Melatonin (N-acetyl-5-methoxytryptamine)

• Background
• Related terms
• Evidence
• Dosing
• Safety
• Methodology
• Selected references

• RSS Feeds

Melatonin (N-acetyl-5-methoxytryptamine)

Background

Melatonin is a hormone produced in the brain by the pineal gland from the amino acid tryptophan. The synthesis and release of melatonin are stimulated by darkness and suppressed by light, suggesting the involvement of melatonin in circadian rhythm and regulation of diverse body functions. Levels of melatonin in the blood are highest prior to bedtime.

Synthetic melatonin supplements have been used for a variety of medical conditions, most notably for disorders related to sleep.

Melatonin possesses antioxidant activity, and many of its proposed therapeutic or preventive uses are based on this property.

New drugs that block the effects of melatonin are in development, such as BMS-214778 or luzindole, and they may have uses in various disorders.

Related terms

5-Methoxy-N-acetyltryptamine, 6-sulfatoxymelatonin, acetamide, agomelatine, aMT6s, beta-methyl-6-chloromelatonin, BMS-214778, CAS 73-31-4, hypnotic, indole, luzindole, mel, MEL, melatonine, MLT, MT, N-2-(5-methoxyindol-3-ethyl)-acetamide, N-acetyl-5-methoxytryptamine, neurohormone, ramelteon (CAS 196597-26-9, TAK-375), tryptophan.

Brand names : Accurate Release®; Appleheart Melatonin®; Circadin®; Inspired by Nature®; Mel®; Melatonin-BioDynamax®; Melatonin Controlled Release®; Melatonin-Metabolic Response Modifier®; Melatonin-New Hope Health Products®; Melatonin Olympian Labs®; Melatonin-Optimum Nutrition®; Melatonin Tablets®; Melatonin Time Release®; Melaxen®; Nature's Bounty®; Puritan's Pride®; Rozerem®; Twinlab® Melatonin; Valdoxan®.

Combination product examples : Melatonex® (vitamin B6); Melatonin Forte® ( Piper methysticum , kavalactones, valeriana); Melatonin PM Complex® (vitamin B6, vitamin B2, vitamin B3); Melatonin spray® (gamma-aminobutyric acid, pyridoxal-5-phosphate); Super Snooze with Melatonin® (valerian root, hop, skullcap, chamomile, passion flower).

Evidence

These uses have been tested in humans or animals. Safety and effectiveness have not always been proven. Some of these conditions are potentially serious, and should be evaluated by a qualified healthcare provider.

Grading rationale

Uses based on tradition or theory

The below uses are based on tradition or scientific theories. They often have not been thoroughly tested in humans, and safety and effectiveness have not always been proven. Some of these conditions are potentially serious, and should be evaluated by a qualified healthcare provider.

Acetaminophen toxicity, acute respiratory distress syndrome (ARDS), adaptogen, addiction, ADHD, adrenal insufficiency, aflatoxin toxicity, aging, alcoholic liver disease, alopecia (baldness), aluminum toxicity, Alzeimer's disease, amenorrhea, amyotrophic lateral sclerosis (ALS), analgesic, antioxidant, antiparasitic, anxiety (travel anxiety in animals), ataxia (Machado-Joseph disease), atopic dermatitis, autoimmune diseases (demyelination), beta-blocker sleep disturbance, bipolar disorder, bladder disorders, bone diseases (fibrous dysplasia), bone healing, brain injuries, cachexia, cardiac syndrome X, cardiovascular conditions, cataracts, central nervous system diseases (Venezuelan equine encephalomyelitis virus), chemotherapy toxicity, cholestatic liver injury, colic, colitis, contraception, coronary artery disease, delirium, dental conditions, Duchenne muscular dystrophy, duodenal ulcer, eating disorders (low-level, enhanced circadian rhythm), eczema, edema (swelling), endometriosis, erectile dysfunction, esophagitis (inflammation of the esophagus), exercise recovery, fetal development, fibromyalgia, food preservation, fragile X syndrome, gastric ulcers, gastritis (inflammation of the stomach lining), gastroesophageal reflux disease (GERD), gentamicin toxicity, growth (growing pains), heart attack prevention, heart disease, helminthic infections, hepatic encephalopathy, hormonal/endocrine disorders (McCune-Albright syndrome), hyperpigmentation, immune system diseases (Langerhans cell histiocytosis), immunostimulant, infant development / neonatal care, interstitial cystitis, intestinal motility disorders, ischemia-reperfusion injury protection, ischemic stroke (impaired nocturnal excretion), itching, jaundice, jellyfish stings, kidney protection (amikacin-induced, cyclosporin-induced), lead toxicity, liver damage, lung inflammation, major depressive disorder (low nocturnal melatonin), malaria, mania, melatonin deficiency, metabolic disorders, migraine (impaired pineal function), movement disorders, multiple sclerosis, myocardial injury, nerve regeneration, neurodegenerative disorders, neurofibromatous scoliosis, neurological disorders, neuropathy (neuronal damage from bacterial meningitis), neuroprotective, nitrate tolerance, noise-induced hearing loss, non-Hodgkin's lymphoma, obesity, obstructive sleep apnea, organophosphate poisoning, osteoarthritis, ovarian disorders, pain, pancreatitis, phenylketonuria (PKU), photoprotection, polycystic ovarian syndrome (PCOS), postmenopausal osteoporosis, post-operative adjunct, post-operative delirium, pregnancy nutritional supplement, premenstrual dysphoric disorder (PMDD), protection against alcohol toxicity, psychiatric disorders, pulmonary fibrosis, radiation protection, retinal protection, rheumatic diseases, scalds, schizophrenia, sepsis, sexual activity enhancement, shock, spinal cord injury, spine problems (idiopathic scoliosis), stomach ulcers, stomatitis, stroke, sudden infant death syndrome (SIDS) prevention, surgical recovery, tachycardia, testicular damage, toluene neurotoxicity, toxic liver damage, toxicity, transplants (ovary), tuberculosis, ulcer, ulcerative colitis, uterine disorders, Wilson's disease, wound healing.

Dosing

The below doses are based on scientific research, publications, traditional use, or expert opinion. Many herbs and supplements have not been thoroughly tested, and safety and effectiveness may not be proven. Brands may be made differently, with variable ingredients, even within the same brand. The below doses may not apply to all products. You should read product labels, and discuss doses with a qualified healthcare provider before starting therapy.

Adults (over 18 years old)

Studies have evaluated 0.1-80 milligrams of melatonin taken nightly by mouth for up to three years for a variety of conditions. Research suggests that quick-release melatonin may be more effective than sustained-release formulations for sleep-related conditions. Intramuscular injections of 20 milligrams of melatonin have also been studied.

In studies of patients with melanoma, melatonin preparations have been applied to the skin. Patients are advised to discuss cancer treatment plans with an oncologist and pharmacist before considering use of melatonin either alone or with other therapies. For the prevention of sunburn, melatonin preparations, alone and in combination with ascorbic acid and vitamin E, in doses ranging from 20-100 milligrams in 70% ethanol, have been studied.

Intranasal melatonin (1% solution in ethanol) at a dose of two milligrams daily for one week has also been studied for high blood pressure.

A dose of 0.5 milligrams of transbuccal melatonin for two sessions on four consecutive nights, at least three days apart, has been studied for insomnia in the elderly.

There are other uses with limited supportive research and unclear effectiveness or safety. Use of melatonin for any condition should be discussed with a primary healthcare provider, appropriate specialist, and pharmacist prior to starting, and it should not be substituted for more proven therapies.

Children (under 18 years old)

There is limited study of melatonin supplements in children, and its safety is not established. Doses of up to up to nine or 10 milligrams per kilogram of body weight, as a single dose or over several months, have been studied. Use of melatonin should be discussed with the child's physician and pharmacist prior to starting.

Safety

The U.S. Food and Drug Administration does not strictly regulate herbs and supplements. There is no guarantee of strength, purity or safety of products, and effects may vary. You should always read product labels. If you have a medical condition, or are taking other drugs, herbs, or supplements, you should speak with a qualified healthcare provider before starting a new therapy. Consult a healthcare provider immediately if you experience side effects.

Allergies

Avoid in those with known allergies to melatonin or related products. There are rare reports of allergic skin reactions after taking melatonin by mouth. Melatonin has been linked to a case of autoimmune hepatitis.

Side Effects and Warnings

Based on available studies and clinical use, melatonin is generally regarded as safe in recommended doses (five milligrams daily) for up to two years. Available trials report that overall adverse effects are not significantly more common with melatonin than placebo.

Commonly reported adverse effects include fatigue, dizziness, headache, irritability, drowsiness, and sleepiness, although these effects may occur due to jet lag and not due to melatonin itself. Fatigue may occur particularly with morning use or high doses, and irregular sleep-wake cycles may occur. Disorientation, ataxia (difficulties with walking and balance), confusion, sleepwalking, vivid dreams, and nightmares have also been noted, with effects often resolving after the cessation of melatonin. Due to the risk of drowsiness or sedation, use caution if driving or operating heavy machinery.

Mild gastrointestinal distress commonly occurs, including nausea, vomiting, cramping, stomach pain, altered taste, abnormal feces, increased appetite, or diarrhea. Melatonin has been linked to the triggering of Crohn's disease symptoms.

Other side effects include skin rash, infection, decreased mental performance, increased risk of inflammation, and increased urination.

It has been suggested that melatonin may lower the seizure threshold and increase the risk of seizure, particularly in children with severe neurologic disorders. However, multiple other studies actually report reduced incidence of seizure with regular melatonin use. This remains an area of controversy. Patients with seizure disorder taking melatonin should be monitored closely by a healthcare professional.

Mood changes have been reported, including giddiness and dysphoria (sadness). Psychotic symptoms have been reported, including hallucinations and paranoia, possibly due to overdose. Patients with underlying major depression or psychotic disorders taking melatonin should be monitored closely by a healthcare professional.

Melatonin may increase the risk of bleeding. Caution is advised in patients with bleeding disorders or those taking drugs that may increase the risk of bleeding. Dosing adjustments may be necessary.

Melatonin may cause drops in blood pressure. Caution is advised in patients taking medications that may also lower blood pressure.

Based on preliminary evidence, increases in cholesterol levels may occur. Caution is therefore advised in patients with high cholesterol levels or atherosclerosis, or in those at risk for cardiovascular disease. Abnormal heart rhythms have been associated with melatonin.

Hyperglycemia (elevated blood sugar levels) has been reported in patients with type 1 diabetes (insulin-dependent diabetes), and low doses of melatonin have reduced glucose tolerance and insulin sensitivity. Caution is advised in patients with diabetes or hypoglycemia, and in those taking drugs, herbs, or supplements that affect blood sugar. Serum glucose levels may need to be monitored by a healthcare provider, and medication adjustments may be necessary.

Hormonal effects have been reported, including decreases or increases in levels of luteinizing hormone, progesterone, estradiol, thyroid hormone (T4 and T3), growth hormone, prolactin, cortisol, oxytocin, and vasopressin. Gynecomastia (increased breast size) has been reported in men, as well as decreased sperm count (both which resolved with the cessation of melatonin). Decreased sperm motility and decreased libido have been reported in rats and humans.

It has been theorized that high doses of melatonin may increase intraocular pressure and the risk of glaucoma, age-related maculopathy and myopia, or retinal damage. However, there is preliminary evidence that melatonin may actually decrease intraocular pressure in the eye, and it has been suggested as a possible therapy for glaucoma. Patients with glaucoma taking melatonin should be monitored by a healthcare professional.

Use cautiously in patients using anesthetics, cytochrome P450 1A2 inhibitors like fluvoxamine, methamphetamine, nifedipine (a calcium channel blocker), or in children with a history of enuresis.

Avoid in patients using CNS depressants, including benzodiazepines and alcohol, as concomitant use may cause increased sedation.

Avoid use in women who are pregnant or are attempting to become pregnant, based on possible hormonal effects and a possible increased risk of developmental disorders.

Avoid with known allergies to melatonin or related products.

Pregnancy and Breastfeeding

Melatonin supplementation should be avoided in women who are pregnant or attempting to become pregnant, based on possible hormonal effects. High levels of melatonin during pregnancy may increase the risk of developmental disorders. In animal studies, melatonin was detected in breast milk and therefore should be avoided during breastfeeding. In men, decreased sperm motility and decreased sperm count are reported with the use of melatonin.

Methodology

This patient information is based on a professional level monograph edited and peer-reviewed by contributors to the Natural Standard Research Collaboration (www.naturalstandard.com).

Monograph methodology

Selected references

1. Bendz LM, Scates AC. Melatonin treatment for insomnia in pediatric patients with attention-deficit/hyperactivity disorder. Ann Pharmacother 2010 Jan;44(1):185-91.
2. Bjorvatn B, Stangenes K, Oyane N, et al. Randomized placebo-controlled field study of the effects of bright light and melatonin in adaptation to night work. Scand J Work Environ Health 2007 Jun;33(3):204-14.
3. Caumo W, Levandovski R, Hidalgo MP. Preoperative anxiolytic effect of melatonin and clonidine on postoperative pain and morphine consumption in patients undergoing abdominal hysterectomy: a double-blind, randomized, placebo-controlled study. J Pain 2009 Jan;10(1):100-8.
4. Hallam KT, Begg DP, Olver JS, et al. An investigation of the effect of immediate and extended release venlafaxine on nocturnal melatonin and cortisol release in healthy adult volunteers. Hum Psychopharmacol 2008 Mar;23(2):129-37.
5. Kandil TS, Mousa AA, El-Gendy AA, et al. The potential therapeutic effect of melatonin in Gastro-Esophageal Reflux Disease. BMC Gastroenterol 2010 Jan18;10:7.
6. Lopez-Gonzalez MA, Santiago AM, Esteban-Ortega F. Sulpiride and melatonin decrease tinnitus perception modulating the auditolimbic dopaminergic pathway. J Otolaryngol 2007 Aug;36(4):213-9.
7. Medeiros CA, Carvalhedo de Bruin PF, et al. Effect of exogenous melatonin on sleep and motor dysfunction in Parkinson's disease. A randomized, double blind, placebo-controlled study. J Neurol 2007 Apr;254(4):459-64.
8. Rahman SA, Kayumov L, Shapiro CM. Antidepressant action of melatonin in the treatment of Delayed Sleep Phase Syndrome. Sleep Med 2010 Feb;11(2):131-6.
9. Rimmele U, Spillmann M, Bärtschi C, et al. Melatonin improves memory acquisition under stress independent of stress hormone release. Psychopharmacology (Berl) 2009 Mar;202(4):663-72.
10. Schemmer P, Nickkholgh A, Schneider H, et al. PORTAL: pilot study on the safety and tolerance of preoperative melatonin application in patients undergoing major liver resection: a double-blind randomized placebo-controlled trial. BMC Surg 2008 Jan 23;8:2.
11. Schmidt CM, Knief A, Deuster D, et al. Melatonin is a useful alternative to sedation in children undergoing brainstem audiometry with an age dependent success rate--a field report of 250 investigations. Neuropediatrics 2007 Feb;38(1):2-4.
12. Serfaty MA, Osborne D, Buszewicz MJ, et al. A randomized double-blind placebo-controlled trial of treatment as usual plus exogenous slow-release melatonin (6 mg) or placebo for sleep disturbance and depressed mood. Int Clin Psychopharmacol 2010 May;25(3):132-42.
13. Suresh Kumar PN, Andrade C, Bhakta SG, Singh NM. Melatonin in schizophrenic outpatients with insomnia: a double-blind, placebo-controlled study. J Clin Psychiatry 2007 Feb;68(2):237-41.
14. Todisco M. Low-grade non-Hodgkin lymphoma at advanced stage: a case successfully treated with cyclophosphamide plus somatostatin, bromocriptine, retinoids, and melatonin. Am J Ther 2007 Jan-Feb;14(1):113-5.
15. Wade AG, Ford I, Crawford G, et al. Efficacy of prolonged release melatonin in insomnia patients aged 55-80 years: quality of sleep and next-day alertness outcomes. Curr Med Res Opin 2007 Oct;23(10):2597-605.

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