Magnesium

THE ROLE OF MAGNESIUM

Magnesium is the fourth most abundant mineral and the second most abundant intracellular divalent cation. It is a cofactor in over 300 metabolic pathways. Magnesium is found in 50% of the bones, 50% of the tissues and organs, and 1% of the blood^[1]. Magnesium is also necessary for structural function of proteins, nucleic acids or mitochondria. It is required for DNA and RNA synthesis, and for both aerobic and anaerobic energy production oxidative phosphorylation and glycolysis either indirectly as a part of magnesium-ATP complex, or directly as an enzyme activator^[2].

Magnesium homeostasis is maintained by the intestine, the bone and the kidneys. Magnesium is absorbed primarily in the small intestine, which was shown by ²⁸Mg isotope measurements, although some is also taken up via the large intestine. Only around 24% – 76% of the total dietary magnesium intake is absorbed in the gut; the remainder is excreted in the feces^[2].

FOOD SOURCES OF MAGNESIUM

Despite the fact that magnesium is a fairly common mineral, no major food has a significant amount of it. Magnesium-rich foods include include unrefined (whole) grains, spinach, nuts, legumes, and potatoes (tubers)^[1].

MAGNESIUM DEFICIENCY

Magnesium deficiency is not uncommon among the general population. Hypomagnesaemia is defined as serum magnesium concentration <0.75 mmol/L. Loss of appetite, lethargy, nausea, vomiting, fatigue, and weakness are early non-specific signs of magnesium deficiency. More pronounced magnesium deficiency presents with symptoms of increased neuromuscular excitability such as tremor, carpopedal spasm, muscle cramps, tetany and generalized seizures. Hypomagnesemia can cause cardiac arrhythmias including atrial and ventricular tachycardia, prolonged QT interval and torsades de pointes^[2].

Other electrolyte disorders, such as hypokalemia and hypocalcaemia, are usually associated with hypomagnesaemia. Alcoholism, poorly controlled diabetes, malabsorption (e.g., Crohn’s disease, ulcerative colitis, coeliac disease, short bowel syndrome, Whipple’s disease), endocrine causes (e.g., aldosteronism, hyperparathyroidism, hyperthyroidism), renal disease (e.g., chronic renal failure, dialysis, Gitelman’s syndrome), and medication use are all factors that can cause hypomagnesemia^[2].

USE AND EFFECTIVENESS

1) Tension-headaches and Migraine

Headache refers to pain occurring in the head, face, and neck regions. The most common headaches and migraines are tension-type headaches and migraines. And magnesium has also been implicated in the pathophysiology of these two forms of headaches^[3].

Tension-type headaches are typically bilateral and diffuse throughout the head, forehead, and neck. Because the actual causes are unknown, it is generally difficult to treat them effectively. In addition to bad posture or muscle tension, magnesium is suggested in the etiology and heal of tension-type headaches. Ionized magnesium levels of the serum, salivary secretions, and platelets are known to decrease in patients with tension-type headaches. Magnesium treatment reportedly improved the symptoms of episodic or chronic tension-type headaches for at least one year^[3].

Migraine symptoms include a severe throbbing headache with nausea, vomiting, and extreme sensitivity to light or sound. Auras are warning symptoms that accompany migraines, such as visual flashes of light, blind patches, a tingling sensation in the face, and difficulty speaking. Magnesium plays an important role in migraine headaches by modulating neurotransmitter production, synaptic transmission via cortical spreading depression, and platelet aggregation, despite the fact that the pathophysiology of migraine is yet unknown. As a result, hypomagnesemia has been seen in migraine patients. Furthermore, a low magnesium serum concentration is an independent risk factor for migraine attacks. Magnesium supplementation has been shown to be effective in the treatment or prevention of migraine headaches^[3]. 

2) Neuropathic Pain

Neuropathic pain is caused by any disease or lesion in the somatosensory system that results in the disordered transmission of sensory signals to the spinal cord or brain. Magnesium has been recommended as an alternative option for neuropathic pain in preclinical and clinical settings because it can block the N-methyl-D-aspartate (NMDA) receptor. Neuropathic pain and functional disability following spinal cord injury can improve with magnesium^[3]. 

Neuropathic pain includes diabetic neuropathy, postherpetic neuralgia (PHN), cancer-related pain, trigeminal neuralgia, post-amputation pain, polyneuropathy, radiculopathy, and post-stroke pain^[3].

3) Alzheimer’s Disease

Alzheimer’s disease (AD) is a degenerative neurological disorder that is characterized by synaptic loss and cognitive impairments that include deterioration in learning and memory^[4]. Recent studies have demonstrated that the brain, serum and ionized magnesium levels are decreased in AD patients; nevertheless, the exact role of magnesium in AD pathogenesis is unknown. Magnesium deficiency, particularly in the hippocampus, appears to be a key pathogenic component in AD. Magnesium has an impact on a number of metabolic systems that are important for neuronal characteristics and synaptic plasticity^[2].

4) Anxiety and Depression

Anxiety and depression are both mediated by altered glutamatergic neurotransmission, which may account for this comorbidity. Since magnesium has the potential to modulate glutamatergic neurotransmission through its action at the N-methyl-D-asparate (NMDA) receptor, hypomagnesaemia may play a role in both neurological and psychiatric manifestations^[4]. Magnesium deficiency appears to be related with major and suicidal depression in particular. According to research, the magnesium content in the cerebrospinal fluid was low in patients with a history of suicidal behavior, whereas the calcium to magnesium ratios in the serum and cerebrospinal fluid were frequently elevated in intensely depressed people when compared to healthy people^[5].

The mechanism of action of magnesium’s antidepressant-like effect is still unknown. Magnesium has been shown to alter various systems associated with development of depression. This cation is known to modulate NMDA and gamma aminobutyric acid (GABA) receptor activation, play an important role in suppression of hippocampal kindling and release of adrenocorticotropic hormone and interact with the limbic-hypothalamus-pituitary-adrenal (HPA) axis, frequently dysregulated in depressives. Besides, it probably affects access of corticosteroids to the brain via influence on P-glycoprotein, participates in the inactivation of protein kinase C neurotransmission and stimulates activity of Na+/K+ ATPase^[5]. 

Magnesium depletion, a physiological voltage-dependent blocker of the NMDA receptor ion channel, allows calcium and sodium ions to enter and potassium ions to depart the postsynaptic neuron. Increased calcium ion influx causes neuronal swelling and death, as well as the formation of harmful reactive oxygen species and a hazardous amount of nitric oxide radicals. In ATP deficiency in neurons, neuronal dysfunction and depression are detected as a result of an excessive leak of calcium into cells, which triggers synaptic release of glutamate, depolarization of neurons, and an increase in calcium ions^[5].

5) Type 2 Diabetes and Metabolic Syndrome

Magnesium supplementation improved fasting blood glucose and some insulin sensitivity markers significantly when compared to placebo. The results show that magnesium supplementation increases insulin sensitivity in normomagnesemic, overweight, non-diabetic subjects, highlighting the need of optimizing magnesium level early in life to avoid insulin resistance and type 2 diabetes^[2].

6) Cardiovascular Disease 

Magnesium is involved in blood pressure regulation. Intracellular magnesium hinders the calcium depolarization that leads to muscle contraction, leading to vascular relaxation and thus decreased blood pressure^[1].

Magnesium is also an essential cofactor for the delta-6-desaturase enzyme, which is the rate-limiting step for the conversion of linoleic acid (LA) to gamma-LA (GLA). GLA, which elongates to become DGLA (dihomo-gamma-lineleic acid), a vasodilator and platelet inhibitor, is the precursor for prostaglandin E1 (PGE1). Low magnesium levels result in insufficient PGE1, resulting in vasoconstriction and elevated blood pressure^[6].

Cardiovascular disease, such as coronary heart disease, ischemic stroke, and cardiac arrhythmias, can be prevented or treated with magnesium consumption, but this has yet to be demonstrated completely^[6].

CONTRAINDICATIONS, ADVERSE EFFECTS, AND INTERACTIONS

Although oral magnesium supplementation is well tolerated, magnesium can cause gastrointestinal symptoms, including nausea, vomiting, and diarrhea. Magnesium overdose may cause thirst, hypotension, drowsiness, muscle weakness, respiratory depression, cardiac arrhythmia, coma, and death^[7].

Concomitant use of magnesium and urinary excretion reducing medicines, such as calcitonin, glucagon, and potassium-sparing diuretics, may increase serum magnesium levels, as may doxercalciferol. Fluoroquinolones, aminoglycosides, bisphosphonates, calcium channel blockers, tetracyclines, and skeletal muscle relaxants may be affected by concurrent oral magnesium consumption. As a result, concurrent use should be closely monitored or avoided whenever possible^[7].

Due to the fact that magnesium is eliminated by the kidneys, patients with renal insufficiency (creatinine clearance less than 30 mL per minute [0.50 mL per second]) may be at an elevated risk of heart block or hypermagnesemia; thus, magnesium levels should be monitored^[7].

References

1. Volpe S. Magnesium in disease prevention and overall health. Advances in Nutrition. [Internet]. 2013 [cited 2022 Feb 10]; 4: 378-83. Available from:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3650510/    
2. Gröber U, Schmidt J, Kisters K. Magnesium in Prevention and Therapy. Nutrients. [Internet]. 2015 [cited 2022 Feb 10]; 7: 8199-226. Available form:
   https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4586582/             
3. Shin H, Na H, Do S. Magnesium and Pain. Nutrients. [Internet]. 2020 [cited 2022 Feb 10]; 12: 1-13. Available from:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468697/ 
4. Kirkland A, Sarlo G, Holton K. The Role of Magnesium in Neurological Disorders. Nutrients. [Internet]. 2018 [cited 2022 Feb 10]; 10: 1-23. Available from:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6024559/             
5. Serefko A, Szopa A, Wlaź P, Nowak G, Radziwoń-Zaleska M, Skalski M, Poleszak E. Magnesium in depression. Pharmacological Reports. [Internet]. 2013 [cited 2022 Feb 10]; 65: 547-54. Available from:https://pubmed.ncbi.nlm.nih.gov/23950577/   
6. Houston M. The role of magnesium in hypertension and cardiovascular disease. The Journal of Clinical Hypertension (Greenwich). [Internet]. 2011 [cited 2022 Feb 10]; 13: 843-7. Available from:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108907/   
7. Guerrera MP, Volpe SL, Mao JJ. Therapeutic uses of magnesium. American Family Physician. [Internet]. 2009 [cited 2022 Feb 10]; 80: 157-62. Available from:https://www.aafp.org/afp/2009/0715/p157.html