By Traci Pantuso, ND, MS

Adjunct Faculty, Research Investigator, Bastyr University, Seattle, WA

Dr. Pantuso reports no financial relationships relevant to this field of study.

EXECUTIVE SUMMARY

Magnesium is the fourth most common cation in the human body.

Magnesium is considered to be a shortfall nutrient and is a public health concern.

Magnesium deficiencies have been shown to increase chronic inflammatory responses in animal models and are associated with chronic diseases in humans.


Editor’s Note: Magnesium, an important dietary ingredient and supplement, has both long-standing and emerging clinical evidence for efficacy in treating a variety of health conditions. To do this mineral justice, we are covering this extensive information in two parts. Part 1 will focus on basic science and physiology, general dietary recommendations, supplemental forms, laboratory testing, and dosing. Part 2 will review some of the clinical trials and research on the connection between low magnesium intake and diseases, such as diabetes, as well as the data on the use of supplemental magnesium for treatment of these diseases.
— David Kiefer, MD, Editor

An essential mineral required by the human body, magnesium is involved in a diverse range of physiological functions and is a cofactor in an estimated 600 enzymatic reactions.1-3 These enzymatic reactions include those involved with the synthesis of nucleic acids and proteins involved with deoxyribonucleic acid and ribonucleic acid, mitochondrial function, glycolysis, and the maintenance of ionic gradients between intracellular and extracellular compartments.1-3 Because of the importance of magnesium in the body, its availability is closely regulated in the human body through a number of mechanisms.1-6 The three main mechanisms include gastrointestinal (GI) absorption, renal excretion and reabsorption, and exchange between bone magnesium stores and magnesium throughout the rest of the body.1-6 When there is decreased intake of magnesium, there is increased absorption of magnesium in the GI tract and decreased renal excretion in the urine, and magnesium is progressively liberated from bone reserves.5,6 Adequate magnesium in the diet results in decreased absorption in the GI tract, increased magnesium excreted into urine, and a higher amount of magnesium stored in the bone.5,6 As a result of the body’s ability to maintain magnesium homeostasis, it has been difficult to establish clinically relevant tests that reflect the body’s magnesium status.7 However, decreased magnesium levels demonstrated through dietary intakes, serum magnesium concentrations, and urinary magnesium excretions have been associated with a number of chronic diseases, including cardiovascular disease, prediabetes, type 2 diabetes, and chronic kidney disease.1-4,7-11

Signs and symptoms describing magnesium deficiency in humans were first reported in 1969; since then, experts have suggested various dietary reference intakes.1-3,12,13 Symptoms of elevated magnesium (hypermagnesemia) and low magnesium (hypomagnesemia) are varied because of the number of diverse reactions in which magnesium is involved.1-7 Hypermagnesemia symptoms include nausea, vomiting, flushing, muscle weakness, slurred speech, tachycardia, and, on EKG, prolongation of PR, QRS, and/or QT complexes.1-4 Hypomagnesemia symptoms depend on the severity of the deficiency and on any concurrent electrolyte disturbances, such as hypocalcemia and or hypokalemia.1-4 A general symptom is fatigue, but more specific symptoms include neuromuscular symptoms, such as tremors, tetany, nystagmus, and arrhythmias.1-4 A classic sign of severe hypomagnesemia is hypocalcemia.1-4

Clinical magnesium deficiency signs have not been recognized routinely in the healthy population. Individuals with chronic health issues, such as migraine, obesity, cardiovascular disease, and diabetes, have been found to have low magnesium intake and/or magnesium status.1-4 The normal total serum magnesium concentration range is considered to be between 1.7 and 2.3 mg/dL.1-4 Patients with serum magnesium levels < 1.7 mg/dL are considered to be hypomagnesemic, and patients with levels < 1.2 mg/dL are considered to have severe hypomagnesemia.1-4 Patients with serum levels > 2.5 mg/dL are hypermagnesemic and this level is rarely seen in people with normal kidney function.1-4 Because 99% of magnesium is intracellular, serum magnesium concentrations are not reflective of total body magnesium levels, and may not be the most accurate laboratory test for quantifying magnesium status.1-4

Recent population studies have demonstrated decreased magnesium intake. For example, the U.S. Department of Agriculture reports that the average magnesium intake is 228 mg/day for women and
323 mg/day for men, which is below the RDA.14 In the National Health and Nutrition Examination Survey I (NHANES) 2007-2010 report, the authors found that the majority of teens and adults over the age of 70 years consumed less than their estimated average requirement (EAR) of magnesium per day.15 These reports of decreased magnesium intake instigated the 2015 Dietary Guidelines Advisory Committee to consider magnesium a shortfall nutrient that is being under-consumed relative to the EAR for many Americans.16

Recommended Dietary Allowance (RDA) and Estimated Average Requirement (EAR)

RDA for magnesium varies by age and sex. For females 19-30 years of age it is 310 mg/day and for males 19-30 years of age it is 400 mg/day.12 (See Table 1.) Requirements for magnesium increase during pregnancy and lactation.12 (See Table 2.)

Tolerable upper limits exist only for supplemental magnesium and are as follows: 350 mg for all adults, 110 mg for children between 4 and 8 years of age, and 65 mg for children between 1 and 3 years of age.12

Table 1: Recommended Dietary Allowance for Magnesium in Males and Females12

Age

Male

Female

Birth to 6 months

30 mg

30 mg

7-12 months

75 mg

75 mg

1-3 years

80 mg

80 mg

4-8 years

130 mg

130 mg

9-13 years

240 mg

240 mg

14-18 years

410 mg

360 mg

19-30 years

400 mg

310 mg

31-51+ years

420 mg

320 mg

Table 2: Recommended Dietary Allowance for Magnesium in Females During Pregnancy and Lactation12

Age

Pregnancy

Lactation

14-18 years

400 mg

360 mg

19-30 years

350 mg

310 mg

31-51+ years

360 mg

320 mg

Current RDAs are determined from the EAR that is set by official committees.2,7,17 The EARs are defined as the daily intake required to meet 50% of the healthy population needs.2,7 The RDA is the daily intake that is required to meet 98% of the healthy population’s daily requirement.2,7 Since researchers investigating the EARs and RDAs of magnesium have not been able to adequately determine total body magnesium status and associate that value with
magnesium intake, the current RDAs are thought to be inadequate.2,7,17 Additionally, the current RDAs and EARs have been called into question since the U.S. food supply has changed and the incidence of diseases, such as diabetes and obesity, affect magnesium status.2,4,7,17

Magnesium Physiology

Magnesium is absorbed throughout the GI tract, with the ileum and jejunum absorbing an estimated 78% of dietary magnesium.1-4 Two transport mechanisms are responsible for the absorption of magnesium.1,2,5 One transport mechanism is passive and the other is active.1,2,5 The passive diffusion of magnesium occurs in the small intestine and is responsible for 80-90% of magnesium absorption. The active transport mechanism is the prevailing mechanism when intestinal magnesium concentrations are low, and it relies on the transient receptor potential channel melastatin proteins (TRPM6 and TRPM7).1,2,5 The active transport system is responsible for 10-20% of total magnesium absorbed in the distal small intestine and colon.5 However, when magnesium levels are low, the active transport system can increase absorption to 30-50% of ingested magnesium.1,2,5,18 Once magnesium is absorbed into the bloodstream it is distributed throughout the body. Blood magnesium is found in the serum (0.3% of total body magnesium) and red blood cells (0.5% of total body magnesium). The bone is the most significant storage area for magnesium; an estimated 53% of total body magnesium is in the bone. The homeostasis of magnesium is largely managed by the kidney, GI tract, and bone. Magnesium excretion is controlled mostly by the kidney, which can filter up to 2,400 mg of magnesium per day, with approximately 5% excreted in the urine and 95% reabsorbed. The majority of the reabsorption of magnesium takes place in the loop of Henle and not in the proximal tubule.The plasma concentration of magnesium is the main factor in the reabsorption of magnesium by the kidney. However, reabsorption also is affected by hormones (parathyroid hormone, calcitonin, glucagon, and estrogen) and certain medications.1,2,5,18 (See Table 3.) For example, diuretics and certain chemotherapy medications can cause abnormally high magnesium excretion.19-21 Use of proton pump inhibitors (PPIs) for a year or more are associated with hypomagnesemia.20,21 The PPIs may decrease the active absorption of magnesium through the TRPM protein channels.20,21

Table 3: Effects of Medications on Magnesium Status and Recommendations for Clinical Dosing

Medication Class

Effect on Magnesium Status

Clinical Recommendation

Bisphosphonates

High levels of magnesium can decrease the absorption of oral bisphosphonates used to treat osteoporosis.

Separate administration of magnesium and bisphosphonate by two hours.

Some antibiotics

Formation of insoluble complexes occurs with tetracyclines as well as quinolones.

Take antibiotics two hours before or four to six hours after magnesium-containing supplements.

Diuretics

Loop diuretics increase the urinary excretion of magnesium, which can lead to magnesium depletion.

Potassium-sparing diuretics reduce magnesium excretions.

Consider alternative medication classes.

Proton pump inhibitors (PPI)

Can cause hypomagnesemia when taken for prolonged periods, such as more than one year.

Magnesium oral supplementation normally will increase the magnesium levels; however, in a quarter of cases, supplements did not raise the serum magnesium level after the PPI was discontinued.

FDA advises healthcare professionals to consider measuring patients’ serum magnesium levels prior to initiating long-term PPI treatment and to periodically check magnesium levels in these patients.

When medications are coupled with diseases that either reduce absorption through the gut or increase excretion through the kidney, hypomagnesemia can result.1,2,20,21 There also are heritable contributions to serum magnesium that negatively affect magnesium status including TRPM6 mutations, which decrease the absorption of magnesium and result in renal magnesium wasting.1

The Effect of Magnesium on Animal Physiology

Magnesium deficiency has been found to induce inflammatory responses and acute phase proteins in animal and in-vitro studies.2,4,8 It was first reported in 1932 that magnesium deprivation in rats resulted in an increased inflammatory response.22 Research continued on magnesium and its effects on the immune response, and in 2007, it was reported that limiting magnesium to 10% or less than the animals daily requirement affected an increased inflammatory response.23 These animal studies had short durations and the results are not likely translational.2,8 However, the authors of smaller animal studies have demonstrated that a long-term magnesium deficiency that is 25-50% of the requirement also resulted in increased inflammatory responses.2,8 The effects of a marginal magnesium deficiency are further affected by deficiencies in other anti-inflammatory compounds, such as omega-3 fatty acids, vitamin E, and selenium.2,8 The plausible mechanism of action of how magnesium deficiency increases inflammation is through increased priming of phagocytic immune cells.2,8 The increased intracellular calcium results from magnesium deficiency interfering with calcium transport, which may result in increased priming of the phagocytic immune cells.2,8 Increased priming in the phagocytic immune cells results in increased production and release of pro-inflammatory cytokines, such as substance P and tumor necrosis factor-alpha. The priming of the phagocytic cells also increases the activation of the transcription factor nuclear factor-kappa B, which results in the expression of numerous inflammation-related genes.2,8 Chronic activation of the phagocytic cells increases the generation of reactive oxygen species, which leads to inflammatory stress that is related to the development of chronic diseases.2,4,8

Measuring Magnesium Status

Serum magnesium. Total serum magnesium is the test most frequently ordered to assess magnesium status, but investigators have found it to be unreliable in recent literature reviews.9 In addition to not accurately reflecting total body magnesium status, the reference ranges for the total serum magnesium test were established from data taken from a U.S. study conducted during 1971 through 1974 in 15,820 participants who were between 18 and 74 years of age and who were presumed healthy. The normal reference range for the total serum magnesium test was established by taking the central 95th percentile, resulting in the normal reference range of 1.7-2.3 mg/dL.9,24 This reference range is problematic and may not be relevant as Americans in the 21st century have been found to consume less dietary magnesium.9,15 Investigators have found recently that individuals with chronic disease risk factors, such as inflammation, glucose intolerance, and elevated blood pressure, had a subclinical or chronic latent magnesium deficiency, with total magnesium serum levels between 1.7 and 2.0 mg/dL.4,9

Red blood cell magnesium testing. Erythrocytes contain elevated concentrations of magnesium compared to the serum.2,9,18,25 Erythrocyte magnesium levels vary depending on the age of the erythrocyte.9 However, the bulk of the studies using red blood cell (RBC) magnesium endpoints are not considered to be sufficiently robust or reliable.9 Also, the studies measuring RBC magnesium did not use a method that is validated through intercompartmental sampling.9 Because of the lack of studies demonstrating that RBC magnesium testing is reliable and an adequate representation of the body’s magnesium pool, it is not a recommended standalone test to evaluate magnesium levels in the body.9

Urinary magnesium. Because magnesium is excreted by the kidneys into the urine, and excretion changes depending on whether an individual is deficient or sufficient, urine magnesium testing may be valuable in evaluating magnesium status.9 No standard has been set for urinary magnesium excretion that indicates a deficiency.9 Controlled experiments that measure 24-hour urinary magnesium excretion have found that 40-80 mg is the range that is excreted when magnesium intake is < 250 mg/day, and 80-160 mg is the daily range excreted when intakes are > 250 mg/day. These amounts are independent of gender. Urinary magnesium excretion changes within a few days when the magnesium intake changes to > or < 250 mg/day.9

Ruling out hypomagnesemia in patients who are symptomatic with a total serum magnesium level is important. For patients who may be at risk for a subclinical or chronic latent deficiency and/or suffer from a chronic disease, ordering a total serum magnesium level is warranted.1,2,4,9 Combining the total serum magnesium level with a urinary magnesium excretion (available at most major labs) along with a dietary magnesium history appears to be the best method for getting a valid assessment of magnesium status.1,9,21 Magnesium deficiency should be considered as a potential contributing factor to chronic diseases when a total serum magnesium level is < 2.0 mg/dL, urinary magnesium excretion is < 80.0 mg/day, and magnesium intake is < 250 mg/day.4,9

Food Sources

Food sources rich in magnesium include whole seeds, unmilled grains, leafy green vegetables, legumes, and nuts.5 For example, almonds contain 80 mg of magnesium per 1 ounce serving and cooked black beans contain 60 mg per half cup.12 It is theorized that one major contributor to decreased magnesium consumption is lower amounts of magnesium in the food supply.4,17 The mineral content of the soil correlates directly to the concentration of minerals in the plants growing in that soil. Studies investigating the changes in concentrations of minerals in produce from the 1940s to the end of the 20th century indicate median declines of between 5% and 40% in fruits and vegetables.17 The magnesium content of cheese and meat also has declined, most likely due to decreased magnesium in animal feed. The exact measurement of magnesium content in foods is difficult to define since many variables, including processing, pretreatment of foods, and different methods of analysis, affect magnesium concentration in foods.17

Different Supplementation Forms

Oral supplementation. Magnesium absorption efficiency is affected by other dietary factors and, when given as a supplement, its chemical form. Lactose, fructose, and glucose enhance magnesium absorption, while other dietary factors, including fiber, high levels of zinc, oxalate, and free fatty acids, are known to inhibit magnesium absorption. Absorption of magnesium ranges from 35% to 70% in human studies investigating low-to-high magnesium intake. Normal intakes demonstrate that 30-40% of dietary magnesium is absorbed.5 However, in patients with decreased absorption due to inflammatory bowel disease, other inflammatory conditions affecting the small intestine, or surgical modifications, magnesium deficiency may be more common. A number of different forms of magnesium are sold in supplement form. Some evidence suggests that magnesium supplements that dissolve in liquid are better absorbed, and that magnesium in the forms of citrate, chloride, lactate, and aspartate are more bioavailable than magnesium in its oxide or sulfate forms.12 These studies need to be taken with a grain of salt since they are small and it is difficult to assess magnesium status, as noted earlier.

Labdoor, a third-party company that analyzes supplements for quality and label claims, analyzed 34 oral magnesium supplements on the market for elemental magnesium levels and contamination of heavy metals.26 Of the 34 supplements, the magnesium per serving ranged from 38.1 to 691.2 mg, with an average of 331 mg per serving.26 The supplemental magnesium amounts deviated from the label claims by an average of 11.5%. Of the products reviewed, 19 exceeded the tolerable upper intake level of magnesium, while 15 met the daily RDA.26 The products deviated from their label claims in the amount of magnesium in the supplement, with one supplement only containing 9.5% of the label claim and another having 97.5% more than the label claim.26 In 25 of the 34 supplements, the level of arsenic per serving was projected to exceed California Proposition 65’s proposed safe daily intake limit for inorganic arsenic.26 Six products contained the adulterant titanium dioxide, used as a whitening agent.26 Magnesium is sourced from sea water and mining, which makes heavy metal testing an important consideration when recommending magnesium supplements. Another independent supplement testing company, ConsumerLab, tested 27 oral magnesium supplements and determined that four were inadequate.27 It was found that one product did not reflect the amount on the label, two products failed the capsule/tablet disintegration test, and one product made health claims not consistent with FDA regulations.27

Skin absorption. There is limited, contradictory evidence regarding the transdermal absorption of magnesium.28 Much more research needs to be performed to understand whether clinically significant amounts of magnesium are absorbed through the skin.28,29

Intravenous. Intravenous (IV) magnesium is used to treat a number of conditions. Major medical organizations worldwide recommend magnesium sulfate for the prevention of eclampsia in women with pre-eclampsia.30 Magnesium sulfate also is a first-line therapy for long QT-related ventricular ectopic beats or torsades de pointes.11,21 Benefits are noted in patients who have normal serum magnesium levels at baseline. Magnesium sulfate also is recommended in multifocal atrial tachycardia in IV form if serum magnesium measures < 1.4 mg/dL.11,21 Integrative care providers that perform nutrient IV therapies commonly use magnesium, which is also a component of the Myers’ cocktail previously reviewed in this publication (See Integrative Medicine Alert, April 2017).31

Summary

Magnesium is one of the least studied macrominerals, especially when compared to iron and calcium. Research has been hampered by less than ideal diagnostic tests and the difficulty of making a clinical diagnosis using the nonspecific clinical signs and symptoms. Also, the presence of common comorbidities, such as diabetes and cardiovascular disease, further complicates the suspicion and diagnosis of magnesium deficiency. Currently, there is concern that the U.S. population may not be consuming enough magnesium through dietary intake. About 48% of Americans are not consuming enough magnesium, which may increase their risk of chronic disease and mortality, a fact that is further complicated by comorbidities and certain medication use.2,4

Magnesium deficiency may be an important factor in patients’ health. At this time, it is difficult to assess the parameters for a subclinical magnesium deficiency in patients. Better testing is needed to assess magnesium deficiency, particularly in its mild to moderate forms. Much more research needs to be performed so that we know the ideal daily magnesium intake for various demographics and can develop better testing to detect deficiencies in our patients.

Part two of this magnesium review will appear in an upcoming issue and address human clinical trials and clinical recommendations.

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