Magnesium

Synonym(s): magnesium bisglycinate, magnesium carbonate, Magnesium citrate, magnesium gluconate, magnesium gluconate, magnesium glycerophosphate, magnesium malate, magnesium oxide

Nutrient group: Minerals & trace elements

Sources and physiological effects

Dietary sources
Due to its wide distribution in the animal and plant kingdom, magnesium is found in various quantities in foodstuffs. However, in the case of normal mixed diets, more than ²/₃ of the absorbed magnesium comes from vegetables and cereals. Magnesium is an essential component of chlorophyll and is abundant in all green vegetables. In addition, wholemeal products, oat flakes, nuts and pulses contain significant amounts of the mineral. Fruits rich in magnesium include berries and bananas. Animal sources such as meat, fish, milk and dairy products contribute to meeting demand. Various mineral and drinking waters are also good sources of magnesium. In the diet, certain nutrients may reduce or increase the bioavailability of the mineral. A high fiber content can be inhibiting, as complex formation occurs. Lactose and probably also other carbohydrates can improve magnesium absorption through bacterial fermentation of the intestinal flora. The magnesium content of food can also be reduced by various preparation and processing methods. Significant losses occur during vegetable preparation by soaking, blanching and cooking in lots of water (if the cooking water is discarded). In cereals processing, significantly higher losses than with other minerals are recorded due to milling.
Physiological effects
Enzymatic activity	As a coenzyme involved in over 300 enzymatic reactions, e.g. protein and nucleic acid synthesis
Energy metabolism	Activator of enzymes in the citrate cycle Oxidative phosphorylation of ATP Activation of cholesterol esterase in fat metabolism
Nervous system and muscles	Maintenance of membrane permeability As a cofactor of the sodium-potassium pump responsible for membrane stabilization Regulation of the excitation system as antagonist of calcium
Hormonal balance	Release of hormones (e.g. insulin) and neurotransmitters (e.g. dopamine, glutamate) Regulation of cellular signal transmission (second messenger)
Cardiovascular system	Regulation of cardiac pump function and rhythm Anti-thrombotic function by reducing platelet aggregation Regulation of vascular muscle tone, vasodilatation

EFSA Health Claims

Health Claims		EFSA Opinion
Magnesium	Contributes to the reduction of fatigue and fatigue Contributes to normal muscle function Contributes to normal mental function
Magnesium	Contributes to electrolyte equilibrium Contributes to a normal energy metabolism Contributes to a normal function of the nervous system Contributes to normal protein synthesis Contributes to the preservation of normal bones Contributes to the maintenance of normal teeth Magnesium has a function in cell division

Recommended intake

D-A-CH recommended nutrient intake (Reference values EFSA and NHI )
	Age	Magnesium (mg /d)
Infants (months)
	0-4	24
	4-12	60
Children (years)
	1-4	80
	4-7	120
	7-10	170
	10-13	240
	13-15	310
Teenagers/adults (years)		Women	Men
	15-19	350	400
	19-25	310	400
	25-51	300	350
	51-65	300	350
	> 65	300	350
Pregnant women	310
Breast-feeding women	390
Increased need	Stress, sports, aluminum exposure, alcohol abuse, renal dysfunction, hyperthyroidism, chronic inflammatory bowel disease, short bowel syndrome, pancreatitis
Special group at risk of deficiency	Competitive sports, hyperthyroidism, type 1 and type 2 diabetes

Recommended intake according to the food fabelling regulations
(=100 % TB marking on label)		375 mg
Safety of the nutrient
UL	Long-term daily intake, at which no negative health effects are to be expected	350 mg/d as supplement (according to EFSA)
NOAEL	Maximum intake, with no observed adverse effect	250 mg/d
Safety	EFSA has looked at the safety of magnesium

Detailed information

Pharmacokinetics and bioavailability of various magnesium compounds

The bioavailability of magnesium, i.e. the actual amount of magnesium absorbed from different compounds, is a much-discussed topic. The pH plays a decisive role in the dissociation of magnesium from its compound into the cation form. The presence of magnesium as an ion is necessary so that it can be actively coupled to a carrier protein or, at higher concentrations, passively absorbed into the mucosa cell.
The solubility of a magnesium compound is determined by its physicochemical properties (pK value as negative decimal logarithm of the dissociation constant) and by the pH at the site of absorption. Magnesium compounds are generally more soluble in the acidic range than in the alkaline environment (1).

Bioavailability determined by pH

The determination of the solubility of 8 different magnesium compounds was the objective of a laboratory test carried out by the German LEFO Institute. It was found that all salts demonstrated the highest solubility at an acidic pH of 5 (Fig. 1). At a pH value of 6 to 7, significant differences between the salts became noticeable, whereas at pH values of 8 to 9, only the citrate, gluconate and glycerophosphate compounds were relatively well bioavailable.
Under physiological conditions, this underpins the importance of the acidic stomach environment for magnesium solubility. If this is not ensured, the ability of individual compounds to dissolve even in a less acidic environment comes into play. In practice, however, the magnesium content of a compound must also be considered: For example, magnesium oxide, which performs worst in an alkaline environment, provides 63% more magnesium ions in an acidic environment than magnesium gluconate, with only 5.8%. Based on these results, it can therefore be assumed that a mixture of several compounds with different solubility profiles and different magnesium contents is advantageous for physiological use (2).

The physiological functions of magnesium

The total amount of magnesium in a healthy adult is 20 – 30 g. Magnesium, like potassium, is a typical intracellular ion found in 60% of bone cells and 35% of skeletal and cardiac muscle cells. In addition to structure-forming properties, magnesium is a cofactor of 300 different enzymes is involved in a wide variety of functions in the body. Among other roles, magnesium regulates the membrane permeability and the ion transport of sodium and potassium between the intra- and extracellular space and thus plays a central role in the regulation of muscle excitation and contraction (3).
The symptoms of magnesium deficiency affect four body areas: the CNS, cardiovascular system, gastrointestinal tract and muscles. A small magnesium deficiency leads to unspecific symptoms such as fatigue, nervousness or loss of appetite. A manifest deficiency can manifest itself in muscle cramps, neuromuscular overexcitation, cardiac arrhythmias, vasospasms, dizziness, numbness and tingling in the hands and in diarrhea alternating with constipation (3).

Stress, endothelial dysfunction and hypertension

Magnesium plays a special role in stress metabolism. High doses of magnesium can positively influence reactions to stress. When magnesium plasma levels are high, the blood-brain barrier is overcome, which triggers central nervous effects (e.g. inhibition of voltage-dependent glutamate receptors). The release of stress hormones can also be reduced by magnesium supplements (2). Chronic stress also leads to magnesium depletion in the cells, which is seen as the cause of endothelial dysfunctions that occur in arteriosclerotic changes (4). Poor magnesium status leads to proinflammatory, prothrombotic and proatherogenic conditions at the endothelial cell level and thus plays an important role in the development of cardiovascular diseases (5). Recent studies have shown a link between reduced serum magnesium levels and increased levels of C-reactive protein (6), a risk factor for cardiovascular disease and biomarkers for inflammatory processes. Oral magnesium supplementation improves the values for C-reactive protein and seems to be a suitable means to interrupt the inflammation cascade (7).
The direct relationship between magnesium status and endothelial dysfunction may also explain the therapeutic success of magnesium substitution in hypertensive patients. The effect is particularly well documented in the case of high blood pressure during pregnancy (8).

Magnesium in heart disease

Magnesium supplementation also has strong cardioprotective effects. In patients with chronic heart failure, arterial elasticity, hemodynamic parameters and performance improved after a 3-month intervention with 800 mg/day of magnesium (9). In patients with coronary artery disease, oral magnesium supplementation at 15 mmol twice daily for 6 months showed a significant increase in magnesium levels combined with an improvement in ventricular function at rest and under stress (10). The use of magnesium in atrial and supraventricular tachyarrhythmias and ventricular tachycardia is also well documented in the scientific literature (2).

Migraine, depression and PMS

Magnesium deficiencies can also play a role in the pathogenesis of migraine attacks due to the membrane-stabilizing effect and the resulting influence on the excitation of the nerves. Migraine patients often have a sub-optimal magnesium status (11) and respond well to supplementation. In clinical studies, magnesium substitution of 600 mg/day reduced both the duration and frequency of migraine attacks (12). Intraneural magnesium deficiencies also appear to be involved in depression. Various studies have found a rapid improvement with 7 days of a thrice daily intake of 125 – 300 mg magnesium (12). Therapeutic magnesium intake is also effective for emotional fluctuations, as can occur in premenstrual syndrome (13) (14).

Magnesium – performance increase in athletes

Sport can deplete the body's magnesium stores, which can affect energy metabolism, oxygen uptake and electrolyte balance (15). In addition, magnesium is essential for muscle metabolism, as neuromuscular coordination and all enzyme reactions in the muscle require the presence of a magnesium ions. A lack of magnesium in athletes is particularly evident in the form of muscle cramps and stiffness as well as accelerated muscular fatigue (2). Athletes show increased erythrocyte and hemoglobin levels after magnesium supplementation, which can positively influence performance (16).
In the case of intracellular acidosis caused by exercise, cell performance is reduced because phosphate absorbs protons in an acidic environment, thereby inhibiting ATP synthesis. The charge changes also impair the function of the structural proteins. This reduces performance in hyper-acidified muscles and increases the risk of injury and microtrauma (17). Deacidification measures can lead to the maintenance and improvement of endurance performance in athletes (18) (19) (20).

Magnesium and proton pump inhibitors

Proton pump inhibitors (PPI) are at the top of the list of most frequently prescribed drugs. The classic indications for PPI are reflux diseases, with and without erosions, and ulcer treatment including eradication of Helicobacter pylori. PPI is now also recommended as a co-medication in therapy with non-steroidal anti-inflammatories (NSAID) and ASA and is increasingly used as a prophylaxis of intestinal erosions and ulcerations. Long-term use leads to disorders of the micronutrient balance, because the desired pH shift in the stomach can reduce the bioavailability of vitamins and minerals (21). The result is a lowered micronutrient status, which in turn can contribute to the development of further diseases (22). The German BfArM and the Austrian Agency for Drug Safety have issued warnings on magnesium. Several epidemiological studies in recent years suggest that long-term treatment with PPI can lead to dose-dependent disorders of bone metabolism and increased osteoporotic fractures (22). In addition, the risk of intestinal and lung infections due to bacterial colonization in the upper gastrointestinal tract seems to increase. Studies have also shown the occurrence of arrhythmias and other cardiological complaints due to the long-term use of PPIs (23).

Reference values

Parameter	Substrate	Reference values	Description
Magnesium in the blood	Serum	0,80-1,05 mmol/l	Determination of magnesium in serum is of limited importance, since 70 % of magnesium is intracellular.
	Whole blood	Women: 1.23 mmol-1.54 mmol/l Men: 1.28 mmol/l-1.6 mmol/l	Magnesium is 70 % erythrocytically bound. Hematocrit-correlated whole blood analysis enables the correct interpretation values.
Magnesium in urine	24-h-urine	3,0-6,0 mmol/24h	Excess magnesium is excreted through the kidneys.
Interpretation
Decreased values		Magnesium deficiency
Increased values		Normally, excess magnesium is excreted through the kidneys. Increases in magnesium therefore occur mainly in kidney diseases or when taking large amounts of magnesium-containing drugs.
Note on the measurement results
Low serum magnesium concentrations indicate a deficiency. Whereas normal values do not exclude a deficiency, since a deficiency may still exist at the cellular level.

Deficiency symptoms

Impact on	Symptoms
General health	Restlessness, anxiety, low stress tolerance
Cardiovascular system	Arrhythmias, extrasystoles, tachycardia Hypertension, circulatory disorders
Musculature	Muscle cramps/calf cramps, muscle twitching numbness, tingling, paresthesia
Nervous system	Depression, mood swings, lack of concentration, migraine headaches, sleep disorders
Blood	Hypocalcemia, hypokalemia
Bone metabolism	Disorder of vitamin D₃-metabolism

Indications

Effect	Indication	Dosage
Physiological effects at a low intake	For an adequate magnesium status	150-300 mg/d
	To ensure adequate magnesium store in case of insufficient dietary intake	300-500 mg/d
	In case of increased needs from exercise, pregnancy or increased stress	300-450 mg/d
	If magnesium excretion is increased by alcohol abuse or medication (ACE inhibitors, ciclosporin A, laxatives, diuretics)	300-450 mg/d
Pharmacological effects at a high intake	Complementary therapy for hypertension, migraine, asthma, dizziness, stomach and intestinal cramps and cardiovascular diseases	500-900 mg/d
Pharmacological effects at a high intake	Competitive sports	300-1000 mg/d

Administration

General mode of administration
When	Magnesium should be taken between meals for optimal absorption
Side effects
Magnesium can have a laxative effect at higher doses. It is therefore better to spread the intake of larger quantities throughout the day.
Contraindications
Severe renal insufficiency, Ca-Mg ammonium phosphate stones

Interactions

Drug interactions
Cardiac glycosides (z.B. Digitoxin)	Magnesium improves potassium utilization, which improves cardiac glycoside tolerance and reduces side effects (arrhythmias).
Thiazides, loop diuretics	Loop diuretics lead to a large loss of magnesium and potassium.
Beta blocker	Magnesium optimizes migraine prophylaxis. Supports the antihypertensive effect.
Calcium channel blocker	Magnesium supports the antihypertensive effect.
Antacids (z.B. PPI)	Interferes with magnesium absorption, which increases the long-term risk of severe magnesium deficiencies.
Isphosphonate (e.g. alendronate, risedronate)	Impairment of magnesium absorption.
Antibiotics (quinolones, tetracyclines)	Impairment of magnesium absorption by complex formation.
Antibiotics (Aminoglykoside)	Nephrotoxicity of aminoglycosides is associated with increased renal magnesium excretion.
Glucocorticoids	Increases renal magnesium excretion which leads to a decrease in magnesium serum levels (Magnesium substitution is recommended).
Estrogen (hormone replacement therapy, oral contraceptives)	Fosters a decrease in magnesium serum levels by storing magnesium in tissue/bone.
Insulin	Magnesium reduces insulin resistance and promotes insulin secretion in type 2 diabetes.
Psychostimulants (methylphenidate)	Magnesium can improve the effect.
Nutrient interactions
Trace elements	Zinc, phosphorus and calcium can impair magnesium absorption. Potassium and magnesium support each other in their effects.
Vitamins	Vitamin B₆is required for the cellular uptake of magnesium. Vitamin D supports the bioavailability of magnesium.

Description and related substances

Description
Mineral nutrients
Related substances
Inorganic compounds (e.g. carbonate, oxide, sulfate) Amino acid bound (e.g. glycinate, taurinate, lysinate) Natural occurrence in combination with calcium (dolomite, sangocorals) Organic compounds (e.g. citrate, gluconate, malate, lactate) Note: The highly soluble organic magnesium compounds (e.g. citrate, gluconate, malate, lactate) are generally more bioavailable than the inorganic compounds (e.g. carbonate, oxide, sulfate). Magnesium orotate is only approved for drugs. All approved substances: magnesium acetate, magnesium ascorbate, magnesium bisglycinate, magnesium carbonate, magnesium chloride, magnesium salts of citric acid, magnesium gluconate, magnesium glycerophosphate, magnesium salts of orthophosphoric acid, magnesium lactate, magnesium L-lysinate, magnesium hydroxide, magnesium malate, magnesium oxide, magnesium L-pidolate, magnesium potassium citrate, magnesium pyruvate, magnesium succinate, magnesium sulphate, magnesium taurate, magnesium acetyl taurate
Magnesium citrate (provides approx. 15 % elemental magnesium) Magnesium oxide (provides approx. 63 % elemental magnesium) Magnesium gluconate (provides approx. 5 % elemental magnesium) Magnesium carbonate (provides approx. 32% elemental magnesium) Magnesium malate (provides approx. 15 % elemental magnesium) Magnesium glycerophosphate (provides approx. 12 % elemental magnesium) Magnesium glycinate (provides approx. 12% elemental magnesium) Okinawa sangocorals (provides about 10% elemental magnesium and 20% calcium)

References

1) Golf, S. 2011. Pharmakologie und Bioverfügbarkeit von Magnesiumverbindungen. Pharmazeutische Zeitung.
2) Kasel, U., Rempfer. N. 2013. PH-abhängiges Lösungsverhalten. Magnesiumverbindungen im Vergleich. Biogena inside Mineralienschau.
3) Niestroj, I. 2000. Praxis der Orthomolekularen Medizin. Physiologische Grundlagen, Therapie mit Mikro-Nährstoffen.
4) Takase, B. et al. 2004. Effect of chronic stress and sleep deprivation on both flowmediated dilation in the brachial artery and the intracellular magnesium level in humans. Clin Cardiol 27(4):223-7.
5) Maier, J. A. et al. 2004. Low magnesium promotes endothelial cell dysfunction: implication for atherosclerosis, inflammation and thrombosis. Biochim Biophys Acta. 1689(1):13-21.
6) Rodriguez-Moran, M., Guerrero-Romero, F. 2007 Serum magnesium and C-reactive protein levels. Arch Dis Child.
7) Almoznino-Sarafian, D. et al: Magnesium and C-reactive protein in heart failure: an anti-inflammatory effect of magnesium administration? Eur J Nutr. 46(4):230-7.
8) Lechner, W. et al. 2001. Reduktion des diastolischen Blutdruckanstiegs in der Schwangerschaft durch Magnesium. J Hyperton. (1):30-4.
9) Fuentes, J. C. et al. 2006. Acute and chronic oral magnesium supplementation: effects on endothelial function, exercise capacity, and quality of life in patients with symptomatic heart failure. Congest Heart Fail. 12(1):9-13.
10) Pokan, R. et al. 2006. Oral magnesium therapy, exercise heart rate, exercise tolerance, and myocardial function in coronary artery disease patients. Br J Sports Med. 40(9):773-8.
11) Assarzadegan, F. et al. 2016. Serum concentration of magnesium as an independent risk factor in migraine attacks. International Clinical Psychopharmacology. 31(5):287-292.
12) Köseoglu, E. et al. 2008. The effects of magnesium prophylaxis in migraine without aura. Magnes Res. 21(2):101-8.
13) Facchinetti, F. et al. 1991. Oral magnesium successfully relieves premenstrual mood changes. Obstet Gynecol. 78(2):177-81.
14) Kia, A. S. et al. 2015. The association between the risk of premenstrual syndrome and vitamin D, calcium, and magnesium status among university students: a case control study. health promotion perspectives health promot perspect. 5(3):225-230.
15) Siegler, J. C. et al. 2008. Pre-exercise alkalosis and acid-base recovery. Int J Sports Med. 29(7):545-51.
16) Cinar, V. et al. 2007. Effects of magnesium supplementation on blood parameters of athletes at rest and after exercise. Biol Trace Elem Res. 115(3):205–12.
17) Worlitschek, M. Praxis des Säure-Basen-Haushalts. Grundlagen und Therapie. 2008.
18) Oöpik, V. et al. 2003. Effects of sodium citrate ingestion before exercise on endurance performance in well trained college runners. Br J Sports Med. 37(6):485–489.
19) König, D. et al. 2009. Effect of a supplement rich in alkaline minerals on acidbase balance in humans. Nutr J. 8:23.
20) Laires, M. J., Monteiro, C. 2008. Exercise, magnesium and immune function. Magnes Res. 21(2):92-6.
21) helm, S. M. et al. 2013. Perils and pitfalls of long-term effects of proton pump inhibitors. Expert Rev Clin Pharmacol. 6(4):443-51.
22) S. et al. 2013. Clinical redictors associated with proton pump inhibitor-induced hypomagnesemia. Am J Ther.
23) El-Charabaty E. et al. 2013. Effects of proton pump inhibitors and electrolyte disturbances on arrhythmias. nt J Gen Med. 6:515-8.

References Interactions
Stargrove, M. B. et al. Herb, Nutrient and Drug Interactions: Clinical Implications and Therapeutic Strategies, 1. Auflage. St. Louis, Missouri: Elsevier Health Sciences, 2008.
Gröber, U. Mikronährstoffe: Metabolic Tuning –Prävention –Therapie, 3. Auflage. Stuttgart: WVG Wissenschaftliche Verlagsgesellschaft Stuttgart, 2011.
Gröber, U. Arzneimittel und Mikronährstoffe: Medikationsorientierte Supplementierung, 3. aktualisierte und erweiterte Auflage. Stuttgart: WVG Wissenschaftliche Verlagsgesellschaft Stuttgart, 2014.