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Riboflavin

Evidence Fact Sheet

Vitamin B2

Riboflavin (vitamin B2) is the precursor of the FAD/FMN flavocoenzymes that drive mitochondrial energy metabolism, glutathione regeneration and MTHFR-dependent homocysteine handling. Human evidence is strongest for migraine prophylaxis and MTHFR 677TT homocysteine lowering; blood-pressure and redox effects are uncertain/null.

Also known as: Vitamin B2 · Riboflavin 5'-phosphate (FMN) · Lactoflavin · E101

Overview

Riboflavin (vitamin B2) is a water-soluble vitamin and the metabolic precursor of the flavocoenzymes FMN and FAD, which serve as electron-carrier cofactors for the mitochondrial electron-transport chain (Complex I/II), glutathione reductase (regenerating reduced glutathione), the MTHFR enzyme in homocysteine remethylation, and acyl-CoA dehydrogenases in fatty-acid beta-oxidation. General adult adequacy is met at roughly 1.1-1.6 mg/day; research on migraine prophylaxis has used a far higher educational reference dose of 400 mg/day for about three months, and MTHFR 677TT homocysteine studies have used about 1.6 mg/day. It is a well-established nutrient: FDA GRAS by regulation (21 CFR 184.1695), an EFSA-permitted vitamin carrying nine authorized Article 13.1 health claims (the most of any B-vitamin), and permitted under ANVISA and Chinese GB fortification standards. It is water-soluble with no established tolerable upper limit; excess is excreted in urine.

Mechanism of Action

FAD/FMN cofactor for electron transport chain Complex I/II (ATP production) · Glutathione reductase cofactor regenerating reduced glutathione (GSH) · MTHFR flavin cofactor in homocysteine remethylation · Fatty-acid beta-oxidation cofactor (acyl-CoA dehydrogenase family) · Iron-metabolism cofactor (ferritin iron mobilization + erythrocyte maturation)

Body systems: Mitochondrial & Cellular Energy · Neurological & Cognitive · Skin & Connective Tissue · Vision · Blood & Hematopoiesis · Cellular Renewal

Evidence-Based Benefits

Each benefit below is anchored to a specific PubMed-indexed study. Effect sizes, sample sizes, and p-values are reported as published; no values are inferred. Honest negatives and null results are kept alongside the positive findings, and disease-research populations are described as such — Riboflavin is not characterized as a treatment for any disease.

Migraine Prophylaxis

Meta-analysis supported
  • 8 RCT + 1 CCT9 articles pooled
  • 673 subjectstotal participants
  • p = .001attack frequency

In a systematic review and meta-analysis pooling eight randomized controlled trials and one controlled clinical trial (673 subjects), riboflavin (vitamin B2) 400 mg/day for three months was associated with statistically significant reductions in migraine days, attack duration, frequency, and pain score. The abstract reports p-values and heterogeneity (I-squared) but no pooled mean differences or confidence intervals, and heterogeneity was high for several outcomes.

Reported effect: Eight randomized controlled trials and one controlled clinical trial with 673 subjects; migraine days (p = .005, I2 = 89%), duration (p = .003, I2 = 0), frequency (p = .001, I2 = 65%), pain score (p = .015, I2 = 84%)

“Nine articles...Eight randomized controlled trials and one controlled clinical trial with 673 subjects. Vitamin B2 400 mg/day for three months supplementation had significant effect on days, duration, frequency, and pain score of migraine attacks.”

Source: PMID 33779525 · Chen 2022 · Nutr Neurosci

Homocysteine Lowering (MTHFR 677TT Genotype)

RCT supported
  • −22%tHcy · TT group · P=0.003
  • n=32TT genotype analyzed

In a placebo-controlled RCT of adults preselected by MTHFR 677C->T genotype, riboflavin 1.6 mg/day for 12 weeks lowered plasma homocysteine specifically in the homozygous TT group (by as much as 22%), with no response in the CC or CT groups. The effect was most marked (40%) in TT individuals with lower baseline riboflavin status, supporting a gene-nutrient interaction rather than a general homocysteine-lowering effect.

Reported effect: Homocysteine responded only in the TT group, with levels decreasing by as much as 22% overall (from 16.1+/-1.5 to 12.5+/-0.8 micromol/L; P=0.003; n=32); markedly so (by 40%) in those with lower riboflavin status at baseline (P=0.010; n=16); no homocysteine response in the CC or CT groups

“homocysteine responded only in the TT group, with levels decreasing by as much as 22% overall (from 16.1+/-1.5 to 12.5+/-0.8 micromol/L; P=0.003; n=32) ... markedly so (by 40%) in those with lower riboflavin status at baseline ... No homocysteine response was observed in the CC or CT groups despite being preselected for suboptimal riboflavin status.”

Source: PMID 16380544 · McNulty 2006 · Circulation

Blood Pressure

Null / no benefit Meta-analysis supported
  • 4 RCTs374 participants
  • −1.94 mmHgsystolic · P=0.32 · NS
  • −3.03 mmHgdiastolic · P=0.04

A 2025 Cochrane systematic review pooling four RCTs (374 participants) found the evidence very uncertain about riboflavin's effect on blood pressure: the systolic reduction was not statistically significant and the small diastolic reduction came from only two studies, all rated very low-certainty evidence. The authors conclude large, well-conducted trials are needed. This is an honest negative for blood-pressure lowering.

Reported effect: systolic blood pressure MD -1.94 mmHg, 95% CI -5.74 to 1.86 mmHg; P = 0.32; 3 studies, 320 participants; diastolic blood pressure MD -3.03 mmHg, 95% CI -5.97 to -0.09 mmHg; P = 0.04; 2 studies, 271 participants; very low-certainty evidence

“We included four RCTs, which contributed 374 total participants for quantitative synthesis ... The evidence is very uncertain about the effect of riboflavin on systolic blood pressure (MD -1.94 mmHg, 95% CI -5.74 to 1.86 mmHg; P = 0.32; 3 studies, 320 participants; very low-certainty evidence) and diastolic blood pressure (MD -3.03 mmHg, 95% CI -5.97 to -0.09 mmHg; P = 0.04; 2 studies, 271 participants; very low-certainty evidence).”

Source: PMID 41123035 · Bradbury 2025 · Cochrane Database Syst Rev

Systemic Redox / Antioxidant Status

Null / no benefit RCT supported
  • P > 0.05free thiols · no change
  • 50 / 100 mgdaily doses tested

In a post-hoc analysis of the RIBOGUT trial in healthy volunteers, riboflavin 50 or 100 mg daily did not significantly change albumin-adjusted serum free thiols (a marker of systemic redox status) versus placebo. Observed thiol changes were inversely associated with C-reactive protein, but the primary redox endpoint was null. This tempers the idea that supplemental riboflavin broadly raises antioxidant status in already-replete people.

Reported effect: Participants randomized to placebo (n = 34), riboflavin 50 mg daily (n = 32), or riboflavin 100 mg daily (n = 33); albumin-adjusted serum free thiols did not significantly change (P > 0.05); changes inversely associated with C-reactive protein (r = -0.22, P < 0.05)

“Participants were randomized to either placebo (n = 34), riboflavin 50 mg daily (n = 32), or riboflavin 100 mg daily (n = 33). After intervention with either placebo or riboflavin, albumin-adjusted serum free thiols did not significantly change (P > 0.05) ... observed changes were inversely associated with changes in C-reactive protein (CRP) levels (r = -0.22, P < 0.05).”

Source: PMID 35973668 · Bourgonje 2022 · Free Radic Biol Med

Riboflavin Status Biomarkers

Meta-analysis supported
  • 18 studiesup to 14 biomarkers
  • P < 0.00001EGRAc responsive
  • 14 studiesEGRAc validated

A systematic review of 18 supplementation studies reporting up to 14 biomarkers found that the erythrocyte glutathione reductase activation coefficient (EGRAc) and basal glutathione reductase activity reliably tracked changes in riboflavin intake (P < 0.00001), validating EGRAc as the functional status marker. Notably, plasma total homocysteine was NOT an effective biomarker of riboflavin status in the general population, consistent with the genotype-restricted homocysteine effect seen in MTHFR 677TT trials.

Reported effect: Eighteen supplementation studies reporting up to 14 biomarkers; EGRAc (14 studies) and basal glutathione reductase activity (5 studies) were effective biomarkers of altered riboflavin intake (P < 0.00001); plasma total homocysteine was not an effective biomarker of riboflavin status in the general population

“Eighteen supplementation studies reporting up to 14 biomarkers were included. EGRac (14 studies) and basal glutathione reductase activity (5 studies) were effective biomarkers of altered riboflavin intake (P < 0.00001). Plasma total homocysteine was not an effective biomarker of riboflavin status in the general population.”

Source: PMID 19403631 · Hoey 2009 · Am J Clin Nutr

Dosage (research context · not a recommendation)

RDA/AI 1.1-1.6 mg/day (general adult adequacy) · migraine-research dosing 400 mg/day x 3 months (adults · educational reference, exceeds routine supplement levels in CN/BR/EU) · MTHFR 677TT homocysteine research 1.6 mg/day x 12 weeks

Regulatory Status · 4 Markets

US · FDA
GRAS by regulation (21 CFR 184.1695 Riboflavin · 21 CFR 184.1697 Riboflavin 5'-phosphate) · lawful dietary-supplement ingredient · structure/function claims permitted with FDA disclaimer
EU · EFSA
Directive 2002/46/EC Annex I permitted vitamin · Reg 432/2012 — 9 authorized Art.13.1 health claims (most of any B-vitamin)
CN · China
Established nutrient — SAMR-permitted vitamin B2 source (riboflavin / riboflavin 5'-phosphate sodium, FMN-Na) under GB 14880 food-fortifier and GB 2760 standards; usable in health foods and general food fortification (NRV 1.4 mg/day; adult RNI 1.2-1.4 mg/day). Migraine-prophylaxis dosing (400 mg/day) is outside routine supplement scope.
BR · ANVISA
RDC 269/2005 + RDC 243/2018 dietary-supplement framework · IN 28/2018 daily-maximum monitored · riboflavina constituent permitted · no derivative-specific compliance divergence

Authorized Claims

EFSA — “Riboflavin contributes to normal energy-yielding metabolism” (Reg (EU) 432/2012 Annex)

EFSA — “Riboflavin contributes to normal energy-yielding metabolism” (Reg 432/2012)

EFSA — “Riboflavin contributes to the normal functioning of the nervous system” (Reg 432/2012)

EFSA — “Riboflavin contributes to the maintenance of normal mucous membranes” (Reg 432/2012)

EFSA — “Riboflavin contributes to the maintenance of normal red blood cells” (Reg 432/2012)

EFSA — “Riboflavin contributes to the maintenance of normal skin” (Reg 432/2012)

EFSA — “Riboflavin contributes to the maintenance of normal vision” (Reg 432/2012)

EFSA — “Riboflavin contributes to normal metabolism of iron” (Reg 432/2012)

EFSA — “Riboflavin contributes to the protection of cells from oxidative stress” (Reg 432/2012)

EFSA — “Riboflavin contributes to the reduction of tiredness and fatigue” (Reg 432/2012)

Safety

Water-soluble · no established UL (excess excreted in urine) · harmless bright-yellow urine common above ~25-30 mg/dose (absorption saturates ~25-30 mg/meal, split high doses) · light-sensitive (store dark/foil) · avoid during neonatal jaundice blue-light phototherapy (riboflavin photodegrades) · no adequate riboflavin-specific monotherapy data for pregnancy/lactation beyond RDA · consult a healthcare provider before high-dose use

Goals: cognitive-support

Lifestyles: senior-60-plus

References

PubMed-indexed citations anchoring the benefit findings above. Effect sizes are reported as published.

  1. PMID 33779525 · Chen 2022 · Nutr Neurosci — Migraine Prophylaxis
  2. PMID 16380544 · McNulty 2006 · Circulation — Homocysteine Lowering (MTHFR 677TT Genotype)
  3. PMID 41123035 · Bradbury 2025 · Cochrane Database Syst Rev — Blood Pressure
  4. PMID 35973668 · Bourgonje 2022 · Free Radic Biol Med — Systemic Redox / Antioxidant Status
  5. PMID 19403631 · Hoey 2009 · Am J Clin Nutr — Riboflavin Status Biomarkers

Frequently Asked Questions

1. What does the research say about riboflavin and migraine?

The strongest human evidence is a systematic review and meta-analysis of eight RCTs plus one controlled clinical trial (673 subjects) in which riboflavin 400 mg/day for three months was associated with significant reductions in migraine days, duration, frequency (p = .001) and pain score. The abstract reports p-values and high heterogeneity but no pooled mean differences, so the magnitude of benefit is not quantified. Note this 400 mg/day research dose is far above the roughly 1.1-1.6 mg/day general adequacy level.

2. Does riboflavin lower homocysteine for everyone?

No. In a placebo-controlled RCT, riboflavin 1.6 mg/day for 12 weeks lowered homocysteine by as much as 22% (P=0.003) only in people homozygous for the MTHFR 677TT genotype, with no response in the CC or CT genotypes. This is a gene-nutrient interaction, not a general homocysteine-lowering effect, and a separate systematic review found plasma total homocysteine is not an effective biomarker of riboflavin status in the general population.

3. Can riboflavin lower blood pressure?

The evidence is very uncertain. A 2025 Cochrane review of four RCTs (374 participants) found the systolic effect non-significant (MD -1.94 mmHg, P=0.32) and only a small diastolic reduction (MD -3.03 mmHg, P=0.04) from two studies, all rated very low-certainty. The Cochrane authors conclude that large, well-conducted trials are needed before any firm statement can be made.

4. Is riboflavin safe at higher intakes?

Riboflavin is water-soluble with no established tolerable upper limit; excess is excreted in urine, and a harmless bright-yellow urine color is common at higher doses. It is FDA GRAS by regulation and an EFSA-permitted vitamin carrying nine authorized health claims. This page reports research findings only and is not clinical guidance; the 400 mg/day migraine-research dose exceeds routine supplement levels, so consult a healthcare provider before high-dose use.

Last evidence review: 2026-06-13

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