens. Overt biotin deficiency likely also causes abnormalities in glucose regulation in humans (see Function). One early human study reported lower serum biotin concentrations in 43 patients with type 2 diabetes mellitus compared to 64 control subjects without the disease; an inverse relationship between fasting blood glucose and biotin concentrations was observed as well (42). In a small, randomized, placebo-controlled intervention study in 28 patients with type 2 diabetes, daily supplementation with 9 milligrams (mg) of biotin for one month resulted in a 45% decrease in mean fasting blood glucose concentrations (42). Yet, another small study in 10 patients with type 2 diabetes and 7 controls without diabetes found no effect of biotin supplementation (15 mg/day) for 28 days on fasting blood glucose concentrations in either group (43). A more recent double-blind, placebo-controlled study by the same research group showed that the same biotin regimen lowered plasma triglyceride concentrations in patients with hypertriglyceridemia — independent of whether they had type 2 diabetes (44). In this study, biotin administration did not affect blood glucose concentrations in either patient group. Additionally, a few studies have shown that co-supplementation with biotin and chromium picolinate may be a beneficial adjunct therapy in patients with type 2 diabetes (45-48). For information on chromium supplementation as a monotherapy for type 2 diabetes, see the article on Chromium.

Potential mechanisms for the glucose and lipid effects have been suggested. As a cofactor of carboxylases required for fatty acid synthesis, biotin may increase the utilization of glucose for fat synthesis. Also, biotin stimulates glucokinase, a liver enzyme that increases synthesis of glycogen, the storage form of glucose. Biotin also triggers the secretion of insulin in the pancreas of rats and improves glucose homeostasis (50). Yet, reduced activity of ACC1 and ACC2 would be expected to reduce fatty acid synthesis and increase fatty acid oxidation, respectively. Hence, whether pharmacologic doses of biotin benefits the management of hyperglycemia in patients with impaired glucose tolerance remains unclear. Moreover, whether supplemental biotin lowers the risk of cardiovascular complications in patients with diabetes by reducing serum triglycerides and LDL-cholesterol remains to be proven (44-46).

Brittle fingernails (onychorrhexis)

The finding that biotin supplements were effective in treating hoof abnormalities in hoofed animals suggested that biotin might also be helpful in strengthening brittle fingernails in humans (50-52). Three uncontrolled trials examining the effects of biotin supplementation (2.5 mg/day for several months) in women with brittle fingernails have been published (53-55). In two of the trials, subjective evidence of clinical improvement was reported in 67%-91% of the participants available for follow-up at the end of the treatment period (53, 54). One trial that used scanning electron microscopy to assess fingernail brittleness reported less fingernail splitting and a 25% increase in the thickness of the nail plate in patients supplemented with biotin for 6 to 15 months (55). Biotin supplementation (5 mg/day) was also found to be effective in controlling unruly hair and splitting nails in two toddlers with inherited uncombable hair syndrome (56). Although preliminary evidence suggests that supplemental biotin may help strengthen fragile nails (reviewed in 57), larger placebo-controlled trials are needed to assess the efficacy of high-dose biotin supplementation for the treatment of brittle fingernails.

Hair loss (alopecia)

Biotin administration has been associated with alopecia reversal in children treated with the anticonvulsant valproic acid (see Drug interactions), as well as with hair regrowth or normal hair growth in some children with inborn errors of biotin metabolism or other genetic disorders (i.e., uncombable hair syndrome) (reviewed in 58). Yet, while hair loss is a symptom of severe biotin deficiency (see Deficiency), there are no published scientific studies that support the claim that high-dose biotin supplements are effective in preventing or treating hair loss in men or women (59, 60). Randomized, placebo-controlled trials in healthy individuals would be needed to evaluate this claim.


Food sources

Biotin is found in many foods, either as the free (i.e., unbound) form that is directly taken up by enterocytes or as biotin bound to dietary proteins. Egg yolk, liver, and yeast are rich sources of biotin. Estimates of average daily intakes of biotin from small studies ranged between 40 and 60 micrograms (μg) per day in adults (1). However, US national nutritional surveys have not yet been able to estimate biotin intake due to the scarcity and unreliability of data regarding biotin content of food. Food composition tables for biotin are incomplete such that dietary intakes cannot be reliably estimated in humans. A study by Staggs et al. (61) employed a high-performance liquid chromatography method rather than bioassays (62) and reported relatively different biotin content for some selected foods. Table 2 lists some food sources of biotin, along with their content in μg.

Table 2. Some Food Sources of Biotin (61, 62)
Food Serving Biotin (μg)
Yeast 1 packet (7 grams) 1.4-14
Bread, whole-wheat 1 slice 0.02-6
Egg, cooked 1 large 13-25
Cheese, cheddar 1 ounce 0.4-2
Liver, cooked 3 ounces* 27-35
Pork, cooked 3 ounces* 2-4
Salmon, cooked 3 ounces* 4-5
Avocado 1 whole 2-6
Raspberries 1 cup 0.2-2
Cauliflower, raw 1 cup 0.2-4
*A three-ounce serving of meat is about the size of a deck of cards.

Bacterial synthesis

A majority of bacteria that normally colonize the small and large intestine (colon) synthesize biotin (63). Whether the biotin is released and absorbed by humans in meaningful amounts remains unknown. The uptake of free biotin into intestinal cells via the human sodium-dependent multivitamin transporter (hSMVT) has been identified in cultured cells derived from the lining of the small intestine and colon (64), suggesting that humans may be able to absorb biotin produced by enteric bacteria — a phenomenon documented in swine.


Biotin is available as a single-nutrient supplement in various doses (many containing 5,000 μg [5 mg] of biotin) and is often included in B-complex and multivitamin-mineral supplements. Several multivitamin supplements contain 30 μg of biotin, although the amount varies by product (65).



Biotin is not known to be toxic. In people without disorders of biotin metabolism, doses of up to 5 mg/day (5,000 μg) for two years were not associated with adverse effects (66). Oral biotin supplementation has been well tolerated in doses up to 200 mg/day (nearly 7,000 times the AI) in people with hereditary disorders of biotin metabolism (1). Daily supplementation with a highly concentrated formulation of biotin (100-600 mg) for several months was also found to be well tolerated in individuals with progressive multiple sclerosis (36, 67). However, there is one case report of life-threatening eosinophilic pleuropericardial effusion in an elderly woman who took a combination of 10 mg/day of biotin and 300 mg/day of pantothenic acid (vitamin B5) for two months (68). Because reports of adverse events were lacking when the Dietary Reference Intakes (DRIs) for biotin were established in 1998, the Food and Nutrition Board did not establish a tolerable upper intake level (UL) for biotin (1).

Nutrient interactions

Large doses of pantothenic acid (vitamin B5) have the potential to compete with biotin for intestinal and cellular uptake by the human sodium-dependent multivitamin transporter (hSMVT) (69, 70). Biotin also shares the hSMVT with lipoic acid (71). Pharmacologic (very high) doses of lipoic acid have been found to decrease the activity of biotin-dependent carboxylases in rats, but such an effect has not been demonstrated in humans (72).

Drug interactions

Individuals on long-term anticonvulsant (anti-seizure) therapy reportedly have reduced blood biotin concentrations, as well as an increased urinary excretion of organic acids (e.g., 3-hydroxyisovaleric acid) that indicate decreased carboxylase activity (see Markers of biotin status) (5). Potential mechanisms of biotin depletion by the anticonvulsants, primidone (Mysoline), phenytoin (Dilantin, Phenytek), and carbamazepine (Carbatrol, Epitol, Equetro, Tegretol), include inhibition of biotin intestinal absorption and renal reabsorption, as well as increased biotin catabolism (73). Use of the anticonvulsant valproic acid in children has resulted in hair loss reversed by biotin supplementation (74-77). Long-term treatment with antibacterial sulfonamide (sulfa) drugs or other antibiotics may decrease bacterial synthesis of biotin. Yet, given that the extent to which bacterial synthesis contributes to biotin intake in humans is not known, effects of antimicrobial drugs on biotin nutritional status remain uncertain (73).

Interference with lab assays

In 2017, the US Food and Drug Administration (FDA) released a safety communication regarding high-dose biotin supplementation and its potential interference with streptavidin (avidin)-biotin immunoassays, including assays of thyroid hormones, reproductive hormones, and the cardiac protein, troponin. Such interference can cause aberrant results — either falsely high or falsely low depending on the method of the particular assay — and potential misdiagnosis of disease (78-81). An updated FDA communication in 2019 focused on biotin interference in certain lab assays of troponin that have not addressed the concern of falsely low blood concentrations (82). Troponin in blood is a marker of cardiac damage and often used in the clinical diagnosis of a myocardial infarction (heart attack). When blood work is planned, patients should routinely inform their health care provider concerning supplementation of biotin at doses substantially greater than those in usual diets or in routine daily multivitamins.

Linus Pauling Institute Recommendation

Little is known regarding the amount of dietary biotin required to promote optimal health or prevent chronic disease. The Linus Pauling Institute supports the recommendation made by the National Academy of Medicine, which is 30 micrograms (μg) of biotin per day for adults. A varied diet should provide enough biotin for most people. However, following the Linus Pauling Institute recommendation to take a daily multivitamin-mineral supplement will generally provide an intake of at least 30 μg/day of biotin.

Older adults (>50 years)

Presently, there is no indication that older adults have an increased requirement for biotin. If dietary biotin intake is not sufficient, a daily multivitamin-mineral supplement will generally provide an intake of at least 30 μg of biotin per day.

Authors and Reviewers

Originally written in 2000 by: 
Jane Higdon, Ph.D. 
Linus Pauling Institute 
Oregon State University

Updated in June 2004 by: 
Jane Higdon, Ph.D. 
Linus Pauling Institute 
Oregon State University

Updated in August 2008 by: 
Victoria J. Drake, Ph.D. 
Linus Pauling Institute 
Oregon State University

Updated in July 2015 by:
Barbara Delage, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in July 2022 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in March 2023 by: 
Donald Mock, M.D., Ph.D. 
Professor Emeritus
Departments of Biochemistry and Molecular Biology and Pediatrics 
University of Arkansas for Medical Sciences

Copyright 2000-2024  Linus Pauling Institute


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44. Revilla-Monsalve C, Zendejas-Ruiz I, Islas-Andrade S, et al. Biotin supplementation reduces plasma triacylglycerol and VLDL in type 2 diabetic patients and in nondiabetic subjects with hypertriglyceridemia. Biomed Pharmacother. 2006;60(4):182-185.  (PubMed)

45. Geohas J, Daly A, Juturu V, Finch M, Komorowski JR. Chromium picolinate and biotin combination reduces atherogenic index of plasma in patients with type 2 diabetes mellitus: a placebo-controlled, double-blinded, randomized clinical trial. Am J Med Sci. 2007;333(3):145-153.  (PubMed)

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  • Folate is a generic term referring to both natural folates in food and folic acid, the synthetic form used in supplements and fortified food. Folate is critical in the metabolism of nucleic acid precursors and several amino acids, as well as in methylation reactions. (More information) 
  • Severe deficiency in either folate or vitamin B12 can lead to megaloblastic anemia, which causes fatigue, weakness, and shortness of breath. Improper treatment of vitamin B12-dependent megaloblastic anemia with high-dose supplemental folic acid can potentially delay the diagnosis of vitamin B12 deficiency and thus leave the individual at risk of developing irreversible brain and nervous system damage. (More information)
  • Folate status is influenced by the presence of genetic variations in folate metabolism enzymes, particularly polymorphisms of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene. (More information) 
  • Inadequate folate status during early pregnancy increases the risk of congenital anomalies. The introduction of mandatory folic acid fortification of refined grain products in the US in 1998 has reduced the prevalence of neural tube defects (NTDs) in newborns. Yet, folate status is considered inadequate in a majority of women of childbearing age worldwide. Moreover, genetic factors might modify the risk of NTDs by increasing the susceptibility to folate deficiency during pregnancy. Several studies have investigated the role of folic acid supplementation in the prevention of congenital anomalies other than NTDs. (More information) 
  • Folate deficiency and elevated concentrations of homocysteine in the blood are associated with increased risk of cardiovascular disease. Although folic acid supplementation has been proven effective to control circulating homocysteine concentrations, homocysteine lowering has not affected the incidence of cardiovascular disease in supplementation trials. Yet, supplementation with folic acid and other B vitamins does appear to lower the risk of stroke. (More information) 
  • Low folate status has been linked to increased cancer risk. However, intervention trials with high doses of folic acid have not generally shown any benefit on cancer incidence. There is some concern that high doses of supplemental folic acid might increase the risk of certain cancers, but further study is needed. (More information) 
  • Prospective cohort studies have reported an inverse association between folate status and colorectal cancer risk, especially among men. However, the relationship between folate status and cancer risk is complex and requires further research. (More information) 
  • Folate is essential for brain development and function. Low folate status and/or high homocysteine concentrations are associated with cognitive dysfunction in aging (from mild impairments to dementia). However, whether supplemental folic acid confers long-term benefits in maintaining cognitive health is not yet known. (More information) 
  • Several autosomal recessive disorders affecting folate transport and metabolism can be treated with high doses of folinic acid, a folate derivative. (More information) 

Folate is a water-soluble B-vitamin, which is also known as vitamin B9 or folacin. Naturally occurring folates exist in many chemical forms; folates are found in food, as well as in metabolically active forms in the human body. Folic acid is the major synthetic form found in fortified foods and vitamin supplements. Other synthetic forms include folinic acid (Figure 1) and levomefolic acid. Folic acid has no biological activity unless converted into folates (1). In the following discussion, forms found in food or the body are referred to as "folates," while the form found in supplements or fortified food is referred to as "folic acid."

Folate Figure 1. Chemical Structures. Chemical structures of folic acid (C19H19N7O6), 5-methyltetrahydrofolate (C20H25N7O6), and folinic acid (C20H23N7O7)


One-carbon metabolism

The only function of folate coenzymes in the body appears to be in mediating the transfer of one-carbon units (2). Folate coenzymes act as acceptors and donors of one-carbon units in a variety of reactions critical to the metabolism of nucleic acids and amino acids (Figure 2) (3).

Folate Figure 2. Overview of One-carbon Metabolism. 5,10-methylenetetrahydrofolate is required for the synthesis of nucleic acids, and 5-methyltetrahydrofolate is required for the formation of methionine from homocysteine. Methionine, in the form of methyl donor S-adenosylmethionine (SAM), is essential to many biological methylation reactions, including DNA methylation. Methylenetetrahydrofolate reductase (MTHFR) is a riboflavin (FAD)-dependent enzyme that catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate.

Nucleic acid metabolism

Folate coenzymes play a vital role in DNA metabolism through two different pathways: (1) The synthesis of DNA from its precursors (thymidine and purines) is dependent on folate coenzymes. (2) A folate coenzyme is required for the synthesis of methionine from homocysteine, and methionine is required for the synthesis of S-adenosylmethionine (SAM). SAM is a methyl group (one-carbon unit) donor used in most biological methylation reactions, including the methylation of a number of sites within DNA, RNA, proteins, and phospholipids. The methylation of DNA plays a role in controlling gene expression and is critical during cell differentiation. Aberrations in DNA methylation have been linked to the development of cancer (see Cancer).

Amino acid metabolism

Folate coenzymes are required for the metabolism of several important amino acids, namely methionine, cysteine, serine, glycine, and histidine. The synthesis of methionine from homocysteine is catalyzed by methionine synthase, an enzyme that requires not only folate (as 5-methyltetrahydrofolate) but also vitamin B12. Thus, folate (and/or vitamin B12) deficiency can result in decreased synthesis of methionine and an accumulation of homocysteine. Elevated blood concentrations of homocysteine have been considered for many years to be a risk factor for some chronic diseases, including cardiovascular disease and dementia (see Disease Prevention).

Nutrient interactions

Vitamin B12 and vitamin B6

The metabolism of homocysteine, an intermediate in the metabolism of sulfur-containing amino acids, provides an example of the interrelationships among nutrients necessary for optimal physiological function and health. Healthy individuals utilize two different pathways to metabolize homocysteine (Figure 3). One pathway (methionine synthase) synthesizes methionine from homocysteine and is dependent on both folate and vitamin B12 as cofactors. The other pathway converts homocysteine to another amino acid, cysteine, and requires two vitamin B6-dependent enzymes. Thus, the concentration of homocysteine in the blood is regulated by three B-vitamins: folate, vitamin B12, and vitamin B6 (4). In some individuals, riboflavin (vitamin B2) is also involved in the regulation of homocysteine concentrations (see the article on Riboflavin). 

Folate Figure 3. Homocysteine Metabolism. Homocysteine is methylated to form the essential amino acid methionine in two pathways. The reaction of homocysteine remethylation catalyzed by the vitamin B<sub>12</sub>-dependent methionine synthase captures a methyl group from the folate-dependent one-carbon pool (5-methyltetrahydrofolate). A second pathway requires betaine (N,N,N-trimethylglycine) as a methyl donor for the methylation of homocysteine catalyzed by betaine homocysteine methyltransferase. The catabolic pathway of homocysteine, known as the transsulfuration pathway, converts homocysteine to the amino acid cysteine via two vitamin B<sub>6</sub> (PLP)-dependent enzymes. Cystathionine beta synthase catalyzes the condensation of homocysteine with serine to form cystathionine, and cystathionine is then converted to cysteine, alpha-ketobutyrate, and ammonia by cystathionine gamma lyase.


Although less well recognized, folate has an important metabolic interaction with riboflavin. Riboflavin is a precursor of flavin adenine dinucleotide (FAD), a coenzyme required for the activity of the folate-metabolizing enzyme, 5,10-methylenetetrahydrofolate reductase (MTHFR). FAD-dependent MTHFR in turn catalyzes the reaction that generates 5-methyltetrahydrofolate (see Figure 2). This active form of folate is required to form methionine from homocysteine. Along with other B-vitamins, higher riboflavin intakes have been associated with decreased plasma homocysteine concentrations (5). The effects of riboflavin on folate metabolism appear to be greatest in individuals homozygous for the common c.677C>T polymorphism (i.e., TT genotype) in the MTHFR gene (see Genetic variation in folate requirements) (6). These individuals (up to 32% of the population) typically present with low folate status, along with elevated homocysteine concentrations, particularly when folate and/or riboflavin intake is suboptimal. The elevated homocysteine concentration in these individuals, however, is highly responsive to lowering with riboflavin supplementation. In addition, riboflavin supplementation has been shown to reduce blood pressure in hypertensive individuals homozygous for the MTHFR c.677C>T polymorphism (7, 8), confirming the importance of the riboflavin-MTHFR interaction (9, 10).  


Dietary folates exist predominantly in the polyglutamyl form (containing several glutamate residues), whereas folic acid — the synthetic vitamin form — is a monoglutamate, containing just one glutamate moiety. In addition, natural folates are reduced molecules, whereas folic acid is fully oxidized. These chemical differences have major implications for the bioavailability of the vitamin such that folic acid is considerably more bioavailable than naturally occurring food folates at equivalent intake levels. 

The intestinal absorption of dietary folates is a two-step process that involves the hydrolysis of folate polyglutamates to the corresponding monoglutamyl derivatives, followed by their transport into intestinal cells (11). There, folic acid is converted into a naturally occurring folate, namely 5-methyltetrahydrofolate, which is the major circulating form of folate in the human body (see Figure 1).

The bioavailability of naturally occurring folates is inherently limited and variable. There is much variability in the ease with which folates are released from different food matrices, and the polyglutamyl "tail" is removed (de-conjugation) before uptake by intestinal cells. Also, other dietary constituents can contribute to instability of labile folates during the processes of digestion. As a result, naturally occurring folates show incomplete bioavailability compared with folic acid. The bioavailability of folic acid, in contrast, is assumed to be 100% when ingested as a supplement, while folic acid in fortified food is estimated to have about 85% the bioavailability of supplemental folic acid.

Of note, folate recommendations in the US and certain other countries are now expressed as Dietary Folate Equivalents (DFEs), a calculation that was devised to take into account the greater bioavailability of folic acid compared to naturally occurring dietary folates (see The Recommended Dietary Allowance).


Folate and its coenzymes require transporters to cross cell membranes. Folate transporters include the reduced folate carrier (RFC), the proton-coupled folate transporter (PCFT), and the folate receptor proteins, FRα and FRβ. Folate homeostasis is supported by the ubiquitous distribution of folate transporters, although abundance and importance vary among tissues (12). PCFT plays a major role in folate intestinal transport since mutations affecting the gene encoding PCFT cause hereditary folate malabsorption. Defective PCFT also leads to impaired folate transport into the brain (see Disease Treatment). FRα and RFC are also critical for folate transport across the blood-brain barrier when extracellular folate is either low or high, respectively. Folate is essential for the proper development of the embryo and the fetus. The placenta is known to concentrate folate to the fetal circulation, leading to higher folate concentrations in the fetus compared to those found in the pregnant woman. All three types of receptors have been associated with folate transport across the placenta during pregnancy (13).



Although folate deficiency is uncommon in the United States, it is estimated to be more prevalent worldwide (11). Most often caused by a dietary insufficiency, folate deficiency can also occur in a number of other situations. Chronic, heavy alcohol consumption is associated with diminished absorption of folate (in addition to low dietary intake), which can lead to folate deficiency (14). Smoking is also associated with low folate status. In one study, folate concentrations in blood were about 15% lower in smokers compared to nonsmokers (15). Additionally, impaired folate transport to the fetus has been described in pregnant women who either smoked or abused alcohol during their pregnancy (16, 17).

Pregnancy is a time when the folate requirement is greatly increased to sustain the demand for rapid cell replication and growth of fetal, placental, and maternal tissue. Conditions such as cancer or inflammation can also result in increased rates of cell division and metabolism, causing an increase in the body's demand for folate (18). Moreover, folate deficiency can result from some malabsorptive conditions, including inflammatory bowel diseases (Crohn’s disease and ulcerative colitis) and celiac disease (11, 19). Several medications can contribute to folate deficiency (see Drug interactions). Finally, a number of genetic diseases affecting folate absorption, transport, or metabolism can cause folate deficiency or impede its metabolic functions (see Disease Treatment).


Clinical folate deficiency leads to megaloblastic anemia, which is reversible with folic acid treatment. Rapidly dividing cells like those derived from bone marrow are most vulnerable to the effects of folate deficiency since DNA synthesis and cell division are dependent on folate coenzymes. When folate supply to the rapidly dividing cells of the bone marrow is inadequate, blood cell division is reduced, resulting in fewer but larger red blood cells. This type of anemia is called megaloblastic or macrocytic anemia, referring to the enlarged, immature red blood cells. Neutrophils, a type of white blood cell, become hypersegmented, a change that can be found by examining a blood sample microscopically. Because normal red blood cells have a lifetime in the circulation of approximately four months, it can take months for folate-deficient individuals to develop the characteristic megaloblastic anemia. Progression of such an anemia leads to a decreased oxygen carrying capacity of the blood and may ultimately result in symptoms of fatigue, weakness, and shortness of breath (1). It is important to point out that megaloblastic anemia resulting from folate deficiency is identical to the megaloblastic anemia resulting from vitamin B12 deficiency, and further clinical testing is required to diagnose the true cause of megaloblastic anemia (see Toxicity).

Individuals in the early stages of folate deficiency may not show obvious symptoms, but blood concentrations of homocysteine may increase (see Disease Prevention). Yet, the concentration of circulating homocysteine is not a specific indicator of folate status, as elevated homocysteine can be the result of vitamin B12 and other B-vitamin deficiencies, lifestyle factors, and renal insufficiency. Subclinical deficiency is typically detected by measurement of folate concentrations in serum/plasma or in red blood cells.

The Recommended Dietary Allowance (RDA)

Determination of the RDA

Traditionally, the dietary folate requirement was defined as the amount needed to prevent a deficiency severe enough to cause symptoms like anemia. The most recent RDA (1998; Table 1) was based primarily on the adequacy of red blood cell folate concentrations at different levels of folate intake, as judged by the absence of abnormal hematological indicators. Red cell folate has been shown to correlate with liver folate stores and is used as an indicator of long-term folate status. Plasma or serum folate reflects recent folate intake and is not a reliable biomarker for folate status, especially when used as a one-time assessment (11). Maintenance of normal blood homocysteine concentrations, an indicator of one-carbon metabolism, was considered only as an ancillary indicator of adequate folate intake.

Because pregnancy is associated with a significant increase in cell division and other metabolic processes that require folate coenzymes, the RDA for pregnant women is considerably higher than for women who are not pregnant (3). However, the prevention of neural tube defects (NTDs) was not considered when setting the RDA for pregnant women. Rather, reducing the risk of NTDs was considered in a separate recommendation for women capable of becoming pregnant (see Disease Prevention), because the crucial events in the development of the neural tube occur before many women are aware that they are pregnant (20).

Dietary Folate Equivalents (DFEs)

When the Food and Nutrition Board of the US Institute of Medicine (now the National Academy of Medicine) last revised the dietary recommendations for folate, they introduced a new unit, the Dietary Folate Equivalent (DFE) (1). Use of the DFE reflects the higher bioavailability of synthetic folic acid found in supplements and fortified food compared to that of naturally occurring food folates (20).

  • 1 microgram (μg) of food folate provides 1 μg of DFEs
  • 1 μg of folic acid taken with meals or as fortified food provides 1.7 μg of DFEs
  • 1 μg of folic acid (supplement) taken on an empty stomach provides 2 μg of DFEs

For example, a serving of food containing 60 μg of folate would provide 60 μg of DFEs, while a serving of pasta fortified with 60 μg of folic acid would provide 1.7 x 60 = 102 μg of DFEs due to the higher bioavailability of folic acid. A folic acid supplement of 400 μg taken on an empty stomach would provide 800 μg of DFEs. It should be noted that DFEs were determined in studies with adults and whether folic acid in infant formula is more bioavailable than folates in mother's milk has not been studied. Use of DFEs to determine a folate requirement for the infant would not be desirable.

Table 1. Recommended Dietary Allowance for Folate in Dietary Folate Equivalents (DFEs)
Life Stage Age Males (μg/day) Females (μg/day)
Infants 0-6 months 65 (AI) 65 (AI)
Infants 7-12 months 80 (AI) 80 (AI)
Children 1-3 years 150 150
Children 4-8 years 200 200
Children 9-13 years 300 300
Adolescents 14-18 years 400 400
Adults 19 years and older 400 400
Pregnancy all ages - 600
Breast-feeding all ages - 500

Genetic variation in folate requirements

A common polymorphism or variation in the sequence of the gene for the enzyme, 5, 10-methylenetetrahydrofolate reductase (MTHFR), known as the MTHFR c.677C>T polymorphism, results in a thermolabile enzyme (21). The substitution of a cytosine (C) by a thymine (T) at nucleotide 677 in the exon 4 of MTHFR gene leads to an alanine-to-valine transition in the catalytic domain of the enzyme. Depending on the population, 20% to 53% of individuals may have inherited one T copy (677C/T genotype), and 3% to 32% of individuals may have inherited two T copies (677T/T genotype) for the MTHFR gene (22). MTHFR catalyzes the reduction of 5,10-methylenetetrahydrofolate (5,10-methylene THF) into 5-methyl tetrahydrofolate (5-MeTHF). The latter is the folate coenzyme required to form methionine from homocysteine (see Figure 2). MTHFR activity is greatly diminished in heterozygous 677C/T (-30%) and homozygous 677T/T (-65%) individuals compared to those with the 677C/C genotype (23). Homozygosity for the mutation (677T/T) is linked to lower concentrations of folate in red blood cells and higher blood concentrations of homocysteine (24, 25). Improving folate nutritional status in elderly women with the T allele reduced plasma homocysteine concentration (26). An important unanswered question about folate is whether the present RDA is enough to compensate for the reduced MTHFR enzyme activity in individuals with at least one T allele, or whether those individuals have a higher folate requirement than the RDA (27).

Disease Prevention

Adverse pregnancy outcomes

Neural tube defects

Fetal growth and development are characterized by widespread cell division. Adequate folate is critical for DNA and RNA synthesis. Neural tube defects (NTDs) arise from failure of embryonic neural tube closure between the 21st and 28th days after conception, a time when many women may not even realize they are pregnant (28). NTDs include various malformations, such as lesions of the brain (e.g., anencephaly, encephalocele) or lesions of the spine (spina bifida), which are devastating and life-threatening (29). The worldwide prevalence of NTDs is estimated to be 2 per 1,000 births, which translates to 214,000-322,000 cases annually (30).

Results of randomized trials have demonstrated 60% to 100% reductions in NTD cases when women consumed folic acid supplements in addition to a varied diet during the periconceptional period (about one month before and at least one month after conception) (31, 32). To decrease the incidence of NTDs in the US (about 1 NTD case per 1,000 pregnancies; 1), the Food and Drug Administration implemented legislation in 1998 requiring the fortification of all enriched grain products with 1.4 mg of folic acid per kg of grain (see Sources). The required level of folic acid fortification in the US was initially estimated to provide 100 μg of additional folic acid in the average person's diet, though it probably provides even more due to overuse of folic acid by food manufacturers (27, 33). As a result of this fortification mandate, a 30% decrease in the prevalence of NTDs was noted compared to the pre-fortification period; the post-fortification prevalence of NTDs was found to be 0.69 cases per 1,000 live births and fetal deaths (34). Recent estimates indicate an NTD prevalence less than 0.5 cases per 1,000 live births and that fortification strategies in the US prevent 1,326 NTDs each year (35). To date, 58 nations worldwide have established mandatory programs of folic acid fortification of staple grains (30, 36), and an estimated 22% of NTDs have been prevented through such programs (36). Many countries in Europe, Asia, and Africa, however, have not mandated folic acid fortification of staple foods (37).

The US Public Health Service recommends that all persons capable of becoming pregnant consume 400 μg of folic acid daily to prevent NTDs. Those with a previously affected pregnancy were also advised to receive 4,000 μg (4 mg) of folic acid daily in order to reduce NTD recurrence (38). These recommendations were made to all persons of childbearing age because adequate folate must be available very early in pregnancy, and because many pregnancies in the US are unplanned (39). Despite the effectiveness of folic acid supplementation in improving folate status, it appears that globally only 30% of women who become pregnant correctly follow the recommendation, and there is some concern that young women from minority ethnic groups and lower socioeconomic backgrounds are the least likely to follow the recommendation (40-43).

Also, a genetic component in NTD etiology is evidenced by the increased risk in women with a family history of an NTD and also by variations in risk among ethnicities (44). Moreover, NTD occurrence can be attributed to specific folate-gene interactions. The MTHFR c.677C>T polymorphism and other genetic variations can increase the folate requirement and susceptibility for an NTD-affected pregnancy. Prior to the fortification era, a case-control study showed that both red blood cell and serum folate concentrations were significantly lower in pregnant women with the T/T and C/T variants compared to the wild-type C/C genotype (24), suggesting inadequate folate metabolism with specific maternal genotypes. A meta-analysis of 34 case-control studies, including 3,018 case mothers and 8,746 control mothers, showed a positive association between the maternal MTHFR c.677C>T polymorphism and NTDs (45). Another MTHFR variant, an A-to-C change at position 1298, has also been associated with reduced MTHFR activity and increased NTD risk in some (46, 47), but not all (48), populations. Individuals heterozygous for both of these MTHFR variants (677C/T + 1298A/C) exhibit lower plasma folate and higher homocysteine concentrations than individuals with 677C/T + 1298A/A (49). Combined genotypes with homozygosity G/G for the reduced folate carrier transporter (RFC-1) polymorphism (c.80A>G) could further contribute to NTD occurrence (50). The degree of NTD risk was also assessed with additional MTHFR polymorphisms (c.116C>T, c.1793G>A) (51), as well as with mutations affecting other enzymes of the one-carbon metabolism, including methionine synthase (MTR c.2756A>G) (52), methionine synthase reductase (MTRR c.66A>G) (53), and methylenetetrahydrofolate dehydrogenase (MTHFD1 c.1958G>A) (54, 55). While maternal genotype can impact pregnancy outcome, it appears that gene-gene interactions between mother and fetus influence it further. The risk of NTD was increased by certain genetic combinations, including maternal (MTHFR c.677C>T)-fetal (MTHFR c.677C>T) and maternal (MTRR c.66A>G)-fetal (MTHFR c.677C>T) interactions (52, 53, 56). Finally, vitamin B12 status has been associated with NTD risk modification in the presence of specific polymorphisms in one-carbon metabolism (57).

Cardiovascular malformations

Congenital anomalies of the heart are a major cause of infant mortality but also cause deaths in adulthood (58). Using data from the European Registration of Congenital Anomalies and Twins (EUROCAT) database, a case-control study, involving 596 cases and 2,359 controls, found that consumption of at least 400 μg/day of folic acid during the periconceptual period (one month before conception through eight weeks' post-conception, covering the period of embryonic heart development) was associated with an 18% reduced risk of congenital heart defects (59). Meta-analyses of 20 to 25 case-control and family-based studies observed positive associations between maternal, fetal, or paternal MTHFR c.677C>T variant and incidence of congenital heart defects (60, 61). Additional studies are needed to elucidate the effects of gene-nutrient interactions on the risk of congenital heart defects; however, the currently available research indicates that adequate folate intake may play an important role.

Orofacial clefts

Maternal folate status during pregnancy may influence the risk of congenital anomalies called orofacial clefts, namely cleft lip with or without cleft palate (CL/P) (62). Most orofacial clefts are non-syndromic clefts, meaning no other congenital malformations are present (63). In a recent systematic review and meta-analysis of 39 observational studies, use of folic acid-containing supplements preconceptionally or during pregnancy was associated with a 42% lower risk of CL/P (95% CI, 0.49-0.70) (64). While some studies have suggested that polymorphisms in the cystathionine β-synthase (CBS) gene (c.699C>T) or MTHFR gene (c.677C>T) might be protective of orofacial clefts at low folate intakes (65, 66), this pooled analysis did not find an association between MTHFR polymorphisms and orofacial clefts (64). An earlier meta-analysis of observational studies evaluating mandatory programs of folic acid fortification globally found that folic acid fortification was only associated with a reduced risk of non-syndromic CL/P (5 studies) and not with orofacial clefts in total (24 studies), CL/P (16 studies), or cleft palate only (16 studies) (67). It is important to note that the observational studies to date are highly heterogeneous, which presents challenges when pooling study results in a meta-analysis.

Other adverse pregnancy outcomes

Low birth weight has been associated with increased risk of mortality during the first year of life and may also influence health outcomes during adulthood (68). A systematic review and meta-analysis of eight randomized controlled trials found a positive association between folic acid supplementation and birth weight; no association with length of gestation was observed (69). Additionally, a prospective cohort study of 306 pregnant adolescents associated low folate intakes and maternal folate status during the third trimester of pregnancy with higher incidence of small for gestational age births (birth weight <10th percentile) (70). Moreover, the maternal c.677C>T MTHFR genotype and increased homocysteine concentrations, considered an indicator of functional folate deficiency, have been linked to lower birth weights (71).

Elevated blood homocysteine concentrations have also been associated with increased incidence of miscarriage and other pregnancy complications, including preeclampsia and placental abruption (72). A large retrospective study showed that high plasma homocysteine in Norwegian women was strongly related to adverse outcomes and complications, including preeclampsia, premature delivery, and very low birth weight, in previous pregnancies (73). A meta-analysis of 51 prospective cohort studies linked the c.677C>T MTHFR variant with increased risk of preeclampsia in Caucasian and East Asian populations, reinforcing the notion that folate metabolism may play a role in the condition (74). However, it is not known whether maternal folic acid supplementation during pregnancy reduces the risk of preeclampsia, although results of a meta-analysis of 12 studies (11 cohort studies and 1 randomized controlled trial) suggested a lower risk (RR, 0.69; 95% CI 0.58-0.83) (75). A large international, multicenter, double-blind, placebo-controlled trial, the Folic Acid Clinical Trial (FACT), was initiated to evaluate whether high-dose folic acid supplementation throughout pregnancy could prevent preeclampsia and other adverse outcomes (e.g., maternal death, placental abruption, preterm delivery) (76). In this trial in 2,301 pregnant women at high risk of preeclampsia, 4.0-5.1 mg/day of supplemental folic acid from 8 to 16 weeks’ gestation until delivery did not lower risk of preeclampsia or any other adverse outcome when compared to placebo (subjects in the placebo group could take up to 1.1 mg/day of folic acid) (77).

Overall, findings of observational studies on the association of maternal folic acid supplementation and autism spectrum disorders in the offspring have been inconsistent (reviewed in 78, 79). Additionally, systematic reviews of observational studies have found no evidence of an association between folate exposure during pregnancy and childhood asthma or allergies (80, 81).

Adequate folate intake throughout pregnancy is known to protect against megaloblastic anemia (82). Thus, it seems reasonable to maintain folic acid supplementation throughout pregnancy, even after closure of the neural tube, in order to decrease the risk of other problems during pregnancy.

Cardiovascular disease

Homocysteine and cardiovascular disease

The results of more than 80 observational studies indicate that even moderately elevated concentrations of homocysteine in the blood increase the risk of cardiovascular disease (CVD) (4). Possible predispositions to vascular accidents have also been linked to genetic deficiencies in homocysteine metabolism in certain populations (83). The mechanism by which homocysteine may increase the risk of vascular disease has been the subject of a great deal of research, but it may involve adverse effects of homocysteine on blood clotting, arterial vasodilation, and thickening of arterial walls (84). Although increased homocysteine concentrations in the blood have been consistently associated with increased risk of CVD, it is unclear whether lowering circulating homocysteine will reduce CVD risk (see Folate and homocysteine). Elevated homocysteine may instead be a biomarker of cardiovascular disease rather than a causative factor (85).

Research had initially predicted that a prolonged decrease in serum homocysteine level of 3 micromoles/liter would lower the risk of CVD by up to 25% and be a reasonable treatment goal for individuals at high risk (86, 87). However, the analysis of clinical trials of B-vitamin supplementation has shown that lowering homocysteine concentrations did not prevent the occurrence of a second cardiovascular event in patients with existing CVD (88-90). Consequently, the American Heart Association recommends screening for elevated total homocysteine concentrations only in "high risk" individuals, for example, in those with personal or family history of premature cardiovascular disease, malnutrition or malabsorption syndromes, hypothyroidism, kidney failure, lupus, or for individuals taking certain medications (nicotinic acid, theophylline, bile acid-binding resins, methotrexate, and L-dopa.

Folate and homocysteine

Folate-rich diets have been associated with decreased risk of CVD, including coronary artery disease, myocardial infarction (heart attack), and stroke. A study that followed 1,980 Finnish men for 10 years found that those who consumed the most dietary folate had a 55% lower risk of an acute coronary event when compared to those who consumed the least dietary folate (91). Of the three B vitamins that regulate homocysteine concentrations, folic acid has been shown to have the greatest effect in lowering basal concentrations of homocysteine in the blood when there is no coexisting deficiency of vitamin B12 or vitamin B6 (see Nutrient interactions) (92). Increasing folate intake through folate-rich food or supplements has been found to reduce homocysteine concentrations (93). Moreover, blood homocysteine concentrations have declined since the FDA mandated folic acid fortification of the grain supply in the US (27). A meta-analysis of 25 randomized controlled trials, including almost 3,000 subjects, found that folic acid supplementation with 800 μg/day or more could achieve a maximal 25% reduction in plasma homocysteine concentrations. In this meta-analysis, daily doses of 200 μg and 400 μg of folic acid were associated with a 13% and 20% reduction in plasma homocysteine, respectively (94). A supplement regimen of 400 μg of folic acid, 2 mg of vitamin B6, and 6 μg of vitamin B12 has been advocated by the American Heart Association if an initial trial of a folate-rich diet (see Sources) is not successful in adequately lowering homocysteine concentrations (95).  

Several polymorphisms in folate/one-carbon metabolism modify homocysteine concentrations in blood (96). In particular, the effect of the c.677C>T MTHFR variant has been examined in relation to folic acid fortification policies worldwide. The analysis of randomized trials, including 59,995 subjects without a history of CVD, revealed that the difference in homocysteine concentrations between T/T and C/C genotypes was greater in low-folate regions compared to regions with food fortification policy (3.12 vs. 0.13 micromoles/liter) (97). Although folic acid supplementation effectively decreases homocysteine concentrations, it is not yet clear whether it also decreases risk for CVD. A meta-analysis of 19 randomized clinical trials, including 47,921 subjects with preexisting cardiovascular or renal disease, found that homocysteine lowering through folic acid and other B-vitamin supplementation failed to reduce the incidence of CVD despite significant reductions in plasma homocysteine concentrations (90). Other meta-analyses have confirmed the lack of causality between the lowering of homocysteine and the risk of CVD (96-98). Consequently, the American Heart Association removed its recommendation for using folic acid to prevent cardiovascular disease in high-risk women (99). However, more recent evidence suggests that homocysteine-lowering therapy with B vitamins may help prevent stroke in particular. A meta-analysis of three randomized controlled trials in patients with existing vascular disease found a benefit of B-vitamin supplementation on prevention of recurrent stroke (HR, 0.71; 95% CI, 0.58-0.88) (100). Other recent meta-analyses of randomized controlled trials have found that folic acid supplementation decreases the risk of stroke or cerebrovascular events in patients with existing CVD (101-103), as well as in those without CVD (104). A recent systematic review and meta-analysis of 21 randomized controlled trials — mostly in patients with existing CVD — found that folic acid supplementation slightly lowers systolic (1.10 mm Hg) and diastolic (-0.24 mm Hg) blood pressure (105).

Moreover, some studies have investigated the effect of folic acid supplementation on the development of atherosclerosis, a known risk factor for vascular accidents. The measurement of the carotid intima-media thickness (CIMT) is a surrogate endpoint for early atherosclerosis and a predictor for cardiovascular events (106). The meta-analysis of 10 randomized trials testing the effect of folic acid supplementation showed a significant reduction in CIMT in subjects with chronic kidney diseases and in those at risk for CVD, but not in healthy participants (107). Endothelial dysfunction is a common feature in atherosclerosis and vascular disease. High doses of folic acid (400-10,000 μg/day) have been associated with improvements in vascular health in both healthy and CVD subjects (108). A meta-analysis of 21 randomized, placebo-controlled trials found that folic acid supplementation improves endothelial function by increasing flow-mediated vasodilation (109).

Although some trials have failed to demonstrate any cardiovascular protection from folic acid supplementation, low folate intake is a known risk factor for vascular disease, and more research is needed to explore the role of folate in maintaining vascular health (110).  


Cancer is thought to arise from DNA damage in excess of ongoing DNA repair and/or the inappropriate expression of critical genes. Because of the important roles played by folate in DNA and RNA synthesis and methylation, it is possible that inadequate folate intake contributes to genome instability and chromosome breakage that often characterize cancer development. In particular, DNA replication and repair are critical for genome maintenance, and the shortage in nucleotides caused by folate deficiency might lead to genome instability and DNA mutations. A decrease in 5,10-methylene THF can compromise the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP) by the enzyme thymidylate synthase (TYMS), causing uracil accumulation and thymine depletion. This could then lead to uracil misincorporation into DNA during replication or repair, and cause DNA damage, including point mutations and strand breaks (111). Since 5,10-methylene THF is also the MTHFR enzyme substrate, it is plausible that a reduction of MTHFR activity with the c.677C>T polymorphism may increase the use of 5,10-methylene THF for thymidylate synthesis and prevent DNA damage. However, this hypothesis might only be valid in a situation of folate deficiency (112). Conversely, it was argued that folic acid supplementation could fuel DNA synthesis, therefore promoting tumor growth. This is supported by the observation that TYMS can function like a tumor promoter (oncogene), while a reduction in TYMS activity is linked to a lower risk of cancer (113, 114). Additionally, antifolate molecules that block the thymidylate synthesis pathway are successfully used in cancer therapy (115). Folate also controls the homocysteine/methionine cycle and the pool of S-adenosylmethionine (SAM), the methyl donor for methylation reactions. Thus, folate deficiency may impair DNA and protein methylation and alter the expression of genes involved in DNA repair, cell proliferation, and cell death. Global DNA hypomethylation, a typical hallmark of cancer, causes genome instability and chromosome breaks (reviewed in 116).

The consumption of at least five servings of fruit and vegetables daily has been consistently associated with a decreased incidence of cancer (117, 118). Fruit and vegetables are excellent sources of folate, which may play a role in their anti-carcinogenic effect. Observational studies have found diminished folate status to be associated with site-specific cancers. While food fortification is mandatory in the US (since 1998; see Sources), concerns about the impact of high folic acid intakes on health have delayed the practice in several other countries (119). However, meta-analyses of folic acid intervention trials (supplemental doses ranging from 500 to 5,000 μg/day for at least one year) did not show any specific benefit or harm regarding total and site-specific cancer incidence (120, 121). In 2015, an expert panel convened by the US National Toxicology Program and the US Office of Dietary Supplements concluded that folic acid supplementation does not reduce cancer incidence in folate replete individuals and that further research is needed to determine whether supplemental folic acid might promote cancer growth (122).

Colorectal cancer

A pooled analysis of 13 prospective cohort studies, which followed a total of 725,134 individuals for a 7 to 20-year period, revealed a modest, inverse association between dietary and total (from food and supplements) folate intake and colon cancer risk. Specifically, a 2% decrease in colon cancer risk was estimated for every 100 μg/day increase in total folate intake (123). A large US prospective study, which followed 525,488 subjects, ages 50 to 71 years between 1995 and 2006, correlated higher intakes of dietary folate, supplemental folic acid, and total folate (diet and supplements combined) with decreased colorectal cancer (CRC) risk (124). However, when stratified by gender, there was no association between dietary folate intake and CRC risk in women (124, 125). A lack of association between CRC risk and dietary, supplemental, and total folate intakes was also reported in another prospective study that followed more than 90,000 US postmenopausal women during an 11-year period encompassing pre- and post-fortification periods (126). Yet, in the long-term follow up (followed for up to 24 years) of 86,320 women participating in the prospective Nurses’ Health Study, higher total intakes of folate at baseline, as well as higher supplemental folic acid intakes, were associated with lower risks of CRC (127).

Finally, a meta-analysis of 18 case-control studies found a slight reduction in CRC risk with folate from food (128). However, it is important to note that the case-control studies were highly heterogeneous, and that the authors stated that dietary fiber, vitamins, and alcohol intake could have confounded their results. Moreover, the lower limit of the highest quantile of folate intake was highly variable, ranging from 270 to 1,367 μg/day (128).

While most observational research shows a protective association of folate against colorectal cancer development, it has been suggested that high doses of supplemental folic acid may actually accelerate tumor growth in cancer patients (129). Whereas higher folate status within the normal dietary range is widely considered to be protective against cancer, some investigators remain concerned that exposure to excessively high folic acid intakes may increase the growth of pre-existing neoplasms (129). Several clinical trials addressed the effect of folic acid supplementation in patients with a history of colorectal adenoma, with trials finding a risk reduction or no effect of supplemental folic acid (130-133). A meta-analysis of three large randomized controlled trials in high-risk subjects did not demonstrate any increase in colorectal adenoma recurrence in subjects supplemented with 500 or 1,000 μg/day of folic acid for 24 to 42 months when compared with placebo treatment (134). The B-PROOF study was a randomized, double-blind, placebo-controlled trial examining whether supplemental folic acid and vitamin B12 affected risk of osteoporotic fracture in older adults (≥65 years) with hyperhomocysteinemia (135). In a secondary analysis of 2,524 older adults participating in B-PROOF, co-supplementation with folic acid (400 μg/day) and vitamin B12 (500 μg/day) for 2 to 3 years significantly increased risk of colorectal cancer (HR 1.77; 95% CI, 1.08-2.90) (136).

As suggested above, the MTHFR 677T/T genotype might prevent uracil misincorporation and protect DNA integrity and stability under low-folate conditions. A meta-analysis of 62 case-control and two cohort studies revealed that while the T/T variant reduces CRC risk by 12% compared to both C/T and C/C genotypes, the risk was decreased by 30% with high (348-1,583 μg/day) versus low total folate intakes (264-450 μg/day), irrespective of the genotype (137). A common polymorphism (c.2756A>G) in the MTR gene, which codes for methionine synthase, was also examined in relation with the risk of colorectal adenoma and cancer. Methionine synthase catalyzes the simultaneous conversion of homocysteine and 5-methylene THF into methionine and TFH, respectively. Meta-analyses of case-control studies have found no association between MTR variants and colorectal cancer risk (138, 139).

Alcohol consumption interferes with the absorption and metabolism of folate (18). One case-control and five prospective cohort studies have reported either reduction in CRC risk among nondrinkers compared to drinkers or a lack of association (128). In a large prospective study that followed more than 28,000 male health professionals for 22 years, intake of more than two alcoholic drinks (>30 grams of alcohol) per day augmented CRC risk by 42% during the pre-fortification period. CRC risk was not increased during the post-fortification period, suggesting that it is the combination of high alcohol and low folate intake that might increase CRC risk. Yet, another prospective study that followed more than 69,000 female nurses for 28 years did not report a significant increase in CRC risk with alcohol intake before and after the mandatory folic acid fortification (140). In some studies, individuals who are homozygous for the c.677C>T MTHFR polymorphism (T/T) have been found to be at decreased risk for colon cancer when folate intake is adequate. However, when folate intake is low and/or alcohol intake is high, individuals with the (T/T) genotype have been found to be at increased risk of colorectal cancer (141, 142).

Breast cancer

Several prospective cohort and case-control studies investigating whether folate intake is associated with breast cancer have reported mixed results (143). A meta-analysis of 39 prospective cohort and case-control studies found dietary folate intake to be inversely associated with risk of breast cancer, but data stratification revealed the association was evident in premenopausal women and not in postmenopausal women (144). Another meta-analysis of only prospective cohort studies (n=23) found a similar protective association in premenopausal women (145).

Moderate alcohol intake has been associated with increased risk of breast cancer in women (146). Results from prospective studies have also suggested that increased folate intake may reduce the risk of breast cancer in women who regularly consume alcohol (145, 147-150). Thus, high folate intake might be associated with a risk reduction only in women whose breast cancer risk is raised by alcohol consumption. A very large prospective study in more than 88,000 nurses reported that folic acid intake was not associated with breast cancer in women who consumed less than one alcoholic drink per day. However, in women consuming at least one alcoholic drink per day, folic acid intake of at least 600 μg daily resulted in about half the risk of breast cancer compared with women who consumed less than 300 μg of folic acid daily (149). Nevertheless, how alcohol consumption increases breast cancer risk is still subject to discussion (151).

Finally, meta-analyses evaluating the influence of polymorphisms in one-carbon metabolism on cancer risk found that specific variants in the genes encoding thymidylate synthase (152, 153), methionine synthase (154), methionine synthase reductase (154), and MTHFR (154) increase the risk of breast cancer in certain ethnic populations.

Childhood cancers

The incidence of Wilms' tumors (kidney cancer) and certain types of brain cancers (neuroblastoma, ganglioneuroblastoma, and ependymoma) in children has decreased since the mandatory fortification of the US grain supply in 1998 (155). However, incidence rates were unchanged between the pre- and post-fortification periods for leukemia – a predominant childhood malignancy. Overall, the findings of observational studies of maternal folic acid supplementation during pregnancy and childhood cancers have been mixed. A recent meta-analysis of case-control studies found a protective association of maternal folic acid supplementation during pregnancy with childhood acute lymphoblastic leukemia (ALL; OR, 0.75; 95% CI 0.66-0.86; 11 studies) but not with acute myeloid leukemia (5 studies) or childhood brain cancers (6 studies) (156).

Additionally, several meta-analyses have found little to no protective association of MTHFR polymorphisms; however, the most recent meta-analysis of 66 case-control studies found a reduction in the risk of ALL with the c.677C>T variant, driven mainly by a protective association in Caucasians and Asians (157).

Alzheimer's disease and cognitive impairment

Alzheimer’s disease (AD) is the most common form of dementia, affecting more than 5 million people 65 years or older in the US (158). β-amyloid plaque deposition, Tau protein-forming tangles, and increased cell death in the brain of AD patients have been associated with cognitive decline and memory loss. One study associated increased consumption of fruit and vegetables, which are abundant sources of folate, with a reduced risk of developing dementia and AD in women (159). In the Baltimore Longitudinal Study of Aging that followed 579 nondemented older adults for an average of 9.3 years, daily folate intakes of at least 400 μg at baseline were associated with a 55% lower risk of developing Alzheimer’s disease compared to lower intakes (160). Through its role in nucleic acid synthesis and methyl donor provision for methylation reactions, folate is critical for normal brain development and function, not only throughout pregnancy and postnatally but also later in life (161). In one cross-sectional study of elderly women, AD patients had significantly higher homocysteine and lower red blood cell folate concentrations compared to healthy individuals. However, there was no difference in the level of serum folate between groups, suggesting that long-term folate status, rather than recent folate intake, may be associated with the risk of AD (162).

Several investigators have described associations between increased homocysteine concentrations and cognitive impairment in the elderly (163), but prospective cohort studies examining dietary or total daily folate intake and cognition have reported mixed results (164-169). Higher homocysteine concentrations were found in individuals suffering from dementia, including AD and vascular dementia, compared to healthy subjects (170, 171).

Over the past few decades, hyperhomocysteinemia in older adults has become recognized as a modifiable risk factor for cognitive decline, dementia, and Alzheimer’s disease (172-174). A Cochrane review of 14 placebo-controlled trials found that B-vitamin supplementation (folic acid, vitamin B6, vitamin B12) in older adults who were primarily "cognitively healthy" (but many had cardiovascular disease or other conditions) had no significant benefits on global cognitive function (175). Moreover, a recent meta-analysis of 14 randomized, placebo-controlled trials in older adults found that any benefits of B-vitamin supplementation were limited to slowing cognitive decline (176). Stratification of the data revealed that cognitive benefits were seen only in those without dementia at baseline and in trials of more than one year in duration (176). However, not every trial included in these meta-analyses supplemented with folic acid.

Some trials have examined the effects of B-vitamin supplementation in older adults experiencing cognitive impairment, with a few finding cognitive benefit. A two-year randomized, placebo-controlled trial in 168 elderly subjects with mild cognitive impairment described the benefits of a daily regimen of 800 μg of folic acid, 500 μg of vitamin B12, and 20 mg of vitamin B6 (177, 178). Atrophy of specific brain regions affected by AD was observed in individuals of both groups, and this atrophy correlated with cognitive decline; however, the B-vitamin treatment group experienced a smaller loss of gray matter compared to the placebo group (0.5% vs. 3.7%). A greater benefit was seen in subjects with higher baseline homocysteine concentrations, suggesting the importance of lowering circulating homocysteine in prevention of cognitive decline and dementia. Three randomized controlled trials conducted in Chinese adults ages 65 years or older found that supplementation with 400 μg/day of folic acid for 6 to 24 months improved some measures of cognitive function compared to a no-treatment control/conventional treatment (179-181), suggesting that supplemental folic acid in populations without mandated folic acid fortification may confer cognitive benefit. Large double-blind, placebo-controlled trials are needed to understand whether folic acid supplementation late in life might help decrease age-related cognitive impairments or the risk of Alzheimer’s disease and other dementias. Yet, it is prudent to ensure adequate intakes of folate and other B vitamins throughout life for brain — and overall — health.  

Disease Treatment

Metabolic diseases

Folinic acid (see Figure 1; also known as leucovorin), a tetrahydrofolic acid derivative, is used in the clinical management of rare inborn errors that affect folate transport or metabolism (reviewed in 182). Such conditions are of autosomal recessive inheritance, meaning only individuals receiving two copies of the mutated gene (one from each parent) develop the disease. Folinic acid can be administered orally, intravenously, or intramuscularly.

Hereditary folate malabsorption

Hereditary folate malabsorption is caused by mutations in the SLC46A1 gene coding for the folate transporter PCFT and typically affects gastrointestinal folate absorption and folate transport into the brain (183). Patients present with low to undetectable concentrations of folate in serum and cerebrospinal fluid; anemia (often macrocytic), thrombocytopenia, and/or pancytopenia (low number of all blood cells); impaired immune responses that increase susceptibility to infections; and a general failure to thrive (184, 185). Neurologic symptoms, including developmental delays, cognitive disorders, and seizures, have also been observed (185, 186). Clinical improvements have been recorded following provision of folinic acid parenterally (187, 188) as well as intramuscularly (188, 189).

Cerebral Folate Deficiency (CFD) syndrome

CFD is characterized by low levels of folate coenzymes in cerebrospinal fluid despite often normal concentrations of folate in blood. Folate transport across the blood-brain barrier is compromised in CFD and has been linked either to the presence of autoantibodies blocking the folate receptor-alpha (FRα) or to mutations in the FOLR1 gene encoding FRα (190-193). Neurological abnormalities, along with visual and hearing impairments, have been described in children with CFD; autism spectrum disorder (ASD) is present in some cases. CFD has also been described in adults presenting with neurological symptoms (194).

Folinic acid can enter the brain and normalize the level of folate coenzymes and has been shown to normalize folate concentrations and improve various social interactions in CFD, including mood, behavior, and verbal communication in children with ASD (190, 195, 196).

Dihydrofolate reductase (DHFR) deficiency

DHFR is the NADPH-dependent enzyme that catalyzes the reduction of dihydrofolic acid to tetrahydrofolic acid. DHFR is also required to convert folic acid to DHF. DHFR deficiency is characterized by megaloblastic anemia and cerebral folate deficiency causing intractable seizures and mental deficits. Although folinic acid treatment can alleviate the symptoms of DHFR deficiency, early diagnosis is essential to prevent irreversible brain damage and improve clinical outcomes (197, 198).


Food sources

Green leafy vegetables (foliage) are rich sources of folate and provide the basis for its name. Citrus fruit juices, legumes, and fortified foods are also excellent sources of folate (1); the folate content of fortified cereal varies greatly. A number of folate-rich foods are listed in Table 2, along with their folate content in micrograms (μg). For more information on the nutrient content of specific foods, search USDA's FoodData Central.

Table 2. Some Food Sources of Folate and Folic Acid
Food Serving Folate (μg DFEs)
Lentils (cooked, boiled) ½ cup 179
Garbanzo beans (chickpeas, boiled) ½ cup 141
Asparagus (boiled) ½ cup (~6 spears) 134
Spinach (boiled) ½ cup 132
Lima beans (boiled) ½ cup 78
Orange juice 6 fl. oz. 56
Bread (enriched) 1 slice 50*
Spaghetti (enriched, cooked) 1 cup 180*
White rice (enriched, cooked) 1 cup 153-180*
*To help prevent neural tube defects, the US FDA required the addition of 1.4 milligrams (mg) of folic acid per kilogram (kg) of grain to be added to refined grain products, which were already enriched with niacin, thiamin, riboflavin, and iron, as of January 1, 1998. The addition of nutrients to food in order to prevent a nutritional deficiency or restore nutrients lost in processing is known as fortification. The FDA initially estimated that this level of fortification would increase dietary intake by an average of 100 μg folic acid/day (28). However, further evaluations based on observational studies suggested increases twice that predicted by the FDA (33). On April 14, 2016, the FDA approved the voluntary fortification of corn masa flour up to 1.5 mg of folic acid per kg corn flour (199).


The principal form of supplemental folate is folic acid. It is available as a single-ingredient supplement and also included in combination products, such as B-complex vitamins and multivitamins. Doses of 1 mg or greater require a prescription (200). 5-Methyltetrahydrofolate is also available as a supplement (201).

Additionally, folinic acid, a tetrahydrofolic acid derivative, is used to manage certain metabolic diseases (see Disease Treatment). Further, the US FDA has approved the supplementation of folate in oral contraceptives. The addition of levomefolate calcium (the calcium salt of MeTHF; 451 μg/tablet) to oral contraceptives is intended to raise folate status in women of childbearing age (202). According to a US national survey, only 24% of non-pregnant women aged 15-44 years are meeting the current recommendation of 400 μg/day of folic acid (203).



No adverse effects have been associated with the consumption of excess folate from food. Concerns regarding safety are limited to synthetic folic acid intake. Deficiency of vitamin B12, though often undiagnosed, may affect a significant number of people, especially older adults (see the separate article on Vitamin B12). One symptom of vitamin B12 deficiency is megaloblastic anemia, which is indistinguishable from that associated with folate deficiency (see Deficiency). There is concern that large doses of folic acid given to an individual with an undiagnosed vitamin B12 deficiency could correct megaloblastic anemia without correcting the underlying vitamin B12 deficiency, leaving the individual at risk of developing irreversible neurologic damage. Such cases of neurologic progression in vitamin B12 deficiency have been mostly seen in case studies at folic acid doses of 5,000 μg (5 mg) and above. In order to be very sure of preventing irreversible neurologic damage in vitamin B12-deficient individuals, the Food and Nutrition Board of the US National Academy of Medicine advises that all adults limit their intake of folic acid (supplements and fortification) to 1,000 μg (1 mg) daily (Table 3). The Board also noted that vitamin B12 deficiency is very rare in women in their childbearing years, making the consumption of folic acid at or above 1,000 μg/day unlikely to cause problems (1); however, there are limited data on the effects of large doses (78).

Table 3. Tolerable Upper Intake Level (UL) for Folic Acid
Age Group UL (μg/day)
Infants 0-12 months Not possible to establish*
Children 1-3 years 300
Children 4-8 years 400
Children 9-13 years 600
Adolescents 14-18 years 800
Adults 19 years and older 1,000
*Source of intake should be from food and formula only.

The saturation of DHFR metabolic capacity by oral doses of folic acid has been associated with the appearance of unmetabolized folic acid in blood (204). Exposure to folic acid in the food supply is also associated with unmetabolized folic acid in the blood. A US national cross-sectional survey, NHANES 2007-2008, detected unmetabolized folic acid in 96% of serum samples of Americans (≥1 year of age) (205). In an ancillary study of the Folic Acid Clinical Trial, maternal supplementation with 4.0-5.1 mg/day of folic acid during pregnancy (starting at 8 to 16 weeks’ gestation) led to higher maternal blood concentrations of unmetabolized folic acid and 5-methylTHF at 24 to 26 weeks’ gestation compared to dosages of 1.1 mg/day or less (206). However, no differences were seen in other markers of one-carbon metabolism, including serum concentrations of THF, 5-formylTHF, 5,10-methenylTHF, vitamin B12, and pyridoxal 5’-phosphate (206). A randomized controlled trial in 126 pregnant women found that continuing folic acid supplementation of 400 μg/day beyond the first trimester of pregnancy (i.e., gestational weeks 14 throughout the second and third trimesters) did not increase blood concentrations of unmetabolized folic acid at 36 weeks’ gestation compared to placebo despite increases in plasma total folate, plasma 5-MTHF, and red blood cell folate (207). Maternal folic acid supplementation throughout pregnancy also did not increase unmetabolized folic acid detected in neonatal cord blood samples compared to placebo (207).

Evidence of adverse health effects of unmetabolized folic acid is quite limited. Hematologic abnormalities and poorer cognition have been associated with the presence of unmetabolized folic acid in vitamin B12-deficient older adults (≥60 years) (208, 209). A small study conducted in postmenopausal women also raised concerns about the effect of exposure to unmetabolized folic acid on immune function (210). Recent observational studies have found no link between circulating maternal unmetabolized folate during pregnancy and allergic disease in infancy (211) or autistic traits or language impairment in early childhood (212). In a small, randomized, open-label trial in 38 women of reproductive age receiving 30 weeks of daily multivitamin supplements, daily supplementation with either 1.1 mg or 5 mg of folic acid resulted in the transient appearance of unmetabolized folic acid in blood over the first 12 weeks of supplementation (213). However, unmetabolized folic acid concentrations returned to baseline levels at the end of the study, suggesting that adaptive mechanisms eventually converted folic acid to reduced forms of folate. Nonetheless, the use of supplemental 5-methyltetrahydrofolate may provide an alternative to prevent any potential negative effects of unconverted folic acid in older adults.

Drug interactions

When nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin or ibuprofen, are taken in very large therapeutic dosages (i.e., to treat severe arthritis), they may interfere with folate metabolism. In contrast, routine use of NSAIDs has not been found to adversely affect folate status. The anticonvulsant, phenytoin, has been shown to inhibit the intestinal absorption of folate, and several studies have associated decreased folate status with long-term use of the anticonvulsants, phenytoin, phenobarbital, and primidone (214). However, few studies controlled for differences in dietary folate intake between anticonvulsant users and nonusers. Also, taking folic acid at the same time as the cholesterol-lowering agents, cholestyramine and colestipol, may decrease the absorption of folic acid (200). Methotrexate is a folic acid antagonist used to treat a number of diseases, including cancer, rheumatoid arthritis, and psoriasis. Some of the side effects of methotrexate are similar to those of severe folate deficiency, and supplementation with folic or folinic acid is used to reduce antifolate toxicity. Other antifolate molecules currently used in cancer therapy include aminopterin, pemetrexed, pralatrexate, and raltitrexed (11, 115). Further, a number of other medications have been shown to have antifolate activity, including trimethoprim (an antibiotic), pyrimethamine (an antimalarial), triamterene (a blood pressure medication), and sulfasalazine (a treatment for ulcerative colitis). Early studies of oral contraceptives (birth control pills) containing high doses of estrogen indicated adverse effects on folate status; however, this finding has not been supported in more recent studies that used low-dose oral contraceptives and controlled for dietary folate (215).

Linus Pauling Institute Recommendation

The available scientific evidence shows that adequate folate intake prevents neural tube defects and other poor outcomes of pregnancy; is helpful in lowering the risk of some forms of cancer, especially in genetically susceptible individuals; and may lower the risk of stroke. The Linus Pauling Institute recommends that adults take a daily multivitamin/mineral supplement, which typically contains 400 μg of folic acid, the Daily Value (DV). Even with a larger than average intake of folic acid from fortified food, it is unlikely that an individual's daily folic acid intake would regularly exceed the tolerable upper intake level of 1,000 μg/day established by the Institute of Medicine (see Safety).

Older adults (>50 years)

The recommendation for 400 μg/day of supplemental folic acid as part of a daily multivitamin/mineral supplement, in addition to a folate-rich diet, is especially important for older adults because blood homocysteine concentrations tend to increase with age (see Disease Prevention).

Authors and Reviewers

Originally written in 2000 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in April 2002 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in September 2007 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in June 2014 by:
Barbara Delage, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in October 2023 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in December 2023 by:
Martha S. Field, Ph.D.
Division of Nutritional Sciences
Cornell University

Copyright 2000-2024  Linus Pauling Institute


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  • Dietary precursors of nicotinamide adenine dinucleotide (NAD), including nicotinic acid, nicotinamide, and nicotinamide riboside, are collectively referred to as niacin or vitamin B3. The essential amino acid tryptophan can also be converted into NAD via the kynurenine pathway. (More information)
  • NAD can be phosphorylated (NADP) and reduced (NADH and NADPH). NAD functions in oxidation-reduction (redox) reactions and non-redox reactions. (More information)
  • Pellagra is the disease of severe niacin deficiency. It is characterized by symptoms affecting the skin, the digestive system, and the nervous system; pellagra can lead to death if left untreated. (More information)
  • Causes of niacin deficiency include inadequate oral intake, poor bioavailability from unlimed grains, defective tryptophan absorption, metabolic disorders, and the long-term use of chemotherapeutic treatments. (More information)
  • Dietary intake requirements for niacin are based on the urinary excretion of niacin metabolites. (More information)
  • NAD is the sole substrate for PARP enzymes and sirtuins involved in DNA repair activities; thus, NAD is critical for genome stability. Several studies, mostly using in vitro and animal models, suggest a possible role for niacin in cancer prevention. In a recent phase III trial, a daily pharmacologic dose of nicotinamide was found to reduce the rate of premalignant skin lesions and nonmelanoma cancers in high-risk subjects. (More information)
  • Despite promising initial results, nicotinamide administration has failed to prevent or delay the onset of type 1 diabetes mellitus in high-risk relatives of type 1 diabetic patients. Future research might explore the use of nicotinamide in combined therapy and evaluate activators of NAD-dependent enzymes. (More information)
  • At pharmacologic doses, nicotinic acid improved lipid profiles of patients with a history of vascular disease yet failed to reduce recurrent cardiovascular events or mortality. (More information)
  • Elevated tryptophan breakdown in the kynurenine pathway and niacin deficiency have been reported in HIV-positive people. However, at present, a better understanding of the role of kynurenine pathway and other NAD biosynthetic pathways during HIV infection is needed to establish whether this population could benefit from niacin supplementation. (More information)
  • Most adverse effects of niacin (nicotinic acid and nicotinamide) have been reported with pharmacological doses of nicotinic acid. The tolerable upper intake level (UL) for niacin is based on preventing skin flushing, nicotinic acid’s most prominent side effect. The co-administration of laropiprant — a prostaglandin D2 receptor-1 antagonist — helps reduce nicotinic acid-induced skin flushing. (More information)

Niacin or vitamin B3 is a water-soluble vitamin used by the body to form the nicotinamide coenzyme, NAD+. The term ‘niacin’ is often used to refer to nicotinic acid (pyridine-3-carboxylic acid) only, although other vitamers with a pyridine ring, including nicotinamide (pyridine-3-carboxamide) and nicotinamide riboside, also contribute to NAD+ formation (1). None of the vitamers are related to the nicotine found in tobacco, although their names are similar. Likewise, nicotine — but not nicotinic acid — is an agonist of the nicotinic receptors that respond to the neurotransmitter, acetylcholine.


Essential to all forms of life, the nicotinamide coenzyme NAD+ is synthesized in the body from four precursors that are provided in the diet: nicotinic acid, nicotinamide, nicotinamide riboside, and tryptophan (Figure 1).

Figure 1. Precursors of Nicotinamide Adenine Dinucleotide (NAD+) in the Diet. Chemical structures of nicotinic acid (pyridine-3-carboxylic acid; often referred to as 'niacin'); nicotinamide (pyridine-3-carboxamide, niacinamide); tryptophan; and nicotinamide riboside.

[Figure 1 - Click to Enlarge]

Figure 2 illustrates the separate biosynthetic pathways that lead to NAD+ production from the various dietary precursors. NAD+ is synthesized from nicotinamide and nicotinamide riboside via two enzymatic reactions, while the pathway that yields NAD+ from nicotinic acid - known as the Preiss-Handler pathway — includes three steps. The kynurenine pathway is the longest NAD+ biosynthetic pathway: the catabolism of tryptophan through kynurenine produces quinolinic acid, which is then converted to nicotinic acid mononucleotide, an intermediate in NAD+ metabolism. NAD+ is then synthesized from nicotinic acid mononucleotide in the Preiss-Handler pathway (2).

All pathways generate intermediary mononucleotides — either nicotinic acid mononucleotide or nicotinamide mononucleotide. Specific enzymes, known as phosphoribosyltransferases, catalyze the addition of a phosphoribose moiety onto nicotinic acid or quinolinic acid to produce nicotinic acid mononucleotide or onto nicotinamide to generate nicotinamide mononucleotide. Nicotinamide mononucleotide is also generated by the phosphorylation of nicotinamide riboside, catalyzed by nicotinamide riboside kinases (NRKs). Further, adenylyltransferases catalyze the adenylation of these mononucleotides to form either nicotinic acid adenine dinucleotide or NAD+. Nicotinic acid adenine dinucleotide is then converted to NAD+ by glutamine-dependent NAD+ synthetase (NADSYN), which uses glutamine as an amide group donor (Figure 2) (2). Of note, nicotinic acid adenine dinucleotide has been reported to form following the administration of high-dose nicotinamide riboside, suggesting that a potential deamidation could occur to convert NAD+ to nicotinic acid adenine dinucleotide when the pool of NAD+ is high (1).

Figure 2. Synthesis of Nicotinamide Adenine Dinucleotide (NAD+). Tryptophan can be converted to quinolinic acid in the kynurenine pathway; QPRT catalyzes the conversion of quinolinic acid to nicotinic acid mononucleotide. Nicotinic acid mononucleotide is also the product of the reaction of phosphoribosylation of nicotinic acid catalyzed by NAPRT. Nicotinic acid mononucleotide is then converted to nicotinic acid adenine dinucleotide in a reaction catalzyed by NMNATs; NADSYN catalyzes the amidation of nicotinic acid adenine dinucleotide into NAD+. Both nicotinamide and nicotinamide riboside are precursors of nicotinamide mononucleotide. The adenylation of nicotinamide mononucleotide catalyzed by NMNATs produces NAD+. NADSYN, Nicotinamide adenine dinucleotide synthase; NAPRT, Nicotinic acid phosphoribosyltransferase; NMNATs, Nicotinamide mononucelotide adenylyltransferase; QPRT, Quinolinate phosphoribosyltransferase.

[Figure 2 - Click to Enlarge]

NAD kinase catalyzes the phosphorylation of NAD into NADP using adenosyl triphosphate (ATP) as the phosphoryl donor (3). The oxidation-reduction (redox) properties of the dinucleotide are not affected by the phosphorylation such that the redox pairs NAD+/NADH and NADP+/NADPH show similar redox potentials (4). Oxidation and reduction of the C-4 position of the nicotinamide moiety of NADand its phosphorylated form are essential for electron-transfer reactions supporting vital metabolic and bioenergetic functions in all cells (see Function). Thus, NAD and NADP are recycled back and forth between oxidized (NAD+ and NADP+) and reduced forms (NADH and NADPH), as shown in Figure 3.

Figure 3. NAD(P) Oxido-reduction Balance. The phosphorylation of NAD(H) to NADP(H) is catalyzed by a highly conserved enzyme, NAD kinase. Oxidoreductases catalyze the transfer of electrons and hydrogens between molecules using NAD(P)+ and NAD(P)H as electron acceptors and donors, respectively. Thus, in electron-transfer reactions, dinucleotides are recycled back and forth between their oxidized (NAD+ and NADP+) and reduced (NADH and NADPH) forms.

[Figure 3 - Click to Enlarge]


NAD as a coenzyme in electron-transfer reactions

Living organisms derive most of their energy from redox reactions, which are processes involving the transfer of electrons. Over 400 enzymes require the niacin coenzymes, NAD and NADP, mainly to accept or donate electrons for redox reactions (5). NAD and NADP appear to support distinct functions (Figure 4). NAD functions most often in energy-producing reactions involving the degradation (catabolism) of carbohydrates, fats, proteins, and alcohol. NADP generally serves in biosynthetic (anabolic) reactions, such as in the synthesis of fatty acids, steroids (e.g., cholesterol, bile acids, and steroid hormones), and building blocks of other macromolecules (4). NADP is also essential for the regeneration of components of detoxification and antioxidant systems (4). To support these functions, the cell maintains NAD in a largely oxidized state (NAD+) to serve as oxidizing agent for catabolic reactions, while NADP is kept largely in a reduced state (NADPH) to readily donate electrons for reductive cellular processes (4, 6).

Figure 4. Simplified Overview of NAD/NADP Function in Catabolic and Anabolic Pathways. In catabolic pathways, the oxidation of macronutrients (proteins, fats, carbohydrates) is coupled with the reduction of NAD+; NAD+ accepts electrons and becomes reduced (NADH). In anabolic pathways, the oxidationof NADPH provides electrons needed for the biosynthesis of macromolecules (e.g., proteins, lipids, polysaccharides, nucleic acids); NADPH donates electrons and becomes oxidized (NADP+).

[Figure 4 - Click to Enlarge]

NAD as a substrate for NAD-consuming enzymes

The niacin coenzyme, NAD, is the substrate (reactant) for at least four classes of enzymes. Two classes of enzymes with mono adenosine diphosphate (ADP)-ribosyltransferase and/or poly (ADP-ribose) polymerase activities catalyze ADP-ribosyl transfer reactions. Silent information regulator-2 (Sir2)-like proteins (sirtuins) catalyze the removal of acetyl groups from acetylated proteins, utilizing ADP-ribose from NAD as an acceptor for acetyl groups. Finally, ADP-ribosylcyclases are involved in the regulation of intracellular calcium signaling.


Enzymes with ADP-ribosyltransferase activities were formerly divided between mono ADP-ribosyltransferases (ARTs) and poly (ADP-ribose) polymerases (PARPs). ARTs were first discovered in certain pathogenic bacteria — like those causing cholera or diphtheria — where they mediate the actions of toxins. These enzymes transfer an ADP-ribose residue moiety from NAD to a specific amino acid of a target protein, with the creation of an ADP-ribosylated protein and the release of nicotinamide.

Because most PARPs have been found to exhibit only mono ADP-ribosyltransferase activities, a new nomenclature was proposed for enzymes catalyzing ADP-ribosylation: A family of mono ADP-ribosyltransferases with homology to bacterial diphteria toxins was named ARTD, while enzymes with either mono or poly ADP-ribosyltransferase activities and related to C2 and C3 clostridial toxins were included in the ARTC family (7, 8).

  • ARTCs are extracellular enzymes that catalyze the mono ADP-ribosylation of membrane or secreted proteins involved in innate immunity and cell communication (2).
  • ARTDs are intracellular enzymes with either mono or poly ADP-ribosyltransferase activities. At least 18 ARTDs have been identified. All ARTDs possess a diphtheria toxin-like catalytic domain that binds NAD+. Only ARTDs 1, 2, 5, and 6 catalyze poly (ADP-ribose) transfers; the others have mono ADP-ribosyltransferase activities. ARTDs were shown to be involved in DNA repair and stress responses, cell signaling, transcription regulation, apoptosis, cell differentiation, maintenance of genomic integrity, and antiviral defense (reviewed in 8).
NAD-dependent deacetylation

Seven sirtuins (SIRT 1-7) have been identified in humans. Sirtuins are a class of NAD-dependent deacetylase enzymes that remove acetyl groups from the acetylated lysine residues of target proteins. During the deacetylation process, the acetyl group is transferred onto the ADP-ribose moiety cleaved off NAD, producing O-acetyl-ADP-ribose. Nicotinamide can exert feedback inhibition to the deacetylation reaction (9). Like ADP-ribosylation, acetylation is a post-translational modification that affects the function of target proteins. The initial interest in sirtuins followed the discovery that their activation could mimic caloric restriction, which has been shown to increase lifespan in lower organisms. Such a role in mammals is controversial, although sirtuins are energy-sensing regulators involved in signaling pathways that could play important roles in delaying the onset of age-related diseases (e.g., cardiovascular disease, cancer, dementia, arthritis). To date, the spectrum of their biological functions includes gene silencing, DNA damage repair, cell cycle regulation, and cell differentiation (10).

Calcium mobilization

In humans, CD38 and CD157 belong to a family of NAD+ glycohydrolases/ADP-ribosylcyclases. These enzymes catalyze the formation of key regulators of calcium signaling, namely (linear) ADP-ribose, cyclic ADP-ribose, and nicotinic acid adenine dinucleotide phosphate (Figure 5). Cyclic ADP-ribose and nicotinic acid adenine dinucleotide phosphate works within cells to provoke the release of calcium ions from internal storage sites (i.e., endoplasmic reticulum, lysosomes, mitochondria), whereas ADP-ribose stimulates extracellular calcium entry through cell membrane TRPM2 cation channels (2). Another TRPM2 agonist, 2’-deoxy-ADP-ribose, was recently identified in vitro. CD38 was found to catalyze the synthesis of 2’-deoxy-ADP-ribose from nicotinamide mononucleotide and 2’-deoxy-ATP (11). O-acetyl-ADP-ribose generated by the activity of sirtuins also controls calcium entry through TRPM2 channels (6). Intracellular calcium-mediated signal transduction is regulated by transient calcium entry into the cell or release of calcium from intracellular stores. Calcium signaling is critically involved in processes like neurotransmission, insulin release from pancreatic β-cells, muscle cell contraction, and T-lymphocyte activation (6).

Figure 5. Calcium-mobilizing Derivatives of Niacin. Chemical structures of ADP-ribose, cyclic ADP-ribose, 2'-deoxy-ADP-ribose, O-acetyl-ADP-ribose, and nicotinic acid adenine dinucleotide phosphate.

[Figure 5 - Click to Enlarge]

NAD as a ligand

NAD+ has been identified as an endogenous agonist of purinergic membrane receptors of the P2Y subclass. In particular, NAD was found to bind to P2Y1 receptor and act as an inhibitory neurotransmitter at neuromuscular junctions in visceral smooth muscles (12). Extracellular NAD+ was also found to behave like a proinflammatory cytokine, triggering the activation of isolated granulocytes. NAD+ binding to the P2Y11 receptor at the granulocyte surface activated a signaling cascade involving cyclic ADP-ribose and the rise of intracellular calcium, eventually stimulating superoxide generation and chemotaxis (13). Similar observations were made with lipopolysaccharide-activated monocytes (14). Extracellular NAADP+ and ADP-ribose might also bind to P2Y receptors and trigger intracellular NAADP+- and ADP-ribose-dependent calcium mobilization (see Calcium mobilization) (15, 16).

Lipid-lowering effects with pharmacologic doses of nicotinic acid

For over half a century, pharmacologic doses of nicotinic acid, but not nicotinamide, have been known to reduce serum cholesterol (see Disease Treatment) (17). However, the exact mechanisms underlying the lipid-lowering effect of nicotinic acid remain speculative. Two G-protein-coupled membrane receptors, GPR109A and GPR109B, bind nicotinic acid with high and low affinity, respectively. These nicotinic acid receptors are primarily expressed in adipose tissue and immune cells (but not lymphocytes). They are also found in retinal pigmented and colonic epithelial cells, keratinocytes, breast cells, microglia, and possibly at low levels in the liver (18). Thus, lipid-modifying effects of nicotinic acid are likely to be mediated by receptor-independent mechanisms in major tissues of lipid metabolism like liver and skeletal muscle. Early in vitro data suggested that nicotinic acid could impair very-low-density lipoprotein (VLDL) secretion by inhibiting triglyceride synthesis and triggering ApoB lipoprotein degradation in hepatocytes (19). In another study, nicotinic acid affected the hepatic uptake of ApoAI lipoprotein, thereby reducing high-density lipoprotein (HDL) removal from the circulation (reviewed in 20). In adipocytes, the binding of nicotinic acid to GPR109A was found to initiate a signal transduction cascade resulting in reductions in free fatty acid production via the inhibition of hormone-sensitive lipase involved in triglyceride lipolysis (21). Nonetheless, recent observations have suggested that the lipid-lowering effect of nicotinic acid was not due to its anti-lipolytic activity (22). Trials showed that synthetic agonists of GPR109A acutely lowered free fatty acids yet failed to affect serum lipids (22). Aside from its impact on HDL and other plasma lipids, nicotinic acid has exhibited anti-atherosclerotic activities in cultured monocytes, macrophages, or vascular endothelial cells, by modulating inflammation and oxidative stress and regulating cell adhesion, migration, and differentiation (reviewed in 18).




The late stage of severe niacin deficiency is known as pellagra. Early records of pellagra followed the widespread cultivation of corn in Europe in the 1700s (23). The disease is generally associated with poorer social classes whose chief dietary staple consisted of cereal like corn or sorghum. Pellagra was also common in the southern United States during the early 1900s where income was low and corn products were a major dietary staple (24). Interestingly, pellagra was not known in Mexico, where corn was also an important dietary staple and much of the population was also poor. In fact, if corn contains appreciable amounts of niacin, it is present in a bound form that is not nutritionally available to humans. The traditional preparation of corn tortillas in Mexico involves soaking the corn in a lime (calcium oxide) solution, prior to cooking. Heating the corn in an alkaline solution results in the release of bound niacin, increasing its bioavailability (25). Pellagra epidemics were also unknown to Native Americans who consumed immature corn that contains predominantly unbound (bioavailable) niacin (24).

Niacin deficiency or pellagra may result from inadequate dietary intake of NAD precursors, including tryptophan. Niacin deficiency — often associated with malnutrition — is observed in the homeless population, in individuals suffering from anorexia nervosa or obesity, and in consumers of diets high in maize and poor in animal protein (26-29). Deficiencies of other B vitamins and some trace minerals may aggravate niacin deficiency (30, 31). Malabsorptive disorders that can lead to pellagra include Crohn’s disease and megaduodenum (32, 33). Patients with Hartnup’s disease, a hereditary disorder resulting in defective tryptophan absorption, have developed pellagra (see Niacin-responsive genetic disorders). Carcinoid syndrome, a condition of increased secretion of serotonin and other catecholamines by carcinoid tumors, may also result in pellagra due to increased utilization of dietary tryptophan for serotonin rather than niacin synthesis. Further, prolonged treatment with the anti-tuberculosis drug isoniazid has resulted in niacin deficiency (34). Other pharmaceutical agents, including the immunosuppressive drugs azathioprine (Imuran) and 6-mercaptopurine, the anti-cancer drug 5-fluorouracil (5-FU, Adrucil), and levodopa/carbidopa (Sinemet; two drugs given to people with Parkinson’s disease), are known to increase the reliance on dietary niacin by interfering with the tryptophan-kynurenine-niacin pathway (35). Finally, other populations at risk for niacin deficiency include dialysis patients, cancer patients (36, 37), individuals suffering from chronic alcoholism (38), and people with HIV (see HIV/AIDS below). Further, chronic alcohol intake can lead to severe niacin deficiency through reducing dietary niacin intake and interfering with the tryptophan-to-NAD conversion (30).

Symptoms of deficiency

The most common symptoms of niacin deficiency involve the skin, the digestive system, and the nervous system. The symptoms of pellagra are commonly referred to as the three "Ds": sun-sensitive dermatitis, diarrhea, and dementia. A fourth "D," death, occurs if pellagra is left untreated (5). In the skin, a thick, scaly, darkly pigmented rash develops symmetrically in areas exposed to sunlight. In fact, the word "pellagra" comes from "pelle agra," the Italian phrase for rough skin. Symptoms related to the digestive system include inflammation of the mouth and tongue ("bright red tongue"), vomiting, constipation, abdominal pain, and ultimately, diarrhea. Gastrointestinal disorders and diarrhea contribute to the ongoing malnourishment of the patients. Neurologic symptoms include headache, apathy, fatigue, depression, disorientation, and memory loss and are more consistent with delirium than with the historically described dementia (38). Disease presentations vary in appearance since the classic triad rarely presents in its entirety. The absence of dermatitis, for example, is known as pellagra sine pellagra.


To treat pellagra, the World Health Organization (WHO) recommends administering nicotinamide to avoid the flushing commonly caused by nicotinic acid (see Safety). Treatment guidelines suggest using 300 mg/day of oral nicotinamide in divided doses, or 100 mg/day administered parenterally in divided doses, for three to four weeks (37, 39). Because patients with pellagra often display additional vitamin deficiencies, administration of a vitamin B-complex preparation is advised (39).

The Recommended Dietary Allowance (RDA)

Niacin equivalent (NE)

The term "niacin equivalent" (NE) is used to describe the contribution to dietary intake of all the forms of niacin that are available to the body. In healthy individuals, less than 2% of dietary tryptophan is converted to NAD in the kynurenine pathway (40). The synthesis of NAD from tryptophan is fairly inefficient and depends on enzymes requiring vitamin B6 and riboflavin, as well as a heme (iron)-containing enzyme. Nonetheless, tryptophan is essential as a precursor for NAD+. Inherited defects in tryptophan transport and metabolism result in severe clinical disorders attributed to NAD+ depletion (see Niacin-responsive genetic disorders). On average, 60 milligrams (mg) of tryptophan are considered to correspond to 1 mg of niacin or 1 mg of NE.

Daily recommended intakes

The recommended dietary allowance (RDA) for niacin is based on the prevention of deficiency. Pellagra can be prevented by about 11 mg NE/day, but 12 mg to 16 mg NE/day has been found to normalize the urinary excretion of niacin metabolites (breakdown products) in healthy young adults. Because pellagra represents severe deficiency, the Food and Nutrition Board (FNB) of the US Institute of Medicine chose to use the excretion of niacin metabolites as an indicator of niacin nutritional status rather than symptoms of pellagra (41). However, it has been argued that cellular NAD and NADP content may be more relevant indicators of niacin nutritional status (24).

Table 1. Recommended Dietary Allowance (RDA) for Niacin
Life Stage Age Males (mg NE*/day) Females (mg NE/day)
Infants 0-6 months 2 (AI 2 (AI) 
Infants  7-12 months  4 (AI)  4 (AI) 
Children  1-3 years 
Children  4-8 years 
Children  9-13 years  12  12 
Adolescents  14-18 years  16  14 
Adults  19 years and older  16  14 
Pregnancy  all ages  18 
Breast-feeding  all ages  17
*NE, niacin equivalent: 1 mg NE = 60 mg of tryptophan = 1 mg niacin

Disease Prevention


Studies of cultured cells (in vitro) provide evidence that NAD content influences mechanisms that maintain genomic stability. Loss of genomic stability, characterized by a high rate of damage to DNA and chromosomes, is a hallmark of cancer (42). The current understanding is that the pool of NAD is decreased during niacin deficiency and that it affects the activity of NAD-consuming enzymes rather than redox and metabolic functions (43). Among NAD-dependent reactions, poly ADP-ribosylations catalyzed by PARP enzymes (ARTDs) are critical for the cellular response to DNA injury. After DNA damage, PARPs are activated; the subsequent poly ADP-ribosylations of a number of signaling and structural molecules by PARPs were shown to facilitate DNA repair at DNA strand breaks (44). Cellular depletion of NAD has been found to decrease levels of the tumor suppressor protein p53, a target for poly ADP-ribosylation, in human breast, skin, and lung cells (45). The expression of p53 was also altered by niacin deficiency in rat bone marrow cells (46). Impairment of DNA repair caused by niacin deficiency could lead to genomic instability and drive tumor development in rat models (47, 48). Both PARPs and sirtuins have been recently involved in the maintenance of heterochromatin, a chromosomal domain associated with genome stability, as well as in transcriptional gene silencing, telomere integrity, and chromosome segregation during cell division (49, 50). Neither the cellular NAD content nor the dietary intake of NAD precursors necessary for optimizing protective responses following DNA damage has been determined, but both are likely to be higher than that required for the prevention of pellagra.

Bone marrow

Cancer patients often suffer from bone marrow suppression following chemotherapy, given that bone marrow is one of the most proliferative tissues in the body and thus a primary target for chemotherapeutic agents. Niacin deficiency was found to decrease bone marrow NAD and poly-ADP-ribose levels and increase the risk of chemically induced leukemia in rats (51). Conversely, a pharmacologic dose of either nicotinic acid or nicotinamide was able to increase NAD and poly ADP-ribose in bone marrow and decrease the development of leukemia in rats (52). It has been suggested that niacin deficiency often observed in cancer patients could sensitize bone marrow tissue to the suppressive effect of chemotherapy. However, little is known regarding cellular NAD levels and the prevention of DNA damage or cancer in humans. One study in two healthy individuals involved elevating NAD levels in blood lymphocytes by supplementation with 100 mg/day of nicotinic acid for eight weeks. Compared to non-supplemented individuals, the supplemented individuals had reduced DNA strand breaks in lymphocytes exposed to free radicals in a test tube assay (53). However, nicotinic acid supplementation of up to 100 mg/day for 14 weeks in 21 healthy smokers failed to provide any evidence of a decrease in cigarette smoke-induced genetic damage in blood lymphocytes compared to placebo (54). More recently, the frequency of chromosome translocation was used to evaluate DNA damage in peripheral blood lymphocytes of 82 pilots chronically exposed to ionizing radiation, a known human carcinogen. In this observational study, the rate of chromosome aberrations was significantly lower in subjects with higher (28.4 mg/day) compared to lower (20.5 mg/day) dietary niacin intake (55). Higher availability of NAD+ in X-irradiated peripheral blood lymphocytes was found to favor DNA repair by enhancing survival, particularly through SIRT-mediated p53 deacetylation (56).

Upper digestive tract

Generally, relationships between dietary factors and cancer are established first in epidemiological studies and followed up by basic cancer research at the cellular level. In the case of niacin, research on biochemical and cellular aspects of DNA repair has stimulated an interest in the relationship between niacin intake and cancer risk in human populations (57). A large case-control study found increased consumption of niacin, along with antioxidant nutrients, to be associated with decreased incidence of oral (mouth), pharyngeal (throat), and esophageal cancers in northern Italy and Switzerland. An increase in daily niacin intake of 6.2 mg was associated with about a 40% decrease in cases of cancers of the mouth and throat, while a 5.2 mg increase in daily niacin intake was associated with a similar decrease in cases of esophageal cancer (58, 59).


Niacin deficiency can lead to severe sunlight sensitivity in exposed skin. Given the implication of NAD-dependent enzymes in DNA repair, there has been some interest in the effect of niacin on skin health. In vitro and animal experiments have helped gather information, but human data on niacin/NAD status and skin cancer are very limited. One study reported that niacin supplementation decreased the risk of ultraviolet light (UV)-induced skin cancers in mice, despite the fact that mice convert tryptophan to NAD more efficiently than rats and humans and thus do not get severely deficient (60). Hyper-proliferation and impaired differentiation of skin cells can alter the integrity of the skin barrier and increase the occurrence of pre-malignant and malignant skin conditions. A protective effect of niacin was suggested by topical application of myristyl nicotinate, a niacin derivative, which successfully increased the expression of epidermal differentiation markers in subjects with photodamaged skin (61). The activation of the nicotinic acid receptors, GPR109A and GPR109B, by pharmacologic doses of niacin could be involved in improving skin barrier function. Conversely, differentiation defects in skin cancer cells were linked to the abnormal cellular localization of defective nicotinic acid receptors (62). Nicotinamide restriction with subsequent depletion of cellular NAD was shown to increase oxidative stress-induced DNA damage in a precancerous skin cell model, implying a protective role of NAD-dependent pathways in cancer (63). Altered NAD availability also affects sirtuin expression and activity in UV-exposed human skin cells. Along with PARPs, NAD-consuming sirtuins could play an important role in the cellular response to photodamage and skin homeostasis (64).

A pooled analysis of two large US prospective cohort studies that followed 41,808 men and 72,308 women for up to 26 years suggested that higher versus lower intake of niacin (from diet and supplements) might be protective against squamous-cell carcinoma but not against basal-cell carcinoma and melanoma (65). A phase III, randomized, double-blind, placebo-controlled trial in 386 subjects with a history of nonmelanoma skin cancer recently examined the effect of daily nicotinamide supplementation (1 g) for 12 months on skin cancer recurrence at three-month intervals over an 18-month period (66). Nicotinamide effectively reduced the rate of premalignant actinic keratose (-11%), squamous-cell carcinoma (-30%), and basal-cell carcinoma (-20%) compared to placebo after 12 months, yet this protection was not sustained during the six-month post-supplementation period (66). Larger trials are needed to assess whether nicotinamide could reduce the risk of melanomas, which are not as common as other skin cancer but are more deadly (67).

Type 1 diabetes mellitus

Type 1 diabetes mellitus in children is caused by the autoimmune destruction of insulin-secreting β-cells in the pancreas. Prior to the onset of symptomatic diabetes, specific antibodies, including islet cell autoantibodies (ICA), can be detected in the blood of high-risk individuals (68). In an experimental animal model of diabetes, high levels of nicotinamide are administered to protect β-cells from damage caused by streptozotocin (69).

Yet, pharmacologic doses of nicotinamide (up to 3 g/day) have not been found to be effective in delaying or preventing the onset of type 1 diabetes in at-risk subjects. An analysis of 10 trials, of which five were placebo-controlled, found evidence of improved β-cell function after one year of treatment with nicotinamide, but the analysis failed to find any clinical evidence of improved glycemic control (70). A large, multicenter randomized controlled trial of nicotinamide in ICA-positive siblings (ages, 3-12 years) of type 1 diabetic patients also failed to find a difference in the incidence of type 1 diabetes after three years (70). A randomized, double-blind, placebo-controlled multicenter trial of nicotinamide (maximum of 3 g/day) was conducted in 552 ICA-positive relatives of patients with type 1 diabetes. The proportion of relatives who developed type 1 diabetes within five years was comparable whether they were treated with nicotinamide or placebo (71). Nicotinamide could reduce inflammation-related parameters in these high-risk subjects yet was ineffective to prevent disease onset (72). More recently, case reports of the combined use of nicotinamide (25 mg/kg/day) and acetyl-L-carnitine (50 mg/kg/day) in children at risk for type 1 diabetes showed promising results, warranting further investigation (73).

Disease Treatment

Niacin supplements at pharmacologic doses (i.e., doses much larger than those needed to prevent deficiency) have been used in an attempt to treat a range of conditions, some of which are discussed below.

Niacin-responsive genetic disorders

Congenital NAD deficiency-related disorders can result from mutations in genes involved in the uptake and transport of the various dietary NAD+ precursors or in the distinct metabolic pathways leading to NAD+ production (see Metabolism). Some of these disorders might respond to niacin supplementation. For example, defective transport of tryptophan into cells results in Hartnup disease, which features signs of severe niacin deficiency (74). Hartnup disease is due to mutations in the SLCA19 gene, which codes for a sodium-dependent neutral amino acid transporter expressed primarily in the kidneys and intestine. Disease management involves supplementation with nicotinic acid or nicotinamide (75). Recessive mutations in genes coding for enzymes of the kynurenine pathway — namely kynureninase and 3-hydroxyanthranilic-acid 3,4-dioxygenase — lead to combined vertebral, anal, cardiac, tracheo-esophageal, renal, and limb (VACTERL) congenital malformations (76). Depletion of NAD+, rather than accumulation of intermediate metabolites in the kynurenine pathway, was found to be responsible for these malformations. Niacin supplementation throughout pregnancy ensured adequate levels of NAD+ and prevented congenital anomalies in mice with kynurenine pathway mutations (76). In humans, the dose of NAD+ precursors necessary to avert NAD deficiency-induced congenital VACTERL malformations has yet to be defined (77).

Nicotinamide may also rescue NAD+ depletion secondary to an ultra-rare inborn error of glutamine metabolism (78). Glutamine is required for the conversion of nicotinic acid adenine dinucleotide to NAD+ catalyzed by NAD+ synthetase (Figure 2). Thus, inherited glutamine synthetase deficiency specifically affects the synthesis of NAD+ from the NAD+ precursors, tryptophan and nicotinic acid. If the combined deficiencies of glutamine and NAD+ are responsible for the severe clinical phenotype of subjects with inherited glutamine synthetase deficiency, it is likely that supplementation with both glutamine and nicotinamide would provide some relief (78).

Finally, many inborn errors of metabolism result from genetic mutations decreasing cofactor binding affinity and, subsequently, enzyme efficiency (79). In many cases, the administration of high doses of the vitamins serving as precursors of cofactors can restore enzymatic activity — at least partially — and lessen signs of the genetic diseases (79). Given the large number of enzymes requiring NAD, it is speculated that many of the conditions due to defective enzymes might be rescued by niacin supplementation (5).

Cardiovascular disease

Cardiovascular risk factors

Nicotinic acid is a well-known lipid-lowering agent: Nicotinic acid therapy markedly increases high-density lipoprotein (HDL) cholesterol concentrations, decreases serum lipoprotein(a) concentrations, and shifts small, dense low-density lipoprotein (LDL) particles to large, buoyant LDL particles. All of these changes in the blood lipid profile are considered cardioprotective. Low concentrations of HDL-cholesterol are one major risk factor for coronary heart disease (CHD), and an increase in HDL concentrations is associated with a reduction of that risk (80). Because of the adverse side effects associated with high doses of nicotinic acid (see Safety), nicotinic acid has most often been used in combination with other lipid-lowering medications at slightly lower doses (17). In particular, low-dose nicotinic acid is often co-administered with 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins), the cornerstone of treatment of hyperlipidemia, a major risk factor for CHD. A placebo-controlled study in 39 patients taking statins (cerivastatin, atorvastatin, or simvastatin) found that a very low dose of nicotinic acid (100 mg/day) increased HDL-cholesterol by only 2.1 mg/dL, and the combination had no effect on LDL-cholesterol, total cholesterol, or triglyceride concentrations (81).

The Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2 study — a double-blind, placebo-controlled trial — investigated the incremental effect of adding nicotinic acid (1 g/day) to statin therapy in 167 patients with known CHD and low HDL concentrations on carotid intima-media thickness (CIMT) (82), a surrogate endpoint for the development of atherosclerosis. The addition of extended-release nicotinic acid to simvastatin prevented the increase in CIMT compared to simvastatin monotherapy. A post-hoc analysis of data from ARBITER2 showed that the blockade of atherosclerotic progression was related to the increase in HDL concentrations in patients with normal glycemic status. However, in the presence of additional risk factors, such as impaired fasting glucose or diabetes mellitus, the increase in HDL concentrations was not predictive of CIMT reduction and atherosclerotic retardation (83). A comparative efficacy trial (ARBITER6) also showed a significant reduction of baseline CIMT with extended-release nicotinic acid (2 g/day for 14 months), as opposed to ezetimibe (a cholesterol-lowering drug), in patients taking statins (84).

Additional studies have examined the impact of nicotinic acid on endothelium-dependent brachial flow-mediated dilation (FMD) in patients at risk of CHD or with established CHD. The measurement of FMD is often used as a surrogate marker of endothelial function; FMD values are inversely correlated with the risk of future cardiovascular events (85). A meta-analysis of seven randomized controlled trials, including 441 participants, showed a significant, 2% increase with nicotinic acid (1-2 g/day) administered for 12 weeks to one year (86).

Cardiovascular events

Several randomized, placebo-controlled, multicenter trials have investigated the efficacy and safety of nicotinic acid therapy, alone or in combination with other lipid-lowering agents, on outcomes of cardiovascular disease (CVD). Specifically, the Coronary Drug Project (CDP) followed over 8,000 men with a previous myocardial infarction for six years (87). Compared to the placebo group, patients who took 3 g of immediate-release nicotinic acid daily experienced an average 10% reduction in total blood cholesterol, a 26% decrease in triglycerides, a 27% reduction in recurrent nonfatal myocardial infarction, and a 26% reduction in cerebrovascular events (stroke and transient ischemic attacks). In addition, nine-year follow-up post-trial revealed a 10% reduction in total deaths with nicotinic acid treatment.

The HDL-Atherosclerosis Treatment Study (HATS), a three-year randomized controlled trial in 160 patients with documented CHD and low HDL concentrations, found that a combination of simvastatin and nicotinic acid (2-3 g/day) increased HDL concentrations, inhibited the progression of coronary artery stenosis (narrowing), and decreased the frequency of cardiovascular events, including myocardial infarction and stroke, compared to placebo (88). A subgroup analysis of the HATS patients with metabolic syndrome showed a reduction in rate of primary clinical events even though glucose and insulin metabolism were moderately impaired by nicotinic acid (89). Moreover, a review of nicotinic acid safety and tolerability among the HATS subjects showed glycemic control in diabetic patients returned to pretreatment values following eight months of disease management with medication and diet (90). Similarly, the cardiovascular benefit of long-term nicotinic acid therapy outweighed the modest increase in risk of newly onset type 2 diabetes in patients from the CDP study (91).

In contrast, the AIM-HIGH (Atherothrombosis intervention in metabolic syndrome with low HDL/high triglycerides: impact on global health outcomes) trial, which examined the incremental effect of extended-release nicotinic acid (1.5-2 g/day) on 3,414 patients who had established CVD and atherogenic dyslipidemia and were treated with simvastatin (+/- ezetimibe), provided disappointing results. Indeed, in these patients who had achieved target concentrations of LDL-cholesterol (<70 mg/dL) before randomization, the HDL-raising effect of nicotinic acid treatment failed to reduce the number of cardiovascular events after a mean follow-up of three years (92, 93). While some limitations, like a greater use of simvastatin and ezetimibe in the control group, may have confounded the results, it was also suggested that low HDL-cholesterol might be a marker of risk rather than a causal risk factor for predicting CVD (93). In addition, a post-hoc analysis of 505 participants with stage 3 chronic kidney disease found an increase in all-cause mortality in those randomized to nicotinic acid compared to those in the placebo group (94).

Although nicotinic acid failed to reduce the number of cardiovascular events in simvastatin-treated patients with low LDL-cholesterol, these results cannot be extrapolated to patients with higher LDL-cholesterol at baseline. A much larger multicenter, randomized, double-blind, placebo-controlled trial — the HPS2-THRIVE (Heart protection study 2: treatment of HDL to reduce the incidence of vascular events) trial — in 25,673 participants with vascular disease examined the incremental effect of extended-release nicotinic acid (2 g/day) and laropiprant (a prostaglandin D2 receptor-1 antagonist; 40 mg/day) on the incidence of vascular events. Compared to placebo, nicotinic acid/laropiprant reduced LDL-cholesterol by an average of 10 mg/dL, decreased triglycerides by 33 mg/dL, and increased HDL-cholesterol by 6 mg/dL after a median 3.9-year follow-up period. Nonetheless, nicotinic acid/laropiprant showed no effect on the incidence of major vascular events and death of any cause (95).

A recent meta-analysis of 23 randomized controlled trials — including the CDP, AIM-HIGH, and HPS2-THRIVE trials — in 39,195 subjects with a history of vascular disease compared the effect of nicotinic acid alone or as an add-on to other lipid-lowering agents. No cardiovascular benefits were associated with nicotinic acid therapy: the number of fatal and non-fatal myocardial infarctions and strokes was not decreased with nicotinic acid supplementation (median dose of 2 g/day for a median period of 11.5 months) (96).

Despite the lack of evidence for a role of nicotinic acid in CVD prevention (96, 97), the use of nicotinic acid therapy has rapidly increased over the years in the US (98).

Friedreich’s ataxia

Friedreich’s ataxia, a common form of inherited ataxia, is an early onset recessive disorder with clinical features that includes progressive ataxia, scoliosis, dysarthria, cardiomyopathy, and diabetes mellitus (99). Most affected subjects carry homozygous guanine-adenine-adenine (GAA) repeat expansions in the first intron of the gene FXN coding for the protein frataxin. These abnormal and unstable GAA repeats trigger gene silencing through heterochromatin formation, leading to significantly reduced frataxin expression (100). Frataxin is a mitochondrial protein needed for the making of iron-sulfur clusters (ISC). ISC-containing subunits are especially important for the mitochondrial respiratory chain and for the synthesis of heme-containing proteins (99).

Predominantly localized in the nucleus, SIRT1 is a NAD+-dependent deacetylase that promotes gene silencing through heterochromatin formation. Nicotinamide has been shown to antagonize heterochromatization of the FXN locus and upregulate frataxin expression in lymphoblastoid cells derived from Friedreich’s ataxia-affected patients, possibly through inhibiting SIRT1 activity (100). In an open-label, dose escalating pilot trial in 10 adult patients with Friedreich’s ataxia, single and repeated doses of nicotinamide (2-8 g) for up to eight weeks were found to be well tolerated (101). Repeated daily doses of 3.5 to 6 g of nicotinamide led to significant increases in frataxin concentration in peripheral white blood cells (101). Yet, no neurological improvements were reported, suggesting that the duration of the treatment was too short and/or the nervous system of the participants was unresponsive to increases in frataxin (102). To our knowledge, there is currently no ongoing trial designed to further investigate the effect of nicotinamide in Friedreich’s ataxia-affected patients.


The first step in the kynurenine pathway is catalyzed by the extrahepatic enzyme, indoleamine 2,3-dioxygenase (IDO), which is responsible for the oxidative cleavage of tryptophan. The chronic stimulation of tryptophan oxidation, mediated by an increased activity of IDO and/or inadequate dietary niacin intakes, is observed with the infection of human immunodeficiency virus (HIV), the virus that causes acquired immunodeficiency syndrome (AIDS). Interferon-gamma (IFN-γ) is a cytokine produced by cells of the immune system in response to infection. Through stimulating the enzyme IDO, IFN-γ increases the breakdown of tryptophan, thus supporting the finding that the average tryptophan concentration in blood is significantly lower in HIV patients compared to uninfected subjects (40). An increased degradation of tryptophan via the kynurenine pathway appears to coexist with intracellular niacin/NAD deficiency in HIV infection (103). An explanatory model for these paradoxical observations incriminates the oxidative stress induced by multiple nutrient deficiencies in HIV patients (103). In particular, the activation of PARP enzymes (ARTDs) by oxidative damage to DNA could be responsible for inducing niacin/NAD depletion (see Function). The breakdown of tryptophan would then be a compensatory response to inadequate niacin/NAD levels.

However, metabolites derived from the oxidation of tryptophan in the kynurenine pathway regulate specific T-lymphocyte subgroups. As mentioned above, circulating IFN-γ, but also viral and bacterial products, can activate IDO during HIV infection. The overstimulation of the tryptophan pathway has been involved in the loss of normal T-lymphocyte function, which characterizes HIV infection (104, 105). The increased IDO activity has been linked to the altered immune response that contributes to the persistence of HIV (104). Antiretroviral therapy (ART) only partially restores normal IDO activity, without normalizing it, yet induces viral suppression and CD4 T-cell recovery (106). In a monkey model for HIV infection, a partial and transient blockade of IDO with IDO inhibitor 1-methyl tryptophan proved ineffective to reduce the viral load in plasma and intestinal tissues beyond the level achieved by ART (107). At present, a better understanding of the role of kynurenine pathway and other NAD biosynthetic pathways during HIV infection is needed before the relevance and clinical implications of niacin supplementation in HIV treatment could be considered.

Nonetheless, pharmacologic doses of nicotinic acid have been shown to be well tolerated in HIV patients with hyperlipidemia (108). Abnormal lipid profiles observed in patients have been attributed to the HIV infection and to the highly active antiretroviral treatment (HAART) (109). Moreover, insulin resistance has been detected together with dyslipidemia in ART-treated patients (110). Cardiovascular disease (CVD) is the second most frequent cause of deaths in the HIV population, and the rate of CVD is predicted to increase further as patients are living longer due to successful antiretroviral therapies. As for the general population, statin-based therapy appears to benefit HIV patients in terms of atherogenic protection and CVD risk reduction, although contraindications exist due to drug interactions with ART. Other first-line treatments include lipid-lowering fibrates, which are preferred to nicotinic acid due to the increased risk of glucose intolerance and insulin resistance (111). Nevertheless, an unblinded, controlled pilot study showed that extended-release nicotinic acid (0.5-1.5 g/day for 12 weeks) could effectively improve endothelial function of the brachial artery in ART-treated HIV subjects with low HDL-cholesterol and no history of CVD (112). In addition, a combined treatment of fibrates, extended-release nicotinic acid (0.5-2 g/day), and lifestyle changes (low-fat diet and exercise) for 24 weeks was effective in normalizing lipid parameters in a cohort of 191 ART-treated patients. Increased risk of liver dysfunction was detected in subjects receiving both fibrates and niacin, but insulin sensitivity was not affected by nicotinic acid treatment given alone or when combined with fibrates (113). Another 24-week, open-label, uncontrolled trial in 99 ART-treated patients found that randomization to extended-release nicotinic acid (0.5-2 g/day) or fenofibrates increased blood HDL-cholesterol but did not reduce inflammatory markers or improve endothelial function when compared to baseline (114).


Schizophrenia is a neurologic disorder with unclear etiology that is diagnosed purely from its clinical presentation. Because neurologic disorders associated with pellagra resemble acute schizophrenia, niacin-based therapy for the condition was investigated during the 1950s-70s (reviewed in 115). The adjunctive use of nutrients like niacin to correct deficiencies associated with neurologic symptoms is called orthomolecular psychiatry (116). Such an approach has not been included in psychiatric practice; practitioners have instead relied solely on antipsychotic drugs to eliminate the clinical symptoms of schizophrenia. Nevertheless, recent scientific advances and new hypotheses on the benefit of nutrient supplementation in the treatment of psychiatric disorders have suggested the re-assessment of orthomolecular medicine by the medical community (117, 118).

Skin flushing is one major side effect of the therapeutic use of nicotinic acid and the primary reason for non-adherence to treatment (see Toxicity). Flushing is caused by the activation of phospholipase A2, an enzyme that stimulates the production of a specific lipid from the prostanoid family called prostaglandin D2. Prostaglandin D2, synthesized by antigen-presenting cells of the skin and mucosa (i.e., the Langerhans cells), can induce the dilation of blood vessels and trigger a flushing response. Interestingly, patients with schizophrenia tend not to flush following treatment with nicotinic acid. This blunted skin flushing response suggests abnormal prostanoid signaling in schizophrenic patients (119, 120). An association has been found between the altered niacin sensitivity and greater functional impairment in schizophrenic subjects (121), which supports other findings suggesting that altered lipid metabolism could critically impair brain development and contribute to the disease (122). Interestingly, blunted skin flushing responses are more prevalent in first-degree relatives of people with schizophrenia than in the general population, suggesting that reduced niacin sensitivity is a heritable trait within affected families (123).


Food sources

Good sources of niacin include yeast, meat, poultry, red fish (e.g., tuna, salmon), cereal (especially fortified cereal), legumes, and seeds. Milk, green leafy vegetables, coffee, and tea also provide some niacin (124). In plants, especially mature cereal grains like corn and wheat, niacin may be bound to sugar molecules in the form of glycosides, which significantly decrease its bioavailability (25).

In the United States, the average dietary intake of niacin is about 30 mg/day for young adult men and 20 mg/day for young adult women. In a sample of adults over the age of 60, men and women were found to have an average dietary intake of 21 mg/day and 17 mg/day, respectively (41). Some foods with substantial amounts of niacin are listed in Table 2, along with their niacin content in milligrams (mg). Food composition tables generally list niacin content without including niacin equivalents (NE) from tryptophan or any adjustment for niacin bioavailability. For more information on the nutrient content of specific foods, search USDA's FoodData Central database; data included in Table 2 are from this database (125).

Table 2. Some Food Sources of Niacin
Food Serving Niacin (mg)
Chicken (light meat, cooked without skin) 3 ounces* 8.9
Tuna (light, canned, packed in water) 3 ounces 8.6
Turkey (light meat, cooked without skin) 3 ounces 9.9
Salmon (chinook, cooked) 3 ounces 8.5
Beef (90% lean, cooked) 3 ounces 4.4
Cereal (unfortified) 1 cup 5-7
Cereal (fortified) 1 cup 20-27
Peanuts (dry-roasted) 1 ounce 4.1
Pasta (enriched, cooked) 1 cup 1.9-2.4
Lentils (cooked) 1 cup 2.1
Lima beans (cooked) 1 cup 0.8
Bread (whole-wheat) 1 slice 1.4
Coffee (brewed) 1 cup 2
*A three-ounce serving of meat is about the size of a deck of cards.


Niacin supplements are available as nicotinamide or nicotinic acid. Nicotinamide is the form of niacin typically used in nutritional supplements and in food fortification. Nicotinic acid is available over the counter and with a prescription as a cholesterol-lowering agent (126). Nicotinic acid for anti-hyperlipidemic use is available in three formulations: immediate-release (crystalline) nicotinic acid (absorption time, 1-2 hrs), extended-release nicotinic acid (absorption time, 8-12 hrs), and sustained-release nicotinic acid (absorption time, >12 hrs) (127). At the pharmacologic dose required for cholesterol-lowering effects, the use of nicotinic acid should be approached as if it were a drug (see Safety). Individuals should only undertake cholesterol-lowering therapy with nicotinic acid under the supervision of a qualified health care provider in order to minimize potentially adverse effects and maximize therapeutic benefits.



Nicotinic acid

Common side effects of nicotinic acid include flushing, pruritus (severe itching of the skin), skin rashes, and gastrointestinal disturbances, such as nausea and vomiting (97). Transient episodes of low blood pressure (hypotension) and headache have also been reported. Hepatotoxicity (liver cell damage), including elevated liver enzymes and jaundice, has been observed at intakes as low as 750 mg/day of nicotinic acid (128). Although hepatitis has been observed with extended-release nicotinic acid at dosages as little as 500 mg/day for two months, almost all reports of severe hepatitis have been associated with doses of 3 to 9 g/day used to treat high cholesterol for months or years (41). It is unclear whether immediate-release (crystalline) nicotinic acid is less toxic to the liver than extended-release forms (41). Yet, immediate-release nicotinic acid is often used at higher doses than extended-release forms, and severe liver toxicity has occurred in individuals who substituted extended-release nicotinic acid for immediate-release nicotinic acid at equivalent doses (126). Large doses of nicotinic acid have been observed to impair glucose tolerance, likely because of a decrease in insulin sensitivity. Impaired glucose tolerance in susceptible (pre-diabetic) individuals could result in elevated blood glucose concentrations and clinical type 2 diabetes mellitus. An analysis of the HPS2-THRIVE trial (see Cardiovascular disease), using data from 17,374 participants without type 2 diabetes at baseline, found a significantly higher proportion of newly diagnosed cases among those randomized to nicotinic acid/laropiprant than to placebo (5.7% versus 4.3%) over a 3.9 year-period (95). Likewise, randomization to nicotinic acid/laropiprant significantly increased the risk of serious disturbances in diabetes control (leading to hospitalization) compared to placebo among 8,299 participants with diabetes at baseline (95). Elevated blood concentrations of uric acid, occasionally resulting in attacks of gout in susceptible individuals, have also been observed with high-dose nicotinic acid therapy (126). Niacin at doses of 1.5 to 5 g/day has resulted in a few case reports of blurred vision and other eye problems, which have generally been reversible upon discontinuation (41). People with abnormal liver function or a history of liver disease, diabetes, active peptic ulcer disease, gout, cardiac arrhythmias, inflammatory bowel disease, migraine headaches, or alcoholism may be more susceptible to the adverse effects of excess niacin intake than the general population (41).


Nicotinamide is generally better tolerated than nicotinic acid; it does not generally cause flushing (126). However, nausea, vomiting, and signs of liver toxicity (elevated liver enzymes, jaundice) have been observed at very high doses (≥10 g/day) (126).

Nicotinamide riboside

A study in 12 healthy subjects found that nicotinamide riboside at three single doses (100 mg, 300 mg, and 1,000 mg) safely increased blood NAD+. Two of the participants self-reported skin flushing after taking the 300-mg dose, and two others reported feeling hot following intake of 1,000 mg of nicotinamide riboside (1). In a recent randomized, placebo-controlled trial in 120 healthy adults (ages, 60-80 years), daily supplementation with nicotinamide riboside (250 mg or 500 mg) and pterostilbene (a SIRT activator; 50 mg or 100 mg) for eight weeks showed a favorable side effect profile, with no evidence of higher incidence of adverse effects compared to placebo (129). Most recently, a randomized, placebo-controlled trial in 40 obese men (ages, 40-70 years) found that daily supplementation with nicotinamide riboside (2,000 mg/day divided into two daily dosages) for 12 weeks was associated with reports of only minor side effects, including excessive sweating, pruritus, and mild gastrointestinal symptoms like bloating (139).

The tolerable upper intake level (UL)

Flushing of the skin primarily on the face, arms, and chest is a common side effect of nicotinic acid and may occur initially at doses as low as 30 mg/day. Although flushing from nicotinamide is rare, the Food and Nutrition Board set the tolerable upper intake level (UL) for niacin (nicotinic acid and nicotinamide) at 35 mg/day in adults to avoid the adverse effect of flushing (41). Analysis of data from the US National Health and Nutrition Examination Survey (NHANES) 2003-2006 found that 15.8% of children and adolescents (ages 2-18 years) and 8.5% of adults (≥19 years) had total usual niacin intakes exceeding the UL (130). The UL applies to the general population and is not meant to apply to individuals who are being treated with a nutrient under medical supervision (e.g., high-dose nicotinic acid for elevated blood cholesterol concentrations).

Table 3. Tolerable Upper Intake Level (UL) for Niacin
Age Group  UL (mg/day) 
Infants 0-12 months  Not possible to establish* 
Children 1-3 years  10
Children 4-8 years  15
Children 9-13 years  20
Adolescents 14-18 years  30
Adults 19 years and older  35
*Source of intake should be from food and formula only.

Drug interactions

The occurrence of rhabdomyolysis is increased in patients treated with statins (HMG-CoA reductase inhibitors). Rhabdomyolysis is a relatively uncommon condition in which muscle cells are broken down, releasing enzymes and electrolytes into the blood, and sometimes resulting in kidney failure (131). Co-administration of nicotinic acid with a statin seems to enhance the risk of rhabdomyolosis (132). A new drug, laropiprant, blocks prostanoid receptors and reduces nicotinic acid-induced flushing (133). A randomized, placebo-controlled trial was designed to identify possible adverse effects of the niacin/laropiprant combination in over 25,000 simvastatin-treated subjects (134). When added to the statin therapy, niacin/laropiprant increased the risk of myopathy and rhabdomyolosis, particularly in Asian subjects. It is possible that the niacin/laropiprant combination further reduces the poor tolerability to statin treatment observed in certain populations (135).

In the three-year, randomized controlled HATS study, concurrent therapy with antioxidants (1,000 mg/day of vitamin C, 800 IU/day of RRR-α-tocopherol, 100 µg/day of selenium, and 25 mg/day of β-carotene) diminished the protective effects of the simvastatin-nicotinic acid combination (136). Although the mechanism for these effects is not known, the benefit of concurrent antioxidant therapy in patients on lipid-lowering agents has been questioned (137).

Adverse effects of large doses of nicotinic acid may be exacerbated by the concomitant use of certain medications. The risk of myopathy may be further increased in those taking nicotinic acid and bile acid sequestrants (e.g., cholestyramine, colestipol) or the anti-lipidemic drug, gemfibrozil (Lopid), and the risk of hepatotoxicity observed with nicotinic acid might be enhanced by drugs like paracetamol, amiodarone (Cordarone), or carbamazepine (Tegretol) (35). In addition, large doses of nicotinic acid may reduce uric acid excretion, thereby opposing the action of uricosuric agents like probenecid (Probalan) (35).  

Several other medications may interact with niacin therapy or with absorption and metabolism of the vitamin (126). Estrogen and estrogen-containing oral contraceptives increase the efficiency of niacin synthesis from tryptophan, resulting in a decreased dietary requirement for niacin (138). Long-term administration of chemotherapy agents has been reported to cause symptoms of pellagra; therefore, niacin supplementation may be needed (see Pellagra causes).

Linus Pauling Institute Recommendation

The optimum intake of niacin for health promotion and chronic disease prevention is not yet known. The RDA (16 mg NE/day for men and 14 mg NE/day for women) is easily obtainable by consuming a varied diet and should prevent deficiency in most people. Following the Linus Pauling Institute recommendation to take a daily multivitamin/mineral supplement, containing 100% of the Daily Value (DV) for niacin, will provide at least 20 mg of niacin daily.

Authors and Reviewers

Originally written in 2000 by: 
Jane Higdon, Ph.D. 
Linus Pauling Institute 
Oregon State University

Updated in August 2002 by:
Jane Higdon, Ph.D.
Linus Pauling Institute 
Oregon State University

Updated in June 2007 by:
Victoria J. Drake, Ph.D
Linus Pauling Institute 
Oregon State University

Updated in July 2013 by: 
Barbara Delage, Ph.D. 
Linus Pauling Institute 
Oregon State University

Updated in December 2017 by:
Barbara Delage, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in March 2018 by:
Mirella Meyer-Ficca, Ph.D.
Research Assistant Professor
Utah State University

The 2017 update of this article was supported by a grant from ChromaDex, Inc.

Last updated 8/10/18  Copyright 2000-2024  Linus Pauling Institute


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113.  Balasubramanyam A, Coraza I, Smith EO, et al. Combination of niacin and fenofibrate with lifestyle changes improves dyslipidemia and hypoadiponectinemia in HIV patients on antiretroviral therapy: results of "heart positive," a randomized, controlled trial. J Clin Endocrinol Metab. 2011;96(7):2236-2247.  (PubMed)

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Pantothenic Acid

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  • Pantothenic acid — also known as vitamin B5 — is a water-soluble vitamin that is a precursor in the synthesis of coenzyme A. Coenzyme A is essential to many biochemical reactions that sustain life. Also, the phosphopantetheinyl moiety of coenzyme A is required for the biological activity of several proteins, including the acyl-carrier protein involved in fatty acid synthesis. (More information)
  • Pantothenic acid is essential to all forms of life. It is ubiquitously found in foods of plant and animal origin, and dietary deficiency is very rare. (More information)
  • The Food and Nutrition Board of the National Academy of Medicine set an adequate intake (AI) of 5 milligrams (mg)/day for adults based on the estimated daily average intake of pantothenic acid. (More information)
  • Evidence from limited intervention studies suggests that pantothenic acid and/or pantothenol (alcohol analog) might improve the healing process of skin wounds. Yet, additional larger studies are warranted. (More information)
  • Treatment with high-dose pantethine — a pantothenic acid derivative — has been shown to lower serum cholesterol and lipid concentrations. Although pantethine therapy appears to be well tolerated, medical supervision is indispensable. (More information)
  • Foods rich in pantothenic acid include animal organs (liver and kidney), fish, shellfish, milk products, eggs, avocados, legumes, mushrooms, and sweet potatoes. (More information)
  • Little or no toxicity has been associated with dietary and supplemental pantothenic acid such that no tolerable upper intake level (UL) has been set. (More information)

Pantothenic acid, also known as vitamin B5, is essential to all forms of life (1). Pantothenic acid is found throughout all branches of life in the form of coenzyme A, a vital coenzyme in numerous chemical reactions (2, 3)


Synthesis of pantothenic acid cofactors

Coenzyme A

Pantothenic acid is a precursor in the biosynthesis of coenzyme A (CoA) (Figure 1), an essential coenzyme in a variety of biochemical reactions that sustain life (see Coenzyme A). Pantothenic acid kinase 2 (PANK2) catalyzes the initial step of phosphorylation of pantothenic acid to 4’-phosphopantothenic acid. Coenzyme A and its derivatives inhibit the synthesis of 4’-phosphopantothenic acid, but the inhibition can be reversed by carnitine, required for the transport of fatty acids into the mitochondria (4). The subsequent reactions in this biosynthetic pathway include the synthesis of the intermediate 4’-phosphopantetheine, as well as the recycling of coenzyme A to 4’-phosphopantetheine (Figure 1). 

Figure 1. Coenzyme A Synthesis from Pantothenic Acid. Pantothenic acid is a precursor in the synthesis of coenzyme A. The initial phosphorylation reaction that converts pantothenic acid into 4'-phosphopantothenic acid is impaired in individuals with an inherited defect in the gene (PANKII) coding for pantothenic acid kinase II.


The 4’-phosphopantetheinyl moiety of coenzyme A can be transferred to enzymes in which 4’-phosphopantetheine is an essential cofactor for their biological activities (see 4’-Phosphopantetheinylation). 

Cofactor and co-substrate function

Coenzyme A

Coenzyme A reacts with acyl groups, giving rise to thioester derivatives, such as acetyl-CoA, succinyl-CoA, malonyl-CoA, and 3-hydroxy-3-methylglutaryl (HMG)-CoA. Coenzyme A and its acyl derivatives are required for reactions that generate energy from the degradation of dietary fat, carbohydrates, and proteins. In addition, coenzyme A in the form of acetyl-CoA and succinyl-CoA is involved in the citric acid cycle; in the synthesis of essential fats, cholesterol, steroid hormones, vitamins A and D, the neurotransmitter acetylcholine; and in the fatty acid β-oxidation pathway. Coenzyme A derivatives are also required for the synthesis of the hormone, melatonin, and for a component of hemoglobin called heme. Further, metabolism of a number of drugs and toxins by the liver requires coenzyme A (5)

Coenzyme A was named for its role in acetylation reactions. Most acetylated proteins in the body have been modified by the addition of an acetate group that was donated by the coenzyme A thioester derivative, acetyl-CoA. Protein acetylation alters the overall charge of proteins, modifying their three-dimensional structure and, potentially, their function. For example, acetylation is a mechanism that regulates the activity of peptide hormones, including those produced by the pituitary gland (6). Also, protein acetylation, like other posttranslational modifications, has been shown to regulate the subcellular localization, the function, and the half-life of many signaling molecules, transcription factors, and enzymes. Notably, the acetylation of histones plays a role in the regulation of gene expression by facilitating transcription (i.e., mRNA synthesis), while deacetylated histones are usually associated with chromatin compaction and gene silencing. The acetylation of histones was found to result in structural changes of the chromatin, which affect both DNA-protein and protein-protein interactions. Crosstalk between acetylation marks and other posttranscriptional modifications of the histones also facilitate the recruitment of transcriptional regulators to the promoter of genes that are subsequently transcribed (reviewed in 7). 

Finally, a number of signaling molecules are modified by the attachment of long-chain fatty acids donated by coenzyme A. These modifications are known as protein acylation and have central roles in cell-signaling pathways (5)


Specific multi-enzyme complexes, which need to carry out several reactions in an orderly manner, may require the covalent attachment of a 4’-phosphopantetheine arm to a “carrier” domain (or protein). This carrier domain holds substrates or reaction intermediates during the progression through the various enzymatic reactions. In mammals, the transfer of the 4’-phosphopantetheinyl moiety from coenzyme A to a conserved serine residue of a specific carrier domain is catalyzed by one unique phosphopantetheinyl transferase (8). The 4’-phosphopantetheinylation is necessary for the conversion of apo-enzymes into fully active holo-enzymes (see below). 

Acyl-carrier protein

Lipids are fat molecules essential for normal physiological function and, among other types, include sphingolipids (essential components of the myelin sheath that enhances nerve transmission), phospholipids (important structural components of cell membranes), and fatty acids. Fatty acid synthase (FAS) is a multi-enzyme complex that catalyzes the synthesis of fatty acids. Within the FAS complex, the acyl-carrier protein (ACP) requires pantothenic acid in the form of 4'-phosphopantetheine for its activity as a carrier protein (4). A group, such as the 4’-phosphopantetheinyl moiety for ACP, is called a prosthetic group; the prosthetic group is not composed of amino acids and is a tightly bound cofactor required for the biological activity of some proteins (Figure 2). Acetyl-CoA, malonyl-CoA, and ACP are all required for the synthesis of fatty acids in the cytosol. During fatty acid synthesis, the acyl groups of acetyl-CoA and malonyl-CoA are transferred to the sulfhydryl group (-SH) of the 4’-phosphopantetheinyl moiety of ACP. The prosthetic group is used as a flexible arm to transfer the growing fatty acid chain to each of the enzymatic centers of the type I FAS complex. In the mitochondria, 4'-phosphopantetheine also serves as a prosthetic group for an ACP homolog present in mitochondrial type II FAS complex (9)

Figure 2. 4'-Pantetheinylation of Acyl-Carrier Protein (ACP). A prosthetic group – in this case, a 4'-phosphopantetheinyl moiety – is required for the biological function of ACP. The addition of the prosthetic group occurs after ACP synthesis (post-translation) in a reaction catalyzed by 4'-phosphopantetheinyl transferase. The enzyme catalyzes the hydrolysis of coenzyme A to 3',5'-adenosine diphosphate and 4'-phosphopantetheine, and the transfer of the 4'-phosphopantetheinyl moiety to a serine residue at the active site of ACP. ACP, acyl-carrier protein; apo-ACP, biologically inactive ACP; holo-ACP, biologically active ACP.

10-Formyltetrahydrofolate dehydrogenase

The enzyme 10-formyltetrahydrofolate dehydrogenase (FDH) catalyzes the conversion of 10-formyltetrahydrofolate to tetrahydrofolate, an essential cofactor in the metabolism of nucleic acids and amino acids (Figure 3). Similar to ACP, FDH requires a 4’-phosphopantetheine prosthetic group for its biological activity. The prosthetic group acts as a swinging arm to couple the activities of the two catalytic domains of FDH (10, 11). A homolog of FDH in mitochondria also requires 4’-phosphopantetheinylation to be biologically active (12)

Figure 3. 4'-Pantetheinylation of Formyltetrahydrofolate Dehydrogenase (FDH). (a) The generation of TH4 from 10-CHO-TH4 is catalyzed by FDH, an enzyme requiring 4'-phosphopantetheine as a prosthetic group to be biologically active. Of note, 10-CHO-TH4 can also be hydrolyzed to TH4 (and formate) in another reaction catalyzed by formyltetrahydrofolate deformylase. (b) The enzyme 4'-phosphopantetheinyl transferase catalyzes the transfer of a 4'-phosphopantetheinyl moiety from coenzyme A to a specific serine residue of FDH, converting apo-FDH to holo-FDH. FDH, formyltetrahydrofolate dehydrogenase; apo-FDH, biologically inactive FDH; holo-FDH, biologically active FDH; 10-CHO-TH4, 10-formyltetrahydrofolate; TH4, tetrahydrofolate; NADP+/NADPH, nicotinamide adenine dinucleotide phosphate oxidized/reduced.

α-Aminoadipate semialdehyde synthase

4’- Phosphopantetheinylation is required for the biological activity of the apo-enzyme a-aminoadipate semialdehyde synthase (AASS). AASS catalyzes the initial reactions in the mitochondrial pathway for the degradation of lysine — an essential amino acid for humans. AASS is made of two catalytic domains. The lysine-ketoglutarate reductase domain first catalyzes the conversion of lysine to saccharopine. Saccharopine is further converted to a-aminoadipate semialdehyde in a reaction catalyzed by the saccharopine dehydrogenase domain (Figure 4). 

Figure 4. 4'-Pantetheinylation of α-Aminoadipate Semialdehyde Synthase (AASS). AASS is a mitochondrial enzyme responsible for the conversions of lysine to saccharopine, and saccharopine to α-aminoadipate semialdehyde in the mitochondrial pathway for lysine degradation. The first reaction is catalyzed by the lysine-ketoglutarate reductase domain of AASS, and the saccharopine dehydrogenase domain catalyzes the second reaction. Apo-AASS requires 4'-phosphopantetheine as a prosthetic group to be biologically active. The enzyme 4'-phosphopantetheinyl transferase catalyzes the transfer of a 4'-phosphopantetheinyl moiety from coenzyme A to a specific residue of AASS, converting apo-AASS to holo-AASS. The 4'-phosphopantetheinyl arm is thought to serve as a swinging arm that couples the activities of the two enzymatic domains of AASS. AASS, α-aminoadipate semialdehyde synthase.


Naturally occurring pantothenic acid deficiency in humans is very rare and has been observed only in cases of severe malnutrition. World War II prisoners in the Philippines, Burma, and Japan experienced numbness and painful burning and tingling in their feet; these symptoms were relieved specifically by pantothenic acid supplementation (5). Pantothenic acid deficiency in humans has been induced experimentally by co-administering a pantothenic acid kinase inhibitor (ω-methylpantothenate; Figure 1) and a pantothenic acid-deficient diet. Participants in this experiment complained of headache, fatigue, insomnia, intestinal disturbances, and numbness and tingling of their hands and feet (13). In another study, participants fed only a pantothenic acid-free diet did not develop clinical signs of deficiency, although some appeared listless and complained of fatigue (14)

Calcium homopantothenate (or hopantenate) is a pantothenic acid antagonist with cholinergic effects (i.e., similar to those of the neurotransmitter, acetylcholine). This compound is used in Japan to enhance mental function, especially in Alzheimer’s disease. A rare side effect was the development of hepatic encephalopathy, a condition of abnormal brain function resulting from the failure of the liver to eliminate toxins. The encephalopathy was reversed by pantothenic acid supplementation, suggesting that it was due to homopantothenate-induced pantothenic acid deficiency (15). Of note, autosomal recessive mutations in the human gene PANK2, which codes for pantothenic acid kinase 2 (Figure 1), result in impaired synthesis of 4'-phosphopantetheine and coenzyme A (see Function). This rare disorder, called pantothenate kinase-associated neurodegeneration (PKAN), is associated with iron accumulation in the brain and characterized by visual and intellectual impairments, dystonia, speech abnormalities, behavioral difficulties, and personality disorders (16-18). Two forms of the disorder have been described: classic PKAN with symptom onset early in life (before age 10 years) and atypical PKAN with symptom onset after age 10, sometimes in early adulthood (19)

Yet, because pantothenic acid is widely distributed in nature and deficiency is extremely rare in humans, most information regarding the consequences of deficiency has been gathered from experimental research in animals (reviewed in 4). Pantothenic acid-deficient rats developed damage to the adrenal glands, while pantothenic acid-deficient monkeys developed anemia due to decreased synthesis of heme, a component of hemoglobin. Dogs with pantothenic acid deficiency developed low blood glucose, rapid breathing and heart rates, and convulsions. Chickens developed skin irritation, feather abnormalities, and spinal nerve damage associated with the degeneration of the myelin sheath. Pantothenic acid-deficient mice showed decreased exercise tolerance and diminished storage of glucose (in the form of glycogen) in muscle and liver. Mice also developed skin irritation and graying of the fur that was reversed with pantothenic acid administration. 

The diversity of symptoms emphasizes the numerous functions of pantothenic acid in its coenzyme forms. 

Moreover, some recent case-control studies have documented cerebral pantothenic acid deficiency in patients with Alzheimer’s disease (20) and in those with Huntington’s disease (21)

The Adequate Intake (AI)

Because there was little information on the requirements of pantothenic acid in humans, the Food and Nutrition Board of the Institute of Medicine (now the National Academy of Medicine) set an adequate intake (AI) based on observed dietary intakes in healthy population groups (Table 1) (22)

Table 1. Adequate Intake (AI) for Pantothenic Acid
Life Stage  Age  Males (mg/day)  Females (mg/day) 
Infants  0-6 months  1.7  1.7 
Infants  7-12 months  1.8  1.8 
Children  1-3 years 
Children  4-8 years 
Children  9-13 years 
Adolescents  14-18 years 
Adults  19 years and older 
Pregnancy  all ages  - 
Breast-feeding  all ages 7

Disease Treatment

Wound healing

The addition of calcium D-pantothenate and/or pantothenol (Figure 5) to the medium of cultured skin fibroblasts given an artificial wound was found to increase cell proliferation and migration, thus accelerating wound healing in vitro (23, 24). Likewise, in vitro deficiency in pantothenic acid induced the expression of differentiation markers in proliferating skin fibroblasts and inhibited proliferation in human keratinocytes (25). The application of ointments containing either calcium D-pantothenate or pantothenol& — also known as D-panthenol or dexpanthenol — to the skin has been shown to accelerate the closure of skin wounds and increase the strength of scar tissue in animals (4)

The effects of topical dexpanthenol on wound healing in humans are unclear. In a placebo-controlled study that included 12 healthy volunteers, the application of dexpanthenol-containing ointment (every 12 hours for 1 to 6 days) in a model of skin wound healing was associated with an enhanced expression of markers of proliferation, inflammation, and tissue repair (26). However, the study failed to report whether these changes in response to dexpanthenol treatment improved the wound-repair process compared to placebo (26). In a randomized, double-blind, placebo-controlled study, the use of dexpanthenol pastilles (300 mg/day for up to 14 days post surgery) was found to accelerate mucosal healing after tonsillectomy in children (27)

Few studies have explored the effects of oral supplementation with pantothenic acid. Early randomized controlled trials in patients undergoing surgery for tattoo removal found that daily co-supplementation with 1 gram or 3 grams of vitamin C and 200 mg or 900 mg of pantothenic acid for 21 days did not significantly improve the wound-healing process (28, 29)

High cholesterol

Early studies suggested that pharmacological doses of pantethine, a pantothenic acid derivative, might have a cholesterol-lowering effect (30, 31). Pantethine is made of two molecules of pantetheine joined by a disulfide bond (chemical bond between two molecules of sulfur) (Figure 5). Pantethine is structurally related to coenzyme A and is found in the prosthetic group that is required for the biological function of acyl-carrier protein, formyltetrahydrofolate dehydrogenase, and α-aminoadipate semialdehyde synthase (see Function)

In a 16-week, randomized, double-blind, placebo-controlled study, daily pantethine supplementation (600 mg/day for 8 weeks, followed by 900 mg/day for another 8 weeks) significantly improved the profile of lipid parameters in 120 individuals at low-to-moderate risk of cardiovascular disease. After adjusting to baseline, pantethine was found to be significantly more effective than placebo in lowering the concentrations of low-density lipoprotein (LDL) cholesterol and apolipoprotein B (apoB), as well as reducing the ratio of triglycerides to high-density lipoprotein-cholesterol (TG:HDL-C) (32). In a randomized controlled trial of 24 individuals at low-to-moderate cardiovascular risk, pantethine supplementation (600 mg/day of pantethine for 8 weeks, followed by 900 mg for 8 weeks) decreased concentrations of total cholesterol, LDL cholesterol, and non-HDL cholesterol at 16 weeks compared to placebo (33). Although it appears to be well tolerated and potentially beneficial in improving cholesterol metabolism, pantethine is not a vitamin, and the decision to use pharmacological doses of pantethine to treat elevated blood cholesterol or triglycerides should only be made in collaboration with a qualified healthcare provider who provides appropriate follow up. 

Figure 5. Chemical Structures of Some Pantothenic Acid Derivatives.

Graying of hair

Mice that are deficient in pantothenic acid developed skin irritation and graying of the fur, which is reversed by pantothenic acid administration (34). In humans, evidence that taking pantothenic acid as supplements or using shampoos containing pantothenic acid can prevent or restore hair color is lacking. 

Hair loss

A case report of nine patients (35) and two small studies (36, 37) suggested some benefit of intramuscular injections of dexpanthenol in the treatment of alopecia or pattern hair loss; however, placebo-controlled trials would be needed to determine whether the drug has any effects on hair loss. 


Food sources

Pantothenic acid is available in a variety of foods, usually as a component of coenzyme A (CoA) and 4’-phosphopantetheine (see Figure 1). Upon ingestion, dietary coenzyme A and phosphopantetheine are hydrolyzed to pantothenic acid prior to intestinal absorption (4). Animal liver and kidney, fish, shellfish, pork, chicken, egg yolk, milk, yogurt, legumes, mushrooms, avocados, broccoli, and sweet potatoes are good sources of pantothenic acid. Whole grains are also good sources of pantothenic acid; processing and refining grains result in significant losses, up to 55% for wheat and up to 88% for maize (38). Freezing and canning of foods result in similar losses (22). Food preparation and cooking methods don’t substantially affect the vitamin due to its stability, but like other water-soluble vitamins, pantothenic acid can leach into cooking liquids (38).   

Large nutritional surveys in the United States have failed to estimate pantothenic acid intake, mainly because of the scarcity of data on the pantothenic acid content of food (22). Smaller studies estimated average daily intakes of pantothenic acid to be between 4 and 7 mg/day in adults. Table 2 lists some rich sources of pantothenic acid, along with their content in milligrams (mg). For more information on the nutrient content of foods, search USDA's FoodData Central

Table 2. Some Food Sources of Pantothenic Acid
Food Serving Pantothenic Acid (mg)
Beef liver (pan fried) 3 ounces* 5.9
Mushrooms (shiitake, cooked) ½ cup 2.6
Sunflower seed kernels (dry-roasted) 1 ounce 2.0
Fish, trout (cooked, dry heat) 3 ounces 1.9
Lobster (cooked, moist heat) 3 ounces 1.4
Yogurt (plain, low-fat) 8 ounces 1.3
Avocado (raw, California) ½ fruit 1.0
Sweet potato (baked, with skin) 1 medium 1.0
Milk (skim) 1 cup (8 fluid ounces) 0.87
Pork (tenderloin, lean, roasted) 3 ounces 0.86
Chicken (light meat, roasted) 3 ounces 0.77
Egg (hard-boiled) 1 large 0.70
Lentils (mature seeds, boiled) ½ cup 0.63
Split peas (mature seeds, boiled) ½ cup 0.59
Broccoli (boiled) ½ cup 0.48
Orange (navel) 1 whole 0.37
Peanuts (dry-roasted) 1 ounce 0.29
Cheese, feta 1 ounce 0.27
Whole-wheat bread 1 slice 0.21
*A 3-ounce serving of meat or fish is about the size of a deck of cards.

Intestinal bacteria

The bacteria that normally colonize the colon (large intestine) are capable of synthesizing pantothenic acid. A specialized transporter for the uptake of biotin and pantothenic acid was identified in cultured cells derived from the lining of the colon, suggesting that humans may be able to absorb pantothenic acid and biotin produced by intestinal bacteria (39). However, the extent to which bacterial synthesis contributes to pantothenic acid intake in humans is not known (38, 40).


Pantothenol and pantothenate

Supplements commonly contain pantothenol (panthenol), a stable alcohol analog of pantothenic acid, which can be rapidly converted to pantothenic acid by humans. Calcium D-pantothenate, the calcium salt of pantothenic acid, is also available as a supplement (41)


Pantethine is used as a cholesterol-lowering agent in Japan and is available in the US as a dietary supplement (42)



Pantothenic acid is not known to be toxic in humans. The only adverse effect noted was diarrhea resulting from very high intakes of 10 to 20 g/day of calcium D-pantothenate (43). However, there is one case report of life-threatening eosinophilic pleuropericardial effusion in an elderly woman who took a combination of 10 mg/day of biotin and 300 mg/day of pantothenic acid for two months (44). Due to the lack of reports of adverse effects when the Dietary Reference Intakes (DRI) for pantothenic acid were established in 1998, the Food and Nutrition Board of the Institute of Medicine (now the National Academy of Medicine) did not establish a tolerable upper intake level (UL) for pantothenic acid (22). Pantethine is generally well tolerated in doses up to 1,200 mg/day. However, gastrointestinal side effects, such as nausea and heartburn, have been reported (42). Also, topical formulations containing up to 5% of dexpanthenol (D-panthenol) have been safely used for up to one month. Yet, several cases of skin irritation, allergic contact dermatitis, and eczema have been reported with the use of dexpanthenol-containing ointments (45-49)

Nutrient interactions

Large doses of pantothenic acid have the potential to compete with biotin for intestinal and cellular uptake by the human sodium-dependent multivitamin transporter (hSMVT) (39, 50)

Drug interactions

Oral contraceptives (birth control pills) containing estrogen and progestin may increase the requirement for pantothenic acid (43). Use of pantethine in combination with cholesterol-lowering drugs called statins (HMG-CoA reductase inhibitors) or with nicotinic acid (see the article on Niacin) may produce additive effects on blood lipids (42)

Linus Pauling Institute Recommendation

More data are needed to define the amount of dietary pantothenic acid required to promote optimal health or prevent chronic disease. The Linus Pauling Institute supports the recommendation by the Food and Nutrition Board of 5 mg/day of pantothenic acid for adults. A varied diet should provide enough pantothenic acid for most people. Following the Linus Pauling Institute recommendation to take a daily multivitamin/mineral supplement that contains 100% of the Daily Value (DV) for pantothenic acid will ensure an intake of at least 5 mg/day.

Older adults (>50 years)

There is currently little evidence that older adults differ in their intake of or their requirement for pantothenic acid. Most multivitamin/mineral supplements provide at least 5 mg/day of pantothenic acid.

Authors and Reviewers

Originally written in 2000 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in August 2002 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in May 2004 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in April 2008 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in April 2015 by:
Barbara Delage, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in April 2023 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in July 2015 by:
Robert B. Rucker, Ph.D.
Distinguished Professor Emeritus
Department of Nutrition and School of Medicine
University of California, Davis

Copyright 2000-2024  Linus Pauling Institute


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Riboflavin is a water-soluble B vitamin, also known as vitamin B2. Riboflavin is primarily found as an integral component of the coenzymes flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) (1). Coenzymes derived from riboflavin are termed flavocoenzymes, and enzymes that use a flavocoenzyme are called flavoproteins (2).


Oxidation-reduction (redox) reactions

Living organisms derive most of their energy from redox reactions, which are processes that involve the transfer of electrons. Flavocoenzymes participate in redox reactions in numerous metabolic pathways (3). They are critical for the metabolism of carbohydrates, lipids, and proteins. FAD is part of the electron transport (respiratory) chain, which is central to energy production. In conjunction with cytochrome P-450, flavocoenzymes also participate in the metabolism of drugs and toxins (4).

Antioxidant functions

Glutathione reductase is a FAD-dependent enzyme that participates in the redox cycle of glutathione. The glutathione redox cycle plays a major role in protecting organisms from reactive oxygen species, such as hydroperoxides. Glutathione reductase requires FAD to regenerate two molecules of reduced glutathione from oxidized glutathione. Riboflavin deficiency has been associated with increased oxidative stress (4) Measurement of glutathione reductase activity in red blood cells is commonly used to assess riboflavin nutritional status (5)

Glutathione peroxidases (GPx), selenium-containing enzymes, require two molecules of reduced glutathione to break down hydroperoxides. GPx are involved in the glutathione oxidation-reduction (redox) cycle (Figure 1).

Figure 1. Gutathione Oxidation-Reduction (Redox) Cycle. One molecule of hydrogen peroxide is reduced to two molecules of water, while two molecules of glutathione (GSH) are oxidized in a reaction catalyzed by the selenoenzyme, glutathione peroxidase.

Xanthine oxidase, another FAD-dependent enzyme, catalyzes the oxidation of hypoxanthine and xanthine to uric acid. Uric acid is one of the most effective water-soluble antioxidants in the blood. Riboflavin deficiency can result in decreased xanthine oxidase activity, reducing blood uric acid levels (6).

Nutrient interactions

Riboflavin (as FAD or FMN) is required for the synthesis of niacin from tryptophan, and in the metabolism of vitamin B6 and iron. It is also essential for folate and related one-carbon metabolism, where FAD is required as a cofactor for methylenetetrahydrofolate reductase (MTHFR), a key folate-metabolizing enzyme.

B-complex vitamins

Flavoproteins are involved in the metabolism of several other vitamins: vitamin B6, niacin, vitamin B12, and folate. Therefore, low and deficient riboflavin status can affect several enzyme systems. The conversion of vitamin B6 to its active coenzyme form in tissues, pyridoxal 5'-phosphate (PLP), requires the FMN-dependent enzyme, pyridoxine 5'-phosphate oxidase (PPO) (7). Human studies have provided evidence of the metabolic dependency of vitamin B6 on riboflavin status in older (8-10) and younger (10) adults. The synthesis of the niacin-containing coenzymes, NAD and NADP, from the amino acid tryptophan, requires the FAD-dependent enzyme, kynurenine 3-monooxygenase. Severe riboflavin deficiency can thus decrease the conversion of tryptophan to NAD and NADP, increasing the risk of niacin deficiency (3).

Methylenetetrahydrofolate reductase (MTHFR) is an FAD-dependent enzyme that plays a key role in one-carbon metabolism by catalyzing the reduction of 5,10 methyleneTHF to 5 methylTHF. Once formed, 5 methylTHF is used by methionine synthase for the vitamin B12-dependent conversion of homocysteine to methionine and the formation of THF (Figure 2). Both FMN and FAD are coenzymes for the enzyme methionine synthase reductase, which is responsible for the regeneration of methylcobalamin, the biologically active form of vitamin B12 acting as a coenzyme for methionine synthase (11). Along with other B vitamins (folate, vitamin B12, and vitamin B6), higher dietary riboflavin intakes have been associated with lower plasma concentrations of homocysteine (12). In individuals homozygous for the C677T polymorphism in the MTHFR gene, low riboflavin status is associated with elevated plasma homocysteine, and in turn linked with a higher risk of cardiovascular disease and other chronic diseases (13, 14). Furthermore, supplementation with riboflavin results in marked lowering of homocysteine concentrations specifically in individuals with the variant MTHFR 677TT genotype (15). Such results illustrate that chronic disease risk may be influenced by complex interactions between genetic and dietary factors.

Figure 2. Folate and Nucleic Acid Metabolism. 5-10-methylenetetrahydrofolate is required for the synthesis of nucleic acids, and 5-methyltetradydrofolate is required for the formation of methionine from homocysteine. Methionine, in the form of S-adenosylmethionine, is required for many methylations reactions, including DNA methylation. Methylenetetrahydrofolate reductase is a flavin-dependent enzyme required to catalyze the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahdrofolate.


Riboflavin deficiency alters iron metabolism. Although the mechanism is not clear, research in animals suggests that riboflavin deficiency may impair iron absorption, increase intestinal loss of iron, and/or impair iron utilization for the synthesis of hemoglobin (16). In humans, low dietary intake of riboflavin has been associated with an increased risk for anemia (17), and improving riboflavin nutritional status has been found to increase circulating hemoglobin levels (18). Correction of riboflavin deficiency in individuals who are both riboflavin and iron deficient improves the response of iron-deficiency anemia to iron therapy (19). Anemia during pregnancy, a worldwide public health problem, is responsible for considerable perinatal morbidity and mortality (20, 21). The management of maternal anemia typically involves supplementation with iron alone or iron in combination with folic acid (22). It is possible that the inclusion of riboflavin could enhance the effects of iron-folic acid supplementation in treating maternal anemia, but the evidence is limited. There are, however, randomized, double-blind intervention trials conducted in pregnant women with anemia in Southeast Asia showing that a combination of folic acid, iron, vitamin A, and riboflavin improved hemoglobin levels and decreased anemia prevalence compared to iron-folic acid supplementation alone (23, 24).


Ariboflavinosis is the medical name for clinical riboflavin deficiency, which occurs commonly in low- and middle-income countries. Riboflavin deficiency is rarely found in isolation; it typically occurs in combination with deficiencies of other water-soluble vitamins. Clinical signs of riboflavin deficiency include sore throat, redness and swelling of the lining of the mouth and throat, cracks or sores on the outsides of the lips (cheliosis) and at the corners of the mouth (angular stomatitis), inflammation and redness of the tongue (magenta tongue), and a moist, scaly skin inflammation (seborrheic dermatitis). Other signs may involve the formation of blood vessels in the clear covering of the eye (vascularization of the cornea) and decreased red blood cell count in which the existing red blood cells contain normal levels of hemoglobin and are of normal size (normochromic normocytic anemia) (1, 3). Subclinical deficiency (low status) of riboflavin without clinical signs may be widespread, including in high-income countries, but usually goes undetected because riboflavin biomarkers are very rarely measured in human studies. Low or deficient riboflavin status may result in decreased conversion of vitamin B6 to its active coenzyme form (PLP) and decreased conversion of tryptophan to niacin (see Nutrient interactions).

Preeclampsia is defined as the presence of elevated blood pressure, protein in the urine, and edema (significant swelling) during pregnancy. About 5% of women with preeclampsia progress to eclampsia, a significant cause of maternal and fetal death. Eclampsia is characterized by seizures, in addition to high blood pressure and increased risk of hemorrhage (severe bleeding) (25). A study in 154 pregnant women at increased risk of preeclampsia found that those who were riboflavin deficient were 4.7 times more likely to develop preeclampsia than those who had adequate riboflavin nutritional status (26). The cause of preeclampsia-eclampsia is not known. Decreased intracellular levels of flavocoenzymes could cause mitochondrial dysfunction, increase oxidative stress, and interfere with nitric oxide release and thus blood vessel dilation – all of these changes have been associated with preeclampsia (26).

A 2015 meta-analysis of 54 case-control studies found that the MTHFR C677T polymorphism was associated with an increased risk of preeclampsia, especially in Caucasian and Asian populations (27). The reduction in the flavoprotein MTHFR activity observed in individuals with the variant MTHFR 677TT genotype leads to an increase in plasma homocysteine (14); higher homocysteine concentrations have been associated with preeclampsia (28). One small randomized controlled trial in 450 pregnant women in West Africa, without specified MTHFR genotype but at high risk for preeclampsia, found that supplementation with 15 mg of riboflavin daily was not effective in preventing the condition (29), but the study was likely underpowered to detect a significant effect. Further studies are needed to assess the potential benefit of riboflavin supplementation in reducing perinatal complications generally and specifically in preeclamptic women with the MTHFR 677TT genotype.

Risk factors for riboflavin deficiency

Alcoholics are at an increased risk of riboflavin deficiency, likely due to decreased dietary intake, decreased absorption, and/or impaired utilization of riboflavin. Interestingly, the elevated blood homocysteine concentrations associated with riboflavin deficiency rapidly decline during alcohol withdrawal (30). Additionally, people with anorexia rarely consume adequate dietary riboflavin, and those who are lactose intolerant are unlikely to meet requirements due to the avoidance of dairy products, the major dietary sources of riboflavin. The conversion of riboflavin into the active cofactor forms FAD and FMN is impaired in hypothyroidism and adrenal insufficiency (3, 4). Further, people who are very active physically (athletes, laborers) may have slightly increased riboflavin requirements. However, riboflavin supplementation has not generally been found to increase exercise tolerance or performance (31) unless the individuals are riboflavin deficient (32).  

The Recommended Dietary Allowance (RDA)

The RDA for riboflavin, revised in 1998, is based on the prevention of deficiency (Table 1). Clinical signs of deficiency in humans appear at intakes of less than 0.5 to 0.6 milligrams (mg)/day, and urinary excretion of riboflavin is seen at intake levels of approximately 1 mg/day (1).

Table 1. Recommended Dietary Allowance (RDA) for Riboflavin
Life Stage Age Males (mg/day) Females (mg/day)
Infants  0-6 months  0.3 (AI 0.3 (AI) 
Infants  7-12 months  0.4 (AI)  0.4 (AI) 
Children  1-3 years  0.5  0.5 
Children  4-8 years  0.6  0.6 
Children  9-13 years  0.9  0.9 
Adolescents  14-18 years  1.3  1.0 
Adults  19 years and older  1.3  1.1 
Pregnancy  all ages  1.4 
Breast-feeding  all ages  1.6

Disease Prevention


Age-related cataracts are the leading cause of visual disability in the US and other developed countries. Research has focused on the role of nutritional antioxidants because of evidence that light-induced oxidative damage of lens proteins may lead to the development of age-related cataracts. A case-control study found significantly decreased risk of age-related cataracts (33% to 51%) in men and women in the highest quintile of dietary riboflavin intake (median of 1.6 to 2.2 mg/day) compared to those in the lowest quintile (median of 0.08 mg/day in both men and women) (33). Another case-control study reported that individuals in the highest quintile of riboflavin status, as measured by red blood cell glutathione reductase activity, had approximately one-half the occurrence of age-related cataract as those in the lowest quintile of riboflavin status, though the results were not statistically significant (34). A cross-sectional study of 2,900 Australian men and women, 49 years of age and older, found that those in the highest quintile of riboflavin intake were 50% less likely to have cataracts than those in the lowest quintile (35). A prospective cohort study of more than 50,000 women did not observe a difference between rates of cataract extraction between women in the highest quintile of riboflavin intake (median of 1.5 mg/day) and women in the lowest quintile (median of 1.2 mg/day) (36). However, the range between the highest and lowest quintiles was small, and median intake levels for both quintiles were above the RDA for riboflavin. A study in 408 women found that higher dietary intakes of riboflavin were inversely associated with a five-year change in lens opacification (37). A randomized controlled trial using a fractional factorial design showed that compared with placebo, the combined supplementation with riboflavin (3 mg/day) and niacin (40 mg/day) for five to six years reduced the prevalence of nuclear cataract but increased the progression of posterior subcapsular cataracts in population affected by multiple nutrient deficiency living in rural China (38). Of note is that the results of this trial are somewhat conflicting, and the study design does not allow the effects of riboflavin and niacin to be differentiated. In summary, there is some evidence predominantly from observational studies, that suggests higher riboflavin status might be beneficial; however, more evidence from well-designed, randomized controlled trials is needed to confirm a role for riboflavin in the prevention of cataracts. 


The flavoprotein, methylenetetrahydrofolate reductase (MTHFR), plays a pivotal role in folate-mediated one-carbon metabolism. MTHFR converts 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, the cofactor form necessary for the re-methylation of homocysteine to methionine (see Figure 2 above). The conversion of homocysteine to methionine is of importance for homocysteine detoxification and for the production of S-adenosylmethionine (SAM), the methyl donor for the methylation of DNA and histones. Folate deficiency and elevated homocysteine concentrations may increase cancer risk (see the article on Folate). Aberrant methylation changes are also known to alter the structure and function of DNA and histones during cancer development (39). Since MTHFR controls the detoxification of homocysteine and the supply of methyl groups for SAM synthesis, a reduction in its activity can affect homocysteine metabolism and disturb cellular methylation processes. The substitution of a cytosine by a thymine in position 677 (c.677C>T) in the MTHFR gene is a polymorphism that affects the binding of FAD and leads to an increased propensity for MTHFR to lose its flavin coenzyme (40). Subjects homozygous for this mutation (MTHFR 677TT genotype) exhibit reduced MTHFR activity and increased risk for a wide variety of cancers (41-43), but the evidence of an association between this polymorphism and cancer is inconsistent, with some reports suggesting a reduction in colorectal cancer risk with the T allele (44).

As mentioned above (see B-complex vitamins), riboflavin intake is a determinant of homocysteine concentration. This suggests that riboflavin status can influence MTHFR activity and the metabolism of folate, thereby affecting cancer risk (43). In a randomized, double-blind, placebo-controlled study, 93 subjects with colorectal polyps and 86 healthy subjects were given a placebo, folic acid (400 or 1,200 μg/day), or folic acid (400 μg/day) plus riboflavin (5 mg/day) for 45 days. These interventions significantly improved folate and riboflavin status in vitamin-supplemented individuals compared to those taking the placebo. Interestingly, riboflavin enhanced the effect of 400 μg folic acid on circulating 5-methyltetrahydrofolate (5-MTHF) specifically in the polyp patients with the C677T genetic variant (45). This suggests that riboflavin may improve the response to folic acid supplementation in individuals with a reduced MTHFR activity. Additionally, a prospective cohort study of 88,045 postmenopausal women found total (dietary plus supplemental) intake of riboflavin to be inversely correlated with colorectal cancer risk when comparing the highest (>3.97 mg) and lowest (<1.80 mg) quartiles of daily intake (46); intake in the reference group was well above the RDA for riboflavin of 1.1 mg/day. The subjects in this study were not prescreened to identify those with the variant MTHFR 677TT genotype, and the association between this polymorphism and colorectal cancer remains unclear, with some reports suggesting a reduction in cancer risk with the T allele (44). Two meta-analyses have found inverse associations between riboflavin intake and risk of colorectal cancer (47, 48). The most recent of these was a dose-response meta-analysis that pooled results from five prospective cohort studies, nine case-control studies, and two studies reporting blood concentrations of riboflavin. This analysis found that higher intakes of riboflavin were associated with a significantly lower risk of colorectal cancer (RR=0.87; 95% CI, 0.81-0.93); inverse associations were observed for both dietary riboflavin intake and total daily intake from the diet and supplements (48).

Associations between riboflavin intake and cancer risk have also been evaluated in other types of cancer. A seven-year intervention study evaluated the use of riboflavin-fortified salt in 22,093 individuals at high risk for esophageal cancer in China. Riboflavin status and esophageal pathology (percent normal, dysplastic, and cancerous tissues) improved in the intervention group compared to the control group, but the lower incidence of esophageal cancer found in the intervention group was not statistically significant (49). Additionally, a 25-year follow up of an intervention trial in patients at high risk for gastric cancer found that dietary supplementation with riboflavin (3.2 mg/day) and niacin (40 mg/day) for five years decreased the risk of mortality from esophageal cancer by 8% but had no effect on mortality from gastric cancer (50). In the Melbourne Collaborative Cohort Study, which followed 41,514 men and women over a 15-year period, weak inverse associations were found between riboflavin intake and lung cancer (51) and breast cancer (52); no association of riboflavin intake with prostate cancer was observed in this cohort (53). A 2017 meta-analysis of 10 observational studies found an overall inverse association of riboflavin intake and breast cancer incidence and reported a 6% lower risk with each 1 mg/day increment of riboflavin intake (54). Further, studies to date have not found riboflavin intake or measures of riboflavin status to be associated with renal cell carcinoma, as reviewed in a recent meta-analysis (55).

Disease Treatment

Migraine headaches

Some evidence indicates that impaired mitochondrial oxygen metabolism in the brain may play a role in the pathology of migraine headaches. Since riboflavin is the precursor of the two flavocoenzymes (FAD and FMN) required by the flavoproteins of the mitochondrial electron transport chain, supplemental riboflavin has been investigated as a treatment for migraine. A randomized controlled trial examined the effect of very high dose riboflavin (400 mg/day) for three months on migraine prevention in 54 men and women with a history of recurrent migraine headaches (56). Riboflavin compared to placebo reduced attack frequency and the number of headache days, though the beneficial effect was most pronounced during the third month of treatment (56). Another study by the same investigators found that treatment with either a β-blocker drug or high-dose riboflavin (400 mg/day) for four months resulted in clinical improvement, but each therapy appeared to act on a distinct pathological mechanism: β-blockers on abnormal cortical information processing and riboflavin on decreased brain mitochondrial energy reserve (57). A small study in 23 patients reported a reduction in median migraine attack frequency after supplementation with 400 mg of riboflavin daily for three months (58). A single-blinded, randomized, parallel group trial in 85 patients with migraine headaches (ages 15-55 years), high-dose riboflavin supplementation (400 mg/day) for 12 weeks decreased migraine frequency, duration, and severity compared to baseline and was as effective as sodium valproate (500 mg/day) (59), a medication with established efficacy in migraine preventative therapy (60). Riboflavin elicited significantly fewer adverse effects compared to the drug (59). Thus, although the available trials have been small and short term, most studies to date suggest that high-dose riboflavin supplementation might be a useful adjunct therapy in adults with migraine headaches.

A few randomized controlled trials have investigated the effect of riboflavin supplementation on the frequency and severity of headache attacks in children with migraines. An initial study evaluated riboflavin at 200 mg/day for 12 weeks in 48 children of ages 5 to 15 years old (61). A second study was a cross-over trial with half of the 42 children, ages 6 to 13, receiving 50 mg/day riboflavin for 16 weeks then placebo (100 mg/day carotene) for 16 weeks (with a four-week washout period in between each), while the other half were first given the placebo then riboflavin (62). Neither study showed differences in the frequency, duration, or intensity of migraines between treatments. However, a more recent trial found a benefit of intervention with higher dose riboflavin: children with migraine treated with 400 mg/day of riboflavin for 12 weeks (n=30) had reductions in migraine frequency and duration, but not intensity, compared to placebo (n=30), yet no benefit was seen in children taking 200 mg/day for 12 weeks in this study (63). Additionally, a randomized controlled trial in 98 adolescents, ages 12 to 19 years, found that 400 mg/day of riboflavin for three months decreased both headache frequency and duration and improved migraine-related disability compared to placebo (64). Retrospective studies of children and adolescents suffering from migraine have also suggested some benefit associated with supplemental riboflavin (65-67). Thus, studies to date are somewhat conflicting, and more research is needed to understand whether riboflavin supplementation might have utility in the treatment of childhood migraine and the most effective dose required for any beneficial effects.

Metabolic disorders

Increasing evidence from case reports indicates that patients with autosomal recessive disorders caused by defective FAD-dependent enzymes could benefit from riboflavin supplementation.

Multiple acyl-CoA dehydrogenase deficiency (MADD)

MADD, also known as type II glutaric aciduria (or acidemia), is a fatty acid metabolism disorder characterized by the accumulation of short-, medium-, and long-chain acyl-carnitines in various tissues. MADD is classified into three separate types based on age of onset and clinical symptoms: type I MADD is evident in the neonatal period and is characterized by the presence of congenital anomalies; type II MADD is present in the neonatal period but lacks congenital defects; and type III is characterized by late onset, from infancy through adulthood (68), and even as late as the seventh decade of life (69). Clinical symptoms of type I and II MADD present shortly after birth and include hypoglycemia, hyperammonemia, metabolic acidosis, hepatomegaly, and respiratory distress (68, 70); these forms of MADD are often fatal in infancy, even if treated. Type III MADD usually presents later in life and includes milder symptoms, varying from periodic vomiting, rhabdomyolysis, muscle pain and weakness, and exercise intolerance (68, 70). Peripheral neuropathy has also recently been reported as a symptom of adult-onset MADD (71).

MADD is caused by autosomal recessive mutations in genes that impair the activity of enzymes involved in the transfer of electrons from acyl-coenzyme A (acyl-CoA) to coenzyme Q10/ubiquinone inside the mitochondria (Figure 3). ETFA, ETFB, and ETFDH code for the two subunits of the electron transfer flavoprotein (ETF-A and -B) and for ETF dehydrogenase/ubiquinone oxidoreductase (ETFDH/ETFQO), respectively. Deficiencies in these enzymes (ETF or ETFDH) lead to a decrease in oxidized FAD, which becomes unavailable for FAD-dependent dehydrogenation reactions, including the first step in β-oxidation – a major fatty acid catabolic process that takes place in the mitochondria. A defect in fatty acid β-oxidation causes lipid accumulation in skeletal muscles, leading to lipid storage myopathy characterized by muscle pain and weakness and exercise intolerance.

Together with a low-fat, high-carbohydrate diet, riboflavin supplementation has led to significant clinical improvements in patients with ETFDH mutations. The specific type of the mutation in ETF/ETFDH contributes to age of onset, severity, and responsiveness to riboflavin treatment (70, 72). Additionally, the report of a 20-year-old man with riboflavin-responsive MADD failed to find mutations in ETF and ETFDH genes, suggesting that other sites of mutation should not be excluded (73). Finally, secondary deficiencies in the respiratory chain are observed in MADD and appear to respond favorably to riboflavin supplementation (72, 74).

Figure 3. Fatty Acid Beta-Oxidation and the Electron Transfer Flavoprotein System. Multiple Acyl-CoA Dehydrogenase Deficiency (MADD) is caused by mutations in the genes coding for the electron transfer flavoprotein and the electron transfer flavoprotein-ubiquinone oxidoreductase system. These flavoproteins are essential for electron transfer from the fatty acid beta-oxidation pathway to the respiratory chain.

Acyl-CoA dehydrogenase 9 deficiency (ACAD9)

Acyl-CoA dehydrogenase family member 9 (ACAD9) is an FAD-dependent enzyme with important roles in both the electron transport chain and β-oxidation of fatty acids in the mitochondria. Recessive mutations in the ACAD9 gene coding for ACAD9 have been found in patients with mitochondrial complex I deficiency, a respiratory chain disorder (75). Complex I carries electrons from NADH to coenzyme Q10 in the electron transport chain. Defective oxidative phosphorylation (ATP synthesis by the respiratory chain) due to complex I deficiency has been linked to a broad variety of clinical manifestations, from neonatal death to late-onset neurodegenerative diseases. The clinical symptoms of complex I deficiency due to ACAD9 mutations typically include muscle weakness, exercise intolerance, lactic acidosis, and hypertrophic cardiomyopathy (76). However, symptoms can be of varying severity, likely due to the remaining functional activity of ACAD9. For example, affected patients have been reported to exhibit a spectrum of cardiac deficits, including isolated, mild ventricular hypertrophy to severe hypertrophic cardiomyopathy (77).

Riboflavin supplementation (100-300 mg/day) has been shown to increase complex I activity in patients with childhood-onset clinical forms of ACAD9 deficiency. Improvements in muscle strength and exercise tolerance have also been associated with riboflavin supplementation (78-80). A review of cases of ACAD9 deficiency presenting in infancy (i.e., cases with severe symptoms) found riboflavin treatment to be associated with improved survival: 7 of 22 patients treated with riboflavin succumbed to the illness compared to 16 out of 17 untreated patients (76)

Defective riboflavin transport-associated disorders

SLC52A1, SLC52A2, and SLC52A3 genes code for the human riboflavin transporters RFVT1, RFVT2, and RFVT3, respectively. Mutations in these genes lead to riboflavin transporter deficiency, a rare neurodegenerative condition with variable age of onset, from infancy to early stages of adulthood. Autosomal recessive mutations in SLC52A2 or SLC52A3 respectively cause disorders known as riboflavin transporter deficiency type 2 (RFVT2 deficiency) and riboflavin transporter deficiency type 3 (RFVT3 deficiency). These genetic disorders were formerly called Brown-Vialetto-Van Laere syndrome and Fazio-Londe syndrome (81). Riboflavin transporter deficiency caused by mutation of SLC52A1 is exceedingly rare and has been reported in only three cases (reviewed in 82).

Clinical features of riboflavin transporter deficiency can include muscle weakness in the arms and legs, sensory ataxia, bulbar palsy with hypotonia and facial weakness, sensorineural deafness, and respiratory insufficiency (83, 84). High-dose, oral supplementation with riboflavin improves many of these symptoms in the majority of affected patients; such treatment should be given at the time of suspected riboflavin transporter deficiency for a better prognosis (84). A 2016 review of the published literature found that oral supplementation with riboflavin – at doses ranging from 7 to 60 mg/kg/day – led to improved symptoms in 71% of the patients (n=39) and to no deaths (83). In contrast, all of the untreated patients (n=31) had a progression of the disease and a mortality rate of at least 48% (83).

Riboflavin-responsive trimethylaminuria

Primary trimethylaminuria is caused by defective oxidation of trimethylamine by a liver flavoprotein called flavin containing mono-oxygenase 3 (FMO3). Individuals with FMO3 deficiency have increased levels of trimethylamine in urine, sweat, and breath (85). This socially distressing condition is known as "fish odor syndrome" due to the fishy odor and volatile nature of trimethylamine. FMO3 gene mutations are usually associated with mild or intermittent trimethylaminuria; the condition is sometimes limited to peri-menstrual periods in female subjects or to the consumption of trimethylamine-rich food. The clinical management of the condition includes dietary restriction of trimethylamine and its precursors, such as foods rich in choline and seafood, as well as cruciferous vegetables that contain both trimethylamine precursors and FMO3 antagonists (86). The use of riboflavin supplements was reported in a 17-year-old female patient affected by pyridoxine non-responsive homocystinuria (87). The disease was initially treated with betaine (a choline derivative), which caused body odor secondary to FMO3 deficiency. Riboflavin supplementation (200 mg/day) reduced trimethylamine excretion and the betaine treatment-related body odor. Similar effects were seen with riboflavin supplementation in two pediatric patients (88). The data suggest that riboflavin might help maximize residual FMO3 enzyme activity in patients with primary trimethylaminuria. Moreover, a recent case report in a 35-year-old male with HIV described supplemental riboflavin as an effective treatment for secondary trimethylaminuria caused by antiretroviral therapy (89).


Hypertension in adulthood is recognized as the leading risk factor contributing to mortality worldwide primarily from cardiovascular disease, while hypertension in pregnancy leads to serious adverse fetal and maternal outcomes. A number of risk factors are recognized to contribute to the development of hypertension. In recent years, evidence has emerged from genetic and clinical studies pointing to the role of one-carbon metabolism in blood pressure (90). The common MTHFR C677T polymorphism, affecting 1 in 10 adults globally, is associated with higher blood pressure, although this is much less well recognized compared with the phenotype of elevated homocysteine concentrations that was established at the time of discovery of this polymorphism and its link with cardiovascular disease (91). Meta-analyses show that this polymorphism is associated with an increased risk of hypertension by up to 87% and of heart disease and stroke by up to 40% (92). The MTHFR C677T polymorphism is also associated with a significantly higher risk of hypertension in pregnancy (93) and with preeclampsia (27).

Since FAD is required as a cofactor for the MTHFR enzyme and the MTHFR C677T polymorphism results in decreased MTHFR activity, studies have investigated whether affected individuals may benefit from riboflavin supplementation. In an initial randomized controlled trial in 77 healthy young adults stratified by MTHFR genotype, riboflavin supplementation at dietary levels (1.6 mg/day for 12 weeks) resulted in marked lowering of homocysteine concentrations in the MTHFR 677TT genotype group, but not in the 677CC or 677CT genotype groups who exhibited normal plasma homocysteine at baseline (15). Three randomized controlled trials subsequently investigated the effect of riboflavin on blood pressure in patients with hypertension with or without overt cardiovascular disease (91, 94, 95). The results of these trials showed that supplementation with low-dose riboflavin (1.6 mg/day for 16 weeks) resulted in significant lowering of blood pressure and reduction in incidence of hypertension specifically in those patients with the variant MTHFR 677TT genotype. Riboflavin intervention reduced mean systolic/diastolic blood pressure in those with the TT genotype from 144/87 to 131/80 mm Hg, with no response observed in those without the genetic variant (i.e., the CT or CC genotypes) (89). Notably, the 13 mm Hg decrease in systolic blood pressure occurred even though over 80% of the patients were taking one or more antihypertensive drugs at recruitment, and the addition of supplemental riboflavin was shown to greatly enhance the achievement of goal blood pressure with routine antihypertensive drugs (89, 91). Furthermore, the magnitude of blood pressure response achieved with riboflavin in these trials compares very favorably with typical decreases from other interventions, such as dietary salt reductions of 3 g/day (3.6/1.9 mm Hg) and 6 g/day (7.1/3.9 mm Hg). The trial findings therefore suggest that the excess risk of hypertension linked to this genetic polymorphism can be overcome by low-dose riboflavin supplementation. Also, analysis of plasma samples from individuals participating in these trials showed lower concentrations of S-adenosylmethionine (SAM), an important methyl group donor for methylation reactions, in those with the MTHFR 677TT genotype versus the CC genotype (96). However, riboflavin supplementation (1.6 mg/day) for 12 weeks was shown to increase plasma concentrations of SAM and another one-carbon metabolite, cystathionine (96), and thus may have potential in correcting the altered one-carbon metabolism arising with the variant TT genotype.

Thus, studies to date indicate that riboflavin supplementation may have benefits in lowering blood pressure and reducing hypertension in individuals (and sub-populations) affected by the common MTHFR C677T polymorphism. However, the mechanisms explaining the blood pressure phenotype and its responsiveness to riboflavin remain unclear. Future studies examining the effects of riboflavin supplementation on one-carbon metabolism may help to elucidate the biological mechanisms involved. Interestingly, a recent randomized controlled trial found that riboflavin supplementation in those with the variant MTHFR 677TT genotype resulted in altered DNA methylation of certain genes known to be involved in blood pressure regulation (97).


Anticancer agents often display various side effects that may force patients to limit the dose or to discontinue the treatment. The antioxidant effect of co-administering riboflavin (10 mg/day), niacin (50 mg/day), and coenzyme Q10 (100 mg/day) was evaluated in 78 postmenopausal patients with breast cancer treated with tamoxifen for 90 days. This supplementation effectively prevented the oxidative stress associated with tamoxifen treatment (98).

Riboflavin can also act as a photosensitizer, and this property may have value in photodynamic therapy of cancer. A mouse model was used to assess the effect of riboflavin in combination with cisplatin, one of the most effective anticancer agents. Under light exposure, riboflavin administration reduced cisplatin-induced DNA damage in the liver and kidneys (99). These results are promising, but human studies are needed to examine whether riboflavin is an effective adjunct to chemotherapy.

Corneal disorders

Corneal ectasia is an eye condition characterized by irregularities of the cornea that affect vision. Corneal cross-linking – a fairly new procedure used by professionals to limit the progression of corneal damage –involves the use of topical riboflavin in conjunction with ultraviolet-A irradiation. Riboflavin functions as a photosensitizer in the reaction. Cross-linking modifies the properties of the cornea and strengthens its architecture (100, 101).

Multiple sclerosis

Multiple sclerosis (MS) is an autoimmune disease of unknown etiology that is characterized by the progressive destruction of myelin and nerve fibers in the central nervous system, causing neurological symptoms in affected individuals (102). Riboflavin appears to have a role in the formation of myelin (103), and oxidative stress has been implicated in the pathogenesis of MS; thus, riboflavin may be helpful in treatment of the disease. A strong inverse association between dietary riboflavin intake and risk for MS was initially observed in a case-control study (104). In a mouse model of MS (i.e., experimental autoimmune encephalomyelitis), riboflavin supplementation improved clinical measures of the disease (105). However, a randomized, double-blind, placebo-controlled pilot study in 29 patients with MS found that supplementation with 10 mg/day of riboflavin for six months had no effect on MS-related disability, assessed by the Expanded Disability Status Scale (106).  Large-scale randomized, placebo-controlled trials are needed to determine whether riboflavin supplementation has a beneficial effect in the treatment of MS.


Food sources

Most plant- and animal-derived foods contain at least small quantities of riboflavin. In the US, wheat flour and bread have been enriched with riboflavin (as well as thiamin, niacin, and iron) since 1943. Data from a US national survey indicate that the average dietary intake of riboflavin is 2.5 mg/day for men and 1.8 mg/day for women (107); these intakes are well above the RDA values of 1.3 mg/day for men and 1.1 mg/day for women. Surveys of adults of ages 70 years or older showed similar intakes: 2.2 mg/day for older men and 1.8 mg day for older women (107).

Riboflavin is heat-stable, but it is easily destroyed upon exposure to light. For instance, up to 50% of the riboflavin in milk contained in a clear glass bottle can be destroyed after two hours of exposure to bright sunlight (6). Nationally representative surveys from the US, Ireland, and the UK showed that milk and other dairy products were the main dietary contributors to riboflavin intake, followed by meat and ready-to-eat breakfast cereals (108-110). Some foods with substantial amounts of riboflavin are listed in Table 2, along with their riboflavin content in milligrams (mg). For more information on the nutrient content of food, search USDA's FoodData Central.

The bioavailability of riboflavin from food is reported to be very high, nearly 95% (108). Limited data exist for the relative bioavailability of riboflavin from different food sources, however a cross-over study in healthy women using stable isotopes and kinetic modeling did not find significant differences in riboflavin absorption from milk and spinach (111).

Table 2. Some Food Sources of Riboflavin
Food Serving Riboflavin (mg)
Fortified breakfast wheat, puffed cereal 1 cup 0.22
Milk (low-fat, 1%) 1 cup 0.42
Cheddar cheese 1 ounce 0.12
Egg (cooked, hard-boiled) 1 large 0.26
Almonds, unsalted 1 ounce 0.33
Salmon (chinook, cooked) 3 ounces* 0.13
Halibut (greenland, cooked, dry-heat) 3 ounces 0.09
Chicken, light meat (roasted) 3 ounces 0.09
Chicken, dark meat (roasted) 3 ounces 0.16
Beef (ground, cooked) 3 ounces 0.16
Broccoli (boiled, chopped) ½ cup 0.10
Asparagus (boiled) ½ cup 0.13
Spinach (boiled) ½ cup 0.21
Bread, whole-wheat 1 slice 0.05
Bread, white (enriched) 1 slice 0.07
*A three-ounce serving of meat is about the size of a deck of cards.


The most common forms of riboflavin available in supplements are riboflavin and riboflavin 5'-monophosphate. Riboflavin is commonly found in multivitamin and vitamin B-complex preparations (112)



No toxic or adverse effects of high riboflavin intake in humans are known. Studies in cell culture indicate that excess riboflavin may increase the risk of DNA strand breaks in the presence of chromium (VI), a known carcinogen (113). This may be of concern to workers exposed to chrome, yet no data in humans are available. High-dose riboflavin therapy has been found to intensify urine color to a bright yellow (flavinuria), but this is a harmless side effect. The Food and Nutrition Board did not establish a tolerable upper intake level (UL) when the RDA was revised in 1998 (1)

Drug interactions

Several early reports indicated that women taking high-dose oral contraceptives had diminished riboflavin biomarker status. However, when investigators controlled for dietary riboflavin intake, no differences between users of oral contraceptives and non-users were found (1). Phenothiazine derivatives like the anti-psychotic medication, chlorpromazine (Thorazine), and tricyclic antidepressants inhibit the conversion of riboflavin to FAD and FMN, as do the anti-malarial medication, quinacrine, and the cancer chemotherapy agent, adriamycin (4). Long-term use of the anticonvulsant, phenobarbitol, may increase destruction of riboflavin by liver enzymes, increasing the risk of deficiency (3). Additionally, chronic alcohol consumption has been associated with riboflavin deficiency. In rats chronically fed alcohol, the inhibition of riboflavin transporters caused impairment in intestinal absorption and renal re-uptake of the vitamin (114).

Linus Pauling Institute Recommendation

The RDA for riboflavin (1.3 mg/day for men and 1.1 mg/day for women), which should prevent deficiency in most individuals, is easily met by eating a varied diet. Consuming a varied diet should supply 1.5 mg to 2 mg of riboflavin a day. Following the Linus Pauling Institute recommendation to take a multivitamin/mineral supplement containing 100% of the Daily Values (DV) will ensure an intake of at least 1.3 mg/day of riboflavin.

Older adults (>50 years)

Some experts in nutrition and aging feel that the RDA (1.3 mg/day for men and 1.1 mg/day for women) leaves little margin for error in people over 50 years of age (115, 116). A study of independently living people between 65 and 90 years of age found that almost 25% consumed less than the recommended riboflavin intake, and 10% had biochemical evidence of deficiency (117). Epidemiological studies of cataract prevalence indicate that riboflavin intakes of 1.6 to 2.2 mg/day may reduce the risk of developing age-related cataracts. Additionally, older people suffering from acute ischemic stroke were found to be deficient for riboflavin (118), and riboflavin deficiency has been linked to a higher risk of fracture in postmenopausal women with the MTHFR 677T variant (119). Individuals whose diets may not supply adequate riboflavin, especially those over 50 years of age, should consider taking a multivitamin/mineral supplement, which generally provides at least 1.3 mg/day of riboflavin.

Authors and Reviewers

Originally written in 2000 by: 
Jane Higdon, Ph.D. 
Linus Pauling Institute 
Oregon State University

Updated in September 2002 by: 
Jane Higdon, Ph.D. 
Linus Pauling Institute 
Oregon State University

Updated in June 2007 by: 
Victoria J. Drake, Ph.D. 
Linus Pauling Institute 
Oregon State University

Updated in July 2013 by: 
Barbara Delage, Ph.D. 
Linus Pauling Institute 
Oregon State University

Updated in August 2021 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in July 2022 by:
Kristina Pentieva, MD, Ph.D. and Helene McNulty, RD, Ph.D.
Nutrition Innovation Centre for Food and Health (NICHE)
Ulster University, Coleraine, Northern Ireland

Copyright 2000-2024  Linus Pauling Institute


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  • Thiamin pyrophosphate (TPP), the active form of thiamin, is involved in several enzyme functions associated with the metabolism of carbohydrates, branched-chain amino acids, and fatty acids(More information)
  • Severe thiamin deficiency leads to beriberi, a disease that affects multiple organ systems, including the central and peripheral nervous systems. (More information)
  • Wernicke’s encephalopathy refers to an acute neurologic disorder secondary to thiamin deficiency. The Wernicke-Korsakoff syndrome results in persistent alterations in memory formation, along with the encephalopathy-related symptoms. (More information)
  • Thiamin deficiency can result from poor dietary intake, inadequate provision in parenteral nutrition, reduced gastrointestinal absorption, increased metabolic requirements, or excessive loss of thiamin. Chronic alcohol consumption is the primary cause of thiamin deficiency in industrialized countries. (More information)
  • Alteration in glucose metabolism has been associated with decreased plasma thiamin concentrations in patients with diabetes. Correction of thiamin deficiency may reduce the risk of vascular complications in these patients. (More information)
  • Alzheimer’s disease has been associated with altered glucose metabolism and thiamin deficiency. Although some promising results have been observed in animal models, it is not known whether supplementation with thiamin or benfotiamine (a synthetic precursor of thiamin) might slow the cognitive decline in patients with Alzheimer’s disease. (More information)
  • A recent study found decreased levels of thiamin in the brain of patients with Huntington’s disease. Clinical trials are needed to evaluate whether vitamin supplementation might be a potential therapy. (More information)
  • Diuretic-induced thiamin excretion may increase the risk of thiamin deficiency and disease severity in subjects with congestive heart failure. Further studies are needed to assess the inclusion of thiamin supplementation in the management of this disease. (More information)
  • Intravenous thiamin has been studied as potential treatment for sepsis, either as a monotherapy or in combination with other agents like vitamin C and corticosteroids. Large-scale clinical trials are needed to determine its efficacy. (More information)

Thiamin (also spelled thiamine) is a water-soluble B vitamin, also known as vitamin B1 or aneurine (1). Isolated and characterized in the 1930s, thiamin was one of the first organic compounds to be recognized as a vitamin (2). Thiamin occurs in the human body as free thiamin and as various phosphorylated forms: thiamin monophosphate (TMP), thiamin triphosphate, adenosine thiamin triphosphate, and thiamin pyrophosphate (TPP), which is also known as thiamin diphosphate.


Coenzyme function

The synthesis of TPP from free thiamin requires magnesium, adenosine triphosphate (ATP), and the enzyme, thiamin pyrophosphokinase. In humans, TPP is required as a coenzyme in the metabolism of carbohydrates and branched-chain amino acids. Forms of thiamin are also needed for ribose synthesis and for α-oxidation of 3-methyl-branched fatty acids.

Pyruvate dehydrogenase, α-ketoglutarate dehydrogenase, 2-oxoadipate dehydrogenase, and branched-chain α-ketoacid dehydrogenase (BCKDH) each comprise a different enzyme complex found within cellular organelles called mitochondria. They catalyze the decarboxylation of pyruvate, α-ketoglutarate, 2-oxoadipate, and branched-chain amino acids (BCAA) to form acetyl-coenzyme A (CoA), succinyl-CoA, glutaryl-CoA, and derivatives of BCAA, respectively (Figure 1). All products play critical roles in the production of energy from food through their connection to the citric acid (Krebs) cycle (2). BCAA, including leucine, isoleucine, and valine, are eventually degraded into acetyl-CoA and succinyl-CoA to fuel the citric acid cycle. The catabolism of the three BCAAs also contributes to the production of cholesterol and donates nitrogen for the synthesis of the neurotransmitters, glutamate and g-aminobutyric acid (GABA) (3). In addition to the thiamin coenzyme (TPP), each dehydrogenase complex requires a niacin-containing coenzyme (NAD), a riboflavin-containing coenzyme (FAD), and lipoic acid.

Transketolase catalyzes critical reactions in another metabolic pathway occurring in the cytosol, known as the pentose phosphate pathway. One of the most important intermediates of this pathway is ribose-5-phosphate, a phosphorylated 5-carbon sugar required for the synthesis of the high-energy ribonucleotides, such as ATP and guanosine triphosphate (GTP). Nucleotides are the building blocks of nucleic acids, DNA, and RNA. The pentose phosphate pathway also supplies various anabolic pathways, including fatty acid synthesis, with the niacin-containing coenzyme NADPH (1, 4). Because transketolase decreases early in thiamin deficiency and, unlike most thiamin-dependent enzymes, is present in red blood cells, measurement of its activity in red blood cells has been used to assess thiamin nutritional status (2, 5, 6).

2-Hydroxyacyl-CoA lyase is a TPP-dependent enzyme in peroxisomes that catalyzes the catabolism of 3-methyl-branched fatty acids through the process of α-oxidation, the oxidative removal of a single carbon atom from fatty acids like phytanic acid (7).

 Figure 1. Metabolic Pathways Requiring Thiamin Pyrophosphate (TPP). Pyruvate dehydrogenase, α-ketoglutarate dehydrogenase, 2-oxoadipate dehydrogenase, and branched-chain α-ketoacid dehydrogenase each comprise a different enzyme complex found within the mitochondria. They catalyze the decarboxylation of pyruvate, α-ketoglutarate, 2-oxoadipate, and branched-chain amino acids to form acetyl-coenzyme A (CoA), succinyl-CoA, glutaryl-CoA, and derivatives of BCAA, respectively. All products play critical roles in the production of energy from food through their connection to the citric acid cycle


Beriberi, the disease resulting from severe thiamin deficiency, was described in Chinese literature as early as 2600 B.C. Thiamin deficiency affects the cardiovascular, muscular, gastrointestinal, and central and peripheral nervous systems (2). Beriberi has been subdivided into dry, wet, cerebral, or gastrointestinal, depending on the systems affected by severe thiamin deficiency (1, 8).

Dry beriberi

The main feature of dry (paralytic or nervous) beriberi is peripheral neuropathy. Early in the course of the neuropathy, "burning feet syndrome" may occur. Other symptoms include abnormal (exaggerated) reflexes, as well as diminished sensation and weakness in the legs and arms. Muscle pain and tenderness and difficulty rising from a squatting position have also been observed (9).

Wet beriberi

In addition to neurologic symptoms, wet (cardiac) beriberi is characterized by cardiovascular manifestations of thiamin deficiency, which include rapid heart rate, enlargement of the heart, severe swelling (edema), difficulty breathing, and ultimately, congestive heart failure. The Japanese literature describes the acute fulminant form of wet beriberi as “shoshin” (10).

Cerebral beriberi

Cerebral beriberi may lead to Wernicke's encephalopathy and Korsakoff's psychosis, especially in people who abuse alcohol. The diagnosis of Wernicke's encephalopathy is based on a "triad" of signs, which include abnormal eye movements, stance and gait ataxia, and cognitive impairment. Due in part to an overlap of symptoms with alcoholic delirium, Wernicke’s encephalopathy is thought to be underdiagnosed (11). If left untreated, the irreversible neurologic damage can cause additional clinical manifestations known as Korsakoff’s psychosis. This syndrome – also called Korsakoff’s dementia, Korsakoff's amnesia, or amnestic confabulatory syndrome – involves a confused, apathetic state and a profound memory disorder, with severe amnesia and loss of recent and working memory.

Thiamin deficiency affecting the central nervous system is referred to as Wernicke's disease when the amnesic state is not present and Wernicke-Korsakoff syndrome (WKS) when the amnesic symptoms are present along with the eye-movement and gait disorders. Rarer neurologic manifestations can include seizures (12). Most WKS sufferers are alcoholics, although it has been observed in other disorders of gross malnutrition, including stomach cancer and AIDS. Administration of intravenous thiamin to WKS patients generally results in prompt improvement of the eye symptoms, but improvements in motor coordination and memory may be less, depending on how long the symptoms have been present. Evidence of increased immune cell activation and increased free radical production in the areas of the brain that are selectively damaged suggests that oxidative stress plays an important role in the neurologic pathology of thiamin deficiency (13).

Gastrointestinal beriberi

TPP is critical for metabolic reactions that utilize glucose in glycolysis and the citric acid cycle (see Figure 1). A decrease in the activity of thiamin-dependent enzymes limits the conversion of pyruvate to acetyl-CoA and the utilization of the citric acid cycle, leading to accumulation of pyruvate and lactate. Lactic acidosis, a condition resulting from the accumulation of lactate, is often associated with nausea, vomiting, and severe abdominal pain in a syndrome described as gastrointestinal beriberi (8).

Causes of thiamin deficiency

Thiamin deficiency may result from inadequate thiamin intake, increased requirement for thiamin, excessive loss of thiamin from the body, consumption of anti-thiamin factors in food, or a combination of these factors.

Inadequate intake

Inadequate consumption of thiamin is the main cause of thiamin deficiency in developing countries (2). Thiamin deficiency is common in low-income populations whose diets are high in carbohydrate and low in thiamin (e.g., milled or polished rice). Breast-fed infants whose mothers are thiamin deficient are vulnerable to developing infantile beriberi. Alcoholism, which is associated with low intake of thiamin among other nutrients, is the primary cause of thiamin deficiency in industrialized countries. Some of the non-alcoholic conditions associated with WKS include anorexia nervosa, bariatric surgery (weight-loss surgery), gastrointestinal malignancies, and malabsorption syndromes (14-17). Obese individuals may also be at heightened risk of thiamin deficiency (18, 19). Moreover, cases of Wernicke’s encephalopathy have been linked with hyperemesis gravidarum (severe nausea and vomiting during pregnancy) (20, 21), and with parenteral nutrition lacking vitamin supplementation (22, 23).

Increased requirement

Conditions resulting in an increased requirement for thiamin include strenuous physical exertion, fever, pregnancy, breast-feeding, and adolescent growth. Such conditions place individuals with marginal thiamin intake at risk for developing symptomatic thiamin deficiency.

Malaria patients in Southeast Asia were found to be thiamin deficient more frequently than non-infected individuals (24, 25). Malarial infection leads to a large increase in the metabolic demand for glucose. Because thiamin is required for enzymes involved in glucose metabolism, the stresses induced by malarial infection could exacerbate thiamin deficiency in predisposed individuals. HIV-infected individuals, whether or not they had developed AIDS, were also found to be at increased risk for thiamin deficiency (26). Further, chronic alcohol abuse impairs intestinal absorption and utilization of thiamin (1); thus, alcoholics have increased requirements for thiamin. Thiamin deficiency is also observed as a complication of the refeeding syndrome: the introduction of carbohydrates in severely starved individuals leads to an increased demand for thiamin in glycolysis and the citric acid cycle that precipitates thiamin deficiency (27).

Excessive loss

Excessive loss of thiamin may precipitate thiamin deficiency. By increasing urinary flow, diuretics may prevent reabsorption of thiamin by the kidneys and increase its excretion in the urine (28, 29). The risk of thiamin deficiency is increased in diuretic-treated patients with marginal thiamin intake (30) and in individuals receiving long-term, diuretic therapy (31). Individuals with kidney failure requiring hemodialysis lose thiamin at an increased rate and are at risk for thiamin deficiency (32). Alcoholics who maintain a high fluid intake and high urine flow rate may also experience increased loss of thiamin, exacerbating the effects of low thiamin intake (33).

Anti-thiamin factors (ATF)

The presence of anti-thiamin factors (ATF) in foods contributes to the risk of thiamin deficiency. Certain plants contain ATF, which react with thiamin to form an oxidized, inactive product. Consuming very large amounts of tea or coffee (including decaffeinated), as well as chewing tea leaves and betel nuts, might lower thiamin status due to the presence of ATF (34, 35). ATF include mycotoxins (molds) and thiaminases that break down thiamin in food. Individuals who habitually eat certain raw fresh-water fish, raw shellfish, or ferns are at higher risk of thiamin deficiency because these foods contain thiaminase that normally is inactivated by heat in cooking (16). In Nigeria, an acute, neurologic syndrome (seasonal ataxia) has been associated with thiamin deficiency precipitated by a thiaminase in African silkworms, a traditional, high-protein food for some Nigerians (36).

The Recommended Dietary Allowance (RDA)

The RDA for thiamin, revised in 1998 by the Food and Nutrition Board of the Institute of Medicine, was based on the prevention of deficiency in generally healthy individuals (37; Table 1).

Table 1. Recommended Dietary Allowance (RDA) for Thiamin
Life Stage Age Males (mg/day) Females (mg/day)
Infants 0-6 months  0.2 (AI) 0.2 (AI)
Infants 7-12 months 0.3 (AI) 0.3 (AI)
Children 1-3 years 0.5 0.5
Children 4-8 years 0.6 0.6
Children 9-13 years 0.9 0.9
Adolescents 14-18 years 1.2 1.0
Adults 19 years and older 1.2 1.1
Pregnancy all ages - 1.4
Breast-feeding all ages  - 1.4

Disease Prevention


A cross-sectional study of 2,900 Australian men and women, 49 years of age and older, found that those in the highest quintile of thiamin intake were 40% less likely to have nuclear cataracts than those in the lowest quintile (38). In addition, a study in 408 US women found that higher dietary intakes of thiamin were inversely associated with five-year change in lens opacification (39). However, these cross-sectional associations have yet to be elucidated by studies of causation.

Diabetes mellitus and vascular complications

Patients with diabetes mellitus have been reported to have low plasma concentrations and high renal clearance of thiamin (40, 41), suggesting that individuals with type 1 or type 2 diabetes are at increased risk for thiamin deficiency. Two thiamin transporters, thiamin transporter-1 (THTR-1) and THTR-2, are involved in thiamin uptake by enterocytes in the small intestine and re-uptake in the proximal tubules of the kidneys. One study suggested that hyperglycemia in patients with diabetes could affect thiamin re-uptake by decreasing the expression of thiamin transporters in the kidneys (42). Conversely, thiamin deficiency appears to impair the normal endocrine function of the pancreas and exacerbate hyperglycemia. Early studies showed that insulin synthesis and secretion were altered in the endocrine pancreatic cells of thiamin-deficient rats (43, 44). In humans, thiamin deficiency caused by recessive mutations in the gene encoding THTR-1 leads to diabetes mellitus in the thiamin-responsive megaloblastic anemia syndrome (see Metabolic diseases below).

In a randomized, double-blind pilot study, high-dose thiamin supplements (300 mg/day) were given for six weeks to hyperglycemic individuals (either glucose intolerant or newly diagnosed with type 2 diabetes). Thiamin supplementation prevented any further increase in fasting glucose and insulin concentrations compared with placebo treatment but did not reduce the hyperglycemia (45). However, one study suggested that thiamin supplementation might improve fasting glucose concentrations in early stages of type 2 diabetes (i.e., pre-diabetes) (46).

Disease Treatment

Alzheimer's disease

Some older adults are at increased risk for developing subclinical thiamin deficiency secondary to poor dietary intake, reduced gastrointestinal absorption, and multiple medical conditions (47, 48). Since thiamin deficiency can result in a form of dementia (Wernicke-Korsakoff syndrome), its relationship to Alzheimer's disease (AD) and other forms of dementia have been investigated. AD is characterized by a decline in cognitive function in elderly people, accompanied by pathologic features that include β-amyloid plaque deposition and neurofibrillary tangles formed by hyperphosphorylated Tau protein (49).

Using positron emission tomography (PET) scanning, reduced glucose metabolism has been observed in brains of AD patients (50). A large, multicenter PET study using a radiolabeled glucose analog, 18F-Fluoro-deoxyglucose (FDG), correlated a reduction in FDG uptake (a surrogate marker for glucose metabolism) with the extent of cognitive impairment in AD patients. This study, which included 822 subjects over 55 years of age that were cognitively normal (n=229), displayed mild cognitive impairment (n=405), or had mild AD (n=188), demonstrated that brain glucose utilization could predict the progression from mild cognitive impairment to AD (51). A nine-year longitudinal study associated the presence of diabetes mellitus in older people (above 55 years old) with an increased risk for developing AD (52). Emerging evidence links type 2 diabetes and AD, conditions that may involve insulin resistance in the brain (reviewed in 53).

A reduction in thiamin-dependent processes in the brain appears to be related to the altered glucose metabolism in patients with AD (54-56). Case-control studies have found blood levels of thiamin, TPP, and TMP to be lower in those with dementia of Alzheimer's type (DAT) compared to control subjects (57, 58). Moreover, several investigators have found evidence of decreased activity of TPP-dependent enzymes, α-ketoglutarate dehydrogenase and transketolase, in the brains of patients who died of AD (59). The finding of decreased brain levels of TPP in the presence of normal levels of free thiamin and TMP suggests altered TPP synthesis rather than poor thiamin bioavailability. However, it is not clear whether the activities of TPP-metabolizing enzymes (including thiamin pyrophosphokinase) are altered in AD patients (60, 61). Chronic administration of the thiamin derivative benfotiamine alleviated cognitive alterations and decreased the number of β-amyloid plaques in a mouse model of AD without increasing TMP and TPP levels in the brain. This suggested that the beneficial effects of benfotiamine in the brain were likely mediated by the stimulation of TPP-independent pathways (62). Chronic benfotiamine administration was also shown to decrease the number of neurofibrillary tangles in certain brain regions and improve survival in a mouse model (63). In a rat model of neurodegeneration, long-term oral benfotiamine supplementation increased thiamin pyrophosphate concentrations and led to improvements in insulin signaling and cognitive deficits (64).

Thiamin deficiency has been linked to increased β-amyloid production in cultured neuronal cells and to plaque formation in animal models (65, 66). These pathological hallmarks of AD could be reversed by thiamin supplementation, suggesting that thiamin could be protective in AD. Other disorders, including mitochondrial dysfunction and chronic oxidative stress, have been linked to both thiamin deficiency and AD pathogenesis and progression (13, 55, 67). Presently, there is only slight and inconsistent evidence that thiamin supplements are of benefit in AD. A double-blind, placebo-controlled study of 15 patients (10 completed the study) reported no beneficial effect of 3 grams/day of thiamin on cognitive decline over a 12-month period (68). A preliminary report from another study claimed a mild benefit of 3 to 8 grams of thiamin per day in DAT, but no additional data from that study are available (69). A mild beneficial effect in patients with AD was reported after 12 weeks of treatment with 100 mg/day of a thiamin derivative (thiamin tetrahydrofurfuryl disulfide), but this study was not placebo-controlled (70). A 2001 systematic review of randomized, double-blind, placebo-controlled trials of thiamin in patients with DAT found no evidence that thiamin was a useful treatment for the symptoms of Alzheimer's disease (71). More recently, a small uncontrolled study in five patients with mild-to-moderate AD reported cognitive improvement, measured by the Mini-Mental Status Examination, following supplementation with 300 mg/day of benfotiamine for 18 months (72). In a placebo-controlled study of 70 β-amyloid positive patients with either amnestic mild cognitive impairment (a precursor to AD) or mild AD, those receiving 600 mg/day of benfotiamine for 12 months experienced less cognitive decline compared to placebo, but the differences did not reach statistical significance (p=0.125; 73). Large-scale, randomized controlled trials are needed to determine whether supplemental thiamin or benfotiamine might help slow progression of cognitive decline in those with Alzheimer’s disease.

Huntington’s disease

Huntington’s disease is an inherited neurodegenerative disorder characterized by selective degeneration of nerve cells known as striatal spiny neurons. Symptoms, such as movement disorders and impaired cognitive function, typically develop in the fourth decade of life and progressively deteriorate over time. A recent study found decreased levels of the thiamin transporter-2 (THTR-2) protein in the striatum and frontal cortex of patients with Huntington’s disease compared to age-and sex-matched healthy controls (74). Compared to control subjects, this study also found lower concentrations of TPP in the striatum and lower concentrations of TMP in the cerebrospinal fluid of patients with Huntington’s disease (74). Mutations in the SLC19A3 gene that encodes THTR-2 causes biotin-thiamin-responsive basal ganglia disease, which is treated with high-dose co-supplementation with biotin and thiamin for life (see Biotin-thiamin-responsive basal ganglia disease below). In a mouse model of Huntington’s disease, high-dose supplementation with both of these vitamins improved neuropathological and motor deficits but had no effect on lifespan (p=0.15) (74). A phase II, open-label clinical trial evaluating the effect of combined thiamin-biotin supplementation, at moderate (600 mg/day of thiamin and 150 mg/day of biotin) and high (1,200 mg/day of thiamin and 300 mg/day of biotin) dosages, in Huntington’s disease is currently underway (75).

Congestive heart failure 

Severe thiamin deficiency (wet beriberi) can lead to impaired cardiac function and ultimately congestive heart failure (CHF). Although cardiac manifestations of beriberi are rarely encountered in industrialized countries, CHF due to other causes is common, especially in the elderly. Loop diuretics used in the treatment of CHF, notably furosemide, increase thiamin excretion, potentially leading to thiamin deficiency (76, 77). Patients with CHF might also have altered thiamin metabolism, including reduced absorption of thiamin in the small intestine (78). A 2015 meta-analysis of nine observational studies found a 2.5 times higher risk of thiamin deficiency in patients with heart failure compared to control subjects (78). As in the general population, older CHF patients were found to be at higher risk of thiamin deficiency than younger ones (79).

An important measure of cardiac function in CHF is the left ventricular ejection fraction (LVEF), which can be assessed by echocardiography. One study in 25 patients found that furosemide use at doses of 80 mg/day or greater was associated with a 98% prevalence of thiamin deficiency (31). In a randomized, double-blind study of 30 CHF patients, all of whom had been taking furosemide (80 mg/day) for at least three months, intravenous (IV) thiamin therapy (200 mg/day) for seven days resulted in an improved LVEF compared to IV placebo (80). When all 30 of the CHF patients in that study subsequently received six weeks of oral thiamin therapy (200 mg/day), the average LVEF improved by 22%. This finding may be relevant because improvements in LVEF have been associated with improved survival in CHF patients (81). However, clinical trials of oral thiamin supplementation in heart failure patients have not found any benefit. In a randomized, double-blind, placebo-controlled trial in 52 patients with systolic heart failure, 300 mg/day of supplemental thiamin for one month did not improve LVEF compared to placebo (82). A randomized, double-blind, placebo-controlled trial in 64 patients with heart failure reported that 200 mg/day or supplemental thiamin for six months did not improve LVEF (83).  

Although little evidence supports the routine use of supplemental thiamin in CHF patients, trials specifically in CHF patients with marginal thiamin status have not been done, and some suggest that it may be prudent to screen patients on long-term diuretic therapy for thiamin deficiency and treat accordingly (84).

Type 2 diabetes mellitus and vascular complications

Chronic hyperglycemia in individuals with diabetes mellitus contributes to the pathogenesis of microvascular diseases. Diabetes-related vascular damage can affect the heart (cardiomyopathy), kidneys (nephropathy), retina (retinopathy), and peripheral nervous system (neuropathy). In subjects with diabetes, hyperglycemia alters the function of bone marrow-derived endothelial progenitor cells (EPC) that are critical for the growth of blood vessels (85). Interestingly, a higher daily intake of thiamin from the diet was correlated with more circulating EPC and with better vascular endothelial health in 88 individuals with type 2 diabetes (86). An inverse association has also been found between plasma concentrations of thiamin and the presence of soluble vascular adhesion molecule-1 (sVCAM-1), a marker of vascular dysfunction, in patients with diabetes (40, 87). Early markers of diabetic nephropathy include the presence of serum albumin in the urine, known as microalbuminuria. Administration of thiamin or benfotiamine (a thiamin derivative) prevented the development of renal complications in chemically-induced diabetic rats (88). A randomized, double-blind, placebo-controlled study conducted in 40 patients with type 2 diabetes with microalbuminuria found that high-dose thiamin supplementation (300 mg/day) decreased excretion of urinary albumin over a three-month period (87). Since thiamin treatment has shown promising results in cultured cells and animal models (89-91), the effects of thiamin and its derivatives on vascular complications should be examined in patients with diabetes.


Thiamin deficiency and Wernicke-Korsakoff syndrome have been observed in some cancer patients with rapidly growing tumors (92, 93). Research in cell culture and animal models indicates that rapidly dividing cancer cells have a high requirement for thiamin (94). All rapidly dividing cells require nucleic acids at an increased rate, and some cancer cells appear to rely heavily on the TPP-dependent enzyme, transketolase, to provide the ribose-5-phosphate necessary for nucleic acid synthesis. One study found that the levels of THTR-1, transketolase, and TPP mitochondrial transporters were increased in samples of human breast cancer tissue compared to normal tissue, suggesting an adaptation in thiamin homeostasis in support of cancer metabolism (95). Other studies have found that the gene encoding THTR-2 is downregulated in certain cancers (96). Moreover, use of the chemotherapeutic drug, 5-fluorouracil, inhibits phosphorylation of thiamin to thiamin pyrophosphate and may thus lead to thiamin deficiency (97, 98).

Thiamin supplementation in cancer patients is common to prevent thiamin deficiency, but Boros et al. caution that too much thiamin may actually fuel the growth of some malignant tumors (99), suggesting that thiamin supplementation be reserved for those cancer patients who are actually deficient in thiamin. Presently, there is no evidence available from studies in humans to support or refute this theory. However, it would be prudent for individuals with cancer who are considering thiamin supplementation to discuss it with the clinician managing their cancer therapy. Intravenous, high-dose thiamin has been suggested as a treatment for cancer patients with confirmed Wernicke-Korsakoff (93).


Sepsis is a life-threatening critical illness caused by a dysregulated host response to an infection. The widespread inflammation can lead to tissue and organ damage and to death (100). Because thiamin deficiency is common among septic patients (101), several studies have investigated the treatment effect of intravenous thiamin – alone or in combination with other agents like vitamin C and hydrocortisone.

Observational studies examining the association of intravenous thiamin as a monotherapy have mainly looked at its association with lactic acidosis, which commonly occurs in both thiamin deficiency and sepsis, and with mortality. One retrospective study in 123 septic patients and 246 matched controls found that intravenous thiamin administration within 24 hours of hospital admission was linked to improvements in both lactate clearance and 28-day mortality (102). In a small retrospective study of 53 alcohol-use disorder patients presenting with septic shock, lower mortality was observed in the 34 patients who received intravenous thiamin compared to the 19 patients who did not (103).

A few randomized controlled trials have evaluated the effect of intravenous thiamin in the treatment of sepsis. A randomized, double-blind, placebo-controlled trial in 88 patients with sepsis and elevated blood concentrations of lactate reported that intravenous thiamin (200 mg twice daily for seven days or until discharge from the hospital) did not decrease lactate concentrations at 24 hours post initiation of treatment – the primary endpoint of the trial (104). No differences between the treatment and placebo groups were found for the secondary endpoints, which included survival (104). In a subsequent analysis of data from this trial, the septic patients that were given parenteral thiamin (n=31) had lower creatinine concentrations throughout the treatment and were less likely to need renal replacement therapy compared to placebo (n=39; 105).

A 2020 meta-analysis of four studies – one observational and three randomized controlled trials – found no benefit of intravenous thiamin for improving lactate concentrations, length of hospital stay in intensive care, or overall survival (106). Large-scale clinical trials are needed to determine whether parenteral administration of thiamin is beneficial in the treatment of sepsis. Administering thiamin in combination  with vitamin C and corticosteroids may be more efficacious to treat sepsis (107); some clinical trials of such treatments are currently underway (see clinicaltrials.gov/).

Metabolic diseases

Thiamin supplementation is included in the clinical management of genetic diseases that affect the metabolism of carbohydrates and branched-chain amino acids (BCAAs).

Thiamin-responsive pyruvate dehydrogenase complex (PDHC) deficiency

Mutations in PDHC prevent the efficient oxidation of carbohydrates in affected individuals. PDHC deficiency is commonly characterized by lactic acidosis, neurologic and neuromuscular degeneration, and death during childhood. The patients who respond to thiamin treatment (from a few mg/day to doses above 1,000 mg/day) exhibit PDHC deficiency due to the decreased affinity of PDHC for TPP (108, 109). Although thiamin supplementation can reduce lactate accumulation and improve the clinical features in thiamin-responsive patients, it does not constitute a cure (110).

Maple syrup urine disease

Inborn errors of BCAA metabolism lead to thiamin-responsive branched-chain ketoaciduria, also known as maple syrup urine disease. Alterations in the BCAA catabolic pathway result in neurologic dysfunction caused by the accumulation of BCAAs and their derivatives, branched-chain ketoacids (BCKA). The therapeutic approach includes a synthetic diet with reduced BCAA content, and thiamin (10-1,000 mg/day) is supplemented to patients with mutations in the E2 subunit of the BCKDH complex (111). In thiamin-responsive individuals, the supplementation has been proven effective to correct the phenotype without recourse to the BCAA restriction diet. 

Thiamin-responsive megaloblastic anemia

Mutations in the SLC19A2 gene that encodes THTR-1 impairs intestinal thiamin uptake and causes thiamin deficiency, leading to thiamin-responsive megaloblastic anemia (112). This syndrome, which is also called thiamin metabolism dysfunction syndrome-1, is characterized by megaloblastic anemia, diabetes mellitus, and deafness. A review of 30 cases reported additional neurologic, visual, and cardiac impairments (113). High-dose oral supplementation with thiamin (up to 300 mg/day) helps to maintain health and correct hyperglycemia in prepubescent children. A recent study in 32 individuals with found no additional benefit of oral doses above 150 mg/day (114). After puberty, a decline in pancreatic function results in the requirement of insulin together with thiamin to control the hyperglycemia. One study also reported that the treatment of a four-month-old girl with 100 mg/day of thiamin did not prevent hearing loss at 20 months of age (115). Early diagnosis of the syndrome and early treatment with thiamin is important for a better prognosis (114).

Biotin-thiamin-responsive basal ganglia disease

Biotin-thiamin-responsive basal ganglia disease (also called biotin-responsive basal ganglia disease, thiamin transporter-2 deficiency, and thiamin metabolism dysfunction syndrome-2) is caused by an autosomal recessive mutation in the SLC19A3 gene that codes for THTR-2. The disease usually presents around 3 to 10 years of age (116), but an early infantile form of the disease exists with onset as early as one month of age (117). Clinical features include subacute encephalopathy (confusion, drowsiness, altered level of consciousness), ataxia, and seizures.

A retrospective study of 18 affected individuals from the same family or the same tribe in Saudi Arabia showed that biotin monotherapy (5-10 mg/kg/day) efficiently abolished the clinical manifestations of the disease, although one-third of the patients suffered from recurrent acute crises. Often associated with poor outcomes, acute crises were not observed for a five-year follow-up period following thiamin supplementation (300-400 mg/day) – early diagnosis and immediate treatment with biotin and thiamin led to positive outcomes (118). Recent studies have found supplemental thiamin to be important in treating the condition. In an open-label study of 20 pediatric patients with the disease, supplemental thiamin alone was as effective as combined biotin-thiamin supplementation when given for 30 months (119). Lifelong high-dose supplementation with a combination of biotin and thiamin is generally the treatment for biotin-thiamin-responsive basal ganglia disease (116). Early diagnosis and treatment is important to ensure a better prognosis (117120).

Other thiamin metabolism dysfunction syndromes

Supplemental thiamin has limited utility in treating other inborn errors of thiamin metabolism. Mutations in the SLC25A19 gene that codes for the mitochondrial TPP transporter can result in either thiamin metabolism dysfunction syndrome-3 (THMD3) or thiamin metabolism dysfunction syndrome-4 (THMD4). Of these rare syndromes, THMD3 (also called Amish-type microcephaly or Amish lethal microcephaly) has the more severe phenotype, resulting in a congenital microcephaly, elevated concentrations of α-ketoglutarate in urine, and usually death in infancy (121). THMD4 is characterized by episodic encephalopathy and weakness, which often presents following a viral infection or febrile illness in childhood. Some patients affected with THMD4 may respond to high-dose thiamin supplementation (122).

Mutations in the TPK1 gene result in thiamin pyrophosphokinase 1 deficiency and thiamin metabolism dysfunction syndrome-5 (THMD5), which usually manifests in early childhood. While the clinical presentation of THMD5 varies, affected individuals often experience episodic ataxia, dystonia, and lactic acidosis (123). Only a few cases of THMD5 have been reported to date; two of these patients experienced limited improvement of symptoms upon supplementation with thiamin, in conjunction with adherence to a high-fat diet (124).


Humans obtain thiamin from dietary sources and from the normal microflora of the colon, although the contribution of the latter towards the body’s requirement for thiamin is not clear (125).

Food sources

A varied diet should provide most individuals with adequate thiamin to prevent deficiency. In the US the average dietary thiamin intake for young adult men is about 2 mg/day and 1.2 mg/day for young adult women. A survey of people over the age of 60 found an average dietary thiamin intake of 1.4 mg/day for men and 1.1 mg/day for women (37). However, institutionalization and poverty both increase the likelihood of inadequate thiamin intake in the elderly (126). Whole-grain cereals, legumes (e.g., beans and lentils), nuts, lean pork, and yeast are rich sources of thiamin (1). Because most of the thiamin is lost during the production of white flour and polished (milled) rice, white rice and foods made from white flour (e.g., bread and pasta) are fortified with thiamin in many Western countries. A number of thiamin-rich foods are listed in the table below, along with their thiamin content in milligrams (mg). For more information on the nutrient content of foods, search USDA's FoodData Central.

Table 2. Some Food Sources of Thiamin
Food Serving Thiamin (mg)
Lentils (cooked, boiled) ½ cup 0.17
Green peas (cooked, boiled) ½ cup 0.21
Long-grain, brown rice (cooked) ½ cup 0.18
Long-grain, white rice, enriched (cooked) ½ cup 0.13
Long-grain, white rice, unenriched (cooked) ½ cup 0.016
Whole-wheat bread 1 slice 0.13
White bread, enriched 1 slice 0.31
Fortified breakfast cereal (wheat, puffed) 1 cup 0.31
Wheat germ breakfast cereal (toasted, plain) 1 cup 1.88
Pork, lean (loin, tenderloin, cooked, roasted) 3 ounces* 0.80
Pecans 1 ounce (19 halves) 0.19
Spinach (cooked, boiled) ½ cup 0.09
Orange 1 fruit 0.11
Cantaloupe ½ fruit 0.11
Milk 1 cup 0.10
Egg (cooked, hard-boiled) 1 large 0.03
*Three ounces of meat is a serving about the size of a deck of cards


Thiamin is available in dietary supplements and in fortified foods, most commonly as thiamin hydrochloride or thiamin mononitrate (127). Multivitamin supplements typically contain at least 1.2 mg of thiamin, the Daily Value (DV) for adults and children 4 years and older (128).

Benfotiamine is a synthetic, lipid-soluble precursor of thiamin that is available as a dietary supplement. It has higher bioavailability compared to thiamin (129).



The Food and Nutrition Board did not set a tolerable upper intake level (UL) for thiamin because there are no well-established toxic effects from consumption of excess thiamin in food or through long-term, oral supplementation (up to 200 mg/day). A small number of life-threatening anaphylactic reactions have been observed with large intravenous doses of thiamin (37).

Drug interactions

Reduced blood concentrations of thiamin have been reported in individuals with seizure disorders (epilepsy) taking the anticonvulsant medication, phenytoin, for long periods of time (130). 5-Fluorouracil, a drug used in cancer therapy, inhibits the phosphorylation of thiamin to TPP (131). Diuretics, especially furosemide, may increase the risk of thiamin deficiency in individuals with marginal thiamin intake due to increased urinary excretion of thiamin (29). Moreover, chronic alcohol abuse is associated with thiamin deficiency due to low dietary intake, impaired absorption and utilization, and increased excretion of the vitamin (1). Chronic alcohol feeding to rats showed a decrease in the active absorption of thiamin linked to the inhibition of thiamin membrane transporter THTR-1 in the intestinal epithelium (132). Alcohol consumption in rats also decreases the levels of THTR-1 and THTR-2 in renal epithelial cells, thus limiting thiamin re-uptake by the kidneys (133).

Linus Pauling Institute Recommendation

The Linus Pauling Institute supports the recommendation by the Food and Nutrition Board of 1.2 mg/day of thiamin for men and 1.1 mg/day for women. A varied diet should provide enough thiamin for most people. Following the Linus Pauling Institute recommendation to take a daily multivitamin/mineral supplement, containing 100% of the Daily Values (DV), will ensure an intake of at least 1.5 mg/day of thiamin.

Older adults (>50 years)

Presently, there is no evidence that the requirement for thiamin is increased in older adults, but some studies have found inadequate dietary intake and thiamin insufficiency to be more common in elderly populations (126). Thus, it would be prudent for older adults to take a multivitamin/mineral supplement, which will generally provide at least 1.5 mg/day of thiamin.

Authors and Reviewers

Originally written in 2000 by: 
Jane Higdon, Ph.D. 
Linus Pauling Institute 
Oregon State University

Updated in September 2002 by: 
Jane Higdon, Ph.D. 
Linus Pauling Institute 
Oregon State University

Updated in June 2007 by: 
Victoria J. Drake, Ph.D. 
Linus Pauling Institute 
Oregon State University

Updated in June 2013 by: 
Barbara Delage, Ph.D. 
Linus Pauling Institute 
Oregon State University

Updated in July 2021 by: 
Victoria J. Drake, Ph.D. 
Linus Pauling Institute 
Oregon State University

Reviewed in October 2021 by:
Lucien Bettendorff, Ph.D.
Research Director, F.R.S.-FNRS
University of Liège, Belgium

Copyright 2000-2024  Linus Pauling Institute


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Vitamin A

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  • Vitamin A is a generic term that refers to fat-soluble compounds found as preformed vitamin A (retinol) in animal products and as provitamin A carotenoids in fruit and vegetables. The three active forms of vitamin A in the body are retinol, retinal, and retinoic acid. (More information)
  • Vitamin A is involved in regulating the growth and specialization (differentiation) of virtually all cells in the human body. Vitamin A has important roles in embryonic development, organ formation during fetal development, normal immune functions, and eye development and vision. (More information)
  • Vitamin A deficiency is a major cause of preventable blindness in the world. It is most prevalent among children and women of childbearing age. Vitamin A deficiency is associated with an increased susceptibility to infections, as well as to thyroid and skin disorders. (More information)
  • The recommended dietary allowance (RDA) is 700 micrograms of retinol activity equivalents (μg RAE)/day for women and 900 μg RAE/day for men. (More information)
  • Vitamin A prophylaxis appears to significantly reduce childhood mortality (especially from diarrheal illnesses) in regions at high risk of vitamin A deficiency. Further, high-dose vitamin A supplementation is widely recommended for children over six months of age when they are infected with measles while malnourished, immunodeficient, or are at risk of measles complications. (More information) 
  • Retinoic acid and analogs are used at pharmacological doses in the treatment of acute promyelocytic leukemia and various skin diseases. (More information) 
  • Animal food sources rich in preformed vitamin A include dairy products, fortified cereal, liver, and fish oils. Rich sources of provitamin A carotenoids include orange and green vegetables, such as sweet potato and spinach. (More information) 
  • Overconsumption of preformed vitamin A can be highly toxic and is especially contraindicated prior to and during pregnancy as it can result in severe birth defects. The tolerable upper intake level (UL) for vitamin A in adults is set at 3,000 μg RAE/day. The UL does not apply to vitamin A derived from carotenoids. (More information) 

Vitamin A is a generic term that encompasses a number of related compounds (Figure 1). Retinol and retinyl esters are often referred to as preformed vitamin A. Retinol can be converted by the body to retinal, which can be in turn be oxidized to retinoic acid, the form of vitamin A known to regulate gene transcription. Retinol, retinal, retinoic acid, and related compounds are known as retinoids. β-Carotene and other food carotenoids that can be converted by the body into retinol are referred to as provitamin A carotenoids (see the article on Carotenoids). Hundreds of different carotenoids are synthesized by plants, but only about 10% of them are capable of being converted to retinol (1). The following discussion will focus mainly on preformed vitamin A compounds and retinoic acid.

Figure 1. Chemical structures of beta-carotene, retinyl palmitate, all-trans-retinol, all-trans-retinal, 11-cis-retinal, all-trans-retinoic acid, 12-cis-retinoic acid, and 9-cis-retinoic acid.


Vitamin A compounds are essential fat-soluble molecules predominantly stored in the liver in the form of retinyl esters (e.g., retinyl palmitate). When appropriate, retinyl esters are hydrolyzed to generate all-trans-retinol, which binds to retinol binding protein (RBP) before being released in the bloodstream. The all-trans-retinol/RBP complex circulates bound to the protein, transthyretin, which delivers all-trans-retinol to peripheral tissues (reviewed in 2). Vitamin A as retinyl esters in chylomicrons was also found to have an appreciable role in delivering vitamin A to extrahepatic tissues, especially in early life (3, 4).

Visual system and eyesight

Located at the back of the eye, the retina contains two main types of light-sensitive receptor cells — known as rod and cone photoreceptor cells. Photons (particles of light) that pass through the lens are sensed by the photoreceptor cells of the retina and converted to nerve impulses (electric signals) for interpretation by the brain. All-trans-retinol is transported to the retina via the circulation and accumulates in retinal pigment epithelial cells (Figure 2) (5). Here, all-trans-retinol is esterified to form a retinyl ester, which can be stored. When needed, retinyl esters are broken apart (hydrolyzed) and isomerized to form 11-cis-retinol, which can be oxidized to form 11-cis-retinal. 11-cis-retinal can be shuttled across the interphotoreceptor space to the rod photoreceptor cell that is specialized for vision in low-light conditions and for detection of motion. In rod cells, 11-cis-retinal binds to a protein called opsin to form the visual pigment rhodopsin (also known as visual purple). Absorption of a photon of light catalyzes the isomerization of 11-cis-retinal to all-trans-retinal that is released from the opsin molecule. This photoisomerization triggers a cascade of events, leading to the generation of a nerve impulse conveyed by the optic nerve to the brain’s visual cortex. All-trans-retinal is converted to all-trans-retinol and transported across the interstitial space to the retinal pigment epithelial cells, thereby completing the visual cycle.

A similar cycle occurs in cone cells that contain red, green, or blue opsin proteins required for the absorption of photons from the visible light spectrum (2). Vitamin A is also essential for mammalian eye development (6). Thus, because vitamin A is required for the normal functioning of the retina, dim-light vision, and color vision, inadequate retinol and retinal available to the retina result in impaired dark adaptation. In the severest cases of vitamin A deficiency, thinning and ulceration of the cornea leads to blindness (see Deficiency).

Figure 2. The Visual Cycle. Retinol is transported to the retina via the circulation, where it moves into retinal pigment epithelial cells. There, retinol is esterified to form a retinyl ester that can be stored. When needed, retinyl esters are broken apart (hydrolyzed) and isomerized to form 11-cis-retinol, which can be oxidized to form 11-cis-retinal. 11-cis-retinal can be shuttled to the rod cell, where it binds to a protein called opsin to form the visual pigment, rhodopsin (also known as visual purple). Absorption of a photon of light catalyzes the isomerization of 11-cis-retinal to all-trans-retinal and results in its release. This isomerization triggers a cascade of events, leading to the generation of an electrical signal to the optic nerve. The nerve impulse generated by the optic nerve is conveyed to the brain where it can be interpreted as vision. Once released, all-trans-retinal is converted to all-trans-retinol, which can be transported across the interphotoreceptor matrix to the retinal epithelial cell to complete the visual cycle.

Regulation of gene expression

Regulatory capacity of retinoic acid

In cells, all-trans-retinol can be either stored (in the form of retinyl ester) or oxidized to all-trans-retinal by alcohol dehydrogenases. In turn, retinaldehyde dehydrogenases can catalyze the conversion of all-trans-retinal into two biologically active isomers of retinoic acid (RA): all-trans-RA and 9-cis-RA. RA isomers act as hormones to affect gene expression and thereby influence numerous physiological processes. All-trans-RA and 9-cis-RA are transported to the nucleus of the cell bound to cellular retinoic acid-binding proteins (CRABP). Within the nucleus, RA isomers bind to specific nuclear receptor proteins that are ligand-dependent transcription factors. In vitro studies have indicated that both all-trans-RA and 9-cis-RA can bind to retinoic acid receptors (RARα, RARβ, and RARγ) and that 9-cis-RA can bind to retinoid X receptors (RXR) (7). RAR and RXR subtypes form either complexes of two of the same protein (RAR/RAR and RXR/RXR homodimers) or complexes of two different proteins (RAR/RXR heterodimers). RAR/RXR heterodimers can bind to a regulatory DNA sequence called retinoic acid response element (RARE) located within the promoter of retinoid-responsive genes. The transcriptional activity of RAR/RXR heterodimers appears to be mainly driven by the binding of all-trans-RA to RAR.

The activation of RAR by RA binding triggers the recruitment of transcriptional coregulators to target promoters, thereby inhibiting or allowing the transcription of genes (8). RXR also forms heterodimers with several other nuclear receptors, including thyroid hormone receptor, vitamin D receptor, steroid receptors, and peroxisome proliferator-activated receptor (PPAR) (9). In this way, vitamin A may interact with thyroid hormone, vitamin D, steroids (e.g., estrogen), or PPAR ligands signaling pathways and influence the transcription of a broad range of genes.

There is also evidence that RA/RAR can affect gene expression in a RARE-independent manner. For example, it was reported that RAR could interfere with TGFβ/Smad signaling pathway through direct interaction of RAR with the heterodimeric transcription factor, Smad3/Smad4. In the absence of RA, RAR was found to act as a coactivator of Smad3/Smad4-mediated transcription, while RAR agonists repressed the transcriptional activity of Smad3/Smad4 (10). In retinoblastoma cells, RAR was also involved in RA-induced activation of signaling cascades mediated by tyrosine kinases known as phosphoinositide 3-kinase (PI3K) and leading to cell differentiation (11, 12). RA also appeared to induce neuronal differentiation by activating ERK1/2 MAP kinase signaling pathway that phosphorylated transcription factor, CREB (cyclic AMP response element binding protein). Phosphorylated CREB can subsequently bind to the CREB response element in the promoter of genes involved in cell differentiation (13). Also, independently of RAR, RA was found to inhibit ERK1/2 phosphorylation/activation and subsequent AP1-mediated expression of interleukin-6 in synovial cells (14). Hence, RA can influence the expression of genes whose promoters do not contain RARE.  

By regulating the expression of over 500 retinoid-responsive genes (including several genes involved in vitamin A metabolism itself), retinoic acid isomers play major roles in cellular proliferation and differentiation (i.e., cell commitment to highly specialized functions).

Regulatory capacity of retinol

In the eye and tissues like white adipose and muscle, retinol plasma membrane receptor/transporter STRA6 accepts retinol from extracellular RBP and unloads it to intracellular retinol-binding protein (CRBP). STRA6 also cooperates with lecithin:retinol acyltransferase (LRAT), an enzyme that catalyzes retinol esterification and storage, to maintain an inward concentration gradient of retinol (15). Interestingly, retinol uptake by STRA6 was found to trigger the activation of a signaling cascade mediated by tyrosine kinases known as Janus kinases (JAK) and associated transcription factors (STAT). JAK/STAT signaling pathway regulates the expression of a wide range of cytokines, hormones, and growth factors (16). Animal studies have reported that an increased expression of genes, such as SOCS3 by the JAK/STAT pathway, could result in the inhibition of insulin signaling. Hence, obese mice lacking LRAT or STRA6 appear to be protected from retinol/STRA6-induced insulin resistance (17, 18).

Regulatory capacity of retinal

Apart from its role as a ligand for opsin in the visual cascade (see Visual system and eyesight), retinal has been specifically implicated in the regulation of genes important for lipid metabolism. In humans, two types of adipose tissue have been distinguished based on their respective functions: white adipose tissue (WAT) stores fatty acids as triglycerides, and brown adipose tissue (BAT) oxidizes fatty acids to generate heat (thermogenesis). In the mitochondrial respiratory chain of brown adipose cells, the processes of electron transport and ATP production are uncoupled (dissociated) to permit the rapid production of heat from fatty acid oxidation (19).

Retinaldehyde dehydrogenase 1 (RALDH1), which converts retinal to retinoic acid, is highly expressed in WAT but not in BAT. The suppression of RALDH1 expression in WAT can induce a thermogenic phenotype resembling that of BAT (20). During adipocyte differentiation, the stimulation of cells with all-trans retinal has been found to activate the UCP1 gene required for thermogenesis while inhibiting genes promoting adipogenesis, such as PPARγ (20). Retinal also appeared to regulate lipid metabolism and adiposity in bone marrow by inhibiting PPARγ/RXR heterodimer-mediated gene expression (21). In addition, retinal was found to inhibit gluconeogenic gene expression and glucose production in the liver of mice deficient in RALDH1 (22).


Vitamin A was initially coined "the anti-infective vitamin" because of its importance in the normal functioning of the immune system (23). The skin and mucosal cells, lining the airways, digestive tract, and urinary tract function as a barrier and form the body's first line of defense against infection. Retinoic acid (RA) is produced by antigen-presenting cells (APCs), including macrophages and dendritic cells, found in these mucosal interfaces and associated lymph nodes. RA appears to act on dendritic cells themselves to regulate their differentiation, migration, and antigen-presenting capacity. In addition, the production of RA by APCs is required for the differentiation of naïve CD4 T-lymphocytes into induced regulatory T-lymphocytes (Tregs). Critical to the maintenance of mucosal integrity, the differentiation of Tregs is driven by all-trans-RA through RARα-mediated regulation of gene expression (see Regulation of gene expression). Also, during inflammation, all-trans-RA/RARα signaling pathway promotes the conversion of naïve CD4 T-lymphocytes into effector T-lymphocytes — type 1 helper T-cells (Th1) — (rather than into Tregs) and induces the production of proinflammatory cytokines by effector T-lymphocytes in response to infection.

A recent meta-analysis of randomized, placebo-controlled trials found that vitamin A supplementation decreased serum concentrations of TNF-α (5 studies) and IL-6 (9 studies) but increased serum C-reactive protein (CRP) concentrations (9 studies) (24). There is also substantial evidence to suggest that RA may help prevent the development of autoimmunity (reviewed in 25).

Prenatal and postnatal development

Both vitamin A excess and deficiency are known to cause birth defects. Retinoid signaling begins soon after the early phase of embryonic development known as gastrulation. During fetal development, RA is critical for the development of organs, including the heart, eyes, ears, lungs, as well as other limbs and visceral organs. Vitamin A has been implicated in fetal lung maturation (2). Vitamin A status is lower in preterm newborns than in full-term infants (26). There is some evidence to suggest that vitamin A supplementation may help reduce the incidence of chronic lung disease and mortality in preterm newborns (see Disease Prevention). Retinoid signaling is also involved in the expression of many proteins of the extracellular matrix (ECM; material surrounding cells), including collagen, laminin, and proteoglycans (27). Vitamin A deficiency may then result in alterations of the ECM composition, thus disrupting organ morphology and function (reviewed in 27).

Red blood cell production (erythropoiesis)

Red blood cells (erythrocytes), like all blood cells, are derived from pluripotent stem cells in the bone marrow. Studies involving in vitro culture systems have suggested a role for retinoids in stem cell commitment and differentiation to the red blood cell lineage. Retinoids might also regulate apoptosis (programmed cell death) of red blood cell precursors (erythropoietic progenitor cells) (28). However, whether retinoids regulate erythropoiesis in vivo has not been established. Yet, vitamin A supplementation in vitamin A deficient-individuals has been shown to increase hemoglobin concentrations. Additionally, vitamin A appears to facilitate the mobilization of iron from storage sites to the developing red blood cell for incorporation into hemoglobin, the oxygen carrier in red blood cells (28, 29).

Nutrient interactions


Zinc deficiency is thought to interfere with vitamin A metabolism in several ways (30): (1) zinc deficiency results in decreased synthesis of retinol-binding protein (RBP), which transports retinol through the circulation to peripheral tissues and protects the organism against potential toxicity of retinol; (2) zinc deficiency results in decreased activity of the enzyme that releases retinol from its storage form, retinyl palmitate, in the liver; and (3) zinc is required for the enzyme that converts retinol into retinal (31). The health consequences of zinc deficiency on vitamin A nutritional status in humans are yet to be defined (30)


Vitamin A deficiency often coexists with iron deficiency and may exacerbate iron deficiency anemia by altering iron metabolism (28). Vitamin A supplementation has beneficial effects on iron deficiency anemia and improves iron nutritional status among children and pregnant women (28, 29, 32). The combination of supplemental vitamin A and iron seems to reduce anemia more effectively than either supplemental iron or vitamin A alone (33). Moreover, studies in rats have shown that vitamin A deficiency interferes with erythropoiesis (34) and iron deficiency also alters plasma and liver levels of vitamin A (35, 36).


Vitamin A deficiency usually results from inadequate intakes of vitamin A from animal products (as preformed vitamin A) and fruit and vegetables (as provitamin A carotenoids). In developing countries, vitamin A deficiency and associated disorders predominantly affect children and women of reproductive age. Other individuals at risk of vitamin A deficiency are those with poor absorption of lipids due to impaired pancreatic or biliary secretion and those with inflammatory bowel diseases, such as Crohn’s disease and celiac disease (2).

Subclinical vitamin A deficiency is often defined by serum retinol concentrations lower than 0.70 μmol/L (20 μg/dL). In severe vitamin A deficiency, vitamin A body stores are depleted and serum retinol concentrations fall below 0.35 μmol/L (10 μg/dL). Other biomarkers have been calibrated to assess vitamin A nutritional status (reviewed in 37). Of note, the World Health Organization considers vitamin A deficiency in a population to be a moderate public health problem when the prevalence of low serum retinol (<0.70 μmol/L) among children ages 6-71 months is at least 10% but less than 20% and a severe public health problem when the prevalence is 20% or greater (38).

Vitamin A deficiency-related disorders

Disease of the eye and blindness

With an estimated 250,000 to 500,000 children becoming blind annually, vitamin A deficiency constitutes the leading preventable cause of blindness in low- and middle-income nations (39). The earliest symptom of vitamin A deficiency is impaired dark adaptation known as night blindness or nyctalopia. The next clinical stage is the occurrence of abnormal changes in the conjunctiva (corner of the eye), manifested by the presence of Bitot's spots. Severe or prolonged vitamin A deficiency eventually results in a condition called xerophthalmia (Greek for dry eye), characterized by changes in the cells of the cornea (clear covering of the eye) that ultimately result in corneal ulcers, scarring, and blindness (40). Immediate administration of 200,000 international units (IU; 60 mg RAE) of vitamin A for two consecutive days is required to prevent blinding xerophthalmia (40).

There is an estimated 19.1 million pregnant women worldwide (especially in Sub-Saharan Africa, Southeast Asia, and Central America) with vitamin A deficiency and over half of them are affected by night blindness (41). The prevalence of vitamin A deficiency and night blindness is especially high during the third trimester of pregnancy due to accelerated fetal growth. Prenatal vitamin A supplementation lowers the risk of maternal night blindness (42). Approximately 190 million preschool-age children have low serum retinol concentrations (<0.70 μmol/L), with 5.2 million suffering from night blindness. Moreover, half of the children affected by severe vitamin A deficiency-induced blinding xerophthalmia are estimated to die within a year of becoming blind (41). The World Health Organization (WHO) and the United Nations Children’s Fund (UNICEF) promote vitamin A supplementation as a public health intervention to reduce child mortality in areas and populations where vitamin A deficiency is prevalent (see the section on Childhood morbidity and mortality) (43).

Susceptibility to infectious diseases

Infectious diseases have been associated with depletion of vitamin A hepatic reserves (already limited in vitamin A-deficient subjects), reduced serum retinol concentrations, and increased loss of vitamin A in the urine (41). Infection with the measles virus was found to precipitate conjunctival and corneal damage, leading to blindness in children with poor vitamin A status (44). Conversely, vitamin A deficiency can be considered a nutritionally acquired immunodeficiency disease (45). Even children who are only mildly deficient in vitamin A have a higher incidence of respiratory complications and diarrhea, as well as a higher rate of mortality from measles infection compared to children consuming sufficient vitamin A (46). Because vitamin A supplementation may decrease both the severity and incidence of measles complications in developing countries (see Disease Prevention), WHO recommends that children aged at least one year receive 200,000 IU of vitamin A (60 mg RAE) for two consecutive days in addition to standard treatment when they are infected with measles virus and live in areas of vitamin A deficiency (47).

A prospective cohort study, conducted in 2,774 Colombian children (ages, 5-12 years old) followed for a median 128 days, also reported an inverse relationship between plasma retinol concentrations and rates of diarrhea with vomiting and cough with fever, the latter being a strong predictor of influenza infection (flu) (48). A review of five randomized, placebo-controlled studies that included 7,528 HIV-positive pregnant or breast-feeding women found no substantial benefit of vitamin A supplementation in reducing the mother-to-child transmission of HIV (49). One early observational study found that HIV-infected women who were vitamin A deficient were three to four times more likely to transmit HIV to their infants (50). Yet, no trial to date has provided any information on potential adverse effects of vitamin A supplementation on mother-to-child HIV transmission (51).

Thyroid dysfunction

In North and West Africa, vitamin A deficiency and iodine deficiency induced-goiter can coexist in up to 50% of children. The response to iodine prophylaxis in iodine-deficient populations appears to depend on various nutritional factors, including vitamin A status (52, 53). Vitamin A deficiency in animal models was found to interfere with the pituitary-thyroid axis by (1) increasing the synthesis and secretion of thyroid-stimulating hormone (TSH) by the pituitary gland, (2) increasing the size of the thyroid gland, (3) reducing iodine uptake by the thyroid gland and impairing the synthesis and iodination of thyroglobulin, and (4) increasing circulating concentrations of thyroid hormones (reviewed in 54, 55). A cross-sectional study of 138 children with concurrent vitamin A and iodine deficiencies found that the severity of vitamin A deficiency was associated with higher risk of goiter and higher concentrations of circulating TSH and thyroid hormones (53). These children received iodine-enriched salt with either vitamin A (200,000 IU [60 mg RAE] at baseline and 5 months) or placebo in a randomized, double-blind, 10-month trial. This vitamin A supplementation significantly decreased TSH concentration and thyroid volume compared to placebo (53). In another trial, supplementation of vitamin A to iodine-deficient children had no additional effect to iodine on thyroid status compared to placebo, but vitamin A supplementation alone (without iodine) reduced the volume of the thyroid gland, as well as TSH and thyroglobulin concentrations (56).

Other disorders

Phrynoderma or follicular hyperkeratosis is a skin condition characterized by an excessive production of keratin in hair follicles. The lesions first appear on the extremities, shoulders, and buttocks and may spread over the entire body in the severest cases (57). While vitamin A deficiency may contribute to the occurrence of phrynoderma, the condition has been strongly associated with multiple nutritional deficiencies and is considered a sign of general malnutrition. A rare case of esophagitis (inflammation of the esophagus) has been attributed to hyperkeratosis secondary to vitamin A deficiency (58).

Also, vitamin A deficiency affects iron mobilization, impairs hemoglobin synthesis, and precipitates iron deficiency anemia that is only alleviated with supplementation of both vitamin A and iron (see Nutrient interactions) (28).

The Recommended Dietary Allowance (RDA)

Retinol Activity Equivalents (RAE)

Vitamin A can be obtained from food as preformed vitamin A in animal products or as provitamin A carotenoids in fruit and vegetables (see Food sources). Yet, while preformed vitamin A is effectively absorbed, stored, and hydrolyzed to form retinol, provitamin A carotenoids like β-carotene are less easily digested and absorbed, and must be converted to retinol and other retinoids by the body after uptake into the small intestine. The efficiency of conversion of provitamin A carotenes into retinol is highly variable, depending on factors such as food matrix, food preparation, and one’s digestive and absorptive capacities (59).

The most recent international standard of measure for vitamin A is retinol activity equivalents (RAE), which represent vitamin A activity as retinol. It has been determined that 2 micrograms (μg) of β-carotene in oil provided as a supplement could be converted by the body to 1 μg of retinol giving it an RAE ratio of 2:1. However, 12 μg of β-carotene from food are required to provide the body with 1 μg of retinol, giving dietary β-carotene an RAE ratio of 12:1. Other provitamin A carotenoids in food are less easily absorbed than β-carotene, resulting in RAE ratios of 24:1. RAE ratios are shown in Table 1 (60).

Table 1. Retinol activity equivalents (RAE) Ratios for Preformed Vitamin A and Provitamin A Carotenoids
Quantity Consumed Quantity Bioconverted to Retinol RAE Ratio
1 μg of dietary or supplemental vitamin A  1 μg of retinol*  1:1 
2 μg of supplemental β-carotene  1 μg of retinol  2:1 
12 μg of dietary β-carotene  1 μg of retinol  12:1 
24 μg of dietary α-carotene  1 μg of retinol  24:1 
24 μg of dietary β-cryptoxanthin 1 μg of retinol  24:1
*1 IU is equivalent to 0.3 microgram (μg) of retinol, and 1 μg of retinol is equivalent to 3.33 IU of retinol.

Determination of the RDA

The RDA for vitamin A was revised by the Food and Nutrition Board of the US National Academy of Medicine in 2001. The RDA is based on the Estimated Average Requirement (EAR), which is defined as the biological requirement for 50% of the population. The RDA is the recommended intake needed by nearly all of the population to ensure adequate hepatic stores of vitamin A in the body (20 μg/g for four months if the person consumes a vitamin A-deficient diet) to support normal reproductive function, immune function, gene expression, and vision (for details of calculations, see 60). Table 2 lists the RDA values in micrograms (μg) of Retinol Activity Equivalents (RAE) per day.

Table 2. Recommended Dietary Allowance (RDA) for Vitamin A as Preformed Vitamin A (micrograms [μg] of Retinol Activity Equivalents [RAE]/day)
Life Stage Age Males (μg/day) Females (μg/day)
Infants   0-6 months  400 (AI) 400 (AI)
Infants  7-12 months  500 (AI)  500 (AI)
Children  1-3 years  300 300
Children  4-8 years  400 400
Children  9-13 years  600 600
Adolescents  14-18 years  900 700
Adults  19 years and older  900 700
Pregnancy  18 years and younger  750
Pregnancy  19 years and older 770
Breast-feeding  18 years and younger  1,200
Breast-feeding  19 years and older  1,300

Disease Prevention

Bronchopulmonary dysplasia in preterm infants

Preterm infants are born with inadequate body stores of vitamin A, placing them at risk of developing diseases of the eye and the respiratory and gastrointestinal tracts. About one-third of preterm infants born between 22 and 28 weeks of gestation develop bronchopulmonary dysplasia (BPD), a chronic lung disease that can be fatal or result in life-long morbidities in survivors. A few randomized controlled trials have investigated the effect of postnatal vitamin A administration on the incidence of BPD and the risk of mortality in very low birth weight infants (VLBW; ≤1,500 g) requiring respiratory support (61-63). In the largest, multicenter, randomized, blinded, placebo-controlled trial that enrolled 807 extremely low birth weight (ELBW; ≤1,000 g) preterm newborns, the intramuscular administration of 5,000 IU (1,500 μg RAE) of vitamin A three times a week for four weeks significantly, though modestly, reduced the risk of BPD or death at 36 weeks’ postmenstrual age (gestational age plus chronological age) (62). While vitamin A supplementation was included in some neonatal programs after this trial (64), a national shortage in vitamin A supply that has affected US neonatal intensive care units since 2010 has led to a significant reduction in the use of vitamin A supplementation in premature newborns (401-1,000 g at birth) with respiratory failure (65, 66). However, a retrospective analysis of US nationwide data from 6,210 preterm infants born between 2010 and 2012 found that a reduction in vitamin A prophylaxis from 27.2% to 2.1% during the same period had no significant impact on the incidence of BPD or death before hospital discharge (66). A Cochrane review that pooled six randomized controlled trials in VLBW (≤1,500 g) or premature (less than 32 weeks' gestation) infants found vitamin A administration (5 trials of intramuscular administration and one trial or oral administration) only slightly reduced the risk of chronic lung disease or death at 28 days post birth (RR, 0.93; 95% CI, 0.88-0.99) (67).

In a retrospective study, the nonrandomized use of vitamin A supplementation with inhaled nitric oxide (iNO) was found to result in a lower incidence of BPD (but not mortality) compared to iNO therapy alone in preterm newborns with a birth weight of 750-999 g (68). Neurodevelopment index scores at one year of age were also improved in the vitamin A group of newborns weighing 500-749 g at birth. Yet, caution is advised with the interpretation of the results, especially because the trial was not designed to assess the effect of vitamin A. In Germany, a large, multicenter, randomized study — the NeoVitaA trial — is underway to explore the effect of high-dose oral vitamin A (5,000 IU/kg/day) for 28 days on the incidence of BPD and mortality at 36 weeks' postmenstrual age (69, 70).

While high doses of vitamin A during early pregnancy can cause birth defects (see Safety), vitamin A supplementation during late pregnancy may improve maternal and fetal vitamin A status (71). However, it is not known whether vitamin A supplementation during pregnancy might reduce BPD incidence in infants.   

Childhood morbidity and mortality

A 2022 Cochrane review and meta-analysis of randomized controlled trials evaluating the preventive effect of vitamin A on childhood mortality indicated that high-dose vitamin A supplementation in children ages 6 to 59 months reduced all-cause mortality by 12% (19 studies) and diarrhea-specific mortality by 12% (9 studies) (72). However, vitamin A administration in this age group had no preventive effect on mortality from respiratory disease (9 studies), measles (6 studies), or meningitis (3 studies). However, in this pooled analysis, vitamin A supplementation reduced the incidence of diarrhea by 15% (15 studies), measles by 50% (6 studies), Bitot’s spots by 58% (5 studies) and night blindness by 68% (2 studies) but had no effect on the incidence of respiratory disease (72).

Current WHO policy recommends vitamin A supplementation at routine vaccination contacts in children after six months of age living in regions at high risk of vitamin A deficiency (73). Supplementation with high doses of vitamin A — 100,000 IU (30 mg RAE) for infants 6 to 11 months of age and 200,000 IU (60 mg RAE) for children 12 to 59 months of age — is thought to provide adequate protection for up to six months (74). See the WHO website for the current guidelines. Because beneficial effects are lacking, WHO does not recommend vitamin A supplementation in the neonatal period (in the 28 days following birth) (75) or in children under 6 months of age (reviewed in 76) to prevent infant morbidity and mortality.

There is some concern that vitamin A supplementation may interfere with vaccine effectiveness in young children. The timing of vitamin A interventions needs to be further examined in relation to the timing of vaccinations in order to maximize their benefits. Future studies should also examine whether the effects of vitamin A supplementation are modified by sex (75), as observed in at least one randomized controlled trial (77).

Complications from measles infection

An earlier meta-analysis of seven randomized controlled trials examining specifically the role of vitamin A supplementation in 2,069 children with measles found no overall reduction on the risk of mortality (78). Yet, the pooled analysis of four studies that reported the age distribution of participants found an 83% lower risk of mortality with two doses of 200,000 IU (60 mg RAE) of vitamin A in children younger than two years. In addition, the pooled analysis of three studies indicated a 67% reduction in the risk of pneumonia-led mortality (78). Similar to WHO and UNICEF guidelines, the American Academy of Pediatrics recommends vitamin A supplementation for children over six months of age when they are infected with measles while malnourished, immunodeficient, or are at risk of measles complications or vitamin A deficiency disorders (79). Although measles infection has been associated with vitamin A deficiency and blindness, there is currently no evidence to suggest that vitamin A supplementation reduces the risk of blindness in children infected with measles (80).


Studies in cell culture and animal models have documented the capacity for natural and synthetic retinoids to reduce carcinogenesis significantly in skin, breast, liver, colon, prostate, and other sites. However, the results of human studies examining the relationship between the consumption of preformed vitamin A and cancer do not currently suggest that consuming vitamin A at intakes greater than the RDA benefit in the prevention of cancer (2).

Lung cancer

The results of the β-Carotene And Retinol Efficacy Trial (CARET) suggested that high-dose supplementation of preformed vitamin A and β-carotene should be avoided in people at high risk for lung cancer (81). In the CARET study, about 9,000 people (smokers and people with asbestos exposure) were assigned a daily regimen of 25,000 IU (7,500 μg RAE) of retinyl palmitate and 30 mg of β-carotene, while a similar number of people were assigned a placebo. After four years of follow-up, the incidence of lung cancer was 28% higher in the supplemented group compared to the placebo group; however, the incidence was not different six years after the intervention ended (82). A possible explanation for an increase in lung cancer is that the oxidative environment of the lung, created by smoke or asbestos exposure, could give rise to unusual carotenoid cleavage products, which might promote carcinogenesis (83). Interestingly, a case-control study that included 749 lung cancer cases and 679 controls from the CARET trial found a significant association between lung cancer risk reduction and high vitamin D intakes (≥400 IU/day) in individuals who received the active CARET supplements or in those with vitamin A intakes equal to or greater than 1,500 μg RAE/day (84). Further, a meta-analysis of four randomized controlled trials, including a total of 202,924 participants at low risk of lung cancer, indicated that supplementation with retinol and/or β-carotene had no significant effect on lung cancer incidence (85). While an inverse association has been observed between blood retinol concentration and lung cancer incidence in a dose-response meta-analysis of eight prospective cohort studies (86), randomized controlled trials have not shown that preformed vitamin A (e.g., retinol) lowers the risk of lung cancer.

Disease Treatment

Retinoids may be used at pharmacological doses to treat several conditions, including, acute promyelocytic leukemia, retinitis pigmentosa, and various skin diseases. It is important to note that treatment with high doses of natural or synthetic retinoids overrides the body's own control mechanisms; therefore, retinoid therapies are associated with potential side effects and toxicities. Additionally, all of the retinoid compounds have been found to cause fetal deformations. Thus, women who have a chance of becoming pregnant should avoid treatment with these medications. Retinoids tend to be very long acting: side effects and birth defects have been reported to occur months after discontinuing retinoid therapy (2). The retinoids discussed below are prescription drugs and should not be used without medical supervision.

Acute promyelocytic leukemia

Normal differentiation of myeloid stem cells in the bone marrow gives rise to platelets, red blood cells, and white blood cells (also called leukocytes) that are important for the immune response. Altered differentiation of myeloid cells can result in the proliferation of immature white blood cells, giving rise to leukemia. Reciprocal chromosome translocations involving the promyelocytic leukemia (PML) gene and the gene coding for retinoic acid receptor α (RARα) lead to a specific type of acute myeloid leukemia called acute promyelocytic leukemia (APL). The fusion protein PML/RARα represses transcription by binding to RARE in the promoter of retinoid-responsive genes involved in hematopoietic cell differentiation. Gene repression by PML/RARα is achieved by the recruitment of several chromatin modifiers, including histone deacetylases (HDACs) and DNA methyltransferases (DNMTs). Contrary to RARα wild-type receptor, PML/RARα appears to be insensitive to physiological concentrations of retinoic acid (RA) such that only treatments with high doses of all-trans-RA can restore normal differentiation and lead to significant improvements and complete remission in some APL patients (87). Combination therapy with arsenic trioxide (or chemotherapy) improves long-term remission (reviewed in 88).

More information on APL treatment can be found on the Leukemia & Lymphoma Society website.

Diseases of the skin

Both natural and synthetic retinoids have been used as pharmacologic agents to treat disorders of the skin. Acitretin is a synthetic retinoid that has been FDA-approved for the treatment for psoriasis (89, 90). Topical tretinoin (all-trans-retinoic acid) and oral isotretinoin (13-cis-retinoic acid) have been used successfully to treat mild-to-severe acne vulgaris (91, 92). Retinoids exhibit anti-inflammatory properties and regulate the proliferation and differentiation of skin epithelial cells, as well as the production of sebum. Use of pharmacological doses of retinoids (especially oral isotretinoin) by pregnant women causes birth defects and is therefore contraindicated prior to and during pregnancy (see Safety in pregnancy).

For more information on the use of retinoids in the management of acne, see the article on Vitamin A and Skin Health.

Retinitis pigmentosa

Retinitis pigmentosa (RP) affects approximately 1.5 million people worldwide and is a leading cause of inherited blindness. RP describes a broad spectrum of genetic disorders that result in the progressive loss of photoreceptor cells (rods and cones) in the retina of the eye (93). While at least 45 loci have been associated with RP, mutations in the rhodopsin gene (RHO), the usherin gene (USH2A), and the RP GTPase regulator gene (RPGR) account for about 30% of all RP cases (94).

Early symptoms of RP include impaired dark adaptation and night blindness, followed by the progressive loss of peripheral and central vision over time (94). The results of a randomized controlled trial in 601 patients with common forms of RP indicated that supplementation with 4,500 μg RAE/day of retinyl palmitate significantly slowed the loss of retinal function over a period of four to six years (95). In contrast, supplementation with 400 IU/day of vitamin E (dl-α-tocopherol) modestly but significantly increased the loss of retinal function, suggesting that patients with common forms of RP may benefit from long-term vitamin A supplementation but should avoid high-dose vitamin E supplementation. Up to 12 years of follow-up in these patients did not reveal any signs of liver toxicity as a result of excess vitamin A intake (96). Because neither children nor adults affected by less common forms of RP were included in the trial, no formal recommendation about vitamins A and E could be made (94). Evidence of a beneficial effect of vitamin A supplementation on the progression of RP is lacking, as concluded in a 2020 Cochrane review (97). Nevertheless, use of high-dose vitamin A supplementation in RP would require close medical supervision and must be discontinued if there is a possibility of pregnancy (see Safety).


Food sources

Free retinol is not generally found in food. Retinyl esters (including retinyl palmitate) are the storage form of retinol in animals and thus the main precursors of retinol in food from animals. Plants contain carotenoids, some of which are precursors for vitamin A (e.g., α-carotene, β-carotene, and β-cryptoxanthin). Yellow- and orange-colored vegetables contain significant quantities of carotenoids. Green vegetables also contain carotenoids, though yellow-to-red pigments are masked by the green pigment of chlorophyll (1). Additionally, certain foods, including milk, margarines, and breakfast cereals, may be fortified with retinyl esters or β-carotene (2).

Table 3 lists a number of good food sources of vitamin A, including fruit and vegetables, along with their vitamin A content. The retinol activity is indicated in micrograms of retinol activity equivalents (μg RAE). For information on this unit of measurement, see the section on RAE. In addition, use the USDA’s FoodData Central database to check foods for their content of carotenoids without vitamin A activity, such as lycopene, lutein, and zeaxanthin.

Vitamin A international units (IUs)

In the past, vitamin A was listed on food and supplement labels in international units instead of μg RAE ('μg' on labels). In contrast to RAE, the number of IUs of vitamin A does not reflect the bioavailability of vitamin A from different food sources. Conversion rates between IUs and μg RAE are as follows:

  • 1 IU of retinol is equivalent to 0.3 μg RAE
  • 1 IU of supplemental β-carotene is equivalent to 0.3 μg RAE
  • 1 IU of dietary β-carotene is equivalent to 0.05 μg RAE
  • 1 IU of α-carotene or β-cryptoxanthin to 0.025 μg RAE

Table 3 lists some foods rich in vitamin A; the amounts of preformed vitamin A (retinol) and the RAE, which account for bioavailability, are both listed.

Table 3. Some Food Sources of Vitamin A
Food Serving Preformed Vitamin A (Retinol), μg Vitamin A, μg RAE
Beef liver, cooked 1 slice (68 g) 6,410* 6,420*
Cod liver oil 1 teaspoon 1,350 1,350
Fortified breakfast cereal (oats) 1 serving (1 oz) 230 766
Egg 1 large 97 98
Butter 1 tablespoon 95 97
Whole milk 1 cup (8 fl oz) 110 112
2% fat milk (vitamin A added) 1 cup (8 fl oz) 134 134
Nonfat milk (vitamin A added) 1 cup (8 fl oz) 157 157
Sweet potato (canned) ½ cup 0 555
Sweet potato (baked) ½ cup 0 960
Pumpkin (canned) ½ cup 0 955
Carrot (raw) ½ cup 0 534
Cantaloupe ½ medium melon 0 467
Mango 1 fruit 0 181
Spinach (cooked) ½ cup 0 472
Broccoli (cooked) ½ cup 0 60
Kale (cooked) ½ cup 0 86
Collards (cooked) ½ cup 0 361
Squash, butternut (cooked) ½ cup 0 570
*Above the tolerable upper intake level (UL) of 3,000 μg RAE/day.


The principal forms of preformed vitamin A in supplements are retinyl palmitate and retinyl acetate. β-Carotene is also a common source of vitamin A in supplements, and many supplements provide a combination of retinol and β-carotene (98). If a percentage of the total vitamin A content of a supplement comes from β-carotene, this information may be included in the Supplement Facts label under vitamin A. While many multivitamins available in the US contain the daily value of 900 μg RAE of vitamin A, some may provide up to 1,500 μg RAE from preformed vitamin A, which is substantially more than the current RDA for vitamin A.



The condition caused by vitamin A toxicity is called hypervitaminosis A. It is caused by overconsumption of preformed vitamin A, not carotenoids. Preformed vitamin A is rapidly absorbed and slowly cleared from the body. Therefore, toxicity from preformed vitamin A may result acutely from high-dose exposure over a short period of time or chronically from a much lower intake (2). Acute vitamin A toxicity is relatively rare, and symptoms include nausea, headache, fatigue, loss of appetite, dizziness, dry skin, desquamation, and cerebral edema. Signs of chronic toxicity include dry itchy skin, desquamation, anorexia, weight loss, headache, cerebral edema, enlarged liver, enlarged spleen, anemia, and bone and joint pain. Also, symptoms of vitamin A toxicity in infants include bulging fontanels. Severe cases of hypervitaminosis A may result in liver damage, hemorrhage, and coma. Generally, signs of toxicity are associated with long-term consumption of vitamin A in excess of 10 times the RDA (8,000-10,000 μg RAE/day). However, more research is necessary to determine if subclinical vitamin A toxicity is a concern in certain populations (99). There is evidence that some populations may be more susceptible to toxicity at lower doses, including the elderly, chronic alcohol users, and some people with a genetic predisposition to high cholesterol (100). In January 2001, the Food and Nutrition Board of the US National Academy of Medicine set the tolerable upper level (UL) of vitamin A intake for adults at 3,000 μg RAE/day of preformed vitamin A (60).

Table 4. Tolerable Upper Intake Level (UL) for Preformed Vitamin A
Age Group μg RAE/day
Infants 0-12 months  600
Children 1-3 years  600
Children 4-8 years  900
Children 9-13 years  1,700 
Adolescents 14-18 years  2,800
Adults 19 years and older  3,000

Safety in pregnancy

Although normal fetal development requires sufficient vitamin A intake, consumption of excess preformed vitamin A (such as retinol) during early pregnancy is known to cause birth defects, mainly of the cardiovascular and central nervous systems (101). No increase in the risk of vitamin A-associated birth defects has been observed at doses of preformed vitamin A from supplements below 3,000 μg RAE/day (60). Of note, in 2011, the World Health Organization (WHO) recommended vitamin A supplementation (up to 3,000 μg RAE/day or 7,500 μg RAE/week) during pregnancy in areas with high prevalence of vitamin A deficiency for the prevention of blindness (102). In industrialized countries, pregnant or potentially pregnant women should monitor their intake of vitamin A from fortified food and food naturally high in preformed vitamin A (e.g., liver) and avoid taking daily multivitamin supplements that contain more than 1,500 μg RAE of vitamin A. There is no evidence that consumption of vitamin A from β-carotene might increase the risk of birth defects.

The synthetic derivative of retinol, isotretinoin, is known to cause serious birth defects and should not be taken during pregnancy or if there is a possibility of becoming pregnant (91). Tretinoin (all-trans-retinoic acid), another retinol derivative, is prescribed as a topical preparation that is applied to the skin. Although percutaneous absorption of topical tretinoin is minimal, its use during pregnancy is not recommended (103).

Do high intakes of vitamin A increase the risk of osteoporosis?

Results from some prospective studies have suggested that long-term intakes of preformed vitamin A in excess of 1,500 μg RAE/day are associated with reduced bone mineral density (BMD) and increased risk of osteoporotic fracture in older adults (104-106). However, other investigators failed to observe such detrimental effects on BMD and/or fracture risk (107-110). A meta-analysis of four prospective studies, including nearly 183,000 participants over 40 years of age, found that highest versus lowest quintiles of retinol (preformed vitamin A) intake significantly increased the risk of hip fracture (111). A 2017 meta-analysis found similar results, and additionally, did not find higher retinol intakes to be associated with an increased risk of total fracture (112). Only excess intakes of retinol, not β-carotene, have been associated with adverse effects on bone health. The earlier meta-analysis indicated a U-shaped relationship between circulating retinol and risk of hip fracture, suggesting that both elevated and reduced retinol concentrations in the blood were associated with an increased risk of hip fracture (111). It is important to note that the available data on retinol intake and bone fracture come from observational studies, not randomized controlled trials.

To date, limited experimental data have suggested that vitamin A (as all-trans-retinoic acid) may affect the development of bone-remodeling cells and stimulate bone matrix degradation (resorption) (reviewed in 113). Vitamin A may also interfere with the ability of vitamin D to maintain calcium balance (114). In the large Women’s Health Initiative prospective study, the highest versus lowest quintile of retinol intake (≥1,426 μg/day vs. <474 μg/day) was found to be significantly associated with increased risk of fracture only in women with the lowest vitamin D intakes (≤440 IU/day) (115).

It is advisable for older individuals to consume multivitamin supplements that contain no more than 750 μg of preformed vitamin A (usually labeled vitamin A acetate or vitamin A palmitate) and no more than 750 μg RAE of additional vitamin A as β-carotene.

Drug interactions

Chronic alcohol consumption results in depletion of liver stores of vitamin A and may contribute to alcohol-induced liver damage (cirrhosis) (116). However, the liver toxicity of preformed vitamin A (retinol) is enhanced by chronic alcohol consumption, thus narrowing the therapeutic window for vitamin A supplementation in alcoholics (116). Oral contraceptives that contain estrogen and progestin increase retinol binding protein (RBP) synthesis by the liver, increasing the export of all-trans-retinol/RBP complex to the circulation. Whether this increases the dietary requirement of vitamin A is not known. Also, the use of cholesterol-lowering medications (like cholestyramine and colestipol), as well as orlistat, mineral oil, and the fat substitute, olestra, which interfere with fat absorption, may affect the absorption of fat-soluble vitamins, including vitamin A (98). Further, intake of large doses of vitamin A may decrease the absorption of vitamin K. Retinoids or retinoid analogs, including acitretin, all-trans-retinoic acid, bexarotene, etretinate, and isotretinoin, should not be used in combination with single-nutrient vitamin A supplements, because they may increase the risk of vitamin A toxicity (98).

Linus Pauling Institute Recommendation

The RDA for vitamin A (700 μg RAE/day for women and 900 μg RAE/day for men) is sufficient to support normal gene expression, immune function, and vision. However, following the Linus Pauling Institute’s recommendation to take a multivitamin/mineral supplement daily could supply as much as 1,500 μg RAE/day of vitamin A as retinol, the amount that has been associated with adverse effects on bone health in older adults. For this reason, we recommend taking a multivitamin/mineral supplement that provides no more than 750 μg RAE of preformed vitamin A (usually labeled vitamin A acetate or vitamin A palmitate) and no more than 750 μg RAE of additional vitamin A as β-carotene. High potency vitamin A supplements should not be used without medical supervision due to the risk of toxicity.

Older adults (>50 years)

Presently, there is little evidence that the requirement for vitamin A in older adults differs from that of younger adults. Additionally, vitamin A toxicity may occur at lower doses in older adults than in younger adults. Further, data from observational studies suggested an inverse association between intakes of preformed vitamin A in excess of 1,500 μg RAE day and risk of hip fracture in older people (see Safety). Yet, following the Linus Pauling Institute’s recommendation to take a multivitamin/mineral supplement daily could supply as much as 1,500 μg RAE/day of retinol, the amount that has been associated with adverse effects on bone health in older adults in some studies. For this reason, the Linus Pauling Institute recommends taking a multivitamin/mineral supplement that provides no more than 750 μg RAE of preformed vitamin A (usually labeled vitamin A acetate or vitamin A palmitate) and no more than 750 μg RAE of additional vitamin A as β-carotene. As for all age groups, high potency vitamin A supplements should not be used without medical supervision due to the risk of toxicity.

Authors and Reviewers

Originally written in 2000 by: 
Jane Higdon, Ph.D. 
Linus Pauling Institute 
Oregon State University

Updated in December 2003 by: 
Jane Higdon, Ph.D. 
Linus Pauling Institute 
Oregon State University

Updated in November 2007 by: 
Victoria J. Drake, Ph.D. 
Linus Pauling Institute 
Oregon State University

Updated in January 2015:
Barbara Delage, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in January 2024 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in February 2024 by:
A. Catharine Ross, Ph.D.
Professor of Nutrition, Texas A&M University
Professor of Nutrition Emeritus, The Pennsylvania State University

Copyright 2000-2024  Linus Pauling Institute


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Vitamin B6

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  • Vitamin B6 and its derivative pyridoxal 5'-phosphate (PLP) are essential to over 100 enzymes mostly involved in protein metabolism. (More information)
  • High levels of circulating homocysteine are associated with an increased risk of cardiovascular disease. Randomized controlled trials have demonstrated that supplementation with B vitamins, including vitamin B6, could effectively reduce homocysteine levels. However, homocysteine lowering by B vitamins has failed to lower the risk of adverse cardiovascular outcomes in high-risk individuals. (More information)
  • Growing evidence from experimental and clinical studies suggests that systemic inflammation underlying most chronic diseases may impair vitamin B6 metabolism. (More information)
  • Although supplementation with vitamin B6 and other B vitamins has not been associated with improved cognitive performance or delayed cognitive deterioration in the elderly, recent studies suggest that vitamin B6 might help reduce the risk of late-life depression. (More information)
  • Pharmacologic doses of vitamin B6 are used to treat seizures in rare inborn errors of vitamin B6 metabolism. Also, randomized controlled trials support the use of vitamin B6 to treat morning sickness in pregnant women and suggest a possible benefit in the management of premenstrual syndrome and carpal tunnel syndrome. (More information)
  • Vitamin B6 is found in a variety of foods, including fish, poultry, nuts, legumes, potatoes, and bananas. (More information)
  • Several medications, including anti-tuberculosis drugs, anti-parkinsonians, nonsteroidal anti-inflammatory drugs, and oral contraceptives, may interfere with vitamin B6 metabolism. (More information)

Vitamin B6 is a water-soluble vitamin that was first isolated in the 1930s. The term vitamin B6 refers to six common forms, namely pyridoxal, pyridoxine (pyridoxol), pyridoxamine, and their phosphorylated forms. The phosphate ester derivative pyridoxal 5'-phosphate (PLP) is the bioactive coenzyme form involved in over 4% of all enzymatic reactions (Figure 1) (1-3).

Figure 1. Chemical Structures of pyridoxine, pyridoxal, pyridoxamine, and pyridoxal 5'-phosphate (PLP). Non-phosphorylated forms of vitamin B6 include pyridoxine, pyridoxal, and pyridoxamine. While all three of these variants can be phosphorylated, the phosphate ester derivative of pyridoxal, pyridoxal 5'-phosphate (PLP), is the cofactor of most vitamin B6-dependent enzymes in the body.


Vitamin B6 must be obtained from the diet because humans cannot synthesize it. PLP plays a vital role in the function of over 100 enzymes that catalyze essential chemical reactions in the human body (4). PLP-dependent enzymes have been classified into five structural classes known as Fold Type I-V (5):

  • Fold Type I - aspartate aminotransferase family
  • Fold Type II - tryptophan synthase family
  • Fold Type III - alanine racemase family
  • Fold Type IV - D-amino acid aminotransferase family
  • Fold Type V - glycogen phosphorylase family

The many biochemical reactions catalyzed by PLP-dependent enzymes are involved in essential biological processes, such as hemoglobin and amino acid biosynthesis, as well as fatty acid metabolism. Of note, PLP also functions as a coenzyme for glycogen phosphorylase, an enzyme that catalyzes the release of glucose from stored glycogen. Much of the PLP in the human body is found in muscle bound to glycogen phosphorylase. PLP is also a coenzyme for reactions that generate glucose from amino acids, a process known as gluconeogenesis (6).

Nervous system function

In the brain, the PLP-dependent enzyme aromatic L-amino acid decarboxylase catalyzes the synthesis of two major neurotransmitters: serotonin from the amino acid tryptophan and dopamine from L-3,4-dihydroxyphenylalanine (L-Dopa). Other neurotransmitters, including glycine, D-serine, glutamate, histamine, and γ-aminobutyric acid (GABA), are also synthesized in reactions catalyzed by PLP-dependent enzymes (7).

Hemoglobin synthesis and function

PLP functions as a coenzyme of 5-aminolevulinic acid synthase, which is involved in the synthesis of heme, an iron-containing component of hemoglobin. Hemoglobin is found in red blood cells and is critical to their ability to transport oxygen throughout the body. Both pyridoxal and PLP are able to bind to the hemoglobin molecule and affect its ability to pick up and release oxygen. However, the impact of this on normal oxygen delivery to tissues is not known (6, 8). Vitamin B6 deficiency may impair hemoglobin synthesis and lead to microcytic anemia (3).

Tryptophan metabolism

Deficiency in another B vitamin, niacin, is easily prevented by adequate dietary intakes. The dietary requirement for niacin and the niacin coenzyme, nicotinamide adenine dinucleotide (NAD), can be also met, though to a fairly limited extent, by the catabolism of the essential amino acid tryptophan in the tryptophan-kynurenine pathway (Figure 2). Key reactions in this pathway are PLP-dependent; in particular, PLP is the cofactor for the enzyme kynureninase, which catalyzes the conversion of 3-hydroxykynurenine to 3-hydroxyanthranilic acid. A reduction in PLP availability appears to primarily affect kynureninase activity, limiting NAD production and leading to higher concentrations of kynurenine, 3-hydroxykynurenine, and xanthurenic acid in blood and urine (Figure 2) (9). Thus, while dietary vitamin B6 restriction impairs NAD synthesis from tryptophan, adequate PLP levels help maintain NAD formation from tryptophan (10). The effect of vitamin B6 inadequacy on immune activation and inflammation may be partly related to the role of PLP in the tryptophan-kynurenine metabolism (see Disease Prevention).

Figure 2. Overview of the Tryptophan-Kynurenine Metabolic Pathway. Pyridoxal 5'-phosphate, a vitamin B6 coenzyme, is required for the activity of several key enzymes in tryptophan catabolic pathway: KAT (kynurenine aminotransferase), KMO (kynurenine 3-monooxygenase), and kynureninase. As explained in the article text, tryptophan is metabolized to kynurenine, which is further metabolized with the vitamin B6-dependent enzymes, KAT or KMO. Through metabolism with KMO, 3-hydroxykynurenine is created, which can ultimately generate NAD. Dietary restriction of vitamin B6 most prominently affects kynureninase activity and results in the shift from 3-hydroxykynurenine metabolism and NAD formation to the production of kynurenic acid and xanthurenic acid.

Hormone function

Steroid hormones, such as estrogen and testosterone, exert their effects in the body by binding to steroid hormone receptors in the nucleus of target cells. The nuclear receptors themselves bind to specific regulatory sequences in DNA and alter the transcription of target genes. Experimental studies have uncovered a mechanism by which PLP may affect the activity of steroid receptors and decrease their effects on gene expression. It was found that PLP could interact with RIP140/NRIP1, a repressor of nuclear receptors known for its role in reproductive biology (11). Yet, additional research is needed to confirm that this interaction can enhance RIP140/NRIP1 repressive activity on steroid receptor-mediated gene expression. If the activity of steroid receptors for estrogen, progesterone, testosterone, or other steroid hormones can be inhibited by PLP, it is possible that vitamin B6 status may influence one's risk of developing diseases driven by steroid hormones, such as breast and prostate cancers (6).

Nucleic acid synthesis

The synthesis of nucleic acids from precursors thymidine and purines is dependent on folate coenzymes. The de novo thymidylate (dTMP) biosynthesis pathway involves three enzymes: dihydrofolate reductase (DHFR), serine hydroxymethyltransferase (SHMT), and thymidylate synthase (TYMS) (Figure 3). PLP serves as a coenzyme for SHMT, which catalyzes the simultaneous conversions of serine to glycine and tetrahydrofolate (THF) to 5,10-methylene THF. The latter molecule is the one-carbon donor for the generation of dTMP from deoxyuridine monophosphate (dUMP) by TYMS.

Figure 3. De Novo Thymidylate Biosynthesis. Folate coenzymes are essential intermediates in the synthesis of nucleic acid precursors thymidine and purines. Thymidylate biosynthesis pathway involves three enzymes: dihydrofolate reductase, serine hydroxymethyltransferase, and thymidylate synthase. Pyridoxal 5'-phosphate (PLP), a vitamin B6 coenzyme, is required by serine hydroxymethyltransferase, which uses serine as a one-carbon donor for the generation of 5,10-methylenetetrahydrofolate (5,10-methylene THF) from THF. 5,10-methylene THF is then used in both methionine transmethylation cycle (not shown in the figure) and thymidylate biosynthesis.


Severe deficiency of vitamin B6 is uncommon. Alcoholics are thought to be most at risk of vitamin B6 deficiency due to low dietary intakes and impaired metabolism of the vitamin. In the early 1950s, seizures were observed in infants as a result of severe vitamin B6 deficiency caused by an error in the manufacture of infant formula (7). Abnormal electroencephalogram (EEG) patterns have also been reported in vitamin B6-deficient adults. Other neurologic symptoms observed in severe vitamin B6 deficiency include irritability, depression, and confusion; additional symptoms include inflammation of the tongue, sores or ulcers of the mouth, and ulcers of the skin at the corners of the mouth (12).

The Recommended Dietary Allowance (RDA)

Since vitamin B6 is involved in many aspects of metabolism, especially in amino acid metabolic pathways, an individual's protein intake is likely to influence the requirement for vitamin B6 (13). Unlike previous recommendations issued by the Food and Nutrition Board (FNB) of the Institute of Medicine, the most recent RDA for vitamin B6 was not expressed in terms of protein intake, although the relationship was considered in setting the RDA (14). The current RDA was revised by the FNB in 1998 and is presented in Table 1.

Table 1. Recommended Dietary Allowance (RDA) for Vitamin B6
Life Stage Age Males (mg/day) Females (mg/day)
Infants  0-6 months 0.1 (AI) 0.1 (AI)
Infants  7-12 months   0.3 (AI)  0.3 (AI)
Children  1-3 years  0.5  0.5 
Children 4-8 years  0.6  0.6 
Children  9-13 years  1.0  1.0 
Adolescents  14-18 years  1.3  1.2 
Adults  19-50 years  1.3  1.3 
Adults  51 years and older  1.7  1.5 
Pregnancy  all ages  1.9 
Breast-feeding  all ages  2.0

Disease Prevention

Immune dysfunction

Several enzymatic reactions in the tryptophan-kynurenine pathway are dependent on vitamin B6 coenzyme, pyridoxal 5'-phosphate (PLP) (see Figure 2 above) (see Tryptophan metabolism). This pathway is known to be activated during pro-inflammatory immune responses and plays a critical role in immune tolerance of the fetus during pregnancy (15). Key intermediates in the tryptophan-kynurenine pathway are involved in the regulation of immune responses. Several tryptophan derivatives have been found to induce the death (apoptosis) or block the proliferation of certain types of immune cells, such as lymphocytes (in particular T-helper 1). They can also inhibit the production of pro-inflammatory cytokines (reviewed in 15). There is evidence to suggest that adequate vitamin B6 intake is important for optimal immune system function, especially in older individuals (16, 17). Yet, chronic inflammation that triggers tryptophan degradation and underlies many diseases (e.g., cardiovascular disease and cancers) may precipitate the loss of PLP and increase vitamin B6 requirements. Additional research is needed to evaluate whether vitamin B6 intakes higher than the current RDA could prevent and/or reverse immune system impairments (see also Vitamin B6 and inflammation).

Cardiovascular disease

The use of multivitamin supplements (including vitamin B6) has been associated with a 24% lower risk of incidental coronary artery disease (CAD) in a large prospective study of 80,082 women from the US Nurses' Health Study cohort (18). Using food frequency questionnaires, the authors observed that women in the highest quintile of vitamin B6 intakes from both food and supplements (median, 4.6 mg/day) had a 34% lower risk of CAD compared to those in the lowest quintile (median, 1.1 mg/day). CAD is characterized by the abnormal stenosis (narrowing) of coronary arteries (generally due to atherosclerosis), which can result in a potentially fatal myocardial infarction (heart attack). More recently, a prospective study that followed a Japanese cohort of over 40,000 middle-aged individuals for 11.5 years reported a 48% lower risk of myocardial infarction in those in the highest (mean, 1.6 mg/day) versus lowest quintile (mean, 1.3 mg/day) of vitamin B6 intakes in non-supplement users (19).

Early observational studies have also demonstrated an association between suboptimal pyridoxal 5'-phosphate (PLP) plasma level, elevated homocysteine blood level, and increased risk of cardiovascular disease (20-22). More recent research has confirmed that low plasma PLP status is a risk factor for CAD. In a case-control study, which included 184 participants with CAD and 516 healthy controls, low plasma PLP levels (<30 nanomoles/liter) were associated with a near doubling of CAD risk when compared to higher PLP levels (≥30 nanomoles/liter) (23). In a nested case-control study based on the Nurses' Health Study cohort and including 144 cases of myocardial infarction (of which 21 were fatal), women in the highest quartile of blood PLP levels (≥70 nanomoles/liter) had a 79% lower risk of myocardial infarction compared to those in the lowest quartile (<27.9 nanomoles/liter) (24).

Vitamin B6 and homocysteine

Even moderately elevated levels of homocysteine in the blood have been associated with increased risk for cardiovascular disease (CVD), including cardiac insufficiency (heart failure), CAD, myocardial infarction, and cerebrovascular attack (stroke) (25). During protein digestion, amino acids, including methionine, are released. Methionine is an essential amino acid and precursor of S-adenosylmethionine (SAM), the universal methyl donor for most methylation reactions, including the methylation of DNA, RNA, proteins, and phospholipids (Figure 4). Homocysteine is an intermediate in the metabolism of methionine. Healthy individuals utilize two different pathways to regenerate methionine from homocysteine in the methionine remethylation cycle (Figure 5). One pathway relies on the vitamin B12-dependent methionine synthase and the methyl donor, 5-methyl tetrahydrofolate (a folate derivative), to convert homocysteine back to methionine. The other reaction is catalyzed by betaine homocysteine methyltransferase, which uses betaine as a source of methyl groups for the formation of methionine from homocysteine. Moreover, two PLP-dependent enzymes are required to convert homocysteine to the amino acid cysteine in homocysteine transsulfuration pathway: cystathionine β synthase and cystathionine γ lyase (Figure 5). Thus, the amount of homocysteine in the blood may be influenced by nutritional status of at least three B vitamins, namely folate, vitamin B12, and vitamin B6.

Figure 4. Overview of One-Carbon Metabolism. Methionine is an essential amino acid and precursor of S-adenosylmethionine (SAM), the universal methyl donor for most methylation reactions, including the methylation of DNA, RNA, proteins, and phospholipids. SAM is converted to S-adenosylhomocysteine (SAH) and then to homocysteine, which can be metabolized to cysteine via the vitamin-B6 dependent transsulfuration pathyway. Homocysteine can be converted to methionine with an enzyme that requires 5-methyl-tetrahydrfolate and vitamin B12.

Vitamin B Figure 5. Homocysteine Metabolism. Homocysteine is methylated to form the essential amino acid methionine in two pathways. The reaction of homocysteine remethylation catalyzed by the vitamin B12-dependent methionine synthase captures a methyl group from the folate-dependent one-carbon pool (5-methyl tetrahydrofolate). A second pathway requires betaine (N,N,N-trimethylglycine) as a methyl donor for the methylation of homocysteine catalyzed by betaine homocysteine methyltransferase. The catabolic pathway of homocysteine, known as transsulfuration pathway, converts homocysteine to the amino acid cysteine via two vitamin B6 (PLP)-dependent enzymes: cystathionine beta synthase catalyzes the condensation of homocysteine with serine to form cystathionine, and cystathionine is then converted to cysteine, alpha-ketobutyrate, and ammonia by cystathionine gamma lyase.

Deficiencies in one or all of these B vitamins may affect both remethylation and transsulfuration processes and result in abnormally elevated homocysteine levels. An early study found that vitamin B6 supplementation could lower blood homocysteine levels after an oral dose of methionine was given (i.e., a methionine load test) (26), but vitamin B6 supplementation might not be effective in decreasing fasting levels of homocysteine. In a recent study conducted in nine healthy young volunteers, the rise of homocysteine during the postprandial period (after a meal) was found to be greater with marginal vitamin B6 deficiency (mean plasma PLP level of 19 nanomoles/liter) as compared to vitamin B6 sufficiency (mean PLP level of 49 nanomoles/liter) (27). The authors reported an increased rate of cystathionine synthesis with vitamin B6 restriction, suggesting that homocysteine catabolism in the transsulfuration may be maintained or enhanced in response to a marginal reduction in PLP availability. Yet, the flux ratio between methionine cycle and transsulfuration pathway appeared to favor homocysteine clearance by remethylation rather than transsulfuration in six out of nine participants (27).

Numerous randomized controlled trials, many in subjects with existing hyperhomocysteinemia and vascular dysfunction, have demonstrated that supplementation with folic acid, alone or combined with vitamin B6 and vitamin B12, could effectively reduce fasting plasma homocysteine concentrations. In 19 intervention studies recently included in a meta-analysis, reductions in homocysteine level in the blood following B-vitamin supplementation ranged between 7.6% and 51.7% compared to baseline levels (28). In contrast, studies supplementing individuals with only vitamin B6 have usually failed to show an effect on fasting levels of homocysteine (29, 30). Of the three supplemental B vitamins, folic acid appears to be the main determinant in the regulation of fasting homocysteine levels when there is no coexisting deficiency of vitamin B12 or vitamin B6 (31). Yet, the effect of homocysteine lowering on CVD risk reduction is debated. A recent meta-analysis of nine randomized controlled trials reported a 10% reduction in stroke events with supplemental B vitamins, with greater benefits for high-risk subjects (e.g., those with kidney disease) (32). However, most systematic reviews and meta-analyses of B-vitamin intervention studies to date have indicated a lack of causality between the decrease of fasting homocysteine levels and the prevention of cardiovascular events (28, 33-35). Moreover, B-vitamin supplementation trials in high-risk subjects have not resulted in significant changes in carotid intima-media thickness (CIMT) and flow-mediated dilation (FMD) of the brachial artery, two markers of vascular health used to assess atherosclerotic progression (36). Finally, in the Western Norway B Vitamin Intervention Trial (WENBIT), a randomized, double-blind, placebo-controlled trial in 87 subjects with suspected CAD, vitamin B6 supplementation (40 mg/day of pyridoxine) for a median of 10 months had no effect on coronary stenosis progression, assessed by quantitative angiography (37).

It has been suggested that antiplatelet therapy used in the primary prevention of CVD might interfere with the effect of homocysteine lowering by B vitamins on CVD risk (38). In this context, a post-hoc subgroup analysis of the multicenter, randomized, double blind, placebo-controlled VITATOPS trial (39) proposed that the small benefit of homocysteine-lowering by B vitamins might be cancelled in patients treated with antiplatelet drugs (40). Yet, the benefit of B-vitamin supplementation in primary prevention (i.e., in non-antiplatelet users) remains to be established.

Vitamin B6 and inflammation

A growing body of evidence currently suggests that low vitamin B6 status may increase the risk of cardiovascular disease through mechanisms independent of homocysteine lowering (41-43). Markers of immune activation and inflammation have been associated with hyperhomocysteinemia (homocysteine levels >15 micromoles/liter) in individuals with coronary artery disease (CAD) (44). In fact, inflammation is involved in the early steps of atherosclerosis in which lipids deposit in plaques (known as atheromas) within arterial walls and increase the risk of CAD (45). In a case-control study that included 267 patients with CAD and 475 healthy controls, plasma PLP concentrations were inversely correlated with the levels of two markers of systemic inflammation, C-reactive protein (CRP) and fibrinogen (46). Yet, the study suggested that suboptimal PLP levels (<36.3 nanomoles/liter) might contribute to an increased risk of CAD independently of inflammation since the risk was unchanged after adjustment for inflammation markers (unadjusted odds ratio (OR): 1.71 vs. multivariate adjusted OR: 1.73). Furthermore, the analysis of inflammation markers in 2,686 participants of the US National Health and Nutrition Examination Survey (NHANES) 2003-2004 indicated that serum CRP concentrations were inversely related to total vitamin B6 intakes (from both food and supplements). Specifically, the risk of having serum CRP levels greater than 10 mg/L (corresponding to high inflammatory activity) was 57% higher in individuals with vitamin B6 intakes lower than 2 mg/day compared to those with intakes equal to and above 5 mg/day (41). In addition, the prevalence of inadequate vitamin B6 status (plasma PLP levels <20 nanomoles/liter) with intakes lower than 5 mg/day was systematically greater in individuals with high versus low serum CRP concentrations (>10 mg/L vs. ≤3 mg/L), suggesting that inflammation might impair vitamin B6 metabolism. These observations were confirmed in the study of another cohort (Framingham Offspring Study) in which vitamin B6 status was linked to an overall inflammatory score based on the levels of 13 inflammation markers (including CRP, fibrinogen, tumor necrosis factor-α, and interleukin-6) (42). Specifically, plasma PLP levels were 24% lower in individuals in the highest versus lowest tertile of inflammatory score. Moreover, the inverse correlation between PLP levels and inflammatory scores remained significant regardless of vitamin B6 intakes, questioning again the nature of this relationship. Interestingly, a recent analysis of data collected in the WENBIT study demonstrated that systemic inflammation was associated with an increased degradation of pyridoxal (PL) to 4-pyridoxic acid (PA), supporting the use of the ratio PA:(PL+PLP) as a marker of both vitamin B6 status and systemic inflammation (47). Finally, while inflammation may contribute to lower vitamin B6 status, current evidence fails to support a role for vitamin B6 in the control of inflammation in patients with cardiovascular disease (48, 49).

Cognitive decline and Alzheimer's disease

A few observational studies have linked cognitive decline and Alzheimer's disease (AD) in the elderly with inadequate status of folate, vitamin B12, and vitamin B6 (50). Yet, the relationship between B vitamins and cognitive health in aging is complicated by both the high prevalence of hyperhomocysteinemia and signs of systemic inflammation in elderly people (51). On the one hand, since inflammation may impair vitamin B6 metabolism, low serum PLP levels may well be caused by processes related to aging rather than by malnutrition. On the other hand, high serum homocysteine may possibly be a risk factor for cognitive decline in the elderly, although the matter remains under debate. Specifically, the meta-analysis of 19 randomized, placebo-controlled trials of B-vitamin supplementation failed to report any difference in several measures of cognitive function between treatment and placebo groups, despite the treatment effectively lowering homocysteine levels (52). In a recent randomized, double-blind, placebo-controlled study of 2,695 stroke survivors with or without cognitive impairments, daily supplementation with 2 mg of folic acid, 0.5 mg of vitamin B12, and 25 mg of vitamin B6 for 3.4 years resulted in significant reductions in mean homocysteine levels (by 28% and 43% in cognitively unimpaired and impaired patients, respectively) compared to placebo. Yet, the B-vitamin intervention had no effect on either the incidence of newly diagnosed cognitive impairments or on measures of cognitive performance when compared to placebo (53). In contrast, another recent placebo-controlled trial found that a daily B-vitamin regimen that led to significant homocysteine lowering in high-risk elderly individuals could limit the progressive atrophy of gray matter brain regions associated with the AD process (54). Yet, the authors attributed the changes in homocysteine levels primarily to vitamin B12. Because of mixed findings, it is presently unclear whether supplementation with B vitamins might blunt cognitive decline in the elderly. Evidence is needed to determine whether marginal B-vitamin deficiencies, which are relatively common in the elderly, even contribute to age-associated declines in cognitive function, or whether both result from processes associated with aging and/or disease.


Late-life depression is a common disorder sometimes occurring after acute illnesses, such as hip fracture or stroke (55, 56). Coexistence of symptoms of depression and low vitamin B6 status (plasma PLP level ≤20 nanomoles/liter) has been reported in a few cross-sectional studies (57, 58). In a prospective study of 3,503 free-living people aged 65 and older from the Chicago Health and Aging Project, total vitamin B6 intakes (but not dietary intakes alone) were inversely correlated with the incidence of depressive symptoms during a mean follow-up period of 7.2 years (59). In a randomized, double-blind, placebo-controlled trial in 563 individuals who suffered from a recent stroke, daily supplementation of 2 mg of folic acid, 0.5 mg of vitamin B12, and 25 mg of vitamin B6 halved the risk of developing a major depressive episode during a mean follow-up period of 7.1 years (60). This reduction in risk was associated with a 25% lower level of plasma homocysteine in supplemented patients compared to controls. Additional evidence is needed to evaluate whether B vitamins could be included in the routine management of older people at high risk for depression.


Chronic inflammation that underlies most cancers may enhance vitamin B6 degradation (see Vitamin B6 and inflammation). In addition, because PLP is required for the methionine cycle, homocysteine catabolism, and thymidylate synthesis, low vitamin B6 status might affect these pathways and potentially increase the risk for chronic conditions. The systematic review of nine prospective studies found either inverse or positive associations between vitamin B6 intakes and colorectal cancer (CRC) risk (61). Inconsistent evidence regarding the link between vitamin B6 intakes and breast cancer was also recently reported in a meta-analysis (62). Yet, a prospective study that followed nearly 500,000 older adults for nine years observed that the risk of esophageal and stomach cancers was lower in participants in the highest versus lowest quintile of total vitamin B6 intakes (median values, 2.7 mg/day vs. 1.4 mg/day) (63). Additionally, a meta-analysis of four nested case-control studies reported a 48% reduction in CRC risk in the highest versus lowest quartile of blood PLP level (61). Another meta-analysis of five nested case-control studies found higher versus lower serum PLP levels to be associated with a 29% lower risk of breast cancer in postmenopausal, but not premenopausal, women (62).

Very few randomized, placebo-controlled trials investigating the nature of the association between B vitamins and cancer risk have focused on vitamin B6. Two earlier studies conducted in subjects with coronary artery disease failed to observe any benefit of supplemental vitamin B6 (40 mg/day) on CRC risk and mortality (reviewed in 64). A recent randomized, double-blind, placebo-controlled study conducted in 1,470 women with high cardiovascular risk showed that daily supplementation with 2.5 mg of folic acid, 1 mg of vitamin B12, and 50 mg of vitamin B6 for a mean treatment period of 7.3 years had no effect on the risk of developing colorectal adenoma when compared to placebo (65).

Kidney stones

A large prospective study examined the relationship between vitamin B6 intake and the occurrence of symptomatic kidney stones in women. A group of more than 85,000 women without a prior history of kidney stones were followed over 14 years, and those who consumed 40 mg or more of vitamin B6 daily had only two-thirds the risk of developing kidney stones compared with those who consumed 3 mg or less (66). However, in a group of more than 45,000 men followed for 14 years, no association was found between vitamin B6 intake and the occurrence of kidney stones (67). Limited experimental data have suggested that supplementation with high doses of pyridoxamine may help decrease the formation of calcium oxalate kidney stones and reduce urinary oxalate levels, an important determinant of calcium oxalate kidney stone formation (68, 69). Presently, the relationship between vitamin B6 intake and the risk of developing kidney stones requires further study before any recommendations can be made.

Disease Treatment

Vitamin B6 supplements at pharmacologic doses (i.e., doses much larger than those needed to prevent deficiency) have been used in an attempt to treat a wide variety of conditions, some of which are discussed below.

Metabolic diseases

A few rare inborn metabolic disorders, including pyridoxine-dependent epilepsy (PDE) and pyridoxamine 5'-phosphate oxidase (PNPO) deficiency, are the cause of early-onset epileptic encephalopathies that are found to be responsive to pharmacologic doses of vitamin B6. In individuals affected by PDE and PNPO deficiency, PLP bioavailability is limited, and treatment with pyridoxine and/or PLP have been used to alleviate or abolish epileptic seizures characterizing these conditions (70, 71). Pyridoxine therapy, along with dietary protein restriction, is also used in the management of vitamin B6 responsive homocystinuria caused by the deficiency of the PLP-dependent enzyme, cystathionine β synthase (72).

Morning sickness

Nausea and vomiting in pregnancy (NVP), often referred to as morning sickness, can affect up to 85% of women during early pregnancy and usually lasts between 12 and 16 weeks (73). Vitamin B6 has been used since the 1940s to treat nausea during pregnancy. Vitamin B6 was originally included in the medication Bendectin, which was prescribed for NVP treatment and later withdrawn from the market due to unproven concerns that it increased the risk for birth defects. Vitamin B6 itself is considered safe during pregnancy and has been used in pregnant women without any evidence of fetal harm (74). The results of two double-blind, placebo-controlled trials, including 401 pregnant women that used 25 mg of pyridoxine every eight hours for three days (75) or 10 mg of pyridoxine every eight hours for five days (76), suggested that vitamin B6 may be beneficial in reducing nausea. A recent systematic review of randomized controlled trials on NVP symptoms during early pregnancy found supplemental vitamin B6 to be somewhat effective (77). It should be noted that NVP usually resolves without any treatment, making it difficult to perform well-controlled trials. More recently, NVP symptoms were evaluated using Pregnancy Unique Quantification of Emesis (PUQE) scores in a randomized, double-blind, placebo-controlled study conducted in 256 pregnant women (7-14 weeks' gestation) suffering from NVP (78). Supplementation with pyridoxine and the drug doxylamine significantly improved NVP symptoms, as assessed by lower PUQE scores compared to placebo. Moreover, more women supplemented with pyridoxine-doxylamine (48.9%) than placebo-treated (32.8%) asked to continue their treatment at the end of the 15-day trial. The American and Canadian Colleges of Obstetrics and Gynecology have recommended the use of vitamin B6 (pyridoxine hydrochloride, 10 mg) and doxylamine succinate (10 mg) as first-line therapy for NVP (73).

Premenstrual syndrome

Premenstrual syndrome (PMS) refers to a cluster of symptoms, including but not limited to fatigue, irritability, moodiness/depression, fluid retention, and breast tenderness, that begin sometime after ovulation (mid-cycle) and subside with the onset of menstruation (the monthly period). A systematic review and meta-analysis of nine randomized, placebo-controlled trials suggested that supplemental vitamin B6, up to 100 mg/day, may be of value to treat PMS, including mood symptoms; however, only limited conclusions could be drawn because most of the studies were of poor quality (79). Another more recent review of 13 randomized controlled studies also emphasized the need for conclusive evidence before recommendations can be made (80).


The importance of PLP-dependent enzymes in the synthesis of several neurotransmitters (see Nervous system function) has led researchers to consider whether vitamin B6 deficiency may contribute to the onset of depressive symptoms (see Disease Prevention). There is limited evidence suggesting that supplemental vitamin B6 may have therapeutic efficacy in the management of depression. In a randomized, placebo-controlled trial conducted in 225 elderly patients hospitalized for acute illness, a six-month intervention with daily multivitamin/mineral supplements improved nutritional B-vitamin status and decreased the number and severity of depressive symptoms when compared to placebo (81). In addition, while supplement intake effectively reduced plasma homocysteine levels compared to placebo, the effect of supplementation on depressive symptoms at the end of the trial was greater in treated subjects in the lowest versus highest quartile of homocysteine levels (≤10 micromoles/liter vs. ≥16.1 micromoles/liter) (82). Yet, the etiology of late-onset depression is unclear and evidence is currently lacking to suggest whether supplemental B vitamins (including vitamin B6) could relieve depressive symptoms.

Carpal tunnel syndrome

Carpal tunnel syndrome (CTS) causes numbness, pain, and weakness of the hand and fingers due to compression of the median nerve at the wrist. It may result from repetitive stress injury of the wrist or from soft-tissue swelling, which sometimes occurs with pregnancy or hypothyroidism. Early studies by the same investigator suggested that supplementation with 100-200 mg/day of vitamin B6 for several months might improve CTS symptoms in individuals with low vitamin B6 status (83, 84). In addition, a cross-sectional study in 137 men not taking vitamin supplements found that decreased blood levels of PLP were associated with increased pain, tingling, and nocturnal awakening—all symptoms of CTS (85). However, studies using electrophysiological measurements of median nerve conduction have largely failed to find an association between vitamin B6 deficiency and CTS (86). While a few studies have noted some symptomatic relief with vitamin B6 supplementation, double-blind, placebo-controlled trials have not generally found vitamin B6 to be effective in treating CTS (86). Yet, despite its equivocal effectiveness, vitamin B6 supplementation is sometimes used in complementary therapy in an attempt to avoid hand surgery. Patients taking high doses of vitamin B6 should be advised by a physician and monitored for vitamin B6-related toxicity symptoms (see Toxicity) (87).


Food sources

The analysis of data collected in the US NHANES 2003-2004 has indicated that vitamin B6 intakes from food only averaged about 1.9 mg/day (88). Yet, despite values well above the current RDA, total vitamin B6 intakes (combining food and supplements) below 2 mg/day appear to be associated with relatively high proportions of low vitamin B6 status in all age groups (see Supplements). Many plant foods contain a unique form of vitamin B6 called pyridoxine glucoside; this form of vitamin B6 appears to be only about half as bioavailable as vitamin B6 from other food sources or supplements (7). Vitamin B6 in a mixed diet has been found to be approximately 75% bioavailable (14). In most cases, including foods in the diet that are rich in vitamin B6 should supply enough to meet the current RDA. However, those who follow a very restricted vegetarian diet might need to increase their vitamin B6 intake by eating foods fortified with vitamin B6 or by taking a supplement. Some foods that are relatively rich in vitamin B6 and their vitamin B6 content in milligrams (mg) are listed in Table 2. For more information on the nutrient content of specific foods, search USDA's FoodData Central.

Table 2. Some Food Sources of Vitamin B6
Food Serving Vitamin B6 (mg)
Fortified breakfast cereal 1 cup 0.5-2.5
Salmon, wild (cooked) 3 ounces* 0.48-0.80
Potato, Russet, with skin (baked) 1 medium 0.70
Turkey, light meat (cooked) 3 ounces 0.69
Avocado 1 medium 0.52
Chicken, light meat without skin (cooked) 3 ounces 0.51
Spinach (cooked) 1 cup 0.44
Banana 1 medium 0.43
Dried plums, pitted 1 cup 0.36
Hazelnuts (dry roasted) 1 ounce 0.18
Vegetable juice cocktail 6 ounces 0.13
*A three-ounce serving of meat or fish is about the size of a deck of cards.


Vitamin B6 is available as pyridoxine hydrochloride in multivitamin, vitamin B-complex, and vitamin B6 supplements (89). In NHANES 2003-2004, low vitamin B6 status (plasma PLP level <20 nanomoles/liter) was reported in 24% of non users of supplements and 11% of supplement users. Moreover, total vitamin B6 intakes (from food and supplements) lower than 2 mg/day were associated with high proportions of low plasma PLP levels: 16% in men aged 13-54 years, 24% in menstruating women, and 26% in individuals aged 65 years and older. Finally, the prevalence of low PLP levels was found to be greater in individuals consuming less than 2 mg/day of vitamin B6 compared to higher intakes. For example, only 14% of men and women aged 65 and older had low PLP values with total vitamin B6 intakes of 2-2.9 mg/day compared to 26% in those consuming less than 2 mg/day of vitamin B6 (88).



Because adverse effects have only been documented from vitamin B6 supplements and never from food sources, safety concerning only the supplemental form of vitamin B6 (pyridoxine) is discussed. Although vitamin B6 is a water-soluble vitamin and is excreted in the urine, long-term supplementation with very high doses of pyridoxine may result in painful neurological symptoms known as sensory neuropathy. Symptoms include pain and numbness of the extremities and in severe cases, difficulty walking. Sensory neuropathy typically develops at doses of pyridoxine in excess of 1,000 mg per day. However, there have been a few case reports of individuals who developed sensory neuropathies at doses of less than 500 mg daily over a period of months. Yet, none of the studies in which an objective neurological examination was performed reported evidence of sensory nerve damage at intakes below 200 mg pyridoxine daily (90). To prevent sensory neuropathy in virtually all individuals, the Food and Nutrition Board of the Institute of Medicine set the tolerable upper intake level (UL) for pyridoxine at 100 mg/day for adults (Table 3) (14). Because placebo-controlled studies have generally failed to show therapeutic benefits of high doses of pyridoxine, there is little reason to exceed the UL of 100 mg/day.

Table 3. Tolerable Upper Intake Level (UL) for Vitamin B6
Age Group UL (mg/day)
Infants 0-12 months Not possible to establish*
Children 1-3 years 30
Children 4-8 years   40
Children 9-13 years   60
Adolescents 14-18 years 80
Adults 19 years and older 100
*Source of intake should be from food and formula only.

Drug interactions

Certain medications interfere with the metabolism of vitamin B6; therefore, some individuals may be vulnerable to a vitamin B6 deficiency if supplemental vitamin B6 is not taken. In the NHANES 2003-2004 analysis, significantly more current and past users of oral contraceptives (OCs) among menstruating women had low plasma PLP levels compared to women who have never used OCs, suggesting that the estrogen content of OCs may interfere with vitamin B6 metabolism (see Side effects of oral contraceptives) (88). Anti-tuberculosis medications (e.g., isoniazid and cycloserine), the metal chelator penicillamine, and anti-parkinsonian drugs like L-Dopa can all form complexes with vitamin B6 and limit its bioavailability, thus creating a functional deficiency. PLP bioavailability may also be reduced by methylxanthines, such as theophylline used to treat certain respiratory conditions (7). The long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs; e.g. celecoxib and naproxen) may also impair vitamin B6 metabolism (91). Conversely, high doses of vitamin B6 have been found to decrease the efficacy of two anticonvulsants, phenobarbital and phenytoin, and of L-Dopa (6, 90).

Side effects of oral contraceptives

Because vitamin B6 is required for the metabolism of the amino acid tryptophan, the tryptophan load test (an assay of tryptophan metabolites after an oral dose of tryptophan) has been used as a functional assessment of vitamin B6 status. Abnormal tryptophan load tests in women taking high-dose oral contraceptives (OCs) in the 1960s and 1970s suggested that these women were vitamin B6 deficient, which led to the prescription of high doses of vitamin B6 (100-150 mg/day) to women taking OCs. However, most other indices of vitamin B6 status were normal in women on high-dose OCs, and the estrogen content of OCs appeared to be more likely responsible for the abnormality in tryptophan metabolism (88). Yet, more recently, the use of lower dose formulations has also been associated with vitamin B6 inadequacy (88, 92). Although it is not known whether OCs actually impair vitamin B6 metabolism or merely affect the tissue distribution of PLP, the use of OCs may place women at higher risk of vitamin B6 deficiency when they discontinue OCs and become pregnant (93). Whether OC users are at higher risk of cardiovascular disease despite normal homocysteine levels also needs to be determined. Finally, although high doses of vitamin B6 (pyridoxine) have demonstrated no benefit in preventing the risk of side effects from OCs (94), the use of vitamin B6 supplements may be warranted in current and past OC users.

Linus Pauling Institute Recommendation

The Linus Pauling Institute supports the RDA for vitamin B6. LPI recommends that all adults take a daily multivitamin/mineral supplement, which usually contains at least 1.7 mg of vitamin B6

Older adults (>50 years)

Early metabolic studies have indicated that the requirement for vitamin B6 in older adults is approximately 2 mg daily (95). Yet, the analysis of the US population survey (NHANES) 2003-2004 showed that adequate vitamin B6 status and low homocysteine levels were associated with total vitamin B6 intakes equal to and above 3 mg/day in people aged 65 years and older (88). Moreover, a longitudinal study of 360 older adults (60 years or older) in Germany found that vitamin B6 status, measured by serum PLP concentration, did not decline over an 18-year period, although more than one-third of participants had PLP concentrations less than 30 nmol/L (96). The Linus Pauling Institute recommends that older adults take a daily multivitamin/mineral supplement, which generally provides at least 1.7 mg of vitamin B6. Taking a daily multivitamin, along with including vitamin B6-rich foods in the diet, will help ensure adequate vitamin B6 status in older adults.

Authors and Reviewers

Originally written in 2000 by: 
Jane Higdon, Ph.D. 
Linus Pauling Institute 
Oregon State University

Updated in February 2002 by: 
Jane Higdon, Ph.D. 
Linus Pauling Institute 
Oregon State University

Updated in November 2007 by: 
Victoria J. Drake, Ph.D. 
Linus Pauling Institute 
Oregon State University

Updated in May 2014 by: 
Barbara Delage, Ph.D. 
Linus Pauling Institute 
Oregon State University

Reviewed in June 2014 by: 
Jesse F. Gregory, Ph.D. 
Professor, Food Science and Human Nutrition 
University of Florida

The 2014 update of this article was underwritten, in part, by a grant from Bayer Consumer Care AG, Basel, Switzerland.

Copyright 2000-2024  Linus Pauling Institute


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49.  Potter K, Lenzo N, Eikelboom JW, Arnolda LF, Beer C, Hankey GJ. Effect of long-term homocysteine reduction with B vitamins on arterial wall inflammation assessed by fluorodeoxyglucose positron emission tomography: a randomised double-blind, placebo-controlled trial. Cerebrovasc Dis. 2009;27(3):259-265.  (PubMed)

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57.  Merete C, Falcon LM, Tucker KL. Vitamin B6 is associated with depressive symptomatology in Massachusetts elders. J Am Coll Nutr. 2008;27(3):421-427.  (PubMed)

58.  Pan WH, Chang YP, Yeh WT, et al. Co-occurrence of anemia, marginal vitamin B6, and folate status and depressive symptoms in older adults. J Geriatr Psychiatry Neurol. 2012;25(3):170-178.  (PubMed)

59.  Skarupski KA, Tangney C, Li H, Ouyang B, Evans DA, Morris MC. Longitudinal association of vitamin B-6, folate, and vitamin B-12 with depressive symptoms among older adults over time. Am J Clin Nutr. 2010;92(2):330-335.  (PubMed)

60.  Almeida OP, Marsh K, Alfonso H, Flicker L, Davis TM, Hankey GJ. B-vitamins reduce the long-term risk of depression after stroke: The VITATOPS-DEP trial. Ann Neurol. 2010;68(4):503-510.  (PubMed)

61.  Larsson SC, Orsini N, Wolk A. Vitamin B6 and risk of colorectal cancer: a meta-analysis of prospective studies. JAMA. 2010;303(11):1077-1083.  (PubMed)

62.  Wu W, Kang S, Zhang D. Association of vitamin B6, vitamin B12 and methionine with risk of breast cancer: a dose-response meta-analysis. Br J Cancer. 2013;109(7):1926-1944.  (PubMed)

63.  Xiao Q, Freedman ND, Ren J, Hollenbeck AR, Abnet CC, Park Y. Intakes of folate, methionine, vitamin B6, and vitamin B12 with risk of esophageal and gastric cancer in a large cohort study. Br J Cancer. 2014;110(5):1328-1333.  (PubMed)

64.  Zhang XH, Ma J, Smith-Warner SA, Lee JE, Giovannucci E. Vitamin B6 and colorectal cancer: current evidence and future directions. World J Gastroenterol. 2013;19(7):1005-1010.  (PubMed)

65.  Song Y, Manson JE, Lee IM, et al. Effect of combined folic acid, vitamin B(6), and vitamin B(12) on colorectal adenoma. J Natl Cancer Inst. 2012;104(20):1562-1575.  (PubMed)

66.  Curhan GC, Willett WC, Speizer FE, Stampfer MJ. Intake of vitamins B6 and C and the risk of kidney stones in women. J Am Soc Nephrol. 1999;10(4):840-845.  (PubMed)

67.  Taylor EN, Stampfer MJ, Curhan GC. Dietary factors and the risk of incident kidney stones in men: new insights after 14 years of follow-up. J Am Soc Nephrol. 2004;15(12):3225-3232.  (PubMed)

68.  Chetyrkin SV, Kim D, Belmont JM, Scheinman JI, Hudson BG, Voziyan PA. Pyridoxamine lowers kidney crystals in experimental hyperoxaluria: a potential therapy for primary hyperoxaluria. Kidney Int. 2005;67(1):53-60.  (PubMed)

69.  Scheinman JI, Voziyan PA, Belmont JM, Chetyrkin SV, Kim D, Hudson BG. Pyridoxamine lowers oxalate excretion and kidney crystals in experimental hyperoxaluria: a potential therapy for primary hyperoxaluria. Urol Res. 2005;33(5):368-371.  (PubMed)

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75.  Sahakian V, Rouse D, Sipes S, Rose N, Niebyl J. Vitamin B6 is effective therapy for nausea and vomiting of pregnancy: a randomized, double-blind placebo-controlled study. Obstet Gynecol. 1991;78(1):33-36.  (PubMed)

76.  Vutyavanich T, Wongtra-ngan S, Ruangsri R. Pyridoxine for nausea and vomiting of pregnancy: a randomized, double-blind, placebo-controlled trial. Am J Obstet Gynecol. 1995;173(3 Pt 1):881-884.  (PubMed)

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Vitamin B12

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Vitamin B12 has the largest and most complex chemical structure of all the vitamins. It is unique among vitamins in that it contains a metal ion, cobalt. For this reason cobalamin is the term used to refer to compounds having vitamin B12 activity. Methylcobalamin and 5-deoxyadenosylcobalamin are the forms of vitamin B12 used in the human body (1). The form of cobalamin used in most nutritional supplements and fortified foods, cyanocobalamin, is readily converted to 5-deoxyadenosylcobalamin and methylcobalamin in the body. In mammals, cobalamin is a cofactor for only two enzymes, methionine synthase and L-methylmalonyl-coenzyme A mutase (2).


Cofactor for methionine synthase

Methylcobalamin is required for the function of the folate-dependent enzyme, methionine synthase. This enzyme is required for the synthesis of the amino acid, methionine, from homocysteine. Methionine in turn is required for the synthesis of S-adenosylmethionine, a methyl group donor used in many biological methylation reactions, including the methylation of a number of sites within DNA, RNA, and proteins (Figure 1) (3). Aberrant methylation of DNA and proteins, which causes alterations in chromatin structure and gene expression, are a common feature of cancer cells. Inadequate function of methionine synthase can lead to an accumulation of homocysteine, which has been associated with increased risk of cardiovascular disease and age-related neurodegenerative disease (e.g., Alzheimer’s disease).

Figure 1. Vitamin B12 and Homocysteine Metabolism. Methionine synthase is a vitamin B12-dependent enzyme that catalyzes the formation of methionine from homocysteine using 5-methyltetrahydrofolate (5-methyl TH4), a folate derivative, as a methyl donor. Another pathway catalyzed by betaine homocysteine methyltransferase also remethylates homocysteine to methionine using betaine as a methyl donor (not shown here). Methionine, in the form of S-adenosylmethionine, is required for most biological methylation reactions, including DNA methylation.

Cofactor for L-methylmalonyl-coenzyme A mutase

5-Deoxyadenosylcobalamin is required by the enzyme that catalyzes the conversion of L-methylmalonyl-coenzyme A to succinyl-coenzyme A (succinyl-CoA), which then enters the citric acid cycle (Figure 2). Succinyl-CoA plays an important role in the production of energy from lipids and proteins and is also required for the synthesis of hemoglobin, the oxygen-carrying pigment in red blood cells (3).

Figure 2. Metabolic Pathway Requiring 5-Deoxyadenosylcobalamin. 5-deoxyadenosylcobalamin is required by L-methylmalonyl-CoA mutase, which converts L-methylmalonyl-CoA to succinyl-CoA.


In healthy adults, overt vitamin B12 deficiency is uncommon, mainly because total body stores can exceed 2,500 μg, daily turnover is slow, and dietary intake of only 2.4 μg/day is sufficient to maintain adequate vitamin B12 status (see RDA) (4). Among elderly individuals, vitamin B12 deficiency is more common, primarily because of impaired intestinal absorption that can result in marginal to severe vitamin B12 deficiency in this population. In certain regions of the world, marginal or subclinical vitamin B12 deficiency may be fairly common in other age groups as well, including children, premenopausal women, and pregnant women, primarily due to low intake of animal-source foods (reviewed in 5).

Causes of vitamin B12 deficiency

Absorption of vitamin B12 from food requires normal function of the stomach, pancreas, and small intestine. Stomach acid and enzymes free vitamin B12 from food, allowing it to bind to R-protein (formerly known as transcobalamin I and now called haptocorrin), found in saliva and gastric fluids. In the alkaline environment of the small intestine, R-proteins are degraded by pancreatic enzymes, freeing vitamin B12 to bind to intrinsic factor (IF), a protein secreted by specialized cells in the stomach (parietal cells). Receptors on the surface of the terminal ileum (the distal portion of the small intestine) take up the IF-B12 complex only in the presence of calcium, which is supplied by the pancreas (6). Vitamin B12 can also be absorbed by passive diffusion, but this process is very inefficient — only about 1% to 2% of the oral vitamin B12 dose is absorbed passively (2). The prevalent causes of vitamin B12 deficiency are (1) an autoimmune condition known as pernicious anemia, and (2) a disorder called food-bound vitamin B12 malabsorption. Both conditions have been associated with a chronic inflammatory disease of the stomach known as atrophic gastritis.  

Atrophic gastritis

Atrophic gastritis is thought to affect 10%-30% of people over 60 years of age (7). The condition is frequently associated with the presence of autoantibodies directed towards stomach cells (see Pernicious anemia) and/or infection by the bacteria, Helicobacter pylori (H. pylori) (8). H. pylori infection induces chronic inflammation of the stomach, which may progress to peptic ulcer disease, atrophic gastritis, and/or gastric cancer in some individuals. Diminished gastric function in individuals with atrophic gastritis can result in bacterial overgrowth in the small intestine and cause food-bound vitamin B12 malabsorption. Vitamin B12 levels in serum, plasma, and gastric fluids are significantly decreased in individuals with H. pylori infection, and eradication of the bacteria has been shown to significantly improve vitamin B12 serum concentrations (9).

Pernicious anemia

Pernicious anemia has been estimated to affect approximately 2% to 3% of individuals over 65 years of age (5). Although anemia is often a symptom, the condition is actually the end stage of an autoimmune inflammation of the stomach known as autoimmune atrophic gastritis, resulting in destruction of stomach cells by one's own antibodies (autoantibodies). Progressive destruction of the cells that line the stomach causes decreased secretion of acid and enzymes required to release food-bound vitamin B12 (5). Antibodies to intrinsic factor (IF) bind to IF and prevent formation of the IF-B12 complex, further inhibiting vitamin B12 absorption. Absorption of vitamin B12 is inhibited from both dietary sources and from the bile (enterohepatic circulation) and thus depletion of vitamin B12 body stores can occur relatively quickly. About 20% of the relatives of pernicious anemia patients also have the condition, suggesting a genetic predisposition. It is also thought that H. pylori infection could be involved in initiating the autoimmune response in a subset of individuals (10). Further, co-occurrence of autoimmune atrophic gastritis with other autoimmune conditions, especially autoimmune thyroiditis and type 1 diabetes mellitus, has been reported (11, 12).

Treatment of pernicious anemia generally requires intramuscular injections of vitamin B12 to bypass intestinal absorption. High-dose oral supplementation may be another treatment option, because consuming 1,000 μg (1 mg) per day of vitamin B12 orally should result in the absorption of about 10 μg/day (1% of dose) by passive diffusion. However, the effect of oral vitamin B12 varies among patients (13), and the available randomized controlled trials comparing the two treatment regimens are considered to be of low quality (14). Large-scale, well-designed trials with proper randomization and blinding are needed to determine whether high-dose oral supplementation is as effective as intramuscular injection for increasing vitamin B12 status and alleviating clinical symptoms of vitamin B12 deficiency.

Food-bound vitamin B12 malabsorption

Food-bound vitamin B12 malabsorption is defined as an impaired ability to absorb food- or protein-bound vitamin B12; individuals with this condition can fully absorb the free form (15). While the condition is the major cause of poor vitamin B12 status in the elderly population, it is usually associated with atrophic gastritis, a chronic inflammation of the lining of the stomach that ultimately results in the loss of glands in the stomach (atrophy) and decreased stomach acid production (see Atrophic gastritis). Because stomach acid is required for the release of vitamin B12 from the proteins in food, vitamin B12 absorption is diminished. Decreased stomach acid production also provides an environment conducive to the overgrowth of anaerobic bacteria in the stomach, which further interferes with vitamin B12 absorption (3). Because vitamin B12 in supplements is not bound to protein, and because intrinsic factor (IF) is still available, the absorption of supplemental vitamin B12 is not reduced as it is in pernicious anemia. Thus, individuals with food-bound vitamin B12 malabsorption do not have an increased requirement for vitamin B12; they simply need it in the crystalline form found in fortified foods and dietary supplements.

Other causes of vitamin B12 deficiency

Other causes of vitamin B12 deficiency include surgical resection of the stomach or portions of the small intestine where receptors for the IF-B12 complex are located. Conditions affecting the small intestine, such as malabsorption syndromes (celiac disease and tropical sprue), may also result in vitamin B12 deficiency. Because the pancreas provides critical enzymes, as well as calcium required for vitamin B12 absorption, pancreatic insufficiency may contribute to vitamin B12 deficiency. Since vitamin B12 is found predominantly in foods of animal origin, strict vegetarian and vegan diets can result in vitamin B12 deficiency (2, 16). Moreover, alcoholics may experience reduced intestinal absorption of vitamin B12 (2), and individuals with acquired immunodeficiency syndrome (AIDS) appear to be at increased risk of deficiency, possibly related to a failure of the IF-B12 receptor to take up the IF-B12 complex (3). Further, long-term use of acid-reducing drugs and the anti-diabetes drug metformin and repeated exposure to nitrous oxide have been implicated in vitamin B12 deficiency (see Drug interactions).

Inherited disorders of vitamin B12 absorption

Rare cases of inborn errors of vitamin B12 metabolism have been reported in the literature (reviewed in 6). Imerslund-Gräsbeck syndrome is an inherited vitamin B12 malabsorption syndrome that causes megaloblastic anemia and neurologic disorders of variable severity in affected subjects. Similar clinical symptoms are found in individuals with hereditary IF deficiency (also called congenital pernicious anemia) in whom the lack of IF results in the defective absorption of vitamin B12. Additionally, mutations affecting vitamin B12 transport and intracellular metabolism have been identified (17).

Symptoms of vitamin B12 deficiency

Vitamin B12 deficiency results in impairment of the activities of vitamin B12-requiring enzymes. Impaired activity of methionine synthase results in elevated blood concentrations of homocysteine, while impaired activity of L-methylmalonyl-CoA mutase results in increased concentrations of a metabolite of methylmalonyl-CoA called methylmalonic acid (MMA) in blood and urine. While individuals with mild vitamin B12 deficiency may not experience symptoms, blood homocysteine and/or MMA may be elevated (18). While elevated MMA blood concentration is considered the specific indicator of deficiency (19), other clinical assays are often used as biomarkers of vitamin B12 status — sometimes in combination. These include blood concentrations of total cobalamin, holo-transcobalamin (vitamin B12 bound to transcobalamin, one of the two carrier proteins in blood; called 'active vitamin B12'), and homocysteine (5). Yet, there is no ‘gold standard’ blood test, and the manifestation of clinical symptoms is important in the diagnosis of vitamin B12 deficiency (13).

Megaloblastic anemia

Diminished activity of methionine synthase in vitamin B12 deficiency inhibits the regeneration of tetrahydrofolate (THF) and traps folate in a form that is not usable by the body (Figure 3), resulting in symptoms of folate deficiency even in the presence of adequate folate. Thus, in both folate and vitamin B12 deficiencies, folate is unavailable to participate in DNA synthesis. This impairment of DNA synthesis affects the rapidly dividing cells of the bone marrow earlier than other cells, resulting in the production of large, immature, hemoglobin-poor red blood cells (macrocytosis), as well as effects on white blood cells, including abnormal (hypersegmented) neutrophils and reduced overall cell counts (pancytopenia). The resulting anemia is known as megaloblastic anemia and is the symptom for which the disease, pernicious anemia, was named (3). Supplementation with folic acid will provide enough usable folate to restore normal red blood cell formation. However, if vitamin B12 deficiency is the cause, it will persist despite the resolution of the anemia. Thus, megaloblastic anemia should not be treated with folic acid until the underlying cause has been determined (20).

Figure 3. Vitamin B12 and Nucleic Acid Metabolism. 5,10-Methylene tetrahydrofolate (TH4) is required for the synthesis of nucleic acids, while 5-methyl TH4 is required for the formation of methionine from homocysteine. Methionine, in the form of S-adenosylmethionine, is required for many biological methylation reactions, including DNA methylation. Methylene TH4 reductase is a flavin-dependent enzyme required to catalyze the reduction of 5,10-methylene TH4 to 5-methyl TH4.

Neurologic symptoms

The neurologic symptoms of vitamin B12 deficiency are myriad and include numbness and tingling of the hands and, more commonly, the feet (peripheral neuropathy); difficulty walking (gait ataxia); memory loss and other cognitive impairments; disorientation; alterations in mood, including depression and anxiety; and dementia that can resemble Alzheimer’s disease (13). Although the progression of neurologic complications is generally gradual, such symptoms may not be reversed with treatment of vitamin B12 deficiency, especially if they have been present for a long time. Neurologic complications are not always associated with megaloblastic anemia and are the only clinical symptom of vitamin B12 deficiency in about 25% of cases (21). Although vitamin B12 deficiency is known to damage the myelin sheath covering cranial, spinal, and peripheral nerves, the biochemical processes leading to neurologic damage in vitamin B12 deficiency are not yet fully understood (22).

Gastrointestinal symptoms

Tongue soreness, appetite loss, and constipation have also been associated with vitamin B12 deficiency. The origins of these symptoms are unclear, but they may be related to the stomach inflammation underlying some cases of vitamin B12 deficiency and to the progressive destruction of the lining of the stomach (21).

The Recommended Dietary Allowance (RDA)

The RDA for vitamin B12 was last revised by the Food and Nutrition Board (FNB) of the US Institute of Medicine (now the National Academy of Medicine) in 1998 (Table 1). Because of the increased risk of food-bound vitamin B12 malabsorption in older adults, the FNB recommended that adults over 50 years of age get most of the RDA from fortified food or vitamin B12-containing supplements (21).

Table 1. Recommended Dietary Allowance (RDA) for Vitamin B12
Life Stage Age Males (μg/day) Females (μg/day)
Infants  0-6 months  0.4 (AI 0.4 (AI) 
Infants  7-12 months  0.5 (AI)  0.5 (AI) 
Children  1-3 years  0.9  0.9 
Children 4-8 years  1.2  1.2 
Children  9-13 years  1.8  1.8 
Adolescents  14-18 years  2.4  2.4 
Adults  19-50 years  2.4  2.4 
Adults  51 years and older  2.4*  2.4* 
Pregnancy  all ages  2.6 
Breast-feeding  all ages  2.8
*Vitamin B12 intake should be from supplements or fortified foods due to the age-related increase in food-bound malabsorption.

Disease Prevention

Cardiovascular disease

As mentioned above, chronic atrophic gastritis and infection by H. pylori can cause deficiency in vitamin B12 secondary to malabsorption disorders (see Causes of vitamin B12 deficiency). Some studies, but not all, have found H. pylori infection or chronic atrophic gastritis to be associated with adverse cardiovascular events, including myocardial infarction and stroke (reviewed in 23-25).

Homocysteine and cardiovascular disease

Observational studies indicate that even moderately elevated blood concentrations of homocysteine raise the risk of cardiovascular disease (CVD), although randomized controlled trials of homocysteine-lowering therapy have generally not translated to reductions in adverse cardiovascular outcomes (26, 27). The mechanism by which homocysteine might increase CVD risk remains the subject of a great deal of research (28). The amount of homocysteine in the blood is regulated by at least four vitamins: folate, vitamin B6, riboflavin, and vitamin B12 (see Figure 1). An early analysis of the results of 12 randomized controlled trials showed that folic acid supplementation (0.5-5 mg/day) had the greatest lowering effect on blood homocysteine concentrations (25% decrease); co-supplementation with folic acid and vitamin B12 (500 μg/day) provided an additional 7% reduction (32% decrease) in blood homocysteine concentrations (29). The results of a sequential supplementation trial in 53 men and women indicated that after optimization of folate status with folic acid supplements, vitamin B12 became the major determinant of plasma homocysteine levels (30). In addition, in a population of older adults (age >60 years) exposed to folic acid fortification, the main determinants of plasma homocysteine were renal function and vitamin B12 (31). It is thought that the elevation of homocysteine levels might be partly due to vitamin B12 deficiency in individuals over 60 years of age. Two studies found blood methylmalonic acid (MMA) levels to be elevated in more than 60% of elderly individuals with elevated homocysteine levels. In the absence of impaired kidney function, an elevated MMA level in conjunction with elevated homocysteine suggests either a vitamin B12 deficiency or a combined vitamin B12 and folate deficiency (32). Thus, it appears important to evaluate vitamin B12 status, as well as kidney function, in older individuals with elevated homocysteine levels prior to initiating homocysteine-lowering therapy. For more information regarding homocysteine and CVD, see the article on folate.

Intervention studies

Although increased intake of folic acid and vitamin B12 is effective in decreasing blood concentrations of homocysteine, whether these B vitamins lower risk of CVD remains controversial. Several randomized, placebo-controlled trials have been conducted to determine whether homocysteine-lowering through folic acid, vitamin B12, and vitamin B6 supplementation reduces the incidence of CVD. A 2017 meta-analysis of data from 15 trials, including more than 71,000 participants at risk of or with existing CVD, showed that B-vitamin supplementation had no significant effect on risk of myocardial infarction (heart attack) or all-cause mortality but reduced risk of stroke by 10% (RR, 0.90; 95% CI, 0.82-0.99) (33). This analysis excluded trials in those with end-stage renal disease, who are at high risk of cardiovascular events and mortality. Two recent meta-analyses that pooled data from patients with end-stage renal disease found no benefit of B-vitamin supplementation on stroke outcomes (34, 35). Some have raised concern over potential toxicity of high-dose supplemental cyanocobalamin in individuals with impaired kidney function (34, 36); alternate supplement formulations of vitamin B12, such as methylcobalamin and hydroxycobalamin, have been suggested for this patient population.

A meta-analysis of 12 clinical trials measuring flow-mediated vasodilation (FMD; a surrogate marker of vascular health) in response to homocysteine reduction revealed that B-vitamin supplementation was accompanied by improved FMD in short-term (<8 weeks) but not in long-term studies conducted in subjects with preexisting vascular diseases (37). Some of the studies included in these meta-analyses did not use vitamin B12, and folate administration on its own has shown a protective role on vascular function and stroke risk (38, 39). Also, the high prevalence of malabsorption disorders and vitamin B12 deficiency in elderly individuals might warrant the use of higher doses of vitamin B12 than those used in these trials (40).


Folate is required for synthesis of DNA, and there is evidence that decreased availability of folate results in strands of DNA that are more susceptible to damage. Deficiency of vitamin B12 traps folate in a form that is unusable by the body for DNA synthesis. Both vitamin B12 and folate deficiencies result in a diminished capacity for methylation reactions (see Figure 3). Thus, vitamin B12 deficiency may lead to an elevated rate of DNA damage and altered methylation of DNA, both of which are important risk factors for cancer. A series of studies in young adults and older men indicated that increased levels of homocysteine and decreased levels of vitamin B12 in the blood were associated with a biomarker of chromosome breakage in white blood cells (reviewed in 41). In a double-blind, placebo-controlled study, the same biomarker of chromosome breakage was minimized in young adults who were supplemented with 700 μg of folic acid and 7 μg of vitamin B12 daily in cereal for two months (42).

Breast cancer

While results from two early case-control studies suggested higher intakes of vitamin B12 might help protect against breast cancer (43, 44), nested case-control studies and prospective cohort studies in different populations have found no associations between breast cancer incidence and dietary or total intake of vitamin B12 (dietary plus supplemental) (45-51) or blood concentrations of vitamin B12 (52-54). However, a nested case-control study within the Women’s Health Study (participants ≥45 years at baseline) reported a positive association between the highest quintile of total vitamin B12 intake (>10.5 μg/day) and breast cancer compared to the lowest quintile (≤4.3 μg/day; RR, 1.44; 95% CI, 1.02-2.04), but this study did not find an association between plasma concentrations of vitamin B12 and breast cancer (55). A more recent nested case-control study within the Nurses’ Health Study II reported a positive association between plasma concentrations of vitamin B12 and breast cancer risk; participants in this study were mostly premenopausal women (56). While additional studies are needed to determine whether elevated vitamin B12 status may be related to cancer development, including evaluating whether it might be a potential marker of cancer, it is important for observational studies to adequately control for potential confounders, such as age, menopausal status, alcohol use, and intake of the B-vitamin folate.

Neural tube defects

Neural tube defects (NTD) may result in anencephaly or spina bifida, which are often fatal congenital malformations of the central nervous system. The defects arise from failure of the embryonic neural tube to close, which occurs between the 21st and 28th days after conception, a time when most women are unaware of their pregnancy (57). Randomized controlled trials have demonstrated 60 to 100% reductions in NTD cases when women consumed folic acid supplements in addition to a varied diet during the month before and the month after conception. The homocysteine-lowering effect of folic acid may play a critical role in reducing the risk of NTD (58, 59). Homocysteine accumulates in the blood when there is inadequate folate and/or vitamin B12 for effective functioning of the methionine synthase enzyme (see Function). However, disruption in folate metabolism may be the underlying cause of folic acid-responsive NTD, and elevated homocysteine may simply be coincidental.

While the etiology of NTD is multifactorial, some studies have found that blood concentrations of homocysteine or holo-transcobalamin to be lower in NTD-affected infants and mothers compared to non-affected controls (reviewed in 59). Polymorphisms in various genes involved in vitamin B12 metabolism, including the genes encoding the intrinsic factor-cobalamin receptor (60) and the holo-transcobalamin receptor (61), have been associated with increased NTD risk in some studies. However, it is not known whether vitamin B12 supplementation, in addition to folic acid supplementation, may be beneficial in the prevention of NTD (62) — randomized controlled trials are needed to address this question.

Cognitive decline, dementia, and Alzheimer's disease

The occurrence of vitamin B12 deficiency prevails in the elderly population and has been frequently associated with Alzheimer's disease (reviewed in 63, 64). One study found lower vitamin B12 levels in the cerebrospinal fluid of patients with Alzheimer's disease than in patients with other types of dementia, though blood levels of vitamin B12 did not differ (65). The reason for the association of low vitamin B12 status with Alzheimer's disease is not clear. Vitamin B12 deficiency, like folate deficiency, may lead to decreased synthesis of methionine and S-adenosylmethionine (SAM), thereby adversely affecting methylation reactions. Methylation reactions are essential for the metabolism of components of the myelin sheath of nerve cells, as well as for synthesis and metabolism of neurotransmitters (22). Other metabolic implications of vitamin B12 deficiency include the accumulation of homocysteine and methylmalonic acid, which might contribute to the neuropathologic features of dementia (63). Indeed, elevated homocysteine is now recognized as a strong risk factor for cognitive impairment and dementia, including Alzheimer’s disease (66-68).

Observational studies

A large number of cross-sectional and prospective cohort studies have associated elevated blood homocysteine concentrations with measures of poor cognitive scores and increased risk of dementia, including Alzheimer's disease (reviewed in 67, 69). A case-control study of 164 patients with dementia of Alzheimer's type included 76 cases in which the diagnosis of Alzheimer's disease was confirmed by examination of brain cells after death. Compared to 108 control subjects without evidence of dementia, subjects with dementia of Alzheimer's type and confirmed Alzheimer's disease had higher blood levels of homocysteine and lower blood levels of folate and vitamin B12. Measures of general nutritional status indicated that the association of increased homocysteine levels and diminished vitamin B12 status with Alzheimer's disease was not due to dementia-related malnutrition (70). In a sample of 1,092 men and women without dementia followed for an average of 10 years, those with higher plasma homocysteine levels at baseline had a significantly higher risk of developing Alzheimer's disease and other types of dementia. Specifically, those with plasma homocysteine levels greater than 14 μmol/L had nearly double the risk of developing Alzheimer's disease (71). A study in 650 elderly men and women reported that the risk of elevated plasma homocysteine levels was significantly higher in those with lower cognitive function scores (72). A prospective study in 816 elderly men and women reported that those with hyperhomocysteinemia (homocysteine levels >15 μmol/L) had a significantly higher risk of developing Alzheimer's disease or dementia. Although raised homocysteine levels might be partly due to a poor vitamin B12 status, the latter was not related to risk of dementia or Alzheimer's disease in this study (73). Several meta-analyses of observational studies have found elevated blood concentrations of homocysteine to be linked with an increased risk of dementia (74) or Alzheimer’s disease (68, 75-78).

A systematic review of 35 prospective cohort studies assessing the association between vitamin B12 status and cognitive deterioration in older individuals with or without dementia at baseline did not support a relationship between serum vitamin B12 concentrations and cognitive decline, dementia, or Alzheimer’s disease (79). More recent meta-analyses of prospective cohort studies in older adults have not found a relationship between blood cobalamin concentration or dietary vitamin B12 intake and cognitive decline or dementia (80, 81). Nevertheless, studies utilizing more specific biomarkers of vitamin B12 status, including measures of holo-transcobalamin and methylmalonic acid, have shown more consistent results and a trend towards associations between poor vitamin B12 status and faster cognitive decline and increased risk of Alzheimer’s disease (82-86). Interestingly, two longitudinal studies in older adults (>60 years) found lower blood concentrations of holo-transcobalamin (and cobalamin) at baseline were associated with increased brain volume loss over a period of five (87) and six years (88).

Intervention studies

High-dose B-vitamin supplementation has been proven effective for treating hyperhomocysteinemia in elderly individuals with or without cognitive impairment. However, homocysteine-lowering trials have produced equivocal results regarding the prevention of cognitive deterioration in this population. A recent systematic review and meta-analysis of 21 randomized, placebo-controlled trials examining the effect of B-vitamin supplementation found the supplementation decreased homocysteine concentrations and improved measures global cognitive function but had no effect on individual measures of executive function, information processing speed, or episodic memory (89). This analysis pooled results from trials of participants with mild cognitive impairment (6 trials) and trials of participants without cognitive impairment (15 trials). A separate meta-analysis that pooled results of trials in older adults with mild cognitive impairment found B-vitamin supplementation (6 to 24 months, depending on the trial) had no benefits on various cognitive parameters, including executive function, information processing speed, and episodic memory (90). The trials of this meta-analysis employed different dosages of B vitamins, with vitamin B12 included in four of five trials.

A two-year, randomized, placebo-controlled study in older adults (>70 years) with mild cognitive impairment reported that a daily regimen of 800 μg of folic acid, 500 μg of vitamin B12, and 20 mg of vitamin B6 significantly reduced the rate of brain atrophy compared to placebo treatment (0.5% vs. 3.7%) (91, 92). Compared to placebo, B-vitamin supplementation in these older subjects also improved a measure of executive function, a secondary outcome of the trial (93). Interestingly, greater benefits were seen in those with high compared to low homocysteine concentrations at baseline, suggesting the importance of lowering homocysteine levels in prevention of brain atrophy and cognitive decline (91-93). The authors attributed the changes in homocysteine levels primarily to vitamin B12 (92). Yet, very few clinical trials have looked at the effect of vitamin B12, solely, on cognitive endpoints. A randomized, double-blind, placebo-controlled trial in 191 older adults (≥75 years) with moderate vitamin B12 deficiency (serum cobalamin concentrations of 107-210 pmol/L) without anemia provided participants with 1 mg/day of cyanocobalamin for one year (94). Compared to baseline, the vitamin B12 supplementation increased serum cobalamin and holo-transcobalamin levels and decreased blood homocysteine concentrations, but had no effect on measures of cognitive function, including assessments of memory, processing speed, and executive function (94). It is important to note that the participants in this trial were not experiencing clinical symptoms of vitamin B12 deficiency.

While it is known that B-vitamin supplementation effectively treats hyperhomocysteinemia, there is a need for well-designed, large trials to evaluate the effect of B-vitamin supplementation on long-term outcomes, such as age-related cognitive decline and the incidence of Alzheimer’s disease. The authors of one trial (95) included in the above-mentioned meta-analysis (89) noted that little cognitive decline was observed in the placebo group over their two-year trial, which may have limited their power to detect an effect of the B-vitamin intervention (95).


A few observational studies have found higher dietary intakes of vitamin B12 to be associated with lower risk of developing depression, especially among women. One study found as many as 30% of patients hospitalized for depression were deficient in vitamin B12 (96). A cross-sectional study of 700 community-living, physically disabled women over the age of 65 found that vitamin B12-deficient women were twice as likely to be severely depressed as non-deficient women (97). A population-based study in 3,884 elderly men and women with depressive disorders found that those with vitamin B12 deficiency were almost 70% more likely to experience depression than those with normal vitamin B12 status (98). A recent meta-analysis of 12 observational studies found that higher dietary intake of vitamin B12 was associated with a 23% lower risk of depression compared to lower intakes, but stratifying the data revealed a significant protective association in females, not in males (99). Similarly, a meta-analysis of nine observational studies in older adults found low serum vitamin B12 concentration to be associated with increased risk for depression, with significant association only in women (100). More recently, a longitudinal study among 3,849 community-living older adults in Ireland found that low vitamin B12 serum concentrations (<185 pmol/L) at baseline were associated with a 51% increased risk of developing symptoms of depression over a four-year period compared to those with normal concentrations (>258-601 pmol/L) (101).

The reasons for a link between vitamin B12 deficiency and depression are not clear but may involve a shortage in S-adenosylmethionine (SAM). SAM is a methyl group donor for numerous methylation reactions in the brain, including those i