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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.
SYNOPSIS: Prospective outcomes studies are demonstrating that individuals are not meeting their daily magnesium intake needs and this may be contributing to a number of chronic health conditions including diabetes, hypertension, short sleep, and some pain conditions.
• The effects of chronic decreased magnesium dietary intake in humans is understudied and may be a contributor to chronic diseases.
• The absorption of magnesium in the human body has been found to have a genetic contribution of approximately 30%.
• The role of supplemental magnesium in the diet and its effects on the body are unknown.
Editor’s Note: This is the second of two parts exploring the clinical connections of this important mineral. Part 1 (see Integrative Medicine Alert, October 2019) detailed the physiology of magnesium, the epidemiology of hypomagnesemia, recommended intake levels, food sources, medication interaction, supplementation forms, and testing. In this review, the clinical applications are described, including connections between hypomagnesemia and various disease states, and the possible use of supplemental magnesium in disease treatment.
— David Kiefer, MD, Editor
Magnesium, a divalent cation, was first reported by Dr. Nehemiah Grew, who identified magnesium sulfate as the major ingredient of Epsom salt.1,2 Epsom salt was extracted from a well in Epsom, England, and used to treat constipation, muscle strains, and abdominal pain. Magnesium was first isolated by Sir Humphrey Davy in 1808.1,2 It has been theorized to be involved in the pathogenesis of numerous diseases and is used as a treatment for migraine, cardiovascular disease, and diabetes, among other conditions.2-4 In this clinical review, we will cover clinical evidence for magnesium in preeclampsia, eclampsia, hypertension, insulin resistance, diabetes, pain, and sleep.
Ten percent of pregnant women will have elevated blood measurements at some time before delivery.5,6 Preeclampsia is defined as the new onset of hypertension with significant end-organ dysfunction with or without proteinuria in pregnancy and is estimated to occur in approximately 5% of pregnancies worldwide.5,6 Eclampsia is defined as the presence of grand mal seizure in addition to preeclampsia. Pregnant women who have mild to moderate hypertension without proteinuria have similar pregnancy outcomes to women with normal blood pressure.5,6 However, women with severe hypertension or hypertension proteinuria have worse outcomes than women without hypertension or proteinuria. Although there are some management approaches for preeclampsia, the only cure for the condition is delivery.5,6
Major medical organizations worldwide consider magnesium sulfate as the drug of choice to prevent seizures in women with preeclampsia. The exact mechanism of action of magnesium is not well understood in either the development of preeclampsia or the treatment of eclampsia and preeclampsia. It is hypothesized that magnesium increases vasodilation through the relaxation of vascular smooth muscle. One line of inquiry into the pathophysiology of preeclampsia found a significant relationship between serum magnesium levels in the first trimester of pregnancy and the risk of developing preeclampsia.7 Serum magnesium levels of ≤ 1.97 mg/dL measured in the first trimester had a sensitivity of 77% and specificity of 71.6% for the detection of subsequent preeclampsia.7 In a Cochrane Review, authors found that magnesium sulfate treatment in women with preeclampsia showed a trend toward lower mortality (relative risk [RR] 0.54; 95% confidence interval [CI], 0.26-1.10).8 One review showed that magnesium sulfate treatment in preeclamptic women reduced the risk of eclampsia by more than 50% (RR 0.41; 95% CI, 0.29-0.58).8
The use of magnesium in eclampsia and pre-eclampsia is a high-acuity situation that should take place in a hospital environment with definitive care and monitoring available. There are strict protocols for the use of magnesium, administered intravenously, in this situation.5-8
The largest contributor to cardiovascular disease worldwide is hypertension.9 The World Health Organization estimates that 62% of all strokes and 49% of coronary heart disease events are due to hypertension.9-12 Hypertension is a multifactorial disease with contributors including genetic factors, diet, physical inactivity, toxins, and psychosocial factors.9-12 Diets that are high in fruits and vegetables and low in sodium (e.g., the Dietary Approaches to Stop Hypertension [DASH] diet) have been found to reduce blood pressure.11-13 Such dietary approaches also are higher in magnesium, potassium, and calcium because of their emphasis on whole foods and decreased reliance on processed foods.14 Interestingly, potassium intake has been associated with lower blood pressure by both clinical and epidemiologic evidence.13,14
There also may be a connection between magnesium and blood pressure; low serum magnesium has been linked to elevated blood pressure.15 It is theorized that magnesium induces vasodilation by reducing intracellular calcium levels within vascular smooth muscle cells.15 High concentrations of extracellular magnesium increase prostacyclin levels and decrease the production of nitric oxide, leading to increased vasodilation.15 This association has borne out in clinical trials. One meta-analysis that pooled dietary magnesium estimates and hypertension risk from six prospective cohort studies with 180,566 participants (and included 20,119 cases) demonstrated a statistically significant inverse association relationship between dietary magnesium and hypertension risk (RR, 0.92; 95% CI, 0.86-0.98).16,17 Notably, a 100 mg/day increment in magnesium intake was associated with a 5% reduction in the risk of hypertension (RR, 0.95; 95% CI, 0.90-1.00).17
The first report of using supplemental magnesium via intravenous infusion to lower blood pressure was in 1925.2 A number of studies have demonstrated that oral magnesium intake reduces systolic and diastolic blood pressure; however, overall, the evidence is mixed. A Cochrane systematic review that included 12 randomized controlled trials with 545 participants investigated the effect of oral magnesium. Throughout eight to 26 weeks of blood pressure follow-up, researchers found a small decrease in diastolic blood pressure (DBP; -2.2 mmHg; 95% CI, -3.4 to -0.9), but not in systolic blood pressure (SBP; -1.3 mmHg; 95% CI, -4.0 to 1.5) when participants’ average intake of oral magnesium was 413.6 mg per day.10 Due to the low quality and heterogeneity of the studies, the authors suggest that larger, longer duration studies are required to assess the effects of magnesium supplementation on blood pressure.10 Another meta-analysis found a dose-dependent effect of magnesium on blood pressure. For each 243.3 mg/day of magnesium, there was a corresponding drop of -4.3 mmHg SBP (95% CI, -6.3 to -2.2) and -2.3 mmHg DBP (95% CI, -4.9 to 0.0).15 A meta-analysis of a subset of studies including patients being treated for hypertension with drugs found a more significant effect of oral magnesium on SBP (-18.7 mmHg; 95% CI, -14.95 to -22.45) and DBP (-10.9 mmHg; 95% CI -8.73 to -13.1).15 In addition, Zhang and colleagues conducted a meta-analysis of randomized, double-blind, controlled trials and found that 300 mg of oral magnesium daily for one month may be sufficient to decrease SBP by 2.00 mmHg and DBP by 1.78 mmHg.17
There is an association between hypomagnesemia and the incidence of both insulin resistance and type 2 diabetes mellitus (T2DM), and with increased rates of diabetic complications and mortality from diabetes.2,18 The pathophysiological connection may be through insulin receptors, which are a member of the kinase receptor family and require magnesium for signal function.2 In addition, hypomagnesemia is associated with increased production of cytokines and other effectors, including IL-1, IL-6, IL-8, tumor necrosis factor (TNF) alpha, norepinephrine, epinephrine, and reactive oxygen species that are known to increase insulin resistance.19 There appears to be a genetic component, because common single nucleotide polymorphisms in the TRPM6 gene responsible for magnesium transport are associated with increased insulin resistance and diabetes.2
Serum Magnesium. At this time, a test to measure or to reflect total body magnesium is not available. Serum magnesium is used most frequently to measure magnesium levels, but it is not necessarily a reflection of total body magnesium. Therefore, measuring both dietary intake and serum levels is performed in observational studies.
The Canadian Health Measures Survey Cycle 3 found that people with type 1 or 2 diabetes were more likely to have lower serum magnesium levels.20 Serum magnesium concentrations also have been found to be negatively associated with diabetes, body mass index, serum glucose and insulin, hemoglobin A1C, and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) values.21 Data from the National Health and Nutrition Examination Survey (NHANES) 2001-2010, a secondary analysis of 14,338 adults, suggest that those who had sufficient magnesium intake were less likely to have metabolic syndrome. These respondents also were found to have higher high-density lipoprotein levels.21
In a recent study conducted in the Netherlands that measured serum magnesium levels in a cohort of patients with T2DM, the authors reported that 9.6% of the 929 patients had hypomagnesemia with a serum magnesium level < 1.7 mg/dL.22 Another study with 589 white participants assessed cardiometabolic risk in individuals carrying at least one risk factor (i.e., overweight/obesity, hypertension, dyslipidemia, dysglycemia, and family history for T2DM) and reassessed participants at follow-up, which was 5.6 ± 0.9 years.23 The authors of this study found a significant negative correlation between magnesium levels, fasting glucose, and two-hour glucose tolerance test results.23 These authors also found that magnesium levels were negatively correlated with fasting insulin levels and positively correlated with the lipid profile. They found a 20% decreased risk of T2DM for each 1 mg/dL increase of circulating magnesium.23
There appears to be a considerable genetic component in serum magnesium levels, with an estimated 30% heritable contribution.3,24 In a recent study, 15,366 participants of European descent were evaluated for single nucleotide polymorphisms (SNPs) across the genome in association with micronutrients.25 It was found that six different regions of the genome that contained the variants were involved.6,25 These SNPs also were found to be associated with clinically defined hypomagnesemia and traits linked to serum magnesium levels, including kidney function, fasting glucose, and bone mineral density (BMD).6,25
Dietary Factors. Another meta-analysis of 25 prospective cohort studies with a total of 637,922 participants with 26,828 T2DM incident cases found an 8-13% reduction in the risk of T2DM for every 100 mg/day increment of dietary magnesium.26
Another interesting study has arisen from the fact that ketogenic diets sometimes are recommended for people with diabetes or insulin resistance; however, hypomagnesemia may occur from these types of diets.27 Given the physiological role that magnesium plays in glucose control and insulin effects, there may be some concern about the long-term consequences of ketogenic or high-fat nutritional approaches in this demographic.
In a randomized, double-blind, controlled trial published in 2003, 65 participants with T2DM and a serum magnesium level ≤ 1.8 mg/dL were randomized to placebo (n = 31) or a magnesium chloride solution (total of 2.5 g magnesium chloride daily) (n = 32). The participants were given 5 mg of glibenclamide three times daily and were instructed to follow the same diet and exercise instructions for three months prior to the trial of magnesium chloride. The authors reported that the magnesium group had an increase in serum magnesium concentration (15.5%; P < 0.001) and reductions in fasting glucose (-37.5%; P < 0.05), hemoglobin A1C (-30.4%; P < 0.05), and HOMA-IR index (-9.5%; P < 0.05) more significant than those in the placebo group.28
In a 2017 systematic review investigating the effects of magnesium on insulin resistance in humans, the authors identified 1,720, but only 12 qualified.29 The duration of the studies was between six and 24 weeks. Forms of supplemental magnesium included elemental magnesium, magnesium oxide, magnesium chloride, magnesium sulfate, magnesium picolinate, and magnesium L-aspartate hydrochloride.29 All studies evaluated the HOMA-IR and fasting glucose, and five of them rated the oral glucose tolerance test. Eleven of the studies measured fasting glucose, four measured hemoglobin A1C, and only one evaluated the HOMA of B cell function and the quantitative insulin sensitivity check index (QUICKI) or the insulin sensitivity index (ISI) (either the ISI-Gutt or the ISI-Matsuda). The authors found that most of the studies demonstrated an improved fasting glucose and insulin resistance index. Few studies measured the effect of magnesium on fasting insulin or hemoglobin A1C.29
The observational evidence for hypomagnesemia being associated with metabolic syndrome, diabetes, and an increasing risk for diabetes complications is concerning. The research data in the form of randomized, controlled clinical trials are underwhelming, and much more work needs to be done. For now, we can advise that patients should be getting the recommended dietary intake of magnesium.
An estimated 50-60% of magnesium is stored in the bone, and serum magnesium levels are related closely to bone metabolism.2 Magnesium is involved with the creation of new bone and has been shown to increase the solubility of phosphorus and calcium, affecting the crystal size and formation of the new bone.2 Low levels of magnesium can result in elevated levels of cytokines such as TNF-alpha, interleukins, and substance P, which can lead to bone resorption.2,19 In addition, low magnesium levels may lead to low levels of parathyroid hormone and vitamin D levels, again relevant to bone health.2,19 In addition, low serum magnesium levels have been shown to be associated with osteoporosis.2,30 The majority of the research investigating magnesium and osteoporosis has been performed in postmenopausal women.3,30 In a 1991 study, researchers investigated the effects of 600 mg/day of magnesium and found an 11% increased BMD after 12 months.30 However, this study also included a number of other supplemental compounds, including calcium, which prohibits limiting the study findings to just the effects of magnesium. Multiple small studies have shown that supplemental magnesium does increase BMD in limited amounts (1-3%).2,31,32 Larger, high-quality studies need to be performed to further understand the effects of magnesium on bone, and specifically the role for magnesium supplementation in people with osteopenia and osteoporosis.
Muscle Cramps. Muscle contractions are dependent on calcium being released from the sarcoplasmic reticulum and binding to troponin C and myosin, resulting in the conformation changes that result in contraction.2,34 Magnesium is a calcium antagonist on calcium-permeable channels and binding proteins, which competes for the calcium-binding sites. When muscle cells are at rest, the intracellular concentration of magnesium is 10,000 times that of calcium. When the calcium is released from the sarcoplasmic reticulum, it competes with the magnesium for binding sites to result in a muscle contraction.2,34 Lower magnesium levels lead to less calcium being required to displace magnesium, which leads to hypercontractility, clinically presenting as muscle cramps and spasms.
The evidence to support the treatment of muscle cramps and spasms with magnesium is mixed. A 2012 Cochrane Review included seven trials, with 406 individuals, 118 of which were involved in crossover studies.35 The studies had lengths of 14 to 42 days, and the elemental magnesium dose per day ranged from 84 mg to 486 mg.35 The authors did not show any significant reduction in the number of cramps after magnesium treatment (-3.93%; 95% CI, -21.12 to 13.26).35
Headaches and Migraines. The majority of the research investigating the effects of magnesium in the treatment of headache has been done in individuals with migraines. The first reports of using magnesium as a treatment for migraine were in the 1960s and 1970s.2 Cortical spreading depression (CSD) is one theory for the etiology of migraine headache.2 CSD is the term used to describe the neuronal membrane depolarization and repolarization phenomenon that occurs in neurons and glial cells. Low levels of magnesium in cerebrospinal fluid (CSF) can activate N-methyl-D-aspartate (NMDA) receptors, which may initiate CSD. Magnesium levels in the serum and CSF of migraine patients have been found to be lower. Lower levels may result in increased neuronal membrane excitability that results in CSD and leads to migraine.
Magnesium has demonstrated anti-inflammatory effects through the inhibition of IL-6 and TNF-alpha. Magnesium also has alpha-adrenergic antagonistic effects and inhibits calcium-mediated neuroendocrine secretion, which may affect nociceptive processing. Intravenous (IV) magnesium has demonstrated mixed results in delivering benefit for acute migraine and cluster headache.2 The authors of a meta-analysis published in 2016 found that IV magnesium treatment for acute migraines demonstrated significant relief for 15-45 minutes (odds ratio [OR], 0.23), 120 minutes (OR, 0.20), and 24 hours (OR, 0.27).36 Also, oral magnesium was shown to significantly reduce the frequency (OR, 0.20) and the intensity of attacks (OR, 0.27).36
Previous research has indicated an important role of magnesium in the sleep/wake cycle. Animal studies have demonstrated that low magnesium intake affects sleep organization and wakefulness, which was reversed when dietary magnesium was included in the diet. Magnesium fluxes occur daily and are theorized to regulate cellular time keeping. Magnesium also facilitates NMDA receptor function, which is important in sleep regulation. Magnesium also is a cofactor in the synthesis of melatonin. There is some clinical evidence supporting a connection between magnesium and sleep. The 2007-2008 NHANES analysis demonstrated lower magnesium intake was associated with very short (less than five hours) sleep.37 The Jiangsu Nutrition Study conducted from 2002 to 2007 found that dietary magnesium consumption was inversely associated with falling asleep during the day in women, but not in men.38 In addition, one placebo-controlled study conducted in the elderly demonstrated improvement in various sleep parameters, including sleep onset latency, sleep efficiency, and sleep time, with magnesium supplementation.39
Overall: Magnesium and Inflammation
Magnesium’s efficacy in improving clinical conditions may be restricted to magnesium-depleted individuals.18,19 Individuals with low magnesium intake that may not be detectable with a serum magnesium level may have increased C-reactive protein (CRP) levels.18,19 CRP is an acute phase protein that is produced in response to inflammation and is associated with an increased risk of chronic disease, including cardiovascular disease.18,19 A number of studies have found that dietary magnesium intake is inversely associated with serum or plasma CRP levels.18-19 Magnesium supplementation lowered elevated CRP levels in 17 patients with heart failure and in 62 men and nonpregnant women with prediabetes and hypomagnesemia.16-19 The doses of magnesium used in these trials ranged from 300 mg to 382 mg/day.16-19 Another study of 300 patients older than 25 years of age who had coronary heart disease found that elevated CRP was decreased in participants with a dietary magnesium intake of > 350 mg/day, measured by two-day dietary recall.16-19
Unfortunately, serum magnesium tests may not accurately measure total body magnesium. If patients have low serum magnesium and are asymptomatic with elevated CRP, repleting with oral supplementation is warranted while evaluating the elevated CRP (i.e., ruling out infection or other causes of inflammation). For patients who have hypertension, a trial of oral supplementation with magnesium also is warranted. However, choosing a high-quality magnesium supplement that has been tested by a third party is required to evaluate the amount contained within the supplement, as well as any heavy metals it may contain.
Research on the use of supplemental magnesium in human studies is lacking, which makes it difficult to recommend supplemental magnesium use to patients across the board. Prospective outcomes studies demonstrate that a lack of dietary magnesium intake has numerous effects on the body, which is not surprising because magnesium is involved with more than 600 enzymatic reactions. Based on the existing evidence, counseling patients about the importance of a whole foods diet and foods rich in magnesium is fundamental. If patients have low serum magnesium without symptoms of hypomagnesemia, recommending a magnesium supplement is warranted. Also, clinicians should recommend supplemental magnesium to patients with insulin resistance, diabetes, or hypertension who have elevated CRP. There are a number of different forms of magnesium on the market, but research is lacking on whether one form is better than another. Another difficulty with recommending magnesium supplementation is that the body increases absorption of magnesium when it is depleted, so increased oral dosing may not be effective. Product quality should not be assumed, and recommending a product that has been third-party tested is ideal. Advising patients to get 350 mg/day of combined dietary and supplemental magnesium is good clinical practice at this time.
Because there is a lack of research on the clinical use of magnesium and it is involved in a diverse profile of enzymatic reactions, one should exercise caution. Clinically, the most common adverse effect of the use of magnesium is its laxative effect, which usually is dose dependent. The magnesium oxide supplemental form has the more pronounced laxative effect. Magnesium should be used with caution in patients with renal disease. There also are specific medical conditions for which magnesium may be problematic. For example, magnesium sulfate, especially in the intravenous form used in preeclampsia and eclampsia, is contraindicated in people with myasthenia gravis since it can precipitate a severe myasthenic crisis.5-8
There is evidence to support the use of supplemental magnesium for several clinical conditions, including eclampsia/preeclampsia, migraine and other headaches, diabetes, bone health, hypertension, and insomnia. Given the widespread suboptimal intake of magnesium in the United States, clinicians should be aware of clinical correlates of hypomagnesemia and situations when magnesium can be used therapeutically. Furthermore, a discussion of food sources of magnesium, supplemental forms, and adverse effects should be a part of any clinical encounter, but especially in those involving disease processes as reviewed in this magnesium overview.
Financial Disclosure: Integrative Medicine Alert’s Executive Editor David Kiefer, MD; Peer Reviewer Suhani Bora, MD; Associate Editor Journey Roberts; Editor Jason Schneider; Relias Media Editorial Group Manager Leslie Coplin; and Accreditations Manager Amy M. Johnson, MSN, RN, CPN, report no financial relationships relevant to this field of study.