Hypothesis for Magnesium Depletion, Calcium and Glutamate Overload as Cause of most
Major Depression and Related Mental Health Issues: A Review of the Neurobiochemistry,
Animal and Human evidence with a Suggested Treatment Protocol
George Eby
George Eby Research Institute
2109 Paramount Avenue
Austin, Texas 78704 telephone (512) 263-0805
Background
Norman 1 in 2006 reported that depression is the most common cause of disability in the United
States. According to the National Institutes of Health, clinical depression will affect up to 25 percent of the American population. People with depression suffer in many areas of their lives, including sleep, eating, relationships, school, work, and self-image. Most distressing, Americans are developing major depression at higher rates and younger ages than previously. For example, people born around 1900 never had childhood or early adult depression and only about one percent ever developed depression. Meyer et al.
2
in 2004 writing in “Psychopharmacology:
Drugs, the Brain and Behavior” showed that people born between 1935 and 1944 had a 1 percent incidence of depression by age 15, a 2 percent rate of depression by age 25 and 9 percent incidence by age 45. People born in 1955, had a one percent incidence of depression by age 15 and a 6 percent incidence by age 25, and a lifetime incidence of 25 percent. The onset of depression has both greatly increased in incidence and has affected people much earlier in their lives during the 20th century, thus depression can be defined as a “modern” disease which is explained only by changes in the diet over the last century.
Depression is more than the normal feelings of sadness that people experience from time to time.
It is a clearly defined disorder that affects both mind and body. People suffering from clinical depression cannot just will their blues away, and in most cases the depression will not subside without active intervention. Unfortunately, however, many people do not seek professional treatment for their depression, so the disorder is likely to be under diagnosed. Among those who do seek professional help, many people do not find relief for their condition among conventional therapies.
Treatment for depression is usually multifaceted, and there is no doubt that nutrition, especially magnesium, plays an important role. Research has shown that the body chemistry of depressed people is altered in various ways and deficiencies in neurotransmitters, hormonal imbalances, and other nutritional deficits can contribute to clinical depression. Also, many people with depression do not eat enough, overeat, or eat non nutritious foods. New research has also connected depression to inflammation and oxidative stress, which are both appropriately managed with nutritional supplements.

Ultimately, the treatment of depression usually touches on many facets of a person’s life.
Exercise is important, and treatments such as massage and acupuncture have a long history of effectiveness when used as part of a treatment program. Counseling and psychiatric therapy can also help people deal with the feelings of anxiety and hopelessness that accompany depression.
The good news is that depression can be treated successfully. Many people who seek treatment for their depression realize they may have been suffering its symptoms for a long time and respond favorably to treatment.
Diagnosing Depression
Major depressive disorder is sometimes called clinical depression, or unipolar depression.
Unipolar depression is so named because the disorder is characterized only by depression, as opposed to bipolar disorder, which is characterized by both depression and episodes of mania.
People with major depressive disorder may have recurrent episodes of depression, and there is recent evidence that many people experience their first episodes of depression at a young age.
3
Episodes of depression may be separated by years or months and may become more common as a person ages. After an episode is over, most people will recover completely. People who recover only partially are more likely to experience another episode. Among adolescents, clinical depression is associated with substance abuse and suicide, and even among adults, as many as 15 percent of people diagnosed with depression die by suicide. Ninety percent of all suicides are associated with major depression. Clinical depression is also associated with vascular and cerebrovascular disease.
4
Guidelines for the diagnosis of depression can be found in the fourth edition of the American
Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders. To be diagnosed with clinical depression, the patient must experience at least five of the nine symptoms below for two weeks or more, most of the time, almost every day, and must include either a depressed mood or loss of interest.

Depressed mood

Reduced level of interest or pleasure in activities

A considerable loss or gain of weight or appetite

Insomnia or excessive sleeping

Behavior that is agitated or slowed down

Fatigue or diminished energy

Thoughts of worthlessness or guilt

Reduced ability to think or concentrate

Frequent thoughts of suicide or death, or suicide attempts
In addition, the following conditions must be present:

The symptoms are not part of a mixed episode of psychiatric disorders.

The symptoms are a cause of distress at home, work, school, or other social settings.

The symptoms are not caused by a substance, including alcohol or illicit drugs.


The symptoms are not caused by normal bereavement, they continue for more than two months, or they cause difficulty in functioning.
The causes of clinical depression are not fully known to medical science, however, it is likely that several factors, including nutritional deficits, especially magnesium deficiency, stress, poor diet, a genetic predisposition, hormone imbalances, work together in any particular individual to bring on a depressive episode. One of the leading factors associated with depression is reduced levels of norepinephrine, serotonin, and dopamine (the so-called amine theory),
5 although magnesium deficits are found with reduced levels of serotonin and appear to cause more cases of depression than any other single factor. There is also evidence that the structure of the brain itself may become altered in depression, especially the hippocampus,
6
although few studies have been conducted on effective treatment for these changes. Other factors that may contribute to depression include oxidative stress, which can cause cell membrane and DNA destruction in the brain, 7 inflammation, 8 and hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis.
9
The Problem with Conventional Treatment of Depression
Conventional medicine’s track record in treating depression has improved in recent decades, but many patients are still unable to find relief from their condition with conventional antidepressants, or they face the prospect of unpleasant and even dangerous side effects from their therapy. In 2004, for example, a federal advisory panel announced its safety recommendations for the newest and most common class of antidepressants, selective serotonin reuptake inhibitors (SSRIs). These drugs do not increase serotonin or other neuroamines, rather they conserve and recycle existing supplies.
The panel found that SSRIs not only increase the risk of suicide for some younger patients but are often ineffective. The panel urged the Food and Drug Administration (FDA) to impose its strongest caution—known as a black box warning—regarding the use of this class of antidepressants in children and adolescents (FDA 2004). In October 2004, the FDA adopted the recommendation and mandated warnings for all SSRI drugs.
The panel’s investigation came on the heels of several highly publicized incidents in which children and adolescents on the drugs committed suicide, and it highlighted the downside of antidepressant drugs. Although only Prozac® is approved by the FDA for the treatment of depression in children and adolescents, they are often given prescriptions for other medications, such as Zoloft®, Paxil®, and Celexa®. All of these drugs belong to the SSRI class of antidepressants and are believed to work similarly.
The debate in the United States was prompted in 2005, when British officials banned all SSRIs except Prozac® for use in children. Despite that action, most experts agree it is unlikely that
Prozac® is inherently safer than other SSRIs for use in children and adolescents. Although the various SSRIs differ chemically, their mechanism of action in the body is essentially the same.
All inhibit activity at structures known as uptake pumps, located on nerve endings. Most affect the reuptake of serotonin from the synapses, or spaces, between nerve endings. Some affect another messenger chemical, norepinephrine, in a similar manner. These drugs are known as serotonin norepinephrine reuptake inhibitors.

Serotonin and norepinephrine are neurotransmitters that regulate mood, sleep, appetite, and emotion and are involved in a variety of physiological and behavioral functions. If the immediate reuptake of serotonin (or norepinephrine) is prevented, more of these precious brain chemicals remain available to do their intended work.
10
Antidepressant Therapy’s High Cost
Unfortunately, even in adults, the depression relief afforded by SSRIs often comes at a steep price, and not just in monetary terms, though most SSRIs are far from inexpensive. The list of potential side effects includes headache, nausea, diarrhea, anxiety, sleep disturbances, weight gain, fatigue, and most common of all, sexual dysfunction.
11
The latter strikes up to 60 percent of patients taking SSRIs and usually manifests as loss of libido, insufficient lubrication or arousal, or an inability to achieve orgasm.
12
Among men who experience sexual side effects, erectile dysfunction occurs in up to 90 percent of cases.
13
Understandably, many patients find this side effect particularly distressing.
Drug interactions with antidepressants are also a concern. Alcohol, the most common drug of all, may be especially risky. It causes potentially perilous sedation when mixed with antidepressants.
Because of these side effects, many patients discontinue their medication and risk sinking back into depression. Not all patients respond to SSRIs, even when they follow the dosage recommendations of the prescribing physician. Treatment failures range from 40 to 60 percent, and relapse rates are similarly discouraging. According to a recent report from Duke University
Medical Center, an analysis of more than a decade of research on the subject shows that recurrence and relapse rates for drug-treated depression range as high as 80 percent.
14
The same report noted that up to 44 percent of patients starting drug therapy discontinue the drug within three months. Many patients (28 percent) discontinue drug therapy due to intolerable side effects, often within the first month, before the drug takes effect.
What does the American Psychological Association say about these antidepressants? Well, to put it politely they think that their main effects are placebo effects. They found that the mean effect sizes for changes in depression were calculated for 2,318 patients who had been randomly assigned to either antidepressant medication or placebo in 19 double-blind clinical trials. As a proportion of the drug response, the placebo response was constant across different types of medication (75%), and the correlation between placebo effect and drug effect was 0.90
(extremely high correlation). Their data indicated that virtually all of the variation in drug effect size was due to the placebo characteristics of the studies. The effect size for active medications that are not regarded to be antidepressants was as large as that for those classified as antidepressants, and in both cases, the inactive placebos produced improvement that was 75% of the effect of the active drug. Their data raised the possibility that the apparent drug effect (25% of the drug response) is actually an active placebo effect. Examination of effect sizes among depressed individuals assigned to no-treatment or wait-list control groups suggested that approximately one quarter of the drug response is due to the administration of an active medication, one half is a placebo effect, and the remaining quarter is due to other nonspecific factors.
15

Hippocampal Volume Changes in Depression
Lee et al.
16 in 2002 showed an association between major depression and selective and persistent loss of hippocampal volume. Overt hippocampal neuron death could cause this loss. Depression associated with hippocampal atrophy typically involves significant hyper secretion of glucocorticoids, the adrenal steroids secreted during stress. These steroids have a variety of adverse affects, direct and indirect, in the hippocampus. Thus glucocorticoids play a contributing role toward neuron death. Glucocorticoids cause or exacerbate cellular changes associated with hippocampal neuron loss.
Various Nutrient Roles in Treating Depression
Although physicians, and in particular physiatrists, rarely - if ever - consider nutritional issues as the cause of modern diseases, especially mental illnesses, many nutrients can influence the body’s management of vital neurotransmitters. Much like the prescription drugs used to treat depression, these natural chemicals act by increasing production of neurotransmitters or reducing their rates of degradation or providing direct neuronal nutritional support. Unlike prescription drugs, however, natural therapies can also minimize the effects of oxidative stress and inflammation that contribute to depression and they are free of side effects.
Studies have shown that elevated homocysteine is associated with depressive disorders and anger attacks caused by depression.
17
Homocysteine levels can be lowered by increasing the dietary consumption of the folic acid, vitamin B-6, vitamin B-12, trimethylglycine, zinc, SAMe, selenium, N-acetylcysteine, cysteine and creatine.
Omega-3 fatty acids are long-chain polyunsaturated fatty acids found in fish and various oils, such as flaxseed or canola oil.
18
The brain has a high concentration of polyunsaturated fatty acids,
19 and depressed people have slightly lower levels of omega-3 fatty acids compared with the pro-inflammatory omega-6 fatty acids.
20
Adding the omega-3 fatty acid to conventional antidepressant treatment relieved depressive symptoms within 30 days .21
Among children with depression, supplementation with omega-3 fatty acids has shown “highly significant” effects on symptom scores.
22
In 2006, researchers analyzed results from six published studies on depression and omega-3 fatty acids. They found that omega-3 fatty acids can reduce symptoms of depression among adults.
23
Vitamin C is a well-known antioxidant. Studies indicate that levels of vitamin C are lower in people with depression than in those without depression.
24
Ascorbic acid indirectly inhibits oxidative stress by enhancing the activity of other antioxidants, such as vitamin E according to
McKee writing in Bichemistry: An Introduction . in 1999.
25
Low serum levels of vitamin E are linked to major depression.
26
Lower serum high-density lipoprotein cholesterol (HDL-C) is found in major depression and in depressed men with serious suicidal attempts.
27 Cholesterol is the main ingredient found in the brain where it serves as an insulator to preserve the electrical circuitry of the brain.

St. John’s wort (Hypericum perforatum) is a medicinal herb used for the treatment of neurological and psychiatric disorders, including depression.
28
Compared to placebo, H. perforatum extract was useful in treating mild to moderate depression, reducing symptoms and recurrence rate.
29
It appeared more effective than fluoxetine (Prozac) and showed a trend toward superiority over placebo.
30
However, other studies did not found it to be effective in treating major depression, 31 and it appeared to increase salivary cortisol.
32
Tryptophan and 5-hydroxytryptophan (5-HTP) are immediate precursors to serotonin. In some countries, tryptophan is licensed as an antidepressant.
33
In one study, healthy women given tryptophan for 14 days experienced increased recognition of happy faces and words and decreased recognition of negative words. The research team concluded that tryptophan had improved the study participants’ supply of serotonin, much like a conventional SSRI and it provided benefit to the same fraction of people as did SSRIs.
Before man developed the habit of salting food with sodium chloride, potassium was common and sodium was rare in the diet requiring conservation of sodium by the kidneys while potassium did not. Aldosterone, a steroid hormone found to be high in depression, is produced in the adrenal gland to regulate sodium and potassium balance in the blood. Potok and Rybakowski
34 in 1981 showed that potassium was low in patients with clinical depressive disorders.
Harrington et al.
35 in 2006 showed that very small increases in cerebrospinal fluid sodium resulted in migraine headaches. Ramsey et al.
36
in 1979 showed that patients with a primary affective disorder had significantly higher plasma sodium than control subjects. There is no U.S.
RDA (RDI) for sodium, while the USDA suggests that salt intake in adults be restricted to less than 2.3 grams sodium [equivalent to 5.8 grams (one teaspoon) of table salt], while the RDA for adults for potassium is 4.7 grams [equivalent to 9.4 grams (1.5 teaspoons) of potassium chloride]. The most common symptom of potassium depletion is severe fatigue. Wacker and
Parisi in 1968 found that magnesium deficiency has a profound influence on other metals and a decrease in potassium and increase in sodium in muscle and liver have been reported resulting directly from magnesium deficiency.
37
Where did Anti Depression Drugs Go Wrong?
Have you wondered where pharmaceutical drugs for depression came from? Who thought them up? Some of those drugs were the subject of a Nobel Prize in Physiology and Medicine. One of them, Nobel laureate Dr. Avid Carlson, wrote in 1999 that he was originally working on calcium metabolism in brain research 50 years ago, until he was told by an advisory panel of "experts" that calcium had no role in neurobiochemistry.
38 Here we now see exactly where and when neuroscience went in the wrong direction. Perhaps had Dr. Carlson not been ill advised, he would have found the missing magnesium and calcium links to depression 50 years ago.
Magnesium in Nutrition?
Magnesium deficiency with calcium and glutamate excesses underlies much of what causes mental health problems, especially depression and related mood and behavioral disorders.
Magnesium has been removed from nearly all wheat products, except breakfast cereals made by
General Mills of Minneapolis, Minnesota . Refined wheat products are relied upon for their

sources of carbohydrates and protein. These micronutrient depleted foods include bread, cakes, biscuits, cookies, waffles, pancakes, doughnuts, flour tortillas, spaghetti, pasta, pizza crust, hamburger buns, hotdog buns, toast, macaroni and thousands of other delicacies found in the center sections of grocery stores.
From the table below, one can see that the more highly processed the food, the more of it is needed to obtain 400 mg of magnesium [the U.S. Recommended Daily allowance (RDA)] for magnesium. These foods also contain large amounts of mono sodium glutamate or other glutamates and cause people to over eat. Over consumption is a desired feature of these foods for corporate profit reasons, and according to a 2006 report by Hermanussen et al,
39
it is the main cause of obesity, short stature in children and magnesium deficiency in the U.S. and throughout the refined wheat consuming world.
Table 1. Foods Containing 400 mg of magnesium. From “The Magnesium Miracle”, by Carolyn
Dean MD, ND, Balantine Books, 2006.

Magnesium is mainly found in nuts, grains, beans, seeds, grain and green leafy vegetables.
Meats, eggs, dairy, fruits and other vegetables are poor sources. Whole wheat is an excellent source of magnesium, while refined wheat, white flour, has had all but 16% of its magnesium removed. People who are concerned over their weight tend to avoid nuts and seeds due to their high content of oils and calories, greatly increasing their chances of magnesium deficiency.
As is shown in this report, over consumption of these refined wheat (white flour) foods with disregard for proper nutrition, particularly magnesium and zinc, can now be recognized as the main cause of depression, mood disorders and behavioral problems in adults and children.
People know that sugar and fats are harmful, but who would guess that refined wheat is the cause of much illnesses and early death. Prior to 1900, when grain refining was invented, bread was the “staff of life”. Now, we need to consider bread as the “staff of death”, due to the nutrients that have been removed during the refining process. Bread and all wheat products (refined or whole) remain a good source of carbohydrates and protein.
Figure 1. The Grain Drain. From "Harvard Health Letters", November 2002.
Special consideration must be given to refined wheat, flour as is shown in figure 1. The refining process removes most of the critical nutrients required for health. The loss of magnesium is not made up by any other foods found in the American and Western diets, therefore massive magnesium deficiency has occurred, and it has occurred in the most insidious manner humanly possible. Magnesium deficiency started with the advent of refining wheat in 1900. Prior to that time cardiovascular disease, depression, mood and behavior problems and other magnesium deficiency-induced disease were essentially non existent. The world has “grown up” in an environment of inadequate magnesium, and health issues resulting from that are considered to be

“normal” and are diseases that people “catch”. Nothing could be further from the truth, and repletion of magnesium nation-wide would solve many health care problems, and such could bankrupt medicine, hospitals and pharmaceutical companies that have sprung up to “treat” diseases with complex medical treatments and drugs, all for the want of magnesium.
Campbell 40 in 2001 suggested that poor mental health and behavioral conditions are related to deficiencies of essential minerals or excesses of toxic minerals. Most deficient minerals were chromium, magnesium and zinc. Aluminum was found to be the most frequent toxic mineral.
Mineral abnormalities were caused by an over consumption of nutrient-poor, highly processed foods such as white flour, sugar and harmful fats. Such a diet promotes poor lifestyles such as smoking, drug abuse, alcoholism and criminal activity due to lack of magnesium in diet. Poor diets and dangerous lifestyles precede the development of highly prevalent diseases such as cardiovascular disease and depression, which have increased at an alarming rate in the last century.
Diseases Caused by Magnesium Deficiency
A growing but still incomplete list of magnesium deficiency-induced diseases or conditions include (alphabetically) acute heart attacks, agoraphobia, anxiety, angina pectoris, asthma, back pain, behavior problems, breast tenderness, cardiac arrhythmias, chronic fatigue syndrome, can't take a deep breath, carbohydrate craving (especially of chocolate) and carbohydrate intolerance, chest tightness, chronic cardiovascular disease, chronic fatigue syndrome, coronary artery disease, cramps, depression, diabetes, difficulty swallowing, eclampsia of pregnancy, feeling uptight, frequent sighing, epilepsy, headaches, high blood pressure, hyperactivity, insomnia, jaw joint (TMJ) dysfunction, kidney stones (calcium oxalate), lump in the throat-especially provoked by eating sugar, menstrual cramps, mood disorders, muscle soreness, muscle tension, mitral valve prolapse, musculoskeletal disorders, neck pain, numbness, palpitations, panic disorder, preeclampsia, premenstrual syndrome, photophobia, panic attacks, restlessness with constant movement, salt craving, tingling, twitches, urinary spasms, zips, zaps and vibratory sensations.
Magnesium deficiency is also a principle cause of osteoporosis, 41, 42, 43 and cardiovascular disease.
44, 45, 46
Neurobiochemistry of Magnesium, Calcium and Glutamate
Concerning the role of magnesium in mental health, magnesium occupies the central role in the regulation of calcium ion flow within neurons. Without magnesium the neuron operates much like an automobile without brakes, blasting calcium through the synapses causing great harm to the brain with severe disruption of thinking, mood and behavior. Sapolsky
47
writing in “Stress, the Aging Brain and the Mechanisms of Neuron Death” in 1992 suggested that magnesium depletion was likely to be deleterious to neurons possibly by causing NMDA-coupled calcium channels to be biased towards opening. Sapolsky was correct with the damage to neurons appearing to the individual as depression and related mood and behavior disorders.

Figure 2. Magnesium has a pivotal role in regulating neuronal function
In this figure from Department of Cognitive Science, University of California, San Diego, one can see that glutamate, magnesium and calcium are involved in the N-methyl-D-aspartate
(NMDA) nerve cell electrical conduction activity across brain cell synapses. Too much calcium ion and glutamate and not enough magnesium ion, particularly in the hippocampus, play a vital role in brain cell synaptic dysfunction leading to depression and other mood and behavioral disorders.
Krnjevic et al.
48
in 1979 showed that the intracellular effects of magnesium ion are thus mainly opposite to those of calcium ion, possibly owing to competition at sites where calcium ion activates potassium ion channels. Decollogne et al.
49
in 1997 showed that the ion channel of the
NMDA receptor complex is subject to a voltage-dependent regulation by magnesium ions. Under physiological conditions, this channel is supposed to be blocked by a high concentration of magnesium in extracellular fluids.
NMDA receptors are normally activated by glutamate and/or aspartate which represent the principal neurotransmitters for excitatory synaptic transmission in the vertebrate central nervous system. Morris
50
showed in 1992 that magnesium deficiency produces epileptic-form activity in the CNS which can be blocked by NMDA receptor antagonists such as ketamine. Other mechanisms, including alterations in Na+/K(+)-ATPase activity, cAMP/cGMP concentrations and calcium currents in pre- and postsynaptic membranes, may also be at least partially responsible for the neuronal effects associated with low brain magnesium.
Most of the better known neurotransmitter systems - dopamine, noradrenalin, serotonin (5HT), and acetylcholine in particular - have modulatory roles; and when they are defective require specific drugs (SSRIs) to restore their balance. Receptors for these neurotransmitters tend to operate fairly slowly, taking milliseconds or longer to communicate. Rather than directly changing the potential of the neuron, they often trigger second-messenger responses. On the

other hand, most of the brain's regular functions operate quickly, and involves the excitatory and inhibitory amino acids glutamate and aspartate in the NMDA receptors. The receptors for amino acids are calcium and magnesium ion channels (between 80 and 90 percent) and to a lesser extent calcium and zinc (10 to 20 percent). When the receptors are activated, these ions enter or exit the cell, which change the cell’s potential.
Langley and Mann
51
showed in 1991 that the central nervous system concentration of magnesium appears to have a critical level below which neurological dysfunction occurs. The interchange of magnesium ions between the cerebrospinal fluid, extracellular fluid, and bone is more rapid and dynamic than has been believed. This is especially so when the hypertrophied parathyroid gland is associated with significant skeletal depletion of magnesium as judged by history rather than serum level. Magnesium, much like calcium, has a large presence in bone and has a negative feedback relationship with the parathyroid gland. A decline in central nervous system magnesium may occur when the skeletal buffer system - orchestrated largely by the parathyroid glands - is activated by an increase in serum calcium. The transfer of magnesium from the extracellular fluid into bone during mineralization processes is extensive. If the inhibition of the hypertrophied parathyroid gland is prolonged and the skeletal depletion of magnesium extreme, serious neurologic symptoms, including seizures, coma, and death, may occur. Noise, excitement, and bodily contact appear to precipitate neurological symptoms in magnesium-deficient human subjects as it has been documented to occur in magnesium-deficient experimental animals. The similarity of the acute central nervous system demyelinating syndromes with reactive central nervous system magnesium deficiency has been demonstrated.
Calcium enables neurons to do many functions, including carry nerve signals and promote memory. Healthy neurons are very careful about the amount of calcium they allow in because they use minute changes in levels of internal calcium to interpret messages from other neurons.
Too much calcium inside neurons leads to cell death.
The earliest indication that glutamate and many synthetic glutamate receptor agonists are toxic was obtained in the 1970's by Olney and Ho.
52, 53, 54, 55 Marka 56 in 2001 showed that glutamate, although it is vital for every neuronal transaction, when present in the tiniest excess is more toxic to neurons than cyanide. However, most surprising was the finding that even endogenous glutamate may cause neurotoxicity via over-excitation under certain conditions - a situation called "excitotoxicity". Processes that increase the sensitivity of glutamate receptors or affect glutamate homeostasis often induce cell death usually connected with calcium overload.
Over-stimulation of both non-NMDA and NMDA receptors with glutamate results in a large influx of calcium into the cell interior, particularly the neuronal mitochondria. Although normal levels are necessary for many cellular processes, if the intra neuronal mitochondrial concentration of calcium is excessive, such can result in a series of calcium-depended enzymes that are normally suppressed, becoming activated. When these enzymes, like lipid peroxidase, nitric oxide synthetase, and xanthine oxidase, are activated, they cause the production of free radicals and nitric oxide, cytoskeletal breakdown, failure to generate ATP (the cells' energy source), lipid peroxidation, and nucleic acid fragmentation, which leads to neuronal death.

NMDA receptors are unique for several reasons. Unlike most neuronal receptors, they require two agonists (glutamate or aspartate, plus glycine) before the channel opens. These two agonists bind to two different locations on the NMDA receptor. After both agonists have bound to the channel, it opens enough for potassium to enter. Normally, a magnesium ion is bound to a specific location at the opening of the channel as may be seen from Figure 1 above. The magnesium ion allows potassium to pass through but prevents calcium from passing through.
NMDA receptors are only activated following depolarization of the post synaptic membrane, which relieves their voltage-dependent blockade by magnesium ions. Once the cell becomes activated enough, the cell potential rises enough that the magnesium ion is no longer stuck to the cell. Calcium can enter the cell through the fully open NMDA channel. Once inside, calcium sets into motion a series of responses, which enhance the strength of the synapse. Potassium is the most common metallic ion found inside cells.
NMDA receptors are involved in excitotoxicity nerve cell death via over-stimulation. The chemicals that agonize (activate) NMDA receptors can also kill the very same nerve cells they are activating. Glutamic and aspartic acid, are capable of doing extreme damage, and can be more toxic than cyanide to these cells. This excitotoxicity is directly responsible for much of the damage attributed to various types of brain trauma and insult to the CNS from several diseases including depression.
Unfortunately, American processed food manufacturers add large amounts of these two neurotoxins to packaged foods, impairing mental health and causing depression, obesity and childhood growth suppression in many unsuspecting people according to Krnjevic et al.
57 in
2006.
Calcium channel blockers, especially magnesium ions, alter influx of calcium from the extracellular fluid to the cytosol of cells through calcium channels, which is vital for the release of neurotransmitters from presynaptic neurons. Thus magnesium ions act presynaptically rather than by blocking receptors postsynaptically to prevent toxic over stimulation by calcium, and are therefore nature's true neuronal calcium-channel blockers.
Animal Studies
Ault et al.
58
in 1980 found that a single dose of magnesium organic salts given orally to normal mice rapidly increases the plasma magnesium serum concentrations, and revealed a significant dose-dependent antagonist effect of magnesium on the latency of NMDA-induced convulsions, demonstrating that oral administration of magnesium to normal animals can antagonize NMDAmediated responses and lead to antidepressant-like effects that are comparable to those of strong antidepressant drugs. Magnesium, at physiological concentrations, blocks N-methyl-D-aspartate
(NMDA) receptors in neurons.
Singewald et al.
59
in 2004 examined in mice whether magnesium depletion would alter behavior in established animal models of depression and anxiety and whether these effects would be sensitive to antidepressants. Compared to control mice fed with normal diet, mice receiving a low magnesium diet (10% of daily requirement) for several weeks displayed increased immobility time in the forced swim test, indicating enhanced depression-like behavior. In

addition, the partial magnesium-depletion increased anxiety-related behavior in the light/dark and open field test, while locomotor activity or motor coordination was not influenced.
Magnesium depletion led to enhanced depression- and anxiety-related behavior in mice, which was further validated by the reversibility of the behavioral changes by antidepressant and anxiolytic substances. A relation between magnesium status and mood disorders was suggested.
Poleszak et al.
60, 61 ,62, 63, conducted research from 2004 through 2006 in mice which showed that immobility-induced stress caused depression-like behavior in the forced swim test in mice and rats, and that magnesium provided strong anti-depressant activity.
Fromm et al.
64
in 2004 showed that brain magnesium levels decline after traumatic brain injury
(TBI) in rats, a decline believed associated with ensuing neuronal cell death and subsequent functional impairment. They investigated the incidence of post-traumatic depression/anxiety in an animal model of diffuse TBI, and found that magnesium sulfate reduced the incidence of posttraumatic depression/anxiety in these animals from 61 percent to less than 30 percent.
Human Studies
The earliest substance to be reported having calcium-channel blocking effects in the treatment of agitated depression in humans was magnesium. These findings were reported by Weston
65
in
1921 to ameliorate excited psychotic states. Weston showed that 220 doses out of 250 doses of magnesium sulfate (one or two cc of a 25 or 50 percent solution) given hypodermically to 50 patients having agitated depression caused patients to relax and sleep from four to six hours resulting in a 90% success rate for magnesium. He noted that the sedative side effects from giving too much magnesium were quickly and easily reversed by giving small amounts of intravenous calcium chloride.
Plasma magnesium and calcium were noted as being altered in depression as early as 1967 by several researchers, and some suggested that magnesium deficiency was the cause of major depression.
66, 67, 68, 69
Wacker and Parisi
70
reported in 1968 that magnesium deficiency could cause numerous neuromuscular symptoms including hyperexcitability, depression, behavior disturbances, tetany, headaches, generalized tonic-clonic as well as focal seizures, ataxia, vertigo, muscular weakness, tremors, irritability, and psychotic behavior, each of which were reversible by magnesium repletion. By 1980, Wacker and Parisi showed that magnesium was involved in 300 different enzymes, with most of them being brain enzymes.
71
Fischbach
72 in 1971 noted changes in calcium and magnesium metabolism in depression and delirium tremens. Herzberg and Bold 73 in 1972 suggested that there are sex differences in serum-magnesium levels in depression.
Seelig et al.
74 in 1975 suggested that marginal magnesium deficit occurs in patients with anxiety, depression, and psychological complaints, showing the necessity for further consideration of the possibility that chronic magnesium-deficit may contribute to latent tetany, depression and weakness.

Herzburg and Herzburg
75
in 1977 noted that magnesium is an essential ion in many enzyme systems and lithium is of value in the treatment of manic-depressive disease. A significant difference in mean plasma magnesium levels was reported in 44 depressed patients.
Carman and Wyatt 76 in 1979 showed that decreases in cerebrospinal fluid calcium accompany mood elevation and motor activation in depressed patients. Similarly, decreases in cerebrospinal fluid calcium occur during acute psychotic agitation or mania. On the other hand, periodic recurrences of such agitated states are accompanied at their onset by transient increases in serum calcium and phosphorus. Several observations suggest that such serum ion shifts may trigger the more enduring and opposite shifts in cerebrospinal fluid calcium and, in turn, the manic behavior. Progressive restriction of dietary calcium was earlier reported to mitigate and finally abolish both rhythmic rises in serum calcium and periodic agitated episodes. Conversely, a modest oral calcium lactate supplement (approximately one additional Recommended Daily
Allowance of dietary calcium) intensified agitation and worsened depression. In patients, manic symptomatology grew significantly and substantially worse during 2 to 6 weeks of oral vitamin
D administration. On the other hand, in 12 patients, subcutaneous injections of synthetic salmon calcitonin decreased serum calcium and phosphorus, increased cerebrospinal fluid calcium, and decreased agitation while augmenting depressive symptomatology. Salmon calcitonin, which lowers blood calcium levels, also decreased quantified motor activity, frequency and severity of periodic agitated episodes, serum creatine phosphokinase and prolactin, and nocturnal sleep, while vitamin D or calcium lactate raised them.
In a study of electrolytes in CSF from depression patients, Jimerson et al.
77
in 1979 showed a positive correlation between calcium concentration and symptom severity in hospitalized depressed patients was found. CSF calcium levels tended to decrease as patients improved. In rapidly cycling patients, CSF calcium was higher during depression than during mania.
Frazer et al.
78
in 1983 showed that depressed and manic patients had higher total plasma magnesium than did healthy control subjects, but concentrations of ultrafiltrable ionic magnesium did not differ.
Durlach 79 in 1984 suggested that anxiety due to magnesium deficiency was caused by increased production of epinephrine (adrenaline) in magnesium deficiency and that taurine was the antidote.
Banki et al.
80
in 1985 measured magnesium and calcium concentrations in the cerebrospinal fluid
(CSF) of 15 neurological controls and 41 psychiatric patients suffering from major depression (n
= 16), schizophrenic disorder (n = 15), or adjustment disorder (n = 10). All subjects were women
19-67 years of age and free from drugs at the time of the study. CSF was evaluated for 5hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and cortisol (CS) levels, and all patients received a dexamethasone suppression test (DST) following lumbar puncture. CSF calcium levels did not differ among groups, although we found a trend toward higher mean levels in both depression and schizophrenia. By contrast, CSF magnesium was found to be significantly lower in both depression and adjustment disorder; if, however, patients who had made suicide attempts were excluded, the difference became insignificant. Patients who had

made suicide attempts (by using either violent or nonviolent means) had significantly lower mean CSF magnesium level irrespective of the diagnosis. CSF calcium did not correlate with magnesium, 5-HIAA, HVA, CS, global severity, therapeutic response, or DST, but CSF magnesium correlated significantly with CSF 5-HIAA, especially after correcting for age and body height. Both variables seemed to be primarily related to recorded suicide attempts, but decreased magnesium was not limited to violent cases. Hakim et al.
81 in 1975 and Pliszka et al.
82 in 1984 found similar results.
Banki et al.
83
in 1986 showed that both cerebrospinal fluid 5-hydroxyindoleacetic acid (5-HIAA) and magnesium ions are low in suicidal depressives, but not modestly depressed patients, suggesting that inadequate magnesium reduces serotonin levels and that its repletion might be effective in the treatment of depressive disorders. Also, cerebrospinal Ca/Mg ratios were found to be elevated in the depressed patients compared with the controls.
Galland
84
in 1988 showed that magnesium deficiency is a frequent complication of inflammatory bowel disease (IBD) demonstrated in up to 88% of patients. Decreased oral intake, malabsorption and increased intestinal losses are the major causes of magnesium deficiency. The complications of magnesium deficiency included: cramps, bone pain, delirium, acute crises of tetany, fatigue, depression, cardiac abnormalities, urolithiasis, impaired healing and colonic motility disorders. Oral requirements may be as great as 700 mg/day depending on the severity of malabsorption.
Linder et al.
85 showed in 1989 that there are differences between plasma and serum calcium and magnesium concentrations in affective disorder compared to controls. These findings may be interpreted as showing a shift of magnesium from intracellular to extracellular compartments, thus deficits of intracellular and intraneuronal magnesium occur.
Hashizume et al.
86
in 1990 measured serum magnesium in 6,252 patients. Hypomagnesemia was seen in patients with various diseases such as cancer, hepatic cirrhosis, cerebrovascular disease, and generally poor condition. The most common clinical findings of hypomagnesemia were personality changes and depression. Rasmussen
87 showed that the psychiatric symptoms of magnesium deficiency are unspecific, ranging from apathy to psychosis, and may be attributed to other disease processes associated with poor intake, defective absorption, or excretion of magnesium. Liebscher and Liebscher
88
showed that a low serum value (less than 0.9 mmol/l
Mg) suggests magnesium deficiency, but the diagnosis is reinforced with analyses of magnesium in the urine and a loading test with magnesium. Magnesium can be given orally or intramuscular/intravenously. The psychiatric symptoms of magnesium deficiency were unspecific, ranging from apathy and depression to psychosis.
Shealy 89 in 1992 showed that patients having depression with chronic pain were always magnesium deficient. He also showed that taurine is low or absent in 100 percent of people with depression and chronic pain.
Widmer et al.
90
showed in 1992 that elevated serum magnesium normalized with resolution of clinical depression. Reflecting the findings that 99 percent of the body’s magnesium is found intracellularly, Widmer et al.
91, 92
in 1993 and 1995, showed that both elevated erythrocyte and

plasma magnesium were associated with the intensity of the depression. Highly depressed patients had the highest erythrocyte magnesium values, again showing that there has been a shift of intracellular magnesium to extracellular compartments.
Levine et al.
93
in 1999 showed that severe depression is marked by an elevated calcium to magnesium ratio in the cerebrospinal fluid of patients.
Heiden et al.
94
in 1999 showed that magnesium sulphate was useful for the clinical management of severe therapy-resistant manic agitation.
Levine et al.
95 in 2000 found that depressed patients had significantly higher cerebrospinal fluid
(CSF) glutamine/glutamate concentrations associated with the NMDA receptor systems in patients with depression.
Paul
96
in 2001 showed that major depression is accompanied by hyperactivity of subcellular calcium signaling.
Cernak et al.
97 in 2000 showed that chronic stress decreases both free and total plasma ionized magnesium and simultaneously increased oxidative stress in humans. These findings support the need for magnesium supplementation for people living in conditions of chronic stress. However, about 70% of United States and the West have diets containing less than the recommended 400 mg of magnesium per day and up to 20% have diets with less than one-half the recommended intake. Increased stress builds up further worsening magnesium deficiency, with health issues such as depression resulting.
Lee et al.
98
in 2002 showed that in major depression there is a selective and persistent loss of hippocampal volume. Overt hippocampal neuron death could cause this loss. The subtypes of depression associated with hippocampal atrophy typically involve significant hyper secretion of glucocorticoids, the adrenal steroids secreted during stress. These steroids have a variety of adverse affects, direct and indirect, in the hippocampus. Thus glucocorticoids contribute to neuron death. Glucocorticoids cause or exacerbate cellular changes associated with hippocampal neuron loss. Thus, stress, whether physical (i.e. exertion, heat, cold, trauma--accidental or surgical, burns), or emotional (i.e. pain, anxiety, excitement or depression) increases need for magnesium.
Reflecting the findings that 99 percent of the body’s magnesium is found intracellularly, serum magnesium levels were found by Imada et al.
99
in 2002 to be significantly higher in patients with mood disorders than in controls.
Kalinin et al.
100 in 2004 tested magnesium lactate and vitamin B6 (pyridoxine) in the treatment of 25 patients with anxiety-depression and epilepsy. Kalinin et al. showed that the combination exerted a positive non-specific influences on patient’s mental state, especially with regard to affective disorders. The positive effect of the magnesium emerged on 14th day of the treatment and achieved a statistically significant level by the 28th day. Treatment was well tolerated and did not cause any side effects.

Enya et al.
101 in 2004 reported a case of hypokalemia in a 69-year-old woman, which had been treated by oral potassium for more than ten years without benefit. She complained of headache, knee joint pain, sleeplessness and paresthesia (an abnormal or unexplained tingling, pricking, or burning sensation on the skin) in extremities and, most prominently, depression. Laboratory data suggested Gitelman's syndrome. Intravenous supplement of magnesium sulfate dramatically improved both the depression and the paraesthesia (an abnormal or unexplained tingling, pricking, or burning sensation), suggesting that hypomagnesemia played a role in the clinical manifestations.
Murck
102
in 2002 showed that magnesium ions have therapeutic potential in major depression.
He showed that examinations of the sleep-electroencephalogram (EEG) and of endocrine systems point to the involvement of the limbic-hypothalamus-pituitary-adrenocortical axis as magnesium affects all elements of this system. Magnesium has the property to suppress hippocampal kindling, to reduce the release of adrenocorticotrophic hormone (ACTH) and to affect adrenocortical sensitivity to ACTH. The role of magnesium in the central nervous system could be mediated via the NMDA-antagonistic, gamma-aminobutyric acid-agonistic or a angiotensin II-antagonistic property of this ion. A direct impact of magnesium on the function of the transport protein p-glycoprotein at the level of the blood-brain barrier has also been demonstrated, possibly influencing the access of corticosteroids to the brain. Furthermore, magnesium dampens the calcium ion-protein kinase C related neurotransmission and stimulates the Na-K-ATPase. All these systems have been reported to be involved in the pathophysiology of depression. Despite the antagonism of lithium to magnesium in some cell-based experimental systems, similarities exist on the functional level, i.e. with respect to kindling, sleep-EEG and endocrine effects.
Siwek et al.
103
in 2005 remarked that magnesium is an important modulator of NMDA-receptor activity in humans. Recent data indicate that disturbances of glutamatergic transmission
(especially via NMDA-receptor) are involved in pathogenesis of mood disorders. Magnesium deficiency is related to a variety of psychological symptoms especially depression. Moreover magnesium exhibits antidepressant-like and antianxiety-like effects in animal models of depression.
Eby and Eby 104 in 2006 showed that magnesium has long been used both in medicine and homeopathy to treat depression, but that its use is not current. They reported that magnesium ions regulate calcium ion flow in neuronal calcium channels, helping to regulate neuronal nitric oxide production. In magnesium deficiency, neuronal requirements for magnesium may not be met, which causes neuronal damage which manifests as depression, mood and behavior problems. Magnesium treatment was found to be effective in treating major depression.
Magnesium ion neuronal deficits can be induced by stress hormones, excessive dietary calcium as well as dietary deficiencies of magnesium. Case histories were presented showing rapid recovery (less than 7 days) from major depression using 125–300 mg of magnesium (as glycinate and taurinate) with each meal and at bedtime, while restricting calcium and glutamates.
Magnesium was found usually effective for treatment of depression in general use by thousands of depressives, resulting from an Internet page concerning magnesium and depression
(http://george-eby-research.com/html/depression-anxiety.html). Related and accompanying mental illnesses in those case histories included traumatic brain injury, headache, suicidal

ideation, anxiety, irritability, insomnia, postpartum depression, cocaine, alcohol and tobacco abuse, hypersensitivity to calcium, short-term memory loss and IQ loss, which were also benefited. Dietary deficiencies of magnesium, coupled with excess calcium and stress may cause many cases of other related symptoms including agitation, anxiety, irritability, confusion, asthenia, sleeplessness, headache, delirium, hallucinations and hyperexcitability. They suggested that the possibility of magnesium deficiency is the cause of most major depression and related mental health problems including IQ loss and addiction was enormously important to public health. They recommended fortifying refined grain and drinking water with biologically available magnesium to pre-twentieth century levels.
Severe traumatic brain injuries (TBI) in humans were generally not responsive to magnesium treatment,
105, 106, 107
while a minor TBI resulting in a loss of IQ and short term memory was responsive to magnesium when given orally over a long term. (Eby and Eby)104
While over 100,000 Internet pages were found using the search terms “major depression” and
“magnesium”, there were only 12 medical journal articles found with the same search terms, suggesting that the public is far more interested in magnesium for depression than is medical science.
Calcium
In health, exquisite homeostatic regulation of serum calcium levels exists, and alterations from the norm in calcium serum levels cause serious mental illness. Bowden et al.
108 in 1988 showed that free intracellular calcium-ion concentrations are elevated in platelets and lymphocytes of manic and bipolar depressed patients but not in control or unipolar depressed patients or in patients made euthymic (normal, neither elated nor depressed) by various medications or electroconvulsive therapy. While calcium is being overemphasized in America and intake of calcium is skyrocketing often to toxic levels often without benefit to bones since magnesium is essentially missing from the diet, magnesium has been relegated to the trash heap of corporate greed and denied from the public in what appears to be an effort designed to destroy the Western mind, bones and heart.
Taurine
Louzada et al.
109
in 2004 showed that taurine, a sulfur containing amino acid found at high concentrations in the brain, protects neurons in culture against the neurotoxicity of glutamate receptor agonists and beta-amyloid peptides. These results suggest that activation of GABA receptors decreases neuronal vulnerability to excitotoxic damage and that pharmacological manipulation of the excitatory and inhibitory neurotransmitter tonus may protect neurons against a variety of insults, including depression and Alzheimer’s disease. Taurine prevents the toxic effects of glutamate. Wu et al.
110
in 2005 showed that taurine prevents glutamate-induced membrane depolarization and protects neurons against glutamate excitotoxicity by preventing glutamate-induced membrane depolarization, probably through its effect in opening of chloride channels and, therefore, preventing the glutamate-induced increase in calcium influx and other downstream events. Taurine modulates excitatory amino acid transmission mediated by Nmethyl-D-aspartate (NMDA) receptors and has potent anti anxiety benefits by inhibiting

adrenaline when taken in 2 to 5 gram doses three times a day. Abdeslem et al.
111
in 1999 showed that taurine prevent glutamate excitotoxicity in the brain through regulation of calcium ion and mitochondrial energy metabolism.
Chahine et al.
112
showed in 1994 that taurine was an anticonvulsant. They studied its effects on noradrenergic transmission. At the highest concentration, it decreased the spontaneous release of the transmitter and enhanced its catabolism. These results suggested that taurine may reduce the peripheral sympathetic activity by accelerating noradrenaline catabolism and decreasing its release probably via its ability to prevent a rise of intracellular calcium ion, thus lowering blood pressure. Shustova et al.
113
showed in 1986 that taurine helped regulate potassium and calcium ions in vivo and in vitro. Taurine also has anti-anxiety properties perhaps from its effects on noradrenalin, at 3 to 5 grams taurine per meal.
Zinc
Zinc according to a number of writers has an identical function as magnesium in the NMDA receptors, but to a less (10 to 20%) extent.
114, 115, 116, 117, 118, 119, 120, 121, 122
Zinc is an antagonist of the glutamate/N-methyl-D-aspartate (NMDA) receptor like magnesium, and it exhibits antidepressant-like activity in rodent tests/models of depression. Similarly to antidepressants, zinc induces brain derived neurotrophic factor gene expression. Clinical observations demonstrated serum hypozincemia in depression, which was normalized by effective antidepressant treatment. Correcting zinc homeostasis in the therapy of depression results in antidepressant activity.
Nowak et al.
123
in 2002 showed that zinc had a regulatory function in the human nervous system.
It not only promotes creation of new brain cells but acts as an antioxidant, decreasing oxidative stress. McLoughlin and Hodge
124
in 1990 and Maes et al.
125
in 1997 showed that decreased blood levels of zinc are associated with depression. Takeda
126
in 2000 demonstrated that maintaining a healthy zinc level in the brain is essential to normal brain function. Levenson
127
in
2006 showed that low serum zinc levels is linked to major depression, and zinc treatment has an antidepressant effect. Van West and Maes
128
in 1999 demonstrated that major depression is accompanied by various direct and indirect indicators of a moderate activation of the inflammatory response system (IRS). Increased production of proinflammatory cytokines, such as interleukin-1 (IL-1), IL-6 and interferon (IFN-gamma), may play a crucial role in the immune and acute phase response in depression. The reciprocal relationships between IRS activation and hypothalamic-pituitary-adrenal (HPA)-axis hyperactivity, alterations in HP thyroid (HPT)-axis function and the availability of tryptophan to the brain suggests that these neuroendocrine changes in depression are indicators of IRS activation and that a combined dysregulation of the
IRS, the turnover of serotonin (5-HT) and the HPA-axis is an integral component of depression.
Additionally, Eby 129 showed in 2007 that 30 mg of zinc a day has been shown to eliminate all signs and symptoms of menstrual cramping and bloating, thus removing one source of monthly depression in women.
Ketamine

Ketamine is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist with the thalamo-neocortical projection system as the primary site of action. Werner et al.
130
in 1997 showed that the protective effect results from decreases in calcium influx and maintenance of brain tissue magnesium levels by the cerebral vasodilating potency of ketamine based on a mechanism involving blockade of calcium channels.
Zarate et al.
131 in 2006 pointed out that existing therapies for major depression have a lag of onset of action of several weeks, resulting in considerable morbidity. Exploring pharmacological strategies that have rapid onset of antidepressant effects within a few days and that are sustained would have an enormous impact on patient care. Converging lines of evidence suggest the role of the glutamatergic system in the pathophysiology and treatment of mood disorders. They tried to determine whether a rapid antidepressant effect can be achieved with an antagonist at the Nmethyl-D-aspartate receptor (Ketamine) in subjects with major depression. They designed a randomized, placebo-controlled, double-blind crossover study from November 2004 to
September 2005. They did the work at the Mood Disorders Research Unit at the National
Institute of Mental Health. They had eighteen subjects with DSM-IV major depression (very treatment resistant). After a 2-week drug-free period, subjects were given an intravenous infusion of either ketamine hydrochloride (0.5 mg/kg) or placebo on 2 test days, a week apart.
Subjects receiving ketamine showed significant improvement in depression compared with subjects receiving placebo within 110 minutes after injection, which remained significant throughout the following week. The effect size for the drug difference was very large after 24 hours and moderate to large after 1 week. Of the 17 subjects treated with ketamine, 71% met response and 29% met remission criteria the day following ketamine infusion. Thirty-five percent of subjects maintained response for at least 1 week. Zarate et all showed that a robust and rapid antidepressant effects resulted from a single intravenous dose of an N-methyl-D-aspartate antagonist with onset occurring within 2 hours post infusion and continued to remain significant for 1 week. Those findings corroborate earlier findings by Berman et al. in 2000.
132
Other studies have shown that agents that block the NMDA receptor reduce depression-like behaviors in animals.
Ketamine is the first drug to enhance the effect of magnesium and lower calcium in managing the toxic effects of calcium in the brain. Ketamine may also function by directly enhancing the amount of magnesium ions in the brain in the same manner as it does in enhancing the amount of magnesium ion in the heart as shown by Kim
133
in 2006.
Ketamine is a general dissociative anaesthetic for human and veterinary use. Pharmacologically it is similar to other dissociative anesthetics such as tiletamine, memantine, and phencyclidine (PCP). Ketamine is classified as an
NMDA receptor antagonist. As with other pharmaceuticals of this type, ketamine has been used as a recreational drug.
Ketamine has a wide range of effects in humans, including analgesia, dissociativeness, hallucination, arterial hypertension, and bronchodilation. It is primarily used for the induction and maintenance of general anesthesia, usually in combination with some sedative drug.
Ketamine blocks nerve paths without depressing respiratory and circulatory functions, and therefore acts as a safe and reliable anaesthetic. Other uses include sedation in intensive care, analgesia (particularly in emergency medicine), and treatment of bronchospasm. It is also a popular anesthetic in veterinary medicine. It is commonly injected intramuscularly, but can also

be taken orally and nasal pharyngealically. Ketamine is only available to physicians, and is occasionally sold as an illicit drug. Ketamine was placed in Schedule III in August, 1999 making it illegal to possess in the United States without a license or prescription. It is not being prescribed for depression since appropriate New Drug Applications have not been approved by the U.S. food and Drug Administration. Due to its dissociative effects, it has become a party and rave drug of choice.
Mental Illnesses Associated with Increasingly Severe Neuronal Magnesium Deficiency
There is a cascade of mental illnesses associated with magnesium deficiency and they can be arranged according to the severity of magnesium deficits.
Foremost and most common are headaches, 134 migraines, 135, 136, 137, 138, 139 cluster headaches, 140, various other types of headaches,
141 insomnia,
142 and restless leg syndrome,
143, 144 irritability,
145,
146
habituations such as cigarette smoking,
147
inappropriate behavior,
70, 71 (Wacker and Parisi 1968), 79
(Durlach 2002) tingling, pricking and burning sensation, 101 (Enya 2004) all occurring at modest neuronal magnesium deficiencies.
Neuroses including anxiety, 74 (Seelig 1975), 59 (Singewald et al. 2004), 148, 149, 104 (eby and eby 2006), 150, 151, 152 irritability with intractable seizures,
153 compulsive behavior perhaps like Tourette’s syndrome,
154 confusion,
155
panic attacks,
79, 156
ataxia,
79 (Wacker and Parisi 1968),
excessive sighing,
100 (Kalinin 2004) hyperemotionality,
157, 158
habituations including smoking cigarettes,
159
drug (cocaine) abuse
104,
160 and alcohol abuse, 104, 161, 162 delirium tremens , 162 tetany, 162 attention deficit hyperactivity, 163,
164, 165, 166, 167, 168
autism,
169, 170, 171, 172
bruxism and tics,
173, 174
inattention,
175
hallucinations,
152 (Kirov
1990)
delirium,
(Galland 1988), (Baker and Worthley 2002)176
neuromuscular hyperactivity including hyperexcitability, (Durlach et al. 1997)177, (Durlach 2002)178 hyperventilation, 158 (Durlach 1997) spasmophilia,
158 (Durlach 1997)
seasonal affective depression,
179
traumatic brain injury,
104 (Eby and Eby, 2006) tetany,
84 (Galland 1988), 156 (Taborska 1995), 158 (Durlach 1997), 176 (baker 2002)
generalized tonic-clonic as well as focal seizures,
184 (Wacker and Parisi 1968), 180
vertigo,
184 (Wacker and Parisi 1968), 181
sudden hearing loss,
182 muscular weakness,
184 (Wacker and Parisi 1968), 179 (Durlach 2002)
tremors,
183, 184 (Wacker and Parisi 1968) fibromyalgia,
179 (Durlach 2002)
chronic fatigue syndrome,
179 (Durlach 2002) psychotic behavior,
184 nystagmus (rapid, involuntary, oscillatory motion of the eyeball),
185
difficulty in swallowing,

158 (Durlach 1997)
apathy,
186
hypocalcemia which is responsive only to magnesium therapy;
186 (Flink 1981) all occur at moderate levels of magnesium deficiency.
The above modest and moderate magnesium deficiency disorders often precede more serious health issues associated with severe magnesium deficiency including cardiovascular disease,
187,
188, 189 cardiac arrhythmias including ventricular fibrillation (Torsades de pointes ) and sudden death,
190 and mental health disorders like bipolar disorder,
191,
epilepsy,
192, 193, 100 (Kalinin 2004)
post partum depression,
104 (Eby and Eby)
seizures,
194, (Baker 2002) delirium,
155 (Baker et al. 2002)
convulsions,
58 (Ault
1980), 186 (Flink 1981)
coma,
195
Parkinsonism,
196, 197, 198, 199, 200
early Alzheimer’s disease (symptoms of severe depression, IQ loss and memory loss),
104 (Eby and Eby 2006)
(Note: Advanced Alzheimer’s disease appears to be caused by a deficiency of both magnesium and niacin,
201
perhaps due to the liver’s inability to convert tryptophan to niacin in aging), major depression, 104 (Eby and Eby 2006) suicidal ideation 104 (Eby and Eby 2006) and suicide 83 (Banki 1986), 104 (Eby and Eby 2006) .
Each of the above mental illnesses (except suicide) appears most effectively treated with magnesium (sometimes with additive Vitamin B-6) since there are no major side effects and treatment seems curative. However, there are no large, double-blind, placebo-controlled clinical trials proving that 5-HTP, magnesium or zinc will cure depression and other mental health illnesses.
Schizophrenia
Schizophrenia is another serious mental illness that has low intraneuronal magnesium. Levine et al.
202
in 1996 measured the serum and cerebrospinal fluid levels of calcium and magnesium in acute schizophrenics and in schizophrenic patients in remission. The acute schizophrenics demonstrated statistically significant lower levels of cerebrospinal fluid magnesium.
Medical Conditions that Adversely Affect Magnesium Balance
Alcoholism and drinking alcohol depletes magnesium and is an important cause of low intraneuronal magnesium, depression and related mood and behavior problems. Although it has been known for many years that prolonged ingestion of ethanol is associated with numerous side effects, among them cardiovascular disease and mental health issues, a direct cause and effect between alcohol and injury to the cardiovascular system and the brain has only been recently shown.
203, 204, 205, 206
Galland in 1988 showed that magnesium deficiency is a frequent complication of inflammatory bowel disease (IBD) demonstrated in up to 88% of patients, therefore patients with IBD must resolve IBD before depression can effectively be treated with magnesium.
84
Gatewood et al.
207
in 1975 showed that hypomagnesemic patients have an immediate rise in the serum immunoreactive parathyroid hormone (IPTH) concentration after magnesium administration. In contrast, normal individuals and patients with primary and secondary hyperparathyroidism responded to magnesium administration with either a decrease or little change in the serum IPTH concentration. This indicates that an acute stimulation of PTH secretion induced by magnesium is characteristic of the magnesium-deficient state. Scott et al.
208

in 1976 suggested that hyperparathyroidism due to magnesium deficiency should be considered a possible cause of depression, catatonia, confusion, disorientation, fatigue, and lethargy.
Parathyroidectomy results in hypocalcaemia and magnesium deficiency, both of which respond to administration of magnesium. Rude et al.
209 in 1978 suggested that the consistency of this response suggested that impaired PTH secretion is a significant factor contributing to the hypocalcemia of magnesium deficiency.
Galland
210
in 1985 observed a high frequency of chronic Candida albicans infection and of allergic sensitization to candida among patients with normocalcemic latent tetany (LT) (low serum magnesium). Among 50 LT patients, 34% suffered from recurrent or chronic candida infection by history, 24% showed evidence of active infection and 48% demonstrated type I hypersensitivity to C. albicans extract on intradermal testing. Treatment with oral antifungal drugs and allergy desensitization to Candida produced complete relief of symptoms in 44% of the patients, with remission occurring for symptoms of depression, irritable bowel syndrome, fatigue, premenstrual tension, headache, anxiety and back pain. There is a complex relationship between candidiasis and magnesium deficit. Depression patients with LT, refractory symptoms and a history of prolonged antibiotic exposure or recurrent candida infection should be considered for oral antifungal therapy and candida desensitization as well as magnesium.
Hasey
211
in 1993 showed that hypothyroidism is associated with hypomagnesia, and that hypothyroidism causes depression and other mental health issues and cardiovascular disease by keeping magnesium blood levels low. Joffe
212
in 1996 showed that magnesium blood levels can not be raised until thyroid issues are resolved.
Al-Ghamdi et al.
146
in 1994 showed that serum magnesium concentration is maintained within a narrow range by the kidney and small intestine since under conditions of magnesium deprivation both organs increase their fractional absorption of Magnesium. If Magnesium depletion continues, the bone store contributes by exchanging part of its content with extracellular fluid
(ECF). The serum magnesium can be normal in the presence of intracellular magnesium depletion, and the occurrence of a low level usually indicates significant magnesium deficiency.
Hypomagnesemia is frequently encountered in hospitalized patients and is seen most often in patients admitted to intensive care units. The detection of magnesium deficiency can be increased by measuring Magnesium concentration in the urine or using the parenteral magnesium load test. Hypomagnesemia may arise from various disorders of the gastrointestinal tract, conditions affecting magnesium renal handling, or cellular redistribution of magnesium. The gastrointestinal causes include the following: protein-calorie malnutrition, the intravenous administration of magnesium-free fluids and total parenteral nutrition, chronic watery diarrhea and steatorrhea, short bowel syndrome, bowel fistula, continuous nasogastric suctioning, and, rarely, primary familial Magnesium malabsorption. The renal causes include Bartter's and
Gitelman's syndrome, post obstructive diuresis, post acute tubular necrosis, renal transplantation, and interstitial nephropathy. Many therapeutic agents cause renal magnesium wasting and subsequent deficiency. These include loop and thiazide diuretics, aminoglycosides, cisplatin, pentamidine, and foscarnet. Magnesium deficiency is seen frequently in alcoholics and diabetic patients, in whom a combination of factors contributes to its pathogenesis. Refractory hypokalemia and hypocalcemia can be caused by concomitant hypomagnesemia and can be corrected with magnesium therapy.

Seelig
213 in 1994 reported that stress intensifies release of catecholamines (adrenaline, noradrenaline and dopamine) and corticosteroids driving down magnesium. Catecholamines are hormones released by the adrenal glands in situations of stress that increase survival of normal animals when their lives are threatened. When magnesium deficiency exists, stress paradoxically increases risk of cardiovascular damage and depression. Dietary imbalances such as high intakes of fat and calcium can intensify magnesium inadequacy, especially under conditions of stress.
Adrenergic stimulation of lipolysis can intensify its deficiency by complexing magnesium with liberated fatty acids. A low Mg/Ca ratio increases release of catecholamines, which lowers tissue magnesium levels. It also favors excess release or formation of factors that are vasoconstrictive and platelet aggregating. A high Ca/Mg ratio also directly favors blood coagulation, which is also favored by excess fat and its mobilization during adrenergic lipolysis.
Auto-oxidation of catecholamines yields free radicals, which explains the enhancement of the protective effect of magnesium by anti-oxidant nutrients against damage caused by catecholamines.
An Effective and Natural Depression Treatment Protocol
Treatment of depression often takes place on several fronts. Depressed patients may benefit from exercise and other strategies, such as acupuncture, yoga, or meditation, each of which reduces stress and magnesium-depleting catecholamines such as adrenaline. In addition, psychiatric, physiological and religious counseling can help people deal with the feelings of sadness and hopelessness that accompany depression, again with the notion of stress reduction. Avoid stressful situations, even if it means changing jobs. Avoid stress. There are many ways in which one can reduce stress. Get a job doing manual labor. Go to church regularly. Take long walks in the park. Go swimming. Get a pet. Ride a horse. Go on picnics. Go shopping. Return to nature. Avoid listening to the news. Listen to soothing music, not rap. Simplify, simplify, simplify. Find your own way of relaxing. These ideas will beneficially lower stress hormones and allow magnesium to be more efficiently absorbed.
If there are any underlying medical conditions, they should be treated. Heart and vascular disease are associated with depression,
214
usually because of inadequate dietary magnesium. Be certain to have hypothyroidism, hyperparathyroidism and kidney diseases treated.
For about 15 to 30 percent of depressives, simply taking 5-HTP will do the same job as more expensive SSRI drugs prescribed by a physician without the side effects of the SSRIs. However there is some concern about serotonin buildup in blood, and dosing precautions should be followed. The remainder of depressives will very likely respond to magnesium or zinc as described below.
Avoiding refined (nutritionally depleted) wheat products will also greatly limit your exposure to the neurotoxic glutamates. Glutamates drive calcium into neurons greatly worsening depression.
Avoid aspartame (the artificial sweetener) since it contains aspartate, which is converted by the liver into glutamate. These are critically important steps. In place of refined grains, substitute salt-free nuts, such as cashews, Brazil nuts, pecans, peanuts, walnuts, almonds and macadamia nuts. These taste wonderful and are very healthy due to their high magnesium and other mineral

content. There are no foods higher in magnesium than nuts. Avoiding eating flour products will reduce calorie intake sufficiently that one need not worry about the calories in nuts.
Eat plenty of fresh vegetables and fruit. Eat fresh meat and eggs. Eat fish, especially cold water which is rich in alpha omega-3 EFAs. Eat around the walls of grocery stores and avoid the centers of grocery stores which are filled with nutrient-depleted manufactured food-like substances. Remember that these food-like substances are depleted of micronutrients and are especially low in magnesium.
Alcohol
215
and tobacco
216
deplete magnesium and alcoholic drinks and smoking must be avoided to recover from depression and all other mental health disorders. Drinking alcohol and smoking cigarettes, even occasionally, will prevent recovery. They must be avoided.
Nutrients found in prepared foods must be biologically available. Magnesium oxide, very widely sold as a magnesium dietary supplement and widely used as a source of magnesium in foods, is not biologically available.
217, 218, 219 Consequently, magnesium oxide must not be use to treat depression or any other human condition, and it must not be relied upon for nutritional support. Likewise, zinc oxide is another substance which is not very biologically available.
220
Have your magnesium blood serum levels tested by a physician or clinic. Ignore his interpretation of the results because his results will always be “normal”. Misinterpretation of magnesium serum levels is universal. If the magnesium serum level is below 0.9 mmol/l Mg, then magnesium deficiency is present. This misinterpretation of magnesium is the cause of the neglect universally shown by physicians to this life-giving nutrient. The reason it has been misinterpreted is because 99% of all of the body’s magnesium is inside cells and not in the serum. Consequently, serum levels only report the content of the serum, which is only 1% of the total.
Rebalance intraneuronal nutrients. Although there are no large scale clinical trial proving that depression and related mental illnesses can be effectively treated with nutrients like magnesium and zinc, there are many articles that demonstrate why magnesium and zinc should be effective from neurobiochemistry, animal and human studies.
There is no corporate profit to be made with magnesium and zinc and there is consequently no corporate interest in testing them for depression. Perhaps U.S. government agencies like the
National Institute of Health will eventually test them as treatments for depression. There is little or no risk associated with taking these nutrients, while there is a risk of suicide and many adverse side effects by taking physician prescribed SSRI drugs for depression.
Try magnesium glycinate in doses of 100 to 300 mg magnesium on an empty stomach one hour before each meal (or with meals if not possible to take it on an empty stomach) and at bedtime.
This totals 1 to 3 times the RDA for magnesium. If magnesium glycinate is not available, try magnesium lactate, magnesium malate, magnesium chloride, magnesium sulfate (Epsom Salts) or magnesium gluconate, however these compounds are more likely to cause diarrhea. Small people may need to take smaller doses to avoid intestinal problems, regardless they too need as much magnesium as their intestinal track can tolerate without diarrhea.

The main side effect of taking “too much” magnesium is diarrhea, which is often caused by intestinal candidiasis. Treating for candida albicans with antifungals, garlic, kefir and coconut oil, and especially 200 mg of indole-3-carbinol (I-3-C) four times a day. Antifungals including garlic and coconut oil will often cause side effects (Herxheimer reactions). Indole-3 carbinol is usually effective in terminating diarrhea by restoration of intestinal immunity to candida without causing side effects. Kefir of is outstanding in the treatment of candida and it helps prevent candida infection, and it is also without side effects. Candida impairs the absorption of magnesium in the intestinal tract, and depression can not be cured without eliminating candida intestinal overgrowth. Stop diarrhea immediately by reducing the amount of magnesium ingested or by taking kefir and indole-3 carbinol or both.
Never take magnesium oxide, magnesium hydroxide, magnesium glutamate or magnesium aspartate, because they are either ineffective or neurotoxic. Magnesium glutamate and magnesium aspartate (which converts to glutamate in the liver) are commonly available magnesium compounds sold as dietary supplements. They should be considered as neurotoxic to depressives, and perhaps all people, and should not be used during treatment of depression, anxiety or similar hyperemotional disorders. Food and drink products containing monosodium glutamate and aspartame (aspartate) should never be used by depressives.
Try 30 to 60 mg of zinc a day. Any compound of zinc is acceptable, although zinc oxide is not very biologically available and should be avoided. Additionally, 30 to 60 mg of zinc a day will eliminate all signs and symptoms of menstrual cramping and bloating, 221 thus removing one source of monthly depression in women.
Greatly reduce calcium intake. Do not take any calcium dietary supplements or calcium antacids or other drugs containing calcium. Do not consume any dairy products (no milk, no cheese, no yogurt) except for Kefir, which contains considerable amounts of inulin (vital for magnesium absorption)
222
and beneficial intestinal fungi and bacteria which are all required for magnesium absorption. Do not worry about osteoporosis from “inadequate” intake of calcium, since magnesium deficiency is more likely to cause osteoporosis in the Unites States with its overemphasis on calcium,
41 (Matsuzaki 2006)
and you will not need to stay away from calcium for a long time.
If you want to try an ill-advised experiment to convince yourself that calcium is bad for depressives, try taking a 500 mg calcium (calcium carbonate) dietary supplement and notice that depression symptoms become greatly worsened within an hour. Recovery can be rapid, within one hour, and it is done by immediately taking 400 to 500 mg of magnesium.
If there is concurrent anxiety, low energy or substantial fatigue, increase taurine intake to as much as 3 to 5 grams with each meal and at bedtime.
Throw away your salt shaker and never use plain sodium chloride salt again to protect both your heart and brain. Imbalances of sodium and potassium in the brain contribute to mental illness and make recovery from depression difficult. In the United States, consumption of too much

sodium (sodium chloride salt) is endemic and very harmful. “Salt” your food with a blend of sodium and potassium chloride (Morton’s Lite Salt).
Recovery from depression should take place within 7 to 14 days. After recovery, continue with the dietary program recommended. This treatment is usually a “cure” and as long as magnesium and or zinc are taken.
Although magnesium imbalances are the focal point of this natural treatment, ketamine (a sedative prescription drug) can be used to initiate a very rapid recovery from depression. It is believed that ketamine induces a rapid restoration of magnesium in the neurons allowing a person to recover fully within an hour or two after a single ketamine injection. The antidepressant effect of ketamine lasts about 7 days, however, such might be extended indefinitely by also taking magnesium and limiting calcium, glutamate and sodium as described above.
Ketamine is a restricted prescription drug used for sedation. It is not a FDA approved drug for use in treating depression, and finding a physician to prescribe and administer it for depression may be problematic.
Conclusions
About 15 to 30 percent of all cases of major depression may respond to 5-HTP or SSRIs and the remainder may respond to either magnesium or zinc. Of the metal-treated cases, about 80% to
90% may respond to magnesium and 10 to 20 percent may respond to zinc. Consequently, 15% to 30% may respond to 5-HTP or SSRIs, 63% to 76.5% may respond to magnesium and 7% to
8.5% may respond to zinc. Therefore, magnesium deficiency can be seen as the most likely cause of major depression and suicide. Most neurotic behavior can also be seen as related to magnesium deficiency. Stress is harmful, and it will cause and worsen depression. Irritability, a common facet of magnesium deficiency leads to anger and possibly violent or even criminal behavior. Although there is no direct link reported between magnesium deficiency and criminal behavior, one should be suspected. Clearly, magnesium deficiency and stress are not good for the brain, mood or behavior, and its supplementation is suggested to be an effective treatment for mental illnesses like depression, remembering that there are no large-scale, double-blind, placebo-controlled clinical trials to prove efficacy.
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