original Prilosec warning edited
A recently released government statement states that some people using proton pump inhibitors for more than a year may end up with low magnesium levels. [1] Low magnesium can be life threatening but it can also just be tiring and painful. Magnesium helps block over active muscle cramping and reduces headaches and diabetic nerve pain. It is essential for white blood cell function and prevention of osteoporosis.
The proton pump inhibitor medications may be inhibiting the active absorption of magnesium in the intestines in some individuals. In other words, the drug may be blocking proton pumps in the intestinal cell membrane that are necessary to actively move magnesium from the intestines into the cell. Some people were not able to improve their magnesium levels with supplements until after the medication was stopped. Magnesium levels dropped again when the medication was re-started.
A simple serum magnesium test only shows acute deficiency. If you are concerned about your risk of chronic magnesium deficiency then ask for a red blood cell or muscle cell biopsy lab test to check intracellular serum levels. The serum lab test that is commonly used usually doesn't show a chronic magnesium deficiency. Only one percent of the body’s magnesium is found in the blood serum. The concentration is carefully regulated and deficiency would be severe or acute before serum levels of magnesium would drop.
Basing a decision on observable symptoms may be more helpful and budget friendly. Skip the blood tests or look at calcium level in the CBC panel. Hypocalcemia is a protective measure the body will adopt if possible when magnesium is low. Potassium levels can also be low. [3]
If you are having symptoms then a magnesium foot soak or bath in Epsom salts can bypass the intestinal absorption problems and provide some relief- while you are working on stopping the medication with your medical provider. Magnesium containing skin creams like the Ahava line may also provide relief. (I still like the body lotion but had to stop the face product - sensitivity reaction).
I have recently started using a Magnesium Glycinate supplement that I found at my local Food Coop . The tablet is quite large and sweet because it is a glyco-compound which should help it dissolve and absorb better. (See my blogs about the glycocalyx for more information about benefits of glyco-nutrients.) However it is more expensive than my mixed magnesium caplet, which contains magnesium oxide, citrate and malate. The only negative side effect that may occur with magnesium supplements is temporary loose stools (not explosive diarrhea, unless it was a really big dose like Milk of Magnesia, just really soft BM). The glycinate form may not trigger the smooth muscle fiber relaxation the way the free ions would. It is the rapid relaxation of the intestinal muscle lining that can trigger diarrhea/loose stools, so the magnesium glycinate may cost a bit more ($17 vs $6) but if it is better absorbed and is less likely to cause side effects than it seems like a fair deal.
A Government Statement you may not hear about [1, 2]:
Proton Pump Inhibitor drugs (PPIs): Drug Safety Communication - Low Magnesium Levels Can Be Associated With Long-Term Use
Prescription PPIs include Nexium (esomeprazole magnesium), Dexilant (dexlansoprazole), Prilosec (omeprazole), Zegerid (omeprazole and sodium bicarbonate), Prevacid (lansoprazole), Protonix (pantoprazole sodium), AcipHex (rabeprazole sodium), and Vimovo (a prescription combination drug product that contains a PPI (esomeprazole magnesium and naproxen).
Over-the-counter (OTC) PPIs include Prilosec OTC (omeprazole), Zegerid OTC (omeprazole and sodium bicarbonate), and Prevacid 24HR (lansoprazole).
[Posted 03/02/2011]
AUDIENCE: Consumer, Gastroenterology, Family Practice
ISSUE: FDA notified healthcare professionals and the public that prescription proton pump inhibitor (PPI) drugs may cause low serum magnesium levels (hypomagnesemia) if taken for prolonged periods of time (in most cases, longer than one year). Low serum magnesium levels can result in serious adverse events including muscle spasm (tetany), irregular heartbeat (arrhythmias), and convulsions (seizures); however, patients do not always have these symptoms. Treatment of hypomagnesemia generally requires magnesium supplements. In approximately one-quarter of the cases reviewed, magnesium supplementation alone did not improve low serum magnesium levels and the PPI had to be discontinued.
BACKGROUND: PPIs work by reducing the amount of acid in the stomach and are used to treat conditions such as gastroesophageal reflux disease (GERD), stomach and small intestine ulcers, and inflammation of the esophagus.
RECOMMENDATION: Healthcare professionals should consider obtaining serum magnesium levels prior to initiation of prescription PPI treatment in patients expected to be on these drugs for long periods of time, as well as patients who take PPIs with medications such as digoxin, diuretics or drugs that may cause hypomagnesemia. For patients taking digoxin, a heart medicine, this is especially important because low magnesium can increase the likelihood of serious side effects. Healthcare professionals should consider obtaining magnesium levels periodically in these patients. For additional information, refer to the Data Summary section of the FDA Drug Safety Communication.
Healthcare professionals and patients are encouraged to report adverse events, side effects, or product quality problems related to the use of these products to the FDA's MedWatch Safety Information and Adverse Event Reporting Program:
Complete and submit the report Online: www.fda.gov/MedWatch/report.htm1
Download form2 or call 1-800-332-1088 to request a reporting form, then complete and return to the address on the pre-addressed form, or submit by fax to 1-800-FDA-0178
_____________________________________________________________________________
Bibliography
2. http://www.medscape.com/viewarticle/738442, PPI-Related Hypomagnesemia: Putting it in Perspective, David A. Johnson, MD, Posted: 03/07/2011, From: Medscape Gastroenterology > Johnson on Gastroenterology
3. http://jasn.asnjournals.org/content/20/11/2291.long Kevin J. Martin, Esther A. González and Eduardo Slatopolsky, Clinical Consequences and Management of Hypomagnesemia, doi: 10.1681/ASN.2007111194 (JASN November 1, 2009 vol. 20 no. 11 2291-2295)
4. http://www.raysahelian.com/ulcer.html
Stomach and duodenal ulcer diet, herbs, vitamins, natural treatment with diet, supplements and home remedy by Ray Sahelian, M.D.
“Melatonin or l-tryptophan accelerates healing of gastroduodenal ulcers in patients treated with omeprazole. Three groups (A, B and C) of 14 patients in each treatment group with gastroduodenal chronic ulcers were treated with omeprazole (20 mg twice daily) combined either with placebo (group A), melatonin (group B) or with Trp (group C). On day 7, omeprazole by itself (group A) had not healed any ulcers, but four ulcers were healed with omeprazole plus melatonin and two with omeprazole plus tryptophan. At day 21, all ulcers were healed in patients treated with melatonin or Trp, but only 10-12 ulcers were healed in placebo-treated patients. Plasma gastrin level also rose significantly during treatment with omeprazole plus melatonin or Trp, but it was also significantly increased in patients treated with omeprazole plus placebo. Plasma ghrelin levels did not change significantly after treatment with melatonin or Trp, while plasma leptin increased significantly in patients treated with melatonin or Trp but not with placebo. We conclude that melatonin or Trp, when added to omeprazole treatment, accelerates ulcer healing and this likely depends mainly upon the significant increments in plasma melatonin. J Pineal Res. 2011.”
“Antioxidant, antimicrobial, antiulcer and analgesic activities of nettle (Urtica dioica L.). Ataturk University, Erzurum, Turkey. J Ethnopharmacol. 2004. In this study, water extract of stinging nettle (Urtica dioica L.) was studied for antioxidant, antimicrobial, antiulcer and analgesic properties. The antioxidant properties of stinging nettle were evaluated using different antioxidant tests, including reducing power, free radical scavenging, superoxide anion radical scavenging, hydrogen peroxide scavenging, and metal chelating activities. Stinging nettle had powerful antioxidant activity. The 50, 100 and 250 microg amounts of stinging nettle showed 39, 66 and 98% inhibition on peroxidation of linoleic acid emulsion, respectively, while 60 microg/ml of alpha-tocopherol, exhibited only 30% inhibition. Moreover, stinging nettle had effective reducing power, free radical scavenging, superoxide anion radical scavenging, hydrogen peroxide scavenging, and metal chelating activities at the same concentrations. In addition, total phenolic compounds in the stinging nettle were determined as pyrocatechol equivalent. Stinging nettle also showed antimicrobial activity against nine microorganisms, antiulcer activity against ethanol-induced ulcerogenesis and analgesic effect on acetic acid-induced stretching.”5. http://www.raysahelian.com/methylmethioninesulfonium.html ***cysteine and MMSC (methylmethionine sulfonium chloride) supplementation for ulcers6. http://www.gihealth.com/newsletter/previous/071.html
***This 2007 newsletters is assuring us of the safety of the PPI's for the heart (but turns out not for everybody's heart - the genetic canaries who handle magnesium and calcium a little differently do need to avoid PPI use. The increased fracture risk reported would be related not just to decreased calcium absorption but also to the decreased magnesium absorption in the genetically more at risk individuals.
"There was one study reported from England last year that suggested that acid suppression from PPI treatment may reduce calcium absorption from the diet and increase the risk of hip fracture, especially in the elderly. The study found a similar but smaller risk of hip fractures for another class of acid-fighting drugs called H2 blockers. Those drugs include Tagamet, Zantac, Axid and Pepcid. So far, this conclusion seems true, but most doctors feel that this risk can be averted by properly monitoring the bone density of elderly people taking the drugs and recommending calcium-rich diets to all patients."
7. http://www.pnas.org/content/101/9/2894.long
Vladimir Chubanov *, Siegfried Waldegger †, Michael Mederos y Schnitzler *, Helga Vitzthum ‡, Martin C. Sassen †, Hannsjörg W. Seyberth †, Martin Konrad †, and Thomas GudermannDisruption of TRPM6/TRPM7 complex formation by a mutation in the TRPM6 gene causes hypomagnesemia with secondary hypocalcemia doi: 10.1073/pnas.0305252101 PNAS March 2, 2004 vol. 101 no. 9 2894-2899§ To whom correspondence should be addressed at: Institute for Pharmacology and Toxicology, Philipps University Marburg, Karl-von-Frisch Strasse 1, 35033 Marburg, Germany. E-mail: guderman@staff.uni-marburg.de.
Magnesium references From Bibliography for Dietitian Recommends Stop Vitamin D and Calcium ASAP
8. http://www.ijkd.org/index.php/ijkd/article/view/140 Assadi, F., Hypomagnesemia, An Evidence-Based Approach to Clinical Cases, (Iranian Journal of Kidney Diseases, Vol 4, No 1 (2010)
18. http://www.ncbi.nlm.nih.gov/pubmed/20081245 Magdalena Bujalska, Helena Makulska-Nowak, Stanis³aw W. Gumuka Magnesium ions and opioid agonistsin vincristine-induced neuropathy , Department of Pharmacodynamics, Medical University of Warsaw, Krakowskie Przedmieoecie 26/28, PL 00-927 Warszawa, Poland
19. Magnesium: an emerging drug in anaesthesia, , Editorial I, M. F. M. James, British Journal of Anaesthesia, 103 (4): 465-7 (2009) DOI:10.1093/bja/aep242
23. http://www.ncbi.nlm.nih.gov/pubmed/17823441 Dai Q, Shrubsole MJ, Ness RM, Schlundt D, Cai Q, Smalley WE, Li M, Shyr Y, Zheng W., The relation of magnesium and calcium intakes and a genetic polymorphism in the magnesium transporter to colorectal neoplasia risk. ( Am J Clin Nutr. 2007 Sep;86(3):743-51)
24. Joan L Caddell, Geriatric cachexia: a role for magnesium deficiency as well as for cytokines?, Letter to the Editor, , (Am J Clin Nutr 2000;;71:844-53. pp 851-853)
25. Carl J Johnson, M.D., Donald R. Peterson, M.D., Elizabeth K. Smith, PhD, Myocardial tissue concentrations of magnesium and potassium in men dying suddenly from ischemic heart disease, (Am J Clin Nutr 32: MAY 1979, pp 967-970)
29. Geeta Sharma and Charles f Stevens, A mutation that alters magnesium block of N-methyl-D-aspartate receptor channels, Pub: Proceedings of the National Academy of Sciences of The united States 93.n17 (August 20, 1996): pp9259+. InfoTrac General Science Collection.
30. Beasley R, Aldington S, Magnesium in the treatment of asthma..Medical Research Institute of New Zealand, Wellington, New Zealand., Richard.Beasley@mrinz.ac.nz, Curr Opin Allergy Clin Immunol. 2007 Feb;7(1):107-10
32. Maged M. Costantine, MD, Steven J. Weiner, MS, Effects of Antenatal exposure to Magnesium Sulfate on Neuroprotection and Mortality in Preterm Infants: A Meta Analysis, Obstet Gynecol. 2009 August; 114(2 Pt 1): 354-364 DOI:10.1097/AOG0b013e3181ae98c2
33. Burton M. Altura, Bella T. Altura and Anthony Carella., Magnesium deficiency-induced spasms of umbilical vessels: relation to preeclampsia, hypertension, growth retardation. Pub:Science, 221 (July 22, 1983): pp376(2)
34. Burton M. Altura, Bella T. Altura, Asefa Gebrewold, Harmut Ising and Theo Gunther, Magnesium deficiency and hypertension: correlation between magnesium-deficient diets and microcirculatory changes in situ.,. Pub: Science, 223.(March 23, 1984): pp1315(3).
35. http://www.livestrong.com/article/182614-magnesium-for-skin-care/
www.awakeningskincare.com/skincare/category/ingredients/
http://www.magnesiumhealthwatch.com/magnesium-and-skin-care-benefits/
37. http://ahavaus.com/site/dead_sea_wonders.html Line of skin care products containing magnesium.
42. Magnesium intake from food and supplements is associated with bone mineral density in healthy older white subjects. (elderly health), Kathryn M. Ryder, Ronald I Shorr, Andrew J. Bush, Tamara Harris, Katie Stone and Frances A Tylavsky. Journal of the American Geriatrics Society, 53.11 (Nove 2005): p1875-1881. Academic One File. Web. 13 Dec. 2010
43. DASH Diet May Cut Heart Disease Risk, - source John Hopkins Medicine, Today’s Dietitian, Vol . 12, No. 10, Oct. 2010, p 25
44. Christine Feillet-Coudray, Charles Coudray, Zjean-Claude Tressol, Denise Pepin, Andrzej Mazur, Steven A Abrams, Exchangeable magnesium pool masses in healthy women: effects of magnesium supplementation, Yves Rayssiguier, Am J Clin Nutr 2002;75;72-8
45. http://www.highbeam.com/doc/1P3-2180507851.html "Researchers Identify Protein that Regulates Magnesium and Can Restart Stem Cells." Targeted News Service. Targeted News Service LLC. 2010. HighBeam Research. 16 Feb. 2011 . “An international team led by researchers at the University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School has published new findings that demonstrate how a specific protein controls the body's ability to balance magnesium levels. Magnesium is an essential element for good health and is critical to more than 300 biochemical reactions that occur in the body. "Currently more than half of the US population does not consume an adequate amount of magnesium in their diet," said Alexey G. Ryazanov, Ph.D., one of the study's authors and a professor of pharmacology and member of The Cancer Institute of New Jersey at UMDNJ-Robert Wood Johnson Medical School. "Magnesium deficiency may be associated with many medical disorders including hypertension, atherosclerosis, anxiety, asthma and a host of other disorders." “The team of researchers from the United States, France and Poland demonstrated for the first time that a protein called TRPM7 plays a key role in the maintenance of magnesium homeostasis (balance within the body) and is essential for proliferation of embryonic stem cells.”
77. Neuromed Phamaceuticals and Merck & Co., Inc. Announce Agreement for Novel N-type Calcium channel Compounds, from Business Wire, March 20, 2006, High Beam Research - **Neuromed is a pharmaceutical company focusing on calcium channel blockers. “blocking pain signaling through the N-type calcium channel is a novel approach for the treatment of pain” said Christopher Gallen,MD, PhD, President and Chief Executive Officer of Neuromed. **Providing adequate magnesium would be a less novel way to block nerve pain caused by overexcitation by excess calcium. Citation #9 demonstrated that diabetic neuropathy pain could be reduced by magnesium injection alone – why bother with the opioid or the synthetic calcium channel blocker. They are an expensive and dangerous class of pharmaceuticals that would be pretty much not necessary if we weren’t being drained of magnesium reserves by excessive calcium and acidity intakes.
95 [also 3 above]. http://jasn.asnjournals.org/content/20/11/2291.long Kevin J. Martin, Esther A. González and Eduardo Slatopolsky, Clinical Consequences and Management of Hypomagnesemia, doi: 10.1681/ASN.2007111194 (JASN November 1, 2009 vol. 20 no. 11 2291-2295)
96. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2639130/?tool=pubmed Karl T. Weber, William B. Weglicki, and Robert U. Simpson, Macro- and micronutrient dyshomeostasis in the adverse structural remodelling of myocardium, (Cardiovasc Res. 2009 February 15; 81(3): 500–508.) Published online 2008 October 3. doi: 10.1093/cvr/cvn261.
More Magnesium references:
“Possible Interactions with: Magnesium,” http://www.umm.edu/altmed/articles/magnesium- 000968.htm.
B Grimaldi, “The central role of magnesium deficiency in Tourette's syndrome: causal relationships between magnesium deficiency, altered biochemical pathways and symptoms relating to Tourette's syndrome and several reported comorbid conditions,” Medical Hypotheses 58, no. 1 (1, 2002): 47-60.
G Eby, “Rescue treatment and prevention of asthma using magnesium throat lozenges: Hypothesis for a mouth–lung biologically closed electric circuit☆,” Medical Hypotheses 67, no. 5 (2006): 1136-1141.
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“Magnesium and the inflammatory response: potential... [Arch Biochem Biophys. 2007] - PubMed result,” http://www.ncbi.nlm.nih.gov/pubmed/16712775.
“[Magnesium and inflammation: lessons from animal m... [Clin Calcium. 2005] - PubMed result,” http://www.ncbi.nlm.nih.gov/pubmed/15692164.
P Chambers, “Lone atrial fibrillation: Pathologic or not?,” Medical Hypotheses 68, no. 2 (2007): 281-287.
“Complementary vascular-protective actions of magnesium and taurine: A rationale for magnesium taurate,” http://www.medical-hypotheses.com/article/S0306-9877(96)90007-9/abstract.
Abe E. Sahmoun and Brij B. Singh, “Does a higher ratio of serum calcium to magnesium increase the risk for postmenopausal breast cancer?,” Medical Hypotheses 75, no. 3 (9, 2010): 315-318.
“Epidemiological evidence associating dietary calci... [Am J Nephrol. 1986] - PubMed result,” http://www.ncbi.nlm.nih.gov/pubmed/2950755.
“High fructose consumption combined with low dietar... [Magnes Res. 2006] - PubMed result,” http://www.ncbi.nlm.nih.gov/pubmed/17402291.
..AppDataRoamingMozillaFirefoxProfiles5z5xh8vb.defaultzoterostorage4MGSRXSW9789241563550_eng.pdf Cotruvo J, Bartram J, eds. Calcium and Magnesium in Drinking-water : Public health significance, Geneva, World Health Organization, 2009.
“Protein peroxidation, magnesium deficiency and fib... [Magnes Res. 1996] - PubMed result,” http://www.ncbi.nlm.nih.gov/pubmed/9247880.
E Planells et al., “Effect of magnesium deficiency on vitamin B2 and B6 status in the rat,” Journal of the American College of Nutrition 16, no. 4 (August 1997): 352-356.
Sivan Ben-Avraham et al., “Dietary strategies for patients with type 2 diabetes in the era of multi-approaches; review and results from the Dietary Intervention Randomized Controlled Trial (DIRECT),” Diabetes Research and Clinical Practice 86 Suppl 1 (December 2009): S41-48.
“Utility of magnesium as antiarrhythmic agent reviewed. - Health & Medicine Week | HighBeam Research - FREE trial,” http://www.highbeam.com/doc/1G1-121345520.html.
Barbara Chipperfield and JohnR. Chipperfield, “Relation of Myocardial Metal Concentrations to Water Hardness and Death-Rates from Ishchaemic Heart Disease,” The Lancet 314, no. 8145 (October 6, 1979): 709-712.
Barbara Chipperfield et al., “Magnesium and Potassium Content of Normal He3art Muscle in Areas of Hard and Soft Water,” The Lancet 307, no. 7951 (January 17, 1976): 121-122.
“Regulation of Contraction in Striated Muscle -- Gordon et al. 80 (2): 853 -- Physiological Reviews,” http://physrev.physiology.org/cgi/content/full/80/2/853.
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“Magnesium: Its proven and potential clinical significance.(Statistical Data Included) - Southern Medical Journal | HighBeam Research - FREE trial,” http://www.highbeam.com/doc/1G1-82553295.html#.
“Magnesium Treatment for Sudden Hearing Loss - The Annals of Otology, Rhinology & Laryngology | HighBeam Research - FREE trial,” http://www.highbeam.com/doc/1P3-679636211.html#.
“Magnesium supplementation decreases oxidative stress in diabetic rats. - Biotech Week | HighBeam Research - FREE trial,” http://www.highbeam.com/doc/1G1-104471960.html#.
“Magnesium requirement of kittens is increased by high dietary calcium - The Journal of Nutrition | HighBeam Research - FREE trial,” http://www.highbeam.com/doc/1P3-37651279.html#.
Daniel G. Chausow et al., “Experimentally-induced magnesium deficiency in growing kittens,” Nutrition Research 6, no. 4 (April 1986): 459-468.
Yuhei Kawano et al., “Effects of Magnesium Supplementation in Hypertensive Patients : Assessment by Office, Home, and Ambulatory Blood Pressures,” Hypertension 32, no. 2 (August 1, 1998): 260-265.
Robert E. Kleiger et al., “Effects of chronic depletion of potassium and magnesium upon the action of acetylstrophanthidin on the heart,” The American Journal of Cardiology 17, no. 4 (April 1966): 520-527.
Andrew D Hershey, “Current approaches to the diagnosis and management of paediatric migraine,” The Lancet Neurology 9, no. 2 (2, 2010): 190-204.
A M Gordon and E B Ridgway, “Cross-bridges affect both TnC structure and calcium affinity in muscle fibers,” Advances in Experimental Medicine and Biology 332 (1993): 183-192; discussion 192-194.
Karin Ladefoged and Kikki Hagen, “Correlation between concentrations of magnesium, zinc, and potassium in plasma, erythrocytes and muscles,” Clinica Chimica Acta 177, no. 2 (October 14, 1988): 157-166.
“Common genetic variants of the ion channel transient receptor potential membrane melastatin 6 and 7 ( TRPM6 and TRPM7 ), magnesium intake, and risk of type 2 diabetes in women.(Research article)(Report) - BMC Medical Genetics | HighBeam Research - FREE trial,” http://www.highbeam.com/doc/1G1-193482837.html#.
M Fu et al., “Association between Unhealthful Eating Patterns and Unfavorable Overall School Performance in Children,” Journal of the American Dietetic Association 107, no. 11 (11, 2007): 1935-1943.
“Antenatal magnesium treatment and neonatal illness severity as measured by the Score for Neonatal Acute Physiology (SNAP) - Journal of Maternal - Fetal & Neonatal Medicine | HighBeam Research - FREE trial,” http://www.highbeam.com/doc/1P3-856244151.html#.
“Acid-Base Status Affects Renal Magnesium Losses in Healthy, Elderly Persons1 - The Journal of Nutrition | HighBeam Research - FREE trial,” http://www.highbeam.com/doc/1P3-1123831511.html#.
“Ancient Minerals Launches Comprehensive Online Magnesium Health Resource. - PRWeb Newswire | HighBeam Research - FREE trial,” http://www.highbeam.com/doc/1G1-241203537.html#.
K Michaelsen, “Inadequate Supplies of Potassium and Magnesium in Relief Food? Implications and Countermeasures,” The Lancet 329, no. 8547 (6, 1987): 1421-1423.
“High Dietary Intake of Magnesium May Decrease Risk of Colorectal Cancer in Japanese Men1,2 - The Journal of Nutrition | HighBeam Research - FREE trial,” http://www.highbeam.com/doc/1P3-1998563311.html.
“Magnesium - The Clinical Advisor : For Nurse Practitioners | HighBeam Research - FREE trial,” http://www.highbeam.com/doc/1P3-2195246591.html.
“Magnesium prevents chemotherapy side effects.(Editorial)(Report) - Townsend Letter | HighBeam Research - FREE trial,” http://www.highbeam.com/doc/1G1-206620332.html#.
J Caddell, “Magnesium Deprivation in Sudden Unexpected Infant Death,” The Lancet 300, no. 7771 (8, 1972): 258-262.
“Magnesium builds bones in pre-pubertal and adolescent girls.(ABSTRACTS OF INTEREST)(Clinical report) - Original Internist | HighBeam Research - FREE trial,” http://www.highbeam.com/doc/1G1-166995340.html#.
J D Potter, S P Robertson, and J D Johnson, “Magnesium and the regulation of muscle contraction,” Federation Proceedings 40, no. 12 (October 1981): 2653-2656.