Examining coenzyme Q10 for migraine relief

Migraine^[1] is a neurovascular disorder^[2] characterized by recurrent moderate to severe pulsating headaches which, if left untreated, usually last for four to 72 hours^[3]. The word “migraine” comes from the Greek “ημικρανία” (hemi-krania) which translates to “half-skull.” This makes sense, as migraines typically affect half of the head. Symptoms^[4] associated with migraines include nausea, vomiting, and sensitivity to light, sound, smell, and movement.

According to the Global Burden of Disease project^[5], migraine is the sixth most disabling disorder in the world, and the most disabling of all neurological disorders, with a worldwide prevalence^[6] of around 15%. Moreover, it has been characterized as a predominantly female disorder with a nearly threefold higher prevalence in women compared to men. The burden imposed by migraines on sufferers’ daily life translates to a significant negative socioeconomic impact in terms of reduced quality of life^[7], and lost work^[8] and school^[9] productivity.

A migraine attack is generally divided into four phases^[10]: (i) the prodrome or premonitory phase (which occurs hours to days before the headache), (ii) the aura phase (which immediately precedes or accompanies the headache), (iii) the headache phase, and (iv) the postdrome or “migraine hangover” phase (which follows the headache). These phases involve several signs and symptoms, can be overlapping, and are not necessarily experienced by all migraine sufferers. This complexity reflects the variable involvement of multiple neural networks and brain regions.

The causes of migraine are complex and still poorly understood, but are believed to be related to a mix of genetic and environmental factors^[11]. According to the trigeminovascular theory^[12], depicted in Figure 1, once a migraine is “triggered,” the trigeminovascular system releases inflammatory cytokines, neuroinflammatory peptides, and calcitonin gene-related peptide, which produce vasodilation and neurogenic inflammation. The vasodilation and neurogenic inflammation sensitize the trigeminovascular sensory fibers that carry signals to the trigeminal nuclei, which are finally transmitted to the thalamus and cerebral cortex, where they are felt as pain.

Management^[13] of migraines includes pharmacological and non-pharmacological acute (aimed at aborting a migraine episode once it occurs) and prophylactic (aimed at preventing future migraine occurrence, and reducing attack duration and severity) treatments. There are some nutraceuticals^[14] among the prophylactics that are being investigated, such as coenzyme Q10 (CoQ10), magnesium, butterbur root extract, and feverfew. All four have shown promise for the treatment of migraines.

Coenzyme Q10^[15] (CoQ10) is a molecule found in mitochondria that is both produced by the body and absorbed from foods, and which is an essential element of the mitochondrial electron transport chain. It is also an antioxidant. As the neuronal and vascular dysfunction observed in migraines has been proposed by some to be, at least partly, related to mitochondrial dysfunction^[16], CoQ10 may be a promising agent for the prevention of migraines. However, trials investigating the effects of CoQ10 supplementation in participants with migraine have reported conflicting results. The study under review is a meta-analysis that pooled these trials together to examine the overall impact of CoQ10 supplementation on the frequency, severity, and duration of migraine attacks.

Migraine is a neurovascular disorder characterized by recurrent moderate to severe pulsating headaches, which typically affect half of the head. According to the World Health Organization, it is the sixth most disabling disorder in the world, and the most disabling of all neurological disorders. While the pathology of migraine is complex and poorly understood, mitochondrial dysfunction is thought to be, at least partly, implicated. As coenzyme Q10 (CoQ10) is an essential element of the mitochondrial electron transport chain, it has been studied as a potential preventive treatment. The study under review is a meta-analysis that aimed to assess the efficacy of CoQ10 for treating the clinical features of migraine.

This was a PRISMA^[17]-compliant systematic review and meta-analysis evaluating the effects of CoQ10 supplementation on clinical features of migraine. Eligible studies had to be randomized placebo-controlled trials published in English investigating the effects of CoQ10 in isolation on the frequency, severity, or duration of migraine attacks in humans.

Four studies involving a total of 221 participants met the inclusion criteria and were included in the meta-analysis. Of these, all four reported on the frequency of migraine attacks, while three also reported on the duration and severity of migraine attacks. Studies lasted from 12 to 16 weeks with an average of 14 weeks, involved between 42 and 73 participants, and used between 100 and 400 milligrams of CoQ10 per day. Three studies included both men and women, while one study included only women. The participants’ age ranged from six to 65 years, with an average age of 29 years.

According to the authors, the Cochrane Collaboration’s^[18] risk of bias assessment tool for RCTs was used to assess individual study quality, but the results of this assessment were not reported. Instead, it seems like individual study quality was reported using the Jadad^[19] scale, meaning methodological quality was assessed on the basis of randomization, blinding, and reporting of withdrawals and dropouts, and given a rating of between 0 (very poor) and 5 (rigorous).

The primary outcomes of the meta-analysis were the change in frequency, severity, and duration of migraine attacks as compared to placebo. To analyse the data, a fixed effects model was used in analyses where heterogeneity was found to be under 50%. Otherwise, a random effects model was used. The other outcome of interest was the existence of a non-linear dose-response relationship between the CoQ10 dose and the difference in the aforementioned clinical features. The study was not pre-registered.

This was a systematic review and meta-analysis of four studies and 221 individuals comparing the effects of CoQ10 to placebo on the improvement in the frequency, severity, and duration of migraine attacks. The studies included lasted from 12 to 16 weeks, involved between 42 and 73 men and women with an average age of 29 years, and had participants supplement between 100 and 400 milligrams of CoQ10 per day.

The study under review found a statistically significant reduction in the frequency of migraine attacks with CoQ10 supplementation as compared to placebo (-1.9 attacks per month, with a baseline frequency of around eight attacks per month). However, there was no statistically significant difference for the change in severity and duration of migraine attacks with CoQ10 relative to placebo, although there were trends for a reduction in both of these outcomes.

Moreover, there was no significant non-linear dose-response relationship between CoQ10 dose and the clinical features of migraine.

In the context of the frequency of migraine attacks, no significant heterogeneity (i.e. variation in the in terms of design, outcomes, and results of the included studies) was detected (I²=37%, p=0.192). However, significant heterogeneity was detected for the severity (I²=98%, p<0.001) and duration (I²=83%, p=0.003) of migraine attacks analyses.

In terms of the quality assessment of individual studies, three studies received a Jadad score of 3 or more, while one study received a score of 2 or less.

A statistically significant reduction in the frequency of migraine attacks was found with the use of CoQ10 relative to placebo. However, there was no statistically significant improvement in the severity and duration of migraine attacks between treatments.

The study under review suggests that CoQ10 supplementation is an effective therapy for reducing migraine attack frequency. However, there is currently no strong evidence to support its use for the reduction of migraine attack severity and duration. Moreover, a closer inspection of the methodology reveals several limitations that warrant discussion.

According to the authors, studies included in the meta-analysis had to be placebo-controlled. However, as highlighted in Figure 2, one^[20] of the four trials that was included did not use a placebo in the control group. Instead, the control group simply continued to receive their preventive drugs, while the treatment group continued using their preventive drugs while also supplementing with CoQ10. This means that the placebo^[21] effect could have interfered with the results, since the therapeutic effects observed in the CoQ10 group could have been produced, at least partially, by the placebo effect of the supplement. To better understand the possible magnitude of the placebo effect, consider the results of the other three trials included in the meta-analysis. In one^[22] of the trials, there was no effect of placebo on migraine frequency. However, in the other two trials^[23][24], migraine attacks per month were reduced from 6.4 to 3.5 (a 45% reduction) after eight weeks, and from 13.5 to 7.3 (a 46% reduction) after 16 weeks in the placebo treatments. This means that, theoretically, up to around 45% of the 63% reduction (from 2.7 to 1.0 per month) in migraine attack frequency observed with CoQ10 supplementation in the non-placebo controlled trial could have been produced by the placebo effect. Moreover, it’s worth noting that the calculated effect size of CoQ10 on the frequency of migraine attacks in the non-placebo controlled trial was the largest out of the four trials included in the meta-analysis, and exclusion of this trial from the analysis would have likely changed the overall results of this analysis to non-significant. Furthermore, the methodological quality of the aforementioned trial was quite poor, as the trial was non-randomized (which is, again, grounds for exclusion from the meta-analysis, according to the authors) and non-blinded.

Another issue that warrants discussion is the use of a fixed effects model to analyze the data on the frequency of migraine attacks. According to the authors, a fixed effects model was to be used in analyses where heterogeneity was found to be under 50%. A fixed effects model analysis assumes that the studies employed similar methodologies. As such, it tends to give narrower confidence intervals than a random effects model and is more likely to detect significant results. Considering that the I² statistic (which was used to assess heterogeneity) can be imprecise and substantially biased^[25] in meta-analyses where the number of included studies is small, like in the case of this meta-analysis, it may have been more appropriate to use a random effects model to analyze the data, even though no significant heterogeneity was detected. Of course, using a random effects model means that there would be a higher probability that the results relating to the frequency of migraine attacks would not have reached statistical significance.

Following from the above, even though a random effects model was used for the severity and duration of migraine attacks analyses, the high degree of heterogeneity for these outcomes (I² = 98% and 83%) suggests that the trials included in the analyses may have been too dissimilar in terms of design and results, and that it may not have been appropriate to conduct a meta-analysis in the first place. This means that much trust can’t be placed in the specific numbers obtained from the severity and duration analyses either.

The quality assessment of the trials included in the meta-analysis is also worth looking at. Strangely, while the authors mention that they used the Cochrane Collaboration’s^[18] risk of bias assessment tool for RCTs to assess individual study quality, the results of this assessment are nowhere to be found. Instead, it seems like study quality was reported using the Jadad^[19] scale, although there is no explicit mention of this scale in the paper. According to the authors, three studies received a score of 3 or more, which is generally considered as good quality, while one study received a score of 2 or less, which is generally considered as poor quality. Despite its wide use, the Jadad scale has been criticized as being overly simplistic and incomplete^[26], and as having low consistency^[27] between raters. In fact, the use of the Jadad scale is explicitly discouraged in the Cochrane Guidelines[^[28]. This means that there is no assurance that the studies included in the meta-analysis were of high quality.

Finally, it’s important to mention that this meta-analysis included a very small number of trials with relatively small sample sizes, which lowers editorial confidence in the results^[29], both in terms of the possibility of the frequency outcome being a false positive, and in terms of the possibility of the severity and duration outcomes being false negatives. This is made even worse by the context of one out of the four assessed studies rated as being of poor methodological quality. Keep in mind that the quality of the remaining three studies is questionable as well, due to the way that the researchers conducted the quality assessment and reported its results.

This systematic review and meta-analysis found that CoQ10 can potentially reduce the frequency of migraine attacks. However, there is no strong evidence to support its use for the reduction of migraine attack severity and duration. The small number of studies included in the analysis, the inclusion of a non-randomized, non-placebo controlled trial, the use of a fixed effects model to analyze some of the results, and the suboptimal quality assessment make the results of the meta-analysis questionable.

CoQ10 is a good candidate for preventing migraine attacks since its modes of action relate to mitochondrial pathways, oxidative stress, and inflammation, all of which may play some role in the condition’s onset. For example, CoQ10 plays an important part in cellular energy production^[15] due to its role as an electron carrier in the mitochondrial electron transport chain. Given the evidence for mitochondrial energy depletion^[30] in migraine, CoQ10 supplementation may help restore mitochondrial energy stores and alleviate migraine symptoms. Moreover, CoQ10 may help prevent migraine attacks by reducing brain levels of calcitonin gene-related peptide^[23] (CGRP), a peptide that likely plays an important role^[31] in migraine pathophysiology.

However, despite the plausible mechanisms of action through which CoQ10 supplementation may prevent migraine attacks, the results of the available research suggest that the evidence to support the use of CoQ10 for the prevention of migraines is currently weak.

For example, a recent systematic review and meta-analysis^[32] examining the use of vitamins and minerals for migraine prophylaxis reported that CoQ10 supplementation in adults did not result in a significant improvement in migraine attack frequency, severity, or duration. Only two trials examining the effects of CoQ10 were included in this meta-analysis, however. This is probably due to a literature search process and inclusion/exclusion criteria that differed from the current meta-analysis.

Another recent systematic review and meta-analysis^[33], which included five trials, found that CoQ10 supplementation can reduce the duration, but not the frequency or severity of migraine attacks, as compared to placebo. However, out of the five studies included, two were observational studies, and two were publications that were derived from the same trial. Also, the analysis of the effect of CoQ10 on the duration of migraine attacks only included three studies, one^[20] of which was the non-randomized, non-placebo controlled, non-blinded trial mentioned in the previous section, and the other two being the aforementioned duplicate publications.

Other reviews, such as this 2018 review^[14] of non-pharmacological migraine treatments, this 2018 review in children^[34] migraine sufferers, and this 2019 systematic review^[35], have all come to similar conclusions: that although some preliminary evidence suggests that CoQ10 may help prevent migraine attacks, most of the available trials suffer from methodological limitations that prevent researchers from being able to draw definitive conclusions.

This is one of three meta-analyses carried out to date looking at the effects of CoQ10 supplementation on clinical features of migraine. While the results of these meta-analyses are mixed, a closer inspection of the methodologies employed and the trials included in the analyses suggests that the evidence to recommend CoQ10 as a preventive migraine treatment is weak.

Q. Does CoQ10 supplementation have any adverse effects?

In general, CoQ10 seems to be well-tolerated^[36], even up to doses of 1200 milligrams per day. The adverse effects associated with its supplementation have been minor and infrequent, and include stomach upset, nausea, vomiting, and diarrhea. Documented side effects that are even rarer include dizziness, photophobia, irritability, headache, heartburn, and fatigue. Moreover, taking CoQ10 close to bedtime may cause mild insomnia in some people.

Q. Can I get therapeutic amounts of CoQ10 from my diet alone?

As you can see in Figure 3, the richest dietary sources^[37] of CoQ10 are meats and fish, and mainly the heart. However, most dietary sources generally provide under three milligrams of CoQ10 per serving, which means that it’s very unlikely that you can get therapeutic amounts of CoQ10 just from food.

Q. Are there different forms of CoQ10 and, if so, which form should I take?

Yes, there are two forms of CoQ10: ubiquinone (the oxidized form) and ubiquinol (the reduced form). While both forms can increase circulating levels of CoQ10 in the body, in general, it seems that ubiquinone has relatively lower bioavailability^[38] as compared to ubiquinol because of its lipophilicity, crystalline state, and high molecular weight.

For example, one study^[39] in ten older men who were randomized to take 200 milligrams per day of ubiquinone or ubiquinol for 14 days found that ubiquinol led to significantly larger increases in total CoQ10 plasma levels, compared to ubiquinone.

The above results are consistent with the results of another study^[40] in younger participants, which reported that ubiquinol supplementation at a dose of 200 milligrams per day increased plasma CoQ10 levels significantly more than ubiquinone supplementation after four weeks.

With the above studies in mind, it’s probably best to use a CoQ10 supplement that contains the reduced form of CoQ10 (ubiquinol).

Q. What other non-drug therapies are there that may help treat migraines?

A number of non-drug migraine therapies^[14] have been investigated, including nutraceuticals, behavioral techniques, and invasive and non-invasive neuromodulation.

The most commonly used nutraceuticals, excluding CoQ10, which have shown some evidence in migraine prevention are riboflavin (vitamin B2), magnesium, butterbur root extract, and feverfew. Out of these, the evidence for riboflavin, magnesium, and feverfew is limited and has been mixed. The evidence has been more positive for butterbur root extract. However, recent concerns related to possible liver toxicity from its use mean that it currently can’t be recommended as a migraine treatment.

Behavioral techniques include a series of strategies, such as relaxation, thermal and electromyographic feedback, and cognitive behavioral therapy. There is some evidence^[41] supporting the use of these techniques in migraine therapy, especially in people who can’t use pharmacologic treatments, or as an add-on to ongoing treatments.

Invasive neuromodulation techniques include occipital nerve stimulation^[42] (ONS), sphenopalatine ganglion stimulation^[43] (SGS), and high cervical spinal cord stimulation^[44]. For the former two techniques, there is currently insufficient evidence^[14] to recommend them as migraine therapy, while, for the latter technique, the evidence is limited but quite promising.

Non-invasive neuromodulation techniques^[14] act by stimulating the nervous system centrally or peripherally with an electric current through the skin or with a fluctuating magnetic field. While there is good evidence supporting the use of some of these techniques for migraine treatment, they are only available at specialized centers in some countries.

Migraine is a neurovascular disorder characterized by recurrent moderate to severe pulsating headaches, which typically affect half of the head. While the pathology of migraine is complex and poorly understood, mitochondrial dysfunction is thought to be implicated. As CoQ10 is an essential element of the of the mitochondrial electron transport chain, it has been investigated as a potential preventive treatment. The meta-analysis under review aimed to assess the efficacy of CoQ10 for treating the clinical features of migraine.

According to the results of this meta-analysis, CoQ10 may be effective for reducing migraine attack frequency. However, the meta-analysis used suboptimal methods, and its results are based on a small number of trials, some of which are of very low methodological quality. At this point in time, higher quality evidence is needed before researchers can draw any firm conclusions on the topic.