Oral coenzyme Q10 supplementation in patients with migraine: Effects on clinical features and inflammatory markers

Abstract

Backgrounds and aims: Migraine and inflammation are correlated. Coenzyme Q10 (CoQ10) as an anti-inflammatory agent has shown useful effects in other diseases. The present study aimed to assess the effect of CoQ10 supplementation on inflammation and clinical features of migraine.
Methods: This randomized double-blind placebo-controlled clinical trial was conducted among 45 non-menopausal women aged 18–50 years, diagnosed for episodic migraine according to the International Headache Society. After one month run-in period, subjects received CoQ10 (400 mg/day CoQ10, n = 23) or placebo (wheat starch, n = 22) for three months. All the patients got prophylactic medication too. Serum CoQ10 concentration, Calcitonin gene-related peptide (CGRP), interleukin (IL)-6, IL-10 and tumor necrosis factor-α (TNF-α) were measured at the beginning and end of the study.
Results: CoQ10 supplementation reduced CGRP and TNF-α significantly (p = 0.011 and p = 0.044, respectively), but there were no significant differences in serum IL-6 and IL-10 between the two groups. Significant increase in serum CoQ10 levels was evident with CoQ10 therapy (P < 0.001). A significant improvement was found in frequency (p = 0.018), severity (p = 0.001) and duration (p = 0.012) of migraine attacks in CoQ10 group compared to placebo.
Conclusion: CoQ10 supplementation may decrease CGRP and TNF-α with no favorable effects on IL-6 and IL-10 in patients with migraine.

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Nutritional Neuroscience
An International Journal on Nutrition, Diet and Nervous System
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Oral coenzyme Q10 supplementation in patients
with migraine: Effects on clinical features and
inflammatory markers
Monireh Dahri, Ali Tarighat-Esfanjani, Mohammad Asghari-Jafarabadi &
Mazyar Hashemilar
To cite this article: Monireh Dahri, Ali Tarighat-Esfanjani, Mohammad Asghari-Jafarabadi &
Mazyar Hashemilar (2018): Oral coenzyme Q10 supplementation in patients with migraine:
Effects on clinical features and inflammatory markers, Nutritional Neuroscience, DOI:
10.1080/1028415X.2017.1421039
To link to this article: https://doi.org/10.1080/1028415X.2017.1421039
Published online: 03 Jan 2018.
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Oral coenzyme Q10 supplementation in
patients with migraine: Effects on clinical
features and inflammatory markers
Monireh Dahri
1
, Ali Tarighat-Esfanjani
2
, Mohammad Asghari-Jafarabadi
3
,
Mazyar Hashemilar
4
1
Student Research Committee, Faculty of Nutrition and Food Sciences, Tabriz University of Medical Sciences,
Tabriz, Iran,
2
Nutrition Research Center, Faculty of Nutrition and Food Sciences, Tabriz University of Medical
Sciences, Tabriz, Iran,
3
Road Traffic Injury Research Center, Tabriz University of Medical Sciences, Tabriz, Iran,
4
Department of Neurology, Tabriz University of Medical Sciences, Tabriz, Iran
Backgrounds and aims: Migraine and inflammation are correlated. Coenzyme Q10 (CoQ10) as an anti-
inflammatory agent has shown useful effects in other diseases. The present study aimed to assess the
effect of CoQ10 supplementation on inflammation and clinical features of migraine.
Methods: This randomized double-blind placebo-controlled clinical trial was conducted among 45 non-
menopausal women aged 18–50 years, diagnosed for episodic migraine according to the International
Headache Society. After one month run-in period, subjects received CoQ10 (400 mg/day CoQ10, n=23)
or placebo (wheat starch, n=22) for three months. All the patients got prophylactic medication too.
Serum CoQ10 concentration, Calcitonin gene-related peptide (CGRP), interleukin (IL)-6, IL-10 and tumor
necrosis factor-α(TNF-α) were measured at the beginning and end of the study.
Results: CoQ10 supplementation reduced CGRP and TNF-αsignificantly (p=0.011 and p=0.044,
respectively), but there were no significant differences in serum IL-6 and IL-10 between the two groups.
Significant increase in serum CoQ10 levels was evident with CoQ10 therapy (P<0.001). A significant
improvement was found in frequency ( p=0.018), severity (p=0.001) and duration (p=0.012) of
migraine attacks in CoQ10 group compared to placebo.
Conclusion: CoQ10 supplementation may decrease CGRP and TNF-αwith no favorable effects on IL-6 and
IL-10 in patients with migraine.
Keywords: Coenzyme Q10, Inflammation, Migraine, CGRP, Randomized controlled trial
Introduction
Migraine is a disabling neurovascular disorder which
is characterized by a moderate to severe throbbing,
unilateral headache usually accompanied with
nausea or vomiting, photophobia, and phonophobia.
1
It is also known as the sixth most debilitating medical
disorder in the world.
2
Migraine is three times more
common in women than in men, with a worldwide
prevalence of 14.7%.
3
The prevalence of migraine
was estimated as 14% in Iran, which was similar to
that reported worldwide.
4
Results from previous studies suggest that migraine
and inflammation are linked.
5,6
Cytokines which are
small proteins released by most cells are considered
to be pain mediators in neurovascular inflammation.
Cytokines levels have been measured in different
body fluids such as serum, plasma, saliva, and cere-
brospinal fluid of migraine patients. Although contro-
versial, it has been shown that cytokines levels are
altered in migraineurs, as observed in other immuno-
logic and inflammatory conditions.
6–9
Endogenous
inflammatory mediators such as tumor necrosis
factor (TNF)-αcan stimulate calcitonin gene-related
peptide (CGRP) transcription.
10
CGRP is a 37
amino acid neuropeptide, predominantly produced in
up to 50% of trigeminal neurons of the nervous
system
11
and released by perivascular nerve endings
following trigeminal nerve activation. CGRP acts as
a potent dilator of peripheral and cerebral blood
vessels.
10
Evidences suggest that CGRP concentration
correlates with migraine and pain; thus, an integral
role has been considered for CGRP in the pathophy-
siology of migraine. The CGRP-related treatments
such as gepants do not cause vasoconstriction and
Correspondence to: Mazyar Hashemilar, Department of Neurology,
Tabriz University of Medical Sciences, Tabriz, 5166614766, Iran. Email:
mhashemilar@yahoo.com
© 2018 Informa UK Limited, trading as Taylor & Franc is Group
DOI 10.1080/1028415X.2017.1421039 Nutritional Neuroscience 2018 1
Downloaded by [Tabriz University of Medical Sciences], [Ali Tarighat-Esfanjani] at 08:33 06 January 2018

this outstanding property sets it as a new target in
migraine treatment.
12,13
Patients with severe frequent migraine attacks need
both acute and preventive therapies.
14
Although a
small portion of patients use preventive treatments,
15
it could improve response to acute drugs and reduce fre-
quency, severityand duration of the attacks. The use of
nutraceuticals such as magnesium, vitamin B
2
, vitamin
B
12
, feverfew and butterbur is expanding in migraineurs
due to their potential effect for migraine relief, and
minimal side effects and drug dependence.
16,17
There
have been also evidences that Coenzyme Q10
(CoQ10) which is a key cofactor of mitochondrial elec-
tron transport chain, might be effective against
migraine attacks presumably owing to its antioxidant
and anti-inflammatory properties.
17–20
Migraine physiopathology is not completely under-
stood yet. Studies with phosphorus magnetic reson-
ance spectroscopy (31P-MRS) have disclosed altered
energy metabolism in the brain of migraineurs. Both
of the supposed theories for migraine including vascu-
lar and neuronal dysfunction can be explained by
impaired oxygen metabolism resulting from mitochon-
drial dysfunction.
21,22
Regarding mitochondrial
impairment in at least a subset of patients with
migraine and the vital role of CoQ10 in mitochondrial
energy stores, CoQ10 could be considered as a
migraine preventive supplement. In addition, CoQ10
as an anti-inflammatory agent can improve the inflam-
matory component of migraine. However, there have
been just few controlled clinical trials evaluating the
effectiveness of CoQ10 in adult migraine and no pub-
lished study has investigated the anti-inflammatory
effects of CoQ10 in patients with migraine.
Thus, we aimed to investigate the effects of CoQ10
supplementation on prevention of migraine attacks,
CGRP concentration, and anti-inflammatory factors
in an Iranian adult women population in a random-
ized, placebo-controlled add-on clinical trial.
Materials and methods
Study design
This was done as a randomized double-blind placebo-
controlled add-on trial with the registration number:
IRCT201508265670N10 in the Iranian registry of
clinical trials.
Patients
This study included 52 patients recruited from among
outpatients referred to the clinic of Tabriz University
of Medical Sciences at Razi hospital (Tabriz, Iran).
Diagnosis was made according to the International
Headache Society
23
criteria for episodic migraine
(<15 headache days/month) by a neurologist at the
first visit session. Patients were all women and aged
between 18 and 50 years. Participants had a history
of migraine for more than one year with at least two
attacks per month. The study was conducted accord-
ing to the Declaration of Helsinki, and the whole
study protocol was reviewed and approved by the
ethics committee of Tabriz University of Medical
Sciences (reference number
TBZMED.REC.1394.835). All patients gave informed
consent for supplementation and blood sampling,
before commencement of the study.
Exclusion criteria
Exclusion criteria were suffering from continuous
attacks or other types of headaches, menopause,
serious organic or inflammatory diseases, past stroke,
or myocardial infarction, taking prophylactic medi-
cations during the preceding six months, use of
CoQ10 or other antioxidants supplements for at least
three months prior to enrollment, using non-steroidal
anti-inflammatory drugs, smoking, lactation, preg-
nancy, or intention of pregnancy.
Sample size
Sample size was based on an expected 14% between-
group differences in the main variable, CGRP, and
according to the previously reported data on its
mean and standard deviation.
24
With 80% power
and confidence interval of 95%, the sample size of
21 per group was considered which was increased to
26 to accommodate a probable 20% dropout rate.
Intervention
After assessment of the patients’eligibility based on
inclusion criteria and a visit session with a neurologist,
52 patients were enrolled in the current study. A one
month run-in period was considered before starting
the treatment phase (three months). All the patients
were administered an anticonvulsant and a tricyclic
antidepressant (as prophylactic medications) at their
first visit, by the neurologist in consideration of
ethical issues. At the end of the first month, patients
were randomly assigned into either the CoQ10 or
placebo groups. Allocation was done based on ran-
domized block procedure in equal blocks of four
cases, stratified by age, history of prophylactic drug
use, and years since migraine was diagnosed
25
; the
sequence was generated using STATA11 software.
The patients in the CoQ10 group received 400 mg
CoQ10 per day divided into 2 equal doses of 200 mg
capsules, and those in the placebo group received 2
capsules of placebo (wheat starch) in addition to the
preventive drugs, for 12 weeks. The placebo capsules
had the same appearance as the supplement capsules.
The dose of 400 mg/day of CoQ10 was chosen based
on the previous studies
18,19,26,27
and in consideration
of the observed safe level.
28,29
Since CoQ10 is a fat-soluble substance, patients
were advised to take the capsules with their main
Dahri et al. Oral Coenzyme Q10 supplementation in patients with migraine
Nutritional Neuroscience 2018
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meals. They were also asked to keep their usual diet
and physical activity throughout the study. Patients
and researchers were blinded to group assignments
during the study. Patients were visited monthly for
probable side effects of supplementation. The remain-
ing capsules were counted to assess compliance, at
each visit session. CoQ10 serum concentration was
also measured at the beginning and end of the study
to assay adherence to the intervention.
Physical activity, anthropometry, and food
intake assessment
Physical activity level was assessed using the short
form of the international physical activity question-
naire, and patients were categorized into three
groups (high, moderate, and low) regarding their phys-
ical activity level.
30
All the patients completed a general questionnaire
at the first visit and underwent anthropometric
measurements at the beginning and end of the study.
Body weight, height, waist, and hip circumferences
were measured, and body mass index (BMI) was cal-
culated as the weight in kilogram divided by the
square of the height in meters. Body composition
was also assessed by body bioelectrical impedance
analyzer (Tanita BC418). Patients completed three-
day (two weekdays and one weekend) food records a
week before, and during the last week of the study
course. Dietary intake was analyzed by Nutritionist
IV software, modified for Iranian foods.
Blood sampling
After an overnight fast of 12 hours, 7 mL of venous
blood sample was collected at the beginning and end
of the study. All the patients were asked to attend the
laboratory on a headache-free day. To separate serum,
whole blood samples were centrifuged at 3200 rpm for
10 minutes and were stored at −80°C until analysis.
Biochemical measurements
Serum CGRP, TNF-α, interleukin (IL)-6, and IL-10 were
measured by relevant enzyme-linked immune sorbent
assay (ELISA) kits (Crystal Day Bio-Tec, Shanghai,
China).
CoQ10 levels
Serum levels of total CoQ10 were determined for all
the subjects at the study initiation and end of the
third month, to assess the impact of supplementation
on serum levels. ELISA kit (Crystal Day Bio-Tec,
China) was used to measure serum CoQ10 levels.
The reference range for CoQ10 has been proposed to
be 0.5–1.5 μg/mL (500–1500 ng/ml).
27
Clinical status assessment
Headache frequency per month, average severity of
attacks as determined using the visual analog scale
(VAS) on a 0–10 numeric scale, and also the average
duration of migraine attacks (in hours) was used for
clinical assessment. The patients were given a migraine
diary at the run-in period and were asked to continue
completing it during the study as well; the diary was
used to determine the patients’baseline condition the
patients and also measure their response to treatment.
Statistical analyses
Statistical analyses were performed using SPSS for
Windows version 17.0 (SPSS Inc., Chicago, IL,
USA). In all the analyses, P<0.05 was considered as
statistically significant. Kolmogorov–Smirnov test
was used to assess the normal distribution of the vari-
ables. Numeric and normal and non-normal variables
were expressed as mean (SD) and geometric mean
(minimum–maximum), respectively; categorical vari-
ables were presented as frequency and percentage.
Independent samples t-test and chi-square tests were
performed to explore the differences between the
placebo and CoQ10 groups at baseline in quantitative
and categorical variables, respectively. Within-group
differences before and after the intervention were eval-
uated by the paired t-test. Analysis of covariance
(ANCOVA) was used to evaluate the effects of CoQ10
on the serum levels of variables, considering the influ-
ence of potential confounders (age, years with migraine,
changes in BMI, body fat, physical activity, energy
intake, selenium, vitamin E, and vitamin C). Due to
non-normal distribution of variables for frequency,
severity, duration of migraine attacks, and serum
TNF-αlevels, logarithmic transformation was applied.
Results
A total of 7 patients did not complete the study, and
overall 22 patients in the placebo and 23 patients in
the CoQ10 group were included in the analyses
(Fig. 1). There were no significant differences in base-
line characteristics between the two groups, as pre-
sented in Table 1. Migraine with aura was seen in 13%
of CoQ10 and 18.2% of placebo group. Energy and
antioxidant nutrients (such as vitamins A, E, and C,
ß-carotene, α-tocopherol, selenium, and zinc) intake
showed no differences between the groups at baseline,
and did not change during the study (data are not
shown). Patients did not report any serious adverse
side effects for the supplements throughout the trial.
Missing outcomes and non-adherence to the study
protocol are two main reasons for which, ‘intention-
to-treat’analysis are recommended according to
CONSORT BMJ 2010
31
; these two were not the case
in our study.
Migraine frequency, severity, and duration
Results indicated a significant reduction from baseline
to the end of the study, in frequency, severity, and
Dahri et al. Oral Coenzyme Q10 supplementation in patients with migraine
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duration of migraine attacks within both groups (P<
0.05 for all comparisons). In the same pattern,
between-groups comparison based on ANCOVA
adjusted for baseline values and confounder variables
showed significant reduction in frequency (P=0.018),
severity (P=0.001), and duration (P=0.012) of
Figure 1 Study flow chart.
Table 1 General characteristics of patients with migraine at baseline
Variable CoQ10 (n=23) Placebo (n=22) P-value
Age
a
32.35 ±6.60 32.32 ±7.52 0.989
Marital status
b
Single 6 (26.1) 8 (36.4) 0.457
Married 17 (73.9) 14 (63.6)
Job
b
Housewife 13 (56.5) 12 (54.5) 0.894
Employee 10 (43.5) 10 (45.5)
Education
b
Under diploma and diploma 12 (52.2) 11 (50.0) 0.884
University educated 11 (47.8) 11 (50.0)
Positive migraine family history
b
10 (43.5) 16 (72.7) 0.047
Years with migraine
a
10.35 ±6.09 9.00 ±5.98 0.458
Migraine with aura
b
3 (13.0) 4 (18.2) 0.634
BMI
a
26.30 ±3.97 24.80 ±4.20 0.232
Body fat percent
a
33.37 ±5.04 30.32 ±7.68 0.120
Waist circumference
a
83.78 ±8.91 80.64 ±8.12 0.223
Hip circumference
a
104.49 ±7.90 100.86 ±8.48 0.151
Physical activity level
b
High 0 (0) 0 (0) 0.233
Moderate 3 (13.0) 6 (27.3)
Low 20 (87.0) 16 (72.7)
a
The results are described as mean ±standard deviation (SD) and P-value is reported based on the analysis of
independent sample t-test.
b
The results are described as number (percentage) and P-value is reported based on the analysis of chi-square test.
Dahri et al. Oral Coenzyme Q10 supplementation in patients with migraine
Nutritional Neuroscience 2018
4
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migraine attacks in CoQ10 group compared to
placebo, at the end of the study (Table 2).
Migraine attacks frequency per month dropped to
less than 50% compared to baseline, in 82.6% of
patients in the CoQ10 group in comparison with
54.5% in the placebo group (P=0.043).Also, 52.2
and 82.6% of the patients treated with CoQ10 had
mean reduction of at least 50% in the migraine severity
and duration, respectively; these were 18.2 and 40.9%
for the placebo group. Between-group differences were
significant for migraine severity and duration (P=
0.018,P=0.005,respectively). The number-needed-
to-treat (NNT) for 50%-responder-rate was calculated
as 3.6, 2.9, and 2.4 for frequency, severity, and dur-
ation of attacks, respectively.
CoQ10 levels
After intervention, the total CoQ10 levels reached
from 108.19 ±26.86 to 113.35 ±27.51, and from
119.70 ±17.35 to 176.61 ±39.50 ng/mL in placebo
and CoQ10 groups, respectively. Baseline CoQ10
level was comparable in the groups at baseline, and
it was under normal range in both groups.
Total CoQ10 serum levels of the patients in CoQ10
group increased significantly (P<0.001), while those
who did not receive the supplement, had no significant
change in their levels over time (P=0.275,Table 3).
CGRP and serum inflammatory markers
As illustrated in Table 3, the results revealed no signifi-
cant differences between the two groups for any of the
measured serum markers, at baseline. At the end of the
study, serum levels of CGRP increased in placebo
group, whereas CoQ10 supplementation led to a sig-
nificant decrease in CGRP serum levels. Results of
ANCOVA adjusted for baseline values and
confounder variables also showed a significant differ-
ence between the groups for CGRP serum levels at
the end of the study. The same trend was seen for
TNF-αserum concentration; only the CoQ10 group
had a significant reduction in TNF-αserum levels by
the end of the intervention. The percent changes for
serum levels of CGRP and TNF-αin CoQ10 com-
pared to placebo group were −13.14 vs. 6.12% and
−12.63 vs. 4.53%, respectively. Comparisons of the
IL-6 and IL-10 indicated that their levels did not
change significantly neither within, nor between
groups.
Discussion
As migraine patients have higher level of inflammation
and have been reported to have CoQ10 deficiency,
CoQ10 supplementation may be a beneficial comp-
lementary treatment in migraineurs. In the current
study, we evaluated the effect of CoQ10 oral sup-
plementation on migraine frequency, severity, and dur-
ation, and for the first time on CGRP and
inflammatory factors (TNF-α, IL-6, and IL-10) of
the patients suffering from migraine. Results of the
present study indicated that CoQ10 supplementation
at a dose of 400 mg/day for three months decreased
serum levels of CGRP and TNF-α; however, the
serum levels of IL-6 and IL-10 were not affected by
the supplementation.
Our findings also showed a significant prophylactic
effect of the CoQ10 supplementation on migraine
attacks which resulted in less severe, shorter, and less
frequent headaches.
Serum CoQ10 concentration significantly increased
after the intervention in the CoQ10 group and the sup-
plement showed anti-inflammatory effects in this
Table 2 Within and between group comparisons of headache characteristics of patients with migraine before and
after the intervention
Variables CoQ10 (n=23) Placebo (n=22) P-value
Migraine frequency(per month)
Baseline 8.47 (3.00–15.00) 6.36 (2.00–15.00) 0.062
a
After 3.10 (1.00–12.00) 3.46 (1.00–14.00) 0.018
b
GMD, P-value −5.37, <0.001
c
−2.9, <0.001
c
Migraine severity(VAS scale)
Baseline 8.05 (6.00–10.00) 7.68 (5.00–10.00) 0.364
a
After 4.19 (2.00–7.00) 5.34 (3.00–9.00) 0.001
b
GMD, P-value −3.86, <0.001
c
−2.34, <0.001
c
Migraine duration(hour)
Baseline 11.33 (4.00–24.00) 13.02 (1.00–24.00) 0.516
a
After 4.16 (1.00–24.00) 7.63 (1.00–24.00) 0.012
b
GMD, P-value −7.17, <0.001
c
−5.39, 0.002
c
Data are expressed as geometric mean (minimum–maximum).
a
P-value for comparing baseline migraine characteristics based on the analysis of Independent sample t-test after
logarithmic transformation on outcome variable.
b
P-value for comparing the changes of migraine characteristics between groups based on ANCOVA adjusted for
baseline values and also confounder variables (including age, years with migraine, changes in BMI, body fat, physical
activity, energy intake, selenium, vitamin E, and vitamin C) after logarithmic transformation on outcome variable.
c
GMD: geometric mean difference; P-value for comparing the changes of migraine characteristics within groups based
on the analysis of paired t-test after logarithmic transformation on outcome variable.
Dahri et al. Oral Coenzyme Q10 supplementation in patients with migraine
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group. As mentioned in the results, dietary antioxidant
intake did not change during the study in neither of the
groups; therefore, the observed changes can be attrib-
uted to the study supplement with more confidence.
Previous studies have demonstrated that
cytokines
5–9
and CGRP
10,11,13,24
may be involved in
the pathogenesis of migraine, and migraine patients
have been reported to have impaired serum levels of
these markers. Also, it has been shown that CoQ10 is
negatively associated with inflammatory molecules.
32
Few studies have investigated CoQ10 effect on IL-10
levels. In agreement with the finding of our study on
IL-10, Kumar et al. showed that combination of
CoQ10 and L-carnitine had no effect on IL-10 in
patients with heart failure, when administered for 12
weeks.
33
In contrast to our results, animal models
showed that CoQ10 increases IL-10 levels in rats.
34–36
It is probable that CoQ10 exerts its anti-inflamma-
tory properties by attenuating pro-inflammatory cyto-
kines, rather than elevating the anti-inflammatory
cytokines.
Numerous researches have assessed the effect of
CoQ10 supplementation on cytokine levels in other
diseases. Similar to our results, Abdollahzad et al.
found that taking 100 mg/day oral CoQ10 for two
months caused significant decrease in TNF-αlevels,
with no effect on IL-6 levels, in rheumatoid arthritis
patients.
37
In a study by Lee et al. 12 weeks of sup-
plementation with CoQ10 at a dose of 300 mg/day
in patients with coronary artery disease under statins
therapy, led to similar results on TNF-αand IL-6
serum levels.
38
Farsi et al. reported that 100 mg/day
CoQ10 in NAFLD patients for three months
reduced liver aminotransferases, hs-CRP, TNF-α,
and the grades of NAFLD; however, no significant
changes occurred in serum levels of IL-6.
39
In
another study, oral CoQ10 supplementation before
strenuous exercise decreased TNF-αlevels after exer-
cise and reduced the subsequent muscle damage via
modulating the inflammatory signaling; the sup-
plementation had no effect on IL-6, though.
40
In the
study by Sanoobar et al. supplementation of CoQ10
at a higher dose (500 mg/day) for 12 weeks in multiple
sclerosis patients resulted in decreased serum levels of
TNF-α, IL-6, and MMP-9, with no changes on IL-4
and TGF-βlevels.
41
Same positive effects of CoQ10
supplementation have been demonstrated on inflam-
mation in hepatocellular carcinoma patients after
surgery
42
and breast cancer patients undergoing
Tamoxifen therapy.
43
The anti-inflammatory effect
of Co-Q10 has been reported in animal studies as
well.
44–46
The anti-inflammatory effects of the
Table 3 Within and between group comparisons of CoQ10, CGRP, and serum inflammatory markers of patients with migraine
before and after the intervention
Variables CoQ10 (n=23) Placebo (n=22) MD (95% CI), P-value
CoQ10 (ng/ml)
Baseline 119.70 ±17.35 108.19 ±26.86 11.51 (−2.03, 25.04), 0.094
a
After 176.61 ±39.50 113.35 ±27.51 54.60 (35.95, 73.25), <0.001
b
MD (95% CI), P-value 56.91 (43.27,70.56), <0.001
c
5.16 (−4.41, 14.73), 0.275
c
CGRP (ng/L)
Baseline 76.87 ±53.94 54.93 ±33.53 21.93 (−5.21, 49.08), 0.111
a
After 66.77 ±42.81 58.29 ±35.67 −11.51 (−20.16,−2.85), 0.011
b
MD (95% CI), P-value −10.10 (−17.06,−3.14), 0.006
c
3.36 (−1.23, 7.95), 0.143
c
IL-6 (ng/L)
Baseline 16.56 ±9.82 13.54 ±7.24 3.03 (−2.18,8.24), 0.248
a
After 15.56 ±10.31 13.43 ±7.59 −1.71 (−3.91, 0.48), 0.122
b
MD (95% CI), P-value −1.00 (−2.21, 0.20), 0.099
c
−0.11 (−1.48, 1.27), 0.872
c
IL-10 (ng/L)
Baseline 47.10 ±28.69 38.98 ±22.85 8.13 (−7.51, 23.76), 0.301
a
After 56.29 ±37.55 46.00 ±26.98 7.36 (−7.04, 21.75), 0.306
b
MD (95% CI), P-value 9.18 (−1.22, 19.58),0.081
c
7.01(−1.14, 15.17),0.088
c
TNF-α
d
(ng/L)
Baseline 17.02 (7.62–59.00) 12.57 (7.70–58.00) 0.132
After 14.87 (7.32–49.70) 13.14 (7.27–65.70) 0.044
GMD , P-value −2.15, 0.034 0.57, 0.236
Data are expressed as mean ±standard deviation (SD) for CoQ10, CGRP, IL-6, IL-10, and as geometric mean (minimum–maximum)
for TNF-α.
CGRP: calcitonin gene-related peptide, IL-6: interleukin-6, IL-10: interleukin-10, TNF-α: tumor necrosis factor alpha. GMD: geometric
mean difference.
a
MD (95% CI); P-value for comparing baseline serum markers based on the analysis of Independent sample t-test.
b
MD (95% CI); P-value for comparing the changes of serum markers between groups based on ANCOVA adjusted for baseline
values and also confounder variables (including age, years with migraine, changes in BMI, body fat, physical activity, energy intake,
selenium, vitamin E, and vitamin C).
c
MD (95% CI); P-value for comparing the changes of serum markers within groups based on the analysis of paired t-test.
d
P-value for comparing baseline TNF-αbased on the analysis of Independent sample t-test, comparing the changes of TNF-α
between groups based on ANCOVA adjusted for baseline values and also confounder variables (including age, years with migraine,
changes in BMI, body fat, physical activity, energy intake, selenium, vitamin E, and vitamin C) and comparing the changes of TNF-α
within groups based on the analysis of paired t-test, after logarithmic transformation on outcome variable.
Dahri et al. Oral Coenzyme Q10 supplementation in patients with migraine
Nutritional Neuroscience 2018
6
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reduced form of CoQ10 on pro-inflammatory cyto-
kines and chemokines have been reported by
Schmelzer et al. in an in vitro study.
47
On the contrary, in a recent study reported by
Raygan et al. inflammatory markers were not affected
by consumption of 100 mg/day CoQ10 for eight
weeks, in patients with metabolic syndrome. The
authors suggested that this effect might be due to the
study design, duration, and dosages of CoQ10 sup-
plements.
48
Administration of 100 mg/day CoQ10
for eight weeks in the study by Gökbel et al. did not
affect IL-6 and TNF-αin healthy subjects, probably
due to the normal levels of cytokines at baseline or
insufficient dose of the supplement.
49
The exact mechanisms by which CoQ10 exerts its
anti-inflammatory effect is still unknown; however,
reducing nuclear factor kappa B via inhibiting its sig-
naling pathway and preventing its activity by scaven-
ging free radicals can be considered as a probable
mechanism.
38,41,42
TNF-αand IL-6 have pivotal role
in inflammatory cascade as effector or regulatory mol-
ecules
50
; hence, suppressing their activity seems to be
an effective objective.
On the other hand, there is a correlation between
neurologic inflammation and CGRP release in
migraine. Likewise, CGRP transcription can be stimu-
lated by endogenous inflammatory molecules, such as
TNF-α, which increases the CGRP promoter activity
and actuates MAPK pathway.
10
In our study,
reduction of TNF-αin CoQ10 treated group was
accompanied with CGRP decrease, which can be
explained by the above-mentioned mechanism.
CGRP is considered as a pain mediator, and we
expected that a reduction in CGRP serum levels
leads to a clinical improvement in the patients. As
our results showed, migraine attacks in terms of fre-
quency, severity, and duration attenuated during the
study period in CoQ10 group with a significant differ-
ence from that in the placebo group.
Similar to our results, previous studies confirmed
the efficacy of CoQ10 in migraine. Three months of
supplementation in adult migraine patients with
150 mg/day CoQ10, in an open-label study caused a
61.3% reduction of least 50% in the number of days
with migraine headaches.
19
In another randomized
double-blinded placeo-controlled trial (RDBPC) by
Sándor et al. administration of the higher dose of
300 mg/day CoQ10 was tried in adult migraineurs.
After three months of treatment, 50% responder rate
for headache frequency was 47.6% in CoQ10 group
with a significant difference compared to the placebo
group.
18
Shoeibi et al. reported in a recent RDBPC
that receiving 100 mg CoQ10 daily in patients diag-
nosed with migraine headache led to a significant
reduction in severity and duration and number of
attacks per month with a NNT =1.6, after three
months.
20
CoQ10 efficacy in migraine prevention has
been evaluated in children too. Preventive abilities of
CoQ10 have been studied in an open-label study on
patients with deficient levels of CoQ10; the results
revealed a clinical improvement following the sup-
plementation.
26
On the contrary, in another RDBPC
crossover add-on study by Slater et al. daily intake of
100 mg CoQ10 in a multidisciplinary treatment did
not lead to any changes in headache outcomes.
27
Study design, dose, and duration of the supplemen-
tation and patients’age group may have in part con-
tributed to the different results obtained from this
study.
Studies based on 31P-MRS (Phosphorus magnetic
resonance spectroscopy) obviously confirm that
impaired brain oxidative metabolism results in
deficient energy production in at least a subgroup of
migraineurs.
51–53
Recent biochemical, morphologic,
genetic, and therapeutic data provide support for the
mitochondrial theory in the pathogenesis of
migraine.
21
Considering the predominant role of
CoQ10 both as an antioxidant agent, and also a mito-
chondrial electron transporter, and taking into
account the mitochondrial dysfunction in migraine
pathogenesis, CoQ10 could prevent migraine attacks
via improving the oxidative status.
Safe level of 1200 mg/day has been proposed for
CoQ10 by Hathcock
29
; therefore, we tested higher
doses of CoQ10 as a migraine preventive agent com-
pared to the previous studies on migraine. It was
well-tolerated at the dose of 400 mg/day with no
reported side effects related to use of CoQ10 during
the study. Moreover, the NNT for at least 50%-respon-
der-rate of 2.4–3.6 was obtained for migraine attacks.
Safety of the supplementation together with the accep-
table NNT, present CoQ10 as an adjuvant therapy in
the prevention of migraine. Beside clinical features,
CoQ10 had almost suitable effect on biochemical
serum factors of the patients.
Our study had several limitations; first, the add-on
design of the study made it difficult to detect either
the pure impact of the CoQ10 on the attacks or its
synergistic effectiveness with the current prophylactic
therapy. Second, migraine symptoms such as nausea,
vomiting, and photophobia were not assessed.
Finally, longer intervention duration in larger sample
size is needed to observe long-term effects of CoQ10
on anti-inflammatory cytokines.
Conclusion
In conclusion, this clinical trial was the first to show
that a dose of 400 mg/day of CoQ10 for three
months could significantly reduce CGRP and TNF-α
in migraine patients, but did not affect IL-6 and IL-
10 levels. Clinical symptoms of migraine attacks
also improved at the end of the supplementation
Dahri et al. Oral Coenzyme Q10 supplementation in patients with migraine
Nutritional Neuroscience 2018 7
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period. We suggest that migraine patients might
benefit from CoQ10 supplementation as a comp-
lementary therapy. Further studies are needed to
confirm our findings.
Acknowledgements
The participation of all patients in this study is grate-
fully acknowledged.
Disclaimer statement
Contributor None.
Funding This work was supported by the Research
Vice-chancellor and Nutrition Research Center of
Tabriz University of Medical Sciences.
Conflicts of interest None.
Ethics approval None.
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