Vitamin

Vitamin B1 (thiamine) is a water-soluble vitamin essential for energy metabolism, acting as a coenzyme in carbohydrate metabolism and mitochondrial function. It plays a critical role in nervous system health by supporting nerve conduction and maintaining myelin sheath integrity. Deficiency leads to conditions such as beriberi and Wernicke-Korsakoff syndrome, particularly in individuals with alcohol use disorder or malabsorption. Emerging evidence suggests high-dose thiamine may improve metabolic disturbances, including hepatic steatosis under overnutrition conditions, by enhancing oxidative catabolism (PMID 34684464). Thiamine, along with other neurotropic B vitamins (B6 and B12), is also implicated in the management of peripheral neuropathy due to its role in neuronal energy production and antioxidant defense (PMID 37449697, PMID 31490017). While no direct cancer prevention role is established, excessive intake of certain B vitamins has raised concerns about potential promotion of cancer progression, though specific data on B1 are limited (PMID 40076592).

Vitamin B2 (riboflavin) is a water-soluble vitamin essential for energy metabolism, cellular function, and antioxidant defense through its role in flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) coenzyme formation. It supports redox reactions and helps maintain glutathione in its reduced form, contributing to oxidative stress reduction. Evidence suggests that adequate riboflavin intake may help prevent deficiencies commonly observed in chronic conditions such as type 2 diabetes and cardiovascular diseases. Supplementation has been shown to improve vitamin status and clinical outcomes in patients with hypertension, ischemic heart disease, and diabetes, likely due to increased antioxidant capacity and improved metabolic function (PMID 11338339, PMID 20560486, PMID 35596636). However, high dietary intake of B2 has been associated with a modestly increased risk of bladder cancer in some observational studies, though causality remains unclear (PMID 35129646).

Vitamin B6 (pyridoxine) is a water-soluble vitamin essential for amino acid metabolism, neurotransmitter synthesis, and homocysteine regulation. It acts as a coenzyme in over 100 enzymatic reactions, particularly in the production of serotonin, dopamine, and GABA, which may explain its role in mood regulation. Research suggests that adequate B6 status, often in combination with folate and B12, is associated with reduced homocysteine levels—a biomarker linked to cardiovascular disease, stroke, and depression (PMID 32503038, 39960689). Observational data indicate a potential inverse relationship between dietary B6 intake and stroke risk, with dose-response effects observed in meta-analyses (PMID 32503038). In clinical trials, supplementation with B6 (25 mg/day) alongside B12 and folic acid did not significantly improve depression outcomes in older adults receiving antidepressants, though trends favored the intervention (PMID 35257064, 20096138). Additionally, a combination of magnesium and vitamin B6 (30 mg/day) demonstrated superior reduction in perceived stress compared to magnesium alone in stressed adults with low magnesium levels (PMID 30562392). However, evidence for B6 in cancer prevention or treatment remains inconclusive and potentially context-dependent, warranting caution in high-dose use among oncology patients (PMID 37231628).

Vitamin B9 (folate or folic acid) is essential for DNA synthesis, repair, and methylation, playing a critical role in cell division and amino acid metabolism. Adequate intake is particularly important during pregnancy, as it significantly reduces the risk of neural tube defects (NTDs) when supplemented periconceptionally (PMID 38474883). Folate also lowers plasma homocysteine levels, and supplementation with folic acid, particularly in combination with vitamins B12 and B6, reduces stroke risk by approximately 10% through homocysteine reduction (PMID 30022794, 16210710). However, excessive intake of synthetic folic acid, especially in the post-fortification era, may pose risks, including potential adverse effects on offspring neurodevelopment and molecular changes when maternal intake is too high (PMID 38474883). Natural food folate and bioavailable forms like L-methylfolate may offer advantages in individuals with impaired folate metabolism, such as those with MTHFR polymorphisms.

Vitamin A is essential for vision, immune function, cellular differentiation, and epithelial integrity. It plays a critical role in reducing child mortality and morbidity, particularly in populations with vitamin A deficiency or high infectious disease burden. Supplementation in deficient children significantly reduces the risk of death, measles, and diarrhea (PMID 12649946, 18558638). In very low birth weight infants, vitamin A supplementation reduces the risk of chronic lung disease and mortality, likely due to its role in lung development and respiratory tract integrity (PMID 27552058). Maternal supplementation postpartum can improve breast milk retinol levels and infant vitamin A status, though effects vary by baseline deficiency (PMID 17391562). However, in well-nourished populations or at high doses, vitamin A supplementation may not benefit and could potentially increase risks, such as in cancer prevention where a U-shaped response curve is observed—benefit in deficient individuals but potential harm in those with adequate or high status (PMID 22524186). In HIV-positive pregnant women, vitamin A supplementation did not significantly reduce disease progression or mortality, though multivitamins showed benefit (PMID 15229304). Evidence for adjunctive use in tuberculosis treatment is lacking (PMID 20958890).

Vitamin B1 (thiamine) is an essential water-soluble vitamin involved in energy metabolism, particularly in glucose utilization and nerve function. It acts as a coenzyme in the citric acid cycle and is critical for normal neurological function. Thiamine deficiency can lead to serious conditions such as beriberi and Wernicke-Korsakoff syndrome, particularly in individuals with poor nutrition, alcohol use disorder, or malabsorption. Emerging evidence suggests potential benefits of thiamine supplementation in specific clinical contexts. A randomized, double-blind, placebo-controlled trial found that adjuvant thiamine (100 mg/day) significantly improved depressive symptoms in patients with major depressive disorder when added to standard SSRI therapy (PMID 26984349). Other studies have explored B-vitamin combinations, including thiamine, in critically ill patients and those with elevated homocysteine, though effects specific to B1 were not isolated in several trials (PMID 23591663, PMID 36108676). While thiamine's role in cognitive and cardiovascular health via homocysteine modulation is less clear, it remains crucial for metabolic and neurological health.

Vitamin B12 (cobalamin) is essential for DNA synthesis, red blood cell formation, neurological function, and homocysteine metabolism. Deficiency can lead to megaloblastic anemia, neurological impairments, and elevated homocysteine levels, a potential risk factor for cardiovascular and cognitive disorders. High-dose oral vitamin B12 (1000 μg daily) has been shown to be effective in normalizing serum B12 levels in deficient individuals, with efficacy comparable to intramuscular administration, supporting its use even in those with malabsorption issues (PMID 21600388). Supplementation significantly reduces plasma homocysteine concentrations, particularly in individuals with baseline deficiency, as confirmed by a meta-analysis of 21 RCTs (PMID 37495210). However, despite its homocysteine-lowering effects, clinical trials have not consistently demonstrated benefits of B12 supplementation—alone or in combination with folic acid and B6—on cardiovascular events, cognitive decline, or depressive symptoms in high-risk populations (PMID 18460663, 23440809, 08460809, 17210874).

Vitamin B2 (riboflavin) is a water-soluble vitamin essential for energy production, cellular function, and metabolism of fats, drugs, and steroids. It serves as a precursor for flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), cofactors involved in redox reactions and mitochondrial electron transport. Riboflavin also plays a role in homocysteine metabolism, with some evidence suggesting that supplementation may help lower plasma homocysteine levels, particularly when combined with other B vitamins such as folic acid and B12 (PMID 23591663, 23440809). However, trials evaluating B vitamin combinations for cardiovascular risk reduction have shown inconsistent results, with no significant benefit in high-risk populations (PMID 18460663, 23440809). In critically ill patients, including those with COVID-19, low-dose riboflavin supplementation (4 mg/day) did not significantly alter clinical or biochemical outcomes (PMID 36108676). Evidence for cognitive benefits from B2 supplementation is lacking, as systematic reviews of B vitamins have not shown consistent improvements in cognitive function (PMID 17210874). Overall, riboflavin deficiency is rare in well-nourished populations, and routine supplementation beyond recommended levels is not supported by current evidence for general health or disease prevention (PMID 34818175).

Vitamin B3, also known as niacin or nicotinamide, is a precursor to nicotinamide adenine dinucleotide (NAD+), a critical coenzyme involved in cellular energy production, DNA repair, and regulation of metabolic and immune responses. Supplementation with nicotinamide has demonstrated clinical benefits in specific populations, most notably in reducing the incidence of nonmelanoma skin cancers among individuals with a history of these conditions. In a phase 3 randomized trial, 500 mg of nicotinamide twice daily significantly reduced the rate of new nonmelanoma skin cancers over 12 months (PMID 26488693). However, evidence for broader metabolic or neurocognitive benefits in humans remains limited. While nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) increase blood NAD+ levels in a dose-dependent manner (PMID 36108676, 31278280, 38430946), clinical outcomes such as insulin sensitivity, physical performance, or cognitive function have not consistently improved in human trials (PMID 37478182). Overall, the strongest evidence supports nicotinamide use for skin cancer chemoprevention, while other proposed benefits require further validation.

Vitamin B5 (pantothenic acid) is a water-soluble vitamin essential for the synthesis of coenzyme A (CoA), a critical molecule in energy metabolism, fatty acid synthesis, and the production of neurotransmitters and steroid hormones. It plays a vital role in maintaining cellular function and integrity, particularly in tissues with high metabolic activity. Research indicates that adequate pantothenic acid status supports antioxidant defenses by enhancing the activity of antioxidant enzymes, as demonstrated in animal models where dietary supplementation improved antioxidant status (PMID 32867987). Pantothenic acid is also involved in maintaining neurological function, with implications for nerve health and potential neuroprotective effects, possibly through its role in myelin synthesis and mitochondrial function (PMID 33401674, PMID 40919693). Additionally, it is transported into the brain via the sodium-dependent multivitamin transporter, which also carries biotin and lipoic acid, highlighting its importance in central nervous system homeostasis (PMID 17645457).

Vitamin B6, or pyridoxine, is a water-soluble vitamin essential for over 100 enzyme reactions, primarily in protein metabolism. It plays a critical role in neurotransmitter synthesis, red blood cell formation, and immune function. The biologically active form, pyridoxal 5'-phosphate (PLP), serves as a cofactor in amino acid, glucose, and lipid metabolism. Adequate B6 status is associated with optimal cognitive and neurological function, though supplementation trials in older adults have not consistently demonstrated cognitive benefits (PMID 17210874). While B6, along with B12 and folic acid, effectively lowers homocysteine levels—a potential cardiovascular risk factor—large randomized trials have not shown a reduction in cardiovascular events or depression incidence with long-term supplementation (PMID 18460663, PMID 20096138, PMID 25573400). A plasma PLP concentration above 30 nmol/L is considered adequate, and many older adults have suboptimal levels, suggesting a need for improved intake or supplementation in at-risk populations (PMID 36608063).

Biotin (vitamin B7) is a water-soluble vitamin essential for carboxylase enzyme function in energy metabolism, fatty acid synthesis, and amino acid catabolism. It also plays a role in gene expression and skin, hair, and nail health. While frank biotin deficiency is rare, marginal deficiency may occur during pregnancy and could increase the risk of birth defects, suggesting a potential role for supplementation in this population (PMID 28701385). High-dose biotin (100 mg three times daily, totaling 300 mg/day) has been investigated as a therapeutic agent in progressive multiple sclerosis, with one randomized, double-blind, placebo-controlled trial showing a signal toward disability reversal, though larger confirmatory studies are needed (PMID 27589059). Despite widespread use for hair and nail strengthening, robust evidence supporting biotin supplementation for dermatologic conditions in non-deficient individuals is limited, and large-scale randomized trials are lacking (PMID 32360756). Excessive intake of biotin supplements may lead to adverse effects, including interference with laboratory assays (e.g., falsely elevated troponin or falsely low TSH), which poses clinical risks (PMID 34785002, PMID 28701385).

Vitamin B9, also known as folate or folic acid, is essential for DNA synthesis, repair, and methylation, as well as red blood cell formation and homocysteine metabolism. It plays a critical role in fetal neural tube development, making adequate intake crucial during pregnancy to prevent neural tube defects (NTDs). Folic acid supplementation effectively reduces homocysteine levels, a biomarker associated with cardiovascular disease and cognitive decline, although clinical trials have not consistently demonstrated reductions in cardiovascular events or cognitive improvement (PMID 18460663, 23440809). Long-term supplementation with folic acid and other B vitamins has not shown significant benefits in preventing depression in older women or improving cognitive function in randomized trials, though some observational data suggest potential benefits in specific populations (PMID 17210874, 25573400). A trial in female migraine with aura patients found that 1 mg folic acid did not significantly reduce homocysteine or migraine frequency, highlighting variability in response (PMID 27339806).

Vitamin C (ascorbic acid) is a potent antioxidant that supports immune function, collagen synthesis, and iron absorption. It plays a critical role in enhancing resistance to infections by supporting epithelial barrier integrity, leukocyte function, and reducing oxidative stress during inflammation. Evidence suggests regular vitamin C supplementation may modestly reduce the duration and severity of respiratory tract infections, though its effect on incidence is limited in the general population (PMID 34967304). However, in individuals under physical stress or with low baseline vitamin C levels, supplementation shows more consistent benefits in preventing respiratory illness. Vitamin C also demonstrates blood pressure-lowering effects, particularly in hypertensive and diabetic individuals, with a mean reduction of 3.0 mmHg in systolic blood pressure observed in a meta-analysis (PMID 37791386, 22492364). High-dose vitamin C may support critically ill patients, including those with pneumonia or COVID-19, by restoring depleted plasma and leukocyte levels and exerting antiviral, anti-inflammatory, and immunomodulatory effects (PMID 32337708, 34791642, 33113146).

Vitamin D is a fat-soluble nutrient essential for calcium homeostasis, bone health, and immune function. It is synthesized in the skin upon exposure to sunlight and can also be obtained through diet or supplementation. Research indicates that vitamin D status is associated with thresholds below which disease risk increases, particularly for acute respiratory infections and bone disorders (PMID 29751504, 32474141). Supplementation effectively raises serum 25-hydroxyvitamin D [25(OH)D] levels, with evidence supporting both daily and intermittent dosing regimens. Achieving a 25(OH)D concentration of at least 30 ng/mL is linked to reduced disease risk, especially in deficient individuals (PMID 22784845, 24980662). Vitamin D3 (cholecalciferol) appears more effective than D2 (ergocalciferol) in raising and maintaining serum levels (PMID 38458370). Long-term high-dose supplementation is generally safe and may support immune health, including during viral pandemics such as COVID-19 (PMID 32474141, 24980662).

Vitamin D3 (cholecalciferol) is a fat-soluble vitamin essential for calcium homeostasis, bone health, immune function, and modulation of cell growth. It is synthesized in the skin upon exposure to sunlight and can also be obtained through diet or supplementation. The primary marker of vitamin D status is serum 25-hydroxyvitamin D [25(OH)D], with levels below 30 ng/mL (75 nmol/L) generally indicating insufficiency and levels below 20 ng/mL (50 nmol/L) indicating deficiency. Supplementation with vitamin D3 effectively increases serum 25(OH)D concentrations in a dose-dependent manner, with higher and more frequent dosing regimens producing greater increases (PMID 26151178, 22784845). Vitamin D3 is more potent and produces more sustained increases in 25(OH)D levels compared to vitamin D2, particularly with daily dosing and in individuals with higher BMI or lower baseline levels (PMID 28231782, 38458370). Evidence suggests a threshold effect, where benefits of supplementation are more pronounced in individuals with baseline deficiency, supporting targeted correction of low vitamin D status (PMID 29751504).

Vitamin E is a fat-soluble antioxidant that exists in eight forms, including four tocopherols (alpha-, beta-, gamma-, delta-) and four tocotrienols. Alpha-tocopherol is the primary form in humans and has the highest bioavailability, traditionally recognized for its role in protecting cell membranes from oxidative damage. While early studies suggested potential benefits in cancer and cardiovascular disease prevention due to its antioxidant properties, large-scale clinical trials with high-dose alpha-tocopherol supplementation have largely failed to show protective effects (PMID 19748925, 16190316, 15671241). Notably, high-dose alpha-tocopherol supplementation may reduce plasma levels of gamma-tocopherol, a form with strong anti-inflammatory and potentially superior cancer-preventive activity (PMID 19748925, 16190316, 32017273). Emerging evidence highlights the unique health benefits of gamma-tocopherol and tocotrienols, which exhibit neuroprotective, anti-cancer, and cholesterol-lowering effects not seen with alpha-tocopherol (PMID 16943450, 16458936). Additionally, short-term high-dose alpha-tocopherol (1,200 IU/day) combined with vitamin C may enhance UVB photoprotection (PMID 12013192). Overall, the form and balance of vitamin E isomers may be critical for health outcomes.

Vitamin K1 (phylloquinone) is primarily known for its essential role in blood coagulation, serving as a cofactor for the activation of hepatic vitamin K-dependent clotting factors. Beyond coagulation, emerging evidence suggests vitamin K1 supports bone health by promoting the carboxylation of osteocalcin, a protein involved in bone mineralization. Supplementation with vitamin K1 has been shown to reduce undercarboxylated osteocalcin levels, indicating improved bone metabolism, particularly in individuals with low baseline vitamin K status (PMID 16547688, 17030114). While some studies suggest potential benefits for insulin sensitivity and glucose homeostasis (PMID 18614743), results from randomized trials have been mixed, with no significant effects observed on inflammatory markers in rheumatoid arthritis patients at a dose of 10 mg/day (PMID 30786829). Additionally, dietary phylloquinone contributes to menaquinone-4 (MK-4) synthesis in tissues, including breast milk, suggesting a broader physiological impact (PMID 12064330). However, evidence for cardiovascular protection remains inconclusive, with interindividual variability in response potentially influenced by plasma triglyceride levels (PMID 31533195).

Vitamin K2, particularly as menaquinone-4 (MK-4) and menaquinone-7 (MK-7), acts as a cofactor for the carboxylation of vitamin K-dependent proteins, including osteocalcin in bone and matrix Gla protein (MGP) in vascular tissue. Properly carboxylated osteocalcin enhances bone mineralization, while activated MGP inhibits vascular calcification, suggesting dual benefits for skeletal and cardiovascular health. Clinical evidence indicates that vitamin K2 supplementation improves biochemical markers of bone and vascular health, such as reducing undercarboxylated osteocalcin (ucOC), a marker of vitamin K deficiency and poor bone quality (PMID 30816822, PMID 32219282). However, long-term trials have shown mixed results on bone mineral density (BMD), with one 3-year trial in postmenopausal women showing no significant difference in BMD or microarchitecture between MK-7 and placebo groups despite adequate calcium and vitamin D intake (PMID 33030563). Conversely, combining vitamin K2 with vitamin D appears to have synergistic effects, significantly improving total BMD and reducing ucOC levels compared to placebo (PMID 32219282). High-dose MK-4 (45 mg/day) has been shown to maximally reduce ucOC in women with osteoporosis, suggesting a dose-dependent effect on osteocalcin carboxylation (PMID 30816822). Emerging research is exploring the role of high-dose K2 (720 μg/day) in slowing coronary artery calcification progression, particularly when combined with vitamin D3 (PMID 37451735).