Summary: Magnesium, important for the human body for many reasons, can help with hot flashes due to menopause and treatment for breast and prostate cancer.

Hot flashes occur during the onset of menopause as abrupt changes in estrogen levels elicit vasomotor reactions through the hypothalamus, and they can also occur as estrogen levels are suppressed by chemotherapy in breast cancer treatment. A study recently published in the journal Supportive Care in Cancer presents evidence that magnesium helps to reduce menopausal hot flashes in breast cancer patients.

The authors derived a hot flash score from frequency and severity of hot flashes in breast cancer patients who had been experiencing at least 14 hot flashes a week, before and after taking 400 mg of magnesium oxide 400 mg for 4 weeks. The study subjects were allowed to increase the dose to 800 mg if needed. The results were impressive…

“The average age was 53.5 years; six African American, the rest Caucasian; eight were on tamoxifen, nine were on aromatase inhibitors, and 14 were on anti-depressants. Seventeen patients escalated the magnesium dose. Hot flash frequency/week was reduced from 52.2 to 27.7, a 41.4% reduction… Hot flash score was reduced from 109.8, a 50.4% reduction. Of 25 patients, 14 (56%) had a >50% reduction in hot flash score, and 19 (76%) had a >25% reduction. Fatigue, sweating, and distress were all significantly reduced. Side effects were minor: two women stopped the drug including one each with headache and nausea, and two women had grade 1 diarrhea. Compliance was excellent, and many patients continued treatment after the trial.”

These results are welcome because magnesium, the fourth most abundant mineral in the human body plays a vital role in hundreds of important pathways and is frequently subject to depletion. It is the ‘calming mineral’. The patients whose hot flashes were reduced likely obtained other benefits. The authors conclude:

“Oral magnesium appears to have helped more than half of the patients and was well tolerated. Side effects and cost ($0.02/tablet) were minimal.”

These findings are echoed in another report published in the Journal of Clinical Oncology. The author states:

“Hot flashes are common with natural menopause or induced estrogen deficiency from chemotherapy, tamoxifen, raloxifene, or the aromatase inhibitors. As many as 90% of perimenopausal women have hot flashes, and 40% of survivors of breast cancer rate their hot flashes rate the effect as “quite a bit” to “severe”.”

He notes that the common medications for hot flashes…

“…have potential adverse effects. Antidepressants can cause mental, emotional, and physical adverse effects. Megestrol acetate and medroxyprogesterone acetate, while effective, can potentially cause fluid retention, premenstrual symptoms, and deep vein thrombosis.”

He goes on to report clinical experience consonant with the previous study:

“Recently I saw two patients with breast cancer who volunteered that when they began magnesium supplements for reasons other than hot flashes, their hot flashes diminished within 24 hours and had not returned. In each case, the person was not expecting any relief from magnesium, so placebo effect is unlikely.”

It should be noted that men undergoing hormone blockade therapy for prostate cancer can also suffer from hot flashes. The potential benefits of magnesium apply to them too.

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Summary: Magnesium is important for the prevention and treatment of type 2 diabetes.

The frequency of suboptimal levels of magnesium almost compares to the many critical functions it plays a role in throughout the body. A study just published in the journal Diabetes Care offers fresh evidence of the link between magnesium intake and type 2 diabetes. The authors state:

“Emerging epidemiological evidence suggests that higher magnesium intake may reduce diabetes incidence. We aimed to examine the association between magnesium intake and risk of type 2 diabetes by conducting a meta-analysis of prospective cohort studies.”

They conducted a database search to identify prospective cohort studies of magnesium intake and risk of type 2 diabetes, and applied a random-effects model to compute the summary risk estimates. Data crunching yielded a significant result:

“Meta-analysis of 13 prospective cohort studies involving 536,318 participants and 24,516 cases detected a significant inverse association between magnesium intake and risk of type 2 diabetes (relative risk [RR] 0.78)…In the dose-response analysis, the summary RR of type 2 diabetes for every 100 mg/day increment in magnesium intake was 0.86. Sensitivity analyses restricted to studies with adjustment for cereal fiber intake yielded similar results. Little evidence of publication bias was observed.”

In other words, there was an overall decrease in risk of 22%, and a 14% drop in risk for very 100 mg/day of magnesium consumed. The authors conclude:

“This meta-analysis provides further evidence supporting that magnesium intake is significantly inversely associated with risk of type 2 diabetes in a dose-response manner.”

Clinicians, wondering whether your patient has a significant deficiency but aware that serum and erythrocyte magnesium are poor indicators of intracellular levels? X-ray fluorescence is a validated method for determining reliable tissue levels of magnesium. And it’s easy to collect cellular specimen in the office.

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The symposium proceedings on Oxidative Stress and Cardiovascular Injury of the Southern Society for Clinical Investigation presented during this year’s scientific session of the Southern Society for Clinical Investigation included an important paper on critical role of magnesium (Mg2+) deficiency in oxidative stress-induced cardiomyopathy.

“As emphasized by Weglicki and coworkers, Mg2+ deficiency is all too common and carries with it an increased risk of associated adverse cardiovascular events, including oxidative stress. Hypomagnesemia appears when dietary Mg2+ intake is restricted. It may also be the result of drug-induced Mg2+ wasting, such as occurs with loop diuretics and chemotherapeutics, or the neurohormonal activation that accompanies acute and chronic stressor states (ie, CHF, diabetes and the metabolic syndrome).”

The authors demonstrated that magnesium deficiency results in a rise in neurotransmitter substance P (SP) which in turn triggers a systemic inflammatory effect that includes cardiac and intestinal tissues. Elevations in substance P are sustained when the enzyme neutral endopeptidase (NEP) that is supposed to degrade it is impaired by reactive oxygen and nitrogen species. Importantly…

“An associated increase in intestinal permeability with evidence of mucosal invasion by inflammatory cells and accompanying fall in mucosal barrier function with endotoxemia are seen with Mg2+ deficiency. Endotoxin can stimulate the secretion of tumor necrosis factor-α from diverse cellular sources, including macrophages and cardiomyocytes, and can be attenuated by SP receptor blockade. Thus, this neurogenic signal-transduction pathway involving SP, endotoxemia and elevated tumor necrosis factor-α can contribute to the progressive nature of heart failure, including a decline in myocardial contractility.”

In other words, magnesium deficiency is a potent promoter of inflammatory damage to the heart (and the intestinal lining). This further explains why antagonizing magnesium with calcium supplementation can contribute to cardiovascular disease. Clinicians should bear in mind the concluding statement:

“The importance of careful monitoring of serum Mg2+ in the prevention and prompt correction of hypomagnesemia cannot be overemphasized.”

Readers may wish to read the previous posts on antacids and magnesium deficiency and increase in heart attack risk with calcium supplements.

A paper published only a couple months earlier in the journal Magnesium Research adds further emphasis. The authors state:

“Hypomagnesemia continues to cause difficult clinical problems, such as significant cardiac arrhythmias where intravenous magnesium therapy can be lifesaving. Nutritional deficiency of magnesium may present with some subtle symptoms such as leg cramps and occasional palpitation…We found that neuronal sources of the neuropeptide, substance P (SP), contributed to very early prooxidant/proinflammatory changes during Mg deficiency. This neurogenic inflammation is systemic in nature, affecting blood cells, cardiovascular, intestinal, and other tissues, leading to impaired cardiac contractility similar to that seen in patients with heart failure…Our findings emphasize the essential role of this cation in preventing cardiomyopathic changes and intestinal inflammation in a well-studied animal model, and also implicate the need for more appreciation of the potential clinical relevance of optimal magnesium nutrition and therapy.”

Clinical Pearl: serum and even erythrocyte membrane levels of magnesium reflect tissue levels poorly. Results of the intracellular x-ray fluorescence test (performed on cells scraped from the floor of the mouth) reliably correlate with heart, muscle and deep organ tissue mineral content.

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More evidence that magnesium improves insulin function to treat metabolic syndrome and prevent type 2 diabetes is presented in a study just published in the journal Diabetes, Obesity and Metabolism. The authors note:

“The incidence of insulin resistance and metabolic syndrome correlates with the availability of magnesium (Mg). We studied the effect of oral Mg supplementation on insulin sensitivity and other characteristics of the metabolic syndrome in normomagnesemic, overweight, insulin resistant, non-diabetic subjects.”

Note that the study subjects were ‘normal’ (normomagnesemic) according to the standard blood (serum) test for magnesium. Their study subjects were screened for eligibility with an oral glucose tolerance test and randomized to either a magnesium supplement or placebo. After 6 months they were evaluated for several insulin sensitivity indices (ISI), plasma glucose, serum insulin, blood pressure and lipids. After the intervention period…

“Mg supplementation resulted in a significant improvement of fasting plasma glucose and some ISI compared to placebo…Several mechanisms may be responsible for the beneficial effect of magnesium on insulin resistance…These include direct effects of magnesium on the insulin receptor and its downstream signaling processes, enhanced enzyme activities involved in glucose utilization, prevention of an intracellular calcium overload supposed to negatively affect insulin sensitivity, and finally, anti-inflammatory effects known to improve insulin resistance.”

The authors’ conclusion adds to the mountain of documentation for the potential value of magnesium supplementation:

“The results provide significant evidence that oral Mg supplementation improves insulin sensitivity even in normomagnesemic, overweight, non-diabetic subjects emphasizing the need for an early optimisation of Mg status to prevent insulin resistance and subsequently type 2 diabetes.“

The magnesium blood test used commonly reported and used in this study is not a reliable marker. It is sensitive only to the most severe magnesium deficiencies and does not accurately reflect tissue content. I suggest to the clinicians reading this that they consider testing sublingual epithelial cell magnesium [Mg]i. This can be performed on a simple buccal scrape by IntraCellular Diagnostics, Inc.

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More evidence for the importance of magnesium in cardiovascular disease in general and sudden cardiac death in particular is offered in a paper recently published in The American Journal of Clinical Nutrition. The authors state:

“Magnesium has antiarrhythmic properties in cellular and experimental models; however, its relation to sudden cardiac death (SCD) risk is unclear…We prospectively examined the association between magnesium, as measured in diet and plasma, and risk of SCD.”

They examined magnesium intake for 88,375 women participating in the Nurses’ Health Study along with other nutrients and lifestyle factors for 26 years. During this time 505 cases of sudden or arrhythmic death were documented. Within this group they correlated plasma magnesium for 99 SCD cases and 291 controls who were matched for relevant variables such as age, smoking, and other elements of cardiovascular disease. What did their data show?

“After multivariable adjustment for confounders and potential intermediaries, the relative risk of SCD was significantly lower in women in the highest quartile compared with those in the lowest quartile of dietary and plasma magnesium. The linear inverse relation with SCD was strongest for plasma magnesium, in which each 0.25-mg/dL increment in plasma magnesium was associated with a 41% lower risk of SCD.”

In other words, the women with the highest levels of plasma and dietary magnesium had a significantly lower risk for sudden cardiac death. The association was particularly strong for plasma magnesium (our functional reference range for plasma magnesium is 2.0-2.5 mg/dL). The authors conclude:

“In this prospective cohort of women, higher plasma concentrations and dietary magnesium intakes were associated with lower risks of SCD. If the observed association is causal, interventions directed at increasing dietary or plasma magnesium might lower the risk of SCD.”

This data was generated within the Nurses’ Health Study, but there is no reason to assume that the practical implications don’t apply to men. You can easily see earlier reports on magnesium and cardiovascular disease by typing ‘magnesium’ in the search box. Clinicians and interested laypersons will further appreciate a forthcoming post on the association of intracellular magnesium and glutathione recycling, a critical process in the regulation of inflammation and nitric oxide production.

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Readers here are likely to know that magnesium is necessary for more than two hundred enzymes involved in cell metabolism including the production of ATP (the cellular ‘energy currency’). It is less well known that long term use of proton pump inhibitors (PPIs, such as omeprazole, aka Prilosec; Prevacid, Nexium, Protonix, etc.) can cause severe magnesium deficiencies. The authors of a study published in the journal Clinical Endocrinology set out to…

“…explore the mechanism underlying severe hypomagnesaemia in long-term users of proton-pump inhibitors (PPIs).”

One of the most common symptoms of suboptimal magnesium is muscle spasms or cramps. In the subjects they examined, the deficiency was so severe that they were having hypocalcemic seizures (calcium utilization also depends on magnesium). What did they find?

“Both patients were severely magnesium-depleted and had avid renal magnesium retention, implicating a failure of intestinal magnesium absorption…The hypomagnesaemia could be partially corrected by high dose oral magnesium supplementation, and resolved on withdrawal of PPIs.”

In other words, the kidneys were trying their best to compensate for the failure of intestinal absorption due to the PPIs but it wasn’t enough. Clinicians and any individuals taking PPIs long-term should bear in mind the authors’ conclusions:

“PPI use can inhibit active magnesium transport in the intestine…Long-term PPI users who are highly adherent to treatment can eventually deplete total body magnesium stores and present with severe complications of hypomagnesaemia.“

There are often more physiological therapies effective for conditions such as gastroesophageal reflux disease (GERD) for which PPIs are commonly prescribed.

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Magnesium is important for a multitude of functions and functional deficiencies of magnesium are extremely common. A study just published in the journal Diabetes Care illuminates the role of magnesium in the chronic inflammation associated with insulin resistance and diabetes. The authors set out…

“To investigate the long-term associations of magnesium intake with incidence of diabetes, systemic inflammation and insulin resistance among young American adults.”

They examined 4,497 Americans, aged 18-30 years and without diabetes, for magnesium intake and the subsequent onset of diabetes; along with key inflammatory markers (high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), and fibrinogen) and the homeostasis model assessment of insulin resistance (HOMA-IR). What did the data show?

“During 20-year follow-up, 330 incident diabetic cases were identified. Magnesium intake was inversely associated with incidence of diabetes [those with the lowest magnesium had 53% more chance of developing diabetes]…Consistently, magnesium intake was significantly inversely associated with hs-CRP, IL-6, fibrinogen, and HOMA-IR; and serum magnesium levels were inversely correlated with hs-CRP and HOMA-IR.”

The association between magnesium and the inflammation markers hs-CRP, IL-6 and fibrinogen is significant for more than diabetes because chronic inflammation is a hallmark of most chronic diseases including cardiovascular disease and cancer. The same goes for insulin resistance as indicated by HOMA-IR. Serum magnesium is not a sensitive indicator of deficiency. Measuring magnesium concentration in the red blood cells is a more accurate representation. Urinary organic acids can also indicate when key metabolic pathways are impaired due to magnesium deficiency. Muscle cramps at rest are very often associated with magnesium deficiency and clear up when magnesium sufficiency has been restored.

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Magnesium deficiency is so common that it’s hard to find individuals with optimal levels. A study just published in the American Heart Journal adds to the growing body if evidence for the great importance of magnesium in cardiovascular disease. The authors state:

“We hypothesized that serum magnesium (Mg) is associated with increased risk of sudden cardiac death (SCD).”

They assessed risk factors and levels of serum Mg in 14,232 45- to 64-year-old subjects and followed them for an average of 12 years. During that time there were 264 cases of SCD that they used to evaluate the association of serum Mg with risk of SCD. The data made a clear statement:

“Individuals in the highest quartile of serum Mg were at significantly lower risk of SCD in all models. This association persisted after adjustment for potential confounding variables, with an almost 40% reduced risk of SCD in quartile 4 versus 1 of serum Mg observed in the fully adjusted model.”

This is a potent result, summed by the authors’ conclusion:

“This study suggests that low levels of serum Mg may be an important predictor of SCD.”

A whole body of emerging research is illuminating the mechanisms by which suboptimal magnesium levels can have this effect. In a study just published in the journal Diabetes Care the authors set out…

“To investigate the long-term associations of magnesium intake with incidence of diabetes, systemic inflammation and insulin resistance among young American adults.”

The authors followed 4,497 Americans aged 18-30 (who had no diabetes at the beginning) for 20 years. During that time they identified 330 cases of diabetes which they correlated with quintiles of magnesium intake. They also investigated the associations between magnesium intake and inflammatory markers including high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), and fibrinogen, and the homeostasis model assessment of insulin resistance (HOMA-IR). What did the data show?

“Magnesium intake was inversely associated with incidence of diabetes after adjustment for potential confounders…Consistently, magnesium intake was significantly inversely associated with hs-CRP, IL-6, fibrinogen, and HOMA-IR; and serum magnesium levels were inversely correlated with hs-CRP and HOMA-IR.”

As you know, these are powerful markers for cardiovascular disease risk. As the authors state in their conclusion:

“This inverse association may be explained, at least in part, by the inverse correlations of magnesium intake with systemic inflammation and insulin resistance.”

An earlier paper published in the journal Magnesium Research documents how low magnesium in conjunction with high fructose consumption promotes inflammation associated with metabolic syndrome. The authors begin by observing:

“The metabolic syndrome is a cluster of common pathologies: abdominal obesity linked to an excess of visceral fat, insulin resistance, dyslipidemia and hypertension. This syndrome is occurring at epidemic rates, with dramatic consequences for human health worldwide, and appears to have emerged largely from changes in our diet and reduced physical activity. An important but not well-appreciated dietary change has been the substantial increase in fructose intake, which appears to be an important causative factor in the metabolic syndrome. There is also experimental and clinical evidence that the amount of magnesium in the western diet is insufficient to meet individual needs and that magnesium deficiency may contribute to insulin resistance.”

They present present experimental evidence showing that metabolic syndrome, high fructose intake and low magnesium diet may all be linked to the inflammatory response. The data they gathered showed that:

“…a few days of experimental magnesium deficiency produces a clinical inflammatory syndrome characterized by leukocyte and macrophage activation, release of inflammatory cytokines, appearance of the acute phase proteins and excessive production of free radicals. Because magnesium acts as a natural calcium antagonist, the molecular basis for the inflammatory response is probably the result of a modulation of the intracellular calcium concentration.”

These findings remind of the recent research linking calcium supplementation to increased heart attacks.  The authors conclude:

“Since magnesium deficiency has a pro-inflammatory effect, the expected consequence would be an increased risk of developing insulin resistance when magnesium deficiency is combined with a high-fructose diet. Accordingly, magnesium deficiency combined with a high-fructose diet induces insulin resistance, hypertension, dyslipidemia, endothelial activation and prothrombic changes in combination with the upregulation of markers of inflammation and oxidative stress.”

It goes without saying that these are primary inducers of cardiovascular disease. Another paper published last year in the same journal note the association of magnesium deficiency and C-reactive protein:

“Recent findings from epidemiologic studies support that magnesium intake is inversely associated with C-reactive protein concentration, an important marker of inflammation strongly associated with cardiovascular disease risk.”

A fascinating study published in the American Journal of the Medical Sciences investigates magnesium deficiency promotes inflammation and cardiovascular disease through neurogenic pathways:

“This review highlights some key observations that helped formulate the hypothesis that release of substance P (SP) [an inflammatory signalling molecule] during experimental dietary Mg deficiency (MgD) may initiate a cascade of deleterious inflammatory, oxidative, and nitrosative events, which ultimately promote cardiomyopathy, in situ cardiac dysfunction, and myocardial intolerance to secondary stresses.”

The authors further state:

“…SP-mediated events may…facilitate development of in situ cardiac dysfunction, especially with prolonged dietary Mg restriction.”

Additional intriguing research published in the British Journal of Anaesthesia adds even more evidence to the assertion that magnesium helps reduce cardiovascular disease by opposing calcium.  The authors begin by stating:

“Magnesium sulphate (MgSO4) has potent anti-inflammatory capacity. It is a natural calcium antagonist and a potent L-type calcium channel inhibitor. We sought to elucidate the possible role of calcium, the L-type calcium channels, or both in mediating the anti-inflammatory effects of MgSO4.”

And magnesium sulphate is not the most bioavailable form of magnesium supplementation. When the authors induced inflammation by exposure to lipopolysaccharide (LPS) as evidenced by macrophage inflammatory protein-2, tumour necrosis factor-α, interleukin (IL)-1β, IL-6, nitric oxide/inducible nitric oxide synthase, prostaglandin E2/cyclo-oxygenase-2, and NF-κB activation.

“MgSO4…significantly inhibited the LPS-induced inflammatory molecules production and NF-κB activation. Moreover, the effects of MgSO4 on inflammatory molecules and NF-κB were reversed by extra-cellular calcium supplement with CaCl2 and L-type calcium channel activator BAY-K8644.”

In other words, in addition to opposing inflammation, magnesium is nature’s calcium channel blocker. The authors conclude:

“MgSO4 significantly inhibited endotoxin-induced up-regulation of inflammatory molecules and NF-κB activation… The effects of MgSO4 on inflammatory molecules and NF-κB may involve antagonizing calcium, inhibiting the L-type calcium channels, or both.”

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A paper published last month in the journal Magnesium Research sheds light on the study reported in the last post offering evidence for the link between calcium supplementation and heart attacks. The authors investigated the role of magnesium deficiency in the calcium-activated inflammation of metabolic syndrome.

“The concept that metabolic syndrome is an inflammatory condition may explain the role of Mg [magnesium]. Mg deficiency results in a stress effect and..activates the hypothalamic-pituitary-adrenal axis (HPA) axis and the sympathetic nervous system. The activation of the renin-angiotensin-aldosterone system is a factor in the development of insulin resistance by increasing oxidative stress [and]…leads to an inflammatory phenotype.”

They further describe how this develops an inflammatory milieu in blood vessels:

“One of the earliest events in the acute response to stress is endothelial [blood vessel 'lining'] dysfunction…Experimental Mg deficiency in rats induces a clinical inflammatory syndrome characterized by leukocyte and macrophage activation, synthesis of inflammatory cytokines and acute phase proteins, extensive production of free radicals. An increase in extracellular Mg concentration decreases inflammatory effects, while reduction in extracellular Mg results in cell activation. The effect of Mg deficiency in the development of insulin resistance in the rat model is well documented.”

They then elucidate how magnesium deficiency promotes atherosclerosis with the vascular inflammation characteristic of cardiovascular diseases including heart attacks:

“Inflammation occurring during experimental Mg deficiency is the mechanism that induces hypertriglyceridemia and pro-atherogenic changes in lipoprotein metabolism. The presence of endothelial dysfunction and dyslipidemia triggers platelet aggregability [stickiness], thus increasing the risk of thrombotic events [blood clots]. Oxidative stress contributes to the elevation of blood pressure. The inflammatory syndrome induces activation of several factors, which are dependent on cytosolic [inside the cell] Ca [calcium] activation. Recent findings support the hypothesis that the Mg effect on intracellular Ca 2+ homeostasis may be a common link between stress, inflammation and a possible relationship to metabolic syndrome.“

In other words, as calcium goes up in ratio to magnesium cardiovascular inflammation develops. This is important in light of the previous post on calcium supplementation and heart attacks.

The author of a review in the same issue of Magnesium Research notes:

“Hypomagnesemia is associated with an increased incidence of diabetes mellitus, metabolic syndrome, mortality rate from CAD [coronary artery disease] and all causes. Magnesium supplementation improves myocardial metabolism, inhibits calcium accumulation and myocardial cell death; it improves vascular tone, peripheral vascular resistance, afterload and cardiac output, reduces cardiac arrhythmias and improves lipid metabolism. Magnesium also reduces vulnerability to oxygen-derived free radicals, improves human endothelial function and inhibits platelet function, including platelet aggregation and adhesion, which potentially gives magnesium physiologic and natural effects similar to adenosine-diphosphate inhibitors such as clopidogrel [blood clot prevention].”

If you’re reading this, whether you are a man or woman it is highly likely that you have a functional deficiency of magnesium and should not be taking calcium.

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As the authors of this paper recently published in the journal Neuron state:

“Learning and memory are fundamental brain functions affected by dietary and environmental factors.” The authors “show that increasing brain magnesium…leads to the enhancement of learning abilities, working memory, and short- and long-term memory…”

Facilitation (the pathways become more efficient) and long-term potentiation (the synapses become more efficient) are the means by which learning and memory are ‘sculpted’ in the brain. The authors go on to conclude:

“Our findings suggest that an increase in brain magnesium enhances both short-term synaptic facilitation and long-term potentiation and improves learning and memory functions.”

Though they used a novel form, it’s the magnesium in the brain, not the form, that does the job. This is another item added to the long list of reasons to keep your magnesium up. The next time you suffer a leg or foot cramp remember—this may be affecting your brain too.

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