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Institute of Medicine (US) Committee on Nutrition, Trauma, and the Brain; Erdman J, Oria M, Pillsbury L, editors. Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel. Washington (DC): National Academies Press (US); 2011.

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Nutrition and Traumatic Brain Injury: Improving Acute and Subacute Health Outcomes in Military Personnel.

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Magnesium is an essential nutrient that serves as a cofactor for more than 300 enzymes involved in biological reactions important for cellular energy metabolism, protein synthesis, maintenance of cardiovascular health, regulation of blood glucose levels, and normal nervous system functioning. Approximately 50 percent of the magnesium in the body is found in bone, while the other 50 percent is found predominantly in soft tissue (Fleet and Cashman, 2001; Shils, 1999). Magnesium levels in the body are tightly regulated by absorption and excretion of the mineral. Increasing dietary magnesium intake leads to reductions in magnesium absorption and increases in urinary output. Conversely, reductions in magnesium intake are compensated by more efficient gastrointestinal absorption and renal reabsorption (Shils, 1999).


Magnesium, which is transported to the brain by an active mechanism, plays an important role in brain functioning. Under normal conditions, magnesium inhibits the actions of the excitatory neurotransmitter glutamate. More specifically, magnesium blocks the calcium channel of the N-methyl-D-aspartate (NMDA) glutamate receptor, and thereby regulates calcium entry into the postsynaptic neuron. Magnesium also relaxes vascular smooth muscle, resulting in vasodilation and increased cerebral blood flow.

Moreover, magnesium plays an important role in the homeostatic regulation of the pathways involved in the secondary phase of brain injury (Sen and Gulati, 2010). Following traumatic brain injury (TBI), reduction in magnesium levels in the brain is associated with an influx of glutamate and calcium into the postsynaptic neuron. The entry of these compounds into the brain is considered to be the predominant contributor to neuronal degeneration and cell death, secondary to the original insult (Bullock et al., 1998; Faden et al., 1989; Fleet and Cashman, 2001; McKee et al., 2005a; Sen and Gulati, 2010). Magnesium has also been linked to antidepressant effects in experimental studies because it affects the functioning of monoaminergic and serotonergic neurotransmitter systems, which are disrupted as part of the secondary injury cascade following TBI, and alters the activity of the hypothalamic-pituitary-adrenocortical system (Fromm et al., 2004).

A relevant selection of human and animal studies (years 1990 and later) examining the effectiveness of magnesium intake in providing resilience or treating TBI in the acute phase of injury is presented in Table 12-1. This table elaborates on the treatment methodology and includes review articles on magnesium intake in humans for other central nervous system (CNS) injuries such as subarachnoid hemorrhage, stroke, and hypoxia in the case of human studies. The occurrence or absence of adverse effects in humans is included if reported by the authors.

TABLE 12-1. Relevant Data Identified for Magnesium.

TABLE 12-1

Relevant Data Identified for Magnesium.


The Recommended Dietary Allowance (RDA) for magnesium ranges from 80 mg/day in children between the ages of one and three, to 420 mg/day in males over the age of 30 and 320 mg/day in females over the age of 30. Recommendations for military personnel in garrison training are the same as those for adults over 30 years of age (IOM, 2006). Good dietary sources of magnesium include green leafy vegetables, beans, nuts, seeds, and unrefined whole grains.

According to 2005–2006 data from the National Health and Nutrition Examination Survey (NHANES), just more than half (56 percent) of all individuals aged one year and older had inadequate intakes of magnesium.1 The percentage below the Estimated Average Requirement (EAR) was greatest among 14- to 18-year-olds and adults aged 71 years and over. Two small research studies assessing dietary intake of Army Rangers and Special Forces soldiers in garrison found that approximately 40 percent of these individuals were not meeting the EAR for magnesium, and about 60 percent were not meeting the RDA (IOM, 2006). Although a 2006 analysis found that First Strike Rations and Meals, Ready-to-Eat (MREs) contained sufficient magnesium (IOM, 2006), the Institute of Medicine Committee on Mineral Requirements for Cognitive and Physical Performance of Military Personnel concluded that the information on magnesium status of military personnel in various types of training was too limited to provide evidence of magnesium sufficiency (IOM, 2006).

Magnesium toxicity is not a problem in the context of normal dietary intake. However, intake of magnesium supplements can lead to decreased blood pressure, abdominal cramping, and nausea. These adverse effects have been observed primarily with pharmacological uses of magnesium, rather than intake from food and water. Derived from studies on excessive intake from nonfood sources, the Tolerable Upper Intake Level (UL) of 350 mg/ day for individuals nine years of age and over is based on diarrhea as the critical endpoint (IOM, 1997). The risk of magnesium-induced diarrhea mediates against the use of high-dose magnesium supplements. Symptoms of magnesium toxicity are more likely to occur in individuals suffering from renal failure, when the kidney loses its ability to remove excess magnesium (Fleet and Cashman, 2001; IOM, 1997).2


Human Studies

The committee’s review of the literature found no clinical trials investigating the effects of magnesium on resilience for TBI or related diseases or conditions (i.e., subarachnoid hemorrhage, intracranial aneurysm, stroke, anoxic or hypoxic ischemia, or epilepsy). An observational study by Larsson and colleagues (2008) examined the relationship between dietary magnesium intake and the risk of stroke among the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort of more than 26,000 male Finnish smokers. The subjects were 50 to 69 years of age and free from stroke at baseline. After adjusting for age and cardiovascular risk factor, magnesium intake was significantly inversely associated with risk of cerebral infarction, but not intracerebral or subarachnoid hemorrhage. This association was found to be strongest in men younger than 60 years of age. A similar inverse association was observed in the Health Professionals Follow-up Study of more than 43,000 U.S. men. Specifically, magnesium intake was significantly inversely associated with risk of total stroke, most strongly among hypertensive subjects (Ascherio et al., 1998). Other cohort studies did not find a significant association between magnesium intake and risk of stroke (Iso et al., 1999; Song et al., 2005).

Animal Studies

The majority of recent animal studies of magnesium therapy for TBI have investigated its effectiveness as a treatment for physiological events that occur during the secondary injury process. However, early animal head-injury models involving magnesium examined its prophylactic use to determine whether an intervention before injury would improve neurological outcome and decrease mortality by attenuating the postinjury decline of intracellular magnesium concentration (McIntosh et al., 1988; Vink and McIntosh, 1990; Vink et al., 1988). The prevention of such postinjury decline of intracellular magnesium levels was associated with enhanced neurological recovery following intravenous magnesium sulfate administration 15 minutes before fluid percussion brain injury (McIntosh et al., 1988). Rats receiving prophylactic administration of magnesium chloride prior to electrolytic lesions of the somatic sensorimotor cortex also had more improved sensorimotor recovery than control rats (Hoane et al., 1998). Enomoto and colleagues reported in 2005 that intravenous administration of magnesium 5 to 20 minutes before the induction of traumatic brain damage by a lateral fluid percussion brain injury model prevented injury-induced neuronal loss in the hippocampus, as well as injury-induced impairments in working and reference memory on the Morris water maze, a test of spatial memory.

Experimental studies have also examined the effect of preinjury magnesium deficiency on postinjury outcomes. When compared to controls fed a normal diet, rats fed a magnesium-deficient diet for two weeks prior to lateral fluid percussion brain injury responded with significantly greater neurological impairment that persisted for four weeks postinjury, as well as increased mortality (McIntosh et al., 1988).


Human Studies

Based on studies demonstrating negative correlations between serum magnesium levels and the severity of neurological deficits following brain trauma as well as the neuroprotective effects of magnesium observed in experimental animals, a number of clinical studies have assessed the contribution of magnesium to recovery following stroke. Overall, the results of these studies indicate that intravenous administration of magnesium sulfate raises cerebrospinal fluid and brain extracellular levels of magnesium. Magnesium administration also appears to be well tolerated, with few side effects reported (Dorhout Mees et al., 2007; McKee et al., 2005a; Meloni et al., 2006).

The results of studies examining the neuroprotective effects of magnesium have been mixed. On the positive side, Dhandapani and colleagues (2008) reported that patients given parenteral magnesium sulfate within 12 hours after closed head injury displayed less brain swelling and lower mortality than patients not given magnesium. Further evidence of beneficial effects of magnesium comes from work demonstrating that patients given magnesium sulfate within the first 24 hours after a stroke displayed more functional independence one month after the stroke than patients given a placebo (Lampl et al., 2001). Patients given magnesium within 4 days of suffering a subarachnoid hemorrhage, and then for the subsequent 20 days, also reportedly had less risk of delayed cerebral ischemia than patients given a placebo. However, the authors did note that a high concentration of serum magnesium could have a negative effect on clinical outcome (Dorhout Mees et al., 2007).

Although the results of some clinical studies indicate a neuroprotective role for magnesium, results of other studies have been less positive (Kidwell et al., 2009; McKee et al., 2005a; Stippler et al., 2007; Temkin et al., 2007). In a double-blind trial, Temkin and colleagues (2007) evaluated the effects of intravenous administration of two doses of magnesium sulfate or placebo given within eight hours of traumatic brain injury and continuing for five days in 499 patients. Magnesium had no significant positive effects on survival, seizure occurrence, or neurobehavioral functioning. Similarly, the Intravenous Magnesium Efficacy in Stroke (IMAGES) trial failed to demonstrate a survival benefit in more than 2,500 patients with acute ischemic stroke who received either magnesium sulfate or placebo within 12 hours of stroke onset (IMAGES Study Investigators, 2004). Moreover, in a subsequent report of a substudy within the IMAGES trial using magnetic resonance imaging, there were no differences in infarct growth observed between patients who had received magnesium and those who had not (Kidwell et al., 2009). In an analysis of three randomized control trials, a Cochrane review concluded that magnesium therapy in patients with acute brain injury is not currently supported by the evidence (Arango and Mejia-Mantilla, 2006).

Animal Studies

More than 20 years ago, Vink and colleagues (Heath and Vink, 1998; Vink et al., 1988) reported that TBI in laboratory rodents was associated with a decline in intracellular free magnesium and further noted that the greater the reduction in magnesium, the more severe the trauma-induced neurological deficits. In subsequent work, these investigators demonstrated that magnesium deficiency exacerbated the physiological and behavioral outcomes of traumatic brain injury, while pretreatment with magnesium improved them (McIntosh et al., 1988, 1989). More specifically, they found that rats receiving a magnesium-deficient diet for 14 days before a fluid percussion injury displayed more profound neurological impairments and higher mortality rates than rats fed a standard laboratory diet. In comparison, rats given intravenous infusions of magnesium sulfate 15 minutes before injury demonstrated improved cellular bioenergetics and neurological functioning relative to rats fed the standard diet (McIntosh et al., 1988).

Since 1990, a variety of animal models of TBI that included fluid percussion injury, impact-acceleration injury, cortical contusion injury, and focal and global cerebral ischemia has repeatedly documented that treatment with magnesium shortly after the induction of injury is effective in limiting the detrimental neural and behavioral consequences of brain trauma (for reviews see: Hoane, 2007; Meloni et al., 2006; Sen and Gulati, 2010). Administration of magnesium prevents the postinjury decline in free magnesium, reduces cortical and hippocampal cell loss, ameliorates cortical alterations in microtubule-associated protein, and enhances cellular bioenergetic status (Enomoto et al., 2005; Heath and Vink, 1999b; Saatman et al., 2001; Turner et al., 2004). Treatment with magnesium can also attenuate the development of brain edema (Feldman et al., 1996), avert apoptotic changes in neurons (Park and Hyun, 2004), and diminish defects in the blood-brain barrier that result from TBI (Esen et al., 2003).

Magnesium also can improve the behavioral consequences of TBI. Heath and Vink (1999a) reported that the administration of magnesium salts after severe TBI resulted not only in dose-related increases in brain intracellular free magnesium, but also led to improvements in motor behavior. Similarly, Hoane et al. (2003) found that magnesium chloride therapy facilitated reduction of sensorimotor deficits in a dose-dependent manner following bilateral damage to the anterior medial cortex.

The effects of magnesium on recovery are not limited to the transient phase of secondary injury, but rather have long-term functional significance. Research has demonstrated that posttraumatic administration of magnesium sulfate diminishes spatial and motor deficits and attenuates anxiety in rats for up to four weeks after the induction of severe diffuse TBI (Vink et al., 2003). Further evidence of the potential long-term effects of magnesium comes from Browne and colleagues, who reported that magnesium given 15 minutes after fluid percussion injury significantly reduced tissue loss in the hippocampus when measured eight months after the induction of brain damage. However, although magnesium did reduce tissue loss, there were no differences observed in cognitive behavior between treated and untreated animals (Browne et al., 2004).

Most studies examining the therapeutic effects of magnesium following TBI in experimental animals have concentrated on recovery of sensory functions, motor functions, or both. Studies conducted since 2000, however, also indicate that magnesium therapy can improve deficits in cognitive function that result from TBI (Enomoto et al., 2005; Hoane, 2007; Hoane et al., 2003). As mentioned in the earlier section on resilience, a significant reduction in ipsilateral hippocampal cell loss was seen when magnesium therapy was administered prior to fluid percussion brain injury; accordingly, the magnesium therapy prevented injury-induced cognitive dysfunction in the Morris water maze (Enomoto et al., 2005). Hoane (2007) similarly reported that rats given magnesium chloride shortly after brain injury displayed fewer deficits in both reference and working memory on the Morris water maze than controls not given magnesium. It should be noted, however, that magnesium did not improve all aspects of cognitive behavior. In fact, daily administration of a high dose of magnesium produced amnesia and impairments in the acquisition of reference memory task on the Morris water maze. These findings indicate that the type of task used must be considered when evaluating the effects of magnesium on recovery of function following TBI.

TBI can affect brain regions and neurotransmitter systems involved in the modulation of mood, making depression and anxiety common occurrences in brain-damaged individuals (Bombardier et al., 2010; Jorge and Starkstein, 2005). It has been hypothesized that magnesium could be useful in alleviating mood disturbances related to TBI. In support of this hypothesis, rats given magnesium sulfate 30 minutes after impact-acceleration injury displayed less anxiety in an open field test 1 and 6 weeks after injury than brain-damaged animals not given magnesium (Fromm et al., 2004).

Taken together, the results of the previous animal studies strongly suggest that magnesium plays a role in the pathophysiological processes following TBI, and that magnesium therapy may be useful in recovery of both neural functioning and behavior. It is important to note, however, that not all studies have confirmed the neuroprotective effects of magnesium (Hoane, 2007; Hoane and Barth, 2002; Meloni et al., 2006); in reviewing studies that investigated the neuroprotective effects of magnesium in animals that had experienced global or focal cerebral ischemia, Meloni et al. (2006) reported that approximately 40 percent of the studies failed to find any positive effect for magnesium. These conflicting findings are important, because they suggest that the types of brain damage; the dose, route, and timing of magnesium administration; the species and strain of animal; and temperature can influence the neuroprotective effects of magnesium (see below).

One obvious factor that could contribute to the discrepancies in the results of studies assessing the neuroprotective effects of magnesium is the dosage used. With few exceptions (Heath and Vink, 1999b; Hoane et al., 2003), researchers have not examined dose-related responses to magnesium. Across studies, doses of magnesium have ranged from 80 mg/kg to more than 2,000 mg/kg, and in some studies animals were given only one dose of magnesium, while in others they were given multiple doses (Meloni et al., 2006). Unfortunately, there are no consistent relationships evident between dosage and the neuroprotective effects of magnesium.

Results of a number of studies suggest that the timing of administration is another important factor in determining whether magnesium can provide neuroprotective effects. Most studies demonstrating such an effect had administered magnesium either immediately before or very shortly (15 to 30 minutes) after the induction of brain injury. It is therefore likely that magnesium levels in the brain were elevated at the time of the injury or shortly thereafter (Meloni et al., 2006). When administration of magnesium was delayed for several hours, neuroprotective effects have been less consistent. For example, although motor behavior improved in response to magnesium treatment provided up to 24 hours after brain damage, earlier treatments provided the most significant benefit (Heath and Vink, 1999a; Hoane and Barth, 2002). Cell death following brain injury was likewise reduced when magnesium was given 15 minutes after injury, but not when it was given either 8 or 24 hours after injury (Hoane and Barth, 2002).

The extent of the damage following TBI may also moderate the neuroprotective effects of magnesium. Following impact-acceleration injury, magnesium treatment improved brain magnesium levels and motor behavior in rats that did not develop subdural hematomas. However, no such improvement was observed in rats that did develop subdural hematomas (Heath and Vink, 2001).

It has been hypothesized that magnesium’s neuroprotective effects following the induction of cerebral ischemia are only observed when combined with post-ischemia hypothermia (Campbell et al., 2008; Meloni et al., 2006, 2009; Zhu et al., 2004). Most studies have not considered body temperature following the induction of brain damage. In studies that have monitored body temperature, however, magnesium treatment reduced the death of hippocampal neurons in rats that were mildly hypothermic in the immediate hours after the induction of brain damage, but did not reduce neuronal death in animals that were normothermic (Campbell et al., 2008; Meloni et al., 2006).


A number of variables including dose and duration of treatment could modify the neuro-protective effects of magnesium. Findings from both human and animal studies indicate that the most critical issue yet to be addressed is the window of opportunity for magnesium use in the treatment of TBI. Animal studies suggest that the therapeutic window within which neuroprotective effects of magnesium are observed is very brief. As described in preceding paragraphs, most animal studies demonstrating a beneficial effect of magnesium have administered the mineral within 60 minutes following brain damage, which may not be practical or feasible in an uncontrolled environment, such as in combat operations. Results of studies employing longer time intervals between injury and magnesium administration have not been as positive. With respect to clinical trials, results from a small number of patients in the IMAGES trial indicated a beneficial effect of magnesium when it was given within three hours of injury.3 To further evaluate the importance of rapid treatment with magnesium, the Field Administration of Stroke Therapy—Magnesium (FAST-MAG) phase III clinical trial (Saver et al., 2004) is comparing the effects of magnesium given intravenously by paramedics within 1 to 2 hours of symptom onset on scales of global handicap, neurological deficits, quality of life, and mortality, to placebo three months following injury.4 Results of this study have yet to be published.

Results of studies employing experimental animals have shown that magnesium can protect against a number of the secondary consequences of traumatic brain injury. Clini cal studies have had more mixed results, however, with several large trials (e.g., IMAGES) failing to observe a beneficial effect of the mineral on recovery from stroke; indeed, a Cochrane review concluded that the evidence does not currently support magnesium therapy in patients with acute brain injury. No large clinical studies have assessed the neuroprotective effects of magnesium on other types of brain injury, including TBI.

At present, there is no clear evidence that magnesium would be useful in the treatment of TBI occurring in military personnel. However, it is recommended that the results of the FAST-MAG trial be monitored to determine if administration of magnesium within a two-hour window after brain damage can alleviate some of the detrimental consequences of TBI.


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Available online at http://www​.cdc.gov/nchs/nhanes.htm (accessed December 22, 2010).


Available online at http://ods​.od.nih.gov​/factsheets/magnesium/ (accessed December 22, 2010).


Available online at http://www​.fastmag.info/sci_bkg.htm (accessed December 22, 2010).


Available online at http://www​.fastmag.info/sci_bkg.htm (accessed December 22, 2010).

Copyright 2011 by the National Academy of Sciences. All rights reserved.
Bookshelf ID: NBK209305


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