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Magnesium Facts

Magnesium (Mg) is the fourth most abundant body mineral. Balance is tightly regulated keeping plasma Mg2+ levels within a typically normal range of 0.7-0.85 mmol/l. Total body content in an average adult is 25 grams with approximately 60% present bone which serves as a reservoir (1).  A further 20% is localised to muscle and the remaining 20% is present in soft tissue and liver (2). In the kidney, approximately 2.5 g of Mg is filtered daily, but, approximately 95%of this load is reabsorbed. (3) Hypomagnesaemia is defined as a serum concentration of less than 0.70 mmol/l and chronic depletion generally becomes clinically evident at serum concentrations of <0.40 mmol/l. (4)

Magnesium is needed for more than 300 biochemical reactions. It is important in the maintenance of normal nerve and muscle function, strong bones, a steady heart rhythm, and a healthy immune system and a deficiency results in numerous medical conditions. (7,8)

About 60% of US adults do not consume the estimated average requirement, yet despite this, widespread pathological conditions attributed to deficiency are not reported. (10) The main reason may be that serum levels are the most commonly used tool to assess mineral status. A study of geriatric outpatients, found that whilst serum Mg levels were within the normal range in all patients, the intra-erythrocyte measurements were low in 57%. (11)  Another study, measuring total serum levels as subjects aged, showed no apparent change, but when the intracellular free Mg concentration was measured, there was clearly a progressive decrease. (12)

US studies also show that between 8% and 30% of hospitalized patients have hypomagnesemia and evidence suggests that the ‘‘American-type diet’’ is low in magnesium. The authors observe that an ‘‘Oriental diet,’’ consisting of more fruits and vegetables, is linked to higher magnesium levels and may attribute to lower levels of coronary heart disease (CHD) amongst oriental populations (13-15).

Three types of diuretics are known to cause hypomagnesaemia-osmotic diuretics, loop diuretics and thiazide-type diuretics. (89)

In many patients serum Mg2+ concentrations during EGFR-targeting treatment are decreased. (90). In trials, 54% of treated patients developed hypomagnesaemia and in 6% of patients hypomagnesaemia was severe. (91, 92). The incidence of Mg2+ deficiency during treatment with cisplatin is around 30% and is amplified with increased dosage or prolonged duration of treatment (93).

Several studies have described proton pump inhibitor-induced hypomagnesaemia in patients treated for more than one year. (94-98) Patients recover relatively quickly upon discontinuation but relapse within days when medication is restarted. Patients suffering from hypomagnesaemia due to PPIs can be treated with supplements or switched to a histamine H2 receptor antagonist.

As many as 25% of aminoglycoside-antibiotic treated patients will develop hypomagnesaemia. (99)  The effect seems to be related to cumulative doses received by the patient during treatment. Onset of hypomagnesaemia can take up to two weeks and can persist after cessation of treatment for several months (100)

Calcineurin inhibitors commonly lead to hypomagnesaemia due to renal Mg2+ wasting, hypercalciuria and hypokalaemia (101).

Sources of magnesium

Leafy vegetables, unrefined grains and nuts generally have higher magnesium contents than meats and dairy products. Tap water varies greatly depending on the mineral content of the supply.  Approximately 300 mg of Mg is ingested on a daily basis, of which 25–75% is absorbed, depending on the bioavailability of the form consumed and needs of the body. (5,6)

Magnesium in health and disease

Asthma

Of nine published studies, seven are randomized controlled trials investigating an intervention of magnesium supplements. (16-24). Four relate to children and five evaluate the benefits in adults. Seven articles reported a statistically significant correlation between high magnesium intake and a decrease in severity of asthma symptoms. (16-19, 22-24)  Of the studies that found positive correlations, five randomized controlled trials used an intervention dose of 340-400 mg/day for adults and 200-300 mg/day for children to produce one or more  significant outcome measures.

Intravenous (IV) magnesium to treat acute asthma attacks in adults is effective in improving peak expiratory flow rate and FEV1. Administration in addition to bronchodilators is safe and beneficial for people with severe asthma attacks or for those in whom bronchodilators do not work (25).  Another study supported the use of nebulised magnesium sulphate in addition to a b2-agonist in the treatment of an acute asthma exacerbation and reported a decrease in hospital admissions. (26)

Migraine

Multiple studies have found IV magnesium successful in the treatment of migraines. It is most effective in participants with acute migraines who are known to be deficient in magnesium. (27-32) Seven studies show a significant correlation between oral magnesium supplementation and a decrease in the frequency or severity of migraines. (33-39) Five were randomized control trials that used a dose ranging between 360-600 mg/day for adults, and 9 mg/kg/day for children.  Duration was either 12 or 16 weeks and each study measured migraine headache frequency and severity as primary outcomes.

A recent paper suggests migraine sufferers may develop deficiency due to genetic inability to absorb magnesium, inherited renal magnesium wasting, excretion of excessive amounts due to stress, and low nutritional intake. It proposes when trials have produced mixed results, it is most likely due to both magnesium deficient and non-deficient patients being assessed. Considering deficiency may be present in 50% of migraine patients, and routine blood tests are not indicative of status, it recommends empiric treatment with at least oral magnesium is warranted in all sufferers. (40) The recommended dose for the prophylaxis of migraine headaches is 600 mg a day of a chelated magnesium preparation. (41)

Coronary Heart Disease

A magnesium rich diet results in fewer complications such as ischemic heart disease, arrhythmias, angina, lower mortality and fewer sudden deaths. (42) Elsewhere, CHD risks have been shown to be inversely correlated to dietary magnesium supplementation.(43-45).  A review of six studies examining the relationship between magnesium and CHD or CHD risk reported supplementation, resulted in better small artery elasticity, favourable effects on exercise tolerance and a reduced risk of CHD (46). Magnesium could also be important in the pathogenesis of sudden death. (47)

Dietary magnesium assessments in 58,615 healthy Japanese found intake was inversely associated with mortality from haemorrhagic stroke in men and with mortality from total and ischemic strokes, coronary heart disease, heart failure and total cardiovascular disease in women.(48)

Compared to controls, patients with heart failure (HF) demonstrated higher baseline C-reactive protein (CRP) levels, independent of co-existing conditions, and lower serum Mg values. Following Mg administration CRP decreased significantly and targeting the inflammatory cascade this way might prove a useful tool for improving the prognosis in HF. (49)

Hypertension

A review of 44 studies examined the use of oral magnesium supplementation for the treatment of hypertension (50). In studies of patients taking antihypertensive medications, the dose range necessary to produce a decrease in blood pressure (BP) was 240-480/day. In studies of patients not receiving antihypertensive medications, seven of the ten found a significant decrease in blood pressure in subjects supplemented with ≥480 mg of magnesium per day. In the studies of participants who were either normotensive or pre-hypertensive, results showed no changes in blood pressure after daily doses of between 97-600 mg. Consumption of 500-1000 mg of magnesium may lower BP as much as 2.7-5.6 mm Hg systolic and 1.7-3.4 mm Hg diastolic (51). Combining magnesium with taurine has additive antihypertensive effects and lowers intracellular sodium and calcium.

Pre-eclampsia

Today, magnesium sulphate is the drug of choice in patients with severe pre-eclampsia and eclampsia. (52)  In one large study, patients who received magnesium sulphate supplementation had a 58% lower risk of eclampsia than those receiving placebo and had lower mortality rates with no substantive harmful effects on either the mother or baby at the time of delivery, no difference in the risk of death or disability for children at 18 months post-delivery, nor for the women at two years after treatment. (53-55)

Diabetes Mellitus

Magnesium plays an important role in glucose metabolism and could influence the release and activity of insulin. (56) In insulin-sensitive tissues, insulin stimulates magnesium uptake. (57)  A study of obese non-diabetic children noted that the dietary magnesium intake was significantly lower in obese children and inversely associated with fasting insulin levels, concluding that the association between insulin resistance and magnesium deficiency was present in childhood, and that increasing magnesium levels could be important in the prevention of type 2 diabetes in children who are obese. (58)  Low magnesium status is also often found in people with the metabolic syndrome and type 2 diabetes, which are associated with higher plasma CRP concentrations. Because a low magnesium status apparently occurs more often in obese than non-obese individuals, one of the stressors causing the activation of inflammatory pathways may be magnesium deficiency.

A review of seven studies found intake was inversely associated with the incidence of type 2 diabetes suggesting that increasing the amount of magnesium in consumed could reduce the risk of developing type 2 diabetes.(59) A further report suggests magnesium supplementation improved insulin sensitivity and could be helpful with cardiovascular risk reduction in patients with mild uncomplicated hypertension. (60)

Diabetic patients, who received 300 mg/day magnesium for more than five years were followed to determine whether long-term supplementation influenced the natural evolution of polyneuropathy. Long-term supplementation was able to normalise magnesium levels and positively influence polyneuropathy.(61)

Depression and Stress 

60% of cases of clinical depression are considered to be treatment-resistant depression (TRD) and brain magnesium has been found low in TRD using phosphorous nuclear magnetic resonance spectroscopy, an accurate means for measuring magnesium. (62) Oral administration of magnesium to animals led to effects  comparable to those of strong anti-depressant drugs (63). Taurine and glycine are also found to be low in TRD and are each important in regulating magnesium homeostasis. (64)

A 1921 study first showed success in TRD cases, but a 2008 randomized clinical trial showed magnesium as effective as the tricyclic anti-depressant imipramine in treating depression in diabetics, without any of the side effects of imipramine (65,66).  Intravenous and oral magnesium in specific protocols have been reported to rapidly terminate TRD safely and without side effects (67). Benefits of IV magnesium treatment of TRD have been found to be extremely rapid and unequivocally strong and are suggested for treatment initiation. (68)

Depression-inducing severe loss of IQ, memory and attention in children due to loss of neuronal Mg has been reported in conditions of exceptional stress. Stress worsened mental health by Mg depletion, but was minimized with magnesium supplementation. (69) Memory loss, IQ loss and attention deficits associated with onset of severe depression appeared completely reversible upon magnesium treatment in a case report (70). In familial depression with low IQ, poor memory and concentration, vitamin B6, magnesium, zinc and manganese deficiencies were common in diets of families of depressives (71). Test anxiety in students resulted in increased losses of magnesium in the urine. (72)

Fibromyalgia (FMS)

Magnesium deficits have been shown to be a causal mechanism in the development of FMS in part because of the role of magnesium in the production of ATP (77). One paper suggests that low magnesium levels are common among FMS patients and supplementation may benefit this subgroup.(78)

In a double-blinded cross-over trial, subjects received either a fixed dose of malic acid and magnesium or  placebo. (79) No treatment effects were observed as measured by tender point index, dolorimetery reading of the tender point average, or pain. In contrast, positive results were obtained on all three of these outcome variables in a subsequent six-month open-label, un-blinded trial. A further open-label randomized, placebo-controlled cross-over trial administered a higher dose of magnesium and malate over eight weeks.(80) Significant differences in tender point index scores in the intervention group were observed, and significant worsening when subjects were crossed-over to placebo.

There are clear indications that IV magnesium has a positive effect on FMS after five and ten weeks of treatment. There are indications that a large subgroup benefits from this treatment. (81)

Chronic Fatigue Syndrome (CFS)

Two systematic reviews of CAM treatments for CFS conclude most supplements failed to show beneficial effects for CFS, with the exception of NADH and magnesium. (82,83) The key trial compared a magnesium supplement with placebo and found beneficial effects on patients’ symptom profiles. (84).

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