Vitamin B6

Vitamin B6 (Pyridoxine)

1. Identity: Chemical Names, Natural Sources, and Common Forms

1.1 Chemical Identity and Vitamers

Vitamin B6 is a water-soluble vitamin that is naturally present in many foods, added to others, and available as a dietary supplement. It is the generic name for six compounds (vitamers) with vitamin B6 activity: pyridoxine, an alcohol; pyridoxal, an aldehyde; and pyridoxamine, which contains an amino group; and their respective 5′-phosphate esters. Collectively, vitamin B6 is a complex of six vitamers — pyridoxal, pyridoxine, pyridoxamine, and their three respective 5′-phosphate esters, namely pyridoxal 5′-phosphate (PLP), pyridoxine 5′-phosphate (PNP), and pyridoxamine 5′-phosphate (PMP).

Vitamin B6 is a generic term that refers to the pyridine-based compounds pyridoxine, 4-pyridoxic acid, pyridoxamine, pyridoxal, and their phosphorylated derivatives. Pyridoxal-5′-phosphate (PLP) is the biologically active form and serves as a cofactor for more than 140 different enzyme reactions, representing 4% of all known catalytic activity.

The chemical structure of the pyridoxine vitamer is formally described as a pyridine derivative, 3-hydroxy-4,5-dihydroxy-methyl-2-methyl-pyridine. György proposed the term pyridoxine for this derivative.

Absorbed pyridoxine (PN) is converted to pyridoxamine 5′-phosphate (PMP) by the enzyme pyridoxal kinase, with PMP further converted to pyridoxal 5′-phosphate (PLP), the metabolically active form, by the enzymes pyridoxamine-phosphate transaminase or pyridoxine 5′-phosphate oxidase, the latter of which also catalyzes the conversion of pyridoxine 5′-phosphate (PNP) to PLP. Pyridoxine 5′-phosphate oxidase is dependent on flavin mononucleotide (FMN) as a cofactor produced from riboflavin (vitamin B2).

1.2 Natural Food Sources

Vitamin B6 is found naturally in many foods and is added to others. Recommended amounts can be obtained by eating a variety of foods, including poultry, fish, and organ meats (which are all rich in vitamin B6), potatoes and other starchy vegetables (which are some of the major sources for Americans), and fruit other than citrus.

Other rich sources of vitamin B6 are beef liver, other organ meats, and fortified soy-based meat substitutes. Good sources are meat, fish, and poultry, and starchy vegetables such as potatoes, plantains, and winter squash. Plant foods including bananas, avocados, and legumes such as chickpeas and lentils also contribute meaningfully to dietary intake.

Bioavailability from a mixed diet (containing animal- and plant-sourced foods) is estimated at approximately 75% — higher for PLP from meat, fish, and fowl, and lower from plants, as those are mostly in the form of pyridoxine glucoside, which has approximately half the bioavailability of animal-sourced B6 because removal of the glucoside by intestinal cells is not 100% efficient. The primary forms of vitamin B6 in meats are esters, and the dominant plant source is pyridoxine, which is less bioavailable.

1.3 Common Preparations and Supplement Forms

Vitamin B6 is available in multivitamins, in supplements containing other B complex vitamins, and as a stand-alone supplement. The most common vitamin B6 vitamer in supplements is pyridoxine (in the form of pyridoxine hydrochloride [HCl]), although some supplements contain PLP. Vitamin B6 supplements are available in oral capsules or tablets (including sublingual and chewable tablets) and liquids.

Because of its chemical stability, pyridoxine hydrochloride is the form most commonly given as a vitamin B6 dietary supplement. The administration of vitamin B6 can be both via oral and intravenous routes. Oral vitamin B6 is the most prevalent form available, while the intravenous form is useful in some special cases, such as malabsorption syndromes, anorexia, and in patients on parenteral nutrition. Pyridoxine is also available in intramuscular and subcutaneous forms. Intravenous dosage forms intended to be administered intravenously or intramuscularly are available in 100 mg per mL. Oral formulation pyridoxine hydrochloride tablets are available in 25 mg, 50 mg, and 500 mg of active ingredient per dosage form.

2. Discovery and Historical Context

2.1 Scientific Discovery

In the 1930s, Rudolf Peters showed that young rats kept on a semi-synthetic diet with added thiamin and riboflavin but no other supplement developed "rat acrodynia," a condition characterized by severe cutaneous lesions. In 1934, Paul György showed that the factor which cured "rat acrodynia" was vitamin B6. Other studies soon showed that vitamin B6 deficiency produced convulsions in rats, pigs, and dogs, and a microcytic anemia in certain animals.

Samuel Lepkovsky isolated and crystallized vitamin B6 in 1938. The following year, Leslie Harris and Karl Folkers, and Richard Kuhn and his associates independently showed that vitamin B6 was a pyridine derivative, 3-hydroxy-4,5-dihydroxy-methyl-2-methyl-pyridine. György proposed the term pyridoxine for this derivative.

Kuhn and his assistants first isolated vitamin B6 in yeast in early 1939. Within a few months, they established its chemical composition and structure, then synthesized the vitamin. Weygand, Wendt, and Westphal were deeply involved in this work. Kuhn called it adermin (pyridoxine), and this immediately became a new focal point of his research strategy.

Esmond Snell developed a microbiological growth assay in 1942 that led to the characterization of pyridoxamine, the animated product of pyridoxine, and pyridoxal, the formyl derivative of pyridoxine. Further studies showed that pyridoxal, pyridoxamine, and pyridoxine have largely equal activity in animals and owe their vitamin activity to the ability of the organism to convert them into the enzymatically active form pyridoxal-5-phosphate.

In the 1930s and 1940s, Merck scientists reported a series of advances in the study of the vitamin B complex, including the isolation, structure determination, and industrial synthesis of B6 (pyridoxine, pyridoxamine, and pyridoxal).

2.2 Historical and Traditional Use Contexts

Unlike many botanical dietary supplements, vitamin B6 does not have a discrete pre-modern traditional medicine history as an isolated compound, since its existence as a discrete chemical entity was not recognized until the 20th century. However, foods that are now known to be rich in vitamin B6 — including liver, meat, legumes, whole grains, and certain vegetables — have been cornerstone ingredients in the dietary traditions of cultures worldwide for millennia. The understanding of the vitamin's specific role emerged from nutrition science rather than from herbal or botanical medicine traditions.

The earliest formal therapeutic application arose almost immediately after the compound's isolation. In the late 1950s and early 1960s, pyridoxine was widely administered as part of treatment regimens for isoniazid-induced neuropathy in tuberculosis patients, a pharmacological use that continues to the present day. The 1970s and 1980s saw broad lay interest in vitamin B6 for premenstrual syndrome and for carpal tunnel syndrome — uses that grew primarily from anecdotal reports and small clinical studies and were subsequently subjected to formal clinical scrutiny.

3. Key Constituents and Mechanisms of Action

3.1 The Coenzyme Role of Pyridoxal 5′-Phosphate (PLP)

Vitamin B6 in coenzyme forms performs a wide variety of functions in the body and is extremely versatile, with involvement in more than 100 enzyme reactions, mostly concerned with protein metabolism. Both PLP and PMP are involved in amino acid metabolism, and PLP is also involved in the metabolism of one-carbon units, carbohydrates, and lipids.

PLP is involved in several aspects of macronutrient metabolism, histamine synthesis, neurotransmitter synthesis, hemoglobin synthesis, and gene expression. Biochemically, PLP serves as a cofactor (coenzyme) for various enzymatic reactions including transamination, decarboxylation, elimination, racemization, beta-group interconversion, and replacement.

3.2 Neurotransmitter Synthesis

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.

Beyond its essential role in neurotransmitter production, PLP also acts as a coenzyme in one-carbon unit generation and homocysteine metabolism, supports carbohydrate and fat synthesis as well as breakdown, and helps releasing food-bound energy that is needed for the metabolism of proteins and amino acids. PLP also serves as a cofactor in sphingolipid synthesis and is thereby important for myelin formation.

3.3 Homocysteine Metabolism

Homocysteine metabolism is dependent on PLP, which acts as a cofactor for enzymes involved in the conversion of homocysteine to cysteine. Thus, high homocysteine levels can result from pyridoxine deficiency. 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.

3.4 Immune Function, Heme Synthesis, and Glucose Metabolism

Vitamin B6 is involved in gluconeogenesis and glycogenolysis, immune function (for example, it promotes lymphocyte and interleukin-2 production), and hemoglobin formation. PLP functions as a coenzyme of 5-aminolevulinic acid synthase, which is involved in the synthesis of heme, an iron-containing component of hemoglobin. 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.

3.5 Gene Expression Modulation

The physiologically active form of vitamin B6, pyridoxal 5′-phosphate (PLP), is known to function as a cofactor in many enzymatic reactions in amino acid metabolism. Recent studies have shown that, apart from its role as a coenzyme, PLP acts as a modulator of steroid hormone receptor-mediated gene expression. Specifically, elevation of intracellular PLP leads to a decreased transcriptional response to glucocorticoid hormones, progesterone, androgens, and oestrogens.

3.6 Absorption and Metabolism

The human body absorbs vitamin B6 in the jejunum. After absorption, pyridoxine, pyridoxamine, and pyridoxal are transported into hepatic cells by facilitated diffusion. Pyridoxal kinase phosphorylates pyridoxal, pyridoxine, and pyridoxamine into PLP, PNP, and PMP, respectively. Subsequently, PMP and PNP are converted into PLP by pyridoxine (pyridoxamine) phosphate oxidase found exclusively in the liver, kidney, and brain.

4. Recommended Intake, Dietary Reference Values

The Recommended Dietary Allowance (RDA) for men ages 14–50 years is 1.3 mg daily; for men 51 and older, 1.7 mg. The RDA for women ages 14–18 years is 1.2 mg; 19–50 years, 1.3 mg; and 51 and older, 1.5 mg. For pregnancy and lactation, the amount increases to 1.9 mg and 2.0 mg, respectively.

In 2023, the Panel on Nutrition, Novel Foods and Food Allergens of the European Food Safety Authority (EFSA) released a scientific opinion on the tolerable upper intake levels for vitamin B6. Based on systematic reviews that examined associations between vitamin B6 and peripheral neuropathy, the panel set an upper limit for vitamin B6 of 12 mg/day for all adults, including women who are pregnant or lactating, with lower amounts ranging from 2.2 to 10.7 mg/day for infants and children, depending on age.

5. Scientific Evidence by Area of Use

5.1 Nausea and Vomiting of Pregnancy (NVP)

This is among the best-studied and most clinically supported applications of vitamin B6 supplementation. Nausea and vomiting occur in as many as 80% of all pregnant women between 6 and 12 weeks of gestation.

First-line treatment recommendations for nausea and vomiting during pregnancy per the American College of Obstetricians and Gynecologists (ACOG) include pyridoxine or pyridoxine plus doxylamine. A large, double-blind, placebo-controlled study suggests that vitamin B6 at a dose of 30 mg daily may be helpful for treating nausea in pregnancy.

The combination of pyridoxine (vitamin B6) with doxylamine (an antihistamine) has been the subject of extensive regulatory review. The FDA approved Diclegis (Duchesnay), a product combining doxylamine and pyridoxine, after 30 years during which no FDA-approved medications existed for this indication. The FDA's approval of Diclegis was based on efficacy and safety data from a randomized, placebo-controlled clinical trial and also took into account extensive data showing that combined treatment with doxylamine succinate and pyridoxine hydrochloride is not teratogenic. The study drug was a combination tablet containing 10 mg of doxylamine and 10 mg of pyridoxine (vitamin B6) in a delayed-release formulation.

The American College of Obstetricians and Gynecologists recommends with Level A evidence the use of vitamin B6 in combination with doxylamine as first-line pharmacotherapy for treatment of NVP.

Despite the widespread clinical adoption of pyridoxine for NVP, a Cochrane review of pyridoxine supplementation during pregnancy more broadly concluded that there is at present not enough evidence to show any important clinical benefit of providing vitamin B6 supplementation in pregnancy beyond the specific indication of nausea and vomiting, and that future well-designed trials evaluating neonatal outcomes such as cardiovascular malformations, orofacial clefts and long-term neurological development, as well as maternal outcomes such as preterm birth and pre-eclampsia, are warranted.

Evidence strength: Strong for the reduction of NVP symptoms, with the doxylamine–pyridoxine combination being FDA-approved and endorsed as first-line therapy by ACOG. Evidence for pyridoxine alone is more modest.

5.2 Premenstrual Syndrome (PMS)

Some evidence suggests that vitamin B6 supplements could reduce the symptoms of premenstrual syndrome (PMS), but conclusions are limited due to the poor quality of most studies. A meta-analysis of nine published trials involving almost 1,000 women with PMS found that vitamin B6 is more effective in reducing PMS symptoms than placebo, but most of the studies analyzed were small and several had methodological weaknesses.

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.

Not all analyses are in agreement. For example, the two most famous uses of vitamin B6 — carpal tunnel syndrome and premenstrual syndrome (PMS) — have no reliable supporting evidence according to some evaluators, and the best-designed studies have found this vitamin ineffective for either of these purposes.

Evidence strength: Mixed. Meta-analytic data trend positive but are based predominantly on methodologically weak trials. The NIH ODS characterizes the evidence as limited in quality. High-quality, adequately powered RCTs are lacking.

5.3 Cardiovascular Disease and Homocysteine Reduction

Scientists have hypothesized that certain B vitamins (folic acid, vitamin B12, and vitamin B6) might reduce cardiovascular disease risk by lowering homocysteine levels. Several clinical trials have assessed the safety and efficacy of supplemental doses of B vitamins to reduce heart disease risk. However, 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.

Two large controlled trials including participants receiving only vitamin B6 found no beneficial effects on major cardiovascular events in those with ischemic heart disease. Higher intake of vitamin B6 reduces the level of homocysteine in the blood, a substance that might accelerate cardiovascular diseases such as heart disease, strokes, and related conditions. However, there is no meaningful evidence that reducing homocysteine is beneficial, and considerable evidence that it is not.

Homocysteine lowering by B vitamins has generally failed to lower the risk of adverse cardiovascular outcomes in high-risk individuals.

Evidence strength: Weak to negative for vitamin B6 specifically reducing cardiovascular events, despite its well-documented homocysteine-lowering effect. The lack of isolated B6 arms in major trials makes definitive conclusions difficult. Current evidence does not support B6 supplementation for cardiovascular prevention.

5.4 Cognitive Function, Dementia, and Alzheimer's Disease

Some research indicates that elderly people who have higher blood levels of vitamin B6 have better memory. However, 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.

Findings from short-term studies suggest that B-vitamin supplements (B12, B6, and folic acid) do not help cognitive functioning in adults ages 50 or older with or without dementia. However, a meta-analysis of 95 longer-term studies (more than 12 months) suggests that B vitamin supplementation may be associated with slowing cognitive decline. A 2018 Cochrane systematic review of 5 trials involving 879 participants concluded that there is no evidence for beneficial effects on cognition of supplementation with B vitamins for 6 to 24 months.

The reviewers noted that evidence from one study of a reduced rate of brain atrophy in participants taking B vitamins and a beneficial effect of B vitamins on episodic memory in those with higher plasma homocysteine at baseline warrants attempted replication.

Although high blood homocysteine levels in older adults is a modifiable risk factor for cognitive decline, dementia, and Alzheimer's disease, it is not yet clear whether supplementation with vitamin B6 and other B-vitamins might lower the risk of developing dementia late in life.

The intervention doses administered in the VITACOG trial were well in excess of recommended dietary intakes, and whilst the VITACOG papers provide powerful evidence of a role for folate, vitamin B12, and/or vitamin B6 in cognition, the relevance of these results to nutrition and thus prevention of cognitive dysfunction in ageing is unclear.

Evidence strength: Inconclusive. Observational data suggest associations between higher B6 status and better memory in the elderly, but RCTs have not demonstrated consistent benefit. The Cochrane review is negative. A subset of individuals with elevated homocysteine may warrant further study.

5.5 Depression and Mood

Pyridoxal 5′-phosphate (PLP) acts as a coenzyme in the synthesis of serotonin, dopamine, and gamma-aminobutyric acid, neurotransmitters that are closely linked to mood regulation. Vitamin B6 plays a crucial role in various biological functions, including neurotransmitter synthesis, homocysteine metabolism, and immune function. Previous studies have suggested that vitamin B6 may help modulate inflammation and homocysteine levels, both of which are implicated in the pathophysiology of depression.

The importance of PLP-dependent enzymes in the synthesis of several neurotransmitters has led researchers to consider whether vitamin B6 deficiency might contribute to the onset of depressive symptoms. 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.

Evidence strength: Preliminary. The mechanistic rationale is compelling, but most evidence is observational or derived from combination B-vitamin studies. Isolating the specific contribution of B6 to antidepressant effects remains methodologically challenging.

5.6 Pyridoxine-Dependent Epilepsy (Vitamin B6-Dependent Seizures)

Pyridoxine-dependent epilepsy (PDE-ALDH7A1) is characterized by seizures not well controlled with anti-seizure medication that are responsive clinically and electrographically to large daily supplements of pyridoxine (vitamin B6). This is true across a phenotypic spectrum that ranges from classic to atypical PDE-ALDH7A1.

Vitamin B6-dependent epilepsies include treatable diseases responding to pyridoxine or pyridoxal-5-phosphate, including ALDH7A1 deficiency, PNPO deficiency, PLP binding protein deficiency, hyperprolinemia type II, and hypophosphatasia and glycosylphosphatidylinositol anchor synthesis defects. A systematic review fulfilling PRISMA guidelines identified 497 published patients. Seizure onset manifested at a mean of 59.8 days, with 67.8% of cases in the first month of life.

Pyridoxine-dependent seizures, unlike other seizures, are not responsive to typical anticonvulsants but do usually respond rapidly to pyridoxal phosphate administration. Although extremely rare, this genetic condition is treatable and should always be considered when a neonate or young infant presents with seizures.

Pyridoxine dosage in these patients ranged between 1 and 55 mg/kg/day. Complete seizure freedom was achieved in 160 patients out of 497, while a significant seizure reduction occurred in 38.

Evidence strength: Well-established for this specific, rare genetic disorder. Pyridoxine represents a recognized, life-changing treatment for pyridoxine-dependent epilepsy syndromes.

5.7 Isoniazid-Induced Neuropathy Prevention

Studies have reported that ensuring adequate levels of vitamin B6 is important for preventing peripheral neuropathy induced by isoniazid (INH). INH is a tuberculosis medication that interferes with vitamin B6 activity, potentially leading to nerve damage. Pyridoxine (vitamin B6) at a dosage of 10 to 50 mg/day may prevent or attenuate isoniazid-related peripheral neuropathy and is recommended for patients at risk.

Evidence strength: Well-established for this prophylactic application. Pyridoxine co-administration with isoniazid has been standard clinical practice for decades and is supported by clinical guidelines worldwide.

5.8 Sideroblastic Anemia

Vitamin B6 is effective at treating hereditary sideroblastic anemia, a genetic type of anemia. The role of PLP in the first step of heme biosynthesis via 5-aminolevulinic acid synthase provides the mechanistic basis for this application.

Evidence strength: Well-established for pyridoxine-responsive sideroblastic anemia, a rare inherited condition. Response rates and dosages are documented in clinical literature.

5.9 Cancer Risk

Observational studies have linked higher dietary intakes of vitamin B6 with lower risks of breast and gastrointestinal (esophageal, stomach, and colorectal) cancers. However, the controlled trials' findings did not support a protective effect of this vitamin against cancer.

Evidence strength: Weak. Observational associations exist but intervention trials have not confirmed a protective role. This area requires further investigation before any conclusions can be drawn.

5.10 Tardive Dyskinesia

A series of studies suggests that vitamin B6 may be helpful for the treatment of tardive dyskinesia (TD). This evidence base, while preliminary, has prompted investigation into high-dose pyridoxine as an adjunctive therapy in patients with antipsychotic-induced movement disorders.

Evidence strength: Preliminary. Evidence is based on a small number of studies; further large-scale RCTs are needed.

6. Deficiency: Symptoms, At-Risk Populations, and Clinical Consequences

6.1 Signs and Symptoms of Deficiency

Marginal vitamin B6 deficiency causes oral stomatitis, glossitis, and cheilosis. Irritability, confusion, and depression may also occur. Severely deficient adults may present with seborrheic dermatitis, microcytic anemia, and seizures.

Vitamin B6 deficiency causes peripheral neuropathy and a pellagra-like syndrome, with seborrheic dermatitis, glossitis, and cheilosis, and, in adults, can cause confusion, electroencephalogram abnormalities, and seizures. Tryptophan is a precursor to several neurotransmitters and is required for niacin production. Thus, pyridoxine deficiency can cause a syndrome indistinguishable from pellagra.

6.2 At-Risk Populations

People who have kidney disease or conditions that prevent the small intestine from absorbing nutrients from foods (malabsorption syndromes) are more likely to be vitamin B6 deficient. Certain autoimmune disorders, some epilepsy medications, and alcohol dependence also can lead to vitamin B6 deficiency.

Deficiencies can occur in people with mutations of pyridoxal kinase or pyridoxine 5′-phosphate oxidase, as well as in individuals who are pregnant, have kidney disease, are severely malnourished, or have malabsorption. Additionally, deficiencies have been observed with the usage of certain drugs such as isoniazid, penicillamine, benserazide, and carbidopa.

This may be clinically significant for adults and children consuming an exclusively plant-based diet who may benefit from supplementation.

7. Body Systems and Health Areas

• Nervous system: The biologically active form PLP is a crucial coenzyme in numerous enzymatic activities related to the metabolism of carbohydrates, proteins, and lipids, as well as the production of neurotransmitters. PLP is required for myelin formation and supports both central and peripheral nervous system integrity.
• Hematopoietic system: Vitamin B6 helps form hemoglobin, which carries oxygen in the blood. Deficiency can cause microcytic or sideroblastic anemia.
• Immune system: Vitamin B6 contributes to interleukin-2 production, supporting immune cell proliferation.
• Cardiovascular system: B6 is required for the enzymatic conversion of homocysteine, and elevated homocysteine is an established risk factor for cardiovascular disease, though supplementation has not proven clinically cardioprotective.
• Endocrine/reproductive system: PLP acts as a modulator of steroid hormone receptor-mediated gene expression; elevation of intracellular PLP leads to a decreased transcriptional response to glucocorticoid hormones, progesterone, androgens, and oestrogens.
• Metabolic system: PLP is involved in gluconeogenesis, glycogenolysis, and multiple pathways of amino acid catabolism and interconversion.

8. Dosage Forms and Dosages Reported in Clinical Studies

The following dosages are as reported in clinical studies and regulatory guidance, not as general recommendations:

• In a double-blind RCT in 94 women for PMS: 80 mg pyridoxine per day over three menstrual cycles.
• In a large placebo-controlled study for nausea in pregnancy: 30 mg/day.
• In the pivotal FDA registration trial for Diclegis for NVP: a combination tablet of 10 mg doxylamine and 10 mg pyridoxine in delayed-release formulation.
• In the HOPE 2 trial for cardiovascular outcomes: 50 mg/day vitamin B6, used alongside 1 mg/day vitamin B12 and 2.5 mg/day folic acid.
• Typical pyridoxine doses used for co-treatment with isoniazid: 10 to 25 mg/day.
• In pyridoxine-dependent epilepsy (pediatric): dosage ranged between 1 and 55 mg/kg/day.
• Intravenous pyridoxine (for clinical use, e.g., isoniazid overdose antidote): available in 100 mg/mL formulation.
• In a placebo-controlled trial of B vitamin supplementation for memory function in healthy adult women: 75 mg/day of vitamin B6 (alongside folate and B12).

9. Safety Considerations and Drug Interactions

9.1 Toxicity and Peripheral Neuropathy

Both vitamin B6 deficiency and high B6 intake have been described as risk factors for developing peripheral neuropathy (PN). This vitamin is unique in that either deficiency or excess can cause peripheral neuropathy.

Almost all cases of vitamin B6 toxicity are from supratherapeutic dosing, either iatrogenic or from laypersons self-treating with over-the-counter supplements. Daily dietary intake will not provide enough pyridoxine to cause toxicity.

Pyridoxine toxicity typically manifests as neurologic symptoms, including paresthesias in the extremities and, in severe cases, difficulty with ambulation. This sensory neuropathy usually develops at doses of pyridoxine above 1,000 mg per day. There are some case reports of sensory neuropathies at doses of less than 500 mg per day in patients taking supplements for months. However, none of the reviewed studies documented sensory nerve damage at a daily intake below 200 mg of pyridoxine per day.

Higher vitamin B6 levels, which usually occur following the taking of nutritional supplements, may lead to the development of a predominantly, if not exclusively, sensory neuropathy of the axonal type. After pyridoxine discontinuation, such patients subjectively report improved symptoms.

High intakes of vitamin B6 from food sources have not been reported to cause adverse effects.

The EFSA's 2023 upper intake level of 12 mg/day for adults is substantially more conservative than the U.S. Tolerable Upper Intake Level, reflecting a precautionary approach to potential neuropathy risk at lower supplemental doses. While Australia has set an upper limit of 50 mg/day, the Therapeutic Goods Administration requires a label warning about peripheral neuropathy if the daily dose is predicted to exceed 10 mg/day.

9.2 Drug Interactions

Vitamin B6 can interact with certain medications, and several types of medications might adversely affect vitamin B6 levels.

• Antiepileptic drugs: Some antiepileptic drugs, including valproic acid, carbamazepine, and phenytoin, increase the catabolism rate of vitamin B6 vitamers, resulting in low plasma PLP concentrations and hyperhomocysteinemia. High homocysteine levels in antiepileptic drug users might increase the risk of epileptic seizures and systemic vascular events, including stroke, and reduce the ability to control seizures in patients with epilepsy.
• Isoniazid and other tuberculosis drugs: Isoniazid, phenelzine, hydralazine, penicillamine, levodopa, and chemotherapy treatments are among medications that might lead to pyridoxine shortages because they interfere with its metabolism.
• Cycloserine: Cycloserine (Seromycin) is a broad-spectrum antibiotic used to treat tuberculosis and is known to lower vitamin B6 levels.
• Levodopa: Vitamin B6 can accelerate the peripheral conversion of levodopa to dopamine, reducing the amount of levodopa available to the brain; this interaction is relevant primarily when levodopa is used without a dopa-decarboxylase inhibitor.
• Phenobarbital and phenytoin: High doses of pyridoxine lower the blood level of phenobarbital and phenytoin.

9.3 Deficiency-Inducing Drug Classes

Several medication classes reduce vitamin B6 bioavailability or accelerate its catabolism. Cyclosporine, isoniazid, L-dopa, and penicillin form complexes with vitamin B6 and reduce its bioavailability. Patients on long-term therapy with these agents may require monitoring of vitamin B6 status.

9.4 Special Populations

Individuals who are pregnant, have kidney disease, are severely malnourished, or have malabsorption are at particular risk of vitamin B6 deficiency. The daily dietary intake of vitamin B6 is approximately 1.9 mg/day in the United States, which is generally sufficient for most healthy adults consuming a varied diet.

References

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