Does magnesium cross the blood-brain barrier (BBB)?

Does Magnesium Cross the Blood-Brain Barrier?

Magnesium does cross the blood-brain barrier, but only to a very limited extent—even with sustained high-dose intravenous administration, cerebrospinal fluid magnesium concentrations increase by only 11-18% above baseline levels. 1, 2

Mechanism of BBB Transport

• Magnesium is actively transported across the blood-brain barrier, resulting in CSF magnesium concentrations that are normally higher than plasma ultrafiltrable (diffusible) magnesium concentrations under physiological conditions 3
• The blood-brain barrier maintains tight regulation of brain magnesium levels through active transport mechanisms, even in the setting of acute brain injury 2
• Cellular entry of extracellular Mg²⁺ into brain endothelial cells is mediated primarily by two receptors: transient receptor potential melastatin 7 (TRPM7) and magnesium transporter subtype 1 (MagT1) 4

Evidence from Clinical Studies

Limited Penetration Despite High-Dose Administration

• In patients with acute brain injury undergoing 24 hours of induced hypermagnesemia (serum magnesium 2.1-2.5 mmol/L), total CSF magnesium increased by only 15% and ionized CSF magnesium by only 11% relative to baseline 2
• This marginal increase occurred despite sustained, therapeutically elevated serum magnesium concentrations, demonstrating that BBB regulation of magnesium is largely maintained even following acute brain injury 2
• High-dose magnesium therapy used in eclampsia treatment increases CSF magnesium concentrations by only approximately 11-18% above physiological concentrations 3

Animal Studies Show Greater Penetration

• In contrast to humans, animal studies demonstrate more substantial BBB penetration: peripheral magnesium sulfate administration in rats significantly increased magnesium concentrations in the cortex and hippocampus, with the largest changes occurring after 2 hours of sustained serum elevation 5
• There was a significant correlation between blood and CSF magnesium concentrations in rats (r = 0.80, p < 0.0001) 5
• Magnesium sulfate increased the electrical threshold required to induce hippocampal seizures by 34% in rats, demonstrating central anticonvulsant effects 5
• Neonatal animals may achieve even greater CSF penetration, with neonatal swine showing CSF magnesium concentrations similar to their plasma concentrations following magnesium treatment 3

Clinical Implications of Poor BBB Penetration

Neurological Disorders and Magnesium Deficiency

• Under conditions of magnesium deficiency, CSF concentrations decline, although this decline lags behind and is less pronounced than changes in plasma magnesium 3
• Decreased CSF magnesium correlates with alterations in extracellular brain magnesium and is associated with epileptiform activity and seizure development 3
• Magnesium deficiency produces neurological disturbances including hyperexcitability, convulsions, and psychiatric symptoms ranging from apathy to psychosis, some reversible with supplementation 3

Therapeutic Limitations

• One of the major limiting factors in using magnesium for treatment of neurological disorders is its poor blood-brain barrier permeability 6
• Various approaches have been attempted to improve BBB permeability, including administration of organic salts (pidolate and threonate forms) and combination with polyethylene glycol or mannitol 6
• These experimental approaches have shown efficacy in animal models, but studies regarding safety and efficacy in humans are currently underway 6

Beneficial Effects on BBB Function

Despite limited penetration, elevated magnesium levels significantly reduce BBB permeability itself and enhance barrier function 4:

• Magnesium enhances overall BBB barrier properties and increases expression of low-density lipoprotein receptor-related protein 1 (LRP1) and phosphatidylinositol binding clathrin assembly protein (PICALM) 4
• Elevated magnesium induces accelerated clearance of amyloid-β peptide from brain to blood via BBB transcytosis, while reducing influx from blood to brain 4
• Magnesium reduces expression of receptor for advanced glycation end products (RAGE) and caveolin-1, which mediate harmful amyloid-β influx 4

Important Caveats

• The limited BBB penetration of magnesium in humans contrasts sharply with more robust penetration observed in animal models, which may explain discrepancies between preclinical neuroprotective studies and clinical outcomes 5, 2
• CSF magnesium can be readily repleted following supplementation in deficiency states, but achieving supraphysiological brain concentrations for therapeutic purposes remains challenging 3
• The active transport mechanism maintaining higher CSF than plasma magnesium concentrations is preserved even in acute brain injury, limiting therapeutic brain bioavailability 2