1. Introduction

Riboflavin (vitamin B2) is an essential water-soluble vitamin that helps prevent various medical conditions, such as sepsis, ischemia, and some cancers [1]. Riboflavin’s biological effects, including antioxidant, anti-aging, anti-inflammatory, and anti-nociceptive effects, have been extensively studied. The pathophysiology of migraines is linked to oxidative stress with mitochondrial dysfunction [2,3,4], and neuroinflammation by the glial cell network [5]. Riboflavin might help improve migraines through various mechanisms, including oxidative stress and neuroinflammation reduction [6].

Riboflavin is heat stable, and cooking does not lower riboflavin levels; however, exposure to light can destroy it. Riboflavin is found in a variety of food sources. Milk products are a rich source, and green vegetables, such as broccoli, collard greens, and turnips, are moderate sources of riboflavin. Surprisingly, 10–15% of the world’s population is genetically restricted in riboflavin absorption and utilization, and there is a potential for biochemical riboflavin deficiency worldwide [7]. Riboflavin deficiency across European countries ranges from 7–20% [8]. Metabolic triggers of migraines, such as fasting and skipping meals, directly link with energy homeostasis and may be associated with riboflavin deficiency. However, there is no evidence that riboflavin deficiency causes or aggravates migraine headaches.

Why is riboflavin administered to migraineurs i.e., patients with migraines? Patients with mitochondrial encephalomyopathy suffer from migraine-like headaches that are relieved by riboflavin; thus, prophylactic riboflavin administration has been attempted [9]. Riboflavin prophylaxis is recommended in adult guidelines [10,11] and has been shown to be somewhat effective in children [12,13]. A migraine is a common yet highly disruptive disease [14]. A rigorous trial on the effectiveness of pharmacological interventions for preventing migraines in children and adolescents found amitriptyline and topiramate to be ineffective [15]. Such results may have led many clinicians to use nutritional supplements with fewer side effects, such as riboflavin, as an optional treatment before using drugs [13,16]. Riboflavin continues to be used for migraine prophylaxis; however, the underlying mechanism of action is still unclear.

In order to better understand the relationship between migraines and riboflavin, this review focuses on the antioxidant and anti-inflammatory properties of riboflavin and mitochondrial damage. In addition, we summarize the current clinical evidence for riboflavin’s efficacy on migraines.

2. Oxidative Stress in Migraines

Studies have indicated the involvement of oxidative stress in migraine pathogenesis and investigated various oxidative stress markers [20,21,22,23]. This review summarizes some of the representative oxidative stress markers and the antioxidant properties of riboflavin ( Table 1 ).

A study of patients with migraines without aura showed decreased levels of total antioxidants (TAS), increased levels of total oxidants (TOS), and the oxidative stress index (OSI) compared with controls [23].

Summary of oxidative stress markers in migraineurs.

Dramatic metabolic changes in the cerebral cortex associated with intracellular calcium overload during CSD could induce transient oxidative stress [41,42]. CSD causes oxidative stress in the cerebral cortex, meninges, and even in the trigeminal ganglion, which is not directly exposed to the trigger substance [43]. Additionally, it suggests a direct stimulatory effect of reactive oxygen species (ROS) on nociceptor firing via transient receptor potential ankyrin subtype 1 (TRPA1 ) ion channels and an indirect role for ROS in sensitizing sensory afferents via the release of a major migraine mediator calcitonin gene-related peptide (CGRP) from nociceptor neurons [43]. TRPA1 ion channels enable CGRP release from dural afferents, and mediate the behavioral picture of neurogenic inflammation and migraines in animal models [44]. TRPA1 undergoes oxidative stress and initiates a neuroinflammatory response in migraines. In other words, TRPA1 might be a bridge between oxidative stress and neuroinflammation in migraines [44].

3. Mitochondrial Dysfunction

Mitochondria play an important role in a wide range of cellular functions, such as energy generation, ROS production, Ca 2+ homeostasis regulation, and apoptosis [71]. Mitochondrial disease symptoms occur in almost all organs, but primarily in high energy-consuming organs, such as the brain and muscles [71].

Interestingly, the seemingly unrelated migraine triggers, such as ovarian hormone changes, weather changes, alcohol, strong smells, strong light, and loud noises, have a potential common denominator in the form of changes in the mitochondrial metabolism and oxidative stress [78,79]. Disturbances in mitochondrial metabolism might contribute to the pathogenesis of migraines by lowering the threshold for migraine attack propagation [80,81]. Furthermore, mitochondrial genome analysis demonstrated that polymorphisms account for a significant portion of the genetic factors involved in migraine etiology [82], and clinical evidence of the link between migraine and mitochondrial dysfunction is slowly accumulating [2,75,76,83,84].

This current research showed that common migraine triggers have the ability to generate oxidative stress through mitochondrial dysfunction, calcium excitotoxicity, microglia and NADPH oxidase activation, and as a byproduct of monoamine oxidase (MAO), cytochrome P450, or NO synthase [78]. In particular, mitochondria are key to the primary mechanism of intracellular Ca 2+ sequestration; therefore, mitochondrial dysfunction can lead to pain hypersensitivity [85]. Vasoconstriction during CSD is also triggered by an increase in Ca 2+ concentrations in the astrocytes through a process mediated by phospholipase A2, a metabolite of arachidonic acid [86]. Mitochondria play a crucial role in the normal functioning of neurons, and a Ca 2+ imbalance can lead to an imbalance in various downstream processes, and thus further increase susceptibility to migraines [3].

The migraine model demonstrated abnormalities in the mitochondrial biogenesis capacity of trigeminal neurons, with reduced copy numbers of mitochondrial DNA and altered mRNA levels of the peroxisome proliferator-activated receptor-γ coactivator 1-α [87], which are essential regulators of mitochondrial biogenesis [23]. These experimental findings indicate that mitochondrial dysfunction is an important hallmark of migraines.

4. Clinical Evidence of Riboflavin Efficacy

Seven studies (including three RCTs) in adults have evaluated the role of riboflavin in preventing adult migraines ( Table 2 ). The dose of riboflavin was 400 mg, except in one case (100 mg) [11]. All studies demonstrated the effectiveness of riboflavin [9,11,96,97,98,99,100].

Summary of studies on riboflavin for pediatric migraines.

RCT, randomized controlled trial; MIDAS, Migraine Disability Assessment; N/A, not available. The asterisk (*) indicates a study with a negative result.

Summary of studies on riboflavin for adult migraine.

RCT, randomized controlled trial; N/A, not available.

Although no serious side effects have been reported to date, and there is a widespread perception that riboflavin has no side effects, some adverse effects have been reported. Studies utilizing high doses of riboflavin reported orange discoloration of the urine, polyuria, diarrhea, vomiting, and an increased appetite without weight gain [9,89,93,95]; studies using low doses did not report any adverse effects [91,94].

This entry is adapted from the peer-reviewed paper 10.3390/nu13082612