Magnesium

The most common and abundant non-supplemental sources of magnesium are leafy green vegetables, nuts, legumes and beans, as well as animal tissue.^[18]

A few dietary supplements, usually those that are herbs or food products, may also contain Magnesium. These include:

• Basella Alba (Indian Spinach) at 114+/-1mg/100g^[19]
• King Oyster (Mushroom) at 740+/-230mcg/g^[20]
• Seeds of Mucuna Pruriens^[21]
• Seeds of Irvingia Gabonensis (African Mango) at 429+/-0.3ppm dry weight^[22]
• Royal Jelly at 217.493mg/kg^[23]
• Schisandra Chinensis at trace levels^[24]

The RDA of Magnesium (amount predicted to meet the needs of 97-98% of the population) in the US was set in 1999 in the range of 310-420mg.^[25] Specifically, Magnesium varies between 360-410mg in the 14-18 age bracket (higher values for males), is attenuated to 310-400mg in the 18-30 age bracket, and then is slightly increased to 320-420mg daily for those 31 years or older; values for females are increased 30-40mg during pregnancy with no alterations during lactation.^[25]

Based on this RDA, approximately 68% of adults in the US eat below the recommended intake of Magnesium with 19% consuming less than half the RDA.^[26] These results are slightly more promising than the United States NHANES 2005-2006 survey, which recorded that 60% of adults ate less than the EAR (set at 255-265mg depending on age group).^[27]

Magnesium deficiency, at least to a minor degree, appears to affect a large percentage of adults

Magnesium is used in the body primarily as an electrolyte and a mineral cofactor for enzymes. As an electrolyte it serves to maintain fluid balance, and as a cofactor it serves a purpose in over 300 enzyme systems, most notably ATP, Adenyl Cyclase, and required for the activation of creatine kinase as well as many of the enzymes in the glycolysis pathway.^[28]

Body stores of magnesium are approximately between 21-28g (in a reference 70kg adult male), of which half is deposited in bone tissue. The majority of the rest of magnesium is located inside of cells. Non-bone and extracellular magnesium stores make up 0.3% of overall body magnesium stores, and exist as 55% free form magnesium, 33% bound to protein (such as enzymes) and 12% in anion complexes.^[29]

Typical serum levels of magnesium range from 1.7-2.5mg/dL.^[29]

The state of obesity may induce a Magnesium deficiency, which can be treated with injections of Vitamin D and may be more reflective of abnormalities in Vitamin D metabolism of which low Magnesium is a symptom.^[30]

Diabetic persons (Type II) appear to have a greater risk of deficiency, approaching 25-38% of all persons.^[31]

Measurement of Magnesium can be done in serum (from the blood) but does not tend to correlate well with bodily stores of Magnesium ions.^[32] Better measurements are erythrocytic (red blood cell) and mononuclear (white blood cell) with the latter correlating best with intramuscular Magnesium stores; muscles themselves can be subject to biopsy and measured.^[33][34]

Magnesium absorption takes place in the intestines after oral administration, with some evidence for both paracellular (between intestinal cells) and trancellular (via intestinal cells) absorption, with the majority (up to 90%) occurring through the paracellular route.^[35] The permeability of the paracellular route is determined by proteins making up the tight junctions, which act to regulate the width of gaps between intestinal cells (a dysfunction of tight junctions being a determinent of what is known as 'leaky gut'^[36]). It is well known that Magnesium absorption is regulated in response to serum and body stores of Magnesium, with absorption increasing in periods of deficiency and decreasing in periods of sufficiency,^[37] but the concentration gradient of the lumen (1-5mM) to the blood (0.5-0.7mM) suggests regulation in the paracellular route.^[37] It is thought that this regulation is at the level of tight junctions, which is currently unexplored.^[37]

In regards to transcellular absorption, which makes up the remaining 10% of Magnesium absorption,^[37] it tends to be credited mostly to two transporters belonging to the transient receptor potential melastatin family known as TRPM6 and TRPM7.^[37][38][39] These transports also belong to a class of eukaryotic α-kinases due to possessing a Thr/Ser kinase, and are dubbed chanzymes.^[37] TRPM7 is known to be negatively regulated by the Magnesium ion,^[40] which supports the decreased bioavailability from the lumen to the blood during Magnesium sufficiency; interestingly, TRPM7 exists in most cells in the body whereas TRPM6 is mostly limited to the intestines but expressed in the kidneys, lung, and testes.^[38][39] TRPM6 appears to be critical to dietary magnesium intake due to a genetic flaw in TRPM6 causing genetic hypomagnesia with secondary hypocalcemia.^[39]

Additionally, during dietary deficiency of Magnesium the mRNA content for TRPM6 increases; possibly as a feedback mechanism to enhance absorption.^[41] Vitamin D does not appear to influence TRPM6, at least in the kidneys.^[41]

TRPM6 and TRPM7 also respond to other divalent cations such as Calcium, Zinc, Manganese, and Cobalt with Nickel being a substrate of both but preferring TRPM6.^[37][38][39]

Intestinal absorption of Magnesium is mediated by paracellular (between intestinal cells, also known as enterocytes) and by transcellular (via enterocytes) mechanisms; both of these appear to be regulated by how much Magnesium the body has, reducing absorption when sufficient and increasing absorption during deficiency

When consumed through the diet (assuming varied), total magnesium bioavailability appears to be in the 20-30% range.^[42][43][44] Some bioactives also present in the diet, such as dietary inulin (a fiber), may enhance absorption rates^[45] while dietary phytic acid may reduce magnesium absorption by 60% due to binding to Magnesium^[46] and oxalate may reduce magnesium absorption as well, but to a lower extent than phytic acid.^[47] Leafy vegetables appear to have slightly higher Magnesium absorption rates in the 40-60% range^[48] and is slightly more bioavailable than Magnesium Sulfate,^[49] with the higher range being those lower in oxalate content.^[48]

In regards to the diet, leafy green vegetables appear to be better sources of Magnesium when considering the percentage absorption (with no regard to overall Magnesium content) as oxalates impair Magnesium absorption to a less apparent degree than do Phytates. A mixed diet appears to have 20-30% bioavailability, which may be increased if Magnesium sources favor vegetables rather than grains

In immune cells, where Magnesium appears to act as a secondary messenger, molecule^[50] intracellular accumulation may be mediated by a novel MagT1 receptor.^[51] This MagT1 receptor might be regulated in a similar manner to TRPM6/7 in regards to Magnesium levels, as evidenced by rumen epithelial cells.^[52]

After daily consumption of 500mg elemental Magnesium for one month, this one study noted that the hypomagnesia (low blood magnesium) was abolished in the 43% of persons who had low blood magnesium at the start of the study; the same amount of persons became deficient in magnesium again after 4 weeks cessation of the supplement, indicating that full elimination occurs within one month of cessation of supplementation.^[53]

The main neuronal mechanism of Magnesium ions in the brain is that of an inhibitory ion to counteract calcium at NMDA receptors,^[54][55] excitatory receptors involved in long-term learning and excitation; Magnesium exists as an endogenous calcium channel blocker^[56] and is regulatory of calcium metabolism.^[57][58] Low Magnesium levels are associated with neuronal hyperexcitation and random firing, and secondary to higher activation of NMDA receptors more calcium appears to be released.^[59]

At resting membrane potential (when neurons are not directed to fire) magnesium occupies these ion channels and prevents activation of neurons,^[60][61] while activation of neurons intentionally displaces magnesium;^[62] making Magnesium at normal concentrations not necessarily inhibitory but more of a placeholder, although it can exert antagonistic effects when superloaded.^[63][64] Drugs that do not get displaced during neuronal activation, and effectively block activation via NMDA, include Memantine^[60] and Ketamine.^[65]

Acute regulation of Magnesium is highly regulated both by sets of ionic pumps on neurons^[66] and the choroid plexus, which acts in concert with the blood brain barrier to establish a constant concentration of Magensium.^[66][67][68] Decreases in cerebral Magnesium stores are only seen over prolonged periods of inadequate Magnesium ingestion.^[69]

Magnesium is critical to preserving neuronal functon during periods of downtime, when the neuron is not firing. A deficiency of Magnesium in the brain (which tends to only occur during chronic deprivation of dietary magnesium) makes cells have more activation during periods where they are not intentionally activated

Excitotoxicity, or toxic effects in a neuron that are secondary to excessive excitation (activation) of the neuron, are mediated via calcium signalling via calcium-dependent enzymes when there is excessive calcium entry into a cell;^[60][70] the influx of which Magnesium may block to a greater degree when not deficient.^[71]

There is some evidence that preservation of Magnesium after neural injury (where Magnesium can decline) can preserve neuronal function by attenuating toxicity indirectly by excessive NDMA firing; although this study used injections and may not be applicable to supplementatal Magnesium.^[72]

Chronic activation of NMDA receptors, or excessive activation acutely, exerts neurotoxic effects via calcium-dependent mechanisms. Magnesium attenuates this toxicity mostly during periods when the neuron is not intentionally fired, and these toxic results do not extend to calcium supplement per se due to its extensive regulation like Magnesium

At least one study, elaborated more in the Learning subsection, has indicated that sufficient and supraphysiological Magnesium levels in the brain (the latter being achieved orally in rats with Magnesium L-Threonate) can enhance excitatory function during periods of excitation, due to an upregulation of excitatory receptors during this downtime.^[62]

Possible hormetic benefits to excitation when the down-time from neuronal firing is maintained

Magnesium concentration in the brain is higher than that of serum, with a homeostatic balance achieved at the blood-brain barrier maintained by active transport; at least one study that elevated serum Magnesium with intravenous Magnesium Sulfate failed to find such alterations in neural concentrations of Magnesium,^[73] with increases of 100-300% in serum correlating roughly 10-19%.^[74] This has been noted elsewhere, where supraphysiological concentrations of Magnesium increased neural stores merely 11-18%.^[75]

One study assessing Magnesium L-Threonate (MgT), said to increase neural concentrations of Magnesium to a greater degree than other forms (all forms standardized to 50mg Magnesium), noted that while Magnesium Gluconate and Magnesium Citrate were able to normalize Magnesium levels (which appeared to decline at day 24 in control mice, as measuring cerebrospinal fluid reduced Magnesium inherently), Magnesium L-Threonate caused elevations at day 12 and 24; the degree of increase was slightly less than 10%, but corrected to approximately 15% when taking measurement into consideration.^[62] Only one other study currently has assessed Magnesium L-Threonate but did not measure cerebrospinal concentrations,^[76] so currently higher doses of MgT causing higher levels of neural Magnesium stores has not yet been evaluated.

There appears to be a rate limit that occurs in the 11-18% range with magnesium superloading on the brain, and this can be mimicked with low dose supplementation of Magnesium L-Threonate (50mg Magnesium, 604mg total). Magnesium L-Threonate has not yet been tested in humans, and no dose-dependency study has been conducted

Magnesium deficiency may be more common in children with diagnosed ADHD, with one study of 116 children noting a deficiency rate of 95%^[77] and another study noting a reduced Magnesium content in the saliva of children with ADHD relative to control children, where control saliva had a concentration of 0.70+/-0.2mmol/L and ADHD had a concentration of 0.23+/-0.06mmol/L.^[78] At least one study dividing children into subgroups of ADD and ADHD (with the difference being the presence of hyperactivity) noted that Magnesium deficiency only occurred in the hyperactive subgroup and not the inattentive group or control.^[79]

Subsequently, an intervention of 50 diagnosed children (7-12yrs) with ADHD and dietary magnesium deficiency, there was a significant improvement in hyperactivity (relative to baseline) as assessed by two rating scales in response to daily ingestion of 200mg Magnesium over 6 months.^[80] These benefits may be augmented by fish oil omega 3 fatty acids, as evidenced by one cohort of 810 children followed for 12 weeks that showed benefit to symptoms as assessed by SNAP-IV (a rating scale different from the one in the previous study).^[81]

Currently, there is some evidence for Magnesium being of use to children with ADHD as ADHD may be related to Magnesium deficiency. There is not enough evidence to assess the potency of Magnesium in this regard, but it may have value as adjunct therapy alongside standard drug therapy

One study measuring blood flow velocity in the middle cerebral artery (MCAv) noted that Magnesium supplementation at 4g Magnesium Sulphate was able to act to normalize the reduced blood flow that occurs at high altitudes, but failed to prevent altitude-related mountain sickness.^[82] Intravenous magnesium is associated with some improvements, but they were deemend to not be clinically significant.^[83]

No significant benefit of Magnesium supplementation on mountain sickness is apparent

One study using 50mg/kg elemantal magnesium (604mg/kg Magnesium-L-Threonate) failed to find any noticeable changes to waking locomotion in rats over the course of a month.^[62]

Magnesium appears to have some role in sleep due to sedative-like actions, and being significantly but weakly correlated with the late midpoint of sleep independent of dietary energy composition, where the quartile with least magnesium also had the most delayed sleep midpoint.^[84] This may be more of an effect than a cause, as intentional sleep deprivation (sleeping 80% of normal length) for 4 weeks has been shown to reduce erythrocytic Magnesium levels by 3.5%.^[85]

In a study on 12 healthy elderly persons, effervescent Magnesium (10mmol, working up to 30mmol) over 20 days led to an increase in slow-wave sleep (63.3%) and reduced sleeping cortisol levels, which acted to normalize age-related changes in sleep patterns.^[86] Benefits to sleep have also been found in persons aged 59+/-8 years who consumed less than the EAR for magnesium via their diets (265-350mg^[87]) where 320mg Magnesium Citrate over 7 weeks improved sleep quality and some inflammatory parameters additionally; interestingly, magnesium supplementation did not increase serum magnesium any more than placebo overall, but only when looking at deficient persons.^[88]

Magnesium is associated with depression due to persons with depression having lower erythrocytic Magensium levels than healthy controls (75-77% of control in Major Depression), with some anti-depressants (amytriptiline and sertraline) increasing Magnesium stores in erythrocytes.^[89] However, this correlation is not noted at all times,^[90] and there doesn't appear to be a good relationship between serum Magnesium and depression.^[91][90][92] Additionally, removal of Magnesium from the diet of rats appears to result in anxiety and depressive-like symptoms.^[93]

One review^[94] notes that increased rates of depression in society coincide with dietary reduction of Magnesium, with the beginning phases of wheat processing reducing Magnesium content of breads to 19% of their former (wheat) value and reducing the 450mg average intake in the 19th century to 250mg or less in subsequent centuries.^[94] When looking at the diets of persons suffering from depression, there appears to be an inverse relationship between dietary Magnesium intake and depressive symptoms which, although it was attenuated from 0.70 to 0.86 (Odds ratio) when controlling for both socioeconomic and lifestyle factors, was still statistically significant.^[26]

One hypothesis ^[94] notes that a Magnesium deficiency, causing NDMA receptors to be chronically active, may lead to a form of neuronal injury misdiagnosed as treatment-resistant depression based on the phenotype.

At least one study in elderly diabetic (type II) persons with newly diagnosed depression and low serum magnesium levels (less than 1.8mg/dL) has noted that 450mg Elemental Magnesium (as Magnesium Chloride) daily for 12 weeks duration was equally effective as 50mg imipramine (anti-depressant) for reducing depressive symptoms.^[95]

During stress in animals (induced by immobility) Magnesium appears to be effective in reducing depressive symptoms (assessed by Forced Swim Test).^{[96][97][98][99]}

Mechanistically, an increase of Magnesium from 0.8mM to 1.2mM can reduce amplitude of NMDA receptor currents at resting membrane potential by up to 50% despite not affecting currents during depolarization.^[62] This was hypothesized to be due to Magnesium blocking NMDA at resting potential but being expelled during activation of the neuron.^[100] Chronically (rather than acutely), 1.2mM Magnesium (elevated levels) is associated with an increased amplitude of NMDA currents, suggesting a compensatory increase in NMDA receptors.^[62] This upregulation was seen in rats fed 604mg/kg Magnesium-L-Threonate for a month, where the NB2M subunit was increased 60% (replicated elsewhere at 42%,^[76] affecting the prefrontal cortex and hippocampus but not amygdala), and signalling was claimed to be enhanced by 36% higher BDNF levels (replicated elsewhere at 55% in the prefrontal cortex with no increase in the amygdala)^[76] (BDNF is downstream of CREB activation that was increased 57%, a result of NMDAR activation)^[62] NMDAR signalling^[101] and particularly the NB2M subunit^[102] play roles in synaptic plasticity^[103] and memory function, with genetic overexpression of NB2M being causative of increased associative memory formation in young and old rats.^[104] The NR2A subunit does not appear to be affected.^[76]

As the excitatory post-synaptic currents (EPSCs) of NMDA were enhanced from neurons of orally treated rats (Magnesium-L-Threonate) from 8.8+/-3.1% to 24.1+/-3.6% (273% increase in sensitivity) in response to ifenprodil, an NB2M selective agonist; enhanced sensitivity to neuronal bursts was seen rather than single action potentials.^[62] Increased hippocampal frequency has been noted previously, although this study did not elaborate as much on mechanisms.^[105]

Magnesium may increase NMDA transmission potential, despite not affecting resting potential; a possible hormetic role, with possible synergism for cognitive enhancement with NMDAR agonists (such as D-Aspartic Acid). This was seen with Magnesium L-Threonate, and may apply to superloaded Magnesium

In male rats, Magnesium (L-Threonate) at 604mg/kg daily (50mg/kg elemental Magnesium in addition to 0.15% already in food pellets; deemed the minimum effective dose) over a month was able to increase brain Magnesium levels by 7% relative to baseline, which may have been an increase up to 15% as the in vivo measurement technique reduced magnesium levels.^[62] This dose was associated with an increase in spatial memory (short and long term), memory recall, and working memory (short term only) in aged rats, and spatial memory appeared to be increased in young rats as well although not other parameters; enhancement of learning was abolished in young rats upon cessation of treatment, while it endured up to 12 days in older rats.^[62]

_In vivo_supplementation of Magnesium-L-Threonate has shown efficacy in enhancing memory in young and old rats, with more efficacy in older rats

Migraines, like other conditions, appear to be correlated with a lower Magnesium content in persons who experience Migraines relative to controls.^[106][107]

In a sample of persons with migraines without auras for at least two years duration and 2-5 attacks per month noted that supplementation of 600mg elemental Magnesium (as Magnesium Citrate) daily for 3 months was associated with less severity of Migraines (with frequency reduced in both Magnesium and Placebo), with the Visual Analogue Score (VAS) being decreased from 7.57+/-0.86 to 4.00+/-1.53, indicating almost a 50% reduction in severity.^[108]

In one pilot study, 38 women given 250mg time-release Magnesium prior to their cycles noted significant reduction in general PMS-related symptoms when self-assessed (33.5%) and investigator-assessed (35.1%) and tended to be general rather than reducing specific symptoms significantly; with supplementation lasting on average 27.9 days (from a day previous to the first cycle, with supplementation ceased upon starting their second cycles);^[109] It should be noted that the study used the brand Sincromag which is patented by their grant supported, Zambon Group. However, another study using 200mg Magnesium noted slight benefits to premenopausal symptoms and noted a small but synergistic reduction of anxiety-related symptoms with 50mg Pyridoxine (B6),^[110] which was not seen with 200mg Magnesium in isolation for up to two months of usage.^[111]

Reduced serum magnesium levels (indicative of a deficiency) is related to heart arrythmia and hypertension amongst other ailments,^[29] with chronic intentional Magnesium deprivation in rats able to induce cardiac apoptosis.^[112]

There is a rough correlation between low levels of Magnesium and increased risk of heart disease and related ailments.^[113][114] In those that are deficient in Magnesium, supplemental Magnesium is able to reduce the risk of coronary heart disease and other heart ailments.^[115] The heart healthy effects of Magnesium are not as reliable in those not deficient in this mineral.

Magnesium levels in serum appear to be somewhat predictive of blood pressure complications, even after controlling for the state of obesity.^[116]

One study in rats noted that Magnesium injections (doses much higher than practical with supplementation) was able to attenuate the increase in adrenaline in electrically shocked rats by 92.6%, with subsequent in vitro testing suggesting these high levels acted as calcium channel blockers even during periods of stimulation.^[63]

May interact with adrenaline release in blood vessels, which is reflective of serum concentrations of Magnesium rather than erythrocytic content (the latter being more accurate in assessing 'Magnesium Deficiency')

One study conducted in diabetic adults that failed to find any influence on glucose or lipid metabolism following 360mg Magnesium for 3 months found an association between serum Magnesium levels and the reduction in Diastolic blood pressure, which is distinct from other benefits of Magnesium which may need to be increased in muscular stores.^[117]

In regards to studies on people with normal blood pressure but low magnesium status, one study that normalized a deficient state (from 0.66mM to 0.78mM using 2.5g Magnesium Chloride for 3 months) found reductions in blood pressure by 7.1% (systolic) and 4.7% (diastolic)^[118] while another supplementing 336mg Magnesium (as Lactate) in females with low dietary intake (239+/-79mg) noted decreases in blood pressure but these failed to reach significance.^[119]

In one study that investigated Magnesium deficiency and hypertensive adults with diabetes, the observed reduction in blood pressure following 2.5g Magnesium Chloride solution (450mg elemental magnesium) daily for 4 months was noted to be highly significant at -20.4+/-15.9mmHg systolic and -8.7+/-16.3mmHg diastolic.^[120] Another study using the same dosing parameters in diabetic adults with average blood pressure in the hypertensive range (148.3/86.3) noted reductions of 6.5% and 4.2% respectively, but failed to reach significance.^[121]

In persons who are Magnesium deficient, Magnesium supplementation might reduce blood pressure; the effect size (potency) of this is moderate, with some studies not noting significant reductions

600mg Magnesium pidolate daily for 12 weeks in persons with recently diagnosed hypertension (high blood pressure) in addition to standard intervention, compared against standard intervention with placebo, resulted in significant reduction in systolic (-5.6+/-2.7mmHg) and diastolic (-2.8+/-1.8mmHg) blood pressure when measured over 24 hours;^[122] this may have been associated with a decrease in intracellular calcium and sodium in the Magnesium supplemented group only, which coincided with an increase of serum magnesium from 2.3mg/dL to 2.44mg/dL.^[122] This 24-hour measurement of blood pressure has been measured earlier with 480mg Magnesium (as Oxide), which noted reductions of blood pressure ranging from 2-3.7mmHg systolic and 1.4-1.7mmHg diastolic with more efficacy in persons with higher baseline blood pressure.^[123]

Some studies that note no significant effect on blood pressure as a whole in response to Magnesium supplementation do, however, find significance when only assessing the subgroup with elevated blood pressure; this study noted significant reductions in blood pressure in persons with higher than 140mmHg systolic.^[124]

May reduce blood pressure in persons with hypertension regardless of pre-existing Magnesium status, the degree of blood pressure reduction appears to be quite small

One study using Magnesium at 200mg (confounded with 30mg Zinc) in type II diabetics failed to find reductions in blood pressure, although these reductions were noted when Vitamin C and Vitamin E were added; this may be attributed to the effect of Vitamin C on blood pressure.^[125]

Currently, studies conducted in completely healthy persons with Magnesium supplementation above what is deemed a sufficient diet note no changes in a cohort of healthy young females^[126] and a cohort of Korean adults noting that Magnesium was unable to reduce systolic blood pressure significantly at 300mg elemental Magnesium, with the decrease in diastolic being significant (−2.91+/-8.84mmHg) via t-test but not ANOVA.^[124]

No good evidence to suggest Magnesium reduces blood pressure in persons who have neither hypertension nor poor dietary Magnesium intake/Magnesium deficiency

One intervention in healthy persons (aged 41.5 on average) given Magnesium Chloride at 500mg acutely alongside a meal (bread roll with butter) significantly reduced the post-meal spike in triglycerides and non-esterified fatty acids (NEFA).^[127] This was deemed to be from reducing absorption, as chylomicron-TAG had its peak concentration delayed from 3 hours to 6 hours after the meal and the C_max reduced from 5.8-fold higher than baseline to 3.6-fold; these changes were independent of changes in calcium and cholesterol metabolism, which were similar between groups.^[127] Other studies in animals^[128][129] and humans^[130] have noted increased fecal lipid content following ingestion of Divalent minerals (such as Magnesium and Calcium) which has been credited to their ability to form insoluble salt complexes with fatty acids;^[131][132] the authors of the previous study noted that increased chylomicron clearance could also have been a possibility.^[127]

Long term studies have failed to demonstrate reductions in triglycerides following 450mg elemental magnesium for 4 months in deficient hypertensive adults.^[120]

Currently, the best results on triglycerides may have been secondary to a betterment of glucose metabolism. This study using 2.5g Magnesium Chloride (450mg elemental Magnesium) in Magnesium deficient, insulin resistant adults that noted improved glucose and insulin sensitivity also noted a reduction in triglycerdes over 3 months by 39.3% (2.8+/-2.1mmol/L to 1.7+/-0.6mmol/L) that accompanied a serum increase of Magnesium from 0.61+/-0.08mmol/L to 0.81+/-0.08mmol/L.^[133]

One study using 300mg Elemental Magnesium daily for 12 weeks in otherwise healthy and Magnesium sufficient adults failed to notice any significant alteration of HDL-C, LDL-C, or total cholesterol between Magnesium and placebo.^[124]

One study has noted an increase in HDL-C, which was measured at 0.1+/-0.6mmol/L and conducted with 450mg elemental magnesium in a population of magnesium deficient hypertensive adults with diabetes,^[120] which was also noted in magnesium deficient pre-diabetic adults as well from 0.9+/-0.4mmol/L to 1.1mmol/L (22% increase).^[133]

One study in healthy persons with hypomagnesia (low blood magnesium levels; 0.7mM or less) given 2.5g Magnesium Chloride daily (as 5% solution) for three months noted a reduction in fasting blood glucose (8%) and insulin (12%) as well as an improvement in insulin sensitivity (32.8%, HOMA-β) that was associated with an increase in average blood Magnesium levels from 0.66+/-0.08 to 0.78+/-0.12mM; this was said to be secondary to a betterment of pancreatic beta-cell function.^[118]

Normalizing a Magnesium deficiency corrects abnormalities and insulin resistance induced by the deficiency

Type I diabetics (insulin-dependent; more commonly genetic or immune-related rather than diet-related) appear to have higher rates of Magnesium deficiency, which can be seen at up to 25%^[134][135] while a correlation exists between lower erythrocyte Magnesium content (more indicative of Magnesium status than serum) and more polyneuropathic symptoms.^[136] In type II diabetics as well, subsamples of persons with more diabetic neuropathy appear to be at even greater risk of Magnesium deficiency (intracellular) relative to diabetics without symptoms of neuropathy; with diabetics (Type I and II) in general being at greater risk than healthy controls.^[31]

One study conducted in insulin-dependent diabetes (Type I) using Magnesium supplementation at a dose of 300mg noted that the disease-related decline in nerve function (diabetic polyneuropathy) appeared to have its rate reduced; while 69% of control had a worsening of neuropathy and 31% stasis, Magnesium supplementation had 12% of its sample worsen and 49% of patients in stasis. The amount of improvement was 8% in placebo and 39% in Magnesium.^[137] These benefits were independent of changes in HbA1c or insulin requirements, but were associated with a small improvement of serum Magnesium (+5.7%) and erythrocyte Magnesium (+17.3%).^[137]

Magnesium supplementation potentially has a role as adjuvant in reducing the negative effects of the diabetic state on nerve health, thus being protective against Diabetic Neuropathy

At least one study measuring oxidation of LDL and vLDL in type I diabetics with low Magnesium failed to find protective anti-oxidative effects of Magnesium on this parameter.^[138]

In a study on overweight and insulin resistant persons with normal Magnesium levels (not deficient), supplementation of Magnesium (as Aspartate-Chloride) for 6 months at the dose of 365mg was able to reduce fasting blood glucose (6.3%) and improved insulin sensitivity as assessed by the Matsuda Index and HOMA, but failed to note reductions in insulin or in postprandial glucose.^[139] This study noted a high dropout rate (52/98) with no differences between groups.^[139] Insulin resistant non-diabetic persons with Magnesium deficiency experience a greater increase in insulin sensitivity following Magnesium supplementation for 3 months after 2.5g Magnesium chloride solution (450mg elemental Magnesium), and this is accompanied by reductions in glucose (13.8%) and insulin (32%) in one study^[133] with another study recording improvements in insulin sensitivity (24%), blood glucose (22.3%), and HbA1c (20.8% reduction).^[121]

In insulin-resistant but not clinically diabetic persons, Magnesium supplementation appears to be associated with improvements in glucose metabolism. The clinical significance (potency) of these effects appears to be variable, with more efficacy in persons who are also Magnesium deficient but working in both scenarios

The aformentioned reduction of blood glucose has failed to be replicated following 450mg Magnesium supplementation in hypertensive and magnesium-deficient adults with Type II Diabetes (insulin resistance), where HbA1c was reduced (13.4 to 8.9%; this 33% decrease was not significant due to a large decrease in placebo).^[120] Lack of influence on glucose metabolism has been noted elsewhere in insulin-requiring type II diabetics in response to 360mg Magnesium for 3 months, where erythrocytic Magnesium levels failed to be increased.^[117]

Another study conducted in Type II diabetics noted that 30 days supplementation of approximately 500mg Magnesium (as oxide) failed to influence serum Magnesium levels while a higher dose (1g daily) was effective in reducing fructosamine levels (-73% of baseline).^[31]

Studies in those diagnosed with Type II diabetes tend to show less promise relative to insulin resistant persons

A nonsignificant reduction in insulin (-2.2μU/mL) has been noted in healthy overweight persons given 500mg Magnesium Citrate for 1 month^[53] and insulin has failed to be influenced by 300mg Elemental Magnesium in persons without pre-diabetes or hypertension and of normal weight over 3 months; this study also failed to find any influence on fasting blood glucose or insulin sensitivity.^[124]

Insufficient evidence to suggest improvements in glucose metabolism to persons who do not have insulin resistance

In athletes, supplementation of Magnesium in the athletes (n=10) relative to athletic controls (n=10) mangesium was associated with a slight increase in serum glucose at rest and during fatigue with no significant differences in insulin;^[140] This study did not state the dose given, only that Magnesium Sulphate was used for 4 weeks.^[140] Another study using Magnesium in atheletes has replicated this increase in serum glucose, where triathletes (highly trained atheltes) given 17mmol Magnesium Orotate daily for 4 weeks prior to testing noted that blood glucose was increased during exercise in both groups but 135% higher in Magnesium-treated, while insulin increased 39% in control yet decreaed 65% from baseline in Magnesium treated.^[141]

Glucose may be increased during exercise with Magnesium supplementation according to two studies in healthy subjects, but the subjects used (Tae kwon do; Triathletes) may make this exclusive to elite athletes

Dietary and serum magnesium and its subsequent deficiency state may be a biomarker for the state of obesity, rather than a contributing factor;^[142] aside from one study in an elderly cohort noting decreased waist circumference and body fat associated with a higher magnesium intake^[143] and one study in youth that did not control for confounds,^[144] most other research notes that while healthy obese persons and healthy lean controls may not have varying Magnesium concentrations that a correlation exists between low magnesium status in already obese persons and a wide range of health disorders such as insulin resistance,^[145] cardiovascular risk factors,^[146] and inflammatory biomarkers.^[147] In general, there is no per se association between magnesium and body fat but reduced magnesium levels correlate with disease states (such as metabolic syndrome^[148]) and those disease states are associated with higher body fat.

Magnesium is correlated with obesity a tad, but may play more of a role as a biomarker rather than a contributing factor towards obesity; appears to be more related to glucose metabolism and cardiovascular health

One study has noted that Magnesium supplementation was able to reduce the AUC of triglycerides in serum when 500mg Magnesium was consumed alongside a fatty meal, which was thought to be due to magnesium forming insoluble complexes with fatty acids and preventing absorption.^[127]

May have the ability to hinder fat absorption

At least one study has noted that menstration-related water weight gain can be slightly attenuated with Magnesium supplementation, but this study only noted it during the second menstral cycle of supplementation.^[111] Not inherntly related to fat mass, but may cause false positive if measuring overall weight.

May attenuate bloating during menstruation

Skeletal Muscle appears to store approximately 35% of the body's total Magnesium stores,^[149] where it can act as an endogenous calcium channel blocker and help regulate muscle contraction.^[150] Severe depletions of Magnesium (in a clinical setting) are known to induce cramping and severe muscular pain.^[151][152] During muscle contraction, cytosolic levels of Magnesium appear to increase in correlation to decreasing pH (an increase in acidity)^[153] turning exponential any lower than pH 6.5; this relationship appears to be causal as it does not exist in a contracting muscle without increases in pH.^[154]

The role of Magnesium in skeletal muscle tissue (contractile muscle) is similar to that in neurons, acting as a placeholder to work against calcium to prevent inappropriate firing

One study in persons with alcoholic liver disease (a condition where muscular strength is reduced^[155] and magnesium deficiency exists^[156]) failed to note any increased muscular stores of Magnesium in response to oral and intravenous magnesium oxide treatment for 6 weeks.^[157]

One study in otherwise healthy women using 212mg Magnesium (as Oxide) daily for 14 weeks noted that supplementation was sufficient to restore the relative Magnesium deficiency that these women had, but restoring this deficiency did not significantly improve anaerobic or aerobic physical performance.^[158]

However, one study in Triathletes given 17mmol Magnesium (as Orotate) daily for a period of 4 weeks prior to testing (simulated Triathalon testing) noted that there was a significant increase in blood glucose, where the exercise-induced spike in glucose was 135.6% the level of placebo, a decrease in blood proton level (90% higher than baseline with Magnesium, rather than 98% with placebo), and improved blood oxygenation as indicated by less venous CO2 (66% in Magnesium relative to baseline, while it was 74% in placebo) and higher venous O2 levels with Magnesium (208% of baseline with Magnesium, rather than 126% with placebo).^[141] These biomarkers were paired with improved times on swimming 500m (88% of placebo's time), biking 20km (98% of placebo), and running 5km (92.6% of placebo), although only swimming time was statistically significant.^[141]

A single study suggests remarkable effects from high dose Magnesium supplement and appears to be structured well, but it has not been replicated; studies in sedentary or lightly active persons have failed to replicated the effects seen in these Marathon runners

Magnesium is thought to be related to muscle cramping mainly due to correlations between a higher rate of muscle cramping coinciding with reduced serum magnesium levels which applies to pregnant women^[159][160] and some persons experiencing night cramps in the calf muscle.^[161] Additionally, severe hypomagnesia (low serum magnesium) has been noted to be associated with severe muscle cramping^[151] and muscle pain.^[152]

That being said, in a relatively broad Cochrane meta-analysis it was found that Magnesium (any form in any patient) was not able to reduce cramps in a clinically relevant manner; bridging statistical significance and insignificant results.^[162]

In general, Magnesium supplementation for the purpose of reducing leg cramps has mixed evidence; even the evidence suggesting it is useful is relatively low powered and likely not clinically relevant

Magnesium supplementation is investigated for pregnancy related cramping in part due to the connection between Magnesium and cramps in general, but also since there appears to be a decline in Magnesium levels in the serum of the mother during pregnancy which correlates with the appearance of cramps.^[159][160]

One study in pregnant women given 360mg elemental Magnesium daily (as a mixture of Magnesium Citrate and Lactate) noted that, when powered to detect a 50% reduction in leg cramps, that Magnesium intervention was unable to cause this degree of reduction when assessing mean number of days leg cramps were present and average subjective intensity.^[163] This does was based on recommendations of Magnesium for pregnant women (Scandinavian).^[163] A subsequent study (assessing how many participants had a 50% reduction in symptoms) noted that Magnesium benefitted 86% of persons while placebo benefitted 60.5% in regards to cramp frequency and benefitted 69.8% of persons while placebo benefitted 48.8% of persons in regards to cramp intensity; these differences were deemed significant;^[164] this study was not included in the aforementioned Cochrane review.^[162]

Oddly, one study lasting 3 weeks noted improvements in both placebo and the Magnesium group and statistically greater benefits in Magnesium but did not note any improvements in serum Magnesium levels.^[165]

Mixed evidence for Pregnancy-related cramping. It appears to be more beneficial than placebo (which is, in and of itself, beneficial to leg cramps) but the degree it is better than placebo is sometimes insignificant and sometimes clinically relevant

A geriatric study investigating rest cramps (noctural cramping) in persons with 8 or more cramps per month noted that intravenous Magnesium at 20mmol (5g) Magnesium sulfate failed to find differences in frequency, pain, and duration of cramps relative to placebo when both groups were compared to baseline; specifically, Magnesium had a reduction in cramp frequency of 26.8% but placebo also experienced a reduction of 21.3%.^[161] Another study using 900mg oral Magnesium Citrate also failed to find benefit to nocturnal leg cramps in suffers.^[166]

One study has found limited benefit to leg cramps in sufferers of nocturnal cramping, where the amount of subjects reporting significant improvements in leg cramping was 78% with Magnesium (300mg Elemental as Citrate) and 56% with placebo; the actual frequency of cramps neared but failed to be statistically significant.^[167]

Same motifs appear to be carried over into noctural cramps. There appears to be benefit to both placebo and Magnesium Intervention, with the degree that Magnesium is better than placebo being small enough to many times be deemed statistically insignificant

In one study where martial artists took 10mg/kg Magnesium Sulfate 5 times a week for 4 weeks (during training) noted that the increase in testosterone resulting from a fatigue test was increased from 104.7% to 108.7% in control and increased from 118% to 117% in Magnesium with all differences between groups due to differences at baseline and the differences in free testosterone were also insignificantly different between the two tested groups but with the supplemented group having higher baseline Testosterone.^[168] A nonsignificant trend to increase testosterone and free testosterone was seen in all groups when comparing resting values of baseline and week 4.^[168]

Has the possibility to either increase or normalize testosterone levels, but the evidence on Magnesium and testosterone is minimal. When increases in testosterone are seen, they are minimal

At least one study has noted that supplementation of Magnesium (10mg/kg bodyweight) was associated with a lesser reduction of thyroid hormones (free T3, total T3 and T4) that occurs during exercise.^[169] This study, duplicated in Pubmed,^[170] notes that the form of supplementation was Magnesium Sulfate.

At 10mg/kg bodyweight in sportsmen, Magnesium appears to acutely raise cortisol (statistically insignificant) and after 4 weeks of supplementation this increase appeared at rest; again statistically insignificant (with a magnitude of 2.8%).^[170]

ACTH levels, at 10mg/kg Magnesium (as Sulfate) do not appear to be significantly influenced during exercise or at rest.^[170]

One study using 500mg elemental Magnesium (as Citrate) daily in overweight adults for a month noted that, in regards to genomic signalling involved in inflammation, that there were no highly significant patterns noted aside from an increase in IL-6 (+0.23pg/mL after Magnesium, −0.37pg/mL after placebo).^[53]

A cohort study of 61,433 women (40-75yrs) was conducted on women without cancer for 3 years prior to the study, in which they were followed for 14.8 years; after controlling for confounds (BMI, education level, caloric intake, and nutrients that are known to interact with colon cancer such as folic acid), it was concluded that women in the highest quintile of Magnesium intake (greater than 255mg daily) relative to the lowest quintile (less than 209mg daily) had a significantly reduced risk of colorectal cancer, with an RR of 0.59 (CI: 0.40-0.87); this reduced risk applied to both colon and rectal cancer.^[171] A later study taking information from the Women's Health Study (38,345 women) and developing quintiles on Magnesium intake from food frequency questionnaires noted that the highest quartile of intake (greater than 392mg) relative to the lowest quartile (lesser than 279mg) noted that this reduced risk was lowered to 0.97, but this study did not control for anything (and noted folic acid intake was higher, which is associated with colorectal cancer)^[172] and elsewhere it has been noted that every dietary increase of 100mg Magnesium from food sources was associated with 13% less risk of colorectal adenocarcinomas (OR 0.87; 95% CI 0.75-1.00) and 12% reduced risk of colorectal cancer (RR 0.88; 95% CI 0.81-0.97) with a case-control study conducted alongside the meta-analysis failing to find a protective effect in young non-obese persons.^[173]

There appears to be an association between higher dietary magnesium and lower colorectal cancer risk. This protective effect is linked to foods containing magnesium rather than supplements (which has not yet been investigated)

One study has noted that 50mg/kg bodyweight oral Magnesium coadministered with a subtoxic dose of the heavy metal Cadmium (30mg/kg) was able to normalize changes in oxidative biomarkers (SOD, MDA, O2) when administered one hour prior; pro-oxidative effects followed Cadmium in isolation.^[174] These effects have been noted previously in renal tissue,^[175] and are thought to be through Magnesium modulating Cadmium deposition in tissues in a dose-dependent manner,^[176] and may a trait of bivalent minerals as they apply to Zinc as well.^[177]

One human intervention in young males noted that 30 days of supplementation of Magnesium at 365mg (as Carbonate and Oxide), despite not influencing circulating levels of Magnesium, was able to suppress intact Parathyroid Hormone (iPTH) in serum up to 24%.^[178]

Low magnesium levels in serum^[179] and perhaps a low magnesium:calcium ratio^[180] are associated with an increased risk of periodontal diseases and lesser tooth integrity.

One intervention in otherwise healthy and magnesium sufficient young adult females that took Magnesium supplementation in addition to a plentiful diet failed to find any influence of Magnesium on bone metabolism, despite increasing erythrocyte Magnesium content by 5%.^[126]

In 20 postmenopausal women without history of bone disease aside from osteoporosis given 1830mg Magnesium Citrate daily for one month noted that, in women without magnesium deficiency but with osteoporosis, that Magnesium supplementation failed to alter serum Magnesium or ions yet resulted in favorable changes in a few blood biomarkers indicative of reduced bone turnover (43.7% increase in osteocalcin, reduction in Parathyroid hormone).^[181] This study did not note any correlations with Magnesium and the parameters, however, and merely noted that the Magnesium group experienced the changes.^[181]

One study in young girls (8-14) who were selected due to having a low dietary Magnesium intake (220mg or less daily) noted increased bone mineral content in the hip and a trend to increase lumbar spine density (although it was deemedn statistically insignificant) after one year of therapy in response to 300mg Magnesium as Oxide.^[182]

At least one intervention has noted that in obese women with normal blood pressure but deficient in Magnesium noted that Magnesium supplementation at 450mg Magnesium Chloride was able to normalize Alanine aminotransferase (ALT) levels and trended to normalize C-Reactive protein (nonsignificant).^[183]

One study using Magnesium Orotate (3g daily) over the course of 90 days failed to significantly influence male fertility or any seminal parameter in infertile men, although it led to a significant increase in magnesium concent of ejaculate.^[184]

One open-label study of 532mg Magnesium daily over the course of three months in a small group of persons (19) with moderate to severe tinnitus noted that Magnesium supplementation reduced the perceived handicap of tinnitus and some perceptions of tinnitus itself, despite not altering perception of frequency external to the ear.^[185]

In persons with mild to moderate asthma (diagnosed via NHLBI guidlines^[186]) 340mg of Magnesium (Citrate) daily for 6.5 months was associated with a significant decline in subjective measures of how much asthma impeded lifestyle (assessed by AQLQ and ACQ surveys) and the average dose of methacholine required to reduce airway function was increased, indicating resiliance in the Magnesium group.^[187] Interestingly, this study did not note any Magnesium deficiency state and no differences in dietary magnesium or mangesium retention between placebo and supplemental groups.^[187] Positive results have also been found in children with asthma, where 300mg Magnesium daily for 2 months was associated with more bronchial resiliance (similar methacholine test) and reported less salbutamol use (asthmatic medication) during the trial,^[188] which has been noted elsewhere with 200-290mg Magnesium via Citrate with once daily dosing in youth.^[189]

Contrary to the above studies, at least one study noted that 450mg Magnesium supplementation over 16 weeks failed to show benefit to a sample of 300 persons who were using at least one dose of inhaled corticosteroids daily,^[190] and one study using 400mg Magnesium as a supplement to a Magnesium deficient diet noted improvements in subjective symptoms yet failed to find empirical improvements in forced expiratory volume.^[191]

Some benefit appears to exist for asthmatic persons who either do not use medication or only use medication in a reactive manner, but the only study to investigate Magnesium alongside corticosteroid usage noted no effect. There appears to be a reliable but small effect size that benefits asthma and may reduce reactive usage of medication, but would be redundant alongside daily anti-asthmatic medication

One study noted that supplemental Potassium-Magnesium Citrate was able to increase the pH of the urine and increase urinary Magnesium levels, both of which act to reduce the formation of calcium-dependent kidney stones.^[192] This study, however, failed to note any reduction in the formation of calcium oxalate salts whereas the formation of other salts (urate, brushate, octacalcium phosphate) appeared to be reduced correlated to pH changes.^[192]

Cisplatin-induced nephrotoxicity tends to deplete Magnesium levels in the kidneys due to interfering with tubular resorption^[193] which can exacerbate damage;^[194][195] due to this, Magnesium is sometimes recommended to oncotherapy patients recieving cisplatin due to possibly attenuate deficiencies.^[196] That being said, at least one animal study in cisplatin-induced nephropathy noted that Magnesium in oral doses of 20, 80, or 200mg/kg as Magnesium Sulfate failed to exert protective effects on the kidneys; the lowest dose group appeared to exacerbate damage.^[197]

Magnesium Oxide (MgO) typically has lower bioavailability in the body than several other forms,^{[198][199][200]} but can be increased to 10% with the introduction of effervescent tablets.^[201][198] However, it contains more elemental magnesium by weight than most other magnesium salts, so may not actually be a bad source.^[200] Due to the low intestinal bioavailability, this form of Magnesium tends to be used for laxative purposes or is otherwise used as filler due to the low molecular weight of magnesium oxide.

Magnesium oxide has lower absorption than most magnesium salts, but more elemental magnesium. It may not be a bad choice for increasing magnesium levels, but its low absorption can cause gastrintestinal upset and a strong laxative effect. Note that Magnesium Oxide is sometimes paired with Calcium supplement to mitigate the pro-constipative effects of Calcium

Magnesium Hydroxide (MgOH₂) is Milk of Magnesia and commonly used for laxatative purposes.^[202] It may possess antacid effects, but is not suited for nutritional supplementation.

The most commonly used form of Magnesium supplementation, due to its high water solubility and possible usage in liquids. Magnesium bound to Citrate appears to have a higher bioavailability at around 25-30%, probably due to its increased water solubility relative to oxide chelations (as it is hypothesized that small molecular weight acids hold this potential).^[203][204] Magnesium bound to tartaric acid (Magnesium-L-Tartrate), and likely Magnesium-L-malate, have similar effects and properties.

When looking at rat studies, citrate also appears to be largely bioavailable but Magnesium Gluconate showed highest bioavailability.^[205][206] These results, however, should be taken with a grain of salt as the rats were magnesium deficient which may increase bioavailability independent of the chelation.^[207]

Three-fold higher bioavailability relative to oxide, although still a relatively small absorption percentage. Tends to be the most common form of supplemental Magnesium due to low costs

Magnesium bound to amino acids (Magnesium L-Aspartate) show increased bioavailability relative to Oxide^[208] but tend to be lesser than Citrate.^[203] One exception is Magnesium Monoaspartate, which has been found to have bioavailability of 42% relative to citrate's 30%.^[209]

Magnesium Diglycinate has inceased bioavailability relative to Oxide, and is absorbed in different areas of the gut than traditional magnesium supplementation.^[210]

Magnesium Orotate (Orotic acid) appears to have favorable kinetics when in systemic circulation^[211] and a large safety profile^[212], but gastrointestinal uptake rate is not known.

Magnesium L-Threonate has begun to be looked into for specifically increasing brain magnesium levels and learning.^[62][76] Unpublished data from some of the aforementioned researchers suggest that Magnesium L-Threonate and Magnesium Gluconate dissolved in milk have higher bioavailabilities than Citrate, Glycinate, Oxalate, and Gluconate by itself.^[62][213]

ZMA is a blend of Zinc, Magnesium (as L-Asparate), and Vitamin B6; it is falsely deemed a testosterone booster. A few studies appear to be conducted on ZMA formulations themselves, which fail to find benefits to performance^[214] or hormonal status.^[214][215]

Possible uses of ZMA include an economical means to get both Zinc and Magnesium supplementation, and the Vitamin B6 content tends to be in the dosage range where synergistic benefit to anxiolysis in PMS.^[110]

A cheap way to get both minerals via supplementation, but nothing inherently magical about the combination

Magnesium and Calcium are commonly supplemented alongside each other due to their interactions in vivo regarding bone metabolism, and also possibly since Magnesium Oxide (a laxatative compound) can attenuate possible pro-constipative side-effects of calcium supplementation.

When investigating the absorption rates of a supplement containing both Calcium and Magnesium, the absorption of calcium appeared to be reduced by 23.5% when coingested with Magnesium when Calcium and Magnesium are ingested in doses of 15mg and 250mg; respectively.^[216] Another study that was not suited to answer bioavailability data noted, however, that consumption of 500mg Calcium alongside 250mg Magnesium was able to raise serum calcium levels 3.1%.^[217]

Vitamin D is currently the only Essential Vitamin or Mineral which appears to have deficiency rates at a similar level to Magnesium, if not greater. The metabolism of Vitamin D inherently is linked to Magnesium.

Magnesium levels in the brain can be negatively regulated by an excess of parathyroid hormone (PTH), where PTH causes release of calcium into the blood (being met with an increase of magnesium to retain homeostasis) possibly being a contributing factor to chronic depletion of magnesium concentration in neural tissue.^[218] As vitamin D reliably suppresses excess PTH,^[219][220] it may exert neural benefits secondary to preservation of Magnesium levels in the brain.

Pyridoxine (vitamin B6) is integrated with Magnesium kinetics in vivo^[221] and can increase intestinal absorption when a dose of over 1g Pyridosine is used.^[222] This is not typically recommended however, due to the proximity to the chronic toxicity levels of B6.^[222][223]

Can increase Magnesium absorption, but at doses of Pyridoxine that may not be advisable; limiting how practical this combination can be

One study in a model of premenopausal syndrome (PMS) noted a slight but synergistic reduction in anxiety related symptoms with 200mg Magnesium and 50mg Vitamin B6, similar to the doses commonly used in ZMA supplements.^[110] A previous study using 200mg Magnesium in isolation and also measuring anxiety in PMS failed to find any interaction between the two.^[111]

A pharmaceutical immunosuppressant called cyclosporin A is known to induce nephrotoxicity, and seems to also be able to deplete magnesium levels.^{[224][225][226]}<a href="#ref-227" id="ref-link-227" class="ref-link popover" data-tooltip="<div><p class="mb-3">Ikari A, et al. <a href="https://www.ncbi.nlm.nih.gov/pubmed/18026717" target="_blank" rel="noopener noreferrer">Do

wn-regulation of TRPM6-mediated magnesium influx by cyclosporin A</a>.</p>Naunyn Schmiedebergs Arch Pharmacol (2008)</div>">^[227] It may act via inhibiting reuptake in the tubules^[228]<a href="#ref-227" id="ref-link-227" class="ref-link popover" data-tooltip="<div><p class="mb-3">Ikari A, et al. <a href="https://www.ncbi.nlm.nih.gov/pubmed/18026717" target="_blank" rel="noopener noreferrer">Do

wn-regulation of TRPM6-mediated magnesium influx by cyclosporin A</a>.</p>Naunyn Schmiedebergs Arch Pharmacol (2008)</div>">^[227] and is usually recommended (by a physician) for magnesium supplementation alongside cyclosporin usage.

A combination of Magnesium and L-Carnitine both at 500mg daily (and the former as Magnesium Oxide) was tested over 12 weeks in persons suffering from Migraines was found to be effective in reducing subjective migraine parameters.^[229]

Inulin, a dietary fiber from chicory root, appears to increase the absorption of Magnesium (in this study, elemental magnesium) by 5.2+/-2.9%.^[45] This also applied to calcium supplementation to a similar degree, and was in response to ingestion of a 5g Inulin supplement containing 2.5g of Inulin (with 2.5g oligofructose).^[45] The mechanisms of increased absorption may be through positively modulating the intestinal TRPM6 and TRPM7 transporters.^[230]

Due to Inulin positively influencing transporters, it may be prudent to ingest Magnesium supplements (if taking) alongside vegetables with an inulin content

At least one study on nicotine dependent psychiatric patients has noted that magnesium administration was able to reduce the amount of cigarettes smoked daily after 28 days, which coincided with an increase of serum Magnesium from 17.2+/-1.2mg/L to 26.1+/-1.6mg/L.^[231] This study was confounded with usage of benzodiazepines, and practical relevance to non-psychiatric patients is not known.

The most common side effect assocaited with Magnesium tends to be diarrhetic effects, which is highest with Magnesium Oxide (due to having the least absorption, and the greatest percentage of oral dose being rectally excreted).

1g of Magnesium Oxide daily is sufficient to induce diarrhea as a reported side effect in 12% of the study group in this study.^[31]

In a rat model, magnesium (chloride) at an intake of up to 2.5% of food intake resulted in no significant toxic effects.^[232]

There has been a single report on supplementation of Magnesium-Orotate causing toxicity symptoms in a young boy suffering from low blood magnesium levels.^[233] The cause of this is not known.