RIBOFLAVIN SUPPLEMENTATION REDUCES THE ONSET AND SEVERITY OF ENCEPHALOMYOPATHY IN

PATIENTS WITH MIGRAINE HEADACHES Brittnee A. Williams

INTRODUCTION A migraine headache is generally experienced as a throbbing sensation felt in

one area of the head, that is usually accompanied by an array of other symptoms affecting the

central nervous system and other muscular tissues. These symptoms, known collectively as

encephalomyopathies, can include muscle weakness or temporary paralysis, visual and

auditory abnormalities, altered consciousness and severe headaches. The physiological

processes associated with the onset of migraine headaches have yet to be completely

understood, however, recent research has suggested the genetic encoding of mitochondria in

brain cells may be partially responsible. An inheritable mutation in certain mitochondria can limit

the ability of the brain cell to generate energy from its normal metabolic processes. Impaired

oxidative metabolism involves disruptions in the TCA cycle therefore the production of energy is

not sufficient enough for normal cellular function. This in turn, can lead to impaired neurological

function that may explain the symptoms that can accompany the migraine. Additionally, as

mitochondrial function is inhibited, increasing levels of pyruvate can be converted to lactate,

accounting for the concurrent accumulation of lactic acid in the body that is seen along with

some combination of these stroke like symptoms in migraine sufferers. There is difficulty in

testing for these mutations, however, because several genes within the mitochondrial DNA are

proportionally responsible for the degree of impairment1 and subsequent abnormal cortical

information processing.

Riboflavin is a precursor for the coenzyme FMN and FAD which are essential in the

oxidation of glucose and the transport of electrons for mitochondrial production of energy.

Although low intakes, or a deficiency of riboflavin does not generally contribute to the

pathogenesis of migraines or headaches 2, high supplementation may be able to enhance

electron transport to improve mitochondrial energy production and mitigate the effects of the

mutation.3 Therefore, the purpose of this paper is to determine whether trials of riboflavin
supplementation have been shown to be effective in the prevention, and reduction in severity of,

headaches in migraine sufferers.

METHODS An initial search of the UNF online library resource database, using OneSearch and

keywords ‘riboflavin’ and ‘migraine’, populated a few articles that were published in the peer

reviewed journals Headache, Cephalalgia, Neurology, and the Journal of Child Neurology.

Through full text access links, the key search terms were repeated to locate relevant articles.

Upon identification of the mitochondrial involvement, this keyword was used to search for

introductory articles, but was generally omitted in locating studies involving riboflavin

supplementation. Study designs considered for the research and purpose of this paper included

one open pilot study4, two randomized control trials5,6, and two placebo-controlled, randomized,

double-blind trials7,8. One additional placebo-controlled, randomized, double-blind trial9 included

a cross-over component, and finally an open trial of supplementation was included that tested

blindly for mitochondrial DNA haplogroups10.

MAIN FINDINGS The evidence prompting trials with riboflavin supplementation were the result of

magnetic resonance spectroscopy testing that revealed low availability of free energy in the

brain and muscle cells of migraineurs. Therefore, an initial pilot study4 was conducted where 49

patients suffering from migraines were openly treated with 400 mg of riboflavin daily for a three

month period, in an effort see if riboflavin could replenish the deficient mitochondrial energy

production. Although 23 of these patients also received 75 mg of aspirin in addition to the

riboflavin, there was still an overall reduction of 68.2% in migraine severity. There were no

other significant differences between the two groups of patients, thus researchers concluded the

efficacy of riboflavin, combined with its lack of apparent side-effects, merited a proper placebo

controlled study whose successful results5 were published four years later.

In a separate, trial6 researchers took 26 migraine patients and supplemented 11 of them

with cardio selective beta-blockers and the other 15 with 400 mg of riboflavin daily, over a four

month period. Their study outcomes focused on the neurological component of migraines by
measuring auditory evoked cortical potentials in each group. Although there was no significant

change in the group with riboflavin supplementation, improvements were seen in patients taking

beta-blocker medications. Riboflavin did, however, seem to be just as effective as beta-

blockers in reducing the prevalence of migraine attacks at 53% and 55% respectively.

Additionally, it accomplished this without demonstrating any of the side effects experienced by

patients taking beta-blockers.

The next trial7 for consideration was a three month randomized double-blind trial which

supplemented one group of patients with a combination 400 mg riboflavin, 300 mg magnesium

and 100 mg feverfew daily, as compared to a group that received a placebo pill for the duration

of the study. Successful outcomes were to be measured by a 50% or greater reduction in

migraines to which they observed “no difference” between participants in the combination group

and participants in the placebo groups (42% and 44% respectively). However, when compared

to the baseline, both groups showed a significant reduction in number of migraines, migraine

days, and migraine index. A limitation of this study, however, is that the “placebo” contained 25

mg riboflavin. Therefore, there was never a true placebo to which they could compare results.

In assuming 25 mg would not be enough to account for an observable difference, they instead

reported the effect for the placebo exceeded that of previous migraine trials. Thus, in an attempt

to test the superior effects of a combined drug versus riboflavin alone, they instead concluded

that even 25 mg of riboflavin was enough to have an effect on reducing migraine onset.

This next study8 conducted was the first to evaluate the efficacy of riboflavin for migraine

prevention in children. Designed as a randomized, double-blind trial, 27 children were given

200 mg of riboflavin daily, and the other 21, a placebo. The main outcome measure was the

standard number of patients achieving a 50% or greater reduction in the number of migraine

attacks (similar to the aforementioned study7) over 4 weeks, in addition to measuring average

severity of migraine per day, average duration of migraine, days with nausea or vomiting,

analgesic use, and other adverse effects. A 50% or greater reduction in headaches was seen
at a higher rate of 66.7% of patients in the placebo group as compared to 44.4% of patients in

the riboflavin group. Therefore, this was not conclusive enough to suggest that riboflavin was

effective in preventing migraines in children.

More recently a 40-week study9 examining the effects of riboflavin supplementation in

children included 42 participants, ages 6–13 years, suffering from migraine and tension type

headaches. The age of the target population prompted researchers’ interest in riboflavin

supplementation for its minimal, or rather non-existent side effects. After a 4-week baseline

period was established, all children received a placebo for 16 weeks, then 50 mg riboflavin

supplementation daily for 16 weeks, or vice versa, with a 4 week washout period in between.

The measured outcome was based on a reduction in average frequency of migraine attacks and

tension-type headache in the last 4 weeks of the riboflavin and placebo supplementation

phases, as compared to the baseline and wash-out period. Additionally, they measured severity

and average duration of migraine and tension-type headaches as compared to the baseline or

wash-out period. The study found there to be no difference in the reduction of frequency of

migraine attacks in the last month of treatment between the placebo phase and riboflavin phase.

However, a significant reduction in frequency was reported for those with tension-type

headaches in the last 4 weeks of the riboflavin phase of treatment. The researchers therefore

concluded that, for this study population, there was no evidence that riboflavin had a

preventative effect on migraine attacks. There was, however, some evidence that the riboflavin

may have had a protective effect on mild migraine-like or tension-type headaches in the

children. In retrospect, the study did suggest that 50 mg riboflavin may not have been a high

enough dose. The original study design was to supplement 100 mg riboflavin but based on the

previously discussed study involving riboflavin, magnesium and feverfew7, they decided to

reduce supplementation to 50 mg.

Finally, in further exploration of riboflavin and migraine headaches, a 4 month open

trial10 found 400 mg of supplementation to be more effective in specific mitochondrial DNA

haplogroups, or genetically related populations. Mitochondrial haplogroup H is the most

frequent haplogroup of western Eurasia and was identified in 45.3% of the subjects. The

remaining 54.7% of the subjects were classified as the non-H group. Forty patients were

responsive to supplementation and the other 24 were not. Riboflavin responders were more

numerous in the non-H group (67.5%) while non-responders were mostly H (66.7%). Therefore,

genetics and ethnicities may be an important factor for consideration in the use of riboflavin

supplementation for migraine headaches.

CONCLUSION There have been limited trials demonstrating riboflavin supplementation and its

effectiveness in preventing the onset of migraine headaches, however, the results are promising

so far. Most study designs observed significant decreases in migraine prevalence and severity

when adults were supplemented with 400 mg of riboflavin. As for children, studies suggest 200

mg may be sufficient, as it was concluded that 50 mg was most likely far too low to address the

amounts needed for mitochondrial contributions of more severe migraine headaches in children.

Although the reviewed studies involving children did not have any conclusive evidence for

riboflavin effectiveness so far, they did show supplementation of 200 mg, or possibly more, to

be generally free from side effects, which holds promise for side-effect free supplementation of

any age group. There is still much to be understood about the pathogenesis of headaches,

migraine headaches, and the various neurological abnormalities associated with them but,

riboflavin supplementation does seem play a preventative role. The discussion of its effect on

any symptoms other than headache, however, was brief. Regardless, evidence for the

association between the mitochondrial defect and subsequent neuronal dysfunction is strong

and seems to be growing. Genotyping could provide more insight as to predictors of migraine

headache susceptibility, however, comorbidities, and even concomitant illnesses, should also

be considered for migraine causation and correlation11. In the meantime, riboflavin may be an

affordable alternative type of migraine therapy that is virtually free from any major side effects.
REFERENCES
1. Markley H. CoEnzyme Q10 and riboflavin: The mitochondrial connection. Headache.

2012;52:81-87.

2. Montagna P. High-dose riboflavin as a prophylactic treatment. Cephalalgia. 1994;14:317-19.

3. Colombo B, Saraceno L, Comi G. Riboflavin and migraine: the bridge over troubled

mitochondria. J Neurol Sci. 2014;35:141-144.

4. Schoenen J, Lenaerts M, Bastings E. High-dose riboflavin as a prophylactic treatment of

migraine: Results of an open pilot study. Cephalalgia. 1994;14(5):328-329.

5. Schoenen J, Jacquy J, Lenaerts M. Effectiveness of high-dose riboflavin in migraine

prophylaxis: a randomized controlled trial. Neurology. 1998;50:466–470.

6. Sandor P, Afra J, Ambrosini A, Schoenen J. Prophylactic treatment of migraine with beta-

blockers and riboflavin: Differential effects on the intensity dependence of auditory evoked

cortical potentials. Headache. 2000;40(1):30.

7. Maizels M, Blumenfeld A, Burchette R. A combination of riboflavin, magnesium, and

feverfew for migraine prophylaxis: A randomized trial. Headache. 2004;44:885-890.

8. MacLennan S, Wade F, Forrest K, Ratanayake P, Fagan E, Antony J. High-dose riboflavin

for migraine prophylaxis in children; a double-blind, randomized, placebo controlled trial. J

Child Neurol 2008;23: 1300–1304.

9. Bruijn J, Duivenvoorden H, Passchier J, Locher H, Dijkstra N, Arts W. Medium-dose

riboflavin as a prophylactic agent in children with migraine: A preliminary placebo-controlled,

randomised, double-blind, cross-over trial. Cephalalgia. 2010;30(12):1426-1434.

10. Di Lorenzo C, Pierelle F, Coppola G, et al. Mitochondrial DNA haplogroups influence the

therapeutic response to riboflavin in migraineurs. Neurology. 2009;72:1588–1594.

11. Silberstein S, Dodick D, FreitagF, PearlmanS, Hahn S,Scher A, Lipton R. Pharmacological

Approaches to Managing Migraine and Associated Comorbidities-Clinical Considerations for

Monotherapy Versus Polytherapy. Headache. 2007;47:585-599.