Woman taking butterbur supplement to reduce migraine headache frequency

Migraine Headache

Migraine Headache

Last Section Update: 04/2022

Contributor(s): Shayna Sandhaus, PhD; Carrie Decker, ND, MS

1 Overview

Summary and Quick Facts for Migraine Headache

  • Migraines are recurrent and potentially debilitating headaches, often accompanied by nausea and sensitivity to light. They are regularly triggered by stress, lack of sleep or hormonal factors.
  • This protocol will help you understand the pathology of migraine headaches and what treatments are available. Complementing medications with specific dietary changes may make migraines more manageable.
  • Supplementation with butterbur extract has been shown to reduce migraine frequency, in a clinical trial.

What are Migraine Headaches?

Migraine headaches are severe headaches that are generally accompanied by nausea and sensitivity to light and/or sound. People with recurrent migraines may not be able to continue with normal daily activity during an attack. Attacks typically last several hours, and sometimes persist for several days.

Migraines might be preceded by prodromes (physical and/or psychological changes) or auras (sensory and/or movement disturbances) hours or even days before their onset. People who experience these phenomena may be able to prevent the headache from fully manifesting.

Natural interventions such as butterbur root and coenzyme Q10 may help prevent and provide relief for migraine headaches.

What Causes Migraine Headaches?

Note: The causes of migraine headaches are complex and not entirely understood. Possible causes include:

  • Low serotonin levels
  • Hormonal imbalances (which may account for the disproportionate number of women who suffer from migraines)

What are Conventional Medical Treatments for Migraine Headaches?

Acute treatments:

  • Non-steroidal anti-inflammatory drugs (NSAIDs) and/or mild analgesics such as acetaminophen, sometimes combined with caffeine
  • Triptan drugs (eg, sumatriptan, rizatriptan)
  • Other drugs such as ergot alkaloids, opioids, and corticosteroids

Preventive treatments (generally for frequent recurring migraines):

  • Blood pressure medications
  • Tricyclic antidepressants
  • Anticonvulsants

What Dietary and Lifestyle Changes Can Be Beneficial for Migraine Headaches?

  • Avoid headache triggers (common triggers include nicotine, monosodium glutamate, nitrites, and red wine). Keep a migraine diary to track and pinpoint triggers.
  • Reduce stress
  • Improve sleep hygiene
  • Relaxation, massage, chiropractic manipulation, etc.
  • Get sufficient exercise and stretch frequently

What Natural Interventions May Be Beneficial for Migraine Headaches?

  • Butterbur root. Butterbur extracts possess analgesic, anti-inflammatory, anti-spasmodic, and vasodilatory properties. Standardized butterbur extract has been shown to be safe and effective for preventing migraines and was recommended by the American Academy of Neurology (AAN) and American Headache Society (AHS).
  • Coenzyme Q10. Coenzyme Q10 (CoQ10) is an important component of cellular energy production. Highly active areas, such as the brain, may rapidly deplete stores. Supplemental CoQ10 has been shown to be beneficial for preventing and reducing the frequency of migraines.
  • Riboflavin. Riboflavin (vitamin B2) is effective for preventing migraines among both children and adults. This may be due in part to its ability to enhance mitochondrial energy production.
  • Feverfew. Feverfew inhibits the production of several inflammatory mediators that may be involved in migraine onset, suggesting it may be promising in managing migraine attacks.
  • Magnesium. Magnesium deficiency has been linked with multiple processes implicated in migraine pathology. Studies with magnesium citrate and magnesium oxide showed the incidence and severity of migraines was reduced with supplementation. Magnesium-L-threonate is another form of magnesium that may better penetrate the central nervous system.
  • Melatonin. Melatonin levels are often low in migraine patients, especially during an attack. Some preliminary clinical studies showed melatonin supplementation improved symptoms and reduced number of attacks.
  • S-adenosylmethionine (SAMe). SAMe takes part in a variety of biochemical processes in the body, especially in the central nervous system. Long-term supplementation with SAMe may relieve pain among migraine sufferers, possibly due to its ability to increase serotonin.
  • L-tryptophan. L-tryptophan is a precursor to serotonin. Dietary tryptophan depletion exacerbates migraine symptoms, and an older clinical study showed supplementation was effective for preventing migraine attacks.
  • Other natural interventions that may benefit migraines sufferers include ginkgo biloba, lipoic acid, vitamin B6, and ginger.

2 Introduction

Migraine headaches are recurrent, painful headaches often accompanied by nausea, photophobia (i.e., light sensitivity) and/or phonophobia (i.e., sound sensitivity). A migraine is often unilateral and pulsating, and may occur with or without an aura (Rakel 2011; Ferri 2012; NINDS 2012; Goldman 2011; NIH MedlinePlus 2012; Mayo Clinic 2011; D'Amico 2008; Univ. of Maryland Medical Center 2012).

About 23 million adults in the United States are reported to experience migraine headaches, and they are one of the most common complaints encountered by neurologists in day to day practice (Cutrer 2012; American Academy of Neurology 2012). Nonetheless, migraine disorder remains a commonly underdiagnosed and undertreated condition (Lipton 2011; Durham 2004; Moloney 2011; Diamond 2007).

Conventional pharmacologic migraine treatments often meet with limited success and may have intolerable side effects or be contraindicated with other common co-existing conditions (Chaibi 2011a; Magis 2011; Rothrock 2011; Sarchielli 2006).

On the other hand, avoiding migraine triggers such as intense emotional stress, poor sleep habits, and unbalanced hormone levels may reduce the occurrence of attacks (Shugart 2012b; Mayo Clinic 2011; Dzugan 2006). In addition, there are a variety of safe and effective natural treatment approaches available for migraine management (Schiapparelli 2010).

Upon reading this protocol, you will learn what causes migraine and how conventional medicine treats migraine headaches. You will also discover how to avoid common migraine triggers and read about natural options that can help you manage migraine headaches.

3 What is a Migraine Headache?

Migraine headache is often described as intense throbbing or pulsating head pain that interferes with a person's ability to go about normal daily functioning (Rizzoli 2012; NINDS 2012). Migraine headache pain is often made worse by physical activity (Walling 2012).

Migraine sufferers frequently describe the pain as being limited to one side of the head (Digre 2011a). However, some people do experience migraines on both sides of the head (Digre 2011b). Migraine is commonly associated with nausea, as well as light and/or sound sensitivity (Cutrer 2012). Although migraine duration varies from patient to patient, a typical attack lasts for several hours, and sometimes persists for up to several (e.g. 2-3) days (Walling 2012).

Various physical and/or psychological changes sometimes precede the onset of a migraine headache by a few hours to a few days. This phase of a migraine is called prodrome. The experience of prodrome varies from person to person but can include such things as appetite changes, loss of balance, mood changes, tiredness, neck stiffness, and changes in alertness. The prevalence of a distinct prodrome phase is not entirely clear because studies have reported differing rates, but a significant portion of migraineurs indicate that they experience symptoms that predict the onset of migraine. Individuals who have experienced migraine preceded by prodrome in the past may be able to recognize an impending headache based upon their prodrome symptoms and plan accordingly for the next hours or few days by taking steps such as avoiding rigorous or stressful activity and ensuring that they have adequate stock of migraine relief medication (Rossi 2005).

Approximately 25% of migraineurs will experience a pre-migraine phenomena called aura, which is a neurologic abnormality causing mostly visual, but also other sensory and/or movement disturbances that manifests within a few hours of a migraine headache (Cutrer 2012; Digre 2011c). Most experts believe that migraine aura is caused by a phenomena in the brain called cortical spreading depression (CSD), a slowly progressing wave of excitability followed by long-lasting neuronal inhibition (Bogdanov 2011a).

4 Nutrients

Natural therapies (e.g., dietary supplements) are well tolerated, and many have been shown to reduce migraine symptoms (O'Brien 2010; Schiapparelli 2010).

Butterbur root

Butterbur (Petasites hybridus) is a plant that flourishes in moist conditions, and has been used for a wide range of medicinal purposes in Europe since ancient times (Pothmann 2005). Butterbur extracts possess analgesic, anti-inflammatory, anti-spasmodic, and vasodilatory properties, which may explain their efficacy for migraine prevention (Pothmann 2005; Oelkers-Ax 2008). Butterbur root extract (standardized to 15% petasins) has been shown to be both safe and effective for the prevention of migraines (Diener 2004; Lipton 2004; Pothmann 2005). In one study, researchers split 245 patients into three groups to receive: 75 mg of butterbur extract twice a day, 50 mg of butterbur extract twice a day, or placebo. At the end of a four-month treatment period, those taking the 75 mg dosage experienced a whopping 48% reduction, on average, in the frequency of migraine attacks (Lipton 2004).

Butterbur is so effective for reducing the frequency and severity of migraine attacks, that the American Academy of Neurology (AAN) and the American Headache Society (AHS) have recommend it as an effective treatment for migraine (Holland 2012).

Coenzyme Q10

Coenzyme Q10 (CoQ10) is a potent antioxidant and an important component of mitochondrial energy production, both of which may contribute to its beneficial effect on migraines. Preclinical research has demonstrated that supplemental CoQ10 can elevate CoQ10 levels in the brain (Tatsuta 2017). Researchers have found that organs with high metabolic rate, such as the brain, appear to quickly deplete CoQ10 stores, potentially leading to a deficiency (Ross 2011). A 2021 meta-analysis of six clinical trials concluded that CoQ10 reduced the frequency and duration of migraine attacks compared with placebo. However, it did not significantly reduce migraine severity (Sazali 2021). Doses of CoQ10 shown to clinically benefit migraine sufferers range from 30 to 800 mg daily. Typically, CoQ10 is taken for an extended period (months) with a high level of safety of this endogenous antioxidant/nutrient (Slater 2011; Hershey 2007).

CoQ10 has also been shown to be of benefit in reducing migraine severity, duration, and frequency when taken at the low dose of 30 mg in combination with 500 mg L-carnitine daily (Hajihashemi 2019). Potentially synergistic effects have been observed with the combined treatment of 300 mg CoQ10 with 80 mg of a highly bioavailable form of curcumin. The combined treatment led to significant improvements in migraine severity, duration, and frequency compared with either nutrient alone (Parohan 2021).


Riboflavin (i.e., Vitamin B2) contributes to cell growth, enzyme function, and energy production (AMR 2008). High quality data indicate that riboflavin is effective for the prevention of migraine among both children and adults (Condo 2009; Boehnke 2004), and may decrease the need for traditional rescue medications (Boehnke 2004). It is believed that riboflavin's beneficial effects are due to its ability to enhance mitochondrial energy production (Brenner 2010), this is based on data indicating that riboflavin is especially effective among migraine patients with mitochondrial genetic abnormalities (DiLorenzo 2009).

One study involving 23 participants showed that supplementation with 400 mg riboflavin daily reduced headache frequency by an impressive 50% at three months, with improvement persisting through six months (Boehnke 2004). Riboflavin is also cost-effective and has a minimal side effect profile (Condo 2009).


Feverfew (Tanacetum parthenium) is a small, daisy-like flower with a distinctively strong, bitter odor (Goodyear-Smith 2010). Recent evidence has revealed that feverfew inhibits the production of several inflammatory mediators that may be involved in migraine including arachidonic acid, cyclooxygenase-2, TNF-α, IL-1, MCP-1. Due to these anti-inflammatory properties, feverfew's use in the management of migraine attacks is promising (Goodyear-Smith 2010; Saranitzky 2009; Chen 2007). However, a review of randomized controlled trials revealed mixed results for the effectiveness of feverfew (Pittler 2004). For example, a study that used dried leaf revealed a decrease in the frequency of migraines while another using a CO2 extract did not show significant benefit (Pittler 2004). A combination of ginger and feverfew has also been shown to be effective for migraine prevention with minimal side effetcs (Cady 2011; Ernst 2000). A dosage of 100-300 mg up to 4 times daily is recommended (Pareek 2011).


Magnesium modulates many important neural and vascular processes involved in the development of a typical migraine attack. Migraine patients commonly exhibit low magnesium levels (in the serum, tissue, and lymphocytes), especially during an attack (Qujeq 2012; Talebi 2011; Sun-Edelstein 2009b). Furthermore, magnesium deficiency can trigger cortical spreading depression (CSD), platelet aggregation, vasoconstriction, and substance P release; all of which are have been implicated in migraine pathology (Sun-Edelstein 2009b).

Magnesium citrate – In a study of 40 patients with migraine without aura, oral magnesium citrate (600 mg daily) decreased the frequency of attacks by 33% and severity of attacks by 47% (Koseoglu 2008). In a multi-center crossover study that enrolled 43 participants with migraine, magnesium citrate, 600 mg/day, led to a significant reduction in incidence of migraine attacks (Taubert 1994). In another multi-center, randomized, double-blind study that enrolled 81 participants with migraine, 600 mg trimagnesium dicitrate daily for 12 weeks led to significant reductions in the mean number of migraine attacks (Peikert 1996). In a guideline to practitioners published in 2012, the Canadian Headache Society included magnesium citrate on their list of preventive drugs that received a strong recommendation for migraine prophylaxis (Pringsheim 2012).

Magnesium oxide – In a clinical trial, oral magnesium oxide (500 mg daily) given to 77 adults for preventing migraines significantly reduced the severity of headaches and led to a statistically non-significant decrease in the number of migraine days. Supplementation significantly increased serum magnesium concentration in the treatment group with no difference noted in the control group (Talebi 2013).

In two patients with headaches that did not respond to other treatments, intravenous magnesium followed by 200 mg oral magnesium oxide daily was reported to help their headaches (Mijalski 2016). In another study, daily use of a supplement containing 600 mg magnesium oxide, 400 mg riboflavin, 150 mg coenzyme Q10, and several vitamins and trace elements for three months improved migraine frequency, with a trend towards but without reaching statistical significance (Gaul 2015). A 23-year-old woman with migraines for three months, who did not respond to musculoskeletal or pharmaceutical therapies, was given a multivitamin, magnesium oxide, and Ulmus rubra. She showed a reduction in frequency of migraines after one week with three migraines in the first month; after one year of supplementation, she reported not having anymore migraines (Martin 2015).

Magnesium-L-threonate – In rats, oral magnesium L-threonate, but not other forms of magnesium, raised the concentration of magnesium in the cerebrospinal fluid, and improved learning, short- and long-term memory, and working memory (Slutsky 2010). In another rat study, oral magnesium L-threonate also helped neuropathic pain induced by chemotherapy (Xu 2017). In a mouse model of neuroinflammation, magnesium L-threonate injection into the brain cavity inhibited neuroinflammation by suppressing IL-1β expression (Wang 2017). Magnesium L-threonate also improved spatial memory and reduced synaptic loss in mice with Alzheimer disease (Huang 2018).  In another study on adult male rats, magnesium L-threonate administered orally, 609 mg/kg/day for two weeks, prevented and restored memory deficits associated with neuropathic pain (Wang 2013).


Melatonin is a natural compound produced by the pineal gland that helps regulate the sleep-wake cycle (ie, circadian rhythms). It possesses potent antioxidant and analgesic properties (Wilhelmsen 2011). Since melatonin is often found in lower-than-normal levels among migraine sufferers (especially during an attack), it is thought that melatonin may play an important role in migraine pathology (Masruha 2008; Masruha 2010). Some researchers hypothesize that migraines are triggered by an irregularity in pineal gland function (Gagnier 2001). When this imbalance is corrected through melatonin supplementation, some migraine patients experience an improvement in symptoms (Vogler 2006).

A 2020 systematic review and meta-analysis assessed nocturnal levels of melatonin as well as the effect of melatonin supplementation in people affected by migraines. Lower nocturnal melatonin levels and/or its urinary metabolite, 6-sulfatoxymelatonin, were found in migraine patients compared with healthy controls, and melatonin was shown to be more effective than placebo for the prevention of migraine in adults. In adult studies that compared melatonin with other treatments, which included sodium valproate, amitriptyline, and propranolol, there was no difference in efficacy (Liampas 2020). The dosage of melatonin used in the included adult studies was generally 2‒3 mg/day, taken at bedtime. Melatonin has been found to be safe and associated with little or no side effects (Gagnier 2001; Gelfand 2020; Fallah 2015).

S-adenosylmethionine (SAMe)

SAMe is a nutritional supplement derived from the amino acid methionine and adenosine triphosphate, a nucleic acid (De Silva 2010). It is a naturally occurring substance produced by the body to perform a variety of important biochemical processes, especially involving the central nervous system (CNS) (Carpenter 2011). Some data suggest that long-term supplementation with SAMe may relieve pain among migraine sufferers, possibly due to its ability to increase serotonin (Gatto 1986; Fetrow 2001).


The amino acid L-tryptophan is a precursor to serotonin. Several lines of evidence indicate that low serotonergic signaling within the brain may precipitate migraine (Hamel 2007). Therefore, supporting serotonin synthesis by providing precursors like L-tryptophan may help avoid physiological conditions that promote migraine headache. Indeed, in an older clinical trial, supplementation with 2 - 4 grams of L-tryptophan daily was as effective at preventing migraine attacks as the medication methysergide (Sicuteri 1973). Also, a more recent trial found that dietary tryptophan depletion caused exacerbation of migraine symptoms (Drummond 2006).

Lipoic Acid

Multiple clinical trials have studied the antioxidant lipoic acid for the treatment of migraines. Lipoic acid contains two thiol (-SH) groups. As lower levels of thiols have been observed in the serum of migraine sufferers, this is one mechanism by which lipoic acid may help improve migraines (Eren 2015).

Multiple randomized controlled trials have shown that lipoic acid may benefit people who suffer from migraines. In one randomized controlled trial of migraine patients (both with and without aura), 44 subjects were given either 600 mg lipoic acid or placebo daily for three months (Magis 2007). Compared with baseline, there was a significant reduction in migraine attack frequency, headache severity, and number of headache days in those taking lipoic acid, while those taking placebo experienced no change.

In another randomized controlled trial of 79 women with episodic migraines without aura, supplementation with 300 mg lipoic acid twice daily was found to significantly reduce mood symptoms of depression, anxiety, and stress (assessed by DASS-21, a standardized scoring system) compared with placebo (Rezaei Kelishadi 2021). Additionally, levels of malondialdehyde, a marker of oxidative stress, and C-reactive protein, an inflammatory marker, were significantly decreased in the women taking lipoic acid compared with placebo. Other migraine-related parameters such as severity and frequency were not assessed.

In a pilot study of 32 migraine sufferers with insulin resistance, supplementation with 400 mg lipoic acid twice daily for six months significantly reduced the number of migraine attacks and days needing treatment, with improvements seen as early as two months (Cavestro 2018). A placebo group was not included in this exploratory study.

Other Antioxidants

Various other antioxidants, including N-acetylcysteine (NAC) (another thiol-containing compound), vitamin C, and vitamin E have been studied in combination and shown to be of potential benefit to migraine sufferers. Vitamin E alone (taken at a dose of 400 IU/day for five days around the start of menstruation) was shown to significantly improve pain severity, light and noise sensitivity, nausea, and functional disability compared with placebo in women with menstrual migraines (Ziaei 2009). A combination of vitamin C (500 mg), vitamin E (167.5 mg [250 IU]), and NAC (600 mg) taken twice daily for three months was shown to significantly decrease monthly headache and migraine frequency compared with placebo (Visser 2020). In subjects taking the nutrient combination, average monthly migraine days, moderate/severe headache days, migraine duration, headache pain scores, and acute headache medication use were all significantly decreased.

Miscellaneous Beneficial Ingredients

The following list of natural ingredients may also be useful for managing migraine symptoms, though definitive clinical data is lacking:

  • Ginkgo Biloba (Schiapparelli 2010)
  • Vitamin B6 (Ross 2011)
  • Ginger (Mustafa 1990)

5 What Causes a Migraine?

In the early years of migraine research, scientists believed that the headache portion of a migraine resulted from the dilation of blood vessels, while the aura portion of migraine was caused by vasoconstriction (Cutrer 2012). However, more recent evidence suggests that these vascular changes are not the cause of migraine, but rather an epiphenomenon that accompanies the pain (Rizzoli 2012). Today, migraine is viewed as a result of complex dysfunction within the central nervous system (Charles 2009). Various factors that contribute to this dysfunction are reviewed below.

Oxidative Stress

Elevated levels of oxidative stress and related DNA damage have been observed in some clinical studies of migraine patients; however, the specific mechanisms by which oxidative stress may contribute to migraine are unknown (Goschorska 2020). Increased oxidative stress can affect blood vessel dilation, neurotransmitter signaling, and mitochondrial function—each of which may play a role in migraines (Yilmaz 2007; Borkum 2021; Tuncel 2008).

Antioxidants such as N-acetylcysteine (NAC) and lipoic acid contain thiol (-SH) groups. Lower serum thiol levels have been observed in migraine patients and are associated with increased migraine-related disability (Eren 2015).


The neurotransmitter serotonin (5-hydroxytryptamine [5-HT]) plays a role in the development of migraine attacks. This conclusion is supported by evidence indicating that migraine patients tend to have low levels of serotonin in their brains (Panconesi 2008). Additional support for this theory is found in data indicating that tricyclic antidepressants, which increase serotonin signaling, reduce the frequency of migraine attacks (Cutrer 2012).

Furthermore, melatonin, an active metabolite of serotonin (Gyermek 1996), has also been found to be deficient among migraine patients (Masruha 2008; Masruha 2010), and melatonin supplementation has resulted in symptom improvement among some migraine patients (Vogler 2006).

Although the exact mechanism linking low serotonin levels to migraine pathology has not yet been fully described (Hamel 2007), researchers have hypothesized that serotonin may interfere with pain processing in the brain. Serotonin also affects on the dilation and contraction of blood vessels in the brain (Cutrer 2012).

Though low serotonin levels may give rise to an attack, some evidence suggests that elevated serotonin levels may contribute to migraine pathology during an attack (Sakai 2008; Chugani 1999). Due to the complexity of serotonin's role in migraine, further study is needed to fully characterize the effects of modulating serotonin levels and/or signaling in migraine patients.

The Role of Hormones

Migraine disproportionately affects women – females make up about 70% of all migraine patients – suggesting a potential hormonal link (Dhillon 2011).

Although many hormonal events in a female's life may influence the occurrence of migraine (e.g., menarche, menstruation, pregnancy, and menopause) (Sacco 2012), menstruation appears to be the most important. For example, 70% of female patients who experience migraine report some type of menstrual link (Calhoun 2012). A phenomenon called "estrogen withdrawal," which occurs in the late luteal phase of the menstrual cycle and is characterized by an abrupt decline in estrogen levels, is likely an important migraine trigger in some women (MacGregor 2009, Lay 2009).

Fluctuations in estrogens levels associated with migraine produce biochemical changes in prostaglandin production, prolactin release, and endogenous opioid regulation (Dzugan 2004, 2006).

Prostaglandin E2 (PGE-2) is a well-defined mediator of fever and inflammation. PGE-2 increases vasodilatation and thereby induces pain. Estrogens increase the production of PGE-2. An excess of estrogens, deficit of progesterone, or dominance of estrogens can cause increased production of PGE-2, resulting in migraine.

Elevation of the prolactin level or increased sensitivity to prolactin leads to a decreased level of prostaglandin E1 (PGE-1). Patients with migraine may have prostaglandin-induced hyper-sensitivity to prolactin. PGE-1 is a substance that in fact improves the microcirculation and leads to the development of collateral circuits with a consequent improvement in local hemodynamics.

If a patient has a dominance of PGE-2, vasodilatation of major arteries with spasm of collateral circuits would be expected, which in turn can cause pain. Restoration of hormonal levels and balance between them can stabilize levels of prostaglandins.

Steroid hormones also influence the metabolism of calcium and magnesium. Estrogens regulate calcium metabolism, intestinal calcium absorption, and parathyroid gene expression and secretion, triggering fluctuations across the menstrual cycle. Alterations in calcium homeostasis have long been associated with many affective disturbances.

Clinical trials in women with premenstrual syndrome have found that calcium supplementation may help alleviate most mood and somatic symptoms. Evidence to date indicates that women with symptoms of premenstrual syndrome have an underlying calcium abnormality (Thys-Jacobs 2000). A low brain magnesium level can be an expression of neuronal hyperexcitability of the visual pathways and be associated with a lowered threshold for migraine attacks (Aloisi 1997). Clinically, it is known that magnesium supplementation relieves premenstrual problems (for example, migraine, bloating, and edema) that occur late in the menstrual cycle, and that migraine, particularly in women, is associated with deficiencies in brain and serum magnesium levels. Testosterone was not shown to produce any significant alteration in magnesium levels, but estrogens and progesterone do (Li 2001).

Among women with menstrual-related migraines, using hormone therapy to minimize monthly declines in estrogen concentration may be effective in preventing migraine attacks (Calhoun 2009). Studies suggest that non-oral routes of estrogen therapy, such as a topical cream to be applied to the skin, are more likely to improve migraine than oral estrogens (MacGregor 2009).

More information about hormone testing and restoration is available in the Female Hormone Restoration protocol.

The Neurohormonal and Metabolic Dysbalance Hypothesis of Migraine

Some researchers suspect that an important cause of migraine is an imbalance between estrogens and progesterone levels, rather than the absolute levels of these hormones. Indeed, therapies aimed at improving the ratio of estrogens to progesterone have successfully relieved severe menstrual migraine in preliminary reports (Holdaway 1991).

Some innovative physicians believe that consideration should be given to the balance of other sex hormones as well, including testosterone, dehydroepiandrosterone (DHEA), and pregnenolone (Dzugan 2006).

According to the Neurohormonal and Metabolic Dysbalance Hypothesis of Migraine, migraine is not a single disorder, but a collection of disorders involving faulty hormonal feedback in the hypothalamic-pituitary-adrenal-gonadal axis.

Contributing to this hormonal abnormality is an imbalance between two of the three arms of the autonomic nervous system (the sympathetic and parasympathetic nervous systems), which causes a decline in the brain's pain threshold. Because of disequilibrium between intra- and extracellular calcium and magnesium, the polarity of the cell membrane is changed, which affects the electrical stability of the cell membrane and sensitivity to neurohormonal impulses (steroid hormones, melatonin, and serotonin).

Although well-controlled clinical trials designed to test the hypothesis that comprehensive hormone testing and balancing may relieve migraine headaches are lacking, several case reports present positive outcomes using this novel approach (Dzugan 2006).

One link between hormonal imbalance and migraine may stem from the opposing roles of estrogen and progesterone within the brain. While estrogen stimulates neural excitability, progesterone exhibits inhibitory actions in central neurons (Finocchi 2011). Therefore, imbalance between these neuromodulatory hormones may give rise to physiological conditions that alter susceptibility to migraine (Finocchi 2011).

Tailored hormonal replacement therapy (HRT) aimed at minimizing estrogen/progesterone imbalance and stabilizing estrogen levels may be effective for preventing migraines among pre- and post-menopausal women (Nappi 2009; Shuster 2011; Schurks 2010; Calhoun 2012). In the words of some forward thinking migraine researchers - "clinical experience strongly supports the notion that migraine can be managed only when levels of all the basic hormones—pregnenolone, DHEA, testosterone, estrogen, and progesterone—are optimal with the physiological cycle" (Dzugan 2003).

Women suffering migraines without relief through conventional medical treatments should consider comprehensive hormone testing and restoration of hormonal balance using bioidentical hormone replacement therapy.

6 Diagnosis

History and physical examination are used to diagnose migraine headaches (Cutrer 2012; Katsarava 2012; NHF 2012; Walling 2011; Goldman 2011; Univ. of Maryland Medical Center 2012).

Migraine headache is often misdiagnosed as sinus headache or tension-type headache (NHF 2012). This is especially true when the headache complaints are not accompanied by the typical features of migraine such as nausea, light/sound sensitivity, and exacerbation upon physical activity (Cutrer 2012).

Some less common but potentially more serious disorders including subarachnoid hemorrhage, intracranial mass lesions, cerebral vasculitis, and others can cause migraine-like symptoms. Therefore, it is important that your doctor rule out other possible causes of headache, especially in the absence of history of migraine (Merck Manual 2012; Kwiatkowski 2009; Bope 2012; Ferri 2012).

When physicians are not sure that migraine is the proper diagnosis, tests such as computerized tomography (CT), magnestic resonance imaging (MRI), and a spinal tap (lumbar puncture) may be used to help rule out other possible conditions (Mayo Clinic 2012; Kwiatkowski 2009).

7 Conventional Treatment

Most migraine treatment plans involve both acute and preventive strategies (Braun 2010).

Acute Treatment

The goal of acute or abortive treatment is to relieve the intensity and/or duration of an imminent or ongoing migraine as quickly as possible (Hershey 2011).

First tier options for acute migraine management may include non-steroidal anti-inflammatory drugs (NSAIDs) and/or mild analgesics (e.g., acetaminophen or aspirin) (Hershey 2011; Bajwa 2012). Caffeine, due to its vasocontrictive properties, is sometimes combined with aspirin and/or acetaminophen as well (Aukerman 2002). However, these options may not be sufficient for treating severe migraines, in which case a variety of drugs in the triptan class may be considered (Hershey 2011).

The triptan drugs (e.g., sumatriptan, rizatriptan, eletriptan, and almotriptan) act on several specific mechanisms of a migraine headache, such as promoting vasoconstriction and blocking pain pathways in the brainstem. Triptans mediate these effects by activating certain serotonin receptors in cranial blood vessels (Bajwa 2012).

Although the triptans are arguably the most effective treatment for acute relief of a migraine headache (i.e., the "gold standard"), they have a number of side effects (Cady 2011). For example, triptans should be avoided (when possible) in patients who are at risk for cardiovascular events and stroke (i.e., patients with heart disease). Furthermore, triptans require careful monitoring because they are known to interact with a large number of other commonly used medications (Bajwa 2012).

Other drugs that may be used to treat migraine include ergot alkaloids, which cause blood vessel constriction, opioids, and, less commonly, corticosteroids (MD Consult 2011).

Medicating as early as possible during migraine increases the chances of successfully aborting an attack or reducing its intensity (Aukerman 2002).

Preventive Treatment

The main goals of preventive therapy are to reduce migraine frequency, severity, and duration, as well as improve responsiveness to acute treatment(s). Preventive treatment options include headache trigger avoidance, daily medication, physical therapy, and/or behavioral therapy (Braun 2010).

Drugs used to prevent migraines include blood pressure medications (e.g., beta blockers, calcium channel blockers, ACE inhibitors, and angiotensin receptor blockers), tricyclic antidepressants (e.g., amitriptyline [Elavil®]), and anticonvulsants (e.g., valproate [Depakote®], gabapentin [Neurontin®], and topiramate [Topamax®]). These drugs should be started at low doses, and given adequate time to reach peak effectiveness. Therefore, depending upon the chosen medication, a proper drug trial could take anywhere from four weeks to three months to take effect (Bajwa 2010).

Ironically, taking too much migraine prevention medication for too long can lead to "medication overuse headache". Medication overuse headache can become a chronic, self-perpetuating condition called "chronic daily headache", in which patients experience daily headaches caused by medication overuse, but continue to use medication to relive the headaches. To prevent medication overuse headache, migraine patients should (on average) limit use of NSAIDs to 15 or fewer days a month and limit triptan or over-the-counter combination analgesic use to 9 or fewer days a month (Garza 2012; Young 2001).

Lifestyle Considerations

Although there are a wide variety of acute and preventive drugs available for treating migraines, many patients will not experience significant symptom relief unless healthy lifestyle modifications are made (Sun-Edelstein 2009a). The following lifestyle interventions may prevent migraines (Chaibi 2011b; Gallagher 2012; Linde 2009; Honaker 2008, Hauge 2011 ):

  • avoidance of caffeine, nicotine, red wine, and other migraine triggers
  • stress reduction (see the Stress Management protocol)
  • improving sleep hygiene (see the Insomnia protocol)
  • massage therapy
  • chiropractic manipulation
  • acupuncture
  • getting sufficient exercise
  • and frequent stretching

8 Dietary Interventions

A significant association between dietary intake and migraine incidence exists; one out of every four migraine patients report that certain foods can trigger an attack (Mueller 2007). Furthermore, the avoidance of food allergies and/ or sensitivities may reduce or eliminate migraine symptoms for some patients (Ross 2011).

Common nutritional migraine triggers include (Mueller 2007):

  • Monosodium glutamate (MSG) is a commonly used flavor-enhancer found in some soups and Chinese food.
  • Nitrites are preservatives found in processed meats such as hot dogs.
  • Tyramines are natural compounds found in wines and aged foods (e.g., cheeses).
  • Phenylethylamine is a stimulant compound found in chocolate, garlic, nuts, raw onions, and seeds.

Many of these nutritional migraine triggers have vasoactive properties (causes constriction or dilation of blood vessels)(Gallagher 2012), which is why they may contribute to migraine attacks.

Other potential dietary triggers include cow's milk, wheat, eggs, alcohol, artificial sweeteners, citrus fruits, pickled products, and vinegar (Mueller 2007; Ross 2011).

It is important to note that not all migraine patients are susceptible to the aforementioned nutritional triggers, thus the complete elimination of these items is not always necessary (Mueller 2007). In order to identify nutritional triggers, experts suggest the use of food diaries because they are simple, inexpensive, and removal of trigger foods is associated with a reduction in migraine headaches (Sun-Edelstein 2009a).

Also, food allergy and sensitivity testing to measure immunologic reactivity to foods may allow for identification of potential migraine triggers (Ross 2011; Arroyave Hernandez 2007; Mylek 1992).

In addition to the above triggers, dietary fasting for longer than 4 hours should also be avoided (when possible) since it has been linked to an increased risk of migraine (Gallagher 2012; Fukui 2008).


  • Apr: Added section on oxidative stress to What Causes Migraine?
  • Apr: Updated sections on coenzyme Q10, melatonin, and lipoic acid, and added a section on other antioxidants in Nutrients


  • Jul: Comprehensive update & review

Disclaimer and Safety Information

This information (and any accompanying material) is not intended to replace the attention or advice of a physician or other qualified health care professional. Anyone who wishes to embark on any dietary, drug, exercise, or other lifestyle change intended to prevent or treat a specific disease or condition should first consult with and seek clearance from a physician or other qualified health care professional. Pregnant women in particular should seek the advice of a physician before using any protocol listed on this website. The protocols described on this website are for adults only, unless otherwise specified. Product labels may contain important safety information and the most recent product information provided by the product manufacturers should be carefully reviewed prior to use to verify the dose, administration, and contraindications. National, state, and local laws may vary regarding the use and application of many of the therapies discussed. The reader assumes the risk of any injuries. The authors and publishers, their affiliates and assigns are not liable for any injury and/or damage to persons arising from this protocol and expressly disclaim responsibility for any adverse effects resulting from the use of the information contained herein.

The protocols raise many issues that are subject to change as new data emerge. None of our suggested protocol regimens can guarantee health benefits. Life Extension has not performed independent verification of the data contained in the referenced materials, and expressly disclaims responsibility for any error in the literature.

Aloisi P, Marrelli A, Porto C, et al. Visual evoked potentials and serum magnesium levels in juvenile migraine patients. Headache. 1997 Jun;37(6):383-5.

American Academy of Neurology. Ramadan NM. Silberstein SD, Freitag FG, et al. Evidence-Based Guidelines for Migraine Headache in the Primary Care Setting: Pharmacological Management for Prevention of Migraine. Available at: http://www.aan.com/professionals/practice/pdfs/gl0090.pdf Accessed 6/29/2012.

AMR (Alternative Medicine Review) Riboflavin. Monograph. Altern Med Rev. 2008;13(4):334-340.

Arroyave Hernandez CM, Echavarría Pinto M, and Hernández Montiel HL. Food allergy mediated by IgG antibodies associated with migraine in adults. Rev Alerg Mex. 2007 Sep-Oct;54(5):162-8.

Aukerman G, Knutson D, and Miser W. Management of the Acute Migraine Headache. Am Fam Physician. 2002 Dec 1;66(11):2123-2131.

Bajwa Z., Acute treatment of migraine in adults. In: UpToDate, Swanson J., Dashe J. (Eds), UpToDate, Waltham, MA, 2012.

Bajwa Z., Preventive treatment of migraine in adults. In: UpToDate, Swanson J., Dashe J. (Eds), UpToDate, Waltham, MA, 2010.

Boehnke C, Reuter U, Flach U, Schuh-Hofer S, Einhaupl KM, Arnold G. High-dose riboflavin treatment is efficacious in migraine prophylaxis: an open study in a tertiary care centre. Eur J Neurol. 2004;11(7):475-477.

Bogdanov VB, Multon S, Chauvel V, et al. Migraine preventive drugs differentially affect cortical spreading depression in rat. Neurobiol Dis. 2011;41(2):430-435.

Bope and Kellerman: Conn's Current Therapy 2012, 1st ed. Walling A (ed.) Copyright © 2011 Saunders, An Imprint of Elsevier. Available at: http://www.mdconsult.com/books/page.do?sid=1328661388&eid=4-u1.0-B978-1-4557-0738-6..00010-3--sc0050&isbn=978-1-4557-0738-6&uniqId=343672168-780 Accessed 7/3/2012.

Borkum JM. Brain Energy Deficit as a Source of Oxidative Stress in Migraine: A Molecular Basis for Migraine Susceptibility. Neurochem Res. Aug 2021;46(8):1913-1932. doi:10.1007/s11064-021-03335-9

Braun, E., (2010) Chapter 17: Pain Management in the Head and Neck Patient (pg. 247). In: Flint, P. (Ed.), Cummings Otolaryngology: Head & Neck Surgery (5th ed.). Mosby, An Imprint of Elsevier.

Braun, E., (2010) Chapter 17: Pain Management in the Head and Neck Patient (pg. 246). In: Flint, P. (Ed.), Cummings Otolaryngology: Head & Neck Surgery (5th ed.). Mosby, An Imprint of Elsevier.

Brenner SR. Mitochondrial DNA haplogroups influence the therapeutic response to riboflavin in migraineurs: Neurology. 2010 Jan 12;74(2):182-3; author reply 183.

Cady RK, Goldstein J, Nett R, Mitchell R, Beach ME, Browning R. A double-blind placebo-controlled pilot study of sublingual feverfew and ginger (LipiGesic M) in the treatment of migraine. Headache. 2011;51(7):1078-1086.

Calhoun A. Estrogen-associated migraine. In: UpToDate, Barbieri R., Swanson J. (Eds), UpToDate, Waltham, MA, 2012.

Calhoun AH, Hutchinson S. Hormonal therapies for menstrual migraine. Curr Pain Headache Rep. 2009;13(5):381-385.

Carpenter DJ. St. John's wort and S-adenosyl methionine as "natural" alternatives to conventional antidepressants in the era of the suicidality boxed warning: what is the evidence for clinically relevant benefit? Altern Med Rev. 2011;16(1):17-39.

Cavestro C, Bedogni G, Molinari F, Mandrino S, Rota E, Frigeri MC. Alpha-Lipoic Acid Shows Promise to Improve Migraine in Patients with Insulin Resistance: A 6-Month Exploratory Study. Journal of medicinal food. Mar 2018;21(3):269-273. doi:10.1089/jmf.2017.0068

Chaibi A, Tuchin PJ, Russell MB. Manual therapies for migraine: a systematic review. J Headache Pain. 2011;12(2):127-133.

Charles A. Advances in the basic and clinical science of migraine. Ann Neurol. 2009;65(5):491-498.

Chen CF, Leung AY. Gene response of human monocytic cells for the detection of antimigraine activity of feverfew extracts. Can J PhysiolPharmacol. 2007;85(11):1108-1115.

Chugani DC, Niimura K, Chaturvedi S, et al. Increased brain serotonin synthesis in migraine. Neurology. 1999 Oct 22;53(7):1473-9.

Condo M, Posar A, Arbizzani A, Parmeggiani A. Riboflavin prophylaxis in pediatric and adolescent migraine. J Headache Pain. 2009;10(5):361-365.

Cutrer F., et al. Pathophysiology, clinical manifestations, and diagnosis of migraine in adults. In: UpToDate, Jerry W Swanson, John F Dashe (Eds), UpToDate, Waltham, MA, 2012.

D'Amico D and Tepper SJ. Prophylaxis of migraine: general principles and patient acceptance. Neuropsychiatr Dis Treat. 2008;4(6):1155-1167.

De Silva V, El-Metwally A, Ernst E, Lewith G, Macfarlane GJ. Evidence for the efficacy of complementary and alternative medicines in the management of fibromyalgia: a systematic review. Rheumatology. 2010;49(6):1063-1068.

Dhillon KS, Singh J, and Lyall JS. A new horizon into the pathobiology, etiology and treatment of migraine. Med Hypotheses. 2011 Jul;77(1):147-51.

Diamond S, Bigal ME, Silberstein S, et al. Patterns of diagnosis and acute and preventive treatment for migraine in the United States: results from the American Migraine Prevalence and Prevention study. Headache. 2007;47(3):355-63.

Diener HC, Rahlfs VW, Danesch U. The First Placebo-Controlled Trial of a Special Butterbur Root Extract for the Prevention of Migraine: Reanalysis of Efficacy Criteria. European Neurology. 2004;51(2):89-97.

Digre K. (2011a). Chapter 405: Headaches and other pain: Migraine Headache (pg. 2247). In Lee Goldman, Andrew I. Schafer (Ed.), Goldman’s Cecil Medicine (24th ed.). Saunders, An Imprint of Elsevier.

Digre K. (2011b). Chapter 405: Headaches and other pain. Migraine Headache (pg. 2247). In Lee Goldman, Andrew I. Schafer (Ed.), Goldman’s Cecil Medicine (24th ed.). Saunders, An Imprint of Elsevier.

Digre K. (2011c). Chapter 405: Headaches and other pain. Migraine Headache (pg. 2247). In Lee Goldman, Andrew I. Schafer (Ed.), Goldman’s Cecil Medicine (24th ed.). Saunders, An Imprint of Elsevier.

DiLorenzo C, Pierelli F, Coppola G, Grieco G, Rengo C. Mitochondrial DNA haplogroups influence the therapeutic response to riboflavin in migraineurs. Neurology 2009;72:1588–1594.

Drummond PD. Tryptophan depletion increases nausea, headache and photophobia in migraine sufferers. Cephalalgia. 2006 Oct;26(10):1225-33.

Durham PL. CGRP-Receptor Antagonists – A Fresh Approach to Migraine Therapy? N Engl J Med. 2004;350:1073-1075.

Dzugan SA and Smith RA. The simultaneous restoration of neurohormonal and metabolic integrity as a very promising method of migraine management. Bull Urg Rec Med. 2003;4(4):622-8.

Dzugan SA. An Innovative New Treatment for Migraine. Life Extension magazine. September, 2004

Dzugan SA. The Migraine Cure. United States Lynn Sonberg Book Associates. ©2006.

Emel Köseoglu, Abdullah Talaslioglu, Ali Saffet Gönül, Mustafa Kula. The effects of magnesium prophylaxis in migraine without aura. Magnes Res. 2008 Jun;21(2):101-8.

Eren Y, Dirik E, Neşelioğlu S, Erel Ö. Oxidative stress and decreased thiol level in patients with migraine: cross-sectional study. Acta neurologica Belgica. Dec 2015;115(4):643-9. doi:10.1007/s13760-015-0427-y

Ernst E, Pittler MH. The efficacy and safety of feverfew (Tanacetumparthenium L.): an update of a systematic review. Public Health Nutr. 2000;3(4A):509-514.

Fallah R, Shoroki FF, Ferdosian F. Safety and efficacy of melatonin in pediatric migraine prophylaxis. Curr Drug Saf. 2015;10(2):132-5. doi:10.2174/1574886309666140605114614

Ferri: Ferri's Clinical Advisor 2013, 1st ed. Copyright © 2012 Mosby, An Imprint of Elsevier Available at: http://www.mdconsult.com/books/page.do?sid=1327231261&eid=4-u1.0-B978-0-323-08373-7..00017-0--sc0025&isbn=978-0-323-08373-7&uniqId=342348469-680#4-u1.0-B978-0-323-08373-7..00017-0--sc0025 Accessed 6/29/2012.

Fetrow CW, Avila JR. Efficacy of the dietary supplement S-adenosyl-L-methionine. Ann Pharmacother. 2001;35(11):1414-1425.

Finocchi C and Ferrari M. Female reproductive steroids and neuronal excitability. Neurol Sci. 2011 May;32Suppl1:S31-5.

Fukui PT, GonçalvesTR, Strabelli CG, et al. Trigger factors in migraine patients. Arq Neuropsiquiatr. 2008;66(3A):494-9.

Gagnier JJ. The therapeutic potential of melatonin in migraines and other headache types. Altern Med Rev. 2001;6(4):383-389.

Gallagher, M., (2012) Chapter 1: Symptomatic Care Pending Diagnosis (pg. 1). In: Bope, E. (Ed.), Conn's Current Therapy 2012 (1st ed.). Saunders, An Imprint of Elsevier.

Garza I., Medication overuse headache: Treatment and prognosis. In: UpToDate, Swanson J., Dashe J. (Eds), UpToDate, Waltham, MA, 2012.

Gatto G, Caleri D, Michelacci S, Sicuteri F. Analgesizing effect of a methyl donor (S-adenosylmethionine) in migraine: an open clinical trial. Int J ClinPharmacol Res. 1986;6(1):15-17.

Gaul C, Diener HC, Danesch U. Improvement of migraine symptoms with a proprietary supplement containing riboflavin, magnesium and Q10: a randomized, placebo-controlled, double-blind, multicenter trial. The journal of headache and pain. 2015;16:516.

Gelfand AA, Ross AC, Irwin SL, Greene KA, Qubty WF, Allen IE. Melatonin for Acute Treatment of Migraine in Children and Adolescents: A Pilot Randomized Trial. Headache. Sep 2020;60(8):1712-1721. doi:10.1111/head.13934

Goldman: Goldman's Cecil Medicine, 24th ed. Copyright © 2011 Saunders, An Imprint of Elsevier Available at: http://www.mdconsult.com/books/page.do?sid=1327227253&eid=4-u1.0-B978-1-4377-1604-7..00405-X--s0045&isbn=978-1-4377-1604-7&uniqId=342348469-680#4-u1.0-B978-1-4377-1604-7..00405-X--s0045 Accessed 6/29/2012.

Goodyear-Smith F. Feverfew. Bachelor's buttons, Featherfew (Tanacetumparthenium L. aka Chrysanthemum parthenium L. aka Pyrethrum parthenium L.). J Prim Health Care. 2010;2(4):337.

Goschorska M, Gutowska I, Baranowska-Bosiacka I, Barczak K, Chlubek D. The Use of Antioxidants in the Treatment of Migraine. Antioxidants (Basel, Switzerland). Jan 28 2020;9(2)doi:10.3390/antiox9020116

Gyermek L. Pharmacology of serotonin as related to anesthesia. J ClinAnesth. 1996;8(5):402-425.

Hajihashemi P, Askari G, Khorvash F, Reza Maracy M, Nourian M. The effects of concurrent Coenzyme Q10, L-carnitine supplementation in migraine prophylaxis: A randomized, placebo-controlled, double-blind trial. Cephalalgia. Apr 2019;39(5):648-654. doi:10.1177/0333102418821661

Hamel E. Serotonin and migraine: biology and clinical implications. Cephalalgia. 2007;27(11):1293-300.

Hauge AS, Kirchmann M, and Olesen J. Characterization of consistent triggers of migraine with aura. Cephalalgia. 2011 Mar;31(4):416-38.

Hershey, A., (2011) Chapter 588: Headaches (pg. 2040). In: Kliegman, R. (Ed.), Nelson Textbook of Pediatrics (19th ed.). Saunders, An Imprint of Elsevier.

Hershey AD, Powers SW, Vockell AL, et al. Coenzyme Q10 deficiency and response to supplementation in pediatric and adolescent migraine. Headache. Jan 2007;47(1):73-80. doi:10.1111/j.1526-4610.2007.00652.x

Holdaway IM, Parr CE, France J. Treatment of a patient with severe menstrual migraine using the depot LHRH analogue Zoladex. Aust N Z J Obstet Gynaecol. 1991;31(2):164-5.

Holland S, Silberstein SD, Freitag F, DodickDW, Argoff C, Ashman E. Evidence-based guideline update: NSAIDs and other complementary treatments for episodic migraine prevention in adults: Report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012;78(17):1346-53

Honaker J, Samy RN. Migraine-associated vestibulopathy. CurrOpinOtolaryngol Head Neck Surg. 2008;16(5):412-5.

Huang Y, Huang X, Zhang L, Han F, Pang KL, Li X, Shen JY. Magnesium boosts the memory restorative effect of environmental enrichment in Alzheimer's disease mice. CNS neuroscience & therapeutics. Jan 2018;24(1):70-79.

Katsarava Z, Buse DC, Manack AN, Lipton RB. Defining the differences between episodic migraine and chronic migraine. Curr Pain Headache Rep. 2012;16(1):86-92.

Kwiatkowski T, Alagappan K (eds.) Marx: Rosen's Emergency Medicine, 7th ed. Copyright © 2009 Mosby, An Imprint of Elsevier. Availble at: http://www.mdconsult.com/books/page.do?sid=1328667371&eid=4-u1.0-B978-0-323-05472-0..00101-8&isbn=978-0-323-05472-0&uniqId=343672168-795 Accessed 7/3/2012.

Lay CL, Broner SW. Migraine in women. NeurolClin. 2009;27(2):503-511.

Li W, Zheng T, Altura BM, Altura BT. Sex steroid hormones exert biphasic effects on cytosolic magnesium ions in cerebral vascu- lar smooth muscle cells: possible relationships to migraine frequency in premenstrual syndromes and stroke incidence. Brain Res Bull. 2001 Jan 1;54(1):83-9.

Liampas I, Siokas V, Brotis A, Vikelis M, Dardiotis E. Endogenous Melatonin Levels and Therapeutic Use of Exogenous Melatonin in Migraine: Systematic Review and Meta-Analysis. Headache. Jul 2020;60(7):1273-1299. doi:10.1111/head.13828

Linde K, Allais G, Brinkhaus B, Manheimer E, Vickers A, White AR. Acupuncture for migraine prophylaxis. Cochrane Database Syst Rev. 2009;21(1).

Lipton RB, Gobel H, Einhaupl KM, Wilks K, Mauskop A. Petasiteshybridus root (butterbur) is an effective preventive treatment for migraine. Neurology. 2004;63(12):2240-2244.

Lipton RB. Chronic migraine, classification, differential diagnosis, and epidemiology. Headache. 2011;2:77-83.

MacGregor EA. Estrogen replacement and migraine. Maturitas. 2009;63(1):51-55.

Magis D, Ambrosini A, Sándor P, Jacquy J, Laloux P, Schoenen J. A randomized double-blind placebo-controlled trial of thioctic acid in migraine prophylaxis. Headache. Jan 2007;47(1):52-7. doi:10.1111/j.1526-4610.2006.00626.x

Magis D, Schoenen J. Treatment of migraine: update on new therapies. CurrOpin Neurol. 2011;24(3):203-10.

Martin BR, Seaman DR. Dietary and Lifestyle Changes in the Treatment of a 23-Year-Old Female Patient With Migraine. Journal of chiropractic medicine. Sep 2015;14(3):205-211.

Masruha MR, de Souza Vieira DS, Minett TS, et al. Low urinary 6-sulphatoxymelatonin concentrations in acute migraine. J Headache Pain. 2008;9(4):221-224.

Masruha MR, Lin J, de Souza Vieira DS, et al. Urinary 6-sulphatoxymelatonin levels are depressed in chronic migraine and several comorbidities. Headache. 2010a Mar;50(3):413-9. Epub 2008 Oct 8.

Masruha MR, Lin J, de Souza Vieira DS, et al. Urinary 6-sulphatoxymelatonin levels are depressed in chronic migraine and several comorbidities. Headache. 2010;50(3):413-419.

Mayo Clinic. Migraine 6/4/2011. Available at: http://www.mayoclinic.com/health/migraine-headache/DS00120 Accessed: 6/29/2012.

Mayo Clinic. Migraine: Causes. Available at: http://www.mayoclinic.com/health/migraine-headache/ds00120/dsection=causes. Accessed July 2, 2012.

MD Consult. Migraine. Updated 4/22/2011. Available at: http://www.mdconsult.com/das/pdxmd/body/344049714-3/0?type=med&eid=9-u1.0-_1_mt_1017198#Contributors Accessed 7/5/2012.

Merck Manual. Migraine. Available at: http://www.merckmanuals.com/professional/neurologic_disorders/headache/migraine.html?qt=migraine&alt=sh#v1040393 Accessed 6/28/2012.

Mijalski C, Dakay K, Miller-Patterson C, Saad A, Silver B, Khan M. Magnesium for Treatment of Reversible Cerebral Vasoconstriction Syndrome: Case Series. The Neurohospitalist. Jul 2016;6(3):111-113.

Moloney MF, Johnson CJ. Migraine headaches: diagnosis and management. J Midwifery Womens Health. 2011;56(3):282-292.

Mueller LL. Diagnosing and managing migraine headache. J Am Osteopath Assoc. 2007;107(10 Suppl 6):ES10-16.

Mustafa T, Srivastava KC. Ginger (Zingiberofficinale) in migraine headacheJEthnopharmacol. 1990 Jul;29(3):267-73.

Mylek D. [Migraine as one of the symptoms of food allergy]. Pol TygLek. 1992 Jan 20-27;47(3-4):89-91.

Nappi RE, Sances G, Detaddei S, Ornati A, Chiovato L, Polatti F. Hormonal management of migraine at menopause. Menopause Int. 2009;15(2):82-6.

NHF (Nation Headache Foundation) Migraine. Accessed 05/22/2012. Available online at: http://www.headaches.org/education/Headache_Topic_Sheets/Migraine. Copyright 2012.

NIH-MedlinePlus. Migraine Availabel at: http://www.nlm.nih.gov/medlineplus/migraine.html Accessed 6/29/2012.

NINDS (National Institute of Neurological Disorders and Stroke). NINDS Migraine Information Page. Available at: http://www.ninds.nih.gov/disorders/migraine/migraine.htm. Last updated March 1, 2012. Accessed July 2, 2012.

O'Brien HL, Hershey AD. Vitamins and paediatric migraine: Riboflavin as a preventative medication: Cephalalgia. 2010 Dec;30(12):1417-8. Epub 2010 Jul 27.

Oelkers-Ax R, Leins A, Parzer P, et al. Butterbur root extract and music therapy in the prevention of childhood migraine: an explorative study. Eur J Pain. 2008;12(3):301-13.

Panconesi A. Serotonin and migraine: a reconsideration of the central theory. J Headache Pain. 2008;9(5):267-76.

Pareek, A, Suthar M, Rathore G, et al. Feverfew (Tanacetumparthenium L.): A systematic review. Pharmacogn Rev. 2011 Jan-Jun; 5(9): 103–110.

Parohan M, Sarraf P, Javanbakht MH, Foroushani AR, Ranji-Burachaloo S, Djalali M. The synergistic effects of nano-curcumin and coenzyme Q10 supplementation in migraine prophylaxis: a randomized, placebo-controlled, double-blind trial. Nutritional neuroscience. Apr 2021;24(4):317-326. doi:10.1080/1028415x.2019.1627770

Peikert A, Wilimzig C, Kohne-Volland R. Prophylaxis of migraine with oral magnesium: results from a prospective, multi-center, placebo-controlled and double-blind randomized study. Cephalalgia : an international journal of headache. Jun 1996;16(4):257-263.

Pittler MH, Ernst E. Feverfew for preventing migraine. Cochrane Database Syst Rev. 2004;(1):CD002286.

Pothmann R, Danesch U. Migraine prevention in children and adolescents: results of an open study with a special butterbur root extract. Headache. 2005;45(3):196-203.

Pringsheim T, Davenport W, Mackie G, Worthington I, Aube M, Christie SN, . . . Becker WJ. Canadian Headache Society guideline for migraine prophylaxis. The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques. Mar 2012;39(2 Suppl 2):S1-59.

Qujeq D, Zandemami M, Ahanger AA, Shahabadin ME. Evaluation of intracellular magnesium and calcium concentration in patients with migraine. Neurosciences. 2012;17(1):85-86.

Rakel: Textbook of Family Medicine, 8th ed. Copyright © 2011 Saunders, An Imprint of Elsevier Available at: http://www.mdconsult.com/books/page.do?sid=1327235022&eid=4-u1.0-B978-1-4377-1160-8..10042-9--s0085&isbn=978-1-4377-1160-8&uniqId=342348469-671 Accessed 6/29/2012

Rezaei Kelishadi M, Alavi Naeini A, Askari G, Khorvash F, Heidari Z. The efficacy of alpha-lipoic acid in improving oxidative, inflammatory, and mood status in women with episodic migraine in a randomised, double-blind, placebo-controlled clinical trial. International journal of clinical practice. Sep 2021;75(9):e14455. doi:10.1111/ijcp.14455

Rizzoli PB. Talking about migraine. Harvard Health Letter. www.health.hardvard.edu. January 2012.

Ross SM. Clinical applications of integrative therapies for prevention and treatment of migraine headaches. Holist NursPract. 2011;25(1):49-52.

Ross SM. Coenzyme q10: ubiquinone: a potent antioxidant and key energy facilitator for the heart. Holist NursPract. 2007;21(4):213-214.

Rossi P, Ambrosini A, and Buzzi MG. Prodromes and predictors of migraine attack. Funct Neurol. 2005 Oct-Dec;20(4):185-91.

Rothrock JF. Understanding Migraine: A Tale of Hope and Frustration. Headache: The Journal of Head and Face Pain. 2011;51(7):1188-1190.

Sacco S, Ricci S, Degan D, Carolei A. Migraine in women: the role of hormones and their impact on vascular diseases. J Headache Pain. 2012;13(3):177-189.

Sakai Y, Dobson C, Diksic M, et al. Sumatriptan normalizes the migraine attack-related increase in brain serotonin synthesis. Neurology. 2008 Feb 5;70(6):431-9.

Saranitzky E, White CM, Baker EL, Baker WL, Coleman CI. Feverfew for migraine prophylaxis: a systematic review. J Diet Suppl. 2009;6(2):91-103.

Sarchielli P, Mancini ML, Calabresi P. Practical considerations for the treatment of elderly patients with migraine. Drugs Aging. 2006;23(6):461-89.

Sazali S, Badrin S, Norhayati MN, Idris NS. Coenzyme Q10 supplementation for prophylaxis in adult patients with migraine-a meta-analysis. BMJ open. Jan 5 2021;11(1):e039358. doi:10.1136/bmjopen-2020-039358

Schiapparelli P, Allais G, CastagnoliGabellari I, Rolando S, Terzi MG, Benedetto C. Non-pharmacological approach to migraine prophylaxis: part II. Neurol Sci. 2010;31(1):S137-139.

Schurks M, Rist PM, Kurth T. Sex hormone receptor gene polymorphisms and migraine: a systematic review and meta-analysis. Cephalalgia. 2010;30(11):1306-1328.

Shugart C. Management of migraine headache: an overview of current practice. Jaapa. 2012;25(2):48-52.

Shuster L, Faubion S, Sood R, Casey P. Hormonal Manipulation Strategies in the Management of Menstrual Migraine and Other Hormonally Related Headaches. Current Neurology and Neuroscience Reports. 2011;11(2):131-138.

Sicuteri F. The ingestion of serotonin precursors (L-5-hydroxytryptophan and L-tryptophan) improves migraine headache. Headache. 1973 Apr;13(1):19-22.

Slater SK, Nelson TD, Kabbouche MA, et al. A randomized, double-blinded, placebo-controlled, crossover, add-on study of CoEnzymeQ10 in the prevention of pediatric and adolescent migraine. Cephalalgia. 2011;31(8):897-905.

Slutsky I, umaria N, Wu LJ, et al. Neuron. 2010 Jan 28;65(2):165-77. Enhancement of learning and memory by elevating brain magnesium. Neuron. 2010 Jan 28;65(2):165-77.

Sun-Edelstein C, Mauskop A. Foods and supplements in the management of migraine headaches. Clin J Pain. 2009;25(5):446-452.

Sun-Edelstein C, Mauskop A. Role of magnesium in the pathogenesis and treatment of migraine. Expert Rev Neurother. 2009;9(3):369-379.

Talebi M, Goldust M. Oral magnesium; migraine prophylaxis. JPMA. The Journal of the Pakistan Medical Association. Feb 2013;63(2):286.

Talebi M, Savadi-Oskouei D, Farhoudi M, et al. Relation between serum magnesium level and migraine attacks. Neurosciences. 2011;16(4):320-323.

Tatsuta Y, Kasai K, Maruyama C, et al. Imaging mass spectrometry analysis of ubiquinol localization in the mouse brain following short-term administration. Scientific Reports. 2017;7(1):12990. doi:10.1038/s41598-017-13257-8

Taubert K. [Magnesium in migraine. Results of a multicenter pilot study]. Fortschritte der Medizin. Aug 30 1994;112(24):328-330.

Thys-Jacobs S. Micronutrients and the pre-menstrual syndrome: the case for calcium. J Am CollNutr. 2000 Apr;19(2):220-7.

Tuncel D, Tolun FI, Gokce M, Imrek S, Ekerbiçer H. Oxidative stress in migraine with and without aura. Biol Trace Elem Res. Winter 2008;126(1-3):92-7. doi:10.1007/s12011-008-8193-9

Univ. of Maryland Medical Center. Migraine headache. Available at: http://www.umm.edu/altmed/articles/migraine-headache-000072.htm Accessed 6/29/2012.

Visser EJ, Drummond PD, Lee-Visser JLA. Reduction in Migraine and Headache Frequency and Intensity With Combined Antioxidant Prophylaxis (N-acetylcysteine, Vitamin E, and Vitamin C): A Randomized Sham-Controlled Pilot Study. Pain Pract. Sep 2020;20(7):737-747. doi:10.1111/papr.12902

Vogler B, Rapoport AM, Tepper SJ, Sheftell F, Bigal ME. Role of melatonin in the pathophysiology of migraine: implications for treatment. CNS Drugs. 2006;20(5):343-350.

Walling A. (2012). Chapter 10: The Nervous System: Migrine Headache (pg.621). In Edward T. Bope, Rick D. Kellerman (Ed.), Conn's Current Therapy (1st ed.). Saunders, An Imprint of Elsevier.

Wang J, Liu Y, Zhou LJ, Wu Y, Li F, Shen KF, . . . Liu XG. Magnesium L-threonate prevents and restores memory deficits associated with neuropathic pain by inhibition of TNF-alpha. Pain physician. Sep-Oct 2013;16(5):E563-575.

Wang P, Yu X, Guan PP, Guo JW, Wang Y, Zhang Y, . . . Wang ZY. Magnesium ion influx reduces neuroinflammation in Abeta precursor protein/Presenilin 1 transgenic mice by suppressing the expression of interleukin-1beta. Cellular & molecular immunology. May 2017;14(5):451-464.

Wilhelmsen M, Amirian I, Reiter RJ, Rosenberg J, Gögenur I. Analgesic effects of melatonin: a review of current evidence from experimental and clinical studies. Journal of Pineal Research. 2011;51(3):270-277.

Xu T, Li D, Zhou X, Ouyang HD, Zhou LJ, Zhou H, . . . Liu XG. Oral Application of Magnesium-L-Threonate Attenuates Vincristine-induced Allodynia and Hyperalgesia by Normalization of Tumor Necrosis Factor-alpha/Nuclear Factor-kappaB Signaling. Anesthesiology. Jun 2017;126(6):1151-1168.

Yilmaz G, Sürer H, Inan LE, Coskun O, Yücel D. Increased nitrosative and oxidative stress in platelets of migraine patients. The Tohoku journal of experimental medicine. Jan 2007;211(1):23-30. doi:10.1620/tjem.211.23

Young WB. Medication Overuse Headache. Curr Treat Options Neurol. 2001 Mar;3(2):181-188.

Ziaei S, Kazemnejad A, Sedighi A. The effect of vitamin E on the treatment of menstrual migraine. Med Sci Monit. Jan 2009;15(1):Cr16-9.