[Minerals] Vol. 18 No. 3 May/June 2013 Current Research on Comparative Utility of Magnesium Supplements By Robert DiSilvestro, Contributing Editor Magnesium is an essential nutrient with multiple functions; it is a cofactor in enzymes that require adenosine triphosphate (ATP) for activity, cell membrane stabilization, bone strengthening and various physiological signaling actions.1 These functions can impact the development and/or severity of multiple health problems. In addition, magnesium can play a role in exercise performance and recovery.2 Magnesium is best known by consumers to aid with the reduction of stress.3 Supplementing with magnesium has shown benefits for the heart,4 brain5 and skeletal system.6 Often, magnesium intake falls below recommended levels in healthy people. Moreover, magnesium requirements can be raised by a variety of circumstances such as physiological stress and the use of certain drugs, including proton pump inhibitors (used for digestive problems).7 Manifestations of a magnesium-deficient state may include cardiac arrhythmias, low blood pressure, restless leg syndrome, muscle spasm and weakness, agitation and anxiety, hyperventilation, nausea and vomiting, irritability, confusion, sleep disorders, insomnia, poor nail growth and even seizures.8 The response to correct such a deficiency should be to consume foods high in magnesium. However, the average American diet is poor in magnesium, and making dietary changes is not the typical response to nutrient insufficiencies. In some cases, a change in diet may not be possible due to financial restrictions or food availability. The next course of action is to take dietary supplements to amend the deficiency. A significant number of magnesium supplements are available, but it can be difficult for physicians and general consumers to know which magnesium form would be best to use. The form of magnesium taken is important. It could be assumed that taking any magnesium supplement it is better than nothing. However, studies have shown that just taking any magnesium may not help, and in some cases, may be detrimental due to poorly tolerated side effects. Magnesium Research Magnesium is available in two broad forms for supplementation: inorganic and organic. Inorganic refers to forms of magnesium which are not bound to a hydrocarbon molecule. It is difficult to ascribe direct biological benefits for humans from chemical properties or animal studies, or even single-dose bioavailability studies. The state of the research available for magnesium is far from complete, and the conclusions that have been drawn are far from clear. It would be reasonable to assume that better-absorbed magnesium supplements will exert desirable effects to a greater degree and more consistently than lesser-absorbed supplements. However, the effectiveness of a magnesium supplement may depend not only on absorption, but also on body retention and incorporation into functional sites. While these assumptions are logical, they cannot be verified to any great extent by existing data. To fully verify these concepts, a series of comparison studies would have to be done with multiple types of magnesium supplements, subjects and endpoints. The collection of such an accumulation of data would be an expensive endeavor and is not likely to be forthcoming any time soon. However, the general consumer is not completely without some relevant information that could point the way, albeit www.naturalproductsinsider.com Page 1 [Minerals] Vol. 18 No. 3 May/June 2013 incomplete. Comparisons of some supplement types have been measured related to absorption, and there is even a very small amount of comparative data for medium-term body accumulation based on serum or plasma magnesium; however, this is now recognized as a relatively insensitive measure of body accumulation of this mineral.1 Magnesium is, in fact, a difficult mineral to measure in a clinical setting. One reason for this is that the body has a large store of magnesium in the skeletal system. Bone accounts for 60 to 65 percent of total body magnesium content. The same hormonal systems that deposit or release calcium to or from the bone release magnesium in similar fashion.9 This dynamic interaction between metabolic needs and exogenous supply is played out first in the gastrointestinal (GI) tract, where the state of magnesium balance will regulate GI absorption between 24 and 76 percent,¹⁰ and then in the kidneys, where filtration and reabsorption can vary between 0.5 and 70 percent depending on the body’s need to conserve or excrete.¹¹ In healthy, magnesium-replete individuals, 24-hour urinary magnesium output after an acute dosage is assumed to be a relevant clinical measurement of bioavailability.12 However, with advances in measurement of isotopes, another research group found 24 hours is insufficient for complete collection of the given dose. Using stable isotopes of magnesium, a 72-hour urinary collection is necessary to accurately define fractional absorption.13 Additionally, science hasn't established a well-defined and universally accepted clinical measurement of magnesium status. Many measurements are commonly used for bioavailability of magnesium, but each has its limitations. Serum magnesium is one of the most common measurements of magnesium bioavailability. However, it may not accurately reflect intracellular magnesium status. It is also influenced by changes in serum albumin, other non-ionic ligands and pH. Additionally, certain disease states, such as diabetes, alcoholism, drug dependencies and malabsorption, can cause abnormally low intracellular magnesium, but have normal levels of serum magnesium. Additionally, confounding factors, such as age and sex, can influence serum magnesium.14 Intracellular magnesium levels are generally considered the best measurement of magnesium status. They are also the most difficult to measure, requiring advanced collection techniques and analytical equipment. One of the most promising is erythrocyte-ionized magnesium tests. The sample volume, although large, is easily collected. The downside to this method is that it requires nuclear magnetic resonance (NMR) analytical procedures, which are not common. Others advocate that total intracellular magnesium measurements are not sufficient for determination of magnesium status and bioavailability. Using NMR techniques, they suggest the comparison of bound versus free magnesium in intracellular tissues provides a more complete and accurate picture.15 Based on the lack of clearly defined clinical marker and the limitations of each method, the best design would look at multiple measurements of magnesium supplementation. These measurementsmay include giving the supplements for a substantial period of time with endpoints that include various indicators of magnesium functional status (e.g., erythrocyte total potassium and ionized magnesium contents, magnesium tolerance tests, etc.), as well as benefit indicators (e.g., markers of inflammation, symptom reductions, exercise performance, etc.). This approach is preferred to acute absorption measures since the former accounts for sustained absorption, retention and incorporation into functional and relevant biological sites. www.naturalproductsinsider.com Page 2 [Minerals] Vol. 18 No. 3 May/June 2013 The lack of uniformity of analytic methods and the frequent use of measurement methods now considered inadequate have created a confusing body of work to guide physicians and consumers. The evaluation can become baffling and marketing claims of various magnesium supplements only adds to the uncertainty. Inorganic Magnesium It is generally assumed that inorganic magnesium forms are not well absorbed; however, the use of such forms is common because inorganic forms generally cost less and have higher magnesium concentrations than organic forms. The most used form of inorganic magnesium in dietary supplements is magnesium oxide. Magnesium oxide has not performed well in a number of studies comparing it to other forms of magnesium. This reinforces a commonly expressed opinion that magnesium oxide, despite its wide availability to consumers, does not absorb well. A study that used seven-day urine collection demonstrated magnesium oxide was not absorbed well. When compared to placebo and magnesium aspartate, magnesium oxide was absorbed 52-percent over placebo, where the organic form was absorbed at a 115-percent rate over placebo.16 Similarly, in a 60-day trial, magnesium oxide did not show differences versus placebo for magnesium in serum, urine or saliva.17 In contrast, magnesium citrate altered all three parameters. In another study, magnesium oxide capsules were compared to an effervescent form taken in water.18 The background diet was controlled in this study. The effervescent form did twice as well in terms of 24-hour urine magnesium after intake of a 450-mg supplement. Although it is hard to compare these results to other work due to lack of data on effervescent magnesium, one result does stand out. The 24-hour urine values for magnesium oxide, though higher in mean value than the control collection, did not give a statistically significant difference from control. In a four-week rat feeding study, magnesium oxide, when compared to magnesium citrate and two other magnesium complexes, showed lesser long term effects on urinary magnesium and on diet- induced kidney stone formation.19 The urinary magnesium may not be a reliable measure of magnesium absorption, however the latter measure merits special attention because