Magnesium is the fourth most common mineral in the human body after calcium, sodium, and potassium and is the second most common intracellular cation after potassium.(1)
Magnesium plays a central role in approximately 800 biochemical reactions within the human body. Its distinctive physical and chemical attributes render it an indispensable stabilizing factor in the orchestration of diverse cellular reactions and organelle functions, thereby rendering it irreplaceable in processes directly impacting muscle health(2).
Magnesium Deficiency
Today, magnesium deficiency is a common condition among the general population, and given its importance in the functioning of many reactions of the human body, this deficiency can increase the risk of physical, cardiovascular disease and mental health illness over time.(3)
A combination of factors, including low magnesium intake, reduced gastrointestinal absorption, and increased renal excretion, contribute to the common occurrence of chronic magnesium deficiency among aging populations(2)
Subclinical magnesium deficiency does not manifest as clinically apparent symptoms and thus is not easily recognized by the clinician.
Subclinical magnesium deficiency likely leads to hypertension, arrhythmias, arterial calcifications, atherosclerosis, heart failure and an increased risk for thrombosis.(4)
Low magnesium status correlates with increased low-grade systemic inflammation and can impact mast cells by affecting their histamine secretion, and histamine is a key component in inflammatory responses.(2)
Stress could increase magnesium loss, causing a deficiency; and in turn, magnesium deficiency could enhance the body’s susceptibility to stress, resulting in a magnesium and stress vicious circle.(3)
Recommended Daily Allowance:
The recommended intake levels (RDA) of Mg were provided by the United States Food and Nutrition Board (Food and Nutrition Board 1997). These values are generally higher in men than women, and in certain situations, such as pregnancy or breastfeeding. More precisely, in the adult man the reference value varies from 400 to 430 mg/day, while in the adult woman the reference value varies from 310 to 320 mg/day.(5)
Various dietetic investigations carried out have shown that many people (about 20%) constantly consume lower quantities of Mg than recommended; moreover, in this category, a lower bone mineral density and a higher fracturing risk have been found several times.(5)
Magnesium and pain:
Magnesium has been found beneficial in patients suffering from neuropathic pain, such as in those with malignancy-related neurologic symptoms, postherpetic neuralgia, diabetic neuropathy, and chemotherapy-induced peripheral neuropathy. In addition, magnesium therapy has been shown to be effective in alleviating dysmenorrhea, headaches, and acute migraine attacks.(6)
A recurrent question concerns the best choice of Mg pharmaceutical form and Mg dosage for pain alleviation. While Mg sulphate is commonly used intravenously, bioavailability studies recommend the use of second- (e.g., gluconate, citrate, lactate, pidolate, L-aspartate) and third-generation (e.g., glycerophosphate and bisglycinate) Mg salts compared to the first generation (e.g., carbonate, chloride and oxide), but RCTs vary in Mg dosages and duration, making it difficult to identify a reference salt and an optimal duration of Mg supplementation.(7)
In terms of antinociceptive action, the main mode of action of magnesium involves its antagonist action at the N-methyl-d-aspartate (NMDA) receptor, which prevents central sensitization and attenuates preexisting pain hypersensitivity.(8)
The oral and parenteral administration of magnesium via the Intravenous, intrathecal, or epidural route may alleviate pain and perioperative anesthetic and analgesic requirements.(8)
Mechanism of magnesium as an analgesic.
Central sensitization produces pain hypersensitivity, that is, it causes pain even when peripheral stimuli are not intense and continues to cause pain after the initiating stimuli have disappeared (Latremoliere and Woolf, 2009; Woolf, 1983; Woolf and Salter, 2000. (6)
NMDA receptor activation has been demonstrated to be essential for initiating and maintaining central sensitization.(6)
The NMDA receptor is a membrane ion channel expressed in the central nervous system.(6)
Magnesium has no direct analgesic effect, it inhibits calcium ions entering cells by blocking NMDA receptors, which causes an antinociceptive effect. Furthermore, this antinociceptive effect is related to its prevention of central sensitization caused by peripheral tissue injury (Woolf and Thompson, 1991).(6)
NMDA receptors regulate the cellular inflows of Na+ and Ca2+, and the outflow of K+. This voltage-dependent ion channel is blocked non-competitively in the resting state by the magnesium ion and others. On the other hand, the NMDA receptor channel is opened by membrane depolarization induced by the sustained release of glutamate and neuropeptides, which include substance P and calcitonin gene-related peptide.(6)
Extracellular magnesium blocks the NMDA receptor in a voltage-dependent manner (Mayer et al., 1984), and thus, can prevent the establishment of central sensitization and abolish existing hypersensitivity.(6)
Magnesium in Musculoskeletal problems:
Magnesium plays multifaceted roles in muscle function, including its roles in contraction, electrolyte balance, energy provision, and anti-inflammatory and antioxidant defense, and has emerged as a critical mineral in preserving muscle health and functionality.(2)
Collective findings generally highlight magnesium’s positive impact on muscle health, attributed to its performance-enhancing, analgesic, and anti-inflammatory properties.(2)
Mechanism of action of Magnesium in Musculoskeletal problems.
The cycle of muscle contraction fundamentally hinges on the supply of energy, primarily achieved through ATP hydrolysis. This process is initiated by the release of calcium ions (Ca2+) stored within the sarcoplasmic reticulum upon stimulation from the central nervous system . Upon release, Ca2+ binds to troponin C and myosin, leading to conformational alterations in these proteins and subsequently precipitating muscle contraction.(2)
Magnesium is an antagonist to calcium that competes for the same Ca2+-binding sites and thereby exerts regulatory control over the muscle contraction process . In the quiescent state, magnesium is present in muscle cells in concentrations approximately 10,000 times higher than calcium, effectively occupying all available Ca2+ binding sites. It is only upon the release of Ca2+ from the sarcoplasmic reticulum that magnesium is displaced. However, under conditions of magnesium deficiency, even minimal amounts of calcium can displace magnesium. This results in hypercontractility, marked by muscle cramps and spasms.(2)
In cases of inadequate ATP reserves, muscle fibers remain in a contracted state, preventing the release of actin and myosin chains and consequently leading to muscle cramps.(2)
Magnesium ions play a pivotal role in maintaining the electrolyte equilibrium of calcium, potassium, and sodium within skeletal muscle cells.(2)
Magnesium facilitates the energization of ion channels, thus supporting their proper functioning [182]. Thus, the multifaceted role of magnesium in muscle contraction highlighting the need for adequate magnesium levels, especially as individuals age.(2)
Magnesium plays a pivotal role in protein synthesis, influencing both transcriptional and translational processes in skeletal muscle tissue. Its involvement in RNA synthesis, ribosomal stabilization, and activation of the mammalian target of rapamycin or mTOR signaling pathway highlights its importance in maintaining muscle health.(2)
It is well known that adequate magnesium levels are helpful for exercise because magnesium helps increase the availability of glucose in the blood, muscles, and brain while reducing the accumulation of lactic acid in the muscles.(8)
Magnesium deficiency may supersaturate bodily fluids with octacalcium phosphate calcifying soft tissues, whereas magnesium therapy may stop or even prevent soft tissue calcifications.(4)
Mg and bone health:
From the various studies carried out since 2009 on the serum concentration of Mg and its relationship with the bone, it has been shown that lower values are related to the presence of osteoporosis, and that about 30–40% of the subjects analyzed (mainly menopausal women) have hypomagnesaemia.(5))
Magnesium is required for conversion of vitamin D into its active form which, in turn, supports calcium absorption and metabolism.(1)
Higher Mg intake has been associated with higher Bone Mass Density (BMD) (1)
Oral Mg supplementation has been shown to suppress bone turnover in postmenopausal women and young adult males.(1)
Both excessively high and low Mg levels, however, appear to be detrimental to bone health. an increase in wrist fractures was seen in the Women's Health Initiative Study in those with the highest Mg levels.(1)
Magnesium and cramps:
Although the use of Mg is safe for muscle cramps, solid evidence is still lacking. One explanation for this may be that deficiencies of other elemental nutrients including calcium and potassium have also been implicated in muscle cramps and spasms. It may be that Mg is potentially helpful in situations of Mg deficiency but is not of use if the problem is related to deficiency of another nutrient. With the confounder of multiple potential etiologies for a single presentation and no easy means to verify tissue Mg levels, it will be difficult to conclusively prove a direct link at this time.(1)
Findings reported by this Cochrane Systematic Review (CSR) demonstrated that magnesium supplementation probably makes little or no difference in reducing frequency of muscle cramps and makes little or no difference in term of treatment response, largely in older adults.(9)
Different methods of magnesium intake:
Dietary Intake
Supplementation
Nebulized Mg and eye and ear drops, as well as vaginal Mg douches.
Transdermal use
What does the literature say about Mg supplementation( Oral, intravenous, intramuscular , intraosseous)?
Numerous studies demonstrate the effectiveness of oral therapeutic or preventive magnesium supplementation.
There is good evidence for the use of supplemental Mg in preeclampsia/eclampsia, various cardiac arrhythmias, migraine headache, metabolic syndrome, diabetes and diabetic complications, premenstrual syndrome, hyperlipidemia, and asthma. Magnesium should also be considered as an adjunct for depression, attention deficit disorder, prevention of renal calculi, prevention of cataracts, smoking cessation, and a number of other conditions.(1)
There is promising evidence supporting magnesium supplementation’s role in muscle health.(2)
Studies reported favorable outcomes with magnesium supplementation, enhancing muscle power, torque, exercise performance, lean body mass, handgrip strength, and reducing muscle soreness and markers of muscle damage.(2)
Considering the studies published to date on supplementation with Mg, most have used this mineral in the form of citrate, carbonate or oxide. In all studies there was a benefit both in terms of bone mineral density and fracture risk.(10)
The low molecular weight of MgSo4 also makes it suitable for the treatment of deeper tissues due to better penetration, resulting in superior therapeutic effects(11)
Topical/ Transdermal use of Magnesium
Use of transdermal magnesium- a myth or reality?
There are two types of Mg, namely Magnesium Chloride and Magnesium Sulfate used commonly for topical application. Let us look at their differences:
Magnesium Chloride | Magnesium Sulphate |
Also known as Mg Flakes | Also known as Epsom salt |
More easily absorbed into the body,(due to its molecular structure) | Great for relieving muscle pain, but more rapidly excreted through the kidneys, |
The effects are more intense | More amounts are needed for desired effects |
Effects are longer lasting. | Results don’t last long |
Safer to use | Less safer to use due to toxicity. |
What does the literature say about the effectiveness of topical application of Mg?
Transdermal use of Mg is being used in many individuals who have difficulty tolerating oral Mg.(1)
There is insufficient published research in the medical literature on the use and absorption of these agents but various lotions, creams, sprays, oils, compresses, and bath products are in common use to purportedly compensate for insufficient oral intake in some individuals.(1)
The results of various studies are contentious. A few of them are here for you to refer :
1. ) Based on the current studies it is extremely alarming if a successful treatment of magnesium fails by propagation of transdermal magnesium, a scientifically not yet proven form of magnesium application.(12)
We suggest that future research should focus on a larger number of human subjects given higher concentrations of, for example, a magnesium cream application administered for longer durations to investigate whether transdermal application may show a significant contribution to improvement in magnesium status.(12)
Magnesium might be able to get into the lymphatic system beneath the dermis and enter the circulatory system, bypassing the regulation through the GI tract and hereby increasing serum magnesium. However, we cannot yet recommend the application of transdermal magnesium.(12).
A 2017 review concluded that while there is evidence that the body can absorb a small amount of magnesium through the skin, large-scale studies are necessary to determine its effectiveness. (12)
2) Upon topical application of magnesium solution, we found that magnesium penetrates through human stratum corneum and it depends on concentration and time of exposure. We also found that hair follicles make a significant contribution to magnesium penetration.(13)
3.) In magnesium chloride solution, magnesium is present in ionized form and therefore not able to penetrate a lipophilic layer. In addition, the radius of the hydrated magnesium ion (86 pm) has been reported to be 400 times higher than its dehydrated form, leading to the assertion that it is almost impossible for magnesium ions to pass through biological membranes(12)
A recently published study showed that magnesium ions can penetrate the stratum corneum in a concentration and time dependent manner which is significantly facilitated by hair follicles. However, hair follicles and sweat glands constitute only 0.1% to 1% of the skin surface. Even if a substance is absorbed in this area, the question of the clinical relevance of absorbed amounts needs to be addressed(12)
4). There is no good evidence that magnesium sulfates are absorbed into your body through the skin. The claim that Mg is absorbed via Epsom salt baths is not based on any available evidence. Research shows that magnesium sulfate is very poorly absorbed, even when taken orally(8)
5.) MgSO4 is routinely used in therapeutics despite its toxicity. Considering that the two salts have both similar and proper effects, a clear-cut conclusion is not easy to draw. However, choosing MgCl2 seems advisable because of its more interesting clinical and pharmacological effects and its lower tissue toxicity as compared to MgSO4.(10)
Research:
Injection of magnesium sulfate is an effective treatment measure for myofascial trigger points. However, further studies with a proper design addressing the limitations of the current study are necessary.(11)
Magnesium sulfate is excreted via the kidneys, so careful intake and output monitoring is indicated. In the presence of renal impairment, the likelihood of magnesium toxicity is increased. Magnesium sulfate is contraindicated in patients with myasthenia gravis(14)
Disclaimer:
For use of any supplements and for the types and dosage of Magnesium, we recommend you to make sure you get in touch with your physician. Based on any prevailing conditions, certain methods, types or dose of supplementation that are advocated by your physician will be more effective and meaningful than the damage that may be invited otherwise.
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Sources:
(1) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5637834/#B39 The Importance of Magnesium in Clinical Healthcare
(2) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10745813/ The Integral Role of Magnesium in Muscle Integrity and Aging: A Comprehensive Review.
(3) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761127/ Magnesium Status and Stress: The Vicious Circle Concept Revisited
(4) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5786912/ Subclinical magnesium deficiency: a principal driver of cardiovascular disease and a public health crisis
(5)https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8313472/ An update on magnesium and bone health
(6) https://www.ncbi.nlm.nih.gov/books/NBK507245/# The role of magnesium in pain
(7) https://www.mdpi.com/2072-6643/13/5/1397 Magnesium for Pain Treatment in 2021? State of the Art
(8) https://pubmed.ncbi.nlm.nih.gov/32718032/ Magnesium and Pain.
(9) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020016/ What is the role of magnesium for skeletal muscle cramps? A Cochrane Review summary with commentary
(10) https://pubmed.ncbi.nlm.nih.gov/16259379/ Magnesium chloride or magnesium sulfate: a genuine question.
(11) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9484239/# Clinical efficacy of magnesium sulfate injection in the treatment of masseter muscle trigger points: a randomized clinical study.
(12) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5579607/ Myth or Reality—Transdermal Magnesium?
(13) https://pubmed.ncbi.nlm.nih.gov/27624531/# Permeation of topically applied Magnesium ions through human skin is facilitated by hair follicles
(14) Uterotonics and tocolytics, Jeffrey S. Fouche-Camargo, in Clinical Pharmacology During Pregnancy (Second Edition), 2022,18.3.1, Magnesium Sulphate
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