Magnesium Supplements as a Treatment for Affective Disorders

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Abstract

Major Depressive Disorder and Generalized Anxiety Disorder are among some of the most disruptive conditions in first world countries. This article will explore using supplemental magnesium as a treatment for these affective disorders. This will be done by compiling research that has been done about the effectiveness of magnesium in treating such disorders. Magnesium has comparable effects on the brain to that of Ketamine. Ketamine has recently discovered as an effective treatment for depression and anxiety. However, Ketamine has many undesirable side effects. It is also explained that due to current farming practices This research concludes that magnesium is a safe alternative to Ketamine therapy in the treatment of affective disorders. 

Introduction

Affective Disorders such as Major Depressive Disorder and Generalized Anxiety Disorder are some of the leading causes of disability worldwide. These disorders cause billions of dollars in damage in the United States alone. The purpose of this research paper is to establish the link between low intracellular magnesium levels and the occurrence of affective disorders such as Major Depressive Disorder (M.D.D.) and Generalized Anxiety Disorder (G.A.D.) This link will be shown by compiling some of the latest research on magnesium’s role in the body, specifically its role in neurotransmission and glutamatergic signaling. It has been shown by many studies that affective disorders and low magnesium levels have a link. It will also be addressed in this article how water supplies in first world countries have had their magnesium filtered from the water. This may explain rising Affective Disorder (A.D.) levels in such countries. The challenges of testing for magnesium deficiency is also addressed.

Research

Major Depressive Disorder (MDD) is characterized by long term depressed mood with symptoms such as: agitation, anxiety, somnolence, suicidal ideation, rapid weight gain or weight loss, apathy, guilt, hopelessness, restlessness, insomnia and difficulty concentrating. MDD is currently considered one of the worlds 4 most important health problems (Stasiuk, Weronika, Monika Prendecka, Krzysztof Chara, & Teresa Małecka-Massalska. 2018). With current depression rates on the rise within the next decade MDD will rank second (after cardiovascular disease) as a leading cause of disability world-wide (Stasiuk et al. 2018).

Major Depressive Disorder is very common among first world countries around the world. For the last 50 years it has been thought by the medical community that Major Depressive Disorder is caused by a low concentration of monoamines in the synaptic cleft. One monoamine, serotonin, when in low concentrations was thought to be the cause of MDD. Most treatments of the last half century have focused on this theory. Most antidepressants aim to increase the levels of serotonin in the synaptic cleft. Many of them do this by blocking the reuptake of serotonin. Blocking the reuptake effectively increases the level in the cleft. The most used medications for this purpose are Selective Serotonin Reuptake Inhibitors such as Prozac, Paxil, Celexa, Zoloft, Lexapro and Latuda. These medications are effective at increasing serotonin levels however, it is a strain on the body’s neurons because they depend on the materials recycled from the reuptake to create more serotonin. This means that many times the benefits of such medications are short lived.

Since the introduction of Selective Serotonin Reuptake Inhibitors (SSRI’s) there hasn’t been a novel approach derived in the treatment of Major Depressive Disorder (MDD). It is estimated that only 60-70% of people treated with current methods obtain any relief from their symptoms (Stasiuk et al. 2018). Of those only an estimated 30% receive complete remission from their symptoms. Of those who only receive partial relief from their symptoms tend to relapse. Also, those who are on SSRI treatment experience many unwanted side effects, creating new problems for patients. This shows that we have great need for new, novel approaches to treating depression.

Ketamine, a well-known party drug called “Special K” has shown in studies that it has the ability to rapidly reduce symptoms of depression (Stasiuk et al. 2018). Ketamine has no action on the monoamine system of brain signaling such as SSRI’s and older antidepressants. Its primary target is the N-Methyl D-Aspirate (NMDA) glutamate receptor in the brain. The brain has several main sources of synaptic signaling. The Monoamine system is more well known and as discussed earlier has been the main target for antidepressant treatments, specifically serotonin (a monoamine). Another, the glutamate system which is primarily responsible for neuronal excitability, is the target of drugs like Ketamine. Ketamine acts as an antagonist of the NMDA receptor and effectively blocks the binding of glutamate which will dampen the neurons excitability making it more difficult to fire an action potential. This rapidly relieves depression symptoms (in a way that is still investigational) and is also showing promise in reducing the depressive symptoms of those with bipolar disorder. It’s also thought that Ketamine is effective for treating depression by not only reducing the function of the NMDA receptor but also enhancing the ability of the AMPA receptor (another glutamate receptor). It is also thought that Ketamine’s ability to cause “induction of the CREB transcription agent (c-AMP response element-binding)” (Stasiuk et al. 2018) helps create the long-lasting antidepressant effect.

The newly discovered ability of Ketamine to reduce depression and anxiety symptoms is what has inspired this research. It has shown the importance of the NMDA receptor in treating Affective Disorders. The NMDA receptor is complicated and has many binding sites. However, it is worth noting that Magnesium and Ketamine have very similar binding sites within the NMDA channel. They both act as antagonists. It is worth noting that magnesium has no psychotomimetic effects that are common with Ketamine use.

Magnesium (2+) is very important in regulating our NMDA receptors. Magnesium acts as a natural antagonist of the receptor. The NMDA receptor blockade produced by magnesium is removed when the neuron is depolarized. It is said that this effect plays an important role in synaptic plasticity (creating new neuronal connections) as well as long term potentiation (Ghasemi, M., Phillips, C., Trillo, L., De Miguel, Z., Das, D., & Salehi, A. 2014). This could indicate that a deficiency in magnesium intake could produce depression symptoms. Hypomagnesemia (low blood magnesium) is an issue in the United States and may play a role in rising depression rates.

A study by Harald Murck (2013) agrees that magnesium levels play a crucial role when targeting the NMDA receptor for depression therapy. According to Murck, magnesium plays an extremely similar role to that of Ketamine since they both block (antagonize) the NMDA receptor. He claims that intracellular magnesium levels could indicate the effectiveness of NMDA targeting drugs such as Ketamine. He states that Ketamine could be taking over the function of magnesium in magnesium deficient patients. This could mean that instead of treating the cause of affective disorders we are merely treating the symptoms with medications such as ketamine. According to this study’s results, intracellular magnesium levels should be the first thing looked at when considering the source of affective disorders.

A study done by Tarleton, E. K., Littenberg, B., MacLean, C. D., Kennedy, A. G., & Daley, C. (2017), also reinforces the importance of magnesium in proper nerve function. In order to determine the effect magnesium supplementation had, Tarleton et al. found 112 candidates with depression and treated half of them with magnesium chloride. The other half were given placebo. The magnesium supplementation was tolerated well throughout the study with no drop-outs due to adverse effects. Of the 112 candidates 61% continued with their magnesium supplementation beyond the test. This is strong evidence of the relief that test subjects received and shows the potential of magnesium as an adjunctive treatment for affective disorders. However, with only 112 candidates involved in this study it is small scale. More large-scale studies need to be done to solidify the results of this study.

Further studies have shown that magnesium has effects on several different pathological pathways of depression. A study performed by H. Murck (2002) has shown that magnesium has the ability to reduce hippocampal excitement. As stated by Murck “Magnesium has the property to suppress hippocampal kindling, to reduce the release of adrenocorticotrophic hormone (ACTH) and to affect adrenocortical sensitivity to ACTH.” Murck discovered this by comparing sleep EEGs of patients who were had different levels of magnesium present in their bodies. What can be concluded from this statement is that magnesium helps regulate the effects that ACTH has on the body. The body keeps a level of magnesium present in synaptic regions in order to regulate the effects of ACTH. It can logically be assumed that when there is a lack of magnesium to normalize the effects of ACTH the body may be susceptible to overexcitement and anxiety. 

There are many current theories as to why there are rising rates of affective disorders throughout the world. Depression and Anxiety rates are specifically high and rising in developed, first-world countries such as the United States, Canada and Europe. A lack of micronutrients, specifically magnesium may provide an explanation. In recent years magnesium has been filtered out of water sources. Especially with the growing popularity of water softeners, which replace magnesium ions with potassium ions water sources are lacking in magnesium which can contribute to deficiency. It has been shown that in the United States 1 Liter of tap water may now only contribute to 2.8% of our daily recommended value where in the past it has been much higher (Patterson, K. Y., Pehrsson, P. R., & Perry, C. R. 2013).

There is also an increasing lack of dietary intake of magnesium in first world countries. Magnesium is often found in leafy green foods. These types of foods are increasingly rare in first world diets. It has also been shown that due to current farming techniques the mineral content of our foods is severely lacking and may only provide 20% of the nutrients that they used to. As stated by Jayme L. Workinger, Robert. P. Doyle, & Jonathan Bortz “Increasing demand for food has caused modern farming techniques to impact the soil’s ability to restore natural minerals such as magnesium. In addition, the use of phosphate-based fertilizers has resulted in the production of aqueously insoluble magnesium phosphate complexes, for example, further depriving the soil of both components” A lack of proper magnesium intake combined with a deficient intake of other micronutrients such as zinc and calcium can have extremely detrimental effects on neurotransmission and can contribute to symptoms of affective disorders.  

Magnesium deficiency is also a condition that is difficult to detect. Most physicians rely on simple blood panels to determine whether a patient is deficient or not. However, a blood test is not enough to rule out magnesium deficiency. Magnesium is unique in the way it is metabolized and compartmentalized within the human body. The normal blood serum magnesium levels were established in the 1970’s through study of presumably healthy males and females. Blood levels are far from telling whether the body has a sufficient level of magnesium. Most of the body’s stores of magnesium are outside of the blood with approximately 90% of magnesium stored within the muscles, bones, liver and heart. “In fact, the much larger exchangeable pool of magnesium is more often called upon to augment blood levels to maintain a narrow range preferentially, which is a key reason why blood measurements can easily mask deficiency” (Jayme L. Workinger, Robert. P. Doyle, & Jonathan Bortz. 2018). Workinger et al. claim that accepted norms of magnesium levels needs to be revisited and likely revised. This means that our current standard of healthy magnesium levels may be incorrect. 

Conclusion

From the research presented in this article it can be reasonably concluded that magnesium may be an effective treatment for patients that suffer with an affective disorder. The connection between rising affective disorder rates and current farming practices is undeniable with magnesium levels in food as the link. It can also be concluded that water softeners may prevent hard water build up, but they may be taking vital nutrients out of the water. Intracellular magnesium levels should be among the first things tested when dealing with an affective disorder. 

Bibliography

Derom, M.-L., Sayón-Orea, C., Martínez-Ortega, J. M., & Martínez-González, M. A. (2013). Magnesium and depression: A systematic review. Nutritional Neuroscience, 16(5), 191–206. https://doi.org/10.1179/1476830512Y.0000000044

Jayme L. Workinger, Robert. P. Doyle, & Jonathan Bortz. (2018). Challenges in the Diagnosis of Magnesium Status. Nutrients, Vol 10, Iss 9, p 1202 (2018), (9), 1202. https://doi.org/10.3390/nu10091202

Jessica Wang, Phoebe Um, Barbra A. Dickerman, & Jianghong Liu. (2018). Zinc, Magnesium, Selenium and Depression: A Review of the Evidence, Potential Mechanisms and Implications. Nutrients, Vol 10, Iss 5, p 584 (2018), (5), 584. https://doi.org/10.3390/nu10050584

Murck, H. (2002). Magnesium and Affective Disorders. Nutritional Neuroscience, 5(6), 375–389. Retrieved from A.N. 11549753

Murck, H. (2013). Ketamine, magnesium and major depression—From pharmacology to pathophysiology and back. Journal of Psychiatric Research, 47(7), 955–965. https://doi.org/10.1016/j.jpsychires.2013.02.015

Patterson, K. Y., Pehrsson, P. R., & Perry, C. R. (2013). Original Research Article: The mineral content of tap water in United States households. Journal of Food Composition and Analysis, 31, 46–50. https://doi.org/10.1016/j.jfca.2013.03.004

Tarleton, E. K., Littenberg, B., MacLean, C. D., Kennedy, A. G., & Daley, C. (2017). Role of magnesium supplementation in the treatment of depression: A randomized clinical trial. PLoS ONE, 12(6), 1–15. https://doi.org/10.1371/journal.pone.0180067