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By Adriane Fugh-Berman, MD
Migraines are twice as common in women than men. sever- al trials indicate that two dietary supplements—magnesium and riboflavin—have excellent safety profiles and may be promising in the prophylaxis of migraines.
Magnesium is an essential mineral necessary for the function of many enzymes; it is essential for all reactions using ATP and is vital to each step involved in DNA replication and transcription and mRNA translation.1 It’s the fourth most common cation in the body.
Few women obtain adequate magnesium from the diet. Estimates from NHANES III (1988-91) indicate that magnesium intake was lower than the RDI in males and females ages 12-60 in all racial and ethnic groups of adults (with the single exception of non-Hispanic white males).2 Magnesium deficiency is quite common, at least among inpatients: 65% of those in intensive care, up to 12% on general wards, and 30% of hospitalized alcoholics have hypomagnesemia.1
Role in Headaches of Vascular Origin
Prevention of migraine with oral magnesium supplementation has been shown effective in two of three double-blind trials of migraine. One open-pilot study showed significant relief of acute migraine pain with intravenous magnesium.
Prevention of Menstrual Migraine
In one trial of 24 women with menstrual migraine,3 women received magnesium (360 mg magnesium pyrrolidine carboxylic acid tid—equivalent to 360 mg magnesium ion daily) or placebo from the 15th day of their cycle until menses. During this phase of the trial, both groups reported reduction in pain total index (a measure of both frequency and intensity of attacks). Women receiving magnesium had significantly less pain than the placebo group, and the number of days with headache decreased only in the magnesium group. After two months the trial became an open-label trial in which magnesium was given to all patients for an additional two months. Significant decreases in pain total index were seen in both groups between the second and fourth months.
It does not appear that subjects in this trial were routinely asked about side effects, but it is noted that two of the four dropouts were due to side effects; one patient in the magnesium group reported diarrhea and one in the placebo group reported continuous headache.
Prevention of Migraine
In the second positive study, 81 migraine patients aged 18-65, with a mean migraine frequency rate of 3.6/month, received either magnesium (24 mmol or 600 mg trimagnesium dicitrate qd) or placebo for 12 weeks.4 In weeks 9-12 frequency of migraine attacks was reduced by 41.6% in the magnesium group, compared with 15.8% in the placebo group. The number of days with migraine was also significantly decreased in the magnesium group; there was no significant change in the duration or intensity of migraine attacks, nor in drug consumption during an attack. Diarrhea was reported in 18.6% and gastric irritation in 4.7% of patients receiving magnesium.
A third placebo-controlled, double-blind trial of 69 subjects with migraine showed no benefit of magnesium over placebo on migraine.5 Patients were treated with magnesium 10 mmol bid (equivalent to a daily dose of 500 mg) or placebo for 12 weeks, and the endpoints were reduction of migraine intensity or duration by at least 50%.
This trial, originally designed to enroll 150 patients, was stopped after interim analysis of 69 patients showed no benefit of magnesium. An equivalent number of patients experienced reduction of migraine intensity or duration (28.6% of those receiving magnesium and 29.4% of those receiving placebo). Mild adverse effects were experienced by 45.7% of those receiving magnesium and 23.5% of those on placebo; diarrhea or soft stool was the most common complaint in the magnesium group.
It would have been preferable for the investigators to allow this trial to progress to completion. It is quite possible that this trial had an unusually high number of placebo responders, and that the situation would have straightened itself out with increased enrollment. Trials are usually stopped at interim analysis only when there is such a large difference in either benefit or risk between the groups that it is deemed unethical to continue in the face of what is known at that point. It’s peculiar to stop a trial at interim analysis simply because the treatment isn’t winning, and results are not statistically significant.
Treatment of Acute Migraine
An uncontrolled trial that found that intravenous infusion of magnesium sulfate caused prompt and sustained relief in 21/40 patients with acute migraine. A significant correlation was found between response and serum ionized magnesium levels. Of the 21 patients with serum IMG++ levels above 0.54 mmol/L, 86% had sustained (more than 24-hour) relief of pain and associated symptoms.6
The conventional view of migraine is that vascular spasm causes neurological symptoms and subsequent vasodilation causes headache and tenderness. There is debate about the etiology and pathogenesis of migraine. One theory concerns the fact that platelets aggregate during a migraine attack, and subsequently release serotonin (5-hydroxytryptamine or 5HT), a potent vasoconstrictor of cerebral arteries (this is why sumatriptan and other serotonin receptor antagonists are thought to be effective). Although the exact mechanism of magnesium’s effects is unclear, it may interrupt the process at the vasoconstriction stage; magnesium has strong vasodilating effects and also inhibits platelet aggregation in a dose-dependent manner.6
Too much magnesium causes diarrhea, an effect seen in any trial that collected this data. The risk of hypermagnesemia is pronounced in renal patients.
Serum magnesium levels, however, will not be helpful in determining which migraine patients will respond to supplementation; studies are mixed as to whether serum magnesium levels are decreased in migraine patients.
Intracellular levels of magnesium are probably more important than serum levels; it is not uncommon for intracellular levels of magnesium to be decreased while serum levels are normal. In one study of 40 patients with acute migraine attacks,7 50% had ionized magnesium levels below 0.54 mmol/L (normal adult IMg++ levels are 0.54-0.65 mmol/L). The authors suggest that total magnesium levels are less important than ionized magnesium.
Differences Among Magnesium Preparations
Various magnesium formulations are available. Although it has been claimed that chelated magnesium diglycinate is better absorbed then other preparations, there is no convincing evidence that this type is superior to magnesium oxide, magnesium chloride, or magnesium gluconate. Inorganic forms (magnesium oxide, magnesium chloride) may be more likely to cause diarrhea than organic forms (magnesium citrate, magnesium aspartate), but diarrhea can occur with any preparation.
Riboflavin, a water-soluble B vitamin, is an enzyme cofactor necessary to the production of ATP. Although gross riboflavin deficiency is very rare in Western countries, marginal deficiency is relatively frequent, especially among the elderly and adolescents.
A randomized, placebo-controlled, three-month trial in 55 patients with migraine found that high-dose riboflavin (400 mg/d) was superior to placebo in reducing attack frequency and headache days.8 The proportion of patients who improved by at least 50% was 59% in the riboflavin group and 15% in the placebo group. Two of three patients who reported mild adverse effects (polyuria and diarrhea) were in the treatment group.
A previous open-label pilot study by the same investigators compared 26 patients who received 400 mg riboflavin daily for three months with 23 patients who received both riboflavin and low-dose (75 mg) aspirin.9 Mean global improvement was 68.2% and there were no significant differences between the groups. One patient in the riboflavin with aspirin group withdrew due to gastric intolerance; otherwise no adverse effects were reported.
The dose of riboflavin used in these trials is quite high, especially given that the RDI for females 11-50 is 1.3 mg. However, riboflavin is extraordinarily benign. In dogs, 2 g/kg po causes no ill effects. Researchers have established a lethal dose for rats only by giving doses inconsistent with reason; the LD50 (a lethal dose for 50% of rats tested) is 560 g/kg, intraperitoneally.10 It seems safe to assume that pouring half of a rat’s body weight of anything into its peritoneum would kill it.
Magnesium may be effective for preventing both menstrual and non-menstrual migraine. High doses of riboflavin also may be helpful in migraine prophylaxis. Although clinical trial evidence is limited, both nutrients have low toxicity profiles and may be worth trying in patients with migraine.
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