B Vitamins: Benefits, Best Forms, Dosing, and Side Effects

B Vitamins: Benefits, Best Forms, Dosing, and Side Effects

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Table of Contents

Overview

The B vitamins are a family of eight water-soluble nutrients that serve as essential coenzymes in cellular metabolism, energy production, DNA synthesis, neurotransmitter formation, and red blood cell development [1][2]. Unlike fat-soluble vitamins, B vitamins are not stored in the body in significant quantities (with the notable exception of vitamin B12, which accumulates in the liver with stores lasting several years), and excess intake is generally excreted in urine [1][3]. This means consistent dietary or supplemental intake is required to maintain adequate status.

The eight B vitamins are:

  • Thiamine (B1) — nervous system function, energy metabolism
  • Riboflavin (B2) — energy production, antioxidant recycling, immune function
  • Niacin (B3) — DNA repair, cholesterol metabolism, energy release
  • Pantothenic acid (B5) — hormone and neurotransmitter synthesis, coenzyme A production
  • Pyridoxine (B6) — amino acid metabolism, neurotransmitter synthesis, immune function
  • Biotin (B7) — fatty acid synthesis, gluconeogenesis, nutrient metabolism
  • Folate (B9) — cell division, DNA synthesis, neural tube development
  • Cobalamin (B12) — myelin formation, red blood cell production, DNA synthesis

These vitamins function synergistically. For example, vitamins B6, B12, and folate collaborate in one-carbon metabolism and homocysteine regulation, while riboflavin-dependent enzymes assist in the synthesis of niacin's active form (NAD) [2][4]. Deficiency in one B vitamin often co-occurs with deficiencies in others, particularly among populations with poor nutritional intake, chronic alcohol use, malabsorption conditions (celiac disease, Crohn's disease, inflammatory bowel disease), or use of medications that deplete B vitamins (proton pump inhibitors, metformin, certain anticonvulsants) [1][5][6].

B-complex supplements are widely available but two of the most common reasons for taking them — reducing cardiovascular risk and boosting energy — are not well supported in the absence of deficiency. Despite evidence that B6, B12, and folate can lower homocysteine (a cardiovascular risk factor), clinical trials have failed to show that this combination reduces cardiovascular events themselves, leading the American Heart Association to conclude that the evidence is "inadequate to recommend folate and other B vitamin supplements as a means to reduce cardiovascular disease risk" [7]. Similarly, supplementing with B vitamins does not improve energy or performance in individuals who are not deficient [8].

Caution is warranted with megadoses. An analysis of studies following over 36,000 Swedish men and women for an average of 11 years found that use of high-dose B vitamin supplements (providing at least 10 times recommended daily requirements) was associated with increased risk of age-related cataracts, with the greatest increase (88%) among middle-aged individuals using B-complexes or single B supplements estimated to provide an average of 25 times the recommended daily intakes [9]. Use of high-dose vitamin B6 and B12 from individual supplements (not from multivitamins) was associated with a 30-40% increase in lung cancer risk among men (driven primarily by male smokers using >20 mg/day of B6 and/or >55 mcg/day of B12, who were 3-4 times more likely to develop lung cancer) [10].

Forms and Bioavailability

MTHFR Gene Mutations and B Vitamin Metabolism

The MTHFR gene encodes an enzyme involved in breaking down homocysteine and converting folate to its active form, L-methylfolate. Approximately 33% of Americans carry one copy of the C677T mutation, while an estimated 11% carry two copies, which causes an approximately 70% reduction in enzyme activity and is associated with 16% higher risk of coronary heart disease and elevated homocysteine levels [11][12].

People with C677T mutations may also be more likely to have vitamin B12 deficiency [13]. Taking riboflavin (B2) may be helpful for people with C677T mutations who also have high blood pressure — a 16-week, placebo-controlled study showed that 10 mg/day of riboflavin lowered elevated daytime systolic blood pressure by almost 4 mmHg in this population [14]. Methylfolate has been promoted for MTHFR carriers, but even people with these mutations appear able to use folic acid, although with reduced efficiency, and either form can reduce homocysteine levels [15].

Only about 7-12% of North Americans have the A1298C mutation. Those with two A1298C mutations have a 40% decrease in enzyme function but this does not lead to elevated homocysteine and is not associated with significant health risks [16].

Are You Getting the Right B Vitamins?

MTHFR gene variations affect up to 40% of the population and can impair B vitamin metabolism. Get a personalized health plan that accounts for your unique nutritional needs.

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Ensuring adequate intake of folate, choline, B12, B6, and riboflavin is important for all individuals regardless of MTHFR status. If adequate nutrition cannot be attained through diet alone, supplementation with methylfolate (or folinic acid) and B vitamins is considered appropriate [11].

Thiamine (B1) Forms

  • Thiamine hydrochloride — most common supplement form; adequate for general use
  • Thiamine mononitrate — equally effective standard form
  • Benfotiamine — a synthetic thiamine derivative that significantly increases blood and tissue levels of thiamine compared to hydrochloride and mononitrate forms [17][18]. A daily dose of 200 mg for 3 weeks significantly improved neuropathy scores and reduced pain in diabetic patients with polyneuropathy [19]. In people with kidney disease associated with type 2 diabetes, 900 mg/day for 3 months significantly improved thiamin status but did not improve kidney function measures [20]. Oral doses in studies range from 200-800 mg per day. No established UL; no reports of toxicity.
  • Thiamine tetrahydrofurfuryl disulfide (TTFD) — another synthetic derivative that increases tissue levels more than standard forms. Approved outside the US as a drug for thiamine deficiency. Preliminary evidence for diabetic neuropathy, fatigue, and other conditions [21].

Riboflavin (B2) Forms

Standard riboflavin and riboflavin 5'-phosphate (the active coenzyme form) are available. Riboflavin is best absorbed when taken with a full meal (approximately 62% absorption vs. 16-21% without food or with just a light breakfast) [22]. When taken with a light breakfast after fasting, only about 27 mg of riboflavin can be absorbed, so higher doses may not provide additional benefit [23]. Excess riboflavin causes bright yellow urine, which is harmless. Riboflavin may affect results from certain urinary dipstick tests.

Niacin (B3) Forms

  • Nicotinic acid (niacin) — causes flushing at doses above the UL (35 mg). Used at high doses (1,000-4,000 mg) for cholesterol management, though clinical trials have not shown cardiovascular benefit when added to statins [24][25].
  • Niacinamide (nicotinamide) — does not cause flushing and does not lower cholesterol. Better tolerated. The UK has set a UL of 500 mg and the EU 900 mg for adults. A review by a UK Food Standards Agency expert group concluded that 560 mg per day "would not be expected to result in any adverse effects" [26].
  • Inositol hexanicotinate (hexaniacinate) — reportedly causes less flushing than regular niacin. About 85% niacin by weight. One small study found 4 g/day significantly reduced attacks in people with Raynaud's disease compared to placebo [27]. May reduce cholesterol levels based on limited data.
  • Nicotinamide riboside (NR) — a precursor to NAD+. Sold as Niagen. Several studies show it raises blood NAD+ levels: 100 mg, 300 mg, and 1,000 mg daily doses increased whole blood NAD+ by 22%, 51%, and 142% respectively within two weeks, with increases maintained through 8 weeks [28]. A study in 24 healthy older adults (ages 55-79) found 500 mg twice daily for six weeks increased NAD+ by 60% compared to placebo [29]. However, clinical benefits remain unproven — a study in 40 overweight men with insulin resistance found 1,000 mg twice daily for 3 months did not improve fasting blood sugar, HbA1c, or insulin sensitivity [30]. The National Advertising Division (NAD/BBB) recommended discontinuing broad "clinically proven" health benefit claims [1]. Theoretical concerns exist about promoting growth of existing cancers [31]. There are no long-term safety studies.
  • Extended-release niacin — may be more hepatotoxic than immediate-release forms at equivalent doses [32].

Vitamin B6 Forms

  • Pyridoxine hydrochloride — the most common supplement form. Must be converted to pyridoxal-5-phosphate (PLP, or P-5-P) in the body.
  • Pyridoxal-5-phosphate (P-5-P) — the active coenzyme form. Must still undergo conversion in the intestine to be absorbed, so bioavailability may be no better than pyridoxine for most people [33]. However, P-5-P may not cause the nerve damage associated with excessive pyridoxine. In-vitro research showed that pyridoxine was the most toxic form to nerve cells, and that it inhibits P-5-P, possibly explaining why high-dose pyridoxine supplementation sometimes causes neurological symptoms resembling B6 deficiency [34].
  • People with certain conditions that prevent conversion of pyridoxine to P-5-P (such as pyridoxal 5'-phosphate-dependent epilepsy) may be prescribed the P-5-P form specifically [33].

Mild B6 deficiency is common (10.5% of the US population is deficient according to the CDC), particularly in the elderly and children [35]. Pyridoxine in amounts meeting the RDAs is easily available from the diet (fortified cereals, meats, starchy vegetables, chickpeas, bananas).

Biotin (B7) Forms

Standard biotin (d-biotin) is the only supplemental form. No significant bioavailability differences between delivery methods. The critical concern with biotin is laboratory test interference — doses of 5 mg (5,000 mcg) or more can cause misleading results in troponin, thyroid, hormone, PSA, vitamin D, and other tests that use biotin-based immunoassay technology [36][37]. The American Association for Clinical Chemistry advises waiting at least 8 hours after consuming 5-10 mg of biotin before blood collection, and at least 3 days for very high doses (100 mg+) [38]. Even regular daily consumption of 5,000 mcg was reported to cause unnecessary diagnostic testing in a 48-year-old woman due to misleading hormone and cortisol results [39].

Folate (B9) Forms

  • Naturally-occurring dietary folate — found in leafy greens, legumes, and certain fruits. Less stable and approximately 60% as bioavailable as synthetic folic acid [40].
  • Folic acid — synthetic form used in supplements and food fortification. More stable and approximately 1.7 times as bioavailable as natural folate (and twice as well if taken on an empty stomach). Mandatory fortification of enriched cereal grain products in the US since 1998 has reduced folate deficiency to less than 1% of Americans [40][41].
  • L-5-methyltetrahydrofolate (methylfolate) — the biologically active form. Sold as Metafolin (calcium salt) and Quatrefolic (glucosamine salt). Somewhat more bioavailable than folic acid in short-term use. A study in 75 Malaysian women found Metafolin achieved moderately higher serum folate levels (23 vs 17.7 ng/mL) than folic acid after 3 months, though both were equally effective at reducing homocysteine [42]. A potential advantage: methylfolate may not mask vitamin B12 deficiency (unlike folic acid) [43]. Both Metafolin and Quatrefolic contain a very small amount of D-5-methylfolate, which is not a natural compound and may hypothetically reduce bioavailability [44].
  • Folinic acid (leucovorin) — a reduced form also used in chemotherapy rescue. Surprisingly, a 4-week Australian study of 30 adults (87% with MTHFR mutations) found folinic acid was even more effective than methylfolate in raising serum folate levels (45% increase vs. 27%), irrespective of MTHFR status [45].

Folate labeling uses "dietary folate equivalents" (DFE): 1 mcg DFE = 1 mcg natural folate = 0.6 mcg folic acid from supplements/fortified foods. If an older label says "Folic Acid 400 mcg, 100% DV" it actually provides the equivalent of about 667 mcg of natural folate [40].

Vitamin B12 Forms

  • Cyanocobalamin — most common supplement form. Contains a cyanide molecule but is very safe (even at 5,000 mcg, it provides about 1,000 times less cyanide than is toxic, and the cyanide is excreted in urine) [46]. Not advisable in people with kidney failure who may have impaired cyanide excretion. More stable and less expensive than methylcobalamin.
  • Methylcobalamin — marketed as the "active" form. However, all forms of B12 are converted to a common intermediate (cobalamin) before being converted to the two active forms used by the body (methylcobalamin and adenosylcobalamin) [47]. A study in Romanian vegans found those supplementing with cyanocobalamin had higher B12 levels (133.7 pmol/L) than those using methylcobalamin (81.5 pmol/L), despite the methylcobalamin group taking higher average doses (2,988 vs 582 mcg) [48].
  • Hydroxocobalamin — a small study found cyanocobalamin resulted in a more than two-fold increase in B12 levels compared to hydroxocobalamin in people with low or normal B12 levels [49]. For rare genetic defects in cobalamin metabolism (typically diagnosed in the first year of life), the hydroxocobalamin form may be better utilized [47].
  • Adenosylcobalamin — the other active coenzyme form. Less commonly available in supplements.

Absorption of B12 is limited by intrinsic factor — only about 1.5 mcg can be actively absorbed from a single dose via intrinsic factor, with an additional approximately 1% absorbed passively through diffusion [50]. Whether you take 5 mcg or 50 mcg, about 1.5 mcg is absorbed. At 1,000 mcg, approximately 11.5 mcg total is absorbed (1.5 mcg via intrinsic factor + ~10 mcg by passive diffusion). To get the most B12 from a meal and a supplement, take them at different times of the day [50].

Dr Brad Stanfield's MicroVitamin includes a full B-complex with methylated B12 (12 mcg) and methylated folate (200 mcg DFE) alongside B1 (0.6 mg), B2 (0.65 mg), B3 (8 mg), B5 (2.5 mg), B6 (0.85 mg), and biotin (15 mcg) — low, evidence-based doses designed to fill dietary gaps without megadosing.

Evidence for Health Benefits

Cognitive Function and Dementia

The relationship between B vitamins and cognitive health centers on homocysteine metabolism. Elevated homocysteine is an established risk factor for cognitive decline and dementia, and vitamins B6, B12, and folate are essential cofactors in homocysteine metabolism [4][51].

Folic acid and cognitive function in low-folate populations: A study among adults in China with low blood folate levels (~5.5 ng/mL) and mild to moderate Alzheimer's disease found that 1,250 mcg of folic acid plus standard medication (donepezil) daily for 6 months resulted in less inflammation and slightly better maintained cognitive function compared to medication alone [52]. However, participants achieved average blood folate levels similar to US adults (10-12 ng/mL), so it is uncertain whether supplementation would benefit people with already adequate levels.

B12 deficiency and reversible dementia: Multiple case reports document cognitive impairment, hallucinations, delirium, and dementia-like symptoms due to B12 deficiency that reversed with B12 treatment [53][54][55]. B12 deficiency has been misdiagnosed as progressive multiple sclerosis and progressive dementia [56][57]. A preliminary study found that correcting B12 deficiency led to small but significant short-term improvement in cognitive function [58]. Significant psychiatric symptoms — depression, auditory and visual hallucinations, and delirium — were reported in a 57-year-old man with B12 deficiency due to poor diet and atrophic gastritis, which normalized with IV methylcobalamin followed by 3,000 mcg oral methylcobalamin daily [53].

Warning — high folate with low B12: Older people with high folate levels but low B12 levels performed worse on tests measuring processing speed, attention, and working memory compared to those with low B12 and low folate. When B12 levels are normal, high folate levels may be protective against cognitive impairment [43][59]. An analysis of 466,224 people from the UK Biobank found that supplementing with folate/folic acid alone was associated with 34% greater risk of Alzheimer's disease and 61% greater risk of vascular dementia, but supplementing with folate along with other B vitamins showed no increased risk [60].

Folic acid did not improve cerebral small vessel disease: A study of 220 Chinese adults with cerebral small vessel disease-related cognitive impairment showed that 800 mcg of folic acid daily for 6 months did not reduce cognitive impairment or improve cognitive function compared to placebo [61].

Niacinamide and Alzheimer's disease: High doses of niacinamide protected mice from memory loss associated with Alzheimer's disease (equivalent to 2-3 g/day in humans), but a study in 31 men and women (average age 79) with mild to moderate Alzheimer's found 1,500 mg twice daily of extended-release niacinamide for 6 months did not improve cognitive function or daily functioning compared to placebo [62].

Depression and Mood

Methylfolate as antidepressant adjunct: Very high-dose methylfolate (15 mg/day as Metafolin) for 60 days improved response rates in patients with major depressive disorder who did not respond to SSRI therapy alone: 32.3% response rate vs. 14.6% for placebo. A lower starting dose of 7.5 mg was not effective [63]. A subsequent one-year open-label study suggested sustained efficacy [64]. Agitation or manic symptoms have developed in some patients, resolving days after discontinuation — the mechanism may relate to methylfolate increasing brain levels of norepinephrine, dopamine, and serotonin [65].

B vitamins and stress/mood: Supplementation with B-complex vitamins has been shown to improve mood, reduce perceived stress, and enhance neurocognitive function under demanding conditions, with benefits most notable in individuals experiencing high stress or with suboptimal B vitamin status. These effects typically become noticeable after consistent daily supplementation over 28-90 days [2][66].

Vitamin B6 and depression: Deficiency in B6 can cause depression and confusion. B6 plays a key role in the biosynthesis of serotonin, dopamine, and GABA [4][67].

Stroke Prevention

A large study in China among adults being treated for hypertension found that adding 800 mcg of folic acid to antihypertensive medication significantly reduced stroke risk. Over 4.5 years, 2.7% of those receiving folic acid experienced a stroke compared to 3.4% of those who did not. The benefit was most pronounced among participants with the lowest baseline folate levels (~5.6 ng/mL), where 4.6% of those not receiving folic acid experienced strokes [68]. Unlike in the US, food in China is not fortified with folic acid, and adult folate levels in the US average 10-12 ng/mL, so similar supplementation may not provide equivalent benefit in populations with adequate folate status.

Cardiovascular Disease and Homocysteine

B6, B12, and folate reduce elevated homocysteine levels, a recognized cardiovascular risk factor. However, clinical trials have consistently failed to demonstrate that lowering homocysteine with B vitamins reduces cardiovascular events. The American Heart Association concluded that evidence is "inadequate to recommend folate and other B vitamin supplements as a means to reduce cardiovascular disease risk" [7].

Concerning findings in kidney disease: A study of diabetes patients with advanced nephropathy given high-dose B vitamins (folic acid 2,500 mcg, B6 25 mg, B12 1,000 mcg daily) showed worsening kidney function and a doubling of the risk of myocardial infarction, stroke, and death in the B-vitamin group compared to placebo — despite the expected decrease in homocysteine levels [69].

Niacin metabolites and cardiovascular risk: A possible explanation for why high-dose niacin (500-2,000 mg/day) does not reduce cardiovascular events despite improving cholesterol: excess niacin metabolism increases levels of two metabolites (2PY and 4PY) that are associated with increased cardiovascular risk, possibly due to inflammatory reactions in blood vessels [70].

Blood Pressure

Riboflavin (B2) and MTHFR-related hypertension: Individuals with the MTHFR 677TT genotype (about 10% of people worldwide, higher in Northern China at 20% and Mexico at 32%) are predisposed to hypertension, with a 27-87% increased risk. A small placebo-controlled study showed that 1.6 mg of riboflavin daily for 16 weeks reduced systolic and diastolic blood pressure by approximately 9.2 mmHg and 6.0 mmHg, respectively — notably in patients already taking antihypertensive medication who had not achieved target blood pressure [14][71].

Niacin and blood pressure: Getting adequate niacin (up to ~15.6 mg daily) from foods was associated with decreased risk of developing hypertension in a Chinese study, though higher intake was associated with increased risk [72]. In clinical trials, effects of high-dose niacin supplementation on blood pressure have been inconsistent [73][74].

Cholesterol and Lipid Management (Niacin)

When taken in very high doses (1,000-4,000 mg/day), niacin can lower LDL cholesterol, raise HDL cholesterol, and lower triglycerides. However:

  • Adding high-dose niacin (1,500-2,000 mg extended-release) to statin therapy did not reduce cardiovascular events despite improving lipid profiles in a large trial that was stopped early after 32 months, with a small increase in ischemic stroke noted [24].
  • A 4-year study using 2,000 mg of extended-release niacin plus laropiprant in patients already taking statins showed no benefit and was associated with increased diabetes control disturbances (3.7 percentage points higher), increased infections, new-onset diabetes, GI and musculoskeletal problems, bleeding, and skin problems [25].
  • Approximately 0.67% of patients treated with very high-dose niacin develop niacin maculopathy, impairing vision [75].

High-dose niacin is NOT recommended for use alongside statins or red yeast rice (which contains natural statin compounds) based on clinical trial data.

Neuropathy and Nerve Health

Vitamin B12 deficiency neuropathy: B12 deficiency can cause subacute combined degeneration of the spinal cord — progressive degeneration of nerve fibers controlling movement and sensation [76][77]. A 53-year-old vegetarian woman developed reduced mobility, abnormal gait, and recurrent falls. MRI showed deterioration of the myelin sheath in the spinal cord. After treatment with 1,000 mcg of B12 every other day for 2 weeks, she improved and was able to move independently indoors [77]. Lower B12 levels may also cause muscle cramps: a 65-year-old woman with nighttime calf and thigh spasms and low B12 (212 pmol/L) had complete resolution four weeks after starting 1,000 mcg daily, which increased her levels to 625 pmol/L [78].

Vitamin B6 deficiency neuropathy: A 76-year-old man lost the ability to walk after developing nerve pain and weakness due to B6 deficiency (3.5 ng/mL). Three weeks after supplementation with 60 mg of pyridoxal phosphate daily, symptoms improved significantly and he regained the ability to walk, with blood levels rising from 3.5 to 39.3 ng/mL [79]. Metformin-induced B6 deficiency has caused muscle cramps that resolved with B6 replacement [80].

Diabetic neuropathy (B12): A study of 90 diabetic patients on metformin with neuropathy and low B12 found that 1,000 mcg of methylcobalamin for one year modestly improved nerve function and reduced pain compared to placebo. A higher dose of 2,000 mcg was not more effective and was associated with a significant decline in kidney function [81][82].

Warning — high-dose B6 causes neuropathy: Paradoxically, excessive pyridoxine can cause the same nerve damage that B6 deficiency produces. Severe effects are generally seen at doses over 1,000 mg/day, but rare cases have occurred at 200 mg/day and even as low as 6 mg/day from a supplement [83][84][85]. The European Food Safety Authority suggests a UL of just 12 mg/day for adults [86]. In some cases, nerve damage from excessive B6 does not fully reverse after stopping supplementation [83][87].

Neural Tube Defects and Pregnancy

Adequate folate intake before and during early pregnancy reduces the risk of neural tube defects (NTDs) including spina bifida. Mandatory folic acid fortification of grain products in the US since 1998 has reduced NTD prevalence by approximately 25-50% [88][89].

  • All women capable of becoming pregnant should consume 600 mcg DFE from approximately 400 mcg of folic acid from supplements or fortified foods in addition to dietary folate [40].
  • Folic acid supplementation around the time of conception was associated with 39% lower risk of autism spectrum disorder and 45% lower risk of severe language delay in offspring in a Norwegian study [90]. A study in Israel found folic acid/multivitamin use before pregnancy was associated with 61% lower ASD risk, and 73% lower risk when used during pregnancy [91].
  • Women on antiepileptic drugs are more likely to have children showing autistic traits, but this risk is lower if they take folic acid around the time of conception [92].

Caution against excessive folate in pregnancy: Taking 1,000 mcg or more of folic acid daily during the periconception period was associated with lower cognitive development scores in children at 4-5 years of age compared to moderate doses (400-999 mcg) in a Spanish study [93]. Taking 800 mcg or more starting at least one month before pregnancy was associated with 32% higher risk of gestational hypertension in a Chinese study [94]. Excessively high blood folate levels (>59 nmol/L) in pregnant women were associated with approximately twofold increased risk of autism spectrum disorder, and when combined with excessive B12 levels, the risk was 17.6 times greater [95].

Skin Cancer Prevention (Niacin)

High-dose nicotinamide (500 mg twice daily) for 12 months reduced the risk of non-melanoma skin cancer by 23% in older adults with a history of these lesions in a placebo-controlled Australian study. Benefits were evident within 3 months but disappeared 6 months after stopping — it only helped while being taken [96]. A longer 10-year retrospective study of 33,822 people suggested 500 mg twice daily for 30 days or longer reduced new non-melanoma skin cancer risk by 56% after first diagnosis, with smaller reductions (30% and 9%) among those with histories of 3 or 5 skin cancer lesions. Nicotinamide did not reduce risk among solid organ transplant recipients [97]. A review of over 13,000 older adults found no increased risk of adverse cardiovascular events among nicotinamide users [98].

Getting at least the RDA for niacin from diet and/or supplements may help: adults with highest dietary niacin intake (~37 mg/day) had 49% lower risk of cancer-related death compared to lowest intake (~10 mg/day) over 15 years [99]. Women with average daily intakes of 20.5 mg or higher were about 20% less likely to develop squamous cell cancer over 16 years [100].

Parkinson's Disease (Niacin)

Preliminary research suggests niacin may reduce neuroinflammation in Parkinson's disease. A placebo-controlled study of 46 people found 100 mg daily improved quality of life [101]. A follow-up showed slight improvement with 250 mg slow-release niacin daily for one year, including improvements in handwriting, stance, mood, and fatigue — though the study lacked a placebo control, and oddly, the 100 mg dose seemed more effective in the 3-month preliminary comparison [102]. Very high-dose niacin (500 mg twice daily) in one patient improved rigidity but caused severe nightmares and skin rash [103]. A longer, placebo-controlled study using 100 mg of niacin or niacinamide twice daily was underway [104].

Parkinson's Disease and Vitamin B12/B6

People with Parkinson's tend to have lower B12 levels, linked with increased progression, cognitive impairment, and neuropathy risk [105]. High-dose levodopa (>2 g/day) can deplete B12 and B6 over years. New-onset epilepsy due to levodopa-associated B6 deficiency has been reported [106]. Taking 10-25 mg of B6 may reduce levodopa effectiveness, but this is prevented by carbidopa — people taking Sinemet (carbidopa/levodopa) can safely receive B6 [107].

Acne and Pantothenic Acid

A controlled study in 41 young adults (average age 28) found that 1.1 g of pantothenic acid (Pantothen) twice daily with food for 12 weeks reduced total facial acne lesions by 68.21% compared to placebo [108]. However, the American Academy of Dermatology stated in 2024 guidelines that there is insufficient evidence to recommend pantothenic acid for acne treatment [109].

Rheumatoid Arthritis (Pantothenic Acid)

A 1980 study of 94 people with arthritis found that escalating doses of calcium pantothenate (up to 2,000 mg daily) for 2 months reduced morning stiffness, disability, and pain among those with rheumatoid arthritis but not osteoarthritis or other arthritic conditions [110]. No subsequent studies appear to have replicated this finding.

Migraine Prevention (Riboflavin)

Several studies suggest very high-dose riboflavin (400 mg/day) may help reduce migraine frequency [111]. This dose far exceeds the RDA of 1.1-1.3 mg but riboflavin has no established UL and appears to be non-toxic at high doses.

Hearing Loss

Lower levels of both folate and B12 have been linked with hearing loss among older women. In a study of 55 healthy women, those with impaired hearing had 31% lower folate levels and 38% lower B12 levels than those with normal hearing [112]. Low B12 has also been linked with tinnitus, but supplementing with 500 mcg daily for one month did not improve tinnitus severity compared to placebo [113].

Glaucoma (Nicotinamide)

Small, short-term studies suggest that high-dose nicotinamide (1,000-3,000 mg/day) along with standard IOP-lowering therapy may modestly improve inner retinal function in glaucoma, though no decrease in IOP was found [114][115]. However, there have been at least two reports of liver injury in trials, and the American Glaucoma Society and American Academy of Ophthalmology advise against supplementation in people with liver disease and recommend against high-dose use (>3,000 mg/day) outside of clinical trials [116].

Brittle Nails and Hair (Biotin)

A controlled study in women with brittle nails found that 2,500 mcg of biotin daily for 6-9 months increased nail thickness by 25% and reduced splitting [117]. A study in 38 young adults showed 2,500 mcg daily for 28 days slightly increased nail growth rate by 13% (though without placebo control) [118]. However, biotin does not further strengthen healthy nails. There are no studies to suggest biotin improves hair growth or texture in people who are not deficient [119].

Multiple Sclerosis (Biotin)

A study of 154 people with progressive MS found that 100 mg of biotin three times daily for 12 months reversed MS-related disability in 13% compared to none on placebo [120]. However, a larger study of 642 people with progressive MS using the same dose found no benefit [121]. Based on this, biotin should not be recommended for progressive MS treatment.

Fibromyalgia (Thiamine)

Suggestive but uncontrolled evidence: three people with fibromyalgia experienced abrupt improvements in symptoms (widespread pain, fatigue, depression, anxiety, trouble concentrating) when taking high-dose oral thiamine (600-1,800 mg/day) [122]. One observational study showed people with fibromyalgia had lower blood levels of thiamine [123]. No clinical trials have confirmed this.

POTS (Thiamine)

A small study found that 6% of people with postural tachycardia syndrome (POTS) were mildly deficient in thiamine, and supplementing with 100 mg daily appeared to significantly improve all symptoms in one of four such patients within two weeks [124].

Fertility (Folate and Zinc)

While several small studies suggested that combined folic acid and zinc supplementation could improve sperm count and quality, a large US study found that high-dose folic acid (5 mg) and zinc (30 mg) taken daily for six months did not improve sperm count, quality, or live birth rates among men seeking fertility treatment [125].

Muscle Cramps (B-Complex)

A study in Taiwan among 28 older adults with hypertension and nighttime cramps found that 86% of those taking a B-complex (B12 250 mcg, B6 30 mg, riboflavin 5 mg, and thiamine derivative 50 mg, three times daily) for 3 months had significant reduction in nighttime cramps, while there was no reduction with placebo. Blood levels of these vitamins were not measured, so it is unclear if any had deficiencies [78].

Vitamin Adult RDA/AI Pregnancy Lactation
B1 (Thiamine) 1.1-1.2 mg 1.4 mg 1.4 mg
B2 (Riboflavin) 1.1-1.3 mg 1.4 mg 1.6 mg
B3 (Niacin) 14-16 mg 18 mg 17 mg
B5 (Pantothenic acid)* 5 mg 6 mg 7 mg
B6 (Pyridoxine) 1.3-1.7 mg 1.9 mg 2.0 mg
B7 (Biotin)* 30 mcg 30 mcg 35 mcg
B9 (Folate) 400 mcg DFE 600 mcg DFE 500 mcg DFE
B12 (Cobalamin) 2.4 mcg 2.6 mcg 2.8 mcg

*AI value (RDA not established)

Tolerable Upper Intake Levels (ULs)

Vitamin UL (Adults 19+) Notes
B1 (Thiamine) None established Appears non-toxic
B2 (Riboflavin) None established Excess causes yellow urine (harmless)
B3 (Niacin) 35 mg Applies to supplements/fortified foods only. Based on flushing risk
B5 (Pantothenic acid) None established
B6 (Pyridoxine) 100 mg (US); 12 mg (EFSA) Nerve damage possible at much lower doses in susceptible individuals
B7 (Biotin) None established High doses interfere with lab tests
B9 (Folate) 1,000 mcg Applies to synthetic forms only. Can mask B12 deficiency
B12 (Cobalamin) None established Very safe for most; associations with increased cancer risk at high blood levels

Dosing by Condition

Thiamine deficiency/heart failure: 100 mg twice daily to counter effects of diuretics [126].

Benfotiamine for diabetic neuropathy: 200 mg/day (50 mg four times daily) for 3 weeks minimum [19].

Riboflavin for migraine prevention: 400 mg/day [111].

Riboflavin for MTHFR-related hypertension: 1.6-10 mg/day [14][71].

Niacin for cholesterol (under medical supervision only): 1,000-4,000 mg/day. Liver function monitoring required. NOT recommended alongside statins based on clinical trial data [24][25].

Nicotinamide for skin cancer prevention (in those with history): 500 mg twice daily [96][97].

Pyridoxine for morning sickness: 30 mg/day [127].

Pyridoxine to counter levodopa-related B6 depletion: 25 mg/day under physician supervision (only with carbidopa/levodopa, not levodopa alone) [107].

Folic acid for women of childbearing age: 400 mcg/day from supplements or fortified foods in addition to dietary folate [40].

Folic acid for stroke prevention in low-folate populations: 800 mcg/day [68].

Methylfolate as antidepressant adjunct: 15 mg/day (prescription medical food; under physician supervision) [63].

B12 for deficiency correction: Oral: 1,000-2,000 mcg daily. A 3-month study found 50 mcg of sublingual B12 daily was sufficient to restore adequate levels in vegans with marginal deficiency; 2,000 mcg weekly was no better [128]. High-dose oral B12 (1,000 mcg/day) appears as effective as injections for most patients, including those with pernicious anemia [129][130]. One study of 26 adults with pernicious anemia showed 1,000 mcg oral cyanocobalamin daily corrected deficiency in 89% within one month and 100% within 12 months [130].

B12 maintenance for vegans/vegetarians: 50 mcg daily or 2,000 mcg weekly [128]. Stopping supplementation for more than a few weeks can result in notable decline in blood levels [131].

Label Reading Notes

Be aware that Daily Value (DV) percentages on supplement labels changed in 2016 and labels were not required to reflect this until 2020-2021. Products with older labels may show higher DVs. The change of most concern relates to folate, as older labels can mislead people into taking far more than recommended [1]. Remember that 1,000 mcg = 1 mg, and 1,000 mg = 1 gram.

Dietary Sources

Thiamine (B1) — DV: 1.2 mg

Food Amount B1 Content
Black beans, raw 1 cup 1.75 mg
Peas, raw 1 cup 1.4 mg
Canned tomatoes 1 cup 1.38 mg
Pork loin, broiled 3 oz 0.75 mg
Hazelnuts, chopped 1 cup 0.74 mg
Sunflower seeds, toasted 1 cup 0.44 mg

Coffee and tea contain anti-thiamin factors (caffeic acid, chlorogenic acid, tannic acid) that can break down thiamin, though this is generally not an issue for people getting adequate dietary thiamin [132]. Coffee has not been shown to affect other B vitamins [133].

Riboflavin (B2) — DV: 1.3 mg

Food Amount B2 Content
Almonds 1 cup 1.63 mg
Feta cheese, crumbled 1 cup 1.63 mg
Yeast extract spread 1 tsp 1.05 mg
Beef plate steak, grilled 3 oz 0.72 mg
Red sockeye salmon 1 fillet 0.59 mg
Yogurt, vanilla, non-fat 1 cup 0.49 mg

Niacin (B3) — DV: 16 mg

Food Amount B3 Content
Turkey, roasted 1 breast 101.4 mg
Peanuts, roasted 1 cup 21.95 mg
Tuna, cooked 3 oz 18.76 mg
Brown rice flour 1 cup 10.02 mg
Sockeye salmon, cooked 3 oz 8.60 mg
Peaches, dried slices 1 cup 7.00 mg

Pantothenic Acid (B5) — DV: 5 mg

Food Amount B5 Content
Turkey, roasted 1 breast 11.13 mg
Sunflower seeds, dry roasted 1 cup 9.37 mg
Shiitake mushrooms, cooked 1 cup 5.21 mg
Avocado, puréed 1 cup 3.36 mg
Hardboiled egg, chopped 1 cup 1.90 mg

Vitamin B6 — DV: 1.7 mg

Food Amount B6 Content
Turkey, roasted 1 breast 7.16 mg
Pistachio nuts 1 cup 2.09 mg
Canned chickpeas 1 cup 1.14 mg
Sunflower seeds, dry roasted 1 cup 1.03 mg
Ground turkey, pan broiled 3 oz 0.92 mg
Banana 1 medium 0.4 mg

Biotin (B7) — DV: 30 mcg

Food Amount B7 Content
Whole egg 1 egg 10 mcg
Peanuts, roasted 1 oz 4.91 mcg
Pork chop, cooked 1 chop 3.57 mcg
Sunflower seeds, roasted 1.2 oz 2.42 mcg
Fresh strawberries 4 oz 1.67 mcg

Folate (B9) — DV: 400 mcg DFE

Naturally-occurring folate:

Food Amount Folate Content
Mung beans, raw 1 cup 1,294 mcg
Chickpeas, raw 1 cup 1,114 mcg
Lentils, raw 1 cup 920 mcg
Peanuts, raw 1 cup 359 mcg
Spinach, boiled/drained 1 cup 263 mcg
Green peas, raw 1 cup 94.2 mcg

Soaking dry beans for 12 hours can more than double folate content; boiling for 20 minutes reduces it by 64-82% due to heat and leaching [134]. Less than 1% of Americans are now deficient in folate since mandatory fortification began in 1998, though up to 80% of people with Crohn's disease may have low levels [40][135].

Folic acid (added to foods):

Food Amount Folic Acid / DFE
Kellogg's Special K 1 cup 394 mcg / 676 mcg DFE
General Mills Cheerios 1 cup 195 mcg / 336 mcg DFE
Enriched white rice, cooked 1 cup 87 mcg / 153 mcg DFE

Vitamin B12 — DV: 2.4 mcg

Food Amount B12 Content
Clams, cooked 3 oz 84.06 mcg
Beef liver, cooked 1 slice 67.34 mcg
Salmon, sockeye, cooked 1 fillet 19.55 mcg
Tuna, cooked 3 oz 9.25 mcg
Beef, top loin 1 fillet 4.82 mcg
Yogurt, vanilla, non-fat 1 cup 1.30 mcg

Plant-based foods are generally not adequate sources of B12 unless fortified. The Academy of Nutrition and Dietetics states that non-fortified nutritional yeast, tempeh, nori, spirulina, and chlorella are not adequate or practical B12 sources [136]. Fortified nutritional yeast can provide substantial B12: a 5-gram portion of fortified nutritional yeast provides 7.5 mcg of B12 (310% DV) along with significant amounts of riboflavin, niacin, and B6 [137].

Safety and Side Effects

Thiamine (B1)

No UL established. Appears to be non-toxic at all studied doses. Deficiency can occur in people taking loop diuretics for congestive heart failure (where deficiency itself can worsen heart function), those who abuse alcohol, individuals with inflammatory bowel disease (where it can rarely lead to Wernicke's encephalopathy), and approximately 2-3 months after bariatric surgery in adolescents who do not maintain supplementation [126][138][139]. Deficiency can be fatal — Wernicke's encephalopathy can develop after as few as 3-4 weeks of water-only fasting or severe dietary restriction [140]. Thiamine deficiency can also occur due to aspirin use, which increases urinary excretion [141].

Riboflavin (B2)

No UL established. Excess causes harmless bright yellow urine. May affect urinary dipstick tests. Deficiency is extremely rare in the US due to food fortification, but can occur in people with thyroid disease, women taking birth control pills, and those on vegan diets [142]. Severe deficiency can impair metabolism of other B vitamins and, if prolonged, can cause anemia and cataracts [1]. A case of severe riboflavin deficiency causing life-threatening hypoglycemia and lactic acidosis was reported in a one-day-old infant whose mother maintained a strict vegan diet without riboflavin supplementation [143].

Niacin (B3)

Flushing: The most common side effect, occurring at doses above the UL (35 mg). Involves reddening, burning, tingling, itching, and pain. Starting with lower doses and gradually increasing may help, as may taking with food [1]. Rarely, severe reactions including diffuse rash, hives, lip swelling, and difficulty breathing have occurred [144].

Liver toxicity: At doses at or above 1,500 mg of niacin or 3,000 mg of nicotinamide per day, liver toxicity can occur. Extended-release forms may be more hepatotoxic — a case of fatal acute liver failure occurred when a 74-year-old woman was switched from immediate-release to extended-release niacin at the same dose (500 mg three times daily) [32]. Another case: a 24-year-old woman taking 2-3 g daily for two months, with up to 5 g on several days, developed liver failure requiring ICU treatment for a week [145]. Elevated liver enzymes may occur without symptoms in up to 20% of people taking >500 mg/day [146].

Glucose control: High-dose niacin can impair glucose control and elevate blood glucose levels [1].

Gout: High-dose niacin (typically 2,000 mg+) is associated with increased uric acid and gout risk. Experts recommend monitoring uric acid while increasing to maintenance dose, then every 6 months [147].

Fainting: Taking 500 mg of immediate-release niacin after an abrupt dose increase from 100 mg has caused syncope with urinary incontinence [148].

Vision: Approximately 0.67% of patients treated with very high-dose niacin develop niacin maculopathy. One case: 3,000-6,000 mg daily for several months caused severe macular edema and blurry vision, which resolved completely within two months of stopping [75].

Blood counts: Progressive declines in platelet counts (10-20%), red and white blood cells have been reported with long-term high-dose extended-release niacin (average 2,250 mg/day for a year+) [149].

Pantothenic Acid (B5)

No UL established. Deficiency is rare and found mainly in alcoholics. Very high doses (900 mg/day) of the related pantothenate have been used for cholesterol and triglyceride management [150].

Vitamin B6

UL: 100 mg (US), 12 mg (EFSA).

The most important safety concern among B vitamins. Excessive pyridoxine causes the same nerve damage as B6 deficiency. Severe effects generally occur at >1,000 mg/day but documented cases exist at much lower doses:

  • A woman consuming energy drinks with 40 mg B6/serving plus a B-complex had no symptom improvement one year after stopping [83].
  • A 54-year-old man experienced progressive numbness and neuropathy over several years of taking up to 30 mg/day plus high B6 energy drinks [84].
  • A 73-year-old man taking a multivitamin with just 6 mg B6 for 10 years developed peripheral neuropathy (blood B6: 260 nmol/L; normal: 2-125) [85].
  • A 71-year-old man developed burning feet after just a few weeks of a multivitamin with 6 mg B6 (blood B6: 923 nmol/L; normal: 35-110). Symptoms improved but did not fully resolve after stopping [151].
  • A 40-year-old man taking 95 mg/day developed severe muscle twitching that progressed over 8 months to his legs, arms, trunk, neck, and face — completely resolving 4 months after stopping [87].
  • Joint pain and cognitive deficits from high B6 levels attributed to consuming large quantities of nuts daily [152].

P-5-P (pyridoxal-5-phosphate) may be safer than pyridoxine at higher doses based on in-vitro data, as pyridoxine itself appears to inhibit the active P-5-P form [34].

Cancer risk: Men supplementing with >20 mg B6 daily for 10 years had 82% greater lung cancer risk (even greater among smokers). No increased risk in women [10]. Higher B6 intake was associated with 97% greater rectal cancer risk in one study of older women [153]. B6 intake >8.6 mg/day was associated with lower survival in nasopharyngeal carcinoma patients receiving radiation [154].

Hip fracture risk: 40 mg B6 daily for 1-3 years was associated with 42% increased hip fracture risk in older adults with cardiovascular disease [155]. Postmenopausal nurses taking >35 mg B6 had 29% increased hip fracture risk, increasing to 47% when combined with high B12 (>30 mcg) [156].

Biotin (B7)

No UL established but high doses create serious practical problems.

Laboratory test interference is the primary safety concern. The FDA has warned that doses of 5,000-10,000 mcg (5-10 mg) can cause falsely low or high results in troponin, thyroid hormones, cortisol, testosterone, PSA, vitamin D, hCG, insulin, ferritin, B12, and tests for HIV, hepatitis B, and hepatitis C [36][37][38]. The FDA received a report of a patient who died following falsely low troponin results [36]. Doses as low as 300 mcg have caused misleading thyroid results in some patients [157].

Migraine: One case report linked 10,000 mcg/day with progressive increase in migraine frequency and severity, improving within one week of stopping [158].

Folate (B9)

UL: 1,000 mcg from synthetic forms (supplements and fortified foods).

Masking B12 deficiency: Folic acid can correct the anemia of B12 deficiency while allowing neurological damage to progress [43][59]. A potential benefit of L-5-methylfolate forms over folic acid is that they may not mask B12 deficiency [43].

Cancer concerns: Folic acid at 1,000 mcg DFE/day from supplements was associated with more than doubling of prostate cancer risk (dietary folate was not associated) [159]. In people with a history of colorectal adenomas, 1,000 mcg folic acid for 3+ years appeared to increase precancerous growths [160]. However, the largest study (86,320 women, 36 years) found no increased colorectal cancer risk even at highest intakes (~1,430 mcg DFE), with long-term higher folate actually associated with slightly lower risk after 12-16 years [161].

Peripheral neuropathy risk: Even with normal B12, high folate intake (>800 mcg DFE) dramatically increases neuropathy risk in people with a TCN2 gene variant (found in ~25% of older Americans), with seven-fold higher odds [162].

Kidney damage: Prolonged excessive folic acid intake can cause kidney damage [1].

Allergic reactions: Rare but serious anaphylactic reactions to synthetic folic acid have been reported (15 cases of anaphylaxis and 16 serious non-anaphylactic reactions in Canada, 2008-2013). The reaction does not appear to occur with naturally-occurring dietary folate but may be more common in people allergic to antifolate drugs such as methotrexate [163].

Vitamin B12

No UL established. Generally very safe, but important associations at high levels:

Cancer associations: 500 mcg B12 plus 400 mcg folic acid daily for 2-3 years in people 65+ was associated with 77% higher colorectal cancer risk (3.4% vs 2%) and 25% higher overall cancer rates [164]. Use of B12 supplements before/during chemotherapy was associated with 83-104% higher risk of poorer survival [165].

Mortality associations: Middle-aged men with blood B12 >455 pg/mL had 85% higher death risk over 8 years vs. <339 pg/mL [166]. In type 2 diabetes, B12 levels 506-703 pg/mL: 79% higher cardiovascular death risk; ≥703.5 pg/mL: 132% higher risk, vs. 369-506 pg/mL. Those with the lowest levels (<369 pg/mL) also had 74% higher risk — suggesting moderate levels may be optimal [167].

Acne: B12 at 20 mcg/day or more (or 1,000 mcg injection) has caused acne outbreaks, primarily on face, upper back, chest, and shoulders, typically 1 week to 5 months after starting. The mechanism involves oversupply of B12 causing skin bacteria (P. acnes) to overproduce inflammatory proteins. Acne resolved within 3-6 weeks of stopping in reported cases [168][169].

Insomnia: Cases associated with high B12 blood levels have been reported. A study among 418 Chinese adults with type 2 diabetes found those with B12 >517.5 pg/mL were ~61% more likely to experience insomnia [170].

Allergic reactions: Approximately 2.7% of the population may be allergic to cobalt (a component of all B12 forms). Systemic allergic dermatitis has been reported with oral cyanocobalamin. Rarely, anaphylactic reactions to injections occur — many with anaphylaxis to one form can tolerate the other. One reported case of anaphylaxis was actually due to an excipient (polyethylene glycol/Macrogol 400), not to B12 itself [171][172].

Drug Interactions

Drugs That Deplete B Vitamins

Drug B Vitamin Affected Clinical Implications
Proton pump inhibitors (PPIs) B12 Long-term use reduces stomach acid needed for B12 absorption from food. 38-59% of PPI users may be B12 deficient depending on specific PPI. People taking PPIs daily for >3 years should be monitored [173][174].
Metformin B12, B6 Estimated 30% of long-term users develop B12 deficiency. Metformin may cause increased B12 uptake by gut bacteria, leaving less to absorb. Monitor B12 every 2-3 years even without symptoms [175][176].
Loop diuretics (furosemide) B1 Thiamine deficiency can adversely affect heart function in CHF patients [126].
Anticonvulsants (phenytoin, carbamazepine) B6, B9 Enzyme-inducing AEDs can cause B6 deficiency. Also reduce folate levels [177][178].
High-dose aspirin (3,900 mg/day) B9 May increase folate excretion. Low-dose aspirin does not have this effect [141].
Levodopa (high-dose, >2 g/day) B6, B12 B6 depleted during dopamine conversion. B12 may also decline [107].
Cycloserine (Seromycin) B6 Increases B6 requirements [179].
Isoniazid B3, B6 Interferes with tryptophan-to-niacin conversion and depletes B6 [1].
Birth control pills B2 May inhibit riboflavin absorption [142].
Nitrous oxide (N2O) B12, B9 Inactivates B12 and interferes with folate metabolism. Even a single dental exposure can inactivate B12 for several days. AAPD guidelines advise against N2O use in children with untreated B12 deficiency [180].
Penicillamine (Cuprimine) B6 Increases B6 requirements [179].

B Vitamins That Affect Drug Efficacy

B Vitamin Drug Interaction
B6 (10-25 mg) Levodopa (without carbidopa) Reduces effectiveness by increasing peripheral dopamine conversion. Not an issue with Sinemet (carbidopa/levodopa) [107].
B6 (200 mg) Phenytoin (Dilantin) May reduce anticonvulsant effectiveness [181].
B6 Antihypertensives (diltiazem, amlodipine) Preliminary evidence suggests B6 could increase antihypertensive effects [107].
B9 (folic acid) Methotrexate May partially counteract methotrexate's antifolate activity (intentional in some protocols). Cross-reactivity allergies possible [163].
High-dose niacin Warfarin Case of INR >12.3 (from 2.4) when extended-release niacin increased from 500 to 1,000 mg/day. High-dose/extended-release niacin should be used with caution alongside anticoagulants [149].
High-dose biotin (>5 mg) Laboratory tests Interferes with biotin-based immunoassays. Stop 8+ hours before testing (3+ days for very high doses) [36][37][38].

Are You Getting the Right B Vitamins?

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References

    1. ConsumerLab. "B Vitamins Review." Accessed 2025. https://www.consumerlab.com/reviews/review-best-b-vitamins-and-complexes-energy-b6-b12-biotin-niacin-folic-acid/bvitamins/

    2. Kennedy DO. "B Vitamins and the Brain: Mechanisms, Dose and Efficacy — A Review." *Nutrients*. 2016;8(2):68. doi: 10.3390/nu8020068

    3. NIH Office of Dietary Supplements. "Vitamin B6 — Health Professional Fact Sheet." https://ods.od.nih.gov/factsheets/VitaminB6-HealthProfessional/

    4. Kennedy DO. "B Vitamins and the Brain: Mechanisms, Dose and Efficacy." *Nutrients*. 2016;8(2):68. doi: 10.3390/nu8020068

    5. Weisshof R, Chermesh I. "Micronutrient deficiencies in inflammatory bowel disease." *Curr Opin Clin Nutr Metab Care*. 2015;18(6):576-581. doi: 10.1097/MCO.0000000000000226

    6. Bell DS. "Metformin-induced vitamin B12 deficiency presenting as a peripheral neuropathy." *South Med J*. 2010;103(3):265-267. doi: 10.1097/SMJ.0b013e3181ce0e4d

    7. American Heart Association. "Homocysteine, Folic Acid and Cardiovascular Disease." *Circulation*. 2006.

    8. Lukaski HC. "Vitamin and mineral status: effects on physical performance." *Nutrition*. 2004;20(7-8):632-644. doi: 10.1016/j.nut.2004.04.001

    9. Selin JZ, et al. "High-dose supplements of vitamins C and E, low-dose multivitamins, and the risk of age-related cataract." *Br J Nutr*. 2017;118(6):445-452.

    10. Brasky TM, et al. "Long-Term, Supplemental, One-Carbon Metabolism-Related Vitamin B Use in Relation to Lung Cancer Risk." *J Clin Oncol*. 2017;35(30):3440-3448. doi: 10.1200/JCO.2017.72.7735

    11. NIH Genetic and Rare Disease Information Center. "MTHFR gene variant." Accessed 2025.

    12. Liew SC, Gupta ED. "Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism." *Eur J Med Genet*. 2015;58(1):1-10. doi: 10.1016/j.ejmg.2014.10.004

    13. Zittan E, et al. "MTHFR C677T and vitamin B-12." *Am J Physiol Heart Circ Physiol*. 2007.

    14. Hughes CF, et al. "Riboflavin and blood pressure in MTHFR 677TT genotype." *Proc Nutr Soc*. 2018.

    15. Prinz-Langenohl R, et al. "Methylfolate increases plasma folate more effectively than folic acid in women with MTHFR polymorphism." *Br J Pharmacol*. 2009;158(8):2014-2021. doi: 10.1111/j.1476-5381.2009.00492.x

    16. Moll S, Varga EA. "Homocysteine and MTHFR mutations." *Circulation*. 2015;132(1):e6-e9. Friedman G, et al. *J Nutr*. 1999.

    17. Bitsch R, et al. "Bioavailability of benfotiamine." *Ann Nutr Metab*. 1991;35(5):292-296.

    18. Xie F, et al. "Pharmacokinetics of benfotiamine." *J Clin Pharmacol*. 2014.

    19. Haupt E, et al. "Benfotiamine in diabetic polyneuropathy." *Int J Clin Pharmacol Ther*. 2005;43(2):71-77.

    20. Alkhalaf A, et al. "Benfotiamine in diabetic nephropathy." *Diabetes Care*. 2010;33(7):1598-1601.

    21. Lonsdale D. "A review of the biochemistry, metabolism and clinical benefits of thiamine derivatives." *Med Sci Monit*. 2004;10(4):RA258-267. PMID: 16617192

    22. Danserau R, et al. "Riboflavin absorption." *Int J Pharmaceut*. 1997.

    23. Zempleni J, et al. "Pharmacokinetics of orally administered riboflavin." *Am J Clin Nutr*. 1996;63(1):54-66.

    24. Boden WE, et al. "Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy." *N Engl J Med*. 2011;365(24):2255-2267. doi: 10.1056/NEJMoa1107579

    25. Landray MJ, et al. "Effects of extended-release niacin with laropiprant." *N Engl J Med*. 2014;371(3):203-212. doi: 10.1056/NEJMoa1300955

    26. UK Food Standards Agency Expert Group on Vitamins and Minerals. Safety review of nicotinamide.

    27. Sunderland GT, et al. "Hexopal in primary Raynaud's disease." *Clin Rheumatol*. 1988;7(1):46-49.

    28. Conze D, et al. "Safety of long-term NIAGEN administration." *Sci Rep*. 2019;9(1):9772. doi: 10.1038/s41598-019-46120-z

    29. Martens CR, et al. "Chronic nicotinamide riboside supplementation elevates NAD+ in healthy older adults." *Nat Commun*. 2018;9(1):1286. doi: 10.1038/s41467-018-03421-7

    30. Dollerup OL, et al. "Nicotinamide riboside does not alter insulin sensitivity in overweight men." *Am J Clin Nutr*. 2018.

    31. Poljsak B, et al. "Cancer etiology and NAD+ raising compounds." *J Clin Exp Oncol*. 2016.

    32. Leung K, et al. "Fatal hepatotoxicity from extended-release niacin." *Hepatol Commun*. 2018.

    33. European Food Safety Authority. "Opinion on pyridoxal 5'-phosphate." 2008.

    34. Vrolijk MF, et al. "The vitamin B6 paradox: high-dose pyridoxine decreases vitamin B6 function." *Tox in Vitro*. 2017;44:206-212. doi: 10.1016/j.tiv.2017.07.009

    35. CDC. NHANES data on vitamin B6 status.

    36. FDA. "Biotin May Interfere with Lab Tests." 2017, updated 2022. https://www.fda.gov/medical-devices/safety-communications/fda-warns-biotin-may-interfere-lab-tests

    37. Biscolla RP, et al. "Effect of a single 10 mg dose of biotin on thyroid function tests." *Thyroid*. 2017;27(11):1446-1449.

    38. AACC. "Guidance Document on Biotin Interference in Laboratory Tests." 2022.

    39. Stieglitz HM, et al. "Biotin interference with hormone immunoassays." *J Endocr Soc*. 2018.

    40. Institute of Medicine (US). Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. National Academies Press; 1998.

    41. CDC. Folate deficiency rates after mandatory fortification.

    42. Henderson AM, et al. "L-5-Methyltetrahydrofolate is more effective than folic acid at increasing serum folate." *J Nutr*. 2018;148(5):698-705.

    43. Morris MS, et al. "Folate and vitamin B-12 status in relation to cognitive impairment in older Americans." *Am J Clin Nutr*. 2007;85(1):193-200.

    44. Willems FF, et al. "Pharmacokinetic study on the utilisation of 5-methyltetrahydrofolate vs folic acid." *Br J Pharmacol*. 2004;141(5):825-830.

    45. Bayes J, et al. "Comparing effectiveness of folinic acid, folic acid and methylfolate." *Adv Integ Med*. 2019.

    46. Spence JD. "Metabolic vitamin B12 deficiency." *Clin Chem Lab Med*. 2013.

    47. Obeid R, et al. "Cobalamin coenzyme forms are not likely superior to cyano- and hydroxyl-cobalamin." *Mol Nutr Food Res*. 2015;59(7):1364-1372. doi: 10.1002/mnfr.201500019

    48. Zugravu C, et al. "Vitamin B-12 status among Romanian vegans." *Exp Ther Med*. 2021;21(3):234. doi: 10.3892/etm.2021.9665

    49. Greibe E, et al. "Cyanocobalamin vs hydroxocobalamin." *Eur J Nutr*. 2017.

    50. Institute of Medicine (US) Food and Nutrition Board. DRIs for B12. 1998. Abels J, et al. *J Intern Med*. 1959.

    51. Smith AD, Refsum H. "Homocysteine, B Vitamins, and Cognitive Impairment." *Annu Rev Nutr*. 2016;36:211-239. doi: 10.1146/annurev-nutr-071715-050947

    52. Chen H, et al. "Folic acid supplementation mitigates Alzheimer's disease." *Mediators Inflamm*. 2016.

    53. Kimoto S, et al. "Psychiatric symptoms and cognitive impairment due to B-12 deficiency." *Prim Care Companion CNS Disord*. 2020.

    54. Wong S, et al. "Reversible dementia due to B-12 deficiency." *BMJ Case Rep*. 2022.

    55. Sahoo S, et al. "Psychotic episodes linked with B-12 deficiency." *Cureus*. 2024.

    56. Feldman ML, et al. "B-12 deficiency misdiagnosed as MS." *BMJ Case Rep*. 2019.

    57. Silva R, et al. "B-12 deficiency misdiagnosed as progressive dementia." *BMJ Case Rep*. 2019.

    58. Ueno A, et al. "Correcting B-12 deficiency and cognitive improvement." *Nutrients*. 2022.

    59. Bailey RL, et al. "High folic acid with low B-12 and cognition." *Am J Clin Nutr*. 2022.

    60. Ling J, et al. "Folate/folic acid supplementation and dementia risk in UK Biobank." *J Gerontol A Biol Sci Med Sci*. 2023.

    61. Liu D, et al. "Folic acid in cerebral small vessel disease." *J Prev Alzheimers Dis*. 2025.

    62. Phelan MJ, et al. "Nicotinamide for mild to moderate Alzheimer's disease." *J Geriatr Med Gerontol*. 2017. Green KN, et al. *J Neurosci*. 2008.

    63. Papakostas GI, et al. "L-methylfolate as adjunctive therapy for SSRI-resistant major depression." *Am J Psychiatry*. 2012;169(12):1267-1274. doi: 10.1176/appi.ajp.2012.11071114

    64. Shelton RC, et al. "Adjunctive L-methylfolate for major depressive disorder." *Prim Care Companion CNS Disord*. 2013.

    65. Robinson D. "L-methylfolate and agitation in depression." *Psychiatr Times*. 2020.

    66. Stough C, et al. "High dose vitamin B-complex and work stress." *Hum Psychopharmacol*. 2011;26(7):470-476.

    67. Hvas AM, et al. "B6 level and depression symptoms." *Psychother Psychosom*. 2004;73(6):340-343.

    68. Huo Y, et al. "Folic acid and stroke prevention in hypertension." *JAMA*. 2015;313(13):1325-1335. doi: 10.1001/jama.2015.2274

    69. House AA, et al. "B-vitamin therapy and diabetic nephropathy." *JAMA*. 2010;303(16):1603-1609. doi: 10.1001/jama.2010.490

    70. Hazen SL, et al. "Niacin metabolite 4PY and cardiovascular risk." *Nat Med*. 2024. doi: 10.1038/s41591-023-02793-8

    71. Wilson CP, et al. "Riboflavin for MTHFR 677TT hypertension." *Am J Clin Nutr*. 2012;95(3):766-772.

    72. Zhang K, et al. "Dietary niacin and hypertension." *JAMA Netw Open*. 2021.

    73. Canner PL, et al. "Niacin and metabolic syndrome." *Am J Cardiol*. 2006.

    74. Lawson JA, et al. "Niacin and blood pressure." *J Hum Hypertens*. 2000.

    75. Lee J, et al. "Niacin maculopathy." *J Vitreoretin Dis*. 2019.

    76. Pourshams A, et al. "SCD due to B-12 deficiency." *Cureus*. 2024.

    77. Saeed M, et al. "SCD of spinal cord from B-12 deficiency in vegetarian." *Cureus*. 2024.

    78. Chan P, et al. "B complex for nighttime leg cramps." *J Clin Pharmacol*. 1998. Anang J, et al. "B-12 for nighttime muscle spasms." *Neurology*. 2021.

    79. Yasuda H, et al. "Recovery of walking ability after B-6 supplementation." *Am J Med*. 2022.

    80. Zhou Q, et al. "Metformin-related B-6 deficiency and muscle cramps." *Am J Med Sci*. 2020.

    81. Didangelos T, et al. "B-12 supplementation in diabetic neuropathy." *Nutrients*. 2021.

    82. Mansour A, et al. "B-12 dose comparison for neuropathy." *J Nutr*. 2026.

    83. Bacharach R, et al. "Pyridoxine toxicity from energy drinks." *J Clin Neuromuscul Dis*. 2017.

    84. Malek N, et al. "Pyridoxine neuropathy." *Acta Neurol Belg*. 2018.

    85. Paluszny J, et al. "B-6 toxicity from 6 mg daily multivitamin." *Cureus*. 2023.

    86. European Food Safety Authority. "B-6 tolerable upper intake level." 2023.

    87. Krishnana J, et al. "B-6 related muscle twitching." *Med J Aust*. 2023.

    88. CDC. Neural tube defect surveillance data.

    89. Williams J, et al. "NTDs prevented by mandatory folic acid fortification." *MMWR*. 2015.

    90. Suren P, et al. "Maternal folic acid and autism spectrum disorder risk." *JAMA*. 2013;309(6):570-577. doi: 10.1001/jama.2012.155925

    91. Levine SZ, et al. "Folic acid/multivitamin and autism risk in Israel." *JAMA Psychiatry*. 2018.

    92. Bjork M, et al. "Folic acid and autistic traits in children of mothers on AEDs." *JAMA Neurol*. 2017.

    93. Valera-Gran D, et al. "High-dose folic acid and child neuropsychological development." *Am J Clin Nutr*. 2017;106(4):1011-1019.

    94. Li Z, et al. "Folic acid and gestational hypertension." *Hypertension*. 2020.

    95. Raghavan R, et al. "Maternal folate/B-12 levels and autism risk." International Meeting for Autism Research. 2016.

    96. Chen AC, et al. "Nicotinamide for skin-cancer chemoprevention." *N Engl J Med*. 2015;373(17):1618-1626. doi: 10.1056/NEJMoa1506197

    97. Breglio AT, et al. "Oral nicotinamide and skin cancer risk." *JAMA Dermatol*. 2025.

    98. Wheless L, et al. "Nicotinamide and cardiovascular events." *JAMA Derm*. 2025.

    99. Ying H, et al. "Dietary niacin and cancer-related death." *BMC Cancer*. 2022.

    100. Park SM, et al. "Niacin intake and skin cancer." *Int J Cancer*. 2017.

    101. Wakade C, et al. "Niacin and Parkinson's disease quality of life." *J Neuroimmunol*. 2018.

    102. Chong R, et al. "Niacin enhancement for Parkinson's disease." *Front Aging Neurosci*. 2021.

    103. Alisky JM. "High-dose niacin and Parkinson's." *Nutr Neurosci*. 2005.

    104. ClinicalTrials.gov. NCT number for niacin/niacinamide in Parkinson's. 2021.

    105. McCarter SJ, et al. "Low B12 and Parkinson disease progression." *Mayo Clin Proc*. 2019.

    106. Modica C, et al. "Levodopa-associated B-6 depletion and epilepsy." *Neurology*. 2020.

    107. Canissario R, et al. "B-6 and B-12 for levodopa-associated neuropathy." *J Neurol Sci*. 2021.

    108. Yang M, et al. "Pantothenic acid for facial acne." *Dermatol Ther (Heidelb)*. 2014;4(1):93-101. doi: 10.1007/s13555-014-0052-3

    109. Reynolds RV, et al. "AAD guidelines for acne management." *J Am Acad Dermatol*. 2024.

    110. "Calcium pantothenate in arthritic conditions." *Practitioner*. 1980;224:208-211.

    111. Thompson DF, Saluja HS. "Prophylaxis of migraine with riboflavin." *J Clin Pharm Ther*. 2017;42(4):394-403.

    112. Houston DK, et al. "Hearing loss, B-12, and folate in elderly women." *Am J Clin Nutr*. 1999;69(3):564-571.

    113. Dadgarnia MH, et al. "B-12 and tinnitus." *Am J Otolaryngol*. 2023.

    114. Hui F, et al. "Nicotinamide and inner retinal function in glaucoma." *Clin Exp Ophthalmol*. 2020.

    115. De Moraes CG, et al. "Nicotinamide and pyruvate for glaucoma." *JAMA Ophthalmol*. 2022.

    116. Shukla R, et al. "AGS/AAO guidelines on nicotinamide for glaucoma." *Ophthalmol Glaucoma*. 2025.

    117. Colombo VE, et al. "Biotin for brittle fingernails." *J Am Acad Dermatol*. 1990;23(6):1127-1132.

    118. Garbers L, et al. "Biotin and nail growth rate." *Exp Dermatol*. 2021.

    119. Trueb RM. "Biotin deficiency in women with hair loss." *Int J Trichology*. 2016;8(2):73-77.

    120. Tourbah A, et al. "High-dose biotin for progressive MS." *Mult Scler*. 2016.

    121. Cree BAC, et al. "High-dose biotin in progressive MS: negative results." *Lancet Neurol*. 2020.

    122. Costantini A, et al. "High-dose thiamine for fibromyalgia." *BMJ Case Rep*. 2013. doi: 10.1136/bcr-2013-009019

    123. Joustra ML, et al. "Vitamin status in chronic fatigue and fibromyalgia." *PLoS One*. 2017.

    124. Blitshteyn S. "POTS and thiamine deficiency." *Neurol Res*. 2017.

    125. Schisterman EF, et al. "Folic acid and zinc for semen quality." *JAMA*. 2019;323(1):35-48. doi: 10.1001/jama.2019.18714

    126. Oudman E, et al. "Thiamine deficiency in IBD." *Nutrition*. 2021.

    127. Institute of Medicine. DRIs for B6. Morning sickness dosing recommendation.

    128. Del Bo C, et al. "Restoring B-12 in vegans: 50 mcg daily vs 2,000 mcg weekly." *Clin Nutr*. 2019.

    129. Sanz-Cuesta T, et al. "Oral vs intramuscular B-12." *BMJ Open*. 2020.

    130. Lacombe V, et al. "Oral cyanocobalamin for pernicious anemia." *Am J Clin Nutr*. 2024.

    131. Storz MA, et al. "B-12 decline after stopping supplementation in a vegan." *Nutrition*. 2024.

    132. Marrs C, Lonsdale D. "Modern thiamine deficiency." *Cells*. 2021;10(10):2595. doi: 10.3390/cells10102595

    133. Ulvik A, et al. *Clin Chem*. 2008. Urgert R, et al. *Am J Clin Nutr*. 2000.

    134. Liang J, et al. "Soaking and boiling effects on legume folate." *J Food Compos Anal*. 2022.

    135. Weisshof R, et al. "Folate deficiency in Crohn's disease." *Curr Opin Clin Nutr Metab Care*. 2015.

    136. Melina V, et al. "Position of the Academy of Nutrition and Dietetics: Vegetarian Diets." *J Acad Nutr Diet*. 2016;116(12):1970-1980. doi: 10.1016/j.jand.2016.09.025

    137. USDA FoodData Central. Nutritional yeast data. 2004.

    138. Vig S, et al. "Thiamine deficiency after bariatric surgery in adolescents." *Eur J Paediatr Neurol*. 2024.

    139. Aweer R, et al. "Wernicke's encephalopathy following water-only fasting." *Clin Case Rep*. 2025.

    140. Hutcheaon ML, et al. "Thiamine depletion during fasting." *Nutr Clin Pract*. 2014.

    141. Renaud B, et al. "Aspirin and thiamine/folate excretion." *Nutrients*. 2024.

    142. Mahabadi N, et al. "Riboflavin deficiency." *StatPearls*. 2022.

    143. Jaeger B, et al. "Severe riboflavin deficiency in neonate from vegan mother." *Neonatology*. 2022.

    144. Wong AW, et al. "Niacin-triggered severe skin reaction." *Ann Allergy Asthma Immunol*. 2021.

    145. Duffy M, et al. "Liver failure from high-dose niacin." *Cureus*. 2024.

    146. Harb JN, et al. "Acute hepatitis from niacin in energy drinks." *BMJ Case Rep*. 2016.

    147. Stone NJ, et al. "Monitoring uric acid during niacin therapy." *J Am Coll Cardiol*. 2014.

    148. Huang E, et al. "Syncope from high-dose niacin." *Cureus*. 2023.

    149. O'Connell J, et al. "Thrombocytopenia from high-dose niacin." *Am J Hematol*. 2016. Christopher M, et al. "Niacin-warfarin INR interaction." *Ann Pharmacother*. 2011.

    150. ConsumerLab. Pantothenic acid for cholesterol. B Vitamins Review. 2025.

    151. O'Sullivan P, et al. "B-6 neuropathy from 6 mg multivitamin." *AJGP*. 2025.

    152. Koscinska-Shukla B, et al. "B-6 toxicity from dietary nuts." *Rheumatol Int*. 2025.

    153. Harnack LJ, et al. "B-6 and rectal cancer." *Nutr Cancer*. 2009.

    154. Li J, et al. "B-6 intake and nasopharyngeal carcinoma outcomes." *Clin J Nutr*. 2020.

    155. Lopez MG, et al. "B-6 and hip fracture risk." *J Bone Miner Res*. 2017.

    156. Meyer HE, et al. "B-6 and B-12 intake and hip fracture in nurses." *JAMA Netw Open*. 2019.

    157. Charles K, et al. "Biotin interference at low doses." *Nutrition*. 2019.

    158. Sanosi N, et al. "High-dose biotin and migraine." *Int Med Case Rep J*. 2025.

    159. Figueiredo JC, et al. "Folic acid and prostate cancer risk." *J Natl Cancer Inst*. 2009;101(6):432-435. doi: 10.1093/jnci/djp019

    160. Passarelli MN, et al. "Folic acid and colorectal adenoma recurrence." *Am J Clin Nutr*. 2019.

    161. Wang Y, et al. "Long-term folate and colorectal cancer." *Am J Clin Nutr*. 2021.

    162. Sawaengsri H, et al. "Folate and TCN2 variant neuropathy risk." *Am J Clin Nutr*. 2016.

    163. Kerr SM, et al. "Anaphylaxis to folic acid." *Allergy Asthma Clin Immunol*. 2014. Harper CE, et al. BSACI Abstracts. 2023. Lis K, et al. *Curr Issues Mol Biol*. 2025.

    164. Araghi SO, et al. "B-12 and folic acid and cancer risk." *Cancer Epidemiol Biomarkers Prev*. 2018.

    165. Ambrosone CB, et al. "Supplement use during chemotherapy and survival." *J Clin Oncol*. 2020;38(8):804-814. doi: 10.1200/JCO.19.01204

    166. Flores-Guerrero JL, et al. "B-12 and mortality." *JAMA Netw Open*. 2020.

    167. Liu X, et al. "B-12 and cardiovascular death in type 2 diabetes." *JAMA Netw Open*. 2022.

    168. Kang D, et al. "B12 modulates skin microbiota in acne." *Sci Transl Med*. 2015;7(293):293ra103. doi: 10.1126/scitranslmed.aab2009

    169. Veraldi S, et al. "Acne from B-12 supplementation." *J Cosmet Dermatol*. 2017.

    170. Xiong L, et al. "B-12 and insomnia in type 2 diabetes." *Nutr Diabetes*. 2022.

    171. El Rhermoul FZ, et al. "Allergic reactions to vitamin B-12." *J Allergy Clin Immunol Pract*. 2023.

    172. Ullah A, et al. "Anaphylaxis to B-12 injection." *Cureus*. 2018.

    173. Lam JR, et al. "PPI/H2 blocker use and B-12 deficiency." *JAMA*. 2013;310(22):2435-2442. doi: 10.1001/jama.2013.280490

    174. Nafea OE, et al. "B-12 deficiency by PPI type." *Cureus*. 2026.

    175. Aroda VR, et al. "Long-term metformin and B-12 deficiency." *J Clin Endocrinol Metab*. 2016;101(4):1754-1761. doi: 10.1210/jc.2015-3754

    176. Yao B, et al. "Metformin and B-12 via gut microbiota." *Commun Biol*. 2023.

    177. Mintzer S, et al. "AEDs and B-6 deficiency." *Epilepsy Behav*. 2012.

    178. Porter KM, et al. "AEDs and B vitamin status." *J Clin Endocrinol Metab*. 2019.

    179. Merck Manual. "Drug-nutrient interactions." 2018.

    180. Lacassie HJ, et al. "Nitrous oxide and B-12 inactivation." *Br J Anaesth*. 2006.

    181. Hansson O, Sillanpaa M. "Pyridoxine and phenytoin." *Lancet*. 1976.

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About Dr. Brad Stanfield

Dr Brad Stanfield

Dr. Brad Stanfield is a General Practitioner in Auckland, New Zealand, with a strong emphasis on preventative care and patient education. Dr. Stanfield is involved in clinical research, having co-authored several papers, and is a Fellow of the Royal New Zealand College of General Practitioners. He also runs a YouTube channel with over 319,000 subscribers, where he shares the latest clinical guidelines and research to promote long-term health. Keep reading...

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