Magnesium plays many key roles in the body, including the role as an intracellular cofactor for more than 300 enzymes. Among its numerous functions, magnesium is involved in intracellular transmission, regulation of neurotransmitter transmission, and synapse formation and maintenance. Magnesium status may also influence the body’s response to stress. There may be a bidirectional relationship between magnesium status and stress, with low levels of magnesium affecting susceptibility to stress and high levels of stress affecting magnesium status.

Magnesium may modulate the hypothalamic-pituitary-adrenal (HPA) axis function. In one mouse model, mice that were deficient in magnesium exhibited alterations to the HPA axis function and displayed more anxiety-related behavior. The researchers found an association between low magnesium levels and an upregulated stress system, including an increased transcription of corticotropin-releasing hormones and elevated plasma levels of adrenocorticotropic hormones. 

Additionally, magnesium may reduce neuronal hyperexcitability by inhibiting N-methyl-D-aspartate (NMDA) receptor activity. Glutamate is the primary excitatory neurotransmitter, which acts on NMDA receptors. Magnesium is necessary for the activation of receptors that modulate glutamatergic and gamma-aminobutyric acid (GABA)ergic systems, promoting mainly an inhibitory effect. Imbalances in glutamate and GABA levels influence neuronal hyperexcitability that may contribute to anxiety, depression, and other mental health conditions. Excess neuronal hyperexcitability also affects the susceptibility to stress and HPA axis function.

There are many forms of magnesium in supplements. Researchers have found that magnesium L-threonate is one form that is more effective at crossing the blood-brain barrier. One rat study compared magnesium chloride, magnesium sulfate, and magnesium L-threonate (MgT) on memory and depression-related behavior. All three versions of magnesium led to improvement, but MgT significantly improved memory the most and decreased depression-like symptoms compared to controls and enhanced cholinergic function. MgT also led to higher increases in plasma levels of magnesium. 

Threonate may also play a role in central nervous system function, as it has been found to be present in cerebrospinal fluid at approximately 5 times the levels of the periphery. Threonate may regulate structural and functional density in the central nervous system, and it may benefit mitochondrial function and support synaptic plasticity. Threonate may also help increase neuronal magnesium levels, especially when taken in combination with magnesium, providing a synergistic effect.

Research has yet to study the impact of MgT on stress. However, researchers have found the potential for magnesium supplementation to reduce stress, especially in those with a magnesium deficiency. The potential for MgT to be able to cross the blood-brain barrier and to increase plasma levels may contribute to its potential use in promoting a normal stress response.* 

By Kendra Whitmire, MS, CNS