Unlocking the Neuroprotective Potential of Magnesium

Importance of Magnesium

Magnesium is an important macro-mineral that we obtain from our diets and plays a multitude of roles in the body serving as a cofactor for more than 300 enzymatic reactions. Magnesium helps to regulate muscle contraction including the heart muscle; blood pressure; DNA, RNA, and protein synthesis; insulin metabolism; and in the nervous system magnesium helps provide optimal nerve transmission and neuromuscular coordination. As a vital component of cells, magnesium engages in many physiological functions. Magnesium is the most frequently found metal ion cofactor in enzymatic systems such as DNA/RNA polymerases and all enzymes that function in ATP (adenosine triphosphate) metabolism. Under normal conditions, the magnesium ion is bound to biologically active ATP and ATP metabolism is essential for normal neurological functions, muscle contraction and relaxation, and the release of neurotransmitters.1,2

More than 50% of the U.S. population does not meet their dietary requirements for magnesium, which may predispose individuals to magnesium deficiency and multiple health issues such as fatigue, weakness, seizures, abnormal heart rhythms, and coronary spasms.3 Severe deficiencies can also lead to hypocalcemia and hypokalemia due to the disruption of mineral homeostasis.4 A deficiency of magnesium in the brain can cause unbalanced neural function and has been linked to neurodegeneration and neuro-inflammation.5

Magnesium Neuroprotection - Neurotransmitters - Neuro-Hormones

Magnesium affects several neurotransmitter systems such as the glutamatergic, serotonergic, and adrenergic neurotransmitter systems by inhibiting the release of excitatory neurotransmitters. Magnesium has been shown to increase brain-derived neurotrophic factor (BDNF) expression; a protein and neurotransmitter modulator that plays a crucial role in promoting the survival, growth, and plasticity of neurons.3 In depressed patients, research demonstrates that magnesium supplementation can increase blood levels of BDNF. Furthermore, increasing brain magnesium through a diet rich in magnesium-containing foods enhances neuronal plasticity and long-term memory in vivo. In rodents, magnesium has exerted anti-depressant activity through the BDNF pathway. In humans, supplemental vitamin D and magnesium has shown increased circulating levels of BDNF and reduced tumor necrosis factor alpha (TNFα) and interleukin-6 (IL-6), proinflammatory cytokines by the inhibition of nuclear factor kappa (NF-κB) activation.5 

Magnesium helps to protect the function and integrity of the blood-brain barrier (BBB) which is the semi-permeable cellular scaffold that regulates the central nervous system (CNS) homeostasis and thereby maintains healthy neurological function. The BBB bi-directionally controls the movement of molecules between the blood and the CNS and is responsible for protecting the brain against pathogens and toxins.5 

In the brain, magnesium plays a role in counteracting oxidative stress and inhibiting the release of vasoactive molecules such as substance P (SP). Substance P (SP) is the most abundant tachykinin in the brain that acts as a neurotransmitter and modulator of pain perception and promotes inflammation. When magnesium levels are deficient, SP cannot be broken down, which contributes to neuro-inflammation and changes the redox balance and leads to enhanced nitric oxide (NO) production. The neuroprotective effects of magnesium can inhibit NO production and mitigate the over-production of ROS.5 

Magnesium Mellows Moods

Magnesium is also a γ-Aminobutyric acid (GABA) agonist that along with being a natural NMDA antagonist promotes relaxation that may help to facilitate sleep. A close association between sleep architecture especially slow-wave sleep (SWS) has been demonstrated by the activity of the glutamatergic and GABAergic system.6 Magnesium depletion has been associated with the disruption of sleep patterns and decreased melatonin.7 Supplemental magnesium has been associated with significant improvements in the insomnia severity index, sleep onset latency, sleep efficiency, melatonin, serum cortisol and renin concentrations.8 Magnesium is an agonist of GABAA-R (type A receptor) that is known to mediate the hypnotic and anxiolytic actions of benzodiazepines.5,8

Magnesium also affects several neuro-hormones involved in the hypothalamic-pituitary-adrenal axis (HPA) such as corticotropin-releasing factor (CRF), which is a major regulator in the body’s response to stress.7 Magnesium helps convert tryptophan to serotonin, a neurotransmitter that is recognized as a major determinant of mood and mental health.8 The anti-depressant actions of magnesium may at least partially be mediated by the modulation of the serotoninergic system. When given with molecules of the serotonin reuptake inhibitor (SSRI) class, magnesium acts as a synergist.3

Magnesium’s MO: NMDA Receptors and Therapeutic Effects

Magnesium is a calcium antagonist. One of the most important neurological roles magnesium plays in the CNS, includes its interaction with glutamate N-methyl-d-aspartate receptors (NMDA-R). By blocking the calcium channel in NMDA-R, magnesium helps to prevent glutamatergic excitatory signaling providing neuroprotective effects. Excessive glutamatergic signaling has been implicated in many neurological and psychiatric disorders such as migraine, depression, anxiety, and chronic pain. Low magnesium levels may be associated with excitotoxicity, oxidative stress, and neuronal cell death. When extracellular magnesium is deficient, NMDA-R can be over-activated by calcium and causes hyper-excitation which leads neurons to excitotoxic cell death.1,3,5,10 Additionally, NMDA-R activation stimulates the release of SP that induces neuroendocrine changes which lead to inflammation and oxidative stress.5 Magnesium's analgesic effects are attributed to its ability to block NMDA-R in the spinal cord, relieving the sensation of pain.11

Magnesium Malate Makes a Difference

In dietary supplements, magnesium can form a variety of compounds which directs its absorption and utilization. Choosing the right form of magnesium can help boost levels of this nutrient and may help with various medical conditions. For example, magnesium malate is an organic salt form of elemental magnesium combined with malic acid. Malic acid participates in energy production in the body and may help support muscle function and reduce muscle pain and fatigue. This form of magnesium is often used by individuals with fibromyalgia or chronic fatigue syndrome.12

Magnesium malate compared with other magnesium forms (i.e., magnesium sulfate, magnesium oxide, magnesium acetyl taurate, magnesium citrate) has been shown to remain high for an extended period because magnesium malate has the highest area under the curve (AUC). At 4 hours post ingestion magnesium malate in rats showed the highest blood magnesium levels indicating fast intestinal absorption compared to other forms of magnesium. At 8 hours, blood magnesium levels were significantly higher compared to other magnesium groups. Magnesium malate has also been shown to have the second highest brain magnesium levels compared to magnesium acetyl taurate.<2

Magnesium – A Missing Element for Neurological Health

Magnesium plays a vital role in the CNS and its deficiency is linked with various neurological and psychiatric conditions. Magnesium may improve mood disorders, stress, and sleep. Magnesium can positively influence inhibitory neurotransmitters GABA and serotonin, both of which can positively affect mood, sleep, anxiety, and pain. Magnesium provides neuroprotective effects from antagonistic interaction with NMDA-R preventing glutamatergic excitotoxicity that have been linked to neurological and psychiatric conditions including pain, inflammation, stress, and anxiety. Magnesium may help derail neuro-inflammation, the most common factor in neurodegenerative disorders. Magnesium inhibits excitatory neurotransmitters, aids in nerve transmission, and neuromuscular coordination making it an essential nutrient for maintaining optimal nervous system function and brain health.

Future Directions: The Multifaceted Role of Magnesium in Neurological Health

The role of magnesium, particularly magnesium malate, in neurological health is both profound and multifaceted. Its influence spans from neurotransmitter modulation to neuroprotection, underscoring its essentiality in maintaining optimal brain function. The evidence highlights the potential consequences of magnesium deficiency, as well as the demonstrated benefits of magnesium supplementation, such as improved mood, reduced stress, and enhanced sleep, which underscore its therapeutic potential. As the understanding of magnesium's role in brain health continues to evolve, magnesium malate could pave the way for therapeutic approaches in the management of various neurological and psychiatric conditions.



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Jenny Perez is an herbal educator, researcher, and writer who has been immersed in the field of nutrition and botanical medicine for more than 20 years. Jenny has created curriculum, content, and educational materials for Premier Research Labs, the American Botanical Council, and Bastyr University’s Botanical Medicine Department where she was Adjunct Faculty, Herb Garden Manager, and Director of the Holistic Landscape Design certificate program.