In practice, Mg is administered by various routes such as intramuscular injection and intravenous infusion. This review will focus only on oral Mg, as this is the form most commonly used by the general public, outside the hospital setting.
DEFICIENCY: TREATMENT AND PREVENTION
Magnesium supplementation is traditionally used to correct deficiency states or avoid deficiency in people at increased risk, such as people with malabsorption syndromes and chronic alcoholics (Saris et al 2000). Low serum Mg levels <0.7 mmol/L (1.8 mg/dL, 1.5 meq/L) are indicative of Mg deficiency, although symptoms occur when serum Mg is <0.5 mmol/L (1.2 mg/dL, 1.0 meq/L).
Low Mg states are associated with several cardiovascular diseases, such as congestive heart failure, ischaemic heart disease, cardiac arrhythmias, hypertension, mitral valve prolapse, stroke, non-occlusive myocardial infarction and hyperlipidaemia.
Although the pathophysiology of each condition is multifactorial, the multiple biological effects of Mg in the cardiovascular system suggest an important cardioprotective role. In the heart, it acts as a calcium-channel blocker and promotes resting polarisation of the cell membrane, thereby reducing arrhythmias. It also helps prevent serum coagulation. Low Mg selectively impairs the release of NO from the coronary endothelium, resulting in vasoconstriction and possibly coronary embolism.
In experimental animals, dietary Mg deficiency exacerbates atherosclerosis and vascular damage because it has a modulatory role in controlling lipid metabolism in the arterial wall.
Mitral valve prolapsed
It has been suggested that hypomagnesaemia is common in patients with mitral valve prolapse and therefore supplementation to correct this deficiency could exert beneficial clinical effects. In 1997, one study of 141 subjects with symptomatic mitral valve prolapse confirmed this suspicion by identifying hypomagnesaemia in 60% of patients. A randomised, double-blind, crossover study followed those Mg-deficient people and found that 5 weeks’ Mg supplementation significantly alleviated symptoms of weakness, chest pain, dyspnoea, palpitation and anxiety. The dose regimen used was 3 tablets of magnesium carbonate 600 mg (7 mmol elementary Mg) daily for the first week followed by 2 tablets daily until the fifth week.
Symptoms of coronary artery disease (CAD)
In 2003, the results from a multicentre, multinational, prospective, randomised, double-blind and placebo-controlled trial showed that 6 months’ oral Mg supplementation in patients with CAD results in a significant improvement in exercise tolerance, exercise-induced chest pain, and QOL. The study used oral magnesium citrate (15 mmol twice daily) as Magnosolv-Granulat (total Mg 365 mg). Previously, randomised placebo-controlled studies have shown that oral Mg supplementation in CAD patients is associated with significant improvement in brachial artery endothelial function and inhibits platelet-dependent thrombosis, providing several potential mechanisms by which Mg could beneficially alter outcomes in these patients.
Magnesium supplementation produces a modest dose-dependent blood pressure-lowering effect according to a 2002 meta-analysis of 20 randomised trials that involved 1220 subjects. For each 10 mmol/day increase in Mg intake, a further reduction of 4.3 mmHg in SBP and of 2.3 mmHg in DBP was observed.
A prospective study of 43,738 men (Health Professional Follow-Up Study) conducted over 8 years showed an inverse association between dietary Mg intake and the risk of total stroke. The inverse association was stronger in hypertensive than normotensive men and was not materially altered by adjustments for blood pressure levels. The study also identified an inverse association between low dietary fibre intake and stroke.
Oral Mg supplementation (magnesium oxide 12 mmol/day) taken over 3 months effectively reduced plasma lipids compared with placebo in people with ischaemic heart disease. The double-blind study showed that Mg produced a 13% increase in molar ratio of apolipoprotein A1 :apolipoprotein B compared with a 2% increase in the placebo group, which was statistically significant. This was caused by a decrease in apolipoprotein B concentrations, which were reduced by 15% in the Mg group as compared with a slight increase in the placebo group. Additionally, triglyceride levels decreased by 27% after Mg treatment. Overall, these beneficial results are associated with a decrease in cardiovascular mortality.
Arrhythmia prevention in congestive heart failure Although Mg is usually administered intravenously when indicated in this condition, one controlled study using oral Mg showed that it significantly reduced the incidence of arrhythmias in patients with stable congestive heart failure. The double-blind crossover study used magnesium chloride (3204 mg/day in divided doses).
MIGRAINE HEADACHES: PREVENTION
People who suffer with recurrent migraines appear to have lower intracellular Mg levels (demonstrated in both red blood cells and white blood cells) than those who do not experience migraines. (See ‘Feverfew’ monograph for more information about migraine aetiology.)
Two randomised, double-blind studies using high-dose oral Mg have found it to be useful in migraine sufferers, reducing frequency and/or number of days with migraine headache. One placebo-controlled study using a lower dose found no benefit in reducing the frequency of migraine headaches.
A dose of 24 mmol Mg (600 mg trimagnesium dicitrate) taken daily over 12 weeks produced a 42% reduction in frequency of attack compared with 16% with placebo in one study of 81 patients, with a mean attack frequency of 3.6 migraine headaches each month. Effects were observed after week 9 and treatment also significantly decreased the number of days with migraine. Significant decreases in migraine frequency were also observed in a crossover study that used the same dose and form of oral Mg.
Menstrual migraine headache Oral Mg supplementation decreases pain, premenstrual symptoms and the number of days with migraine headache, according to one double-blind placebo-controlled study. Treatment consisted of 360 mg/day of Mg (pyrollidone carboxylic acid) starting on day 15 of the menstrual cycle and continuing until the onset of menses.
Migraine prophylaxis in children Oral magnesium oxide (9 mg/kg/day) given in three divided doses with food may decrease headache frequency and severity according to a multicentre, randomised, double-blind, placebo-controlled trial. The 16-week study involved children aged 3-17 years who reported a 4-week history of at least weekly, moderate-to-severe headache with a throbbing or pulsatile quality, associated anorexia/nausea, vomiting, photophobia, sonophobia, or relief with sleep, but no fever or evidence of infection. Of note, 27% of subjects (n = 42 magnesium oxide; n = 44 placebo) failed to complete the study, thereby hindering interpretation of the results.
Clinical note — What is the link between magnesium and migraine?
Magnesium seems to play a significant role in the pathogenesis of migraine, with low brain levels and impaired Mg metabolism reported in migraine sufferers. Magnesium has an effect on serotonin receptors, NO synthesis and release, and a variety of other migraine-related receptors and neurotransmitters. It is also essential for mitochondrial function within the cell. The available evidence suggests that up to 50% of patients during an acute migraine attack have lowered levels of ionised Mg. Pilot studies of migraine patients have suggested that disordered energy metabolism or Mg deficiencies may be responsible for hyperexcitability of neuronal tissue in migraine patients. As such, factors that decrease neuronal excitability, such as Mg, may alter the threshold for triggering attacks.
KIDNEY STONE PREVENTION
Magnesium deficiency is one of many risk factors for the development of kidney stones. Others include nutritional deficiencies of water, calcium, potassium and vitamin B6, excessive intakes of animal protein, fat, sugar, oxalates, colas, alcohol, caffeine, salt and vitamin D, lifestyle factors, and a positive family history.
A prospective double-blind study of 64 patients who were randomly assigned to receive placebo or potassium-magnesium citrate (42 mEq potassium, 21 mEq magnesium and 63 mEq citrate) daily for up to 3 years showed that the combination supplement reduced the risk of developing recurrent calcium oxalate kidney stones by 85%.
Three double-blind studies using oral Mg supplements in women with PMS have produced positive results for decreasing symptoms such as fluid retention and mood swings. According to all studies, clinical effects develop slowly, starting during the second menstrual cycle.
Although it is not clear what mechanism of action is responsible, a number of studies have identified decreased Mg concentrations in both red blood cell and mononuclear blood cells of women with PMS.
A Cochrane review of seven randomised trials investigating the effects of various treatments for dysmenorrhoea included three trials comparing Mg with placebo. Overall, Mg was found to be more effective than placebo for pain relief and resulted in less extra medication being required.
Magnesium comprises about 1% of bone mineral and is involved in a number of activities supporting bone strength, preservation, and remodelling. As the Mg content of bone mineral decreases, bone calcium crystals become larger and more brittle. Therefore, low Mg states increase the risk of osteoporosis. Several studies have investigated the effects of supplemental Mg on bone density, generally finding it has positive effects.
One long-term study has reported an increase in bone density for magnesium hydroxide supplementation in a group of menopausal women. After the 2-year test period, fracture incidence was also reduced. Another 2-year study showed that Mg supplementation in postmenopausal women with osteoporosis results in increased bone mass at the wrist after 1 year, with no further increase after 2 years of supplementation. The regimen used here was oral Mg 750 mg/day for the first 6 months followed by 250 mg/day thereafter.
Clinical note — Peak bone mass
The best opportunity to influence bone mass occurs early in life. It has been estimated that approximately 40% of peak bone mass is accumulated during adolescence with peak bone mass in the hip achieved by age 16-18 years. The spinal vertebrae are still able to increase in mass until the third decade of life, when total peak bone mass reaches 99% by age 26.6 years (±3.7 years). As such, ensuring an adequate intake of calcium and Mg early in life is essential for attaining optimal bone mass.
Magnesium is sometimes used in the treatment of acute asthma because it can influence bronchial vasomotor tone, pulmonary vascular muscle contractility, mast-cell granulation and neurohumoral mediator release. Although it is most often used as an infusion or in an inhaled form for this indication, results of two randomised, double-blind studies suggest that oral supplements also significantly alleviate asthma symptoms. Hill et al found that treatment improved symptoms, although it failed to change objective measures of airflow or airway reactivity and Bede et al found a significant decrease in bronchodilator use after 8 weeks compared with placebo. This was a 12-week study using oral magnesium citrate in 89 children (4-16 years) with mild or moderate persistent bronchial asthma. The dose used was 200 mg daily for children aged 7 years and 290 mg for those older than 7 years.
A 2001 Cochrane review of seven studies involving 2689 women concluded that although not all trials were positive, oral Mg taken before the 25th week of gestation was associated with a lower frequency of preterm birth, a lower frequency of low birthweight, and fewer small-for-gestational-age infants.
Additionally, fewer hospitalisations during pregnancy and fewer cases of antepartum haemorrhage were associated with Mg use.
Unfortunately, a lack of high-quality evidence currently exists to conclusively state that dietary Mg supplementation during pregnancy is beneficial, according to the authors, with further research still required to confirm these findings.
Pregnancy-induced leg cramps
A 2002 Cochrane review of five randomised trials of treatments for leg cramps in pregnancy concluded that the best evidence is for magnesium lactate or citrate taken as 5 mmol in the morning and 10 mmol in the evening for pregnant women experiencing leg cramps.
A strong association between Mg, diabetes and hypertension has been reported in the literature. Deficiency aggravates insulin resistance and predisposes diabetics to cardiovascular diseases.
Several randomised studies investigating oral Mg supplementation have shown improvements in diabetic control. The most recent double-blind trial that involved 53 patients with type 2 diabetes (treated with glibenclamide) and reduced serum Mg levels demonstrated that the addition of oral Mg over 15 weeks significantly improves insulin sensitivity and metabolic control.
In high doses Mg exerts a laxative effect, which is used in practice for the short-term treatment of constipation and in order to get the bowel ready for surgical or diagnostic procedures. It is often used in the form of magnesium hydroxide (milk of magnesia) or magnesium sulfate (Epsom salts).
As magnesium hydroxide (milk of magnesia), Mg is used to reduce symptoms of dyspepsia and gastric acidity and acts as an antacid by forming magnesium chloride in the stomach. Magnesium oxide is also used for its antacid properties, which are greater than magnesium carbonate and sodium bicarbonate. Magnesium trisilicate is the form used when a prolonged antacid activity is required.
CHRONIC LEG CRAMPS
Two randomised, double-blind studies have investigated the use of oral Mg supplements in people with leg cramps. Frusso et al (1999) conducted a crossover trial involving 45 individuals who had experienced at least six cramps during the previous month. Subjects were given 1 month of oral magnesium citrate (900 mg twice daily) followed by a matching placebo for 1 month, or visa versa. This treatment regimen failed to reduce the severity, duration or number of nocturnal leg cramps. In contrast, Roffe et al (2002) tested magnesium citrate equivalent to 300 mg magnesium in subjects suffering regular leg cramps and identified a trend towards fewer cramps with active treatment (P = 0.07). Significantly more subjects thought that the treatment had helped after magnesium than after placebo (35 (78%) and 25 (54%) respectively). Interestingly, in both studies patients improved overtime regardless of the treatment they received.
Magnesium: Other Uses
Oral Mg supplements are used in a variety of different conditions, most notably those involving muscle spasm or tension, pain and/or psychological and physical symptoms of stress and hyperexcitability. This includes IBS, restless legs syndrome, fibromyalgia, chronic fatigue syndrome, anxiety states, tension headaches, ADHD and insomnia. Together with vitamin B6, Mg is a popular treatment in autism. Preliminary evidence also suggests it may be beneficial for women with detrusor muscle instability (incontinence) or sensory urgency.