Relax Cream

Overview of Relax Cream (Magnesium Chloride / Melatonin / Taurine / Theanine)

 

Dosage Strengths of Relax Cream (Magnesium Chloride / Melatonin / Taurine / Theanine)

Relax Cream (Magnesium Chloride / Melatonin / Taurine / Theanine) 10/0.3/10/5%
Relax Max Cream (Magnesium Chloride / Melatonin / Taurine / Theanine) 10/0.3/25/10%

General Information

Magnesium Chloride

Magnesium, a divalent cation as well as the second most common intracellular cation in the body after potassium, plays a fundamental role in a significant number of enzymatic reactions pertaining to nucleic acid synthesis and energy metabolism.1 Additionally, magnesium is important for glycolysis, oxidative phosphorylation, osteogenesis and bone ossification, and RNA as well as DNA synthesis. Magnesium also is integral in the regulation of the enzyme Na+/K+ ATPase which controls the intracellular as extracellular flow of sodium and potassium in living cells.2 3 Generally, magnesium is typically found in food sources such as cereals and legumes, and is excreted renally from the body.4

Clinically, magnesium is administered in the body as magnesium salts. Magnesium chloride is one of the most common magnesium salts that is used clinically. Highly water-soluble, it comprises a magnesium halide bound to two inorganic chloride ions. 5 Administered parenterally, some clinical indications for the use of magnesium chloride include peritoneal dialysis, total parenteral nutrition (TPN), fluid and electrolyte replacement, and the management of cardiovascular diseases such as congestive heart failure, supraventricular tachycardia, ventricular arrhythmia, and atherosclerosis.678 Magnesium chloride is expressed in breast milk in lactating mothers and is classified by the Food and Drug Administration as a pregnancy category C drug; it should only be administered in pregnant mothers when the benefits of administration outweigh the risks. 9

Melatonin

Melatonin or 5-methoxy-N-acetyltryptamine is a neurohormone used to regulate sleep-wake cycles in patients with sleep disorders. Endogenous melatonin is secreted by the pineal gland in all animals exhibiting circadian or circannual rhythms. Melatonin plays a proven role in maintaining sleep-wake rhythms, and supplementation may help to regulate sleep disturbances that occur with insomnia, jet lag, rotating shift-work, depression, chronic kidney disease, critical care unit stays, and various neurological disabilities. Clinical study of melatonin continues to elucidate the role of melatonin in a variety of neurologic, hormonal, gastrointestinal, and neoplastic disorders The effects of melatonin as a hormone were first noted in 1917, when dark-skinned tadpoles fed a pineal gland extract were noted to develop lighter skin. Melatonin was isolated from the pineal gland in 1958. Commercial melatonin products are primarily synthesized from 5-methoxyindole; rarely, commercial products are derived from animal (bovine) pineal glands. Use of animal based melatonin products is not recommended due to the potential risk of contamination from animal-based infectious prions and viruses, which may cause serious illness. Oral melatonin is included in the Natural Health Products ingredients/monograph database for Health Canada.10 In Europe, melatonin is available by prescription only under the brand name Circadin, which is marketed as monotherapy for the short-term treatment of primary insomnia characterised by poor quality of sleep in patients who are aged 55 or over.11 The American Sleep Disorder Association considers melatonin an experimental drug and does not recommend its use without medical supervision. Melatonin has been classified as an orphan drug by the U.S. Food and Drug Administration (FDA) since 1993 for circadian rhythm sleep disorders in blind patients who have no light perception, a condition often known as non-24-hour sleep-wake disorder (non-24), a condition that occurs when the blind patient cannot synchronize their circadian rhythms to a light-dark cycle. In 2013, an additional orphan drug designation was granted by the FDA for the use of melatonin for the treatment of neonatal hypoxic ischemic encephalopathy. Melatonin is also available over the counter in the U.S., and products are marketed under the Dietary Supplement and Health Education Act of 1994 (DSHEA).

NOTE: In the US, nutraceuticals are marketed under the Dietary Supplement and Health Education Act of 1994 (DSHEA). Consequently, scientific data supporting claimed benefit(s) are not always available for nutraceuticals as they are for traditional pharmaceuticals since nutraceuticals are not regulated as drugs. Consumers should also note that rigid quality control standards are not required for nutraceuticals and substantial variability can occur in both the potency and the purity of these products.

Melatonin or 5-methoxy-N-acetyltryptamine is a neurohormone used to regulate sleep-wake cycles in patients with sleep disorders. Endogenous melatonin is secreted by the pineal gland in all animals exhibiting circadian or circannual rhythms. Melatonin plays a proven role in maintaining sleep-wake rhythms, and supplementation may help to regulate sleep disturbances that occur with insomnia, jet lag, rotating shift-work, depression, chronic kidney disease, critical care unit stays, and various neurological disabilities. Clinical study of melatonin continues to elucidate the role of melatonin in a variety of neurologic, hormonal, gastrointestinal, and neoplastic disorders The effects of melatonin as a hormone were first noted in 1917, when dark-skinned tadpoles fed a pineal gland extract were noted to develop lighter skin. Melatonin was isolated from the pineal gland in 1958. Commercial melatonin products are primarily synthesized from 5-methoxyindole; rarely, commercial products are derived from animal (bovine) pineal glands. Use of animal based melatonin products is not recommended due to the potential risk of contamination from animal-based infectious prions and viruses, which may cause serious illness. Oral melatonin is included in the Natural Health Products ingredients/monograph database for Health Canada.10 In Europe, melatonin is available by prescription only under the brand name Circadin, which is marketed as monotherapy for the short-term treatment of primary insomnia characterised by poor quality of sleep in patients who are aged 55 or over.11 The American Sleep Disorder Association considers melatonin an experimental drug and does not recommend its use without medical supervision. Melatonin has been classified as an orphan drug by the U.S. Food and Drug Administration (FDA) since 1993 for circadian rhythm sleep disorders in blind patients who have no light perception, a condition often known as non-24-hour sleep-wake disorder (non-24), a condition that occurs when the blind patient cannot synchronize their circadian rhythms to a light-dark cycle. In 2013, an additional orphan drug designation was granted by the FDA for the use of melatonin for the treatment of neonatal hypoxic ischemic encephalopathy. Melatonin is also available over the counter in the U.S., and products are marketed under the Dietary Supplement and Health Education Act of 1994 (DSHEA).

NOTE: In the US, nutraceuticals are marketed under the Dietary Supplement and Health Education Act of 1994 (DSHEA). Consequently, scientific data supporting claimed benefit(s) are not always available for nutraceuticals as they are for traditional pharmaceuticals since nutraceuticals are not regulated as drugs. Consumers should also note that rigid quality control standards are not required for nutraceuticals and substantial variability can occur in both the potency and the purity of these products.

Taurine

Studies strongly suggest that taurine supplementation, even when taken short-term; may support better physical function, mitigate the cardiovascular risks that can be present after exercising, and improve issues associated with heart failure.1213

Taurine may accomplish this by reducing inflammation and lowering blood pressure. Some research suggests that taurine may calm the nervous system and even improve the function of the left ventricle of the heart.

Although more studies must be conducted to confirm these benefits; the research already conducted is promising for anyone concerned with cardiac health or suffering from heart disease.1213

A meta-analysis review published in the journal Food & Function found, after analyzing animal and human studies; that taurine has an effective action against the symptoms of metabolic syndrome.14

The study found that Taurine may reduce triglycerides, prevent obesity, improving insulin resistance, regulate glucose metabolism, lower cholesterol, and reduce blood pressure.

Taurine might also help heal the damage from periodontal disease. Patients with chronic periodontitis were observed to determine if taurine could help the healing process.  It was determined that taurine significantly improved the healing process. According to this research, it may have done so by enhancing levels of lipid peroxidation products and antioxidant enzymes.15

A study conducted at the University of Stirling evaluated athletes who ran middle distance races before and after they consumed supplemental taurine. The test-subjects consumed 1,000 milligrams of taurine two hours before running, and they were checked to confirm that there was no effect on the athlete’s respiratory system, heart rate or blood lactate levels. Afterward, 90% of the runners showed faster times. According to this research; there is a 99.3% chance that taurine was responsible for the improved performance of the athletes during the time trial.16

Other studies indicate that taurine may have a powerful mood-boosting effect when combined with caffeine. Scientists have found strong evidence that a combination of taurine and caffeine may improve mood and possibly boost cognitive performance.17

Taurine is one of the most copious amino acids in the human eye; where it exceeds the concentration of any other amino acid. Consequently, recent studies have found that maintaining high levels of taurine is crucial to prevent the degeneration of cells in the eye.18

Mechanism of Action

Magnesium Chloride

Magnesium is essential to practically all body systems. Its mechanism of action varies depending on the organ system involved. In the cardiovascular system, it is important in regulating atrioventricular conduction due to its calcium antagonistic property; it decreases calcium uptake as well as potassium efflux across the myocardial cell membrane. As such, one of the clinical manifestations of hypomagnesemia is arrhythmias such as torsades de pointe and ventricular tachycardia. Some studies have shown that parenteral magnesium chloride administration may be effective in the management of ventricular tachyarrhythmias following digitalis toxicity. There has also been a demonstrated improvement in left ventricular end-diastolic pressure in patients with coronary artery disease following the administration of parenteral magnesium chloride.19202122

Neurologically, magnesium acts to block the release of acetylcholine at the neuromuscular junction, thereby inhibiting peripheral neuromuscular transmission. By depressing the central nervous system, magnesium is also used as an anticonvulsant in the management of seizures and preeclampsia. In the brain, magnesium functions as a voltage dependent antagonist and a noncompetitive inhibitor of the N-methyl-D- aspartic acid (NMDA) receptors and ion channels; hypomagnesemia can result in brain injury due to the activation of the NMDA receptors, opening of the calcium channels, and activation of nuclear factor kappa B (NFKB). Magnesium additionally has a direct impact on the blood-brain barrier; hypomagnesemia has been linked to an increase in endothelial permeability, decreased vasodilatation and an increase in the production of vasoconstrictor substances, and rapid damage to micro vessels, leading to focal hemorrhages and cerebral edema. Conversely, normal levels of blood magnesium increase the proliferation of endothelial cells and assists in restoring the integrity of the blood brain barrier following a brain insult. 1923

With 60% of magnesium within the body found in the bones and 27% in the skeletal muscle, magnesium plays an essential role in maintaining the integrity of the musculoskeletal system. Magnesium promotes bone mineralization through the activation of vitamin D; the metabolism of vitamin D into the active form of 1,25(OH)2D is a magnesium-dependent process. 24 Additionally, magnesium is a cofactor in the synthesis of parathyroid hormone, which is important in calcium absorption. Therefore, magnesium deficiency can result in loss of skeletal muscle (sarcopenia) as well as loss of bone density through the inhibition of vitamin D activation and reduced calcium absorption. Furthermore, with hypomagnesemia, bone protection from cytokine induced stimulation of osteoclast activity is also lost which can also predispose to osteoporosis. 25

Magnesium is also known to play a prominent role in the respiratory system, though its mode of action is not clearly defined. There are several studies that have been conducted which demonstrate that hypomagnesemia is associated with increased incidence of wheezing, airway hyperreactivity, and impaired lung function. Pulmonary function values are decreased in individuals with magnesium deficiency in contrast to their normal counterparts. For patients with acute severe asthma, the use of parenteral magnesium is part of the treatment protocol in an inpatient setting if there is no response to traditional first-line treatment modalities. 26

Melatonin

Melatonin is an endogenous hormone secreted by the pineal gland. The suprachiasmatic nuclei of the hypothalamus controls the numerous physiologic and endocrine circadian rhythms of the body, including that of rest and activity. The circadian clock is set via a process called entrainment, which is a response of the suprachiasmatic nuclei to photic input. Synthesis and secretion of endogenous melatonin is controlled by enzymes secreted by the hypothalamus which are activated by darkness and depressed by environmental light. Exactly how melatonin induces sleep is not clear, but it is probably not through a direct hypnotic effect. In patients with jet lag or circadian rhythm disorders, endogenous melatonin secretion does not correspond to the social or solar sleep-wake cycles imposed by their surroundings, and they experience sleep disruption. Administration of exogenous melatonin appears to re-set the body to the environmental clock and allow patients to normalize physiologic and behavioral sleep patterns. Exogenous melatonin maximally advances delayed rhythms when administered before endogenous melatonin levels begin to increase in the evening hours. In addition to circadian phase-shifting effects, melatonin has been shown to decrease nocturnal core body temperature, which helps to facilitate sleep. To date, pharmacological tolerance to melatonin has not been described.

Melatonin is involved in other physiologic processes besides the sleep-wake cycle. Secretion of melatonin from the pineal gland is highest during the pediatric years and tends to decrease with age. This age-related secretion performs important endocrine functions. It is thought that higher pre-pubertal melatonin levels are responsible for keeping the hypothalamic-pituitary-gonadal axis in quiescence, and that decreasing melatonin levels with age play a role in the onset of adolescence and sexual maturation. Melatonin receptors have been found in all male and female sexually responsive tissues, indicating that melatonin has a significant role in normal reproductive capacity. Exogenous melatonin can suppress the release of gonadotropin releasing hormone and lutenizing hormone, leading to anovulation and changes in steroid responsive tissues, especially in higher doses. Contraceptive activity has been noted when women are given melatonin in combination with norethindrone.

Melatonin also exhibits immunostimulatory and antioxidant actions. In neurodegenerative disease models, melatonin appears to neutralize oxidizing free radicals, specifically by preventing the reduction of antioxidant enzyme activity, and reducing beta-amyloid mediated lipid peroxidation of cell membranes. These actions appear to decrease apoptosis of neuronal cells. Further research is needed to determine if melatonin may preserve function in neurologic diseases where free radicals have been implicated as partially causative of the conditions. In epilepsy, the rise and fall of endogenous melatonin levels may influence seizure activity. Melatonin may play a role in certain cancers, and in some cases, may have antiproliferative effects on some tumors. The actions and role of melatonin in other body processes, such as regulation of the gastrointestinal system, continues to be investigated. Melatonin may also stimulate the activity of natural killer (NK) cells, lymphocytes, and various cytokines. Further study in well-controlled trials should answer further questions regarding melatonin's neurologic, immunologic, and oncostatic activities.

Pharmacokinetics

Magnesium Chloride

Magnesium chloride can be administered either orally or intravenously. When orally ingested, magnesium is absorbed primarily by the small intestine by a passive paracellular mechanism, and secondarily by the large intestine. The intestinal absorption of magnesium is proportional to an individual's magnesium status and not to magnesium intake. With low magnesium levels, there is an increase in intestinal magnesium absorption; the converse is also true when magnesium levels are increased.

Approximately 99% of total body magnesium can be found in bone, muscles and non-muscular soft tissue. Roughly 50–60% of magnesium in the bone resides as surface substituents of the mineral hydroxyapatite, with the remaining magnesium contained in skeletal muscle and soft tissue. The magnesium stored within the bone serves as a large exchangeable pool to buffer acute changes in serum magnesium concentration and maintain extracellular magnesium levels within normal ranges.

Extracellular magnesium comprises about 1% of total body magnesium and is primarily found in serum and red blood cells. Extracellular magnesium can be free/ionized, bound to protein or complexed with anions such as phosphate, bicarbonate and citrate or sulfate. About 30% of extracellular magnesium is bound to albumin. 8 27

Normal serum concentrations range 1.4 to 2 mEq/L in adults, 1.5 to 2 mEq/L in children, and 1.5 to 2.3 mEq/L in neonates and infants. The kidneys play an essential role in maintaining serum magnesium homeostasis; urinary excretion of magnesium is the primary means by serum magnesium is regulated. After urinary filtration of magnesium by the renal glomeruli, about 95% is immediately reabsorbed and the rest excreted in the urine. 60 – 70% of magnesium reabsorption occurs in the thick ascending limb of the loop of Henle, while the rest occurs in the distal tubules. The amount of magnesium reabsorbed by the glomeruli is dependent on serum magnesium levels. 27

Melatonin

Melatonin has been administered orally and intravenously. Commercially available dietary supplement formulations of melatonin include oral and sublingual tablets, orally dissolving tablets, soft chews, capsules, teas, lozenges, and oral spray delivery systems. There have been reports of substantial variability in product purity and melatonin content of available products.

Melatonin administration follows a different pharmacokinetic profile than that of the endogenous hormone. Melatonin crosses the blood-brain barrier, and also traverses the placenta in pregnancy. Some accumulation of melatonin in fat tissue may occur with prolonged daily administration. The primary metabolic pathway occurs via the liver via oxidative metabolism via CYP1A (isoenzymes CYP1A2 and CYP1A1), with minor roles by CYP2C19 and possibly CYP2C9. The principal metabolite is 6-sulphatoxy-melatonin (6-S-MT), which is inactive. Elimination of melatonin is by renal excretion of metabolites, 89% as sulphated and glucoronide conjugates of 6-hydroxymelatonin and 2% is excreted as unchanged, active melatonin. The mean elimination half-life (T1/2) after oral administration of immediate-release melatonin is roughly 45 minutes; with intravenous administration, the half-life is approximately 28 minutes.28 The terminal half-life is 3.5 to 4 hours and the excretion of the primary metabolite is completed within 12 hours following a single oral dose of an extended-release product.11

Affected cytochrome P450 isoenzymes and drug transporters: CYP1A2, CYP1A1

Melatonin is primarily and predominantly metabolized by CYP1A2, with some metabolism by CYP1A1, CYP1B1, and minor contributions by CYP2C9 and CYP2C19. Melatonin may exhibit significant interactions with potent CYP1A2 inhibitors, such as fluvoxamine. Melatonin has been observed to induce CYP3A in vitro at supra-therapeutic concentrations only; the clinical relevance of the finding is unknown.11

Route-Specific Pharmacokinetics:

  • Oral Route:
    • After oral administration, melatonin undergoes significant first-pass hepatic metabolism to 6-sulfaoxymelatonin, producing a melatonin bioavailability averages 15% (range: 9—33%); the time to maximum concentrations (Tmax) averages 50 minutes (range: 15 minutes to 210 minutes). Sublingual and oral spray delivery systems may result in greater melatonin bioavailability due to less first-pass metabolism.28 The presence of food appears to delay the time to maximal absorption and lowers maximal concentration, so bedtime doses should be taken without food.11

Special Populations:

  • Hepatic Impairment:
    • Melatonin is primarily and predominantly metabolized by oxidative hepatic metabolism. Plasma melatonin levels in patients with cirrhosis were significantly increased during daylight hours. Patients had a significantly decreased total excretion of 6-sulfatoxymelatonin (the major, inactive metabolite) compared with controls.11
    • Patients with hepatic impairment are recommended to consult their health care provider prior to melatonin use. Melatonin is primarily metabolized by oxidative hepatic metabolism. Published data demonstrates markedly elevated endogenous melatonin levels during daytime hours due to decreased clearance in patients with hepatic impairment. Therefore, exogenous use of melatonin is not recommended in patients with hepatic impairment.11
  • Renal Impairment:
    • The effect of any stage of renal impairment on melatonin pharmacokinetics has not been sufficiently studied.11 In patients with normal renal function, a minimal amount of melatonin is excreted unchanged in the urine. A clinical study in patients with renal impairment indicated there is no accumulation of melatonin after repeated daily dosing of 2 mg oral doses at bedtime.11
  • Geriatric:
    • Melatonin metabolism is known to decline with age. Across a range of doses, higher exposure (AUC) and maximal concentrations (Cmax) have been reported in older patients compared to younger patients, reflecting the lower metabolism of melatonin in the elderly. The Cmax levels are approximately 500 pg/mL and the AUC 3000 pg x h/mL in younger adults versus a Cmax of approximately 1200 pg/mL and an AUC approximately 5000 pg x h/mL in elderly patients age 55 to 69 years.11
  • Gender Differences:
    •  A 3- to 4-fold increase in maximal concentration (Cmax) is apparent for adult women compared to men. However, no pharmacodynamic differences between males and females were found despite differences in blood levels.11
  • Smoking:
    • Patients who are tobacco smokers have increased melatonin clearance due to the induction of CYP1A2 by tobacco.1128
  • Critically Ill patients:
    • Critically ill patients appear to have altered melatonin absorption and clearance.28

Contraindications/Precautions

Magnesium Chloride

Care must be taken to avoid magnesium toxicity when administering magnesium parenterally. Signs of magnesium toxicity begin to manifest when serum levels exceed 5 mEq/L.  Some signs that may be present which are indicative of magnesium toxicity are hypotension, nausea and vomiting, diarrhea, facial flushing, retention of urine, ileus, respiratory depression and paralysis, loss of deep tendon reflexes, muscle weakness, sinoatrial (SA) or atrioventricular (AV) node blocks , and cardiac arrest. The severity of the signs of magnesium toxicity is proportional to serum magnesium levels; the higher the levels of serum magnesium, the more severe the signs of toxicity. Immediate clinical intervention is necessary once features of magnesium toxicity are detected.329

Individuals with significant myocardial disease such as AV block should avoid receiving parenteral magnesium as much as possible as this could lead to a worsening of this condition. Very close monitoring is essential if parenteral magnesium has to be given in the face of an underlying myocardial condition.

Since the primary mode of magnesium excretion is through the kidneys, any form of renal impairment may result in elevated serum magnesium levels and concomitant magnesium toxicity. Renal functions should ideally be assessed before administration of parenteral magnesium. If there is any evidence of renal compromise as evidenced by a reduced creatinine clearance, serum magnesium levels should be closely monitored during parenteral magnesium administration. Parenteral magnesium should be avoided in individuals with a creatinine clearance of less than 20 mL/minute. 19 30

Magnesium is known to block the release of acetylcholine in the neuromuscular system. Individuals with significant neuromuscular disorders such as myasthenia gravis should not be given parenteral magnesium as this may significantly worsen their condition. 31

In addition to the effect that magnesium could have on the various organ systems, parenteral magnesium may contain additional substances such as aluminum and benzyl alcohol which could be harmful to the body in high enough doses. High levels of aluminum in the body can lead to bone and neurological toxicity; this is especially evident in premature neonates and individuals with decreased renal function. In neonates, high levels of benzyl alcohol can result in gasping syndrome compromising metabolic acidosis, respiratory distress, hypotension, seizures, intracranial hemorrhage, and cardiovascular collapse.32

Melatonin

If melatonin is going to be used, a synthetic-source product is recommended. Consumers of melatonin should be informed that rigid quality control standards, as with other dietary supplements, are not required for melatonin and substantial variability can occur in both the potency and the purity of these products. Impurities have been found in many dietary supplement products. including melatonin.33 Impurities may cause allergic reactions or side effects. While melatonin supplements and pharmaceuticals are now almost exclusively produced synthetically, there may be available melatonin supplements derived from the pineal glands of beef cattle, and these should be avoided by those with bovine protein hypersensitivity. The use of animal-source melatonin products is also not recommended due to a potential risk of exposure to infection (e.g., bovine spongiform encephalopathy, also known as "mad cow disease") or other contamination.3435

Patients who develop angioedema, hypersensitivity or other serious allergic-type events due to melatonin should not be rechallenged with the dietary supplement.1011 Patients with asthma should seek health care professional advice prior to melatonin use, as melatonin may play a role in the expression of asthma symptoms.10

Melatonin may cause drowsiness. Driving or operating machinery, or performing other tasks that require mental alertness should be avoided after ingestion of melatonin; patients should confine their activities to those necessary to prepare for bed. Sedation occurring after melatonin use during waking hours may indicate excessive dosage. Complex behaviors such as "sleep-driving" (i.e., driving while not fully awake after ingestion of a hypnotic) and other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex), with amnesia for the event, have been reported in association with hypnotic use and have been reported in the use of melatonin analogs.36 The use of alcohol and other CNS depressants may increase the risk of such behaviors. Patients should also be advised to avoid ethanol ingestion in combination with melatonin as additive effects may occur. Discontinuation of melatonin should be considered for a patient who reports any complex sleep behavior.

Exogenous melatonin should be used with caution in patients with hepatic disease and should be avoided in patients with severe hepatic impairment. Published data demonstrates markedly elevated endogenous melatonin levels during daytime hours due to decreased clearance in patients with hepatic impairment.11 Patients with hepatic disease should consult their health care provider prior to the use of melatonin.

Melatonin acts on the central nervous system and has sedative effects. Melatonin should be used with caution when patients are being treated for a psychiatric condition or neurological disease, such as a seizure disorder, by a health care professional, particularly if they are on prescription medication for such problems; seizures have been reported as a potential adverse effect of melatonin use.1037 Melatonin is not recommended for people who are on prescribed neurologic, psychotropic, or hypnotic medications without the supervision of a qualified health care professional. The failure of insomnia to remit after 7 to 10 days of self-treatment or within 4 weeks of prescription melatonin use may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated. Exacerbation of insomnia and emergence of cognitive and behavioral abnormalities have been seen with melatonin analogs and other hypnotics in clinical use. In primarily depressed patients, worsening of depression (including suicidal ideation and completed suicides) have been reported in association with the use of various hypnotics. As with other melatonin analogs, the emergence of any new changes in mood, cognition, or behavior in a patient taking melatonin requires further evaluation of the patient.36

Patients who are undergoing treatment for certain conditions should not use melatonin without a health professional's supervision due to the potential role of melatonin in hormonal, cellular, and immunomodulatory functions. For example, melatonin appears to influence insulin, glucose, lipid metabolism and antioxidant capacity and thus melatonin supplements may influence glycemic control in patients with diabetes mellitus. Patients with diabetes should monitor their blood sugar. Patients with various other types of endocrine disease should get approval of their health care provider prior to use. There is also evidence that melatonin influences the regulation of certain types of cancer, and until these effects are more fully understood, patients with breast cancer or other neoplastic disease should only use melatonin with the approval of their cancer specialist. Melatonin is not recommended for use in patients with autoimmune disease or a history of organ transplant due to lack of clinical data and a lack of interaction data with drugs used to treat these conditions.1011

As a hormone, melatonin modulates steroid hormone actions, including those in reproductive and mammary tissues. Melatonin and melatonin analogs have been associated with an effect on reproductive hormones in adults (e.g., decreased testosterone levels and increased prolactin levels). It is not known how chronic or intermittent chronic use of melatonin affects reproductive risk or development in males or females.36 Melatonin appears to have important in the regulation of sperm counts, and also has effects related to ovulation in females. Until more is known about its effects on fertility, male and female patients with infertility and those patients who are trying to conceive should avoid melatonin unless their prescriber recommends supplementation.

Melatonin should be considered to be contraindicated in pregnancy at this time.10 In pregnant women, endogenous melatonin crosses the placenta and enters the fetal circulation, and appears to be responsible for setting circadian rhythm influences in utero. Melatonin receptors in the fetus are widespread in both central and peripheral tissues from the third week of fetal development. The administration of exogenous melatonin could potentially disrupt circadian entrainment and other pineal gland influences.38 Thus, fetal exposure to exogenous melatonin use in the mother may be of concern. Effects in non-clinical animal studies of melatonin were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use; however, the data are limited.11 In animal studies, ramelteon, a melatonin analog, produced evidence of developmental toxicity, including teratogenic effects, in rats at doses much greater than the recommended human dose.36 The potential effects of melatonin on the duration of labor and/or obstetric delivery, for either the mother or the fetus, have not been studied. Melatonin has no established use in labor and delivery.

Melatonin should generally be avoided in women who are breast-feeding their infants.1011 Reports describing the use of melatonin dietary supplements in women who are breast-feeding are lacking; however, it is likely to be excreted in human milk. Endogenous melatonin passes into human milk and concentrations have been measured in the breast-milk of lactating women; the results coincided with the women's daily circadian rhythm of melatonin with undetectable levels during the day and high levels at night.39

Safety and efficacy of melatonin have not been established in pediatric patients under 18 years of age.11 Due to a lack of scientific data and an unknown potential for side effects, melatonin should not be used in infants or very young children. Further study is needed to determine if melatonin may be used safely in pre-pubescent and pubescent pediatric patients. Several small, randomized controlled trials suggest the efficacy and relative safety of short-term supplemental melatonin in treating insomnia in children who have autism spectrum disorders (ASD) and other neurologic disorders; however, experts agree larger studies are needed. 4041 Melatonin and melatonin analogs have been associated with an effect on reproductive hormones in adults (e.g., decreased testosterone levels and increased prolactin levels). It is not known what effect chronic or intermittent chronic use of melatonin would have on the reproductive and gonadal function of pre-pubescent or pubescent pediatric patients.36 Education regarding proper sleep hygiene and establishing developmentally appropriate and consistent bedtime schedules are first-line interventions for any child. Caregivers are encouraged to seek the advice of the health care provider prior to the use of melatonin in children.

Pregnancy

Magnesium Chloride

Parenteral magnesium chloride is an FDA pregnancy category C medication. It is expressed in the breast milk of lactating mother, with its concentration in breast milk roughly double maternal serum magnesium concentrations. Not enough clinical studies have been performed to demonstrate any malformative or fetotoxic effects from the administration of parenteral magnesium chloride to pregnant mothers.  Therefore, parenteral magnesium chloride should only be administered to pregnant mothers when the benefits of its use outweigh any risks that may occur. However, some authorities state that parenteral magnesium chloride should not be administered 2 hours or less before delivery because of the risk of respiratory depression secondary to elevated magnesium levels in the neonate.

Magnesium easily crosses the placenta, passing from mother from fetus; maternal serum magnesium levels generally match levels within the fetus. Even though no controlled studies have been done, there have been reported instances of bony abnormalities and congenital rickets in some neonates after 4 to 13 weeks of parenteral administration to pregnant mothers. It is estimated that the risk of major birth defects is somewhere between 2 to 4% and the risk of miscarriages is 15 to 20%. 42

Melatonin

Melatonin should be considered to be contraindicated in pregnancy at this time.10 In pregnant women, endogenous melatonin crosses the placenta and enters the fetal circulation, and appears to be responsible for setting circadian rhythm influences in utero. Melatonin receptors in the fetus are widespread in both central and peripheral tissues from the third week of fetal development. The administration of exogenous melatonin could potentially disrupt circadian entrainment and other pineal gland influences.38 Thus, fetal exposure to exogenous melatonin use in the mother may be of concern. Effects in non-clinical animal studies of melatonin were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use; however, the data are limited.11 In animal studies, ramelteon, a melatonin analog, produced evidence of developmental toxicity, including teratogenic effects, in rats at doses much greater than the recommended human dose.36 The potential effects of melatonin on the duration of labor and/or obstetric delivery, for either the mother or the fetus, have not been studied. Melatonin has no established use in labor and delivery.

Breast-feeding

Magnesium Chloride

Parenteral magnesium chloride is an FDA pregnancy category C medication. It is expressed in the breast milk of lactating mother, with its concentration in breast milk roughly double maternal serum magnesium concentrations. Not enough clinical studies have been performed to demonstrate any malformative or fetotoxic effects from the administration of parenteral magnesium chloride to pregnant mothers.  Therefore, parenteral magnesium chloride should only be administered to pregnant mothers when the benefits of its use outweigh any risks that may occur. However, some authorities state that parenteral magnesium chloride should not be administered 2 hours or less before delivery because of the risk of respiratory depression secondary to elevated magnesium levels in the neonate.

Magnesium easily crosses the placenta, passing from mother from fetus; maternal serum magnesium levels generally match levels within the fetus. Even though no controlled studies have been done, there have been reported instances of bony abnormalities and congenital rickets in some neonates after 4 to 13 weeks of parenteral administration to pregnant mothers. It is estimated that the risk of major birth defects is somewhere between 2 to 4% and the risk of miscarriages is 15 to 20%. 42

Melatonin

Melatonin should generally be avoided in women who are breast-feeding their infants.1011 Reports describing the use of melatonin dietary supplements in women who are breast-feeding are lacking; however, it is likely to be excreted in human milk. Endogenous melatonin passes into human milk and concentrations have been measured in the breast-milk of lactating women; the results coincided with the women's daily circadian rhythm of melatonin with undetectable levels during the day and high levels at night.39

Interactions

Magnesium Chloride

Generally, care must be exercised when administering magnesium concurrently with other medications. Some medications can impair the Na+/Mg2+ transporter within the body which has an impact on intracellular and extracellular magnesium levels. Studies have shown that insulin inhibits the Na+/Mg2+ transporter and increases the intracellular concentration of magnesium; This is the likely reason why diabetics have a high prevalence of hypomagnesemia. Other causes of drug-induced hypomagnesemia are antimicrobials, beta adrenergic agonists, bisphosphonates, cardiac glycosides, proton-pump inhibitors, and some immunosuppressants. 43 Additionally, medications such as calcitonin, glucagon, doxercalciferol, and potassium-sparing diuretics can result in increased serum levels of magnesium. 30

Parenteral magnesium can also impact the effectiveness as well as toxicity of other medications. Magnesium can enhance the vasoactive effects of calcium-channel blockers, which may lead to a worsening hypotension. For individuals taking antiplatelets or anticoagulants, concurrent administration of magnesium may result in increased bruising and bleeding as a result of decreased blood clotting. The risk of side effects and toxic effects is increased in individuals taking magnesium and muscle relaxants at the same time. 44

Adverse Reactions/Side Effects

Magnesium Chloride

Parenteral magnesium administration is generally well tolerated, with minimal side effects. Adverse reactions, when they occur, are usually as a result of magnesium toxicity, the causes and symptoms of which have been previously discussed. Another cause of adverse reactions is toxicity to additional components of magnesium chloride such as aluminum or benzyl alcohol. Adverse reactions may also occur in the event of significant drug interactions. Close monitoring of the individual is generally recommended when magnesium chloride is administered parenterally.

Melatonin

Most central nervous system (CNS) adverse effects of melatonin appear to be infrequent and mild in most patients with a few days of use. Much less is known regarding side effects occurring during the long term melatonin administration. Most clinical trials have involved <= 6 months of daily melatonin use. The most commonly reported adverse reactions are headache and somnolence. Prolonged sedation and drowsiness during waking hours have been noted; patients experiencing excessive drowsiness during waking hours following melatonin use at bedtime may need to consume a lower bedtime dosage. One study reported that subjective drowsiness from melatonin may affect attention and concentration while driving; patients should determine how melatonin affects them before participating in activities requiring alertness. Other CNS and psychiatric adverse reactions include dizziness, abnormal dreams, unspecified sleep disturbances, nightmares, and seizures in the published literature.37 In primarily depressed patients, worsening of depression (including suicidal ideation) have been reported. Hallucinations, as well as behavioral changes such as bizarre behavior, anxiety, agitation, and mania have been reported with the use of melatonin analogs.36 Neuro-psychiatric symptoms may occur unpredictably. Complex sleep-related behaviors such as "sleep-driving" (i.e., driving while not fully awake after ingestion of a hypnotic) and other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex), with amnesia for the event, have been reported in association with hypnotic use, including melatonin analogs.36 The use of alcohol and other hypnotics should be avoided when possible since these may increase the risk of such symptoms. Somnambulism (sleep walking) has been reported when melatonin was used in conjunction with zolpidem. As with other melatonin analogs, the emergence of any new changes in mood, cognition, or behavior requires further evaluation of the patient. Discontinuation of melatonin should be considered for patients who report any complex sleep behavior, worsening depression, or any other unusual changes in moods or behaviors. During excessive melatonin dosage (e.g., 24 to 30 mg of ingestion), impaired cognition, lethargy, disorientation, short-term amnesia, acute psychosis and confusion have been reported.4546 In these cases, the temporal association of melatonin ingestion to the clinical course of the patients supported melatonin as the causative agent.

Gastrointestinal (GI) adverse effects of melatonin appear to be infrequent with a few days of use. Much less is known regarding the long term administration of this hormone. Most clinical trials have involved <= 6 months of daily melatonin administration. Infrequent or rare GI adverse reactions reported in the published literature include abdominal pain, dyspepsia, pyrosis (heartburn), nausea, vomiting, constipation, flatulence, and difficulty swallowing.37

Melatonin may rarely cause allergic or dermatologic reactions. Rash (unspecified), including fixed drug eruptions and exanthema, with or without pruritus, have been reported after melatonin administration. Other reported dermatologic effects include hyperhidrosis (increased sweating) and hot flashes. Rarely, angioedema and anaphylactoid reactions have been reported with the melatonin analog, ramelteon; however, no reports of such reactions to melatonin are found in the published literature.36 A report of "difficulty swallowing and breathing" was reported in one clinical study of melatonin for jet lag; this might have represented an allergic response. Patients experiencing a serious allergic reaction to melatonin should discontinue the agent and not be rechallenged.

Cardiovascular (CV) adverse effects of melatonin appear to be infrequent or rare with a few days of use. Much less is known regarding the long term administration of this hormone. Most clinical trials have involved <= 6 months of daily melatonin administration. Infrequent or rare CV reactions reported in the published literature include palpitations and sinus tachycardia.

One case report exists in the literature describing a temporal association of melatonin use for insomnia with the development of autoimmune hepatitis confirmed by liver biopsy. Discontinuation of the melatonin and the administration of corticosteroid therapy resulted in symptomatic and clinical improvements.47 A case of autoimmune hepatitis has been reported in the literature due to ramelteon, a melatonin agonist.48

Adverse events reported with melatonin appear to be infrequent or rare with a few days of use. Much less is known regarding the long term administration of this hormone. Most clinical trials have involved <= 6 months of daily melatonin administration. Infrequent or rare general adverse reactions reported in the published literature include naso-pharyngitis, arthralgia, and swelling of the arms/legs (fluid retention) following air travel.

Taurine

Taurine is an amino acid that the body synthesizes naturally and is considered a nonessential amino acid. As a naturally produced substance in the body; studies on Taurine have confirmed few adverse effects when consumed in doses of up to 3 grams.49

Storage

Store this medication at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond use date. Do not flush unused medications or pour down a sink or drain.

  • 1. W.J.Fawcett, E.J.Haxby and D.A.Male, “Magnesium: physiology and pharmacology”, British Journal of Anaesthesia, vol.83, no.2, pp.302 – 320, 1999
  • 2. L.Grycova, P.Sklenovsky, Z.Lansky, M.Janovska, M.Otyepka, E.Amler, J.Teisinger, and M.Kubala, “ATP and magnesium drive conformational changes of the Na+/K+ -ATPase cytoplasmic headpiece”, Biochimica et Biophysica Acta (BBA) – Biomembranes, vol. 1788, issue 5, pp. 1081 -1091, May 2009
  • 3. a. b. “Magnesium: Fact Sheet for Health Professionals”, National Institutes of Health.[Online].
  • 4. W.J.Fawcett, E.J.Haxby and D.A.Male, “Magnesium: physiology and pharmacology”, British Journal of Anaesthesia, vol.83, no.2
  • 5. “Magnesium chloride”, National Center for Biotechnology Information (2020). [Online].
  • 6. “DiNicolantonio JJ, Liu J, and O’Keefe JH, “’Magnesium for the prevention and treatment of cardiovascular disease” Open Heart vol. 5, issue 2, 2018.[Online].
  • 7. M.Liu, E.Jeong, H.Liu, A.Xie, E.Young So, G.Shi, G.E.Jeong, A.Zhou, and S.C.Dudley Jr., “Magnesium supplementation improves diabetic mitochondrial and cardiac diastolic function”, JCI insight. [Online].
  • 8. a. b. “Magnesium Chloride”, Drug Bank. [Online].
  • 9. “Magnesium Chloride (Rx)”, Medscape. [Online].
  • 10. a. b. c. d. e. f. g. h. i. j. Health Canada Drugs and Health Products and Natural Health Products Ingredients Database. Melatonin Monograph. First published 2012. Modified May 13, 2013. Web. Accessed August 4, 2015. Available at: webprod.hc-sc.gc.ca/nhpid-bdipsn.
  • 11. a. b. c. d. e. f. g. h. i. j. k. l. m. n. o. p. q. r. s. t. Circadin (oral melatonin) European Medicines Agency official product label. Dublin 2, Republic of Ireland; Flynn Pharma Ltd: 2015 July.
  • 12. a. b. Yamori Y, Taguchi T, Hamada A, Kunimasa K, Mori H, Mori M. Taurine in health and diseases: consistent evidence from experimental and epidemiological studies. J Biomed Sci. 2010 Aug 24;17 Suppl 1:S6. doi: 10.1186/1423-0127-17-S1-S6.
  • 13. a. b. Ahmadian M, Dabidi Roshan V, Ashourpore E. Taurine Supplementation Improves Functional Capacity, Myocardial Oxygen Consumption, and Electrical Activity in Heart Failure. J Diet Suppl. 2017 Jul 4;14(4):422-432. doi: 10.1080/19390211.2016.1267059. Epub 2017 Jan 24.
  • 14. Chen W1, Guo J1, Zhang Y1, Zhang J1. The beneficial effects of taurine in preventing metabolic syndrome. Food Funct. 2016 Apr;7(4):1849-63. doi: 10.1039/c5fo01295c.
  • 15. Sree, S. Lakshmi, and S. Sethupathy. “Evaluation of the Efficacy of Taurine as an Antioxidant in the Management of Patients with Chronic Periodontitis.” Dental Research Journal 11.2 (2014): 228–233. Print.
  • 16. Balshaw TG1, Bampouras TM, Barry TJ, Sparks SA. The effect of acute taurine ingestion on 3-km running performance in trained middle-distance runners. Amino Acids. 2013 Feb;44(2):555-61. doi: 10.1007/s00726-012-1372-1. Epub 2012 Aug 2.
  • 17. Seidl, R., Peyrl, A., Nicham, R. et al. Amino Acids (2000) 19: 635. https://doi.org/10.1007/s007260070013
  • 18. Ripps, Harris & Shen, Wen. (2012). Review: Taurine: A “very essential” amino acid. Molecular vision. 18. 2673-86.
  • 19. a. b. c. M.J. Allen, S. Sharma, “Magnesium”, Treasure Island (FL). StatPearls Publishing, Jan.2020. [Online].
  • 20. M.J. Specter, E. Schweizer, and R.H. Goldman, “Studies on Magnesium's Mechanism of Action in Digitalis-induced Arrhythmias”. [Online}.
  • 21. M.F. Ghani, J.R. Smith, “The effectiveness of magnesium chloride in the treatment of ventricular tachyarrhythmias due to digitalis intoxication”, American Heart Journal, vol. 88, issue 5, pp. 621 – 626, November 1974. [Online}.
  • 22. F. Kraus, “Reversal of diastolic dysfunction by intravenous magnesium chloride”, The Canadian Journal of Cardiology, vol.9, issue 7, pp. 618-620, September 1999. [Online].
  • 23. Kaya M, Ahishali B. “The role of magnesium in edema and blood brain barrier disruption.”, Magnesium in the Central Nervous System [Internet]. University of Adelaide Press, 2011. [Online]
  • 24. A.M. Uwitonze, M.S. Razzaque, “Role of Magnesium in Vitamin D Activation and Function”, The Journal of the American Osteopathic Association, Vol. 118, pp. 181-189, March 2018. [Online].
  • 25. A.A. Welch, J. Skinner, and M. Hickson, “Dietary Magnesium May Be Protective for Aging of Bone and Skeletal Muscle in Middle and Younger Older Age Men and Women: Cross-Sectional Findings from the UK Biobank Cohort”, National Institutes of Health. [Online].
  • 26. B. J. Stojak, E. Halajian, R.A. Guthmann, and J. Nashelsky, “Intravenous Magnesium Sulfate for Acute Asthma Exacerbations”, American family physician, vol. 99, no.2, pp. 127–128. [Online].
  • 27. a. b. W. Jahnen-Dechent, M. Ketteler, “Magnesium basics”, Clinical Kidney Journal. [Online].
  • 28. a. b. c. d. Harpsoe NG, Andersen LP, Gogenur I, et a;. Clinical pharmacokinetics of melatonin: a systematic review. Eur J Clin Pharmacol. 2015;71:901-909.
  • 29. F.A. Ajib, J.M. Childres, “Magnesium Toxicity”. Treasure Island (FL): StatPearls Publishing; Jan. 2020. [Online].
  • 30. a. b. M.P. Guerrera, S.L. Volpe, J.J Mao, “Therapeutic Uses of Magnesium), American Family Physician, vol. 80, issue 2, pp. 157-162, July 2009. [Online].
  • 31. S.J. Bird, “Overview of the treatment of myasthenia gravis”, UpToDate. [Online].
  • 32. “Magnesium Chloride: Drug information”, UpToDate. [Online].
  • 33. Williamson BL, Tomlinson AJ, Mishra PK, et al: Structural characterization of contaminants found in commercial preparations of melatonin:similarities to case-related compounds from L-tryptophan associated with eosinophilia-myalgia syndrome. Chem
  • 34. Naylor S, Gleich GJ. Over-the-counter melatonin products and contamination. Am Fam Physician. 1999;59:284, 287-8.
  • 35. Norton SA. Raw animal tissues and dietary supplements. N Engl J Med 2000;343:304–305.
  • 36. a. b. c. d. e. f. g. h. i. Rozerem (ramelteon) package insert. Lincolnshire, IL: Takeda Pharmaceuticals; 2010 Nov.
  • 37. a. b. c. Waldron DL, Bramble D, Gringras P: Melatonin: Prescribing practices and adverse events. Arch Dis Child 2005;90(11):1206-1207.
  • 38. a. b. Davis FC. Melatonin: role in development. J Biol Rhythms 1997;12:498-508.
  • 39. a. b. Illnerova H, Buresova M, Presl J. Melatonin rhythm in human milk. J Clin Endocrinol Metab 1993;77:838—41.
  • 40. Chase JE, Gidal BE. Melatonin: therapeutic use in sleep disorders. Ann Pharmacother 1997;31:1218-26.
  • 41. McArthur AJ, Budden SS. Sleep dysfunction in Rett Syndrome: a trial of exogenous melatonin treatment. Dev Med Child Neurol 1998;40:186-92.
  • 42. a. b. “Magnesium chloride Pregnancy and Breastfeeding Warnings”. [Online].
  • 43. U. Grober, “Magnesium and Drugs”, International Journal of Molecular Sciences, vol. 20, issue 9, May 2019. [Online].
  • 44. “Magnesium”. RxLIst. [Online].
  • 45. Holliman BJ, Chyka PA. Problems in assessment of acute melatonin overdose. South Med J 1997;90:451-3.
  • 46. Force RW, Hansen L, Bedell M. Psychotic episode after melatonin. Ann Pharmacother 1997;31:1408.
  • 47. Hong YG, Riegler JL. Is melatonin associated with the development of autoimmune hepatitis? J Clin Gastroenterol 1997;25:376-8.
  • 48. Fourman LT, Robert Meyer B. Autoimmune hepatitis in association with ramelteon. J Clin Gastroenterol. 2013 Apr 29. [Epub ahead of print]
  • 49. Shao, Andrew & N Hathcock, John. (2008). Risk assessment for the amino acids taurine, L-glutamine and L-arginine. Regulatory toxicology and pharmacology : RTP. 50. 376-99. 10.1016/j.yrtph.2008.01.004.

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