Magnesium L-threonate (MgT) was first invented in 2010 at the Massachusetts Institute for Technology as a continuation of the post-doctoral work of neurobiologist Dr. Inna Slutsky and is now an exclusively patented compound of Magtein®.1 The initial focus of the research was the enhancement of learning and memory in rodents by increasing brain magnesium concentration.2

Rodent studies are popular options for pre-clinical research for several reasons: environmental control, similar tissue physiology, cost effectiveness, et cetera. But it still begs the question: Does increasing neuronal magnesium concentration result in improved learning and memory in humans?

First, we will examine the need for magnesium supplementation, then explore the physiology of magnesium in the human brain and its potential to change brain chemistry.

 

 

Magnesium: The Essential, Depleted Nutrient

Magnesium is the fourth-most abundant mineral in the body and is required for what is now estimated to be over 600 enzymatic and intracellular processes.3 Unfortunately, studies have found that up to 60% of American do not consume the RDA (Recommended Dietary Allowance).4 The RDA is defined as the daily intake that meets the nutritional requirements of 97.5% of the general population.5

The reason that over half of the population cannot meet their nutritional magnesium needs is multifactorial. First, produce is estimated to contain 80-90% less magnesium than it did a century ago.6 Additionally, ultra processed foods are now the primary calorie source of the American population, and food processing depletes 80-90% of the magnesium content of the food.4,7

Even if someone eats a whole-food, plant-based, locally sourced (thus less likely to be from magnesium-depleted commercial food plots) diet with an abundance of magnesium-rich foods, they are still at risk for magnesium insufficiency or deficiency due to magnesium-depleting factors.

Magnesium can be depleted further in the body due to diet, medications, aging, exercise and stress. Dietary choices can influence magnesium status by either impairing absorption or promoting renal excretion of magnesium.

When magnesium is consumed at the same time as soft drinks containing phosphoric acid or fluoridated water, magnesium becomes bound and precipitates, leading to impaired absorption.6 Magnesium and calcium have natural antagonism in the human body, which begins with competition for absorption in the intestines. A diet high in sodium, protein or diuretic beverages like caffeine or alcohol-containing drinks can cause enhanced renal wasting of magnesium.5

Impairment of absorption or renal wasting are the mechanisms of action for magnesium-depleting pharmaceutical drugs like diuretics, proton pump inhibitors, insulin and bisphosphonates.8 Aging is an established association with magnesium deficiency.10 Exercise is important for mental-emotional and whole-body health, however, both short-term and long-term exercise deplete magnesium.5

The magnesium content of food in the modern diet combined with several magnesium-depleting variables can put even the most health-conscious individual at risk for developing a magnesium deficiency. Now for the clinical challenge: How is magnesium deficiency diagnosed?

Diagnosing Magnesium Deficiency: A Practical Conundrum?

Magnesium deficiency is correlated with headaches, migraines, stress, depression, anxiety, ADHD (attention deficit hyperactivity disorder), bipolar disorder, Alzheimer’s disease, cerebrovascular events, hypertension, diabetes mellitus, metabolic syndrome and osteoporosis, and possibly more!5,10 As a reminder, correlation does not equate to causation.

Several neurological and systemic conditions are impacted by magnesium deficiency, but how can we as clinicians identify a magnesium deficiency for treatment and prevention purposes?

Clinically, we often look for symptoms to help us investigate diagnoses. Unfortunately, when it comes to magnesium deficiency, the symptoms are vague and could have several other causes.

Known magnesium deficiency signs and symptoms include:5,10

  1. Anxiety
  2. Depression
  3. Fatigue
  4. Poor concentration/brain fog
  5. Headaches
  6. Migraines
  7. Insomnia
  8. Irregular heart beats
  9. High blood pressure
  10.  Insulin resistance
  11.  Kidney stones
  12.  Nausea with or without vomiting
  13.  Osteoporosis
  14.  Muscle tightness or cramping

 

Magnesium deficiency is not only difficult to diagnose from signs and symptoms, but also with current testing methods. Blood tests are common practice in primary, specialty and acute care as a low-cost, minimally invasive means to assess and diagnose. Serum magnesium is commonly ordered but may only deserve a place in acute management settings.

Serum magnesium only represents 0.3% of the magnesium content of the body. The remainder in ascending order of bodily magnesium concentration are red blood cell, soft tissue, muscle and bone.6 Serum magnesium must be tightly regulated to maintain the contractility of muscle tissue, most importantly, the heart. When serum magnesium concentration declines, the body will pull magnesium from circulating red blood cells or from the cortical surface of the bone to quickly restore the magnesium level.3 This creates a narrow timeframe when low magnesium would be detected in the serum making it fairly useless to assess chronic deficiency.

Red blood cell magnesium is debatably the superior option to assess for magnesium deficiency. Even though red blood cells also contain a low amount of bodily magnesium, they have advantages over other testing methods. The blood test is low-cost, minimally invasive, reflects intracellular magnesium of living tissue and is a three-to-four-month magnesium status indicator due to the 100-to-120-day lifecycle of the red blood cell.3,11 For those reasons, red blood cell magnesium is, in my opinion, the best of the ulterior options including serum, white blood cell, hair and urinary magnesium. My personal preference is a red blood cell magnesium level greater than 5.5 mg/dL, but some sources recommend a level greater than 6 mg/dL.3

To summarize, most people are at risk of a latent magnesium deficiency but testing methods are limited. Red blood cell magnesium, while also limited, is still the best method for assessing magnesium deficiency as an indicator for magnesium supplementation necessity.  

The long introductory section for this blog post was intentional as I felt it was necessary to elaborate on the pervasiveness of magnesium deficiency in the population, as it is profound yet receives little attention in medical literature—perhaps because serum magnesium remains the go-to for assessment, underpinning the depth of magnesium deficiency. Now that this has been established, we can explore magnesium and the brain.

The Threonate Difference

Magnesium is vital for the health of the whole body, but it has particularly important actions within the brain. A sufficient level of magnesium is critical for the health and function of the brain, as some of its most important functions are to protect the integrity of the blood-brain barrier (BBB), attenuate the inflammatory cascade, support the synthesis of neurotransmitters and nitric oxide, modulate gamma-aminobutyric acid (GABA) and N-methyl-D-aspartate (NMDA) receptors.4,12 The transportation of magnesium from serum to cerebrospinal fluid (CSF) and then into the neurons of the brain is a complex, multi-step process because of the tight regulation of magnesium in serum.

Threonic acid or threonate, is a naturally occurring sugar acid that has been investigated for its ability to enhance delivery of magnesium into cerebrospinal fluid (CSF) and neuronal cells in as little as two weeks.13 Threonic acid can associate with the GLUT 1 receptors on the choroidal epithelial cells of the BBB to facilitate the transportation of magnesium into the CSF.5,13 In the CSF, threonic acid can then associate with the GLUT 3 receptors to enhance magnesium transportation into neuronal cells. Transportation into the CSF and neuronal cells occurs in a concentration-dependent manner. Compared to other forms of magnesium compounds, MgT is the only form of magnesium scientifically demonstrated to increase magnesium concentration within the brain.13 Furthermore, effective supplemental doses of MgT were found at 108-144 mg of elemental magnesium per day, below the current RDA of 320 mg and 420 mg daily magnesium for women and men, respectively.4,14

Magnesium L-Threonate: Brain Health, Function and Quality of Life

Sleep Quality

Poor sleep is a common complaint affecting 62% of adults worldwide.15 Insufficient magnesium intake and reported poor sleep have been correlated in several studies.5 The connection of poor sleep with inadequate magnesium intake could be due to the action of magnesium on GABA receptors, attenuation of the hypothalamic-pituitary-adrenal (HPA) axis stress response lowering cortisol, its role as a cofactor in melatonin synthesis and mechanisms unknown.5,12

In a currently unpublished study of 76 adults with an average Insomnia Severity Index score of 12.46, 1 g of MgT at night resulted in significant improvement in multiple sleep variables. Participants receiving MgT reported improved sleep quality, faster time falling asleep and improved time spent asleep. Additionally, they reported improved mood and mental alertness. Concomitant Oura ring data supported the self-reported improvement by indicating that those receiving MgT had better improvement in readiness score, REM, light and deep sleep compared to those receiving placebo.15

Mental-Emotional Health

Mental-emotional health has risen as a concern over the past years with 53% of adults in the United States reporting frequent stress.16 Magnesium deficiency has been found in up to 60% of people reporting long-term stress.17 In a study of men, the group receiving supplemental magnesium had lower cortisol levels compared to those receiving placebo.

Depression and anxiety can occur independently of stress but are often reported concomitantly.5 Some functions of magnesium in the brain that can be associated with depression and anxiety include a role as a cofactor for the synthesis of dopamine, serotonin and noradrenaline, inhibiting the release of excitatory glutamate and binding on GABA receptors.5,18

In a 12-week, double-blind, placebo-controlled study of 44 older adults with self-reported stress and anxiety, the active group that received either 1.5 g or 2 g of MgT had a significant improvement in stress, anxiety and fear symptoms compared to placebo.18

Memory and Concentration

Memory and mental focus are common complaints that often occur with insomnia, stress and depression.5,15 In an animal model, MgT was the only form of five magnesium compounds including malate, glycinate and citrate that was found to increase the synaptic density and function of neurons. Additionally, treatment of rat hippocampal cells with MgT resulted in increased mitochondrial density and function. In a small 12-week pilot study of adults with ADHD receiving 1-2 g of MgT, most demonstrated significant improvement in IQ (Intelligence Quotient), CGI (Clinical Global Impression) and AISRS (Adult ADHD Investigator Symptom Rating Scale) scores.19

A decline in neuronal synapses, their function and consequent atrophy of the brain are associated with impaired cognition that increases in severity with aging.17 Postmenopausal women often have the most concerns about memory possibly due to the loss of estrogen which is known to be one of few substances to increase hippocampal synaptic density.13 In a 12-week, double-blind, placebo-controlled study of older adults with mild cognitive impairment, those that received 1.5-2 g of MgT daily demonstrated improvement in executive functioning, working and episodic memory.14

Migraine and Concussion Recovery

Migraines are debilitating headaches effecting 15.3% of the overall United States population with twice as many women impacted than men.20 The pathophysiology of migraines was originally hypothesized to be caused by simple vasodilatory-vasoconstriction imbalance, but it has since been shown that NMDA receptor activation, serotonin release from platelets and calcitonin gene-related peptide (CGRP) activation may also be involved. Magnesium can help with migraine pathophysiology by blocking the NMDA receptor, improving nitric oxide synthesis in the brain, blocking inappropriate serotonin release from platelets and decreasing circulating CGRP. A double-blind, placebo-controlled study of adults with frequent migraine found that magnesium supplementation significantly decreased the frequency of migraines and the intensity of pain experienced.21 While MgT has not been specifically researched in people that experience migraines yet, logically it is feasible that enhancing magnesium in the CSF and brain would result in even better outcomes for migraine sufferers.

Concussions are a common occurrence in automotive accidents and contact sport injuries. Depending on the severity of the injury, recovery can be a long, arduous process made worse by recurrent head trauma leading to chronic traumatic encephalopathy.22 A low concentration of magnesium in the CSF has been found in those recovering from traumatic brain or spinal cord injuries which increases oxidative stress, lipid peroxidation of neuronal myelin sheaths and consequently aggravates symptoms.4 In a small study of 30 severe traumatic brain injury patients, those who received magnesium had significant improvements on Glasgow Coma Scale outcomes OR 4.24 (95% CI 1.1-16.36).23 While MgT has also not been specifically studied in those with concussions, it is again logical to assume that improvement in outcomes would be better compared to no intervention, since MgT increases CSF and brain magnesium concentration.

Nutritional Wellbeing Presentation Pad

 The Bottom Line

MgT is a novel magnesium compound that has been shown to significantly impact human health and neurological function. Benefits include improvement with sleep, HPA stress response, anxiety, depression, concentration and age-related memory decline. As a clinician, I am intrigued yet skeptical when a single ingredient claims to have multidimensional benefits that can be applied to a diverse patient type but the research and my personal use in practice support these conclusions. MgT should be a go-to ingredient for any brain health or function concern.

 

 

Megan Borreson, ND is the CM Vitals and WellMatrix Clinical Brand Manager at Lifestyle Matrix Resource Center. She attended undergraduate school at the University of Wisconsin–Eau Claire and received her Bachelor of Science degree in cell biology and a Bachelor of Arts degree in Spanish with a minor in chemistry. Dr. Borreson then enrolled at National University of Health Sciences where she graduated summa cum laude with a Master of Acupuncture and Doctorate of Naturopathic Medicine. 

References

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  15. Currently unpublished study

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