Expanded question: What nutritional supplements have been shown to help with migraines?

Answered on April 2, 2024
Several nutritional supplements have been studied for their potential benefits in migraine prophylaxis. Magnesium supplementation has been associated with a reduction in migraine frequency, although the strength of evidence is limited.[1] Riboflavin (vitamin B2) at a dosage of 400 mg/day for three months has been shown to significantly decrease migraine days, duration, frequency, and pain score.[2] Coenzyme Q10 has also been reported to be beneficial in controlling migraine headache symptoms.[3]
Additionally, evidence suggests that vitamin D and Omega-3 fatty acids may be effective in migraine prophylaxis.[3] A high intake of vitamin B and folate has been associated with a lower risk of severe headache or migraine, with a synergistic interaction observed when both are consumed at high levels.[4] Other nutrients that have been considered for their role in mitochondrial bioenergetics and as natural immuno-modulatory components include carnitine, alpha-lipoic acid, and melatonin.[5]
It is important to note that while these supplements may offer some benefit, further research is required to fully establish their efficacy and optimal dosages for migraine prevention. Clinicians should consider individual patient needs, potential interactions with other medications, and the overall balance of risks and benefits when recommending these supplements.

References

1.
An Evidence-Based Review of Oral Magnesium Supplementation in the Preventive Treatment of Migraine.

Teigen L, Boes CJ.

Cephalalgia : An International Journal of Headache. 2015;35(10):912-22. doi:10.1177/0333102414564891.

Background: Migraine is an incompletely understood, debilitating disorder that lacks a universally effective treatment. Magnesium participates in a variety of biochemical processes related to migraine pathophysiology, and a deficiency could contribute to migraine development.

Methods: A review of the literature from 1990 to the present on magnesium and migraine was conducted.

Review: The authors identified 16 studies aimed at magnesium status assessment in migraine, and four intervention trials assessing the efficacy of oral magnesium supplementation, independent of other therapies, in the prevention of migraine.

Conclusion: The strength of evidence supporting oral magnesium supplementation is limited at this time. With such limited evidence, a more advantageous alternative to magnesium supplementation, in patients willing to make lifestyle changes, may be to focus on increasing dietary magnesium intake.

2.
Effect of Vitamin B2 Supplementation on Migraine Prophylaxis: A Systematic Review and Meta-Analysis.

Chen YS, Lee HF, Tsai CH, et al.

Nutritional Neuroscience. 2022;25(9):1801-1812. doi:10.1080/1028415X.2021.1904542.

Objective: Migraine is a common disease worldwide and migraine prevention is primarily currently based on pharmaceuticals. The mechanism of Vitamin B2 may positively contribute to migraine. This systematic review and meta-analysis aimed to evaluate the impact of Vitamin B2 supplementation on the days, duration, frequency, and pain score of the migraine attack.

Methods: : The PRISMA guideline was used for the studying process. Five electronic databases, PubMed, Embase, Cochrane, CINAHL, and CEPS were searched from 1990 to March 2019. The search terms were Vitamin B2, migraine, and prophylactic. A meta-analysis was performed using Comprehensive Meta-Analysis (CMA) version.

Results: : Nine articles were included in systemic review and finally meta-analysis. Eight randomized controlled trials and one controlled clinical trial with 673 subjects were analyzed using meta-analysis. Vitamin B2 supplementation significantly decreased migraine days (= .005, = 89%), duration (= .003, = 0), frequency (= .001, = 65%), and pain score (= .015, = 84%).

Conclusions: A pooled analysis of available randomized controlled clinical trials demonstrated that Vitamin B2 400 mg/day for three months supplementation had significant effect on days, duration, frequency, and pain score of migraine attacks.

3.
Review on Headache Related to Dietary Supplements.

Ariyanfar S, Razeghi Jahromi S, Togha M, Ghorbani Z.

Current Pain and Headache Reports. 2022;26(3):193-218. doi:10.1007/s11916-022-01019-9.

Purpose Of Review: The lifetime prevalence of headaches is 96%. Approximately 11% of the adult population worldwide has a migraine headache. Migraine is a complex disorder that is more than a simple headache. So far, many underlying mechanisms, i.e. inflammatory, vascular, neurogenic have been hypothesized. In recent years evidences proposed that an energy deficit due to changes in mitochondrial function contributes to migraine pathophysiology as an upstream disorder. Recent insights suggested that the coexistence of sensory-stimuli surplus and energy-reserve shortage activate the trigeminovascular system. Some nutrients are considered as essential elements in mitochondrial bioenergetics and some others are known as natural immuno-modulatory components. Also, evidence showed their beneficial effect in headache prophylaxis and treatment. In present study, we aimed to review the available data in this field.

Recent Findings: Vitamin B group, magnesium, and Coenzyme Q10 (CoQ10) are well-known for their function in mitochondrial energy metabolism. On the other hand, studies support their beneficial role in controlling migraine headache symptoms. For instance, daily intake of 400-milligram riboflavin for 3 months resulted in more than 50% reduction in migraine attacks in more than half of the consumers. According to recent evidence, vitamin D and Omega-3 which are considered as famous immune-modulatory compounds are also reported to be effective in migraine prophylaxis. For example, every 22% reduction in migraine headache occurrence was reported for every 5 ng/ml rise in serum vitamin D. Supplementation with vitamin B group, CoQ10, magnesium, vitamin D and Omega-3 could be considered as an effective, less costly strategy in headache/migraine prophylaxis.

4.
Vitamin B and Folate Intake Are Associated With Lower Risk of Severe Headache or Migraine in Adults: An Analysis Based on NHANES 1999-2004.

Tian S, Yu X, Wu L, et al.

Nutrition Research (New York, N.Y.). 2024;121:51-60. doi:10.1016/j.nutres.2023.11.008.

New Research

Previous studies have shown that B vitamins can relieve migraine. However, the association between vitamin B and folate, 2 important B vitamins consumed in the diet, with migraine have received minimal attention. This study explored the independent relationships between dietary vitamin B and folate intake with migraine and the interaction effect of these 2 nutrients on migraine in US adults. We hypothesized that vitamin B and folate intake would be inversely associated with migraine. This study included cross-sectional data from participants aged 20 years and older who participated in the National Health and Nutrition Examination Survey from 1999 to 2004. We conducted multivariate logistic regression and restricted cubic spline regression to explore the association between dietary vitamin B and folate intake on migraine. Also, relative excess risk due to interaction, attributable proportion of interaction, and synergy index were used to assess additive interactions. A total of 7017 participants were included in this study, 1350 of whom were migraineurs. We determined that vitamin B and folate intake revealed a negative association with severe headache or migraine (0.66; 95% confidence interval [CI], 0.47-0.89; P = .01 and 0.57; 95% CI, 0.42-0.78; P = .002]), respectively. Also, a significant interaction effect between a high mass of vitamin B and folate intake was observed for a lower risk of migraine (relative excess risk due to interaction, 0.28 [95% CI, 0.05-0.51]; attributable proportion of interaction: 0.45 [95% CI, 0.05-0.86]; synergy index: 0.58 [95% CI, 0.40-0.83]). A high mass of vitamin B and folate intake (vitamin B intake ≥ 2.39 mg/day and folate intake ≥ 502.01 µg/day) presented a synergistic interaction with migraine, suggesting that these 2 nutrients might be beneficial in preventing migraine.

5.
Nutrients to Improve Mitochondrial Function to Reduce Brain Energy Deficit and Oxidative Stress in Migraine.

Fila M, Chojnacki C, Chojnacki J, Blasiak J.

Nutrients. 2021;13(12):4433. doi:10.3390/nu13124433. Copyright License: CC BY

The mechanisms of migraine pathogenesis are not completely clear, but P-nuclear magnetic resonance studies revealed brain energy deficit in migraineurs. As glycolysis is the main process of energy production in the brain, mitochondria may play an important role in migraine pathogenesis. Nutrition is an important aspect of migraine pathogenesis, as many migraineurs report food-related products as migraine triggers. Apart from approved anti-migraine drugs, many vitamins and supplements are considered in migraine prevention and therapy, but without strong supportive evidence. In this review, we summarize and update information about nutrients that may be important for mitochondrial functions, energy production, oxidative stress, and that are related to migraine. Additionally, we present a brief overview of caffeine and alcohol, as they are often reported to have ambiguous effects in migraineurs. The nutrients that can be considered to supplement the diet to prevent and/or ameliorate migraine are riboflavin, thiamine, magnesium ions, niacin, carnitine, coenzyme Q10, melatonin, lipoic acid, pyridoxine, folate, and cobalamin. They can supplement a normal, healthy diet, which should be adjusted to individual needs determined mainly by the physiological constitution of an organism. The intake of caffeine and alcohol should be fine-tuned to the history of their use, as withdrawal of these agents in regular users may become a migraine trigger.

Expanded question: What is the recommended dosage and frequency for magnesium, riboflavin (vitamin B2), coenzyme Q10, vitamin D, and Omega-3 fatty acids in migraine treatment? Are there any potential side effects or interactions with other medications when taking these supplements? What research studies support the effectiveness of these supplements in migraine management?

Answered on May 1, 2024
The U.S. Department of Veterans Affairs and U.S. Department of Defense Clinical Practice Guideline does not support the routine use of coenzyme Q10, riboflavin (vitamin B2), vitamin B6, melatonin, or omega-3 for the prevention of migraine.[1] However, the guideline does indicate that oral magnesium has been demonstrated to reduce migraine frequency and intensity compared to placebo.[1] The specific dosages and frequencies for these supplements are not detailed in the guideline, and thus, cannot be provided here.
Regarding potential side effects or interactions with other medications, the guideline does not provide specific information on these supplements. Clinicians should be aware that any supplement can potentially interact with other medications and should be used with caution, especially in patients with complex medical histories or those taking multiple medications.
For the most current and detailed information on dosages, side effects, and interactions, clinicians are encouraged to consult the latest research and comprehensive databases such as UpToDate, which are regularly updated with the latest evidence and expert recommendations.

References

1.
The Primary Care Management of Headache: Synopsis of the 2020 U.S. Department of Veterans Affairs and U.S. Department of Defense Clinical Practice Guideline.

Sico JJ, Macedo F, Lewis J, et al.

Military Medicine. 2022;187(9-10):e1091-e1102. doi:10.1093/milmed/usab490.

There was also evidence to support the use of mindfulness-based therapies to treat chronic headaches. Mindfulness-based therapies include meditation, relaxation, mindfulness-based stress reduction and cognitive therapy, acceptance-based approaches, and yoga. Evidence supports the use of mindfulness meditation as a method to reduce pain intensity and headache frequency.29 Interventions such as mindfulness-based stress reduction significantly improved pain intensity when compared to other forms of meditation (e.g., mindfulness-based cognitive therapy, Vipassana, and Zen). Mindfulness-based stress reduction also had improved efficacy over other interventions such as relaxation, education, pharmacotherapy, or delayed treatment.33 Two systematic reviews assessed the efficacy of acupuncture versus sham treatment for migraine. Per the reviews acupuncture showed no reduction in headache days per month but did show improvements in headache frequency and visual analog scores for pain. However, given the low quality of the evidence, questions remain regarding the utility of acupuncture for the treatment of migraine.34,35
In the acute management of migraine, one systematic review, which included randomized controlled trials with a total of 948 participants, found that intravenous magnesium improved headache pain at 15-45 minutes, 120 minutes, and 24 hours compared to controls.36 In considering the prevention of migraine, two systematic reviews, which included 12 randomized controlled trials with a total of 834 participants, demonstrated a reduction in migraine frequency and intensity with oral magnesium, compared to placebo.37–38 In comparison, for the prevention of migraine, the current evidence base does not support the routine use of coenzyme Q10, feverfew, vitamin B2, vitamin B6, melatonin, or omega-3.37,39–44

In the acute management of migraine, one systematic review, which included randomized controlled trials with a total of 948 participants, found that intravenous magnesium improved headache pain at 15-45 minutes, 120 minutes, and 24 hours compared to controls.36 In considering the prevention of migraine, two systematic reviews, which included 12 randomized controlled trials with a total of 834 participants, demonstrated a reduction in migraine frequency and intensity with oral magnesium, compared to placebo.37–38 In comparison, for the prevention of migraine, the current evidence base does not support the routine use of coenzyme Q10, feverfew, vitamin B2, vitamin B6, melatonin, or omega-3.37,39–44
Current evidence suggests that interventions by a physical therapist can provide valuable relief for TTH.45–48 The interventions performed by a physical therapist included manual therapy, therapeutic exercise, strength and endurance training, self-management training, patient education, and adjunctive modalities. These interventions reduced the frequency of TTHs. The evidence base for these interventions consisted of three systematic reviews that demonstrated a decrease in headache frequency, intensity, and disability (as measured by the Headache Impact Test-6) with large effect sizes favoring all active manual interventions compared to placebo, with combined techniques yielding the greatest impact.45

Expanded question: What are the specific mechanisms of action for magnesium, riboflavin, coenzyme Q10, vitamin D, and Omega-3 fatty acids in treating migraines? Could you provide a detailed overview of the major clinical trials that have investigated the efficacy of these supplements in migraine management? Are there any specific patient populations or migraine subtypes for which magnesium, riboflavin, coenzyme Q10, vitamin D, and Omega-3 fatty acids are particularly effective or contraindicated?

Answered on May 1, 2024
The mechanisms of action for the supplements in question are thought to relate to their roles in mitochondrial energy metabolism, neuroinflammation, oxidative stress, and neurotransmitter modulation, which are all implicated in migraine pathophysiology.
Magnesium is believed to prevent cortical spreading depression, inhibit neurotransmitter release, and prevent platelet aggregation, which are all thought to contribute to the pathogenesis of migraines.[1-2] Riboflavin is involved in mitochondrial energy production and may reduce neuroinflammation and oxidative stress.[3] Coenzyme Q10 also plays a role in mitochondrial energy production and may have a neuroprotective effect.[4] Vitamin D's role may be related to its immunomodulatory effects.[5] Omega-3 fatty acids are thought to exert their effects through anti-inflammatory properties.[5]
Clinical trials have investigated these supplements' efficacy in migraine management. For example, a trial indicated that daily intake of 400 mg riboflavin for 3 months resulted in a significant reduction in migraine attacks.[5] Another study suggested that oral magnesium supplementation could be effective in migraine prophylaxis, particularly in certain subsets of patients.[1]
There is no strong evidence to suggest that these supplements are particularly effective or contraindicated in specific patient populations or migraine subtypes. However, it is generally recommended that any supplementation should be considered on an individual basis, taking into account the patient's overall health, potential drug interactions, and comorbid conditions. The safety profiles of these supplements are generally considered good, although side effects can occur, and high doses of certain supplements may be contraindicated in patients with specific conditions. For instance, magnesium can cause gastrointestinal side effects and should be used cautiously in patients with renal impairment.[1-2]

References

1.
Role of Magnesium in the Pathogenesis and Treatment of Migraine.

Sun-Edelstein C, Mauskop A.

Expert Review of Neurotherapeutics. 2009;9(3):369-79. doi:10.1586/14737175.9.3.369.

Magnesium is an important intracellular element that is involved in numerous cellular functions. Deficiencies in magnesium may play an important role in the pathogenesis of migraine headaches by promoting cortical spreading depression, alteration of neurotransmitter release and the hyperaggregation of platelets. Given this multifaceted role of magnesium in migraine, the use of magnesium in both acute and preventive headache treatment has been researched as a potentially simple, inexpensive, safe and well-tolerated option. Studies have shown that preventive treatment with oral magnesium and acute headache treatment with intravenous magnesium may be effective, particularly in certain subsets of patients. In this review, the pathogenesis of migraine will be discussed, with an emphasis on the role of magnesium. Studies on the use of intravenous and oral magnesium in migraine treatment will be discussed and recommendations will be made regarding the use of magnesium in treating migraine headaches.

2.
The Role of Magnesium in Neurological Disorders.

Kirkland AE, Sarlo GL, Holton KF.

Nutrients. 2018;10(6):E730. doi:10.3390/nu10060730. Copyright License: CC BY

Magnesium is well known for its diverse actions within the human body. From a neurological standpoint, magnesium plays an essential role in nerve transmission and neuromuscular conduction. It also functions in a protective role against excessive excitation that can lead to neuronal cell death (excitotoxicity), and has been implicated in multiple neurological disorders. Due to these important functions within the nervous system, magnesium is a mineral of intense interest for the potential prevention and treatment of neurological disorders. Current literature is reviewed for migraine, chronic pain, epilepsy, Alzheimer’s, Parkinson’s, and stroke, as well as the commonly comorbid conditions of anxiety and depression. Previous reviews and meta-analyses are used to set the scene for magnesium research across neurological conditions, while current research is reviewed in greater detail to update the literature and demonstrate the progress (or lack thereof) in the field. There is strong data to suggest a role for magnesium in migraine and depression, and emerging data to suggest a protective effect of magnesium for chronic pain, anxiety, and stroke. More research is needed on magnesium as an adjunct treatment in epilepsy, and to further clarify its role in Alzheimer’s and Parkinson’s. Overall, the mechanistic attributes of magnesium in neurological diseases connote the macromineral as a potential target for neurological disease prevention and treatment.

3.
Experimental and Clinical Evidence of the Effectiveness of Riboflavin on Migraines.

Yamanaka G, Suzuki S, Morishita N, et al.

Nutrients. 2021;13(8):2612. doi:10.3390/nu13082612. Copyright License: CC BY

Riboflavin, a water-soluble member of the B-vitamin family, plays a vital role in producing energy in mitochondria and reducing inflammation and oxidative stress. Migraine pathogenesis includes neuroinflammation, oxidative stress, and mitochondrial dysfunction. Therefore, riboflavin is increasingly being recognized for its preventive effects on migraines. However, there is no concrete evidence supporting its use because the link between riboflavin and migraines and the underlying mechanisms remains obscure. This review explored the current experimental and clinical evidence of conditions involved in migraine pathogenesis and discussed the role of riboflavin in inhibiting these conditions. Experimental research has demonstrated elevated levels of various oxidative stress markers and pro-inflammatory cytokines in migraines, and riboflavin's role in reducing these marker levels. Furthermore, clinical research in migraineurs showed increased marker levels and observed riboflavin's effectiveness in reducing migraines. These findings suggest that inflammation and oxidative stress are associated with migraine pathogenesis, and riboflavin may have neuroprotective effects through its clinically useful anti-inflammatory and anti-oxidative stress properties. Riboflavin's safety and efficacy suggests its usefulness in migraine prophylaxis; however, insufficient evidence necessitates further study.

4.
Metabolic Treatments of Migraine.

Lisicki M, Schoenen J.

Expert Review of Neurotherapeutics. 2020;20(3):295-302. doi:10.1080/14737175.2020.1729130.

: Most preventive migraine treatments modify the brain's excitation/inhibition balance and/or serotonin metabolism, which likely accounts for their unfavorable adverse effect profile. Novel biological therapies blocking CGRP transmission are effective and better tolerated, but they are expensive and may not influence brain dysfunctions upstream in the pathophysiological cascade of migraine, including premonitory and aura symptoms. Biochemical and clinical studies suggest that there may be another complimentary treatment strategy, the one that targets the underestimated metabolic facet of migraine pathophysiology.: After a brief description of the metabolic abnormalities found in migraine patients, we will review and discuss published data on metabolic treatments of migraine. There is evidence that riboflavin and co-enzyme Q10 are effective for the prevention of migraine and quasi devoid of adverse effects. Response rates are close to those of topiramate, propranolol, and CGRP/CGRPrec mAbs. The evidence is weaker for thioctic acid. Dietary and pharmacological strategies inducing ketosis are novel promising approaches for which preliminary trials with favorable outcomes have been published.: Metabolic treatments of migraine constitute an effective, well-tolerated, inexpensive, and evidence-supported therapeutic option for migraine prophylaxis, and may be considered as first treatment line in many patients, including in children and adolescents.

5.
Review on Headache Related to Dietary Supplements.

Ariyanfar S, Razeghi Jahromi S, Togha M, Ghorbani Z.

Current Pain and Headache Reports. 2022;26(3):193-218. doi:10.1007/s11916-022-01019-9.

Purpose Of Review: The lifetime prevalence of headaches is 96%. Approximately 11% of the adult population worldwide has a migraine headache. Migraine is a complex disorder that is more than a simple headache. So far, many underlying mechanisms, i.e. inflammatory, vascular, neurogenic have been hypothesized. In recent years evidences proposed that an energy deficit due to changes in mitochondrial function contributes to migraine pathophysiology as an upstream disorder. Recent insights suggested that the coexistence of sensory-stimuli surplus and energy-reserve shortage activate the trigeminovascular system. Some nutrients are considered as essential elements in mitochondrial bioenergetics and some others are known as natural immuno-modulatory components. Also, evidence showed their beneficial effect in headache prophylaxis and treatment. In present study, we aimed to review the available data in this field.

Recent Findings: Vitamin B group, magnesium, and Coenzyme Q10 (CoQ10) are well-known for their function in mitochondrial energy metabolism. On the other hand, studies support their beneficial role in controlling migraine headache symptoms. For instance, daily intake of 400-milligram riboflavin for 3 months resulted in more than 50% reduction in migraine attacks in more than half of the consumers. According to recent evidence, vitamin D and Omega-3 which are considered as famous immune-modulatory compounds are also reported to be effective in migraine prophylaxis. For example, every 22% reduction in migraine headache occurrence was reported for every 5 ng/ml rise in serum vitamin D. Supplementation with vitamin B group, CoQ10, magnesium, vitamin D and Omega-3 could be considered as an effective, less costly strategy in headache/migraine prophylaxis.

Expanded question: What are the metabolic pathways involved in the absorption and utilization of magnesium, riboflavin, coenzyme Q10, vitamin D, and Omega-3 fatty acids in the body? How do these supplements interact with standard migraine medications, if at all, and what are the implications for treatment strategies? Are there any known genetic factors or comorbidities that can influence the effectiveness of these supplements in treating migraines?

Answered on May 1, 2024
The metabolic pathways involved in the absorption and utilization of the supplements in question are complex and multifaceted. Magnesium acts as a cofactor in various enzymatic reactions, including those involved in energy production and neurotransmitter release. Riboflavin is a precursor for flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN), which are coenzymes in the mitochondrial electron transport chain. Coenzyme Q10 is also a component of the electron transport chain and is essential for the production of adenosine triphosphate (ATP). Vitamin D receptors are present in many body tissues, and the active form of vitamin D, calcitriol, regulates calcium metabolism. Omega-3 fatty acids, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are incorporated into cell membranes and can affect cell signaling and inflammatory pathways.
Interactions between these supplements and standard migraine medications are not well characterized in the medical literature. However, it is known that some supplements may have additive effects with certain medications or may influence drug metabolism. For example, magnesium can have additive effects with medications that also affect neurotransmitter release or vascular tone.
Genetic factors can influence the effectiveness of these supplements. For instance, certain genetic variants in enzymes such as flavoenzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) can affect homocysteine metabolism and may modify the response to supplements like riboflavin.[1] Comorbidities, such as renal dysfunction, can affect magnesium levels and its supplementation, as magnesium is primarily excreted by the kidneys.
In terms of clinical trials, the literature indicates that supplementation with magnesium, riboflavin, and coenzyme Q10 can reduce migraine frequency and severity.[2-6] For example, a randomized controlled trial showed that a combination of magnesium, riboflavin, and coenzyme Q10 had a significant impact on migraine symptoms and burden of disease.[6] High dosage omega-3 fatty acids have also been shown to outperform other pharmacological options for migraine prophylaxis in terms of efficacy and acceptability.[7]
These supplements may be particularly useful in patient populations where conventional drug therapy cannot be prescribed or may not be well tolerated, such as adolescents, pregnant or breastfeeding women, the elderly with complex drug therapy, or patients with contraindications to usual pharmacological therapies.[8]

References

1.
Vitamin Supplementation as Possible Prophylactic Treatment Against Migraine With Aura and Menstrual Migraine.

Shaik MM, Gan SH.

BioMed Research International. 2015;2015:469529. doi:10.1155/2015/469529. Copyright License: CC BY

Migraine is the most common form of headache disorder globally. The etiology of migraine is multifactorial, with genetic components and environmental interactions considered to be the main causal factors. Some researchers postulate that deficits in mitochondrial energy reserves can cause migraine or an increase in homocysteine levels can lead to migraine attacks; therefore, vitamins could play a vital role in migraine prevention. For instance, riboflavin influences mitochondrial dysfunction and prevents migraine. Genes such as flavoenzyme 5,10-methylenetetrahydrofolate reductase (MTHFR), especially the C677T variant, have been associated with elevated plasma levels of homocysteine and migraine with aura. Homocysteine catalyzation requires the presence of vitamins B6, B12, and folic acid, which can decrease the severity of migraine with aura, making these vitamins potentially useful prophylactic agents for treating migraine with aura. Menstrual migraine, on the other hand, is associated with increased prostaglandin (PG) levels in the endometrium, indicating a role for vitamin E, which is an anti-PG. Vitamin C can also be used as a scavenger of reactive oxygen species for treating neurogenic inflammation in migraine patients. This paper reviews possible therapies based on vitamin supplementation for migraine prophylaxis, focusing on migraine with aura and menstrual migraine.

2.
Review on Headache Related to Dietary Supplements.

Ariyanfar S, Razeghi Jahromi S, Togha M, Ghorbani Z.

Current Pain and Headache Reports. 2022;26(3):193-218. doi:10.1007/s11916-022-01019-9.

Purpose Of Review: The lifetime prevalence of headaches is 96%. Approximately 11% of the adult population worldwide has a migraine headache. Migraine is a complex disorder that is more than a simple headache. So far, many underlying mechanisms, i.e. inflammatory, vascular, neurogenic have been hypothesized. In recent years evidences proposed that an energy deficit due to changes in mitochondrial function contributes to migraine pathophysiology as an upstream disorder. Recent insights suggested that the coexistence of sensory-stimuli surplus and energy-reserve shortage activate the trigeminovascular system. Some nutrients are considered as essential elements in mitochondrial bioenergetics and some others are known as natural immuno-modulatory components. Also, evidence showed their beneficial effect in headache prophylaxis and treatment. In present study, we aimed to... (truncated preview)

3.
Nutrients to Improve Mitochondrial Function to Reduce Brain Energy Deficit and Oxidative Stress in Migraine.

Fila M, Chojnacki C, Chojnacki J, Blasiak J.

Nutrients. 2021;13(12):4433. doi:10.3390/nu13124433. Copyright License: CC BY

The mechanisms of migraine pathogenesis are not completely clear, but P-nuclear magnetic resonance studies revealed brain energy deficit in migraineurs. As glycolysis is the main process of energy production in the brain, mitochondria may play an important role in migraine pathogenesis. Nutrition is an important aspect of migraine pathogenesis, as many migraineurs report food-related products as migraine triggers. Apart from approved anti-migraine drugs, many vitamins and supplements are considered in migraine prevention and therapy, but without strong supportive evidence. In this review, we summarize and update information about nutrients that may be important for mitochondrial functions, energy production, oxidative stress, and that are related to migraine. Additionally, we present a brief overview of caffeine and alcohol, as they are often reported to have ambiguous effects in migraineurs. The nutrients that can be considered to supplement the diet to prevent and/or ameliorate migraine are riboflavin, thiamine, magnesium ions, niacin, carnitine, coenzyme Q10, melatonin, lipoic acid, pyridoxine, folate, and cobalamin. They can supplement a normal, healthy diet, which should be adjusted to individual needs determined mainly by the physiological constitution of an organism. The intake of caffeine and alcohol should be fine-tuned to the history of their use, as withdrawal of these agents in regular users may become a migraine trigger.

4.
The Effects of Magnesium, L-Carnitine, and Concurrent Magnesium-L-Carnitine Supplementation in Migraine Prophylaxis.

Tarighat Esfanjani A, Mahdavi R, Ebrahimi Mameghani M, et al.

Biological Trace Element Research. 2012;150(1-3):42-8. doi:10.1007/s12011-012-9487-5.

Given the conflicting results about the positive effects of magnesium and L-carnitine and as there is no report concerning concurrent supplementation of magnesium and L-carnitine on migraine prophylaxis, the effects of magnesium, L-carnitine, and concurrent magnesium-L-carnitine supplementation on migraine indicators were assessed. In this clinical trial, 133 migrainous patients were randomly assigned into three intervention groups: magnesium oxide (500 mg/day), L-carnitine (500 mg/day), and Mg-L-carnitine (500 mg/day magnesium and 500 mg/day L-carnitine), and a control group. After 12 weeks of supplementation, the checklist of migraine indicators including migraine attacks/month, migraine days/month, and headache severity was completed, and serum concentrations of magnesium and L-carnitine were measured by atomic absorption spectrophotometry and enzymatic UV test, respectively. The results showed a significant reduction in all migraine indicators in all studied groups (p < 0.05). The ANOVA results showed a significant reduction in migraine frequency across various supplemented and control groups (p = 0.008). By separating the effects of magnesium supplementation from other confounding factors such as routine treatments using the repeated measures and nested model, it was clarified that magnesium supplementation had a significant effect on all migraine indicators. Oral supplementation with magnesium oxide and L-carnitine and concurrent supplementation of Mg-L-carnitine besides routine treatments could be effective in migraine prophylaxis; however, larger trials are needed to confirm these preliminary findings.

5.
Energy Metabolism Impairment in Migraine.

Cevoli S, Favoni V, Cortelli P.

Current Medicinal Chemistry. 2019;26(34):6253-6260. doi:10.2174/0929867325666180622154411.

Migraine is a common disabling neurological disorder which is characterised by a recurring headache associated with a variety of sensory and autonomic symptoms. The pathophysiology of migraine remains not entirely understood, although many mechanisms involving the central and peripheral nervous system are now becoming clear. In particular, it is widely accepted that migraine is associated with energy metabolic impairment of the brain. The purpose of this review is to present an updated overview of the energy metabolism involvement in the migraine pathophysiology. Several biochemical, morphological and magnetic resonance spectroscopy studies have confirmed the presence of energy production deficiency together with an increment of energy consumption in migraine patients. An increment of energy demand over a certain threshold creates metabolic and biochemical preconditions for the onset of the migraine attack. The defect of oxidative energy metabolism in migraine is generalized. It remains to be determined if the mitochondrial deficit in migraine is primary or secondary. Riboflavin and Co-Enzyme Q10, both physiologically implicated in mitochondrial respiratory chain functioning, are effective in migraine prophylaxis, supporting the hypothesis that improving brain energy metabolism may reduce the susceptibility to migraine.

6.
Improvement of Migraine Symptoms With a Proprietary Supplement Containing Riboflavin, Magnesium and Q10: A Randomized, Placebo-Controlled, Double-Blind, Multicenter Trial.

Gaul C, Diener HC, Danesch U.

The Journal of Headache and Pain. 2015;16:516. doi:10.1186/s10194-015-0516-6. Copyright License: CC BY

Leading Journal

Background: Non-medical, non-pharmacological and pharmacological treatments are recommended for the prevention of migraine. The purpose of this randomized double-blind placebo controlled, multicenter trial was to evaluate the efficacy of a proprietary nutritional supplement containing a fixed combination of magnesium, riboflavin and Q10 as prophylactic treatment for migraine.

Methods: 130 adult migraineurs (age 18 - 65 years) with ≥ three migraine attacks per month were randomized into two treatment groups: dietary supplementation or placebo in a double-blind fashion. The treatment period was 3 months following a 4 week baseline period without prophylactic treatment. Patients were assessed before randomization and at the end of the 3-month-treatment-phase for days with migraine, migraine pain, burden of disease (HIT-6) and subjective evaluation of efficacy.

Results: Migraine days per month declined from 6.2 days during the baseline period to 4.4 days at the end of the treatment with the supplement and from 6.2.days to 5.2 days in the placebo group (p = 0.23 compared to placebo). The intensity of migraine pain was significantly reduced in the supplement group compared to placebo (p = 0.03). The sum score of the HIT-6 questionnaire was reduced by 4.8 points from 61.9 to 57.1 compared to 2 points in the placebo-group (p = 0.01). The evaluation of efficacy by the patient was better in the supplementation group compared to placebo (p = 0.01).

Conclusions: Treatment with a proprietary supplement containing magnesium, riboflavin and Q10 (Migravent® in Germany, Dolovent® in USA) had an impact on migraine frequency which showed a trend towards statistical significance. Migraine symptoms and burden of disease, however, were statistically significantly reduced compared to placebo in patients with migraine attacks.

7.
High Dosage Omega-3 Fatty Acids Outperform Existing Pharmacological Options for Migraine Prophylaxis: A Network Meta-Analysis.

Tseng PT, Zeng BY, Chen JJ, et al.

Advances in Nutrition (Bethesda, Md.). 2024;15(2):100163. doi:10.1016/j.advnut.2023.100163.

Leading Journal
New Research

Migraine is a highly prevalent neurologic disorder with prevalence rates ranging from 9% to 18% worldwide. Current pharmacologic prophylactic strategies for migraine have limited efficacy and acceptability, with relatively low response rates of 40% to 50% and limited safety profiles. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are considered promising therapeutic agents for migraine prophylaxis. The aim of this network meta-analysis (NMA) was to compare the efficacy and acceptability of various dosages of EPA/DHA and other current Food and Drug Administration-approved or guideline-recommended prophylactic pharmacologic interventions for migraine. Randomized controlled trials (RCTs) were eligible for inclusion if they enrolled participants with a diagnosis of either episodic or chronic migraine. All NMA procedures were conducted under the frequentist model. The primary outcomes assessed were 1) changes in migraine frequency and 2) acceptability (i.e., dropout for any reason). Secondary outcomes included response rates, changes in migraine severity, changes in the frequency of using rescue medications, and frequency of any adverse events. Forty RCTs were included (N = 6616; mean age = 35.0 y; 78.9% women). Our analysis showed that supplementation with high dosage EPA/DHA yields the highest decrease in migraine frequency [standardized mean difference (SMD): -1.36; 95% confidence interval (CI): -2.32, -0.39 compared with placebo] and the largest decrease in migraine severity (

Smd: -2.23; 95%

Ci: -3.17, -1.30 compared with placebo) in all studied interventions. Furthermore, supplementation with high dosage EPA/DHA showed the most favorable acceptability rates (odds ratio: 1.00; 95%

Ci: 0.06, 17.41 compared with placebo) of all examined prophylactic treatments. This study provides compelling evidence that high dosage EPA/DHA supplementation can be considered a first-choice treatment of migraine prophylaxis because this treatment displayed the highest efficacy and highest acceptability of all studied treatments. This study was registered in PROSPERO as CRD42022319577.

8.
Nutraceuticals and Migraine: Further Strategy for the Treatment of Specific Conditions.

Quintana S, Russo M, Torelli P.

Neurological Sciences : Official Journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 2022;43(11):6565-6567. doi:10.1007/s10072-022-06250-1.

Nutraceuticals might be defined as food or dietary supplements that provide medicinal or health benefits. Current preventive treatment of migraine includes nutraceuticals as well as conventional drugs. These non-pharmacological therapies, such as magnesium, coenzyme Q10, feverfew, riboflavin, and phycocyanins, are particularly useful in certain categories of patients (adolescents, pregnant or breastfeeding women, the elderly with complex drug therapy, the patient with contraindication to the usual pharmacological therapies) when a conventional drug therapy cannot be prescribed or may be not well tolerated. The evidence currently available confirms a modest efficacy but a very good safety and tolerability profile.

Expanded question: What are the specific steps involved in the metabolic pathways for magnesium, riboflavin, coenzyme Q10, vitamin D, and Omega-3 fatty acids, and how do they relate to their mechanisms of action in migraine management? How do standard migraine medications interact with these supplements at the molecular level, and what potential implications could these interactions have on treatment strategies? Can you provide an overview of the research investigating genetic factors or comorbidities that may affect the absorption, utilization, or effectiveness of magnesium, riboflavin, coenzyme Q10, vitamin D, and Omega-3 fatty acids in migraine treatment?

Answered on May 1, 2024
The metabolic pathways for the supplements in question are integral to their proposed mechanisms of action in migraine management. Magnesium is involved in numerous cellular functions, including neurotransmitter release and vascular tone regulation, which are relevant to migraine pathophysiology.[1] Riboflavin serves as a precursor for FAD and FMN, necessary for mitochondrial energy production, potentially affecting migraine through mitochondrial dysfunction.[2] Coenzyme Q10 is part of the electron transport chain, essential for ATP production, and may influence migraine by affecting mitochondrial function and energy reserves.[3] Vitamin D, through its active form calcitriol, regulates calcium metabolism and may exert effects on neuroinflammation and immune function.[4] Omega-3 fatty acids are incorporated into cell membranes, influencing cell signaling and inflammatory pathways, which could modulate migraine-related neurogenic inflammation.[4]
The interactions of these supplements with standard migraine medications at the molecular level are not well characterized in the medical literature. However, it is important to consider the potential for additive effects or altered drug metabolism when these supplements are used concomitantly with migraine medications.
Research investigating genetic factors or comorbidities that may affect the absorption, utilization, or effectiveness of these supplements in migraine treatment has suggested that genetic variants, such as those in the MTHFR gene, can influence response to supplementation, particularly with riboflavin and possibly other B vitamins.[2][5] Additionally, comorbidities like renal dysfunction can affect magnesium levels and its supplementation.[1] However, more research is needed to fully understand these interactions and their implications for migraine treatment strategies.

References

1.
Role of Magnesium in the Pathogenesis and Treatment of Migraine.

Sun-Edelstein C, Mauskop A.

Expert Review of Neurotherapeutics. 2009;9(3):369-79. doi:10.1586/14737175.9.3.369.

Magnesium is an important intracellular element that is involved in numerous cellular functions. Deficiencies in magnesium may play an important role in the pathogenesis of migraine headaches by promoting cortical spreading depression, alteration of neurotransmitter release and the hyperaggregation of platelets. Given this multifaceted role of magnesium in migraine, the use of magnesium in both acute and preventive headache treatment has been researched as a potentially simple, inexpensive, safe and well-tolerated option. Studies have shown that preventive treatment with oral magnesium and acute headache treatment with intravenous magnesium may be effective, particularly in certain subsets of patients. In this review, the pathogenesis of migraine will be discussed, with an emphasis on the role of magnesium. Studies on the use of intravenous and oral magnesium in migraine treatment will be discussed and recommendations will be made regarding the use of magnesium in treating migraine headaches.

2.
Vitamin Supplementation as Possible Prophylactic Treatment Against Migraine With Aura and Menstrual Migraine.

Shaik MM, Gan SH.

BioMed Research International. 2015;2015:469529. doi:10.1155/2015/469529. Copyright License: CC BY

Migraine is the most common form of headache disorder globally. The etiology of migraine is multifactorial, with genetic components and environmental interactions considered to be the main causal factors. Some researchers postulate that deficits in mitochondrial energy reserves can cause migraine or an increase in homocysteine levels can lead to migraine attacks; therefore, vitamins could play a vital role in migraine prevention. For instance, riboflavin influences mitochondrial dysfunction and prevents migraine. Genes such as flavoenzyme 5,10-methylenetetrahydrofolate reductase (MTHFR), especially the C677T variant, have been associated with elevated plasma levels of homocysteine and migraine with aura. Homocysteine catalyzation requires the presence of vitamins B6, B12, and folic acid, which can decrease the severity of migraine with aura, making these vitamins potentially useful prophylactic agents for treating migraine with aura. Menstrual migraine, on the other hand, is associated with increased prostaglandin (PG) levels in the endometrium, indicating a role for vitamin E, which is an anti-PG. Vitamin C can also be used as a scavenger of reactive oxygen species for treating neurogenic inflammation in migraine patients. This paper reviews possible therapies based on vitamin supplementation for migraine prophylaxis, focusing on migraine with aura and menstrual migraine.

3.
The Metabolic Face of Migraine - From Pathophysiology to Treatment.

Gross EC, Lisicki M, Fischer D, Sándor PS, Schoenen J.

Nature Reviews. Neurology. 2019;15(11):627-643. doi:10.1038/s41582-019-0255-4.

Leading Journal

Migraine can be regarded as a conserved, adaptive response that occurs in genetically predisposed individuals with a mismatch between the brain's energy reserve and workload. Given the high prevalence of migraine, genotypes associated with the condition seem likely to have conferred an evolutionary advantage. Technological advances have enabled the examination of different aspects of cerebral metabolism in patients with migraine, and complementary animal research has highlighted possible metabolic mechanisms in migraine pathophysiology. An increasing amount of evidence - much of it clinical - suggests that migraine is a response to cerebral energy deficiency or oxidative stress levels that exceed antioxidant capacity and that the attack itself helps to restore brain energy homeostasis and reduces harmful oxidative stress levels. Greater understanding of metabolism in migraine offers novel therapeutic opportunities. In this Review, we describe the evidence for abnormalities in energy metabolism and mitochondrial function in migraine, with a focus on clinical data (including neuroimaging, biochemical, genetic and therapeutic studies), and consider the relationship of these abnormalities with the abnormal sensory processing and cerebral hyper-responsivity observed in migraine. We discuss experimental data to consider potential mechanisms by which metabolic abnormalities could generate attacks. Finally, we highlight potential treatments that target cerebral metabolism, such as nutraceuticals, ketone bodies and dietary interventions.

4.
Review on Headache Related to Dietary Supplements.

Ariyanfar S, Razeghi Jahromi S, Togha M, Ghorbani Z.

Current Pain and Headache Reports. 2022;26(3):193-218. doi:10.1007/s11916-022-01019-9.

Purpose Of Review: The lifetime prevalence of headaches is 96%. Approximately 11% of the adult population worldwide has a migraine headache. Migraine is a complex disorder that is more than a simple headache. So far, many underlying mechanisms, i.e. inflammatory, vascular, neurogenic have been hypothesized. In recent years evidences proposed that an energy deficit due to changes in mitochondrial function contributes to migraine pathophysiology as an upstream disorder. Recent insights suggested that the coexistence of sensory-stimuli surplus and energy-reserve shortage activate the trigeminovascular system. Some nutrients are considered as essential elements in mitochondrial bioenergetics and some others are known as natural immuno-modulatory components. Also, evidence showed their beneficial effect in headache prophylaxis and treatment. In present study, we aimed to... (truncated preview)

5.
Genetics, Pathophysiology, Diagnosis, Treatment, Management, and Prevention of Migraine.

Khan J, Asoom LIA, Sunni AA, et al.

Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie. 2021;139:111557. doi:10.1016/j.biopha.2021.111557.

Leading Journal

Migraine is a neurological ailment that is characterized by severe throbbing unilateral headache and associated with nausea, photophobia, phonophobia and vomiting. A full and clear mechanism of the pathogenesis of migraine, though studied extensively, has not been established yet. The current available information indicates an intracranial network activation that culminates in the sensitization of the trigemino-vascular system, release of inflammatory markers, and initiation of meningeal-like inflammatory reaction that is sensed as headache. Genetic factors might play a significant role in deciding an individual's susceptibility to migraine. Twin studies have revealed that a single gene polymorphism can lead to migraine in individuals with a monogenic migraine disorder. In this review, we describe recent advancements in the genetics, pathophysiology, diagnosis, treatment, management, and prevention of migraine. We also discuss the potential roles of genetic and abnormal factors, including some of the metabolic triggering factors that result in migraine attacks. This review will help to accumulate current knowledge about migraine and understanding of its pathophysiology, and provides up-to-date prevention strategies.

Expanded question: Please give a list of dietary supplements recommended for migraine patients, including doses and formulations.

Answered on May 1, 2024
The European Headache Federation and Lifting The Burden: the Global Campaign against Headache recommend the use of the following supplements for the preventative treatment of migraines, where preparations of pharmaceutical quality are available:
• Coenzyme Q10 (CoQ10): 100 mg three times daily
• Magnesium (as citrate): starting at 100 mg three times daily to avoid diarrhea, and increasing to 200 mg three times daily if tolerated
• Riboflavin: 200 mg twice daily
These dosages are based on the evidence for efficacy and may be tried in migraine prophylaxis.[1] It is important to note that the quality of the supplement is crucial, and healthcare providers should ensure that the products used are of pharmaceutical quality to ensure safety and efficacy.

References

1.
Aids to Management of Headache Disorders in Primary Care (2nd Edition) : On Behalf of the European Headache Federation and Lifting the Burden: The Global Campaign Against Headache.

Steiner TJ, Jensen R, Katsarava Z, et al.

The Journal of Headache and Pain. 2019;20(1):57. doi:10.1186/s10194-018-0899-2. Copyright License: CC BY

Leading Journal

▪ Devices. Many are on the market, some very costly and promoted with insupportable claims of efficacy. “Testimonials” can be attributed to placebo effect and should be disregarded. The only clear recommendation possible is that successful trial usage should precede any expensive purchase.
▪ A range of transcutaneous electrical nerve stimulators (TENS) and noninvasive neuromodulating devices for peripheral vagal nerve, supraorbital nerve and single-pulse transcranial magnetic stimulation are available, with evidence of efficacy in some people.
▪ Herbals are not recommended. Evidence of both efficacy and safety in prolonged use is poor. They may interfere with other medications.
▪ Feverfew preparations are highly variable in content, and not all of pharmaceutical quality. Their toxicity is not well understood.
▪ Butterbur has some efficacy and is approved for use in some countries, but preparations on sale are variable in content and not all of pharmaceutical quality (not guaranteed to be free of liver toxins).
▪ Nutraceuticals are mostly not recommended. The following have some evidence for efficacy, and may be tried where preparations of pharmaceutical quality are available:
▪ coenzyme Q10 (CoQ10) (100 mg three times daily);
▪ magnesium (as citrate, starting at 100 mg three times daily to avoid diarrhoea, and increasing to 200 mg three times daily);
▪ riboflavin (200 mg twice daily).
▪ Homoeopathy is of unproven value. There is no arguable case for over-the-counter sales of homoeopathic remedies.
▪ This is better avoided, and rarely required since migraine often remits during pregnancy.
2.5.6 Management of chronic migraine
Chronic migraine develops in a small minority of people with episodic migraine. It is one of the syndromes characterised by headache on ≥15 days/month, but is not simply migraine that is more frequent: it is often complicated by medication overuse, depression, anxiety and low back and/or neck pain.