11

Role of Magnesium,
Coenzyme Q10,
Riboflavin, and
Vitamin B12 in
Migraine Prophylaxis
Alfredo Bianchi,* Salvatore Salomone,{
Filippo Caraci,{ Vincenzo Pizza,{ Renato
Bernardini,{ and Cesare Colucci D’Amatox
*Department of Pharmaceutical Sciences, University of Salerno
84084 Fisciano, Italy
{
Departments of Pharmaceutical Sciences and
Experimental and Clinical Pharmacology, University of Catania
95125 Catania, Italy
{
Department of Neurology, Second University of Napoli
80138 Napoli (Naples), Italy
x
Neurophysiopatology Service, S. Luca Hospital
84078 Vallo della Lucania (Salerno), Italy

I. Introduction
II. Magnesium
III. Coenzyme Q10
IV. Riboflavin
V. Vitamin B12 and Homocysteine
VI. Conclusions
References

Migraine is a neurovascular syndrome characterized by recurrent

headache associated with other symptoms, eventually preceded by aura.
This chapter reviews the involvement of some mineral, coenzyme, and
Copyright 2004, Elsevier Inc.
Vitamins and Hormones All rights reserved.
Volume 69 297 0083-6729/04 $35.00
298 Bianchi et al.

vitamin defects in the pathogenesis of migraine headaches and focuses on

their potential therapeutic use in the preventive treatment for migraine.
The therapeutic potential of magnesium, coenzyme Q10, riboflavin, and
vitamin B12 can be cautiously inferred from some published open
clinical trials; it should, however, be considered that double-blind
randomized larger studies are needed to correctly estimate the impact of
the placebo effect in these promising therapies. ß 2004 Elsevier Inc.

I. INTRODUCTION

Migraine is a neurovascular syndrome characterized by recurrent

headache attacks associated with photophobia, phonophobia, nausea, and
vomiting. Migraine occurs in about 18% of women and 6% of men,
regardless of race or geographical location (Stewart et al., 1992). The
incidence of migraine is higher between the ages of 20 and 35 and is often
associated with a positive family history of the disease. Currently, migraines
are divided into two categories: migraine without aura (previously termed
common migraine) and migraine with aura (previously termed classical
migraine), preceded by a 15–20-minute episode of visual or sensory aura.
Auras are most commonly visual alterations, such as hemianopsic Weld
defects and scotomas that enlarge and spread peripherally (Greenberg,
1993). Visual auras are associated with spreading cortical depression;
sensory auras are usually experienced as paresthesias of the arm and face.
This chapter reviews the involvement of mineral, coenzyme, and vitamin
defects in the pathogenesis of migraine headaches and focuses on their
potential therapeutic use in the treatment for migraine.
Although the exact etiology of migraine headaches is unknown, several
theories have been proposed. The vascular theory, as proposed in 1938 by
Graham and WolV, attributes migraines to an initial intracranial arterial
vasoconstriction, resulting in reduced blood flow to the visual cortex,
followed by a period of extracranial vasodilation (WolV, 1963). Modern
imaging techniques have shown that during a common migraine attack there
are in fact only minor changes in cerebral blood flow, and the proposed initial
vasoconstrictive phase may actually last much longer than the aura (Campbell
and Caselli, 1991). It has also been hypothesized that migraine suVerers
have an inherent vasomotor instability and are more susceptible to the
vasodilatory eVects of certain physical and chemical agents. This point of
view has been reinforced by the observation that organic nitrates, which are
capable of delivering nitric oxide, trigger migraine attacks in migraineurs, at
low doses, ineVective in normal subjects (Thomsen et al., 1993).
Moskowitz’s theory involves the trigeminovascular complex, which
links the aura and the headache of migraine (Moskowitz, 1984). In this
Vitamins and Migraine 299

FIGURE 1. Hypothetical model of migraine pathogenesis. Trigeminovascular neurons in

response to various triggers release substance P (SP) and calcitonin gene-related peptide
(CGRP), which lead to vasodilation, alteration in vascular permeability, and edema of the
meninges. Excessive trigeminal discharge with the sequential activation of diVerent anatomical
structures involved in pain perception results in migraine headache.

theory the trigeminovascular neurons release substance P and other

neurotransmitters in response to various triggers (Fig. 1). Substance P is
associated with vasodilation, mast cell degranulation, increase in vascular
permeability, and edema of the meninges. All together, these events
configure the phenomenon called neurogenic inflammation. Excessive
trigeminal discharge and neurovascular inflammation of the meninges
ensue in migraine headache.
Migraine drug treatment aims either to blunt the headache attack or to
reduce the intensity and the frequency of the attacks (preventive treatments),
particularly when they are frequent and characterized by intense pain.
Triptans can be considered as the most important drugs for the treatment
of the attack; they act on serotonin (5-HT)1B/D/F receptors located on
presynaptic trigeminal nerve endings (Fig. 1), and possibly on vascular
smooth muscle and in the central nervous system (CNS) (Ferrari et al.,
2002). Other symptomatic drugs include nonsteroidal anti-inflammatory
drugs (NSAIDs) and ergotamine. Several diVerent drug treatments have
been attempted to decrease the intensity and the frequency of migraine
attacks; these include beta-blockers, tricyclics such as amitriptyline, some
5-HT2 receptor antagonists such as methysergide and pizotifen, and calcium
antagonists such as flunarizine (Diener et al., 1998). Unconventional or
alternative treatments, such as acupuncture, also have revealed some eYcacy
in migraine prevention (Allais et al., 2002). In addition to these numerous
preventive treatments, some minerals, coenzymes, and vitamins, often
designed as micronutrients rather than as drugs, have been shown to be
300 Bianchi et al.

eVective in migraine prevention or could be considered as a potential

approach.

II. MAGNESIUM

Several researchers have suggested that magnesium plays an important

role in establishing a threshold for migraine attacks (Welch and Ramadan,
1996). The activities of magnesium in the body include counteracting
vasospasm, inhibiting platelet aggregation, and stabilizing cell membranes,
all of which could be involved in migraine pathogenesis (McCarty, 1996).
Magnesium concentration has an eVect on serotonin receptors, nitric oxide
synthesis and release, inflammatory mediators, and a variety of other
migraine-related receptors and neurotransmitters. Magnesium has also been
shown to inhibit platelet aggregation and adhesion in vitro and reduce the
formation of inflammatory eicosanoids. Intravenous magnesium inhibits
platelet function in vivo, when given in conjunction with aspirin (Gawaz,
1996). Current evidence suggests that up to 50% of migraine patients have
lowered levels of ionized magnesium during an acute migraine attack
(Mauskop and Altura, 1998). Some reports have shown that migraine
patients, both with and without aura, have signiWcantly lower red blood cell
magnesium levels than normal controls (Gallai et al., 1993). One study
found that brain magnesium concentrations were 19% lower in patients
during migraine attack compared with healthy controls (Ramadan et al.,
1989). Based on these Wndings, Piekert et al. (1996) enrolled 81 patients (ages
18–65) with migraine, in a multicenter, placebo-controlled, and double-blind
randomized study. Patients were given either 600 mg oral magnesium
(trimagnesium citrate) or placebo for 12 weeks. During the ninth through
the twelfth week of the study, migraine attack frequency was reduced 41.6%
in the magnesium group versus 15.8% in the placebo group ( p < 0.05). The
number of days with migraine also decreased signiWcantly in the magnesium
group. Duration and intensity of attacks and drug consumption per attack
also decreased in the magnesium group but failed to be signiWcant. Adverse
reactions included diarrhea (18.6%) and gastric irritation (4.7%).
In a Japanese study, Mishima et al. (1997) compared platelet-ionized
magnesium and cyclic adenosine monophosphate (AMP) levels in patients
with tension-type headaches and migraines. Although patients with tension-
type headaches had signiWcantly lower platelet-ionized magnesium, the
migraine group demonstrated increased platelet levels of cyclic AMP,
suggesting possible alterations of neurotransmitters within the platelet.
In light of its potential deWciency in many migraine suVerers, its ability
to inhibit platelet aggregation, and its clinically documented eYcacy, the
prophylactic use of magnesium in migraine seems well indicated.
Vitamins and Migraine 301

III. COENZYME Q10

In some individuals, migraine may be a result of mitochondrial im-

pairment (Bresolin et al., 1991; Koo et al., 1993). A mitochondrial
dysfunction resulting in impaired oxygen metabolism has been suggested
for migraine pathogenesis. DiVerent data, deriving from in vivo magnetic
resonance spectroscopy (MRS) studies, as well as biochemical assays,
support the ‘‘mitochondrial hypothesis of migraine’’ (Lanteri-Minet and
Desnuelle, 1996). Sangiorgi et al. (1994) found a defect of reduced
nicotinamide adenine dinucleotide (NADH) dehydrogenase, citrate
synthase, and cytochrome-c-oxidase platelet activities in migraine patients.
Interestingly, subjects with familial hemiplegic migraine showed a defective
energy metabolism of brain and muscle [i.e., a reduced phosphocreatine
content accompanied by high adenosine diphosphate (ADP) concentration,
and a decreased phosphorylation potential; Uncini et al., 1995]. MRS
studies also suggest an impaired energy metabolism in brain and skeletal
muscle in migraine patients. Lodi et al. (1997) quantiWed skeletal muscle
bioenergetics and proton eZux in 63 patients with migraine (with or without
aura or with prolonged aura or stroke) and in patients with cluster
headache. A reduction of glycolytic flux, related to the severity of the
clinical phenotype, was observed in migraine patients. Okada et al. (1998)
reported a signiWcant increase in lactic and pyruvic acid plasma levels of
migraine patients. If a decreased energy state characterizes the migraineur’s
brain, compounds such as coenzyme Q10, which improves mitochondrial
function, could theoretically be used in migraine prophylaxis.
Coenzyme Q10 (ubiquinone or ubidecarenone) is an endogenous enzyme
cofactor that is produced in all living cells in humans. Coenzyme Q10
functions to promote the proton–electron translocation in mitochondria,
transferring electrons from complex I and II to cytochrome c (Crane and
Navas, 1997). In addition, it protects mitochondria from free radical
damage (Lass and Sohal, 2000; Schopfer et al., 2000) and plays a role in the
permeability transition of the inner mitochondrial membrane (Fontaine
et al., 1998). Coenzyme Q10 which is marketed in the United States as an
over-the-counter (OTC) dietary supplement, is a useful therapeutic agent for
certain conditions associated with increased oxidative stress and in patients
with mitochondrial cytopathies (Chan et al., 1998; Chen et al., 1997).
Coenzyme Q10 improves exercise tolerance and muscle weakness and lowers
serum pyruvate and lactate levels in patients with mitochondrial encepha-
lomyopathies (Ihara et al., 1989; Nishikawa et al., 1989). Furthermore,
coenzyme Q10 administration has been shown to improve brain and muscle
energy metabolism in patients with mitochondrial cytopathies (Barbiroli
et al., 1999).
On the basis of this evidence, Rozen et al. (2002) have investigated in a
open study the eYcacy of coenzyme Q10 as a preventive treatment for
302 Bianchi et al.

migraine headaches. The authors have found that coenzyme Q10 at a dosage
of 150 mg per day determined a greater than 50% reduction in number of
days with migraine headache after 3 months of therapy. Coenzyme Q10
started to work within the Wrst month of initiation of therapy and was
equally eVective in migraineurs with and without a history of aura. It was
extremely well tolerated, and no signiWcant adverse events were reported.
This study was an open-label investigation; therefore, the same authors
recommended a placebo-controlled trial to determine the true eYcacy of
coenzyme Q10 in migraine prophylaxis. Coenzyme Q10 can be administered
orally or parenterally. Dosages greater than 150 mg per day could be used,
considering its safety proWle. Mild gastrointestinal disturbances, such as
nausea and diarrhea, have been reported by other studies only at dosages
greater than 600 mg/day and rarely required discontinuation of coenzyme
Q10 supplementation. If its eYcacy will be conWrmed in controlled studies,
migraine prophylaxis will be enriched with the use of coenzyme Q10, which
could be used even in children with migraine, because of its safety proWle.

IV. RIBOFLAVIN

Riboflavin, or vitamin B2, is an essential constituent and precursor to

riboflavin 50 -phosphate, also known as flavin mononucleotide (FMN) and
flavin adenine dinucleotide (FAD), which is required for the activity of
flavoenzymes involved in the electron transport chain. Flavin coenzymes
participate in one electron transfer and two electron transfer reactions in
biological systems. They also work together with two electron acceptor–
donors nicotinamide adenine dinucleotide (NADþ) and nicotinamide
adenine dinucleotide phosphate (NADPþ), one or two electron donors
(quinones), and a variety of one electron acceptor–donors (cytochrome
proteins).
Altered mitochondrial energy metabolism may play a role in migraine
pathogenesis, and patients with migraines have demonstrated a reduction in
mitochondrial phosphorylation potential in between attacks (Montagna
et al., 1994; Schoenen et al., 1994). Some studies have shown high-dose
riboflavin to be eVective in migraine prophylaxis. Theoretically, riboflavin
may work by increasing mitochondrial energy eYciency. Schoenen et al.
(1998) compared 400 mg riboflavin with placebo in 55 patients with
migraine in a randomized trial of 3 months duration. Riboflavin proved
superior to placebo in reducing both attack frequency ( p ¼ 0.005) and
headache days ( p ¼ 0.012). The number of patients in the study who
improved by at least 50% was 15% in placebo and 59% in the riboflavin
group ( p ¼ 0.02). Three minor adverse reactions were reported. Two
occurred in the riboflavin group (diarrhea and polyuria) and one in the
placebo group (abdominal cramping).
Vitamins and Migraine 303

In the Wrst pilot study (Schoenen et al., 1994), 49 patients with migraine
(45 without aura, 4 with) were treated with a daily dose of 400 mg riboflavin
for at least 3 months. There was a mean global improvement of 68.2%. With
the exception of one subject who withdrew because of gastric intolerance
(this person was also taking small amounts of aspirin), no other side eVects
were reported. In apparent contrast with the established eVect of riboflavin
in migraine prevention is the eVect of amitriptyline on riboflavin meta-
bolism. The tricyclic antidepressant amitriptyline is indeed sometimes
prescribed for migraines. It should be noted, however, that this drug
increases the renal excretion of riboflavin (Pinto and Rivlin, 1987). Whether
this phenomenon could have clinical relevance remains to be determined.
Although supported by only a few clinical reports, prophylactic migraine
therapy using high-dose riboflavin may prove to be part of a safe, low-cost,
and eVective treatment program.

V. VITAMIN B12 AND HOMOCYSTEINE

Cobalamins are vitamin B12 compounds that diVer for the chemical
group bound to cobalt: methylcobalamin and adenosylcobalamin are the
active forms of vitamin B12 in mammals. Besides the two forms mentioned
here, circulating vitamin B12 is also present as hydroxycobalamin. Vitamin
B12 is involved in several pathways. Hydroxycobalamin exerts a scavenging
action against nitric oxide (NO) (Rajanayagam et al., 1993). As mentioned
earlier, nitric oxide has been involved in the pathogenesis of migraine by
Thomsen et al. (1993). Based on the assumption that NO scavenging by
vitamin B12 could be beneWcial in migraine, Van der Kuy et al. (2002)
carried out an open trial on the eVect of hydroxycobalamin in the
prevention of migraine. In this study, intranasal administration of
hydroxycobalamin to 19 patients with migraine decreased the frequency
of attacks by about 50% in 53% of patients. The safety proWle was good
(practically no side eVects), and the compliance to the treatment was
monitored by measuring the serum concentration of cobalamin. This study
was not controlled and of relatively short duration (3 months), but such
impressive results suggested a real signiWcant therapeutic eVect of vitamin
B12, though the placebo component cannot be sized. Migraine is a condition
in which placebo eVect of drug treatment participates to the pain relief in a
striking manner (Van der Kuy and Lohman, 2002). For this reason,
considering the very promising results of the preventive vitamin B12
treatment, a double-blind study will be of particular value for establishing
and deWning the antimigraine preventive eVect of vitamin B12. As mentioned
earlier, other vitamins, such as riboflavin, and coenzymes, such as coenzyme
Q10, have been proposed in the migraine prevention, based on the
assumption that they improve mitochondrial production of adenosine
304 Bianchi et al.

triphosphate (ATP). Interestingly, the existence of a common mechanism

between these compounds and vitamin B12 could be hypothesized. Indeed,
NO has been shown to inhibit respiratory chain by binding to complex I and
III and cytochrome c oxidase (Pearce et al., 2001; Shiva et al., 2001), an
eVect particularly important in the presence of low O2. Similar eVects
have been found for NO donors, which determine the production of
peroxynitrite, toxic toward various subcellular components, including
mitochondria (Brown and Borutaite, 1999). It is also worthy of mention
that mitochondria themselves can produce NO radicals (Sarkela et al.,
2001); they therefore appear as a compartment in which cellular respiration
and NO production are interfering with each other. The interpretation of
the preventive eVects of vitamin B12 on migraine should also consider that
riboflavin can function as a precursor of vitamin B12 biosynthesis (Renz,
1970) and that both these vitamins have been reported to induce an
antinociceptive eVect in animal models of pain associated with inflammation
(Franca et al., 2001). The results of the open study by Van der Kuy et al.
(2002) could therefore be linked to the established preventive eVect of
riboflavin (Schoenen et al., 1998), mentioned earlier.
A relationship between food consumption and migraine has been widely
suggested. The predominance of gastrointestinal symptoms such as nausea,
vomiting, and diarrhea underlines the involvement of gastroenteric
apparatus in migraine. The predominance of functional and organic gastric
aVections such as gastritis has been evidenced in migraine. A gastric mucus
impairment, observed in migrane patients, could be due to the chronic
consumption of NSAIDs, which are largely used in migraine attacks. The
chronic use of nonselective NSAIDs gives gastrointestinal distress, reduces
gastric mucus production with bleeding, and causes gastric ulceration
(Gabriel et al., 1991). Gastric damage decreases the intrinsic factor
production and thus can reduce vitamin B12 absorption, Wnally aVecting
the important metabolic functions regulated by this vitamin. In addition
to food allergies, other gastrointestinal abnormalities have been detected
in migraine patients. When 225 migraine patients were assessed for
Helicobacter pylori with a 13C-urea breath test, 40% tested positive. After
eradicating the H. pylori, intensity, duration, and frequency of migraine
attacks were signiWcantly reduced (Gasbarrini et al., 1998). Humans depend
on exogenous sources of vitamin B12, which is synthesized by microorgan-
isms that grow in the intestinal lumen. Vegetable products are free of
vitamin B12. Eventual alterations in food behavior or an unbalanced diet
can also favor the onset of symptoms related to lack of vitamin B12, such as
cold feet and paresthesias at upper and lower limbs, diminution of vibration,
and position senses with resultant unsteadiness (Pizza et al., 2001, 2002).
A few studies examined the relationship between dysfunction of vitamin
B12 pathway and headache pathogenesis. In particular, serum levels of
homocysteine have been poorly investigated. Hyperhomocysteinemia is an
Vitamins and Migraine 305

independent risk factor for coronary and artery disease (Bostom et al., 1999;
Bots et al., 1997) and is also associated with cerebrovascular disease (Perry
et al., 1995; Selhub et al., 1995). Low serum levels of vitamin B12 and folate
correlate with high levels of homocysteinemia, and plasma homocysteine
levels can be lowered by supplementation with folic acid (Wald et al., 2001).
Vitamin B12 and folate are involved in the remethylation and synthesis of S-
adenosylmethionine (SAMe), the sole methyl donor for numerous reactions
involving proteins, membrane phospholipids, and neurotransmitters in the
CNS. Multiple genetic and environmental factors can lead to hyperhomo-
cysteinemia. In particular, a polymorphism in the 5,10-methylenetetrahy-
drofolate reductase (MTHFR) gene has been described, as well as
individuals homozygous for the mutation C677T, who exhibit reduced
enzymatic activity and elevated homocysteine concentration (Frosst et al.,
1995), particularly in case of folate deprivation (Ueland et al., 2001). The
decreased activity of MTHFR, in the case of mutated enzyme, determines a
reduced cellular availability of methyl tetrahydrofolate, the substrate for
methionine synthase. This enzyme catalyzes the transfer of a methyl group
from methylenetetrahydrofolate to homocysteine, producing tetrahydrofo-
late and methionine. By this way, C677T mutation in the MTHFR gene can
lead to elevated homocysteine concentration. Two diVerent studies have
investigated the prevalence of this mutation in migraine patients (Kara et al.,
2003; Kowa et al., 2000). The MTHFR T allele seems to be more frequent in
the migraine group than in the control group in both studies. Furthermore,
Kara et al. (2003) determined the prevalence of another MTHFR
polymorphism (A1298C) in migraine patients. The C allele of MTHFR1298
was signiWcantly higher in migraine and tension-type headache patients.
Interestingly, migraineurs with aura with C1298C and C677C/C1298C
genotypes were even more profoundly associated with migraine risk than
others. The authors have not analyzed blood homocysteine levels. Hering-
Hanit et al. (2001) examined blood homocysteine in a signiWcant number of
patients with migraine, but they did not Wnd its levels augmented. In a large
group of patients suVering from migraine with or without aura, we have
observed a reduction of vitamin B12 and folate serum concentrations (Pizza
et al., 2002). Moreover, basal levels of homocysteinemia, a reliable marker
of vitamin B12 deWciency, are increased in these patients, especially in
migraineurs with aura. After therapy aimed to correct these deWciencies,
migraine index values were found signiWcantly reduced with respect to basal
ones (Pizza et al., 2002). To the best of our knowledge, no study has been
conducted on the possible correlation between blood homocysteine levels
and migraine severity and on the possible role of hyperhomocysteinemia as
a causative factor in the predisposition to migraine (Fig. 2). In fact, it is well
known that hyperhomocysteinemia may lead to an excessive production of
homocysteic acid (WolV et al., 1995). This compound is an excitotoxin (Kim
et al., 1987), possesses strong excitatory eVects on neurons (Do et al., 1986;
306 Bianchi et al.

FIGURE 2. Role of vitamin B12 in migraine pathogenesis. Gastric pathologies and/or

chronic use of nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) in migraine patients
impair the intrinsic factor production with a reduction in vitamin B12 absorption. Nutritional
deWcits may also contribute to vitamin B12 deWcit. Low plasma levels of B12 and/or mutations in
the methylenetetrahydrofolate reductase (MTHFR) gene can lead to hyperhomocysteinemia.
Elevated homocysteic acid levels, secondary to hyperhomocysteinemia, could activate the
trigeminovascular system, thus favoring the onset of migraine attacks.

Knopfel et al., 1987; Provini et al., 1991), and is released upon

depolarization (Klancnik et al., 1992). Homocysteic acid physiologically
exerts an excitatory role in the CNS by acting as an endogenous agonist of
N-methyl-D-aspartate (NMDA) receptors (Cuenod et al., 1990; Do et al.,
1988). These receptors play a signiWcant role in the initiation, propagation,
and duration of cortical spreading depression, a phenomenon involved in
migraine pathogenesis (Marrannes et al., 1988). The role of glutamate
in migraine pathogenesis has been investigated. Increased levels of
glutamate and aspartate have been found in plasma and cerebrospinal fluid
(CSF) in migraine patients during attacks compared with the resting state
(Ferrari et al., 1990), and higher levels of glutamic and aspartic acid are
present in platelets of patients with migraine with aura (D’Andrea et al.,
1991). Plasma homocysteic acid levels have been only recently studied in
migraine patients (Alam et al., 1998). The authors found increased levels of
Vitamins and Migraine 307

neuroexcitatory amino acid levels (glutamic acid, glutamine, glycine, cysteic

and homocysteic acid) in patients with migraine (with and without aura),
whereas patients with tension headache had values similar to controls. In
this study the authors show that neuroexcitatory amino acids became still
further elevated during a migraine attack. The authors suggest that these
biochemical parameters could determine in migraine patients a high
endogenous CNS excitability, which can be triggered by environmental
factors, including stress. Homocysteic acid, related to hyperhomocystein-
emia, could therefore contribute to neuronal overstimulation and to CNS
excitability in migraine patients. Another possible role also can be suggested
for homocysteic acid in migraine pathogenesis, for its eVects on the
trigeminovascular system (see Fig. 2). It is well known that activation of
elements of the trigeminal innervation could determine painful vasodilata-
tion of cranial vessels and the release of neuropeptides from the perivascular
axons in dura mater (Moskowitz and Macfarlane, 1993). Homocysteic acid
increases trigeminal cell Wring in animal models of craniovascular pain
(Storer and Goadsby, 1997), whereas 5-HT1B/D agonists reduce evoked
activity and spontaneous Wring of trigeminal nucleus cells. In this view,
elevated homocysteic acid levels, secondary to hyperhomocysteinemia,
could sensitize the dura mater and cerebral arteries and/or favor the
activation of the trigeminovascular system, thus predisposing a patient to
migraine attacks or increasing the disease’s severity.

VI. CONCLUSIONS

In consideration of the complex migraine pathogenesis and frequent

comorbidities, involving many receptorial functions and related metabolic
pathways, a number of drugs have been used in the prophylactic therapy,
and among them an increasing credit has in these last years acquired the
approach based on minerals, vitamins, coenzymes, and other nutrients,
which can be associated with all other therapeutic strategies, exerting with
them favorable synergistic activities.
In this chapter, we examined magnesium, coenzyme Q10, and two
vitamins, B2 and B12 the last one together with homocysteine, on which
many research studies have been carried out. Magnesium and vitamin B12
deWciency associated with migraine has been found in several studies, as
previously underlined; therefore, the indication of their supplementation in
these states appears justiWed.
Coenzyme Q10 and riboflavin both play an important role in mitochon-
drial energy production, and the impairment of this activity, critical for
cellular life, seem to be involved in migraine pathogenesis.
Functional interactions between vitamins B2 and B12 and coenzyme Q10
have been hypothetized.
308 Bianchi et al.

Among the molecules analyzed in this chapter, vitamin B12 seems to exert
a prominent role in migraine therapy for its scavenging and neurotrophic
properties, as well as for its other physiological and pharmacodynamic
roles, such as in hepatoprotection and hematopoiesis. An interesting and
intriguing relationship is that existing between vitamin B12 and homocyste-
ine, often based on an inverse order of concentrations in biological means,
the meaning of which is not yet fully elucidated, but oVers many attractive
aspects for fundamental and clinical research with possible applications to
migraine pathogenesis and therapy.

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