Migraine
Definition and Overview
Migraine is an extremely disabling, common neurological disorder characterized by a complex neurobiology, involving a series of central and peripheral nervous system areas and networks. It is a primary headache disorder with a prevalence estimated at approximately 15% globally, and according to the International Classification of Headache Disorders, 3rd edition (ICHD-3), there are three significant types: migraine without aura, migraine with aura, and chronic migraine, the former being the most common.
Migraine affects up to 15% of the global population with enormous socioeconomic and personal impacts. It ranks second among years lived with disability (YLD), with women being the most affected, experiencing a threefold higher prevalence than men. Globally, migraine was the second largest contributor to the disability-adjusted life-years lost due to neurological disorders in 2016, accounting for 16.3% of the attributable DALYs. The global age-standardized prevalence increased by 1.7% from 1990 to 2019, and in 2019 there were 1.1 billion prevalent cases.
Migraine is clinically well characterized by a distinctive sequence of symptoms, including unilateral throbbing or pulsating headache, accompanied by nausea, vomiting, and sensitivity to sound (phonophobia) and light (photophobia).
Clinical Presentation: Phases of a Migraine Attack
The migraine attack is a multiphasic event and can generally be divided into a series of stages: premonitory (prodrome), aura, headache, and postdrome, each presenting with a spectrum of complex and mutable symptoms. The entire migraine attack may extend up to a week, profoundly disrupting the patient's routine existence.
Premonitory (Prodrome) Phase
The premonitory (or pre-headache) phase occurs hours to days before head pain, and a broad array of symptoms has been reported within neuropsychiatric, sensory, and gastrointestinal categories. In a large international survey, pre-headache symptoms were reported by 67% of people with migraine, and these symptoms were common and disabling. Common prodromal features include irritability, depression, fatigue, mood changes, food cravings, frequent urination, thirst, increased sensitivity to light or sound, brain fog, and yawning.
Available evidence suggests that hypothalamic activation is the principal pathogenic driver of premonitory symptoms in migraine and can modulate nociceptive transmission within the trigeminovascular system.
Aura Phase
In one-third of patients, an aura phase may occur during some attacks, and it likely correlates with a cortical spreading depression-like event: a slowly propagating wave of neuronal and glial cell depolarization and hyperpolarization. Cortical spreading depression is an extreme depolarization of glial and neuronal cell membranes that results in disruption of ionic gradients, a rise in extracellular potassium concentrations, release of glutamate, and a transient increase followed by a decrease in cerebral blood flow. The spread of this wave across neural tissue occurs at a rate of 2–6 mm/min, similar to the progression of the fortification spectra seen during aura. Visual disturbances are the most common aura manifestation, though people with migraine also report changes to their sense of smell, hearing, and touch, and speech and movement may also be affected.
Headache Phase
The headache phase typically lasts 4–72 hours. This phase involves activation of the trigeminovascular system, a pathway that is well characterized. The visual aura experienced by some migraineurs arises from cortical spreading depression, and this neuronal event may also activate perivascular nerve afferents, leading to vasodilation and neurogenic inflammation of the meningeal blood vessels and, thus, throbbing pain. The involvement of the parasympathetic system supplying the meninges also causes increased vasodilation and pain. As an acute attack progresses, sensory neurons in the trigeminal nucleus caudalis become sensitized, resulting in the phenomenon of cutaneous allodynia.
Postdrome Phase
The postdrome can last hours or days following the cessation of headache pain. Previously reported postdrome phase symptoms include cognitive difficulties, mood changes, gastrointestinal issues, and tiredness/weakness.
Body Systems Involved
Migraine is a brain disorder involving both headache and altered sensory, limbic, and homeostatic processing, with a complex interplay between neurotransmitter systems, physiologic systems, and pain processing. It is a neural disorder in which a wide range of brain areas and neurochemical systems are implicated, producing a heterogeneous clinical phenotype. Many of these neural pathways are monoaminergic and peptidergic, such as those involving calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide.
The trigeminovascular system consists of peripheral axons from the trigeminal ganglion that innervate the meninges and intracranial blood vessels peripherally, and converge centrally in the trigeminocervical complex (TCC), composed of the spinal trigeminal nucleus caudalis and upper cervical spinal cord. Second-order neurons ascend from the TCC to thalamocortical neurons and further project to key brain nuclei in the diencephalon and brainstem, such as the locus coeruleus, periaqueductal gray, and hypothalamus.
Glutamate is the main neurotransmitter that drives activation of the ascending trigeminal and trigeminothalamic pathways. The neuropeptide CGRP, released by the trigeminal system, plays a crucial role in the neurobiology of headache. Peripheral and central sensitizations associated with trigeminal sensory processing are neurobiologic states that contribute to both the development of headache during a migraine attack and the maintenance of chronic migraine.
Hormonal systems are also prominently involved. Women report more severe migraine symptoms during periods of sex hormone fluctuations, particularly at puberty, during pregnancy, and around perimenopause. The "estrogen withdrawal hypothesis" specifically suggests that changes in serum estradiol levels are capable of precipitating migraine attacks; before puberty, when sex steroid hormones are largely dormant, the prevalence of migraine is equal in boys and girls.
Mitochondrial dysfunction is associated with migraine. Riboflavin, magnesium, and coenzyme Q10 play an important role in the production of energy in the mitochondria. The gut–brain axis has also garnered attention as a potential modulator of migraine pathophysiology. Alterations in the gut microbiota of migraineurs suggest that probiotics and prebiotics could serve as adjunctive therapeutic agents.
Contributing and Associated Factors
Genetic and Demographic Factors
Migraine is largely accepted to be an inherited tendency for the brain to lose control of its inputs. The largest incidence is among females between the ages of 18 and 49. Demographic factors such as sex and race, and lifestyle factors such as caffeine misuse, body weight gain, and sleep disorders, are recognized risk factors.
Common Triggers
The most common triggers of migraine attacks are defined as stress, auditory stimuli, fatigue, hunger, and menstrual periods. In a smartphone-based diary study, the likelihood of a headache on a given day was 57.7% for stress, 55.1% for sleep deprivation, and 48.5% for fatigue; traveling, hormonal changes, noise, alcohol, overeating, and stress also increased the risk of migraines.
Caffeine
The relationship between caffeine intake and migraine is complicated, but data suggest that high caffeine intake, or changes in intake, are associated with migraine attacks. A case-control study found that individuals with chronic daily headache were approximately 50% more likely than those with episodic headache to have been high consumers of dietary and medicinal caffeine prior to onset, with high consumption defined as being in the upper quartile of caffeine consumption. Abrupt change in usual caffeine intake is also a risk factor for migraine attacks.
Obesity and Metabolic Factors
Good evidence supports obesity and metabolism-related comorbidities as risk factors for migraine progression. The association between obesity and increased migraine frequency further supports the role of metabolic interventions.
Sleep Disturbances
Disrupted sleep, irregular mealtime, and sedentariness worsen migraine outcomes. These three arms of lifestyle can alter the epigenetic status of the genome, including modifications of histones, the DNA methylation status of specific genomic regions, and expression of non-coding RNAs.
Psychiatric Comorbidities and Stress
Good evidence also supports selected psychiatric symptoms and chronic extra-cephalic pain conditions as risk factors for migraine progression.
Other Recognized Factors
Various risk factors have been identified including advanced age, head trauma, lower socioeconomic status, caffeine or medication overuse, stress, sleep problems such as snoring, obesity, pain syndrome, and pro-inflammatory or pro-thrombotic states. Migraine is commonly triggered by alterations in homeostasis, such as changes in sleep–wake cycles and missed meals.
Nutrients, Herbs, and Natural Ingredients
Magnesium
Background and Proposed Mechanism
Studies have revealed decreased levels of magnesium in plasma and in the brain of migraine patients. A deficit of this nutrient could play a role in the pathophysiology of migraine. Magnesium is needed in various physiological processes which influence the pathophysiology of migraine including vasoconstriction, platelet inhibition, and secretion of serotonin. Magnesium is also needed as a co-factor for proper functioning of the ATP-synthase which produces ATP. Furthermore, Mg is the physiological antagonist at the NMDA-channel which is involved in the regulation of neuronal excitability.
Traditional Use
Magnesium as a mineral supplement does not have a specific documented traditional or ethnobotanical history of use for migraine in the manner of herbal medicines. Its investigation arose from recognition of its physiological roles in neurovascular function, beginning in earnest in the late 20th century.
Scientific Evidence
Research on the use of magnesium supplements to prevent or reduce symptoms of migraine headaches is limited. A 2018 systematic review of five studies found Grade C (possibly effective) evidence for prevention of migraine with magnesium. However, a 2021 review concluded that even if the preliminary results are very promising, more rigorous studies have to be designed to confirm the efficacy. A 2009 review found that three of four small, short-term, placebo-controlled trials showed modest reductions in the frequency of migraines in patients given up to 600 mg/day magnesium. The American Headache Society (AHS) / American Academy of Neurology (AAN) 2012 guidelines assessed magnesium as Level B evidence (probably effective) for migraine prevention. Overall, the evidence for magnesium is preliminary to moderate; larger, well-powered randomized controlled trials (RCTs) are needed.
Riboflavin (Vitamin B2)
Background and Proposed Mechanism
Riboflavin (Vitamin B2) is involved in energy production, and its deficiency can cause mitochondrial dysfunction, which may play a role in migraine. Riboflavin is a precursor for flavin-mononucleotide (FMN) and flavin-adenine-dinucleotide (FAD), coenzymes essential to the mitochondrial electron transport chain.
Traditional Use
Riboflavin has no specific ethnobotanical or historical traditional use for migraine; its application to migraine emerged from the scientific discovery of mitochondrial dysfunction as a pathophysiological factor in the disorder, primarily in the 1990s.
Scientific Evidence
Of 11 clinical trials reviewed, five showed a positive effect, including a large randomized controlled trial of 400 mg/day that resulted in at least a 50% improvement in 60% of patients. The AHS/AAN 2012 guidelines classified riboflavin as Level B evidence (probably effective) for migraine prevention. The therapeutic potential of riboflavin can be cautiously inferred from published open clinical trials; it should however be considered that double-blind randomized larger studies are needed to correctly estimate the impact of the placebo effect in these promising therapies. In combination studies, treatment with a proprietary supplement containing magnesium, riboflavin, and CoQ10 had an impact on migraine frequency that showed a trend towards statistical significance, and migraine symptoms and burden of disease were statistically significantly reduced compared to placebo in patients with migraine attacks. Evidence strength is moderate; riboflavin is among the better-supported nutraceuticals for migraine prophylaxis, but study populations have generally been small.
Coenzyme Q10 (CoQ10)
Background and Proposed Mechanism
Coenzyme Q10 is an antioxidant and an essential mitochondrial cofactor which has been suggested to improve the clinical features of migraine. CoQ10 may have applications in migraine therapy due to its potent anti-inflammatory and oxidative stress-reducing properties. Furthermore, by improving mitochondrial function, CoQ10 can contribute to the energy supply to brain cells, which is particularly important in migraine.
Traditional Use
CoQ10 has no traditional ethnobotanical use for migraine. Its study for migraine originated from the hypothesis of mitochondrial insufficiency as a contributing factor, with research accelerating from the early 2000s onward.
Scientific Evidence
A systematic review and meta-analysis found that CoQ10 supplementation significantly reduced the frequency of migraine attacks (weighted mean difference: −1.87 attacks/month, 95% CI: −2.69 to −1.05, p < 0.001) without significant heterogeneity among studies. CoQ10 had no significant effect on severity or duration of migraine attacks with high heterogeneity. Pooled analyses of available RCTs suggest that CoQ10 supplementation may reduce frequency without affecting severity or duration.
A PROSPERO-registered meta-analysis included five studies with a total of 326 individuals with confirmed migraine, and CoQ10 was shown to be associated with significant improvement in migraine frequency per month, and migraine duration and severity. The AHS/AAN 2012 guidelines rated CoQ10 as Level C evidence (possibly effective) for migraine prevention. Overall, evidence is preliminary to moderate, with several positive trials but methodological variability across studies.
Feverfew (Tanacetum parthenium)
Traditional Use
Feverfew (Tanacetum parthenium L.) extract is a herbal remedy which has been used for preventing attacks of migraine. Feverfew has been traditionally used in Eastern European cultures for headaches, insect bites, and other pain. Historically, the plant was also employed in British folk medicine for fevers and inflammations, with its name "feverfew" deriving from the Latin febrifugia (fever reducer).
Proposed Mechanism
Parthenolide, the active ingredient, may prevent migraine through its vascular smooth muscle relaxation and anti-inflammatory properties.
Scientific Evidence
A systematic review of RCTs examining herbal treatments for migraine identified nineteen studies, and overall findings on the efficacy of feverfew were mixed. Of six studies reviewed, four had positive outcomes (including the largest study with 170 patients), and two were negative. The most common side effects were nausea, bloating, and mouth ulcers if dried leaves were chewed. Feverfew should not be discontinued abruptly, or withdrawal symptoms including difficulty sleeping, anxiety, and stiff or painful muscles could occur. The AHS/AAN 2012 guidelines rated feverfew as Level B evidence (probably effective) for migraine prevention. Feverfew has shown promise in reducing migraine frequency, yet several studies have failed to replicate these outcomes, likely due to differences in trial design, dosing, and product standardization. Evidence strength is mixed and preliminary; standardization of parthenolide content across products is a significant variable.
Butterbur (Petasites hybridus)
Traditional Use
Butterbur, derived from the leaves of Petasites hybridus, is an herbal supplement that has been found to be effective in the prophylaxis of adult migraines in multiple studies. Historically, butterbur root was used in Central European folk medicine as far back as the Middle Ages for fever, plague, wounds, and pain.
Proposed Mechanism
Anti-migraine effects are primarily attributed to its active sesquiterpenes, petasin and isopetasin. These compounds exert their effects through multiple mechanisms, including blocking voltage-dependent calcium channels, inhibiting CGRP secretion, and activating TRPA1 and TRPV1 channels. Butterbur is also described as having anti-inflammatory properties and being involved in calcium regulation.
Scientific Evidence
Based on two randomized controlled trials, butterbur was classified as having Level A evidence in the AHS/AAN 2012 guidelines. However, concerns over hepatotoxicity with butterbur resulted in these entire guidelines being retired, and new ones are now pending. Butterbur appears to help reduce the frequency of migraines in adults and children. However, butterbur contains pyrrolizidine alkaloids (PA), which are hepatotoxic. The NIH recommends only using butterbur if the product is labeled and certified as PA-free. Butterbur, despite its effectiveness, is overshadowed by safety concerns, including hepatotoxicity, necessitating the use of pyrrolizidine alkaloid-free formulations to mitigate risks. Evidence strength is moderate to strong for efficacy, but safety concerns limit use without confirmed PA-free certification.
Melatonin
Traditional Use
Melatonin has no formal traditional botanical or herbal use for migraine. Its application to migraine stems from late 20th-century research into circadian rhythms and the pineal gland.
Proposed Mechanism
Melatonin is endogenously secreted from the pineal gland and plays a vital role in regulating the circadian cycle. Theoretically, melatonin can be helpful for migraine prophylaxis due to its biological properties, including antioxidant effects, regulation of dopamine-glutamine activity, and inhibition of CGRP release. Due to the involvement of circadian rhythms in migraine, a significant relationship between morning episodic migraine and insomnia, and the role of melatonin in regulating the suprachiasmatic nucleus and circadian rhythms through the hypothalamus-pineal axis, melatonin has been considered for further investigation.
Scientific Evidence
Melatonin has mixed results for improvement, with one positive and one negative study for migraine. A randomized, double-blind clinical trial conducted in 2021 assigned 60 patients with episodic migraine to receive either 3 mg melatonin or placebo along with baseline therapy (propranolol) for two months. In both groups, the frequency, duration, and severity of attacks and MIDAS scores decreased significantly during follow-up. Evidence for melatonin is preliminary and mixed, constrained by small sample sizes and inconsistent outcomes across trials.
Vitamin D
Traditional Use
Vitamin D deficiency has been identified in epidemiological studies as associated with migraine. Its potential relevance to migraine is a recent area of investigation, with no traditional use in migraine management.
Scientific Evidence
Several studies have identified vitamin D deficiency as a risk factor associated with migraine. A recent study showed 4000 IU Vitamin D3/day reduced migraine days, even if baseline vitamin D3 levels were not low. Vitamin D has been included in reviews assessing supplements for migraine treatment. The evidence is preliminary; the mechanism and optimal dosing require further investigation in well-designed RCTs.
Omega-3 Fatty Acids
Traditional Use
Fish and marine oil consumption has been part of traditional diets in coastal populations for millennia, but omega-3 supplementation specifically for migraine is a product of modern nutritional science and was not part of historical herbal or folk medicine practice for headache.
Scientific Evidence
Omega-3 fish oil is anti-inflammatory, and there has been hope for benefit in migraine. A recent systematic review of 13 studies for migraine showed no overall benefit. A recent 2018 study showed benefit over placebo in those also on amitriptyline for chronic migraine. Greater intake of omega-3 polyunsaturated fatty acids was found to be statistically significantly associated with lower prevalence of severe headache or migraine. Diets containing high levels of omega-3 fatty acids and low levels of omega-6 fatty acids have been reported to reduce the duration and frequency of migraine. Evidence is mixed and preliminary; some individual trials and observational data are positive, but systematic review-level evidence has not consistently supported omega-3 supplementation as a standalone intervention.
Ginger (Zingiber officinale)
Traditional Use
Ginger has been used for centuries in Ayurvedic medicine, traditional Chinese medicine, and various folk healing systems for nausea, pain, and inflammation. Its application to headache and migraine is documented in Ayurvedic texts, where it was often prepared as a paste applied to the forehead or taken internally as a decoction.
Scientific Evidence
There were positive, preliminary findings on ginger-related preparations as potential options in migraine management; however, the risk of bias was high for many studies. In a 2014 clinical trial published in Phytotherapy Research, 100 patients who had acute migraine without aura were randomly assigned to be treated with either ginger powder or sumatriptan, a prescription drug used to treat migraine. Evidence is very preliminary with only a few small human trials; larger, independent RCTs are required.
Curcumin (from Curcuma longa)
Traditional Use
Turmeric (Curcuma longa) has been used in Ayurvedic and traditional South Asian medicine for inflammatory conditions and neurological complaints for over two thousand years, typically as a spice, paste, or warm drink preparation.
Scientific Evidence
There were positive, preliminary findings on curcumin as a prophylactic treatment for migraine. One RCT investigated the combination of nano-curcumin and CoQ10 in migraine prophylaxis. However, the risk of bias was high for many studies. Recent interest has grown in the use of nutraceuticals including curcumin for migraine prevention, though the evidence base remains developing. Evidence is very preliminary, largely from small trials with high risk of bias.
Folic Acid, Vitamin B6, and Vitamin B12
Traditional and Scientific Context
The combination of folic acid, B6, and B12 has one positive study and one negative study for migraine. These nutrients are relevant to homocysteine metabolism; elevated homocysteine has been associated with migraine, particularly migraine with aura. Evidence is inconclusive and requires further investigation.
Dietary Factors and Patterns
Food Triggers
Traditional strategies have predominantly focused on the identification and elimination of common dietary triggers such as caffeine, alcohol, monosodium glutamate (MSG), and tyramine-rich foods. Evidence suggests that certain foods, such as alcohol, caffeine, chocolate, MSG, nitrates, and tyramine, can trigger migraines in susceptible individuals. Alcohol (especially red wine) and high, irregular caffeine intake are frequently reported triggers, while evidence for specific foods and additives remains inconsistent.
Ketogenic and Low-Glycemic Diets
Higher adherence to a Mediterranean-style diet is associated with lower migraine frequency and disability in observational cohorts. Very low-calorie ketogenic diets significantly reduced monthly migraine attack frequency compared with isocaloric non-ketogenic comparators in an adult RCT of participants with overweight or obesity, with a ≥50% responder rate of 74%. Low-glycemic index diets showed improvement in migraine frequency both in a diet group and in a control group of patients who took standard migraine-preventive medication.
Mediterranean Dietary Pattern
Dietary interventions including adherence to Mediterranean patterns offer promising avenues for migraine symptom management. Current evidence supports recommending Mediterranean-style eating, consideration of omega-3 supplementation, and selective trials of ketogenic or elimination approaches in appropriate patients, alongside weight management and lifestyle optimization.
Elimination Diets
Elimination diets require the identification of provocative dietary ingredients and their subsequent elimination. One example is the gluten-free diet among patients with celiac disease, which decreases headache or migraine frequency from 51.6 to 100%. Other elimination diets, such as immunoglobulin G-elimination, antihistamine, tyramine-free, and low-fat diets, have contradictory results and might cause malnutrition in cases of total avoidance.
Hydration and Meal Regularity
Regular healthy meals, adequate hydration, and low or stable caffeine intake are recommended within evidence-based lifestyle frameworks for migraine management. Migraine is commonly triggered by alterations in homeostasis, including missed meals.
Lifestyle Factors
Physical Activity
Physical activity has a positive cross-sectional effect on most of the modifiable risk factors of migraine and can improve patients' quality of life. Approximately 150–300 minutes of moderate-intensity aerobic exercise per week and increased lifestyle activities are encouraged. An aerobic exercise program that included relaxation had a similar effect to topiramate in reducing migraine pain intensity and frequency. Exercise prescription and physical activity in conjunction with other lifestyle recommendations is likely to decrease pain frequency, might improve pain intensity and attack duration, and may decrease the disability of both episodic and chronic migraine patients after 6 weeks of intervention with 3–5 sessions per week.
In a nationally representative U.S. sample, engaging in a vigorous plus muscle-strengthening exercise pattern was associated with a 52% reduction in the odds of severe headaches/migraines. Overall, vigorous exercise combined with muscle-strengthening activities consistently associates with a lower likelihood of severe headaches or migraines. These findings suggest that combining vigorous physical activity and muscle-strengthening activities may be most beneficial.
Sleep
Disrupted sleep worsens migraine outcomes. Physical activity improves sleep efficiency and sleep quality, thereby inducing deep sleep, reducing daytime sleepiness, and decreasing the frequency of medication use to aid sleep. Both traditional and digital cognitive behavioral therapy for insomnia (CBT-I) have shown improvements in sleep quality in migraine patients.
Stress Management
The acronym SEED, which means Sleep, Exercise, Eat, and Diary, was proposed in a recent update to summarize the lifestyle changes needed to improve migraine. Stress reduction techniques support the management of both migraine and sleep quality, potentially by decreasing sympathetic nervous system activation and promoting parasympathetic dominance.
Weight Management
Weight loss and regular physical activity may further reduce burden in people with obesity. The migraine-obesity relationship may be bidirectional due to shared lifestyle and biological risk factors, as seen in clinicoepidemiological and interventional studies.
Tobacco and Alcohol Use
Tobacco use is supported by good evidence as a risk factor for migraine disease progression. Alcohol, especially red wine, is a frequently reported migraine trigger.
Evidence Summary Table
- Riboflavin (400 mg/day): Moderate evidence. AHS/AAN Level B. Multiple RCTs show ~50–60% responder rates; larger confirmatory trials still needed.
- Magnesium (up to 600 mg/day): Preliminary to moderate evidence. AHS/AAN Level B. Systematic reviews show Grade C (possibly effective); larger blinded RCTs needed.
- Coenzyme Q10: Preliminary to moderate evidence. AHS/AAN Level C. Meta-analyses support frequency reduction; effects on severity and duration inconsistent.
- Butterbur (Petasites hybridus, PA-free): Moderate to strong for efficacy; significant safety caveats. Former AHS/AAN Level A; hepatotoxicity concerns require PA-free certification.
- Feverfew (Tanacetum parthenium): Mixed and preliminary. AHS/AAN Level B historically; results vary with product standardization.
- Omega-3 fatty acids: Mixed and preliminary. Observational data positive; systematic review of RCTs shows no consistent overall benefit.
- Melatonin: Preliminary and mixed. Some RCT support but inconsistent across trials.
- Vitamin D: Very preliminary. Deficiency associated with migraine risk; one intervention study positive.
- Ginger and Curcumin: Very preliminary. Small, high-bias trials; require replication.
- Mediterranean diet: Observational support. Lower migraine frequency and disability in adherents; RCT evidence emerging.
- Ketogenic diet: Preliminary RCT support, particularly in individuals with overweight or obesity.
References
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