Alternative Headache Treatments

Nutraceuticals, Behavioral and Physical Treatments

Christina Sun-Edelstein, MD; Alexander Mauskop, MD


Headache. 2011;51(3):469-483. 

In This Article


Patients often seek nutraceuticals for headache treatment after finding conventional therapies ineffective or limited by side effects, believing that "natural" substances such as vitamins, minerals, and herbal remedies are less toxic than prescription medications. While the evidence for some of these nutraceuticals is promising, especially for magnesium, many of the existing studies are small and underpowered, sometimes showing inconsistent results. The available evidence for these treatments is discussed below, but larger, better-designed trials are necessary in order to establish strong evidence of efficacy for any of them.


Magnesium, an essential cation that plays a vital role in multiple physiological processes, may have several roles in migraine pathogenesis. Deficiency in magnesium has been associated with cortical spreading depression,[8] neurotransmitter release,[9] platelet aggregation,[10] and vasoconstriction,[11,12] all of which are important aspects of our current understanding of migraine pathophysiology. In addition, magnesium concentration influences serotonin receptors, nitric oxide synthesis and release, inflammatory mediators, and various other migraine-related receptors and neurotransmitters.[13]Magnesium also plays a role in the control of vascular tone and reactivity to endogenous hormones and neurotransmitters, through its relationship with the NMDA receptor.[14,15] Deficiency in magnesium results in the generation and release of substance P,[16] which subsequently acts on sensory fibers, resulting in headache pain.[17]

Magnesium Deficiency Although a relationship between migraine and magnesium deficiency had long been postulated, it was initially difficult to assess, owing to the absence of simple and reliable ways of measuring magnesium levels in soft tissues. While routine laboratory testing generally measures total magnesium levels, it is the ionized magnesium level that truly reflects perturbed magnesium metabolism.[18] The subsequent development of an ion-selective electrode for magnesium has allowed for the accurate and rapid measurement of serum ionized levels.[18,19]

A pilot study of 40 patients with an acute migraine attack found that 50% of the patients had low levels of ionized magnesium.[20] When these patients were given 1 g of intravenous magnesium, basal serum IMg2+ levels correlated with the efficacy of treatment.[20,21] Of the patients in whom pain relief was sustained over 24 hours, 86% had a low serum IMg2+ level; only 16% of patients who had no relief had a low IMg2+ level. Total magnesium levels in all subjects were within normal range. Systemic magnesium deficiency in migraineurs has also been suggested by magnesium retention after oral loading.[22]

Magnesium deficiency may be especially common in women with menstrually related migraine. A prospective study[23] with 270 women, 61 of whom had menstrually related migraine, showed that the incidence of IMg2+ deficiency was 45% during menstrual attacks, 15% during non-menstrual attacks, 14% during menstruation without a migraine, and 15% between menstruations and between migraine attacks.

Low levels of magnesium in the brain[24] and cerebrospinal fluid[25] have also been reported, but interictal studies on serum,[26–30] plasma,[31,32] and intracellular[28,29,32–34] magnesium levels in migraineurs and patients with tension-type headache (TTH) have produced conflicting results. However, interictal levels of red blood cell (RBC) magnesium have been shown to be decreased in migraineurs with[33] and without aura,[28,31] as well as in juvenile migraine patients with and without aura.[35] These results were supported by a study[36] that showed low total magnesium in erythrocytes and low ionized magnesium in lymphocytes in migraine patients, both of which increased significantly after a 2-week trial of drinking mineral water containing 110 mg/L magnesium. Given its commercial availability, the RBC magnesium assay may therefore be a good way of assessing for deficiency. Future trials should focus on patients with deficiencies in ionized or RBC magnesium, as improvements in clinical symptoms correlating with corrected levels would clearly demonstrate the benefits of magnesium supplementation.

Treatment with Oral Magnesium Several randomized controlled trials (RCTs) have shown that Mg2+ supplementation is effective in migraine treatment. In the first, 24 women with menstrual migraine[31] received either 360 mg of magnesium pyrrolidone carboxylic acid or placebo in 3 divided doses. Women received 2 cycles of study medication, taken daily from ovulation to the first day of flow. Magnesium treatment resulted in a significant reduction of the number of days with headache (P < .1), total pain index (P > .03), as well as an improvement of the Menstrual Distress Questionnaire score in the treatment group compared to placebo.

A larger study comprising 81 migraineurs also showed a significant improvement in patients who received magnesium.[37] Attack frequency was reduced by 41.6% in the magnesium group and by 15.8% in the placebo group. The active treatment group received 600 mg of trimagnesium dicitrate in a water-soluble granular powder taken every morning. More recently, Koseoglu et al[38] studied the prophylactic effects of 600 mg/day of oral magnesium citrate supplementation in patients with migraine without aura and found that active treatment resulted in a significant decrease in migraine attack frequency and severity. A 4th RCT showed no effect of oral magnesium on migraine.[39] This negative result was likely because of the use of a poorly absorbed magnesium salt, as diarrhea occurred in almost half of patients in the treatment group.

The most common adverse effect associated with oral magnesium supplementation is diarrhea. While diarrhea itself usually prevents the development of magnesium-related toxicity, patients should be cautioned about this side effect. Magnesium toxicity is marked by the loss of deep tendon reflexes followed by muscle weakness. Severe toxicity can lead to cardiac muscle weakness, respiratory paralysis, and death. Patients with kidney disease are at higher risk of developing toxicity as magnesium is excreted through the kidneys.[40]

Treatment with Intravenous Magnesium Several studies have evaluated the use of intravenous magnesium in acute migraine treatment, with conflicting results. In the pilot study[20] described under "Magnesium Deficiency" a strong correlation between the clinical response and the levels of serum IMg2+ was found (P < .01). Although the study was not double-blinded or placebo-controlled, both the researchers and subjects were blinded to the IMg2+ levels. A subsequent study[21] showed that 1 g of magnesium sulfate resulted in rapid headache relief in patients with low serum IMg2+ levels.

In a single-blind RCT involving 30 patients with moderate to severe migraine attacks[41] treatment with 1 g intravenous magnesium sulfate was superior to placebo in terms of both response rate (100% for magnesium sulfate vs 7% for placebo) and pain-free rate (87% for magnesium sulfate and 0% for placebo). Mild side effects including flushing and a burning sensation in the face and neck were common during the infusion, but subjects were able to continue treatment. Of note, none of the subjects reported headache recurrence during the 24 hours after treatment. Bigal et al[42] in a double-blind RCT, showed that 1 g of magnesium sulfate resulted in a statistically significant improvement in pain and associated symptoms in subjects with migraine with aura, as compared to controls. Although migraine without aura patients did not show a significant difference in pain relief compared to those receiving placebo, they did have a significantly lower intensity of photophobia and phonophobia.

Two RCTs have been conducted in emergency room settings, neither of which showed that magnesium was more effective than placebo in aborting attacks.[43,44]

Supplements and Mitochondrial Dysfunction

Mitochondrial dysfunction, which leads to impaired oxygen metabolism, has been speculated to play a role in migraine pathophysiology[45,46] as migraineurs have been shown to have reduced mitochondrial phosphorylation potential in between headaches.[47,48] An impairment of mitochondrial oxidative metabolism might influence neuronal information processing, therefore reducing the threshold for migraine attacks.[49] This is the rationale for the use of supplements that enhance mitochondrial function in the treatment of migraine, such as riboflavin, CoQ10, and alpha lipoic acid.

Riboflavin Riboflavin, also known as vitamin B2, is a component of 2 coenzymes (flavin adenine dinucleotide and flavin mononucleotide) that are cofactors in the electron transport chain of the Krebs cycle. It plays a vital role in membrane stability and the maintenance of energy-related cellular functions. One well-designed RCT found that it is beneficial in migraine prophylaxis, showing that daily use of 400 mg riboflavin for 3 months resulted in a 50% reduction in attacks in 59% of patients, compared to 15% for placebo. Two minor adverse reactions, diarrhea and polyuria, were reported in the treatment group.[50] In a small study[51] investigating the effects of different treatments on auditory evoked cortical potentials in migrainers, riboflavin and beta-blockers were shown to act on 2 distinct aspects of migraine pathophysiology. The authors thus suggested that combining these treatments might increase their efficacy without concurrently increasing central nervous system side effects.

A recent pharmacogenetic study[52] demonstrated that riboflavin may be more effective in the treatment of migraine patients with non-H mitochondrial DNA haplotypes. As riboflavin is effective in deficiencies of the electron transport chain complex I but not in mitochondriopathies related to an isolated complex IV deficiency,[53,54] the authors suggested that mitochondrial haplogroups differentially influence the activity of the various complexes. These results may have ethnic implications, in that haplogroup H is predominantly found in the European population.

Coenzyme Q10 Coenzyme Q10 is an endogenous enzyme cofactor involved in the mitochondrial electron transport chain, generating energy through its role in aerobic cellular respiration. Because of its activity in mitochondrial function and as an antioxidant, it has been hypothesized to be useful in migraine prevention. Two small studies thus far have shown some benefit of CoQ10 in migraine treatment. In the first, an open-label study[55] of 31 migraineurs who used 150 mg daily of CoQ10 for 3 months, 61% had at least a 50% reduction in migraine days. Notably, supplementation was effective within the first month of treatment. No significant adverse effects were noted. The second study,[56] a small (n = 42) RCT assessing the efficacy of 100 mg of CoQ10 3 times daily, found that CoQ10 significantly decreased attack frequency, headache days, and days with nausea. Gastrointestinal disturbances and "cutaneous allergy" were reported at a low rate.

Coenzyme Q10 supplementation may be especially effective in the prophylaxis of pediatric migraine. CoQ10 levels were measured in a study[57] of 1550 pediatric patients (mean age 13.3 ± 3.5 years) with frequent headaches. Nearly one-third of subjects were below the reference range. Patients with low CoQ10 received supplementation with 1 to 3 mg/kg per day of CoQ10 in liquid gel capsule formulation, resulting in an improvement in total CoQ10 levels, headache frequency and degree of headache disability.

Alpha Lipoic Acid Alpha lipoic acid, also known as thioctic acid, is a naturally occurring fatty acid that can be found in many foods such as yeast, spinach, broccoli, potatoes, and organ meats such as liver or kidney. Like riboflavin and CoQ10, it augments mitochondrial oxygen metabolism and adenosine triphosphate production.[58] In 1 small RCT,[59] 54 subjects received either 600 mg alpha lipoic acid or placebo daily for 3 months. Although there was no significant difference between treatment and placebo for the primary endpoint (50% reduction of monthly attack frequency), there was a trend toward reduction of migraine frequency after treatment with alpha lipoic acid. Within-group analyses also showed a significant reduction in attack frequency, headache days, and headache severity in the treatment group. While these results suggest that alpha lipoic aid may be effective in migraine prevention, larger trials are necessary.

Herbal Preparations

Butterbur (Petasites Hybridus) In recent years, Petasites hybridus root extract, also known as butterbur, has been touted as a promising new treatment for migraine prevention. The butterbur plant is a perennial shrub found throughout Europe and parts of Asia. It was used for many centuries as a remedy for pain, fever, spasms, and wound healing. Although its mechanism of action is not fully understood, Petasites likely acts through calcium channel regulation and inhibition of peptide leukotriene biosynthesis, thus influencing the inflammatory cascade associated with migraine.[60–62] The pharmacologically active compounds in butterbur are sesquiterpenes such as petasin and isopetasin. While the butterbur plant itself also contains pyrrolizidine alkaloids, which are hepatotoxic and carcinogenic, these substances are removed in the commercially available preparations, such as those manufactured by Weber & Weber (Inning am Ammersee, Germany; Petadolex® and others). Nonetheless, patients should be advised to use only butterbur products that are certified and labeled "PA-free."

The efficacy of Petasites hybridus in migraine prevention has been evaluated in several studies. In the first RCT,[63] 50 mg of Petadolex® twice daily showed a significantly reduced number of migraine attacks and migraine days per month compared to placebo. An independent re-analysis of efficacy criteria was subsequently performed[64] because of flawed statistical analyses in the original study, and confirmed the superiority of the butterbur extract over placebo for all primary variables of efficacy. Later, a 3-arm, parallel-group RCT of 245 patients comparing Petasites extract 75 mg twice daily, Petasites extract 50 mg twice daily, and placebo twice daily[65] showed that Petasites extract 75 mg twice daily was more effective than placebo in decreasing the number of monthly migraine attacks. Maximum response was achieved after 3 months, resulting in an attack reduction of 58% with the higher dose of Petadolex®, compared to the placebo response of 28%. Petadolex® was well tolerated in these studies, and no serious adverse events occurred. The most frequently reported adverse reactions were mild gastrointestinal events, especially eructation (burping). Petasites, like most other herbal preparations, should not be taken by pregnant women.

Given its safety and tolerability, Petadolex® may be a good option in the treatment of pediatric migraine. In a multicenter prospective open-label study[66] of Petadolex® in 109 children and adolescents with migraine, 77% of all patients reported a reduction in migraine frequency of at least 50%. Ninety-one percent of participants felt substantially or at least slightly improved after 4 months of treatment.More recently, a prospective, partly double-blind, RCT assessing the efficacy of Petadolex® and music therapy in primary school children with migraine[67] showed that at 6-month follow-up, both music therapy and butterbur root extract were superior to placebo (P = .018 and P = .044, respectively) in reducing headache frequency, but only among those that completed the study. In the analysis including all treated patients, treatment groups did not differ significantly during follow-up.

Feverfew Feverfew is an herbal preparation that was used for centuries in the treatment of fevers, headache, infertility, toothaches, inflammation and arthritis. Although the feverfew plant was originally native to the Balkan mountains in Eastern Europe, it now grows throughout Europe, North America, and South America. It is commercially available as the dried leaves of the weed plant Tanacetum parthenium, and its anti-migraine action is probably related to the parthenolides within these leaves. Feverfew may act in migraine prophylaxis by inhibiting platelet aggregation as well as the release of serotonin from platelets and white blood cells. It may also act as an anti-inflammatory agent through the inhibition of prostaglandin synthesis and phospholipase A.[68–71]

The efficacy of feverfew in migraine prophylaxis has been controversial, as many RCTs[72–77] conducted in the past 3 decades have yielded contradictory results. In addition, a 2004 Cochrane review[78] of double-blind RCTs assessing the clinical efficacy and safety of feverfew in migraine prevention concluded that there was insufficient evidence to suggest that feverfew is more effective than placebo in migraine prophylaxis. No major safety or tolerability issues were identified, although side effects reported in the RCTs included gastrointestinal disturbances, mouth ulcers, and a "post-feverfew syndrome" of joint aches.

Inconsistent results from the above studies were attributed to wide variations in the strength of the parthenolides[79] and differences in the stability of feverfew preparations[80] and subsequently, a new, more stable feverfew extract (MIG-99) was created. In an initial RCT involving 147 patients,[81] none of the MIG-99 doses were significant for the primary endpoint, although a subset of high-frequency migraineurs appeared to benefit from treatment. In a follow-up multicenter RCT with 170 subjects[82] randomized to 6.25 mg t.i.d. of MIG-99 or placebo, a statistically significant and clinically relevant reduction in migraine frequency in the MIG-99 group compared to placebo was reported.

Feverfew should not be used by pregnant women, as it may cause uterine contractions resulting in miscarriage or preterm labor. It can also cause allergic reactions; patients with allergies to other members of the daisy family, including ragweed and chrysanthemums, are more likely to be allergic to feverfew.

Recreational Drugs

Although controversial, the evidence for the use of recreational drugs such as marijuana, lysergic acid diethylamide (LSD) and psilocybin is worth mentioning for the insight it provides regarding the pathophysiology of migraine and cluster headache. Further research on the effects of these substances may result in a greater understanding of the mechanisms of these headache disorders.

Marijuana The recreational and medicinal use of marijuana, or cannabis, has been documented for thousands of years.[83] In the second half of the 19th century, cannabis was a well-regarded acute and preventative treatment for headache in USA and UK, and was even included in the mainstream pharmacopeias for this use.[83]

Synthetic cannabinoids such as dronabinal and nabilone (used in the UK) have been established as useful in the treatment of nausea and vomiting associated with cancer chemotherapy. However, the role of cannabinoids in pain management is less clear. Preclinical evidence has shown that endogenous cannabinoids such as anandamide and cannabinoid agonists are antinociceptive and antihyperalgesic, reducing the allodynia associated with formalin, capsaicin, carrageenan, nerve injury, and visceral persistent pain.[84] After entering the bloodstream, cannabinoids are differentially distributed in the brain and reach high concentrations in the neocortex (especially the frontal cortex), limbic areas, sensory areas, motor areas, and the pons.[85] Therefore, cannabinoid receptors and endogenous cannabinoids may modulate pain, psychomotor control, memory function, appetite, and emesis. Cannabinoid receptors and endogenous cannabinoids are located throughout the pain pathways in peripheral sensory nerve endings, spinal, and supraspinal centers.[86] In migraine, cannabinoids may be effective via an inhibitory effect on serotonin type 3 (5-HT3) receptors[87] or antinociceptive effects in the periaqueductal gray matter.[88]

Clinical data on therapeutic uses of marijuana have been conflicting. A meta-analysis of clinical trials of cannabinoid derivatives in the treatment of pain[89] showed that cannabinoids are no more effective than codeine in pain management, and that central nervous system depressant side effects limit their use in clinical practice. The authors thus concluded that more research is necessary before these treatments could be recommended for neuropathic pain or spasticity. Later, a small RCT[90] showed that the synthetic cannabinoid 1',1'dimethylheptyl-Delta8-tetrahydrocannabinol-11-oic acid (CT-3) was effective in reducing chronic neuropathic pain when compared with placebo. With regard to headache, evidence thus far has been limited to case reports describing the effective use of cannabis or cannabinoids in "chronic headaches,"[91] migraine,[92] pseudotumor cerebri[93] and cluster headache.[94]

Lysergic Acid Diethylamide and Psilocybin A 2006 report[95] on 53 cluster headache patients who used either the ergot alkaloid derivative LSD or the related indolalkylamine psilocybin for their headaches described intriguing results. Twenty-two of 26 psilocybin users reported that psilocybin aborted attacks while 25 of 48 psilocybin users and 7 of 8 LSD users reported cluster period termination. In addition, 18 of 19 psilocybin users and 4 of 5 LSD users reported remission period extension, meaning that the next expected cluster period was delayed or prevented. These results are interesting not only because they describe the effective use of illicit drugs in cluster headache, but also because no other medication has been reported to terminate a cluster period. Furthermore, the drugs were effective at subhallucinogenic doses and effective treatment required very few doses of either drug. LSD reportedly terminated cluster periods after only 1 dose, and psilocybin rarely required more than 3 doses. The study was unblinded, uncontrolled and limited by recall and selection bias. However, further research on the effects of LSD and psilocybin on cluster headaches may be warranted, given the efficacy described in this report.


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