Melatonin: Benefits, Dosage, Contraindications

Antioxidant

The antioxidant properties, or the free radical scavenging properties of melatonin, have been demonstrated in laboratory and human research against reactive species of oxygen and nitrogen. Melatonin can reduce oxidative damage in various conditions where excessive free radical generation is thought to be involved, including protection against neurological damage induced by a stroke, protection against erythema or other UV-induced damage, or protection against other toxins, including heavy metals and radiation. In human research, other potential antioxidant effects of melatonin include increased activity of antioxidant enzymes, glutathione peroxidase, and glutathione reductase. Consequently, melatonin has been proposed as a supplement to prevent or treat many conditions associated with oxidative damage.

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Analgesic

Some clinical evidence shows that melatonin can reduce pain associated with conditions such as endometriosis, fibromyalgia, gastroesophageal reflux disease, irritable bowel syndrome, and migraines. The antinociceptive activity of melatonin may be linked to the activation of MT1 and MT2 receptors (melatonergic receptors), which reduces cyclic AMP formation and attenuates pain; the opening of potassium channels; the inhibition of 5-lipoxygenase and cyclooxygenase-2 expression; and the indirect activation of opioid receptors. However, there does not seem to be a clear relationship between pain perception and urinary concentrations of melatonin metabolites.

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Anti-aging

Evidence from animal research suggests that melatonin might reduce age-related neurodegeneration by reducing oxidative stress-related disorders and apoptosis that occur in the brain during the aging process. Other animal research has indicated that melatonin might improve longevity (cellular and otherwise) by preventing age-related mitochondrial disorders, maintaining youthful rhythmic activity, enhancing monoaminergic neurotransmission, and reversing immunosenescence.

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Cardiovascular

Preliminary clinical research shows that nighttime serum melatonin levels are five times lower in patients with coronary heart disease than in healthy controls. The cardioprotective potential effects of melatonin have been demonstrated in human and animal research. In humans, the inclusion of melatonin in combined treatment of cardiovascular diseases resulted in anti-ischemic and antianginal effects. Melatonin seems to act directly on the cardiovascular system rather than modulating autonomic cardiac activity. There is contradictory evidence regarding the effects of melatonin on blood pressure. In animals and humans, some research has shown that melatonin can either increase or decrease blood pressure. However, other research shows that melatonin does not alter blood pressure in animals or humans. Further research shows melatonin has mixed effects on blood pressure, with decreases at night. Potential mechanisms of action have been suggested. In humans, melatonin might act through direct effects on the hypothalamus, antioxidant activity, by reducing catecholamine levels, relaxing the smooth muscles of the aortic wall, and/or increasing cardiac vagal tone.

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Hormonal Metabolism

In clinical and laboratory studies, melatonin appears to have variable hormonal effects. These effects include changes in cortisol levels in certain studies, and in progesterone, estradiol, thyroid hormones (T4 and T3). Additionally, melatonin is an indirect negative regulator of testosterone in the testes. Despite negative regulation mechanisms, melatonin does not seem to consistently influence testosterone levels in healthy men. On the other hand, melatonin supplementation can acutely increase growth hormone levels in resting, healthy young people. This effect is due to melatonin's ability to sensitize the pituitary gland to the effects of GHRH (Growth Hormone Releasing Hormone, stimulates the production and release of growth hormone) rather than a direct stimulating effect. Melatonin appears to have effects on other hormones such as prolactin, oxytocin, vasopressin, adrenocorticotropic hormone, thyroid-stimulating hormone (TSH), and gonadotropin-inhibitory hormone.

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Immunomodulator

Researchers have noted an increase in platelet count after using melatonin in patients whose platelet count decreased following anti-cancer chemotherapy. Although not clearly demonstrated, studies have indicated a possible stimulation of platelet production (thrombopoiesis). Conversely, the activation of melatonin receptors has been associated with the release of cytokines by type 1 T helper cells (Th1), including gamma interferon (gamma-IFN) and IL-2, as well as new opioid cytokines. There is indirect evidence that melatonin could amplify the immunostimulatory effect of IL-2 in cancer patients. Laboratory research suggests that melatonin could also modulate the immune system through other mechanisms, including suppression of TNF-alpha, IL-1 beta, and IL-6; stimulation of antibody production, and stimulation of mononuclear cell production.

Digestive Effect

In patients with gastrointestinal reflux (GERD), a supplement containing melatonin inhibited gastric acid secretion and nitric oxide synthesis; nitric oxide affects the relaxation of the lower esophageal sphincter which is the major mechanism of GERD. Melatonin may also regulate pancreatic secretion and maintain pancreatic integrity, reduce serotonin-induced intestinal contractions, and inhibit epithelial proliferation. The protective effects of melatonin in the gastrointestinal tract may be due to its effects on prostaglandins and its free radical scavenging activity.

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Sedative

Melatonin, administered during day or night, at doses exceeding the physiological dose, seems to produce a hypnotic effect. Various studies have been conducted in humans. For example, exogenous melatonin exerted hypnotic effects mainly when endogenous circulating melatonin levels were low, and even very low doses can induce sleep when ingested before the onset of endogenous melatonin. Moreover, it has been demonstrated that melatonin decreases the amount of anesthesia needed during surgery, enhances the effects of gamma-aminobutyric acid (GABA) and benzodiazepines, and improves sleep quality when associated with benzodiazepines. Melatonin may directly interact with the GABA-benzodiazepine chloride ion channel as suggested by human and animal research, but not with the benzodiazepine receptor. In human research, exogenous melatonin is capable of altering circadian rhythms, endogenous melatonin secretion, and core body temperature.

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Anticancer

Women with endometrial cancer have been found to have plasma melatonin levels six times lower than those of healthy controls. Postmenopausal women with breast cancer also have lower melatonin levels than non-cancer controls. Clinical evidence suggests that taking high-dose melatonin combined with conventional chemotherapy or interleukin-2 (IL-2) could improve tumor regression rates in patients with breast, lung, kidney, liver, pancreatic, stomach, or colon cancer. The anticancer effects of melatonin are not entirely clear. In animal models, melatonin appears to protect against mammary tumor formation. In vitro, at pharmacological concentrations, melatonin exhibits cytotoxic activity in cancer cells. Melatonin inhibits proliferation and induces apoptosis of various types of cancer cells. At physiological and pharmacological concentrations, melatonin acts as a differentiating agent in certain cancer cells and reduces their invasive and metastatic capabilities by altering adhesion molecules. In other types of cancer cells, melatonin, alone or in combination with other agents, induces apoptotic cell death.

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Anti-inflammatory

In animal research, it was reported that melatonin reduces acute exercise-induced cardiac inflammatory lesions. In human and laboratory research, melatonin appears to decrease levels of pro-inflammatory cytokines. Potential mechanisms of action may include inhibition of nitric oxide and malondialdehyde production (which is naturally present in tissues and is a manifestation of oxidative stress) or an increase in glutathione levels; inhibition of phospholipase A2 or NF-kappaB (a protein involved in the immune response and cellular stress response); or the regulation of mast cells. However, some contradictory evidence from clinical research shows that melatonin may not have anti-inflammatory effects. In patients with rheumatoid arthritis, melatonin induced a pro-inflammatory response, increasing levels of certain inflammatory cytokines.

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Neurological

It has been proposed that melatonin may reduce neurological damage secondary to a stroke due to its antioxidant properties. On the other hand, melatonin seems effective in Alzheimer's disease. Laboratory studies show that it attenuated tau protein phosphorylation (a peptide whose aggregation is a sign of Alzheimer's disease), prevented neuroinflammation, and attenuated mitochondrial dysfunction mediated by beta-amyloid (a protein present in neurons whose aggregation is a sign of Alzheimer's disease). Additionally, in vitro evidence suggests that melatonin may inhibit biochemical processes involved in the development of amyloid plaques found in the brains of patients with Alzheimer's disease; however, the clinical significance is unclear. Melatonin also appears effective in reducing headaches. According to a study, several mechanisms are possible, including the elimination of toxic free radicals, reduction of pro-inflammatory cytokines, activity of nitric oxide synthase, and dopamine release inhibition, membrane stabilization, potentiation of GABA and opioid analgesia, and protection against glutamate neurotoxicity.

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Hypocholesterolemic

In human and animal research, melatonin has reduced cholesterol levels. However, there is evidence in human research that melatonin may increase cholesterol levels, very low-density lipoprotein (VLDL), and triglycerides.

Hepato-protective

In patients with non-alcoholic steatohepatitis, melatonin reduced levels of pro-inflammatory cytokines, triglycerides, and GGTP (gamma-glutamyltranspeptidase: liver enzyme). Additionally, a decrease in transaminases was demonstrated after liver resection.

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