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Summary

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.

Function

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

Synthesis of nucleic acids from the 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.

Deficiency

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).

Plasma or serum concentration of pyridoxal 5’-phosphate (PLP) is commonly used to assess vitamin B6 nutritional status, with concentrations below 30 nmol/L often recognized as inadequate and concentrations below 20 nmol/L considered deficient (13, 14).

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 (15). Unlike previous recommendations issued by the Food and Nutrition Board (FNB) of the Institute of Medicine (now the National Academy of Medicine), the current RDA for vitamin B6 — set by the FNB in 1998 — was not expressed in terms of protein intake, although this relationship was considered in setting the RDA (Table 1) (16).

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) (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 (17). 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 17). There is evidence to suggest that adequate vitamin B6 intake is important for optimal immune system function, especially in older individuals (18, 19). 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 (20). 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). Additionally, 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 (21). More recently, in large prospective cohorts of 59,746 men and 74,734 women in China, higher dietary intakes of vitamin B6 were linked with lower risks of mortality caused by cardiovascular disease or stroke (22). In this study, higher vitamin B6 intakes were also associated with lower mortality from coronary heart disease in men but not in women (22). A meta-analysis that combined the results of these two studies with those of six other prospective cohort studies found a significantly lower risk of coronary heart disease with higher intakes of dietary vitamin B6 (RR, 0.81; 95% CI, 0.70-0.93) (23). Additionally, a meta-analysis of five prospective cohort studies found an inverse association of total daily vitamin B6 intake (combined from diet and supplements) and incident stroke (24).

Early observational studies also demonstrated an association between suboptimal pyridoxal 5'-phosphate (PLP) plasma level, elevated homocysteine blood level, and increased risk of cardiovascular disease (25-27). More recent research has confirmed that low plasma PLP status is associated with CAD. In a case-control study, which included 184 participants with CAD and 516 healthy controls, low plasma PLP levels (<30 nmol/L) were associated with a near doubling of CAD risk when compared to higher PLP levels (≥30 nmol/L) (28). 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 nmol/L) had a 79% lower risk of myocardial infarction compared to those in the lowest quartile (<27.9 nmol/L) (29). Most recently, in a case-control study of 429 CHD cases with ≥70% stenosis of major coronary arteries and 429 controls with <30% stenosis, plasma PLP concentration was inversely associated with coronary heart disease in women but not in men (30). It is important to note that low plasma PLP status is more likely a result of the inflammatory processes of CAD rather than a risk factor for CAD (31). Indeed, a recent population-based cohort study of 6,249 participants, followed for a median of 8.3 years, found lower blood PLP concentrations (<20 nmol/L vs. >30 nmol/L) at baseline to be associated with an increased risk of cardiovascular events, but this overall association was not significant when accounting for inflammation (32). Yet when the authors analyzed the data by gender, lower PLP status in women was associated with cardiovascular events independent of inflammation (32).

Vitamin B6 and homocysteine

Even moderately elevated levels of homocysteine in the blood have been associated with increased risk for cardiovascular disease, including cardiac insufficiency (heart failure), CAD, myocardial infarction, and cerebrovascular attack (stroke) (33). 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) (34). 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.

Deficiencies in one or all of these B vitamins may affect both remethylation and transsulfuration processes and result in abnormally elevated blood homocysteine concentration. 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) (35), but vitamin B6 supplementation might not be effective in decreasing fasting levels of homocysteine. In a 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 nmol/L) as compared to vitamin B6 sufficiency (mean PLP level of 49 nmol/L) (36). 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 the methionine cycle and transsulfuration pathway appeared to favor homocysteine clearance by remethylation rather than transsulfuration in six out of nine participants (36).

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, effectively reduces fasting plasma homocysteine concentration. In 19 intervention studies 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 (37). In contrast, studies supplementing individuals with only vitamin B6 have usually failed to show an effect on fasting levels of homocysteine (38, 39). 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 (40). Yet, the effect of homocysteine lowering on cardiovascular disease risk reduction is debated. In the latest Cochrane review of 12 placebo-controlled trials, supplementation with folic acid, vitamin B6, and vitamin B12 — either alone or in combination — did not affect the risk for myocardial infarction and was associated with only a very small reduction in risk for stroke (RR, 0.90; 95% CI, 0.82, 0.99) (41).

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 (37, 42-44). Joint guidelines from the American College of Cardiology and the American Heart Association do not support the use of circulating homocysteine as a risk factor for coronary heart disease (45). 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 (46). 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 (47).

It has been suggested that antiplatelet therapy used in the primary prevention of cardiovascular disease might interfere with the effect of homocysteine lowering by B vitamins on cardiovascular risk (48). In this context, a post-hoc subgroup analysis of the multicenter, randomized, double-blind, placebo-controlled VITATOPS trial (49) proposed that the small benefit of homocysteine-lowering by B vitamins might be canceled in patients treated with antiplatelet drugs (50). Yet, the benefit of B-vitamin supplementation in primary prevention (i.e., in non-antiplatelet users) remains to be established.

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.

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 (51-53). Markers of immune activation and inflammation have been associated with hyperhomocysteinemia (homocysteine levels >15 micromoles/liter [μmol/L]) in individuals with coronary artery disease (CAD) (54). 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 (55). 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 (56). Yet, the study suggested that suboptimal PLP levels (<36.3 nmol/L) 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 (51). In addition, the prevalence of inadequate vitamin B6 status (plasma PLP levels <20 nmol/L) 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) (52). 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, an 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 (57). 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 (58, 59).

Cognitive decline and Alzheimer's disease

A few observational studies have linked cognitive decline and Alzheimer's disease in older adults with inadequate status of folate, vitamin B12, and vitamin B6 (60), although some meta-analyses have not found an association (61, 62). 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 older individuals (63). 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 older adults, although the matter remains under debate. 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 (64-66). 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 (67). 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 (68). 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 (68). However, some of the trials included in these meta-analyses did not supplement with vitamin B6.

Overall, results from clinical trials to date have been somewhat mixed. For example, a randomized, double-blind, placebo-controlled study of 2,695 stroke survivors with or without cognitive impairments found daily supplementation with 2 mg of folic acid, 0.5 mg of vitamin B12, and 25 mg of vitamin B6 for 3.4 years significantly reduced mean homocysteine levels (by 28% and 43% in cognitively unimpaired and impaired patients, respectively) compared to placebo. However, 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 (69). In contrast, another 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 Alzheimer’s disease process (70). Yet, the authors attributed the changes in homocysteine levels primarily to vitamin B12. Large-scale randomized controlled trials in older adults with hyperhomocysteinemia are needed to determine whether B-vitamin supplementation might help prevent dementia or Alzheimer’s disease.

Depression

Late-life depression is a common disorder sometimes occurring after acute illnesses, such as hip fracture or stroke (71, 72). Coexistence of symptoms of depression and low vitamin B6 status (plasma PLP concentration ≤20 nmol/L) has been reported in a few cross-sectional studies (73, 74) and one longitudinal study (study used a higher PLP cutoff of <30 nmol/L) (75). A recent meta-analysis of 14 observational studies found higher dietary vitamin B6 intakes to be associated with a lower risk of depression (RR, 0.81; 95% CI, 0.71-0.93) (76). Data stratification revealed that this association was statistically significant in women but not in men (76).

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 (77). This reduction in risk was associated with a 25% lower level of plasma homocysteine in supplemented patients compared to controls. More recently, in a randomized, double-blind, placebo-controlled trial in 98 younger adults (ages 18-58 years), high-dose vitamin B6 supplementation (100 mg/day) for one month did not reduce self-reported symptoms of depression, yet this study found significant reductions in self-reported anxiety (78) Additional evidence is needed to evaluate whether supplemental B-vitamins might help people at high risk for depression.

Cancer

Several studies — mostly observational — have investigated whether vitamin B6 might be involved in the development of cancer. Chronic inflammation that underlies most cancers may enhance vitamin B6 degradation (see Vitamin B6 and inflammation). In addition, the requirement of pyridoxal 5'-phosphate (PLP) in the methionine cycle, homocysteine catabolism, and thymidylate synthesis suggests that low vitamin B6 status may contribute to the onset and/or progression of tumors.

Gastrointestinal cancers

A meta-analysis of 45 observational studies found that higher dietary intakes of vitamin B6 were associated with a significantly lower risk of developing any type of gastrointestinal cancer compared to the lowest intakes (RR, 0.57; 95% CI, 0.47-0.69) (79). Pooling of observational data to examine site-specific cancers resulted in significant inverse associations between vitamin B6 intake and esophageal (8 studies), stomach (9 studies), and colorectal (23 studies) cancers (79). Another meta-analysis of 10 prospective cohort studies found an inverse association between vitamin B6 intake and colorectal cancer, but the association failed to reach statistical significance (80). However, when the five studies that provided adequate data for a dose-response meta-analysis were pooled, the authors found significantly lower risks of colorectal cancer with higher vitamin B6 intakes: an 11% lower risk with a 3-mg increase in intake and a 17% lower risk with a 5-mg increase (80).  

An early meta-analysis of four nested case-control studies reported a 48% reduction in risk of colorectal cancer in the highest versus lowest quartile of blood PLP concentration (81). In a more recent meta-analysis of observational studies, higher blood PLP concentrations were associated with a 44% lower risk of gastrointestinal cancers overall (10 studies) and a 44% lower risk of colorectal cancers in particular (5 studies) (79). Moreover, in a study of six prospective cohorts from the US and Europe, including 2,031 patients with stage I, II, or III colorectal cancer, higher preoperative vitamin B6 status (including PLP concentration and a functional biomarker) was associated with improved survival but not with colorectal cancer recurrence (82). It is important to note that observational studies can only show associations and cannot establish causation. Like many other vitamins, higher vitamin B6 status might be a general marker of a healthy diet.   

Randomized controlled trials have generally not found an effect of B-vitamin supplementation (combined folic acid, vitamin B6, and vitamin B12) on development of any tissue-specific cancer (79), but these trials have been done only in patients with cardiovascular disease or kidney disease, with cancer as a secondary endpoint (79). Such data on gastrointestinal cancers in particular are severely limited. A 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 (83).

Breast cancer

A few recent observational studies have suggested an inverse association between dietary vitamin B6 intake and incidence of breast cancer. In a prospective cohort study that followed 10,786 Italian women (ages 35-69 years at baseline) for an average of 16.5 years, the highest quartile of dietary vitamin B6 (median intake, 2.66 mg/day) was associated with a 41% lower risk of breast cancer compared to the lowest intake (median intake, 1.37 mg/day of vitamin B6) (84). In a prospective cohort study in France, which included 27,853 women (ages ≥45 years) followed for a median of 4.2 years, higher dietary and supplemental (and total daily) intakes of vitamin B6 were linked to lower risks of breast cancer (85). However, other studies have reported no association between dietary intake of vitamin B6 and breast cancer (86, 87). A 2017 meta-analysis of observational studies found an inverse association between dietary vitamin B6 and breast cancer (18 studies), but there was no association between blood concentration of PLP and breast cancer (6 studies) (79).

Randomized controlled trials of solely vitamin B6 have not been done. A randomized, double-blind, placebo-controlled trial in 5,442 women (≥42 years at baseline) with existing or at high risk for cardiovascular disease found that daily supplementation with B-vitamins, including 2.5 mg of folic acid, 1 mg of vitamin B12, and 50 mg of vitamin B6, for 7.3 years had no effect on breast cancer development (88).

Kidney stones

A large prospective cohort 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 (89). 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 (90). Moreover, pooled analysis of data from three large US prospective cohort studies, the Nurses' Health Study I (60,003 older women), the Nurses' Health Study II (90,629 younger women), and the Health Professionals Follow-up Study (42,919 men), found no association between vitamin B6 intake and kidney stones (91).

Limited experimental data have suggested that supplementation with high doses of pyridoxamine might help decrease the formation of calcium oxalate kidney stones and reduce urinary oxalate level, an important determinant of calcium oxalate kidney stone formation (92, 93). However, the effect of vitamin B6 supplementation on the development of kidney stones has not been explored in randomized controlled trials.  

Disease Treatment

Vitamin B6 supplements at pharmacological 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 pyridox(am)ine phosphate oxidase (PNPO) deficiency, are the cause of early-onset epileptic encephalopathies that are found to be responsive to pharmacological 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 (94, 95). Pyridoxine therapy, along with dietary protein or methionine restriction, is also sometimes used in the management of vitamin B6 responsive homocystinuria caused by the deficiency of the PLP-dependent enzyme, cystathionine β-synthase (96, 97).

Nausea and vomiting during pregnancy

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 12 to 16 weeks (98). 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 individuals without any evidence of fetal harm (99). 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 (100) or 10 mg of pyridoxine every eight hours for five days (101), suggested that vitamin B6 may be beneficial in reducing nausea. A 2014 systematic review of randomized controlled trials on NVP symptoms during early pregnancy found supplemental vitamin B6 to be somewhat effective (102). More recent systematic reviews have found supplemental vitamin B6 to have some benefit in treating NVP (103, 104), but evidence has been graded to be of very low quality (104). Another review of 14 clinical trials found that pyridoxine treatment was effective for mild cases of NVP (105). The American College of Obstetricians and Gynecologists include oral pyridoxine as a first-line therapy for NVP (106); patients should discuss treatment options with their physician. It should be noted that NVP usually resolves in the second trimester of pregnancy without any treatment, making it difficult to perform well-controlled trials.

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 (107). 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 (98) 

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 (108). Another more recent review of 13 randomized controlled studies also emphasized the need for conclusive evidence before recommendations can be made (109).

Depression

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 might 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 a daily multivitamin/mineral supplement improved nutritional B-vitamin status and decreased the number and severity of depressive symptoms compared to placebo (110). While the supplementation effectively reduced plasma homocysteine levels compared to placebo, its effects on depressive symptoms at the end of the trial were greater in treated subjects in the lowest versus highest quartile of homocysteine level at baseline (≤10 μmol/L vs. ≥16.1 μmol/L) (111). Yet, the etiology of depression is unclear, and evidence is currently lacking to suggest whether supplemental B vitamins (including vitamin B6) might relieve depressive symptoms. Large-scale, placebo-controlled trials are needed to determine whether B-vitamin supplementation has any utility in the treatment of depression.

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 mg/day-200 mg/day of vitamin B6 for several months might improve CTS symptoms in individuals with low vitamin B6 status (112, 113). In addition, a cross-sectional study in 137 men not taking vitamin supplements found that decreased blood concentrations of PLP were associated with increased pain, tingling, and nocturnal wakening — all symptoms of CTS (114). However, studies using electrophysiological measurements of median nerve conduction have largely failed to find an association between vitamin B6 deficiency and CTS (115). 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 (115). 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) (116).

Sources

Food sources

Data collected in a recent US national survey indicate that vitamin B6 intakes from food only averaged 2.6 mg/day in adult males and 1.7 mg/day in adult females — intakes above the RDA (117). 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 (16). 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. A US national, cross-sectional survey found that vegetarians had lower dietary intakes of vitamin B6 compared to meat eaters, but measures of vitamin B6 status — including serum PLP — did not differ between groups, likely due to more frequent use of vitamin B6-containing supplements among vegetarians (118).

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 database. Pyridoxine may also be included in certain beverages, such as those marketed as 'energy drinks' (119).

 
Table 2. Some Food Sources of Vitamin B6
Food Serving Vitamin B6 (mg)
Fortified breakfast cereal 1 cup 0.5-2.5
Turkey, light meat (cooked) 3 ounces* 0.70-0.81
Salmon, wild (cooked) 3 ounces 0.47-0.80
Potato, Russet, with skin (baked) 1 medium 0.61
Chicken, light meat without skin (cooked) 3 ounces 0.51
Spinach (cooked) 1 cup 0.44
Banana 1 medium 0.43
Avocado ½ medium 0.26
Dried plums (prunes), pitted ½ cup 0.18
Hazelnuts (dry roasted) 1 ounce 0.18
Vegetable juice cocktail 6 fluid ounces 0.13
*A three-ounce serving of meat or fish is about the size of a deck of cards.

Supplements

Vitamin B6 is available as pyridoxine hydrochloride in multivitamin, vitamin B-complex, and single-nutrient vitamin B6 supplements (120). In NHANES 2003-2004, low vitamin B6 status (plasma PLP level <20 nmol/L) 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 plasma 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 ages 65 and older had low PLP values with total vitamin B6 intakes of 2 to 2.9 mg/day compared to 26% in those consuming less than 2 mg/day of vitamin B6 (121).

Safety

Toxicity

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 ataxic neuropathy, which can be irreversible (122, 123). Symptoms include pain and numbness of the extremities and in severe cases, difficulty walking. Sensory ataxic 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 to years. For instance, a case report detailed sensory ataxia and/or sensory polyneuropathy in three elderly patients taking 600 mg/day of pyridoxine for 3 to 10 years (124). 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 (125).

To prevent sensory neuropathy in virtually all individuals, the Food and Nutrition Board of the Institute of Medicine (now the National Academy of Medicine) set the tolerable upper intake level (UL) for pyridoxine at 100 mg/day for adults (Table 3) (16). 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. The European Food and Safety authority set their UL for adults at a lower level: 25 mg/day (126).

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 below) (121). Anti-tuberculosis medications (e.g., isoniazid and cycloserine), the metal chelator penicillamine, and anti-parkinsonian drugs like Levodopa (L-Dopa) and carbidopa 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 (127). Conversely, high doses of vitamin B6 have been found to decrease the efficacy of two anticonvulsants, phenobarbital and phenytoin, and of L-Dopa (6, 125).

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 (121). Yet, more recently, the use of lower dose formulations has also been associated with vitamin B6 inadequacy (121, 128, 129).  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 (130). 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 (131), 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 indicated that the requirement for vitamin B6 in older adults is approximately 2 mg daily (132). 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 ages 65 years and older (121). 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 (133). 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.

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

Copyright 2000-2024  Linus Pauling Institute


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