Magnesium

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Magnesium (Mg) is the fourth most abundant cation in the human body and the second most abundant intracellular cation after potassium. It serves as an essential cofactor in over 600 enzymatic reactions, playing a critical role in fundamental biological processes including energy production (ATP metabolism, oxidative phosphorylation), protein and nucleic acid synthesis, carbohydrate metabolism, muscle contraction, nerve impulse transmission, and the maintenance of electrolyte balance and cell membrane stability. Adequate magnesium levels are vital for the proper functioning of virtually all organ systems, particularly the nervous system. Despite its importance, magnesium deficiency is a relatively common condition, often resulting from insufficient dietary intake, certain medical conditions affecting absorption (e.g., gastrointestinal disorders), increased losses (e.g., renal issues, chronic stress), or certain medications.

As a supplement it has received attention in the treatment of conditions related to central sensitisation like migraine, and has been described as one of the 8 types of available NMDA antagonists.

Physiological Role of Magnesium

The NMDA receptor is a complex ligand-gated and voltage-dependent ion channel that requires two conditions the activate: binding of specific chemicals (glutamate and a co-agonist like glycine) and sufficient depolarisation to relieve a voltage-dependent block physically imposed by magnesium allowing the influx of ions particularly calcium.

Lower magnesium concentrations might necessitate less depolarization to relieve the block, potentially rendering neurons more susceptible to entering a state of hyperexcitability and sensitization upon repeated stimulation.

Magnesium can also block certain types of voltage-gated calcium channels and modulate the activity of potassium channels. Magnesium might also interact with peripheral TRP channels (TRPA1, TRPV1, TRPV4) and nitric oxide (NO) pathways, potentially mediating a pronociceptive (pain-promoting) effect upon local subcutaneous injection in animal models. While the clinical relevance of this finding for systemic oral supplementation aimed at central effects is unclear, it highlights the multifaceted nature of magnesium's actions. The net effect of systemic magnesium administration likely depends on the balance between its central antinociceptive actions (primarily NMDA blockade) and any potential peripheral effects, which might vary depending on the specific pain state (e.g., inflammatory vs. neuropathic) and the achieved tissue concentrations.

Clinical Use

Neuropathic Pain

Intravenous magnesium sulfate (bolus doses of 500 mg or 1 g) provided relief in patients with opioid-resistant cancer-related neuropathic pain. In intractable postherpetic neuralgia (PHN), IV magnesium sulfate (30 mg/kg over 30 min) diminished pain, hyperalgesia, and allodynia. IV magnesium chloride (0.16 mmol/kg bolus followed by 0.16 mmol/kg/h infusion) reduced pain and allodynia in patients with peripheral neuropathic pain. Sequential IV followed by oral magnesium therapy reportedly reduced pain intensity and improved lumbar spine mobility in chronic low back pain with a neuropathic component. Magnesium treatment has also shown benefits for neuropathic pain associated with spinal cord injury.

The evidence is not uniformly positive. Meta-analyses regarding the efficacy of IV calcium-magnesium infusions for preventing oxaliplatin-induced peripheral neuropathy have yielded inconclusive results. One review notes conflicting results for IV/IM magnesium in complex regional pain syndrome (CRPS)

Fibromyalgia

Some studies report lower magnesium levels (serum, erythrocyte, or dietary intake) in FM patients compared to controls, potentially linked to increased levels of Substance P, a neurotransmitter involved in pain transmission. However, other studies found no difference in serum Mg levels. This inconsistency suggests that magnesium deficiency may be relevant for a subset of FM patients rather than universally.

Clinical studies are mixed. One study found that oral magnesium citrate (300 mg/day) combined with amitriptyline significantly improved multiple FM parameters (pain, tender points, FIQ, depression); magnesium citrate alone improved tender points, FIQ, and depression scores. Another study reported improved FIQR scores after 8 weeks of transdermal magnesium chloride application. An older open-label trial suggested benefit from oral magnesium (300-600 mg/day) combined with malic acid (1200-2400 mg/day). Conversely, a pilot study using a specific magnesium+malic acid tablet formulation (Super Malic) found no significant improvement compared to placebo, and an IV infusion cocktail containing magnesium (Myers' Cocktail) also failed to show benefit over placebo in a pilot RCT.

Migraine

Hypomagnesemia has been observed in migraine patients, and low serum magnesium is considered an independent risk factor for attacks.

Acute Treatment: IV magnesium sulfate has shown efficacy in rapidly alleviating acute migraine headaches in some studies, potentially being more effective than caffeine in one trial, and possibly more effective in migraine with aura. However, meta-analyses comparing IV magnesium to placebo or other active treatments have yielded somewhat mixed results regarding overall relief rates.

Preventive Treatment: Oral magnesium supplementation (often cited at doses like 600 mg/day) has demonstrated efficacy in reducing the frequency and intensity of migraine attacks in several studies and meta-analyses. However, not all studies show a positive effect, and the evidence is generally considered "possibly effective" (Grade C).

Oral Magnesium Forms

A variety of magnesium salts and chelates are available as dietary supplements. Common forms include:

• Inorganic Salts: Magnesium Oxide (MgO), Magnesium Chloride (MgCl2), Magnesium Sulfate (MgSO4 - primarily known as Epsom salts, less common for oral supplementation due to strong laxative effect), Magnesium Carbonate.
• Organic Salts: Magnesium Citrate, Magnesium Lactate, Magnesium Malate, Magnesium Gluconate.
• Chelates/Complexes: Magnesium Glycinate (or Bisglycinate), Magnesium Taurate, Magnesium Orotate, Magnesium L-Threonate, Magnesium Aspartate.

A key finding from systematic reviews is that organic forms of magnesium generally exhibit higher bioavailability compared to inorganic forms, with magnesium oxide (MgO) often cited as having particularly poor absorption. bsorption is also dose-dependent, meaning the percentage of magnesium absorbed decreases as the single dose increases.

Dosage

A typical therapeutic range often explored appears to be between 300-600 mg of elemental magnesium per day. It is often recommended to take magnesium in divided doses (e.g., two or three times daily) to potentially enhance absorption and minimize gastrointestinal side effects.

It is also worth noting that many studies suggest that magnesium supplementation may be most effective in individuals who have suboptimal magnesium status or documented deficiency to begin with. In individuals who are already magnesium-replete through diet, the body's homeostatic mechanisms may limit absorption and increase excretion, potentially blunting the effect of supplementation. Conditions associated with increased magnesium loss, such as chronic stress, may also warrant consideration for supplementation.

First-Line Considerations:

• Magnesium Glycinate (or Bisglycinate): Often reported as being well-tolerated (low diarrhea risk), potentially due to chelation facilitating absorption via amino acid pathways. While comparative clinical bioavailability data is somewhat mixed or limited, its favorable tolerability profile makes it an attractive option to start with.
• Magnesium Citrate: Demonstrates better bioavailability than magnesium oxide in several studies. However, it carries a moderate risk of laxative effects.
• Magnesium Malate: Some evidence suggests good bioavailability, and it has been used in fibromyalgia research. Tolerability is likely moderate.

Less Preferred:

• Magnesium Oxide: Generally discouraged due to poor bioavailability and high likelihood of causing gastrointestinal upset , potentially delivering insufficient elemental magnesium systemically even at higher doses.
• Magnesium Sulfate (Oral): Not recommended for supplementation due to very poor absorption and strong laxative effects.

• Limited Data: Magnesium L-Threonate requires more comparative bioavailability research before specific recommendations can be made for this indication.

A conservative approach is recommended, starting low and titrating upwards based on tolerance:

• Starting Dose: Begin with a low dose, such as 100-150 mg of elemental magnesium per day, taken with food.
• Titration: Gradually increase the dose every few days to a week (e.g., by 50-100 mg increments) as tolerated, monitoring closely for gastrointestinal side effects (especially diarrhea).
• Target Dose Range: Aim for a total daily dose typically between 200-400 mg of elemental magnesium per day. This range generally stays within or close to the Tolerable Upper Intake Level (UL) of 350 mg/day from supplements and aligns with dosages used in some chronic pain and migraine prevention studies³ Higher doses (up to 600 mg/day) have been used in some research but carry an increased risk of side effects and should only be considered under strict medical supervision.
• Divided Dosing: Take the total daily dose in two or three divided portions (e.g., with meals) rather than a single large dose. This can improve absorption and significantly reduce the likelihood and severity of gastrointestinal side effects.

Central nervous system changes related to sensitization may take time to reverse or modulate. Therefore, an adequate trial period of at least 8 to 12 weeks at the maximum tolerated dose within the target range is suggested to assess potential benefits.

Contraindications and Precautions

Based on the risk of toxicity and magnesium's physiological effects, certain precautions and contraindications exist:

• Renal Impairment: This is the most critical consideration. Magnesium supplements should be used with extreme caution or avoided entirely in individuals with moderate to severe kidney disease.
• Neuromuscular Diseases: Caution is advised in patients with conditions like Myasthenia Gravis, as magnesium inhibits the release of acetylcholine at the neuromuscular junction, potentially worsening muscle weakness.
• Heart Block: Individuals with pre-existing heart block should use magnesium cautiously due to its potential effects on atrioventricular (AV) node conduction.

Drug Interactions

Magnesium supplements can interact with various medications, potentially affecting the absorption or efficacy of either the magnesium or the interacting drug. Key interactions include:

• Antibiotics: Magnesium can bind to tetracycline and quinolone antibiotics in the gut, reducing their absorption and effectiveness. Dosing should be separated by at least 2-4 hours.
• Bisphosphonates: Oral magnesium can decrease the absorption of bisphosphonates used for osteoporosis. Dosing separation is required.
• Diuretics: Some diuretics (e.g., loop, thiazide) can increase magnesium excretion, potentially leading to deficiency with long-term use. Potassium-sparing diuretics may decrease magnesium excretion.
• Proton Pump Inhibitors (PPIs): Long-term use of PPIs has been associated with low magnesium levels (hypomagnesemia).
• Levodopa/Carbidopa (Sinemet): Magnesium oxide may decrease the effectiveness of this Parkinson's medication.
• Digoxin: High doses of magnesium might interfere with digoxin's effects.

Conclusion

Magnesium possesses a strong, physiologically relevant mechanism of action as a voltage-dependent NMDA receptor antagonist. This provides a compelling rationale for its potential role in modulating central sensitization and temporal summation of pain, processes heavily reliant on NMDA receptor activity.

Indirect clinical evidence from studies in conditions like migraine, fibromyalgia, and some neuropathic pain states offers suggestive, albeit inconsistent, support for magnesium's analgesic or symptom-modulating potential.

However, the overall clinical evidence remains modest and requires further substantiation through rigorous research, ideally with less heterogeneity in the patient population.

The choice of oral magnesium form significantly impacts bioavailability and tolerability, with organic forms generally preferred over inorganic magnesium oxide. While magnesium supplementation has a favorable safety profile in individuals with normal kidney function when kept within recommended limits (UL of 350 mg/day supplemental Mg), gastrointestinal side effects are common and dose-limiting, and potential drug interactions necessitate caution.

Resources

Magnesium and Migraine - Dominguez 2025.pdf - 2.79 MB (f)

Magnesium and Pain - Shin 2020.pdf - 242 KB (f)

Magnesium for Pain State of the Art - Morel 2021.pdf - 591 KB (f)

Magnesium in Neurological Disorders - Kirkland 2018.pdf - 4.72 MB (f)