Scientific Name: Melatonin
Other Names: MEL, MLT, N-acetyl-5-methoxytryptamine

Who is this for?

Uses

In the United States, supplemental melatonin is taken mostly for the short-term relief of sleep disturbances—especially jet lag. Results from several controlled studies show that melatonin taken before, during, and after long-distance travel may lessen or prevent sleep disruption. In addition, melatonin may be associated with less daytime drowsiness than prescription sleeping pills. For individuals who have delayed sleep phase syndrome, which keeps them awake long into the night and delays their wake-up times, taking melatonin may help to establish a more conventional sleep-wake cycle. A recent analysis of several studies, however, found that taking melatonin did not improve sleeping significantly for individuals with jet lag or shift changes. It also failed to show a clinically relevant effect on sleep problems due to physical or mental illnesses. Why some individuals with sleep disorders seem to respond to melatonin supplementation while others apparently do not remains to be proved.

Although it is not approved in the United States as a regular prescription drug, melatonin does have a special orphan drug designation from the U.S. Food and Drug Administration (FDA). An orphan drug has extremely limited uses, such as for the treatment of a rare disease. Melatonin is prescribed as an orphan drug for blind individuals who suffer from sleep disturbances because their daily rhythm is distorted by the lack of light-and-dark effects that help to regulate sleeping cycles in sighted individuals. Melatonin is also available as a dietary supplement without a prescription.

For about 15 years, melatonin supplementation has been studied extensively—mainly in Europe—for treating cancer. In studies conducted in laboratory animals or human cancer cell cultures, melatonin appeared to keep some types of tumors from spreading as rapidly as untreated tumors. Several studies have also been conducted in humans with advanced tumors. In general, supplemental melatonin appeared to help prevent or delay the spread of tumors for many of these individuals, theoretically by keeping cancer cells from absorbing and using an essential fatty acid that is necessary to cancer cell survival and growth. Much more study is needed to confirm this finding. In animal studies, certain cancers, such as leukemia, may have been worsened by supplemental melatonin. For the treatment of cancer, melatonin is most often injected into muscle tissue, but injectable melatonin is not available for use in the United States.

Other current research indicates that melatonin is concentrated in specific cells (which also produce large amounts of natural melatonin) in the stomach and intestines. Among other effects, this gastrointestinal (GI) melatonin blocks the production of stomach acid. GI melatonin also increases blood circulation through the small blood vessels in the lining of the stomach, the intestines, and the pancreas. It may have an immune-boosting effect on tissues in the GI tract, as well. Decreased stomach acid, increased blood flow, and enhanced immune function may all help to heal ulcers and prevent damage caused when non-steroidal anti-inflammatory drugs are taken on a long-term basis. Additionally, the antioxidant effects of melatonin may help to relieve inflammatory bowel diseases.

While clinical research continues for the use of melatonin in many other conditions, no definitive results prove that melatonin is effective for any of them. Examples of ongoing study include:

In recent studies, melatonin has shown some value for easing withdrawal symptoms for individuals who have become dependent on benzodiazepine drugs. Benzodiazepines are often used for relieving insomnia or anxiety, but long-term use may result in dependence.

Other studies show that melatonin supplements may also be useful in helping individuals who are trying to stop smoking.

Melatonin supplements have also shown some effectiveness in lowering blood pressure levels in several human studies and reducing blood cholesterol levels in limited animal studies.

Taking melatonin may increase appetite and lead to weight gain for individuals who lose muscle tissue because they have serious chronic illnesses such as AIDS.

In another study, supplemental melatonin may have prevented cluster headaches in individuals susceptible to having that type of headache.

Because very high oral doses of melatonin are believed to decrease fertility for women, some inconclusive research has been done into its use as a contraceptive.

In other studies, a liquid form of melatonin was applied to the skin to protect from ultraviolet light and sunburn. Injected melatonin has helped to reduce the damage from burns on the skin of laboratory animals.

Very early studies in laboratory animals suggest that melatonin may help to prevent or delay the development of Type 1 diabetes and Alzheimer’s disease.

Although melatonin may be given in hospitals to premature infants at risk of developing lung problems, the use of supplemental melatonin for children is not recommended. Because naturally produced melatonin has a role in the development of sexual organs, melatonin supplementation could interfere with normal sexual development.

In high doses, melatonin may hamper the ability to get pregnant by decreasing female fertility. Women who are trying to conceive should not take melatonin. Because it is not known how melatonin affects a pregnant woman or a developing fetus, supplemental melatonin should be avoided during pregnancy.

Melatonin is broken down in the liver, so individuals who drink large amounts of alcoholic beverages and those with known or suspected liver diseases should avoid taking it. If liver function is diminished, high levels of melatonin could build up in the blood, possibly leading to side effects.

Melatonin may promote both immune response and inflammation, making it inappropriate for individuals with autoimmune conditions. Various autoimmune conditions include:

• Crohn's disease
• Multiple Sclerosis (MS)
• Psoriasis
• Rheumatoid Arthritis (RA)
• Systemic Lupus Erythematosus (SLE)
• Type 1 diabetes

Precautions

Some reliable evidence suggests that melatonin supplementation can worsen symptoms for individuals with depression. People who have depression or bipolar disorder should use it only with the supervision of a health professional.

Melatonin can cause drowsiness, so individuals who operate heavy machinery or perform other tasks that require alertness should avoid its use.

Women who are breast-feeding should avoid taking melatonin because not enough is known about its potential effects on infants.

In animal studies, melatonin has decreased the activity of the thyroid gland. Although similar effects have not been seen in humans, individuals with thyroid conditions should consult a doctor before taking melatonin.

What side effects should I watch for?

Major Side Effects

Melatonin can affect the normal body production or the supplemental use of certain hormones. Blood levels of human growth hormone (HGH) may be increased, while luteinizing hormone (LH) may be decreased. HGH stimulates growth in children and helps to regulate metabolism in adults. LH is important in the development of eggs and sperm. Other hormones may be affected, too. While no serious results have been identified, laboratory tests for these hormones may be inaccurate if the tests are performed during the same period that melatonin is taken. Individuals who take melatonin should inform their doctors before having any laboratory blood work.

Less Severe Side Effects

Other side effects reported by individuals taking melatonin include:

• Abdominal cramps
• Confusion
• Depression
• Dizziness
• Drowsiness
• Fatigue
• Headache
• Irritability
• Low blood pressure
• Nausea
• Vomiting

What interactions should I watch for?

Prescription Drugs

Studies have revealed that melatonin may interfere with the blood pressure-lowering effects of nifedipine GITS (Procardia XL). As a result, blood pressure was not controlled. Another medication used for blood pressure, verapamil (Calan, Isoptin, Verelan), reduced the effectiveness of melatonin when they were taken at the same time. Whether melatonin and other high blood pressure medicines interact is not known. Individuals who take medicine for high blood pressure should talk to a doctor or pharmacist before taking melatonin.

Fluvoxamine is an antidepressant that is known to increase natural melatonin production. It may also increase blood levels of melatonin if it is taken at the same time as melatonin supplements. If fluvoxamine and melatonin are taken together, the risk for side effects of melatonin may be increased. Other antidepressant medications may also interact with melatonin. Individuals who take an antidepressant should not take melatonin.

Some preliminary evidence suggests that melatonin can decrease some of the side effects, such as damage to the heart, kidneys, and liver, that may be caused by the immunosuppressant drug, cyclosporine (Neoral, Sandimmune). However, because it can enhance immune system function, melatonin may interfere with the effects of drugs used to suppress the immune system after organ transplants or in other conditions. Taking melatonin is not recommended for patients who take cyclosporine and related drugs such as:

• azathioprine (Imuran)
• CellCept
• corticosteroids
• Prograf
• Rapamune
• Zenapak

Melatonin opposes the action of natural corticosteroids and corticosteroid drugs, which are used for a wide range of inflammatory conditions including arthritis, asthma, cancer, eye conditions, and skin infections. When supplemental melatonin is taken at the same time as a corticosteroid drug, the effects of the corticosteroid may be decreased. It is best not to take melatonin and corticosteroids at the same time. Commonly prescribed corticosteroids include:

• beclomethasone (Beconase, Vancenase)
• dexamethasone (Decadron)
• hydrocortisone
• methylprednisolone (Medrol)
• prednisolone
• prednisone
• triamcinolone (Azmacort, Nasacort)

When melatonin is used with prescription drugs that promote sleepiness, the effects of the drug may be exaggerated, resulting in sedation or mental impairment. Prescription drugs that may cause sleepiness include:

• Anticonvulsants such as carbamazepine, phenytoin, and valproic acid (Depakote)
• Barbiturates such as phenobarbital
• Benzodiazepines such as alprazolam and diazepam (Valium)
• Drugs for insomnia such as Sonata and zolpidem
• Tricyclic antidepressants such as amitriptyline, amoxapine, doxepin and nortriptyline

In animal studies, melatonin has increased the anti-seizure effects of the anticonvulsant drugs, carbamazepine (Tegretol) and phenytoin (Dilantin).

Non-prescription Drugs

The sleep-producing effects of over-the-counter products containing diphenhydramine or doxylamine can be enhanced by taking melatonin at the same time. Diphenhydramine and doxylamine are contained in many over-the-counter sleep aids as well as in some cough and cold products, therefore caution should be used when taking these medications with melatonin because excessive drowsiness may result.

Herbal Products

Melatonin may cause excessive sedation if taken with sedating herbs such as:

• Catnip
• Hops
• Kava
• St. John's Wort
• Valerian

Foods

In several small studies of humans, caffeine has been shown to reduce the amounts of melatonin that the body produces naturally and also to block supplemental melatonin.

No other interactions between melatonin and foods have been reported, but drinking alcohol at the same time as taking melatonin may result in increased drowsiness.

Some interactions between herbal products and medications can be more severe than others. The best way for you to avoid harmful interactions is to tell your doctor and/or pharmacist what medications you are currently taking, including any over-the-counter products, vitamins, and herbals. For specific information on how melatonin interacts with drugs, other herbals, and foods and the severity of those interactions, please use our Drug Interactions Checker to check for possible interactions.

Should I take it?

Melatonin is a hormone primarily produced naturally by the pineal gland of mammals. In humans, the pineal gland is a very small organ located in the brain. Sensitive to light, it produces melatonin only during darkness—with production increasing approximately an hour or so before an individual’s customary sleeping times and then decreasing before usual awakening times. It is now believed that other body tissues, such as the gastrointestinal tract and the retinas, also produce small amounts of melatonin. Children begin producing melatonin at about 3 months of age. Its production increases until about age 20 and then drops off as individuals age. By age 80, natural melatonin levels are estimated at 20% of their peak levels. Melatonin production also appears to be reduced in conditions such as dementia, which are usually associated with aging.

In humans, melatonin affects daily cycles, also called circadian rhythms, such as sleep and body temperature. In other mammals, melatonin plays a role in seasonal changes such as hibernation. Melatonin also seems to promote growth and sexual maturity and it may assist in maintaining balance. Low levels of melatonin have been associated with depression, fibromyalgia, insomnia, some seizure disorders, and other conditions.

Supplemental melatonin should be synthetic—derived from sources that are not animal or human. In the past, some melatonin products were made from animal tissue, which carried the risk of possible contamination with viruses and other toxins. Because of concerns with contamination and safety, Japan currently prohibits the sale of melatonin supplements and Britain restricts their use.

Dosage and Administration

In the United States, supplemental melatonin is most readily available as capsules and tablets—some in controlled-release forms that deliver measured doses of melatonin over extended periods. It also comes in a tablet that dissolves under the tongue. Dosing recommendations vary considerably, with a wide range between 0.1 mg and 10 mg used in studies for various conditions. However, to promote sleep, doses over 0.5 mg generally were no more effective than lower doses. In clinical studies, melatonin has been used for as long as 9 months, but most commonly it is used for a few days at a time. Common recommendations for its use include:

Insomnia: 0.3 mg to 5 mg at bedtime
Jet lag: 0.5 mg to 5 mg at bedtime for up to 5 days, beginning on the day before the trip
Smoking cessation: 0.3mg taken 3 hours to 4 hours after the last cigarette
Benzodiazepine withdrawal: 2 mg controlled-release daily at bedtime for 6 weeks as the benzodiazepine dose is gradually decreased

Individuals who choose to use melatonin should follow exactly the directions on the package of the product that is purchased.

Summary

In the United States, melatonin is used mainly for regulating disturbed sleep that may be caused by traveling across multiple time zones or changing shifts at work.

Melatonin may also have limited usefulness for treating some types of cancer, helping individuals dependent on benzodiazepines to withdraw from the drugs, and assisting smokers to quit smoking. Other uses may include preventing both cluster headaches and sunburn. However, it has not yet been found effective for any of these uses.

Risks

Women who are pregnant or breast-feeding, or who are trying to conceive should not use melatonin supplements. Melatonin may affect fertility in women trying to conceive, and not enough is known about its potential effects on fetal and infant development and growth to recommend it for pregnant or breast-feeding women. Because natural melatonin appears to have an effect on sexual development, supplemental melatonin should not be given to children. Melatonin should also be avoided by individuals with liver conditions, because it may accumulate in the blood—possibly causing side effects. Individuals with depressive disorders should only use supplemental melatonin if a doctor recommends it because melatonin may cause or worsen symptoms of depression. Because melatonin can cause drowsiness, individuals who take it should be careful when performing tasks that require alertness.

Side Effects

Melatonin may affect the body's production and use of some hormones.

In addition, it can cause:

• Abdominal cramps, nausea, and vomiting
• Confusion, drowsiness, and dizziness
• Headache and irritability
• Low blood pressure

Interactions

Melatonin may interfere with the effectiveness of:

• Antidepressants
• Corticosteroids
• Drugs for high blood pressure
• Immunosuppressants
• Sedatives

Melatonin may also increase sleepiness caused by some prescription, non-prescription, and herbal products and by alcohol.

Caffeine may decrease the effectiveness of melatonin.

Last Revised May 16, 2007

References

Anisimov VN. Effects of exogenous melatonin--a review. Toxicology and Pathology. 2003;31(6):589-603.

Anon: Melatonin. In: DerMarderosian A, Beutler JA, eds. Facts and Comparisons: The Review of Natural Products. St. Louis, MO, Facts and Comparisons. January 2002.

Attenburrow ME, Cowen PJ, Sharpley AL. Low dose melatonin improves sleep in healthy middle-aged subjects. Psychopharmacology (Berlin). 1996;126(2):179-181.

Avery D, Lenz M, Landis C. Guidelines for prescribing melatonin. Annals of Medicine. 1998;30(1):122-130.

Bain KT. Management of chronic insomnia in elderly persons. American Journal of Geriatric Pharmacotherapy. 2006;4(2):168-192.

Baltaci AK, Mogulkoc R, Kul A, Bediz CS, Ugur A. Opposite effects of zinc and melatonin on thyroid hormones in rats. Toxicology. 2004;195(1):69-75.

Bandyopadhyay D, Ghosh G, Bandyopadhyay A, Reiter RJ. Melatonin protects against piroxicam-induced gastric ulceration. Journal of Pineal Research. 2004;36(3):195-203.

Bangha E, Elsner P, Kistler GS. Suppression of UV-induced erythema by topical treatment with melatonin (N-acetyl-5-methoxytryptamine). A dose response study. Archives of Dermatology Research. 1996;288(9):522-526.

Bazil CW, Short D, Crispin D, Zheng W. Patients with intractable epilepsy have low melatonin, which increases following seizures. Neurology. 2000;55(11):1746-1748.

Beaumont M, Batejat D, Pierard C, et al. Caffeine or melatonin effects on sleep and sleepiness after rapid eastward transmeridian travel. Journal of Applied Physiology. 2004;96(1):50-58.

Bellipanni G, Bianchi P, Pierpaoli W, Bulian D, Ilyia E. Effects of melatonin in perimenopausal and menopausal women: a randomized and placebo controlled study. Experimental Gerontology. 2001;36(2):297-310.

Blask DE, Dauchy RT, Sauer LA. Putting cancer to sleep at night: the neuroendocrine/circadian melatonin signal. Endocrine. 2005;27(2):179-188.

Bonilla E, Valero N, Chacin-Bonilla L, Medina-Leendertz S. Melatonin and viral infections. Journal of Pineal Research. 2004;36(2):73-79.

Bregani ER, Lissoni P, Rossini F, et al. Prevention of interleukin-2-induced thrombocytopenia during the immunotherapy of cancer by a concomitant administration of the pineal hormone melatonin. Recent Progress in Medicine. 1995;86(6):231-233.

Brinker F. Herb Contraindications and Drug Interactions. 2nd ed. Sandy, OR: Eclectic Medical Publications, 1998.

Brusco LI, Fainstein I, Marquez M, Cardinali DP. Effect of melatonin in selected populations of sleep-disturbed patients. Biological Signals and Receptors. 1999;8(1-2):126-131.

Bubenik GA. Gastrointestinal melatonin: localization, function, and clinical relevance. Digestive Diseases Science. 2002;47(10):2336-2348.

Bubenik GA. Localization, physiological significance and possible clinical implication of gastrointestinal melatonin. Biologic Signals and Receptors. 2001;10(6):350-366.

Bubenik GA, Blask DE, Brown GM, Maestroni GJ, Pang SF, Reiter RJ, et al. Prospects of the clinical utilization of melatonin. Biological Signals and Receptors. 1998;7(4):195-219.

Bubenik GA, Dhanvantari S. Influence of serotonin and melatonin on some parameters of gastrointestinal activity. Journal of Pineal Research. 1989;7(4):333-344.

Cagnacci A, Krauchi K, Wirz-Justice A, Volpe A. Homeostatic versus circadian effects of melatonin on core body temperature in humans. Journal of Biological Rhythms. 1997;12(6):509-517.

Cardinali DP, Garcia AP, Cano P, Esquifino AI. Melatonin role in experimental arthritis. Current Drug Targets for Immune, Endocrine and Metabolic Disorders. 2004;4(1):1-10.

Carman JS, Post RM, Buswell R, Goodwin FKl. Negative effects of melatonin on depression. American Journal of Psychiatry. 1976;(10):1181-1186.

Cavallo A, Ritschel WA. Pharmacokinetics of melatonin in human sexual maturation. Journal of Clinical Endocrinology and Metabolism. 1996;81(5):1882-1886.

Cavallo A, Daniels SR, Dolan LM, Bean JA, Khoury JC. Blood pressure-lowering effect of melatonin in type 1 diabetes. Journal of Pineal Research. 2004;36(4):262-266.

Cavallo A, Daniels SR, Dolan LM, Khoury JC, Bean JA. Blood pressure response to melatonin in type 1 diabetes. Pediatric Diabetes. 2004;5(1):26-31.

Clark AF. Incidences of new prescribing by British child and adolescent psychiatrists: a prospective study over 12 months. Journal of Psychopharmacology. 2004;18(1):115-120.

Claustrat B, Brun J, David M, Sassolas G, Chazot G. Melatonin and jet lag: confirmatory result using a simplified protocol. Biological Psychiatry. 1992;32(8):705-711.

Commentz JC, Uhlig H, Henke A, Hellwege HH, Willig RP. Melatonin and 6-hydroxymelatonin sulfate excretion is inversely correlated with gonadal development in children. Hormone Research. 1997;47(3):97-101.

Conti A, Maestroni GJ. Melatonin rhythms in mice: role in autoimmune and lymphoproliferative diseases. Annals of the New York Academy of Sciences. 1998;840:395-410.

Cupp MJ. Melatonin. American Family Physician. 1997;56(5):1421-1425 and 1428.

De Butte M, Pappas BA. Pinealectomy causes hippocampal CA1 and CA3 cell loss: reversal by melatonin supplementation. Neurobiology and Aging. 2007;28(2):306-313.

Djeridane Y, Touitou Y. Chronic diazepam administration differentially affects melatonin synthesis in rat pineal and Harderian glands. Psychopharmacology (Berlin). 2001;154(4):403-407.

Dolberg OT, Hirschmann S, Grunhaus L. Melatonin for the treatment of sleep disturbances in major depressive disorder. American Journal of Psychiatry. 1998;155(8):1119-1121.

Dollins AB, Lynch HJ, Wurtman RJ, et al. Effect of pharmacological daytime doses of melatonin on human mood and performance. Psychopharmacology (Berlin). 1993;112(4):490-496.

Dollins AB, Zhdanova IV, Wurtman RJ, Lynch HJ, Deng MH. Effect of inducing nocturnal serum melatonin concentrations in daytime on sleep, mood, body temperature, and performance. Proceedings of the National Academy of Sciences USA. 1994;91(5):1824-1828.

Dopfel RP, Schulmeister K, Schernhammer ES. Nutritional and lifestyle correlates of the cancer-protective hormone melatonin. Cancer Detection and Prevention. Epublished ahead of print. April 5, 2007.

Drake MJ, Mills IW, Noble JG. Melatonin pharmacotherapy for nocturia in men with benign prostatic enlargement. Journal of Urology. 2004;171(3):1199-1202.

Dreher F, Gabard B, Schwindt DA, Maibach HI. Topical melatonin in combination with vitamins E and C protects skin from ultraviolet-induced erythema: a human study in vivo. British Journal of Dermatology. 1998;139(2):332-339.

Ebadi M, Govitrapong P, Phansuwan-Pujito P, Nelson F, Reiter RJ. Pineal opioid receptors and analgesic action of melatonin. Journal of Pineal Research. 1998;24(4):193-200.

Elamin EM, Glass M, Camporesi E. Pharmacological approaches to ameliorating catabolic conditions. Current Opinion on Clinical Nutrition and Metabolic Care. 2006;9(4):449-454.

Ellis CM, Lemmens G, Parkes JD. Melatonin and insomnia. Journal of Sleep Research. 1996;5(1):61-65.

Erren TC, Piekarski C. Does winter darkness in the arctic protect against cancer? The melatonin hypothesis revisited. Medical Hypotheses .1999;53(1):1-5.

Esparza JL, Gómez M, Rosa Nogués M, Paternain JL, Mallol J, Domingo JL. Melatonin reduces oxidative stress and increases gene expression in the cerebral cortex and cerebellum of aluminum-exposed rats. Journal of Pineal Research. 2005;39(2):129-136.

Fei GH, Liu RY, Zhang ZH, Zhou JN. Alterations in circadian rhythms of melatonin and cortisol in patients with bronchial asthma. Acta Pharmacologia Sin. 2004;25(5):651-656.

Feng Z, Qin C, Chang Y, Zhang JT. Early melatonin supplementation alleviates oxidative stress in a transgenic mouse model of Alzheimer's disease. Free Radical Biology and Medicine. 2006;40(1):101-109.

Fischer S, Smolnik R, Herms M, Born J, Fehm HL. Melatonin acutely improves the neuroendocrine architecture of sleep in blind individuals. Journal of Clinical Endocrinology and Metabolism. 2003;88(11):5315-5320.

Fischer T, Bangha E, Elsner P, Kistler GS. Suppression of UV-induced erythema by topical treatment with melatonin. Influence of the application time point. Biological Signals and Receptors. 1999;8(1-2):132-135.

Fischer TW, Burmeister G, Schmidt HW, Elsner P. Melatonin increases anagen hair rate in women with androgenetic alopecia or diffuse alopecia: results of a pilot randomized controlled trial. British Journal of Dermatology. 2004;150(2):341-345.

Forsling ML, Wheeler MJ, Williams AJ. The effect of melatonin administration on pituitary hormone secretion in man. Clinical Endocrinology (Oxford). 1999;51(5):637-642.

Fraschini F, Cesarani A, Alpini D, Eposti D, Stankov BM. Melatonin influences human balance. Biological Signals and Receptors. 1999;8(1-2):111-119.

Garfinkel D, Laudon M, Nof D, Zisapel N. Improvement of sleep quality in elderly people by controlled-release melatonin. Lancet. 1995;346(8974):541-544.

Garfinkel D, Zisapel N, Wainstein J, Laudon M. Facilitation of benzodiazepine discontinuation by melatonin, a new clinical approach. Archives of Internal Medicine. 1999;159(20):2456-2460.

Girgert R, Bartsch C, Hill SM, Kreienberg R, Hanf V. Tracking the elusive antiestrogenic effect of melatonin: a new methodological approach. Neuroendocrinology Letter. 2003;24(6):440-444.

Gitto E, Reiter RJ, Amodio A, et al. Early indicators of chronic lung disease in preterm infants with respiratory distress syndrome and their inhibition by melatonin. Journal of Pineal Research. 2004;36(4):250-255.

Gupta YK, Gupta M, Chaudhary G, Kohli K. Modulation of antiepileptic effect of phenytoin and carbamazepine by melatonin in mice. Methods and Findings in Experimental Clinical Pharmacology. 2004;26(2):99-102.

Haimov I, Lavie P, Laudon M, Herer P, Vigder C, Ziaspel N. Melatonin replacement therapy of elderly insomniacs. Sleep. 1995;18(7):598-603.

Hartter S, Grozinger M, Weigmann H, Roschke J, Hiemke C. Increased bioavailability of oral melatonin after fluvoxamine coadministration. Clinical Pharmacology and Therapeutics. 2000;67(1):1-6.

Hartter S, Nordmark A, Rose DM, Bertilsson L, Tybring G, Laine K. Effects of caffeine intake on the pharmacokinetics of melatonin, a probe drug for CYP1A2 activity. British Journal of Clinical Pharmacology. 2003;56(6):679-682.

Hartter S, Wang X, Weigmann H, Friedberg T, Arand M, Oesch F, Hiemke C. Differential effects of fluvoxamine and other antidepressants on the biotransformation of melatonin. Journal of Clinical Psychopharmacology. 2001;21(2):167-174.

Herxheimer A, Petrie KJ. Melatonin for preventing and treating jet lag. Cochrane Database System Review. 2001;1:CD001520.

Humbert W, Pevet P. The decrease of pineal melatonin production with age. Causes and consequences. Annals of the New York Academy of Sciences. 1994;719:43-63.

Jahovic N, Sener G, Cevik H, Ersoy Y, Arbak S, Yegen BC. Amelioration of methotrexate-induced enteritis by melatonin in rats. Cellular Biochemistry and Function. 2004;22(3):169-178.

James M, Tremea MO, Jones JS, Krohmer JR. Can melatonin improve adaptation to night shift? American Journal of Emergency Medicine. 1998;16(4):367-370.

James SP, Sack DA, Rosenthal NE, Mendelson WB. Melatonin administration in insomnia. Neuropsychopharmacology. 1990;3(1):19-23.

Jan JE, O'Donnell ME. Use of melatonin in the treatment of paediatric sleep disorders. Journal of Pineal Research. 1996;21(4):193-199.

Jan JE, Wasdell MB, Freeman RD, Bax M. Evidence supporting the use of melatonin in short gestation infants. Journal of Pineal Research. 2007;42(1):22-27.

Jaworek J. Ghrelin and melatonin in the regulation of pancreatic exocrine secretion and maintaining of integrity. Journal of Physiology and Pharmacology. 2006;57(Suppl 5):83-96.

Jaworek J, Brzozowski T, Konturek SJ. Melatonin as an organoprotector in the stomach and the pancreas. Journal of Pineal Research. 2005;38(2):73-83.

Jellin JM, Gregory P, Batz F, Hitchens K, et al, eds. Pharmacist's Letter/Prescriber's Letter. Natural Medicines Comprehensive Database, 3rd Edition. Stockton CA: Therapeutic Research Facility, 2000.

Jones MP, Melan MA, Witt-Enderby PA. Melatonin decreases cell proliferation and transformation in a melatonin receptor-dependent manner. Cancer Letter. 2000;151:1331-1343.

Jorgensen KM, Witting MD. Does exogenous melatonin improve day sleep or night alertness in emergency physicians working night shifts? Annals of Emergency Medicines. 1998;31(6):699-704.

Kanikkannan N, Andega S, Burton S, Babu RJ, Singh M. Formulation and in vitro evaluation of transdermal patches of melatonin. Drug Development in Indian Pharmacology. 2004;30(2):205-212.

Karasek M, Winczyk K. Melatonin in humans. Journal of Physiology and Pharmacology. 2006;57(Suppl 5):19-39.

Konakchieva R, Mitev Y, Almeida OF, Patchev VK. Chronic melatonin counteracts glucocorticoid-induced dysregulation of the hypothalmic-pituitary-adrenal axis in the rat. Neuroendocrinology. 1998;67(3):171-180.

Konturek SJ, Konturek PC, Brzozowski T. Melatonin in gastroprotection against stress-induced acute gastric lesions and in healing of chronic gastric ulcers. Journal of Physiology and Pharmacology. 2006;57(Suppl 5):51-66.

Kumar AM, Tims F, Cruess DG, et al. Music therapy increases serum melatonin levels in patients with Alzheimer's disease. Alternative Therapeutics in Health and Medicine. 1999;5(6):49-57.

Kunz D, Mahlberg R, Muller C, Tilmann A, Bes F. Melatonin in patients with reduced REM sleep duration: two randomized controlled trials. Journal of Clinical Endocrinology and Metabolism. 2004;89(1):128-134.

Lahiri DK, Chen D, Ge YW, Bondy SC, Sharman EH. Dietary supplementation with melatonin reduces levels of amyloid beta-peptides in the murine cerebral cortex. Journal of Pineal Research. 2004;36(4):224-231.

Lancioni GE, O'Reilly MF, Basili G. Review of strategies for treating sleep problems in persons with severe or profound mental retardation or multiple handicaps. American Journal of Mental Retardation. 1999;104(2):170-186.

Lechner O, Dietrich H, Oliveira dos Santos A, et al. Altered circadian rhythms of the stress hormone and melatonin response in lupus-prone MRL/MP-fas(Ipr) mice. Journal of Autoimmunity. 2000;14(4):325-333.

Lee CO. Complementary and alternative medicines patients are talking about: melatonin. Clinical Journal of Oncology Nursing. 2006;10(1):105-107.

Leibenluft E, Feldman-Naim S, Turner EH, Wehr TA, Rosenthal NE. Effects of exogenous melatonin administration and withdrawal in five patients with rapid-cycling bipolar disorder. Journal of Clinical Psychiatry. 1997;58(9):383-388.

León J, Acuña-Castroviejo D, Escames G, Tan DX, Reiter RJ. Melatonin mitigates mitochondrial malfunction. Journal of Pineal Research. 2005;38(1):1-9.

Leone M, D'Amico D, Moschiano F, Fraschini F, Bussone G. Melatonin versus placebo in the prophylaxis of cluster headache: a double-blind pilot study with parallel groups. Cephalalgia. 1996;16(7):494-496.

Liang FQ, Green L, Wang C, Alssadi R, Godley BF. Melatonin protects human retinal pigment epithelial (RPE) cells against oxidative stress. Experimental Eye Research. 2004;78(6):1069-1075.

Lissoni P, Barni S, Ardizzoia A, Tancini G, Conti A, Maestroni G. A randomized study with the pineal hormone melatonin versus supportive care alone in patients with brain metastases due to solid neoplasms. Cancer 1994;73(3):699-701.

Lissoni P, Barni S, Cattaneo G, et al. Clinical results with the pineal hormone melatonin in advanced cancer resistant to standard antitumor therapies. Oncology 1991;48(6):448-450.

Lissoni P, Barni S, Mandala M, Ardizzoia A, Paolorossi F, Vaghi M, et al. Decreased toxicity and increased efficacy of cancer chemotherapy using the pineal hormone melatonin in metastatic solid tumor patients with poor clinical status. European Journal of Cancer. 1999;35(12):1688-1692.

Lissoni P, Tancini G, Barni S, Paolorossi F, Ardizzoia A, Conti A, Maestroni G. Treatment of cancer chemotherapy-induced toxicity with the pineal hormone melatonin. Supportive Care in Cancer. 1997;5(2):126-129.

Liu JB, Tang TS, Yang HL, Xiao DS. Antioxidation of melatonin against spinal cord injury in rats. Chinese Medical Journal (England). 2004;117(4):571-575.

Luboshitzky R, Wagner O, Lavi S, Herer P, Lavie P. Abnormal melatonin secretion in hypogonadal men: the effect of testosterone treatment. Clinical Endocrinology (Oxford). 1997;47(4):463-469.

Lusardi P, Piazza E, Fogari R. Cardiovascular effects of melatonin in hypertensive patients well controlled by nifedipine: a 24-hour study. British Journal of Clinical Pharmacology. 2000;49(5):423-427.

Maestroni GJ. MLT and the immune-hematopoietic system. Advances in Experimental Medicine and Biology. 1999;460:395-405.

Maestroni GJ, Sulli A, Pizzorni C, Villaggio B, Cutolo M. Melatonin in rheumatoid arthritis: synovial macrophages show melatonin receptors. Annals of the New York Academy of Sciences. 2002;966:271-275.

Maestroni GJ. The immunotherapeutic potential of melatonin. Expert Opinion in Investigational Drugs. 2001;10(3):467-476.

Magri F, Sarra S, Cinchetti W, et al. Qualitative and quantitative changes of melatonin levels in physiological and pathological aging and in centenarians. Journal of Pineal Research. 2004;36(4):256-261.

Manda K, Bhatia AL. Prophylactic action of melatonin against cyclophosphamide-induced oxidative stress in mice. Cellular Biology and Toxicology. 2003;19(6):367-372.

McArthur AJ, Budden S. Sleep dysfunction in Rett syndrome: a trial of exogenous melatonin treatment. Developmental Medicine and Child Neurology. 1998;40(3):186-192.

Mero AA, Vahalummukka M, Hulmi JJ, Kallio P, von Wright A. Effects of resistance exercise session after oral ingestion of melatonin on physiological and performance responses of adult men. European Journal of Applied Physiology. 2006;96(6):729-739.

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

Nagtegaal JE, Laurant MW, Kerkhof GA, Smits MG, van der Meer YG, Coenen AM. Effects of melatonin on the quality of life in patients with delayed sleep phase syndrome. Journal of Psychosomatic Research. 2000;48(1):45-50.

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

Natural Medicines Comprehensive Database, Online Edition. Pharmacist's Letter/Prescriber's Letter. Stockton CA: Therapeutic Research Facility, 2006. Available at: http://www.pharmacistsletter.com/(S(ulqz3s45omt3ag55um4kj345))/home.aspx?li=1&st=1&cs=&s=ND.

Nave R, Peled R, Lavie P. Melatonin improves evening napping. European Journal of Pharmacology. 1995;275(2):213-216.

Niederhofer H, Staffen W, Mair A, Pittschieler K. Brief report: melatonin facilitates sleep in individuals with mental retardation and insomnia. Journal of Autism and Developmental Disorders. 2003;33(4):469-472.

Palm L, Blennow G, Wetterberg L. Long-term melatonin treatment in blind children and young adults with circadian sleep-wake disturbances. Developmental Medicine and Child Neurology. 1997;39(5):319-325.

Paul MA, Gray G, Kenny G, Pigeau RA. Impact of melatonin, zaleplon, zopiclone, and temazepam on psychomotor performance. Aviation, Space and Environmental Medicine. 2003;74(12):1263-1270.

Pandi-Perumal SR, Srinivasan V, Poeggeler B, Hardeland R, Cardinali DP. Drug Insight: the use of melatonergic agonists for the treatment of insomnia-focus on ramelteon. Nature Clinical Practice. Neurology. 2007;3(4):221-228.

Peirce A. The American Pharmaceutical Association Practical Guide to Natural Medicines. New York: The Stonesong Press, 1999:19.

Peled N, Shorer Z, Peled E, Pillar G. Melatonin effect on seizures in children with severe neurologic deficit disorders. Epilepsia. 2001;42(9):1208-1210.

Pentney PT, Bubenik GA. Melatonin reduces the severity of dextran-induced colitis in mice. Journal of Pineal Research. 1995;19(1):31-39.

Pereira Rde S. Regression of gastroesophageal reflux disease symptoms using dietary supplementation with melatonin, vitamins and aminoacids: comparison with omeprazole. Journal of Pineal Research. 2006;41(3):195-200.

Perreau VM, Bondy SC, Cotman CW, Sharman KG, Sharman EH. Melatonin treatment in old mice enables a more youthful response to LPS in the brain. Journal of Neuroimmunology. 2007;182(1-2):22-31.

Persengiev S, Marinova C, Patchev V. Steroid hormone receptors in the thymus: a site of immunomodulatory action of melatonin. International Journal of Biochemistry. 1991;23(12):1483-1485.

Petrie K, Conaglen JV, Thompson L, Chamberlain K. Effect of melatonin on jet lag after long haul flights. British Medical Journal. 1989;298(6675):705-707.

Petrie K, Dawson AG, Thompson L, Brook R. A double-blind trial of melatonin as a treatment for jet lag in international cabin crew. Biology and Psychiatry. 1993;33(7):526-530.

Prototype monograph on melatonin. Institute of Medicine and National Research Council of the National Academies. 2004. http://www.iom.edu/Object.File/Master/19/562/Introduction%20and%20Melatonin%20Prototype%20Monograph.v2.pdf. Accessed: April 6, 2007.

Reiter RJ, Tan DX, Mayo JC, Sainz RM, Leon J, Bandyopadhyay D. Neurally-mediated and neurally-independent beneficial actions of melatonin in the gastrointestinal tract. Journal of Physiology and Pharmacology. 2003;54(Suppl 4):113-125.

Rezzani R, Buffoli B, Rodella L, Stacchiotti A, Bianchi R. Protective role of melatonin in cyclosporine A-induced oxidative stress in rat liver. International Immunopharmacology. 2005;5(9):1397-1405.

Rodriguez C, Mayo JC, Sainz RM, Antolin I, Herrera F, Martin V, Reiter RJ. Regulation of antioxidant enzymes: a significant role for melatonin. Journal of Pineal Research. 2004;36(1):1-9.

Rodriguez-Reynoso S, Leal C, Portilla-de Buen E, Castillo JC, Ramos-Solano F. Melatonin ameliorates renal ischemia/reperfusion injury. Journal of Surgical Research. 2004;116(2):242-247.

Rohr UD, Herold J. Melatonin deficiencies in women. Maturitas. 2002;41(Suppl 1):S85-S104.

Rufo-Campos M. Melatonin and epilepsy. [Article in Spanish] Review of Neurology. 2002;35(Suppl 1):S51-S58.

Ruzsas C, Mess B. Melatonin and aging. A brief survey. Neuroendocrinology Letters. 2000; 21:17-23.

Sainz RM, Mayo JC, Reiter RJ, Antolin I, Esteban MM, Rodriguez C. Melatonin regulates glucocorticoid receptor: an answer to its antiapoptotic action in thymus. FASEB Journal. 1999;13(12):1547-1556.

Salti R, Galluzzi F, Bindi G, et al. Nocturnal melatonin patterns in children. Journal of Clinical Endocrinology and Metabolism. 2000;85(6):2137-2144.

Sanders DC, Chaturvedi AK, Hordinsky JR. Melatonin: aeromedical, toxicopharmacological, and analytical aspects. J0urnal of Analytical Toxicology. 1999;23(3):159-167.

Sasaki M, Jordan P, Joh T, et al. Melatonin reduces TNF-a induced expression of MAdCAM-1 via inhibition of NF-kappaB. BMC Gastroenterology. 2002;2:9.

Scheer FA, Van Montfrans GA, van Someren EJ, Mairuhu G, Buijs RM. Daily nighttime melatonin reduces blood pressure in male patients with essential hypertension. Hypertension. 2004;43(2):192-197.

Secreto G, Chiechi LM, Amadori A, et al. Soy isoflavones and melatonin for the relief of climacteric symptoms: a multicenter, double-blind, randomized study. Maturitas. 2004;47(1):11-20.

Sener G, Balkan J, Cevikbas U, Keyer-Uysal M, Uysal M. Melatonin reduces cholesterol accumulation and prooxidant state induced by high cholesterol diet in the plasma, the liver and probably in the aorta of C57BL/6J mice. Journal of Pineal Research. 2004;36(3):212-216.

Sener G, Jahovic N, Tosun O, Atasoy BM, Yegen BC. Melatonin ameliorates ionizing radiation-induced oxidative organ damage in rats. Life Sciences. 2003;74(5):563-572.

Sener G, Kapucu C, Paskaloglu K, et al. Melatonin reverses urinary system and aorta damage in the rat due to chronic nicotine administration. Journal of Pharmacy and Pharmacology. 2004;56(3):359-366.

Shamir E, Laudon M, Barak Y, et al. Melatonin improves sleep quality of patients with chronic schizophrenia. Journal of Clinical Psychiatry. 2000;61(5):373-377.

Shilo L, Dagan Y, Smorjik Y, et al. Effect of melatonin on sleep quality of COPD intensive care patients: a pilot study. Chronobiology International. 2000;17(1):71-76.

Shilo L, Sabbah H, Hadari R, et al. The effects of coffee consumption on sleep and melatonin secretion. Sleep Medicine. 2002;3(3):271-273.

Singer C, Tractenberg RE, Kaye J, et al; for the Alzheimer's Disease Cooperative Study. A multicenter, placebo-controlled trial of melatonin for sleep disturbance in Alzheimer's disease. Sleep. 2003;26(7):893-901.

Smits MG, van Stel HF, van der Heijden K, Meijer AM, Coenen AM, Kerkhof GA. Melatonin improves health status and sleep in children with idiopathic chronic sleep-onset insomnia: a randomized placebo-controlled trial. Journal of the American Academy of Child and Adolescent Psychiatry. 2003;42(11):1286-1293.

Spitzer RL, Terman M, Williams JBW, et al. Jet lag: clinical features, validation of a new syndrome-specific scale, lack of response to melatonin in a randomized, double-blind trial. American Journal of Psychiatry. 1999;156(9):1392-1396.

Stewart LS. Endogenous melatonin and epileptogenesis: facts and hypothesis. International Journal of Neuroscience. 2001;107(1-2):77-85.

Stone BM, Turner C, Mills SL, Nicholson AN. Hypnotic activity of melatonin. Sleep. 2000;23(5):663-669.

Stoschitzky K, Sakotnik A, Lercher P, et al. Influence of beta-blockers on melatonin release. European Journal of Clinical Pharmacology. 1999;55(2):111-115.

Suhner A, Schlagenhauf P, Johnson R, Tschopp A, Steffen R. Comparative study to determine the optimal melatonin dosage form for the alleviation of jet lag. Chronobiology International. 1998;15(6):655-666.

Sury MR, Fairweather K. The effect of melatonin on sedation of children undergoing magnetic resonance imaging. British Journal of Anaesthesia [sic]. Epublished ahead of print June 17, 2006.

Travis RC, Allen DS, Fentiman IS, Key TJ. Melatonin and breast cancer: a prospective study. Journal of the National Cancer Institute. 2004;96(6):475-482.

Turk J. Melatonin supplementation for severe and intractable sleep disturbance in young people with genetically determined developmental disabilities: short review and commentary. Journal of Medical Genetics. 2003;40(11):793-796.

Ursing C, Wikner J, Brismar K, Rojdmark S. Caffeine raises the serum melatonin level in healthy subjects: an indication of melatonin metabolism by cytochrome P450(CYP)1A2. Journal of Endocrinology Investigation. 2003;26(5):403-406.

Van der Heijden KB, Smits MG, Van Someren EJ, Ridderinkhof KR, Gunning WB. Effect of melatonin on sleep, behavior, and cognition in ADHD and chronic sleep-onset insomnia. Journal of the American Academy of Child and Adolescent Psychiatry. 2007;46(2):233-241.

van der Helm-van Mil AH, van Someren EJ, van den Boom R, van Buchem MA, de Craen AJ, Blauw GJ. No influence of melatonin on cerebral blood flow in humans. Journal of Clinical Endocrinology and Metabolism. 2003;88(12):5989-5994.

von Bahr C, Ursing C, Yasui N, Tybring G, Bertilsson L, Rojdmark S. Fluvoxamine but not citalopram increases serum melatonin in healthy subjects -- an indication that cytochrome P450 CYP1A2 and CYP2C19 hydroxylate melatonin. European Journal of Clinical Pharmacology. 2000;56(2):123-127.

Wagner J, Wagner ML, Hening WA. Beyond benzodiazepines: alternative pharmacologic agents for the treatment of insomnia. Annals of Pharmacotherapy. 1998;32(6):680-691.

Wiechmann AF, Rada JA. Melatonin receptor expression in the cornea and sclera. Experimental Eye Research. 2003;77(2):219-225.

Wiid I, Hoal-van Helden E, Hon D, Lombard C, van Helden P. Potentiation of isoniazid activity against Mycobacterium tuberculosis by melatonin. Antimicrobial Agents in Chemotherapy. 1999;43(4):975-977.

Wright KP Jr, Badia P, Myers BL, Plenzler SC, Hakel M. Caffeine and light effects on nighttime melatonin and temperature levels in sleep-deprived humans. Brain Research. 1997;747(1):78-84.

Wright SW, Lawrence LM, Wrenn KD, Haynes ML, Welch LW, Schlack HM. Randomized clinical trial of melatonin after night-shift work: efficacy and neuropsychologic effects. Annals of Emergency Medicine. 1998 32(3 Pt 1):334-340.

Wu YH, Feenstra MG, Zhou JN, et al. Molecular changes underlying reduced pineal melatonin levels in Alzheimer disease: alterations in preclinical and clinical stages. Journal of Clinical Endocrinology and Metabolism. 2003;88(12):5898-5906.

Wyatt JK, Dijk D-J, Ritz-De Cecco A, Ronda JM, MS; Czeisler CA. sleep-facilitating effect of exogenous melatonin in healthy young men and women is circadian-phase dependent. Sleep. 2006;29(4):1212-1221.

Yamamoto HA, Mohanan PV. In vivo and in vitro effects of melatonin or ganglioside GT1B on L-cysteine-induced brain mitochondrial DNA damage in mice. Toxicologic Science. 2003;73(2):416-422.

Yin S, Hu SL, Shen G, et al. The effect of amino acid nutritional support on serum tryptophan and melatonin in lung cancer patients receiving chemotherapy. [Article in Chinese] Zhonghua Zhong Liu Za Zhi. 2006;28(11):840-843.

Zhdanova IV, Piotrovskaya VR. Melatonin treatment attenuates symptoms of acute nicotine withdrawal in humans. Pharmacology Biochemistry and Behavior. 2000;67(1):131-135.

Zhdanova IV, Wurtman RJ, Lynch HJ, et al. Sleep-inducing effects of low doses of melatonin ingested in the evening. Clinical Pharmacology and Therapeutics. 1995;57(5):552-558.

Zhdanova IV, Wurtman RJ, Regan MM, Taylor JJ, Shi JP, Leclair OUl. Melatonin treatment for age-related insomnia. Journal of Clinical Endocrinology and Metabolism 2001;86(10):4727-4730.

Last Revised May 16, 2007

Note: The above information is not intended to replace the advice of your physician, pharmacist, or other healthcare professional. It is not meant to indicate that the use of the product is safe, appropriate, or effective for you.

In general, herbal products are not subject to review or approval by the U.S. Food and Drug Administration (FDA). They are not required to be standardized, meaning that the amounts of active ingredients or contaminants they contain may vary between brands or between different batches of the same brand. Not all of the risks, side effects, or interactions associated with the use of herbal products are known because few reliable studies of their use in humans have been done.

This information is provided for your education only. Please share this information with your healthcare provider and be sure that you talk to your doctor and pharmacist about all the prescription and non-prescription medicines you take before you begin to use any herbal product.

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