Magnesium Supplementation for Generalized Body Ache and Quality of Life Generalized body ache, tenderness, or soreness with fatigue is a common condition that affects mainly middle-aged women (mean age 40-50 years). The estimate of its prevalence in the general population ranges widely, from 0.75% to 10.5%. Recent studies indicate that individuals experiencing recurring generalized body ache, tenderness or soreness with fatigue display decreased magnesium (Mg) levels in leukocytes compared to control groups. Abraham et al hypothesized that Mg deficiency found in muscle cells may play a role in the development of muscle ache and discomfort. The group demonstrated that a daily supplement of 300-600 mg of Mg malate resulted in improvements of quality of life as well as in the level of discomfort. These findings were later supported by other authors.(8,9) When supplementing with magnesium, there are two goals: 1. Adequately treating potentially reversible factors such as electrolyte imbalances or vitamin deficiency. 2. Identifying a subgroup of individuals that might benefit from Mg supplementation. Most people do not have low serum Mg levels, and serum levels do not reflect the levels of Mg in tissue. However, some individuals appear to suffer from Mg deficiency and it appears important to assess Mg levels in all cases for potential relief of their musculoskeletal discomfort. Pharmacokinetics: Because vitamin B1 administration requires Mg supplementation, there is theoretical biochemical evidence that a combination of Mg and B1 would be more effective than either B1 or Mg alone in supplementation programs. However, there is no clinical data to prove this. Mechanism of Action: Although the exact mechanism of action of Mg remains unknown, it is crucial in many functions in the body. Mg is important for many metabolic functions in the human body. It activates almost all the enzymes of the glycolytic and Kreb’s cycle, which transform fat and sugar into high-energy phosphate (ATP). Low levels of ATP commonly are found in fatigue states, and may play a significant role in the genesis of fatigue conditions. Without Mg, ATP is broken down easily into ADP and inorganic phosphate, which are less efficient than ATP in generating energy for cell metabolism and transport. This process is important in the brain, which stores 20% of total body ATP. A low level of Mg leads to a low level of ATP, which may cause a decline in cognitive function. Both Mg and malic acid, a non-toxic organic dicarboxylic acid, are known to be involved in ATP synthesis under aerobic and hypoxic conditions, which is the basis of the combined use of malic acid and Mg in supplementation programs. Along with calcium, Mg is crucial for adequate muscle metabolism and function. In Mg deficiency, there is excessive muscle tension, which leads to muscle spasms, restlessness, tics, and twitches. Also, histochemical studies show that tenderness in muscle may reflect deficiencyt in ATP. Nuclear magnetic resonance spectroscopy indicates abnormally high-energy phosphate metabolism in exercising tender muscle. Mg inhibits many nerve receptors such as 5HT3 or NMDA, which are related to the origin of certain types of aches or discomfort.14 Additionally, Mg regulates the release of eurohormones such as adrenaline, which increases with the occurrence of stress-related events. Clinical Studies: Relatively few well-designed and clinically significant trials have studied the effectiveness and safety of Mg supplementation in the treatment of muscle ache, soreness and tenderness. Russell et al used a proprietary tablet “supermalic” (SM), which contains 200 mg of malic acid and 50 mg of Mg, in two sequential trials of 24 subjects. The first trial was a randomized, double-blind, placebo-controlled, crossover study for a two-month period (grade I evidence-based). Patients were randomized to either a fixed dose (three tablets, twice daily) of supermalic or to a placebo for four weeks, followed by a two-week washout and crossover to another four-week treatment period. All clinical assessments were conducted by a single examiner. In a subsequent six-month, open-label trial, the effects of escalating doses of supermalic were assessed before and after resumption of the drug. The 24 patients took three tablets of supermalic twice daily and increased their dosage every 3-5 days until they experienced acceptable outcomes or related side effects for a six-month period. All three primary outcomes used in this trial had been validated in prior studies. They included patient self-assessment of discomfort on a visual analog scale; and measures of the extent and degree of muscle tenderness or soreness. The results did not show any clear treatment effect attributable to supermalic in the blinded, fixed low-dose trial. However, the open-label trial with dose escalation and a longer duration of treatment showed a significant reduction in discomfort in all three primary outcomes. In another randomized, placebo-controlled, open-label, crossover trial (grade I evidence-based), Abraham et al used a combination of Mg (300-600 mg) and malate (1,200-2,400 mg) in 15 subjects during an eight-week period. Results showed a statistically significant measured improvement (P < 0.001) in the trial group vs. placebo as measured by two outcomes. Tenderness discomfort scores (± SE) of 19.6 ± 2.1 prior to treatment decreased to 8 ± 1.1 and 6.5 ± 0.74 at four and eight weeks, respectively, on the Mg-malate combination. Conversely, following an average of eight weeks on SM, six subjects were switched to placebo for two weeks. Their tenderness discomfort scores statistically significantly increased (P < 0.001) from 6.8 ± 0.75 to 21.5 ± 1.4. Subjective improvement of general muscle discomfort occurred within 48 hours of Mg supplementation in the Mg-malate group; measures of discomfort worsened in the placebo group. Adverse Events Side effects related to long-term exposure to Mg include headache, muscular pain (usually relieved by aspirin), and mild gastrointestinal symptoms. In short-term trials, the most common side effect is watery diarrhea, which usually is short-lived. In this case, individuals should decrease their next supplementation by 50%. Hypokalemia may occur, in which case, Mg should be discontinued. Contraindications and Precautions Exercise caution when supplementing with Mg with other medications that may impair Mg absorption, thus decreasing its effects. These drugs include allopurinol, tetracycline, digoxin, iron salts, penicillamine, and phenothiazines. Mg supplementation is safe during pregnancy, but it should be started in consultation with and under the supervision of the patient’s obstetrician. Unless it is severe, diarrhea that is not induced by Mg supplements is not a contraindication to Mg supplementation. Patients with renal disease should avoid magnesium supplementation. Formulation In the United States, Mg is sold in various oral forms, such as Mg citrate, Mg aspartate, Mg carbonate, Mg sulfate, Mg gluconate, and Mg oxide, or in combination with malic acid (supermalic). When choosing among these forms, one needs to know that the citrate form has the best absorption record and that the oxide form is the most poorly absorbed and cheapest form available. Also, Mg gluconate and sulfate are easy to digest and should be used if diarrhea has occurred with prior Mg supplementation. Mg hydroxide at an oral dosage of 500 mg/d significantly increases muscle magnesium level and seems to have comparable bioavailability with other forms of Mg preparation (citrate, lactate, and chloride). Most of the clinical trials used Mg hydroxide or gluconate. Dosage The standard dose of Mg in published clinical trials varies from 50 mg to 600 mg PO daily. It is used in combination with malic acid because of its preliminary, theoretical effect in the body’s management of muscle tenderness and soreness. The Mg hydroxide form has a wide margin of safety and superior effectiveness when used in combination with other supplements, such as malate. An oral dosage of 500 mg/d significantly increases muscle Mg level. Conclusion Based on preliminary data, Mg supplementation appears to be effective in reducing some cases of muscle ache, soreness and tenderness when used at high doses and in combination with malic acid. Based on currently available studies, Mg is a reasonable addition for individuals that have low magnesium levels or receive high doses of B1. In addition, based on short-term studies, Mg seems to be effective in relieving general muscle ache, tenderness and soreness, and to be safe with only minimal and infrequent side effects. Further clinical trials with long-term analyses need to be performed to confirm preliminary findings, conduct more extensive investigations, and determine long-term effects of Mg supplementation. Recommendation A trial of Mg supplementation should be prescribed for individuals who have low Mg levels or who have recurring muscle ache, soreness and tenderness. However, Mg cannot be recommended as sole therapy and is not a cure for serious muscle conditions. ____________________________________________ By Georges Ramalanjaona, MD, DSc, FACEP, MBA Dr. Ramalanjaona is Associate Chairman for Academic Affairs, Department of Emergency Medicine, Seton Hall University, School of Graduate Medical Education, South Orange, NJ; and Director of Research, Division of Emergency Medicine, St. Michael’s Hospital, Newark, NJ.