Riboflavin and Blood Pressure: Evidence Remains Uncertain Despite Genetic Promise

Highlights

• Evidence from four randomized controlled trials suggests the effect of riboflavin on blood pressure lowering is very uncertain.
• Mean differences for systolic and diastolic blood pressure were modest and not clinically significant.
• Trials were small, heterogeneous, and at high risk of bias.
• Future well-powered, genotype-specific studies are needed to confirm or refute the potential role of riboflavin in managing hypertension.

Background

Hypertension remains a leading modifiable risk factor for cardiovascular disease (CVD) worldwide, contributing substantially to morbidity and mortality from myocardial infarction, stroke, and heart failure. Despite extensive therapeutic options, blood pressure (BP) control remains suboptimal in many populations. Nutritional interventions have gained attention as potential adjunct strategies for BP management, particularly for individuals whose genetic profiles modulate nutrient metabolism. One such area of interest is riboflavin (vitamin B2), a water-soluble vitamin crucial for several enzymatic reactions in mitochondrial energy metabolism and one-carbon metabolism.

Genetic variation in the methylene tetrahydrofolate reductase (MTHFR) enzyme—specifically the C677T polymorphism—is known to affect vascular function and homocysteine metabolism. Carriers of the TT genotype often exhibit elevated homocysteine levels and endothelial dysfunction, both of which have been linked to elevated BP. Riboflavin acts as a cofactor for MTHFR, and supplementation has been hypothesized to enhance enzymatic activity and restore normal vascular responses in affected individuals. However, the robustness and generalizability of this mechanism remain unclear.

Study Design and Methods

The Cochrane systematic review conducted by Bradbury and colleagues (Cochrane Database Syst Rev. 2025;10(10):CD015464) aimed to synthesize the available evidence on riboflavin supplementation for BP lowering in adults. The researchers searched multiple databases, including the Cochrane Hypertension Specialised Register, MEDLINE, Embase, and clinical trial registries up to October 24, 2024, without restrictions on language or publication status.

Randomized controlled trials (RCTs) were included if they examined oral riboflavin supplementation compared with placebo or no additional treatment in adults. Studies using multivitamin formulations were excluded to isolate the effect of riboflavin alone. Eligible participants could receive standard antihypertensive therapies before and during the trial. The critical outcomes were change in systolic and diastolic BP. Secondary outcomes included antihypertensive medication use, adverse events, and biomarkers of riboflavin status. Risk of bias was assessed using the Cochrane RoB 2 tool, and pooled analyses were performed using fixed-effect meta-analysis models.

Key Findings

Four RCTs met inclusion criteria, involving a total of 374 adults, though sample sizes per outcome varied. Study populations included individuals with both normal and elevated BP, some of whom were identified as carrying the MTHFR C677T TT genotype.

Effects on Systolic Blood Pressure

The meta-analysis found that riboflavin supplementation resulted in a mean difference of -1.94 mmHg in systolic BP (95% confidence interval [CI] -5.74 to 1.86 mmHg; P = 0.32) compared with placebo or no treatment. The evidence was graded as very low-certainty, primarily due to small sample sizes, high risk of bias, and heterogeneity in study populations and intervention doses. This finding suggests minimal to no clinically meaningful effect on systolic BP.

Effects on Diastolic Blood Pressure

For diastolic BP, the pooled effect estimate was -3.03 mmHg (95% CI -5.97 to -0.09 mmHg; P = 0.04) across two RCTs with 271 participants. Although the reduction reached statistical significance, the narrow margin and low-certainty rating caution against drawing firm conclusions. It remains unclear whether the observed effect was clinically relevant or reproducible under more stringent methodological conditions.

Safety Profile and Adverse Events

Only one trial (54 participants) reported data on adverse events. Two events occurred in the riboflavin arm and one in the control arm. Reported symptoms were mild and nonspecific, suggesting that riboflavin supplementation was generally safe and well-tolerated. However, due to the limited dataset, the certainty of the safety evidence was low.

Subgroup and Mechanistic Considerations

Subgroup analyses exploring the impact of the MTHFR C677T genotype were conceptually informative but statistically underpowered. It has been hypothesized that carriers of the TT genotype may respond more favorably to riboflavin due to an enhanced dependency of MTHFR on its flavin adenine dinucleotide (FAD) cofactor. Preliminary observational data support this theory, but it has not been consistently demonstrated in RCTs. The Cochrane review therefore underscores the need for genotype-stratified, adequately powered clinical trials to confirm potential personalized benefits.

Expert Commentary

From a mechanistic standpoint, riboflavin’s role in BP regulation could involve improved vascular nitric oxide bioavailability and reduced homocysteine-mediated endothelial dysfunction. However, the current evidence does not translate these biochemical hypotheses into consistent clinical outcomes. The reviewed trials were constrained by methodological limitations, including inadequate randomization concealment, lack of blinding, short intervention durations, and small participant numbers. Additionally, the included studies varied in riboflavin dose (typically 1.6–10 mg/day) and population characteristics, limiting generalizability.

Clinically, the modest BP reductions observed—if genuine—would be of limited magnitude compared with established pharmacologic therapies. Nevertheless, exploring nutrient–gene interactions remains an exciting frontier in precision nutrition and cardiovascular prevention, particularly given the benign safety profile of B vitamins.

For practicing clinicians, routine use of riboflavin supplementation solely for BP lowering is not supported by high-quality evidence. However, it may remain reasonable as part of comprehensive dietary optimization, especially in individuals with suboptimal dietary intake or confirmed MTHFR polymorphisms pending more definitive evidence.

Conclusion

The current evidence regarding riboflavin supplementation for blood pressure reduction in adults is uncertain and derived from small, methodologically limited RCTs. Although biologically plausible, the intervention does not show consistent or clinically meaningful BP-lowering effects across general or genotype-specific populations. The findings underscore an urgent need for large-scale, well-conducted, genotype-targeted RCTs with longer follow-up and standardized riboflavin dosing to establish clinical relevance.

Until then, riboflavin should not be considered a substitute for established antihypertensive therapies but may warrant further exploration as a low-risk, adjunctive approach within nutrigenomically informed cardiovascular care.

Funding and Registration

Lead author K.E. Bradbury was supported by a Sir Charles Hercus Health Research Fellowship from the Health Research Council (Grant 19/110) and a Senior Heart Foundation fellowship from the Heart Foundation of New Zealand (GR Winn Trust, Grant 3728679). The review protocol was registered in 2023 (DOI: 10.1002/14651858.CD015464).

References

Bradbury KE, Coffey S, Earle N, Ni Mhurchu C, Jull AB. Riboflavin supplements for blood pressure lowering in adults. Cochrane Database Syst Rev. 2025 Oct 22;10(10):CD015464. doi: 10.1002/14651858.CD015464.pub2. PMID: 41123035; PMCID: PMC12541901.