Introduction

Numerous reviews have described the critical importance of magnesium (Mg) for humans, including recent reviews by Volpe [1] and Vormannn [2]. Magnesium is a co-factor in over 600 enzymatic reactions vital for metabolic pathways that include DNA, RNA, protein, and ATP synthesis; cellular energy production and storage; glycolysis; and cellular second messenger systems. Magnesium stabilizes ribonucleotides and deoxyribonucleotides for DNA duplication, transcription, and maintenance, and transfer RNA function. Magnesium influences cellular ion channels, transporters, and signaling, which regulates calcium, potassium, and sodium movement in and out of the cell. These actions result in Mg being a controlling factor in nerve transmission, skeletal and smooth muscle contraction, cardiac excitability, vasomotor tone, blood pressure, and bone turnover.

Because Mg has so many critical functions, the body has mechanisms to assure that magnesium is readily available. During low intakes of magnesium, the percent absorbed from the diet is increased, the amount excreted in urine is decreased, and body reserves are used [1, 2]. When dietary intake of Mg is adequate, the opposite occurs with Mg increasing in urine and body reserves while the percentage absorbed from the diet is decreased [1, 2]. Bone, which contains about 50–60 % of Mg in the body, is a major reserve, but some magnesium can come from intracellular sources when intakes are deficient [1, 2].

The response of the body to maintain Mg homeostasis when changes in dietary intakes occur has made it difficult to establish status indicators and set dietary requirements for Mg. This has resulted in conflicting opinions about the use of serum/plasma and/or urine Mg as status indicators for this nutrient; the dietary requirement for Mg; and whether Mg should be considered a major nutrient of concern for health and well-being beyond those individuals taking medications (e.g., proton pump inhibitors, diuretics) and those who have disorders that inhibit Mg absorption or induce its excretion. In the following, urinary and serum Mg data are presented that were not in previous reports [3–6] of studies in which Mg balance was determined in controlled metabolic ward studies at the Grand Forks Human Nutrition Research Center, Grand Forks, ND. These new data may help to understand why there are conflicting opinions about Mg status indicators and requirements. In addition to these data, some previously published conclusions obtained from balance data [7] will be reviewed because they contribute to understanding the conflict.

Methods

Magnesium Depletion-Repletion Experiments

The following is a synopsis of the experimental designs and methods that have been described in detail previously [3–6] to obtain the data used to generate the new data displays presented here. Table 1 also describes some features of the experiments. The experiments involved postmenopausal, mostly Caucasian, women residing in a metabolic unit that provided a common environment for strict control of food consumption, weight, exercise, and fecal, urine, and blood collection. The women consumed only food and beverages provided by the dietary staff and were chaperoned on all outings from the metabolic unit to ensure compliance with the study protocol. The studies were about 6 months in duration because this was determined to be the maximum time before the restricted living environment, 24-h/day surveillance, and a diet menu that repeated every third day became attrition issues. A 3-day menu rotation was used because it provided some variety but assured that variation in nutrient intake was inconsequential. The diets were composed of normal foods (e.g., meat and refined foods) found often in a Western-type diet. The diets were made low in foods that are good sources of Mg, such as whole grains, some vegetables, and pulses. Generally, the diets provided about 10 % of their energy as protein, 55 % as carbohydrate, and 35 % as fat. To assure adequacy, supplements were used for nutrients in low or unknown quantities in the diet. The diets were based on the 1989 Recommended Dietary Allowances [8] so calcium was only 700–800 mg (17.5–20.0 mmol)/day. Balance data obtained during the studies indicated that the amount of calcium provided was adequate. In all experiments, the caloric intake of each woman was adjusted (often higher than 2000 kcal (8.4 MJ)/day) to maintain body weight. As a result, the mean daily dietary intake of Mg in each experiment when the women were fed the basal deficient diet was higher than the analyzed value for the basal diet. All experiments were approved by the Institutional Review Board of the University of North Dakota.

Table 1 Features of the controlled magnesium depletion-repletion experiments
Full size table

The methods used for balance and serum Mg determinations were similar for all experiments. Duplicate diets of 2000 kcal (8.4 MJ) were prepared daily and blended in a plastic container with stainless steel blades for chemical analysis. Urine and feces were collected completely in plastic containers and bags, respectively. The Mg content of 3- or 6-day composites of diets, urine, and feces as well as serum from weekly blood draws was determined throughout each experiment by using inductively coupled argon plasma emission spectroscopy methods. Balances were calculated as the difference between dietary intake and urinary plus fecal excretion of Mg. The balance calculations did not include surface or phlebotomy losses; these losses probably would have lowered balance by another 3–6 mg/day [9, 10].

Experiment 1 had a depletion-repletion design [3]. Fourteen postmenopausal women were fed a basal diet that provided 101 mg (4.16 mmol) Mg/2000 kcal (8.4 MJ) for 78 days then replenished with Mg by supplementing the diet with 200 mg (8.23 mmol) Mg/day for 58 days. In this experiment, some subjects exhibited heart rhythm changes that resulted in an earlier entry in the magnesium repletion period. Experiment 2 had a depletion-repletion design after a 35-day equilibration period [4]. Ten women consumed diets containing 112 mg (4.61 mmol) Mg/2000 kcal (8.4 MJ) supplemented with 200 mg (8.23 mmol) Mg/day for 35 days (equilibration), then 112 mg (4.61 mmol)/2000 kcal (8.4 MJ) for 93 days (depletion), followed by 112 mg (4.61 mmol) Mg/2000 kcal (8.4 MJ) supplemented with 200 mg (8.23 mmol) Mg/day for 49 days (control). Experiment 3 had a double-blind crossover design after an 18-day equilibration period in which the basal diet was supplemented with 220 mg (9.05 mmol) Mg/day [5]. The supplemental magnesium was higher in this experiment than in the other three experiments because of the lower basal diet magnesium content. The basal diet contained 78 mg (3.20 mmol) Mg/2000 kcal (8.4 MJ). Fourteen women were divided into two groups where one group was fed the basal diet supplemented with a lactose placebo while the other group continued consuming the basal diet supplemented with 220 mg (9.05 mmol) Mg/day for 72 days, then each group switched to the other’s diet for 72 days. Experiment 4 also used a randomized, double-blind, cross-over design after a 10-day equilibration period in which the basal diet was supplemented with 200 mg (8.23 mmol) Mg/day [6]. The basal diet contained 99 mg (4.07 mmol) Mg/2000 kcal (8.4 MJ). In this experiment, nine women were fed a diet containing 1.0 mg (16 μmol) Cu/2000 kcal (8.4 MJ) and 10 women were fed 3.0 mg (47 μmol) Cu/2000 kcal (8.4 MJ) for 162 days. These groups were divided into two where one consumed the basal diet while the other continued consuming the basal diet supplemented with 200 mg (8.23 mmol) Mg/day for 81 days, then each group switched to the other diet for 81 days. The mean daily intakes for each group after equilibration are shown in Table 1.

Cross-Sectional Balance Data Experiment

Balance data using methods described above were obtained from 27 different tightly controlled metabolic unit studies of 93 men and 150 women in which dietary Mg ranged from 84 to 598 mg (3.46 to 246 mmol)/day [7]. The ages of the subjects ranged from 19 to 77 years, and weight ranged from 46 to 136 kg.

Results

Experiment 1

Six days after the start of consuming diets providing a mean of 104 mg (4.28 mmol)/day, mean urinary Mg excretion of the 13 women was 65 mg (2.67 mmol)/day and decreased very slowly to slightly less than 60 mg (2.47 mmol)/day during the next 72 days (Fig. 1). Six days after supplementing the women with 200 mg (8.23 mmol) Mg/day as Mg gluconate for a mean total intake of 308 mg (12.67 mmol)/day, urinary Mg rose to about 92 mg (3.78 mmol)/day and by day 12 had increased to about 105 mg (4.32 mmol)/day, which continued for the last 52 days of the experiment.

Fig. 1
figure 1

Experiment 1, urinary magnesium excretion by 14 postmenopausal women during 78 days of dietary magnesium depletion [mean intake of 104 mg (4.28 mmol)/day] followed by 58 days of magnesium repletion [mean intake of 308 mg (12.67 mmol)/day]

Full size image

Although urine Mg was found to respond significantly and as expected to the Mg depletion-repletion protocol, serum Mg concentration did not significantly change. As shown graphically previously [3], the women began the experiment with a mean serum Mg concentration that was slightly less than 0.79 mmol/L (1.9 mg/dL). During depletion, the concentration dropped to a mean of slightly less than 0.72 mmol/L (1.75 mg/dL) at day 20 but increased to 0.78 mmol at day 40 and varied between 0.80 and 0.78 mmol/L for the rest of the period. The increase in the latter part of depletion likely was partly caused by removal of four women from the data set because of heart rhythm changes: one at 42 days, another at 52 days, and two at 64 days. These women were included in the mean concentrations shown during Mg supplementation period. The supplementation of 200 mg (8.23 mmol)/day for 58 days did not raise the mean serum Mg concentration over 0.74 mmol/L (1.8 mg/dL).

In this experiment, women consuming a mean of 104 mg (4.28 mmol) Mg/day between 42 and 78 days were becoming or became Mg-deficient based on the finding of abnormal heart rhythms, impaired glucose tolerance, and decreased serum cholesterol and erythrocyte superoxide dismutase (SOD) concentrations [3]. In addition, blood pressure increased in one woman. All of these changes were reversed when the women consumed 308 mg (12.67 mmol) Mg/day.

Experiment 2

This depletion-repletion experiment was designed to have all subjects begin the depletion period with a relatively similar Mg status by having an equilibration period of 35 days with a mean Mg intake of 322 mg (13.24 mmol)/day [4]. The mean Mg intake was higher than in experiment 1 during the depletion [146 mg (6.00 mmol)day] and repletion [360 mg (14.8 mmol)/day]. Figure 2 shows that during the equilibration period, the subjects excreted about 110 mg (4.52 mmol) Mg/day in the urine. Within 6 days after starting the depletion period, urinary magnesium excretion decreased to about 75 mg (3.08 mmol)/day and was maintained near that level during the rest of the period. Within 6 days after Mg repletion, urinary Mg rose to near 110 mg (4.52 mmol)/day and stayed at that level during the rest of the period.

Fig. 2
figure 2

Experiment 2, urinary magnesium excretion by 10 postmenopausal women during a 35-day equilibration [mean intake of 322 mg (13.24 mmol)/day], 93 days of dietary magnesium depletion [mean intake of 146 mg (6.01 mmol)/day], and 49 days of magnesium repletion [mean intake of 360 mg (14.81 mmol)/day]

Full size image

Similar to experiment 1, serum Mg concentration did not reflect the changes in dietary Mg well. As shown graphically previously [4], serum Mg concentration was 0.85 mmol/L (2.06 mg/dL) during equilibration, decreased nonsignificantly to 0.82 mmol/L (1.99 mg/dL) during depletion and rose again to 0.85 mmol/L during repletion.

The subjects apparently became or were becoming Mg-deficient during the Mg-deficient period because they exhibited impaired metabolic responses during submaximal exercise. Peak oxygen uptake, total and cumulative net oxygen uptake, and peak heart rate increased during a standardized submaximal work program in the Mg-deprived women [4].

Experiment 3

In this double-blind crossover experiment, after an 18-day equilibration with a diet providing a mean Mg intake of 327 mg (13.45 mmol)/day, the women that continued consuming the Mg-supplemented diet [mean intake 330 mg (13.57 mmol)/day] for 72 days maintained a daily urinary excretion of 110 mg (4.52 mmol)/day (Fig. 3). Women starting on the diet providing a mean of 107 mg (4.40 mmol) Mg/day after the equilibration period decreased their urinary Mg excretion to about 45 mg (1.85 mmol)/day within 6 days and remained near that level for the remaining 60 days of the depletion period. The urinary Mg excretion of this group of women increased to 90 mg (3.70 mmol)/day within 6 days and rose to 100 mg (4.11 mmol) Mg/day by day 12 after Mg supplementation resulting in a mean intake of 324 mg (13.33 mmol)/day, but did not increase to that of the group that started on the Mg-supplemented diet providing a mean intake of 330 mg (13.58 mmol)/day until the last 18 days of the repletion period. The group that started on the Mg-supplemented diet exhibited a decrease in urinary Mg excretion upon being placed on the Mg-deficient diet providing a mean intake of 113 mg (4.65 mmol)/day as rapidly as the women starting on the Mg-deficient diet. Urinary Mg decreased to about 70 mg (3.08 mmol)/day within 6 days and to about 55 mg (2.26 mmol)/day 12 days after starting the Mg-deficient diet (Fig. 3).

Fig. 3
figure 3

Urinary magnesium excretion by 14 postmenopausal women participating in experiment 3 with a double-blind, crossover design. Mean dietary magnesium intake during 72 days for women starting depletion first was 107 mg (4.40 mmol)/day and for women starting depletion second was 113 mg (4.65 mmol)/day. Mean dietary intake during 72 days for women starting supplementation first was 330 mg (13.57 mmol)/day and for women supplemented with magnesium second was 324 mg (13.33 mmol)/day

Full size image

Figure 4 shows that the serum Mg responses to the dietary Mg changes were inconsistent in this experiment. Women that were on the Mg depletion period initially showed changes similar to experiment 1 in that serum Mg slightly declined from about 1.95 mg/dL (0.80 mmol/L) to 1.87 mg/dL (0.77 mmol/L) during the first 3 weeks of the study but then rebounded back to about 1.95 mg/dL (0.80 mmol/L) where it remained during the rest of depletion. Unlike experiment 1, the women in this group responded to Mg supplementation, with serum Mg values ranging from about 2.05 to 2.15 mg/dL (0.84 to 0.88 mmol/L) during the repletion period. Women consuming the Mg-supplemented diet first had mean serum Mg concentrations also in this range during the supplementation period. The women that began the study consuming a mean of 330 mg (13.58 mmol)/day for 90 days did not show a decrease in mean serum Mg concentration even after 72 days of consuming the diet that provided only a mean of 113 mg (4.65 mmol)/day (Fig. 4).

Fig. 4
figure 4

Serum magnesium concentrations in 14 postmenopausal women participating in experiment 3 with a double-blind, crossover design. Mean dietary magnesium intake during 72 days for women starting depletion first was 107 mg (4.40 mmol)/day and for women starting depletion second was 113 mg (4.65 mmol)/day. Mean dietary intake during 72 days for women starting supplementation first was 330 mg (13.57 mmol)/day and for women supplemented with magnesium second was 324 mg (13.33 mmol)/day

Full size image

Although serum Mg concentration did not decrease when Mg depletion followed the Mg supplementation period, three individuals exhibited changes during this depletion period that responded to Mg supplementation [5]. These changes were abnormal heart rhythm, increased blood pressure, and poor wound healing. In addition, the women in this group had a similar decrease in potassium excretion and increase in calcium balance during Mg depletion as women that consumed the Mg-deficient diet first.

Experiment 4

The urine and serum findings in this study [6] were similar to those found in experiment 3. Before entering the double-blind, crossover-designed experiment 4, the 19 women were subjected to a 10-day equilibration period in which they consumed a mean 299 mg (12.30 mmol) Mg/day. Figure 5 shows the urinary Mg excretion after the equilibration period. When the women were fed the basal diet providing 1 mg (16 μmol) Cu/day, mean urinary Mg excretion was 58 mg (2.39 mmol)/day 6 days after they started consuming the basal diet providing a mean of 116 mg (4.77 mmol) Mg/day. This level of excretion changed little throughout the Mg depletion period with the ending mean excretion being 63 mg (2.59 mmol)/day. Six days after starting to consume the basal diet plus a Mg supplement that provided a mean of 426 mg (17.52 mmol) Mg/day, mean urinary Mg excretion was already 132 mg (5.43 mmol)/day, a level that decreased slightly to 127 mg (5.22 mmol)/day at the end of the Mg supplementation period. Women fed the low-copper diet and started the experimental period by consuming the basal diet plus Mg supplementation providing 390 mg (16.04 mmol) Mg/day (a value different from the group consuming the Mg-supplemented diet second because of different caloric intakes) were excreting a mean 130 mg (5.35 mmol) Mg/day by day 6; this level of excretion decreased to 120 mg (4.93 mmol)/day during the last 6 days of this period. Six days after starting the diet supplying a mean 120 mg (4.94 mmol) Mg/day, the mean urinary Mg excretion in these women decreased to 63 mg (2.59 mmol)/day and remained at this level throughout the depletion period. Similar urinary Mg changes in response to changes in dietary Mg were obtained when the women consumed a basal diet providing 3 mg (47 μmol) Cu/day (Fig. 5). However, overall Mg excretion was slightly higher. When the women consumed the high Cu basal diet providing a mean of 122 mg (5.02 mmol) Mg/day first, mean urinary Mg excretion was 75 mg (3.08 mmol)/day by day 6 and remained about that level for the rest of this dietary period. Six days after switching to the diet providing a mean of 424 mg (17.44 mmol) Mg/day, mean urinary Mg excretion was 146 mg (6.01 mmol)/day, a level that was maintained for the rest of the dietary period. Similar daily Mg excretion during Mg depletion and repletion was observed in the group that was fed the Mg-supplemented diet providing a mean of 404 mg (16.62 mmol) Mg/day before the basal diet providing 141 mg (5.80 mmol) Mg/day.

Fig. 5
figure 5

Urinary magnesium excretion by 19 postmenopausal women consuming either a 1.0 mg/2000 kcal (16 μmol/8.4 MJ) or b 3.0 mg/2000 kcal (47 μmol/8.4 MJ) copper (Cu) in experiment 4 with a double-blind crossover design. Mean dietary magnesium during 81 days of depletion for women starting depletion first was 116 mg (4.77 mmol)/day and 122 mg (5.02 mmol)/day in the low and high Cu groups, respectively, and 120 mg (4.94 mmol)/day and 141 mg (5.80 mmol)/day in the low and high Cu groups, respectively, for women starting depletion second. Mean dietary magnesium during 81 days for women starting supplementation first was 390 mg (16.04 mmol)/day and 404 mg (16.62 mmol)/day in the low and high Cu groups, respectively, and 426 mg (17.52 mmol)/day and 424 mg (17.44 mmol)/day in the low and high Cu groups, respectively, for women starting depletion second

Full size image

Similar to the previous three experiments, serum Mg concentrations responded inconsistently to Mg deprivation (Fig. 6). When dietary copper was low, the women consuming the basal diet providing a mean of 122 mg (5.02 mmol) Mg/day first exhibited a slight increase in serum Mg concentration during the first 40 days before decreasing below 2.0 mg /dL (0.82 mmol/L) and then again increasing so the concentration at the end of the 81 days of deprivation was essentially the same as the beginning. When dietary copper was high, serum Mg concentrations in the Mg depletion period did not decrease but instead increased slightly from 1.95 mg/dL (0.80 mmol/L) to 2.05 mg/dL (0.84 mmol/L) before decreasing to about the same level as the beginning of the period. Whether low or high dietary copper was consumed by the women fed the Mg-deficient diet first, serum Mg increased the first 30–40 days after Mg supplementation to concentrations of 2.3 mg/dL (0.95 mmol/L), but after that, decreased to concentrations at the end of the dietary period of 2.2 mg/dL (0.92 mmol/L). When the women were fed the diet providing a mean of 390 or 404 mg (16.04 or 16.62 mmol) Mg/day first, the serum Mg concentration did not vary much from about 2.05 mg/dL (0.84 mmol/L) during this period. Although it appeared that serum Mg concentration decreased to 1.95 mg/dL (0.80 mmol/L) 60 days after Mg depletion started in the women supplemented with Mg first, the concentration returned to 2.05 mg/dL (0.84 mmol/L).

Fig. 6
figure 6

Serum magnesium concentrations by 19 postmenopausal women consuming either a 1.0 mg/2000 kcal (16 μmol/8.4 MJ) or b 3.0 mg/2000 kcal (47 μmol/8.4 MJ) copper in experiment 4 with a double-blind crossover design. Mean dietary magnesium during 81 days of depletion for women starting depletion first was 116 mg (4.77 mmol)/day and 122 mg (5.02 mmol)/day in the low and high Cu groups, respectively, and 120 mg (4.94 mmol)/day and 141 mg (5.80 mmol)/day in the low and high Cu groups, respectively, for women starting depletion second. Mean dietary magnesium during 81 days for women starting supplementation first was 390 mg (16.04 mmol)/day and 404 mg (16.62 mmol)/day in the low and high Cu groups, respectively, and 426 mg (17.52 mmol)/day and 424 mg (17.44 mmol)/day in the low and high Cu groups, respectively, for women starting depletion second

Full size image

Although serum Mg concentrations never decreased to a mean less than 1.95 mg/dL (0.80 mmol/L) during the 81-day Mg depletion periods in this experiment and dietary copper affected the response to Mg deprivation, some women exhibited apparently Mg deficiency signs [6]. Three women consuming the low-copper, Mg-deficient diet exhibited heart rhythm ectopy that responded to Mg supplementation but not copper supplementation. Women consuming the Mg-deficient diet first exhibited decreased serum cholesterol, a finding similar to that obtained in experiment 1 [3].

Cross-Sectional Balance Study

This study [7] found that neutral Mg balance, without considering surface or phlebotomy losses, occurred at an Mg intake of 165 mg (6.79 mmol)/day with a 95 % prediction interval of 113 and 237 mg (4.65 and 9.75 mmol)/day. The balance data also indicated that neutral balance based on body weight was 2.36 mg (0.97 mmol)/kg/day with a 95 % prediction interval of 1.58 to 3.38 mg (0.65 to 1.46 mmol)/kg/day. Urinary excretion data from this study is shown in Fig. 7. These data indicate when intakes were 200 mg (8.22 mmol)/day or lower urinary Mg excretion generally ranged from 40 to 80 mg (1.65 to 3.29 mmol)/day. When dietary Mg intakes were greater than 250 mg (10.28 mmol)/day, urinary Mg excretion generally ranged from 80 to 160 mg (3.29 to 6.58 mmol)/day.

Fig. 7
figure 7

Urinary magnesium excretion by 93 men and 150 women participating in 27 different tightly controlled metabolic unit studies in which dietary magnesium ranged from 84 to 598 mg (3.46–246 mmol)/day

Full size image

Discussion

Nutritional Significance of Magnesium

Based on the estimated average requirements (EARs) and recommended dietary allowances (RDAs) set for various age and gender groups by the Food and Nutrition Board in 1997 [11], deficient Mg intakes commonly occur throughout the world. The EAR and RDA, respectively, for adult women aged between 19 and 30 years were set at 255 and 310 mg (10.49 and 12.75 mmol)/day, and those aged between 31 and 70 years set at 265 and 320 mg (10.90 and (13.16 mmol)/day. The EAR and RDA, respectively, for adult men aged between 19 and 30 years were set at 330 and 410 mg (13.57 and 16.86 mmol)/day, and those aged between 31 and 70 years was set at 350 and 420 mg (14.40 and 17.28 mmol)/day. In the USA, the National Health and Examination Survey (NHANES) in 2005/2006 [12] indicated that approximately 60 % of all adults had deficient dietary magnesium intakes. As a result, the 2015 Dietary Guidelines indicated that magnesium is a shortfall nutrient [13]. Many of the deficient Mg intakes would be in the range of 50 to 99 % of the Dietary Recommended Intakes (DRIs) [12]. If Mg deficiency is present in individuals with these intakes, the deficiency would be considered moderate or marginal, or subclinical. This subclinical deficiency also has been called chronic latent Mg deficiency [14].

Findings from animals indicate that signs of mild or moderate Mg deficiency might be hard to detect unless it is long term or exacerbated by some other factor like chronic inflammatory stress [15, 16]. Nonetheless, subclinical, or chronic latent Mg deficiency suggested by low dietary, serum, plasma, and urinary Mg often has been associated with the risk of chronic disease [10, 17], which makes some scientists conclude that Mg is of significant nutritional importance. However, because relating specific pathological conditions to dietary Mg deficiency alone is difficult [10], other scientists have concluded that Mg is not a nutrient of substantial public health concern [13]. Magnesium often is considered of significant concern for health and well-being mainly for individuals that take medications or have disorders that inhibit its absorption or induce its excretion [18].

These disparate views about the nutritional importance of Mg probably occur because evidence of Mg deficiency is not consistently found in pathological conditions with which it is often associated, and not all individuals considered to be Mg-deficient exhibit some type of pathology. These inconsistencies may be partly caused by the inaccurate diagnosis of Mg deficiency because of faulty DRIs and indicators of status.

Magnesium Requirements

The cross-sectional balance data findings of Hunt and Johnson [7] suggest that the use of the EARs or RDAs for magnesium set in 1997 [11] to indicate when a person is Mg-deficient may have resulted in faulty determinations of the occurrence of Mg deficiency. These DRIs were based on highly variable balance data from 16 men and 18 women on self-selected diets that decreased in Mg during the balance periods [19]; this decrease could have influenced balance values. Some subjects on Mg intakes less than 258 mg (10.61 mmol)/day had equilibrium or positive Mg balance. On the other hand, some subjects with intakes greater than 299 mg (12.30 mmol)/day had a negative Mg balance. The DRIs based on this balance study have been questioned and, based on the cross-sectional balance data [7], may be too high. The neutral balance value and the upper prediction interval value of the cross-sectional balance data [7], without considering surface and phlebotomy losses, suggest that the Mg EAR and RDA for a healthy 70-kg individual would be 170 mg (6.99 mmol)/day and 245 mg (10.08 mmol)/day, respectively [20]. These values likely would be about 5 mg (0.21 mmol)/day higher if surface and phlebotomy losses during the balance determinations had been considered. The neutral balance value based on body weight [2.36 mg (0.097 mmol)/day/kg] indicates that requirements probably should be based on body weight. Support for the suggestion that current EARs and RDAs are too high is the report that balance and absorption data from German women and men indicated that normative Mg requirement was satisfied by an intake of <200 mg (8.23 mmol)/day for women and 250 mg (10.28 mmol)/day for men, or <3.0 mg (0.123 mmol)/day/kg body weight [21]. In addition, a study with female adolescents aged 11–15 years weighing about 55 kg gave findings suggesting that a Mg intake of 2.94 mg (0.121 mmol)/day/kg body weight, or about 150 mg (6.17 mmol)/day, was inadequate and that 4.26 mg (0.175 mmol)/day/kg body weight, or 232 mg (9.54 mmol)/day, was adequate [22]. These balance data suggesting decreased EARs and RDAs indicate that concluding some individuals were Mg-deficient based on deficient intakes according to the 1997 EARs and RDAs may have not been correct. Because individuals were actually consuming adequate Mg, this could be the reason for finding no pathology, or no response with Mg supplementation, in individuals assessed as Mg-deficient.

Magnesium Status Assessment Using Urinary Magnesium

All the urinary data presented here show that urinary Mg excretion is an excellent indicator of Mg intake. This conclusion is consistent with that obtained from the analysis of data from 14 randomized control trials and 5 before/after studies [23]. The present data indicate that a urinary Mg excretion below 80 mg (3.29 mmol)/day would be evidence of a dietary intake of less than 200 mg (8.23 mmol) Mg/day, which would be lower than the suggested RDA of 250 mg (10.28 mmol)/day for a healthy 70-kg male or female [20]. Furthermore, the four Mg experiments indicate that a urinary excretion between 40 and 70 mg (1.65 and 2.88 mmol)/day might be evidence of a Mg intake less than the suggested EAR of 175 mg (7.20 mmol)/day [20]. On the other hand, a urinary Mg excretion >80 mg (3.29 mmol)/day, and especially >100 mg (4.11 mmol)/day, would suggest that intakes generally above 250 mg (10.28 mmol)/day would be adequate for most healthy 70-kg individuals.

The four experiments presented here show that a single determination or short-term 24-h urinary Mg determinations cannot be used as a stand-alone indicator of magnesium status. Because of the rapidity of the change in urinary magnesium excretion in response to the change in dietary intake, such a determination may be showing just a recent deficient or adequate intake of Mg. Thus, an individual could have a low dietary intake or urinary excretion of Mg and still have an adequate Mg status, or vice versa.

However, studies involving a large number of individuals likely will include a majority of long-term Mg-deprived individuals when their urinary Mg excretion is below 80 mg (3.29 mmol)/day and a majority of long-term Mg-adequate individuals when their urinary Mg excretion is above 80 mg (3.29 mmol)/day [23]. Thus, similar to dietary Mg intake assessments, urinary magnesium may be useful in showing an association between a low Mg intake and some pathological conditions. Two recent studies have demonstrated that urinary Mg can be used in this manner. Joosten et al. [24] divided the urinary Mg excretion of 7664 adults into quintiles. The lowest sex-specific quintile (<71 mg (2.93 mmol)/day for men and <60 mg (2.45 mmol)/day for women) had an increased risk for fatal and nonfatal ischemic heart disease compared with the upper four quintiles of urinary Mg excretion. In another multi-center cross-sectional study of 12,335 middle-aged men and women, an inverse relation was found between 24-h urinary Mg and cardiovascular risk factors [25].

Magnesium Status Assessment Using Plasma/Serum Magnesium

Currently, a Mg concentration below 1.82 mg/dL or 0.75 mmol/L often is used as an indication of Mg deficiency. This is based on a reference interval of 0.750 to 0.955 mmol/L (1.82 to 2.32 mg/dL) determined by the distribution of serum Mg in a supposedly normal population [26]. Using the lower value in this distribution as an indicator of Mg deficiency is supported by numerous studies showing an association between Mg deficiency and chronic disease [27–33]. However, some of these studies show that using the lower value as a cutoff point for establishing Mg deficiency in an individual might be invalid. Changes in serum/plasma Mg shown graphically [31–33] indicate that many individuals with concentrations between 0.75 mmol (1.82 mg/dL) and 0.80 mmol/L (1.94 mg/dL) also have an increased chronic disease risk [31–33]. The four Mg experiments described here also show that individuals with serum Mg concentrations approaching 0.85 mmol/L (2.06 mg/dL) may be Mg-deficient; individuals with such serum Mg concentrations while consuming Mg-deficient diets exhibited changes in response to Mg supplementation.

The four experiments also found that consuming a Mg-deficient diet for 72 to 92 days did not markedly decrease serum Mg concentration. Although serum Mg concentration increased immediately after Mg supplementation of magnesium-deprived individuals in the four studies, in two studies the increase shortly thereafter declined to values near to those at the end of depletion, and in one study the increase was not significant. These findings support the conclusion of Elin [14] that changes in serum magnesium concentration to a new equilibrium normally occur very slowly over a period of months to years in the normal individual.

Reported [14] and the present findings indicate that individuals with serum concentrations below 0.75 mmol/L (1.82 mg/dL) most likely are Mg-deficient and individuals with concentrations higher than 0.85 mmol/L (2.06 mg/dL) most likely have an adequate Mg status. Findings from the controlled metabolic unit studies show that serum Mg concentrations between 0.75 and 0.85 mmol/L (1.82 and 2.06 mg/dL) have limited value for assessing Mg status of an individual. In the past, individuals assessed as Mg-adequate based on the current reference interval may have been Mg-deficient, and vice versa. As a result, this has hampered the determination of Mg requirements and the nutritional significance of magnesium.

Conclusions

Metabolic unit Mg balance and depletion/repletion experiments provide reasons for the difficulty in determining whether Mg is a nutrient of public health concern. The major reason is that the determination of the occurrence of Mg deficiency has been hampered by using questionable DRIs and a faulty reference range for serum Mg. Balance data obtained since 1997 indicate that the Mg EAR and RDA for 70-kg healthy individuals are about 175 and 250 mg/day, respectively, and these DRIs decrease or increase based on body weight. Urinary excretion data from tightly controlled metabolic unit balance studies indicate that 40 to 80 mg (1.65 to 3.29 mmol) Mg/day are excreted when Mg intakes are <250 mg (10.28 mmol)/day, and 80 to 160 mg (3.29 to 6.58 mmol) Mg/day when intakes are >250 mg (10.28 mmol)/day. Urinary excretion of Mg changes from >100 mg (4.11 mmol)/day to <80 mg (3.29 mmol)/day within 6 days after dietary Mg is reduced from 300 to 400 mg (12.34 to 16.45 mmol)/day to <150 mg (6.17 mmol)/day, and vice versa. Thus, urinary Mg excretion may be low while an individual still has an adequate status, and vice versa. Urinary Mg as a stand-alone status indicator would be most useful for population studies, and not useful for individual status assessment. Depletion/repletion experiments show that serum Mg concentrations decrease only after a prolonged depletion; more than 80 days are needed if an individual has good Mg reserves at the start of depletion. As a result, some individuals with serum Mg concentrations approaching 0.85 mmol/L (2.06 mg/dL) might be Mg-deficient based on the finding that such individuals can have physiological changes that respond to Mg supplementation. Thus, using the current reference range for serum Mg of 0.750 to 0.955 mmol/L (1.82 to 2.32 mg/dL) to indicate an adequate Mg status needs revision because it can lead to faulty conclusions about the Mg status of an individual. Metabolic unit findings suggest that individuals with serum Mg concentrations >0.75 mmol/L (1.82 mg/L), or as high as 0.85 mmol/L (2.06 mg/dL), could have chronic latent Mg deficiency that would respond to Mg supplementation, stating that the normal concentration for serum magnesium starting in this range may be inappropriate. Determinations of daily dietary intake and urinary excretion of magnesium would be appropriate for individuals with a serum magnesium concentration in this range and with signs of a chronic disease associated with inflammatory stress. A dietary intake history showing <250 mg (10.28 mmol)/day and/or a urinary excretion of <80 mg (3.29 mmol)/day would support the presence of a chronic latent magnesium deficiency.