He that struggles with us strengthens our nerves, and sharpens our skill. Our antagonist is our helper.

–Edmund Burke

or centuries, farmers tending to herds of ruminant animals such as cows, ewes, and goats had been perplexed by the curse of what they called “grass paralysis” – a mysterious condition in which animals grazing on newly–grown springtime grass suffered irritability, confusion, muscle spasms, muscle tightness, difficulty walking, convulsions, and ultimately, sudden death. Even mild stresses such as cold weather or loud noises were often sufficient to trigger the deadly sequence of events in susceptible animals. As far back as the 1930’s, agricultural researchers noticed that many of these symptoms were characteristic of magnesium deficiency. Hypomagnesemia, or low blood levels of magnesium were found in affected animals, and injections of magnesium soon became the standard treatment for the condition, now known as grass tetany.

But, complicating matters a bit, many of the same symptoms, including convulsions and spasms, are also known to be caused by hypocalcemia, or, a low level of calcium in the blood. To this day, farmers and veterinarians treating either condition must be diligent in diagnosing the disorders properly, and in always maintaining the all–important balance between calcium and magnesium in their animals.

In the human body, the absorption and physiological activities of calcium and magnesium are very much interrelated as well – so much so, in fact, that a deficiency of either calcium or magnesium can often manifest with many of the same symptoms. Muscle cramping and spasms, excessive inflammation, kidney stones, bone loss, mood disorders, and the soft–tissue calcification characteristic of aging, for example, can all be caused by a lack of either calcium or magnesium.

In many respects, however, calcium and magnesium can be seen as opposites, as they often act antagonistically to one another. Calcium entry into various cells is required for stress–related functions such as the contraction of muscle (both cardiac and skeletal), nerve firing, and the release of various hormones (e.g. “fight–or–flight” hormones: adrenaline and the related catecholamines).

Adequate magnesium, on the other hand, is needed to ensure that these calcium–stimulated functions don’t spiral out of control. Magnesium calms the firing of nerves, allows muscles to relax, and blunts catecholamine release. Magnesium can not only block the initial entry of calcium into cells but is also required to drive the enzyme systems inside the cells which excrete excess calcium once the stress response is no longer needed. Ultimately, it’s this yin–and–yang–type balance between calcium and magnesium that keeps our metabolism running smoothly. Ensuring the proper relative intakes of both minerals is of the utmost importance for proper health.

But, in recent years, there seems to have developed a cultural over–emphasis on the importance of calcium – while relatively little attention has been given to the importance of magnesium. Playing on the simplistic association most people harbor regarding calcium’s role in bone health, the food industry has recently introduced (and heavily marketed) such products as calcium–fortified fruit juice, calcium–fortified breakfast cereals, and even calcium–fortified candies. At the same time, the supplement industry – often known to cater more to misguided consumer demand than the actual nutritional research – continues to turn out higher–and–higher–dosed calcium supplements for bone health. As a result, This imbalance ultimately predisposes many people to the degenerative and mood–altering effects of magnesium deficiency.

Calcium, Magnesium, and The Stress Response

In the human body, calcium is located mostly outside of cells, while magnesium can largely be found inside of cells as an integral factor in cellular energy production. Calcium is often a component of hardened biological structures such as teeth or bone (or in the pathological calcifications of aging), whereas magnesium is usually found in soft tissue and energy–producing structures such as the heart, brain, and muscles (although magnesium does play a largely underappreciated role in the structure and function of bone as well).

Under normal conditions, when the cells are unstressed and producing energy efficiently, the intracellular concentration of magnesium can be 10,000 times higher than that of calcium. Stressful conditions, however (including a simple lack of magnesium), are almost universally characterized by a massive influx of calcium into the cells. In this respect, we can think of magnesium as a cellular guardian, the simple presence of which prevents the entry of excess calcium.

In a very general sense, the calcium influx into cells amplifies many aspects of the stress response – while magnesium generally restores balance, and exerts many of the exact opposite effects:

Calcium:
Stimulates adrenaline production
Excites Nerves
Promotes muscle contraction
Promotes platelet aggregation (clumping of blood cells)
Promotes blood clotting
Promotes inflammation

Magnesium:
Lowers adrenaline production
Calms nerves
Relaxes muscles
Prevents abnormal blood clotting
Reduces Inflammation

In previous Integrated Supplements Newsletters, we’ve seen that maintaining proper mitochondrial function is the key to forestalling the ravages of aging and disease. Magnesium is integral to cellular energy production; and in aging, disease, and stress, mitochondrial function is compromised due to a progressive loss of magnesium from the cell. The subsequent influx of calcium hinders mitochondrial function even further, and, as calcium accumulates, the result can be various degrees of cellular dysfunction, fibrosis, and even tissue calcification. This “calcium shift” is responsible for problems as simple and as temporary as muscle cramping, or as complex and debilitating as the calcified arteries of atherosclerosis. In either case, calcium influx is well–recognized to be the “final common pathway” of aging, cellular dysfunction, and ultimately, cell death:

Editorial Link – Calcium and Aging.

Quote from the above editorial:

One of the most important characteristics of the living cell in obtaining its energy is the extremely low intracellular calcium concentration in contrast to high extracellular calcium concentrations…All cell functions – secretion, contraction, excitation, proliferation, and differentiation – depend on these gradient differences in calcium distribution. Aging appears to represent a blunting of the large gradient in calcium distribution…Aging might thus be regarded as “slow death” with reference to cellular calcium balance.

Magnesium: Nature’s Calcium Channel Blocker

Calcium catalyzes the chemical spark needed for brain function, nervous transmission, and muscle contraction. In this sense, we can see how calcium is fundamental to the basic animal functions of blood circulation, memory, learning, and movement. Proper calcium signaling is so fundamental to cellular biology across species, that the venom of snakes, spiders, and other animals often exerts its toxicity to various predators by interfering with the influx and outflow of cellular calcium:

Study Link – Portuguese Man–of–war (Physalia physalis) venom induces calcium influx into cells by permeabilizing plasma membranes.

Study Link – Calcium channel blocker peptides isolated from tarantula venom: Identification, characterization and utilization.

Study Link – Calciseptine, a peptide isolated from black mamba venom, is a specific blocker of the L–type calcium channel.

In and around all cells of the body there exists a very delicate balance between calcium and magnesium, (along with other electrolyte mineral ions such as potassium and sodium). When cells are stimulated by an imbalance in intracellular versus extracellular calcium, the electrochemical gradient thus created causes calcium to enter cells through various types of calcium channels.

And knowing that this influx of calcium stimulates “excitable” tissues like nerves, muscles, and blood vessels, it’s easy to see why various “calcium–channel–blocking” drugs are often employed to treat some pathological conditions. Because they inhibit the calcium–stimulated contraction of blood vessels for example, calcium channel blockers are often used to treat high blood pressure and angina. And similarly, blocking the calcium–stimulated firing of brain neurons has been proposed to make calcium channel blockers a potential treatment for the seizure disorder, epilepsy:

Study Link – Contribution of calcium ions to the generation of epileptic activity and antiepileptic calcium antagonism.

Quote from the above study:

Consequently neuronal PDS/EFP were depressed by organic calcium channel blockers. This justifies the hope that calcium channel blockers might be useful in the treatment of human epilepsies.

But knowing that cellular calcium regulation via calcium channels is so fundamental to the biological function of all cells, it’s easy to see why calcium–channel–blocking pharmaceuticals often cause unpredictable side–effects. Even with regard to cardiovascular health for which calcium channel blockers are often prescribed, the drugs are associated with higher risk of heart attack, congestive heart failure, and major cardiovascular events when compared to other types of blood–pressure medications:

Study Link – Health outcomes associated with calcium antagonists compared with other first–line antihypertensive therapies: a meta–analysis of randomised controlled trials.

Quote from the above study:

Compared with patients assigned diuretics, beta–blockers, angiotensin–converting–enzyme inhibitors, or clonidine (n=15,044), those assigned calcium antagonists (n=12,699) had a significantly higher risk of acute myocardial infarction (odds ratio 1.26 [95% CI 1.11–1.43], p=0.0003), congestive heart failure (1.25 [1.07–1.46], p=0.005), and major cardiovascular events (1.10 [1.02–1.18], p=0.018)…In randomised controlled trials, the large available database suggests that calcium antagonists are inferior to other types of antihypertensive drugs as first–line agents in reducing the risks of several major complications of hypertension. On the basis of these data, the longer–acting calcium antagonists cannot be recommended as first–line therapy for hypertension.

And no matter how elegant the drug’s design, it’s simply naïve to assume that calcium channel blockers will only affect calcium channels on target tissues. As calcium channel blockers, to some degree, affect calcium channels on various tissues and organs throughout the body, their overall potential for side effects is profound.

Case in point, the calcium channel blockers used to treat high blood pressure have been found to be associated with gastrointestinal bleeding, increased risk of stroke, and particularly crippling bouts of depression:

Study Link – Evidence of depression provoked by cardiovascular medication: a prescription sequence symmetry analysis.

Quote from the above study:

I found a depression–provoking effect only for angiotensin–converting enzyme (ACE) inhibitors (rate ratio = 1.29; 95% confidence interval = 1.08–1.56) and calcium channel blockers (rate ratio = 1.31; 95% confidence interval = 1.14–1.51).

The depression caused by these drugs appears to often be quite severe, as population–based studies have uncovered a link between the use of calcium channel–blocking drugs and an increased incidence of suicide:

Study Link – Use of calcium channel blockers and risk of suicide: ecological findings confirmed in population based cohort study.

Quote from the above study:

Among the Swedish municipalities the use of each cardiovascular drug group except angiotensin converting enzyme inhibitors correlated significantly and positively with suicide rates. After adjustment for the use of other cardiovascular drug groups, as a substitute for the prevalence of cardiovascular morbidity, only the correlation with calcium channel blockers remained significant (r=0.29, P<0.001)...Use of calcium channel blockers may increase the risk of suicide.

So, it seems clear that calcium channel blockers are remarkably inelegant solutions to the problem of blood pressure control – they treat merely symptoms, while leaving the underlying cause of excessive cellular calcium influx unaddressed.

Physiologically, the dietary element needed to prevent excessive calcium influx into cells is magnesium. Unlike calcium channel–blocking drugs however, magnesium is responsible not only for regulating calcium entry into cells, but also for counter–acting calcium signaling inside the cells. Magnesium also activates the enzyme systems which remove excess calcium from cells. Considering how prevalent magnesium deficiency currently is (both absolute deficiency, and relative deficiency with regard to calcium), ensuring adequate magnesium status is a fundamental and physiologically–sound first step towards rectifying imbalances in cellular calcium, and blunting the stress response:

Editorial Link – Magnesium: Nature’s physiologic calcium blocker.

Quote from the above editorial:

Unlike synthetic calcium blockers, deficiency of magnesium will enhance the activity of calcium.

Not surprisingly, it’s been found that conditions for which calcium channel blockers are considered (e.g., high blood pressure and the toxemias of pregnancy) often respond to magnesium supplementation. Magnesium, although less potent than pharmaceutical calcium antagonists, appears to function under a wider variety of conditions, and is remarkably free of side effects:

Study Link – Mg2+–Ca2+ interaction in contractility of vascular smooth muscle: Mg2+ versus organic calcium channel blockers on myogenic tone and agonist–induced responsiveness of blood vessels.

Quote from the above study:

It is clear from the studies done so far that of all Ca2+ antagonists examined, only Mg2+ has the capability to inhibit myogenic, basal, and hormonal–induced vascular tone in all types of vascular smooth muscle…. Although Mg2+ is three to five orders of magnitude less potent than the organic Ca2+ channel blockers, it possesses unique and potentially useful Ca2+ antagonistic properties.

Study Link – Oral magnesium supplementation in patients with essential hypertension.

Quote from the above study:

These results suggest that oral magnesium supplementation may lower blood pressure through the activation of a cell membrane sodium pump and may reduce serum lipid concentration… Therefore, we concluded that appropriate oral magnesium intake might be effective as a nonpharmacological treatment for essential hypertension.

Study Link – Action of Magnesium Sulfate in the Treatment of Preeclampsia–Eclampsia.

Quote from the above study:

Magnesium sulfate could…prove superior to calcium channel blockers because its action would be mediated by more than membrane receptors and might be effective even with membrane dysfunction.

As relates specifically to mood disorders, we’ve seen that calcium channel blockers are associated with increased incidence of depression and suicide. Magnesium, on the other hand, has been found to improve depression (and anxiety) in both animal and human studies:

Study Link – Efficacy and safety of oral magnesium supplementation in the treatment of depression in the elderly with type 2 diabetes: a randomized, equivalent trial.

Quote from the above study:

In conclusion, MgCl2 is as effective in the treatment of depressed elderly type 2 diabetics with hypomagnesemia as imipramine 50 mg daily.

Study Link – Association between magnesium intake and depression and anxiety in community–dwelling adults: the Hordaland Health Study.

Quote from the above study:

The hypothesis that magnesium intake is related to depression in the community is supported by the present findings. These findings may have public health and treatment implications.

Study Link – Magnesium Attenuates Post–Traumatic Depression/Anxiety Following Diffuse Traumatic Brain Injury in Rats.

Quote from the above study:

At 1 week after injury, non–treated animals had a mean core of 62 ± 13. The incidence of post–traumatic depression/anxiety in these animals was 61%, which is similar to that observed clinically. In contrast, animals treated with MgSO 4 had a mean activity score of 144 ± 23 at 1 week after TBI and an incidence of depression/anxiety of less than 30%.

Study Link – Antidepressant– and anxiolytic–like activity of magnesium in mice.

Quote from the above study:

The results indicate that magnesium induces the antidepressant– and anxiolytic–like effects without tolerance to these activities, which suggests a potential antidepressant and anxiolytic activity of magnesium in these disorders in humans.

While serum levels of magnesium aren’t necessarily indicative of overall magnesium status, magnesium levels in cerebrospinal fluid give a direct indication of the amount of magnesium reaching the brain. Studies have found, no matter what their official diagnosis, patients who had made suicide attempts had significantly lower–than–average cerebrospinal fluid magnesium levels:

Study Link – Cerebrospinal fluid magnesium and calcium related to amine metabolites, diagnosis, and suicide attempts.

Quote from the above study:

Patients who had made suicide attempts (by using either violent or nonviolent means) had significantly lower mean CSF magnesium level irrespective of the diagnosis.

Magnesium And Antidepressant Medications

Despite the “neat–and–tidy” explanations proffered in drug advertisements, the biological actions of antidepressant drugs remain largely a mystery to medical science. The different chemical classes of antidepressant medications, including MAOIs, tricyclics, and even the “selective” serotonin reuptake inhibitors (SSRIs) are known to impact many biological chemicals associated with stress, mood, anxiety, and depression.

Serotonin, dopamine epinephrine, norepinephrine, cortisol, acetylcholine, and histamine are just a few of the mood–related chemicals known to be affected by antidepressants, but there’s no consensus as to exactly what role each of these chemicals plays in mood disorders. For example, although pharmaceutical and nutritional–supplement marketing has posited serotonin as the “feel–good” brain chemical which is deficient in depression and anxiety, much research suggests that an excess of serotonin production is characteristic of depressive states as well:

Study Link – In vivo Serotonin release and learned helplessness.

Quote from the above study:

Learned helplessness, a behavioral depression caused by exposure to inescapable stress, is considered to be an animal model of human depressive disorder. Like human depression, learned helplessness has been associated with a defect in serotonergic function, but the nature of this relationship is not entirely clear… These data support the hypothesis that a cortical serotonergic excess is causally related to the development of learned helplessness.

Though the exact role of serotonin in depression remains unknown, it has been found that patients with mood disorders (aka affective disorders) respond to serotonin with enhanced intracellular calcium signaling. Antidepressant medications actually help to inhibit this intracellular calcium signaling, so in this respect, the drugs act as anti–serotonin agents:

Study Link – Intracellular calcium signaling systems in the pathophysiology of affective disorders.

Quote from the above study:

In this paper, we show the importance of intracellular calcium (Ca2+) signaling systems in the pathophysiology of mood disorders based on our recent work. Patients with affective disorders appear to have an enhanced intracellular Ca2+ rise in response to serotonin… acute application of several classes of antidepressant drugs inhibited intracellular Ca2+ signaling and Ca2+–related signaling.

In some ways, the actions of antidepressant drugs seem to parallel those of the calcium channel blockers – respectively, they serve to inhibit either intracellular calcium signaling or calcium influx. But both are associated with unpredictable and unacceptable side effects. In the case of SSRI antidepressants, it’s interesting to find that their use has been associated with significant bone loss:

Study Link – Association of Low Bone Mineral Density With Selective Serotonin Reuptake Inhibitor Use by Older Men.

Quote from the above study:

[Bone mineral density] was lower among those reporting current SSRI use, but not among users of other antidepressants.

So it seems likely – in some cells, at least – that that these drugs somehow interfere with the proper cellular metabolism of calcium (and, in all likelihood, the balance of magnesium and other minerals is affected as well). In many instances, antidepressant drugs are effective for their stated purpose, but in a large number of people these drugs are either ineffective, or worse yet, are associated with side effects including life–threatening mood alterations. Knowing that calcium signaling is intimately involved in mood disorders, the search for physiologically–sound solutions has led some researchers to investigate the calcium–antagonizing potential of essential minerals such as magnesium:

Study Link – Antidepressant activity of zinc and magnesium in view of the current hypotheses of antidepressant action.

Quote from the above study:

The clinical efficacy of current antidepressant therapies is unsatisfactory; antidepressants induce a variety of unwanted effects, and, moreover, their therapeutic mechanism is not clearly understood. Thus, a search for better and safer agents is continuously in progress. Recently, studies have demonstrated that zinc and magnesium possess antidepressant properties.

Other research has found that magnesium may function synergistically with certain antidepressant medications. In the following study, small doses of magnesium and the tricyclic antidepressant, imipramine – either of which would have been insufficient to exert an antidepressant effect if used alone – were found to impart an antidepressant effect when combined:

Study Link – Enhancement of antidepressant–like activity by joint administration of imipramine and magnesium in the forced swim test: Behavioral and pharmacokinetic studies in mice.

Quote from the above study:

The present data demonstrated an enhancement of the antidepressant–like effect by joint administration of IMI and magnesium in the FST, and further indicate the particular role of magnesium in the antidepressant action.

And, in fact, some researchers have proposed that increasing intracellular concentrations of magnesium may be part of the mechanism by which antidepressant drugs exert their effects. The tricyclic antidepressant, desipramine, and the herbal extract from St. John’s Wort have been shown to counter the depression caused by magnesium deficiency. Also of interest in the following study, is the fact that the researchers propose using a magnesium–restricted diet as a model to evoke depression in laboratory animals:

Study Link – Magnesium–deficient diet alters depression– and anxiety–related behavior in mice––influence of desipramine and Hypericum perforatum extract.

Quote from the above study:

Chronic oral administration of desipramine (30 mg/kg/day), or Hypericum extract LI160 (Hyp, 380 mg/kg/day) prevented the "pro–depression–like" forced swim behavior in Mg–depleted mice. Furthermore, the increase in anxiety–related behavior of Mg–depleted mice was abolished in both the open field and light dark test by Hyp… the utility of Mg–depletion as a new screening model for clinically active antidepressant and anxiolytic drugs is suggested.

Study Link – Magnesium in major depression.

Quote from the above study:

There is a positive correlation between concentrations of magnesium in erythrocytes and the clinical evolution of patients with [major depression]. We consider that increasing intracellular concentration is a component of the antidepressant mechanism of sertraline and amytriptiline and maybe of other antidepressants… An increase of intracellular magnesium may be part of the mechanism of action of antidepressants.

Given the above research, a case could be made that, in certain respects, the calcium channel blockers and antidepressants which alter calcium influx and intracellular calcium signaling are merely acting as crude “pinch–hitters” for magnesium. But unlike the essential mineral itself, pharmaceuticals can’t be expected to rectify a nutrient deficiency. We’ve seen that magnesium depletion can trigger depressive states in laboratory animals, and that supplying magnesium often improves symptoms of anxiety and depression and/or helps pharmaceutical antidepressants function more efficiently in both animal and human studies. The fact that over two–thirds of Americans don’t meet even the modest recommended daily intake for magnesium should be a powerful clue as to the possible role of magnesium deficiency in our modern epidemic of mood disorders.

To be continued in the next Integrated Supplements Newsletter…

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