Vitamin B6

Vitamin B6 is a water-soluble vitamin that is naturally present in many foods, added to others, and available as a dietary supplement. Vitamin B6 is the generic name for six compounds (vitamers) with vitamin B6 activity (Figure 1) ¹, ², ³, ⁴, ⁵, ⁶:

• Pyridoxine (pyridoxol) an alcohol, commonly known as vitamin B6;
• Pyridoxal, an aldehyde;
• Pyridoxamine, which contains an amino group; and their respective 5’-phosphate esters.
• Pyridoxal 5’ phosphate (PLP) and pyridoxamine 5’ phosphate (PMP) are the active coenzyme forms of vitamin B6 involved in over 4% of all enzymatic reactions.

Vitamin B6 must be obtained from the diet because humans cannot synthesize it ⁷. Vitamin B6 is a vitamin that is naturally present in many foods. You can get recommended amounts of vitamin B6 by eating a variety of foods, including the following ⁸:

• Poultry, fish, and organ meats, all rich in vitamin B6.
• Potatoes and other starchy vegetables, which are some of the major sources of vitamin B6 for Americans.
• Fruit (other than citrus), which are also among the major sources of vitamin B6 for Americans.

Your body needs vitamin B6 for more than 100 enzyme reactions, mostly concerned with protein metabolism ⁹. Vitamin B6 is also involved in brain development during pregnancy and infancy as well as immune function ⁸. Both pyridoxal 5’ phosphate (PLP) and pyridoxamine 5’ phosphate (PMP) are involved in amino acid metabolism, and pyridoxal 5’ phosphate (PLP) is also involved in the metabolism of one-carbon units, carbohydrates, and lipids ¹⁰. Vitamin B6 also plays a role in cognitive development through the biosynthesis of neurotransmitters and in maintaining normal levels of homocysteine, an amino acid in the blood ¹⁰. Vitamin B6 is involved in gluconeogenesis (metabolic pathway that results in the generation of glucose or sugar from certain non-carbohydrate breakdown products of lipids (fats) or proteins) and glycogenolysis (metabolic pathway in which glycogen breaks down into glucose or sugar), immune function (for example, it promotes lymphocyte and interleukin-2 production), and hemoglobin formation ¹⁰.

Your body absorbs vitamin B6 in the jejunum, the second part of your small intestine. Phosphorylated forms of vitamin B6 are dephosphorylated, and the pool of free vitamin B6 is absorbed by passive diffusion ². In fruit and vegetables, vitamin B6 is present principally as pyridoxine and its phosphate and glucoside ¹¹. In meat and fish, vitamin B6 is mainly present as pyridoxal 5’ phosphate (PLP) and pyridoxamine 5’ phosphate (PMP) ¹¹. Synthesis of vitamin B6 by the gut microbiota (microorganisms, including bacteria, archaea, fungi, and viruses, that live in the digestive tracts of humans) can make a significant contribution to your vitamin B6 intake and may explain why dietary vitamin B6 deficiency is rare ¹². Vitamin B6 deficiency or pyridoxine deficiency can occur in the first year of life when the gut flora is not fully established ¹¹; in the 1950s, infants fed a milk formula that had been overheated during production developed seizures due to vitamin B6 deficiency (pyridoxine deficiency) ¹³.

Vitamin B6 concentrations can be measured directly by assessing concentrations of pyridoxal 5’ phosphate (PLP); other vitamers; or total vitamin B6 in plasma, red blood cells, or urine ⁹. Vitamin B6 concentrations can also be measured indirectly by assessing either red blood cell aminotransferase saturation by pyridoxal 5’ phosphate (PLP) or tryptophan metabolites. Plasma pyridoxal 5’ phosphate (PLP) is the most common measure of vitamin B6 status ¹⁴.

PLP concentrations of more than 30 nmol/L have been traditional indicators of adequate vitamin B6 status in adults ¹⁰. However, the Food and Nutrition Board at the Institute of Medicine of the National Academies used a plasma PLP level of 20 nmol/L as the major indicator of adequacy to calculate the Recommended Dietary Allowances (RDAs) for adults ⁹, ¹⁰.

Figure 1. Vitamin B6 chemical structures

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What does Vitamin B6 do?

Vitamin B6 includes a group of closely related compounds: pyridoxine, pyridoxal, and pyridoxamine and pyridoxamine 5’ phosphate (PMP) with pyridoxal 5’ phosphate (PLP) being the only active vitamin B6 vitamer that acts as a cofactor involved in over 100 enzymes that catalyze essential chemical reactions in the human body, a role that is enabled by its reactive aldehyde group ¹⁵. Your body needs vitamin B6 for more than 100 enzyme reactions, mostly concerned with protein metabolism ⁹. Vitamin B6 is also involved in brain development during pregnancy and infancy as well as immune function ⁸. Both pyridoxal 5’ phosphate (PLP) and pyridoxamine 5’ phosphate (PMP) are involved in amino acid metabolism, and pyridoxal 5’ phosphate (PLP) is also involved in the metabolism of one-carbon units, carbohydrates, and lipids ¹⁰. Vitamin B6 also plays a role in cognitive development through the biosynthesis of neurotransmitters and in maintaining normal levels of homocysteine, an amino acid in the blood ¹⁰. Vitamin B6 is involved in gluconeogenesis (metabolic pathway that results in the generation of glucose or sugar from certain non-carbohydrate breakdown products of lipids (fats) or proteins) and glycogenolysis (metabolic pathway in which glycogen breaks down into glucose or sugar), immune function (for example, it promotes lymphocyte and interleukin-2 production), and hemoglobin formation ¹⁰.

Pyridoxal 5’ phosphate (PLP) dependent enzymes have been classified into five structural classes known as Fold Type 1-5 ¹⁶:

• Fold Type 1 – aspartate aminotransferase family
• Fold Type 2 – tryptophan synthase family
• Fold Type 3 – alanine racemase family
• Fold Type 4 – D-amino acid aminotransferase family
• Fold Type 5 – 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 ⁷. 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 ¹⁷.

Nervous system function

In the brain, the pyridoxal 5’ phosphate (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) ⁷. Other neurotransmitters, including glycine, D-serine, glutamate, histamine, and γ-aminobutyric acid (GABA), are also synthesized in reactions catalyzed by pyridoxal 5’ phosphate (PLP)-dependent enzymes ¹⁸.

Hemoglobin synthesis and function

Pyridoxal 5’ phosphate (PLP) functions as a coenzyme of 5-aminolevulinic acid synthase, which is involved in the synthesis of heme, an iron-containing component of hemoglobin ⁷. Hemoglobin is found in red blood cells and is critical to their ability to transport oxygen throughout the body. Both pyridoxal and pyridoxal 5’ phosphate (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 ¹⁷, ¹⁹. Vitamin B6 deficiency may impair hemoglobin synthesis and lead to microcytic anemia ⁴.

Tryptophan metabolism

Deficiency in vitamin B3, Niacin, is easily prevented by adequate dietary intakes. The dietary requirement for niacin (vitamin B3) 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 the tryptophan-kynurenine metabolic pathway are pyridoxal 5’ phosphate (PLP)-dependent; in particular, pyridoxal 5’ phosphate (PLP) is the cofactor for the enzyme kynureninase, which catalyzes the conversion of 3-hydroxykynurenine to 3-hydroxyanthranilic acid ⁷. 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) ²⁰. Thus, while dietary vitamin B6 restriction impairs nicotinamide adenine dinucleotide (NAD) synthesis from tryptophan, adequate PLP levels help maintain NAD formation from tryptophan ²¹. 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 ⁷.

Figure 2.  Tryptophan-kynurenine pathway

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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 ²². 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 ¹⁷.

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) ⁷. PLP serves as a coenzyme for serine hydroxymethyltransferase (SHMT), which catalyzes the simultaneous conversions of serine to glycine and tetrahydrofolate (THF) to 5,10-methylene THF ⁷. The latter molecule is the one-carbon donor for the generation of dTMP from deoxyuridine monophosphate (dUMP) by thymidylate synthase (TYMS) ⁷.

Figure 3. Vitamin B6 in nucleic acid synthesis

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Vitamin B6 Benefits

Scientists are studying vitamin B6 to understand how it affects health. Here are some examples of what this research has shown.

Cardiovascular disease

Scientists have hypothesized that certain B vitamins (such as folic acid [vitamin B9], vitamin B12 [cyanocobalamin], and vitamin B6 [pyridoxine]) might reduce cardiovascular disease risk lowering levels of homocysteine, an amino acid in the blood ¹, ²³. Therefore, several clinical trials have assessed the safety and effectiveness of supplemental doses of B vitamins to reduce heart disease risk. Evaluating the impact of vitamin B6 from many of these trials is challenging because these studies also included folic acid and vitamin B12 supplementation. For example, the Heart Outcomes Prevention Evaluation 2 (HOPE 2) trial, which included more than 5,500 adults with known cardiovascular disease, found that supplementation for 5 years with vitamin B6 (50 mg/day), vitamin B12 (1 mg/day), and folic acid (2.5 mg/day) reduced homocysteine levels and decreased stroke risk by about 25%, but the study did not include a separate vitamin B6 group ²⁴.

The use of multivitamin supplements (including vitamin B6) has been associated with a 24% lower risk of incidental coronary artery disease (coronary heart disease) in a large prospective study of 80,082 women from the US Nurses’ Health Study cohort ²⁵. Coronary artery disease (coronary heart disease) 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). 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 coronary artery disease (coronary heart disease) compared to those in the lowest quintile (median, 1.1 mg/day) ²⁵. 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 ²⁶.

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 ²⁷, ²⁸, ²⁹. More recent research has confirmed that low plasma pyridoxal 5’ phosphate (PLP) status is a risk factor for coronary artery disease. In a case-control study, which included 184 participants with coronary artery disease and 516 healthy controls, low plasma PLP levels (<30 nanomoles/liter) were associated with a near doubling of coronary artery disease risk when compared to higher PLP levels (≥30 nanomoles/liter) ³⁰. 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) ³¹.

Even moderately elevated levels of homocysteine in the blood have been associated with increased risk for cardiovascular disease, including heart failure (cardiac insufficiency), coronary artery disease, heart attack (myocardial infarction), and stroke (cerebrovascular accident) ³², ³³, ³⁴, ³⁵. 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 ⁷. 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 4). 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 4). 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 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) ³⁶, 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) ³⁷. 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 ³⁷.

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 ³⁸. In contrast, studies supplementing individuals with only vitamin B6 have usually failed to show an effect on fasting levels of homocysteine ³⁹, ⁴⁰. 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 ⁴¹. Yet, the effect of homocysteine lowering on cardiovascular disease 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) ⁴². 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 ⁴³, ⁴⁴, ³⁸, ⁴⁵. Moreover, B-vitamin supplementation trials in high-risk subjects have not resulted in significant changes in carotid intima-media thickness and flow-mediated dilation of the brachial artery, two markers of vascular health used to assess atherosclerotic progression ⁴⁶. Finally, in the Western Norway B Vitamin Intervention Trial (WENBIT), a randomized, double-blind, placebo-controlled trial in 87 subjects with suspected coronary heart disease, 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.

Although vitamin B supplements do lower blood homocysteine levels, large clinical trials have failed to demonstrate that supplemental B vitamins reduce the risk or severity of heart disease or stroke ¹⁴. For example, a randomized clinical trial in 5,442 women aged 42 or older found no effect of vitamin B6 supplementation (50 mg/day) in combination with 2.5 mg folic acid and 1 mg vitamin B12 on cardiovascular disease risk ⁴⁸. Two large randomized controlled trials, the Norwegian Vitamin Trial and the Western Norway B Vitamin Intervention Trial (WENBIT), did include a group that received only vitamin B6 supplements (40 mg/day). The combined analysis of data from these two trials showed no benefit of vitamin B6 supplementation, with or without folic acid (0.8 mg/day) plus vitamin B12 (0.4 mg/day), on major cardiovascular events in 6,837 patients with ischemic heart disease ²³. In a trial of adults who had suffered a nondisabling stroke, supplementation with high or low doses of a combination of vitamins B6 and B12 and folic acid for 2 years had no effect on subsequent stroke incidence, cardiovascular events, or risk of death ⁴⁹.

The research to date provides little evidence that supplemental amounts of vitamin B6, alone or with folic acid and vitamin B12, can help reduce the risk or severity of cardiovascular disease and stroke ¹⁴.

Figure 4. Homocysteine metabolism

Footnotes: Schematic representation of pathways of homocysteine metabolism, which include a system of transmethylation, remethylation, and transsulfuration paths. In most cells, by transmethylation route homocysteine and methionine cycle metabolically, the methyl group on activated methionine (S-adenosyl-methionine or SAM) may be added to methyl acceptors (DNA, RNA, and protein) by methyltransferases, and the S-adenosyl-homocysteine (SAH) is rapidly hydrolyzed to adenosine and homocysteine, which could improve its concentration ⁵⁰. Transmethylations, chemical reactions transferring a methyl group from one compound to another, are generally regulated by the intracellular concentration of involved compounds; thus, S-adenosyl-methionine (SAM) and S-adenosyl-homocysteine (SAH) concentrations determine a cell’s methylation balance. Once formed, homocysteine can be recycled into methionine or converted into cysteine by remethylation and transsulfuration routes, respectively. homocysteine is remethylated to methionine through two separate reactions catalyzed by three different enzymes. In all tissues, folic acid donates a methyl group across methylenetetrahydrofolate reductase (MTHFR) in a reaction catalyzed by methionine synthase, a vitamin-B12-dependent enzyme ⁵¹. Otherwise, mainly in the human heart, liver, and kidneys, homocysteine is remethylated using betaine, which donates a methyl group by betaine-homocysteine S-methyltransferase (BHMT) by a route independent of the one-carbon metabolism. Betaine can be found in several dietary sources, including wheat germ or bran, spinach, beets, seafood, and legumes. Studies have confirmed betaine’s ability to reduce homocysteine levels in the face of excess methionine intake, as well as the fact that low-dose betaine supplementation leads to immediate and long-term lowering of plasma homocysteine in healthy men and women ⁵², ⁵³. This remethylation process begins when there are low concentrations of homocysteine and methionine ⁵⁴. Alternately, mainly in the liver, but also in the kidneys, small intestine, and pancreas ⁵⁵, homocysteine is enzymatically modified by cystathionine-β-synthase, a B6-dependent enzyme, to irreversibly form cysteine through the intermediate cystathionine. The transsulfuration route results in sulfur metabolites including GSH, a key cellular antioxidant, and hydrogen sulfide (H2S), acting like a gaseous signaling molecule. The transsulfuration path starts to function when the concentrations of homocysteine and methionine increase, for example by post-prandial protein intake ⁵⁶, or cysteine is needed.

Abbreviations: DHFR = dihydrofolate reductase; THF = tetrahydrofolate; SHMT = serinehydroxymethyltransferase; MTHF = methylenetetrahydrofolate; MTHFR = 5,10-methylene-THF reductase; ATP = adenosine triphosphate; MAT = methionine adenosyltransferase; ADP = adenosine diphosphate; SAM = S-adenosylmethionine; SAH = S-adenosylHcy; BHMT = betaine-Hcy S-methyltransferase; CBS = cystathionine β-synthase; CSE = cystathionase; GSH = glutathione; H2S = hydrogen sulphide.

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Cancer

Some research has associated low plasma vitamin B6 concentrations with an increased risk of certain kinds of cancer, such as colorectal cancer ¹⁰. For example, a meta-analysis of prospective studies found that people with a vitamin B6 intake in the highest quintile had a 20% lower risk of colorectal cancer than those with an intake in the lowest quintile ⁵⁷.

Inconsistent evidence regarding the link between vitamin B6 intakes and breast cancer was also recently reported in a meta-analysis ⁵⁸. 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) ⁵⁹. Additionally, a meta-analysis of four nested case-control studies reported a 48% reduction in colorectal cancer risk in the highest versus lowest quartile of blood PLP level ⁵⁷. 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 ⁵⁸.

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 colorectal cancer risk and mortality ⁶⁰. 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 ⁶¹.

However, the small number of clinical trials completed to date has not shown that vitamin B6 supplementation can help prevent cancer or lower the chances of dying from cancer. For example, an analysis of data from two large randomized, double-blind, placebo-controlled trials in Norway found no association between vitamin B6 supplementation and cancer incidence, mortality, or all-cause mortality ⁶².

Cognitive function

Some research indicates that elderly people who have higher blood levels of vitamin B6 have better memory. A few observational studies have linked cognitive decline and Alzheimer’s disease in the elderly with inadequate status of folate, vitamin B12, and vitamin B6 ⁶³. Poor vitamin B6 status has been hypothesized to play a role in the cognitive decline that some older adults experience ⁶⁴. Several studies have demonstrated an association between vitamin B6 and brain function in the elderly. For example, an analysis of data from the Boston Normative Aging Study found associations between higher serum vitamin B6 concentrations and better memory test scores in 70 men aged 54–81 years ⁶⁵.

Yet, the relationship between B vitamins and cognitive health in aging is complicated by both the high prevalence of high serum homocysteine (hyperhomocysteinemia) and signs of systemic inflammation in elderly people ⁶⁶. 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 ⁶⁷. 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 ⁶⁸. 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 ⁶⁸. 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 Alzheimer’s disease process ⁶⁹. Yet, the authors attributed the changes in homocysteine levels primarily to vitamin B12 ⁶⁹. Because of mixed findings, it is presently unclear whether supplementation with B vitamins might blunt cognitive decline in the elderly. Furthermore, taking vitamin B6 supplements (alone or combined with vitamin B12 and/or folic acid) does not seem to improve cognitive function or mood in healthy people or in people with dementia.

More 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 vitamin B6 supplements might help prevent or treat cognitive decline in elderly people ¹⁴, ⁷.

Depression

Late-life depression is a common disorder sometimes occurring after acute illnesses, such as hip fracture or stroke ⁷⁰, ⁷¹. 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 ⁷², ⁷³. 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 ⁷⁴. 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 ⁷⁵. 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 ⁷.

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 ⁷⁶. 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 ⁷⁷. 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 ⁷⁸, ⁷⁹. Presently, the relationship between vitamin B6 intake and the risk of developing kidney stones requires further study before any recommendations can be made.

Premenstrual syndrome (PMS)

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). Some evidence suggests that vitamin B6 supplements could reduce the symptoms of premenstrual syndrome (PMS) such as moodiness, irritability, forgetfulness, bloating, and anxiety, but conclusions are limited due to the poor quality of most studies ⁸⁰. A meta-analysis of nine published trials involving almost 1,000 women with PMS found that supplemental vitamin B6 up to 100 mg/day is more effective in reducing premenstrual syndrome symptoms than placebo, but most of the studies analyzed were small and several had methodological weaknesses ⁸⁰. A more recent double-blind, randomized controlled trial in 94 women found that 80 mg pyridoxine taken daily over the course of three cycles was associated with statistically significant reductions in a broad range of PMS symptoms, including moodiness, irritability, forgetfulness, bloating, and, especially, anxiety ⁸¹. The potential effectiveness of vitamin B6 in alleviating the mood-related symptoms of premenstrual syndrome could be due to its role as a cofactor in neurotransmitter biosynthesis ⁸². Although vitamin B6 shows promise for alleviating PMS symptoms, more research is needed before recommendations can be made ⁸³.

Nausea and Vomiting in Pregnancy (morning sickness)

About half of all women experience “morning sickness” that consists of nausea and vomiting in the first few months of pregnancy, and about 50%–80% experience nausea only ⁸⁴, ⁸⁵. Morning sickness is not life threatening and typically goes away after 12–20 weeks, but its symptoms can disrupt a woman’s social and physical functioning ⁸⁶.

Vitamin B6 has been used since the 1940s to treat nausea during pregnancy ⁷. Vitamin B6 was originally included in the medication Bendectin, which was prescribed for nausea and vomiting in pregnancy and later withdrawn from the market due to unproven concerns that it increased the risk for birth defects. The scientific literature includes isolated case reports of congenital defects in the infants of mothers who took pyridoxine supplements during the first half of pregnancy ¹⁴. Vitamin B6 itself is considered safe during pregnancy and has been used in pregnant women without any evidence of fetal harm ⁸⁷. A more recent observational study found no association between pyridoxine supplementation (mean dose 132.3 ± 74 mg/day) in pregnant people starting at 7 weeks gestation and continuing for 9 ± 4.2 weeks and teratogenic effects in their infants ⁸⁸.

Prospective studies on vitamin B6 supplements to treat morning sickness have had mixed results. In two randomized, placebo-controlled trials, including 401 pregnant women that used 25 mg of pyridoxine every eight hours for three days ⁸⁹ or 10 mg of pyridoxine every eight hours for five days ⁹⁰, suggested that vitamin B6 may be beneficial in reducing nausea in pregnant women who were experiencing nausea. The authors of a recent Cochrane review of studies on interventions for nausea and vomiting in pregnancy could not draw firm conclusions on the value of vitamin B6 to control the symptoms of morning sickness ⁸⁵.

It should be noted that nausea and vomiting in the first few months of pregnancy usually resolves without any treatment, making it difficult to perform well-controlled trials. More recently, nausea and vomiting in pregnancy 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 nausea and vomiting in pregnancy ⁹¹. Supplementation with pyridoxine and the drug doxylamine significantly improved morning sickness 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. Other randomized trials have shown that a combination of vitamin B6 and doxylamine (an antihistamine) is associated with a 70% reduction in nausea and vomiting in pregnant women and lower hospitalization rates for this problem ⁸⁴, ⁹².

The American Congress of Obstetrics and Gynecology (ACOG) recommends monotherapy with 10–25 mg of vitamin B6 (pyridoxine hydrochloride) three or four times a day to treat nausea and vomiting in pregnancy ⁹². If the patient’s condition does not improve, American Congress of Obstetrics and Gynecology (ACOG) recommends adding doxylamine succinate (10 mg) ⁸⁶. However, before taking a vitamin B6 supplement, pregnant women should consult a physician because doses could approach the Tolerable Upper Intake Level (the maximum daily intake unlikely to cause adverse health effects) ¹⁴.

Metabolic diseases

A few rare inborn metabolic disorders, including pyridoxine-dependent epilepsy and pyridoxamine 5′-phosphate oxidase 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 pyridoxine-dependent epilepsy and pyridoxamine 5′-phosphate oxidase deficiency, PLP bioavailability is limited, and treatment with pyridoxine and/or PLP have been used to alleviate or abolish epileptic seizures characterizing these conditions ⁹³, ⁹⁴. 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 beta-synthase ⁹⁵.

Carpal tunnel syndrome

Carpal tunnel syndrome 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 carpal tunnel syndrome symptoms in individuals with low vitamin B6 status ⁹⁶, ⁹⁷. 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 carpal tunnel syndrome ⁹⁸. However, studies using electrophysiological measurements of median nerve conduction have largely failed to find an association between vitamin B6 deficiency and carpal tunnel syndrome (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 carpal tunnel syndrome ⁹⁹. 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 ¹⁰⁰.

How much vitamin B6 do you need?

The amount of vitamin B6 you need depends on your age. Average daily recommended amounts are listed below in milligrams (mg). Intake recommendations for vitamin B6 and other nutrients are provided in the Dietary Reference Intakes (DRIs) developed by the Institute of Medicine ¹. Dietary Reference Intake (DRI) is the general term for a set of reference values used for planning and assessing nutrient intakes of healthy people. These values, which vary by age and gender, include:

• Recommended Dietary Allowance (RDA): Average daily level of intake sufficient to meet the nutrient requirements of nearly all (97%–98%) healthy individuals; often used to plan nutritionally adequate diets for individuals.
• Adequate Intake (AI): Intake at this level is assumed to ensure nutritional adequacy; established when evidence is insufficient to develop an RDA.
• Estimated Average Requirement (EAR): Average daily level of intake estimated to meet the requirements of 50% of healthy individuals; usually used to assess the nutrient intakes of groups of people and to plan nutritionally adequate diets for them; can also be used to assess the nutrient intakes of individuals.
• Tolerable Upper Intake Level (UL): Maximum daily intake unlikely to cause adverse health effects.

Table 1 lists the current Recommended Dietary Allowances (RDAs) for vitamin B6 ¹. For infants from birth to 12 months, the Institute of Medicine Food and Nutritional Board established an Adequate Intake (AI) for vitamin B6 that is equivalent to the mean intake of vitamin B6 in healthy, breastfed infants.

The Food and Nutrition Board has established Tolerable Upper Intake Level (the maximum daily intake unlikely to cause adverse health effects) for vitamin B6 that apply to both food and supplement intakes (Table 2) ¹. The Food and Nutrition Board noted that although several reports show sensory neuropathy occurring at doses lower than 500 mg/day, studies in patients treated with vitamin B6 (average dose of 200 mg/day) for up to 5 years found no evidence of this effect ¹. Based on limitations in the data on potential harms from long-term use, the Food and Nutrition Board halved the dose used in these studies to establish a Tolerable Upper Intake Level (UL) of 100 mg/day for adults. The Tolerable Upper Intake Level (ULs) are lower for children and adolescents based on body size. The Tolerable Upper Intake Level (ULs) do not apply to individuals receiving vitamin B6 for medical treatment, but such individuals should be under the care of a physician.

Table 1. Recommended Dietary Allowances (RDAs) for Vitamin B6

Life Stage	Recommended Amount
Birth to 6 months*	0.1 mg
Infants 7–12 months*	0.3 mg
Children 1–3 years	0.5 mg
Children 4–8 years	0.6 mg
Children 9–13 years	1.0 mg
Teens 14–18 years (boys)	1.3 mg
Teens 14–18 years (girls)	1.2 mg
Adults 19–50 years	1.3 mg
Adults 51+ years (men)	1.7 mg
Adults 51+ years (women)	1.5 mg
Pregnant teens and women	1.9 mg
Breastfeeding teens and women	2.0 mg

Footnote: *Adequate Intake (AI) = Intake at this level is assumed to ensure nutritional adequacy; established when evidence is insufficient to develop an RDA.

[Source ¹⁴ ]

Table 2. Tolerable Upper Intake Levels (ULs) for Vitamin B6

Age	Male	Female	Pregnancy	Lactation
Birth to 6 months	Not possible to establish*	Not possible to establish*
7–12 months	Not possible to establish*	Not possible to establish*
1–3 years	30 mg	30 mg
4–8 years	40 mg	40 mg
9–13 years	60 mg	60 mg
14–18 years	80 mg	80 mg	80 mg	80 mg
19+ years	100 mg	100 mg	100 mg	100 mg

Footnotes: *Breast milk, formula, and food should be the only sources of vitamin B6 for infants.

[Source ¹⁴ ]

Vitamin B6 Supplements

Vitamin B6 is available in multivitamins, in supplements containing other B complex vitamins, and as a stand-alone  supplement that contain only vitamin B6 ¹⁰¹. The most common vitamin B6 vitamer in supplements is pyridoxine (in the form of pyridoxine hydrochloride [HCl]), although some supplements contain PLP ¹⁴.

Vitamin B6 supplements are available in oral capsules or tablets (including sublingual and chewable tablets) and liquids. Absorption of vitamin B6 from supplements is similar to that from food sources and does not differ substantially among the various forms of supplements ¹. Although the body absorbs large pharmacological doses of vitamin B6 well, it quickly eliminates most of the vitamin in the urine ¹⁰².

About 28% to 36% of the general population uses supplements containing vitamin B6 ¹⁰³, ¹⁰⁴. Adults aged 51 years or older and children younger than 9 are more likely than members of other age groups to take supplements containing vitamin B6 ¹⁴.

Can vitamin B6 be harmful?

High intakes of vitamin B6 from food sources have not been reported to cause adverse effects ⁹. People almost never get too much vitamin B6 from food. But taking high levels of vitamin B6 from supplements for a year or longer can cause severe nerve damage, leading people to lose control of their bodily movements. The symptoms usually stop when they stop taking the supplements. Other symptoms of too much vitamin B6 include painful, unsightly skin patches, extreme sensitivity to sunlight, nausea, and heartburn.

What foods provide vitamin B6?

Vitamin B6 is found naturally in many foods and is added to other foods. You can get recommended amounts of vitamin B6 by eating a variety of foods, including the following ⁸:

• Poultry, fish, and organ meats, all rich in vitamin B6.
• Potatoes and other starchy vegetables, which are some of the major sources of vitamin B6 for Americans.
• Fruit (other than citrus), which are also among the major sources of vitamin B6 for Americans.

Vitamin B6 is found in a wide variety of foods ¹, ¹⁰, ¹⁰⁵ and is added to other foods. The richest sources of vitamin B6 include fish, beef liver and other organ meats, potatoes and other starchy vegetables, and fruit (other than citrus).

In the United States, adults obtain most of their dietary vitamin B6 from fortified cereals, beef, poultry, starchy vegetables, and some non-citrus fruits ¹, ¹⁰, ¹⁰⁶. About 75% of vitamin B6 from a mixed diet is bioavailable ¹.

The U.S. Department of Agriculture’s (USDA’s) FoodData website (https://fdc.nal.usda.gov) lists the nutrient content of many foods and provides a comprehensive list of foods containing vitamin B6 arranged by nutrient content (https://ods.od.nih.gov/pubs/usdandb/VitaminB6-Content.pdf) and by food name (https://ods.od.nih.gov/pubs/usdandb/VitaminB6-Food.pdf).

Table 3. Food Sources of Vitamin B6

Food	Milligrams (mg) per serving	Percent Daily Value (DV)*
Chickpeas, canned, 1 cup	1.1	65
Beef liver, pan fried, 3 ounces	0.9	53
Tuna, yellowfin, fresh, cooked, 3 ounces	0.9	53
Salmon, sockeye, cooked, 3 ounces	0.6	35
Chicken breast, roasted, 3 ounces	0.5	29
Breakfast cereals, fortified with 25% of the DV for vitamin B6	0.4	25
Potatoes, boiled, 1 cup	0.4	25
Turkey, meat only, roasted, 3 ounces	0.4	25
Banana, 1 medium	0.4	25
Marinara (spaghetti) sauce, ready to serve, 1 cup	0.4	25
Ground beef, patty, 85% lean, broiled, 3 ounces	0.3	18
Waffles, plain, ready to heat, toasted, 1 waffle	0.3	18
Bulgur, cooked, 1 cup	0.2	12
Cottage cheese, 1% low-fat, 1 cup	0.2	12
Squash, winter, baked, ½ cup	0.2	12
Rice, white, long-grain, enriched, cooked, 1 cup	0.1	6
Nuts, mixed, dry-roasted, 1 ounce	0.1	6
Raisins, seedless, ½ cup	0.1	6
Onions, chopped, ½ cup	0.1	6
Spinach, frozen, chopped, boiled, ½ cup	0.1	6
Tofu, raw, firm, prepared with calcium sulfate, ½ cup	0.1	6
Watermelon, raw, 1 cup	0.1	6

Footnote: *DV = Daily Value. The U.S. Food and Drug Administration (FDA) developed Daily Values (DVs) to help consumers compare the nutrient contents of foods and dietary supplements within the context of a total diet. The Daily Value (DV) for vitamin B6 is 1.7 mg for adults and children age 4 years and older ¹⁰⁷. FDA does not require food labels to list vitamin B6 content unless vitamin B6 has been added to the food. Foods providing 20% or more of the DV are considered to be high sources of a nutrient, but foods providing lower percentages of the DV also contribute to a healthful diet.

[Source ¹⁴ ]

Am I getting enough vitamin B6?

Most children, adolescents, and adults in the United States consume the recommended amounts of vitamin B6 from the foods they eat, according to an analysis of data from the 2003–2004 National Health and Nutrition Examination Survey (NHANES) ¹⁰³. The average vitamin B6 intake is about 1.5 mg/day in women and 2 mg/day in men ¹.

However, 11% of vitamin B6 supplement users and 24% of people in the United States who do not take supplements containing vitamin B6 have low plasma pyridoxal 5’ phosphate (PLP) concentrations (less than 20 nmol/L) ¹⁰³. In the 2003–2004 National Health and Nutrition Examination Survey (NHANES) analysis, plasma pyridoxal 5’ phosphate (PLP) concentrations were low even in some groups that took 2.0–2.9 mg/day, which is higher than the current Recommended Dietary Allowance (RDA). Among supplement users and nonusers, plasma pyridoxal 5’ phosphate (PLP) levels were much lower in women than men, non-Hispanic blacks than non-Hispanic whites, current smokers than never smokers, and people who were underweight than those of normal weight. Teenagers had the lowest vitamin B6 concentrations, followed by adults aged 21–44 years. However, plasma pyridoxal 5’ phosphate (PLP) levels in the elderly were not particularly low, even in those who did not use supplements. Based on these data, the authors of this analysis concluded that the current Recommended Dietary Allowances (RDAs) might not guarantee adequate vitamin B6 status in many population groups ¹⁰³.

Most people in the United States get enough vitamin B6 from the foods they eat. However, these groups of people are more likely than others to have trouble getting enough vitamin B6 ⁸:

• People whose kidneys do not work properly, including people who are on kidney dialysis and those who have had a kidney transplant.
• People with autoimmune disorders, which cause their immune system to mistakenly attack their own healthy tissues. For example, people with rheumatoid arthritis, celiac disease, Crohn’s disease, ulcerative colitis, or inflammatory bowel disease sometimes have low vitamin B6 levels.
• People with alcohol dependence.

What happens if I don’t get enough vitamin B6?

Vitamin B6 deficiency is uncommon in the United States ⁸. People who don’t get enough vitamin B6 can have a range of symptoms, including anemia, itchy rashes, scaly skin on the lips, cracks at the corners of the mouth, and a swollen tongue. Other symptoms of very low vitamin B6 levels include depression, confusion, and a weak immune system. Infants who do not get enough vitamin B6 can become irritable or develop extremely sensitive hearing or seizures.

Vitamin B6 Deficiency

Isolated vitamin B6 deficiency, also known as pyridoxine deficiency, is very rare in the United States; inadequate vitamin B6 status is usually associated with low concentrations of other B-complex vitamins, such as vitamin B12 and folic acid ¹⁰⁸, ², ¹⁰⁹. Vitamin B6 deficiency causes biochemical changes that become more obvious as the deficiency progresses ², ¹¹⁰. Vitamin B6 deficiency is associated with microcytic anemia, peripheral neuropathy, mental status changes, electroencephalographic abnormalities, seborrhoeic dermatitis, angular cheilitis (scaling on the lips and cracks at the corners of the mouth) and glossitis (inflammation of the tongue), depression and confusion, and weakened immune function ¹⁰⁸, ¹, ², ¹¹¹. Individuals with borderline vitamin B6 concentrations or mild deficiency might have no deficiency signs or symptoms for months or even years. Fetal brain development requires adequate vitamin B6, and this continues throughout infancy. In infants, vitamin B6 deficiency causes irritability, abnormally acute hearing, and convulsive seizures ², ¹¹².

Vitamin B6 is one of the vital micronutrients involved in one-carbon metabolism along with folate and vitamin B12 ¹¹³. Pyridoxal 5-phosphate (PLP), the active form of vitamin B6, acts as a cofactor in more than 100 enzymatic reactions in carbohydrate, amino acids and lipid metabolism ¹¹⁴ . It has also been shown to have antioxidant ¹¹⁵, anti-inflammatory properties ¹¹⁶, cognitive functions ¹¹⁷, ⁶³, ⁶⁴, ⁶⁵ and a role in the immune response ¹¹⁸, ¹¹⁹.

Vitamin B6 deficiency is uncommon in the United States ⁸. Most people in the United States get enough vitamin B6 from the foods they eat ¹²⁰, ¹⁰³. However, these groups of people are more likely than others to have trouble getting enough vitamin B6 ⁸, ¹⁰⁸:

• People whose kidneys do not work properly, including people who are on kidney dialysis (hemodialysis or peritoneal dialysis) and those who have had a kidney transplant.
• People with autoimmune disorders, which cause their immune system to mistakenly attack their own healthy tissues. For example, people with rheumatoid arthritis, celiac disease, Crohn’s disease, ulcerative colitis, or inflammatory bowel disease sometimes have low vitamin B6 levels.
• People with protein-energy malnutrition.
• States of decreased consumption and/or absorption. For example, pregnancy, chronic alcohol dependence and post-weight loss surgery.

End-stage renal diseases, chronic renal insufficiency, and other kidney diseases can cause vitamin B6 deficiency ¹⁰. In addition, vitamin B6 deficiency can result from malabsorption syndromes, such as celiac disease, Crohn’s disease, and ulcerative colitis. Certain genetic diseases, such as homocystinuria, can also cause vitamin B6 deficiency ². Some medications, such as antiepileptic drugs, can lead to vitamin B6 deficiency over time.

Vitamin B6 concentrations can be measured directly by assessing concentrations of pyridoxal 5’ phosphate (PLP); other vitamers; or total vitamin B6 in plasma, red blood cells, or urine ⁹. Vitamin B6 concentrations can also be measured indirectly by assessing either red blood cell aminotransferase saturation by pyridoxal 5’ phosphate (PLP) or tryptophan metabolites. Plasma pyridoxal 5’ phosphate (PLP) is the most common measure of vitamin B6 status ¹⁴.

Pyridoxal 5’ phosphate (PLP) concentrations of more than 30 nanomole per liter [nmol/L] have been traditional indicators of adequate vitamin B6 status in adults ¹⁰. However, the Food and Nutrition Board at the Institute of Medicine of the National Academies used a plasma pyridoxal 5’ phosphate (PLP) level of 20 nmol/L as the major indicator of adequacy to calculate the Recommended Dietary Allowances (RDAs) for adults ⁹, ¹⁰. Plasma Pyridoxal 5’ phosphate (PLP) of less than 20 nmol/L is considered vitamin B6 deficiency ¹²¹.

Vitamin B6 deficiency causes

Dietary vitamin B6 deficiency, though rare, can develop because extensive processing can deplete foods of vitamin B6. In the United States and other western cultures, vitamin B6 deficiency is rare due to adequate diets, including vitamin B6 sources from fish, organ meats, poultry, potatoes, grains, legumes, and non-citrus fruits.

Isolated B6 deficiency is rare and is usually found in association with other B vitamin deficiencies such as folic acid and B12.

Secondary vitamin B6 deficiency or pyridoxine deficiency most often results from ¹²², ¹⁰⁸:

• Vitamin B6 or Pyridoxine intake is reduced in cases of severe malnutrition.
• Protein-energy malnutrition
• Malabsorption states such as celiac disease, inflammatory bowel disease (Crohn’s disease, and ulcerative colitis), and post weight loss surgery
• Vitamin B6 or Pyridoxine absorption is reduced in elderly persons and in patients with intestinal disease or who have undergone surgery.
• Chronic alcohol dependence
• Autoimmune diseases, such as rheumatoid arthritis, have increased breakdown and metabolic requirements of vitamin B6, resulting in higher demand for dietary supplementation of vitamin B6.
• Pyridoxine clearance is enhanced by liver disorders, such as hepatitis, and by several medications.
• Pyridoxine breakdown is enhanced in conditions associated with increased alkaline phosphatase levels.
• Use of pyridoxine-inactivating drugs (eg, anticonvulsants, isoniazid, cycloserine, levodopa, hydralazine, corticosteroids, penicillamine) ¹²³, ¹²⁴, ¹²⁵, ¹²⁶
• Excessive loss during hemodialysis and the patient who have undergone kidney transplants are more at risk of vitamin B6 deficiency. Patients with chronic renal failure, especially those receiving hemodialysis or peritoneal dialysis, have low plasma levels of vitamin B6 and usually respond well to oral or parenteral vitamin B6 therapy ¹²⁷, ¹²⁸.
• Pregnancy – Pregnancy can cause a pyridoxine-deficient state; however, a change in the ratio of plasma PLP to pyridoxal does occur, thereby falsely suggesting a deficiency state if only serum PLP is measured.

Rarely, secondary deficiency results from increased metabolic demand (eg, in hyperthyroidism).

Rare inborn errors of metabolism can affect pyridoxine metabolism.

Risk factors for developing vitamin B6 deficiency

Several factors contribute to an increased risk for vitamin B6 deficiency or pyridoxine deficiency ¹²⁹:

• Advanced age
• Medical conditions that may increase the risk for vitamin B6 deficiency or pyridoxine deficiency include the following:
  • Severe malnutrition
  • Sickle cell disease
  • Inflammatory conditions ¹³⁰, ¹³¹
  • Rheumatoid arthritis ¹³⁰
  • Hospitalization
  • Celiac disease
  • Hepatitis and extrahepatic biliary obstruction
  • Hepatocellular carcinoma
  • Chronic renal failure
  • Kidney transplant ¹³²
  • Hyperoxaluria types 1 and 2
  • High serum alkaline phosphatase level, such as in cirrhosis and tissue injury
  • Catabolic state
• Medical procedures that may increase the risk for vitamin B6 deficiency or pyridoxine deficiency include the following:
  • Hemodialysis
  • Peritoneal dialysis
  • Phototherapy for hyperbilirubinemia
• Medications that may increase the risk for vitamin B6 deficiency or pyridoxine deficiency include the following:
  • Cycloserine
  • Hydralazine
  • Isoniazid
  • D-penicillamine
  • Pyrazinamide
• Social-behavioral conditions that may increase the risk for vitamin B6 deficiency or pyridoxine deficiency include the following:
  • Excessive alcohol ingestion (except for pyridoxine-supplemented beer)
  • Tobacco smoking
  • Severe malnutrition
• Other risk factors that may increase the risk for pyridoxine deficiency include the following:
  • Poisoning, such as Gyromitra mushroom poisoning
  • Perinatal factors, such as a pyridoxine-deficient mother
  • Inherited conditions, such as pyridoxine-dependent neonatal seizures ¹³³, ¹³⁴, ¹³⁵

Groups at Risk of vitamin B6 deficiency

Frank vitamin B6 deficiencies are relatively rare in the United States but some individuals might have marginal vitamin B6 status ². The following groups are among those most likely to have inadequate intakes of vitamin B6.

Individuals with impaired kidney function

People with poor kidney function, including those with end-stage renal disease (also called end-stage kidney disease or kidney failure) and chronic renal insufficiency, often have low vitamin B6 concentrations ¹⁰. Plasma pyridoxal 5’ phosphate (PLP) concentrations are also low in patients receiving maintenance kidney dialysis or intermittent peritoneal dialysis, as well as those who have undergone a kidney transplant, perhaps due to increased metabolic clearance of pyridoxal 5’ phosphate (PLP) ¹³⁶. Patients with kidney disease often show clinical symptoms similar to those of people with vitamin B6 deficiency ¹³⁶.

Individuals with Autoimmune Disorders

People with rheumatoid arthritis often have low vitamin B6 concentrations, and vitamin B6 concentrations tend to decrease with increased disease severity ¹⁰. These low vitamin B6 levels are due to the inflammation caused by the disease and, in turn, increase the inflammation associated with the disease. Although vitamin B6 supplements can normalize vitamin B6 concentrations in patients with rheumatoid arthritis, they do not suppress the production of inflammatory cytokines or decrease levels of inflammatory markers ¹⁰, ¹³⁷.

Patients with celiac disease, Crohn’s disease, ulcerative colitis, inflammatory bowel disease, and other malabsorptive autoimmune disorders tend to have low plasma pyridoxal 5’ phosphate (PLP) concentrations ¹⁰. The mechanisms for this effect are not known. However, celiac disease is associated with lower pyridoxine absorption, and low PLP concentrations in inflammatory bowel disease could be due to the inflammatory response ¹⁰.

People with Alcohol Dependence

Plasma pyridoxal 5’ phosphate (PLP) concentrations tend to be very low in people with alcohol dependence ¹. Alcohol produces acetaldehyde, which decreases net pyridoxal 5’ phosphate (PLP) formation by cells and competes with Pyridoxal 5’ phosphate in protein binding ¹. As a result, the PLP in cells might be more susceptible to hydrolysis by membrane-bound phosphatase. People with alcohol dependence might benefit from pyridoxine supplementation ¹⁰.

Vitamin B6 deficiency prevention

The human body cannot store vitamin B6, and therefore a daily source is required. However, in the United States isolated vitamin B6 deficiency is rare, because most children, adolescents, and adults in the United States consume the recommended amounts of vitamin B6, according to an analysis of data from the 2003–2004 National Health and Nutrition Examination Survey ¹⁰³. The average vitamin B6 intake is about 1.5 mg/day in women and 2 mg/day in men ¹.

Vitamin B6 (Pyridoxine) supplementation is indicated in cases of vitamin B6 deficiency, which may be due to poor kidney function, autoimmune diseases, increased alcohol intake (chronic alcohol use), or in people who take these medications: isoniazid, cycloserine, valproic acid, phenytoin, carbamazepine, primidone, hydralazine, and theophylline ¹³⁸, ¹³⁹, ¹⁴⁰, ¹⁴¹, ¹⁸, ¹⁴², ¹⁴³.

Vitamin B6 deficiency is usually found in association with other B vitamin deficiencies such as folic acid and B12. So these B vitamin supplements are also needed.

There is evidence to suggest reduced bioavailability ¹⁴⁴ as well as digestibility ¹⁴⁵ of vitamin B6 from plant foods compared to animal foods. This may be important to those who favor a plant-based diet exclusively (i.e., vegans and vegetarians) ¹⁴⁶. These individuals may need vitamin B6 supplementation. The major vitamin B6 supplement in multivitamins is pyridoxine hydrochloride.

Prophylactic administration of vitamin B6 (Pyridoxine) should be provided when a patient is using certain medications, such as isoniazid (30-450 mg/day, which may be based gram for gram) and penicillamine (100 mg/day) ¹⁴⁷.

Estrogen-induced reduction in tryptophan metabolism may require vitamin B6 (Pyridoxine) supplementation of 20-25 mg/day ¹⁴⁷.

Vitamin B6 Deficiency signs and symptoms

Signs and symptoms of vitamin B6 deficiency or pyridoxine deficiency include the following ¹⁴⁸, ¹⁴⁹, ¹⁵⁰ :

• General symptoms – Weakness, dizziness
• Oral signs and symptoms – Glossitis (inflammation of the tongue), angular cheilitis (scaling on the lips and cracks at the corners of the mouth)
• Dermatologic signs and symptoms – Seborrheic dermatitis
• Neurologic symptoms in adults – Distal limb numbness and weakness, impaired vibration and proprioception, sensory ataxia, generalized seizures
• Neurologic symptoms in neonates and young infants – Hypotonia; irritability; restlessness; focal, bilateral motor, or myoclonic seizures; infantile spasms

Vitamin B6 deficiency in adults causes peripheral neuropathy and a pellagra-like syndrome, with seborrheic dermatitis, glossitis, and angular cheilitis. Additional clinical findings of vitamin B6 deficiency may include mental status changes, depression, confusion, EEG abnormalities, seizures and normocytic, microcytic, or sideroblastic anemia ¹⁵¹.

Rarely, vitamin B6 deficiency may present with seizures in infants ¹⁵², ¹⁵³. Seizures, particularly in infants, may be refractory to treatment with anticonvulsants.

Current studies are evaluating the role of B6 deficiency in heart disease, cancer, attention deficit hyperactivity disorders (ADHD) and cognitive decline as medical conditions that may respond to supplementation ¹⁰⁹, ⁷, ¹⁴. To date, there is no clear evidence to support vitamin B6 supplement use beyond the normal dietary intake. However, some studies indicate a reduction of symptoms in the premenstrual syndrome (PMS) with supplementation of vitamin B6, particularly a decrease in moodiness, irritability, and forgetfulness ⁷, ¹⁴. The American College of Obstetrics and Gynecology recommend vitamin B6 supplementation (1.9 mg per day) for hyperemesis gravidarum (severe nausea and vomiting during pregnancy) ¹⁵⁴.

Figure 5. Glossitis

Figure 6. Angular cheilitis

Figure 7.  Seborrheic dermatitis

Vitamin B6 Deficiency diagnosis

Diagnosis of vitamin B6 deficiency is usually clinical. There is no single accepted laboratory test of vitamin B6 status; measurement of serum pyridoxal phosphate is most common. Plasma Pyridoxal 5’ phosphate (PLP) of less than 20 nmol/L is considered vitamin B6 deficiency ¹²¹.

Early or subclinical vitamin B6 deficiency may have vague or fleeting symptoms; however, new-onset sensory polyneuropathy, altered mental status, dermatitis in adults, or seizures in infancy should raise clinical suspicion of a clinically significant B6 deficiency ¹⁰⁸.

Vitamin B6 deficiency should be considered in ¹⁰⁸:

• Any infant who has seizures
• Any patient who has seizures refractory to treatment with anticonvulsants
• Any patient with deficiencies of other B vitamins, particularly in patients with alcoholism or protein-energy undernutrition

Testing for vitamin B6 can be difficult in real-time in many clinical scenarios. Direct biomarkers B6 vitamers in serum, plasma, red blood cell, and urine are used. Serum measurement of the active vitamin pyridoxal 5′-phosphate (PLP) form is available in some clinical settings. However, the assay is not widely available or timely ¹⁰⁸. Serum or urinary 4-Pyridoxic acid (4PA) is the end product of vitamin B6 catabolism, is an indicator of recent vitamin B6 intake. A clinical alternative is an indirect measurement technique of vitamin B6, which includes measuring urinary excretion of xanthurenic acid (an amino acid catabolite of tryptophan) following a measured bolus of tryptophan ¹⁰⁸. Increased levels of xanthurenic acid may indicate inadequate active B6 for the formation of the amino acid tryptophan ¹⁵⁵. Urinary excretion of xanthurenic acid is usually less than 65 mmol/day following a 2 g tryptophan load. Excretion of xanthurenic acid above this threshold suggests abnormal tryptophan metabolism due to vitamin B6 insufficiency.

Red blood cell transaminase activity, with and without pyridoxal 5′-phosphate (PLP) added, has been used as a functional test of pyridoxine status and maybe a more accurate reflection of vitamin B6 status in critically ill patients ¹⁵⁶. Urinary 4-pyridoxic acid excretion greater than 3.0 mmol/day can be used as an indicator of adequate short-term vitamin B6 status (this is often reported as “urinary pyridoxic acid”) ¹⁰⁸.

Vitamin B6 Deficiency treatment

In vitamin B6-deficient states and illnesses, treatment dosage is variable and depends on the severity of symptoms ¹⁰⁸. Vitamin B6 (Pyridoxine) is available therapeutically in both oral and parenteral formulations. Neonates with vitamin B6 deficiency seizures may require 10 to 100 mg intravenous (IV) Pyridoxine for effective treatment of active seizures. Less serious or less acute presentations can be supplemented with Pyridoxine doses ranging from 25 mg to 600 mg per day orally depending on symptom complex.

Levels of pyridoxine hydrochloride supplementation in various medical conditions are as follows ¹⁵⁷:

• Cirrhosis – 50 mg/d
• Hemodialysis – 5-50 mg/d
• Peritoneal dialysis – 2.5-5 mg/d
• Chronic renal failure – 2.5-5 mg/d
• Sideroblastic anemia – 50-600 mg/d
• Pyridoxine-dependent seizures – 100 mg/d
• Homocystinuria – 100-500 mg/d
• Homocystinemia – 100-500 mg/d
• Gyromitra poisoning – 25 mg/kg IV

At one time, pyridoxine supplementation was given to people with sickle cell anemia; however, no changes were noted in these patients’ hematologic indexes or disease activity.

Importantly, vitamin B6 or Pyridoxine therapy can be life-saving in refractory Isoniazid (a potent antibiotic used in the treatment of tuberculosis) overdose-induced seizures ¹⁰⁸. The vitamin B6 (Pyridoxine) dose is equal to the known amount of Isoniazid (INH) ingested or a maximum of 5,000 mg and is dosed 1,000 to 4,000 mg IV as the first dose, then 1,000 mg IM or IV every 30 minutes ¹⁵⁸. In ethylene glycol overdose, vitamin B6 is recommended at 50 to 100 mg IV every 6 hours to facilitate shunting the metabolism of ethylene glycol to nontoxic pathways leading to glycine (nontoxic) instead of toxic pathways leading to toxic metabolites such as formate.

Additional, less common uses are in hydralazine overdose, where the recommended dose of vitamin B6 is 25 mg/kg, the first third administered intramuscularly, and the remainder as a 3-hour IV infusion. Gyromitra (mushroom) toxicity treatment is at 25 mg/kg infused IV over 30 min ¹⁰⁸.

Hyperemesis gravidarum (severe nausea and vomiting during pregnancy) may respond to vitamin B6 at a dosage of 25 mg orally every 8 hours.

Vitamin B6 Deficiency prognosis

If diagnosed appropriately, vitamin B6 deficiency is effectively treated with adequate oral or parenteral vitamin B6 (pyridoxine) supplementation.

Care should be taken when supplementing pyridoxine, because high pyridoxine states can cause peripheral neuropathy characterized by ataxia and burning pain in the feet, beginning approximately 1 month to 3 years following supplementation ¹⁵⁹. Although this usually occurs at very high supplementation doses, complications have been reported with doses as low as 50 mg/day ¹⁵⁹.

Care should also be taken when prescribing pyridoxine supplementation to postpartum women who are breastfeeding, because high doses of pyridoxine can cause hypocalcaemia (low blood calcium) ¹⁵⁹. A cohort study of postmenopausal women found that a high intake of pyridoxine, coupled with a high intake of vitamin B12, is linked to an increased risk of hip fracture. Compared with women who consumed less than 2 mg/d of total pyridoxine, those whose intake was 35 mg/d or higher had an elevated fracture risk ¹⁶⁰.

Injecting pyridoxine into an infant or neonate can cause a precipitous decrease in blood pressure.

Pyridoxine has the highest adverse outcome per toxic exposure for any vitamin, although no deaths have been reported.

Vitamin B6 Side Effects and 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. The ingestion of megadoses (> 500 mg/day) of vitamin B6 or pyridoxine (eg, taken to treat carpal tunnel syndrome or premenstrual syndrome although efficacy is unproven) may cause painful neurological symptoms known as sensory neuropathy with deficits in a stocking-glove distribution, including progressive sensory ataxia and severe impairment of position and vibration senses ¹⁵¹. Symptoms include pain and numbness of the extremities and in severe cases, difficulty walking ⁷. Senses of touch, temperature, and pain are less affected. Motor and central nervous systems are usually intact.

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 ⁷. 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 ¹⁶¹.

However, chronic administration of 1–6 g oral pyridoxine per day for 12–40 months can cause severe and progressive sensory neuropathy characterized by ataxia (loss of control of bodily movements) ¹⁶², ¹⁶³, ¹⁶⁴, ¹⁶⁵, ¹⁶¹. Symptom severity appears to be dose dependent, and the symptoms usually stop if the patient discontinues the pyridoxine supplements as soon as the neurologic symptoms appear. Other effects of excessive vitamin B6 intakes include painful, disfiguring dermatological lesions; photosensitivity; and gastrointestinal symptoms, such as nausea and heartburn ¹, ¹⁶³, ¹⁶⁴, ².

The scientific literature includes isolated case reports of congenital defects in the infants of individuals who took pyridoxine supplements during the first half of pregnancy ¹⁴. However, a more recent observational study found no association between pyridoxine supplementation (mean dose 132.3 ± 74 mg/day) in pregnant people starting at 7 weeks gestation and continuing for 9 ± 4.2 weeks and teratogenic effects in their infants ⁸⁸.

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 2) ⁹. Because placebo-controlled studies have generally failed to show therapeutic benefits of high doses of pyridoxine, there is little reason to exceed the tolerable upper intake level (UL) of 100 mg/day. The Tolerable Upper Intake Level (ULs) do not apply to individuals receiving vitamin B6 for medical treatment, but such individuals should be under the care of a physician.

• Diagnosis of vitamin B6 toxicity is clinical.
• Treatment of vitamin B6 toxicity is to stop taking vitamin B6. Recovery is slow and, for some patients, incomplete.

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