Neurotransmitters are small molecules involved in the transmission of signals between neural cells in the central nervous system (CNS). They are involved in information transmission and brain health and influence many functions, including emotions, memories, learning, and movements. As a result, disturbances in neurotransmitter homeostasis are associated with many neurological and neurodegenerative disorders [1].
Magnesium or Mg2+ is one of the most abundant intracellular cations and participates in hundreds of enzymatic reactions. Involved in homeostasis maintenance in the brain, it regulates neuronal excitation and inhibits overstimulation by acting on various neurotransmitter receptors. Magnesium influences the glutamatergic and the GABAergic systems via the N-methyl-D-aspartate (NMDA) and gamma-aminobutyric acid (GABA) type A (GABAA) receptors [2]. Magnesium inhibits glutamatergic transmission and enhances GABA activity, producing a predominantly inhibitory effect in the CNS [3,4]. Thus, magnesium reduces neuronal excitation by inhibiting nerve transmission. Maintaining the balance between inhibitory neuronal transmission via GABA and excitatory neuronal transmission via glutamate is essential for neuronal membrane stability and proper neurologic function [5].
At normal membrane potential, magnesium blocks the NMDA receptors. Thus, the glutamate neurotransmitter can only bind and activate the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. AMPA receptor activation causes an increase in neuronal membrane potential, which removes the magnesium block and leads to the activation of NMDA receptors [6].
Magnesium is considered an agonist of GABAA receptors and triggers their activation, which results in the influx of chloride ions, causing neuronal hyperpolarization and inhibition, although the mechanism remains unknown [4]. Experiments in rats showed that physiologically relevant magnesium concentrations affect the GABA response on GABAA receptors. In the presence of GABA, magnesium concentrations up to 1 mM activated GABAA receptors, while at 10 mM, magnesium inhibited them. These findings suggest that magnesium may allosterically potentiate GABA, although its putative binding sites on GABAA receptors remain unknown [7]. In addition, this agonist effect of magnesium is suppressed by flumazenil, a GABAA receptor antagonist [6]. This GABAergic inhibitory mechanism is crucial for balancing the excitatory signals mediated by glutamate. Thus, magnesium and GABA form a powerful duo that helps maintain a balanced and healthy brain, contributing to cognitive function, stress resilience, and neurological stability.
Magnesium supplementation in disorders related to GABA
Low levels of GABA are associated with many disorders, including anxiety, sleep disorders, epilepsy, schizophrenia, autism, and major depressive disorder [8-11]. Given its agonist properties on GABAA receptors, magnesium intake via supplementation has been investigated to treat several GABA-related disorders.
Anxiety
Experiments in mice demonstrated that the anxiolytic effects of magnesium involve GABAA receptor activation. Indeed, these effects were suppressed by flumazenil, a GABAA receptor antagonist. In humans, a systematic review included 18 clinical studies to examine the efficacy of magnesium in alleviating subjective stress and anxiety. Results suggest a beneficial effect of magnesium but the existing evidence is poor. Well-designed randomized controlled trials are needed to establish magnesium supplementation efficacy for treating anxiety [12].
Sleep disorders
Many preclinical studies support associations between magnesium and sleep quality. Experiments in rats fed with magnesium-restricted diets showed that magnesium deficiency was associated with a shorter sleep duration [13]. In mice, magnesium content in the brain correlated with the strength of slow-wave sleep periods, suggesting that magnesium levels in the brain promote sleep quality [14]. In ten healthy men, magnesium supplementation increased the duration of the third sleep cycle with unchanged delta power throughout the night as assessed on sleep electroencephalograms. These findings are consistent with magnesium being an agonist of GABAA and an antagonist of NMDA receptors [15].
Many clinical trials evaluated the efficacy of magnesium supplementation in alleviating sleep disorders. Two recently published systematic reviews, including eight and nine clinical studies, concluded that magnesium is likely useful in treating insomnia in patients with low magnesium at baseline. Although observational studies have identified a link between magnesium levels and sleep quality, randomized clinical trial results remain unclear. Larger, randomized, and well-designed clinical trials are needed to further assess its efficacy [16,17].
Epilepsy
Magnesium possesses anti-convulsant properties. In humans, a higher intake of dietary magnesium correlates with a lower incidence of epilepsy. These effects may involve the GABAA receptors, but further research is needed to understand its mechanism of action [18].
Dietary sources of magnesium
In the United States, the recommended daily allowance for magnesium is 420 mg for men and 320 mg for women [19]. Approximately 10% of this intake comes from drinking water, with the remainder provided by food sources such as green vegetables, nuts, seeds, unprocessed cereals, fruits, fish, meat, and dairy products [6].
Conclusion
Magnesium is a critical regulator of neural balance. It inhibits the excitatory signaling through NMDA receptors and enhances GABAergic inhibition. Individuals can support proper GABAergic system function with adequate magnesium levels and potentially alleviate anxiety, sleep, and epilepsy. Incorporating magnesium-rich foods into the diet, such as leafy greens, nuts, seeds, and whole grains, or considering supplementation when necessary, could be essential in optimizing brain function and supporting long-term mental health.
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References
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