Melatonin: benefits, dosage, contraindications
Scientific name(s)
N-Acetyl-5-methoxytryptamine.
Family or group:
Hormones
Indications
Scoring methodology
EFSA approval.
Sleep disorders ✪✪✪✪✪
Melatonin is the reference drug for the treatment of insomnia, and appears to be very effective at a dose of 3 mg (prolonged-release formulation) or at lower concentrations when taken before sleep. Most clinical research shows that oral melatonin taken at doses of 0.3 mg to 5 mg per day for periods of up to 4 weeks reduces sleep onset time in young adults and children with sleep-onset disorder, and furthermore improves quality of life measures such as mental health, vitality, and bodily pain. On the other hand, oral melatonin improves circadian rhythm sleep disorders in children and adults who are blind. Melatonin has been used at doses of 0.5 to 4 mg per day in children and 0.5 to 10 mg per day in adults for periods of up to 6 years. Some evidence indicates that oral melatonin may be more beneficial in elderly patients with insomnia who may be melatonin-deficient. Taking prolonged-release melatonin preparations at 2 mg per day appears to improve sleep duration and quality in these older individuals, while immediate-release preparations seem to decrease sleep latency. European health authorities (EFSA, European Food Safety Authority and the European Commission) have concluded that melatonin can reduce the time needed to fall asleep, provided that 1 mg of melatonin is delivered per serving and it is taken before bedtime.
Posologie
Oral
1 - 5 mg
4 - weeks
The Effect of Prolonged-Release Melatonin on Sleep Measures and Psychomotor Performance in Elderly Patients With Insomnia
Melatonin in circadian sleep disorders in the blind.
The efficacy and safety of exogenous melatonin for primary sleep disorders.
Nightly Treatment of Primary Insomnia With Prolonged Release Melatonin for 6 Months: A Randomized Placebo Controlled Trial on Age and Endogenous Melatonin as Predictors of Efficacy and Safety
Long-term melatonin treatment in blind children and young adults with circadian sleep-wake disturbances.
Prolonged-release Melatonin Improves Sleep Quality and Morning Alertness in Insomnia Patients Aged 55 Years and Older and Has No Withdrawal Effects
Effects of melatonin on the quality of life in patients with delayed sleep phase syndrome.
The use of exogenous melatonin in delayed sleep phase disorder: a meta-analysis.
Prolonged Release Melatonin in the Treatment of Primary Insomnia: Evaluation of the Age Cut-Off for Short- And Long-Term Response
Antidepressant action of melatonin in the treatment of Delayed Sleep Phase Syndrome.
Jet lag ✪✪✪✪✪
Most evidence shows that melatonin can improve certain symptoms of jet lag such as alertness and psychomotor performance. Melatonin also appears to improve, to a lesser extent, other symptoms of jet lag such as daytime sleepiness and fatigue. Melatonin appears to be more effective for eastward travel across more than five time zones, with a dose of 2 to 3 mg of melatonin, immediate- or prolonged-release, taken at bedtime on the day of arrival and for the following 2 to 5 nights. European health authorities (EFSA, European Food Safety Authority and the European Commission) have determined that melatonin can relieve the subjective effects of jet lag, provided that 0.5 mg of melatonin is delivered per serving and that it is taken before bedtime on the day of departure and on the days following arrival at the destination.
Posologie
Orally
2 - 3 mg
Melatonin Treatment for Eastward and Westward Travel Preparation
Melatonin and Zopiclone as Facilitators of Early Circadian Sleep in Operational Air Transport Crews
Melatonin for the Prevention and Treatment of Jet Lag
Comparative Study to Determine the Optimal Melatonin Dosage Form for the Alleviation of Jet Lag
Gastric ulcer ✪✪✪✪✪
A notable protective effect against aspirin and Helicobacter pylori–induced stomach ulceration is observed with melatonin alone or with other agents (such as omeprazole).rnrnIn patients with stomach ulcers whose Helicobacter pylori test is positive, administration of 5 mg of melatonin twice a day for 21 days (combined with omeprazole) resulted in complete healing of the ulcers.rnrnFurthermore, in the control group receiving only omeprazole, only 3 of the 7 patients experienced complete healing.rnrn
Posologie
Orally
10 mg
21 days
Effects of Melatonin and Tryptophan on Healing of Gastric and Duodenal Ulcers With Helicobacter Pylori Infection in Humans
Melatonin orl-tryptophan accelerates healing of gastroduodenal ulcers in patients treated with omeprazole
High blood pressure ✪✪✪✪✪
Taking prolonged-release melatonin at a dose of 2 to 3 mg before bedtime for a period of up to 4 weeks appears to lower systolic and diastolic blood pressure in people with essential hypertension or elevated nighttime blood pressure. Some data indicate that immediate-release melatonin does not have this effect.
Posologie
Oral
2 - 3 mg
4 - weeks
Melatonin reduces night blood pressure in patients with nocturnal hypertension.
Prolonged melatonin administration decreases nocturnal blood pressure in women.
Effect of melatonin on nocturnal blood pressure: meta-analysis of randomized controlled trials.
Cancer ✪✪✪✪✪
There is evidence that taking high-dose melatonin, combined with conventional chemotherapy or interleukin-2 (IL-2), may improve tumor regression rates in patients with breast, lung, kidney, liver, pancreatic, stomach, or colon cancer. Melatonin given with chemotherapy in patients with metastatic solid tumors appears to increase the regression rate and the one-year survival rate by about 40 to 50% compared with chemotherapy alone. The addition of melatonin also appears to help reduce the toxic effects of chemotherapy, including hematologic complications, cachexia, asthenia, and neuropathy. Melatonin has been used at doses of 10 to 40 mg per day, for varying durations depending on health status, and generally in combination with chemotherapy or other treatments.
Posologie
Oral
10 - 40 mg
Melatonin as Adjuvant Cancer Care With and Without Chemotherapy: A Systematic Review and Meta-Analysis of Randomized Trials
A Randomized Study of Chemotherapy With Cisplatin Plus Etoposide Versus Chemoendocrine Therapy With Cisplatin, Etoposide and the Pineal Hormone Melatonin as a First-Line Treatment of Advanced Non-Small Cell Lung Cancer Patients in a Poor Clinical State
Decreased Toxicity and Increased Efficacy of Cancer Chemotherapy Using the Pineal Hormone Melatonin in Metastatic Solid Tumor Patients With Poor Clinical Status
Melatonin in the Treatment of Cancer: A Systematic Review of Randomized Controlled Trials and Meta-Analysis
A Randomized Study of Chemotherapy With Cisplatin Plus Etoposide Versus Chemoendocrine Therapy With Cisplatin, Etoposide and the Pineal Hormone Melatonin as a First-Line Treatment of Advanced Non-Small Cell Lung Cancer Patients in a Poor Clinical State
UV Exposure ✪✪✪✪✪
Topical application of a gel containing melatonin at 0.05% to 2.5% significantly reduces erythema caused by exposure to ultraviolet (UV) rays.
Posologie
Orally
gel
Suppression of UV-induced Erythema by Topical Treatment With Melatonin. Effect of Application Timing
Suppression of UV-induced Erythema by Topical Treatment With Melatonin (N-acetyl-5-methoxytryptamine). Effect of Application Timing
Migraine ✪✪✪✪✪
Some research indicates that melatonin production may be altered in people suffering from migraines. There is evidence that patients with episodic migraine headaches who take melatonin prophylactically, 3 to 4 mg each night before bedtime, have significantly reduced the frequency of migraines, their intensity and their duration.rnrn
Posologie
Oral
3 - 4 mg
Melatonin 4 mg as Prophylactic Therapy for Primary Headaches: A Pilot Study
Nocturnal Melatonin Excretion Is Decreased in Patients With Migraine Without Aura Attacks Associated With Menses
Melatonin, 3 mg, Is Effective for Migraine Prevention
Irritable bowel syndrome ✪✪✪✪✪
Some clinical research shows that taking melatonin at a dose of 3 mg at bedtime for 8 weeks appears to reduce the severity and frequency of pain, decrease bloating, lessen other associated symptoms such as headaches, heartburn and nausea, and appears to improve the overall quality of life of patients with irritable bowel syndrome.rnrn
Posologie
Oral
3 mg
8 weeks
Influence of Melatonin on Symptoms of Irritable Bowel Syndrome in Postmenopausal Women
Melatonin Improves Abdominal Pain in Irritable Bowel Syndrome Patients Who Have Sleep Disturbances: A Randomized, Double-Blind, Placebo-Controlled Study
Melatonin Improves Bowel Symptoms in Female Patients With Irritable Bowel Syndrome: A Double-Blind, Placebo-Controlled Study
Endometriosis ✪✪✪✪✪
Clinical research shows that daily intake of 10 mg of melatonin for 8 weeks reduces pain by 39.3% and analgesic use by approximately 46%, compared with placebo, in adults with endometriosis.rnrn
Posologie
Oral
10 mg
8 - weeks
AMD ✪✪✪✪✪
Clinical evidence shows that taking melatonin at 3 mg per day for 3 to 6 months may delay the loss of clear vision in people with age-related macular degeneration.rnrn
Posologie
Oral
3 mg
6 - months
Gastroesophageal reflux ✪✪✪✪✪
Taking melatonin at 3 mg per day at bedtime for 8 weeks can improve symptoms of gastroesophageal reflux, including burning sensations and epigastric pain. rnrn
Posologie
Oral
3 mg
8 - weeks
Fibromyalgia ✪✪✪✪✪
Melatonin can reduce the intensity of pain and stiffness, as well as the number of painful joints, in people with fibromyalgia.rnrnMelatonin has been used at 3 mg to 5 mg per day for 60 days.rnrn
Posologie
Oral
3 - 5 mg
60 - days
Smoking cessation ✪✪✪✪✪
A single oral dose of 0.3 mg of melatonin taken 3.5 hours after smoking cessation in smokers appears to reduce subjective symptoms of anxiety, restlessness, irritability, depression, and cigarette craving over the following 10 hours
Posologie
Oral
0.3 mg
Fatty liver (hepatic steatosis) ✪✪✪✪✪
Some clinical evidence shows that taking 5 mg of melatonin twice a day for 12 weeks reduces liver enzyme levels in patients with nonalcoholic steatohepatitis.
Posologie
Oral
10 mg
12 weeks
Effects of Treatment With Melatonin and Tryptophan on Liver Enzymes, Parameters of Fat Metabolism and Plasma Levels of Cytokines in Patients With Non-Alcoholic Fatty Liver disease--14 Months Follow Up
Menopause ✪✪✪✪✪
Some clinical evidence shows that taking melatonin at a dose of 3 mg per night for 6 months may improve the physical symptoms of menopause compared to placebo but does not improve bone density or associated psychological symptoms.
Posologie
Oral
3 mg
6 months
Healthy aging ✪✪✪✪✪
Evidence from animal research suggests that melatonin may reduce age-related neurodegeneration by reducing oxidative stress-related disturbances and apoptosis that occur in the brain during the aging process. Other animal studies have indicated that melatonin may improve longevity (cellular and otherwise) by preventing age-related mitochondrial dysfunction, maintaining youthful rhythmic activity, improving monoaminergic neurotransmission, and reversing immunosenescence.
Posologie
Oral
2 mg
Melatonin and Tryptophan Counteract Lipid Peroxidation and Modulate Superoxide Dismutase Activity in Ringdove Heterophils in Vivo. Effect of Antigen-Induced Activation and Age
Improvement of Leukocyte Functions in Ovariectomized Aged Rats After Treatment With Growth Hormone, Melatonin, Estrogens or Phytoestrogens
Chronic Melatonin Treatment and Its Precursor L-tryptophan Improve the Monoaminergic Neurotransmission and Related Behavior in the Aged Rat Brain
Hormone Replacement Therapy--Growth Hormone, Melatonin, DHEA and Sex Hormones
Effect of Melatonin on Age Induced Changes in Daily Serotonin Rhythms in Suprachiasmatic Nucleus of Male Wistar Rat
Melatonin Reduces Membrane Rigidity and Oxidative Damage in the Brain of SAMP8 Mice
Reducing Oxidative/Nitrosative Stress: A Newly-Discovered Genre for Melatonin
SIRT1 Controls Circadian Clock Circuitry and Promotes Cell Survival: A Connection With Age-Related Neoplasms
The Timing of the Shrew: Continuous Melatonin Treatment Maintains Youthful Rhythmic Activity in Aging Crocidura Russula
Long-term Melatonin Administration Protects Brain Mitochondria From Aging
Cognitive decline ✪✪✪✪✪
A study of elderly subjects (86±6 years) with mild cognitive impairment who were given a combined supplement of melatonin (5 mg), soy phospholipids (160 mg), L-tryptophan (95 mg) and fish oil (720 mg DHA, 286 mg EPA, vitamin E at 16 mg) noted that nightly intake for 12 weeks significantly reduced MMSE and MNA scores (indicative of cognitive improvement) without affecting short- or long-term memory parameters. rnrn
Posologie
Oral
5 mg
Synergies
Properties
Antioxidant
The antioxidant properties, or the free radical scavenging property of melatonin, have been demonstrated in the laboratory and in human research against reactive oxygen and nitrogen species. Melatonin can reduce oxidative damage in various conditions in which excessive free radical generation is thought to be involved, including protection against stroke-induced neurological damage, protection against erythema or other UV-induced damage, or protection against other toxins, including heavy metals and radiation. rnrnIn human research, other potential antioxidant effects of melatonin include increased activity of antioxidant enzymes, such as glutathione peroxidase and glutathione reductase. As a result, melatonin has been proposed as a supplement to prevent or treat many conditions associated with oxidative damage.rnrn
Usages associés
Analgesic
Certain clinical evidence shows that melatonin may reduce pain associated with conditions such as endometriosis, fibromyalgia, gastroesophageal reflux disease, irritable bowel syndrome, and migraines.rnrnThe antinociceptive activity of melatonin may be related to activation of MT1 and MT2 receptors (melatonergic receptors), which reduces cyclic AMP formation and attenuates pain; to the opening of potassium channels; to inhibition of the expression of 5-lipoxygenase and cyclooxygenase-2; and to indirect activation of opioid receptors. However, there does not appear to be a clear relationship between pain perception and urinary concentrations of melatonin metabolites.rnrnrnrn
Usages associés
Anti-aging
Evidence from animal research suggests that melatonin may reduce age-related neurodegeneration by reducing oxidative stress-related disturbances and apoptosis that occur in the brain during the aging process. Other animal research has indicated that melatonin may improve longevity (cellular and otherwise) by preventing age-related mitochondrial dysfunction, maintaining youthful rhythmic activity, improving monoaminergic neurotransmission, and reversing immunosenescence.rnrnrnrn
Usages associés
Cardiovascular
Preliminary clinical research shows that nighttime serum melatonin levels are five times lower in patients with coronary artery disease than in healthy controls. The potential cardioprotective effects of melatonin have been demonstrated in human and animal studies. In humans, inclusion of melatonin in combination therapy for cardiovascular diseases has resulted in anti-ischemic and antianginal effects. Melatonin appears to act directly on the cardiovascular system rather than by modulating autonomic cardiac activity.rnrnRegarding melatonin's effects on blood pressure, the evidence is conflicting. In animals and humans, some studies have shown that melatonin can increase or decrease blood pressure. However, other studies show that melatonin does not alter blood pressure in animals or humans. Still other research indicates that melatonin has mixed effects on blood pressure, with reductions at night. rnrnPotential mechanisms of action have been suggested. In humans, melatonin may act via direct effects on the hypothalamus, through antioxidant activity, by decreasing catecholamine levels, by relaxing the smooth muscle of the aortic wall, and/or by increasing cardiac vagal tone.rnrnrnrn
Usages associés
Hormone metabolism
In clinical and laboratory studies, melatonin appears to have variable hormonal effects. These effects include changes in cortisol levels in some studies, as well as in progesterone, estradiol, and thyroid hormones (T4 and T3). rnrnIn addition, melatonin is an indirect negative regulator of testosterone in the testes. Despite these negative regulatory mechanisms, melatonin does not appear to meaningfully affect testosterone levels in healthy men.rnrnConversely, melatonin supplementation can acutely increase growth hormone levels in healthy, resting young people. This effect is due to melatonin's ability to sensitize the pituitary to the effects of GHRH (Growth Hormone Releasing Hormone, which stimulates the production and release of growth hormone) rather than to a direct stimulatory effect.rnrnMelatonin also appears to affect other hormones such as prolactin, oxytocin and vasopressin, adrenocorticotropic hormone, thyroid-stimulating hormone (TSH), and the gonadotropin-inhibiting hormone.rnrn
Usages associés
Immunomodulatory
Researchers observed an increase in platelet counts after the use of melatonin in patients whose platelet counts had decreased following anticancer chemotherapy. Although this has not been clearly demonstrated, studies have indicated a possible stimulation of platelet production (thrombopoiesis). On the other hand, activation of melatonin receptors has been associated with the release of cytokines by type 1 helper T (Th1) cells, including interferon gamma (gamma-IFN) and IL-2, as well as novel opioid cytokines. There is indirect evidence that melatonin could amplify the immunostimulatory effect of IL-2 in cancer patients. Based on laboratory research, melatonin may 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 gastroesophageal reflux (GER), a supplement containing melatonin inhibited gastric acid secretion and the synthesis of nitric oxide; nitric oxide affects relaxation of the lower esophageal sphincter, which is the major mechanism of GER. Melatonin may also regulate pancreatic secretion and help 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.
Usages associés
Sedative
Melatonin, administered during the day or at night, at doses higher than the physiological dose, appears to produce a hypnotic effect. Various studies have been conducted in humans. For example, exogenous melatonin has produced hypnotic effects mainly when endogenous melatonin levels in the circulation were low, and even very small doses can induce sleep when taken before the onset of endogenous melatonin. rnrnIn addition, melatonin has been shown to decrease the amount of anesthesia required during surgery, potentiate the effects of gamma-aminobutyric acid (GABA) and benzodiazepines, and improve sleep quality when combined with benzodiazepines. Melatonin may interact directly with the GABA-benzodiazepine chloride ion channel as suggested by human and animal research, but not with the benzodiazepine receptor.rnrnIn human research, exogenous melatonin is capable of altering circadian rhythms, as well as endogenous melatonin secretion and core body temperature. rnrn
Usages associés
Anticancer
Women with endometrial cancer have been found to have plasma melatonin levels six times lower than tumor-free controls. Postmenopausal women with breast cancer also have lower melatonin levels than cancer-free controls. There is clinical evidence that high-dose melatonin taken in combination with conventional chemotherapy or interleukin-2 (IL-2) may 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 shows cytotoxic activity in cancer cells. Melatonin inhibits proliferation and induces apoptosis in various types of cancer cells. At physiological and pharmacological concentrations, melatonin acts as a differentiation agent in some 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.
Usages associés
Anti-inflammatory
In animal research, melatonin has been reported to reduce 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 the cellular stress response); or 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.
Usages associés
Neurological
It has been proposed that melatonin may reduce secondary neurological damage following a stroke, due to its antioxidant properties. On the other hand, melatonin appears to be effective in Alzheimer's disease. Laboratory studies show that it reduced phosphorylation of the tau protein (a peptide whose aggregation is a hallmark of Alzheimer's disease), prevented neuroinflammation, and attenuated mitochondrial dysfunction mediated by beta-amyloid (a protein present in neurons whose aggregation is a hallmark of Alzheimer's disease). In addition, in vitro evidence suggests that melatonin could inhibit the 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 at reducing headaches. According to one study, several mechanisms are possible, including removal of toxic free radicals, reduction of pro-inflammatory cytokines, modulation of nitric oxide synthase activity and inhibition of dopamine release, membrane stabilization, potentiation of GABA and opioid analgesia, and protection against glutamate neurotoxicity.
Usages associés
Cholesterol-lowering
In human and animal research, melatonin reduced cholesterol levels. However, there is evidence from human studies that melatonin may increase cholesterol, very-low-density lipoprotein (VLDL), and triglyceride levels.
Hepatoprotective
In patients with nonalcoholic steatohepatitis, melatonin reduced levels of pro-inflammatory cytokines, triglycerides, and GGTP (gamma-glutamyl transpeptidase: liver enzyme). In addition, a decrease in transaminases was demonstrated after liver resection.
Usages associés
Safe dosage
Adults 18 years and older: 2 mg
In clinical trials longer than 12 months, doses of 5 mg per day of melatonin were administered without any significant change in the nature of reported adverse effects. Furthermore, melatonin has been used safely at a dose of 10 mg per day for 2 months. rnrnIn France, regulations allow the marketing of dietary supplements providing less than 2 mg of melatonin per day.rnrn
Interactions
Médicaments
Antiplatelet agents/Anticoagulants: moderate interaction
The combination of melatonin and anticoagulants such as warfarin has led to bleeding and a decrease in clotting factors.
Anticonvulsants: moderate interaction
Melatonin could increase the risk of seizures, particularly in children.
Antidiabetics: moderate interaction
Studies suggest that melatonin may affect glucose utilization and increase insulin resistance.
Antihypertensives: moderate interaction
Some clinical evidence suggests that taking melatonin lowers blood pressure in healthy adults and appears to reduce systolic and diastolic blood pressure in people with untreated essential hypertension. However, melatonin appears to lower blood pressure further in patients who are taking antihypertensive medications, increasing the risk of hypotension.
Benzodiazepines: moderate interaction
Benzodiazepines inhibit the synthesis and release of melatonin. Theoretically, chronic administration of benzodiazepines could decrease endogenous melatonin levels.
Central nervous system depressants: moderate interaction
Using melatonin at the same time as alcohol, benzodiazepines, and other sedatives could worsen sedation.
Oral contraceptives: moderate interaction
Contraceptives can increase endogenous melatonin levels. Theoretically, these medications may increase the side effects of melatonin taken orally.
Cytochrome P450 substrate: moderate interaction
Melatonin is metabolized by cytochrome P450 enzymes. Taking melatonin with other cytochrome P450 substrates could alter its metabolism.
Immunosuppressant: moderate interaction
Melatonin can stimulate immune function and could interfere with immunosuppressive treatments.
Precautions
Epilepsy: avoid
Exogenous melatonin may increase the incidence of seizures.rnrn
Depression: avoid
Melatonin may worsen dysphoria in some people with depression.rnrn
Autoimmune diseases: avoid
Contraindications
Pregnant women: prohibited
In the absence of clinical data, it is not recommended to use melatonin in pregnant women or in women who wish to become pregnant. rnrn
Breastfeeding women: prohibited
Endogenous melatonin has been found in breast milk and, as a result, exogenous melatonin is likely secreted into human breast milk. Data from animal models indicate that melatonin passes from the mother to the fetus via the placenta or during breastfeeding. Therefore, breastfeeding is not recommended for women treated with melatonin.
