Current Research on Comparative Utility of Magnesium Supplements

Home , Magnesium aspartate, Magnesium carbonate, Magnesium glycinate, Magnesium lactate, Magnesium orotate, Magnesium pidolate

[Minerals] Vol. 18 No. 3 May/June 2013

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

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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 it constituted a functional test. Most comparative studies on different forms of magnesium focus mainly on absorption, and not retention or incorporation into functional sites. An effect such as kidney stone formation could evaluate all three factors and constitute a clinically relevant result.

Magnesium carbonate, sulfate and hydroxide are all inorganic magnesium complexes that are sometimes used as oral supplements, though not as much as the oxide form. The sulfate version has been used a fair amount for non-oral magnesium administration (i.e., systemic), but is sometimes given orally. Each of these inorganic magnesium supplements has also been sold as a laxative and/or antacid. None of them as oral magnesium supplements are considered to provide tremendously well absorbed magnesium.1

One might think a magnesium supplement's having an antacid effect would be desirable. TUMS®, a well known antacid brand, used to market its product as an antacid and a calcium source. However, it has been found that the chronic use of proton pump inhibitor antacids can have negative effects on body magnesium measures.7 In two studies, one in rats and one in humans, magnesium carbonate supplementation actually decreased the magnesium content for plasma or certain tissues instead of www.naturalproductsinsider.com Page 3

[Minerals] Vol. 18 No. 3 May/June 2013 increasing it.20,21 This was likely due to the antacid effects outweighing the contribution of increased magnesium intake.

The inadequacy of serum or short-term urinary concentrations as a reliable method of measuring magnesium absorption is not to say inorganic forms are not absorbed. They are absorbed, as demonstrated by more "functional" utilization study designs, such as the improvement of bone mineral content in the hip area of teenage girls when magnesium oxide was used on a daily basis for one year22 and slightly reduced blood pressure when given to hypertensive patients daily for eight weeks.23 In both of these studies, magnesium was given for an extensive amount of time and a clinically relevant outcome was the measure of effectiveness. It should be noted that magnesium plasma content did not change in either study. The question is not whether inorganic magnesium salts get absorbed, but to what extent and whether the consumers seeing higher label claims on products using inorganic salts can infer greater benefit when compared to organic salts. The data, albeit imperfect, does not support this erroneous belief.

Organic Magnesium An organic magnesium form is defined as magnesium bound to a hydrocarbon containing binder or ligand. In several instances, the ligand a mineral is bound to can have a significant effect on the body’s ability to recognize and absorb that mineral. Many organic complexes of magnesium are sold as supplements, but direct comparisons among them remain very limited.

In terms of clinical efficacy measurements, the effect of the ligand could apply to applications where the agent bound to the magnesium may provide some or all of the claimed clinical benefits unrelated to the effect of magnesium. For example, the taurine portion of magnesium taurate has been proposed to contribute to possible remediation of migraine headaches24 and high blood sugar.25 Other examples where the binder may play a role in the claimed effect can be seen with magnesium orotate for use in people with congestive heart failure26 and magnesium citrate for kidney stone prevention.27 In the case of kidney stone prevention, combining magnesium with potassium citrate alters urinary pH in clinically significant levels, and researchers assume the citrate is responsible for the impact.27 However, some studies raise the possibility that magnesium itself, even if provided without citrate, can also lower kidney stone risk.1,17,18 For example, magnesium glycinate affects certain urine properties in moderately magnesium-deficient kidney stone formers in Thailand.26,27 Thus, the idea that some magnesium supplements work in part or in whole via the organic constituent may be valid, but this has not been proven or studied sufficiently.

The most commonly used organic magnesium supplement is magnesium citrate. This form of magnesium has been shown to have a higher solubility28 and absorption than magnesium oxide.12 The absorption of magnesium citrate was high in two comparative studies that included other forms of magnesium supplements.12,29 In one of these studies, which was done on rats, the magnesium citrate effects included a reduction in diet-induced kidney stone formation.29 The relevance of the discussion above can be more fully appreciated, as the citrate itself may have played as much of a role in that effect as the magnesium. Therefore, this "clinically relevant" endpoint for magnesium bioavailability and functional utilization of this mineral may not be a meaningful surrogate after all.

Magnesium pidolate shows better specialized bioactivity than some other magnesium complexes. In rats, although magnesium deficiency-induced aggressive behavior is suppressed by a number of www.naturalproductsinsider.com Page 4

[Minerals] Vol. 18 No. 3 May/June 2013 magnesium salts (chloride, pidolate, aspartate, gluconate and lactate), magnesium pidolate reduced the length and frequency of aggressive behaviors to a greater extent than the comparative salts.30 In another study, which examined some reactions to activity-altering drugs, magnesium as pidolate, but not as lactate or aspartate, induced a neuro-sedative effect.31 These actions may demonstrate a particular pharmacological activity of the magnesium pidolate compound rather than superior magnesium absorption or retention. However, one cannot exclude improved magnesium absorption and retention of this form of magnesium because it has been shown that magnesium pidolate does increase serum and urinary magnesium when compared to placebo.32

Magnesium glycinate is another form of supplemental magnesium. Researchers at USDA found it to have higher absorption than magnesium oxide by evaluation of uptake in a 72-hour urine collection with stable isotopes from either an intravenous dose or when orally administered.13 It was also shown to have better absorptive properties than magnesium oxide in a subgroup of subjects who underwent ileal resection.33 Magnesium glycinate has also shown beneficial actions in a number of non- comparative studies including relief for pregnancy-induced leg cramps,34 improvement of symptoms in children with cystic fibrosis35 and asthma.36 In people prone to kidney stones, an improvement in urinary citrate, magnesium status based on a magnesium loading test, and erythrocyte potassium concentrations was observed with magnesium glycinate.17

One study compared magnesium glycinate to a magnesium-potassium citrate combination in a community known for magnesium deficiency.17 Subjects were treated for one month with one of four treatments (potassium chloride, potassium-sodium citrate, magnesium glycinate or potassium- magnesium citrate). Researchers evaluated the supplements' effects on the sodium-potassium pump, which indicates potassium and magnesium status. In the study, the magnesium glycinate group was the only one without a significant increase in the activity of the erythrocyte sodium-potassium pump; this is also the only group in the study that did not receive supplemental potassium. Administering sodium-potassium citrate without magnesium produced the biggest mean increase of erythrocyte sodium, potassium-pump activity of any of the groups. Interestingly, magnesium glycinate increased erythrocyte potassium contents to close to the same extent as the combination of potassium plus magnesium citrate or potassium-sodium citrate without magnesium. In addition, magnesium glycinate, but not magnesium-potassium citrate, strongly raised plasma potassium readings. These last two results suggested a substantial effect of magnesium glycinate on body potassium retention. Another amino acid-magnesium combination sold is magnesium aspartate. This form has not been featured in many published human intervention studies. In one non-comparative study, this form of magnesium had a positive effect in reducing fasting blood glucose and improving some insulin sensitivity indices, though similar to other studies, which demonstrated clinically significant functional improvements, no significant increase was seen for plasma magnesium.37

Magnesium orotate is another form of organic magnesium available on the market. It has been claimed to benefit patients with severe congestive heart failure by increasing survival rates.38 However, in 2009, the European Food Safety Authority (EFSA) was asked to provide a scientific opinion on the safety of magnesium orotate. Orotic acid is an intermediate in the pyrimidine biosynthesis pathway and can be found in milk from ruminants. EFSA found little support for the bioavailability of magnesium orotate; in fact, long-term animal toxicity studies found the form promoted tumorogenesis. Based on the absence of bioavailability data combined with demonstrated tumor promoting effect in animals, the panel concluded the use of this organic salt was a safety concern.39 www.naturalproductsinsider.com Page 5

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Overall, organic magnesium sources have been shown higher absorptive properties than inorganic forms of magnesium. Another significant clinical differentiation between the magnesium forms is the problem of a laxative side effect. When magnesium is not well-absorbed in the stomach or small intestine, it passes through a majority of the GI tract. Once in the colon, it absorbs a significant amount of water, which creates bulk in the descending colon and produces a laxative effect. Laxation is such a common occurrence that it is often thought of as a "class effect" and is one of the reasons many people do not take any magnesium as a nutritional supplement. However, the laxation is reduced when inorganic salts are taken in a bioavailable form, and seems milder in organic salts such as glycinate, taurate, aspartate and orotate, but not citrate. [insert table two]

It would seem that the best choices for magnesium form would include those with the lowest risk and highest benefit profile which would include absorption. Of those forms evaluated, glycinate and taurate seem to be the top choices for supplementation with the current state of research. Ideally, in the future, more studies need to be done to compare different types of magnesium supplements. Testing protocols should 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), as well as benefit indicators (e.g., markers of inflammation, symptom reductions, exercise performance). This approach is preferred to acute absorption measures since the former accounts for sustained absorption, retention and incorporation into functional sites.

Robert A. DiSilvestro is a professor human nutrition at The Ohio State University. He has conducted research and consulted various supplement companies including Nutrition 21, Glanbia, Albion and Purac of America.

References

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7. Systematic review: hypomagnesaemia induced by proton pump inhibition. Hess, M., et al. 2012, Ailmentary Pharmacology & Therapeutics, Vol. 36, pp. 405-413. 8. University of Maryland Medical Center. Magnesium. University of Maryland Medical Center. [Online] 2011. [Cited: March 26, 2013.] http://www.umm.edu/altmed/articles/magnesium- 000313.htm#ixzz2OgBJKqjH . 9. Berdanier, C.D. Advanced nutrition: micronutrients. Boca Raton : CRC Press, 1998. pp. 152-180. 10. Magnesium basics. Jahnen-Dechent, W. and Ketteler, M. Supplement 1, February 2012, Clinical Kidney Journal, Vol. 5, pp. i3-i14. 11. Regulation of magnesium balance: lessons learned from human genetic disease. de Baaij, J.H.F., Hoenderop, J.G.J. and Bindels, R.J.M. Supplement 1, February 2012, Clinical Kidney Journal, Vol. 5, pp. i15-i24. 12. Magnesium citrate found more bioavailable than other Mg preparations in a randomised double- blind study. Walker, A.F., et al. 3, 2003, Magnesium Research, Vol. 16, pp. 183-191. 13. Abrams, S.A. and et.al. Assessment of magnesium absorption using stable isotopes. [book auth.] Y. Rayssiguier, A. Mazur and J. Durlach. Advances in magnesium research: nutrition and health. s.l. : John Libbey, 2001, pp. 109-114. 14. Dietary reference intakes for calcium, phosphorus, magnesium, vitamin D and flouride. Nathional Academy Press. Washington D.C. : s.n., 1997. 15. Mota de Freitas, D. and Dorus, E. Techniques for measuring magnesium. [book auth.] N.J. Birch. Magnesium and the cell. San Diego : Academic Press, 1993, pp. 51-81. 16. Magnesium-L-aspartate-HCl and magnesium-oxide: bioavailability in healthy volunteers. Muhlbauer, B., et al. 4, 1991, European Journal of Clinical Pharmacology, Vol. 40, pp. 437-438. 17. Magnesium status of patients with renal stones and its effect on urinary citrate excretion. Reungjui, S., et al. 7, November 2002, BJU International, Vol. 90, pp. 635-639. 18. Changes in erythrocyte contents of potassium, sodium and magnesium and Na, K-pump activity after the administration of potassium and magnesium salts. Sriboonlue, P., et al. 12, 2004, Journal of the Medical Association of Thailand, Vol. 87, pp. 1506-1512.17. 19. Clinical symptoms of mitral valve prolapse are related to hypomagnesemia and attenuated by magnesium supplementation. Lichodziejewska, B., et al. 6, March 1997, American Journal of Cardiology, Vol. 79, pp. 768-772.

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20. Balance of magnesium and iron and their content in tissues and body fluids of rats after supplementation with magnesium carbonate. Skrajnowska, D. and R., Oledzka. 4, 2000, Roczniki Panstwowego Zakladu Higieny, Vol. 51, pp. 403-415. 21. The effects of zero magnesium dialysate and magnesium supplements on ionised calcium concentration in patients on regular dialysis treatment. Breuer, J., et al. 5, 1987, Nephrology, Dialysis, Transplantation, Vol. 2, pp. 347-350. 22. A randomized controlled study of effects of dietary magnesium oxide supplementation on bone mineral content in healthy girls. Carpenter, T.O., et al. 12, December 2006, Journal of Clinical Endocrinology and Metabolism, Vol. 91, pp. 4866-4872. 23. Effects of magnesium supplementation in hypertensive patients: assessment by office, home, and ambulatory blood pressures. Kawani, Y., et al. 2, August 1998, Hypertension, Vol. 32, pp. 260-265. 241. Magnesium taurate and fish oil for the prevention of migraine. McCarty, M. 6, December 1996, Medical Hypotheses, Vol. 47, pp. 461-466. 25. Complementary vascular-protective actions of magnesium and taurine: a rationale for magnesium taurate. McCarty, M.F. 2, February 1996, Medical Hypotheses, Vol. 46, pp. 89-100. 26. Magnesium orotate--experimental and clinical evidence. Classen, H.G. 3, 2004, Romanian Journal of Internal Medicine, Vol. 42, pp. 491-501. 27. Urinary citrate and renal stone disease: the preventive role of alkali citrate treatment. Caudarella, R. and Vescini, F. 3, September 2009, Archivio Italiano Di Uroligia, Andrologia, Vol. 81, pp. 182-187. 28. Magnesium bioavailability from magnesium citrate and magnesium oxide. Lindberg, J.S., et al. 1, February 1990, Journal of the American College of Nutrition, Vol. 9, pp. 48-55. 29. Effects of magnesium salts in preventing experimental oxalate urolithiasis in rats. Ogawa, Y., Yamaguchi, K. and Morozumi, M. 2 (part 1), August 1990, Journal of Urology, Vol. 144, pp. 385-389. 30. Inhibition of mouse-killing behaviour in magnesium-deficient rats: effect of pharmacological doses of magnesium pidolate, magnesium aspartate, magnesium lactate, magnesium gluconate and magnesium chloride. Bac, P., et al. 1, March 1995, Magnesium Research, Vol. 8, pp. 37-45. 31. Psychopharmacological properties of three magnesium salts: pidolate, lactate and aspartate. Teste, J.F., Decelle, T. and Henrotte, J.G. 4, 1995, Annales Pharmaceutiques Francaises, Vol. 53, pp. 176-183.

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32. Oral magnesium supplementation reduces ambulatory blood pressure in patients with mild hypertension. Hatzistavri, L.S., et al. 10, October 2009, American Journal of Hypertension, Vol. 22, pp. 1070-1075. 33. Bioavailability of magnesium diglycinate vs. magnesium oxide in patients with ileal resection. Schuette, S.A., Lashner, B.A. and Janghorbani, M. 5, September 1994, Journal of Parenteral and Enteral Nutrition, Vol. 18, pp. 430-435. 34. Oral magnesium for relief in pregnancy-induced leg cramps: a randomised controlled trial. Supakatisant, C. and Phupong, V. August 2012, Maternal and Child Nutrition, p. Epub ahead of pring. 35. Oral magnesium supplementation in children with cystic fibrosis improves clinical and functional variables: a double-blind, randomized, placebo-controlled crossover study. Gontijo-Amaral, C., Guimaraes, E.V. and Camargos, P. 2012, American Journal of Clinical Nutrition, Vol. 96, pp. 50-56. 36. Oral magnesium supplementation in asthmatic children: a double blind, randomizes, placebo controlled trial. Gontijo-Amaral, C., et al. 2007, European Journal of Clinical Nutrition, Vol. 61, pp. 54- 60. 37. Oral magnesium supplementation reduces insulin resistance in non-diabetic subjects - a double- blind, placebo-controlled, randomized trial. Mooren, F.C., et al. 3, March 2011, Diabetes, Obesity and Metabolism, Vol. 13, pp. 281-284. 38. Magnesium orotate in severe congestive heart failure. Stepura, O.B. and Martynow, A.I. 2, January 2009, International Journal of Cardiology, Vol. 131, pp. 293-295. 39. Unexpected toxicity induced by magnesium orotate treatment in congenital hypomagnesemia. Guillard, O., et al. 1, July 2002, Journal of Internal Medicine, Vol. 252, pp. 88-90. 40. Orotic acid salts as sources of orotic acid and various minerals added for nutritional purposes to food supplements. European Food Safety Authority. 2009, The EFSA Journal, Vol. 1187, pp. 1-25. 41. Effect of oral magnesium supplementation on measures of airway resistance and subjective assessment of asthma control and quality of life in men and women with mild to moderate asthma: a randomized placebo controlled trial. Kazaks, A.G., et al. 1, February 2010, The Journal of Asthma, Vol. 47, pp. 83-92.