Worldwide, migraine affects more than 10-12% of the population, with approximately 1 billion migraineurs estimated worldwide.1 It is estimated that there are 39 million migraineurs in the US, accounting for 12% of the US population. Migraine affects 18% of women and 6% of men2,3. Nearly 25% of U.S. households include someone with migraine.
In 2016, migraine was determined to be the 2nd leading cause of all global disability, and the 2nd leading cause of all neurological disease burden4. Migraine accounts for 50% of all neurologic disability. Furthermore, chronic pain in general is the largest contributor to years lived with disability globally5, and is associated with tremendous negative impacts on social, economic, and personal function.
In addition to the attack-related disability, many sufferers live in fear because their migraines disrupt their ability to work, go to school, partake in social activities, or care for their families, and this significantly limits their overall quality of life. More than 90% of migraine sufferers are unable to work or function normally during their attacks. American employers lose more than $20 billion each year as a result of 113 million lost workdays due to migraine.6
Migraine treatment is divided into acute (as needed) and preventive (prophylactic) therapy. Most existing preventive therapies are adopted from anti-epileptic, antidepressant, and antihypertensive medications. However, many of these medications are not well tolerated, resulting in poor compliance. Adherence to oral migraine preventative medication is around 26% at 6 months and declines to 17% at one year.7 This is often due to intolerable side effects. Many patients, due to lack of efficacy of preventative treatments, often resort to overuse of acute medications. This results in additional decline in quality of life and economic burden.8 Onabotulinumtoxin-A (Botox) is currently the only FDA-approved treatment available for chronic migraine. However, most patients must fail at least three preventative treatments prior to receiving Onabotulinumtoxin-A. As such, Onabotulinumtoxin-A is typically a fourth line option for the prevention of chronic migraine. In addition, it is not approved for patients who have episodic migraine. There are 4 calcitonin gene related peptide (CGRP) monoclonal antibody antagonists that have been approved for the prevention of migraine. There also exists a limited number of neuromodulatory devices. Lack of insurance coverage of these devices precludes their routine use in clinical practice. This confers a large unmet need for additional preventive migraine treatments and additional therapeutic targets.
Migraine prevention is a key aspect to maintaining a good quality of life. Abnormal neuronal membrane ion channels, low ionized magnesium levels, increased excitatory glutamatergic activity, and mitochondrial dysfunction with abnormal energy metabolism are associated with migraine. The goal of nutraceuticals is to target these factors in order to improve energy metabolism and reduce neuronal hyperexcitability in the brain. Patients often seek natural migraine treatment with complementary and alternative medicine (CAM) after finding standard prescription treatments intolerable due to side effects, or just ineffective. Many patients feel that “natural” substances are less toxic than prescription medications. Thus, the nutraceutical and herbal supplement industry is a multibillion-dollar industry. CAMs include, but are not limited to, nutraceuticals (vitamins and supplements such as magnesium, coenzyme Q10 (CoQ10), vitamin B2 (riboflavin), alpha lipoic acid, vitamin D, 5-HTP, fish oil, melatonin), and herbal preparations (butterbur, feverfew, ginger, and cannabidiol). Other natural treatments such as yoga and meditation for migraine treatment can also be very helpful.
The use of CAMs has been significantly rising in the US and Europe9–12, and is becoming more evident especially in patients with migraine and other headache disorders. In a recent questionnaire-based survey in Germany and Austria, 81.7% of patients seen in tertiary outpatient headache clinics reported use of CAM13. There are a multitude of different migraine related supplements on the market with variable combinations or sold separately as the individual components. Below, we discuss the most commonly used and studied supplements for migraine prevention.
VITAMINS and SUPPLEMENTS FOR MIGRAINE PREVENTION:
Magnesium has a Level B (2nd highest) evidence recommendation for migraine prevention by the American Academy of Neurology and American Headache Society.14 It is also rated highly and recommended by the Canadian Headache Society.15 This is a higher evidence recommendation than many of the prescription medications we use for migraine prevention. More than 325 enzymes are magnesium dependent, many of which are brain enzymes. Magnesium is involved in all reactions that involve the formation and utilization of adenosine-5′-triphosphate (ATP) in energy metabolism16–19. Proper magnesium levels are known to help normalize blood pressure, have anticoagulant, anti-platelet aggregating effects, regulate cell proliferation, protein synthesis, cellular energy and cell membrane stability, as well as blood sugar levels19–21. Studies have shown low levels of brain magnesium22,23 may be a contributor to migraine pathophysiology. Magnesium influences multiple steps in the current understanding of migraine pathophysiology including cortical spreading depression, serotonin receptor activity, neurotransmitter release, interference with inflammatory mediators, nitric oxide production, platelet aggregation, vascular tone, NMDA receptor interaction, CGRP release, production and release of substance P which activates pain fibers24–31. Magnesium is a mineral that functions as a coenzyme for various neurologic functions and other physiologic mechanisms. According to two double-blind studies, high-dose oral magnesium supplementation appears to be effective in migraine prophylaxis. Trials have shown that magnesium supplementation is very effective in migraine treatment, with migraine attack reductions of up to 42%.32–37 Other studies have also shown benefit in migraine prevention when combined with coenzyme Q10 and feverfew as well.38 Magnesium (250 mg twice a day or 500 mg at bed) has a relaxant effect on smooth muscles such as blood vessels. We often give intravenous magnesium to patients who come into the emergency department for migraine because it helps to break the migraine. Three trials found 40-90% average headache reduction when used as a preventative. Magnesium also demonstrated the benefit in menstrually related migraine. Magnesium is part of the messenger system in the serotonin cascade and it is a good muscle relaxant. Some forms can be useful for constipation which can be a side effect of other medications used to treat migraine. Good sources include nuts, whole grains, and tomatoes.
There are different forms of magnesium, and we’ll discuss the most common types. Magnesium types can be tailored to patient characteristics as follows.39 Magnesium glycinate is a good choice for those with a sensitive stomach who have gastrointestinal side effects such as diarrhea with other forms of magnesium. It is anecdotally also helpful with anxiety and sleep. Magnesium threonate also has low risk of gastrointestinal side effects and anecdotally helpful with cognitive function and brain fog symptoms. Magnesium malate has low gastrointestinal side effects and is reportedly more energizing and anecdotally often helpful in fibromyalgia and chronic fatigue syndrome. Magnesium citrate is one of the most studied, popular, and well-absorbed forms of magnesium. It can also be mixed easily with liquids if you can’t take pills. However, it comes with a higher risk of diarrhea and gastrointestinal side effects, although this could be helpful for those with constipation. Magnesium oxide is also well studied, cheap, and often used for heartburn and indigestion. However, it is not well absorbed and can have some laxative side effects as well, so can also be helpful for constipation.
Dosing should generally be somewhere between 400-800 mg daily. It should preferably contain 24 mmol (600 mg) of elemental magnesium daily as magnesium citrate based on trials that showed benefit with this specific one more than others, and this is the recommendation of the Canadian Headache Society.15 If this type is not tolerated, other forms of magnesium as discussed above are certainly acceptable.
- Vitamin D3 (Cholecalciferol)
Vitamin D deficiency is a worldwide problem. Vitamin D is not actually a vitamin, but a hormone that the body makes from a type of cholesterol in the skin when it is exposed to UVB radiation from the sun. Small amounts also come from diet. It has anti-inflammatory activities, analgesic effects, may reduce nitric oxide and assists in magnesium and calcium absorption. Deficiency is suspected to play a role in mechanisms responsible for migraine and other pain syndromes, and vitamin D levels have been shown to be low in chronic migraineurs40. The best form is vitamin D3 (cholecalciferol) anywhere from 1,000 to 4,000 IU daily.
- 5-HTP (5-Hydroxytryptophan)
This is an amino acid that is made by the body from tryptophan (amino acid you get from your diet), and is involved in mood, sleep, and pain regulation. 5-HTP is typically produced from the seeds of the Griffonia simplicifolia plant. 5-HTP is converted into serotonin (5-hydroxytryptamine), an important brain neurotransmitter involved in migraine pathways and other neurologic pathways. 5-HTP is also converted into melatonin which aids in sleep, as well as dopamine, another important neurotransmitter. The effects of 5-HTP are felt to be similar to the antidepressants that are thought to increase the amount of serotonin available to the brain, and thus a mood enhancing chemical. Some studies have suggested that 5-HTP was as effective as some prescription migraine medications such as propranolol and methysergide (75% improvement in methysergide vs. 71% improvement in 5-HTP) in reducing the frequency and severity of migraines41–45. Side effects can include nausea, diarrhea, and stomach pain, and it should be used cautiously with medications which increase serotonin levels (such as most antidepressants) due to potential risk of serotonin syndrome. Typical doses are around 100–200 mg, 2–3 times per day with meals.
- Fish oil (Eicosapentaenoic acid (EPA) + Docosahexaenoic acid (DHA))
Fish oils are found in the tissues of fish. They contain a certain type of fat called omega-3. Potential mechanisms for anti-inflammatory effects of fish oil include inhibition of inflammatory mediators (eicosanoids and cytokines), and synthesis of lipid suppressors of inflammation (resolvins)46. Eicosapentaenoic acid (EPA) and Docosahexaenoic acid (DHA) give rise to these resolvins which are anti-inflammatory and inflammation resolving47. These compounds may relieve joint pain and stiffness in a similar way as non-steroidal anti-inflammatory drugs (NSAIDs)46,48. One study reported dramatic decreases in headache frequency (15 per month down to 2 per month) and decreases in headache severity (reduction from 5 to 3 on a 7-point scale)49. Fish oils have also been studied and found to be useful in other inflammatory conditions such as rheumatoid arthritis46,48,50–53. Large trials have showed a significant beneficial effect on pain, morning stiffness, number of painful and/or tender joints and NSAID consumption50. Recommended dosing consists of 30% EPA and DHA with a ratio of EPA to DHA of 1.5. Research suggests the minimum dose needed to reduce the joint inflammation associated with arthritis is 2.7 grams of omega-3 (EPA + DHA) daily, which could also be divided such as 900 mg EPA and 450 mg DHA twice daily.
Increasing evidence shows correlation between melatonin secretion and headache conditions. Melatonin supplementation has shown decreased headache intensity and duration. It is widely used as a sleep aid. Sleep is nature’s way of dealing with migraine. A dose of 3 mg is recommended to start for headaches including cluster headache. Higher doses up to 15 mg has been reviewed for use in cluster headache and have been used, if not making too groggy in the morning. The rationale behind using melatonin for cluster is that many theories regarding the cause of cluster headache center around the disruption of the normal circadian rhythm in the brain. This helps restore the normal circadian rhythm. It should be taken at least 2 hours before bedtime.
MITOCHONDRIAL SUPPLEMENTS FOR MIGRAINE PREVENTION:
Mitochondria are the powerhouses within all cells of the body. These crucial metabolic organelles use oxygen to produce ATP, which is the primary energy source for the cell, and thus, for your body. Mitochondrial dysfunction leads to impaired oxygen metabolism and is suspected to play a role in migraine pathophysiology. Some migraineurs have been shown to have reduced mitochondrial activity which may lead to altered neuronal processing, and therefore a lower threshold for migraine attacks54–58. Riboflavin (vitamin B2), CoQ10 (ubiquinone; CoQ10), and alpha lipoic acid (thioctic acid) all play key roles in mitochondrial activity, and therefore have been implicated in migraine treatment by optimizing mitochondrial functioning.
- Riboflavin (Vitamin B2)
Riboflavin assists nerve cells in the production of ATP, a principal energy storing molecule. Riboflavin is an essential precursor to coenzymes involved in electron transport in oxidation reduction reactions within the Krebs cycle. This metabolic cycle is critical in production of ATP and generation of energy in the mitochondria, oxidative metabolism, maintaining membrane stability, and for all energy-related cellular functions59,60. It is necessary for many chemical reactions in the body. Brain riboflavin metabolism is suspected to affect migraine pathophysiology via several mechanisms, providing migraine preventive benefit.36,37
Riboflavin has a Level B (2nd highest) evidence recommendation for migraine prevention by the American Academy of Neurology and American Headache Society.14 This is a higher evidence recommendation than many of the prescription medications we use for migraine prevention. The Canadian Headache Society Guidelines strongly recommend B2 for migraine prevention as well.15 There have been at least 3 clinical trials of riboflavin using 400 mg per day all of which suggested that migraine frequency can be decreased. All 3 trials showed significant improvement in over half of migraine sufferers. Trials of riboflavin have suggested significant improvements in migraine by up to 59%61. Riboflavin (Vitamin B2): 200 mg twice a day (or 400 mg daily). The supplement is found in bread, cereal, milk, meat, and poultry. Most Americans get more riboflavin than the recommended daily allowance, however riboflavin deficiency is not necessary for the supplements to help prevent headache. One side effect to be aware of is that it can turn your urine bright neon yellow, although this is not harmful. Recommended dosing is 200 mg twice daily (or 400 mg once daily).
- Coenzyme Q10 (Ubiquinone; Ubiquinol; CoQ10)
CoQ10 is present in every membrane of all cells in the body62. Similar to riboflavin, CoQ10 plays a crucial role in electron transport and energy metabolism given its heavy involvement in mitochondrial function. CoQ10 is incorporated into the mitochondria, where it facilitates the transformation of fats and sugars into energy, thus it is often marketed to be an “energy enhancer”. Studies have shown that a nutritional supplement of CoQ10 can reduce the frequency of migraine attacks by improving the energy production of cells as with riboflavin. It also functions as an antioxidant by protecting against toxic oxidative reactions in the body, and CoQ10 tissue levels are known to decrease with age19,63. In one study, CoQ10 was found to be low in about 1/3rd of patients studied, and when replaced, headache frequency improved64. Migraine frequency was shown to improve significantly in more than 61% of patients in one study65, and 50% of patients in another study,66 supporting use for migraine prevention.36 Other studies have also shown benefit in migraine prevention when combined with magnesium and feverfew as well.38 The Canadian Headache Society guidelines strongly recommend use of CoQ10.15 Suggested dosing is around 150 mg-200 mg twice a day.
- Alpha Lipoic Acid (Thioctic Acid)
Alpha lipoic acid enhances the metabolism of oxygen and energy production by mitochondria67, and has shown reduction of migraine frequency68 when studied. Doses are typically around 300 mg twice daily.
HERBAL SUPPLEMENTS FOR MIGRAINE PREVENTION:
- Feverfew (Tanacetum parthenium)
Feverfew is a common garden herb native to Europe and popular in Great Britain as a treatment for disorders typically controlled by aspirin. The mechanism of action is unknown but is believed to be related to a chemical called parthenolide which helps the body use serotonin more effectively. Serotonin helps prevent migraine and assists with resolution when it occurs. Parthenolide also inhibits the release of histamine which is linked to pain and inflammation. Consistency of active ingredients in different products can be a problem. Some formulations don’t have the active ingredient (parthenolide) that prevents migraine. A parthenolide content of 0.2% is generally recommended.
Feverfew has a Level B (2nd highest) evidence recommendation for migraine prevention by the American Academy of Neurology and American Headache Society.14 This is a higher evidence recommendation than many of the prescription medications we use for migraine prevention. The anti-migraine action36–38,69–75 of Feverfew is felt to be related to the parthenolides within the leaves. Studies have shown that the parthenolides provide anti-inflammatory and analgesic effects through several mechanisms involved in the migraine process that normally lead to pain. These include inhibition of phospholipase A, prostaglandin biosynthesis and platelet aggregation, and actions on serotonin including release of serotonin from platelets and white blood cells, as well as interaction at various serotonin receptor subtypes19,76–89. Study results have been variable based on wide variations in the strength of the parthenolides and differences in the stability of feverfew preparations used. However, a new, more stable feverfew extract (MIG-99) was created and showed a significant improvement in patients with high-frequency migraine90,91. The recommended dosing is generally around 50 mg twice daily (standardized to a high parthenolide content of 0.7% and stability measures of parthenolide), or, preferably MIG-99 6.25 mg three times daily if it can be found.
- Butterbur Extract (Petasites hybridus)
Butterbur is an extract derived from the petisides hybridus root, which has been used for medicinal purposes since ancient times. Butterbur is a well-researched and proven herbal supplements for migraine prevention36,69,70,92. For many years, it was the only supplement with a Level A (highest) evidence recommendation for migraine prevention by the American Academy of Neurology and American Headache Society,14 with a higher evidence recommendation than many of the prescription medications we use for migraine prevention. However, this recommendation was withdrawn a few years ago given a small handful of cases of liver failure reported in Germany. Although it is classified as an herbal supplement in the US, it is a licensed pharmaceutical medicine in Germany (Petadolex). Its two active compounds, petasin and isopetasin, help reduce cerebral blood vessel spasm and stop the inflammatory cascade which occurs in migraine93–95. Butterbur is thought to act through anti-inflammatory inhibition of leukotriene biosynthesis for its analgesic effects but also has calcium channel regulatory properties, both of which play a role in migraine19.
Studies have also shown anti-inflammatory effects mediated through inhibiting the additional inflammatory enzymes cyclooxygenase and prostaglandin production96. Notably, this is also what gives aspirin its anti-inflammatory effect. Trials have shown very positive results with significant decreases in migraine frequency of up to 58-77%, with 91% reporting overall improvement97–100. Side effects can include burping/belching. Raw butterbur root contains toxic chemicals that must be filtered out during the manufacturing process. To be sure you are choosing a safe product, look for a formulation that does not contain pyrrolizidine alkaloids since these are toxic to the liver. Recommended dosing is typically around 75 mg twice daily (free of Pyrrolizidine Alkaloids (PAs), standardized to contain a minimum of 7.5 mg of petasin and isopetasin).
- Ginger (Zingiber Officinale)
Ginger has anti-histamine and anti-inflammatory properties such as blocking pain-producing prostaglandins101,102, and helps with circulation and potentially headache. It is also widely used to treat nausea and vomiting, which accompany migraine103, and this is what it is primarily useful for. Recommended dosing ranges from 100-200 mg three times per day to 150 mg twice daily (standardized to contain 20% of gingerol and shogaol (dosage).
There have been a multitude of studies documenting the analgesic and anti-inflammatory benefits of medicinal cannabis (marijuana) across many chronic pain syndromes104–106, and it has been a historical treatment for headache and migraine for centuries.105–109 A detailed overview of medical cannabis for the treatment of migraine and chronic pain is discussed here. The vast majority of supporting evidence of cannabis and cannabinoids involves various chronic pain syndromes. These benefits are hypothesized to extend to headache disorders such as migraine given overlapping neurobiological pathways of pain. Some data suggests that cannabinoids appear to work uniquely within the inherent anatomical pathways of migraine (including serotonergic triptan pathways) and pain.104,105,107–139 Unfortunately, the majority of data supporting the use of cannabis and cannabinoids in migraine and headache disorders is based on case series, case reports, surveys and anecdotal evidence.105,107,145–154,108,155–161,134,135,140–144 There has been one retrospective study of cannabis use in the treatment of migraine which reported strong statistically significant findings of benefit.162 There have been only two limited prospective trials of cannabinoids containing a control group in headache disorders. One reported significant benefit in chronic daily headache associated with medication overuse headache,163 and the other reported significant benefit in both the acute and preventive treatment of chronic migraine.164
Given the growing evidence of cannabis and cannabinoids in the treatment of chronic pain and other medical conditions, in February 2019 The World Health Organization (WHO) recommended that cannabis be rescheduled and removed from the most restrictive scheduling category. In January 2017, the National Academies of Sciences, Engineering, and Medicine concluded that the use of cannabis for the treatment of pain is supported by well-controlled clinical trials and that there is substantial evidence that cannabis is an effective treatment for chronic pain in adults.165 In 2014, the Canadian Pain Society revised their consensus statement to recommend cannabinoids as a third-level therapy for chronic neuropathic pain based on the abundance of supporting evidence and a NNT (number needed to treat) estimated at approximately 3.166
Delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are the two predominant cannabinoids found in cannabis and are discussed in more detail here. CBD is several hundred more times anti-inflammatory than aspirin.104 There have been scientific, animal models, and limited human clinical trials documenting its anti-inflammatory and analgesic properties.167–176 In contrast to THC, CBD is non-intoxicating (no “high”).167 In November 2017, The World Health Organization (WHO) concluded that CBD exhibits no evidence for abuse or dependence potential, and that there is no evidence of public health related concerns associated with its use.177 In January 2018, the World Anti-Doping Agency (WADA) removed CBD from their prohibited list, no longer banning use by athletes.178
In December 2018, the Agriculture Improvement Act (Farm Bill) was signed into law in the United States. This legalized the agricultural growth and use of hemp (cannabis strains containing 0.3% THC or less) and hemp derivatives such as CBD, as well as removed hemp and its extracts (including CBD) from the Controlled Substances Act, making it no longer an illegal substance under federal law.
Thus, the use of CBD products has been exploding and is a new industry projected to exponentially increase into a multi-billion dollar industry179,180. Many patients are using these products for a variety of reasons181,182, most commonly in pain, including migraine prevention, given their easy access and availability. However, there are no studies evaluating CBD alone in treatment of migraine or any other headache disorders, so this is purely anecdotal. CBD products can readily be purchased online from a multitude of companies, in local health food and drug stores, and common retail pharmacies.183 CBD and suggested dosing (which are not currently clearly known) are discussed in much greater detail here. Medical marijuana (cannabis) for the treatment of migraine is also discussed in much greater here.
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