Melatonin (N-acetyl-5-methoxytryptamine)

Melatonin (N-acetyl-5-methoxytryptamine)

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Be aware that the U.S. Food and Drug Administration does not strictly regulate herbs and dietary supplements. There is no guarantee of strength, purity or safety of products containing or claiming to contain melatonin. Decisions to use herbs or supplements should be carefully considered. Individuals using prescription drugs should discuss taking herbs or supplements with their pharmacists or health care professionals before starting.

Evidence

Scientists have studied melatonin for the following health problems:

Jet lag When taken by mouth melatonin may reduce the symptoms of jet lag in some people. Melatonin should be started on the day of travel (close to bedtime at the destination) and continued for several days.

Delayed sleep phase syndrome (DSPS) Delayed sleep phase syndrome is a condition that results in a delay in falling asleep, despite a normal bedtime and waking time and time spent sleeping. In several small studies, people using 5 to 6mg of melatonin said they fell asleep faster.

Sleep disturbances in children with neuro-psychiatric disorders Children with various neuro-psychiatric disorders, including mental retardation, autism, psychiatric disorders, visual impairment, or epilepsy, can have problems sleeping for a very long time or falling asleep. Taking 2.5 and 10mg of melatonin by mouth at bedtime may help. Please check with your child’s Pediatrician and Pharmacist before using melatonin.

Insomnia in the elderly Taking melatonin by mouth 30 to 120 minutes prior to bedtime may decrease the amount of time it takes to fall asleep in elderly individuals with insomnia.

Sleep enhancement in healthy people Melatonin may decrease the time it takes to fall asleep, increase sleepiness, and increase sleeping time.

Alzheimer’s disease (sleep disorders) There is limited evidence that melatonin improves sleep disorders associated with Alzheimer’s disease (including nighttime agitation or poor sleep quality in patients with dementia).

Antioxidant (free radical scavenging) Melatonin has not been proven to be an help any health problems with antioxidant effects.

Attention deficit hyperactivity disorder (ADHD) There is limited research of the use of melatonin in children with ADHD.

Benzodiazepine tapering A small amount of research has examined the use of melatonin to assist with tapering or stopping of benzodiazepines such as diazepam (Valium®) or lorazepam (Ativan®).

Bipolar disorder (sleep disturbances) There is limited study of melatonin given to patients with sleep disturbances associated with bipolar disorder (such as insomnia or irregular sleep patterns). No clear benefits have been reported.

Cancer treatment Melatonin combined with other types of treatment, including radiation therapy, chemotherapies (such as cisplatin, etoposide, or irinotecan), hormonal treatments (such as tamoxifen), or immune therapies such as interferon, Interleukin-2, or tumor necrosis factor could help patients with various advanced stage cancer. Results have been mixed, with some patients stabilizing and others progressing. There is no definitive evidence in favor of safe/effective use of melatonin in cancer patients.

Chemotherapy side effects Researchers have examined the effects of melatonin injections on side effects associated with various chemotherapies. Promising early results include reductions in nerve injury (neuropathy), mouth sores (stomatitis), wasting (cachexia), and platelet count drops (thrombocytopenia) with various chemotherapy agents. . Increased blood platelet counts after melatonin use have been observed in patients with decreased platelets due to cancer therapies.

Circadian rhythm entraining (in blind persons) In blind individuals, natural melatonin levels peak at a different hours every night to the point where individuals may sleep during the day and awake at night. Present studies and individual cases suggest that melatonin, administered in the evening, may correct circadian rhythm.

Depression (sleep disturbances) Melatonin may improve sleep patterns in depressed patients although research is limited in this area.

Glaucoma Patients with glaucoma taking melatonin should be monitored by a healthcare professional. Eye pressure may be altered.

Headache prevention Early research suggests possible benefits in treating headache. Further research is needed to confirm these results.

High blood pressure Early research suggests possible blood pressure lowering with melatonin. Further research is needed to confirm these results.

HIV / AIDS There is a lack of well-designed scientific evidence to recommend for or against the use of melatonin as a treatment for AIDS. Melatonin should not be used in place of more proven therapies, and patients with HIV/AIDS are advised to be treated under the supervision of a medical doctor and pharmacist.

Insomnia (of unknown origin in the non-elderly) In several small trials, some studies reported reduced time to fall asleep and subjective sleep quality; other research found no benefits. Better research is needed before a firm conclusion can be drawn.

Parkinson’s disease Due to very limited study to date, a recommendation cannot be made for or against the use of melatonin in Parkinsonism or Parkinson’s disease.

Periodic limb movement disorder There is very limited study to date for the use of melatonin as a treatment in periodic limb movement disorder.

Sedation before surgery/anxiety For sedation or anxiety reduction before general anesthesia for surgery, melatonin may work as well as benzodiazepines such as midazolam (Versed®), and better than a placebo. Melatonin may also work for sedation/anxiety reduction prior to magnetic resonance imaging (MRI). Melatonin has also been suggested as a treatment for delirium following surgery, although there is little evidence in this area.

REM sleep behavior disorder Limited case reports describe benefits in patients with dream (REM) sleep behavior disorder who receive melatonin. However, better research is needed before a clear conclusion can be drawn.

Rett syndrome Rett syndrome is a presumed genetic disorder that affects female children, characterized by decelerated head growth and overall developmental problems. There is limited study of the possible role of melatonin in improving sleep disturbance associated with Rett syndrome. Further research is needed before a recommendation can be made in this area.

Schizophrenia (sleep disorders) There is limited study of melatonin for decreasing the time to fall asleep in patients with schizophrenia. Further research is needed in this area before a clear conclusion can be reached.

Seasonal affective disorder (SAD There are several small, brief studies of melatonin in patients with SAD. Further study is necessary before a clear conclusion can be reached.

Seizure disorder (children) The role of melatonin in seizure disorder is controversial. Better scientific evidence is needed in this area before a clear conclusion can be drawn regarding the safety or effectiveness.

Sleep disturbances due to pineal region brain damage Several published cases report improvements in sleep patterns in young people with damage to the pineal gland area of the brain due to tumors or surgery. Consideration of melatonin in such patients should be under the direction of a qualified healthcare professional.

Sleep in asthma Based on early study, melatonin may improve sleep in patients with asthma. Further research is needed to confirm these results.

Smoking Melatonin may reduce symptoms associated with quitting smoking, such as anxiousness, restlessness, irritability, and cigarette craving. Further study is necessary before a firm conclusion can be reached.

Stroke Melatonin may reduce the amount of neurologic damage patients experience after stroke. More research is needed before a recommendation can be made.

Tardive dyskinesia Tardive dyskinesia (TD) is a serious potential side effect of antipsychotic drugs that cause involuntary muscle movements. Limited small studies of melatonin use in patients with TD report mixed findings.

Thrombocytopenia (low platelets) Increased platelet counts after melatonin use have been observed in patients with decreased platelets due to cancer therapies. Stimulation of platelet production (thrombopoeisis) has been suggested but not clearly demonstrated. Additional research is needed in this area before a clear conclusion can be drawn. Cases of idiopathic thrombocytopenic purpura (ITP) treated with melatonin have been reported.

Ultraviolet light skin damage protection Several small trials have examined the use of melatonin in protecting human skin against UV-light damage. Although this early research reports reductions in skin redness with the use of melatonin, further study is necessary before a clear conclusion can be drawn.

Work shift sleep disorder There are several studies of melatonin use in people who work irregular shifts, such as emergency room personnel. Results are mixed. Additional research is necessary before a clear conclusion can be drawn.

Unproven Uses

Melatonin has been suggested for many other uses, based on tradition or on scientific theories. However, these uses have not been thoroughly studied in humans, and there is limited scientific evidence about safety or effectiveness. Some of these suggested uses are for conditions that are potentially very serious and even life-threatening. You should consult a health care professional before taking melatonin for any unproven use.

Acetaminophen (Tylenol) toxicity Acute respiratory distress syndrome (ARDS) Aging Aluminum toxicity Alzheimer’s disease Amikacin-induced kidney damage Asthma Beta-blocker sleep disturbance Cachexia Cancer prevention Cardiac syndrome X Cognitive enhancement Colitis Contraception Coronary artery disease Critical illness/ICU sleep disturbance Cyclosporin-induced kidney toxicity Depression Edema Erectile dysfunction Fibromyalgia Gastroesophageal reflux disease (GERD) Gentamicin-Induced kidney damage Glaucoma Heart attack prevention Hyperpigmentation Immunostimulant Interstitial cystitis Intestinal motility disorders

Itching Lead toxicity Melatonin deficiency Memory enhancement Multiple sclerosis (MS) Neurodegenerative disorders Noise-induced hearing loss Pancreatitis Polycystic ovarian syndrome (PCOS) Postmenopausal osteoporosis Post-operative adjunct Post-operative delirium Prevention of post-lung transplant ischemia-reperfusion Injury Rheumatoid arthritis Sarcoidosis Sedation Sexual activity enhancement Schistosomiasis Sudden infant death syndrome (SIDS) prevention Tachycardia Tinnitus Toxic kidney damage Toxic liver damage Tuberculosis Tuberous sclerosis Ulcerative colitis Withdrawal from narcotics Wound healing

Potential Dangers

Allergies

There are rare reports of allergic skin reactions after taking melatonin by mouth. Melatonin has been linked to a case of autoimmune hepatitis (liver inflammation).

Side Effects

Based on available studies and clinical use, melatonin is generally regarded as safe in recommended doses for short-term use. However, case reports raise concerns about risks of blood clotting abnormalities (particularly in patients taking blood thinners like warfarin), increased risk of seizure, and disorientation with overdose.

Commonly reported side effects include fatigue, dizziness, headache, irritability, and sleepiness, disorientation, confusion, sleepwalking, vivid dreams and nightmares, nausea, vomiting, or cramping. Due to risk of daytime sleepiness, be careful when driving or operating heavy machinery.

Other side effects include changes in blood pressure, increased cholesterol, increased blood sugar, reduced glucose tolerance, reduced insulin sensitivity, increased risk of seizures, hallucinations, paranoia, hormonal changes, increased breast size in men, reduced sperm motility, mood changes, abnormal heart rhythms, fast heart rate, chest pain, autoimmune hepatitis, and triggering of Crohn’s disease symptoms.

People with seizure disorder, underlying major depression or psychotic disorders, high cholesterol, diabetes, or glaucoma should be closely monitored by a healthcare professional when taking melatonin.

Pregnancy And Breast-Feeding

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 the infant. In animal studies, melatonin is detected in breast milk and therefore should be avoided during breastfeeding. In men, decreased sperm motility and decreased sperm count have been reported with use of melatonin.

Interactions

Interactions with drugs, supplements and other herbs have not been thoroughly studied. The interactions listed below have been reported in scientific publications. If you are taking prescription drugs, speak with your health care professional or pharmacist before using herbs or dietary supplements.

Interactions With Drugs

Melatonin is broken down (metabolized) by the liver's "cytochrome P450" enzyme system. As a result, the levels of melatonin may be decreased in the blood by certain drugs. If you are using any medications, check the package insert and speak with your healthcare professional or pharmacist about possible interactions.

Increased daytime drowsiness is reported when melatonin is used at the same time as the prescription sleep-aid zolpidem (Ambien). Melatonin may increase the amount of drowsiness caused by other sedative drugs, for example benzodiazepines such as lorazepam (Ativan) or diazepam (Valium), barbiturates such as phenobarbital, narcotics such as codeine, some antidepressants, and alcohol. Due to risk of drowsiness, use caution when driving or operating machinery.

Based on early evidence, melatonin should be avoided in patients taking the blood-thinning medication warfarin (Coumadin), and possibly in patients using other blood-thinners anticoagulants) such as aspirin or heparin.

Multiple drugs are reported to lower natural levels of melatonin in the body. It is not clear that there are any health hazards of lowered melatonin levels, or if replacing melatonin with supplements is beneficial. Drugs that may reduce natural melatonin levels include non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen (Motrin, Advil) or naproxen (Naprosyn, Aleve); beta-blocker blood pressure medications such as atenolol (Tenormin) or metoprolol (Lopressor, Toprol); and drugs that reduce levels of vitamin B6 in the body (such as birth control pills, hormone replacement therapy, loop diuretics, hydralazine, theophylline). Other drugs that may alter melatonin levels include diazepam, vitamin B12, verapamil, temazepam, and somatostatin.

Melatonin should be avoided in patients taking drugs for seizures because it may lower 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.

Melatonin may cause drops in blood pressure; it is not known if melatonin causes further drops in blood pressure when taken with antihypertensive drugs. In contrast, blood pressure may increase when melatonin 5mg is taken at the same time as the calcium-channel blocker nifedipine.

Melatonin may elevate blood sugar levels. Patients taking drugs for diabetes by mouth or insulin should discuss melatonin use with a health care professional. Blood sugar levels may need to be monitored by a healthcare professional, and medication adjustments may be necessary.

Caffeine my interact with melatonin. Melatonin may increase the neuromuscular blocking effect of the muscle relaxant succinylcholine (not vecuronium), increase the adverse effects of methamphetamine, aid in reversing symptoms of tardive dyskinesia associated with haloperidol use, and increase the effects of isoniazid. Alcohol consumption seems to affect nocturnal melatonin secretion.

Interactions With Herbs And Dietary Supplements

Melatonin may increase daytime sleepiness or sedation when taken with herbs or supplements that may cause sedation. Examples of such herbs include 5-HTP and ashwagandha.

Elevated blood sugar levels have been reported. Caution is advised when using herbs or supplements that may also raise blood sugar levels, such as arginine and DHEA.

Melatonin may increase the risk of bleeding when taken with herbs and supplements that are believed to increase the risk of bleeding. Multiple cases of bleeding have been reported with the use of Ginkgo biloba, and fewer cases with garlic and saw palmetto. Numerous other agents may theoretically increase the risk of bleeding, although this has not been proven in most cases. Some examples include: alfalfa and American ginseng.

Chasteberry may increase melatonin levels. Severe folate deficiency may reduce the body’s natural levels of melatonin. DHEA and melatonin may stimulate immune function.

Echinacea and melatonin may reduce immune function.

It is not clear if caffeine alters the effects of melatonin supplements in humans.

Dosing

The doses listed below are based on scientific research, publications or traditional use. Because most herbs and supplements have not been thoroughly studied or monitored, safety and effectiveness may not be proven. Brands may be made differently, with variable ingredients even within the same brand. Combination products often contain small amounts of each ingredient and may not be effective. The appropriate dosing should be discussed with a health care professional before starting therapy; always read the recommendations on a product's label. The dosing for unproven uses should be approached cautiously, because scientific information is limited in these areas.

General

Children (Younger Than 18)

There is not enough scientific evidence to recommend melatonin supplements for children at this time. Use of melatonin should be discussed with the child’s physician and pharmacist before starting.

Alzheimer’s Disease (sleep disturbances)

Adults (Aged 18 Or Older)

A dose of 0.5 milligrams of melatonin has been taken nightly by mouth one hour prior to sleep.

Bipolar disorder (sleep disturbances)

Adults (Aged 18 Or Older)

A dose of 10 milligrams of melatonin taken nightly by mouth has been taken.

Cancer

Adults (Aged 18 Or Older)

Various doses of melatonin have been studied in patients with cancer, usually given in addition to other standard treatments such as chemotherapy, radiation therapy, or immune therapy. Doses have ranged between 10 and 50 milligrams taken nightly, with a common dose being 20 milligrams nightly.

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 before considering use of melatonin either alone or with other therapies. Safety and effectiveness are not proven, and melatonin should not be used instead of more proven therapies.

Circadian rhythm entraining (in blind persons)

Adults (Aged 18 Or Older)

A dose of 5 to10 milligrams of melatonin taken by mouth, administered in the evening.

Children (Younger Than 18)

A dose of 2.5 to 10 milligrams of melatonin has been taken by mouth nightly at the desired bedtime.

Critical illness/ICU sleep disturbance

Adults (Aged 18 Or Older)

A dose of 3 milligrams of melatonin taken nightly by mouth.

Delayed sleep phase syndrome

Adults (Aged 18 Or Older)

A dose of 5 milligrams of melatonin has been taken by mouthfive hours prior to bedtime.

Depression (sleep disturbances)

Adults (Aged 18 Or Older)

A dose of 5 milligrams of melatonin has been taken nightly by mouth.

Headache prevention

Adults (Aged 18 Or Older)

A regular dose of 5 to 10 milligrams of melatonin has been taken nightly by mouth.

High blood pressure

Adults (Aged 18 Or Older)

A dose of 1 to 3 milligrams of melatonin has been taken daily by mouth for short periods of time. Intranasal melatonin (1% solution in ethanol) at a dose of 2 milligrams daily for one week has also been taken.

Insomnia in the elderly

Adults (Aged 18 Or Older)

Studies have evaluated melatonin taken by mouth 30 to 120 minutes prior to bedtime for insomnia in the elderly. Low doses (0.1 to 0.3 milligrams taken nightly) appear to be equally effective as higher doses (3 to 5 milligrams nightly).

Insomnia of unknown origin (in the non-elderly)

Adults (Aged 18 Or Older)

Doses ranging from 1 to 5 milligrams have been taken by mouth shortly before bedtime.

Jet lag

Adults (Aged 18 Or Older)

Melatonin may be started on the day of travel (close to the target bedtime at the destination), then taken every 24 hours for several days. Various doses have been used and studied, including low doses between 0.1-0.5 milligrams, a more common dose of 5 milligrams, and a higher dose of 8 milligrams. Overall, 0.5 milligrams appears to be slightly less effective than 5 milligrams for improvement of sleep quality and latency, although this area remains controversial and other research suggests no differences. Slow-release melatonin may not be as effective as standard (quick release) formulations. If the dose is taken too early in the day, it may actually result in excessive daytime sleepiness and greater difficulty adapting to the destination time zone.

Preoperative anxiety

Children (Younger Than 18)

Melatonin 0.1, 0.25 or 0.5 milligrams per kilogram has been studied for alleviating preoperative anxiety in children. Further research is needed to confirm these results.

Schizophrenia (sleep disturbances)

Adults (Aged 18 Or Older)

A dose of 2 milligrams of controlled-release melatonin has been taken by mouth for three weeks.

Seasonal affective disorder

Adults (Aged 18 Or Older)

A dose of 0.25 to 5 milligrams of melatonin has been taken by mouth daily.

Seizure disorder

Children (Younger Than 18)

A dose of 5 to 10 milligrams of melatonin has been taken by mouth. Research is limited in this area, and there are other reports that melatonin may actually increase risk of seizure or lower seizure threshold. Therefore, caution is advised, and use of melatonin should be discussed with the child’s physician and pharmacist.

Sleep enhancement in healthy people

Adults (Aged 18 Or Older)

Various doses of melatonin have been taken by mouth 30 to 60 minutes before bedtime including 0.1, 0.3, 1, 3, 5, and 6 milligram doses. Studies report that 0.1 to 0.3 milligrams may produce melatonin levels in the body within the normal physiologic range of nighttime melatonin, and may be sufficient. Research suggests that quick-release melatonin may be more effective than sustained-release formulations.

Sleep disturbances in children with neuro-psychiatric disorders (mental retardation, autism, psychiatric disorders)

Children (Younger Than 18)

A dose of 0.5 to 10 milligrams of melatonin has been taken nightly by mouth. Fast release melatonin may be most useful for sleep induction and the slow release formulation for sleep maintenance.

Other

Adults (Aged 18 Or Older)

There are other uses with limited study and unclear effectiveness or safety. Use of melatonin for these conditions should be discussed with a primary healthcare professional and should not be substituted for more proven therapies.

Summary

Melatonin is a neurohormone produced in the brain. 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 sedation and disorders related to sleep.

Melatonin may affect cholesterol levels, blood sugar levels, and blood pressure levels. People with seizure disorder, underlying major depression or psychotic disorders, high or low blood pressure, high cholesterol, diabetes, or glaucoma should be closely monitored by a healthcare professional when taking melatonin.

The information in this monograph was prepared by the professional staff at Natural Standard, based on thorough systematic review of scientific evidence. The material was reviewed by the Faculty of the Harvard Medical School with final editing approved by Natural Standard.

Resources

1. Natural Standard: An organization that produces scientifically based reviews of complementary and alternative medicine (CAM) topics

2. National Center for Complementary and Alternative Medicine (NCCAM): A division of the U.S. Department of Health & Human Services dedicated to research

Selected Scientific Studies: Melatonin

Natural Standard reviewed more than 2000 articles to prepare the professional monograph from which this version was created.

Some of the more recent studies are listed below:

1. Almeida Montes LG, Ontiveros Uribe MP, Cortes SJ, et al. Treatment of primary insomnia with melatonin: a double-blind, placebo-controlled, crossover study. J Psychiatry Neurosci 2003;28(3):191-196.

2. Andrade C, Srihari BS, Reddy KP, et al. Melatonin in medically ill patients with insomnia: a double-blind, placebo-controlled study. J Clin Psychiatry 2001;62(1):41-45.

3. Atkinson G, Buckley P, Edwards B, et al. Are there hangover-effects on physical performance when melatonin is ingested by athletes before nocturnal sleep? Int J Sports Med 2001;22(3):232-234.

4. Baskett JJ, Broad JB, Wood PC, et al. Does melatonin improve sleep in older people? A randomised crossover trial. Age Ageing 2003;32(2):164-170.

5. Beloosesky Y, Grinblat J, Laudon M, et al. Melatonin rhythms in stroke patients. Neurosci Lett 2002;319(2):103-106.

6. Bordet R, Devos D, Brique S, et al. Study of circadian melatonin secretion pattern at different stages of Parkinson's disease. Clin Neuropharmacol 2003;26(2):65-72.

7. Cagnacci A, Arangino S, Renzi A, et al. Influence of melatonin administration on glucose tolerance and insulin sensitivity of postmenopausal women. Clin Endocrinol (Oxf) 2001;54(3):339-346.

8. Cagnacci A, Arangino S, Angiolucci M, et al. Effect of exogenous melatonin on vascular reactivity and nitric oxide in postmenopausal women: role of hormone replacement therapy. Clin Endocrinol (Oxf) 2001;54(2):261-266.

9. Cagnacci A, Volpe A. A role for melatonin in PCOS? Fertil Steril 2002;77(5):1089.

10. Calvo JR, Guerrero JM, Osuna C, et al. Melatonin triggers Crohn's disease symptoms. J Pineal Res 2002;32(4):277-278.

11. Campos FL, Silva-Junior FP, de Bruin VM, et al. Melatonin improves sleep in asthma: a randomized, double-blind, placebo-controlled study. Am J Respir Crit Care Med 2004;170(9):947-951.

12. Cardinali DP, Gvozdenovich E, Kaplan MR. A double blind-placebo controlled study on melatonin efficacy to reduce anxiolytic benzodiazepine use in the elderly. Neuroendocrinol Lett 2002;23(1):55-60.

13. Cardinali DP, Brusco LI, Liberczuk C. The use of melatonin in Alzheimer's disease. Neuroendocrinol Lett 2002;23(Suppl 1):20-23.

14. Cerea G, Vaghi M, Ardizzoia A, et al. Biomodulation of cancer chemotherapy for metastatic colorectal cancer: a randomized study of weekly low-dose irinotecan alone versus irinotecan plus the oncostatic pineal hormone melatonin in metastatic colorectal cancer patients progressing on 5-fluorouracil-containing combinations. Anticancer Res 2003;23(2C):1951-1954.

15. Cocco P, Cocco ME, Paghi L, et al. Urinary 6-sulfatoxymelatonin excretion in humans during domestic exposure to 50 hertz electromagnetic fields. Neuro Endocrinol Lett 2005;26(2):136-142.

16. Dalton EJ, Rotondi D, Levitan RD, et al. Use of slow-release melatonin in treatment-resistant depression. J Psychiatry Neurosci 2000;25(1):48-52.

17. Dericks-Tan JS, Schwinn P, Hildt C. Dose-dependent stimulation of melatonin secretion after administration of agnus castus. Exp Clin Endocrinol Diabetes 2003;111(1):44-46.

18. Dodge NN, Wilson GA. Melatonin for treatment of sleep disorders in children with developmental disabilities. J Child Neurol 2001;16(8):581-584.

19. Gagnier JJ. The therapeutic potential of melatonin in migraines and other headache types. Altern Med Rev 2001;6(4):383-389.

20. Gulcin I, Buyukokuroglu ME, Oktay M, et al. On the in vitro antioxidative properties of melatonin. J Pineal Res 2002;33(3):167-171.

21. Gulcin I, Buyukokuroglu ME, Kufrevioglu OI. Metal chelating and hydrogen peroxide scavenging effects of melatonin. J Pineal Res 2003;34(4):278-281.

22. Hanania M, Kitain E. Melatonin for treatment and prevention of postoperative delirium. Anesth Analg 2002;94(2):338-9, table.

23. Hartter S, Wang X, Weigmann H, et al. Differential effects of fluvoxamine and other antidepressants on the biotransformation of melatonin. J Clin Psychopharmacol 2001;21(2):167-174.

24. Hayashi E. Effect of melatonin on sleep-wake rhythm: the sleep diary of an autistic male. Psychiatry Clin Neurosci 2000;54(3):383-384.

25. Jan JE, Hamilton D, Seward N, et al. Clinical trials of controlled-release melatonin in children with sleep- wake cycle disorders. J Pineal Res 2000;29(1):34-39.

26. Jan JE, Freeman RD. Re: Mann--melatonin for ulcerative colitis? Am J Gastroenterol 2003;98(6):1446.

27. Jan MM. Melatonin for the treatment of handicapped children with severe sleep disorders. Pediatr Neurol 2000;23(3):229-232.

28. Jarupat S, Kawabata A, Tokura H, et al. Effects of the 1900 MHz electromagnetic field emitted from cellular phone on nocturnal melatonin secretion. J Physiol Anthropol Appl Human Sci 2003;22(1):61-63.

29. Jockovich M, Cosentino D, Cosentino L, et al. Effect of exogenous melatonin on mood and sleep efficiency in emergency medicine residents working night shifts. Acad Emerg Med 2000;7(8):955-958.

30. Karasek M, Czernicki J, Woldanska-Okonska M, et al. Chronic exposure to 25-80-microT, 200-Hz magnetic field does not influence serum melatonin concentrations in patients with low back pain. J Pineal Res 2000;29(2):81-85.

31. Karasek M, Lerchl A. Melatonin and magnetic fields. Neuroendocrinol Lett 2002;23 Suppl 1:84-87.

32. Kayumov L, Brown G, Jindal R, et al. A randomized, double-blind, placebo-controlled crossover study of the effect of exogenous melatonin on delayed sleep phase syndrome. Psychosom Med 2001;63(1):40-48.

33. Kitajima T, Kanbayashi T, Saitoh Y, et al. The effects of oral melatonin on the autonomic function in healthy subjects. Psychiatry Clin Neurosci 2001;55(3):299-300.

34. Kripke DF, Youngstedt SD, Rex KM, et al. Melatonin excretion with affect disorders over age 60. Psychiatry Res 2003;118(1):47-54.

35. Kunz D, Bes F. Exogenous melatonin in periodic limb movement disorder: an open clinical trial and a hypothesis. Sleep 2001;24(2):183-187.

36. Leppamaki S, Partonen T, Vakkuri O, et al. Effect of controlled-release melatonin on sleep quality, mood, and quality of life in subjects with seasonal or weather-associated changes in mood and behaviour. Eur Neuropsychopharmacol 2003;13(3):137-145.

37. Lewinski A, Karbownik M. REVIEW. Melatonin and the thyroid gland. Neuroendocrinol Lett 2002;23 Suppl 1:73-78.

38. Lissoni P, Rovelli F, Malugani F, et al. Anti-angiogenic activity of melatonin in advanced cancer patients. Neuroendocrinol Lett 2001;22(1):45-47.

39. Lissoni P, Bucovec R, Bonfanti A, et al. Thrombopoietic properties of 5-methoxytryptamine plus melatonin versus melatonin alone in the treatment of cancer-related thrombocytopenia. J Pineal Res 2001;30(2):123-126.

40. Lissoni P, Vaghi M, Ardizzoia A, et al. A phase II study of chemoneuroimmunotherapy with platinum, subcutaneous low-dose interleukin-2 and the pineal neurohormone melatonin (P.I.M.) as a second-line therapy in metastatic melanoma patients progressing on dacarbazine plus interferon-alpha. In Vivo 2002;16(2):93-96.

41. Lockley SW, Skene DJ, James K, et al. Melatonin administration can entrain the free-running circadian system of blind subjects. J Endocrinol 2000;164(1):R1-R6.

42. Luboshitzky R, Shen-Orr Z, Nave R, et al. Melatonin administration alters semen quality in healthy men. J Androl 2002;23(4):572-578.

43. Lusardi P, Piazza E, Fogari R. Cardiovascular effects of melatonin in hypertensive patients well controlled by nifedipine: a 24-hour study. Br J Clin Pharmacol 2000;49(5):423-427.

44. Mann S. Melatonin for ulcerative colitis? Am J Gastroenterol 2003;98(1):232-233.

45. Mayo JC, Tan DX, Sainz RM, et al. Protection against oxidative protein damage induced by metal-catalyzed reaction or alkylperoxyl radicals: comparative effects of melatonin and other antioxidants. Biochim Biophys Acta 2003;1620(1-3):139-150.

46. Mohanan PV, Yamamoto HA. Preventive effect of melatonin against brain mitochondria DNA damage, lipid peroxidation and seizures induced by kainic acid. Toxicol Lett 2002;129(1-2):99-105.

47. Morera AL, Henry M, Villaverde-Ruiz ML, et al. [Efficiency of melatonin in the treatment of insomnia]. Actas Esp Psiquiatr 2000;28(5):325-329.

48. Naguib M, Samarkandi AH. The comparative dose-response effects of melatonin and midazolam for premedication of adult patients: a double-blinded, placebo-controlled study. Anesth Analg 2000;91(2):473-479.

49. Nelson LA, McGuire JM, Hausafus SN. Melatonin for the treatment of tardive dyskinesia. Ann Pharmacother 2003;37(7-8):1128-1131.

50. Nishiyama K, Yasue H, Moriyama Y, et al. Acute effects of melatonin administration on cardiovascular autonomic regulation in healthy men. Am Heart J 2001;141(5):E9.

51. Norman TR, Piccolo J, Voudouris N, et al. The effect of single oral doses of zopiclone on nocturnal melatonin secretion in healthy male volunteers. Prog Neuropsychopharmacol Biol Psychiatry 2001;25(4):825-833.

52. Paavonen EJ, Nieminen-Von Wendt T, Vanhala R, et al. Effectiveness of melatonin in the treatment of sleep disturbances in children with asperger disorder. J Child Adolesc Psychopharmacol 2003;13(1):83-95.

53. Pillar G, Shahar E, Peled N, et al. Melatonin improves sleep-wake patterns in psychomotor retarded children. Pediatr Neurol 2000;23(3):225-228.

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