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1.      Summary

 

Magnesium L-Threonate is a relatively new form of magnesium, developed by researchers at MIT through years of research. The primary purpose of its development was to create a form of supplement that is capable of increasing magnesium levels in the brain. Most forms of magnesium available today increase blood serum content, but do not improve the brain’s magnesium content.[3]

Magnesium is essential for cellular function and acts as a counter to ATP. Protein synthesis, energy metabolism, muscle contraction and relaxation, neurological functions, and the release of neurotransmitters are all dependent on magnesium.[4] In the brain, Magnesium regulates NMDA receptors and is essential for learning, memory, and as an anti-inflammatory compound.[4]

Magnesium L-Threonate provides all the benefits of regular magnesium supplements, including support for healthy sleep, reducing feelings of stress, improving exercise performance and muscle recovery, and supporting a healthy circulatory system.
Almost half of the United States population consumed less than the recommended dietary allowance of Magnesium in 2005 – 2006. According to the latest literature review, most people need to take around 300 mg extra Magnesium per day as a supplement, to avoid symptoms of Magnesium deficiency.[5]

Magnesium deficiency is associated with increased risk of type 2 diabetes, metabolic syndrome, osteoporosis, and other inflammation-related disorders.[6] Magnesium L-Threonate contains comparatively less elemental Magnesium than other common supplement forms, but is the only form capable of improving levels in the brain.[7]

 

2.      Chemical Structure and Biochemical Effects

 

2.1.Chemical Structure and Properties

 

Magnesium is a group 2 element of the period table. It has a relative atomic mass of 24.305 Da and melting point of 648.8°C. In nature, magnesium is usually found in mineral deposits like magnesite (magnesium carbonate) – MgCO3 and dolomite – CaMg(CO3)2. Magnesium salts are highly soluble in water, making them readily available to living organisms. About 99 % of Magnesium in the human body is found in bone, muscles and non-muscular soft tissue.1

 

The IUPAC name for Magnesium L-Threonate is magnesium;(2R,3S)-2,3,4-trihydroxybutanoate and it has a molecular mass of 294.495 g/mol.[8] Its chemical structure is pictured below (source: PubChem).

 

 

 

3.      Dietary Sources and Deficiency

 

3.1.Dietary Sources

 

Around half the United States population is deficient in Magnesium. However, Magnesium is readily available in food sources. Approximately 30-40% of Magnesium in food is absorbed by the body. In terms of dietary supplements, forms that are easily absorbed in water tend to be better absorbed in the gut. These forms include Magnesium aspartate, citrate, lactate, which have greater bioavailability than Magnesium oxide or Magnesium sulphate.[9]

Good dietary sources of Magnesium include:

  • Water (accounts for around 10% of our daily magnesium intake)1
  • Nuts
  • Leafy greens
  • Soymilk
  • Beans
  • Rice
  • Fruits
  • Vegetables
  • Soymilk 9

3.2.Deficiency

 

Magnesium deficiency is the second most common deficiency in developed countries, after vitamin D. According to the latest literature review, most adults in developed countries consume around 4mg / kg / day. For a 75kg person, this would be equal to 300 mg Magnesium, which is below the RDA of 420 mg / day. [5]

Furthermore, the review points out that the RDA suggestions will prevent Magnesium deficiency but may not provide optimal amounts for health and longevity, which may require up to 300 mg additional Magnesium on top of the RDA, for most people. In the United States, around 48% of people consume less than the RDA for magnesium. In Taiwan and Germany, the average intake for the entire population is only around 200 mg / day. [5]

 

Consuming too little Magnesium has detrimental effects on your health and well-being. Although Magnesium deficiency is unlikely to be treated with the L-Threonate form, it is still important to understand them signs and symptoms. Less severe signs can include aggression, irritability, stress, difficulty focussing, muscle cramps, muscle twitches, ringing in the ears, and difficulty falling asleep. More severe symptoms may require hospitalization [5]

 

4.      Human Effects

 

4.1.Cognitive Enhancement

 

Magnesium L-Threonate is the only form of magnesium that can be used for cognitive enhancement. It was developed by researchers at MIT as a functional form of magnesium, with better capability of passing through the blood-brain barrier, and improving magnesium levels in the brain.[10]

In the brain, Magnesium is a regulator of N-methyl-D-aspartate (NMDA) receptors, which are critical for learning and memory. Magnesium L-Threonate supplements are said to confer neuroprotective benefits by protecting the brain against stress, inflammation, and toxins.4

 

Animal studies have indicated that Magnesium L-Threonate is effective at improving memory formation (long-term potentiation) and reducing the decline in short-term memory associated with nerve injury and neuropathic pain.[11] In a similar study, researchers found that improving brain magnesium levels through the use of Magnesium L-Threonate produced substantial neuroprotective effects in a mouse model of Alzheimer’s disease.[12]

In 2014, a call was registered on clinicaltrials.gov to recruit participants for a study into Magnesium L-Threonate’s association with improvement in memory and brain function, in humans. Outcomes measured included cognitive function, brain imaging scans, and magnesium red blood cell counts. The study was undertaken at Stanford. However, results have not yet been posted online.[13]

 

4.2.Stress Reduction

 

In animal studies, researchers have determined that Magnesium interacts with GABA-receptors in the brain to produce an improvement in mood. For example, in 2008, researchers gave mice magnesium supplements for stress, but were able to block these effects through the use of a ‘GABA antagonist’ called flumazenil, which prevents activity at GABA-receptors.[14]

GABA is the body’s natural depressant hormone, used to reduce signals through the central nervous system (CNS). It is an essential neurotransmitter for maintaining sleep quality and mood, along with other important physiological functions.[15] Many natural and man-made substances target GABA-receptors in the brain to reduce stress, improve mood, and support healthy sleep. Common examples include alcohol and benzodiazepines.

In 2017, a review paper examined the available studies relating to Magnesium’s effects on mood, in humans. All-in-all, 18 clinical studies met the criteria of the review. Overall, the results of these studies showed an improvement in mood and stress-reduction, especially after using magnesium supplements for some time. However, the authors suggest that the design of several studies was poor, and that more studies should attempt to compare the effects of Magnesium supplements to other substances used for stress and mood.[16]

One stand-out study was performed in 2007, in which 55 elderly participants with low mood were given Magnesium supplements. Those participants with lowest baseline mood scores tended to have significantly lower serum magnesium, indicating that they were at least partially Magnesium deficient. Statistical analysis of the results showed an independent association between deficient Magnesium levels and poor mood.[17]

 

4.3.Sleep

 

One of Magnesium’s best-known effects is its ability to help support healthy sleep. In fact, it is fast becoming one of the most popular natural sleep aids, partly because of its effectiveness at supporting sleep, and partly because of its array of secondary benefits. Several animal studies have indicated that a low-Magnesium diet produces sleep problems – light sleep and difficulties falling asleep – similar to what many humans experience.[18]

In 2010, a study was conducted on 100 aging adults (mean age of 59 years) with poor sleep quality. The participants were split into two separate groups after baseline measurements were taken. Participants were required to keep a food diary, journaling everything that they ate, for the length of the study. One group received 350 mg Magnesium per day, while the other was given placebo.

Final measurements were taken after 5 and 7 weeks, and were averaged for statistical analysis. Interestingly, around 60% of the participants’ food diaries showed that they were consuming a diet that was Magnesium-deficient. They had a significantly higher BMI and greater concentrations of C-reactive protein.

The Magnesium supplements increased serum-Magnesium levels in the participants who had a baseline concentration of 1.8 mg/dL or less. The results showed an improvement in sleep quality for participants in the active group.[19] Similar studies have produced the same results – where Magnesium supplements improved sleep quality and mood.[20]

4.4.Muscle Recovery and Exercise Performance

 

Magnesium is very important for muscle function, and works as a natural muscle relaxant in your body. Muscles work by contracting and relaxing, in a complex biochemical mechanism. Two key proteins – troponin C and myosin – are involved in this process. On the one hand, calcium binds to these proteins, and causes muscles to contract. Magnesium, on the other hand, prevents calcium binding, and helps muscles to relax. Too little Magnesium can result in cramps and spasms.[21]

In 2017, the Nutrients Journal published a literature review on the effects of magnesium for exercise performance. The review examined previous studies on animals and human participants relating to energy, metabolism, and exercise. Findings from animal studies suggest that magnesium may improve the efficiency of energy expenditure, while human studies suggest that it may improve athletic performance by:

  • Decreasing the accumulation of lactate in muscles
  • Improving muscular power output and strength
  • Supporting a healthy circulatory system.[22]

Possible underlying mechanisms for magnesium’s ability to improve exercise performance include:

  • Mg2+ has a vital role in protein synthesis and energy metabolism[23]
  • Mg2+ helps to supply energy molecules as Mg-ATP, for use during exercise[24]
  • Mg2+ supports and improves the glucose metabolism cycle[25]

4.5.Support for a healthy circulatory system

Several studies have explored the effects of Magnesium supplements on the circulatory system. Magnesium is effective at regulating blood pressure and supporting insulin sensitivity, especially for people who have higher-than-normal blood pressure, are pre-diabetic, or are deficient in Magnesium.[26] [27]

 

For example, in 2011, researchers produced a study exploring the effects of Magnesium supplementation on insulin resistance in overweight, non-diabetic, insulin-resistant participants. After 6 months of supplementation, the results showed a significant improvement of fasting plasma glucose and insulin sensitivity indices (ISIs) compared to placebo. These results indicate that magnesium is important as a preventative measure, to help support healthy blood sugar levels.[28]

 

In another study, the effects of Magnesium were studied in a group of 48 patients with mild hypertension (high blood pressure). Half received Magnesium supplements along with lifestyle recommendations, while the other half were given only lifestyle recommendations. After 12 weeks, small but significant reductions in mean blood pressure levels were observed in the magnesium-group – indicating a mild regulatory effect on blood pressure.[29]

 

Finally, a study in 2009 focused on the effects of Magnesium on inflammation markers in the circulatory system. 63 participants took part in the study. At the end of the 4-month-long study, those participants who received magnesium showed significantly lower inflammatory markers (especially HbA1c) in the blood, than those who received placebo. These results indicate that Magnesium supplements may have an anti-inflammatory effect in the circulatory system.[30]

 

5.      Safety and Toxicity

5.1.Side Effects

 

Magnesium is an essential element for supporting human health. At the recommended serving size, side effects for most types of Magnesium supplements are not reported. However, Magnesium L-Threonate has not been studied extensively in humans and it is not recommended to exceed the suggested serving size.

WebMD lists Magnesium is possibly safe for pregnant and breast-feeding women. However, studies have not been conducted for the L-Threonate form and it is recommended to avoid this supplement if you are pregnant or breast-feeding.

 

5.2.Overdose

 

WebMD suggests that extremely large servings of magnesium can cause serious overdose-like effects, including an irregular heartbeat, low blood pressure, confusion, depressed respiratory system, coma, and death.[31]

Magnesium overdose is extremely unlikely and rare. It is, however, more likely to occur in people with kidney problems or who have chronic alcoholism as these impair the body’s capacity to metabolize Magnesium.  If you have any underlying medical conditions, please speak to your doctor before using this supplement.

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Content Updated On: June 1st, 2019

 

Scientific Support and References

[1] Oregon State University, Micronutrient Information Center. (2018). Magnesium: Summary. Lpi.oregonstate.edu [online]. Available at: https://lpi.oregonstate.edu/mic/minerals/magnesium

[2] Liu, G., Weinger, J. G., Lu, Z. L., Xue, F., & Sadeghpour, S. (2015). Efficacy and Safety of MMFS-01, a Synapse Density Enhancer, for Treating Cognitive Impairment in Older Adults: A Randomized, Double-Blind, Placebo-Controlled Trial. Journal of Alzheimer’s disease : JAD49(4), 971-90.

[3] Berg, B. (2013). Nutritional compositions containing magnesium threonate and uses thereof. United States Patent WO2014109863A1. Available online at https://patents.google.com/patent/WO2014109863A1.

[4] Jahnen-Dechent, W., & Ketteler, M. (2012). Magnesium basics. Clinical kidney journal5(Suppl 1), i3-i14.

 

[5] Di Nicolantonio, J.J., O’Keefe, J.H., & Wilson W. (2018). Subclinical magnesium deficiency: a principal driver of cardiovascular disease and a public health crisis. Open Heart, 5: [e000668].

[6] Rosanoff, A., Weaver, C.M., & Rude, R.K. (2012). Suboptimal magnesium status in the United States: are the health consequences underestimated? Nutr Rev, 70(3):153-64. Review.

[7] Liu, G., Weinger, J. G., Lu, Z. L., Xue, F., & Sadeghpour, S. (2015). Efficacy and Safety of MMFS-01, a Synapse Density Enhancer, for Treating Cognitive Impairment in Older Adults: A Randomized, Double-Blind, Placebo-Controlled Trial. Journal of Alzheimer’s disease, JAD49(4), 971-90.

[8] Magnesium L-Threonate. (2018). Puchem.ncbi.nih.gov [online] Available at https://pubchem.ncbi.nlm.nih.gov/compound/Magnesium__2R_3S_-2_3_4-trihydroxybutanoate

[9] Magnesium: Facts Sheet for Health Professionals. (2018). National Institute of Health, US Department of Health & Human Services. [online] Available at: https://ods.od.nih.gov/factsheets/Magnesium-HealthProfessional/

[10] Sun, Q., Weinger, J. G., Mao, F., & Liu, G. (2016). Regulation of structural and functional synapse density by L-threonate through modulation of intraneuronal magnesium concentration. Neuropharmacology, 108, 426–439.

[11] Wang, J., Liu, Y., Zhou, L.J., Wu, Y., Li, F., Shen, K.F., Pang, R.P., Wei, X.H., Li, Y.Y., & Liu, X.G. (2013). Magnesium L-threonate prevents and restores memory deficits associated with neuropathic pain by inhibition of TNF-α. Pain Physician, 16(5):E563-75.

[12] Li, W., Yu, J., Liu, Y., Huang, X., Abumaria, N., Zhu, Y., Huang, X., Xiong, W., Ren, C., Liu, X. G., Chui, D., … Liu, G. (2014). Elevation of brain magnesium prevents synaptic loss and reverses cognitive deficits in Alzheimer’s disease mouse model. Molecular brain7, 65.

[13] Stanford University. (2014). Magnesium L-Threonate for the Enhancement of Learning and Memory in People With Dementia. Clinicaltrials.gov. [online]. Available at: https://clinicaltrials.gov/ct2/show/NCT02210286

[14] Poleszak, E. (2008). Benzodiazepine/GABA(A) receptors are involved in magnesium-induced anxiolytic-like behavior in mice. Pharmacol Rep, 60(4):483-9.

[15] Boonstra, E., de Kleijn, R., Colzato, L. S., Alkemade, A., Forstmann, B. U., & Nieuwenhuis, S. (2015). Neurotransmitters as food supplements: the effects of GABA on brain and behavior. Frontiers in psychology6, 1520.

[16] Boyle, N.B., Lawton, C., & Dye, L. (2017). The Effects of Magnesium Supplementation on Subjective Anxiety and Stress-A Systematic Review. Nutrients9(5), 429.

[17] Barragan-Rodríguez, L., Rodríguez-Morán, M., & Guerrero-Romero, F. (2007). Depressive Symptoms and Hypomagnesemia in Older Diabetic Subjects. Archives of Medical Research, 38(7), 752–756.

[18] Depoortere, H., Françon, D., & Llopis, J. (1993). Effects of a Magnesium Deficient Diet on Sleep Organization in Rats. Neuropsychobiology, 27(4), 237–245.

[19] Nielsen, F.H., Johnson, L.K., & Zeng, H. (2010). Magnesium supplementation improves indicators of low magnesium status and inflammatory stress in adults older than 51 years with poor quality sleep. Magnes Res, 23(4):158-68.

 

[20] Held, K., Antonijevic, I. A., Künzel, H., Uhr, M., Wetter, T. C., Golly, I. C., … Murck, H. (2002). Oral Mg2+ Supplementation Reverses Age-Related Neuroendocrine and Sleep EEG Changes in Humans. Pharmacopsychiatry, 35(4), 135–143.

[21] Rasman, R. (2018). What Does Magnesium Do for Your Body? Healthline.com. [online]. Available at:  https://www.healthline.com/nutrition/what-does-magnesium-do

[22] Zhang, Y., Xun, P., Wang, R., Mao, L., & He, K. (2017). Can Magnesium Enhance Exercise Performance? Nutrients9(9), 946.

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[23] Nielsen, F.H. & Lukaski., H.C. (2006). Update on the relationship between magnesium and exercise. Magnesium Research, 19(3):180-189.

 

[24] Ko, Y.H., Hong, S., & Pedersen, P.L. (1999). Chemical mechanism of ATP synthase: Magnesium plays a pivotal role in formation of the transition state where ATP is synthesized from ADP and inorganic phosphate. J Biol Chem, 8;274(41):28853-6.

[25] Cinar, V., Polat, Y., Mogulkoc, R., Nizamlioglu, M., & Baltaci, A.K. (2008). The effect of magnesium supplementation on glucose and insulin levels of tae-kwan-do sportsmen and sedentary subjects. Pak J Pharm Sci. 21(3):237-40.

[26] Guerrero-Romero, F., & Rodríguez-Morán, M. (2008). The effect of lowering blood pressure by magnesium supplementation in diabetic hypertensive adults with low serum magnesium levels: a randomized, double-blind, placebo-controlled clinical trial. Journal of Human Hypertension, 23(4), 245–251.

[27] Kawano, Y., Matsuoka, H., Takishita, S., Omae, T. (1998). Effects of magnesium supplementation in hypertensive patients: assessment by office, home, and ambulatory blood pressures. Hypertension, 32(2):260-5.

[28] Mooren, F. C., Krüger, K., Völker, K., Golf, S. W., Wadepuhl, M., & Kraus, A. (2011). Oral magnesium supplementation reduces insulin resistance in non-diabetic subjects – a double-blind, placebo-controlled, randomized trial. Diabetes, Obesity and Metabolism, 13(3), 281–284.

[29] Hatzistavri, L. S., Sarafidis, P. A., Georgianos, P. I., Tziolas, I. M., Aroditis, C. P., Zebekakis, P. E., … Lasaridis, A. N. (2009). Oral Magnesium Supplementation Reduces Ambulatory Blood Pressure in Patients With Mild Hypertension. American Journal of Hypertension, 22(10), 1070–1075.

[30] Rodríguez-Morán M, Guerrero-Romero F. (2003). Oral magnesium supplementation improves insulin sensitivity and metabolic control in type 2 diabetic subjects: a randomized double-blind controlled trial. Diabetes Care, 26(4):1147-52.

[31] Magnesium. (2018). WebMd.com. [online]. Available at:  https://www.webmd.com/vitamins/ai/ingredientmono-998/magnesium