Magnesium is the fourth most abundant mineral in the body and the second most abundant intracellular cation, so the bioavailability of its formulations is critical to ensure safety and efficacy.
It is involved as a cofactor and activator in more than 600 enzymes involved in biochemical reactions in the body.< 15 >
Magnesium is an essential cofactor for many enzymatic reactions, especially those involved in energy metabolism and neurotransmitter synthesis.< 16 >
Magnesium deficiency epidemic
Already in 1971, one of the most historic medical journals, “Minerva Medica Journal”, published a study entitled “Magnesium deficiency: a new social disease” .
However, after 50 years of epidemiological, experimental and clinical studies that have consistently demonstrated that chronic magnesium deficiency is associated with and/or aggravates a number of major health disorders, states have not yet taken concrete action to resolve this epidemic that has lasted for over 50 years.
Blood magnesium levels do not accurately reflect serum magnesium levels
One of the main reasons for this failure is due to the flawed, but now well-established, approach to routine blood testing, which fails to consider the fact that serum magnesium levels do not accurately reflect total magnesium stores in the body .
Specifically, in chronic magnesium deficiency, serum magnesium levels are often within the normal reference range (usually lowest quartile) and may not progress to overt hypomagnesemia.
Thus, normal blood magnesium levels eclipse common magnesium deficiency. Other methods of measuring magnesium, including the magnesium loading test, may provide more accurate reflections of magnesium status and prevent complications related to magnesium deficiency.
Clinical importance
Of clinical importance, approximately 0.3% of total body magnesium is found in serum. Therefore, total and/or ionized magnesium concentrations measured in plasma or serum are not reliable indicators of total body magnesium levels ; since serum magnesium does not reflect total tissue or organ magnesium content and is also a poor indicator of intracellular magnesium content ( Box 1 ) < 16 , 17 >.
Clinical diagnosis
Emerging evidence suggests that the serum magnesium/calcium quotient (0.4 is optimal, 0.36-0.28 too low) is a more practical and sensitive indicator of magnesium status and/or turnover than the serum magnesium level <19> alone.
In chronic latent magnesium deficiency, blood magnesium levels are within a normal range, despite severely depleted magnesium content in tissues and bones.
Therefore, using blood magnesium levels to determine total body magnesium levels may lead to underestimation of magnesium deficiency in both healthy and diseased populations.
Recent studies have shown that individuals with serum magnesium levels around 1.82 mg/dL (0.75 mmol/L) are more likely to have magnesium deficiency, while those with serum magnesium levels above 2.07 mg/dL (0.85 mmol/L) are more likely to have adequate levels < 20 , 21 >.
Of relevance, individuals with serum magnesium levels between 0.75 and 0.85 mmol/L should be tested with additional measurements to confirm body magnesium status.
Magnesium in red blood cells
In humans, red blood cell (RBC) magnesium levels often provide a better reflection of body magnesium status than blood magnesium levels.
When the concentration of magnesium in the blood is low, magnesium is extracted from the cells to maintain blood magnesium levels within normal limits.
Therefore, if you are magnesium deficient, a magnesium blood test might show normal levels, while an RBC magnesium test would provide a more accurate reflection of your body's magnesium status.
For an accurate estimate of red blood cell magnesium levels, individuals are advised not to consume any vitamins or mineral supplements for at least one week prior to collecting red blood cell samples.
A normal red blood cell magnesium level ranges from 4.2 to 6.8 mg/dL. However, some experts recommend aiming for a minimum level of 6.0 mg/dL on the RBC test.
Other methods of measuring magnesium
Although not commonly available, some places use the noninvasive intracellular mineral electrolyte analysis (EXA) test to determine tissue magnesium levels.
Some laboratories prefer to use a hair mineral analysis test, which not only reveals mineral deficiencies but also heavy metal toxicity.
These tests provide information about individual mineral levels and their relationship to other minerals in the tissue.
Additionally, the composition of minerals deposited in hair may reflect overall body chemistry and health status.
Clinical diagnosis of magnesium deficiency is not simple, as the symptoms associated with magnesium deficiency are nonspecific and generally confused with low intake of other nutrients.
Intravenous or oral magnesium loading tests used in combination with magnesium excretion concentrations from a 24-hour urine specimen may be more useful in detecting subclinical magnesium deficiency.
In-depth analysis
The recommended daily intake of magnesium for adults is approximately 300-400 mg/day .
The rate of intestinal absorption of dietary magnesium depends on the amount consumed and the state (molecular form) of magnesium used and the amount of total magnesium in the body; such intestinal absorption occurs by both active and passive absorption.
Active transcellular absorption of magnesium is achieved by magnesium channels in the large intestine, including transient receptor potential melatonin (TRPM) 6 and TRPM 7.
The electrochemical gradient facilitates passive absorption of magnesium, which occurs mainly in the small intestine.
Magnesium homeostasis is maintained by renal reabsorption and urinary excretion < 25 >.
In case of excess magnesium, renal excretion increases while in case of deficiency, renal absorption of magnesium increases to minimize the loss.
Despite such renal conservation, magnesium is also withdrawn from its skeletal storage to maintain serum levels within normal limits, which predisposes an individual to osteopenia, osteoporosis, or fracture, regardless of normal serum magnesium levels.
When magnesium intake is <250 mg/day, approximately 40–80 mg of magnesium per day is excreted; excretion increases to 80–160 mg/day when intake is >250 mg/day < 20 >.
Of importance, urinary magnesium excretion does not change immediately after consumption, but rather takes several days. Therefore, a single estimate of 24-hour urinary magnesium may not provide accurate magnesium status, and the possibility exists that urinary magnesium excretion may be low or high despite normal magnesium excretion < 20 >.
Many naturally grown foods contain magnesium, but its consumption has significantly decreased in recent decades due to changes in climate, environment, agricultural processing techniques and dietary habits; in addition, the removal of magnesium during food processing also contributes to the reduction of magnesium absorption.
Foods that are supposed to be rich in magnesium include almonds, bananas, black beans, broccoli, brown rice, cashews, flaxseeds, green vegetables (spinach), walnuts, oatmeal, seeds (pumpkin, sesame, sunflower), soybeans, sweet corn, tofu, and whole grains.
Because magnesium plays an important role in a wide range of cellular functions, from maintenance of ion gradients to mitochondrial oxidative phosphorylation to DNA/RNA synthesis to cell signaling, it is not surprising to find that magnesium deficiency causes a variety of systemic diseases.
Diabetes and magnesium deficiency
The analysis of a cohort of 286,668 healthy individuals and 10,192 patients with type II diabetes revealed that an inverse association was found between magnesium intake and the incidence of type II diabetes; from the results of this meta-analysis, the authors recommended that a higher consumption of magnesium-rich foods may reduce the risk of type II diabetes < 26 >.
Similar observations were noted in the Canadian Health Measures Survey (cycle 3, 2012-2013); type I and type II diabetes were associated with lower serum magnesium levels (0.04-0.07 mmol/L) compared to individuals without diabetes.
Additionally, body mass index, glycated hemoglobin, serum glucose and insulin concentrations, and homeostatic model assessment of insulin resistance were negatively associated with serum magnesium level < 27 >.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors are clinically used for the treatment of type 2 diabetes.
SGLT2 inhibitors selectively inhibit renal glucose reabsorption and increase urinary glucose excretion to lower glucose levels.
Analysis of data collected from 15,309 patients showed significantly higher serum magnesium levels in patients treated with SGLT2 inhibitors, compared to untreated patients.
Further studies are needed to determine whether the benefits of SGLT2 inhibitor treatment in diabetic patients are achieved in part through SGLT2 inhibitor-induced altered magnesium homeostasis < 28 >.
Magnesium deficiency and development of diseases
A wide range of human diseases, including cardiovascular and metabolic diseases, skeletal disorders, respiratory diseases, and neurological abnormalities (stress, depression, and anxiety) are linked to magnesium insufficiency.
Magnesium is an important constituent of bone and plays a vital role in bone mineralization, in part by influencing the synthesis of active vitamin D metabolites < 33 , 34 >, which support intestinal absorption of calcium and phosphate < 35 , 36 >.
Studies have shown that the mortality risk associated with hypovitaminosis D could be reduced by magnesium consumption < 12 , 37 , 38 , 39 >.
According to data from the National Health and Nutrition Examination Survey (NHANES), increased magnesium absorption reduced the risk of vitamin D deficiency and/or insufficiency in the general population < 40 >.
Therefore, vitamin D supplementation could be reduced by consuming adequate amounts of magnesium, as magnesium helps in activating or stimulating endogenous vitamin D already present in the body to perform its functions < 41 >.
Magnesium and Deficiency Symptoms
Hypomagnesemia is frequently associated with other electrolyte abnormalities such as hypokalemia and hypocalcemia.
Conditions that can lead to hypomagnesemia include alcoholism, poorly controlled diabetes, malabsorption (eg, Crohn's disease, ulcerative colitis, celiac disease, short bowel syndrome, Whipple's disease), endocrine causes (eg, aldosteronism, hyperparathyroidism, hyperthyroidism), renal disease (eg, aldosteronism, hyperparathyroidism, hyperthyroidism). (eg, chronic renal failure, dialysis, Gitelman's syndrome), and drug use.
A variety of medications including antibiotics, chemotherapy agents, diuretics, and proton pump inhibitors can cause magnesium loss and hypomagnesemia.
Furthermore, magnesium deficiency aggravates potassium-mediated arrhythmia, particularly in the presence of digoxin intoxication < 1 >.
Commercial Forms of Magnesium and Bioavailability
In addition to increasing dietary magnesium intake, exogenous magnesium supplementation, taken orally or topically using magnesium oil, may be necessary.
There are various forms of magnesium supplements available, including magnesium citrate, magnesium glycinate, magnesium threonate, and magnesium malate. Different magnesium preparations have different intestinal absorption capacities.
Studies have shown that organic magnesium supplements (asparate, citrate, lactate, chloride) have been shown to be more bioavailable than inorganic magnesium (oxide, sulfate) < 29 >. This is still a developing area of research .
In a recent study “Magnesium Biovailability after administration of Sucrosomial magnesium” the greater efficacy and safety of sucrosomial magnesium compared to other commercial forms was demonstrated .
In this study, evidence was demonstrated in all three compartments, blood, red blood cells and urine.
Worthy of note is certainly the increase in urinary magnesium concentration (+56%) which was 3-4 times higher than reported for other formulations : this result is of particular interest since the concentration of magnesium in this compartment has recently been demonstrated as an accurate indicator of overall bioavailability.
It is important to consider that the bioavailability of magnesium and homeostasis are regulated by the activity of the intestine, bones and kidneys.
Absorption occurs mainly in the intestine. It should be noted that intestinal absorption of magnesium is not proportional to the amount taken but is mainly influenced by the state (molecular form) of magnesium , as observed in studies. In addition, the kidneys have a crucial role in regulating magnesium absorption, in particular renal secretion with urine is the main determinant of serum magnesium concentrations.
Side effects of taking magnesium
A common unpleasant side effect of oral magnesium supplementation has always been diarrhea, with all molecular forms, with some of course it can be more accentuated with others less, this is another valid reason to choose a nanostructured form of magnesium, so as not to alter the intestinal villi.
Another alternative could be to apply magnesium oil on the skin, it could minimize such unwanted side effects of oral magnesium preparations.
Recent studies have stated that transdermal magnesium is absorbed through the sweat glands < 19 >.
Of relevance, topical application of a cream containing 2% magnesium reduced diaper dermatitis and diaper rash in infants <31> .
Epsom salt (magnesium sulfate) baths are used as a home remedy for abdominal pain, constipation, and muscle strains. Epsom salt is also believed to increase magnesium status.
However, high ingestion of Epsom salt can cause unwanted complications < 32 >.
Magnesium may be able to enter the lymphatic system beneath the dermis and enter the circulatory system, bypassing regulation through the gastrointestinal tract and thus increasing serum magnesium < 23 , 24 , 25 >.
However, it is not yet possible to recommend the application of transdermal magnesium due to the lack of evidence, further well-structured studies are needed.
Although hypermagnesemia is not common in clinical practice, it can induce hypotension, bradycardia and in extreme situations coma. Hypermagnesemia is usually related to the administration of high doses of magnesium, magnesium-containing drugs or renal disease.
Aging, another risk factor for magnesium deficiency
Aging is a major risk factor for magnesium deficiency.
Numerous changes occur in the state of magnesium during aging.
Its total level is reduced due to a decrease in bone mass which is the most important source of magnesium in the body.
Epidemiological studies show that, despite the important physiological role of magnesium, its dietary intake is inadequate in various societies,< 17 , 18 , 19 , 20 > and some population groups, particularly the elderly, have low magnesium intake,< 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 > which may be due to an inability to utilize sources of magnesium or their tendency to consume more processed foods and fewer whole grains and green leafy vegetables.
However, it has been shown that magnesium requirements do not change with aging.< 25 > Other aging-related alterations in magnesium metabolism include reduced magnesium intake, reduced intestinal uptake, increased urinary and fecal excretion, and drug induction .< 16 , 26 >
Meanwhile, it appears that reduced magnesium intake plays the most important role in age-related magnesium deficiency.< 26 >
Dietary magnesium deficiency in the elderly is much higher than expected and its intake decreases continuously and exponentially with age, regardless of gender and race.< 21 >
The NHANCES III analysis shows that magnesium intake among older adults in the United States is well below the Recommended Dietary Allowance (RDA), falling below the recommended levels of 420 and 320 mg/day for men and women, respectively, to 225 mg/day for men and 166 mg/day for women.
Magnesium and sleep
Although the effect of magnesium on neural function and sleep behaviors is not fully understood, magnesium plays an essential role in the conductivity of ion channels, such as the N -methyl-D-aspartic acid (NMDA) receptor and the unilateral entry of potassium channels.
Additionally, magnesium is essential for connecting monoamines to their receptors.
Therefore, this cation plays a key role in neural transmission at the cellular level, both in the presynaptic membrane and in the postsynaptic membrane.
Several studies have also recognized the role of magnesium in regulating the excitability of the central nervous system.< 28 >
Therefore, magnesium as a natural NMDA antagonist and GABA agonist appears to play a pivotal role in sleep regulation.
According to the issues mentioned, if magnesium supplementation can prevent the side effects of insomnia through its improvement, it can be used as an alternative treatment to routine medications or in combination with them to reduce their numerous side effects.
Magnesium, Sleep and Circadian Rhythm Regulation
One of the most recently discovered functions of magnesium is its effect on cellular timekeeping and regulation of the circadian rhythm.
Studies supporting this theory have shown that inappropriately low serum magnesium levels are associated with insomnia and poor-quality sleep < 17 >.
Lack of magnesium intake appears to be involved in the development of depression, which increases the risk of insomnia < 12 >.
Magnesium physiologically regulates melatonin
Anyone who has experience with melatonin supplementation knows the difficulty of finding the correct individual amount of melatonin to supplement for each individual every day.
If the ideal amount is not used, which can vary from day to day, it could further desynchronize a person's circadian cycles, making them feel even more tired upon awakening.
Interestingly, a statistically significant increase in serum melatonin concentration was recorded in the experimental group that received magnesium supplementation compared to the placebo group.
In fact, thanks to experience, we have been able to learn that magnesium supplementation can promote the ideal amount of melatonin, hypothesizing that it can thus naturally regulate the complex and systemic framework of mineral-hormone interactions.
Magnesium and natural vitamin B complex
Of the B vitamins, the one that has been best studied in terms of interactions with sleep is vitamin B12. The direct relationship between insomnia and vitamin B12 levels has yet to be established.
However, it is known that vitamin B12 deficiency is involved in the pathophysiology of depression, which may be commonly associated with insomnia < 19 >.
Studies suggest that the use of combined multivitamin supplements, as well as isolated single vitamins, including isolated B vitamins, impairs sleep maintenance, causes higher rates of insomnia, and requires increased use of sleep-related medications.
However, the results of the analyzed studies show that the vitamin B complex , in combination with magnesium and melatonin, has a positive effect on sleep regulation and can be used to treat insomnia.
This could be attributed to the combined additive effect of the components of the prescribed supplement, in contrast to the individual effects of the previously tested isolated molecules.
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