Theodore D Mountokalakis. Cambridge World History of Food. Editor: Kenneth F Kiple & Kriemhild Conee Ornelas. Volume 1. Cambridge, UK: Cambridge University Press, 2000.
Magnesium is one of the most plentiful elements in nature and the fourth most abundant metal in living organisms. It is extremely important in both plant and animal metabolism. Photosynthesis does not proceed when the magnesium atom is removed from the chlorophyll molecule. Magnesium also plays a key role in many enzyme reactions that are critical to cellular metabolism and is one of the main determinants of biological excitation (Aikawa 1981).
Despite its ubiquitous distribution and the multiplicity of its actions, magnesium has long been considered as a microelement with a vague physiological role, and not until the early 1930s was it recognized as an essential nutrient. Magnesium deficiency in humans was only described in 1951, and according to several experts, it continues to be diagnosed less frequently than it should be (Whang 1987).
There are many explanations for the reluctance to allow magnesium deficiency a place in medicine; among them are the difficulties in measuring magnesium, which have restrained the accumulation of knowledge. Moreover, the essentially intracellular location of the magnesium ion has discouraged the detection of its deficit. Lastly, because magnesium is so widely distributed in foods, its dietary intake has been assumed to be sufficient to meet the body’s requirements.
Actually, pure magnesium deficiency is quite rare. Marginal deficiency of magnesium, however, is believed to occur fairly often in the general population. Moreover, in most diseases causing magnesium deficiency, significant nutritional factors exist.
A Note on Etymology
The word “magnesium” originates from the Greek word Magnesia. Magnesia is the eastern peninsular region of Thessaly in central Greece. It was named after the Magnetes, a prehistoric Macedonian people, by whom Magnesia was first inhabited in the twelfth century B.C. The Magnetes are mentioned by Homer, and the port of Magnesia in the Pagassitic Gulf was the place whence the Argonauts sailed on their way to Colchide. Magnesia was also the name of three different overseas colonies established by the Magnetes during the eleventh century B.C.: one in central Crete, and two in the inland of Asia Minor.
Magnetes lithos and Magnesia lithos, which both mean “stone of Magnesia,” were the names given by the ancient Greeks to minerals obtained from the earth of either the metropolitan Magnesia or its Asian colonies. Magnetes lithos ormagnetes (magnet) was the term used for lodestone (native iron oxide that attracts iron). Hippocrates, however, the fifth-century B.C. father of medicine, referred to Magnesia lithos as a cathartic (purgative). He recommended (as translated by Paul Potter) that “if the cavity does not have a spontaneous movement, you must clean it out by giving spurge-flax, Cnidian berry, hippopheos, or magnetic stone” (Hippocrates 1988). (“Stone of Magnesia” or “Magnesian stone” would be a more appropriate translation than “magnetic stone.”) Presumably, the stone mentioned by Hippocrates was native magnesium carbonate (magnesite), the white and light powder that was later called magnesia alba and is still used as an aperient and antacid.
Magnesia alba was prepared from the mother liquors obtained in the manufactures of niter by M. B. Valentini of Giessen, in 1707, but it was confused with “calcareous earth” until 1755, when J. Black of Edinburgh distinguished chemical differences between magnesia and lime. In 1807, Sir Humphrey Davy, conducting his studies on earth compounds in London, succeeded in isolating a number of alkali-earth metals that he named barium, strontium, calcium, and magnium after their oxides baryta, strontia, chalk, and magnesia. Before long, “magnesium” replaced magnium as the name of the element derived from magnesia (Durlach 1988b).
Recognition of Magnesium Deficiency
The Early Years
It was near the end of the nineteenth century when the nutritional significance of minerals was first recognized. That not only organic substances but also nonorganic elements contained in food are necessary for life became evident in about 1870, when the German biologist J. Forster demonstrated the lethal effect in dogs of a diet deprived of inorganic salts (Forster 1873). A few years later, J. Gaube du Gers in France reported that mice fed a diet consisting of magnesium-free bread and distilled water were rendered progressively sterile. Impressed by this finding, he hastened to conclude that magnesium is “the metal of vital activity for what is most precious in life: reproduction and sensation”(Gaube 1895).
By 1900, on the American side of the Atlantic, J. Loeb accomplished his original experiments on the physiology of neuromuscular contractions and was able to state that biological excitation “depends upon the various ions, especially the metal ions (sodium, calcium, potassium, and magnesium) existing in definite proportions in the tissue” (Loeb 1900) (Table IV.B.4.1). About the same time, it was discovered that the magnesium atom occupies the central position in the chlorophyll molecule (Willstatter and Stoll 1913). Thus the most fundamental role of magnesium in nature was discovered, for which a 1915 Nobel Prize was awarded.
As postulated by Jerry Aikawa in recent years, life on earth would not be possible without magnesium, since photosynthesis is absolutely dependent on this element and the photosynthetic process is indispensable for the enrichment of the environment with oxygen (Aikawa 1981).An understanding, however, of the myriad roles of magnesium in biology had to await a method suitable for its measurement in biological materials. The first such method was a gravimetric technique involving the precipitation of magnesium ammonium phosphate. It was introduced by L. B. Mendel and S. R. Benedict in 1909 and was subsequently superseded by its modification to a colorimetric procedure (Alcock 1969).
In the following years, a large number of chemical approaches, including adsorption of titan yellow dye by magnesium hydroxide in the presence of a stabilizer, titrimetric, or colorimetric methods measuring various magnesium-dye complexes, and fluorometric techniques, were used for the determination of magnesium in plasma or serum, urine, or fecal samples. The multiplicity of methods is indicative of the lack of satisfaction among investigators with any one of them.
An impressive step forward in the understanding of the role of magnesium metabolism in health and disease was made by the availability of atomic absorption spectrophotometry. This simple, precise method permits multiple determinations of minute amounts of magnesium in small samples of biological fluids and tissues, in a matter of minutes. The theoretical basis of flame spectrophotometry lies in the discovery made by the famous German physicist Gustav Kirchhoff in 1860, that both emission and absorption of light of a specific wavelength are characteristic of a given element. Emission spectrophotometry was first used to measure serum magnesium by V. Kapuscinski and his co-workers in 1952.The quantitative measurement of atomic absorption was conceived by A. Walsh in 1955. J. Alan applied this technique to the measurement of magnesium in plants in 1958, and two years later, atomic absorption spectrophotometry was used for the determination of serum magnesium by J. Willis (Alcock 1969).
Alkaline phosphatase was the first enzyme shown to be activated by magnesium. The discovery was made by H. Erdtmann in 1927. Since then, as many as 300 enzymes have been known to be activated by this cation in vitro, including all those utilizing adenosine triphosphate or catalyzing the transfer of phosphate. Because magnesium is the second most plentiful intra-cellular cation, it has been postulated that its function also extends to all these enzymes in vivo. By inference, the predominant view has been that magnesium is required for most of the major metabolic pathways in the cell, including membrane transport, protein, nucleic acid, fat and coenzyme synthesis, glucose utilization, and oxidative phosphorylation (Wacker 1969).
Introducing the Concept
The credit for introducing the concept of magnesium deficiency belongs to Jehan Leroy. He showed for the first time that the metal is essential for mammalian metabolisms when he found that white mice fed a diet deficient in magnesium failed to grow (Leroy 1926). However, the most distinctive manifestation of magnesium deficiency was recognized in 1932, when the group led by E. McCollum reported the development of hyperemia and progressive neuromuscular irritability, culminating in generalized and sometimes fatal seizures, in weanling rats fed a diet containing 0.045 millimoles (mmol) per kilogram (kg) of the element (Kruse, Orent, and McCollum 1932).
It should be noted that flaccid paralysis as a pharmacological effect of intravenous magnesium sulfate has been described by French authors since 1869 (Jolyet and Cahours 1869). A distinction, however, should be made between pharmacological properties of a substance and manifestations of its metabolic effect. The fact that a generalized convulsion can be controlled by massive parenteral magnesium administration, for instance, does not necessarily mean that the symptom is due to deficiency of this ion.
During the 1950s and 1960s, the early experiments of McCollum and his colleagues were confirmed and extended by many research groups. Experimental magnesium deficiency produced in rats, dogs, cocks, and other animal species was found to be associated with multiple pathological lesions, including nephrocalcinosis, myocardial necrosis, and calcium deposition in the aorta and the coronary and peripheral vessels; and to be accompanied by other metabolic changes, such as hypercalcemia, azotemia, and tissue potassium depletion.
About the time that McCollum published his original findings on experimental magnesium deficiency, a form of spontaneously occurring hypomagnesemic tetany was observed in adult lactating cattle and sheep. The disease, characterized by neuromuscular irritability, tetany, and convulsions, was termed “grass tetany” because the symptoms developed in the affected animals when they were first allowed to graze on fresh green grass in the spring (Sjollema 1932). Grass tetany has since been reported in many parts of the world, including the United States, many European countries, New Zealand, Australia, and Japan. Although there have been numerous investigations, the etiology of the disease is not clear.
Plasma magnesium is usually low in those afflicted, but grass tetany has also been observed in animals with decreased cerebrospinal magnesium levels whose serum magnesium was normal. The diet of the animals, when they are confined indoors during the winter, consists of silage, grains, and grain mash, which are deficient in magnesium, but symptoms of deficiency do not arise until shortly—sometimes within two days—after the animals are turned out on spring grass. It is of interest that the magnesium content of grasses and grazing vegetation in grass tetany-prone areas has been found to be decreased when compared with the vegetation of non-prone areas (Kubota 1981).
In 1959, a second form of hypomagnesemic tetany of ruminants was recognized when R. Smith reported a gradual development of hypomagnesemia in association with progressive irritability and tetany in calves fed for a long time on a pure milk diet. Magnesium supplementation was found to prevent the disease (Smith 1959). It should be noted that cow’s milk contains magnesium in fair amounts, but its high phosphate and calcium content can adversely interfere with magnesium absorption.
Magnesium Deficiency in Humans
As early as 1932, B. Sjollema and L. Seekles, by extrapolating data from veterinary medicine, postulated that human cases of tetany may be related to hypomagnesemia. In 1934, A. B. Hirschfelder and V. G. Haury described seven patients with hypomagnesemia associated with muscular twitching or convulsions and concluded that a clinical syndrome did indeed exist involving low magnesium (hypomagnesemia) accompanied by twitching or by convulsions. One more case of hypomagnesemic tetany was reported by J. F. Miller in 1944. The patient was a 6-year-old boy with associated osteochondrosis of the capital epiphysis of the femurs. Soon after World War II inanition was recognized as a cause of hypomagnesemia, but clinical manifestations were not mentioned (Flink 1980).
The broad spectrum of full-blown manifestations of the magnesium deficiency syndrome was recognized in the early 1950s, when Edmund B. Flink described the amazing case of a woman who, having been on almost continuous intravenous fluid therapy for several months, developed striking neurological symptoms and signs, including almost every form of involuntary movement. When first seen by Flink in July 1951 at Minnesota University Hospital, the patient was cachectic, dehydrated, and semicomatose and had severe hyponatremia, hypokalemia, hypophosphatemia, and hypochloremic alkalosis. With the appropriate replacement treatment, serum electrolytes returned to normal within a few days. However, on the sixth day of treatment, the patient began having repeated convulsions associated with gross tremor and myoclonic jerks of extremities, jaw, and tongue, facial grimacing, choreiform and athetoid movements, and inability to talk or swallow.
These symptoms continued until the eleventh day, when a blood sample was taken for the determination of serum magnesium level. As stated quite emphatically by Flink, “serum magnesium level was obtained for no better reason than that magnesium and phosphate interact and are important intracellular elements” (Flink 1985). Serum magnesium was determined by the titan yellow method and was found to be very low. This finding prompted the intramuscular administration of magnesium sulfate in the daily dose of 2.0 mg. The response was so dramatic that it was characterized by Flink as “unforgettable” (Flink 1985). Tremor decreased after the first dose, and within 24 hours the patient was oriented and able to speak and eat (Fraser and Flink 1951).
One year later, similar symptoms in a patient with alcoholic cirrhosis stimulated the start of clinical and laboratory research on magnesium metabolism in alcoholism by Flink and his colleagues. Much of the knowledge of normal human magnesium metabolism and its alteration in disease originated from these early studies (Wacker and Parisi 1968).
Initially, the discovery of hypomagnesemia in patients with chronic alcoholism and delirium tremens, together with the response of some of these patients to parenteral administration of magnesium, led to the hypothesis that symptoms of alcohol withdrawal were due to magnesium deficiency. However, it was soon realized that many alcoholic patients with near normal serum magnesium levels also had symptoms, whereas others with very low levels did not. It was, therefore, suggested that serum magnesium might not reflect magnesium status, and balance studies were undertaken to elucidate this issue further. It is now quite clear that the main cause of magnesium depletion in alcoholism is inadequate magnesium intake. These early balance studies established the concept of tissue magnesium depletion in the presence of normal serum magnesium levels and revealed increased urinary losses as a possible mechanism of magnesium deficiency. Thus, a significant amount of parenterally administered magnesium was found to be retained by alcoholic patients, indicating tissue magnesium depletion, whereas acute administration of large doses of alcohol was shown to result in increased renal magnesium excretion (Flink et al. 1954). Urinary excretion of magnesium after a load dose has been subsequently established as a feasible test in clinical practice for the evaluation of magnesium status.
That magnesium depletion is likely to occur as a result of drug treatment was first recognized in 1952, when H. E. Martin, J. Mehl, and M.Wertman reported a fall in serum magnesium in association with increased magnesium excretion in 10 patients with congestive heart failure treated with ammonium chloride and mercurial diuretics. Since that time, other diuretics, such as thiazides and loop diuretics; antibiotics, including aminoglucosides, tircacillin, carbenicillin, andamphotericinB; andalsocisplatinand cyclosporin have been added to the list of iatrogenic causes of magnesium depletion (Whang 1987).
Intestinal disorders were recognized quite early as a common cause of clinical magnesium deficiency. During the late 1950s and the early 1960s, ulcerative colitis and regional enteritis, along with almost every cause of persistent diarrhea, including chronic laxative abuse, and also intestinal malabsorption due to chronic pancreatitis, short bowel syndrome, gluten enteropathy and tropical sprue, have been reported fairly often in association with symptomatic hypomagnesemia.
Data from patients with malabsorption have confirmed previous observations in patients with primary hyperparathyroidism, indicating a relationship between magnesium metabolism and calcium metabolism. Hyperparathyroidism has been recognized as a cause of hypomagnesemia since 1956 (Harman 1956). Although some patients have been found to develop symptoms while hypercalcemic, in most cases hypomagnesemia has accompanied the fall in serum calcium levels after the removal of a parathyroid adenoma and has been attributed to the absorption of magnesium by the “hungry” bones of osteitis fibrosa cystica (Barnes, Krane, and Cope 1957). Since that time, it has been realized that hypercalcemia from any cause, including metastatic osteolysis and multiple myeloma, can be associated with symptomatic hypomagnesemia, because hypercalcemia causes increased excretion of magnesium in the urine (Eliel et al. 1968).
That the two major intracellular cations, potassium and magnesium, behave similarly was originally noted in the course of diabetic ketoacidosis (Martin and Wertman 1947). Similarities between the two ions were further emphasized by the observation that serum potassium and magnesium are both low in cases of primary aldosteronism (Mader and Iseri 1955). Moreover, cardiac arrhythmias, such as ventricular extrasystoles, ventricular tachycardia, and ventricularfibrillation, similartothoseinducedby hypokalemia, have been described in various clinical disorders known to result in depletion of magnesium. As a matter of fact, the demonstration that in hyper-tensive patients treated with diuretics, potassium supplementation alone has little effect on ventricular extrasystoles unless magnesium supplementation is added to the regimen has aroused clinical interest in magnesium deficiency significantly over recent years (Hollifield 1984).
Controversial Issues
A Puzzling Syndrome
During the 1960s, human magnesium deficiency was established as a clinical entity beyond any doubt. However, conflicting reports in the literature may have created the view for many that clinical magnesium deficiency is a puzzling syndrome comprising almost every symptom and sign. Such confusion also results partly from the previously mentioned difficulties in assessing magnesium status along with superimposed nonspecific manifestations related to primary illness or other concomitant metabolic abnormalities.
Thus, in addition to the generally accepted signs and symptoms of neuromuscular hyperactivity and disturbance of cardiac rhythm, a great variety of manifestations, ranging from difficulty in learning to multiple phlebothromboses, have been proposed as components of the clinical picture of magnesium deficiency. Moreover, the observation that even severe magnesium deficiency may have no symptoms or signs has added significantly to the confusion (Martin, Mehl, and Wertman 1952).
The term “spasmophilia” was first introduced by the French physician Nicolas Corvisart in 1852. In 1874, Wilhelm Erb attributed spasmophilia to neuromuscular hyperexcitability, and since then the term has been used to denote “a condition in which the motor nerves show abnormal sensitivity to mechanical or electric stimulations and the patient shows a tendency to spasm, tetany and convulsions”(Dorland 1943).
In 1959, Jean Durlach described a syndrome that he called “hypomagnesemic constitutional spasmophilia.” The syndrome, which was considered to be “the nervous form of primary chronic magnesium deficiency in adults,” comprised a long list of nonspecific neuromuscular, psychological, cardiovascular, and gastrointestinal manifestations, such as anxiety, excessive emotivity, globus hystericus, dyspnea sine materia, dizziness, insomnia, headaches, myalgias, cramps, tremors, tetanic attacks, palpitations, Raynaud’s syndrome, biliary dyskinesia, epigastric cramps, and syncope. Symptoms were ameliorated by oral administration of magnesium salts. Low erythrocyte magnesium, a positive Chvostek’s sign, and abnormal electromyo-graphic, electroencephalographic, and electronystagmographic tracings were reported as characteristic of the syndrome (Durlach and Lebrun 1959).
In the years that followed, the compass of clinical magnesium deficiency was broadened to encompass such divergent manifestations as phlebothrombosis, allergic disorders, intellectual retardation, sight weakness, hepatic dysfunction, cases of dysmenorrhea, spontaneous abortion, and mitral valve prolapse.This broadening of the spectrum of clinical manifestations of magnesium deficiency was based on a great number of cases studied by Durlach and other investigators in continental Europe.
The fact that publication of such cases in English has been rare is indicative of the reluctance of American and British experts to accept the existence of a syndrome such as “idiopathic spasmophilic diathesis” due to magnesium deficiency. However, an incident investigated by the U.S. Food and Drug Administration (FDA) in 1980 and a recent double-blind trial performed in Southampton imply that the idea of the involvement of magnesium deficiency in bizarre clinical syndromes should not be totally rejected.
The incident investigated by the FDA was as follows: 11 high school football players with diet histories suggesting low calcium and magnesium intake were given a phosphate-free, soluble calcium preparation because of leg cramps. They were then subjected to the noise and physical contact of a football game. Over a short period, 8 of them developed serious neuromuscular dysfunction manifested by ataxia, slurred speech, hyperventilation, muscle spasm, and tonicoclonic seizures. All of them recovered without specific treatment, and none developed neurologic sequelae. About 10 years later, W. F. Langley and D. Mann noticed the similarity of this syndrome with grass tetany in animals and postulated that central nervous system magnesium deficiency was responsible for its occurrence. The condition was thought to be brought on by a sudden rise in serum calcium and was termed “reactive symptomatic magnesium deficiency” (Langley and Mann 1991).
The randomized double-blind, placebo-controlled trial in Southampton concerned the effect of intramuscular administration of magnesium sulfate on the symptoms of chronic fatigue syndrome (Cox, Campbell, and Dowson 1991).As stated by the authors, the study was undertaken because many of the symptoms of the chronic fatigue syndrome—anorexia, nausea, learning disability, personality changes, tiredness, and myalgia—are similar to those of magnesium deficiency, and because in a pilot study they found that patients with the syndrome had low red blood cell magnesium concentrations. Within six weeks, red cell magnesium had returned to normal in all patients treated with magnesium. In addition, magnesium administration resulted in improvement in energy, pain perception, emotional reactions, sleep patterns, sense of social isolation, and physical mobility, as scored with the use of the Nottingham health profile. The authors confessed, however, that their trial was small and that there was only 6 weeks of follow-up and, therefore, the results were hardly conclusive (Cox, Campbell, and Dawson 1991).
The “Water Story”
In 1957, J. Kobayashi reported a geographical relationship between stroke-associated mortality and river water acidity in Japan (Kobayashi 1957). This was the beginning of what was later called the “water story.” Following the publication of the Japanese data, H. A. Schroeder (1960) investigated the relationship between mortality from different diseases and mineral content of drinking water in the United States,and concluded that the important determinant was water hardness rather than water acidity. Drinking soft water, he suggested, may promote the prevalence of cardiovascular disease, whereas hard water may exert a protective action. Since then, associations between hardness of drinking water and mortality from cardiovascular disease have been reported in England and Wales, in Sweden, and in Ontario—the softer the water the higher the mortality from cardiovascular disease.
Ten years after the original report of Kobayashi, T. Crawford and M. D. Crawford (1967) compared cardiac lesions found in medicolegal necropsies in cases of sudden death in two areas: Glasgow, a notable soft-water area with a high cardiovascular disease mortality; and London, a city with very hard water and a considerably lower mortality from cardiovascular causes. They realized that despite the large difference in mortality, the incidence of coronary atherosclerosis was similar in both places. This finding was subsequently interpreted to mean that the excess mortality in the soft-water area might correspond to sudden deaths due to fatal ventricular arrhythmias. Moreover, chemical analysis of the coronary arteries revealed very low values for calcium and magnesium in the soft-water area, suggesting that the mineral content of the arteries was related to the mineral content of the drinking water.
On the basis of the evidence just mentioned, a “cardiac water factor” has been postulated to exist. Presumably, such a factor would be either something beneficial in hard water or something harmful in soft water. Since the bulk of water hardness is made up of calcium and magnesium, these two ions have been the more likely candidates for the “cardiac water factor.” Magnesium is a much more abundant intracellular ion than calcium. Furthermore, a considerably greater proportion of the daily magnesium intake, as compared with the daily calcium intake, comes from drinking water. Coupled with the arrhythmogenic potential of magnesium depletion, these facts have led to the hypothesis that magnesium is the cardio-protective factor contained in hard water.
In support of this hypothesis, T. W. Anderson and colleagues (1975) found that magnesium concentrations in myocardial samples obtained from accident victims were significantly lower in five soft-water cities of Ontario than in three hard-water cities of the same province. However, a similar report in England at about the same time (Chipperfield et al. 1976) found a significant difference in mean myocardial magnesium concentration between heart muscle samples obtained from noncardiac deaths in two cities with different water hardness, but the difference was “in the wrong direction.” This discrepancy led Anderson and colleagues to conclude that if there was any sort of ‘water factor’ in Britain, it probably involved something beside magnesium (Anderson et al. 1980).
In the meantime, other simple correlation or multivariate statistical studies, including analysis of the data of the World Health Organization myocardial infarction registry network, have failed to discover a causal relationship between water hardness and heart disease mortality. Schroeder’s report has been criticized as misleadingly simplistic, because it was based on correlations between just one index of environmental exposure and a set of death rates (Hammer and Heyden 1980). In addition, the demonstration that only a small proportion of the daily mineral element intake comes from drinking water has cast doubt on the possible physiological significance of water hardness.
Advocates of the “water factor,” however, have adopted a somewhat different approach that emphasizes not water hardness but the interrelationship of individual elements contained in drinking water, along with the intake of these elements as they are ingested with food (Marier 1981). In this context, of particular interest are the observations of H. Karppanen in Finland, a country with a very high prevalence of cardiovascular disease. Mortality from ischemic heart disease in Finland shows a peculiar geographic distribution: Starting from the eastern areas, where it is extremely high, it decreases continuously toward the western and southwestern part of the country. These regional differences in mortality correlate with differences in the content of exchangeable magnesium in the arable soils: Magnesium concentration in the soil of eastern areas is only about one-third of that of the southwestern areas. Soil is the primary source of magnesium. Low magnesium concentration in soil is, therefore, expected to result in a low magnesium concentration in drinking water, and also in a low magnesium content of the cereal crops, which are a major food source of magnesium.
In addition to these observations, Karppanen has reported a strong positive correlation between the death rate from ischemic heart disease and the estimated average calcium-to-magnesium ratio of the diet in various Organization for Economic Cooperation and Development (OECD) countries. According to Karppanen, this correlation suggests that what really matters in the “water story” is the ratio of calcium-to-magnesium intake rather than the sum or the absolute amount of each of these elements (Karppanen 1981).
Nutrient or Drug?
Magnesium was known as a drug long before it was recognized as a nutrient. Thus, even in the nineteenth century, parenteral magnesium sulfate was used in the management of eclamptic convulsions and also as an ancillary anesthetic agent. In cardiology, magnesium was first introduced in 1935, when L. Zwillinger reported a beneficial effect of intravenous magnesium sulfate on paroxysmal tachycardia and extrasystolic arrhythmia in patients treated with digitalis. Since then, parenteral magnesium salts have been repeatedly used as an antiarrhythmic agent. Intravenous magnesium has also been recognized as a potent vasodilator agent, useful in the treatment of heart failure and angina pectoris.
During the past five years, several randomized clinical trials have examined the effects of intravenous magnesium in acute myocardial infarction. Collectively, these trials strongly suggest that magnesium therapy may result in decreased mortality as well as the frequency of postinfarction arrhythmias. A larger trial with a planned sample size of 2,500 patients was started in 1987 (Woods 1991).
In all these studies and in many of the cases of treatment of cardiac arrhythmias, the beneficial effect of intravenous magnesium has been related to pharmacological action rather than to repletion of a deficit. In fact, when magnesium is given intravenously, serum magnesium levels are usually raised well above normal values. However, hypomagnesemia is an established cause of cardiac arrhythmias, and magnesium deficiency has been shown to be associated with sudden cardiac death and increased mortality in the acute stage of myocardial infarction (Dyckner 1980). Moreover, low levels of magnesium have been found in myocardial tissue obtained at necropsy from patients with acute myocardial infarction. Consequently, under conditions of magnesium deficiency, a supplement of magnesium is expected to have the same favorable effect on cardiac arrhythmias, and possibly the same protective action against myocardial ischemia, as the administration of magnesium salts in pharmacological doses.
On the basis of the evidence just mentioned, it is clear that the characterization of magnesium as a drug or as a nutrient depends on the distinction between pharmacological action and replenishment of deficient stores (Charbon 1989). When there is a proven magnesium deficiency, magnesium acts as a nutrient. The patient is then expected to be completely cured as soon as the deficit is corrected. However, parenteral magnesium salts may be given as a drug. In this case, though, their potency and duration of action will depend on magnesium concentration in plasma, and their effect will be the same in each case of repeated administration.
Adequacy of Intake
Estimates of the daily requirements of magnesium have been largely based on the original calculations published in 1942 by J. Duckworth and G. Warnock, who calculated the magnesium requirements by analyzing the available data from balance determinations done in the 1930s. Currently, the Recommended Dietary Allowance (RDA) proposed by the Food and Nutrition Board of the National Research Institute of the United States is 350 mg per day for men and 300 mg per day for women, providing about 4.5 to 5.0 milligrams (mg) per kilogram of body weight per day (Munro 1980). RDA is increased to 450 mg per day during pregnancy and lactation and to 400 mg per day during adolescence in males. For infants and children the corresponding values are 100 and 200 mg per day.
Magnesium is so plentiful in both plant and animal foods that the recommended daily intake is readily obtained in ordinary diet. Common dietary sources include unprocessed cereal, nuts, legumes, vegetables, seafood, dairy products, meats, and drinking water. However, Mildred Seelig (1964) in the United States and Durlach (1988a) in France have suggested that magnesium intake in developed countries may be insufficient to meet daily needs. Since then this concern has been shared by many nutritionists.
The shortage of magnesium in contemporary diets has been attributed to the increased reliance of people in most Western countries on highly purified foods, such as sugar, starch, soft drinks, and distilled alcohol, that contain very little magnesium. Agricultural techniques of accelerated growth, resulting in decreased magnesium fixation by plants, and the use of magnesium-poor soil fertilizers, and also of pesticides that inhibit magnesium absorption, are considered as additional causes of decreased magnesium content in food items currently available for civilian consumption in industrialized countries. In fact, analysis of sample meals in the United States, Canada, and several European countries has revealed that the contemporary magnesium intake ranges from minimal adequacy to as low as 50 percent of the RDA (Table IV.B.4.6). This observation seems to hold particularly true for special population groups, such as pregnant women, teenage girls, or elderly people, because of increased needs, limited nutritional intake, or the age-associated decline in intestinal magnesium absorption (Mountokalakis 1987). In view of these considerations, Seelig has suggested that the recommendations for daily magnesium intake should be revised upward to as much as 7 to 10 mg/kg body weight.
Other experts opposed to this view have argued that since the RDA includes a generous margin of safety above the current estimates of the minimal daily requirements, the expression of adequacy of magnesium intake as a proportion of the RDA may be misleading. As a matter of fact, metabolic studies have indicated that a positive magnesium balance can be maintained at intakes as low as 60 percent of the currently proposed RDA. The answer to these arguments has been that because RDA is calculated by analyzing the results of metabolic studies conducted under conditions of relative serenity, it does not take into account possible changes of magnesium requirements related to the stresses of everyday life. The advocates of the “magnesium malnutrition” hypothesis emphasize that although the reported suboptimal intakes do not necessarily lead to overt clinical magnesium deficiency, they may represent a “long-term marginal magnesium insufficiency” with the potential risk of increased vulnerability to several disease processes (Marier 1982). The present uncertainty about evaluating the clinical status of magnesium impedes any attempt to clarify this issue further.
Epilogue
The story of magnesium is a story of discovery and also a story of neglect. Over the past few decades, enthusiasm about magnesium has repeatedly turned to indifference. Since 1971, when the First International Symposium on Magnesium Deficit in Human Pathology was held at Vittel (France), five international congresses and several American and European meetings on magnesium have taken place, and three journals exclusively devoted to magnesium have been published. Yet despite all this worldwide research activity, the practicing physician has relatively little interest in magnesium, and hypomagnesemia is currently the most underdiagnosed electrolyte deficiency (Whang 1987). Moreover, essential data for diagnosis and physiopathology are still lacking.
No doubt magnesium is an important intracellular element with a key role in many metabolic functions. The irony is that this multifaceted role of magnesium in the organism has been the main obstacle in understanding its fundamental function. A characteristic example is the physiological interrelationships of magnesium and hormones. Companion to both calcium and potassium, magnesium has long been assumed to interact with the hormones involved in the homeostasis of these two ions. The evidence, however, now shows that neither parathyroid hormone nor aldosterone exerts an overriding control on magnesium metabolism. Yet the facts that magnesium and calcium are mutually influenced and that hypomagnesemia can cause loss of intracellular potassium, in spite of a normal plasma potassium, are not in question.
Some 30 years ago, magnesium was hardly mentioned in the medical textbooks. Since then, much more information has been acquired. Although most of the current textbooks contain adequate data on the subject, they repeatedly state that magnesium is found in so many foods that, ordinarily, magnesium deficiency is rare in healthy people. It should be noted, however, that although magnesium is well conserved by both the kidneys and the bowel when the supply is limited, it is poorly stored so that a regular intake is needed to avoid deficiency. It is, therefore, natural to assume that a marginal deficiency state may be not uncommon. And once it was realized that magnesium has important cardiovascular effects, emphasis shifted from a focus on overt clinical magnesium deficiency to interest in the concept of marginal magnesium deficiency as a risk factor for cardiovascular disease. The importance of this concept is underscored by the characterization of magnesium as “nature’s physiological calcium blocker” (Iseri and French 1984).
Because most of the body’s magnesium is intracellular, the challenge for the future is to develop a feasible test in clinical medicine that will give meaningful information on the overall intracellular magnesium status. The question of intracellular magnesium is, without doubt, the most difficult to resolve. It is, however, the clarification of this issue that will enable us to understand better the relationship of magnesium to health and disease and to ascertain the magnitude of the segment of the population that may be deficient in this important nutrient.