 Magnesium L-threonate is the magnesium salt of a naturally occurring vitamin C metabolite L-threonic acid. Magnesium, a divalent cation, is important for neuronal activity as it is a co-factor for enzymes present
in the neurons or glial cells.1,2 Magnesium and Cognitive Health Two observational studies found that individuals with a diet rich in magnesium have a lower risk of cognitive decline:
Mechanism of Action Magnesium regulates the opening of N-methyl-D-aspartate receptor (NMDAR) in the brain. This receptor plays a critical role in cognitive function and is the target of various neurological treatments.5 Structurally, NMDAR is made up of two glycine-binding NR1 sub-units, and two of four glutamate-binding NR2 sub-units: NR2A, NR2B, NR2C, and NR2D (Figure 1). Research Highlights
Long-Term Potentiation Out of the four NR2 subunits, NR2B is of prime importance because it confers greater synaptic plasticity which helps to create and retain memories. However, the number of NR2B sub-units have been shown to decrease with age in animals.6 Overexpression of the NR2B sub-unit enhanced memory in transgenic rats and mice compared to wild-type littermates.7 NR2B is also thought to influence memory formation by increasing the long-term potentiation (LTP) through the activation of calcium/calmodulin dependent protein kinase II (CaMKII) (Figure 2).8 Long-term potentiation is long lasting increase in synaptic efficacy, which is critical for learning and memory.9 Magnesium L-Threonate Enhances Spatial Memory in Animals Magnesium L-threonate up regulated the expression of NR2B subunit in cultured hippocampal neurons.10 Compared to control, rats treated with magnesium L-threonate had:
This increase in NR2B sub-unit expression and magnitude of LTP by magnesium L-threonate translates into enhanced hippocampus dependent memory. In this study, spatial working memory, memory regarding one’s environment, and spatial orientation, were assessed at day 0 and day 24 by T maze. At day 0, rats in both groups made 30% fewer correct choices, but at day 24 aged rats treated with magnesium L-threonate made about 15% more correct choices than untreated rats (p<0.05). Interestingly, the improvement in spatial memory of aged rats declined within 12 days of stopping the treatment but improved when the treatment was re-initiated. Magnesium L-Threonate Improves Memory in Older Adults The effect of magnesium L-threonate on memory was studied in a randomized double-blind placebo controlled study with 50 men and women between 50-70 years of age with self-reported complaints of memory and concentration. Subjects were treated with 1.5-2 g/day of magnesium L-threonate, along with 200 IU of vitamin D and 30 mg of vitamin C for 12 weeks. Working memory and capacity to store and process information, measured by digit span test, improved by 13.1% at week 6 compared to placebo (p=0.023). However, this effect on working memory approached significance at week 12, which was the end of the study (p=0.064).12 Conclusion Pre-clinical studies demonstrate that magnesium L-threonate may increase synaptic plasticity through increasing the expression of one of the NMDA receptor sub-units. In vivo and clinical study results show that magnesium L-threonate positively influences cognitive measures of memory. More clinical studies are underway to further evaluate effects of magnesium L-threonate on memory and other dimensions of cognition.
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 by Ashley Jordan Ferira, PhD, RDN
Recent research from three well-known cohorts, The Nurses’ Health Study (NHS), NHS2 and Health Professionals’ Follow-Up Study (HPFS), reveals that higher magnesium intake is associated with lower risk of type 2 diabetes (T2D), particularly in diets with poor carbohydrate quality.1 Green leafy vegetables, unrefined whole grains, and nuts are richest in magnesium, while meats and milk contain a moderate amount.2 Refined foods, like carbohydrates (carb), are poor sources of magnesium. Diets with poor carb quality are characterized by higher glycemic index (GI), higher glycemic load (GL), and lower fiber intake. These poor carbs require a higher insulin demand. The typical American diet is low in vegetables and whole grains, resulting in reduced magnesium intake. The Recommended Daily Allowance (RDA) for magnesium is 310-320 mg/day for adult women and 400-420 mg/day for adult men.3 Half of the US population fails to meet their daily magnesium needs, and hypomagnesemia exists in 1/3 of adults.4-5 Magnesium is needed for normal insulin signaling; current research has linked insufficient magnesium intake to prediabetes, insulin resistance and T2D.4 Increased magnesium intake has been inversely associated with T2D risk in observational studies.6 Collaborators from Tufts University, Harvard University, and Brigham and Women’s Hospital, sought to investigate the impact of magnesium intake, from both dietary and supplemental sources, on the risk of developing T2D in subjects who had diets with poor carb quality and raised GI, GL, or low fiber intake.1 They followed three large prospective cohorts, NHS, NHS2 and HPFS (totaling over 202,700 participants). Dietary intake was quantified by validated food frequency questionnaires (FFQ) every 4 years, and T2D cases were captured via questionnaires. Over 28 years of follow-up, there were 17,130 cases of T2D. Major study findings included:1
Similar to the US population estimates, 40-50% of study participants had inadequate magnesium intake. A healthful, varied diet and supplemental magnesium (especially in diets that restrict or exclude carbohydrates, dairy or meat) are essential to ensure sufficient daily magnesium intake. Why is this Clinically Relevant?
Citations
 by Bianca Garilli, ND Magnesium is the 4th most abundant mineral in the human body following calcium, sodium, and potassium. Intracellularly, magnesium is the 2nd most abundant cation behind only potassium.1 The number of essential roles magnesium plays in the body is extraordinary, with over 300 enzymes requiring magnesium as a co-factor for proper functioning.1 This essential element is involved in numerous critical physiological processes such as energy production (ATP metabolism, oxidative phosphorylation, and glycolysis), protein synthesis, muscle contraction, nerve function, blood glucose control, hormone receptor binding, blood pressure regulation, trans membrane ion flux, gating of calcium channels, cardiac excitability, and synthesis of nucleic acids (RNA and DNA).1 Unfortunately, magnesium is one of the most prevalent nutrient gaps in the US. The 2015 Dietary Guidelines Advisory Committee noted a substandard intake of magnesium as compared to the Estimated Average Requirement (EAR), which is the Dietary Reference Intake (DRI) used to assess population sufficiency vs. insufficiency for nutrients.2-3 A 2016 publication in Advanced Nutrition concluded, “Approximately 50% of Americans consume less than the EAR for magnesium, and some age groups consume substantially less”.4 This is especially concerning when one considers the critical implications of long-term, frequently unrecognized magnesium deficiencies. Deficiencies in magnesium can present with overt clinical manifestations such as nausea, vomiting, lethargy, weakness, personality changes, tetany and tremor, seizures, arrhythmia, and muscle fasciculations.5 In other cases, sub clinical deficiencies may be more difficult to recognize yet have equally serious effects if left untreated. Health concerns and disease processes resulting from an underlying, subclinical magnesium deficiency may contribute to low bone mineral density and cardio-metabolic implications such as metabolic syndrome, hypertension, arrhythmia, arterial calcification, atherosclerosis, heart failure, and increased risk for thrombosis.6 A sub clinical magnesium deficiency can also disrupt sleep and cause muscle cramping, two common symptoms often glossed over but which can be signs of a bigger problem if left untreated. The impact of magnesium on these two clinical manifestations will be explored further: Magnesium and sleep A double-blind randomized clinical trial composed of 43 elderly participants between 60-75 years of age with diagnosed insomnia was conducted.7 The experimental group was given 500 mg/day of elemental magnesium for 8 weeks (250 mg elemental magnesium from 414 mg of Mg oxide, twice daily), while the control group received a placebo for the same length of time.7 A statistically significant increase was seen in sleep time, sleep efficiency, and concentration of serum renin and melatonin, as well as a significant decrease in insomnia severity index (ISI) score, sleep onset latency, and serum cortisol level.7 For many individuals, sleep is disrupted by restless leg syndrome (RLS) or periodic limb movements (PLMS).8 A study supplementing 12.4mmol of oral magnesium in the evenings for 4-6 weeks found that the overall sleep efficiency improved from 75 to 85%.9 The Mg-supplemented group also experienced a significant reduction in PLMS associated with arousal (7 PLMS/hr vs. 17 PLMS/hr at baseline).9 Magnesium and muscle cramps Muscle cramping is a common occurrence among women during pregnancy, in athletes, and in the elderly, for which magnesium is often recommended.10 There are only a few studies, however, that have reviewed the efficacy of magnesium for muscle cramping.10 In a Cochrane review, 7 trials (5 parallel, 2 cross-over design) were included, with 3 of these trials studying pregnancy-associated leg cramps in 202 females and 4 trials looking at idiopathic leg cramps in 322 participants.10 Results from the studies noted no significant improvement of muscle cramping in older adults, while results in pregnancy were mixed leading the authors to recommend further studies in this population.10 The authors of a review article in Scientifica note that the mixed findings may be explained by the potential that, “deficiencies of other elemental nutrients including calcium and potassium have also been implicated in muscle cramps and spasms. It may be that magnesium is potentially helpful in situations of magnesium deficiency but is not of use if the problem is related to deficiency of another nutrient.”1 Magnesium: Daily needs and sources Magnesium is an essential macro-mineral required by the human body. The prevalence of deficiency from serum measurements ranges from 12.5-20% of the population.11 Due to the necessity of this cation for over 300 reactions in the human body and the high risk of deficiency, magnesium levels should be routinely monitored either through blood testing and/or a diet diary review. If found to be low, magnesium stores can be replaced through increasing daily intake of the mineral through nutrition as well as routine supplementation. Foods groups high in magnesium content include green leafy vegetables, legumes, nuts, seeds, and whole grains.12 Specific foods with high magnesium levels include spinach, Swiss chard, beet greens, turnip greens, pumpkin seeds, summer squash, soybeans, sesame seeds, quinoa, black beans, cashews, sunflower seeds, brown rice and pinto beans.12 The Recommended Dietary Allowance (RDA) for magnesium varies by age, sex, and whether pregnant or lactating:13  *RDA not able to be determined; Adequate Intake (AI) reported
Supplementation with high-quality magnesium is another, targeted way to reach optimal levels and fill dietary gaps. Supplementation dosing and form can be personalized and taken orally via capsules, tablets, liquid, and even powder. Some of the different forms available in the market include Mg oxide, gluconate, chloride, citrate, sulfate, glycinate, and L-threonate. REFERENCES
Bianca Garilli, ND Dr. Garilli is a former US Marine turned Naturopathic Doctor (ND). She works in private practice in Northern California as well as running a consulting company working with leaders in the natural and functional medicine world such as the Institute for Functional Medicine and Metagenics. She is passionate about optimizing health and wellness in individuals, families, companies and communities- one lifestyle change at a time. Dr. Garilli has been on staff at the University of California Irvine, Susan Samueli Center for Integrative Medicine and is faculty at Hawthorn University. She is the creator of the Veterans for Health Initiative and is the current President of the Children’s Heart Foundation, CA Chapter. Broad health implications for general population, too  by Bianca Garilli, ND, USMC Veteran
Energy drinks have become a common sight in today’s fast-paced, “get the job done” world. In fact, according to the National Institutes of Health (NIH), next to multivitamins, energy drinks are currently the most popular dietary supplement consumed by American teens and young adults.1 These drinks are marketed as a means to improve energy, stamina, athletic performance, and concentration, as well as reducing fatigue.1-3 Energy drinks are sometime considered “functional beverages” while also falling under the umbrella of drinks or dietary supplements.1,3 The main ingredient in energy drinks is caffeine at levels 70-240 mg in a 475 ml drink or 113-200 mg if consumed as an energy “shot”.1 For comparison, a 355 ml can of soda contains around 35 mg of caffeine, while an 235 ml cup of coffee provides approximately 100 mg.1 In addition to caffeine, many energy drinks also contain other ingredients which might include: B vitamins, various forms of sugar, guarana, taurine, ginseng, glucuronolactone, yohimbe, carnitine, and bitter orange; it is important to note that some of these ingredients further increase the quantity of caffeine in the energy drink, while others may substantially spike blood glucose levels.1 There are currently no regulations in place requiring the amount of caffeine to be printed on energy drink labels.1 Sales of energy drinks have skyrocketed dramatically in the past years increasing to $9.7 billion in sales in 2015 in the US alone.3 Consumption of energy drinks may have negative health consequences, including higher levels of risk-seeking behaviors, poor mental health outcomes, adverse cardiovascular effects, and heightened risk for metabolic, renal, and dental conditions.3 With marketing campaigns geared towards teenagers and the young adult population, it’s not surprising to find that males between the ages of 18-34 are the highest consumers of these drinks.1 Moreover, one-third of teenagers consume energy drinks regularly, while 51% of college students report their consumption at least once per month.1,3 Energy drinks have a strong appeal to military service members as well, particularly with the drinks’ promises of reduced fatigue and enhanced mental and physical performance. Due to the specialized nature of their work, military personnel often seek ways to:
Statistics estimate that energy drink consumption by military personnel mirrors or exceeds that of the general public, yet the health consequences of long-term, high energy drink use in military troops has not been adequately researched.2 A recent study aimed to learn more about the associations between energy drink consumption and health outcomes in military personnel post-deployment.2 In particular, mental health variables including sleep problems, depression, anxiety, PTSD, alcohol misuse, aggressive behaviors, and overall fatigue were compared to the frequency and quantity of energy drink consumption in 627 male infantry Army soldiers 7 months post-combat deployment.2 Results from this study published in Military Medicine found that approximately 75% of soldiers reported consuming energy drinks with nearly 30% of those reporting at least daily use and 16.7% reporting high level consumption (≥ 2 drinks/day).2 Additionally, when compared to the low-frequency group (no consumption of energy drink or < 1 drink/week), the high-frequency group (≥ 2 drinks/day) had increased rates of sleep problems, depression, anxiety, PTSD, and alcohol misuse; they were also more likely to demonstrate aggressive behavioral characteristics.2 Similarly, the moderate-frequency group (at least once per week or 1 drink/day) showed greater depressive symptoms when compared to the low-frequency group.2 Although energy drinks are marketed to consumers as a means to reduce fatigue, the results from this study demonstrated that moderate and high energy drink users experienced heightened fatigued when compared to low or no use.2 The high use of energy drink may, in fact, be a hindrance to both the mission objectives and troop welfare. Authors of this study conclude that, “future research should examine whether energy drink use results in greater fatigue over time.”2 Realizing that mental health, aggressive behaviors, and PTSD are potential concerns among military personnel, the high prevalence of energy drink use in this population should be reviewed. Revised guidelines from military healthcare leaders on the consumption of energy drink would be prudent to support safe and appropriate utilization of these drinks within the military. Why is this Clinically Relevant?
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