Vitamin B2 (Riboflavin)

1. Introduction

Riboflavin, also known as Vitamin B2, is a water-soluble vitamin essential for human health. It is a member of the B-vitamin complex and plays a crucial role in cellular energy production and numerous metabolic processes. Riboflavin is the precursor for two major coenzymes: Flavin Adenine Dinucleotide (FAD) and Flavin Mononucleotide (FMN) [1, 2].

Chemical and Biological Basics

Riboflavin is a yellow-orange compound composed of a ribityl side chain and a tricyclic isoalloxazine ring. It is the functional component of the flavoenzymes, FAD and FMN. These coenzymes act as electron carriers, participating in a wide range of oxidation-reduction (redox) reactions [1].

Mechanism of Action

The primary mechanism of action for Riboflavin is through its coenzyme forms, FAD and FMN.

• Energy Production: FAD is a critical component of the electron transport chain, which is central to generating cellular energy (ATP) [1]. It is required for the metabolism of carbohydrates, lipids, and proteins.
• Redox Reactions: FAD and FMN are prosthetic groups for numerous flavoenzymes, which catalyze redox reactions in various metabolic pathways.
• Antioxidant Function: Riboflavin is vital for the regeneration of the antioxidant glutathione. The FAD-dependent enzyme, glutathione reductase, uses FAD to regenerate reduced glutathione, which protects the body from reactive oxygen species [1, 2].
• Nutrient Interaction: Riboflavin is necessary for the proper metabolism of other B vitamins, including the conversion of Vitamin B6 to its active form (pyridoxal 5′-phosphate) and the synthesis of Niacin (Vitamin B3) from tryptophan [1]. It also plays a key role in folate metabolism, as FAD is a required cofactor for methylenetetrahydrofolate reductase (MTHFR) [1].

2. Chemical Composition/Key Bioactive Roles

The primary bioactive forms of Vitamin B2 are the flavin coenzymes, which are integral to the function of numerous flavoenzymes.

Active Compound	Chemical Formula	Key Bioactive Role
Riboflavin (Vitamin B2)	C₁₇H₂₀N₄O₆	Precursor to FAD and FMN
Flavin Mononucleotide (FMN)	C₁₇H₂₁N₄O₉P	Coenzyme for oxidoreductases (e.g., in the electron transport chain)
Flavin Adenine Dinucleotide (FAD)	C₂₇H₃₃N₉O₁₅P₂	Coenzyme for a wide variety of redox enzymes, crucial for energy metabolism

3. Health Benefits

Riboflavin supplementation has been investigated for its role in preventing and treating several conditions, primarily due to its central role in energy metabolism and the MTHFR enzyme system.

Migraine Headaches

High-dose riboflavin has shown efficacy as a prophylactic treatment for migraines, particularly in adults.

• Evidence: A randomized controlled trial found that high-dose riboflavin (400 mg/day) for three months reduced attack frequency and the number of headache days compared to placebo [1].
• Mechanism: The benefit is hypothesized to be related to riboflavin’s role as a precursor to FAD and FMN, which are required for the flavoproteins of the mitochondrial electron transport chain. Impaired mitochondrial oxygen metabolism in the brain may play a role in the pathology of migraines [1].

Cataracts

Riboflavin’s antioxidant properties are linked to a potential protective effect against age-related cataracts.

• Evidence: Several observational studies suggest an inverse association between riboflavin intake and the risk of age-related cataracts. For example, a cross-sectional study of nearly 3,000 men and women found that those in the highest quintile of riboflavin intake were 50% less likely to have cataracts than those in the lowest quintile [1].
• Mechanism: The lens of the eye is continuously exposed to light and oxidative stress. Riboflavin’s role in regenerating the antioxidant glutathione may help protect the lens proteins from oxidative damage [1].

Cardiovascular Disease and Homocysteine

Riboflavin, as a cofactor for MTHFR, is indirectly involved in regulating homocysteine levels, a risk factor for cardiovascular disease.

• Evidence: In individuals with a specific genetic polymorphism in the MTHFR gene (the C677T genotype), low riboflavin status is associated with elevated plasma homocysteine. Supplementation with riboflavin (1.6 mg/day) has been shown to significantly lower homocysteine concentrations specifically in individuals with this genetic variant [1, 3].
• Mechanism: The MTHFR enzyme, which requires FAD, is key to the metabolism of folate and the conversion of homocysteine to methionine. Adequate riboflavin status ensures optimal MTHFR activity, thereby helping to maintain healthy homocysteine levels [1].

4. Dosage and Usage

Recommended Dietary Allowance (RDA)

The RDA for riboflavin varies by age and sex:

• Adult Men (19+ years): 1.3 mg/day [4]
• Adult Women (19+ years): 1.1 mg/day [4]
• Pregnancy: 1.4 mg/day [4]
• Lactation: 1.6 mg/day [4]

Therapeutic Dosage

For specific conditions, much higher doses are used:

• Migraine Prophylaxis: The most common therapeutic dose used in clinical trials is 400 mg/day [1].

Food Sources

Riboflavin is widely available in the diet. Good sources include:

• Dairy products (milk, cheese)
• Meat (liver, lean meats)
• Eggs
• Fortified cereals and breads
• Green vegetables (broccoli, spinach) [4]

5. Safety and Precautions

Riboflavin is considered very safe, as it is a water-soluble vitamin and excess amounts are readily excreted in the urine.

Safety and Side Effects

• Toxicity: No Tolerable Upper Intake Level (UL) has been established for riboflavin due to the lack of evidence of toxicity from high intakes in humans [1, 4].
• Side Effects: Riboflavin is generally well-tolerated, even at high doses (e.g., 400 mg/day). The most common, harmless side effect is a bright yellow-orange discoloration of the urine, known as riboflavinuria [1].

Drug Interactions

Riboflavin can interact with certain medications:

• Tricyclic Antidepressants (TCAs): TCAs (e.g., imipramine, amitriptyline) may inhibit the absorption of riboflavin [1].
• Antipsychotics: Some phenothiazine-based antipsychotics (e.g., chlorpromazine) can interfere with the metabolism of riboflavin, potentially leading to a deficiency [1].
• Antimalarials: Quinacrine, an antimalarial drug, can interfere with riboflavin’s function [1].

Contraindications and Warnings

• General Warning: Individuals with a known hypersensitivity or allergy to riboflavin should avoid supplementation.
• Serious Safety Warning: While riboflavin is safe, it is crucial to note that the high therapeutic dose of 400 mg/day for migraines should only be taken under the guidance of a healthcare professional.

6. References

[1] Linus Pauling Institute. Riboflavin. Oregon State University. Available at: https://lpi.oregonstate.edu/mic/vitamins/riboflavin

[2] Peechakara BV, Gupta V. Vitamin B2 (Riboflavin). StatPearls Publishing; 2024. Available at: https://www.ncbi.nlm.nih.gov/books/NBK525977/

[3] McNulty H, Dowey L, Strain JJ, et al. Riboflavin lowers plasma homocysteine in individuals homozygous for the MTHFR C677T polymorphism. Circulation. 2006;113(15):1825-1830. Available at: https://www.ahajournals.org/doi/full/10.1161/CIRCULATIONAHA.105.580212

[4] Harvard T.H. Chan School of Public Health. Riboflavin (Vitamin B2). The Nutrition Source. Available at: https://nutritionsource.hsph.harvard.edu/riboflavin-vitamin-b2/