Nutrients That May Assist

Magnesium
Magnesium amino acid chelate (Magnesium bisglycinate)
Taurine
Glutamine
Vitamin C
Ascorbic acid
Calcium
Calcium hydrogen phosphate
Potassium
Potassium phosphate
Acetyl-L-carnitine
Acetyl levocarnitine hydrochloride
Vitamin B6
Pyridoxal 5-phosphate
Vitamin B3
Nicotinamide
Vitamin B2
Riboflavin sodium phosphate
Chromium
Chromium nicotinate
Vitamin B12
Mecobalamin
Selenium
Selenomethionine

Actions

• Antispasmodic
• Neuromuscular support
• Metabolic support
• Cellular energy production

Clinical Applications

• Muscle aches, pains, cramps and spasms
• Healthy serum glucose levels
• General wellbeing
• Migraine prevention
• Female health
• Exercise performance

Clinical Overview

Magnesium is one of the key minerals involved in healthy skeletal, cardiac and smooth muscle contractility; as well as vascular reactivity and ion channel regulation. ^[1] It is also essential for adenosine triphosphate (ATP) production. As such, a deficiency in magnesium may result in a range of symptoms and disorders, affecting, amongst others, the neuromuscular system (Figure 1), but also cellular bioenergetics; impacting the majority of cells in the body. Clinically, a magnesium deficit often manifests as muscular cramps and pain, as well as fatigue. However, numerous other metabolic functions may be supported by adequate magnesium intakes including healthy glucose metabolism, particularly when used in addition to appropriate supportive nutritional factors. ^[2] Magnesium, alongside nutrients such as malic acid, taurine, glutamine and acetyl-L-carnitine, can assist in enhancing muscle health and supporting energy production.

Figure 1: The neuromuscular activity of magnesium.

Background Information

The Many Varied Roles Nutrients Play in the Body

Magnesium is either a structural cofactor or activator of more than 300 metabolic reactions in the body. These processes include protein synthesis, cellular energy production and storage, cell growth and reproduction, DNA and RNA synthesis, and stabilisation of mitochondrial membranes. ^[3]

Magnesium deficiency is not uncommon, with a recent Australian Health Survey finding 72% of 14-18 year old females, and an average of just under 40% of all Australian adults consuming inadequate amounts of magnesium daily. ^[4] In addition, dietary imbalances such as high intakes of fat, calcium, coffee and strong tea can worsen magnesium inadequacy, by either reducing absorption or enhancing elimination. ^[5]

Early signs of magnesium deficiency include fatigue, weakness, loss of appetite and/or nausea and vomiting. ^[6] As magnesium levels decrease, patients may experience muscle contractions and cramps, numbness, tingling, personality changes, abnormal heart rhythms, coronary spasms and seizures. ^[7] Severe deficiency may lead to hypocalcaemia (low serum calcium) and hypokalaemia (low serum potassium). Although dietary intake is a common factor; conditions that may also lead to hypomagnesaemia include poorly-controlled diabetes mellitus; chronic malabsorptive problems (e.g. Crohn’s disease, gluten-sensitive enteropathy, regional enteritis); medication use (e.g. diuretics, antibiotics); alcoholism; and older age (e.g. decreased absorption of magnesium, increased renal excretion). ^[8]

Calcium is the most abundant divalent cation in the body, best known for its role in bone metabolism. However, non-osseous calcium is also essential for a range of additional functions including muscle contraction, nerve conduction, blood clotting, enzyme regulation and membrane permeability. ^[9] A common observation in physiology is the partnership of calcium and magnesium: one could almost say calcium is the ‘on’ switch and magnesium the ‘off’ switch. As such, they work together to facilitate healthy muscle contractions and nerve conduction. Calcium is also involved in cellular bioenergetics; regulating mitochondrial function, movement and viability, with the signalling from calcium ions in the body affecting every aspect of a cell’s life and death. ^[10]

Pyridoxine (vitamin B6) has many important roles, one of which is in the synthesis of carnitine (required for fatty acid oxidation) as well as the synthesis of taurine. ^[11] In its coenzyme form, pyridoxal-5-phosphate (P-5-P) is associated with over 100 enzymes, the majority of which are involved in amino acid metabolism. P-5-P is the main circulating form of vitamin B6 exported from the liver and may be more beneficial in patients where conversion is compromised (e.g. liver disease or zinc or magnesium deficiency). ^{[12] , [13]}

Niacin (vitamin B3) is involved in a number of biological functions, such as energy production, fatty acid synthesis, and regulation of gene expression. Studies show it has neuroprotective properties, and deficiency can cause dementia, as well as diarrhoea and dermatitis, or can even been fatal. ^[14] Low vitamin B3 levels have also been associated with peripheral neuropathy. Inadequate niacin status has been reported in 26.7% of older adults. ^[15]

Riboflavin sodium phosphate (vitamin B2), is converted to two coenzymes; flavin monucleotide (FMN) and flavin adenine dinucleotide (FAD). These essential molecules function as coenzymes for a wide variety of different reactions in intermediary metabolism, particularly in energy production and the protection of cells from oxidation. These metabolic functions include:

• Transporting electrons in the electron transport chain (ETC);
• Fatty acid oxidation;
• Vitamin B6 metabolism;
• Synthesis of an active form of folate, (5-methyl tetrahydrofolate);
• The catabolism of choline;
• Metabolism of neurotransmitters such as dopamine and other amines; and
• The reduction of the oxidised form of glutathione (GSSG) to its active reduced form (GSH). ^[16]

Mecobalamin (methylcobalamin) is one of the active co-enzyme forms of cobalamin (vitamin B12), a water-soluble vitamin sourced primarily from animal products in the diet. Methylcobalamin predominates in the cytoplasm and serves as the intermediate cofactor in the transfer of methyl from methyltetrahydrofolate to methionine in the methionine synthase reaction. ^[17] Cobalamin is required for the metabolism of methylmalonic acid, so that it may enter the Krebs cycle. ^[18] Additionally, vitamin B12 is essential for the normal function of all cells and has several key roles, including cell growth and replication; metabolism of carbohydrates, lipids and proteins; nucleic acid synthesis and red blood cell production. ^[19] Furthermore, vitamin B12 is crucial for the maintenance of nerve cells and myelin, and is a coenzyme for the metabolism of homocysteine. Deficiency symptoms can include lethargy (mostly due to the effect of low vitamin B12 leading to haematological disturbances including macrocytic anaemia, or large red blood cells), neurological disturbances including peripheral neuropathy, and psychological disturbances such as impaired memory, irritability and depression. ^[20]

Magnesium Bioavailability

Magnesium bisglycinate has demonstrated superior bioavailability when compared to other forms of supplemental magnesium, such as magnesium oxide and magnesium citrate (Figure 2), in both cell line studies ^[21],[22] and in patients who have compromised magnesium absorption. ^[23]

Figure 2: Magnesium bisglycinate demonstrates superior bioavailability when compared to other forms of supplemental magnesium. ^[24]

The superior bioavailability of magnesium bisglycinate can be explained by several mechanisms:

1. Reduced anti-nutrient binding

Minerals in their ionic (free) form can create complexes with anti-nutrients (phytates, oxalic acid, tannins, etc.) and polyphenols, inhibiting absorption. Magnesium bisglycinate consists of two glycine molecules bound covalently with magnesium. ^{[25] , [26]} This bond is of sufficient strength to prevent magnesium from dissociating in the upper gastrointestinal tract, therefore preventing it from creating complexes. ^{[27] , [28]}

2. Enhanced passive transport

The majority of magnesium is absorbed through passive, paracellular, transport, which relies on particular claudin proteins. ^[29] These proteins are down-regulated as luminal pH increases. ^{[30] , [31]} Additionally, a more alkaline pH reduces the affinity between magnesium and claudins, further reducing absorption. ^{[32] , [33]} When glycine dissociates from magnesium ready for absorption, it acts as a buffer, modulating pH and improving passive absorption. ^[34]

3. High tolerability

Ionic magnesium is densely charged and has a high hydration energy, resulting in a double hydrate shell. This shell must be removed before magnesium is absorbed through the narrow ion channels, a process called dehydration which can be achieved via paracellular claudins and transient receptor potential melastatin 6 (TRPM6) and 7 (transcellular active transport channels). ^[35] The strong attraction of water to magnesium ions is responsible for the common side effect of diarrhoea in response to magnesium supplementation. In this respect, the benefit of magnesium bisglycinate is two-fold. Firstly, the bond between magnesium and glycine reduces magnesium hydration. ^[36] Secondly, the reduction in pH, caused by glycine’s buffering capacity improves the dehydration, and therefore absorption, of magnesium. This minimises laxation, and improves the tolerability of magnesium bisglycinate, ^{[37] , [38], [39]} an effect that has been demonstrated in human clinical trials. ^{[40] , [41]}

4. Dipeptide transport

A portion of magnesium bisglycinate is absorbed intact into the enterocyte, through the dipeptide channels, ^[42] further improving absorption.

5. Solubility

Solubility improves both passive, paracellular, and active, transcellular, transport. Magnesium bisglycinate is easily soluble in water. In addition, solubility reduces as pH increases, further highlighting the benefit of glycine’s buffering capacity. ^{[43],[44],[45]} While solubility is certainly one factor that impacts absorption, it is important to note that it shouldn’t be conflated with bioavailability. Evidence demonstrating that solubility significantly correlates with bioavailability is lacking. For instance, magnesium citrate, an organic magnesium salt, is over 30,000 times more soluble than the inorganic magnesium salt, magnesium oxide (200 g/L vs 0.006 g/L respectively), however, its bioavailability is nowhere near as superior (Figure 2). ^[46],[47]

Antispasmodic

Deficiency of magnesium is associated with muscular cramps, and magnesium has long been recognised for its important therapeutic applications in enhancing muscle relaxation and relieving spasm. ^[48] Magnesium exerts its muscle-relaxing actions by competing with calcium for binding sites on troponin C, allowing the sarcoplasmic reticulum to actively transport calcium out of the sarcomere, thus inhibiting contraction and allowing relaxation. ^[49] (It also provides the energy to pump calcium through the transporter in its role as part of the magnesium adenosine triphosphate (MgATP) complex). Additionally, magnesium causes muscle relaxation by decreasing the amount of acetylcholine liberated at motor nerve terminals, reducing depolarisation and depressing the excitability of the muscle fibre membrane. ^[50]

Furthermore, magnesium is involved in the regulation of a wide variety of enzymatic reactions and phosphorylation-dependent processes essential for neuronal excitability. Therefore, magnesium is required for the correct muscle contractile signalling via motor neurons.

Neuromuscular Support

Amongst magnesium’s many vital roles is its importance in neuromuscular transmission. Magnesium prevents or controls convulsions by blocking neuromuscular transmission and decreasing the release of acetylcholine at the motor nerve terminals. ^[51] Magnesium deficiency should always be included in the differential diagnosis for a patient who presents with persistent or severe muscle pain. ^[52]

Fibromyalgia (FM) is a particularly painful neuromuscular condition, which is most common among women aged 30 to 50. ^[53] This is a common syndrome characterised by long-term, body-wide pain and tenderness in the joints, muscles, tendons, and other soft tissues. The cause is unknown, but FM has also been linked to fatigue, sleep problems, headaches, and anxiety. ^[54] These same symptoms are also found in patients with low magnesium levels, ^[55] with red blood cell magnesium levels being found to be low in fibromyalgic patients. ^[56] People suffering from this condition tend to wake up with body aches and stiffness; with the combination of magnesium and malic acid found to be effective in the reduction of these symptoms. The proposed mechanism of action is via mitochondrial support, as there is evidence of muscle hypoxia and deficient ATP production in FM.

Magnesium can also provide analgesic effects, due to its N-methyl-D-aspartate (NMDA) receptor blocking action. ^[57] Magnesium deficiency is particularly associated with increased susceptibility to painful migraines due to effects on neuroinflammation, NMDA receptor binding, lutamate and nitric oxide activity as well as serotonin receptor affinity. ^[58] Migraines have been linked to brain excitability, with magnesium able to block the excitatory NMDA glutamate receptors, thereby inactivating them. ^[59] Additionally, muscle cramps, muscle strains (and damage) and muscle tension are all associated with magnesium deficiency. Interestingly, approximately 70% of patients who have tension headaches also exhibit muscular tightness and tenderness. It is therefore no surprise that magnesium supplementation is of great benefit for patients presenting with tension-type headaches ^[60] and migraines. ^[61]

Potassium is another important mineral for the proper function of all cells, tissues, and organs in the human body. It plays a key role in skeletal and smooth muscle contraction, making it important for normal neuromuscular function, and with potassium deficiency resulting in muscular weakness. ^[62]

L-glutamine is the most abundant extracellular amino acid, ^[63] and the most numerous amino acid in the human body. ^[64] L-glutamine is stored primarily in skeletal muscles, and can provide anticatabolic/anabolic properties, which can reduce the breakdown of proteins and muscle mass and support muscle tissue growth, due to a sparing effect on skeletal muscle stores. ^[65] Glutamine levels can also be depleted up to 20% following strenuous exercise – symptoms of which are commonly associated with ‘overtraining syndrome’. Glutamine given immediately before exercise can partially protect against elevated ammonia (due to the breakdown of amino acids from muscle tissue being broken down, which commonly causes muscle fatigue). ^[66] Glutamine supplementation (combined with magnesium) can therefore help reduce the effects of post-exercise muscle aches and pains, and potentially increase performance function and recovery time.

Metabolic Support

Hypomagnesaemia has been strongly related to type 2 diabetes mellitus (T2DM) due to magnesium’s many roles in insulin and glucose metabolism (Figure 4). ^[67] Intracellular magnesium regulates glucokinase (an enzyme which plays an important role in the regulation of carbohydrate metabolism), ATP-sensitive potassium (K _ATP) channels, and L-type calcium channels in pancreatic β-cells, prior to insulin secretion. Insulin receptor autophosphorylation (which plays a key role in glucose homeostasis) is dependent on intracellular magnesium, making the mineral a direct factor in the development of insulin resistance (IR). ^[68] Conversely, insulin is an important regulator of magnesium homeostasis, being as the renal magnesium channel transient receptor’s final urinary magnesium excretion is activated by insulin. Therefore, low magnesium is both a cause and consequence of T2DM and insulin dysregulation, whereby hypomagnesaemia can potentiate IR, and IR reduces serum magnesium concentrations. ^[69]

In addition, chromium plays a significant role in glucose metabolism by potentiating the action of insulin. ^[70] For example, it facilitates insulin signalling by augmenting insulin binding through increasing the number of insulin receptors on cells. Chromium also improves insulin sensitivity by increasing insulin receptor phosphorylation through modulation of kinase activity. ^[71] As such, it has important roles not only in glucose but also lipid metabolism. Signs of chromium deficiency in humans consuming standard diets include elevated serum glucose, insulin, cholesterol and triglycerides, and decreased high density lipoprotein (HDL) cholesterol. ^[72] Supplementation with chromium has demonstrated beneficial effects on people with conditions ranging from mild glucose intolerance to overt T2DM, without side effects. ^[73]

Selenium has insulin-like actions on cells through activation of phosphatidylinositol-3-kinase (PI3K) independent of the insulin receptor. ^[74] PI3K is involved in both the glucose transport and antilipolytic actions of insulin in the body. Additionally, selenium stimulates insulin-signalling pathways via mechanisms distinct from that of insulin. ^[75]

Figure 4: Magnesium’s many roles in insulin sensitivity including regulating the insulin signalling pathway, with hypomagnesaemia affecting many downstream pathways. ^[76]

Furthermore, taurine and glutamine are both important for glucose metabolism. Taurine has been shown to be effective at lowering plasma insulin and glucose by participating in glucose homeostasis via gamma-aminobutyric acid (GABA) and somatostatin signalling. Taurine is a potent GABA agonist, playing a role in the feedback mechanism that inhibits further insulin release. It may also act as an antidiabetic agent via inhibition of K _ATP channels. ^[77] Glutamine plays an important role in pancreatic β-cells, as glutamate is not only a substrate for the enzyme glutamic acid decarboxylase (the enzyme that contributes to GABA synthesis, therefore important for insulin secretion regulation), but is also important for maintaining the integrity of the Islets of Langerhans within the pancreas, ^[78] (the α-cells which produce glucagon).

Vitamin B3 protects pancreatic β-cells from inflammation and improves β-cell function in patients with type 1 diabetes, as well as prevents oxidative damage to the β-cells caused by the immune system (via niacin’s antioxidant effects). ^[79] Like chromium, vitamin B3 is an important component of glucose tolerance factor ^[80] and thus a contributor to metabolic health maintenance.

Figure 5: Magnesium’s effect on the mitochondria. ^[81]

Key: A: Normal mitochondria;
B: Lipopolysaccharide (LPS) treated group with mitochondrial swelling, decreased matric density and distortion of cristae;
C: Low dose magnesium alongside LPS treatment shows only moderate swelling;
D: Higher dose magnesium alongside LPS treatment shows mostly-normal mitochondria with only mild swelling in some.

Cellular Energy Production

Magnesium supports mitochondrial function and aerobic energy production, ^[82] with magnesium depletion resulting in both mitochondrial and the associated energy production dysfunction. ^[83] Magnesium has been shown to maintain mitochondrial structure and function in vivo, thus protecting the mitochondria from damage and therefore increasing energy and decreasing fatigue potential (Figure 5). ^[84] Most of the ATP found within cells is bound to magnesium, forming the MgATP molecule. ^{[85] , [86]} MgATP provides energy for many physiological processes in the cell, therefore any alteration in free cellular magnesium can have significant consequences in both cellular and neuromuscular metabolism. ^[87]

Carnitine assists in the transport of fatty acids across cell membranes (particularly in muscle tissues) for use as an energy source. It is essential for mitochondrial fatty acid oxidation, an important fuel source for the skeletal and cardiac muscle. ^[88] Carnitine transports long-chain acyl groups from fatty acids into the mitochondrial matrix, so they can be broken down via β-oxidation to acetyl coenzyme A (acetyl-CoA), which then enters the Krebs cycle for energy production (Figure 6). The mechanism of this transport is called the ‘carnitine shuttle’. ^[89]

Figure 6: Acetyl-CoA and malic acid are intermediaries in the Krebs cycle. ^[90]

Carnitine has been shown to have particularly beneficial effects on the brain and mental energy, enhancing neuronal metabolism in the mitochondria, ^[91] where a cortical neuron in the brain uses 4.7 billion ATP molecules per second. ^[92] Cellular energy production is vital for brain function, as the brain uses approximately 20% of the ATP produced in the body, and is therefore significantly affected by reduced energy production.

In addition, malic acid is a dicarboxylic acid that plays an important role in the body as an intermediate in the Krebs cycle (Figure 6) to assist with energy production.

Interestingly, vitamin C is also beneficial for cellular energy production, as it is involved in two reactions required for the synthesis of carnitine in the body, ^[93] and can also donate electrons to the ETC for the production of ATP. ^[94] Vitamin C is transported into the mitochondria in its oxidised form as dehydroascorbic acid, where through complex mechanisms it will be reduced back to ascorbate, which is able to quench reactive oxygen species - thus protecting the mitochondria (Figure 7). ^[95]

Figure 7: Vitamin C is transported into the mitochondria in its oxidised form as dehydroascorbic acid (DHA) as part of the electron transport chain. ^[96]

Muscle Aches, Pains, Cramps and Spasms

Magnesium is well known as an effective agent to reduce muscle cramps and spasms. In a double-blind randomised placebo-controlled trial on 73 women, it was found that otherwise healthy pregnant patients suffering with leg cramping had a negative magnesium balance. ^[97] Oral supplementation with three doses of 122 mg magnesium daily (one in the morning, two at night) for three weeks effectively reduced cramping in comparison to controls. ^[98]

Furthermore, non-pregnant volunteers suffering regular leg cramps were recruited into a randomised, double-blind, cross-over placebo-controlled trial. ^[99] They were given a supplement equivalent to 300 mg elemental magnesium and matching placebo for six weeks each. The number of cramps was recorded in cramp diaries, with the results showing fewer leg cramps were experienced when the patients received the active treatment of magnesium compared to placebo (Figure 8). ^[100]

Figure 8: Time course of magnesium supplementation on leg cramps over the 12 week trial period. ^[101]

Carnitine has been shown to reduce musculoskeletal pain and myalgic scores in patients with FM, in a randomised, double-blind, placebo-controlled study of 102 patients. ^[102] Additionally, in an open trial to study the effects of a combination of magnesium and malic acid, 15 diagnosed FM patients took a daily dosage of 300-600 mg elemental magnesium and 1200-2400 mg malic acid for eight weeks. ^[103] Tender point scores decreased significantly following eight weeks of treatment (p<0.001), with significant subjective improvement in myalgia within 48 hours.

Healthy Serum Glucose Levels

Hypomagnesaemia is a prominent feature of T2DM, with many studies having been performed to show the effects of magnesium supplementation on patients with prediabetes and diabetes. For example, a recent systematic review and meta-analysis of 18 randomised controlled trials concluded that magnesium supplementation can improve glucose parameters in people with diabetes, and also improves insulin-sensitivity parameters in those at high risk of T2DM. ^[104] Compared with placebo, magnesium treatment was shown to reduce fasting plasma glucose in those with diabetes, and improve plasma glucose levels after a glucose tolerance test in those at high risk of diabetes.

Additionally, a meta-analysis of 13 cohort studies with over 500,000 participants found a significant decrease in the incidence of diabetes with higher magnesium intake. ^[105] Moreover, a 2017 cohort study of 395 patients with T2DM showed 30.6% of patients suffered from hypomagnesaemia, with both plasma triglyceride (p<0.001) and actual glucose levels (p<0.001) negatively correlated with plasma magnesium concentration. ^[106] The patients in this study who were using metformin, proton pump inhibitors or β-adrenergic receptor agonists displayed even further reduced plasma magnesium levels.

Furthermore, the combination of magnesium with chromium has been shown to decrease IR more effectively than either alone. ^[107] One hundred and twenty subjects with IR were randomly divided to receive either placebo, chromium (160 µg/day), magnesium (200 mg/day) or chromium plus magnesium for three months. The results indicated the combination of chromium with magnesium improved the IR more effectively than either alone, with significant decreases in fasting serum glucose (0.37 mmol/L; p<0.01), fasting insulin (2.91 µIU/mL; p<0.01) and IR index (0.60; p<0.01) displayed in the combination group only. Additionally, significant changes in glucose-transporter-4 (2.9-fold increase; p<0.05) and glycogen-synthase-kinase-3β (2.2-fold decrease; p<0.05) mRNA levels in activated T-lymphocytes were observed with the combination of the two minerals, but not in the other groups.

Migraine Prevention

Deficiency in magnesium is associated with neuronal dysfunction, which is found in those who suffer migraines. ^[108] Magnesium is recommended as a migraine prophylactic for those suffering frequent migraines, ^[109],[110] with the more bioavailable magnesium forms demonstrating increased efficacy compared to other less absorbable forms. ^[111]

Several studies have demonstrated significant benefits in patients with the use of magnesium to prevent headaches and migraines. For example, in a double-blind, placebo-controlled trial in women experiencing menstrual migraine, the use of magnesium pyrrolidone carboxylic acid (360 mg/day) starting on the 15th day of their cycle until the next menses, resulted in a significantly reduced pain score, and a reduction in the number of days with headache. ^[112]

Further, in another double-blind randomised study, adults suffering migraines aged 18 to 65 years were given oral magnesium at a dose of 600 mg daily (as trimagnesium dicitrate) over 12 weeks. ^[113] The results demonstrated a substantial 41.6% decrease in migraine attack frequency, compared to only 15.8% in placebo group. Additionally, after three months of oral magnesium citrate (600 mg/day), patients experiencing migraines without aura showed notable reductions in migraine frequency (p=0.005) and severity (p<0.001), ^[114] further displaying the preventative effect of daily magnesium on the recurrence of debilitating migraines.

Female Health

Another aspect of magnesium is its impact on female health. Through its effects on energy production, neuromuscular function and inflammation, magnesium deficiency can be seen to contribute to premenstrual syndrome (PMS), infertility, and problems associated with pregnancy. Deficiencies of magnesium have been implicated in various reproductive events such as congenital anomalies, pregnancy-induced hypertension, placental abruption, premature rupture of membranes, still births and low birth weight. ^[115]

Pregnancy has been shown to induce a significant (15%) decrease in serum magnesium levels, due primarily to increased renal excretion. Pregnant women with hypomagnesaemia have been found to be 47 times more likely to end in full-blown pre-eclampsia than predicted by their body mass index (BMI). ^[116] In addition, vaginal (but not caesarean) delivery results in significant decreases in magnesium; most probably due to the participation of skeletal and uterine muscles during labour. ^[117] Magnesium supplementation during pregnancy has been shown to improve maternal health and foetal outcome, and intravenous magnesium sulphate has been used as a tocolytic agent, to reduce uterine contractility in preterm labour. ^[118]

Furthermore, vitamin B2 deficiency has also been associated with an increased risk of pre-eclampsia. An observational study found 33.8% of pregnant women at increased risk of developing pre-eclampsia to be consistently deficient. ^[119] The incidence rose towards the end of the pregnancies, from 27.3% at 29-36 weeks gestation, in comparison to 53.3% when more than 36 weeks pregnant. The evidence suggested that the mothers with riboflavin deficiency were 28.8% more likely to develop pre-eclampsia than women who had adequate levels. Additionally, sufficient vitamin B2 levels in mothers has shown to have a protective effect against postpartum depression. ^[120]

Exercise Performance

Magnesium has been studied as an ergogenic aid for athletes, due to its role in energy production, muscle function and maintenance of serum glucose levels. ^[121] Athletes in regular training often manifest intracellular magnesium deficiency in exercising muscles due to accelerated demand and use, inadequate dietary intake, and increased losses through sweat and urine.

Magnesium-deficient athletes may suffer muscle weakness, neuromuscular dysfunction, cramping and spasm, or structural damage to skeletal muscles. ^[122] Low magnesium is associated with decreased physical performance ^[123] and increased incidence of muscle cramps, which improve with magnesium supplementation. ^[124] Acute, intense activity results in short-term increases in both urine and sweat losses of minerals, including magnesium, that continues during recovery in the days after exercise. Supplemental magnesium can improve strength and muscle metabolism ^[125] and is an important mineral regarding exercise performance. ^[126]

For example, in a randomised study of professional volleyball players, 350 mg/day magnesium was shown to reduce lactate production and increase their counter-movement jump. ^[127] Moreover, several studies have identified that athletes with adequate intakes for most micronutrients still remained markedly below the daily recommended requirements for magnesium when solely relying on diet. ^[128]

Additionally, studies have shown that supplemental carnitine has been found to decrease muscle atrophy ^[129] and enhance endurance capacity. ^[130] For example, a study performed with 21 healthy men found two weeks of carnitine supplementation (2000 mg/day) had alleviating effects on lipid peroxidation and muscle damage markers following an acute bout of exercise, as measured by creatine kinase activity. ^[131] Animal studies have revealed that deficiency in carnitine can lead to impaired function of the mitochondrial ETC in oxidative muscle (designed for low-intensity long-lasting contractions) and glycolytic muscle (designed for high-intensity short duration contractions) as well as with atrophy and decreased mitochondrial DNA in oxidative muscle. ^[132]

Both vitamin C ^[133] and glutamine ^[134] have been shown to improve immunity when used by athletes. In a study on 200 elite runners and rowers, glutamine or placebo was provided immediately after, and two hours post-strenuous exercise. The researchers found the percentage of athletes reporting no infections was considerably higher in the glutamine group compared to the placebo group. ^[135] In addition, a review of six trials involving 642 marathon runners, skiers and soldiers on sub-arctic exercises found supplementing regularly with vitamin C significantly reduced the incidence of the common cold. ^[136] Vitamin C is often used by athletes to improve recovery and restore immune responses. ^[137] Additionally, it is beneficial for athletes to enhance wound healing, counteract oxidative stress, changes to adrenal hormones and inflammatory responses. ^[138]

Disclaimer: In the interest of supporting health Practitioners, all safety information provided at the time of publishing (Oct 2025) has been checked against authoritative sources. Please note that not all interactions have been listed.

For further information on specific interactions with health conditions and medications, refer to clinical support on 1800 777 648(AU), 0508 227 744(NZ) or via email, anz_clinicalsupport@metagenics.com, or via Live Chat www.metagenics.com.au, www.metagenics.co.nz

Pregnancy

Insufficient reliable information available; avoid using.

Breastfeeding

Appropriate for use during lactation. The upper tolerable limit of selenium per day during lactation is 400 µg. Consider a patient’s total daily intake from all sources.

Prescribing Tips and Notes

Levothyroxine - Calcium reduces levothyroxine absorption, probably by forming insoluble complexes. Advise patients to take levothyroxine and calcium supplements at least 4 hours apart. Be cautious with this combination.

Antibiotics - Calcium seems to reduce the absorption of quinolone and tetracycline antibiotics. Advise patients to take oral quinolones at least 2 hours before or 4-6 hours after calcium supplements or calcium-fortified foods. Magnesium can form insoluble complexes with quinolone antibiotics and tetracycline antibiotics, decreasing their absorption. Advise patients to take these drugs at least 2 hours before, or 4 to 6 hours after, magnesium supplements.

Contraindications

• Allergies and sensitivities - Avoid in people with known allergies to members of the Asteraceae/Compositae family (Stevia rebaudiana is a member of the Asteraceae/Compositae family) or hypersensitivity to cobalamin and/or cobalt. Theoretically, people who are sensitive to MSG might be sensitive to glutamine. Glutamine is metabolised to glutamate in the body.
• Dolutegravir - Calcium seems to reduce levels of dolutegravir. Do not take this combination.
• Elvitegravir - Calcium seems to reduce levels of dolutegravir. Do not take this combination.
• Levodopa/Carbidopa - Magnesium can reduce the bioavailability of levodopa/carbidopa. Do not take this combination.
• Hepatic Disease - Theoretically, glutamine intake might increase the risk of hepatic encephalopathy in patients with liver disease. Glutamine is metabolised to ammonia. Monitor ammonia levels in patients with liver disease or impaired liver function who are taking glutamine. Advise patients with severe liver disease to avoid glutamine supplements.

Cautions

• Anticoagulants - Magnesium may affect blood coagulation and when taken with anticoagulant medications, may increase the risk of bleeding. The evidence for this so far has only been seen in vitro and with infusions.
• Anticonvulsants - Theoretically, glutamine might antagonise the effects of anticonvulsant medications.
• Antihypertensive Drugs - Theoretically, taurine might increase the risk of hypotension when taken with antihypertensive drugs. Theoretically, vitamin B6 may have additive effects when used with antihypertensive drugs.
• Bleeding Disorders - Theoretically, magnesium might increase the chance of bleeding in patients with existing bleeding disorders.
• Bisphosphonates - Calcium and magnesium can decrease absorption of bisphosphonates.
• Calcium- channel blockers: Magnesium inhibits calcium entry into smooth muscle cells and may therefore theoretically have additive effects with calcium channel blockers, potentially resulting in hypotension and neuromuscular weakness.
• Gallbladder Disease - Nicotinamide might exacerbate gallbladder disease, use with caution.
• Kidney Disease - kidney disease reduces magnesium excretion and increases the risk for hypermagnesemia. Use cautiously in individuals with reduced kidney function and avoid use in those with creatinine clearance <20 mL/min due to an increased risk of hypermagnesemia.
• Kidney Stones - Larger amounts of vitamin C can increase the risk of oxalate kidney stones, especially in those prone to oxalate stone formation. People who have a history of oxalate stones seem to be more sensitive to supplemental vitamin C than non-stone formers. In those with a history of oxalate kidney stones (the most common type of nephrolithiasis), supplemental vitamin C 1 gram per day appears to increase stone risk by 40%. Tell patients prone to kidney stone formation to avoid higher doses of vitamin C.Monosodium Glutamate (MSG)
• Myasthenia Gravis - Intravenous magnesium might worsen neuromuscular weakness and respiratory failure in patients with myasthenia gravis and contribute to a myasthenic crisis. Magnesium competes with calcium on the presynaptic membrane of the neuromuscular junction, inhibiting release of acetylcholine (ACh) and exacerbating the reduction in postsynaptic ACh function seen in myasthenia gravis.
• Neuropathy - Vitamin B6 has been linked with neuropathic symptoms such as tingling, burning or numbness. If symptoms occur, discontinue use and investigate all causes of symptoms, including elevated B6 levels.
• Potassium-sparing Diuretics - Potassium-sparing diuretics decrease excretion of magnesium, possibly increasing magnesium levels.
• Thiazide Diuretics - Taking calcium along with thiazides might increase the risk of hypercalcemia and renal failure. Patients may need to have their serum calcium levels and/or parathyroid function monitored regularly.
• Seizure Disorders - Theoretically excess amounts of glutamine and its metabolite, glutamate, might increase the risk of seizures. Glutamine is metabolized to glutamate and an excess amount of both might lower the seizure threshold. This effect has not been reported in humans. Until more is known, advise people with seizure disorders to use glutamine with caution.
• Warfarin - High-dose vitamin C might reduce the levels and effectiveness of warfarin. Lower doses (< 10 grams daily) may be safe, but the anticoagulation activity of warfarin should be monitored.