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Magnesium

Mg24.305

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Atomic Numer

12 282

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THE ROLE OF MAGNESIUM IN CLINICAL PRACTICE:Benefits Supported By Research

Author: Petra Hunter, ND BHSc (Nat) Editor: Michelle Batson, ND

Advanced Clinical InsightsBioCeuticals Copyright 2005

2INTRODUCTIONMagnesium is an essential mineral in human health where it is involved in a wide range of biologicalfunctions, including energy production, nucleic acid and protein synthesis, electrolyte balance, maintenance of cell membrane integrity, regulation of muscle contraction and relaxation, nerve conduction and the regulation of vascular tone.

Total body stores of magnesium are estimated to be between 21-28 g in the average adult.1 The mineral is distributed principally between bone (53%), muscle (27%) and other soft tissues (19%).2 Lessthan 1% is found in serum and red blood cells.2

Magnesium deficiency has been implicated in numerous disease states, including cardiovascular disease, diabetes, obstetric complications, osteoporosis, migraines, and neurological and muscularproblems.

DEFICIENCY CAUSES AND CLINICAL MANIFESTATIONS

FACTORS THAT MAY CAUSE MAGNESIUM DEFICIENCY 2 Reduced dietary intake Poor gastrointestinal absorption or increased gastrointestinal losses (due to diarrhoea, vomit-

ing, or laxative use) Increased renal losses (including diabetes and alcoholism) Drug induced (please see drugs & interactions section for more information) Increased requirements (such as in pregnancy and growth) Excessive sweating

CLINICAL MANIFESTATIONSMagnesium deficiency, unless it is severe, is usually asymptomatic.1 However, it should be kept inmind that the serum level of magnesium (the common way of testing for a magnesium deficiency) is only low in a severe deficiency state, as the body preserves serum levels at the expense of magnesium in cells and bone. For this reason, serum level may appear normal on testing, but a mildto moderate deficiency state may be present. If a test is performed, the recommended screeningmethod is for red blood cell magnesium level.

Symptoms, when they do occur, include cardiovascular effects such as hypertension, arrhythmias, ventricular tachycardia, and coronary and cerebral vasospasms; neurological effects including dizziness, vertigo, seizures, tremors, ataxia, confusion, delirium, personality changes, depression andcoma; and systemic effects such as generalised muscle spasticity, muscular cramping, anorexia, nausea, vomiting, hyperglycaemia, and hypercholesterolaemia.1,3

SOURCES OF MAGNESIUMDIETARYCommon dietary sources of magnesium include cereals, legumes, nuts and green leafy vegetables.1,2

Food processing may lead to a severe depletion of the mineral, leaving only 3-28% of the original content.2 It has been estimated that magnesium intake has declined by more than half during this century.2 Meat, fish, dairy and fruits are quite low in magnesium.

SUPPLEMENTALMagnesium supplements are available in numerous salt forms as well as amino acid chelates; theseinclude magnesium carbonate, magnesium chloride, magnesium citrate, magnesium oxide, magnesiumphosphate, magnesium sulfate, and magnesium diglycinate. Magnesium hydroxide is used as an ingredient in a number of antacids, including Mylanta.

The absorption rate and tolerability may vary greatly between the different supplementalforms. 6,7

Studies done onyoung students andolder adults indicatethat a significantnumber ofAustralians fail to meet the recommended daily intake of magnesium.4,5

It has been established that magnesium intakehas declined by more than half during this century;primarily due to food processing.2

PHARMACOKINETICSAbsorption of magnesium occurs primarily from the ileum and colon.2 The efficiency of absorption ofa magnesium salt appears to largely depend on its solubility in intestinal fluids, as well as on theamount ingested.3 Salts with a high solubility, such as magnesium citrate, appear to be better absorbedthan salts with poor solubility, such as magnesium oxide.3

Magnesium in its inorganic state (simple salt) is absorbed only to the extent of about 5-10%.6 Inorganicminerals must be altered from their natural state before they can penetrate the intestinal barrier. The most efficient way to achieve this goal is by coating them with amino acids.6 This process whichforms a complex composed of the mineral and the amino acid is called chelation. As the amino acidsurrounds the mineral, it neutralises its positive charge shielding it from the attraction of the intestinalwall, which has a strong negative charge and would otherwise bind the mineral, denying it passageinto the blood stream.6

Moreover, the chelation of magnesium to an amino acid allows the mineral to be absorbed, at least inpart, like an amino acid, resulting in faster and more efficient absorption.

The diglycinate chelate (a covalently bonded dipeptide chelate) is a superior form of magnesium chelate supplementation that has been designed for maximum absorption andtolerance.

The results of in vitro and in situ studies show that magnesium diglycinate represents a highlyavailable form of magnesium that is absorbed in part as an intact dipeptide.7

Even in individuals with known malabsorption, magnesium diglycinate absorption has beenshown to be substantially greater than inorganic magnesium salts and is better tolerated.7

The exact mechanism of magnesium absorption (not absorbed as an amino acid) is not fully understood. However, it is thought that the mineral is absorbed by an active transport mechanism aswell as by passive diffusion across the intestinal mucosa.8 It is possible that the active transport system may account for greater magnesium absorption at a lower dietary intake, while absorption athigh dietary intakes may continue due to the passive absorption component.8 Excretion occurs via thekidneys.2

MECHANISMS OF ACTIONMagnesium is involved in more than 300 enzyme systems and has a fundamental role to play in energymetabolism and nucleic acid synthesis. It is also essential for the regulation of ion movements acrosscell membranes, maintaining nerve and muscle electrical potentials and transmitting impulses acrossneuromuscular junctions.

ENERGY PRODUCTION Magnesium serves as a cofactor for many intracellular enzymes that are part of mitochondrial energyproduction. The mineral is heavily involved in the synthesis and function of the universal energy-carrying molecule adenosine triphosphate (ATP), and plays a critical role in the control of glycolysisand the Krebs cycle.2, 9 *Please see diagram on page 4

In addition, magnesium plays an important role in the integrity of the mitochondrial membrane. A deficiency state is associated with swelling and disruption of mitochondrial cristae and a reducednumber of mitochondria per cell.9 A magnesium deficiency is also associated with increased permeability and decreased selectivity of mitochondrial inner membrane and uncoupling of oxidativephosphorylation.9

In addition to magnesium, nutrients such as malic acid and several of the B vitamins are alsoessential in the respiratory chain involved in ATP synthesis.9

SYNTHESIS OF ESSENTIAL MOLECULES The presence of magnesium is important to maintain an adequate supply of nucleotides

required for the increased DNA and RNA synthesis that occurs during cell proliferation.10

Replicating cells must be able to synthesise new protein and this process is highly sensitive tomagnesium depletion.10 3

Several types of supplemental magnesium are poorly tolerated attherapeutic doses due to the mineralscathartic effect.7This problem can beovercome by usingthe diglycinate form.

Many hormones and neurotransmitters exert their effects on cellular activity via the adenylatecyclase (also known as cyclic AMP synthetase) system.10 The presence of magnesium isrequired to activate this enzyme.10

Magnesium also facilitates the endogenous synthesis of glutathione.11,12 Magnesium deficiencymay rapidly reduce cellular glutathione levels.12

ION TRANSPORT ACROSS CELL MEMBRANES The co-existence of secondary electrolyte abnormalities plays a key role in the clinical manifestationsof magnesium deficiency. Magnesium appears to influence the properties of various cell membranes;a process that is thought to occur by means of calcium channels and ion transport mechanisms.1

Through its role in ion transport systems, magnesium affects the conduction of nerve impulses, muscle contraction, and the normal rhythm of the heart.11

Calcium and magnesium connectionMagnesium has been referred to as natures physiological calcium channel blocker. During magnesium depletion, intracellular calcium levels raise.10 Calcium plays an important role in skeletaland smooth muscle contraction; hence a state of magnesium depletion may result in muscle cramps,hypertension, and coronary and cerebral vasospasms.10

Sodium, potassium and magnesium connectionMagnesium is also responsible for the maintenance of transmembrane gradients of sodium and potassium by regulating sodium/potassium-ATPase activity. The arrhythmogenic effect of magnesiumdeficiency may be related to magnesiums role in maintaining intracellular potassium.10 Higher intracellular sodium levels may be the cause of hypertension.1

STRUCTURAL ROLESMagnesium plays a structural role in bone, cell membranes, and chromosomes.114

Clinical observationssupport the view that uncorrectedmagnesium deficiency impairsrepletion of cellularpotassium.13,14For this reason,patients with refractoryhypokalaemia maynot respond to potassium supplementation until magnesium deficiency is corrected. Magnesium deficiencyshould be consideredwhenever severepotassium deficiencyis encountered.13

KREBS (CITRIC ACID) CYCLE

GLYCOLYSIS

Glycogen

Glucose 1-phoshate Glucose

Glucose 6-phosohate

Fructose 6-phosphate

Fructose 1,6-bisphosphate

Dihydroxyacetone phosphate Glyceraldehyde 3-phosphate

1,3-Bisphosphoglycerate

3-Phosphoglycerate

2-Phosphoglycerate

Phosphoenolpyruvate

PyruvateLactate

Acetyl-CoA

Oxaloacetale Citrate

Malate

Fumarate

Isocitrate

2-Oxoglutarate

Succinate Succinyl-CoA

Mg Mg

Mg

Mg

Mg

Mg

Mg

Mg

Mg

Mg

Mg

Mg

Figure adapted from Abraham, 1992 (Reference 9)

EFFECTS OF MAGNESIUM: BENEFITS SUPPORTED BY RESEARCH

Supplemental magnesium has been reported to be beneficial in a wide range of medical conditions, including:

Asthma, COPD Cardiovascular Disease

- Angina/ Coronary Artery Disease- Arrhythmias- Congestive Heart Failure- Hypertension - Myocardial Infarction & Ischaemic Heart Disease- Stroke/ TIA

Behavioural Problems Chronic Fatigue Syndrome & Fibromyalgia Dysglycaemia

- Magnesium & Metabolic Syndrome- Magnesium Deficiency & Insulin Resistance in Obese Children- Synergistic Effects of Chromium

Glaucoma Hearing Loss Migraine Muscular Complaints

- Cramps- Restless Leg Syndrome- Intermittent Claudication- Physical Endurance

Osteoporosis Pain Pregnancy Complications & Infant Health

- Pre-eclampsia (toxaemia)/ eclampsia- SIDS

Premenstrual Syndrome (PMS) Stress

CLINICAL APPLICATIONSASTHMAAsthma is a chronic inflammatory disorder of the airways leading to airflow limitation. A decrease inblood and tissue magnesium levels is frequently reported in asthma sufferers.15 Several different formsof magnesium administration have been shown to be beneficial in the management of the asthmatic patient:

A review of randomised controlled clinical trials shows that the use of nebulised magnesium sulfate,particularly if used in addition to a beta(2)-antagonist in the treatment of an acute asthma exacerbation, may improve pulmonary function and reduce the number of hospital admissions.16

Intravenous (IV) magnesium sulfate, which relaxes smooth muscle resulting in bronchodilation,is considered adjunctive therapy for severe asthma in patients with poor response to beta(2)-antagonists.17 Global Initiative for Asthma (GINA) guidelines confirms the use of IV magnesiumsulfate for hospital management of severe episodes of asthma exacerbation.17

Magnesium is thought to inhibit airway smooth muscle contraction by inhibiting calcium influxvia the voltage-dependent calcium channels.18

A multicentre (emergency departments of eight hospitals) randomised controlled trial showedthat the administration of IV magnesium sulfate improves pulmonary function when used as anadjunct to standard therapy in patients with very severe acute asthma.19

Oral magnesium supplementation is beneficial in mild to moderate asthma and is recommendedas a concomitant treatment in patients with a stable condition.20

A randomised, double-blind, placebo-controlled prospective study of 89 children withmild or moderate persistent bronchial asthma, showed that oral magnesium supplementation (200- 290mg magnesium citrate daily for 12 weeks) may significantlylower the need for bronchodilator use compared to placebo.20 5

Oral magnesium supplementation maysignificantly lowerthe need for bronchodilator use in those with mild tomoderate asthma.20

It has been well documented that experimental hypomagnesaemia in animals evokes, as an early consequence, an inflammatory response.21 This also leads to an increased production of reactive oxygen species resulting in oxidative damage of tissues.21 Several studies have shown that lungs mightbe a specific target of magnesium deficiency.Researchers speculate that this may have implications for at least several different lung pathologies,including allergies, asthma, SIDS (Sudden Infant Death Syndrome) or facilitate formation of lungmetastases.21

CARDIOVASCULAR DISEASEThe term cardiovascular disease (CVD) refers to all heart disease, cerebrovascular disease, and diseasesof the arteries, arterioles and capillaries. According to the Australian Institute of Health and Welfare,heart, stroke and vascular diseases kill more Australians than any other disease group. In 2002, theseconditions accounted for 37.6% of all deaths (a total of more than 50,000 deaths).22

As mentioned under the mechanisms of action section, magnesium exerts numerous effects on thecardiovascular system through its role in the ion transport systems, including regulation of normalheart rhythm and blood pressure. By regulating intracellular calcium levels, magnesium also plays animportant role in smooth muscle contraction and hence coronary and cerebral vasospasms.

Actions noted by magnesium supplementation supportive to cardiovascular health include improvedmyocardial metabolism, inhibition of calcium accumulation and myocardial cell death; improvementof vascular tone, peripheral vascular resistance, afterload and cardiac output; reduced cardiac arrhythmias; and improvement of lipid metabolism.23 Magnesium also reduces vulnerability to oxygen-derived free radicals, improves endothelial function and inhibits platelet aggregation and adhesion.23

Epidemiologic studies have shown an inverse relationship between magnesium levels indrinking water and the frequency of cardiac events and cardiovascular mortality.24,25 Onestudy of more than 15,000 individuals indicates that low serum and dietary magnesium maybe related to the aetiologies of several cardiovascular disorders, including hypertension andatherosclerosis.26

ANGINA/ CORONARY ARTERY DISEASEAngina (angina pectoris) is a type of transient chest pain/pressure/or discomfort that occurs when theheart is not getting enough oxygen-rich blood supply. The most common underlying cause of anginais coronary artery disease (CAD). CAD is a chronic condition in which there is a build up of plaqueon the coronary arteries, causing a gradual hardening and narrowing (atherosclerosis) of these bloodvessels.

Magnesium deficiency has been shown to trigger vasoconstriction and enhance vascularendothelial injury, thus promoting the development and progression of atherosclerosis.27

Additionally, an experimentally induced low plasma level of magnesium has been noted toaccelerate atherogenesis by increasing LDL concentrations and their oxidative modifications,and by promoting inflammation.28

A 10-year study of 400 high-risk subjects predisposed to CAD found that magnesium may beimportant in the pathogenesis of coronary heart disease and sudden death.29

Oral magnesium therapy has been shown to improve endothelial function in patients CAD.28,30

Angina may also be caused by spasm of a coronary artery; a condition known as variant angina. Thistype of angina usually responds well to magnesium supplementation; some reports even suggest thatmagnesium is the treatment of choice for this condition.31

Japanese researchers have demonstrated that the degree of intracellular magnesium deficiencyin female patients with variant angina is closely related to the frequency of chest pain.32

An earlier study also found the magnesium status of patients with variant angina to be closelyrelated to disease activity.33

ARRHYTHMIASArrhythmia is a condition of abnormal heartbeat. There are two major types of arrhythmias; tachycardia(the heart beats too fast) and bradycardia (the heart beats too slow). Arrhythmias can be life-threateningif they cause a severe decrease in the pumping function of the heart.

Arrhythmias are generally classified by the location in the heart that they occur (atria or ventricles).Arrhythmias that start in the atria are referred to as atrial or supraventricular (above the ventricles)arrhythmias. Ventricular arrhythmias begin in the ventricles. 6

It has been shownthat the degree of magnesium deficiency is closelyrelated to the frequency of chestpain in patients with variant angina.32

Numerous clinical studies show that magnesium may be of benefit in several types of arrhythmias. It is considered a first-line agent for torsades de pointes (a type of ventriculartachycardia).34

Atrial fibrillation (AF) is one of the most common complications after coronary artery bypasssurgery.35 A recent meta-analysis of eight randomised controlled trials showed that magnesiumis associated with a significant reduction in the incidence of AF in these patients.35

Another meta-analysis of 17 randomised controlled trials noted that prophylactically administered magnesium reduced the risk of supraventricular arrhythmias after cardiac surgery by 23% (AF by 29%) and of ventricular arrhythmias by 48%.36

In experimental models, magnesium deficiency results in a number of electrocardiographic alterations,as well as changes in automaticity and conduction.1 Among the electrocardiographic changes are prolonged PR interval and QT interval, premature atrial complexes, atrial tachycardia, and fibrillation.1

A probable mechanism by which magnesium acts is by slowing inward calcium current block, thusdecreasing sinus node rate, prolonging AV conduction time and increasing AV node refractorinesswithout major changes in ventricular physiology.2 Magnesium depletion within the heart muscle alsoleads to potassium depletion,31 which in its own right may lead to cardiac arrhythmias.

Potassium and magnesium deficiencies have been linked in clinical studies to an increased frequency in serious arrhythmias and mortality in acute myocardial infarction.37 Magnesiumrepletion has been shown to increase both magnesium and potassium levels and to decreasethe frequency of ventricular ectopic beats.37

CONGESTIVE HEART FAILURECongestive heart failure (CHF) is the inability of the heart to pump a sufficient amount of bloodthroughout the body. Signs and symptoms of heart failure may include pulmonary and peripheraloedema, shortness of breath, exertion, and fatigue.

Magnesium deficiency and other electrolyte abnormalities are common in patients with CHF.38 Lowserum magnesium concentrations are associated with frequent arrhythmias and high mortality in theseindividuals.39 Since magnesium depletion is prevalent in CHF and magnesium has anti-arrhythmic andbeneficial cardiovascular effects, magnesium supplementation should be considered in the patientssuspected to be deficient.38

In addition, common conventional therapies for heart failure (such as digoxin, diuretics, and vasodilators)are influenced by, or associated with, significant alteration in magnesium balance.40 In patients withCHF, the presence of an adequate magnesium store serve as an important prognostic indicator, notonly because of an amelioration of arrhythmias, but also due to digitalis toxicity (see under drug/nutrient interactions) and haemodynamic abnormalities.40

HYPERTENSIONNumerous studies indicate that magnesium may help lower elevated blood pressure and possibly evenhave a preventative effect.42 The mechanisms involved include its regulatory effects on the cellularplacement of cations important to blood pressure (sodium, potassium and calcium) and its relaxanteffect on vascular smooth muscle.43

A meta-analysis of 20 randomised trials detected a dose-dependent reduction of blood pressurefrom magnesium supplementation.44

A Japanese study of 17 patients with untreated, uncomplicated mild-moderate hypertensionshowed that oral magnesium supplementation (600mg elemental magnesium; taken for a period of two weeks) can be a useful approach to treat patients with uncomplicated essential hypertension.45

A four week study of 21 patients receiving oral magnesium supplementation (same dose as above) also supports the findings that oral magnesium intake may be effective in the management of essential hypertension.46 The researchers of this trial also noted that magnesiummay reduce serum lipid concentration.

In a double-blind controlled trial, 91 middle-aged and elderly women with mild-moderatehypertension who were not on antihypertensive medication were randomly assigned to treatment with magnesium aspartate-HCl (20 mmol Mg/d) or placebo for 6 months. The resultsof the study suggest that oral supplementation with magnesium may lower blood pressure insubjects with mild to moderate hypertension.47 7

Magnesium deficiency is one of the most frequentserum electrolyteabnormalities seen in clinical practice.41

Failure to respond to conventional treatment of recurrentventricular tachycardia or fibrillation in patientswith CHF or acutemyocardial infarctionshould alert the clinician to consideradministering magnesium.41

15 patients with uncomplicated mild-moderate primary hypertension were submitted to a double-blind randomised crossover study, receiving either 600mg elemental magnesium perday (in three divided doses) or placebo for a period of 6 weeks. Even though the results werenot homogenous, those who benefited from the treatment noted significantly reduced systolic,diastolic, and mean blood pressures.48 40% of subjects had their blood pressure effectively controlled (10 mmHg reduction in mean blood pressure).

60 patients with office blood pressure >140/90 mm Hg were assigned to an 8-week magnesium supplementation period or an 8-week control period in a randomised crossovertrial.49 The subjects were given 20mmol/d magnesium in the form of magnesium oxide during the intervention period. Results were measured for office, home and ambulatoryblood pressures. All of these parameters were significantly lower in the supplementationperiod than in the control period. The results also indicated that the blood pressure lowering effects of magnesium supplementation is greater in subjects with higher blood pressure.

Unfortunately, the results of clinical studies are inconsistent.1 Some of the negative clinical trials formagnesium replacement did have patients on low salt diets.1 The hypotensive effect of a rigorouslyfollowed low-salt diet decreases the need for magnesium supplementation to improve blood pressure- even in the face of magnesium deficiency.

MYOCARDIAL INFARCTION AND ISCHAEMIC HEART DISEASE

Myocardial infarction, also commonly referred to as a heart attack, is an event in which one of thecoronary arteries becomes blocked, usually by a blood clot, resulting in damage to the heart muscle(myocardium). The outcome of this event depends on the extent of the tissue damage and on the treatment that is given within a short time of the attack.

Evidence suggests that acute myocardial infarction (AMI) is associated with low magnesium levels.50

Because trials have reported varying results, analysis of the literature suggests that successful supplementation in patients with AMI is dependent on correct timing of administration.50

Two large randomised and controlled trials led to different conclusions about whether magnesiumtherapy is beneficial in AMI:

The LIMIT-2 study of 1992 found a 24% reduction in 28-day mortality and a 25% reduction inheart failure during the first month after an AMI in the magnesium treated group.50,51 Theseresults led to the conclusion that the efficacy of IV magnesium administration is comparable tothat of thrombolytic or antiplatelet therapy in reducing early mortality of AMI.

However, the ISIS-4 study found no differences in the mortality rate in any subgroups of thepatients (the elderly, those at risk for magnesium depletion, and those receiving thrombolyticor antiplatelet drugs).50,52

The chief difference in the methodology between the two trials was that magnesium was started concurrently with reperfusion therapy in LIMIT-2, but after reperfusion therapy in ISIS-4. Animal studies have shown that magnesium is protective only if present before or at the time of reperfusion.53

Eight early randomised trials, involving nearly 1000 patients, suggested that magnesium supplementation reduced mortality by as much as 50%.50

A study of 7172 men examined the relationship between magnesium intake and future risk of coronary heart disease (CHD). The investigators found that within 15 years after dietaryassessment higher intakes of dietary magnesium is associated with less risk of CHD.54

The age-adjusted incidence decreased significantly from 7.3 to 4.0 per 1,000 person-years in the lowest (50.3-186 mg/day) versus highest (340-1183 mg/day) quintiles of magnesiumintake.

STROKE/ TRANSIENT ISCHAEMIC ATTACKA stroke, also known as a cerebrovascular accident, is a life-threatening event in which part of thebrain is deprived of adequate oxygen. There are two main types of stroke; ischaemic and haemorrhagic.Ischaemic stroke occurs when the blood supply to the brain is interrupted, commonly by a blood clot.Haemorrhagic stroke occurs when there is bleeding into or around the brain.

A transient ischaemic attack (TIA) is the result of a temporary interruption of blood flow to the brain;the condition is sometimes also called mini-stroke.8

The success of magnesium supplementation inan acute myocardialinfarction is dependent on thecorrect timing ofadministration.50Magnesium has beendemonstrated to be protective only ifpresent before or at the time of reperfusion.53

Magnesium is involved in multiple physiological processes that may be relevant to cerebral ischaemia.It may act as a neuroprotective agent through its vascular effects (increasing blood flow to ischaemictissue, anticonstrictor effects against vascular mediators, vasodilatation of the cerebral circulation) orexert neuronal effects. Neuronal effects include block of the NMDA receptor ion channel, calciumantagonism at voltage-gated channels, and enhanced regeneration of adenosine triphosphate.55

Significant neuroprotection with magnesium has been observed in different models of focalcerebral ischaemia, with infarct volume reductions between 25-61%.56

One study on the prognostic impact of magnesium serum levels with respect to the occurrenceof neurological events in patients with advanced atherosclerosis showed that individuals in the lowest tertile of magnesium serum levels exhibited a 3.29-fold increased adjusted risk forneurological events compared to those in the highest tertile.57

Intravenous magnesium sulfate has been shown to have a significant positive effect on the outcome in patients with acute stroke.58

Elevated homocysteine levels are considered a risk factor for cardiovascular disease. It has been suggested that an increased serum homocysteine concentration causes abnormal metabolism of magnesium in cerebral vascular smooth muscle cells, thus priming these cells for homocysteine-induced atherogenesis, cerebral vasospasm and stroke.59 Research indicates that vitaminsB6, B12 and folic acid may act in synergy with magnesium in occlusive cerebral vascular diseasesinduced by elevated homocysteine levels.59 Homocysteine has been noted to cause a dose-dependentloss of magnesium in cultured cerebral vascular smooth muscle cells.59

BEHAVIOUR PROBLEMSMagnesium deficiency occurs more frequently in children with attention deficit hyperactivity disorder(ADHD) than in healthy controls.

Researchers studied 116 children aged 9-12 years with recognised ADHD for blood serum, redblood cell, and hair levels of magnesium. A deficiency was found in 95% of the subjects.61

In a recent trial, a combination of magnesium and vitamin B6 was shown to reduce the symptoms of hyperexcitability (including physical aggressiveness, instability, and scholarattention) in all study participants (52 children) after 1-6 months of treatment.62

50 children (7-12 years) with diagnosed ADHD who had low magnesium (determined byserum, red blood cell, and hair levels) were given standard treatment together with 200mg ofmagnesium per day for six months. A further 25 magnesium deficient children with ADHD,receiving standard therapy without magnesium, served as a control. Compared to their clinicalstate before supplementation and the control group, the children in the magnesium supplemented group showed a significant decrease in hyperactivity. At the same time,among the children given standard treatment alone, hyperactivity was intensified.63,64

It has also been suggested that magnesium deficiency may play a central role in Tourettes syndromeand comorbid conditions.65

Magnesium, together with vitamin B6, may also be beneficial for autistic patients. While nocure for autism is known, magnesium and B6 supplementation has led to remarkableimprovement in many cases.66 9

Clinical studies showthat oral magnesiumsupplementation maybe of great benefit inchildren withADHD.62,63,64,64

Supplementation with magnesium andvitamin B6 has alsoled to remarkableimprovements inautistic patients.66

SYNERGISTIC EFFECTS OF TAURINE IN CARDIOVASCULAR HEALTHSeveral studies indicate that taurine is an effective therapeutic tool in the management of varioustypes of CVD:60

Taurine assists in the regulation of intracellular calcium levels, thereby protecting the heart from intracellular calcium imbalances, which can lead to cell death and subsequentmyocardial damage;

Taurine may also prevent cardiac arrhythmias by regulating potassium flux in and out of cardiac muscle cells;

Due to its positive inotropic effects, taurine is also capable of lowering blood pressure;

Taurine may improve the clinical manifestations of CHF, including the severity of dyspnoea,palpitations, and oedema, as well as increase exercise capacity in these patients.

CHRONIC FATIGUE SYNDROME & FIBROMYALGIADespite considerable efforts by scientists worldwide, no single aetiology has been identified to explainthe occurrence of chronic fatigue syndrome (CFS). However, a review of literature suggests that a number of marginal nutritional deficiencies may have aetiological relevance.67 These include deficiencies of various B vitamins, vitamin C, magnesium, sodium, zinc, coenzyme Q10, essential fattyacids, and amino acids such as L-carnitine and L-tryptophan.67

Although findings have been mixed, several studies have found lower erythrocyte magnesium levelsin CFS patients than in controls.67,68

32 patients with CFS were randomly allocated to receive either intramuscular magnesium sulfate (n=15) or placebo (n=17) for a period of six weeks.68 At the end of the study, 12 of the15 patients treated with magnesium reported to have improved energy levels, better emotional state and less pain. In contrast, only three of the 17 placebo patients saidthey felt better and only one reported improved energy levels.

This study confirms results obtained in clinical trials already during the 1960s.31 These studiesused oral magnesium and potassium (1 g of each) rather than the injectable form. Out ofalmost 3,000 patients studied, 75-91% experienced relief during treatment, in contrastto only 9-26% of those taking placebo.

When fibromyalgia is a substantial component of the clinical picture, magnesium supplementation may be combined with malic acid. Malate also plays an important role in energy metabolism; specifically the generation of mitochondrial ATP, which may be reduced in thesepatients.9,67

In an open-label trial, patients with primary fibromyalgia were treated orally for an average of eight weeks with 200-600 mg magnesium and 1200-2400mg malate daily.67,69 The subjectsexhibited a significant decrease in mean tender point index from 19.6 to 6.5. However, onlytwo days after six of the 15 patients were switched to placebo, they reported a worsening inmuscle pain. After two weeks, their mean tender point index had risen to 21.5.

DYSGLYCAEMIAMagnesium is known to play a major role in the secretion and effect of insulin. Supplementation withmagnesium has been noted to improve insulin response and action, as well as glucose tolerance.Several studies in patients with blood sugar problems have shown this mineral to be of significant clinical value.

MAGNESIUM & THE METABOLIC SYNDROME

A strong relationship between decreased serum magnesium and the metabolic syndrome has beenestablished.70 Key features of the metabolic syndrome include abdominal obesity, raised triglycerides,reduced HDL cholesterol, raised blood pressure, and raised fasting plasma glucose level. It was recently estimated that 20-25% of Australian adults have the syndrome.71

A growing number of studies suggest that intracellular magnesium plays a key role in modulatinginsulin action and insulin-mediated glucose uptake.72

A randomised, double-blind, placebo-controlled trial of 63 subjects with type 2 diabetes foundoral magnesium supplementation to improve insulin sensitivity and metabolic control.73

In a recently published article, Japanese researchers observed that not only does a deficiencyof magnesium decrease insulin sensitivity and secretion, but also contributes to the pathogenesisand development of lifestyle related diseases, including hypertension and hyperlipidaemia.74

MAGNESIUM DEFICIENCY & INSULIN RESISTANCE IN OBESECHILDREN Magnesium deficiency has been associated with insulin resistance and increased risk for type 2 diabetes in adults.75 The problem has now also been found to extend to obese children.

In a study designed to determine whether obese children exhibit serum magnesium deficiencyand its potential association with insulin resistance, researchers found that the connectionbetween magnesium deficiency and the risk for type 2 diabetes may begin already inchildhood.7510

Observations by clinicians find thatpatients with fatiguemay take a couple of weeks to respondto treatment, whilepatients withfibromyalgia mayrespond in only a couple of days.67

Research indicatesthat magnesium supplementation or increased intakeof magnesium-richfoods may be animportant clinical tool in the preventionof type 2 diabetes in obese children.75

The researchers observed 24 obese non-diabetic children and 24 sex- and puberty-matchedlean control subjects. Serum magnesium was found to be significantly lower in the obese children compared with lean controls and the serum magnesium level was inversely correlatedwith fasting insulin and positively correlated with quantitative insulin sensitivity check index.It was concluded that magnesium supplementation or increased intake of magnesium-rich foods may be an important tool in the prevention of type 2 diabetes in obese children.

GLAUCOMAA subgroup of glaucoma patients in whom vasospasm leads to reduced blood supply to the opticnerve may benefit from supplemental magnesium. These patients are often treated with calcium channel blocker drugs.

Ten patients (six with open-angle glaucoma, four with normal-tension glaucoma) were supplemented with magnesium, a natural calcium channel blocker.84 Magnesium (121.5 mg twice daily) was administered for a month. After the treatment, the visual fields tended toimprove, leading the researchers to the conclusion that magnesium has a beneficial effect inglaucoma patients with vasospasm.

Although these results are very promising, a larger trial is warranted to confirm these results.

HEARING LOSSNoise-induced hearing loss appears to result from energy depletion in the hair cells of the ear. The problem may be further enhanced by hypomagnesaemia induced vasoconstriction.85

Magnesium treatment has been repeatedly shown to reduce the incidence of both temporaryand permanent noise-induced hearing loss.86

Researchers studied 300 young, healthy, and normal-hearing military recruits who underwent2 months of basic training, which includes repeated exposures to high levels of impulse noisewhile using ear plugs. The recruits were assigned to receive either 167mg magnesium aspartate daily or placebo. The study results demonstrated that the rate of noise induced hearing loss was significantly more frequent and more severe in the placebo group.87

Magnesium may also improve hearing in patients with acute-onset hearing loss.

In a prospective, randomised, double-blind, placebo-controlled trial, 28 patients with idiopathicsudden sensorineural hearing loss were treated with either steroids and oral magnesium (study group) or steroids and a placebo (control group).86 Compared to the control group, the magnesium treated group had a significantly higher proportion of patients with improvedhearing. Further analysis of the data also suggested that the magnesium treated individualsexperienced hearing improvement at a larger magnitude than the control subjects.

MIGRAINEMigraine-type headaches are common; Australia is home to 2 million sufferers.88

The activities of magnesium in the body include counteracting vasospasm, inhibiting platelet aggregation,and stabilising cell membranes, all of which are involved in migraine pathogenesis.89 In addition, magnesium concentration has an effect on serotonin receptors, nitric oxide synthesis and release,inflammatory mediators, and a variety of other migraine related receptors and neurotransmitters.89

In order to evaluate the prophylactic effect of oral magnesium, 81 patients with migraine (meanattack frequency 3.6 per month) were given oral magnesium (600mg daily) or placebo for 12weeks. In weeks 9-12 the attack frequency was reduced by 41.6% in the magnesium group andby 15.8% in the placebo group compared to baseline. The number of days with migraine andthe drug consumption for symptomatic treatment per patient also decreased significantly in themagnesium group.90 11

Oral magnesium supplementation significantly reducesthe attack frequencyof migraineheadaches as well as drug consumption forsymptomatic relief.90

SYNERGISTIC EFFECTS OF CHROMIUM IN DYSGLYCAEMIANumerous studies demonstrate that supplemental chromium may have significantly beneficial effects on blood glucose and lipid metabolism in patients with mild to severe glucose intolerance, as encountered in metabolic syndrome and diabetes.76,77,78,79,80,81,82

Some of the proposed mechanisms include an increased insulin binding and subsequent uptake ofglucose into the cell, increased number of insulin receptors, and activation of insulin receptor kinaseleading to increased insulin sensitivity.83

The intravenous (IV) use of magnesium to abort an acute attack has also been studied in a randomised, single-blind, placebo-controlled trial including 30 patients.91 15 patients received1g of IV magnesium sulfate given over 15 minutes; 15 patients served as controls. However,those in the placebo group with persisting complaints of pain accompanying symptoms (suchas nausea and vomiting) after 30 minutes also received the same dose of magnesium as thosein the treatment group.

All patients in the treatment group responded to treatment with magnesium sulfate.The pain disappeared in 13 patients (86.6%); it was diminished in 2 patients (13.4%);and in all 15 patients (100%), accompanying symptoms disappeared.

In the placebo group, a decrease in pain, but persistent accompanying symptoms was notedin 1 patient. Accompanying symptoms disappeared in 3 patents 30 minutes after placeboadministration.

All patients who initially received placebo were subsequently treated with magnesium.All of these patients responded to treatment. In 14 patients (93.3%), the attack ended; in 1 patient (6.6%), pain intensity decreased; and in all 15 patients (100%),accompanying symptoms disappeared.

MUSCULAR Adequate magnesium levels are required at neuromuscular junctions to permit muscles to relax.Chronic magnesium deficiency increases the likelihood of excessive muscle tension, and may lead tomuscle spasms, tics, restlessness, and twitches.92

CRAMPSMuscle cramps are involuntary and often painful contractions of the muscles. During magnesiumdepletion, intracellular calcium levels raise; calcium plays an important role in skeletal and smoothmuscle contraction, hence a state of magnesium depletion may result in muscular cramping.10

Muscle cramps, muscle strains (and damage), and headaches due to muscle tension are allassociated with a magnesium deficiency state.93

Bartl et al. demonstrated that nightly muscle cramps during pregnancy may be a sign of a latentmagnesium deficiency which can be influenced by oral magnesium supplementation.94

Swedish researchers have also found oral magnesium supplementation to be a valuable therapeutic tool in the management of pregnancy-related leg cramps in magnesium deficientpatients.95

Magnesium supplementation may also be of benefit to non-pregnant individuals. Volunteerssuffering regular leg cramps were given magnesium citrate (equivalent to 300 mg magnesium)or placebo for 6 weeks in a randomised, double-blind, cross-over placebo-controlled trial.While no difference in cramp severity or duration was recorded between the groups, there wasa trend towards fewer cramps experienced by those taking magnesium. Significantly more subjects thought that the treatment had helped after magnesium than after placebo (78% and54% respectively).96

RESTLESS LEG SYNDROMERestless leg syndrome (RLS) is a sleep disorder primarily characterised by leg discomfort during sleep,which is only relieved by movement of the legs. RLS can result in decreased quality of sleep with subsequent daytime sleepiness, anxiety, depression, and confusion or slowed thought processes fromlack of sleep.

Researchers have shown oral magnesium supplementation to be a useful therapy in patientswith mild to moderate RLS as well as periodic limb movement during sleep (PLMS) relatedinsomnia.98

INTERMITTENT CLAUDICATIONIntermittent claudication occurs when the leg muscles do not receive enough oxygen rich blood during walking or exercise, causing painful cramping. The condition is caused by atherosclerosis andtherefore shares similar risk factors as for coronary artery disease and is characterised by magnesiumdeficiency.3112

Magnesium deficiency shouldalways be includedin the differentialdiagnosis of patientswho present withpersistent or severemuscle pain.97

PHYSICAL ENDURANCE Physical activity increases the bodys need for energy; magnesium plays many roles in energy metabolism.

Energy for muscle contraction is derived from the hydrolysis of ATP; the enzyme that drives the hydrolysis of ATP, ATPase, requires magnesium. Thus adequate levels of magnesium are required forskeletal muscle function.

187 patients with coronary artery disease were randomised to receive either 365mg magnesium (as magnesium citrate; n=94) or placebo (n=93) for 6 months in a multicentre, randomised, prospective, double-blind trial. Oral magnesium supplementation was reported to significantly increase exercise duration time and lessened exercise-induced chest pain in these patients.99

Serum and erythrocyte magnesium levels were determined in a group of 11 endurance athletesbefore and after a 25 km running race and compared to 30 sedentary controls. The differencesencountered suggest that athletes suffer from a magnesium deficiency that is partially due tophysical exercise.100

A human study demonstrated that, when combined with strength training, supplemental magnesium (8mg/kg body weight/day; including dietary intake) increases muscle strength to a greater extent than strength training without supplementation.101

In addition to magnesium, nutrients such as malic acid (malate) and several of the B vitaminsare also essential in the respiratory chain involved in ATP synthesis.9

Malate plays an important role in generating mitochondrial ATP both under aerobic and hypoxicconditions.9 It has been proposed that malate deficiency is a cause of physical exhaustion.9

OSTEOPOROSISResearch indicates that magnesium may be just as important in the prevention and treatment of osteoporosis as calcium.105,106,107 In addition, adequate serum magnesium levels are necessary for proper calcium metabolism since a state of deficiency can result in hypocalcaemia. Magnesium affectsmineral metabolism in bone by a combination of effects on hormones and other factors that regulatethese processes. A deficiency of this mineral has an inhibitory effect on osteoblasts108 and may resultin increased osteoclast activity.109,110

The benefits of magnesium supplementation were investigated in postmenopausal women whoreceived two to six tablets daily of 125mg magnesium hydroxide for six months and then two tablets for another 18 months in a 2 year, open, controlled trial. Twenty-three symptom-freepostmenopausal women who were found to have osteoporosis but refused treatment served ascontrols. The mean bone density of all the treated women increased significantly, whilein the untreated controls, the mean bone density was significantly decreased.111

Magnesium deficiency occurs frequently in chronic alcoholism and may contribute to the increasedincidence of osteoporosis seen in this population.112 Additionally, magnesium deficiency may contribute to osteoporosis associated with malabsorption.

In a study by Rude RK et al., where patients with a malabsorption syndrome were given magnesium supplements for two years, a significant increase in bone mineral density wasobserved.113 Furthermore, experimental magnesium deficiency in animal models has resulted inimpaired bone growth, osteopenia, and increased skeletal fragility.110 13

THE SYNERGISTIC EFFECTS OF GLUTAMINE IN PHYSICAL ENDURANCEThe amino acid glutamine considered to have an anabolic effect on skeletal muscle, where it stimulates the synthesis and inhibits the degradation of proteins.103

It has been noted that athletes suffering from overtraining syndrome appear to maintain low plasmaglutamine levels for months or years.104 Plasma glutamine responses to prolonged and high intensity exercise are characterised by increased levels during exercise followed by significantdecreases during the post-exercise recovery period, with several hours of recovery required forrestoration of pre-exercise levels. If recovery between exercise bouts is inadequate, the acute effectsof exercise on plasma glutamine level may be cumulative. These observations have important implications for organ functions in these athletes, particularly with regard to the gut and the cellsof the immune system, which may be adversely affected by glutamine deficiency.104

Researchers believe that reduced plasma concentrations of glutamine may be a good indicator of severe exercise stress.104

Magnesium deprivation increasesoxygen requirementsto complete sub maximal exerciseand reducesendurance performance.102

PAINMagnesium is known to block the N-methyl-D-aspartate (NMDA) receptors, which are involved in thepotentiation of pain. This effect is thought to contribute to magnesiums pain reliving action inmigraine headaches, postoperative pain, neuropathic pain, erythromelalgia, Raynauds phenomenon,and possibly other vascular disorders and pain syndromes.

Neuropathic pain may respond poorly to morphine and is often difficult to relieve. Researchersinvestigated the safety and efficacy of IV magnesium sulfate at two doses in 12 patients withneuropathic pain.114

After receiving 500mg, three patients experienced complete pain relief and two experiencedpartial pain relief for up to 4 hours duration; pain was unchanged in one patient. After receiving 1g, one patient experienced complete relief and four experienced partial pain reliefof similar duration; pain was unchanged in one patient.

IV magnesium at these doses appeared to be safe and well tolerated.

In a randomised, double-blind study, 42 patients undergoing elective abdominal hysterectomywith general anaesthesia received magnesium sulfate or placebo intravenously before and 20 hours following surgery. Compared to control subjects, magnesium-treated patients requiredless morphine during the first 48 hours and experienced less discomfort during the first andsecond postoperative days.115

In addition, while the control subjects experienced increased insomnia during the first and secondpostoperative nights, the magnesium-treated patients showed no change in postoperativesleeping patterns compared to preoperative patterns.

When a board member of the Erythromelalgia Association experienced complete remission ofhis disabling erythromelalgia (EM) by taking oral magnesium sulfate (up to 1166 mg daily) afteronly modest improvements on conventional medication, he encouraged other members to trythe same approach and report back to the association.116

Overall, 8 of 13 patients reported improvement (1 remission; 3 major improvements; 2 moderateimprovements; 2 mild improvements). Four patients (30.8%) reported no response to magnesium therapy, and 1 patient's symptoms worsened. Two patients' magnesium dose waslimited because of diarrhoea. (However, this problem may be overcome by using a magnesiumdiglycinate chelate; please refer to the pharmacokinetics section).

This informal survey demonstrates that the use of high dose oral magnesium supplementationmay produce good and sometimes dramatic results in patients unresponsive to many othertreatments. The author concluded that these results suggest a role for oral magnesium in thetreatment of EM and possibly other vascular disorders.

PREGNANCY COMPLCIATIONS AND INFANT HEALTHMagnesium deficiency during pregnancy can induce maternal, foetal, and paediatric consequences thatmay last throughout life.117

Animal studies of gestational magnesium deficiency show that it may have a marked effect on parturition and post uterine involution. A deficiency state may also interfere with foetal growth anddevelopment, and has been linked to an increased incidence of Sudden Infant Death Syndrome (SIDS).117

Furthermore, oral magnesium supplementation during pregnancy has been associated with significantlyfewer maternal hospitalisations, a reduction in preterm delivery, and less frequent referral of the newborn to the neonatal intensive care unit.118

PRE-ECLAMPSIA (TOXAEMIA)/ ECLAMPSIA Pre-eclampsia, or toxaemia, is a complication of pregnancy characterised by elevated blood pressure,albuminuria and/or oedema that may develop between the 20th week of gestation and the end of thefirst week postpartum. If the condition progresses to seizures or coma, it becomes known as eclampsia.The aetiology for pre-eclampsia and eclampsia is unknown.

Magnesium sulfate is the agent of choice for reducing the rate of eclampsia and to prevent recurrentconvulsions.119,120,121

A literature search from 1966 to 2003 shows that magnesium sulfate has long been used in theprophylaxis of eclampsia. Numerous randomised controlled trials and systemic reviews havedemonstrated its efficacy.122 Most studies to date have relied on intravenous administration.14

Oral supplementation of magnesium has been shown to prevent pregnancy inducedhypertension (PIH).123

A prospective randomised double-blind study was carried out in 102 pregnant women; 51 receiving 3g of magnesium gluconate daily from the 28th week of gestation to delivery, and51 served as controls. Four per cent of the pregnant women developed PIH after magnesiumgluconate treatment, which was substantially lower than the 16 per cent in the control group.

SUDDEN INFANT DEATH SYNDROME (SIDS)It has been suggested that SIDS might be due to the foetal consequences of a maternal magnesiumdeficiency, which may be prevented by increased magnesium intake by the mother.124

A recently published study shows that there is a significant trend towards reduced risk of SIDSwith increasing levels of magnesium in drinking water.125

Different mechanisms for SIDS have been proposed:

It is thought that SIDS may be a foetal consequence of maternal magnesium deficiency throughimpaired control of brown adipose tissue thermoregulation mechanisms leading to a modifiedtemperature set point. SIDS can result from dysthermia, both hypo- or hyperthermic types.117

Infants sleeping on their stomach (prone position) can be jeopardised if they lack the musclestrength to shift their position or turn their heads to rescue themselves from potential suffocation.Two major studies from the 1970s showed muscle weakness in the upper half of the body ininfants who died of SIDS and shoulder hypotonia in near-miss for SIDS infants.126

Muscle strength is seriously impaired in the young magnesium deficient subject, while magnesium rapidly reverses muscle weakness.126

A review, published in 1991, of 19 retrospective case-control studies that investigated the relationshipbetween prone sleeping position and SIDS led to a change of recommended sleeping position forinfants away from the prone position. However, despite a decreased incidence of SIDS, it still remainsthe leading cause of death in infants aged 1 month to 1 year of age in industrialised countries.126

PREMENSTRUAL SYNDROME (PMS)Several studies point to the effectiveness of oral magnesium supplementation in the clinical management of PMS.

38 women with PMS symptoms were given 200 mg magnesium daily or placebo for two menstrual cycles. While no effect was noted in the first month of treatment, in the secondmonth there was a greater reduction in the symptoms of PMS-H (weight gain, swelling ofthe extremities, breast tenderness, and abdominal bloating) with magnesium supplementation compared to placebo.128

In a randomised double-blind trial, 32 women were supplemented with 360 mg magnesiumthree times daily (during the second half of the menstrual cycle) or placebo for two cycles. Inthe next two cycles both groups received magnesium.129

The results of this study indicate that magnesium supplementation could represent aneffective treatment for PMS-related mood changes.

In 20 patients with premenstrual migraine, supplementation with magnesium (360 mg/day) orplacebo during the second half of the menstrual cycle reduced the number of days withheadache.130

STRESS Stress hormones, including both catecholamines (adrenalin and noradrenalin) and corticosteroids (e.g.cortisol), can promote a reduction in tissue magnesium levels.67 Stress induces a shift of magnesiumfrom the intracellular to the extracellular space, increasing urinary excretion and eventually depletingbody stores.131 Consequently stress increases the bodys need for magnesium.

When magnesium deficiency exists, chronic stress can promote a further decline in health. Based onhuman and animal research, it has been shown that a variety of nutrients in addition to magnesium, such as vitamin C, a number of B vitamins, and tyrosine, may allow individualsto minimise the systemic effects of stress.132 15

Studies indicate that gestational magnesium deficiency results in suboptimal foetalgrowth and development andmay be linked to anincreased incidenceof SIDS.127

Chronic stress leadsto a tissue depletionof magnesium, consequently increasing the bodysneed for the mineral.

CONTRAINDICATIONS, PRECAUTIONSAND ADVERSE REACTIONS

Magnesium is contraindicated in patients with renal failure.3 It is also contraindicated in those withhigh-grade atrioventricular (AV) block.3

Individuals with myasthenia gravis should also avoid the use of magnesium supplements.133,134

The most common adverse reactions from high-dose supplemental magnesium is diarrhoea;3 this problemcan be overcome by taking a magnesium diglycinate chelate (please see pharmacokinetics section).

DRUG INTERACTIONS Magnesium may decrease the absorption of the following drugs; take at least two hours apart:3,135

Bisphonates Quinolone antibiotics Tetracycline antibiotics Warfarin

Magnesium may also interfere with the efficacy of the following:11,135

Chlorpromazine Digoxin* Nitrofurantoin Penicillinamide Oral anticoagulants

*However, magnesium has also been noted to reduce cardiac arrhythmias due to digoxin poisoning aswell as significantly decrease the frequency and complexity of ventricular arrhythmias in digoxin-treatedpatients with congestive heart failure without digoxin toxicity.136

Caution may also be prudent in patients taking calcium channel blockers (potentiation of effect),potassium-sparing diuretics (may also have magnesium-sparing effects), and skeletal muscle relaxants(potentiating effect).

A large number of medications may lead to magnesium depletion, including cisplatin, corticosteroids, digoxin, erythromycin, gentamycin, loop diuretics, neomycin, oral contraceptives, theophylline, thiazide diuretics.135

SUMMARYMagnesium plays a role in more than 300 enzyme systems and is critically involved in energy production, synthesis of essential molecules, and regulation of ion transport across cell membranes.

Mild to moderate deficiency states are becoming more common due to modern food processing andconsequently a reduced dietary intake.

Conditions that may be associated with magnesium deficiency include cardiovascular disease, behav-ioural problems, fatigue, fibromyalgia, migraine headaches, muscular complaints, osteoporosis, preg-nancy complications, premenstrual syndrome, and reduced tolerance to stress.

Clinicians should consider using magnesium supplementation to prevent deficiency in patients at riskand to treat deficiency when it occurs.

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