Since the onset of the COVID-19 pandemic, numerous studies have investigated the impact of magnesium cations on the transmission and severity of COVID-19, as well as on patient outcome.

Magnesium deficiency could play a role in the pathophysiology of infection with SARS-CoV-2. The primary manifestation of COVID-19 remains respiratory, but the virus can spread to other organs and tissues, complicating the clinical picture, culminating in multi-organ failure ^[1][2][72,84]. The key mechanisms involved in the disease include direct viral cytotoxicity, endothelial dysfunction, and exaggerated release of inflammatory cytokines ^[1][2][3][72,84,85].

Vascular endothelial damage is characteristic of COVID-19 and is likely associated with critical illness and death ^[1][2][72,84]. Magnesium deficiency increases oxidative stress and the release of proinflammatory cytokines from monocytes, macrophages, and leukocytes ^[1][4][5][32,55,72]. The administration of magnesium reduces these phenomena, which may be due to a reduction in the activation of nuclear factor NF-KB ^[1][5][55,72]. At the level of the pulmonary alveoli, magnesium deficiency increases tissue susceptibility to oxidative stress and decreases antioxidant defense, increasing damage and the possibility of a “cytokine storm” ^[6][52]. Moreover, by increasing proinflammatory cytokines, magnesium deficiency leads to endothelial dysfunction ^[7][28]. Thus, in the human body, magnesium deficiency can increase the risk of an inflammatory “cytokine storm” and can increase the possibility of damage to the vascular endothelium and a coagulation cascade, which is followed by disseminated intravascular coagulation phenomena ^[1][6][7][8][28,44,52,72].

It has been reported ^[1][9][10][72,78,86] that low serum magnesium levels are associated with increased thrombotic risk and delayed fibrinolysis, while low intracellular magnesium promotes the process of platelet-dependent thrombosis ^[11][45]. In vivo, Mg²⁺ has antithrombotic effects via reducing platelet aggregation and prolonging the blood coagulation time ^[12][13][77,87]. Moreover, it has been shown that magnesium has antithrombotic effects and reduces mortality in experimentally induced pulmonary thromboembolism ^[1][14][72,88]. All these effects suggest that, in patients with COVID-19, magnesium deficiency increases the risk of disseminated intravascular coagulopathy.

Low magnesium induces a proinflammatory, prothrombotic phenotype in endothelial cells and promotes platelet aggregation, as well as beta-thromboglobulin and thromboxane release, resulting in the development of thromboembolism. Endothelial dysfunction and procoagulant status may explain the high incidence of thromboembolic events in patients with COVID-19 ^[1][2][3][72,84,85]. Magnesium deficits exacerbate the inflammatory response induced by SARS-CoV-2 and maintain and propagate the so-called cytokine storm, followed by acute respiratory distress syndrome, which favors the development of endothelial lesions and coagulopathy, the consequence of which is multiple organ dysfunction syndrome ^[2][3][15][84,85,89]. In addition, other symptoms that have been reported by patients with COVID-19, such as asthenia, myalgias, anxiety, depression, and insomnia, may be related to the presence of a Mg²⁺ deficiency ^[2][16][17][84,90,91].

A sufficient intracellular concentration of magnesium is necessary for the cytotoxic activity of T lymphocytes and natural killer (NK) cells ^[2][84]. Thus, an optimal level of magnesium plays a role in protecting cells against viral infections. In addition, people with magnesium deficiencies have a depressed immune response, an immune deficiency that is partially or almost completely corrected when magnesium supplements are administered ^[18][19][92,93]. Furthermore, intracellular free magnesium levels in natural killer cells and CD8 killer T-cells regulate their cytotoxicity ^[1][3][72,85].

Magnesium is required for the activation of vitamin D ^[1][72]. Magnesium deficiency can also reduce the level of active vitamin D (1,25 dihydroxyvitamin D) and affect the response of the parathyroid hormone ^[20][94]. This action can lead to “Mg²⁺-dependent vitamin D-resistant rachitis” ^[21][95]. Magnesium is also needed to inactivate vitamin D when levels become too high ^[22][96].

Thus, an optimal level of magnesium is necessary to ensure an optimal homeostasis for vitamin D. Vitamin D insufficiency is very common in patients with severe forms of COVID-19 ^[23][97]. This provides an important scientifical argument for vitamin D supplementation in patients diagnosed with COVID-19 infection. In patients who had their vitamin D levels measured one year before testing for COVID-19, the relative risk of becoming positive for COVID-19 was 1.77 times greater for those with a vitamin D deficiencies as compared to those who had sufficient levels ^[1][23][72,97].

Independently, both magnesium and vitamin D are important for the immune system. Together, these may be beneficial in COVID-19 infection, as magnesium is required for vitamin D activation. Given that magnesium and vitamin D are important for immune function and cellular resistance, a deficiency in either may contribute to the “cytokine storm” in SARS-CoV-2 infection ^[23][24][97,98].

In the cross-sectional study of ISARIC/WHO CCP-UK (COVID-19) ^[25][99], vitamin D deficiency or insufficiency was found in the majority of patients hospitalized with COVID-19 or influenza A and was associated with disease severity. Kalichuran et al. ^[26][100] also observed a high prevalence (82%) of vitamin D deficiency or insufficiency among hospitalized patients with COVID-19 and an increased risk of symptomatic disease in patients with vitamin D deficiency.

The SHADE study ^[27][101] revealed that a higher proportion of vitamin D-deficient individuals with SARS-CoV-2 infection became SARS-CoV-2 RNA negative, with a significant decrease in the inflammatory marker (fibrinogen) on short-term, high-dose cholecalciferol supplements. Furthermore, it has been observed that concomitant supplementation with vitamin D, vitamin B12, and Mg²⁺ in patients with COVID-19 may decrease the incidence of intensive care hospitalization and required oxygen therapy ^[15][28][89,102].

It is hypothesized that the initial stages of infection with SARS-CoV-2 could be dependent on cation Mg²⁺. The receptor for the viral protein spike S in the structure of SARS-CoV-2 is angiotensin-converting enzyme 2 (ACE2), which is present in many tissues, thus explaining the pulmonary and extrapulmonary manifestations of COVID-19 ^[29][103].

Similar to other coronaviruses, SARS-CoV-2 needs proteolytic cleavage of the S protein to activate the endocytic pathway for virus entry into the cell. It has been shown that host cellular proteases, including transmembrane protease serine protease 2 (TMPRSS2), cathepsin L, and pre-protein convertase-furin, participate in the cleavage of protein S and activate the entry of SARS-CoV-2 into the cell ^[2][19][84,93]. Magnesium plays an important role in the inhibition of these proteins ^[2][84]. The preliminary results of a study carried out by Fan et al. ^[30][104] suggested that magnesium treatment increased methylation, thus preventing TMPRSS2 transcription from the promoter and, consequently, reducing the expression of this proteolytic enzyme. These findings, if confirmed, provide another mechanism for the role of Mg²⁺ intervention in the prevention of COVID-19 and the treatment of early and mild forms of COVID-19 by modifying the phenotypic expression of the TMPRSS2 gene ^[2][30][84,104]. Furthermore, as a result of its antagonistic function with that of the calcium ion ^[2][18][84,92], magnesium could prevent the activity of furin, a calcium-dependent protein ^[18][31][92,105].

Taking into account what has been said before, it is clear that magnesium deficiency can promote the infectivity of SARS-CoV-2. Thus, in a large, retrospective cohort study ^[32][106] conducted in the United States (287,326,503 people from 1150 counties and 5,401,483 confirmed cases of COVID-19), it was shown that the average level of the cumulative incidence of COVID-19 in counties in areas with low magnesium content was significantly higher compared to control areas. At the same time, a significant negative nonlinear association was observed between magnesium concentration in the environment and the county-level cumulative incidence of COVID-19.

Once the virus enters the cellular level, magnesium deficiency can exacerbate the inflammatory response, contributing to the so-called cytokine storm, which has been shown to be involved in the pathogenesis of severe clinical manifestations of COVID-19 ^[2][3][33][84,85,107]. Moreover, magnesium deficiency mediators are associated with increased proinflammatory mediator concentrations ^[3][10][15][85,86,89]. Low magnesium serum levels, which often go undiagnosed, potentiate the reactivity to various assaults on the immune system and, therefore, become involved in the pathophysiology of multiple-organ damage from COVID-19.

Low dietary intake of the micronutrient Mg²⁺ is associated with a higher incidence of diabetes and cardiovascular disease ^[15][34][35][89,108,109], medical conditions that are linked to severe complications in patients with confirmed SARS-CoV-2 infection ^[36][37][110,111].

Since it has been shown in experimental studies ^[38][39][112,113] that magnesium deficiency can act as a trigger of the inflammatory process, it was hypothesized that a magnesium-rich diet could lead to potential clinical benefits in COVID-19.

Thus, it has been observed ^[15][40][89,114] that a correct daily intake of fruits, vegetables, and whole grains significantly decreases the levels of some proinflammatory markers, such as lipopolysaccharide-binding protein, TNF-alpha, and IL-6. Veronese et al. ^[38][112] in a systematic review and meta-analysis showed the beneficial effects of Mg²⁺ supplementation in the significant reduction in different inflammatory markers (especially CRP) and increasing NO levels.

Furthermore, there have been studies showing that patients with hypomagnesemia are most frequently hospitalized ^{[15][41][42][43][44][45]}[89,115,117,119,120,121], and there have also been reports refs.~^{[44][46][47][48][49]}[57,116,120,122,123] of lower magnesium levels in severe cases of COVID-19 compared to less severe cases.

Thus, magnesium supplementation could have positive effects on many pathologies associated with COVID-19 in a similar way to some of the other therapeutic uses of Mg²⁺ in cardiovascular, nervous, coagulation disorders, and chronic inflammation.

On the other hand, hypermagnesemia was found in critical forms of COVID-19 ^[41][44][115,120]. This fact must be taken into account because hypermagnesemia can have adverse cardiovascular, neurological, and respiratory effects, which can worsen the evolution of a patient infected with SARS-CoV-2. In clinical practice, hypermagnesemia is usually caused by errors in the administration of magnesium-containing preparations ^[41][50][115,124]. In COVID-19, hypermagnesemia can also be explained by the rapid mobilization of the Mg²⁺ cation from tissues in conditions of stress or sepsis to necrotic events and does not seem to be related to kidney damage (nephropathy, on the contrary, being related to a decrease in Mg²⁺ concentration) ^{[2][41][42][44]}[84,115,117,120].

As an enzyme activator, magnesium is essential for various physiological functions, such as the cell cycle, regulation of the metabolism, muscle contraction, and the maintenance of vascular tone. In SARS-CoV-2 infection, by inhibiting inflammation, oxidative stress, and smooth muscle contraction, magnesium intake can relieve pulmonary symptoms, protect the nervous system, and ameliorate cardiovascular function, liver and kidney damage, and blood glucose levels ^[3][85].

Thus, in the pulmonary tissue, magnesium sulfate inhibits proinflammatory molecules, including chemokines (macrophage inflammatory protein-2), cytokines (IL-6), prostaglandin E2, and cyclooxygenase-2, probably by inhibiting L-type calcium channels ^[33][107]. In an acute lung injury experimental model, magnesium sulfate ameliorated hydrochloric-acid-induced pulmonary histopathological lesions, including peribronchial inflammatory cell infiltration, alveolar septal infiltration, alveolar edema, and alveolar exudation ^[51][125]. Moreover, in experimental studies performed on mice, the administration of magnesium has significantly attenuated oxidative stress and the inflammatory response in lipopolysaccharide-induced acute lung lesions ^[3][52][85,126].

Furthermore, magnesium sulfate also inhibits the contraction of airway smooth muscles by blocking voltage-dependent calcium channels, which is a mechanism by which magnesium can be used in the treatment of bronchial asthma ^[3][85].

In severe forms of COVID-19, there is a strong inflammatory response and a “cytokine storm” following the increased release of proinflammatory cytokines (IFN-γ, TNF-α, interleukins, and chemokines), which can increase organ damage and accelerate the deterioration of a patient’s condition ^[53][54][127,128]. As mentioned before, magnesium has antioxidant and anti-inflammatory effects on the lungs, i.e., it decreases the inflammatory response, oxidative stress, and pulmonary inflammation, possibly by inhibiting IL-6, NF-κB, and L-type calcium channels ^[3][51][55][85,125,129]. Therefore, the administration of magnesium sulfate has good prospects for applications in the management of pulmonary symptoms from COVID-19 ^{[3][51][55][56]}[85,118,125,129].

Infection with SARS-CoV-2 induces a prothrombotic and proinflammatory state that can increase the risk of serious thrombotic disorders in patients both during acute infection and in the post-COVID-19 period ^[57][58][59][130,131,132]. In COVID-19, aberrant inflammatory response in combination with hypoxia has been associated with endothelial dysfunction, imbalance of pro- and anticoagulant factors, and thrombin generation, leading to thromboembolic events ^[57][58][60][130,131,133]. In patients with COVID-19, the impairment of lung function can be linked to increases in blood pressure ^[60][133]. Moreover, pulmonary and venous thromboembolisms can cause severe cardiovascular problems, such as myocardial damage and cardiac and cerebral ischemia ^{[57][58][59][60][61]}[130,131,132,133,134].

Coronary artery disease and hypertension are common coexisting disorders in patients with COVID-19 ^[3][62][85,135]. The affinity of the SAR-CoV-2 virus for the ACE-2 receptor has been proposed to be the core of the pathophysiology of the disease. Although SARS-CoV-2 infection predominantly affects the respiratory system, it can also cause cardiovascular complications, such as acute coronary syndrome, myocarditis, heart failure, and arrhythmias. Furthermore, COVID-19 can lead to severe ventricular dysfunction, even without signs and symptoms of pneumonia ^[63][136]. Several mechanisms have been implicated, such as an excessive inflammatory response to the primary infection, immunothrombosis, and myocardial damage. Patients infected with SARS-CoV-2 with a history of cardiovascular disease have increased mortality. Supplemental magnesium therapy can lower blood pressure, reduce the risk of atrial fibrillation, improve subclinical atherosclerosis, and prevent various other cardiovascular diseases ^[64][65][137,138].

In COVID-19 infection, pregnant women are at increased risk of more severe clinical symptoms and complications, especially in the respiratory system, due to associated high metabolic and oxygen consumption. Moreover, newborns from mothers who have had SARS-CoV-2 infection during pregnancy are more prone to complications such as fetal distress, premature birth, respiratory distress, and thrombocytopenia ^[3][66][85,139].

Magnesium sulfate is a category B drug according to FDA classification and, therefore, is safe and nonteratogenic ^[3][85]. In medical practice, MgSO₄ is a drug that is frequently used in obstetrics for the effective prevention and control of premature labor, gestational hypertension, preeclampsia, and eclampsia with few side effects ^[66][67][139,140]. In addition, magnesium sulfate is used for its neuroprotective effect on the fetus because, in premature birth, administration to a pregnant woman before anticipated premature birth decreases the risk of cerebral palsy in premature infants, possibly through anti-inflammatory action ^{[68][69][70][71]}[141,142,143,144]. Considering the beneficial effects of magnesium sulfate on pregnancy-induced hypertension, preeclampsia, and eclampsia and the neuroprotective effect on the fetus, timely administration of magnesium sulfate is strongly recommended for pregnant women infected with SARS-CoV-2 ^[3][69][85,142].

As described above, magnesium is involved in essential enzymatic reactions in cells, including the immune response ^[15][89]. Magnesium may contribute to the body’s immune response during and after SARS-CoV-2 infection by acting as a cofactor for the production of immunoglobulins and other processes required for T- and B-cell activity ^[3][15][72][85,89,145]. Citu I.M. et al. reported that pregnant women who, during pregnancy, received a diet supplemented with calcium, zinc, and magnesium, or with magnesium alone, did not have a different clinical course of disease during SARS-CoV-2 infection but showed a significantly higher titer of anti-SARS-CoV-2 antibodies. A low concentration of Mg²⁺ in the serum or a lack of supplementation with these micronutrients during pregnancy can lead to a less efficient immune response ^[72][145]. Although the observed results may suggest supplementing the nutritional intake of pregnant women with calcium, magnesium, and zinc, causality has not yet been determined.