Magnesium

Support for the cardiovascular system, brain, muscles, and bones

Basic data
How it works
Potential risk
Contraindications
Quick facts
Practical tips
Key areas of impact
Scientific data and sources

Basic data

Magnesium is an essential mineral that supports proper cardiovascular function, brain health, and the musculoskeletal system. Adequate magnesium intake promotes blood pressure regulation, protection against arrhythmias, improved cognitive function, and the maintenance of muscle mass and strength. Supplementation is especially beneficial in individuals with deficiencies and increased risk of chronic diseases.

Impact: Positive

Key areas of impact:

Musculoskeletal system Brain Cardiovascular system

Level of evidence: Good

Level of risk: Low

Before you start implementing any interventions - read our free guide The Road to Longevity , to build a solid foundation that will help you prepare your personalized longevity plan and carry it out safely.

Read

How it works

Magnesium has multifaceted effects: it regulates ion channel functions, which stabilizes heart rhythm and nerve conduction, supports synaptic plasticity in the brain, and protects neurons from overstimulation. In the musculoskeletal system, magnesium promotes muscle protein synthesis, tissue regeneration, and bone mineralization. Additionally, magnesium exhibits anti-inflammatory and antioxidant properties, which improve endothelial function and reduce the risk of heart disease.

Potential risk

Level of risk: Low

Magnesium is well tolerated by most people, and side effects are rare and usually mild. When taken in appropriate doses, the risk of adverse effects is minimal.

Mild gastrointestinal issues such as diarrhea or bloating
Risk of hypermagnesemia with very high doses or in individuals with impaired kidney function
Interactions with certain medications, such as antibiotics or diuretics

Contraindications

Magnesium supplementation is not recommended in individuals with severe renal failure or magnesium metabolism disorders, or in situations where excess magnesium accumulation could occur.

Severe renal failure
Hypermagnesemia
Certain heart conditions requiring strict electrolyte control
Pregnant women should consult a doctor before supplementing

Quick facts

Dosage

Recommended doses typically range from 200 to 400 mg per day, depending on age, gender, and health status.

Form

The most bioavailable forms are magnesium citrate, L-threonate, and lactate.

Onset of effects

Initial effects may be noticeable after a few weeks of regular supplementation.

Time of day

It is best to take magnesium in the evening to support recovery and improve sleep.

Practical tips

Loading protocol

In cases of deficiency, higher doses of magnesium can be used for a few days, followed by a maintenance dose.

Avoiding drug interactions

Magnesium supplementation should be discussed with a doctor, especially if you take diuretics, antibiotics, or heart medications.

Supplementation in older adults

Older individuals may require increased magnesium intake due to reduced absorption and a higher risk of deficiency.

Combining with a magnesium-rich diet

For best results, supplementation should complement a diet rich in nuts, seeds, leafy green vegetables, and whole grain products.

Join our WhatsApp group with AI bot, which with the support of our community and experts will answer all questions related to longevity

Join

Key areas of impact

Musculoskeletal system

Magnesium plays a crucial role in musculoskeletal health, supporting proper muscle and bone function and protecting against weakening, loss of mass, and fracture risk.

Effects of magnesium on muscles

Higher magnesium intake is associated with greater muscle mass and strength, especially in women and older adults.
Magnesium deficiency can lead to muscle weakness and atrophy.
Magnesium supplementation may improve post-exercise recovery and reduce muscle soreness.
Magnesium supports muscle function in athletes and individuals with muscular diseases.

Effects of magnesium on bones

Higher magnesium intake and appropriate blood levels are associated with greater bone mineral density.
Magnesium deficiency increases the risk of osteoporosis and fractures, especially in older adults and postmenopausal women.
Magnesium supports bone regeneration, osteoblast activity, and inhibits inflammatory processes that lead to bone mass loss.

Summary of benefits

Greater muscle mass and strength with higher magnesium intake.
Improved bone mineral density and lower risk of osteoporosis.
Faster muscle recovery and reduced post-exercise soreness.
Reduced fracture risk due to adequate magnesium levels.

Brain

Magnesium plays a key role in nervous system function and brain health, supporting memory, cognitive abilities, and protection against neurodegeneration.

Mechanisms of magnesium action in the brain

Magnesium supports neural signaling and proper communication between neurons.
It protects neurons from excitotoxicity and oxidative stress.
It regulates neurotransmitters and synaptic plasticity, essential for learning and memory.
Magnesium deficiency leads to neuroinflammation and disruption of the blood-brain barrier.

Effects of magnesium on cognition and brain health

Magnesium supplementation (especially L-threonate) improves memory and cognitive function.
Higher magnesium levels are associated with greater brain volume and lower risk of dementia.
Increased magnesium intake reduces the risk of mild cognitive impairment (MCI), especially in women over age 55.
Magnesium may alleviate symptoms of depression and anxiety.

Limitations and recommendations

Optimal blood magnesium levels yield the best results.
High-bioavailability supplements like magnesium L-threonate more effectively increase brain magnesium levels.
Further studies are needed on the long-term effects of supplementation on brain health.

Cardiovascular system

Magnesium plays a vital role in maintaining cardiovascular health, helping protect the heart and blood vessels, and regulating blood pressure and heart rhythm.

Key cardiovascular benefits of magnesium

Reduced risk of stroke and heart failure: higher magnesium intake is linked to lower risk of stroke and heart failure.
Improved vessel flexibility: magnesium supplementation reduces arterial stiffness, potentially lowering cardiovascular risk.
Blood pressure regulation: magnesium helps lower blood pressure, especially in those with deficiencies.
Anti-arrhythmic effects: magnesium stabilizes heart rhythm and is used in the treatment of some arrhythmias.
Endothelial support and anti-inflammatory action: magnesium improves vascular function and reduces inflammation.
Lower cardiovascular mortality: higher magnesium intake is associated with lower cardiovascular-related mortality.

Limitations and caveats

The greatest benefits are seen in people with magnesium deficiency or elevated cardiovascular risk (e.g., diabetes, hypertension).
Study results on magnesium supplementation are mixed; routine supplementation is not recommended without confirmed deficiency.
Some effects may stem from an overall healthier lifestyle in those who consume more magnesium.

Summary

Magnesium benefits cardiovascular health, especially in preventing stroke, heart failure, and arrhythmias.
Regular dietary intake is recommended; supplementation should be considered mainly with confirmed deficiency.

Scientific data and sources

Research summary

Level of evidence Good

Number of included studies: 57

undefined type: 14 studies
literature review: 10 studies
systematic review: 9 studies
meta-analysis: 9 studies
non-rct observational study: 7 studies
rct: 5 studies
non-rct in vitro: 2 studies
non-rct experimental: 1 study

Magnesium in man: implications for health and disease.

Type of study:

Number of citations: 1313

Year: 2015

Authors: J. D. de Baaij, J. Hoenderop, R. Bindels

Journal: Physiological reviews

Journal ranking: Q1

Key takeaways: Magnesium supplementation can benefit treatment of various diseases and is essential for human health, particularly in the brain, heart, and skeletal muscles.

Abstract: Magnesium (Mg(2+)) is an essential ion to the human body, playing an instrumental role in supporting and sustaining health and life. As the second most abundant intracellular cation after potassium, it is involved in over 600 enzymatic reactions including energy metabolism and protein synthesis. Although Mg(2+) availability has been proven to be disturbed during several clinical situations, serum Mg(2+) values are not generally determined in patients. This review aims to provide an overview of the function of Mg(2+) in human health and disease. In short, Mg(2+) plays an important physiological role particularly in the brain, heart, and skeletal muscles. Moreover, Mg(2+) supplementation has been shown to be beneficial in treatment of, among others, preeclampsia, migraine, depression, coronary artery disease, and asthma. Over the last decade, several hereditary forms of hypomagnesemia have been deciphered, including mutations in transient receptor potential melastatin type 6 (TRPM6), claudin 16, and cyclin M2 (CNNM2). Recently, mutations in Mg(2+) transporter 1 (MagT1) were linked to T-cell deficiency underlining the important role of Mg(2+) in cell viability. Moreover, hypomagnesemia can be the consequence of the use of certain types of drugs, such as diuretics, epidermal growth factor receptor inhibitors, calcineurin inhibitors, and proton pump inhibitors. This review provides an extensive and comprehensive overview of Mg(2+) research over the last few decades, focusing on the regulation of Mg(2+) homeostasis in the intestine, kidney, and bone and disturbances which may result in hypomagnesemia.

View study

Type of study: non-rct experimental

Number of citations: 327

Year: 2010

Authors: I. Slutsky, N. Abumaria, Longjun Wu, Chao-Hua Huang, Ling Zhang, Bo Li, Xiang-zhong J. Zhao, A. Govindarajan, Ming-gao Zhao, M. Zhuo, S. Tonegawa, Guosong Liu

Journal: Neuron

Journal ranking: Q1

Key takeaways: Elevating brain magnesium using a newly developed compound (magnesium-L-threonate, MgT) improves learning abilities, working memory, and short- and long-term memory in rats.

View study

Magnesium and the Brain: A Focus on Neuroinflammation and Neurodegeneration

Type of study:

Number of citations: 53

Year: 2022

Authors: J. Maier, L. Locatelli, G. Fedele, A. Cazzaniga, A. Mazur

Journal: International Journal of Molecular Sciences

Journal ranking: Q1

Key takeaways: Magnesium deficiency contributes to neuroinflammation and neurodegeneration, with evidence linking it to multiple sclerosis, Alzheimer's, and Parkinson's diseases.

Abstract: Magnesium (Mg) is involved in the regulation of metabolism and in the maintenance of the homeostasis of all the tissues, including the brain, where it harmonizes nerve signal transmission and preserves the integrity of the blood–brain barrier. Mg deficiency contributes to systemic low-grade inflammation, the common denominator of most diseases. In particular, neuroinflammation is the hallmark of neurodegenerative disorders. Starting from a rapid overview on the role of magnesium in the brain, this narrative review provides evidences linking the derangement of magnesium balance with multiple sclerosis, Alzheimer’s, and Parkinson’s diseases.

View study

Neuroprotective effects of magnesium: implications for neuroinflammation and cognitive decline

Type of study:

Number of citations: 10

Year: 2024

Authors: Veer Patel, N. Akimbekov, William B. Grant, Carolyn Dean, Xiaoqian Fang, Mohammed S Razzaque

Journal: Frontiers in Endocrinology

Journal ranking: Q1

Key takeaways: Magnesium has potential neuroprotective effects by maintaining neuronal ion homeostasis, reducing inflammation, and preventing excitotoxicity, potentially improving cognitive decline in neurodegenerative conditions.

Abstract: Neurodegenerative diseases, which are characterized by progressive neuronal loss and cognitive decline, are a significant concern for the aging population. Neuroinflammation, a shared characteristic of these diseases, is implicated in their pathogenesis. This article briefly summarizes the role of magnesium, an essential mineral involved in numerous enzymatic reactions and critical for neuronal bioactivity, in the context of neuroinflammation and cognitive decline. The potential neuroprotective effects of magnesium, including the mechanisms of neuroprotection by magnesium through maintaining neuronal ion homeostasis, reducing inflammation, and preventing excitotoxicity, are also described. Additionally, we discuss the impact of inadequate magnesium on neuroinflammation and its potential as a therapeutic agent for attenuating cognitive decline to improve neurodegenerative conditions.

View study

Type of study: literature review

Number of citations: 24

Year: 2021

Authors: Runnan Xu, Liping Wang, Liyuan Sun, Jianghui Dong

Journal: Life sciences

Journal ranking: Q1

Key takeaways: Magnesium supplementation shows potential neuroprotective effects in cerebral ischemia, but current clinical trials have not shown a significant improvement in prognosis.

View study

Associations of Serum Magnesium with Brain Morphology and Subclinical Cerebrovascular Disease: The Atherosclerosis Risk in Communities-Neurocognitive Study

Type of study: non-rct observational study

Number of citations: 6

Year: 2021

Authors: Aniqa B. Alam, D.S. Thomas, P. Lutsey, Srishti Shrestha, Á. Alonso

Journal: Nutrients

Journal ranking: Q1

Key takeaways: Higher serum magnesium is associated with greater brain volumes and lower odds of subclinical cerebrovascular disease, suggesting beneficial effects on neurodegeneration and cerebrovascular damage.

Abstract: Circulating magnesium has been associated with a lower risk of dementia, but the physiologic effects by which magnesium may prevent neurological insults remain unclear. We studied 1466 individuals (mean age 76.2 ± 5.3, 28.8% black, 60.1% female) free of prevalent stroke, with measured serum magnesium and with available MRI scans obtained in 2011–2013, participating in the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS). Cross-sectional differences in frontal, temporal, parietal, and occipital lobe volume, along with deep grey matter, total brain, and white matter hyperintensity volume across serum magnesium (categorized into quintiles and per standard deviation increases) were assessed using multiple linear regression. We also examined associations of magnesium with the prevalence of cortical, subcortical, and lacunar infarcts using multiple logistic regression. After adjusting for demographics, biomarkers, medications, and cardiometabolic risk factors, higher circulating magnesium was associated with greater total brain volume and frontal, temporal, and parietal lobe volumes (volumes 0.14 to 0.19 standard deviations higher comparing Q5 to Q1). Elevated magnesium was also associated with lower odds of subcortical infarcts (OR (95%CI): 0.44 (0.25, 0.77) comparing Q5 to Q1) and lacunar infarcts (OR (95%CI): 0.40 (0.22, 0.71) comparing Q5 to Q1). Elevated serum magnesium was cross-sectionally associated with greater brain volumes and lower odds of subclinical cerebrovascular disease, suggesting beneficial effects on pathways related to neurodegeneration and cerebrovascular damage. Further exploration through prospective analyses is needed to assess increasing circulating magnesium as a potential neuroprotective intervention.

View study

Ca:Mg Ratio, APOE Cytosine Modifications, and Cognitive Function: Results from a Randomized Trial

Type of study: rct

Number of citations: 16

Year: 2020

Authors: Xiangzhu Zhu, A. Borenstein, Yinan Zheng, Wei Zhang, D. Seidner, R. Ness, H. Murff, Bingshan Li, M. Shrubsole, Chang Yu, L. Hou, Q. Dai

Journal: Journal of Alzheimer's Disease

Journal ranking: Q1

Key takeaways: Reducing the dietary Ca:Mg ratio through Mg supplementation may improve cognitive function in individuals aged 65 and over, partially through modifications in APOE methylation.

Abstract: Background: Deterioration of ionized calcium (Ca2+) handling in neurons could lead to neurodegenerative disease. Magnesium (Mg) antagonizes Ca during many physiologic activities, including energy metabolism and catalyzation of demethylation from 5-methylcytosine(5-mC) to 5-hydroxymethylcytosine(5-hmC). Objective: To test the hypothesis that actively reducing the Ca:Mg intake ratio in the diet through Mg supplementation improves cognitive function, and to test whether this effect is partially mediated by modified cytosines in Apolipoprotein E (APOE). Methods: This study is nested within the Personalized Prevention of Colorectal Cancer Trial (PPCCT), a double-blind 2×2 factorial randomized controlled trial, which enrolled 250 participants from Vanderbilt University Medical Center. Target doses for both Mg and placebo arms were personalized. Results: Among those aged > 65 years old who consumed a high Ca:Mg ratio diet, we found that reducing the Ca:Mg ratio to around 2.3 by personalized Mg supplementation significantly improved cognitive function by 9.1% (p = 0.03). We also found that reducing the Ca:Mg ratio significantly reduced 5-mC at the cg13496662 and cg06750524 sites only among those aged > 65 years old (p values = 0.02 and 0.03, respectively). Furthermore, the beneficial effect of reducing the Ca:Mg ratio on cognitive function in those aged over 65 years was partially mediated by reductions in 5-mC levels (i.e., cg13496662 and cg06750524) in APOE (p for indirect effect = 0.05). Conclusion: Our findings suggest that, among those age 65 and over with a high dietary Ca:Mg ratio, optimal Mg status may improve cognitive function partially through modifications in APOE methylation. These findings, if confirmed, have significant implications for the prevention of cognitive aging and Alzheimer’s disease. Clinical Trial Registry number and website: #100106 https://clinicaltrials.gov/ct2/show/NCT03265483

View study

Dietary magnesium intake is related to larger brain volumes and lower white matter lesions with notable sex differences

Type of study: non-rct observational study

Number of citations: 10

Year: 2023

Authors: Khawlah Alateeq, E. Walsh, N. Cherbuin

Journal: European Journal of Nutrition

Journal ranking: Q1

Key takeaways: Higher dietary magnesium intake is associated with better brain health in both men and women, with greater neuroprotective effects in post-menopausal women.

Abstract: Abstract Purpose To examine the association between dietary magnesium (Mg) intake and brain volumes and white matter lesions (WMLs) in middle to early old age. Methods Participants (aged 40–73 years) from UK Biobank ( n = 6001) were included and stratified by sex. Dietary Mg was measured using an online computerised 24 h recall questionnaire to estimate daily Mg intake. Latent class analysis and hierarchical linear regression models were performed to investigate the association between baseline dietary Mg, Mg trajectories, and brain volumes and WMLs. Associations between baseline Mg, and baseline blood pressure (BP) measures, and baseline Mg, Mg trajectories and BP changes (between baseline and wave 2) were also investigated to assess whether BP mediates the link between Mg intake and brain health. All analyses controlled for health and socio-demographic covariates. Possible interactions between menopausal status and Mg trajectories in predicting brain volumes and WMLs were also investigated. Results On average, higher baseline dietary Mg intake was associated with larger brain volumes (gray matter [GM]: 0.001% [SE = 0.0003]; left hippocampus [LHC]: 0.0013% [SE = 0.0006]; and right hippocampus [RHC]: 0.0023% [SE = 0.0006]) in both men and women. Latent class analysis of Mg intake revealed three classes: “high-decreasing” (men = 3.2%, women = 1.9%), “low-increasing” (men = 1.09%, women = 1.62%), and “stable normal” (men = 95.71%, women = 96.51%). In women, only the “high-decreasing” trajectory was significantly associated with larger brain volumes (GM: 1.17%, [SE = 0.58]; and RHC: 2.79% [SE = 1.11]) compared to the “normal-stable”, the “low-increasing” trajectory was associated with smaller brain volumes (GM: − 1.67%, [SE = 0.30]; white matter [WM]: − 0.85% [SE = 0.42]; LHC: − 2.43% [SE = 0.59]; and RHC: − 1.50% [SE = 0.57]) and larger WMLs (1.6% [SE = 0.53]). Associations between Mg and BP measures were mostly non-significant. Furthermore, the observed neuroprotective effect of higher dietary Mg intake in the “high-decreasing” trajectory appears to be greater in post-menopausal than pre-menopausal women. Conclusions Higher dietary Mg intake is related to better brain health in the general population, and particularly in women.

View study

High Blood Pressure and Impaired Brain Health: Investigating the Neuroprotective Potential of Magnesium

Type of study: literature review

Number of citations: 1

Year: 2024

Authors: Khawlah Alateeq, Erin Walsh, Nicolas Cherbuin

Journal: International Journal of Molecular Sciences

Journal ranking: Q1

Key takeaways: Magnesium may have the potential to lower blood pressure and promote brain health in the elderly, potentially benefiting neurodegeneration, cognitive function, and dementia.

Abstract: High blood pressure (BP) is a significant contributor to the disease burden globally and is emerging as an important cause of morbidity and mortality in the young as well as the old. The well-established impact of high BP on neurodegeneration, cognitive impairment, and dementia is widely acknowledged. However, the influence of BP across its full range remains unclear. This review aims to explore in more detail the effects of BP levels on neurodegeneration, cognitive function, and dementia. Moreover, given the pressing need to identify strategies to reduce BP levels, particular attention is placed on reviewing the role of magnesium (Mg) in ageing and its capacity to lower BP levels, and therefore potentially promote brain health. Overall, the review aims to provide a comprehensive synthesis of the evidence linking BP, Mg and brain health. It is hoped that these insights will inform the development of cost-effective and scalable interventions to protect brain health in the ageing population.

View study

The Presence of Blood–Brain Barrier Modulates the Response to Magnesium Salts in Human Brain Organoids

Type of study: non-rct in vitro

Number of citations: 6

Year: 2022

Authors: A. Cazzaniga, G. Fedele, S. Castiglioni, J. Maier

Journal: International Journal of Molecular Sciences

Journal ranking: Q1

Key takeaways: The presence of the blood-brain barrier is essential for magnesium to exert its effects on human brain organoids, with 5 mM of MgPid being more effective than MgSO4 in increasing GABA receptors and BDNF levels and decreasing NMDA receptor levels.

Abstract: Magnesium (Mg) is fundamental in the brain, where it regulates metabolism and neurotransmission and protects against neuroinflammation. To obtain insights into the molecular basis of Mg action in the brain, we investigated the effects of Mg in human brain organoids, a revolutionary 3D model to study neurobiology and neuropathology. In particular, brain organoids derived from human induced pluripotent stem cells were cultured in the presence or in the absence of an in vitro-generated blood–brain barrier (BBB), and then exposed to 1 or 5 mM concentrations of inorganic and organic Mg salts (Mg sulphate (MgSO4); Mg pidolate (MgPid)). We evaluated the modulation of NMDA and GABAergic receptors, and BDNF. Our data suggest that the presence of the BBB is essential for Mg to exert its effects on brain organoids, and that 5 mM of MgPid is more effective than MgSO4 in increasing the levels of GABA receptors and BDNF, and decreasing those of NMDA receptor. These results might illuminate novel pathways explaining the neuroprotective role of Mg.

View study

Adequate dietary magnesium intake may protect females but not males older than 55 years from cognitive impairment

Type of study: non-rct observational study

Number of citations: 3

Year: 2023

Authors: Xiang Gao, Yan Sun, Xin Huang, Yutian Zhou, Huichen Zhu, Qingxia Li, Yuxia Ma

Journal: Nutritional Neuroscience

Journal ranking: Q1

Key takeaways: Adequate magnesium intake may reduce the risk of mild cognitive impairment in older women, but not in males aged 55 and older.

Abstract: ABSTRACT Background Magnesium is an essential nutrient required to maintain brain health throughout life, and adequate magnesium intake is positively associated with cognitive performance in older adults. However, sex differences in magnesium metabolism have not been adequately assessed in humans. Objectives We investigated sex differences in the effect of dietary magnesium intake and the risk of different types of cognitive impairment in older Chinese adults. Methods We collected and assessed dietary data and cognitive function status in people aged 55 years and older in northern China who participated in the Community Cohort Study of Nervous System Diseases from 2018 to 2019 to explore the relationship between dietary magnesium intake and the risk of each type of mild cognitive impairment (MCI) in sex-specific cohorts of older adults. Results The study included 612 people: 260 (42.5%) men and 352 (57.5%) women. Logistic regression results showed that for the total sample and women's sample, high dietary magnesium intake reduced the risk of amnestic MCI (ORtotal = 0.300; ORwomen = 0.190) and multidomain amnestic MCI (ORtotal = 0.225; ORwomen = 0.145). The results of restricted cubic spline analysis showed that the risk of amnestic MCI (ptotal = 0.0193; pwomen = 0.0351) and multidomain amnestic MCI (ptotal = 0.0089; pwomen = 0.0096) in the total sample and women's sample gradually decreased with increasing dietary magnesium intake. Conclusions The results suggest that adequate magnesium intake may have a preventive effect against the risk of MCI in older women.

View study

The Impact of Chronic Magnesium Deficiency on Excitable Tissues-Translational Aspects.

Type of study:

Number of citations: 5

Year: 2024

Authors: M. Stanojević, Nadezda Djuricic, Miro Parezanović, Marko Biorac, Dhruba Pathak, S. Spasić, S. Lopicic, S. Kovačević, J. Nesović Ostojić

Journal: Biological trace element research

Journal ranking: Q1

Key takeaways: Chronic magnesium deficiency increases the risk of cardiovascular, respiratory, and neurological conditions, and its supplementation can help treat hyperexcitability.

Abstract: Neuromuscular excitability is a vital body function, and Mg^2+ is an essential regulatory cation for the function of excitable membranes. Loss of Mg^2+ homeostasis disturbs fluxes of other cations across cell membranes, leading to pathophysiological electrogenesis, which can eventually cause vital threat to the patient. Chronic subclinical Mg^2+ deficiency is an increasingly prevalent condition in the general population. It is associated with an elevated risk of cardiovascular, respiratory and neurological conditions and an increased mortality. Magnesium favours bronchodilation (by antagonizing Ca^2+ channels on airway smooth muscle and inhibiting the release of endogenous bronchoconstrictors). Magnesium exerts antihypertensive effects by reducing peripheral vascular resistance (increasing endothelial NO and PgI_2 release and inhibiting Ca^2+ influx into vascular smooth muscle). Magnesium deficiency disturbs heart impulse generation and propagation by prolonging cell depolarization (due to Na^+/K^+ pump and K_ir channel dysfunction) and dysregulating cardiac gap junctions, causing arrhythmias, while prolonged diastolic Ca^2+ release (through leaky RyRs) disturbs cardiac excitation-contraction coupling, compromising diastolic relaxation and systolic contraction. In the brain, Mg^2+ regulates the function of ion channels and neurotransmitters (blocks voltage-gated Ca^2+ channel-mediated transmitter release, antagonizes NMDARs, activates GABA_ARs, suppresses nAChR ion current and modulates gap junction channels) and blocks ACh release at neuromuscular junctions. Magnesium exerts multiple therapeutic neuroactive effects (antiepileptic, antimigraine, analgesic, neuroprotective, antidepressant, anxiolytic, etc.). This review focuses on the effects of Mg^2+ on excitable tissues in health and disease. As a natural membrane stabilizer, Mg^2+ opposes the development of many conditions of hyperexcitability. Its beneficial recompensation and supplementation help treat hyperexcitability and should therefore be considered wherever needed.

View study

Magnesium yields opposite effects on the nuclear and cytosolic cascades of apoptosis in different rat brain regions.

Type of study:

Number of citations: 2

Year: 2022

Authors: B. Koc, S. Kurt, HO F., Görler, A. Argon, M. Ate, S. Kizilda, N. U. Harzadin

Journal: European review for medical and pharmacological sciences

Journal ranking: Q2

Key takeaways: Long-term magnesium use can promote apoptosis in brain tissue by increasing the Bax/Bcl-2 ratio, but this cascade appears to be arrested at later stages.

Abstract: OBJECTIVE Magnesium is considered as potential neuroprotective and therapeutic agent, but certain studies have provided evidence of its apoptotic effectiveness in neurons. We aimed to evaluate the possible apoptotic effects of long-term magnesium use in healthy adult rat brains. MATERIALS AND METHODS Magnesium citrate and magnesium glycinate compounds were administered orally to rats for 8 weeks (36 mg/kg). Expression levels of Bcl-2, Bax and Cyt-C genes were analyzed by real-time polymerase chain reactions (RT-PCR) in the prefrontal cortex, hippocampus and striatum regions. Bcl-2, Bax and CytC protein levels were measured using ELISA kits. Tissue sections were evaluated histopathologically with hematoxylin-eosin staining. RESULTS Compared to the control group, the magnesium-administered groups indicated gene expression reductions in almost all brain regions; pro-apoptotic Bax, anti-apoptotic Bcl-2 and Cyt-C gene expression levels were reduced. With magnesium, the Bcl-2 and Bax protein levels were increased. Bax/Bcl-2 gene and protein ratio were also increased in the striatum and hippocampus, whereas Cyt-C protein levels were decreased or did not change in the magnesium treated groups. There was no pathological finding in histological evaluation. CONCLUSIONS Long-term magnesium usage can promote apoptotic cascade in brain tissue by increasing Bax/Bcl-2 ratio. Cyt-C, a prominent factor processing caspase pathway, was decreased or unchanged. In addition, taking into account the histological evaluation, we supposed that the absence of Cyt-C in the cytosol can prevent the subsequent apoptotic pathway. Consequently, we obtained the findings of apoptotic initiation with magnesium in brain, but this cascade seems to be arrested at later stages.

View study

Magnesium and cardiovascular system

Type of study:

Number of citations: 89

Year: 2010

Authors: Leviev Heart Center

Journal:

Journal ranking: brak

Key takeaways: Magnesium supplementation may improve heart health and reduce arrhythmias in high-risk groups, but its effectiveness in acute myocardial infarction remains unclear.

Abstract: Hypomagnesemia is common in hospitalized patients, especially in the elderly with coronary artery disease (CAD) and/or those with chronic heart failure. Hypomagnesemia is associated with an increased incidence of diabetes mellitus, metabolic syndrome, mortality rate from CAD and all causes. Magnesium supplementation improves myocardial metabolism, inhibits calcium accumulation and myocardial cell death; it improves vascular tone, peripheral vascular resistance, afterload and cardiac output, reduces cardiac arrhythmias and improves lipid metabolism. Magnesium also reduces vulnerability to oxygen-derived free radicals, improves human endothelial function and inhibits platelet function, including platelet aggregation and adhesion, which potentially gives magnesium physiologic and natural effects similar to adenosine-diphosphate inhibitors such as clopidogrel. The data regarding its use in patients with acute myocardial infarction (AMI) is conflicting. Although some previous, relatively small randomized clinical trials demonstrated a remarkable reduction in mortality when administered to relatively high risk AMI patients, two recently published large-scale randomized clinical trials (the Fourth International Study of Infarct Survival and Magnesium in Coronaries) failed to show any advantage of intravenous magnesium over placebo. Nevertheless, there are theoretical potential benefits of magnesium supplementation as a cardioprotective agent in CAD patients, as well as promising results from previous work in animal and humans. These studies are cost effective, easy to handle and are relatively free of adverse effects, which gives magnesium a role in treating CAD patients, especially high-risk groups such as CAD patients with heart failure, the elderly and hospitalized patients with hypomagnesemia. Furthermore, magnesium therapy is indicated in life-threatening ventricular arrhythmias such as Torsades de Pointes and intractable ventricular tachycardia.

View study

Dietary Magnesium and Cardiovascular Disease: A Review with Emphasis in Epidemiological Studies

Type of study: literature review

Number of citations: 137

Year: 2018

Authors: N. Rosique-Esteban, M. Guasch-Ferré, P. Hernández‐Alonso, J. Salas‐Salvadó

Journal: Nutrients

Journal ranking: Q1

Key takeaways: High magnesium intake is associated with lower risk of major cardiovascular risk factors, stroke, and cardiovascular diseases, particularly ischemic heart disease and coronary heart disease.

Abstract: Magnesium (Mg) is an essential dietary element for humans involved in key biological processes. A growing body of evidence from epidemiological studies, randomized controlled trials (RCTs) and meta-analyses have indicated inverse associations between Mg intake and cardiovascular diseases (CVD). The present review aims to summarize recent scientific evidence on the topic, with a focus on data from epidemiological studies assessing the associations between Mg intake and major cardiovascular (CV) risk factors and CVD. We also aimed to review current literature on circulating Mg and CVD, as well as potential biological processes underlying these observations. We concluded that high Mg intake is associated with lower risk of major CV risk factors (mainly metabolic syndrome, diabetes and hypertension), stroke and total CVD. Higher levels of circulating Mg are associated with lower risk of CVD, mainly ischemic heart disease and coronary heart disease. Further, RCTs and prospective studies would help to clarify whether Mg intake and Mg circulating levels may also protect against other CVDs and CVD death.

View study

Exploring the Positive Impact of Magnesium on Cardiovascular Diseases: A Comprehensive Review

Type of study: systematic review

Number of citations: 0

Year: 2025

Authors: Katarzyna Madyniak, Katarzyna Żak, Hubert Jucha, Agnieszka Kluz, Aleksandra Pliszka, Michał Mazur, Weronika Jarych, Krystian Zukierski, Katarzyna Michalak

Journal: Quality in Sport

Journal ranking: brak

Key takeaways: Magnesium deficiency contributes to various cardiovascular conditions, and its therapeutic effects include ionic modulation, vasodilation, and anti-inflammatory properties.

Abstract: Magnesium plays a critical role in cardiovascular health, being essential for various biochemical processes and maintaining physiological balance. Deficiency in magnesium is linked to conditions such as arrhythmias, hypertension, coronary artery disease and pregnancy-related disorders like preeclampsia and eclampsia. This study aims to investigate the role of magnesium in these cardiovascular conditions and highlight its therapeutic potential. Aim of the Study: The aim of this study is to comprehensively review the role of magnesium in cardiovascular diseases, including arrhythmias, hypertension, coronary artery disease, preeclampsia and eclampsia, with an emphasis on its physiological mechanisms, therapeutic applications, and potential clinical benefits. Material and Methods: A literature review was conducted using PubMed as the primary database. The search terms included: "magnesium", "cardiovascular diseases", "arrhythmia", "hypertension", "coronary artery disease", "preeclampsia" and "eclampsia". Conclusions: Magnesium deficiency contributes to various cardiovascular conditions, particularly arrhythmias, hypertension, coronary artery disease and pregnancy-related complications. Its therapeutic effects are primarily linked to ionic modulation, vasodilation, and anti-inflammatory properties, emphasizing the importance of magnesium in cardiovascular disease prevention and treatment.

View study

Magnesium and Cardiovascular Disease.

Type of study:

Number of citations: 112

Year: 2018

Authors: K. Tangvoraphonkchai, A. Davenport

Journal: Advances in chronic kidney disease

Journal ranking: Q2

Key takeaways: Low magnesium levels or intake may increase the risk of cardiovascular diseases, but routine magnesium supplementation is not recommended except for cases of cardiac arrhythmias.

Abstract: Magnesium is the most abundant intracellular divalent cation and essential for maintaining normal cellular physiology and metabolism, acting as a cofactor of numerous enzymes, regulating ion channels and energy generation. In the heart, magnesium plays a key role in modulating neuronal excitation, intracardiac conduction, and myocardial contraction by regulating a number of ion transporters, including potassium and calcium channels. Magnesium also has a role in regulating vascular tone, atherogenesis and thrombosis, vascular calcification, and proliferation and migration of endothelial and vascular smooth muscle cells. As such, magnesium potentially has a major influence on the pathogenesis of cardiovascular disease. As the kidney is a major regulator of magnesium homeostasis, kidney disorders can potentially lead to both magnesium depletion and overload, and as such increase the risk of cardiovascular disease. Observational data have shown an association between low serum magnesium concentrations or magnesium intake and increased atherosclerosis, coronary artery disease, arrhythmias, and heart failure. However, major trials of supplementation with magnesium have reported inconsistent benefits and also raised potential adverse effects of magnesium overload. As such, there is currently no firm recommendation for routine magnesium supplementation except when hypomagnesemia has been proven or suspected as a cause for cardiac arrhythmias.

View study

Dietary magnesium intake and the risk of cardiovascular disease, type 2 diabetes, and all-cause mortality: a dose–response meta-analysis of prospective cohort studies

Type of study: meta-analysis

Number of citations: 197

Year: 2016

Authors: X. Fang, Kai Wang, D. Han, Xuyan He, Jiayu Wei, Lu Zhao, M. Imam, Z. Ping, Yusheng Li, Yuming Xu, J. Min, Fudi Wang

Journal: BMC Medicine

Journal ranking: Q1

Key takeaways: Increasing dietary magnesium intake is associated with a reduced risk of stroke, heart failure, diabetes, and all-cause mortality, but not CHD or total CVD.

Abstract: Although studies have examined the association between dietary magnesium intake and health outcome, the results are inconclusive. Here, we conducted a dose–response meta-analysis of prospective cohort studies in order to investigate the correlation between magnesium intake and the risk of cardiovascular disease (CVD), type 2 diabetes (T2D), and all-cause mortality. PubMed, EMBASE, and Web of Science were searched for articles that contained risk estimates for the outcomes of interest and were published through May 31, 2016. The pooled results were analyzed using a random-effects model. Forty prospective cohort studies totaling more than 1 million participants were included in the analysis. During the follow-up periods (ranging from 4 to 30 years), 7678 cases of CVD, 6845 cases of coronary heart disease (CHD), 701 cases of heart failure, 14,755 cases of stroke, 26,299 cases of T2D, and 10,983 deaths were reported. No significant association was observed between increasing dietary magnesium intake (per 100 mg/day increment) and the risk of total CVD (RR: 0.99; 95% CI, 0.88–1.10) or CHD (RR: 0.92; 95% CI, 0.85–1.01). However, the same incremental increase in magnesium intake was associated with a 22% reduction in the risk of heart failure (RR: 0.78; 95% CI, 0.69–0.89) and a 7% reduction in the risk of stroke (RR: 0.93; 95% CI, 0.89–0.97). Moreover, the summary relative risks of T2D and mortality per 100 mg/day increment in magnesium intake were 0.81 (95% CI, 0.77–0.86) and 0.90 (95% CI, 0.81–0.99), respectively. Increasing dietary magnesium intake is associated with a reduced risk of stroke, heart failure, diabetes, and all-cause mortality, but not CHD or total CVD. These findings support the notion that increasing dietary magnesium might provide health benefits.

View study

Magnesium for the prevention and treatment of cardiovascular disease

Type of study:

Number of citations: 93

Year: 2018

Authors: J. DiNicolantonio, Jing Liu, J. O’Keefe

Journal: Open Heart

Journal ranking: Q1

Key takeaways: Magnesium deficiency increases the risk of cardiovascular events and death, and a high intake of magnesium can help prevent and treat these conditions.

Abstract: Magnesium is an essential mineral found in the body. It is naturally present in many foods and is also available as a dietary supplement.1 It serves as a cofactor in more than 300 enzymatic reactions, such as those responsible for regulating blood pressure, glycaemic control and lipid peroxidation. It is therefore also critical to the cardiovascular system.1 The adult body contains approximately 24 g of magnesium, with 50% to 60% present in bones with the rest being contained in soft tissues. Serum magnesium represents less than 1% of total body magnesium.2 In industrialised western countries, a low intake of magnesium often predisposes to a high prevalence of magnesium deficiency increasing the risk of cardiovascular events and cardiovascular death.3 This article aims to review of effect of magnesium deficiency on the cardiovascular system. In recent studies of hospitalised patients, 42% were shown to be hypomagnesaemic.4 However, physicians request magnesium testing in only 7% of these patients.4 In a study conducted among patients in the intensive cardiac care unit, 53% of patients had mononuclear cell magnesium content below the lowest normal control.5 Clinically, serum magnesium is usually measured despite the fact that less than 1% of magnesium exists extracellularly; hence, serum magnesium does not always accurately reflect total body magnesium stores. In fact, serum magnesium levels may be normal despite depletion of total body magnesium content.5 In experimental settings, total body magnesium stores can be estimated by measuring retention of an oral or intravenous magnesium load; however, measurement is cumbersome and requires a 24-hour urine collection.6 7 In many instances, intracellular levels of magnesium serve as a better indicator for total body magnesium content compared with serum magnesium levels with the most accurate test being blood mononuclear cell magnesium.8 Intracellular mononuclear magnesium …

View study

Magnesium, Oxidative Stress, Inflammation, and Cardiovascular Disease

Type of study: literature review

Number of citations: 107

Year: 2020

Authors: Man Liu, S. Dudley

Journal: Antioxidants

Journal ranking: Q1

Key takeaways: Magnesium deficiency contributes to cardiovascular diseases and may help prevent them by reducing oxidative stress, inflammation, and promoting heart health.

Abstract: Hypomagnesemia is commonly observed in heart failure, diabetes mellitus, hypertension, and cardiovascular diseases. Low serum magnesium (Mg) is a predictor for cardiovascular and all-cause mortality and treating Mg deficiency may help prevent cardiovascular disease. In this review, we discuss the possible mechanisms by which Mg deficiency plays detrimental roles in cardiovascular diseases and review the results of clinical trials of Mg supplementation for heart failure, arrhythmias and other cardiovascular diseases.

View study

Magnesium Deficiency and Cardiometabolic Disease

Type of study:

Number of citations: 28

Year: 2023

Authors: Rémi Fritzen, A. Davies, Miriam Veenhuizen, M. Campbell, Samantha J. Pitt, R. Ajjan, Alan J. Stewart

Journal: Nutrients

Journal ranking: Q1

Key takeaways: Magnesium deficiency can negatively impact cardiovascular and vascular outcomes, and magnesium supplements may help prevent and treat cardiovascular disorders and manage cardiometabolic health.

Abstract: Magnesium (Mg2+) has many physiological functions within the body. These include important roles in maintaining cardiovascular functioning, where it contributes to the regulation of cardiac excitation–contraction coupling, endothelial functioning and haemostasis. The haemostatic roles of Mg2+ impact upon both the protein and cellular arms of coagulation. In this review, we examine how Mg2+ homeostasis is maintained within the body and highlight the various molecular roles attributed to Mg2+ in the cardiovascular system. In addition, we describe how nutritional and/or disease-associated magnesium deficiency, seen in some metabolic conditions, has the potential to influence cardiac and vascular outcomes. Finally, we also examine the potential for magnesium supplements to be employed in the prevention and treatment of cardiovascular disorders and in the management of cardiometabolic health.

View study

Role of dietary magnesium in cardiovascular disease prevention, insulin sensitivity and diabetes

Type of study: literature review

Number of citations: 188

Year: 2008

Authors: S. Bo, E. Pisu

Journal: Current Opinion in Lipidology

Journal ranking: Q1

Key takeaways: Increased dietary magnesium intake may protect against diabetes, metabolic syndrome, hypertension, and cardiovascular disease by improving insulin resistance, serum lipid profiles, and reducing inflammation.

Abstract: Purpose of review This review summarizes the evidence for benefits of magnesium on metabolic abnormalities, inflammatory parameters, and cardiovascular risk factors and related-potential mechanisms. Controversy due to contrasting results in the literature is also discussed. Recent findings Increased dietary magnesium intake confers protection against the incidence of diabetes, metabolic syndrome, hypertension, and cardiovascular disease. It ameliorates insulin resistance, serum lipid profiles, and lowers inflammation, endothelial dysfunction, oxidative stress, and platelet aggregability. Magnesium acts as a mild calcium antagonist on vascular smooth muscle tone, and on postreceptor insulin signaling; it is critically involved in energy metabolism, fatty acid synthesis, glucose utilization, ATPase functions, release of neurotransmitters, and endothelial cell function and secretion. Prospective studies, however, have found only a modest effect for dietary magnesium on incident pathologies. Furthermore, magnesium supplementation on glucose metabolism, blood lipid levels, and ischemic heart disease has given inconsistent results. Summary There is strong biological plausibility for the direct impact of magnesium intake on metabolic and cardiovascular risk factors, but in-vivo magnesium deficiency might play only a modest role. Reverse causality, the strong association between magnesium and other beneficial nutrients, or the possibility that people who choose magnesium-rich foods are more health-conscious may be confounding factors.

View study

Role of Magnesium in Cardiovascular Diseases

Type of study:

Number of citations: 175

Year: 2014

Authors: D. Kolte, K. Vijayaraghavan, S. Khera, D. Sica, W. Frishman

Journal: Cardiology in Review

Journal ranking: Q2

Key takeaways: Magnesium plays a crucial role in regulating cardiovascular function and plays a role in preventing and treating various cardiovascular disorders due to its vasodilatory, anti-inflammatory, anti-ischemic, and antiarrhythmic properties.

Abstract: Magnesium, the fourth most abundant cation in the human body, is involved in several essential physiological, biochemical, and cellular processes regulating cardiovascular function. It plays a critical role in modulating vascular smooth muscle tone, endothelial cell function, and myocardial excitability and is thus central to the pathogenesis of several cardiovascular disorders such as hypertension, atherosclerosis, coronary artery disease, congestive heart failure, and cardiac arrhythmias. This review discusses the vasodilatory, anti-inflammatory, anti-ischemic, and antiarrhythmic properties of magnesium and its current role in the prevention and treatment of cardiovascular disorders.

View study

The Role of Dietary Magnesium in Cardiovascular Disease

Type of study: meta-analysis

Number of citations: 3

Year: 2024

Authors: Forrest H. Nielsen

Journal: Nutrients

Journal ranking: Q1

Key takeaways: Low magnesium levels are associated with cardiovascular disease, making magnesium a public health concern.

Abstract: In the past 20 years, a large number of epidemiological studies, randomized controlled trials, and meta-analyses have found an inverse relationship between magnesium intake or serum magnesium and cardiovascular disease, indicating that low magnesium status is associated with hypertension, coronary artery calcification, stroke, ischemic heart disease, atrial fibrillation, heart failure, and cardiac mortality. Controlled metabolic unit human depletion–repletion experiments found that a mild or moderate magnesium deficiency can cause physiological and metabolic changes that respond to magnesium supplementation, which indicates that these types of deficiencies or chronic latent magnesium deficiency are contributing factors to the occurrence and severity of cardiovascular disease. Mechanisms through which a mild or moderate magnesium deficiency can contribute to this risk include inflammatory stress, oxidative stress, dyslipidemia and deranged lipid metabolism, endothelial dysfunction, and dysregulation of cellular ion channels, transporters, and signaling. Based on USA official DRIs or on suggested modified DRIs based on body weight, a large number of individuals routinely consume less magnesium than the EAR. This especially occurs in populations that do not consume recommended amounts of whole grains, pulses, and green vegetables. Thus, inadequate magnesium status contributing to cardiovascular disease is widespread, making magnesium a nutrient of public health concern.

View study

Effect of magnesium supplementation on type 2 diabetes associated cardiovascular risk factors: a systematic review and meta‐analysis

Type of study: meta-analysis

Number of citations: 87

Year: 2017

Authors: H. Verma, Rajeev Garg

Journal: Journal of Human Nutrition and Dietetics

Journal ranking: Q2

Key takeaways: Magnesium supplementation can improve fasting plasma glucose, HDL, LDL, TG, and systolic blood pressure, potentially decreasing the risk of type 2 diabetes-associated cardiovascular diseases.

Abstract: BACKGROUND Cardiovascular disorders remain the leading cause of death in type 2 diabetic patients. In the present study, a systematic review and a meta-analysis of randomised controlled trials (RCTs) were conducted aiming to evaluate the effect of magnesium supplementation on type 2 diabetes (T2D) associated cardiovascular risk factors in both diabetic and nondiabetic individuals. METHODS PubMed, Scopus, Cochrane, Web of Science and Google Scholar databases were searched from inception to 30 June 2016 aiming to identify RCTs evaluating the effect of magnesium supplementation on T2D associated cardiovascular risk factors. The data were analysed using a random effect model with inverse variance methodology. Sensitivity analysis, risk of bias analysis, subgroup analysis, meta-regression and publication bias analysis were also conducted for the included studies using standard methods. RESULTS Following magnesium supplementation, a significant improvement was observed in fasting plasma glucose (FPG) [weighted mean difference (WMD) = -4.641 mg dL-1 , 95% confidence interval (CI) = -7.602, -1.680, P = 0.002], high-density lipoprotein (HDL) (WMD = 3.197 mg dL-1 , 95% CI = 1.455, 4.938, P < 0.001), low-density lipoprotein (LDL) (WMD = -10.668 mg dL-1 , 95% CI = -19.108, -2.228, P = 0.013), plasma triglycerides (TG) (WMD = -15.323 mg dL-1 , 95% CI = -28.821, -1.826, P = 0.026) and systolic blood pressure (SBP) (WMD = -3.056 mmHg, 95% CI = -5.509, -0.603, P = 0.015). During subgroup analysis, a more beneficial effect of magnesium supplementation was observed in diabetic subjects with hypomagnesaemia. CONCLUSIONS Magnesium supplementation can produce a favourable effect on FPG, HDL, LDL, TG and SBP. Therefore, magnesium supplementation may decrease the risk T2D associated cardiovascular diseases, although future large RCTs are needed for making robust guidelines for clinical practice.

View study

Magnesium and Cardiovascular Disease

Type of study:

Number of citations: 121

Year: 1998

Authors: Mark N. Gomez

Journal: Anesthesiology

Journal ranking: Q1

Key takeaways: Magnesium therapy may be beneficial in preventing cardiovascular complications and improving anesthesia outcomes in patients with cardiovascular disease.

Abstract: [Gomez] Associate Professor.Dennis M. Fisher, M.D., EditorIN 1935, Zwillinger reported that administration of magnesium (Mg (2+)) restored sinus rhythm in patients with digitalis-induced tachyarrhythmias. [1]Since that time, Mg2+has been used for prophylaxis or therapy in a variety of cardiovascular disorders [2]: myocardial ischemia and infarction, [3]coronary spasm, [4]ventricular [5]and supraventricular [6]arrhythmias, digoxin toxicity, [7]preeclampsia-eclampsia, [8]cerebral vasospasm, [9]and stroke. [10]Chronic Mg2+deficiency and acute hypomagnesemia are associated with increased cardiovascular morbidity and mortality. [11–15]Therapeutic effects, however, have been reported after pharmacologic administration, even in the absence of known Mg2+deficiency or hypomagnesemia. Because many of the abnormalities for which Mg2+therapy has been advocated are common among patients undergoing anesthesia and surgery, the anesthesiologist should be familiar with the rational use of this cation. Accordingly, this article addresses (1) the physiology and pharmacology of Mg2+relevant to patients with cardiovascular disease;(2) evidence supporting the use of Mg2+in a variety of disease states; and (3) current applications of Mg (2+) therapy.Mg2+metabolism and its derangements have been reviewed recently. [16–19]Mg2+is the second most abundant cation in the body, the second most abundant intracellular cation after potassium (K+), and a critical cofactor in >300 enzymatic reactions involving energy metabolism and protein and nucleic acid synthesis. Total body stores of Mg (2+) average 1,000 mmol for a 70-kg individual, with >50% in bone, nearly 50% in soft tissues, and <1% in blood. [18]In contrast to the tight hormonal control of concentrations of calcium (Ca2+) in blood, the kidney is the primary regulator of Mg2+balance. Although there is some hormonal influence on the renal handling of Mg2+(primarily by parathyroid hormone, calcitonin, and antidiuretic hormone), changes in dietary intake of Mg2+or concentrations of Mg2+in blood do not evoke hormone secretion. [19]Mg2+(intra- and extracellular) exists in three states:(1) free, ionized fraction (the physiologically active form);(2) complexed to anions (citrate, phosphate, bicarbonate); and (3) protein bound. In extracellular fluid, free Mg2+composes 61% of total Mg2+, 6% is complexed, and 33% is protein bound. [20]In this article, the symbol Mg2+designates total Mg2+cation unless otherwise modified (e.g., ionized Mg2+or complexed Mg2+).The diagnosis of Mg2+deficiency (defined as a reduction in total content of Mg2+in the body [17]) is difficult to establish because (1) it may be asymptomatic [2];(2) concentration of total Mg2+in serum may be normal despite depletion in tissue [21–26]; and (3) measurement of concentrations in tissue is not readily available [22,23]and may be specific for the tissue sampled. [17,22]Nonetheless, studies reporting Mg2+assays on a variety of tissues suggest that many patients with cardiovascular disease exhibit depletion of Mg2+compared with healthy individuals. [21,25,26]For example, Haigney et al. [21]found that (1) concentrations of Mg2+in buccal mucosal cells were reduced in patients with coronary artery disease compared with healthy volunteers, despite normal concentrations in serum, and (2) concentrations of Mg2+in buccal cells correlated well with atrial concentrations of Mg2+.The diagnosis of Mg2+depletion also has been based on the percent of Mg2+retained after an intravenous infusion of Mg2+. [27,28]The Mg2+retention test requires a baseline 24-h urine collection, after which Mg2+(0.2 mEq/kg lean body weight) is infused for 4 h and urine is again collected for 24 h. Mg2+-repleteindividuals should excrete at least 60% of the administered load. [27]Although the retention test is considered highly sensitive for depletion of Mg2+, it has not been possible to correlate the percent retention with the degree of total body Mg2+deficiency. [17]The test has been used to screen critically ill patients [29]and patients with diseases in which deficiency of Mg2+has been implicated as contributory (e.g., variant angina). [30–32]Goto et al. [33]found that patients with vasospastic angina had normal concentrations of total Mg2+in serum, but they excreted only 40 +/- 5% of the Mg2+load, whereas healthy individuals excreted 64 +/- 3%(P < 0.001).In clinical practice, laboratory assessment of Mg2+status usually begins with measurement of concentration of total Mg2+in serum. Serum rather than plasma is used because the anticoagulants (e.g., citrate, ethylene-diaminetetraacetic acid) for plasma affect the assay procedure. [23]This test, however, has several limitations in the assessment of Mg (2+) status, despite its ready availability. First, hypomagnesemia (defined as concentration of Mg2+in serum less than the normal range [22];Table 1) is often not present in patients with chronic depletion of Mg2+because of very slow equilibration of Mg2+among tissue compartments and because the compartment being sampled, namely blood, contains a small fraction of total Mg2+. [17]Second, concentration of total Mg2+in serum may not reflect concentration of ionized Mg2+in serum. [31,34–36]These findings may explain at least part of the beneficial effect of administration of Mg2+in some patients who appear to be normomagnesemic.Although the Mg2+-selectiveelectrode has been commercially available for several years, [37,38]it is not widely used because the clinical utility of ionized Mg2+measurement has not been established. Some authors have recommended measuring ultrafilterable Mg2+(the combination of complexed and ionized Mg2+) to approximate ionized Mg2+, [39–41]but this method also is not widely used.Sequelae. There is substantial evidence that chronic depletion of Mg2+and acute hypomagnesemia are associated with increased cardiovascular morbidity and mortality. [11–15,26,35,42–49]Animal studies have shown that chronic depletion of Mg2+exacerbates hypertriglyceridemia, hypercholesterolemia, and decreased high-density lipoprotein concentrations. [43,44]Dogs fed a Mg2+-freediet and subjected to coronary artery occlusion develop myocardial infarcts twice as large as dogs that are fed a normal diet. [45]Similarly, chronically Mg (2+-depleted) swine have prolonged postischemic myocardial dysfunction (stunning) compared with Mg2+-repletecontrol animals. [46]Human epidemiologic studies indicate that chronic depletion of Mg2+is associated with ventricular arrhythmias [12]and increased atherosclerotic vascular disease and associated cardiovascular mortality. [11,13,14]Myocardial depletion of Mg2+is associated with an increased incidence of arrhythmias after cardiac surgery. [26]Finally, recent results suggest that early and progressive ionized hypomagnesemia during pregnancy is associated with the development of preeclampsia at term. [47]Acute hypomagnesemia in isolated hearts subjected to ischemia worsens postischemic function and arrhythmias. [48]In contrast, Madias et al. [49]found that, in patients with acute myocardial infarction (AMI), low concentrations of Mg2+in serum on admission were not associated with arrhythmias or increased hospital mortality. However, ionized and tissue concentrations of Mg2+were not measured, and patients who were hypomagnesemic in the emergency department were more likely to be treated with MgSO4(P < 0.001). [49]Landmark and Urdal [15]reported that large decreases in concentrations of total Mg2+in serum during AMI were associated with higher peak concentrations of creatine kinase. Finally, hyperventilation-induced acute ionized hypomagnesemia is associated with variant anginal episodes despite normal concentrations of total Mg2+. [35]Mechanisms. Although many patients with chronic heart disease are Mg2+depleted, [21]a variety of superimposed stressors cause additional decreases in concentrations of Mg2+in serum by redistribution (Table 2). [3]Patients presenting with AMI, for example, have a precipitous decrease in concentrations of Mg2+in serum, with the lowest concentrations seen 12–20 h after hospital admission. [50]The postulated mechanism involves catecholamine-induced lipolysis and generation of free fatty acids, which then chelate free Mg2+to form insoluble salts that are sequestered intracellularly. [3,51,52]Catecholamines increase uptake of Mg2+by adipose cells. [53,54]Other high-stress states, such as major burns, sepsis, trauma, alcohol withdrawal, hypothermia, or cardiac surgery, also may be accompanied by catecholamine-induced hypomagnesemia. [50,55,56]Concentrations of total Mg2+in serum decrease significantly during cardiopulmonary bypass (CPB), and these concentrations persist into the post-CPB period, during which they are associated with increased morbidity. [57,58]Recent reports indicate that concentrations of ionized Mg2+also decrease during and after CPB. [34,59]Several factors have been implicated in CPB-related hypomagnesemia. First, measurable preoperative hypomagnesemia is common in patients undergoing cardiac surgery. [39,58,60,61]Second, there may be additional decreases in concentrations of Mg2+in serum after induction of anesthesia but before CPB, probably as a result of hemodilution with Mg2+-freefluids. [39,58]Increasing concentrations of catecholamines also may have contributed to the decrease. Third, during CPB, further decreases in concentrations of Mg2+in serum are caused by additional hemodilution, binding to albumin in the pump prime, and redistribution secondary to catecholamine-induced increases in concentrations of free fatty acid. [39,62]Although urinary excretion of Mg2+may increase slightly during CPB, it is probably not a major factor in CPB-related Mg2+flux unless exogenous Mg2+is administered. [63,64]Intraoperative administration of Mg2+-containingcardioplegia solutions [64](or the equivalent intravenous bolus dose of Mg2+[65]) prevents the decrease in concentrations of total Mg2+seen during and after CPB, but concentrations of ionized Mg2+may still be decreased. [34]Intracellular Mg2+. Although the important pharmacologic actions of Mg2+are primarily extracellular, free cytosolic Mg2+(Mgi2+) modulates the intracellular milieu through its influence on ion channels and transport mechanisms. [66–70]Although this area has been reviewed, [71–74]two general points are important. First, Mgi2+modulates Ca2+flux in pathophysiologic and physiologic states. [71–73]Increasing concentrations of Mgi2+during early ischemia or hypoxia [67,75]have beneficial effects on L-type Ca2+channels during stress [66,69,71,74]; i.e., Ca2+influx is inhibited. [68]Second, depletion of Mgi2+, as occurs after prolonged ischemia and reperfusion, [76]contributes to progressive Ca2+over-load and subsequent cell damage (discussed subsequently). [45]In addition, loss of Mgi2+may promote cystolic Ca2+overload from intracellular sources: Elevated concentrations of Mgi2+inhibit efflux of Ca2+from sarcoplasmic reticulum. [77,78]Extracellular Mg2+. For nearly two decades, extracellular Mg (2+)(and several other divalent cations) has been considered to be a Ca (2+) antagonist because it inhibits Ca2+current in excitable cells. This has several clinical implications because (1) virtually all excitable cells have voltage-gated Ca2+channels [79];(2) in general, these channels transduce electrical signals (that is, membrane depolarization) into various cellular actions (e.g., muscle contraction, neurotransmitter release) via modulation of Ca2+flux [80];(3) Ca2+current supports excitation in the sinoatrial and atrioventricular nodes and conduction through the atrioventricular node [81]; and (4) voltage-sensitive Ca2+channels also play important roles in arrhythmogenesis. [82]Two mechanisms are believed to be involved in inhibition of Ca2+current by extracellular Mg2+:(1) effects mediated by cationic screening of fixed negative external surface charges [83–85]; and (2) competition with permeant ions (Ca2+) for a site within the channel itself. [86]Elevated extracellular divalent cation concentrations stabilize excitable membranes and raise the excitation threshold in voltage-dependent channels. [87,88]The net result for a given voltage-sensitive channel is a shift of the current-voltage relationship so that current is diminished in response to a standard stimulus. [87,89]Divalent cations such as Mg2+effectively neutralize fixed negative charges on the outside of the cell membrane either by binding or, more likely, by electrostatic screening. [83,90]The result is a change in the effective local transmembrane potential sensed by the voltage-sensitive Ca (2+) channel. [91]This offset in the transmembrane potential across the channel, sensed by the voltage sensor, alters any voltage-dependent processes such as gating (i.e., channel activation and inactivation). [85]In addition to alterations of transmembrane potential in the vicinity of the channel, it is also possible that divalent cation screening of fixed negative charges on the channel entrance itself effectively decreases the local permeant cation (Ca2+) concentration, thereby reducing current flow. [85,92]Mg2+affects both L-type and T-type Ca2+channels. [93]Although early studies showed that, during some experimental conditions (i.e., use of Ba2+as charge carrier in the presence of Bay K8644, a Ca2+channel opener [94]), Mg2+has relatively weak direct channel blocking activity, [86]evidence to date indicates that elevated extracellular concentrations of Mg2+effectively decrease Ca (2+) current by altering the membrane surface potential in the vicinity of the Ca2+channel, rather than by lodging in the channel pore itself. [95]Mg2+and Ischemic-Reperfusion Injury. Studies in the 1970s showed that myocardial ischemia followed by reperfusion results in cytoplasmic Ca2+overload. [79,96–99]There is now general agreement that during and after periods of ischemia, transmembrane Ca2+influx occurs by several routes, [97,100–112]and that cytoprotective agents, including Mg2+, attenuate the increase in intracellular Ca2+via multiple mechanisms. [102,103,113–122]Antiischemic Effects. In animals, administration of Mg2+before permanent coronary artery occlusion is highly effective in limiting the size of myocardial infarcts. [123]Clinical management of AMI, however, involves reperfusion therapy as early as possible after the onset of ischemia. Recent attention has shifted toward identifying agents that may be administered before or concurrently with reperfusion therapy, with particular emphasis on drugs that reduce myocardial injury caused by reperfusion. [124]There is experimental evidence that Mg2+is cardioprotective. [125–127]Recent models designed to simulate the clinical setting in which Mg2+is administered during the interval beginning shortly after coronary occlusion and extending through initial reperfusion have shown significant reductions in the size of myocardial infarcts [125,126]and in the severity of regional myocardial stunning. [127]Numerous cardioprotective effects have been attributed to Mg2+(Table 3). [4,119,127–144]Mg2+Cardioplegia. Effects of cardioplegia on reperfusion injury have been reviewed recently. [145–149]A brief period of ischemia causes reversible cell injury, defined by the finding that reperfusion prevents infarction and allows eventual recovery of normal cellular structure, function, and metabolism. [146]Complete recovery, however, is not immediate; profound metabolic and functional abnormalities may persist for hours or days after as few as 5–15 min of coronary occlusion. [147]These abnormalities are manifestations of reperfusion injury and include (1) postischemic contractile dysfunction (stunning);(2) reperfusion arrhythmias (see antiarrhythmic effects); and (3) damaged microvasculature preventing continued reperfusion (no reflow). [148]Stunning occurs in many clinical settings, particularly interventional (and spontaneous) thrombolysis in acute coronary syndromes [145]and in the post-CPB period. [149]Studies using isolated perfused hearts subjected to periods of global ischemia and reperfusion have shown that Mg2+cardioplegia significantly reduces myocardial stunning and cytosolic Ca2+overload [115,116,150–153]when given concurrently with or before reperfusion. [126]Ischemic - reperfusion injury of the microvasculature results in progressive diminution of perfusion to previously ischemic tissues despite restoration of flow in the conduit arteries supplying these tissues, i.e., the noreflow phenomenon. [148]The no-reflow phenomenon is a significant clinical problem. It occurs in 2% of coronary interventions (e.g., balloon angioplasty, directional atherectomy, stent placement)[154]and in 23–27% of patients receiving thrombolytic therapy during AMI. [155,156]No reflow is associated with a higher incidence of early and prolonged congestive heart failure (CHF) compared with the absence of no reflow. [156]The primary insult in no reflow is probably reperfusion-induced (and oxygen free radical-mediated) injury to endothelium. [157–162]Circumstantial evidence suggests that Mg2+reduces endothelial injury. First, deficiency of Mg (2+) potentiates oxygen free radical-induced postischemic injury in working isolated rat hearts. [158]Second, agents that attenuate the initial ischemic injury, namely Ca2+antagonists administered before reperfusion, also reduce the severity of no reflow [163]and preserve endothelial function. [164]Finally, experimental areas of no reflow are decreased, and vascular endothelial and smooth muscle function are preserved after administration of Mg2+cardioplegia (16 mM). [165,166]Mechanisms. Despite improved understanding, pharmacologic control of cardiac arrhythmias is still largely empiric because there are few criteria to differentiate underlying mechanisms. [167]Moreover, many antiarrhythmic agents (including Mg2+) have multiple effects on the key components of arrhythmogenesis (and their interactions), namely substrate, trigger, and modulating factors. [168]The nature and severity of the substrate derangement itself can affect the specificity of antiarrhythmic drug activity. For example, in experimental models of ventricular tachycardia involving different arrhythmogenic mechanisms (e.g., ischemic, digitalis toxic, catecholamine induced), Mg2+possesses class IV (Ca2+channel inhibition [169]) and weak class I (Na+channel inhibition [169]) antiarrhythmic activities. [170]Several specific and related antiarrhythmic mechanisms involving Mg2+have been inferred after nearly seven decades of clinical and experimental observations (Table 4). [113,114,136,167,168,171–179]Electrophysiologic Effects. Administration of MgSO4during electrophysiologic evaluation of patients has demonstrated two effects of Mg (2+) relevant to the treatment of supraventricular tachyarrhythmias:(1) prolongation of atrioventricular nodal conduction time (anterograde and retrograde) and refractory period [6,180–184]; and (2) suppression of conduction in accessory pathways with and without atrioventricular node-like properties, [6,182]although conflicting results have been reported. [184]Prolongation of atrioventricular nodal conduction by Mg2+is most likely attributable to inhibition of Ca2+current, the primary mode of impulse conduction through the atrioventricular node, [81]but also may results from Mg2+-inducedattenuation of sympathetic activity at the atrioventricular node. [184,185]Other antiarrhythmic effects of Mg2+have been reported, although the underlying mechanisms have not been defined:(1) restoration of sinus rhythm in critically ill medical and surgical patients with supraventricular tachycardias [186];(2) suppression of intractable ventricular tachyarrhythmias [5];(3) control of ventricular rate in new-onset atrial fibrillation (AF)[187,188];(4) prophylaxis of AF after coronary artery bypass grafting [189,190];(5) slowing of digoxin-facilitated ventricular rate during AF in Wolff-Parkinson-White syndrome [191];(6) abolition of preexcitation (Delta wave) in patients with Wolff-Parkinson-White syndrome during normal sinus rhythm [192];(7) suppression of multifocal atrial tachycardia [193–194];(8) suppression of digoxin-induced ectopic tachyarrhythmias [1,7];(9) prevention of bupivacaine-induced arrhythmias [195]; and (10) treatment of amitriptyline-induced ventricular fibrillation. [196]Intact Individuals. Circulatory effects of rapid administration of Mg2+in awake individuals are minimal even in the presence of hypertension or moderately severe ventricular dysfunction. In several studies, Mg2+was administered as a bolus dose with or without continuous infusion, sufficient in some cases to achieve a threefold increase in concentrations of Mg2+in serum (Table 5). [141,180,197–203]The most common finding was a small decrease in blood pressure accompanied by a decrease in systemic vascular resistance and an increase in cardiac output and stroke volume. These results suggest that negative inotropic effects of moderately elevated concentrations of Mg2+are effectively counterbalanced by Mg2+-inducedafterload reduction.The few studies that have involved administration of Mg2+in anesthetized individuals (not during CPB) either have not reported hemodynamic effects [7,60]or have involved infusion of Mg2+for control of pathologic hyperdynamic states associated with pheochromocytoma [204,205]or severe tetanus. [138,139]Because volatile anesthetic agents depress intracellular Ca2+flux, [206]however, it is likely that the circulatory effects of high concentrations of Mg2+in serum are potentiated by these agents, particularly in patients with ventricular dysfunction. Recent experimental evidence suggests, however, that a 10-fold increase in concentrations of Mg2+in blood during sevoflurane-N2O or sevoflurane-fentanyl anesthesia results in minimal cardiovascular depression. [207,208]Regional Circulations. Mg2+vasodilates by inhibiting Ca2+influx at the vascular smooth muscle membrane [209–211]and possibly by interfering with release of Ca2+from intracellular sites. [212]Mg (2+) increases renal blood flow in healthy individuals, [141,213]increases uterine blood flow in pregnant patients, [214]and dilates isolated human (pregnant) uterine artery segments. [215]Experimental and clinical observations indicate that Mg2+dilates coronary arteries, particularly when coronary vasoreactivity is pathologic. Mg2+dilates preconstricted segments of human (fresh cadaver) coronary arteries, [128]decreases coronary vascular resistance (and increases coronary blood flow) moderately in healthy individuals, [200]provides rapid relief of vasospastic angina, [4,129]and prevents inducible episodes of vasospastic angina. [129–131,197]In addition, coronary artery spasm occurs in eclampsia, [216]and it is likely (albeit unproven) that one of the myriad beneficial effects of Mg2+in this potentially lethal condition is cardioprotection. [129]The cerebral circulation also responds to changes in concentrations of Mg2+. Withdrawal of Mg2+rapidly increases the tension in canine middle and basilar cerebral arteries. [217]In contrast, sudden increases in Mg2+cause rapid and concentration-dependent relaxation of basal tension in all cerebral arteries tested. [218]Mg2+relaxes preconstricted (by serotonin, prostaglandins, or Ca2+) cerebral arteries [218–220]and arteries subjected to delayed spasm secondary to subarachnoid hemorrhage. [221]Mg2+also produces dose-dependent relaxation of cerebral arterioles (17–30 [micro sign] in diameter). [218]Cerebral arteriolar dilation, with the accompanying increased cerebral blood flow, is one of the salutary effects of administration of Mg2+in severe eclampsia [222]and may account, at least in part, for the anticonvulsant effect of Mg2+in this setting. [8]Diffuse and intense cerebral vasospasm associated with preeclampsia-eclampsia has been documented angiographically. [223–225]Another potential anticonvulsant effect of Mg2+in preeclampsia, in addition to its vascular (antiischemic) actions, is attenuation of ischemia-induced neuronal Ca2+influx via channels associated with the excitatory N-methyl-D-aspartate subtype of glutamate receptor. [226–228]Endothelial Effects. Normal endothelium modulates the state of contraction of the underlying vascular smooth muscle. [229–232]Endothelial dysfunction is implicated in several disease processes, including atherosclerosis, [233]pathologic coronary vasoreactivity with and without significant coronary stenoses, [234]and preeclampsia-eclampsia. [235]Normal endothelium synthesizes the vasodilators prostacyclin and nitric oxide (NO). [236–238]Infusion of Mg2+increases endothelial release of prostacyclin, not only by cultured human endothelial cells [239]but also in healthy nonpregnant volunteers [141]and preeclamptic patients. [240]These results suggest that vascular actions of Mg2+in healthy individuals and preeclamptic patients are mediated, at least in part, by release of prostacyclin. Further, in preeclampsia, Mg2+-inducedrelease of prostacyclin antagonizes pathologic platelet adhesion, aggregation, and resulting microvascular occlusion secondary to endothelial dysfunction in this disorder. [235,239]Similar to the reciprocal or mutant antagonistic relationship between Ca2+and Mg2+at the level of the vascular smooth muscle cell membrane, [212,213,218]there appears to be a reciprocal interaction at the level of the vascular endothelial cell membrane (see subsequent section). Extracellular Ca2+is essential for endothelium-dependent vascular smooth muscle relaxation [241]; an increase in endothelial cell intracellular Ca2+accompanies basal production or release of NO and the release of NO in response to a wide variety of endothelium-dependent dilators. [242]Entry of Ca2+in endothelial cells, however, is not voltage-gated; i.e., these cells are nonexcitable. [243]Rather, Ca2+entry is capacitative: It is activated by depletion of intracellular Ca2+stores. [244]Although the effect of Mg2+on capacitative entry of Ca2+in endothelial cells has not been addressed specifically, elevated extracellular Mg2+has been shown to inhibit capacitative Ca2+entry in other cells. [245]Experimental studies have shown that (1) removal of extracellular Mg2+causes a potent, endothelium-dependent vasodilatory response [246–249];(2) in contrast, removal of Mg2+in arteries with disrupted endothelium leads to vasoconstriction; and (3) both responses are reversible with readdition of Mg2+. [246–249]When concentrations of Mg2+or Ca2+are increased to higher than the physiologic range (>1.2 and >1.5 mM, respectively), the direct endothelium-independent effects dominate. When the concentration of Ca2+is >1.5 mM in the presence of a normal concentration of Mg2+, endothelium-intact rings contract; when the concentration of Mg2+is >1.2 mM, endothelium-intact rings relax. [248]Because Ca2+is obligatory for smooth muscle contraction and basal NO formation or release, and because Mg2+opposes the action of Ca (2+) at both sites, these studies suggest that the responsiveness of vascular smooth muscle to changes in concentrations of Mg2+and Ca2+reflects the sum of responses at the endothelial and smooth muscle cells. [248]Studies of the effects of Mg2+on agonist-induced, NO-mediated relaxation of arteries have produced contradictory results. [250–253]The clinical significance of these results is not clear for two reasons. First, these studies used different types of isolated blood vessels from a variety of species. Second, and more important, most of these studies used extracellular concentrations of Mg2+outside the physiologic range (e.g., Mg2+-freeperfusate). In one study, however, human pial arteries were used to show that even slight changes in extracellular concentration of Mg2+within the physiologic range (i.e., 1.2 mM to 0.8 mM) resulted in relaxation of endothelium-intact arteries and constriction of endothelium-disrupted arteries. [249]These results suggest that normal endothelium protects against the vasospastic effect of low extracellular concentrations of Mg2+. [249]In 1991, Teo et al. [254]reported a metaanalysis of seven small randomized, placebo-controlled trials of Mg2+in AMI conducted during the previous decade. They found a reduction in mortality from AMI of 53% and a significant reduction in serious arrhythmias with Mg2+. A second metaanalysis of eight trials, which included the studies analyzed by Teo et al., yielded similar results. [255]Two additional randomized trials found that Mg2+-treatedpatient groups had significantly lower in-hospital [256]and 30-day mortality. [257]Recently, however, two large randomized trials of Mg2+in AMI yielded conflicting results. It is worthwhile to comment on these trials because significant methodologic differences may account for the disparate findings. Woods et al. [258]studied 2,316* patients in the second Leicester Intravenous Magnesium Intervention Trial (LIMIT-2), which showed that doubling the concentration of Mg2+in serum in the acute phase of AMI improved outcome significantly. Mortality at 28 days, the primary trial end point, was reduced by 24% in the Mg2+group compared with the placebo group (7.8% mortality vs. 10.3% respectively; two-tailed P = 0.04). LIMIT-2 was a single-center, double-blinded trial, and the median interval from onset of symptoms to administration of the study drug was 3 h. Other treatments for AMI were given as clinically indicated; therefore, some patients received a thrombolytic agent, aspirin, or both immediately after receiving the study drug. Analysis of these subgroups and others, including those receiving previous [Greek small letter beta]-adrenergic blocker, diuretic, nitrate, or Ca2+antagonist, showed that Mg2+improved survival significantly in all subgroups. Reduction in mortality was accompanied by a 25% reduction in the incidence of left ventricular failure (two-tailed P = 0.009

View study

Type of study:

Number of citations: 69

Year: 2015

Authors: Z. Massy, T. Drüeke

Journal: Nature Reviews Nephrology

Journal ranking: Q1

Key takeaways: Magnesium supplementation may reduce cardiovascular complications in chronic kidney disease patients, but randomized controlled trials are needed to confirm its effects.

View study

Magnesium and the Risk of Cardiovascular Events: A Meta-Analysis of Prospective Cohort Studies

Type of study: meta-analysis

Number of citations: 178

Year: 2013

Authors: X. Qu, Fang-Chun Jin, Y. Hao, Huiwu Li, Ting‐ting Tang, Hao Wang, Weili Yan, K. Dai

Journal: PLoS ONE

Journal ranking: Q1

Key takeaways: Higher dietary magnesium intake is associated with a nonlinear inverse association with the risk of total cardiovascular events, with the greatest risk reduction occurring when intake increases from 150 to 400 mg/d.

Abstract: Background Prospective studies that have examined the association between dietary magnesium intake and serum magnesium concentrations and the risk of cardiovascular disease (CVD) events have reported conflicting findings. We undertook a meta-analysis to evaluate the association between dietary magnesium intake and serum magnesium concentrations and the risk of total CVD events. Methodology/Principal Findings We performed systematic searches on MEDLINE, EMBASE, and OVID up to February 1, 2012 without limits. Categorical, linear, and nonlinear, dose-response, heterogeneity, publication bias, subgroup, and meta-regression analysis were performed. The analysis included 532,979 participants from 19 studies (11 studies on dietary magnesium intake, 6 studies on serum magnesium concentrations, and 2 studies on both) with 19,926 CVD events. The pooled relative risks of total CVD events for the highest vs. lowest category of dietary magnesium intake and serum magnesium concentrations were 0.85 (95% confidence interval 0.78 to 0.92) and 0.77 (0.66 to 0.87), respectively. In linear dose-response analysis, only serum magnesium concentrations ranging from 1.44 to 1.8 mEq/L were significantly associated with total CVD events risk (0.91, 0.85 to 0.97) per 0.1 mEq/L (Pnonlinearity = 0.465). However, significant inverse associations emerged in nonlinear models for dietary magnesium intake (Pnonlinearity = 0.024). The greatest risk reduction occurred when intake increased from 150 to 400 mg/d. There was no evidence of publication bias. Conclusions/Significance There is a statistically significant nonlinear inverse association between dietary magnesium intake and total CVD events risk. Serum magnesium concentrations are linearly and inversely associated with the risk of total CVD events.

View study

Effect of Magnesium Supplementation on Circulating Biomarkers of Cardiovascular Disease

Type of study: rct

Number of citations: 7

Year: 2020

Authors: Á. Alonso, L. Chen, K. Rudser, F. Norby, M. Rooney, P. Lutsey

Journal: Nutrients

Journal ranking: Q1

Key takeaways: Oral magnesium supplementation did not show statistically significant effects on circulating biomarkers of cardiovascular disease, but proteomic approaches can help investigate potential mechanisms.

Abstract: Background: Magnesium supplementation may be effective for the prevention of cardiometabolic diseases, but mechanisms are unclear. Proteomic approaches can assist in identifying underlying mechanisms. Methods: We collected repeated blood samples in 52 individuals enrolled in a double-blind trial which randomized participants 1:1 to oral magnesium supplementation (400 mg magnesium / day in the form of magnesium oxide) or matching placebo for 10 weeks. Plasma levels of 91 proteins were measured in baseline and follow-up samples using the Olink Cardiovascular Disease III proximity extension assay panel, and modeled as arbitrary units in log2 scale. We evaluated the effect of oral magnesium supplementation on changes in protein levels and the baseline association between serum magnesium and protein levels. The Holm procedure was used to adjust for multiple comparisons. Results: Participants were 73% women, 94% white, and had a mean age of 62. Changes in proteins did not significantly differ between the two intervention groups after correction for multiple comparisons. The most statistically significant effects were on myoglobin [difference -0.319 log2 units, 95% confidence interval (CI) (-0.550, -0.088), p = 0.008], tartrate-resistant acid phosphatase type 5 [-0.187, (-0.328, -0.045), p = 0.011], tumor necrosis factor ligand superfamily member 13B [-0.181, (-0.332, -0.031), p = 0.019], ST2 protein [-0.198, (-0.363, -0.032), p =0.020], and interleukin-1 receptor type 1 [-0.144, (-0.273, -0.015), p = 0.029]. Similarly, none of the associations of baseline serum magnesium with protein levels were significant after correction for multiple comparisons. Conclusion: Though we did not identify statistically significant effects of oral magnesium supplementation in this relatively small study, this study demonstrates the value of proteomic approaches for the investigation of mechanisms underlying the beneficial effects of magnesium supplementation.

View study

Magnesium

Support for the cardiovascular system, brain, muscles, and bones

Table of contents

Basic data

How it works

Potential risk

Contraindications

Quick facts

Dosage

Form

Onset of effects

Time of day

Practical tips

Loading protocol

Avoiding drug interactions

Supplementation in older adults

Combining with a magnesium-rich diet

Key areas of impact

Musculoskeletal system

Effects of magnesium on muscles

Effects of magnesium on bones

Summary of benefits

Brain

Mechanisms of magnesium action in the brain

Effects of magnesium on cognition and brain health

Limitations and recommendations

Cardiovascular system

Key cardiovascular benefits of magnesium

Limitations and caveats

Summary

Scientific data and sources

Research summary

List of studies

Role of Magnesium in Skeletal Muscle Health and Neuromuscular Diseases: A Scoping Review

Dietary Magnesium Is Positively Associated With Skeletal Muscle Power and Indices of Muscle Mass and May Attenuate the Association Between Circulating C‐Reactive Protein and Muscle Mass in Women

Dietary Magnesium May Be Protective for Aging of Bone and Skeletal Muscle in Middle and Younger Older Age Men and Women: Cross-Sectional Findings from the UK Biobank Cohort

An update on magnesium and bone health

Impact of magnesium on bone health in older adults: A systematic review and meta-analysis.

Effects of magnesium supplementation on muscle soreness in different type of physical activities: a systematic review

Can Magnesium Enhance Exercise Performance?

Effect of magnesium deficiency on bone health

Association between dietary magnesium intake and muscle mass among hypertensive population: evidence from the National Health and Nutrition Examination Survey

Severe magnesium deficiency compromises systemic bone mineral density and aggravates inflammatory bone resorption.

Magnesium in man: implications for health and disease.

Magnesium enhances the chondrogenic differentiation of mesenchymal stem cells by inhibiting activated macrophage-induced inflammation

Magnesium and Vitamin D Supplementation on Exercise Performance

Magnesium Matters: A Comprehensive Review of Its Vital Role in Health and Diseases

Magnesium deficiency and its interaction with the musculoskeletal system, exercise, and connective tissue: an evidence synthesis

Magnesium biology

The Role and the Effect of Magnesium in Mental Disorders: A Systematic Review

Effect of Magnesium Supplementation on Chronic Kidney Disease-Mineral and Bone Disorder in Hemodialysis Patients: A Meta-Analysis of Randomized Controlled Trials.

Association between dietary magnesium intake, inflammation, and neurodegeneration

A narrative review on the role of magnesium in immune regulation, inflammation, infectious diseases, and cancer

Enhancement of Learning and Memory by Elevating Brain Magnesium

Magnesium and the Brain: A Focus on Neuroinflammation and Neurodegeneration

Neuroprotective effects of magnesium: implications for neuroinflammation and cognitive decline

Magnesium and Cognitive Health in Adults: A Systematic Review and Meta-Analysis

The Role of Magnesium in Neurological Disorders

A Magtein®, Magnesium L-Threonate, -Based Formula Improves Brain Cognitive Functions in Healthy Chinese Adults

Magnesium (Mg2+): Essential Mineral for Neuronal Health: From Cellular Biochemistry to Cognitive Health and Behavior Regulation.

A Mini Review on the Various Facets Effecting Brain Delivery of Magnesium and Its Role in Neurological Disorders

Neuroprotective effect of magnesium supplementation on cerebral ischemic diseases.

Associations of Serum Magnesium with Brain Morphology and Subclinical Cerebrovascular Disease: The Atherosclerosis Risk in Communities-Neurocognitive Study

Ca:Mg Ratio, APOE Cytosine Modifications, and Cognitive Function: Results from a Randomized Trial

Dietary magnesium intake is related to larger brain volumes and lower white matter lesions with notable sex differences

High Blood Pressure and Impaired Brain Health: Investigating the Neuroprotective Potential of Magnesium

The Presence of Blood–Brain Barrier Modulates the Response to Magnesium Salts in Human Brain Organoids

Adequate dietary magnesium intake may protect females but not males older than 55 years from cognitive impairment

The Impact of Chronic Magnesium Deficiency on Excitable Tissues-Translational Aspects.

Magnesium yields opposite effects on the nuclear and cytosolic cascades of apoptosis in different rat brain regions.

Magnesium and cardiovascular system

Dietary Magnesium and Cardiovascular Disease: A Review with Emphasis in Epidemiological Studies

Exploring the Positive Impact of Magnesium on Cardiovascular Diseases: A Comprehensive Review

Magnesium and Cardiovascular Disease.

Dietary magnesium intake and the risk of cardiovascular disease, type 2 diabetes, and all-cause mortality: a dose–response meta-analysis of prospective cohort studies

Magnesium for the prevention and treatment of cardiovascular disease

Magnesium, Oxidative Stress, Inflammation, and Cardiovascular Disease

Magnesium Deficiency and Cardiometabolic Disease

Role of dietary magnesium in cardiovascular disease prevention, insulin sensitivity and diabetes

Role of Magnesium in Cardiovascular Diseases