Español

Summary

Magnesium plays important roles in the structure and the function of the human body. The adult human body contains about 25 grams (g) of magnesium. About 50 to 60% of all the magnesium in the body is found in the skeleton and the remainder is found in soft tissue, primarily in muscle. Magnesium is the second most abundant intracellular cation after potassium. Blood contains less than 1% of total body magnesium. Only the free, ionized form of magnesium (Mg2+) is physiologically active. Protein-bound and chelated magnesium serve to buffer the pool of free, ionized magnesium (1).

Function

Magnesium is involved in more than 300 essential metabolic reactions, some of which are discussed below (2).

Energy production

The metabolism of carbohydrates and fats to produce energy requires numerous magnesium-dependent chemical reactions. Magnesium is required by the adenosine triphosphate (ATP)-synthesizing protein in mitochondria. ATP, the molecule that provides energy for almost all metabolic processes, exists primarily as a complex with magnesium (MgATP) (3).

Synthesis of essential molecules

Magnesium is required for a number of steps during synthesis of deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and proteins. Several enzymes participating in the synthesis of carbohydrates and lipids require magnesium for their activity. Glutathione, an important antioxidant, requires magnesium for its synthesis (3).

Structural roles

Magnesium plays a structural role in bone, cell membranes, and chromosomes (3).

Ion transport across cell membranes

Magnesium is required for the active transport of ions like potassium and calcium across cell membranes. Through its role in ion transport systems, magnesium affects the conduction of nerve impulses, muscle contraction, and normal heart rhythm (3).

Cell signaling

Cell signaling requires MgATP for the phosphorylation of proteins and the formation of the cell-signaling molecule, cyclic adenosine monophosphate (cAMP). cAMP is involved in many processes, including the secretion of parathyroid hormone (PTH) from the parathyroid glands (see the articles on Vitamin D and Calcium for information on the role of PTH in the body) (3).

Cell migration

Calcium and magnesium concentrations in the fluid surrounding cells affect the migration of a number of different cell types. Such effects on cell migration may be important in wound healing (3).

Nutrient interactions

Zinc

High doses of zinc in supplemental form apparently interfere with the absorption of magnesium. One study reported that zinc supplements of 142 mg/day (well above the tolerable upper intake level (UL) of 40 mg/day for zinc) in healthy adult males significantly decreased magnesium absorption and disrupted magnesium balance (the difference between magnesium intake and magnesium loss) (4).

Fiber

Large increases in the intake of dietary fiber have been found to decrease magnesium utilization in experimental studies. However, the extent to which dietary fiber affects magnesium nutritional status in individuals with a varied diet outside the laboratory is not clear (2, 3).

Protein

Dietary protein intake may affect magnesium absorption. One study in adolescent boys found that magnesium absorption was directly related to protein intake, with magnesium absorption the lowest when protein intake was less than 30 g/day (5).

Vitamin D and calcium

The active form of vitamin D (calcitriol) may slightly increase intestinal absorption of magnesium (6). However, it is not clear whether magnesium absorption is calcitriol-dependent as is the absorption of calcium and phosphate. High calcium intake has not been found to affect magnesium balance in most studies. Inadequate blood magnesium concentrations are known to result in low blood calcium concentrations, resistance to parathyroid hormone (PTH) action, and resistance to some of the effects of vitamin D (2, 3).

Deficiency

Risk factors

Magnesium deficiency in healthy individuals who are consuming a balanced diet is quite rare because magnesium is abundant in both plant and animal foods and because the kidneys are able to limit urinary excretion of magnesium when intake is low. The following conditions increase the risk of magnesium deficiency (7):

Gastrointestinal disorders: Prolonged diarrhea, Crohn's disease, malabsorption syndromes, celiac disease, surgical removal of a portion of the small intestine, and intestinal inflammation due to radiation may all lead to magnesium depletion.

Renal disorders (magnesium wasting): Diabetes mellitus and long-term use of certain diuretics (see Drug interactions) may result in increased urinary loss of magnesium. Multiple other medications can also result in renal magnesium wasting (3).

Endocrine and metabolic disorders: Several conditions, such as diabetes mellitus, parathyroid gland disorders, phosphate depletion, primary aldosteronism, and even excessive lactation, can lead to magnesium depletion.

Poor dietary intake, gastrointestinal problems, and increased urinary loss of magnesium may all contribute to magnesium depletion in people suffering from alcoholism. Older adults have relatively low dietary intakes of magnesium (8, 9). Intestinal magnesium absorption tends to decrease with age, and urinary magnesium excretion tends to increase with age; thus, suboptimal dietary magnesium intake may increase the risk of magnesium depletion in the elderly (2).

Signs and symptoms

Although severe magnesium deficiency is uncommon, it has been induced experimentally. When magnesium deficiency was induced in humans, the earliest sign was a decrease in serum magnesium concentration. Hypomagnesemia usually describes serum magnesium concentrations less than 0.74 millimoles/liter (mmol/L) or 1.40 milliequivalents/liter (mEq/L) or 1.70 milligrams/deciliter (mg/dL). Over time, serum calcium concentration also began to decrease (hypocalcemia) despite adequate dietary calcium. Hypocalcemia persisted despite increased secretion of parathyroid hormone (PTH), which regulates calcium homeostasis. Usually, increased PTH secretion quickly results in the mobilization of calcium from bone and normalization of blood calcium concentration. As the magnesium depletion progressed, PTH secretion diminished to low concentrations. In addition to hypomagnesemia, signs of severe magnesium deficiency included hypocalcemia, low serum potassium concentrations (hypokalemia), retention of sodium, low circulating PTH concentrations, neurological and muscular symptoms (tremor, muscle spasms, tetany), loss of appetite, nausea, vomiting, and personality changes (3).

While mild magnesium deficiency may not elicit clinical symptoms, it may be associated with an increased risk of developing chronic diseases (see Disease Prevention) (1).

Assessing magnesium status

There is currently no reliable indicator of magnesium status. The magnesium tolerance test, which basically determines magnesium retention (using 24-h urine collection) following the intravenous administration of magnesium, is considered to be the gold standard (1). If this method is a good indicator of hypomagnesemia in adults, it appears to be poorly sensitive to changes in magnesium status in healthy people. Moreover, the method is invasive and cumbersome, and thus difficult to use routinely (10). Another method to assess magnesium status is through measurements of plasma ionized magnesium, which represents the physiologically active form of magnesium. However, it is unknown whether plasma ionized magnesium reflect body stores (10).

In practice, magnesium status is usually determined through assessments of dietary magnesium intake, serum magnesium concentration, and/or urinary magnesium concentration (10). However, each of these indicators has limitations. Although predominantly used in epidemiological studies and the sole indicator available to clinicians, serum magnesium concentration has been found to poorly respond to magnesium supplementation. Regarding dietary intakes of magnesium, about 30 to 40% of ingested magnesium is absorbed, yet absorption varies with the amount of magnesium ingested and with the food matrix composition. Finally, a state of magnesium deficiency has not been associated to a clear cutoff concentration of magnesium in the urine. Urinary magnesium concentration fluctuates rapidly with dietary intakes, but measurements of 24-hour urinary magnesium can be used in addition to other indicators to assess population status. Presently, a combination of all three markers — dietary, serum, and urinary magnesium — may be used to get a valid assessment of magnesium status (reviewed in 10).

The Recommended Dietary Allowance (RDA)

In 1997, the Food and Nutrition Board of the Institute of Medicine increased the Recommended Dietary Allowance (RDA) for magnesium, based on the results of tightly controlled balance studies that utilized more accurate methods of measuring magnesium (Table 1) (2). Balance studies are useful for determining the amount of a nutrient that will prevent deficiency; however, such studies provide little information regarding the amount of a nutrient required for chronic disease prevention or optimal health.

Table 1. Recommended Dietary Allowance (RDA) for Magnesium Life Stage Age Males (mg/day) Females (mg/day) Infants 0-6 months 30 (AI*) 30 (AI) Infants 7-12 months 75 (AI) 75 (AI) Children 1-3 years 80 80 Children 4-8 years 130 130 Children 9-13 years 240 240 Adolescents 14-18 years 410 360 Adults 19-30 years 400 310 Adults 31 years and older 420 320 Pregnancy 18 years and younger - 400 Pregnancy 19-30 years - 350 Pregnancy 31 years and older - 360 Breast-feeding 18 years and younger - 360 Breast-feeding 19-30 years - 310 Breast-feeding 31 years and older - 320 *Adequate Intake

Disease Prevention

Metabolic syndrome

Metabolic syndrome refers to the concomitant presentation of several metabolic disorders in an individual, including dyslipidemia, hypertension, insulin resistance, and obesity (11). People with metabolic syndrome are at greater risk of developing type 2 diabetes mellitus, cardiovascular disease, and some types of cancer (12-14). A 2015 analysis of data from the US National Health and Nutrition Examination Survey (NHANES 2001-2010) in 9,148 adults (mean age, 50 years) found a 32% lower risk of metabolic syndrome in those in the highest versus lowest quantile of magnesium intake (≥355 mg/day versus <197 mg/day) (15). Several meta-analyses of primarily cross-sectional studies have also reported an inverse association between dietary magnesium intake and risk of metabolic syndrome (16-18). Moreover, lower serum magnesium concentrations have been reported in individuals with metabolic syndrome compared to controls (18, 19). However, circulating magnesium represents only 1% of total body stores and is tightly regulated; thus, serum magnesium concentrations do not best reflect magnesium status (1). At present, additional evidence is needed from prospectively designed studies to inform the potential relationship between dietary and circulating magnesium and the risk of metabolic syndrome.

Systemic inflammation, which contributes to the development of metabolic disorders, has been inversely correlated with magnesium intakes in a cross-sectional study of 11,686 women (≥45 years). In this study, the lowest prevalence of metabolic syndrome was found in the group of women in the highest quintile of magnesium intakes (median intake, 422 mg/day) (20). Several randomized controlled trials also reported a reduction in circulating C-reactive protein (CRP) — a marker of inflammation — following oral magnesium supplementation (21). This might constitute a potential mechanism through which magnesium could play a role in the prevention of metabolic disorders.

Cardiovascular disease

Hypertension (high blood pressure)

Large prospective cohort studies have examined the relationship between magnesium and blood pressure. However, the fact that foods high in magnesium (fruit, vegetables, whole grains) are frequently high in potassium and dietary fiber has made it difficult to evaluate the independent effect of magnesium on blood pressure. Findings from large cohorts, including the Health Professionals Follow-up Study (HPFS) (22), the Nurses’ Health Study (NHS) (23), the Atherosclerosis Risk in Communities (ARIC) study (24), and the Coronary Artery Risk Development in Young Adults (CARDIA) study (25), have been summarized in a recent meta-analysis (26). The pooled analysis of seven prospective studies showed an 8% lower risk of hypertension with higher versus lower dietary magnesium intakes (26). In one of these studies, data from 5,511 men and women followed for a median period of 7.6 years found that the highest concentrations of urinary magnesium corresponded to a 25% reduction in the risk of hypertension, whereas there was no association between plasma magnesium concentrations and the risk of hypertension (27). There was also no evidence of an association between circulating magnesium concentrations and the risk of hypertension in a meta-analysis of three prospective cohort studies (26).

The relationship between magnesium intake and risk of hypertension suggests that improving diet quality or using magnesium supplements might play a role in the prevention of hypertension in those with inadequate dietary intakes.

Vascular calcification

The buildup of plaque inside arterial walls — a process called atherosclerosis — is an early event in the development of cardiovascular disease. The calcification of atherosclerotic plaques that occurs with the progression of atherosclerosis has been associated with a three- to four-fold increase in the risk of cardiovascular events and mortality (28).

Individuals with chronic kidney disease (CKD): Abnormalities in mineral and bone metabolism are not uncommon in individuals with impaired kidney function and have been associated with an increased risk of cardiovascular disease and mortality (29, 30). In particular, elevated blood phosphorus concentration and increased deposition of calcium phosphate within the vasculature are thought to promote vascular calcification. Since magnesium can function as a calcium antagonist, it has been suggested that it could be utilized to slow down or reverse the calcification of vessels observed in patients with CKD. In a cross-sectional study in patients with pre-dialysis CKD, higher serum magnesium concentrations were associated with lower coronary artery calcification density scores in those in the higher end of normal serum phosphorus concentrations (i.e., ≥3.4 mg/dL) (31). One small randomized, placebo-controlled trial in participants with pre-dialysis CKD examined the effect of oral, slow-release magnesium hydroxide on the calcification propensity of serum by measuring the time needed for primary calciprotein particles (containing amorphous calcium phosphate) to transform into secondary calciprotein particles (containing crystalline hydroxyapatite) (32). Increased serum calcification propensity has been associated with greater risk of mortality in patients with impaired kidney function (33, 34). The trial found an increase in serum magnesium concentration and a reduction in serum calcification propensity — i.e., an increase in the time needed for 50% of the transformation to occur (T 50 ) — with 720 mg/day of supplemental magnesium for eight weeks compared to placebo (32). Serum calcification propensity was also reduced when magnesium concentration was increased (from 1 to 2 mEq/L for 28 days) in the dialysate of patients with established kidney failure (35). A larger randomized controlled trial in patients with pre-dialysis CKD is underway to examine further the effect of oral magnesium on markers of vascular calcification, markers of mineral and bone metabolism, incidence of cardiovascular events, and deterioration of kidney function (36).

Individuals with normal kidney function: The cross-sectional analysis of data from 2,695 middle-aged participants in the Framingham Heart Study showed that the odds of having coronary artery calcification was 58% lower in those in the highest versus lowest quartile of total magnesium intakes (median values, 427 mg/day versus 259 mg/day) (37). Serum magnesium concentration was also found to be inversely associated with vascular calcification in recent population-based cross-sectional studies (38-40). No research has yet examined whether improving magnesium status of generally healthy people could play a role in atherosclerosis prevention.

Risk of cardiovascular disease

Dietary magnesium intakes: Several large prospective cohort studies, including the Health Professionals Follow-up Study (HPFS) and the Nurses’ Health Study (NHS), have examined magnesium intakes in relation to cardiovascular outcomes. In the most recent analysis of the NHS, which followed nearly 90,000 female nurses for 28 years, those in the highest quintile of magnesium intake had a 39% lower risk of fatal myocardial infarction (but not nonfatal coronary heart disease [CHD]) compared to those in the lowest quintile (>342 mg/day versus <246 mg/day) (41). A meta-analysis of nine prospective cohort studies, mostly conducted in participants without cardiovascular disease at baseline, reported a 22% lower risk of CHD per 200 mg/day incremental intake in dietary magnesium (42). A more recent meta-analysis by Fang et al. (43) included six studies and reported a 10% lower risk of CHD with higher versus lower dietary magnesium intakes.

Higher magnesium intakes were associated with an 8 to 11% reduction in stroke risk in two meta-analyses of prospective studies, each including over 240,000 participants (44, 45). The most recent pooled analysis of 14 studies found a 12% lower risk of stroke with higher versus lower magnesium intakes and estimated a 7% risk reduction of stroke associated with each 100-mg increment in daily magnesium intake (43).

Only two prospective studies have examined the risk of heart failure in relation to magnesium intakes. The pooled analysis suggested a 31% lower risk of heart failure with higher dietary magnesium intakes (43).

Finally, a meta-analysis of 13 prospective studies in over 475,000 participants reported that the risk of total cardiovascular events, including stroke, nonfatal myocardial infarction, and CHD, was 15% lower in individuals with higher intakes of magnesium (46). However, in the recent meta-analysis of eight studies by Fang et al. (43), there was no association between dietary magnesium intake and risk of total cardiovascular disease.

It is important to note that while these prospective cohort studies assessed the association between dietary magnesium and cardiovascular disease, they did not account for the use of supplemental magnesium by a significant fraction of participants.

Serum magnesium concentrations: One large prospective study (almost 14,000 men and women) associated higher serum magnesium concentrations with a lower risk of CHD in women but not in men (47). This study was included in a meta-analysis of four studies that showed no evidence of a reduced risk of CHD with increasing serum magnesium concentrations (42). In contrast, a 0.2 mmol/L increment in serum magnesium concentration was associated with a 30% lower risk of total cardiovascular disease in a pooled analysis of eight prospective cohort studies (42). In the recently published British Regional Heart Study that followed 3,523 men for a mean 15 years, there was no association between serum magnesium concentration and incidental CHD events, yet serum magnesium concentration was inversely associated with the risk of heart failure (48).

Cardiovascular mortality

A number of early studies found lower cardiovascular-related mortality in populations who routinely consume "hard" water. Hard (alkaline) water is generally high in magnesium but may also contain more calcium and fluoride than "soft" water, making the cardioprotective effects of hard water difficult to attribute to magnesium alone (49). Additionally, meta-analyses of prospective studies have found no associations between magnesium intake and cardiovascular (50) or all-cause mortality (43). In a prospective analysis of NHANES data from 14,353 participants, followed for a median period of 28.6 years, the risk of all-cause and stroke mortality was significantly increased in those with low rather than normal serum concentrations of magnesium (<0.7 mmol/L versus 0.8-0.89 mmol/L) (51). In contrast, hypermagnesemia (serum magnesium concentration >0.89 mmol/L) — rather than hypomagnesemia — in people with heart failure was associated with an increased risk of cardiovascular and all-cause mortality (52).

Aneurysmal subarachnoid hemorrhage

Occurrence of hypomagnesemia has been reported in patients who suffered from a subarachnoid hemorrhage (a type of stroke) caused by the rupture of a cerebral aneurysm (53). Poor neurologic outcomes following an aneurysmal subarachnoid hemorrhage (aSAH) have been linked to inappropriate calcium-dependent contraction of arteries (known as cerebral arterial vasospasm), leading to delayed cerebral ischemia (54). Because magnesium is a calcium antagonist and potent vasodilator, several randomized controlled trials have examined whether intravenous magnesium sulfate infusions could reduce the incidence of vasospasm after aSAH. A meta-analysis of nine randomized controlled trials found that magnesium therapy after aSAH significantly reduced vasospasm but failed to prevent neurologic deterioration or decrease the risk of death (55). Another meta-analysis of 13 trials in 2,413 aSAH sufferers concluded that the infusion of magnesium sulfate had no benefit regarding neurologic outcome and mortality, despite a reduction in the incidence of delayed cerebral ischemia (56). The post-hoc analysis of a small randomized controlled trial suggested that maintaining magnesium sulfate infusion for 10 days post-aSAH or until signs of vasospasm disappear might protect against secondary cerebral infarction when markers of vasoconstriction and reduced brain perfusion are present (57, 58). Current evidence does not support the use of magnesium supplementation in clinical practice for aSAH patients beyond magnesium status normalization.

Complications of heart surgery

Atrial arrhythmia (also called atrial fibrillation) is a condition defined as the occurrence of persistent heart rate abnormalities; such arrhythmias often complicate the recovery of patients after cardiac surgery. The use of magnesium in the prophylaxis of postoperative atrial arrhythmia after coronary artery bypass grafting has been evaluated as a sole or adjunctive agent to classical antiarrhythmic molecules (namely, β-blockers and amiodarone) in several prospective, randomized controlled trials. A meta-analysis of 21 intervention studies showed that intravenous magnesium infusions could significantly reduce postoperative atrial arrhythmia in treated compared to untreated patients (59). The results of a more recent meta-analysis of 22 placebo-controlled trials suggested that magnesium may effectively reduce atrial arrhythmia when administered post-operatively, as a bolus, and for more than 24 hours (60). However, another meta-analysis of four trials found that magnesium was no more effective than other antiarrhythmic agents (60). Moreover, the meta-analysis of five randomized controlled trials also suggested that intravenous magnesium added to β-blocker treatment did not decrease the risk of atrial arrhythmia compared to β-blocker alone and was associated with more adverse effects (bradycardia and hypotension) (61). Presently, high-quality evidence is still lacking to support the use of magnesium in the prophylaxis of post-operative atrial fibrillation and other arrhythmias in patients with contraindications to first-line antiarrhythmic agents (60).

Diabetes mellitus

Public health concerns regarding the epidemics of obesity and type 2 diabetes mellitus and the prominent role of magnesium in glucose metabolism have led scientists to investigate the relationship between magnesium intake and type 2 diabetes mellitus. A prospective cohort study that followed more than 25,000 individuals, 35 to 65 years of age, for seven years found no difference in incidence of type 2 diabetes mellitus when comparing the highest (377 mg/day) quintile of magnesium intake to the lowest quintile (268 mg/day) (62). However, inclusion of this study in a meta-analysis of eight cohort studies showed that the risk of type 2 diabetes was inversely correlated with magnesium intake (62). The most recent meta-analysis of 25 prospective cohort studies, including 637,922 individuals and 26,828 new cases of type 2 diabetes mellitus, found that higher magnesium intakes were associated with a 17% lower risk of type 2 diabetes mellitus (63). Several meta-analyses conducted to date reported an 8 to 15% decrease in the risk of developing type 2 diabetes mellitus with each 100 mg-increment in dietary magnesium intake (63-66).

Insulin resistance, characterized by alterations in both insulin secretion by the pancreas and insulin action on target tissues, has been linked to inadequate magnesium status. A cross-sectional analysis of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, which included 15 cohorts with a total of 52,684 diabetes-free participants, showed that magnesium intakes were inversely associated with fasting insulin concentrations after multiple adjustments, including various lifestyle factors, body mass index (BMI), caffeine intake, and fiber intake (65). It is thought that pancreatic β-cells, which secrete insulin, could become less responsive to changes in insulin sensitivity in magnesium-deficient subjects (67). A randomized, double-blind, placebo-controlled trial that enrolled 97 healthy adults with significant hypomagnesemia (serum magnesium concentration ≤0.70 mmol/L) showed that daily consumption of 638 mg of magnesium (from a solution of magnesium chloride) for three months improved the function of pancreatic β-cells, resulting in lower fasting glucose and insulin concentrations (68). In a follow-up randomized controlled trial, the administration of 382 mg/day of magnesium for four months to participants (mean age, 42 years) with both hypomagnesemia (serum magnesium concentration <0.74 mmoles/L) and impaired fasting glucose improved serum magnesium concentrations, as well as fasting and post-load glucose concentrations (69). Other metabolic markers, including serum triglycerides, HDL-cholesterol, and a measure of insulin resistance, also improved in magnesium- versus placebo-treated individuals (69). Additionally, similar metabolic improvements have been reported following the supplementation of magnesium (382 mg/day for four months) to participants who were both hypomagnesemic and lean yet metabolically obese (i.e., with metabolic disorders usually associated with obesity) (70). In another study, supplementation with 365 mg/day of magnesium (from magnesium aspartate hydrochloride) for six months reduced insulin resistance in 27 overweight individuals with normal values of serum and intracellular magnesium (71). This latter study suggests that magnesium might have additional effects on glucose tolerance and insulin sensitivity that go beyond the normalization of serum magnesium concentrations in hypomagnesemic individuals.

Osteoporosis

Although decreased bone mineral density (BMD) is the primary feature of osteoporosis, other osteoporotic changes in the collagenous matrix and mineral composition of bone may result in bones that are brittle and more susceptible to fracture (72). Around 60% of total body magnesium is stored in the skeleton and is known to influence both bone matrix and bone mineral metabolism. Magnesium at the surface of bones is also available for dynamic exchange with blood (73). As the magnesium content of bone mineral decreases, hydroxyapatite crystals of bone may become larger and more brittle. Some studies have found lower magnesium content and larger hydroxyapatite crystals in bones of women with osteoporosis compared to disease-free women (74). Inadequate serum magnesium concentrations are known to result in low serum calcium concentrations, resistance to parathyroid hormone (PTH) action, and resistance to some of the effects of vitamin D (calcitriol), all of which can lead to increased bone loss (see the articles on Vitamin D and Calcium). Lower serum magnesium concentrations may not be unusual in postmenopausal women with osteoporosis (75), and hypomagnesemia has been reported as an adverse effect of using the prescription drug teriparatide (Forsteo) in the treatment of osteoporosis (76).

Higher dietary magnesium intakes have been associated with increased site-specific (77) and total-body BMD (78) in observational studies, including studies of older adults. More recently, a large cohort study conducted in almost two-thirds of the Norwegian population found the level of magnesium in drinking water to be inversely associated with the risk of hip fracture (79). In the Women’s Health Initiative study, data analysis from 4,778 participants (mean age, 63 years) followed for about seven years showed that higher magnesium intakes were associated with higher hip and whole-body BMD but not with reduced hip or total fractures (80). Moreover, the highest versus lowest quintile of total magnesium intakes was associated with a 23% increased risk of lower arm and wrist fractures (80). In a case-cohort study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk study, which included 5,319 individuals, total magnesium and potassium intakes were found to be inversely associated with heel bone (calcaneus) broadband ultrasound attenuation (BUA) measurements — which are predictive of the risk of incidental fracture — and with the risk of hip fractures (81).

Few studies have addressed the effect of magnesium supplementation on BMD or osteoporosis in humans. In a small group of postmenopausal women with osteoporosis, magnesium supplementation of 750 mg/day for six months followed by 250 mg/day for 18 more months resulted in increased BMD at the wrist after one year, with no further increase after two years of supplementation (82). A study in postmenopausal women who were taking estrogen replacement therapy and a multivitamin supplement found that supplementation with an additional 400 mg/day of magnesium and 600 mg/day of calcium resulted in increased BMD at the heel compared to postmenopausal women receiving estrogen replacement therapy only (83). A more recent randomized controlled study conducted in 20 postmenopausal women with osteoporosis suggested that high-dose supplementation with magnesium citrate (1,830 mg/day) for one month could reduce the rapid rate of bone loss that characterizes osteoporosis (84). Evidence is not yet sufficient to suggest that supplemental magnesium in excess of the RDA could be effective in the prevention of osteoporosis unless normalization of serum magnesium concentration is required (85).

Sarcopenia

Sarcopenia is a condition characterized by a loss of skeletal muscle mass that increases frailty and risk of falls in older adults (86). Several cross-sectional studies have reported a positive association between dietary magnesium intakes and proxy measures of skeletal muscle mass in middle-age and older adults (87-90). A 2014 randomized controlled study in 139 physically active and healthy older women (mean age, 71.5 years) found little-to-no impact of magnesium supplementation (900 mg/day of magnesium oxide) for 12 weeks on body composition and muscle strength, yet the Short Physical Performance Battery [SPPB] test score — a composite indicator of physical function — improved (91). More research is needed to examine further the effect of magnesium supplementation on body composition, muscle strength, and physical performance in older adults, whether physically active or sedentary, and with normal or inadequate magnesium status.

Disease Treatment

The use of pharmacologic doses of magnesium to treat specific disorders is discussed below. Although many of the cited studies utilized supplemental magnesium at doses considerably higher than the tolerable upper intake level (UL), which is 350 mg/day set by the Food and Nutrition Board (see Safety), it is important to note that these studies were all conducted under medical supervision. Because of the potential side effects of high doses of magnesium, especially in the presence of impaired kidney function, any disease treatment trial using oral magnesium doses higher than the UL should be conducted under medical supervision. Moreover, intravenous magnesium has been used in the management of several conditions.

Pregnancy complications

Preeclampsia and eclampsia

Preeclampsia and eclampsia are hypertensive disorders of pregnancy that may occur at any time after 20 weeks’ gestation and persist up to six weeks following birth. Preeclampsia (sometimes called toxemia of pregnancy) affects approximately 4% of pregnant women in the US (92). Preeclampsia is defined as the presence of elevated blood pressure (hypertension), protein in the urine, and severe swelling (edema) during pregnancy (93). Eclampsia occurs with the addition of seizures to the triad of preeclamptic symptoms and is a significant cause of perinatal and maternal mortality (93, 94). Although cases of preeclampsia are at high risk of developing eclampsia, one-quarter of eclamptic women do not initially exhibit preeclamptic symptoms (95).

Although lower magnesium concentrations have been reported in the blood and brain of women with preeclampsia than in healthy pregnant women, there is no evidence that magnesium imbalance may cause adverse pregnancy events. A 2014 meta-analysis of 10 randomized controlled trials found no effect of oral magnesium salt administration during normal and at-risk pregnancies on the risk of preeclampsia, perinatal mortality, and small-for-gestational age infants (96).

For many years, high-dose intravenous magnesium sulfate has been the treatment of choice for preventing eclamptic seizures that may occur in association with severe preeclampsia in pregnancy or during labor (97, 98). A systematic review of seven randomized trials in 1,396 women with eclampsia compared the effect of magnesium sulfate administration with diazepam (a known anticonvulsant) treatment on perinatal outcomes. Risks of recurrent seizures and maternal death were significantly reduced by the magnesium regimen compared to diazepam. Moreover, the use of magnesium for the care of eclamptic women resulted in newborns with higher Apgar scores; there was no significant difference in the risk of preterm birth and perinatal mortality (95). Additional research has confirmed that infusion of magnesium sulfate should always be considered in the management of severe preeclampsia and eclampsia to prevent initial and recurrent seizures (99). Moreover, the World Health Organization (WHO) recommends the use of magnesium sulfate — administered either intramuscularly or intravenously — as first-line treatment for the prevention of eclampsia in women with severe preeclampsia, in preference to other anticonvulsants (100). Further research is needed to evaluate the efficacy of magnesium salt infusion in eclampsia prophylaxis in women with mild preeclampsia (101). In addition, it is unclear whether prolonging magnesium use post-partum in women who presented with severe preeclampsia during pregnancy is necessary to lower the risk of eclampsia after delivery (102).

Perinatal neuroprotection

While intravenous magnesium sulfate is included in the medical care of preeclampsia and eclampsia, the American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine support its use in two additional situations: specific conditions of short-term prolongation of pregnancy and neuroprotection of the fetus in anticipated premature delivery (103).

Preterm birth, which is defined by the premature delivery of an infant between the 20th and 37th weeks of estimated gestation, is associated with an increased risk of perinatal mortality and both short- and long-term morbidity. The ACOG approves the use of different classes of drugs — known as tocolytics — that are meant to delay delivery for long enough so that antenatal corticoids can be used to accelerate lung maturation in the fetus of women at imminent risk of preterm labor (104). A 2014 meta-analysis of 37 trials found that intravenous infusion of magnesium sulfate was no more efficacious than commonly used tocolytics (e.g., β-adrenergic receptor agonists, calcium channel blockers, prostaglandin inhibitors) in delaying delivery or preventing serious infant outcomes (105). Very limited evidence also suggested that high- versus low-dose magnesium infusion may reduce the length of hospital stays in neonates admitted to intensive care units (106).

The relationship between magnesium sulfate and risk of cerebral damage in premature infants has been assessed in observational studies. A meta-analysis of six case-control and five prospective cohort studies showed that the use of magnesium significantly reduced the risk of cerebral palsy, as well as mortality (107). However, the high degree of heterogeneity among the cohort studies and the fact that corticosteroid exposure (which is known to decrease antenatal mortality) was higher in the cases of children exposed to magnesium compared to controls imply a cautious interpretation of the results. Nonetheless, a meta-analysis of five randomized controlled trials, which included 5,493 women at risk of preterm birth and 6,135 babies, found that magnesium therapy given to mothers delivering before term decreased the risk of cerebral palsy by 32% without causing severe adverse maternal events, but this treatment did not reduce the risk of other neurologic impairments or mortality in early childhood (108). Another meta-analysis conducted on five randomized controlled trials found that intravenous magnesium administration to newborns who suffered from perinatal asphyxia could be beneficial in terms of short-term neurologic outcomes, although there was no effect on mortality (109). Additional trials are needed to evaluate the long-term benefits of magnesium in pediatric care.

Cardiovascular disease

Hypertension

While results from intervention studies have not been entirely consistent (2), the latest review of the data highlighted a therapeutic benefit of magnesium supplements in treating hypertension. A 2012 meta-analysis examined 22 randomized, placebo-controlled trials of magnesium supplementation conducted in 1,173 individuals with either normal blood pressure (normotensive) or hypertension (treated with medication or untreated). Oral supplementation with magnesium (mean dose of 410 mg/day; range of 120 to 973 mg/day) for a median period of 11.3 months significantly reduced systolic blood pressure by 2 to 3 mm Hg and diastolic blood pressure by 3 to 4 mm Hg (110); a greater effect was seen at higher doses (≥370 mg/day). The results of 19 of the 22 trials included in the meta-analysis were previously reviewed together with another 25 intervention studies (111). The systematic examination of these 44 trials suggested a blood pressure-lowering effect associated with supplemental magnesium in hypertensive but not in normotensive individuals.

Magnesium doses required to achieve a decrease in blood pressure appeared to depend on whether participants with high blood pressure were treated with antihypertensive medications, including diuretics. Intervention trials on treated participants showed a reduction in hypertension with magnesium doses from 243 mg/day to 486 mg/day, whereas untreated patients required doses above 486 mg/day to achieve a significant decrease in blood pressure. A more recent meta-analysis of randomized controlled studies with 2,028 participants found that supplemental magnesium at a median dose of 368 mg/day (range: 238-960 mg/day) for a median duration of three months (range: 3 weeks-6 months) increased serum magnesium concentration by 0.05 mmol/L (27 trials) and reduced systolic blood pressure by 2 mm Hg and diastolic blood pressure by 1.78 mm Hg (37 trials) (112). A 2017 meta-analysis restricted to trials in participants with underlying preclinical (insulin resistance or prediabetes) or clinical conditions (type 2 diabetes mellitus or coronary heart disease) found a 4.18 mm Hg reduction in systolic blood pressure and a 2.27 mm Hg reduction in diastolic blood pressure with supplemental doses of magnesium ranging between 365 mg/day and 450 mg/day for one to six months (113).

While oral magnesium supplementation may be helpful in hypertensive individuals who are depleted of magnesium due to chronic diuretic use and/or inadequate dietary intake (7), several dietary factors play a role in hypertension. For example, adherence to the DASH diet — a diet rich in fruit, vegetables, and low-fat dairy and low in saturated and total fats — has been linked to significant reductions in systolic and diastolic blood pressures (114). See the topic page: High Blood Pressure.

Atherosclerosis

Vascular endothelial cells line arterial walls where they are in contact with the blood that flows through the circulatory system. Normally functioning vascular endothelium promotes vasodilation when needed, for example, during exercise, and inhibits the formation of blood clots. Conversely, endothelial dysfunction results in widespread vasoconstriction and coagulation abnormalities. In cardiovascular disease, chronic inflammation is associated with the formation of atherosclerotic plaques in arteries. Atherosclerosis impairs normal endothelial function, increasing the risk of vasoconstriction and clot formation, which may lead to heart attack or stroke (reviewed in 115). A recent systematic review identified six randomized controlled trials that examined the effect of pharmacologic doses of oral magnesium on vascular endothelial function (116). Three out of six trials, which included individuals with coronary artery disease (117), diabetes mellitus (118), or hypertension (119), reported an improvement in flow-mediated dilation (FMD) with supplemental magnesium compared to control. In other words, the normal dilation response of the brachial (arm) artery to increased blood flow was improved. In contrast, there was no evidence of an effect of magnesium supplementation on FMD in three trials conducted in hemodialysis patients (120) or healthy participants with normal (121) or high body mass index (BMI) (122). A pooled analysis of the six trials in 262 participants found that supplementation with 107 to 730 mg/day of magnesium for one to six months resulted in an overall improvement of FMD, regardless of the health status or baseline magnesium concentrations of participants (116).

The measurement of the thickness of the inner layers of the carotid arteries is sometimes used as a surrogate marker of atherosclerosis (123). Higher serum magnesium concentrations have been associated with reduced carotid intima-media thickness (CIMT) in all women and in Caucasian men participating in the Atherosclerosis Risk in Communities (ARIC) study (124). A meta-analysis of four small (145 participants in total) and heterogeneous intervention studies found no effect of magnesium supplementation (98.6 to 368 mg/day for 2 to 6 months) on CIMT (116).

Survival after myocardial infarction

Results from several randomized, placebo-controlled trials have suggested that an intravenous magnesium administered early after a suspected myocardial infarction could decrease the risk of death. The most influential study was a randomized, placebo-controlled trial in 2,316 patients that found a significant reduction in mortality in the group of patients given intravenous magnesium sulfate within 24 hours of suspected myocardial infarction (7.8% all-cause mortality in the experimental group vs. 10.3% all-cause mortality in the placebo group) (125). Follow-up from one to five years after treatment revealed that the mortality from cardiovascular disease was 21% lower in the magnesium-treated group (126). However, a larger placebo-controlled trial in more than 58,000 patients found no significant reduction in five-week mortality in patients treated with intravenous magnesium sulfate within 24 hours of suspected myocardial infarction, resulting in controversy regarding the efficacy of this treatment (127). A US survey of the treatment of more than 173,000 individuals with acute myocardial infarction found that only 5% were given intravenous magnesium in the first 24 hours post-infarction and that mortality was higher in this group compared to the group of patients not treated with magnesium (128). A 2007 systematic review of 26 clinical trials, including 73,363 participants, concluded that intravenous magnesium administration does not appear to reduce post-myocardial infarction mortality and thus should not be utilized as a treatment (129). Thus, the use of intravenous magnesium sulfate in the therapy of acute myocardial infarction remains controversial.

Diabetes mellitus

Magnesium depletion has been associated with type 1 (insulin-dependent) and type 2 diabetes mellitus, as well as with gestational diabetes. Low serum concentrations of magnesium (hypomagnesemia) have been reported in 13.5 to 47.7% of individuals with type 2 diabetes mellitus (130). One cause of the depletion may be an increased urinary loss of magnesium caused by an increased urinary excretion of glucose that accompanies poorly controlled diabetes. Magnesium depletion has been shown to increase insulin resistance in a few studies and may adversely affect blood glucose control in diabetes mellitus (see also Diabetes mellitus under Disease Prevention) (131). A small study in nine individuals with type 2 diabetes mellitus reported that supplemental magnesium (300 mg/day for 30 days), in the form of a liquid, magnesium-containing salt solution, improved fasting insulin but not fasting glucose concentrations (132). One randomized, double-blind, placebo-controlled study in 63 individuals with type 2 diabetes mellitus and hypomagnesemia found that those taking an oral magnesium chloride solution (638 mg/day of elemental magnesium) for 16 weeks had improved measures of insulin sensitivity and glycemic control compared to those taking a placebo (133). The most recent meta-analysis of nine randomized, double-blind, controlled trials concluded that oral supplemental magnesium lowered fasting plasma glucose concentrations in individuals with diabetes (134). However, magnesium supplementation did not improve other markers of glucose homeostasis, such as glycated hemoglobin (HbA1c) concentration, fasting and post-glucose load insulin concentrations, and measures of insulin resistance (134). Another meta-analysis of trials that included participants either at-risk of diabetes mellitus or with diabetes mellitus suggested that evidence to support a benefit of magnesium supplementation on measures of insulin resistance was stronger in subjects who were magnesium deficient than in those with normal serum concentrations of magnesium (135). Correcting existing magnesium deficiencies may improve glucose metabolism and insulin sensitivity in subjects with diabetes, but it remains uncertain whether magnesium supplementation can have any therapeutic benefit in patients with adequate magnesium status.

Asthma

The occurrence of hypomagnesemia may be greater in patients with asthma than in individuals without asthma (136). Several clinical trials have examined the effect of intravenous magnesium infusions on acute asthmatic attacks in children or adults who did not respond to initial treatment in the emergency room. Indeed, magnesium can promote bronchodilation in subjects with asthma by interfering with mechanisms like the activation of N-methyl D-aspartate (NMDA) receptors that trigger bronchoconstriction through facilitating calcium influx in airway smooth muscle cells (137). In a meta-analysis of six (quasi) randomized controlled trials in 325 children with acute asthma treated with a short-acting β 2 -adrenergic receptor agonist (e.g., salbutamol) and systemic steroids, intravenous magnesium sulfate treatment improved measurements of the respiratory function and reduced the risk of hospital admission by 30% compared to control (138). Another meta-analysis of randomized controlled trials primarily conducted in adults with asthma exacerbations indicated that single infusions of 1.2 to 2 g of magnesium sulfate over 15 to 30 minutes could reduce the risk of hospital admission and improve lung function after initial treatments failed (i.e., oxygen, short-acting β 2 agonist, and steroids) (139).

The use of nebulized, inhaled magnesium for treating asthma has also been investigated. A recent systematic review of 25 randomized controlled trials, including adults, children, or both, found little evidence that inhaled magnesium sulfate alone or along with a β 2 -adrenergic receptor agonist and/or a muscarinic anticholinergic (e.g., ipratropium) could improve pulmonary function in patients with acute asthma (140). In addition, oral magnesium supplementation is of no known value in the management of chronic asthma (141-143).

Pain management

The potential analgesic effect of magnesium is attributed in particular to its capacity to block NMDA receptors, which are located in the brain and spinal cord and are involved in pain transduction (144).

Post-operative pain

Several intervention studies have examined the role of magnesium on pain control and analgesic requirement in patients during the immediate post-surgery period.

After cesarean section: Pain management strategies after cesarean section usually involve the injection of an analgesic into either the epidural space (for epidural analgesia) or the subarachnoid space (for spinal [intrathecal] analgesia). A recent meta-analysis of nine randomized controlled trials summarized the evidence regarding the potential use of magnesium sulfate to control or relieve postoperative pain in 827 women who underwent cesarean section (145). All the trials evaluated the effect of a first-line analgesic regimen (i.e., bupivacaine or lidocaine, with or without opioids) with and without the addition of magnesium sulfate. The results suggested that the anesthesia (8 studies) and sensory blockade (6 studies) lasted longer in women who received the additional magnesium sulfate. The use of magnesium sulfate also resulted in lower pain score (3 studies) and in lower postoperative consumption of analgesics (4 studies). Additionally, there was no difference in occurrence of side effects between regimens (145). A recent randomized controlled trial in 60 healthy women undergoing elective cesarean section confirmed that the addition of magnesium sulfate to a bupivacaine/opioid regimen increased the duration of spinal anesthesia and lowered the pain level, yet did not improve the potency of bupivacaine (146). In another study in women with mild preeclampsia who received an epidural injection of ropivacaine after cesarean section, spinal infusion of magnesium sulfate increased the duration of sensory and motor blockade, as well as the time before patients requested an analgesic, compared to midazolam (147).

After a variety of other surgeries: The efficacy of intravenous magnesium has also been examined for local, regional, or systemic pain control following a range of different surgeries. A review of four small randomized controlled studies suggested that, when added to local analgesics, magnesium infusion to patients undergoing tonsillectomy might decrease pain and incidence of laryngospasm, extend the time to first post-operative analgesic requirement, and reduce the number of post-operative analgesic requests (148). Similar observations were reported in two additional meta-analyses, yet there was discrepancy regarding the ability of magnesium to alleviate pain (149, 150). Indeed, the review of eight trials by Xie et al. (150), of which only two scored pain using the same scale, showed no pain reduction with magnesium compared to control. Finally, both meta-analyses reported no reduction in risk of post-operative nausea and vomiting with intravenous magnesium administration (148, 150). A 2018 meta-analysis of four randomized controlled trials in 263 patients also suggested that magnesium sulfate infusion may help reduce pain scores at 2 and 8 hours (but not 24 hours) after laparoscopic cholecystectomy (151). Recent studies have examined the use of magnesium sulfate for pain control after other surgeries, including hysterectomy (152, 153), spinal surgery (154, 155), or during endoscopic sinus (156) or cochlear implantation (157) surgery. Despite conflicting results or reports of limited benefits of magnesium, further research is needed before any conclusions can be drawn.

Neuropathic pain

The effect of magnesium on neuropathic pain has been examined in some clinical studies. The intravenous administration of magnesium sulfate was found to partially or completely alleviate pain in patients with postherpetic neuralgia, a type of neuropathic pain caused by herpes zoster infection (shingles) (158, 159). In a more recent randomized controlled trial in 45 patients with either postherpetic neuralgia or neuropathic pain of traumatic or surgical origin, oral supplementation of magnesium failed to improve measures of pain and quality of life compared to a placebo (160). Another trial is underway to examine the impact of intravenous magnesium with ketamine on neuropathic pain (161).

Migraine headaches

Lower intracellular magnesium concentrations (in both red blood cells and white blood cells) have been reported in individuals who suffer from recurrent migraine headaches compared to migraine-free individuals (162). Additionally, the incidence of hypomagnesemia also appeared to be greater in women who experience migraines with menstruation compared to women without menstrual migraines (163).

A few intervention studies have examined whether an increase in intracellular magnesium concentration with supplemental (oral) magnesium could help decrease the frequency and severity of migraine headaches in affected individuals. Two early placebo-controlled trials demonstrated modest decreases in the frequency of migraine headaches after supplementation with 600 mg/day of magnesium (162, 164). Another placebo-controlled trial in 86 children with frequent migraine headaches found that oral magnesium oxide (9 mg/kg body weight/day) reduced headache frequency over the 16-week intervention (165). However, there was no reduction in the frequency of migraine headaches with 485 mg/day of magnesium in another placebo-controlled study conducted in 69 adults suffering migraine attacks (166). The efficiency of magnesium absorption varies with the type of oral magnesium complex, and this might explain the conflicting results. Although no serious adverse effects were noted during these migraine headache trials, 19 to 40% of individuals taking the magnesium supplements have reported diarrhea and gastric irritation.

The efficacy of magnesium infusions was also investigated in a randomized, single-blind, placebo-controlled, cross-over trial of 30 patients with migraine headaches (167). The administration of 1 gram of intravenous magnesium sulfate ended the attacks, abolished associated symptoms, and prevented recurrence within 24 hours in nearly 90% of the subjects. While this promising result was confirmed in another trial (168), two additional randomized, placebo-controlled studies found that magnesium sulfate was less effective than other molecules (e.g., metoclopramide) in treating migraines (169, 170). The most recent meta-analysis of five randomized, double-blind, controlled trials reported no beneficial effect of magnesium infusion for migraine in adults (171). Another two more recent intervention studies suggested that magnesium sulfate infusion could be more effective and faster than dexamethasone/metoclopramide (172) or caffeine citrate (173) to relieve pain in patients with acute migraine.

The efficacy of magnesium should be examined in larger studies that consider the magnesium status of migraine sufferers (174).

Critical injury or illness

Hypomagnesemia is not uncommon in patients admitted to intensive care units (ICU). Two recent meta-analyses of prospective and retrospective cohort studies reported serum magnesium concentrations ≤0.75 mmol/L in ICU patients at admission or within 24 hours following admission to be associated with a greater need for mechanical ventilation, longer ICU stay, and higher risk of hospital mortality (175, 176). A pooled analysis of three studies also suggested a higher risk of sepsis in ICU patients with hypomagnesemia (175). A recent prospective study conducted in patients admitted with severe head injury found better neurological outcomes after six months in those who presented with normal serum magnesium concentrations at admission compared to those with hypomagnesemia (serum magnesium concentrations <0.65 mmol/L) (177). However, evidence is currently unavailable to suggest that magnesium administration could improve outcomes in critically ill or severely injured patients (178).

Sources

Food sources

The analysis of US national nutrition survey data (NHANES 2003-2006) showed an average magnesium intake in adults (ages ≥19 years) of 278 mg/day when only unfortified food sources were considered (179). Considering all sources of magnesium intakes (i.e., unfortified and fortified food and supplements), the average intake in adults was estimated to be around 330 mg/day — a value close to the estimated average requirements (EAR) for magnesium — suggesting that about one-half of the adult population may be at risk of magnesium inadequacy (179). Yet, the long-term consequences of inadequate dietary intakes remain unclear (1).

Since magnesium is part of chlorophyll, the green pigment in plants, green leafy vegetables are good sources of magnesium. Unrefined grains (whole grains) and nuts also have high magnesium content. Meats and milk have an intermediate content of magnesium, while refined foods generally have the lowest. Water is a variable source of intake; harder water usually has a higher concentration of magnesium salts (2). Some foods that are relatively rich in magnesium are listed in Table 2, along with their magnesium content in milligrams (mg). For more information on the nutrient content of foods, search USDA's FoodData Central.

Food Serving Magnesium (mg) Brazil nuts 1 ounce (6 kernels) 107 Cereal, oat bran ½ cup dry 96 Brown rice, medium-grain, cooked 1 cup 86 Cashews 1 ounce (16 kernels) 83 Fish, mackerel, cooked 3 ounces 82 Spinach, frozen, chopped, cooked ½ cup 78 Almonds 1 ounce (23 kernels) 77 Swiss chard, chopped, cooked ½ cup 75 Lima beans, large, immature seeds, cooked ½ cup 63 Cereal, shredded wheat 2 biscuits 61 Avocado 1 fruit 58 Cereal, all bran (whole wheat) ½ cup, dry 57 Peanuts 1 ounce (28 peanuts) 48 Molasses, blackstrap 1 tablespoon 48 Hazelnuts 1 ounce (21 kernels) 46 Chickpeas, mature seeds, cooked ½ cup 39 Milk, 1% fat 8 fluid ounces 39 Banana 1 medium 32

Supplements

Magnesium supplements are available as magnesium oxide, magnesium hydroxide, magnesium gluconate, magnesium chloride, and magnesium citrate salts, as well as a number of amino acid chelates like magnesium aspartate. Magnesium hydroxide, oxide, or trisilicate salts are used as antacids to mitigate gastric hyperacidity and symptoms of gastroesophageal reflux disease (180).

Safety

Toxicity

Adverse effects have not been identified from magnesium occurring naturally in food. However, adverse effects from excessive magnesium have been observed with intakes of various magnesium salts (i.e., supplemental magnesium) (6). The initial symptom of excess magnesium supplementation is diarrhea — a well-known side effect of magnesium that is used therapeutically as a laxative. Individuals with impaired kidney function are at higher risk for adverse effects of magnesium supplementation, and symptoms of magnesium toxicity have occurred in people with impaired kidney function taking moderate doses of magnesium-containing laxatives or antacids. Elevated serum concentrations of magnesium (hypermagnesemia) may result in a fall in blood pressure (hypotension). Some of the later effects of magnesium toxicity, such as lethargy, confusion, disturbances in normal cardiac rhythm, and deterioration of kidney function, are related to severe hypotension. As hypermagnesemia progresses, muscle weakness and difficulty breathing may occur. Severe hypermagnesemia may result in cardiac arrest (2, 3). The Food and Nutrition Board (FNB) of the US Institute of Medicine set the tolerable upper intake level (UL) for magnesium at 350 mg/day; this UL represents the highest level of daily supplemental magnesium intake likely to pose no risk of diarrhea or gastrointestinal disturbance in almost all individuals. The FNB cautions that individuals with renal impairment are at higher risk for adverse effects from excess supplemental magnesium intake. However, the FNB also notes that there are some conditions that may warrant higher doses of magnesium under medical supervision (2).

Table 3. Tolerable Upper Intake Level (UL) for Supplemental Magnesium Age Group UL (mg/day) Infants 0-12 months Not possible to establish* Children 1-3 years 65 Children 4-8 years 110 Children 9-13 years 350 Adolescents 14-18 years 350 Adults 19 years and older 350 *Source of intake should be from food and formula only.

Drug interactions

Magnesium interferes with the absorption of digoxin (a heart medication), nitrofurantoin (an antibiotic), and certain anti-malarial drugs, which could potentially reduce drug efficacy. Bisphosphonates (e.g., alendronate, etidronate), which are drugs used to treat osteoporosis, and magnesium should be taken two hours apart so that the absorption of the bisphosphonates is not inhibited (181, 182). Magnesium has also been found to reduce the efficacy of chlorpromazine (a tranquilizer), penicillamine, oral anticoagulants, and the quinolone and tetracycline classes of antibiotics (181, 182). Intravenous magnesium might inhibit calcium entry into smooth muscle cells and lead to hypotension and muscular weakness if administered with calcium channel blockers (e.g., nifedipin, nicardipin) (182). Because intravenous magnesium has increased the effects of certain muscle-relaxing medications used during anesthesia, it is advisable to let medical staff know if you are taking oral magnesium supplements, laxatives, or antacids prior to surgical procedures. Moreover, long-term use (three months or longer) of proton-pump inhibitors (drugs used to reduce the amount of stomach acid) may increase the risk of hypomagnesemia (183, 184). High doses of furosemide (Lasix) and some thiazide diuretics (e.g., hydrochlorothiazide), if taken for extended periods, may interfere with magnesium reabsorption in the kidneys and result in magnesium depletion (182). Many other medications may also result in renal magnesium loss (3).

Linus Pauling Institute Recommendation

The Linus Pauling Institute supports the latest RDA for magnesium intake (400 to 420 mg/day for men and 310 to 320 mg/day for women). Despite magnesium being plentiful in foods, it is considered a shortfall nutrient (see the article on Micronutrient Inadequacies in the US Population). Following the Linus Pauling Institute recommendation to take a daily multivitamin/mineral supplement might ensure an intake of at least 100 mg/day of magnesium. Few multivitamin/mineral supplements contain more than 100 mg of magnesium due to its bulk. Eating a varied diet that provides green vegetables, whole grains, and nuts daily should provide the rest of an individual's magnesium requirement.

Older adults (>50 years)

Older adults are less likely than younger adults to consume enough magnesium to meet their needs and should therefore take care to eat magnesium-rich foods in addition to taking a multivitamin/mineral supplement daily (see the article on Micronutrient Inadequacies: Subpopulations at Risk). Since older adults are also more likely to have impaired kidney function, they should avoid taking more than 350 mg/day of supplemental magnesium without medical consultation (see Safety).

Authors and Reviewers

Originally written in 2001 by:

Jane Higdon, Ph.D.

Linus Pauling Institute

Oregon State University

Updated in April 2003 by:

Jane Higdon, Ph.D.

Linus Pauling Institute

Oregon State University

Updated in August 2007 by:

Victoria J. Drake, Ph.D.

Linus Pauling Institute

Oregon State University

Updated in October 2013 by:

Barbara Delage, Ph.D.

Linus Pauling Institute

Oregon State University

Updated in November 2018 by:

Barbara Delage, Ph.D.

Linus Pauling Institute

Oregon State University

Reviewed in February 2019 by:

Stella L. Volpe, Ph.D., RDN, ACSM-CEP, FACSM

Professor and Chair

Department of Nutrition Sciences

Drexel University

Copyright 2001-2020 Linus Pauling Institute

References

1. Volpe SL. Magnesium. In: Erdman Jr. JW, Macdonald IA, Ziegler EE, eds. Present Knowledge in Nutrition. 10th ed: ILSI Press; 2012:459-474.

2. Food and Nutrition Board, Institute of Medicine. Magnesium. Dietary Reference Intakes: Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride. Washington, D.C.: National Academy Press; 1997:190-249. (National Academy Press)

3. Rude RK, Shils ME. Magnesium. In: Shils ME, Shike M, Ross AC, Caballero B, Cousins RJ, eds. Modern Nutrition in Health and Disease. 10th ed. Baltimore: Lippincott Williams & Wilkins; 2006:223-247.

4. Spencer H, Norris C, Williams D. Inhibitory effects of zinc on magnesium balance and magnesium absorption in man. J Am Coll Nutr. 1994;13(5):479-484. (PubMed)

5. Schwartz R, Walker G, Linz MD, MacKellar I. Metabolic responses of adolescent boys to two levels of dietary magnesium and protein. I. Magnesium and nitrogen retention. Am J Clin Nutr. 1973;26(5):510-518. (PubMed)

6. Navarro-Gonzalez JF, Mora-Fernandez C, Garcia-Perez J. Clinical implications of disordered magnesium homeostasis in chronic renal failure and dialysis. Semin Dial. 2009;22(1):37-44. (PubMed)

7. Rude RK. Magnesium. In: Ross AC, Caballero B, Cousins RJ, Tucker KL, Ziegler TR, eds. Modern Nutrition in Health and Disease. 11th ed. China: Williams & Wilkins; 2014:159-175.

8. Moshfegh A, Goldman J, Ahuja J, Rhodes D, LaComb R. What We Eat in America, NHANES 2005-2006: Usual Nutrient Intakes from Food and Water Compared to 1997 Dietary Reference Intakes for Vitamin D, Calcium, Phosphorus, and Magnesium. 2009.

9. Sebastian RS, Cleveland LE, Goldman JD, Moshfegh AJ. Older adults who use vitamin/mineral supplements differ from nonusers in nutrient intake adequacy and dietary attitudes. J Am Diet Assoc. 2007;107(8):1322-1332. (PubMed)

10. Costello RB, Nielsen F. Interpreting magnesium status to enhance clinical care: key indicators. Curr Opin Clin Nutr Metab Care. 2017;20(6):504-511. (PubMed)

11. Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation. 2005;112(17):2735-2752. (PubMed)

12. Esposito K, Chiodini P, Colao A, Lenzi A, Giugliano D. Metabolic syndrome and risk of cancer: a systematic review and meta-analysis. Diabetes Care. 2012;35(11):2402-2411. (PubMed)

13. Ninomiya JK, L'Italien G, Criqui MH, Whyte JL, Gamst A, Chen RS. Association of the metabolic syndrome with history of myocardial infarction and stroke in the Third National Health and Nutrition Examination Survey. Circulation. 2004;109(1):42-46. (PubMed)

14. Sung KC, Lee MY, Kim YH, et al. Obesity and incidence of diabetes: Effect of absence of metabolic syndrome, insulin resistance, inflammation and fatty liver. Atherosclerosis. 2018;275:50-57. (PubMed)

15. Moore-Schiltz L, Albert JM, Singer ME, Swain J, Nock NL. Dietary intake of calcium and magnesium and the metabolic syndrome in the National Health and Nutrition Examination (NHANES) 2001-2010 data. Br J Nutr. 2015;114(6):924-935. (PubMed)

16. Dibaba DT, Xun P, Fly AD, Yokota K, He K. Dietary magnesium intake and risk of metabolic syndrome: a meta-analysis. Diabet Med. 2014;31(11):1301-1309. (PubMed)

17. Ju SY, Choi WS, Ock SM, Kim CM, Kim DH. Dietary magnesium intake and metabolic syndrome in the adult population: dose-response meta-analysis and meta-regression. Nutrients. 2014;6(12):6005-6019. (PubMed)

18. Sarrafzadegan N, Khosravi-Boroujeni H, Lotfizadeh M, Pourmogaddas A, Salehi-Abargouei A. Magnesium status and the metabolic syndrome: A systematic review and meta-analysis. Nutrition. 2016;32(4):409-417. (PubMed)

19. La SA, Lee JY, Kim DH, Song EL, Park JH, Ju SY. Low magnesium levels in adults with metabolic syndrome: a meta-analysis. Biol Trace Elem Res. 2016;170(1):33-42. (PubMed)

20. Song Y, Ridker PM, Manson JE, Cook NR, Buring JE, Liu S. Magnesium intake, C-reactive protein, and the prevalence of metabolic syndrome in middle-aged and older U.S. women. Diabetes Care. 2005;28(6):1438-1444. (PubMed)

21. Dibaba DT, Xun P, He K. Dietary magnesium intake is inversely associated with serum C-reactive protein levels: meta-analysis and systematic review. Eur J Clin Nutr. 2014;68(4):510-516. (PubMed)

22. Ascherio A, Rimm EB, Giovannucci EL, et al. A prospective study of nutritional factors and hypertension among US men. Circulation. 1992;86(5):1475-1484. (PubMed)

23. Ascherio A, Hennekens C, Willett WC, et al. Prospective study of nutritional factors, blood pressure, and hypertension among US women. Hypertension. 1996;27(5):1065-1072. (PubMed)

24. Peacock JM, Folsom AR, Arnett DK, Eckfeldt JH, Szklo M. Relationship of serum and dietary magnesium to incident hypertension: the Atherosclerosis Risk in Communities (ARIC) Study. Ann Epidemiol. 1999;9(3):159-165. (PubMed)

25. He K, Liu K, Daviglus ML, et al. Magnesium intake and incidence of metabolic syndrome among young adults. Circulation. 2006;113(13):1675-1682. (PubMed)

26. Han H, Fang X, Wei X, et al. Dose-response relationship between dietary magnesium intake, serum magnesium concentration and risk of hypertension: a systematic review and meta-analysis of prospective cohort studies. Nutr J. 2017;16(1):26. (PubMed)

27. Joosten MM, Gansevoort RT, Mukamal KJ, et al. Urinary magnesium excretion and risk of hypertension: the prevention of renal and vascular end-stage disease study. Hypertension. 2013;61(6):1161-1167. (PubMed)

28. Rennenberg RJ, Kessels AG, Schurgers LJ, van Engelshoven JM, de Leeuw PW, Kroon AA. Vascular calcifications as a marker of increased cardiovascular risk: a meta-analysis. Vasc Health Risk Manag. 2009;5(1):185-197. (PubMed)

29. Major RW, Cheng MRI, Grant RA, et al. Cardiovascular disease risk factors in chronic kidney disease: A systematic review and meta-analysis. PLoS One. 2018;13(3):e0192895. (PubMed)

30. Palmer SC, Hayen A, Macaskill P, et al. Serum levels of phosphorus, parathyroid hormone, and calcium and risks of death and cardiovascular disease in individuals with chronic kidney disease: a systematic review and meta-analysis. JAMA. 2011;305(11):1119-1127. (PubMed)

31. Sakaguchi Y, Hamano T, Nakano C, et al. Association between density of coronary artery calcification and serum magnesium levels among patients with chronic kidney disease. PLoS One. 2016;11(9):e0163673. (PubMed)

32. Bressendorff I, Hansen D, Schou M, et al. Oral magnesium supplementation in chronic kidney disease stages 3 and 4: efficacy, safety, and effect on serum calcification propensity-a prospective randomized double-blinded placebo-controlled clinical trial. Kidney Int Rep. 2017;2(3):380-389. (PubMed)

33. Pasch A, Block GA, Bachtler M, et al. Blood calcification propensity, cardiovascular events, and survival in patients receiving hemodialysis in the EVOLVE trial. Clin J Am Soc Nephrol. 2017;12(2):315-322. (PubMed)

34. Smith ER, Ford ML, Tomlinson LA, et al. Serum calcification propensity predicts all-cause mortality in predialysis CKD. J Am Soc Nephrol. 2014;25(2):339-348. (PubMed)

35. Bressendorff I, Hansen D, Schou M, Pasch A, Brandi L. The effect of increasing dialysate magnesium on serum calcification propensity in subjects with end stage kidney disease: a randomized, controlled clinical trial. Clin J Am Soc Nephrol. 2018;13(9):1373-1380. (PubMed)

36. Bressendorff I, Hansen D, Schou M, Kragelund C, Brandi L. The effect of magnesium supplementation on vascular calcification in chronic kidney disease-a randomised clinical trial (MAGiCAL-CKD): essential study design and rationale. BMJ Open. 2017;7(6):e016795. (PubMed)

37. Hruby A, O'Donnell CJ, Jacques PF, Meigs JB, Hoffmann U, McKeown NM. Magnesium intake is inversely associated with coronary artery calcification: the Framingham Heart Study. JACC Cardiovasc Imaging. 2014;7(1):59-69. (PubMed)

38. Hisamatsu T, Miura K, Fujiyoshi A, et al. Serum magnesium, phosphorus, and calcium levels and subclinical calcific aortic valve disease: A population-based study. Atherosclerosis. 2018;273:145-152. (PubMed)

39. Lee SY, Hyun YY, Lee KB, Kim H. Low serum magnesium is associated with coronary artery calcification in a Korean population at low risk for cardiovascular disease. Nutr Metab Cardiovasc Dis. 2015;25(11):1056-1061. (PubMed)

40. Posadas-Sanchez R, Posadas-Romero C, Cardoso-Saldana G, et al. Serum magnesium is inversely associated with coronary artery calcification in the Genetics of Atherosclerotic Disease (GEA) study. Nutr J. 2016;15:22. (PubMed)

41. Chiuve SE, Sun Q, Curhan GC, et al. Dietary and plasma magnesium and risk of coronary heart disease among women. J Am Heart Assoc. 2013;2(2):e000114. (PubMed)

42. Del Gobbo LC, Imamura F, Wu JH, de Oliveira Otto MC, Chiuve SE, Mozaffarian D. Circulating and dietary magnesium and risk of cardiovascular disease: a systematic review and meta-analysis of prospective studies. Am J Clin Nutr. 2013;98(1):160-173. (PubMed)

43. Fang X, Wang K, Han D, et al. Dietary magnesium intake and the risk of cardiovascular disease, type 2 diabetes, and all-cause mortality: a dose-response meta-analysis of prospective cohort studies. BMC Med. 2016;14(1):210. (PubMed)

44. Larsson SC, Orsini N, Wolk A. Dietary magnesium intake and risk of stroke: a meta-analysis of prospective studies. Am J Clin Nutr. 2012;95(2):362-366. (PubMed)

45. Nie ZL, Wang ZM, Zhou B, Tang ZP, Wang SK. Magnesium intake and incidence of stroke: meta-analysis of cohort studies. Nutr Metab Cardiovasc Dis. 2013;23(3):169-176. (PubMed)

46. Qu X, Jin F, Hao Y, et al. Magnesium and the risk of cardiovascular events: a meta-analysis of prospective cohort studies. PLoS One. 2013;8(3):e57720. (PubMed)

47. Liao F, Folsom AR, Brancati FL. Is low magnesium concentration a risk factor for coronary heart disease? The Atherosclerosis Risk in Communities (ARIC) Study. Am Heart J. 1998;136(3):480-490. (PubMed)

48. Wannamethee SG, Papacosta O, Lennon L, Whincup PH. Serum magnesium and risk of incident heart failure in older men: The British Regional Heart Study. Eur J Epidemiol. 2018;33(9):873-882. (PubMed)

49. Catling LA, Abubakar I, Lake IR, Swift L, Hunter PR. A systematic review of analytical observational studies investigating the association between cardiovascular disease and drinking water hardness. J Water Health. 2008;6(4):433-442. (PubMed)

50. Xu T, Sun Y, Xu T, Zhang Y. Magnesium intake and cardiovascular disease mortality: A meta-analysis of prospective cohort studies. Int J Cardiol. 2013;167(6):3044-3047. (PubMed)

51. Zhang X, Xia J, Del Gobbo LC, Hruby A, Dai Q, Song Y. Serum magnesium concentrations and all-cause, cardiovascular, and cancer mortality among U.S. adults: Results from the NHANES I Epidemiologic Follow-up Study. Clin Nutr. 2018;37(5):1541-1549. (PubMed)

52. Angkananard T, Anothaisintawee T, Eursiriwan S, et al. The association of serum magnesium and mortality outcomes in heart failure patients: A systematic review and meta-analysis. Medicine (Baltimore). 2016;95(50):e5406. (PubMed)

53. van den Bergh WM, Algra A, van der Sprenkel JW, Tulleken CA, Rinkel GJ. Hypomagnesemia after aneurysmal subarachnoid hemorrhage. Neurosurgery. 2003;52(2):276-281; discussion 281-272. (PubMed)

54. Chen T, Carter BS. Role of magnesium sulfate in aneurysmal subarachnoid hemorrhage management: A meta-analysis of controlled clinical trials. Asian J Neurosurg. 2011;6(1):26-31. (PubMed)

55. Yarad EA, Hammond NE, Winner ABNRPsbE. Intravenous magnesium therapy in adult patients with an aneurysmal subarachnoid haemorrhage: A systematic review and meta-analysis. Aust Crit Care. 2013;26(3):105-117. (PubMed)

56. Golan E, Vasquez DN, Ferguson ND, Adhikari NK, Scales DC. Prophylactic magnesium for improving neurologic outcome after aneurysmal subarachnoid hemorrhage: systematic review and meta-analysis. J Crit Care. 2013;28(2):173-181. (PubMed)

57. Kunze E, Lilla N, Stetter C, Ernestus RI, Westermaier T. Magnesium protects in episodes of critical perfusion after aneurysmal SAH. Transl Neurosci. 2018;9:99-105. (PubMed)

58. Westermaier T, Stetter C, Vince GH, et al. Prophylactic intravenous magnesium sulfate for treatment of aneurysmal subarachnoid hemorrhage: a randomized, placebo-controlled, clinical study. Crit Care Med. 2010;38(5):1284-1290. (PubMed)

59. Arsenault KA, Yusuf AM, Crystal E, et al. Interventions for preventing post-operative atrial fibrillation in patients undergoing heart surgery. Cochrane Database Syst Rev. 2013;1:CD003611. (PubMed)

60. Fairley JL, Zhang L, Glassford NJ, Bellomo R. Magnesium status and magnesium therapy in cardiac surgery: A systematic review and meta-analysis focusing on arrhythmia prevention. J Crit Care. 2017;42:69-77. (PubMed)

61. Wu X, Wang C, Zhu J, Zhang C, Zhang Y, Gao Y. Meta-analysis of randomized controlled trials on magnesium in addition to beta-blocker for prevention of postoperative atrial arrhythmias after coronary artery bypass grafting. BMC Cardiovasc Disord. 2013;13:5. (PubMed)

62. Schulze MB, Schulz M, Heidemann C, Schienkiewitz A, Hoffmann K, Boeing H. Fiber and magnesium intake and incidence of type 2 diabetes: a prospective study and meta-analysis. Arch Intern Med. 2007;167(9):956-965. (PubMed)

63. Fang X, Han H, Li M, et al. Dose-response relationship between dietary magnesium intake and risk of type 2 diabetes mellitus: a systematic review and meta-regression analysis of prospective cohort studies. Nutrients. 2016;8(11). (PubMed)

64. Dong JY, Xun P, He K, Qin LQ. Magnesium intake and risk of type 2 diabetes: meta-analysis of prospective cohort studies. Diabetes Care. 2011;34(9):2116-2122. (PubMed)

65. Hruby A, Ngwa JS, Renstrom F, et al. Higher magnesium intake is associated with lower fasting glucose and insulin, with no evidence of interaction with select genetic loci, in a meta-analysis of 15 CHARGE Consortium Studies. J Nutr. 2013;143(3):345-353. (PubMed)

66. Larsson SC, Wolk A. Magnesium intake and risk of type 2 diabetes: a meta-analysis. J Intern Med. 2007;262(2):208-214. (PubMed)

67. Simental-Mendia LE, Rodriguez-Moran M, Guerrero-Romero F. Failure of beta-cell function for compensate variation in insulin sensitivity in hypomagnesemic subjects. Magnes Res. 2009;22(3):151-156. (PubMed)

68. Guerrero-Romero F, Rodriguez-Moran M. Magnesium improves the beta-cell function to compensate variation of insulin sensitivity: double-blind, randomized clinical trial. Eur J Clin Invest. 2011;41(4):405-410. (PubMed)

69. Guerrero-Romero F, Simental-Mendia LE, Hernandez-Ronquillo G, Rodriguez-Moran M. Oral magnesium supplementation improves glycaemic status in subjects with prediabetes and hypomagnesaemia: A double-blind placebo-controlled randomized trial. Diabetes Metab. 2015;41(3):202-207. (PubMed)

70. Rodriguez-Moran M, Guerrero-Romero F. Oral magnesium supplementation improves the metabolic profile of metabolically obese, normal-weight individuals: a randomized double-blind placebo-controlled trial. Arch Med Res. 2014;45(5):388-393. (PubMed)

71. Mooren FC, Kruger K, Volker K, Golf SW, Wadepuhl M, Kraus A. Oral magnesium supplementation reduces insulin resistance in non-diabetic subjects - a double-blind, placebo-controlled, randomized trial. Diabetes Obes Metab. 2011;13(3):281-284. (PubMed)

72. Castiglioni S, Cazzaniga A, Albisetti W, Maier JA. Magnesium and osteoporosis: current state of knowledge and future research directions. Nutrients. 2013;5(8):3022-3033. (PubMed)

73. Vormann J. Magnesium: Nutrition and Homeostasis. AIMS Public Health. 2016;3(2):329-340. (PubMed)

74. Sojka JE, Weaver CM. Magnesium supplementation and osteoporosis. Nutr Rev. 1995;53(3):71-74. (PubMed)

75. Zheng J, Mao X, Ling J, He Q, Quan J, Jiang H. Association between serum level of magnesium and postmenopausal osteoporosis: a meta-analysis. Biol Trace Elem Res. 2014;159(1-3):8-14. (PubMed)

76. Begin MJ, Ste-Marie LG, Coupal L, Ethier J, Rakel A. Hypomagnesemia during teriparatide treatment in osteoporosis: incidence and determinants. J Bone Miner Res. 2018;33(8):1444-1449. (PubMed)

77. Tucker KL, Hannan MT, Chen H, Cupples LA, Wilson PW, Kiel DP. Potassium, magnesium, and fruit and vegetable intakes are associated with greater bone mineral density in elderly men and women. Am J Clin Nutr. 1999;69(4):727-736. (PubMed)

78. Ryder KM, Shorr RI, Bush AJ, et al. Magnesium intake from food and supplements is associated with bone mineral density in healthy older white subjects. J Am Geriatr Soc. 2005;53(11):1875-1880. (PubMed)

79. Dahl C, Sogaard AJ, Tell GS, et al. Nationwide data on municipal drinking water and hip fracture: Could calcium and magnesium be protective? A NOREPOS study. Bone. 2013;57(1):84-91. (PubMed)

80. Orchard TS, Larson JC, Alghothani N, et al. Magnesium intake, bone mineral density, and fractures: results from the Women's Health Initiative observational study. Am J Clin Nutr. 2014;99(4):926-933. (PubMed)

81. Hayhoe RP, Lentjes MA, Luben RN, Khaw KT, Welch AA. Dietary magnesium and potassium intakes and circulating magnesium are associated with heel bone ultrasound attenuation and osteoporotic fracture risk in the EPIC-Norfolk cohort study. Am J Clin Nutr. 2015;102(2):376-384. (PubMed)

82. Stendig-Lindberg G, Tepper R, Leichter I. Trabecular bone density in a two year controlled trial of peroral magnesium in osteoporosis. Magnes Res. 1993;6(2):155-163. (PubMed)

83. Abraham GE, Grewal H. A total dietary program emphasizing magnesium instead of calcium. Effect on the mineral density of calcaneous bone in postmenopausal women on hormonal therapy. J Reprod Med. 1990;35(5):503-507. (PubMed)

84. Aydin H, Deyneli O, Yavuz D, et al. Short-term oral magnesium supplementation suppresses bone turnover in postmenopausal osteoporotic women. Biol Trace Elem Res. 2010;133(2):136-143. (PubMed)

85. Nieves JW. Bone. Maximizing bone health--magnesium, BMD and fractures. Nat Rev Endocrinol. 2014;10(5):255-256. (PubMed)

86. Landi F, Liperoti R, Russo A, et al. Sarcopenia as a risk factor for falls in elderly individuals: results from the ilSIRENTE study. Clin Nutr. 2012;31(5):652-658. (PubMed)

87. Hayhoe RPG, Lentjes MAH, Mulligan AA, Luben RN, Khaw KT, Welch AA. Cross-sectional associations of dietary and circulating magnesium with skeletal muscle mass in the EPIC-Norfolk cohort. Clin Nutr. 2019;38(1):317-323. (PubMed)

88. Scott D, Blizzard L, Fell J, Giles G, Jones G. Associations between dietary nutrient intake and muscle mass and strength in community-dwelling older adults: the Tasmanian Older Adult Cohort Study. J Am Geriatr Soc. 2010;58(11):2129-2134. (PubMed)

89. Welch AA, Kelaiditi E, Jennings A, Steves CJ, Spector TD, MacGregor A. Dietary magnesium is positively associated with skeletal muscle power and indices of muscle mass and may attenuate the association between circulating C-reactive protein and muscle mass in women. J Bone Miner Res. 2016;31(2):317-325. (PubMed)

90. Welch AA, Skinner J, Hickson M. Dietary magnesium may be protective for aging of bone and skeletal muscle in middle and younger older age men and women: cross-sectional findings from the UK Biobank cohort. Nutrients. 2017;9(11). (PubMed)

91. Veronese N, Berton L, Carraro S, et al. Effect of oral magnesium supplementation on physical performance in healthy elderly women involved in a weekly exercise program: a randomized controlled trial. Am J Clin Nutr. 2014;100(3):974-981. (PubMed)

92. Bibbins-Domingo K, Grossman DC, Curry SJ, et al. Screening for preeclampsia: US Preventive Services Task Force recommendation statement. JAMA. 2017;317(16):1661-1667. (PubMed)

93. Jeyabalan A. Epidemiology of preeclampsia: impact of obesity. Nutr Rev. 2013;71 Suppl 1:S18-25. (PubMed)

94. Duley L. The global impact of pre-eclampsia and eclampsia. Semin Perinatol. 2009;33(3):130-137. (PubMed)

95. Duley L, Henderson-Smart DJ, Chou D. Magnesium sulphate versus phenytoin for eclampsia. Cochrane Database Syst Rev. 2010(10):CD000128. (PubMed)

96. Makrides M, Crosby DD, Bain E, Crowther CA. Magnesium supplementation in pregnancy. Cochrane Database Syst Rev. 2014(4):Cd000937. (PubMed)

97. Sibai BM. Diagnosis, prevention, and management of eclampsia. Obstet Gynecol. 2005;105(2):402-410. (PubMed)

98. Altman D, Carroli G, Duley L, et al. Do women with pre-eclampsia, and their babies, benefit from magnesium sulphate? The Magpie Trial: a randomised placebo-controlled trial. Lancet. 2002;359(9321):1877-1890. (PubMed)

99. McDonald SD, Lutsiv O, Dzaja N, Duley L. A systematic review of maternal and infant outcomes following magnesium sulfate for pre-eclampsia/eclampsia in real-world use. Int J Gynaecol Obstet. 2012;118(2):90-96. (PubMed)

100. World Health Organization. WHO recommendations for prevention and treatment of pre-eclampsia and eclampsia. Implications and actions. Available at: http://www.who.int/reproductivehealth/publications/maternal_perinatal_health/program-action-eclampsia/en/. Accessed 10/9/18.

101. Berhan Y, Berhan A. Should magnesium sulfate be administered to women with mild pre-eclampsia? A systematic review of published reports on eclampsia. J Obstet Gynaecol Res. 2015;41(6):831-842. (PubMed)

102. Vigil-DeGracia P, Ludmir J, Ng J, et al. Is there benefit to continue magnesium sulphate postpartum in women receiving magnesium sulphate before delivery? A randomised controlled study. Bjog. 2018;125(10):1304-1311. (PubMed)

103. American College of Obstetricians and Gynecologists Committee. Committee opinion no. 573: magnesium sulfate use in obstetrics. Obstet Gynecol. 2013;122(3):727-728. (PubMed)

104. Roberts D, Brown J, Medley N, Dalziel SR. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev. 2017;3:Cd004454. (PubMed)

105. Crowther CA, Brown J, McKinlay CJ, Middleton P. Magnesium sulphate for preventing preterm birth in threatened preterm labour. Cochrane Database Syst Rev. 2014(8):Cd001060. (PubMed)

106. McNamara HC, Crowther CA, Brown J. Different treatment regimens of magnesium sulphate for tocolysis in women in preterm labour. Cochrane Database Syst Rev. 2015(12):Cd011200. (PubMed)

107. Wolf HT, Hegaard HK, Greisen G, Huusom L, Hedegaard M. Treatment with magnesium sulphate in pre-term birth: a systematic review and meta-analysis of observational studies. J Obstet Gynaecol. 2012;32(2):135-140. (PubMed)

108. Crowther CA, Middleton PF, Voysey M, et al. Assessing the neuroprotective benefits for babies of antenatal magnesium sulphate: An individual participant data meta-analysis. PLoS Med. 2017;14(10):e1002398. (PubMed)

109. Tagin M, Shah PS, Lee KS. Magnesium for newborns with hypoxic-ischemic encephalopathy: a systematic review and meta-analysis. J Perinatol. 2013;33(9):663-669. (PubMed)

110. Kass L, Weekes J, Carpenter L. Effect of magnesium supplementation on blood pressure: a meta-analysis. Eur J Clin Nutr. 2012;66(4):411-418. (PubMed)

111. Rosanoff A. Magnesium supplements may enhance the effect of antihypertensive medications in stage 1 hypertensive subjects. Magnes Res. 2010;23(1):27-40. (PubMed)

112. Zhang X, Li Y, Del Gobbo LC, et al. Effects of magnesium supplementation on blood pressure: a meta-analysis of randomized double-blind placebo-controlled trials. Hypertension. 2016;68(2):324-333. (PubMed)

113. Dibaba DT, Xun P, Song Y, Rosanoff A, Shechter M, He K. The effect of magnesium supplementation on blood pressure in individuals with insulin resistance, prediabetes, or noncommunicable chronic diseases: a meta-analysis of randomized controlled trials. Am J Clin Nutr. 2017;106(3):921-929. (PubMed)

114. Appel LJ, Moore TJ, Obarzanek E, et al. A clinical trial of the effects of dietary patterns on blood pressure. DASH Collaborative Research Group. N Engl J Med. 1997;336(16):1117-1124. (PubMed)

115. Maier JA. Endothelial cells and magnesium: implications in atherosclerosis. Clin Sci (Lond). 2012;122(9):397-407. (PubMed)

116. Darooghegi Mofrad M, Djafarian K, Mozaffari H, Shab-Bidar S. Effect of magnesium supplementation on endothelial function: A systematic review and meta-analysis of randomized controlled trials. Atherosclerosis. 2018;273:98-105. (PubMed)

117. Shechter M, Sharir M, Labrador MJ, Forrester J, Silver B, Bairey Merz CN. Oral magnesium therapy improves endothelial function in patients with coronary artery disease. Circulation. 2000;102(19):2353-2358. (PubMed)

118. Barbagallo M, Dominguez LJ, Galioto A, Pineo A, Belvedere M. Oral magnesium supplementation improves vascular function in elderly diabetic patients. Magnes Res. 2010;23(3):131-137. (PubMed)

119. Cunha AR, D'El-Rei J, Medeiros F, et al. Oral magnesium supplementation improves endothelial function and attenuates subclinical atherosclerosis in thiazide-treated hypertensive women. J Hypertens. 2017;35(1):89-97. (PubMed)

120. Mortazavi M, Moeinzadeh F, Saadatnia M, Shahidi S, McGee JC, Minagar A. Effect of magnesium supplementation on carotid intima-media thickness and flow-mediated dilatation among hemodialysis patients: a double-blind, randomized, placebo-controlled trial. Eur Neurol. 2013;69(5):309-316. (PubMed)

121. Cosaro E, Bonafini S, Montagnana M, et al. Effects of magnesium supplements on blood pressure, endothelial function and metabolic parameters in healthy young men with a family history of metabolic syndrome. Nutr Metab Cardiovasc Dis. 2014;24(11):1213-1220. (PubMed)

122. Joris PJ, Plat J, Bakker SJ, Mensink RP. Effects of long-term magnesium supplementation on endothelial function and cardiometabolic risk markers: A randomized controlled trial in overweight/obese adults. Sci Rep. 2017;7(1):106. (PubMed)

123. Mookadam F, Moustafa SE, Lester SJ, Warsame T. Subclinical atherosclerosis: evolving role of carotid intima-media thickness. Prev Cardiol. 2010;13(4):186-197. (PubMed)

124. Ma J, Folsom AR, Melnick SL, et al. Associations of serum and dietary magnesium with cardiovascular disease, hypertension, diabetes, insulin, and carotid arterial wall thickness: the ARIC study. Atherosclerosis Risk in Communities Study. J Clin Epidemiol. 1995;48(7):927-940. (PubMed)

125. Woods KL, Fletcher S, Roffe C, Haider Y. Intravenous magnesium sulphate in suspected acute myocardial infarction: results of the second Leicester Intravenous Magnesium Intervention Trial (LIMIT-2). Lancet. 1992;339(8809):1553-1558. (PubMed)

126. Woods KL, Fletcher S. Long-term outcome after intravenous magnesium sulphate in suspected acute myocardial infarction: the second Leicester Intravenous Magnesium Intervention Trial (LIMIT-2). Lancet. 1994;343(8901):816-819. (PubMed)

127. Fourth International Study of Infarct Survival (ISIS-4) Collaborative Group. A randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58,050 patients with suspected acute myocardial infarction. Lancet. 1995;345(8951):669-685. (PubMed)

128. Ziegelstein RC, Hilbe JM, French WJ, Antman EM, Chandra-Strobos N. Magnesium use in the treatment of acute myocardial infarction in the United States (observations from the Second National Registry of Myocardial Infarction). Am J Cardiol. 2001;87(1):7-10. (PubMed)

129. Li J, Zhang Q, Zhang M, Egger M. Intravenous magnesium for acute myocardial infarction. Cochrane Database Syst Rev. 2007(2):CD002755. (PubMed)

130. Pham PC, Pham PM, Pham SV, Miller JM, Pham PT. Hypomagnesemia in patients with type 2 diabetes. Clin J Am Soc Nephrol. 2007;2(2):366-373. (PubMed)

131. Takaya J, Higashino H, Kobayashi Y. Intracellular magnesium and insulin resistance. Magnes Res. 2004;17(2):126-136. (PubMed)

132. Yokota K, Kato M, Lister F, et al. Clinical efficacy of magnesium supplementation in patients with type 2 diabetes. J Am Coll Nutr. 2004;23(5):506S-509S. (PubMed)

133. Rodriguez-Moran M, Guerrero-Romero F. Oral magnesium supplementation improves insulin sensitivity and metabolic control in type 2 diabetic subjects: a randomized double-blind controlled trial. Diabetes Care. 2003;26(4):1147-1152. (PubMed)

134. Veronese N, Watutantrige-Fernando S, Luchini C, et al. Effect of magnesium supplementation on glucose metabolism in people with or at risk of diabetes: a systematic review and meta-analysis of double-blind randomized controlled trials. Eur J Clin Nutr. 2016;70(12):1354-1359. (PubMed)

135. Simental-Mendia LE, Sahebkar A, Rodriguez-Moran M, Guerrero-Romero F. A systematic review and meta-analysis of randomized controlled trials on the effects of magnesium supplementation on insulin sensitivity and glucose control. Pharmacol Res. 2016;111:272-282. (PubMed)

136. Hashimoto Y, Nishimura Y, Maeda H, Yokoyama M. Assessment of magnesium status in patients with bronchial asthma. J Asthma. 2000;37(6):489-496. (PubMed)

137. Irazuzta JE, Chiriboga N. Magnesium sulfate infusion for acute asthma in the emergency department. J Pediatr (Rio J). 2017;93 Suppl 1:19-25. (PubMed)

138. Su Z, Li R, Gai Z. Intravenous and nebulized magnesium sulfate for treating acute asthma in children: a systematic review and meta-analysis. Pediatr Emerg Care. 2018;34(6):390-395. (PubMed)

139. Kew KM, Kirtchuk L, Michell CI. Intravenous magnesium sulfate for treating adults with acute asthma in the emergency department. Cochrane Database Syst Rev. 2014(5):Cd010909. (PubMed)

140. Knightly R, Milan SJ, Hughes R, et al. Inhaled magnesium sulfate in the treatment of acute asthma. Cochrane Database Syst Rev. 2017;11:Cd003898. (PubMed)

141. Monteleone CA, Sherman AR. Nutrition and asthma. Arch Intern Med. 1997;157(1):23-34. (PubMed)

142. Beasley R, Aldington S. Magnesium in the treatment of asthma. Curr Opin Allergy Clin Immunol. 2007;7(1):107-110. (PubMed)

143. Fogarty A, Lewis SA, Scrivener SL, et al. Oral magnesium and vitamin C supplements in asthma: a parallel group randomized placebo-controlled trial. Clin Exp Allergy. 2003;33(10):1355-1359. (PubMed)

144. Na HS, Ryu JH, Do SH. The role of magnesium in pain. In: Vink R, Nechifor M, eds. Magnesium in the Central Nervous System. Adelaide (AU): University of Adelaide Press; 2011. (PubMed)

145. Wang SC, Pan PT, Chiu HY, Huang CJ. Neuraxial magnesium sulfate improves postoperative analgesia in Cesarean section delivery women: A meta-analysis of randomized controlled trials. Asian J Anesthesiol. 2017;55(3):56-67. (PubMed)

146. Xiao F, Xu W, Feng Y, et al. Intrathecal magnesium sulfate does not reduce the ED50 of intrathecal hyperbaric bupivacaine for cesarean delivery in healthy parturients: a prospective, double blinded, randomized dose-response trial using the sequential allocation method. BMC Anesthesiol. 2017;17(1):8. (PubMed)

147. Paleti S, Prasad PK, Lakshmi BS. A randomized clinical trial of intrathecal magnesium sulfate versus midazolam with epidural administration of 0.75% ropivacaine for patients with preeclampsia scheduled for elective cesarean section. J Anaesthesiol Clin Pharmacol. 2018;34(1):23-28. (PubMed)

148. Vlok R, Melhuish TM, Chong C, Ryan T, White LD. Adjuncts to local anaesthetics in tonsillectomy: a systematic review and meta-analysis. J Anesth. 2017;31(4):608-616. (PubMed)

149. Cho HK, Park IJ, Yoon HY, Hwang SH. Efficacy of adjuvant magnesium for posttonsillectomy morbidity in children: a meta-analysis. Otolaryngol Head Neck Surg. 2018;158(1):27-35. (PubMed)

150. Xie M, Li XK, Peng Y. Magnesium sulfate for postoperative complications in children undergoing tonsillectomies: a systematic review and meta-analysis. J Evid Based Med. 2017;10(1):16-25. (PubMed)

151. Chen C, Tao R. The impact of magnesium sulfate on pain control after laparoscopic cholecystectomy: a meta-analysis of randomized controlled studies. Surg Laparosc Endosc Percutan Tech. 2018;28(6):349-353. (PubMed)

152. Abd-Elsalam KA, Fares KM, Mohamed MA, Mohamed MF, El-Rahman AMA, Tohamy MM. Efficacy of magnesium sulfate added to local anesthetic in a transversus abdominis plane block for analgesia following total abdominal hysterectomy: a randomized trial. Pain Physician. 2017;20(7):641-647. (PubMed)

153. Imani F, Rahimzadeh P, Faiz HR, Abdullahzadeh-Baghaei A. An evaluation of the adding magnesium sulfate to ropivacaine on ultrasound-guided transverse abdominis plane block after abdominal hysterectomy. Anesth Pain Med. 2018;8(4):e74124. (PubMed)

154. Martin DP, Samora WP, 3rd, Beebe AC, et al. Analgesic effects of methadone and magnesium following posterior spinal fusion for idiopathic scoliosis in adolescents: a randomized controlled trial. J Anesth. 2018;32(5):702-708. (PubMed)

155. Srivastava VK, Mishra A, Agrawal S, Kumar S, Sharma S, Kumar R. Comparative evaluation of dexmedetomidine and magnesium sulphate on propofol consumption, haemodynamics and postoperative recovery in spine surgery: a prospective, randomized, placebo controlled, double-blind study. Adv Pharm Bull. 2016;6(1):75-81. (PubMed)

156. Hamed MA. Comparative study between magnesium sulfate and lidocaine for controlled hypotension during functional endoscopic sinus surgery: a randomized controlled study. Anesth Essays Res. 2018;12(3):715-718. (PubMed)

157. Hassan PF, Saleh AH. Dexmedetomidine versus magnesium sulfate in anesthesia for cochlear implantation surgery in pediatric patients. Anesth Essays Res. 2017;11(4):1064-1069. (PubMed)

158. Brill S, Sedgwick PM, Hamann W, Di Vadi PP. Efficacy of intravenous magnesium in neuropathic pain. Br J Anaesth. 2002;89(5):711-714. (PubMed)

159. Tanaka M, Shimizu S, Nishimura W, et al. Relief of neuropathic pain with intravenous magnesium [Article in Japanese]. Masui. 1998;47(9):1109-1113. (PubMed)

160. Pickering G, Morel V, Simen E, et al. Oral magnesium treatment in patients with neuropathic pain: a randomized clinical trial. Magnes Res. 2011;24(2):28-35. (PubMed)

161. Delage N, Morel V, Picard P, Marcaillou F, Pereira B, Pickering G. Effect of ketamine combined with magnesium sulfate in neuropathic pain patients (KETAPAIN): study protocol for a randomized controlled trial. Trials. 2017;18(1):517. (PubMed)

162. Mauskop A, Altura BM. Role of magnesium in the pathogenesis and treatment of migraines. Clin Neurosci. 1998;5(1):24-27. (PubMed)

163. Mauskop A, Altura BT, Altura BM. Serum ionized magnesium levels and serum ionized calcium/ionized magnesium ratios in women with menstrual migraine. Headache. 2002;42(4):242-248. (PubMed)

164. Peikert A, Wilimzig C, Kohne-Volland R. Prophylaxis of migraine with oral magnesium: results from a prospective, multi-center, placebo-controlled and double-blind randomized study. Ceph