Synonyms/Common Names/Related Substances:

• 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 Controlled Release®; Melatonin Olympian Labs®; Melatonin Tablets®; Melatonin Time Release®; Melatonin-BioDynamax®; Melatonin-Metabolic Response Modifier®; Melatonin-New Hope Health Products®; Melatonin-Optimum Nutrition®; 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).

Clinical Bottom Line/Effectiveness

Brief Background

• Endogenous melatonin is an indole neurohormone produced in the brain by the pineal gland, from the amino acid tryptophan (1), with regulation of day-night changes in synthesis regulated by changes in the activity of serotonin N-acetyltransferase (2). 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.
• Melatonin acts on MT(1) and MT(2) melatonin receptors located in the hypothalamic suprachiasmatic nuclei, the site of the body's master circadian clock. Melatonin may reset disturbed circadian rhythms and may promote jet lag recovery and other circadian rhythm sleep disorders, including delayed sleep phase syndrome and work shift sleep disorder (3;​4).
• Administration of exogenous melatonin has been used for a variety of medical conditions, most notably for disorders related to sleep, such as jet lag, delayed sleep phase syndrome (DSPS), and insomnia, for which there exists an ample body of research.
• Many of melatonin's proposed therapeutic or preventive uses are based on its antioxidant activity (5;​6;​7;​8;​9;​10;​11;​12;​13;​14;​15;​16;​17;​18;​19;​20;​21;​22;​23;​24;​25;​26;​27;​28;​29;​30;​31;​32;​33;​34;​35;​36;​37;​38;​39;​40).
• 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 (41;​42;​43).
• Ramelteon (Rozerem®) and agomelatine (Valdoxan®) (the latter not yet U.S. Food and Drug Administration (FDA) approved) are drugs that have a high affinity for the melatonin receptors MT1 and MT2, present in the suprachiasmatic nucleus, the circadian pacemaker (44). Details and clinical trials of these drugs are not included in this monograph.

Scientific Evidence for Common/Studied Uses:

Historical or Theoretical Indications That Lack Sufficient Evidence:

• Acetaminophen toxicity (25;​45), acute respiratory distress syndrome (ARDS) (46;​47), adaptogen (48), addiction (49), adrenal insufficiency, aflatoxin toxicity (50;​51), aging (52;​53;​54;​55;​56;​57;​58;​59;​60;​61;​62), alcoholic liver disease (63), alopecia (64), aluminum toxicity (65;​66;​67;​68), Alzheimer's disease (69;​70;​71;​72;​73), amenorrhea (74;​75), amikacin-induced kidney damage (76), amyotrophic lateral sclerosis (ALS) (77), analgesia (78;​79;​80), antioxidant (81;​82;​83;​84;​85;​86;​87;​88;​89;​90;​91;​92;​93;​94;​95;​96;​97;​98;​99;​100;​101;​102;​103;​104;​105;​106;​107;​108;​109), anxiety (travel anxiety in animals), ataxia (Machado-Joseph disease) (110), atopic dermatitis (111), attention-deficit hyperactivity disorder (ADHD) (112), autoimmune diseases (demyelination) (43), beta-blocker sleep disturbance (113;​114), bipolar disorder (115;​116), bladder disorders (117), bone diseases (fibrous dysplasia) (118), bone healing (119;​120;​121), brain injuries (122;​123;​124;​125), cachexia (126;​127), cardiac syndrome X, cardiovascular conditions (acute coronary syndromes) (128), cardiovascular conditions (nicotine-induced vasculopathy) (129), cardiovascular conditions (ventricular fibrosis) (130;​131), cataracts, central nervous system diseases (Venezuelan equine encephalomyelitis virus) (132), chemotherapy toxicity (133;​134;​135;​136), cholestatic liver injury (137), colic (138), colitis (139;​140;​141), contraception, coronary artery disease (142), cyclosporine toxicity (143;​144;​145), cyclosporin-induced kidney toxicity (146;​147), delirium (148;​149), dental conditions (96), Duchenne muscular dystrophy (150) eating disorders (low-level, enhanced circadian rhythm) (151;​152), eczema (153), edema, endometriosis (154), erectile dysfunction (155), esophagitis (156;​157), exercise recovery (158), fetal development (159), fibromyalgia, food preservation (37), fragile X syndrome (160), gastric ulcers (161;​162;​163;​164), gastritis (156), gastroesophageal reflux disease (GERD) (165), gentamicin toxicity (166;​167), gentamicin-induced kidney damage, growth (growing pains) (168), helminthic infections (Schistosoma mansoni) (169), hepatic encephalopathy (diagnosis) (170), hepatoprotection (171;​172;​173), hormonal/endocrine disorders (McCune-Albright syndrome) (118), hyperpigmentation, immune system diseases (Langerhans cell histiocytosis) (174), immunomodulation (175;​176;​177), infant development / neonatal care (178), interstitial cystitis, intestinal motility disorders (179), ischemia-reperfusion injury protection (125;​180;​181;​182;​183;​184;​185;​186;​187;​188;​189;​190;​191;​192;​193;​194;​195), ischemic stroke (impaired nocturnal excretion) (196;​197), itching, jaundice (198), jellyfish stings (199), kidney protection (200;​201;​202;​203), lead toxicity (204), lung inflammation (205;​206), major depressive disorder (low nocturnal melatonin) (207;​208;​209), malaria (liver damage prevention) (210), mania (decreased melatonin production) (211), melatonin deficiency, metabolic disorders (Sanfilippo syndrome) (212), migraine (impaired pineal function) (213;​214;​215;​216;​217), movement disorders (218), movement disorders (normalization of gait) (219), multiple sclerosis (decreased in plasma) (220;​221), myocardial injury (10;​222), nephrotoxicity induced by chemotherapy (223;​224;​225), nerve regeneration (226), neurodegenerative disorders (227;​228;​229), neurofibromatous scoliosis (118), neurological disorders (Smith-Magenis syndrome) (230;​231), neuropathy (232), neuropathy (diabetic) (233), neuropathy (neuronal damage from bacterial meningitis) (234), neuroprotective (69;​124;​235;​235;​236;​237;​238;​238;​239;​240;​241;​242;​243;​244;​245;​246;​247;​248;​249;​250;​251;​252;​253;​254), nitrate tolerance(255), noise-induced hearing loss (256), obesity (257;​258), obstructive sleep apnea (symptoms) (259), organophosphate poisoning (260;​261;​262), osteoarthritis (263), ovarian disorders (264), pain (neuropathic) (265), pancreatitis (266;​267;​268;​269;​270;​271), parasitic infections (272), phenylketonuria (PKU) (273), photoprotection (274;​275;​276), polycystic ovarian syndrome (PCOS) (277), postmenopausal osteoporosis, postoperative adjunct (278;​279;​280;​281;​282;​283;​284;​285), postoperative delirium (149), pregnancy nutritional supplement (286;​287), premenstrual dysphoric disorder (chronobiological abnormalities of melatonin secretion) (288), protection against alcohol toxicity (289), psychiatric disorders (290), pulmonary fibrosis (291), radiation protection(292;​293;​294;​295;​296;​297), retinal protection (298;​299;​300), rheumatic diseases (301), scalds (302), schizophrenia (115;​303), sepsis (304;​305;​306), sexual activity enhancement (307), shock (308;​309), spinal cord injury (310;​311;​312), spine problems (idiopathic scoliosis) (313;​314), stomatitis (156), stroke (315), sudden infant death syndrome (SIDS) (prevention/decreased in plasma) (316;​317;​318), surgical recovery (postpinealectomy syndrome) (319), tachycardia, testicular damage (320), toluene neurotoxicity (321), toxic liver damage, toxicity (cadmium) (322;​323), toxicity (formaldehyde) (324), toxicity (mercury) (325;​326), transplants (ovary) (327), tuberculosis (328), ulcer (156;​329;​330), ulcerative colitis (331), uterine disorders (hormone-dependent, myometrial functioning) (332), Wilson's disease (333), withdrawal from narcotics (334;​335), wound healing (336).

Expert Opinion and Historic/Folkloric Precedent:

• Melatonin is widely recommended for various sleep disorders and for prevention of jet lag. In addition, it is used in conditions believed to be associated with low levels of endogenous melatonin, such as aging, sleep disorders in children, and affective disorders. It has also garnered attention as possibly playing a role in or serving as a treatment for chronic inflammatory diseases (337), cancer (338), and hypertension (339), as well as an antioxidant therapy to counter aging and a variety of metabolic diseases (340).
• A review by Bjorvatn and Pallesen outlines how to estimate circadian rhythm based on a careful patient history and use this estimate to administer melatonin or light to treat delayed sleep phase disorder, advanced sleep phase disorder, free-running, irregular sleep-wake rhythm, jet lag disorder, and shift work disorder (341).
• A physician survey indicated that 25% of doctors polled recommended melatonin as a complementary alternative medicine for children with autism (342).
• Melatonin is not listed on the FDA's Generally Recognized as Safe (GRAS) list.

Brief Safety Summary:

• Likely safe: When used orally for up to two years at a dose of 5mg daily (343).
• Possibly safe: When used in doses up to 40mg for short periods of time (23 days) (344). When beta-methyl-6-chloromelatonin (a melatonin agonist) is used orally at doses up to 100mg for short periods of time (two days) (345).
• Possibly unsafe: When used by patients at risk for seizures, particularly children (346;​346;​347;​348;​349;​350). However, case reports have reported a reduced incidence of seizure with regular melatonin use (351;​352;​353;​354;​355;​356). This remains an area of controversy (347). When used in patients at risk of bleeding, especially in those taking warfarin (348;​349;​357;​358;​359). When used in patients with low blood pressure or those taking antihypertensive medication (360;​361;​362;​363;​364;​365), such as the alpha-blocker drugs clonidine and methoxamine (360), or those using calcium channel blockers (366;​367). When used in patients with diabetes, as melatonin has been associated with hyperglycemia (368;​369) as well as reduced glucose tolerance and insulin sensitivity (370;​371). However, in other research, melatonin supplementation was found to have no significant effect upon measures of glucose homeostasis (372). When used in patients with hormone imbalances or those using medicines that affect hormone levels (358;​373;​374;​375;​376;​377;​378;​379;​379;​380;​381;​382;​382;​383;​383;​384;​385;​386;​387;​388). When used in patients suffering from, or at risk for, glaucoma, age-related maculopathy, or myopia (368), or retinal damage (358), although some studies have found that melatonin may decrease intraocular pressure (389;​390). When used in patients with psychiatric disorders, including dysphoria (sadness), transient depression (391;​392), psychotic symptoms (357;​393), and aggression (394). When used in patients at risk for daytime sleepiness (382;​395;​396;​397;​398;​399;​400;​401) or those taking the prescription sleep-aid zolpidem (Ambien®), as increased daytime drowsiness has been reported with concurrent use of melatonin and zolpidem. When used in patients using anesthetics, as in vitro studies indicate that some anesthetics have been found to alter blood melatonin concentrations in humans (isoflurane increasing and sevoflurane decreasing) (402). When used in patients with atherosclerosis, as, based on preliminary human (403) and animal (404;​405) research that suggests that regular use of melatonin may increase atherosclerotic plaque buildup; however, other animal research has found melatonin to decrease serum cholesterol levels (406). When used children with a history of enuresis, as, based on human research, melatonin is associated with increased risk of enuresis (407;​408). When used in patients using cytochrome P450 1A2 inhibitors like fluvoxamine, as these agents may increase melatonin levels (367;​393;​409;​410). When used in patients using methamphetamine, as, based on animal research, melatonin may increase the adverse effects of methamphetamine on the nervous system (411). When used in patients taking the nifedipine (a calcium channel blocker), as, based on human research, melatonin may interfere with nifedipine therapy and result in increased blood pressure and heart rate (366).
• Likely unsafe: When used in patients using CNS depressants, including benzodiazepines and alcohol, as concomitant use may cause increased sedation (382;​395;​396;​397;​398;​399;​400;​401;​412;​413). When used in women who are pregnant or attempting to become pregnant, based on possible hormonal effects, including alterations of pituitary-ovarian function and potential inhibition of ovulation (414) or uterine contractions (415). High levels of melatonin during pregnancy may increase the risk of developmental disorders (416). When used in patients who are allergic or sensitive to exogenous melatonin administration, based on reports of allergic skin reactions after taking melatonin by mouth (368;​417).

Dosing/Toxicology

General:

• Doses may be based on those most commonly used in available trials, or on historical practice. However, with natural products, the optimal doses to balance efficacy and safety are often unclear. Preparation of products may vary from manufacturer to manufacturer, and from batch to batch within one manufacturer. As it is often not clear what the active component(s) of a product may be, standardization is often not possible, and the clinical effects of different brands may not be comparable.

Standardization:

• There is no well-known standardization for melatonin. Experts note that many brands contain impurities that cannot be characterized, as well as dissimilar amounts of actual hormone. In 2002, Consumer Lab evaluated 18 melatonin-containing supplements (15 quick-release and three time-release products), of which 12 were melatonin-only products. It was reported that 16 of the 18 products contained 100-135% of the claimed amount of melatonin, one rapid-release product contained only 83% of the claimed amount of melatonin, and another rapid-release product contained a small amount of lead (slightly more than 0.5mcg daily based on the recommended serving size of melatonin). Among the 12 melatonin-only products that "passed" these standards are: Nature's Bounty® Melatonin 1mg and 3mg tablets, Puritan's Pride® Inspired by Nature® Melatonin 3mg tablets, Twinlab® Melatonin Caps, Highest Quality, Quick Acting 3mg tablets.
• U.S. Pharmacopeia melatonin has been obtained from Sigma Company (St. Louis, MO) (418).

Adult (age ≥18):

Oral:

• General: Time of melatonin administration is important. When administered orally in the morning, melatonin delays circadian rhythms, but advances circadian rhythms when administered in the afternoon or early evening (419).
• Age-related macular degeneration: Melatonin 3mg each night at bedtime for six months has been shown to protect the retina and delay macular degeneration (420).
• Aging (thermoregulation in the elderly): Melatonin 1.5mg nightly for two weeks has been shown to stabilize body temperature rhythm (421).
• Anti-inflammatory: Melatonin 10mg daily at night over six months has been investigated in patients with rheumatoid arthritis (RA); however, controversial effects on cytokine production were noted, and the anti-inflammatory action and benefit in patients with RA remains unclear (39). Melatonin 5mg the night before and one hour prior to surgery produced anti-inflammatory effects in patients undergoing surgery (40).
• Asthma: Melatonin 3mg for four weeks improved sleep quality in patients with asthma but had no significant benefit on asthma symptoms (422).
• Benzodiazepine tapering: Doses ranging from one to 5mg daily have been studied (423;​424;​425;​426;​427). Treatment duration most commonly lasted several weeks, though one study continued for a year (428).
• Cancer treatment: 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 (126;​344;​429;​430;​431;​432;​433;​434;​435;​436). Safety and effectiveness are not proven, and melatonin should not be used instead of more proven therapies. Oral doses have ranged between one and 40mg daily, with the most common dose being 20mg (126;​344;​429;​430;​431;​432;​433;​434;​435;​436). Dosing regimens generally mirrored conventional therapeutic time courses (several weeks to months). Patients are advised to discuss cancer treatment plans with an oncologist before considering use of melatonin either alone or with other therapies.
• Chronic fatigue syndrome: Melatonin 5mg five hours before dim light melatonin onset during three months improved fatigue, concentration, and activity in patients with chronic fatigue syndrome (437).
• Circadian rhythm entraining (in blind persons): A single dose of 5mg given at 11 p.m. has been found to increase sleep time and sleep efficiency in blind patients (438). A dose of 0.5mg daily at 9 p.m. for 26-81 days was also shown to improve circadian rhythm in blind patients (439).
• Cognitive disorders: Melatonin 1-6mg, administered before bedtime for 1-2 months, has been shown to improve cognition and memory in aging patients (440;​441;​442;​443;​444;​445). It has been used for as little as 10 days (440) and as long as three years (441).
• Delayed sleep phase syndrome (DSPS): Dosages of melatonin for DSPS range from 0.3mg up to 6mg; however, the most frequent dose was 5mg. Melatonin was most commonly administered daily in the hours preceding the desired sleep period for durations of two weeks to three months (446;​447;​448;​449;​450;​451;​452;​453).
• Depression: Melatonin 6mg slow-release at bedtime for four weeks has been shown to improve mood (454).
• Exercise performance: Melatonin 6mg one hour before a heavy-resistance exercise session has been used (455). Melatonin 5mg at bedtime had little benefit on physical performance the morning after (456).
• Gastrointestinal disorders: Melatonin 5mg in the evening for 12 weeks reduced dyspeptic symptoms (457). For IBS, 3mg of melatonin administered daily at bedtime for 2-8 weeks has been used (458;​459;​460;​461;​461;​462).
• Headache (prevention): Studies have evaluated regular use of 5-10mg of melatonin taken nightly by mouth for up to 14 days (463;​464).
• High blood pressure (hypertension): Dosages studied ranged from 1-3mg. Most studies administered treatment in one daily dose prior to bedtime (465;​466;​467;​468), though one study reported daytime administration of 1mg (469). Treatment period was up to four weeks. Melatonin 5mg daily for 90 days has been used (470).
• Insomnia (elderly): Melatonin 1-5mg, regular or controlled-release, at or up to 120 minutes prior to bedtime for up to eight weeks has been used in most studies (471;​472;​473;​474;​475;​475;​476;​477;​478;​479;​480). Although treatment in most clinical trials were often several weeks, some studies continued for several months (481;​482). Melatonin-rich night milk was used for eight weeks in one study (482). Transbuccal melatonin 0.5mg for four nights has been used (472). One study found that low doses (0.1-0.3mg nightly) appear to be as equally effective as higher doses (3-5mg nightly) (483). The most common product used in these studies was the slow-release melatonin, Circadin® (Neurim Pharmaceuticals Ltd., Tel Aviv, Israel).
• Jet lag: Melatonin 0.1-0.5mg, usually started on the day of travel (close to the target bedtime at the destination), then taken every 24 hours for several days (484;​485), or a more common dose of 5mg (392;​484;​485;​486;​487;​488;​489;​490;​491) has been used. Higher doses of 6-8mg have also been studied (492;​493). Overall, 0.5mg appears to be slightly less effective than 5mg for improvement of sleep quality and latency (357), although this area remains controversial, and other research suggests no statistically significant differences (492;​494). Slow-release melatonin may not be as effective as standard (quick-release) formulations (485) for sleep onset, but may be more effective for sleep maintenance. If the dose is taken too early in the day, it may result in excessive daytime sleepiness and greater difficulty adapting to the destination time zone. Formulations were rarely specified; however, one study reported using 2mg of Circadin®, a pharmaceutical-grade time-released formulation of melatonin (Neurim Pharmaceuticals, Tel Aviv, Israel) on circadian sleep and performance in an air crew (495).
• Memory: Melatonin 3mg by mouth prior to exposure to a laboratory stressor and subsequent recall evaluation was used (496).
• Menopause: The use of 3mg at bedtime for six months has been studied for the ability to normalize pituitary and thyroid function in menopausal women (385). Another study administered 3mg of pure melatonin for three months for the relief of menopausal symptoms (497).
• Parkinson's disease: Melatonin 3.0-6.6g daily has been used in patients, some of whom were also treated with levodopa (498).
• Periodic limb movement disorder: One study delivered 3mg of melatonin nightly for a six-week period (499).
• Preoperative sedation / anxiolysis: Melatonin 3-10mg and/or 0.05-0.5mg/kg, either as monotherapy or in combination with other sedatives prior to surgery, has been studied (40;​500;​501;​502;​503;​504;​505;​506;​507;​508).
• REM sleep behavior disorder: Melatonin 3-9mg daily has been used for REM sleep behavior disorder (509;​510).
• Restless leg syndrome: A single dose of 3mg of melatonin improved leg discomfort in patients with restless leg syndrome (511).
• Sarcoidosis: One study reported a treatment regimen lasting two years of 20mg daily in the first year, and 10mg in the second (512).
• Seasonal affective disorder (SAD): One study examined 2mg of sustained-release melatonin 1-2 hours before bed (513). One study has evaluated 0.5mg of melatonin, sublingually, for six days (514).
• Sleep disturbance (Alzheimer's disease): Melatonin 1.5-10mg taken nightly for up to 35 months has been studied in patients with Alzheimer's disease (440;​442;​444;​445;​515;​516). In one study, 5mg in combination with light exposure for 10 weeks increased daytime wake time and activity levels and strengthened the rest-activity rhythm (517).
• Sleep disturbance (autism): In adult patients with autism, a dose of 3mg (increased up to 9mg if ineffective) before bedtime for six months was studied (518). A systematic review of patients with autism noted regimens with doses ranging from 0.75mg to 10mg, administered over two weeks to two months (407).
• Sleep disturbance (cystic fibrosis): Melatonin 3mg at bedtime for 21 days improved sleep measures in patients with cystic fibrosis (519).
• Sleep disturbance (depression): Melatonin 0.5-10mg for three weeks has been used in patients with depressive symptoms (454;​513;​514;​515;​520). Another study administered melatonin for four weeks in conjunction with fluoxetine (521).
• Sleep disturbance (healthy people): Doses studied ranged from 0.3 to 80mg (456;​493;​522;​523;​524;​525;​526;​527;​528;​529;​530;​531;​532;​533;​534;​535). Melatonin was generally administered daily in the evening hours immediately preceding the desired rest period, though some studies investigated the effect of earlier dosing on nighttime sleep (536;​537), as well as daytime naps (538). Most studies occurred over the course of several days, while some lasted multiple weeks (534;​539).
• Sleep disturbance (hemodialysis): In hemodialysis patients, 3mg of melatonin for six weeks has been used (540).
• Sleep disturbance (hospitalized and medically ill): 3-5.4mg of an evening dose of melatonin has been used in hospitalized and medically ill patients (516;​541).
• Sleep disturbance (intellectual disabilities): A meta-analysis of melatonin therapy in patients with intellectual disabilities noted regimens from included studies with doses ranging from 0.5mg to 9mg and lasting from 32 to 73 days (inclusive of washout periods) (542).
• Sleep disturbance (Parkinson's disease): Melatonin 3, 5, and 50mg at bedtime for 2-4 weeks have improved sleep disturbances in patients with Parkinson's disease (543;​544).
• Sleep disturbance (postoperatively): In laparoscopic cholecystectomy patients, a dose of 5mg for three nights postoperatively was used (545).
• Sleep disturbance (psychiatric disorders): Melatonin 3-12mg daily before the desired rest period for up to 12 weeks has been used in patients with psychiatric disorders (546;​547;​548;​549;​550).
• Sleep disturbance (tuberous sclerosis complex): Doses of 5mg and 10mg have been used for the treatment of sleep disturbance related to tuberous sclerosis complex (551;​552).
• Smoking cessation: One study used a 0.3mg dose of melatonin given 3.5 hours after nicotine withdrawal (553).
• Tardive dyskinesia: One study delivered 2mg daily for four weeks (548). Another, later study expanded treatment to 10mg daily for six weeks (554).
• Thrombocytopenia (low platelets): One study administered 20mg daily in the evening for two months (555).
• Tinnitus: Melatonin 3mg daily for up to 80 days has been used (556;​557;​558;​559).
• Traumatic brain injury: A 5mg dose of melatonin for one month has been used (560).
• Urination (nocturia): Studies report using 2mg daily for four weeks (561;​562).
• Work shift sleep disorder: Regimens studied included doses which ranged from 1.8mg to 10mg and were generally administered daily prior to daytime sleep following a night shift schedule (4;​563;​564;​565;​566;​567;​568;​569;​570;​571;​572).
• Other: 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 provider and should not be substituted for more proven therapies.
• Note: Multiple studies performed to date on the functions of endogenous melatonin have utilized exogenous melatonin, often at high doses. However, the most reliable data are obtained at low doses of exogenous melatonin, at which plasma levels are within a physiological range (536;​573). It is not entirely clear what relationships exist between melatonin secretion and pharmacological effects observed at higher concentrations(574).

Topical:

• Cancer treatment: 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. In studies of patients with melanoma, melatonin preparations have been applied to the skin (575). 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.
• UV-induced erythema prevention/sunburn: The use of melatonin in topical applications has been studied in preparations of 20 or 100mg dissolved in 70% ethanol (576), in concentrations of 0.05, 0.1, and 0.5% in gel (577), and as 0.6mg/m² (578), alone or in combination with ascorbic acid and vitamin E (579). 5% melatonin in ethanol, propylene glycol, and water vehicle has been studied (580).

Children (age <18):

Oral:

• General: There is limited study of melatonin supplements in children, and safety is not established.
• Anti-inflammatory: Ten doses of melatonin, at doses of 10mg/kg (the first four doses separated by 2-hour intervals, the fifth and sixth doses separated by four-hour intervals, the seventh and eighth doses separated by eight-hour intervals, and the ninth and tenth doses separated by 12-hour intervals) were administered to newborns (47).
• Insomnia (children): Melatonin 1-5mg once daily at bedtime for up to two months has been used (350;​581;​582;​583).
• Respiratory distress syndrome: Ten doses of melatonin, at doses of 10 mg/kg each (the first four doses separated by 2-hour intervals, the fifth and sixth doses separated by four-hour intervals, the seventh and eighth doses separated by eight-hour intervals, and the ninth and tenth doses separated by 12-hour intervals) were administered to newborns (47).
• Rett's syndrome: Melatonin 2.5-7.5mg once daily at bedtime for up to two years has been used (343;​584).
• Sedation (children): One study used 3 and 6mg doses of melatonin administered 10 minutes prior to standard oral sedation (585).
• Seizure disorder (children): Case reports have evaluated 1.5-9mg of melatonin taken daily over treatment durations ranging from two weeks to three months (352;​353;​354;​586;​587;​588;​589). Research is limited in this area, and there are other reports that melatonin may actually increase risk of seizure or lower seizure threshold (346;​348;​349). In another study exploring the effect of melatonin on insomnia in children, a reported case of mild generalized epilepsy developing four months after the start of the trial was noted (350). Therefore, caution is advised, and use of melatonin should be discussed with the child's primary healthcare provider.
• Sepsis: Two 10mg doses, separated by one hour, administered 12 hours after diagnosis. has been studied (305).
• Sleep disorders (children with behavioral, developmental, or intellectual disorders): Dosages most often varied from 3 to 6mg and were administered daily prior to bedtime (394;​408;​450;​590;​591;​592;​593;​594;​595;​596;​597;​598;​598;​599;​600;​601). Some studies employed lower (0.1-1mg) (418;​602) or higher (up to 10mg) (592;​603;​604;​605) dosages. Treatment duration ranged from one week to a year, with the majority lasting several weeks.
• Sleep disturbance: A case report of one patient reported a dose of 2mg given nightly for four weeks (606) after pinealectomy. Melatonin 6-9mg fast-release melatonin (dose varied depending on the age or size of child), one hour before bedtime, as an add-on to sodium valproate therapy, for four weeks, has been shown to improve sleep behavior in children with epilepsy (607).

Toxicology:

• The LD₅₀ in mice has been reported to be greater than 800mg/kg; in clinical trials, toxicity appeared to be minimal (608) and included mild effects such as diarrhea, headache, and abdominal cramps. A case of melatonin overdose was reported with ingestion of over 24mg for relaxation and sleep prior to surgery inducing symptoms of lethargy and disorientation (398). Ataxia (difficulties with walking and balance) or disorientation may occur following overdose (133). Psychotic symptoms have been reported in at least two cases, possibly due to overdose, and included hallucinations and paranoia (357;​393).

Precautions/Contraindications

Allergy:

• Avoid with known allergies to melatonin or related products. There are rare reports of allergic skin reactions after taking melatonin by mouth (368;​417). Melatonin has been linked to a case of autoimmune hepatitis (609;​610).

Adverse Effects/Post-Market Surveillance:

• General: Based on available studies and clinical use, melatonin is generally regarded as safe in recommended doses for short-term use (three months or less) (611). Similarly, the literature appears free of reported complications associated with long-term use of melatonin in children and adults, and it is even well-tolerated in neonates (178). Overall adverse effects are not significantly more common with melatonin than placebo (357;​412;​453;​476;​485;​612). The most commonly reported adverse events were headaches, dizziness, nausea, and drowsiness (350;​392;​524;​596;​612). However, case reports raise concerns about increased risk of seizure (347;​351;​352;​353;​354;​355;​356) and disorientation with overdose (349). The timing of the melatonin dose appears important: if it is taken early in the day, it may cause sleepiness and delay adaptation to local time (if taken to mediate jet lag) and may diminish neurobehavioral performance (401). Case reports suggest that people with epilepsy and patients taking warfarin may experience harm from melatonin (349;​357;​358;​613).
• Cardiovascular: Melatonin may cause hypotension, as observed in animals (360) and preliminary human research (361;​362;​363;​364;​365;​507;​614;​615). Caution is advised in patients taking medications that may also lower blood pressure. Based on preliminary evidence, increases in cholesterol levels may occur, as well as increases in atherosclerotic plaque buildup in humans (403) and animals (404;​405;​406). Caution is advised in patients with hyperlipidemia or atherosclerosis, or those at risk for cardiovascular disease. There are several rare or poorly described reports of abnormal heart rhythms, fast heart rate, or chest pain, although in most cases, patients were taking other drugs that could account for these symptoms (349;​357;​492).
• Dermatologic: Pruritus was reported in one patient receiving 2mg of melatonin for three weeks (473). Popular skin rash was also reported in a clinical trial (589).
• Endocrine (hormonal effects): Hormonal effects are reported, including alterations (decreases and increases) in levels of luteinizing hormone (373;​374;​375;​376;​377;​378), progesterone (380), estradiol, thyroid hormone (T4 and T3) (381), growth hormone, prolactin (382), cortisol, oxytocin, and vasopressin, although there are other reports of no significant hormonal effects (481;​616;​617;​618). Variations may occur based on underlying patient characteristics. Gynecomastia (increased breast size) has been reported in men, as well as decreased sperm count (both which resolved with cessation of melatonin) (358). Decreased sperm motility has been reported in rats (387) and humans (388).
• Endocrine (hyperglycemia): Elevated blood sugar levels (hyperglycemia) have been reported in patients with type 1 diabetes (insulin-dependent diabetes) (368;​369), and low doses of melatonin have reduced glucose tolerance and insulin sensitivity (370;​371). 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.
• Gastrointestinal: Mild gastrointestinal distress has occurred, including nausea, vomiting, cramping, stomach pain, or diarrhea (368;​476;​589;​612). Altered taste has also been noted (524). Melatonin has been linked to a case of autoimmune hepatitis (609) and with triggering of Crohn's disease symptoms (619). High doses of melatonin have also been shown to inhibit motility by interacting with serotonin and cholecystokinin-2 (CCK2) (620). Melatonin has been used in combination with somatostatin, retinoids, vitamin D, bromocriptine, and cyclophosphamide; mild diarrhea, nausea and vomiting, and drowsiness of grade 1-2 were reported, but the role of melatonin is unclear (621). It has been suggested in a review that melatonin may have a direct effect on bowel function, reducing gut contractions induced by serotonin and inhibiting proliferation of epithelium (622). A study in children with ADHD suffering from insomnia noted abnormal feces at long-term follow-up (408). Increased appetite was noted in one study (607).
• Genitourinary: A systematic review of novel and emerging treatments for autism noted that an adverse effect associated with melatonin was increased enuresis (407). Similarly, a study in children with ADHD suffering from insomnia noted bedwetting at long-term follow-up (408). Decreased libido was noted in one study of melatonin (460).
• Hematologic (blood clotting abnormalities): It has been suggested that there might be a dose-response relationship between the plasma concentration of melatonin and coagulation activity (359). There are at least six reported cases of alterations in prothrombin time (a measurement of blood clotting ability) in patients taking both melatonin and the blood-thinning medication warfarin (Coumadin®) (349). These cases have noted decreases in prothrombin time (PT), which would tend to decrease the effects of warfarin and increase the risk of blood clots. However, blood clots have not been noted in these patients. Minor bleeding was noted in two of these cases (nosebleed and internal eye bleed). This may have been due to the blood-thinning effects of warfarin alone, without a correlation with melatonin use, or may possibly have been due to an interaction between melatonin and warfarin. Evidence pertaining to whether melatonin has effects on blood clotting in people who are not taking warfarin is currently lacking. Based on these reports, melatonin should be avoided in patients using warfarin and possibly in patients taking other blood-thinning medications or those with clotting disorders (358).
• Musculoskeletal: Ataxia (difficulties with walking and balance) may occur following overdose (349).
• Neurologic (general): Commonly reported adverse effects include fatigue, dizziness, headache, irritability, drowsiness, and sleepiness (349;​350;​392;​396;​408;​460;​485;​489;​490;​498;​507;​524;​534;​543;​589;​610;​612;​621). These symptoms are also indications of jet lag, and in some cases, causality may be unclear. Fatigue may occur with morning use or high doses (greater than 50mg) (395), and irregular sleep-wake cycles may occur (623). One study reported that exogenous melatonin also may suppress the secretion of endogenous melatonin (547). A case report of severe migraine has also been noted (624). Disorientation, confusion, sleepwalking, vivid dreams, and nightmares have also been noted, with effects often resolving after cessation of melatonin (349;​357;​394;​397;​398;​489;​563;​564;​625). Nausea, vomiting, amnesia and somnambulia to the point of incapacitation, confusion, and morning sleepiness were also reported in patients treated with a combination of melatonin and zolpidem (491). Due to risk of daytime sleepiness, caution should be taken by those driving or operating heavy machinery (382;​395;​396;​397;​398). Exogenous melatonin may also cause decrements in mental performance, including a slowing of choice-reaction time (399;​400), neurobehavioral performance (401), or learning (574). Other studies have failed to confirm a decrement in performance (626). Rarely, sleeping difficulties have also been reported (392). A systematic review of novel and emerging treatments for autism noted adverse effects associated with melatonin have included morning drowsiness, nighttime awakening, and excitement before going to sleep (407).
• Neurologic (seizure risk): Melatonin may act as a proconvulsant (347) and may lower seizure threshold and increase the risk of seizure (346), particularly in children with severe neurologic disorders, and in an adults with recurring symptoms following repeated melatonin administration (348;​349). However, patients in these studies had no statistically significant exacerbations of seizure disorders requiring a discontinuation of melatonin therapy (348). Another study exploring the effect of melatonin on insomnia in children reported one case of mild generalized epilepsy developing four months after the start of the trial (350). In contrast, multiple case reports indicated reduced incidence of seizure with regular melatonin use (351;​352;​353;​354;​355;​356). This remains an area of controversy (347). Patients with seizure disorder taking melatonin should be monitored closely by a healthcare professional. In one study, the initial dose of melatonin used in the study (3.0mg) was lessened (1.5mg) following the observation of increased seizure frequency in two patients (589).
• Ocular: It has been theorized that due to effects on photoreceptor renewal in the eye, high doses of melatonin may increase intraocular pressure and the risk of glaucoma, age-related maculopathy, and myopia (368), or retinal damage (358). 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 (389;​390). Patients with glaucoma taking melatonin should be monitored by a healthcare professional. In a case-control study of 100 patients with age-related macular degeneration, eight eyes showed more retinal bleeding and six eyes more retinal exudates during treatment with melatonin (420). The authors concluded that these outcomes were likely unrelated to melatonin administration. Human experimentation has suggested that oral melatonin may reduce the function of retinal cones (627).
• Psychiatric: Mood changes have been reported, including giddiness, dysphoria (sadness), and transient depression (391;​392). Psychotic symptoms have been reported in at least two cases, including hallucinations and paranoia, possibly due to overdose (357;​393). An isolated incident of aggressiveness was also noted in a child diagnosed with ADHD and taking prescribed methylphenidate (394). Patients with underlying major depression or psychotic disorders taking melatonin should be monitored closely by a healthcare professional.
• Other: In patients with rheumatoid arthritis, melatonin led to an increase in proinflammatory cytokines (39).

Precautions/Warnings/Contraindications:

• Use cautiously in those at risk for seizures, particularly children, as it has been suggested that melatonin may act as a proconvulsant (347) and may lower seizure threshold and increase the risk of seizure, particularly in children with severe neurologic disorders (346;​348;​349;​350). In contrast, some case reports have indicated reduced incidence of seizure with regular melatonin use (351;​352;​353;​354;​355;​356). This remains an area of controversy (347).
• Use cautiously in those at risk for bleeding, especially those taking warfarin (348;​349;​357), as preliminary evidence suggests that melatonin may decrease prothrombin time (a measurement of blood clotting ability) (349;​358). A dose-response relationship between the plasma concentration of melatonin and coagulation activity has been suggested (359).
• Use cautiously in patients with low blood pressure or those taking antihypertensive medication, as melatonin may cause drops in blood pressure, as observed in animals (360) and in preliminary human research (361;​362;​363;​364;​365), or it may reduce the effects of antihypertensives, such as the alpha-blocker drugs clonidine and methoxamine (360). In humans, blood pressure increases have been observed when 5mg of melatonin was taken at the same time as the calcium-channel blocker nifedipine (366;​367).
• Use cautiously in patients with diabetes, as melatonin has been associated with elevated blood sugar levels (hyperglycemia) in patients with type 1 diabetes (insulin-dependent diabetes) (368;​369), as have reduced glucose tolerance and insulin sensitivity (370;​371). However, in other research, melatonin supplementation was found to have no significant effect upon measures of glucose homeostasis (372)
• Use cautiously in patients with hormone imbalances, as melatonin has reportedly produced varying hormonal effects. Such reports include changes in levels of luteinizing hormone (373;​374;​375;​376;​377;​378;​379), cortisol, progesterone (380), estradiol, thyroid hormone (T4 and T3) (381), growth hormone (379;​382;​383;​384), prolactin (382), oxytocin, and vasopressin (383). Melatonin has further been shown to alter pituitary hormone (LH and FSH) profiles in menopausal women to a more juvenile one (385). Melatonin may also interact synergistically with hormonal anticancer treatments such as tamoxifen (628;​629;​630). Variations may occur based on underlying patient characteristics. Gynecomastia (increased breast size) has been reported in men, as well as decreased sperm count (both which resolved with cessation of melatonin) (358). Decreased sperm motility has also been reported in rats (387) and humans (388). Other research has suggested that melatonin mimics the effect of drugs that act through the estrogen receptor interfering with the effects of endogenous estrogens, as well as those that interfere with the synthesis of estrogens by inhibiting the enzymes controlling the interconversion from their androgenic precursors (386).
• Use cautiously in patients with or at risk for glaucoma, age-related maculopathy, or myopia (368), or retinal damage (358), based on theoretical concerns that high doses of melatonin may increase intraocular pressure, although some studies have found that melatonin may decrease intraocular pressure (389;​390).
• Use cautiously in patients with psychiatric disorders, due to reports of giddiness, dysphoria (sadness), and transient depression (391;​392); and psychotic symptoms, including hallucinations and paranoia, possibly due to overdose (357;​393). There was also an isolated incident of aggressiveness in a child diagnosed with ADHD and taking prescribed methylphenidate after melatonin administration (394).
• Use cautiously in patients using anesthetics, as in vitro studies indicate that some anesthetics have also been found to alter blood melatonin concentrations in humans (isoflurane increasing and sevoflurane decreasing) (402).
• Use cautiously in patients with atherosclerosis, based on preliminary human (403) and animal (404;​405) research that suggests that regular use of melatonin may increase atherosclerotic plaque buildup; however, other animal research has found melatonin to decrease serum cholesterol levels (406).
• Use cautiously in children with a history of enuresis, as, based on human research, melatonin was associated with increased risk of enuresis (407;​408).
• Use cautiously in patients using cytochrome P450 1A2 inhibitors like fluvoxamine, as these agents may increase melatonin levels (367;​393;​409;​410).
• Use cautiously in patients using methamphetamine, as, based on animal research, melatonin may increase the adverse effects of methamphetamine on the nervous system (411).
• Use cautiously in patients taking the nifedipine (a calcium channel blocker), based on human research that melatonin may interfere with nifedipine therapy and result in increased blood pressure and heart rate (366).
• Avoid in patients using CNS depressants, including benzodiazepines and alcohol, as concomitant use may cause increased sedation (382;​395;​396;​397;​398;​399;​400;​401;​412;​413).
• Avoid use in women who are pregnant or are attempting to become pregnant, based on possible hormonal effects (373;​374;​375;​376;​377;​378;​379;​379;​380;​381;​382;​382;​383;​383;​384;​385), including alterations of pituitary contractions (415), and a possible increased risk of developmental disorders, due to high levels of melatonin during pregnancy (416).
• Avoid with known allergies to melatonin or related products.

Pregnancy & Lactation:

• The pineal hormone melatonin is synthesized from the amino acid tryptophan and is known to regulate sleep. There is a lack of available information on the safety on exogenous melatonin during pregnancy and lactation. Breast milk contains tryptophan, and a temporal relationship has been observed between the circadian rhythm of 6-sulfatoxymelatonin (a metabolite of melatonin excreted in the urine) of breastfed babies and that of tryptophan in the mother's milk (631).
• In animal studies, exogenous melatonin has been shown to improve placental efficiency and birthweight in undernourished pregnancies (286).
• Melatonin has not been shown to provide clinical benefit in preeclampsia (632).
• Information on melatonin's effects on lactation is currently lacking in the National Institute of Health's Lactation and Toxicology Database (LactMed).

Interactions

Most herbs and supplements have not been thoroughly tested for interactions with other herbs, supplements, drugs, or foods. The interactions listed below are based on reports in scientific publications, laboratory experiments, or traditional use. 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.

Melatonin/Drug Interactions:

• General: This section discusses both endogenous and exogenous melatonin and the effects of other agents on melatonin and when taken concomitantly with melatonin. As a powerful antioxidant and immunomodulator, melatonin has been widely studied as a pharmacological means of mitigating oxidative damage caused by a number of substances. Specific mention of such interactions are generally omitted due to their positive effect.
• 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. Examples of drugs that may reduce production or secretion of melatonin include nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen (Motrin®, Advil®) or naproxen (Naprosyn®, Aleve®) (633;​634); beta-blocker blood pressure medications, such as propranolol (Inderal®) (635), atenolol (Tenormin®) and metoprolol (Lopressor®, Toprol®) (636;​637); and medications that reduce levels of vitamin B6 in the body, such as oral contraceptives, hormone replacement therapy, loop diuretics, hydralazine, and theophylline (638;​639;​640;​641).
• Anesthesia using 7% sevoflurane decreased melatonin blood concentrations (402). However, using 5% isoflurane, blood levels of melatonin increased (402).
• Melatonin is metabolized in the liver via the hepatic microsome cytochrome P450 system, primarily (but not exclusively) by the CYP2C19 and CYP1A family (particularly CYP1A2) and possibly CYP2C9. It appears to inhibit CYP1A2 and induce CYP3A. Thus, there are potential for interactions and altered levels of drugs and melatonin if used with agents that are substrates, inducers, or inhibitors of these isoenzymes.
• Other agents that may alter synthesis or release of melatonin include caffeine (642;​643), with a more pronounced effect in nonsmokers (644), diazepam (639;​640), estradiol (645), vitamin B12 (646), verapamil (647), temazepam (648), and somatostatin (649).
• Alzheimer's agents: Melatonin levels are often lower in patients with Alzheimer's disease (650;​651;​652;​653;​654;​655). In vitro studies suggest a synergy between tacrine, a cholinesterase inhibitor, and melatonin (656).
• Analgesics: In humans, melatonin use decreased the need for analgesics (464;​505;​507;​508).
• Anesthetics: Based on human research, melatonin may augment standard general anesthetics (500;​502;​504;​657;​658;​659;​660;​661). However, not all trials have been positive (662). In vitro studies indicate that some anesthetics have also been found to alter blood melatonin concentrations in humans (isoflurane increasing and sevoflurane decreasing) (402). Plasma levels of melatonin increased during administration of propofol in humans (657) as well as in rats (663). In humans, melatonin premedication significantly decreased the doses of both propofol and thiopental required to induce anesthesia (502;​504).
• Antiasthma drugs: Asthmatics may have lower levels of endogenous melatonin (664;​665). In vitro studies suggest that melatonin may play a role in influencing nocturnal asthma symptoms in humans (666;​667). Furthermore, in vitro studies suggest that asthmatics may have lower levels of endogenous melatonin (664;​665). The effects of concurrent use of antiasthma drugs and melatonin are not well understood.
• Anticoagulants and antiplatelets: Based on preliminary evidence, melatonin may decrease prothrombin time (a measurement of blood clotting ability) (349;​358). In human research, a dose-response relationship between the plasma concentration of melatonin and coagulation activity has been suggested (359). Based on animal research, melatonin may enhance platelet responsiveness (668).
• Anticonvulsant agents: It has been suggested that melatonin may act as a proconvulsant (347) and may lower seizure threshold and increase the risk of seizure, particularly in children with severe neurologic disorders (346;​348;​349). In another study exploring the effect of melatonin on insomnia in children, a reported case of mild generalized epilepsy developing four months after the start of the trial was noted (350). In contrast, several case reports indicated reduced incidence of seizure with regular melatonin use (351;​352;​353;​354;​355;​356). This remains an area of controversy (347). Increases in the anticonvulsant effects of valproate have been observed in mice (356;​669). In human research, add-on melatonin administration in epileptic children did not alter valproate serum concentrations, suggesting an unlikely interaction between the drugs (670).
• Antidepressant agents: In human research, antidepressants (fluoxetine, duloxetine, and Hypericum perforatum) increased melatonin and 6-hydroxymelatonin (metabolite) levels (671). In human research, concurrent use of fluvoxamine and melatonin resulted in increased levels of melatonin, likely due to reduced metabolism of melatonin by inhibiting CYP1A2 and/or CYP2C9 (367;​409;​410). Venlafaxine had no effect on nocturnal melatonin concentrations in a human study (672).
• Antidiabetic agents: Elevated blood sugar levels (hyperglycemia) have been reported in patients with type 1 diabetes (insulin-dependent diabetes) (368;​369), and low doses of melatonin have reduced glucose tolerance and insulin sensitivity (370;​371). Melatonin in combination with zinc has been found to improve postprandial glycemic control in patients with type 2 diabetes (673;​674). However, in other research, melatonin supplementation was found to have no significant effect upon measures of glucose homeostasis (372).
• Antiglaucoma agents: Theoretical and human studies have suggested that melatonin may increase or decrease intraocular pressure (368;​389;​390). The effects of melatonin and antiglaucoma agents are not well understood.
• Antihypertensives: Melatonin may cause drops in blood pressure, as observed in animals (360;​675) and in preliminary human research (361;​362;​363;​364;​365), although melatonin did not alter blood pressure in a nondipping rat model (676). In human research, suppression of nocturnal melatonin secretion with atenolol (a beta₁-adrenoreceptor antagonist) increased total wake time and decreased REM and slow-wave sleep; these effects were reversed if melatonin was given after the antagonist (113). Serum melatonin levels decreased noticeably with propranolol treatment (635). In animals, melatonin reduced the effects of the alpha-adrenergic agonist clonidine (360). In contrast, in humans, blood pressure increases have been observed when 5mg of melatonin was taken at the same time as the calcium-channel blocker nifedipine (366;​367). Verapamil increased urinary melatonin excretion significantly (by 67%), but left excretion of 6-sulphatoxy-melatonin unaffected in healthy adults infused with calcium as a model for hyperkalemia (647).
• Anti-inflammatory agents: Based on limited human research, melatonin may be an effective anti-inflammatory agent (47), decreasing the upregulation of proinflammatory cytokines (677) as well as inhibiting nitric oxide (NO) and malondialdehyde (MDA) production and increasing glutathione levels (678;​679). However, there is conflicting evidence from human trials, where melatonin induced a proinflammatory response, increasing levels of certain inflammatory cytokines (p>0.05), as well as plasma kynurenine concentrations (p<0.05) in individuals with rheumatoid arthritis (39). The effects of melatonin with anti-inflammatory agents are not well understood.
• Antilipemic agents: According to animal research, melatonin may elicit decreases in free serum cholesterol levels (406). However, research has found that regular use of melatonin may increase atherosclerotic plaque buildup in humans (403) and animals (404;​405). Theoretically, concurrent use of melatonin may interfere with the effects of antilipemic agents.
• Antineoplastic agents: Based on theoretical antioxidant mechanisms and human research, melatonin may interact synergistically with anticarcinogenic agents (344;​431;​433;​435;​629;​680;​681;​682;​683;​684;​684;​685;​686;​687;​688;​689;​690;​691;​692;​693;​694;​695;​696;​697;​698;​699;​700;​701;​702;​703;​704;​705;​706). Melatonin has been combined with other types of treatment, including chemotherapies (such as cisplatin, etoposide, or irinotecan) (344;​628;​629;​630;​697;​700;​707;​708;​709;​710;​711;​712), COX-2 inhibitors (713), or immune therapies, such as interferon (714), interleukin-2 (429;​691;​715;​716;​717;​718;​719;​720;​721;​722;​723;​724;​725;​726;​727;​728;​729;​730;​731;​732), or tumor necrosis factor (730;​733;​734). A number of studies have established melatonin's ability to prevent or mitigate damage from a number of chemical sources including (but not limited to) the following: methamphetamines (109;​735), organophosphorus compounds (260;​261;​262), alcohol (289;​736), nicotine (129), beta-cyfluthrin (737), and benzo(a)pyrene (738).
• Antiobesity agents: Melatonin has been suggested as possibly playing a role in body weight control, possibly via inhibition of adipocyte differentiation (258) or reducing gut motility (739). Other animal research has indicated that exogenous melatonin, however, has no effect on leptin secretion (257).
• Antiparasitic agents: Based on animal research, melatonin therapy may aid in the control of Trypanosoma cruzi proliferation by stimulating the host's immune response (272;​740).
• Antipsychotic agents: Chronic treatment with antipsychotic drugs significantly improved psychotic symptomatology in schizophrenics, but did not change the secretory pattern of melatonin (741). The increase in melatonin secretion, which occurs with the initiation of neuroleptic therapy, may be responsible for the delay in the antipsychotic effects of neuroleptics and may also account for the lag in the development of drug-induced parkinsonism, as well as its disappearance (742). Preliminary human and lab reports suggest that melatonin may aid in reversing symptoms of tardive dyskinesia associated with haloperidol use (548;​554;​743;​744;​745;​746;​747). Based on human evidence, quetiapine did not appear to alter melatonin levels (748).
• Antiviral agents: Based on animal research, the protective effect of melatonin against Venezuelan equine encephalomyelitis virus may be mediated by melatonin receptor activation (749).
• Benzodiazepines: In humans, melatonin has been widely reported as having general and synergistic anxiolytic effects (40;​500;​502;​504;​658;​659;​660;​661). Melatonin has demonstrated effectiveness in reducing benzodiazepine consumption in older patients with established insomnia (423). However, one study reported that low doses of immediate release melatonin (3mg) did not appear to be useful for benzodiazepine tapering in older patients with minor sleep disturbances (423).
• Caffeine: Caffeine is reported to raise natural melatonin levels in the body (643) with a more pronounced effect in nonsmokers (644), possibly due to effects on the liver enzyme cytochrome P450 1A2 (750). It has been proposed that caffeine may increase the bioavailability of endogenous melatonin (751). Caffeine may also alter circadian rhythms in humans, with effects on melatonin secretion (644). It has been reported that caffeine may reduce the onset of nighttime melatonin levels for women in the luteal phase, but that it may have little effect on melatonin levels for oral contraceptive users (752). Another human study has shown that a single dose of 200mg of caffeine may reduce natural melatonin levels (642), though a more recent human study using a twice-daily dose of 200mg of caffeine over seven days found no effect on nighttime salivary melatonin (753).
• Calcium channel blockers: Melatonin may compete with nifedipine and therefore, may impair the antihypertensive efficacy of the calcium channel blocker (366). Verapamil increased urinary melatonin excretion significantly (by 67%), but left excretion of 6-sulphatoxy-melatonin unaffected in healthy adults infused with calcium as a model for hyperkalemia (647).
• CNS depressants: In theory, based on possible risk of daytime sleepiness (382;​395;​396;​397;​398) and reported negative effects on certain cognitive tasks in humans (399;​400;​401), melatonin may exacerbate the amount of drowsiness and reduced mental acuity caused by CNS depressants. Increased daytime drowsiness was reported when melatonin was used at the same time as the prescription sleep aid zolpidem (Ambien®), although it is not clear that effects were greater than with the use of zolpidem alone (176). In human research, remifentanil did not decrease melatonin concentration (413). Melatonin administration also did not prevent remifentanil-induced sleep disturbance.
• CNS stimulants: In human research, there was an isolated case of aggression in a child diagnosed with ADHD and taking prescribed methylphenidate (394). Based on animal research, melatonin may increase the adverse effects of methamphetamine on the nervous system (411). Melatonin has been implicated as having dosing time-dependent effects on the action of psychostimulant drugs such as cocaine and amphetamines (754).
• Cytochrome P450-metabolized agents: Melatonin is metabolized in the liver via the hepatic microsome cytochrome P450 system, primarily (but not exclusively) by the CYP2C19 and CYP1A family (particularly CYP1A2) (755;​756) and possibly CYP2C9. It appears to inhibit CYP1A2 (367;​409;​410) and induce CYP3A. Thus, there are potential for interactions and altered levels of drugs and melatonin if used with agents that are substrates, inducers, or inhibitors of these isoenzymes. In human research, concurrent use of fluvoxamine and melatonin resulted in increased levels of melatonin, likely due to reduced metabolism of melatonin by inhibiting CYP1A2 and/or CYP2C9 (367;​409;​410). Caffeine is reported to raise natural melatonin levels in the body (643) with a more pronounced effect in nonsmokers (644), possibly due to effects on the liver enzyme cytochrome P450 1A2 (644). This effect may be more pronounced in nonsmokers (644). Other human studies suggest that interactions between exogenous melatonin and substrates metabolized by CYP1A2 may differ in individuals before and after smoking abstinence (757).
• Dextromethorphan: Based on animal research, dextromethorphan may interact synergistically with melatonin in relieving neuropathic pain (265).
• Drugs that affect GABA: Animal research suggests a possible role of the GABAergic system in melatonin's effects (758)
• Drugs that may lower seizure threshold: It has been suggested that melatonin may act as a proconvulsant (347) and may lower seizure threshold and increase the risk of seizure, particularly in children with severe neurologic disorders (346;​348;​349). In another study exploring the effect of melatonin on insomnia in children, a reported case of mild generalized epilepsy developing four months after the start of the trial was noted (350). In contrast, several case reports indicated reduced incidence of seizure with regular melatonin use (351;​352;​353;​354;​355;​356). This remains an area of controversy (347).
• Drugs used for osteoporosis: Through free radical scavenging and antioxidant properties, melatonin may impair osteoclast activity and bone resorption (759;​760;​761).
• Flumazenil: In hamsters, the administration of the benzodiazepine antagonist flumazenil blunted the activity of melatonin in these behaviors (762).
• Haloperidol: Preliminary reports suggest that melatonin may aid in reversing symptoms of tardive dyskinesia associated with haloperidol use (548;​554;​743;​744;​745;​746;​747).
• Hormonal agents: In humans, hormone replacement therapy (HRT) is reported to cause a decrease in daily melatonin secretion without disturbing circadian rhythm (763;​764). In clinical and lab studies, melatonin has also been reported as producing varying hormonal effects. Such reports include changes in levels of luteinizing hormone (373;​374;​375;​376;​377;​378;​379), cortisol (765), progesterone (380), estradiol, thyroid hormone (T4 and T3) (381), growth hormone (379;​382;​383;​384), prolactin (382), oxytocin, and vasopressin (383). Melatonin has further been shown to alter pituitary hormone (LH and FSH) profiles in menopausal women to more "juvenile" profiles (385). Clinical trials suggest that melatonin may also interact synergistically with hormonal anticancer treatments such as tamoxifen (628;​629;​630). Other human studies report no significant hormonal effects (481;​616;​617;​618). Gynecomastia (increased breast size) has been reported in men, as well as decreased sperm count (both which resolved with cessation of melatonin) (358). Decreased sperm motility has also been reported in rats (387) and humans (388). Other human and lab studies have suggested that melatonin mimics the effect of drugs that act through the estrogen receptor interfering with the effects of endogenous estrogens, as well as those that interfere with the synthesis of estrogens by inhibiting the enzymes controlling the interconversion from their androgenic precursors (386). In females, blood pressure decreased only in hormone replacement therapy or birth control users and not nonusers (468;​469).
• Immunosuppressants: Based on human research, melatonin may interact positively with immune therapies, such as interferon (714), interleukin-2 (429;​691;​710;​715;​716;​717;​718;​719;​720;​721;​722;​723;​724;​725;​726;​727;​728;​729;​730;​731;​732), or tumor necrosis factor (730;​733;​734). Based on limited human research, researchers concluded that melatonin may be an effective treatment for sarcoidosis (512). Exogenous melatonin has been shown to enhance immune response following veterinary vaccination (766).
• Isoniazid: Based on preliminary in vitro evidence, melatonin may increase the effects of isoniazid against Mycobacterium tuberculosis (328).
• Lithium: Based on human evidence, lithium had a significant effect on sensitivity to light but not on overall melatonin synthesis (767). The clinical significance of lithium and exogenous melatonin interactions are unclear.
• Methamphetamines: Based on animal research, melatonin may increase the adverse effects of methamphetamine on the nervous system (411).
• Methoxamine: In animals, melatonin reduced the effects of the alpha-adrenergic agonist methoxamine (360).
• Neuromuscular blockers: Based on laboratory research, melatonin may increase the neuromuscular blocking effect of the muscle relaxant succinylcholine, but not vecuronium (768).
• Radioprotective drugs: Melatonin has been shown to ameliorate oxidative injury due to ionizing radiation in vitro (292;​769;​770).
• Remifentanil: In human research, remifentanil did not decrease melatonin concentration (413). Melatonin administration also did not prevent remifentanil-induced sleep disturbance.
• Tacrine: In vitro studies suggest a synergy between tacrine, a cholinesterase inhibitor, and melatonin (656).
• Valproic acid: In randomized controlled research, add-on melatonin administration in epileptic children did not alter valproate serum concentrations, suggesting an unlikely interaction between the drugs (670). In one human study, valproate decreased the sensitivity of melatonin to light in patients with bipolar disorder (771).
• Vasodilators: In healthy male volunteers, melatonin significantly increased peripheral blood flow, as measured by distal to proximal skin temperature gradient and finger pulse volume, which demonstrated that melatonin did not have an acute regulatory effect on cerebral blood flow in humans (772).

Melatonin/Herb/Supplement Interactions:

• Alzheimer's herbs: Melatonin levels are often lower in patients with Alzheimer's disease (650;​651;​652;​653;​654;​655;​773). In vitro studies suggest a synergy between tacrine, a cholinesterase inhibitor, and melatonin (656).
• Analgesics: In humans, melatonin use decreased the need for analgesics (464;​505;​507;​508).
• Anesthetics: Based on human research, melatonin may augment standard general anesthetics (500;​502;​504;​657;​658;​659;​660;​661). However, not all trials have been positive (662).
• Antianxiety herbs and supplements: In humans, melatonin has been widely reported as having general and synergistic anxiolytic effects (40;​500;​502;​504;​658;​659;​660;​661).
• Antiasthma herbs and supplements: In vitro studies suggest that melatonin may play a role in influencing nocturnal asthma symptoms (666;​667). Furthermore, in vitro studies suggest that asthmatics may have lower levels of endogenous melatonin (664;​665). The effects of concurrent use of antiasthma drugs and melatonin are not well understood.
• Anticoagulants and antiplatelets: Based on preliminary evidence, melatonin may decrease prothrombin time (a measurement of blood clotting ability) (349;​358). In human research, a dose-response relationship between the plasma concentration of melatonin and coagulation activity has been suggested (359). Based on animal research, melatonin may enhance platelet responsiveness (668).
• Anticonvulsants: It has been suggested that melatonin may act as a proconvulsant (347) and may lower seizure threshold and increase the risk of seizure, particularly in children with severe neurologic disorders (346;​348;​349). In another study exploring the effect of melatonin on insomnia in children, a reported case of mild generalized epilepsy developing four months after the start of the trial was noted (350). In contrast, several case reports indicated reduced incidence of seizure with regular melatonin use (351;​352;​353;​354;​355;​356). This remains an area of controversy (347).
• Antidepressant herbs and supplements: In human research, antidepressants (fluoxetine, duloxetine, and Hypericum perforatum) increased melatonin and 6-hydroxymelatonin (metabolite) levels (671).
• Antiglaucoma herbs and supplements: Theoretical and human studies have suggested that melatonin may increase or decrease intraocular pressure (368;​389;​390). The effects of melatonin and antiglaucoma agents are not well understood.
• Anti-inflammatory herbs: Based on limited human research, melatonin may be an effective anti-inflammatory agent (47), decreasing the upregulation of proinflammatory cytokines (677), as well as inhibiting nitric oxide (NO) and malondialdehyde (MDA) production and increasing glutathione levels (678;​679). However, there is conflicting evidence from human trials, where melatonin induced a proinflammatory response, increasing levels of certain inflammatory cytokines (p>0.05), as well as plasma kynurenine concentrations (p<0.05) in individuals with rheumatoid arthritis (39). The effects of melatonin with anti-inflammatory agents are not well understood.
• Antilipemics: According to animal research, melatonin may elicit decreases in free serum cholesterol levels (406). Preliminary research suggests that regular use of melatonin may increase atherosclerotic plaque buildup in humans (403) and animals (404;​405). Theoretically, concurrent use of melatonin may interfere with the effects of antilipemic agents.
• Antineoplastics: Based on theoretical antioxidant mechanisms and human research, melatonin may interact synergistically with anticarcinogenic agents (344;​431;​433;​435;​629;​680;​681;​682;​683;​684;​684;​685;​686;​687;​688;​689;​690;​691;​692;​693;​694;​695;​696;​697;​698;​699;​700;​701;​702;​703;​704;​705;​706). Melatonin has been combined with other types of treatment, including chemotherapies (such as cisplatin, etoposide, or irinotecan) (344;​628;​629;​630;​697;​700;​707;​708;​709;​710;​711;​712), COX-2 inhibitors (713), or immune therapies, such as interferon (714), interleukin-2 (429;​691;​715;​716;​717;​718;​719;​720;​721;​722;​723;​724;​725;​726;​727;​728;​729;​730;​731;​732), or tumor necrosis factor (730;​733;​734). A number of studies have established melatonin's ability to prevent or mitigate damage from a number of chemical sources including (but not limited to): methamphetamines (109;​735), organophosphorus compounds (260;​261;​262), alcohol (289;​736), nicotine (129), beta-cyfluthrin (737), and benzo(a)pyrene (738).
• Antiobesity herbs and supplements: Melatonin has been suggested as possibly playing a role in body weight control, possibly via inhibition of adipocyte differentiation (258) or reducing gut motility (739). Other animal research has indicated that exogenous melatonin, however, had no effect on leptin secretion (257).
• Antioxidants: A variety of in vitro and in vivo studies have reported on the antioxidative effects of melatonin in a range of tissues and oxidative injury contexts (5;​6;​7;​8;​9;​10;​11;​12;​13;​14;​28;​29;​30;​227;​774;​775;​776;​777;​778;​779;​780;​781;​782;​783;​784;​785;​786;​787;​788); (18;​19;​20;​21;​22;​23;​24;​25;​26;​27;​31;​32;​83;​84;​85;​86;​87;​88;​89;​90;​91;​92;​93;​94;​95;​96;​97;​98;​99;​100;​101;​102;​103;​104;​105;​403;​789;​790;​791;​792;​793;​794;​795;​796;​797;​798). In vivo studies have generally used rats as their model system. Melatonin has been reported as being a more efficient antioxidant than glutathione (799), vitamin C (800;​801), or vitamin E (33;​802;​803;​804;​805;​806). Synergy has also been observed with other antioxidants (35;​807). Reports are by and large positive; however, select failures to observe ameliorative antioxidant function also appear in the literature (808;​809).
• Antiparasitic agents: Based on animal research, melatonin therapy may aid in the control of Trypanosoma cruzi proliferation by stimulating the host's immune response (272;​740).
• Antipsychotics: Chronic treatment with antipsychotic drugs significantly improved psychotic symptomatology in schizophrenics, but did not change the secretory pattern of melatonin (741). The increase in melatonin secretion, which occurs with the initiation of neuroleptic therapy, may be responsible for the delay in the antipsychotic effects of neuroleptics and may also account for the lag in the development of drug-induced parkinsonism, as well as its disappearance (742).
• Antiviral agents: Based on animal research, the protective effect of melatonin against Venezuelan equine encephalomyelitis virus may be mediated by melatonin receptor activation (749).
• Caffeine-containing herbs: Caffeine is reported to raise natural melatonin levels in the body (643)with a more pronounced effect in nonsmokers (644), possibly due to effects on the liver enzyme cytochrome P450 1A2 (644). It has been proposed that caffeine may increase the bioavailability of endogenous melatonin (751). Caffeine may also alter circadian rhythms in humans, with effects on melatonin secretion (644). It has been reported that caffeine may reduce the onset of nighttime melatonin levels for women in the luteal phase, but that it may have little effect on melatonin levels for oral contraceptive users (752). Another human study has shown that a single dose of 200mg of caffeine may reduce natural melatonin levels (642), though a more recent human study using a twice-daily dose of 200mg of caffeine over seven days found no effect on nighttime salivary melatonin (753).
• Chasteberry: Chasteberry may increase natural secretion of melatonin in the body, based on preliminary research (810).
• Cytochrome P450-metabolized herbs and supplements: Melatonin is metabolized in the liver via the hepatic microsome cytochrome P450 system, primarily (but not exclusively) by the CYP2C19 and CYP1A family (particularly CYP1A2) (755;​756) and possibly CYP2C9. It appears to inhibit CYP1A2 (367;​409;​410) and induce CYP3A. Thus, there are potential for interactions and altered levels of drugs and melatonin if used with agents that are substrates, inducers, or inhibitors of these isoenzymes.
• DHEA: In mice, DHEA and melatonin have been noted to stimulate immune function, with slight additive effects when used together (811). Effects of this combination in humans are not clear.
• Echinacea: In mice, a combination of echinacea and melatonin has been noted to slow the maturation of some types of immune cells, which may reduce immune function (812). Effects of this combination in humans are not clear.
• Folate: Severe folate deficiency may reduce the body's natural levels of melatonin, based on preliminary research (813).
• Herbs/supplements that lower seizure threshold: It has been suggested that melatonin may act as a proconvulsant (347) and may lower seizure threshold and increase the risk of seizure, particularly in children with severe neurologic disorders (346;​348;​349;​350). In contrast, several case reports indicated reduced incidence of seizure with regular melatonin use (351;​352;​353;​354;​355;​356). This issue remains an area of controversy (347).
• Hormonal herbs or supplements: Melatonin has been reported as producing varying hormonal effects. Such reports include changes in levels of luteinizing hormone (373;​374;​375;​376;​377;​378;​379), cortisol (765), progesterone (380), estradiol, thyroid hormone (T4 and T3) (381), growth hormone (379;​382;​383;​384), prolactin (382), and oxytocin and vasopressin (383). Melatonin has further been shown to alter pituitary hormone (LH and FSH) profiles in menopausal women (385). Melatonin use has also been linked with gynecomastia, and decreased sperm count (358) and motility in both humans (388) and rats (387). Further work has suggested that melatonin mimics the effect of drugs that act through estrogen receptors, interfering with the effects of endogenous estrogens, as well as those that interfere with the synthesis of estrogens (386). Other studies report no significant hormonal effects (481;​616;​617;​618). Variations may occur based on underlying patient characteristics.
• Hypoglycemics: Elevated blood sugar levels (hyperglycemia) have been reported in patients with type 1 diabetes (insulin-dependent diabetes) (368;​369), and low doses of melatonin have reduced glucose tolerance and insulin sensitivity (370;​371). Melatonin in combination with zinc has been found to improve postprandial glycemic control in patients with type 2 diabetes (673;​674). However, in other research, melatonin supplementation was found to have no significant effect upon measures of glucose homeostasis (372).
• Hypotensives: Melatonin may cause drops in blood pressure, as observed in animals (360;​675) and in preliminary human research (361;​362;​363;​364;​365), although melatonin did not alter blood pressure in a nondipping rat model (676). In human research, suppression of nocturnal melatonin secretion with atenolol (a beta₁-adrenoreceptor antagonist) increased total wake time and decreased REM and slow-wave sleep; these effects were reversed if melatonin was given after the antagonist (113).
• Immunosuppressants: Based on human research, melatonin may interact positively with immune therapies, such as interferon (714), interleukin-2 (429;​691;​710;​715;​716;​717;​718;​719;​720;​721;​722;​723;​724;​725;​726;​727;​728;​729;​730;​731;​732), or tumor necrosis factor (730;​733;​734). Based on limited human research, melatonin may be an effective treatment for sarcoidosis (512). Exogenous melatonin has been shown to enhance immune response following veterinary vaccination (766).
• Intraocular pressure-altering herbs: Theoretical and human research has suggested that melatonin may increase or decrease intraocular pressure (368;​389;​390). The effects of melatonin and antiglaucoma agents are not well understood.
• Neurologic herbs and supplements: Increased daytime drowsiness was reported when melatonin was used at the same time as sleep aids (176). In theory, based on possible risk of daytime sleepiness (382;​395;​396;​397;​398) and reported negative effect on certain cognitive tasks (399;​400;​401), melatonin may exacerbate the amount of drowsiness and reduced mental acuity caused by some neurologic herbs and supplements and sedatives, as well as some antidepressants. Melatonin has been widely reported as improving many measures of sleep quality in healthy and neurologically disturbed patients (both children and adults) (446;​447;​448;​449;​450;​451;​453;​476;​477;​516;​535;​582;​598;​611). Based on laboratory research, melatonin may increase the neuromuscular blocking effect of certain muscle relaxants (768).
• Osteoporosis herbs/supplements: Through free radical-scavenging and antioxidant properties, melatonin may impair osteoclast activity and bone resorption (759;​760;​761).
• Radioprotective agents: Melatonin has been shown to ameliorate oxidative injury due to ionizing radiation (292;​769;​770).
• Sedatives: In theory, based on possible risk of daytime sleepiness (382;​395;​396;​397;​398) and reported negative effect on certain cognitive tasks in humans (399;​400;​401), melatonin may exacerbate the amount of drowsiness and reduced mental acuity caused CNS depressants. Increased daytime drowsiness was reported when melatonin was used at the same time as the prescription sleep aid zolpidem (Ambien®), although it is not clear that effects were greater than with the use of zolpidem alone (176). Based on human research, remifentanil did not decrease melatonin concentration (413). Melatonin administration also did not prevent remifentanil-induced sleep disturbance.
• Stimulants: In human research, there was an isolated case of aggression in a child diagnosed with ADHD and taking prescribed methylphenidate (394). Based on animal research, melatonin may increase the adverse effects of methamphetamine on the nervous system (411). Melatonin has been implicated as having dosing time-dependent effects on the action of psychostimulant drugs such as cocaine and amphetamines (754).
• Vasodilator herbs and supplements: In healthy male volunteers, melatonin significantly increased peripheral blood flow, as measured by distal to proximal skin temperature gradient and finger pulse volume, which demonstrated that melatonin did not have an acute regulatory effect on cerebral blood flow in humans (772).

Melatonin/Food Interactions:

• General: The gastrointestinal effects of melatonin are likely dependent on food intake (814;​815). Food deprivation was found to impair daily rhythms of melatonin content by altering the activity of melatonin-synthesizing enzymes (815). Some foods, such as oats, sweet corn, rice, ginger, tomatoes, bananas, and barley, contain small amounts of melatonin and may increase melatonin levels (816;​817).
• Vegetables: Increased consumption of vegetables raised circulatory melatonin concentrations (818).

Melatonin/Lab Interactions:

• Blood glucose: Elevated blood sugar levels (hyperglycemia) have been reported in patients with type 1 diabetes (insulin-dependent diabetes) (368;​369), and low doses of melatonin have reduced glucose tolerance and insulin sensitivity (370). Melatonin in combination with zinc has been found to improve postprandial glycemic control in patients with type 2 diabetes (673;​674). However, in other research, melatonin supplementation was found to have no significant effect upon measures of glucose homeostasis (372).
• Blood pressure: Melatonin may cause drops in blood pressure, as observed in animals (360) and in preliminary human research (361;​362;​363;​364;​365).
• Coagulation panel: It has been suggested that there might be a dose-response relationship between the plasma concentration of melatonin and coagulation activity (359). There are at least six reported cases of alterations in prothrombin time (a measurement of blood clotting ability) in patients taking both melatonin and warfarin (349). These cases have noted decreases in prothrombin time (PT).
• Glycated hemoglobin (HA1c): In human research, melatonin use resulted in decreases in glycated hemoglobin (673;​674).
• Heart rate: Melatonin has been shown to increase heart rate when administered in patients taking nifedipine (a calcium channel blocker antihypertensive) (366).
• Hormone panel: Melatonin has also been reported to produce varying hormonal effects. Such reports include changes in levels of luteinizing hormone (373;​374;​375;​376;​377;​378;​379), cortisol (380;​438;​765), adrenocorticotropic hormone (ACTH) (438). progesterone (380), estradiol, thyroid hormone (T4 and T3) (381), growth hormone (379;​382;​383;​384), prolactin (382), oxytocin, and vasopressin (383). Melatonin has further been shown to alter pituitary hormone (LH and FSH) profiles in menopausal women to a more "juvenile" one (385).
• Inflammatory markers: Based on limited human research, melatonin may be an effective anti-inflammatory agent (47), decreasing the upregulation of proinflammatory cytokines (677), as well as inhibiting nitric oxide (NO) and malondialdehyde (MDA) production and increasing glutathione levels (678;​679). However, there is conflicting evidence from human trials, where melatonin induced a proinflammatory response, increasing levels of certain inflammatory cytokines (p>0.05), as well as plasma kynurenine concentrations (p<0.05) in individuals with rheumatoid arthritis (39).
• Intraocular pressure: Preliminary evidence in humans suggests that melatonin may decrease intraocular pressure in the eye (389;​390). However, high doses of melatonin may increase intraocular pressure and the risk of glaucoma, age-related maculopathy, and myopia (368), as well as retinal damage (358).
• Lipid profile: According to animal research, melatonin may elicit decreases in free serum cholesterol levels (406). However, research has found that regular use of melatonin may increase atherosclerotic plaque buildup in humans (403) and animals (404;​405).
• Magnetic fields: It has been theorized that chronic exposure to magnetic fields or recurrent cellular telephone use may alter melatonin levels and circadian rhythms. However, several studies suggest that this is not the case (819;​820;​821;​822). Melatonin was seen to reduce the effects of lipid peroxidation, less effectively than vitamin E, in rats exposed to static magnetic fields under laboratory conditions (823).
• Melatonin levels: Melatonin supplementation increased plasma melatonin levels (816;​817;​824).
• Plasma kynurenine concentrations: There is evidence that melatonin may induce a proinflammatory response and increase plasma kynurenine concentrations (p<0.05) in individuals with rheumatoid arthritis (39).
• Temperature: Melatonin use was found to decrease body temperature in various clinical trials (483;​566).

Melatonin/Nutrient Depletions:

• Cholesterol: Melatonin may elicit decreases in free serum cholesterol levels (406).
• Natural melatonin levels (decreases): 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. Examples of drugs that may reduce production or secretion of melatonin include nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen (Motrin®, Advil®) or naproxen (Naprosyn®, Aleve®) (633;​634); beta-blocker blood pressure medications, such as atenolol (Tenormin®) or metoprolol (Lopressor®, Toprol®) (636;​637); and medications that reduce levels of vitamin B6 in the body, such as oral contraceptives, hormone replacement therapy, loop diuretics, hydralazine, and theophylline (638;​639;​640;​641). Anesthesia using 7% sevoflurane decreased melatonin blood concentrations (402). Asthmatics may have lower levels of endogenous melatonin (664;​665). Melatonin levels in serum decreased noticeably with propranolol treatment (635). Other drugs that may reduce melatonin levels (by inducing P450 1A2) include the following: carbamazepine, insulin, 3-methyl cholanthrene, modafinil, nafcillin, nicotine, omeprazole, phenobarbital, phenytoin, primidone, rifampin, and ritonavir, according to anecdotal information.

Mechanism of Action

Pharmacology:

• General: Melatonin acts on the MT(1) and MT(2) melatonin receptors located in the hypothalamic suprachiasmatic nuclei, the site of the body's master circadian clock (3). Based on animal experimental models, melatonin has antidopaminergic effects; repeated administration of melatonin may modify the plasticity of behaviors mediated by central dopaminergic systems (825).
• Endogenous melatonin: Melatonin is an indole synthesized from tryptophan in the pineal gland (1;​179), with regulation of day-night changes in synthesis by serotonin N-acetyltransferase (2). Some synthesis takes place additionally in the retina, gastrointestinal tract, bone marrow, bile, and cells of the immune system (826;​827;​828;​829). The formation and release of melatonin are stimulated by darkness and inhibited by light (830;​831;​832), without significant differences between polarized and nonpolarized light (833;​834). The primary melatonin-controlled events take place in the rods rather than in the cones of retina (834). This response to light may remain in blind subjects, despite apparently complete loss of visual function (835;​836).
• Since beta₁-adrenoreceptor antagonists almost completely inhibit the normal nighttime rise in melatonin, it is thought that human pineal adrenoreceptors are of beta₁-subtype (636;​637;​637;​837;​838;​839;​840). Similar arguments indicate the involvement of alpha₁-adrenoreceptors in the stimulation of melatonin synthesis (841), while alpha₂-adrenoreceptors presumably operate as downregulators (842;​843). As such, the production of melatonin is considered to be regulated by the sympathetic nervous system and its neurotransmitter norepinephrine. With the onset of darkness, norepinephrine release is followed by stimulation of postsynaptic pineal adrenoreceptors and enhancement of melatonin synthesis (1;​844). The involvement of norepinephrine is supported by an increase in nighttime plasma melatonin in humans treated with an inhibitor of norepinephrine uptake (845;​846). Activation of the sympathetic nervous system appears to accelerate melatonin synthesis (847;​848;​849). Animal studies suggest that endogenous melatonin is involved in the suppression of sympathetic activity, with possible negative feedback inhibition (850). Melatonin may reduce circulating norepinephrine in young individuals and in postmenopausal women receiving estradiol replacement, but not in menopausal women (468).
• Melatonin secretion occurs at a constant rate in both young and older men and women (851). Circadian melatonin rhythm appears at the end of the neonatal period and persists thereafter (852;​853), despite functioning vision.
• In humans, the daytime melatonin plasma level is less than 40pM/L. In the middle of the night, the concentration increases to approximately 260pM/L (1). In some species, these values may reach a 50-fold difference (761). Both high- and low-affinity binding sites have been identified in several brain regions (superchiasmatic nuclei of the hypothalamus, thalamus, and pituitary gland), retina, gut, ovaries, blood vessels, lymphocytes, and platelets (1;​573;​854;​855). A recently discovered class of melatonin-binding sites, called orphan receptors, presumably mediate the ability of melatonin to regulate gene expression (761;​856).
• In humans, a pacemaker located in the suprachiasmatic nucleus of the hypothalamus controls the circadian rhythm of melatonin production. By binding to the receptors in the nucleus, melatonin may alter a phase of this pacemaker (e.g., reset the biological clock) (857;​858;​859;​860;​861;​862;​863). The suprachiasmatic nuclei are the target sites for the effect of exogenous melatonin on the amplitude of the endogenous melatonin rhythm (864).
• The following factors may modulate the synthesis, release, or bioavailability of melatonin: nonsteroidal anti-inflammatory drugs (634), diazepam (639;​640), vitamin B12 (646), GABA (865;​866), ethanol (867), micronutrient accumulation and depletion (868), gonadotropin-releasing hormone, gonadotropins/gonadal steroids (869;​870), estrogen plus progesterone (641), testosterone (869), duration of gestation (871), prenatal growth restriction (872), interleukin-2, cancer (873), posture (874), balance (875), phenelzine (876), Thorazine® (877), sleep deprivation (848), hypercalcemia/verapamil (647), temazepam, zopiclone (648), levodopa-related motor complications (878), agnus castus (810), desipramine (879), prazosin (842), intravenous L-tryptophan (828), caffeine (751), and exercise (880). In terms of modulating the synthesis and release of melatonin, current research reports a lack of an effect using somatostatin (649), oral administration of 5-hydoxytryptophan (881), exposure to pulsating magnetic fields (820), nifedipine (882), midazolam, sodium thiopental (883), electroconvulsive therapy, TRH-injection, L-dopa, or bromergocryptine (217;​884).
• Disturbances in the circadian rhythm of melatonin (and declines in nighttime melatonin) have been associated with aging (1;​885;​886;​887;​888;​889;​890;​891).
• The lack of light signal in blind persons leads to various unusual free-running melatonin secretory patterns (892;​893;​894). Low-dose melatonin has been noted to be more effective entraining blind people with a free-running melatonin secretory pattern due to the potential of excess hormone discharging into the wrong zone of the phase-response curve (895). Free-running patterns are also observed after pineal gland damage (896) or under special working regimens (897;​898). The nocturnal onset of melatonin secretion strongly correlates with a steep rise in sleep propensity and precedes it by approximately two hours (899). The specific events taking place during this interval currently remain obscure. It is possible that melatonin does not actively induce sleep but switches off a wakefulness-generated mechanism that opposes a sleep-inducing mechanism (899), the alerting process being dependent on the suprachiasmatic nucleus (858).
• While measuring endogenous melatonin, some authors have not found a link between melatonin secretion and the sleep-waking cycle in humans (900). It has been suggested by some that natural sleep is largely determined by a functioning circadian system without melatonin involvement (863;​886;​901;​902).
• Analgesic effects: Based on review, research has indicated that melatonin may modulate pain perception via activation of MT(1) and MT(2) receptors, opening of potassium channels, inhibition of 5-lipoxygenase and cyclooxygenase-2 expression, and indirect activation of opioid receptors (80).
• Antiaging effects: Melatonin has been identified as countering some of the deleterious effects of aging (52;​53;​54;​55;​56;​57;​58;​59;​60;​61). Animal experimentation has indicated that melatonin may improve longevity (cellular and otherwise) by preventing age-related mitochondrial impairment (57), maintaining youthful rhythmic activity (58), improving monoaminergic neurotransmission (903), and reversing immunosenescence (904;​905). An experimental model of age-induced neuronal apoptosis indicated that melatonin may exert a protective effect via prosurvival Akt and prevention of DNA damage (906).
• Antiarthritic effects: As shown in vitro, melatonin has been suggested as possibly playing a beneficial role in osteoarthritis (263) and other rheumatic diseases (301). Possible mechanisms include the enhancement of cartilage matrix synthesis (263) and the inhibition of fibroblast-like synoviocyte proliferation (301).
• Anticancer properties: Researchers have investigated the outcome of melatonin use as an adjunct to chemotherapy, interleukin-2, radiotherapy, support therapy, and tumor necrosis factor (TNF) therapy (907). According to the "melatonin hypothesis" of cancer, the exposure to light at night and anthropogenic electric and magnetic fields may be related to the increased incidence of cancer and childhood leukemia via melatonin disruption (908).
• In vitro, at pharmacological concentrations, melatonin exhibited cytotoxic activity in cancer cells (909;​910). At both physiological and pharmacological concentrations, melatonin acted as a differentiating agent in some cancer cells and lowered their invasive and metastatic capabilities through alterations in adhesion molecules and maintenance of gap junctional intercellular communication (909). In other cancer cell types, melatonin, either alone or in combination with other agents, induced apoptotic cell death. Biochemical and molecular mechanisms of melatonin's oncostatic action may include regulation of estrogen receptor expression and transactivation, calcium/calmodulin activity, protein kinase C activity, cytoskeletal architecture and function, intracellular pH, melatonin receptor-mediated signal transduction cascades, and fatty acid transport and metabolism (909). These and other possible anticancer mechanisms may include or operate by modulation of apoptosis (911;​912;​913;​914;​915;​916), downregulation of HIF-1 alpha expression (antiangiogenic) (917), antiestrogenic effects (918;​919;​920), antiproliferative effects (921;​922), suppression of linoleic acid uptake and metabolism (923), SIRT1 inhibition (59), cytoskeletal dynamics (inhibition of cancer cell migration) (924;​925), epigenetic regulation (926), reduction of oxidative stress (927), modulation of melatonin receptor expression (928), and stimulation of melatonin receptors and associated biomolecular cascades (929).
• Nuclear signaling appears to play a central role in the function of melatonin (930). At physiological circulating concentrations, melatonin may inhibit cancer cell proliferation via cell cycle-specific effects identified in vitro (909;​910;​931;​932). Women with endometrial cancer have been found to have melatonin plasma levels six times lower than tumor-free controls. It is not clear if this is causative or adaptive, although melatonin antiproliferative activity is hypothesized (933;​934;​935).
• As a chemoprotective agent, daily administration of melatonin for six months was reported to induce a protective effect against the formation of mammary tumors in rat models (936). MT1 (high-affinity melatonin receptor subtype) receptors have been detected in normal and malignant breast epithelium, with high receptor levels occurring more frequently in tumor cells (p<0.001); tumors with moderate or strong reactivity are more likely to be high nuclear grade (p<0.045). It has been proposed that these findings have implications for the use of melatonin in breast cancer therapy (937).
• An oncostatic effect of melatonin (cessation of cell cycle progression) has been reported in human prostate cancer cells (938;​939); nuclear rather than membrane melatonin receptors have been implicated, as have MT1 receptor subtypes. MCF-7 human breast cancer cultured cells have been reported as melatonin sensitive, as well as estrogen receptor positive and estrogen responsive (940), although this finding was not confirmed in a subsequent study (941). Inhibition of cell proliferation may be mediated through G-protein coupled membrane receptors, or via retinoid orphan receptors with involvement of the calcium signaling pathway (942). Downregulation of the receptor level indicates the possibility of an estrogen-responsive mechanism. This notion is supported by melatonin-induced stimulation of expression of the growth-inhibitory factor, TGF-beta (940). However, other investigators have failed to reproduce the oncostatic effect of melatonin on MCF-7 cells or ZR-75-1 and T-47D cell lines (943). Melanoma M 2R cells also responded to melatonin (944). It has also been suggested that melatonin-related growth inhibition of breast cancer cells may be related to enhanced TGF-beta(1) secretion (945).
• Melatonin has been reported to elicit an increase in estrogen receptor activity in breast tumors (877). Low plasma melatonin concentrations were associated with greater amounts of estrogen or progesterone receptors on primary tumors (946).
• Pinealectomy is reported to enhance tumor growth and metastasis in animals (947). In addition, increased neoplastic growth has been noted in some animal models (Morris hepatoma 7288 CTC in rats), when animals are maintained in a constant weak light (0.2 lux), thereby inducing inhibition of melatonin synthesis (948).
• Anticonvulsant effects: Both anticonvulsant (356;​669;​949;​950) and proconvulsant (347) properties have been associated with melatonin in preclinical studies. In animals, intraventricular injection of antimelatonin antibody has elicited transitory epileptiform abnormalities in the electroencephalogram (951). Proposed mechanisms of action include altered brain GABAergic neurotransmission, interactions with benzodiazepine brain receptors, tryptophan metabolite activity, free radical scavenger activity, or modulation of brain amino acids and nitric oxide (NO) production (347;​653;​949).
• Antidiabetic effects: Melatonin may stimulate glycogen synthesis via the PKCzeta-Akt-GSK3beta pathway (952) as well as inhibit insulin secretion via stimulation of melatonin receptors in pancreatic islet cells (953). Exogenous melatonin has also been shown to improve glucose tolerance, increase muscle insulin receptor and GLUT 4 expression, and enhance glucose clearance from the blood in bats (954). Based on findings in rats, melatonin has been suggested as influencing gene expression in insulinoma beta-cells (955).
• Anti-inflammatory effects: Based on limited human research, melatonin may be an effective anti-inflammatory, particularly in infants with respiratory distress (47). Melatonin has been reported to decrease upregulation of proinflammatory cytokines (99;​157;​173;​677;​956). In animal research, melatonin has also been reported to reduce cardiac inflammatory injury induced by acute exercise (957). Other anti-inflammatory effects may be related to inhibition of NO and malondialdehyde (MDA) production or an increase of glutathione levels (678;​679); the suppression of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 (177); the inhibition of phospholipase A2 (958), mitogen-activated protein kinases (312), NF-kappaB (92;​205;​956;​957), or IL-4 and interferon (IFN)-gamma (111); or the regulation of mast cells (175). Use in inflammatory conditions has been proposed (959). However, there is conflicting evidence from human trials, where melatonin induced a proinflammatory response, increasing levels of certain inflammatory cytokines (p>0.05), as well as plasma kynurenine concentrations (p<0.05) in individuals with rheumatoid arthritis (39).
• Antiobesity effects: Melatonin has been suggested as possibly playing a role in body weight control, possibly via inhibition of adipocyte differentiation (258) or reducing gut motility (739). Other animal research has indicated that exogenous melatonin, however, has no effect on leptin secretion (257).
• Antioxidant effects: There are many laboratory and animal studies of the antioxidant (free radical-scavenging) properties of melatonin (15;​16;​17;​33;​34;​35;​36;​37;​38;​794;​795;​796;​797;​798). As a result, melatonin has been proposed as a supplement to prevent or treat many conditions that are associated with oxidative damage. In vitro, melatonin has been observed to act as a direct free radical scavenger with the ability to detoxify both reactive oxygen and reactive nitrogen species (227;​774;​775;​789). Melatonin may reduce oxidative damage under a variety of conditions in which excessive free radical generation is believed to be involved (12;​13;​83;​84;​85;​86;​87;​88;​89;​90;​91;​92;​93;​94;​95;​96;​97;​98;​99;​100;​101;​102;​103;​104;​105;​106;​108;​109). This reduction of oxidative damage has been observed in various animal models of ischemia and reperfusion injury (5;​6;​7;​8;​9;​10;​11;​14;​18;​19;​20;​21;​22;​23;​24;​25;​26;​27;​28;​29;​30;​31;​32;​125;​181;​182;​183;​184;​185;​186;​187;​188;​189;​190;​191;​192;​193;​194;​195;​195;​793), as well as in nerve tissues, including brain, spinal cord, optic nerve, and spinal cord white matter (780). However, in a rat model, melatonin was not effective in attenuating alcohol-induced loss of Purkinje cells (808). Nonetheless, due to its high lipophilicity, melatonin is likely able to reach most tissues (805).
• In preclinical studies, melatonin protected against toxicity related to oxidative damage, such as alloxan-induced pancreatic toxicity (788), 6-hydroxydopamine damage to neuronal PC12 cells, kainic acid injury (784;​785;​786), homocysteine-mediated oxidative stress (403;​787;​792), iron-induced oxidative injury (7;​8;​9;​10), radiation-induced damage of various cell lines (781;​782;​783;​790;​791), ultraviolet light-induced damage (778;​779), and copper-induced LDL oxidation (777). Melatonin has been reported as being a more efficient antioxidant than glutathione (799), vitamin C (800;​801), or vitamin E (33;​802;​803;​804;​805;​806). Synergy has been observed with other antioxidants (35;​807).
• Some data suggest that melatonin as a free radical scavenger may inhibit the microsomal production of hydrogen peroxide in rats treated with aflatoxin (776), although more recent research reports that melatonin does not directly scavenge hydrogen peroxide (960). Other conflicting evidence also exists: exogenous melatonin administered to rats via intraperitoneal injection increased photoreceptor susceptibility to light-induced damage; pinealectomy has been shown to protect photoreceptors, while subsequent melatonin injection has increased destruction (809). It has been proposed that melatonin may reduce the amount of neurologic damage patients experience after stroke, based on antioxidant properties (5;​14;​18;​961;​962;​963;​964;​965). In addition, melatonin levels may be altered in people immediately after stroke (196;​966).
• Melatonin produced an increase in the activity of antioxidant enzymes, glutathione peroxidase, and glutathione reductase in epileptic children receiving valproate (586;​670). It has been suggested that such activity may help protect neurons from oxidatative stress and damage.
• Antiparasitic effects: Based on animal research, melatonin therapy may aid in the control of Trypanosoma cruzi proliferation by stimulating the host's immune response (272;​740).
• Antiviral effects: Based on animal research, the protective effect of melatonin against Venezuelan equine encephalomyelitis virus may be mediated by melatonin receptor activation (749).
• Bone effects: Through free radical-scavenging and antioxidant properties, melatonin may impair osteoclast activity and bone resorption (759;​760;​761).
• Cardiovascular effects: Melatonin may act directly on the cardiovascular system rather than modulate cardiac autonomic activity (967). In humans, melatonin, even in a dose of 1mg, has been observed to reduce blood pressure and decrease catecholamine levels after 90 minutes, possibly via direct effects on the hypothalamus, through antioxidant activity, by decreasing catecholamine levels, or by relaxing smooth muscle in the aorta wall (968). Based on animal research, melatonin may lower blood pressure via GABA(A) receptors (675) and the reduction of oxidative load and restoration of the NO pathway (969). However, a review of the role of melatonin in the pathology of the cardiovascular system noted that further evaluation of the clinical safety and efficacy of melatonin as an antihypertensive therapy is necessary and that such study must take into account melatonin's antagonism of calcium channel inhibitors (970). Dose-dependent relaxation of precontracted rat aorta and reduction of contractile response to alpha-adrenergic but not beta-adrenergic agonists have been observed (360). In healthy humans, melatonin is reported to decrease the pulsatility index and systolic and diastolic blood pressures, blunt noradrenergic activation (361;​362;​363), and increase cardiac vagal tone (364). In healthy postmenopausal women, hypotensive action has been observed only during hormone replacement therapy (365). High concentrations of melatonin may attenuate the reflex sympathetic increases that occur in response to orthostatic stress (971).
• Coagulation effects: Melatonin may play a role in mediating the influence of the psychoendocrine system and of lighting conditions on hematopoiesis. Melatonin seems to regulate hematopoietic cell growth by influencing apoptosis-related mechanisms (555). In humans, melatonin was associated with lower plasma levels of procoagulant factors, and dose-response relationships between the plasma concentration of melatonin and coagulation activity have been hypothesized (359).
• Increased platelet counts after melatonin use have been observed in patients with decreased platelets due to cancer therapies (700;​702;​707;​708;​711;​725;​728). Stimulation of platelet production (thrombopoiesis) has been suggested but not clearly demonstrated. Cases of idiopathic thrombocytopenic purpura (ITP) treated with melatonin have been reported (972;​972;​973).
• Cognitive effects: Although vigilance, reaction time, and tasks in humans undergo circadian variations, they do not seem to correlate with endogenous melatonin levels (397;​401;​974). Exogenous melatonin may cause decrements in performance, including a slowing of choice-reaction time (399;​400) or learning (574). Some studies have failed to confirm a decrement in performance (626;​975;​976), including a study of high-dose melatonin (50mg) in elderly persons (mean age: 84.5 years) (977). Animal research suggests a possible role of the GABAergic system (758).
• Dermatologic effects: Dermatologic use of melatonin has been proposed because of its immunomodulatory and antioxidant abilities. Study findings indicate that melatonin may accumulate in the stratum corneum (576). Melatonin's ability to reduce erythema may be explained by the radical-scavenging mechanism of reducing hydroxyl radicals (OH) prevalent in most cases of sunburn.
• Drug withdrawal: Melatonin has demonstrated effectiveness in reducing benzodiazepine consumption in older patients with established insomnia (423). However, one study reported that low doses of immediate-release melatonin (3mg) did not appear to be useful for benzodiazepine tapering in older patients with minor sleep disturbances (423).
• Exercise performance: In human research, during a heavy-resistance exercise session, melatonin increased the area under the curve of growth hormone (455).
• Endocrine effects: Elevated blood sugar levels (hyperglycemia) have been reported in patients with type 1 diabetes (368;​369). Studies have indicated that low doses of melatonin reduced glucose tolerance and insulin sensitivity (370). In patients with type 2 diabetes mellitus who had suboptimal response to the oral hypoglycemic agent metformin, melatonin and zinc acetate administration improved impaired fasting and postprandial glycemic control and decreased the level of glycated hemoglobin (673;​674).
• In healthy young men, melatonin had no effect on suppressing hypothalamic-pituitary-adrenal system activity (978). However, melatonin did increase plasma prolactin concentrations (p<0.01) and reduce systolic blood pressure in the time interval following induced hypoglycemia (p<0.05). Researchers have studied the effects of the hypothalamic-pituitary-thyroid axis and melatonin in thermogenesis (body temperature regulation). Using a healthy male population, one study indicated that the pineal hormone may modulate hypothalamic-pituitary-thyroid axis function and affect body temperature (979). At night, when melatonin levels increase, thyroid-stimulating hormone (TSH) serum levels were lower and those of free thyroxine (FT4) increased. It has been proposed that administering melatonin to aging women may lead to a recovery of pituitary and thyroid function (385;​497).
• In animal study, melatonin was found to stimulate the release of gonadotropin-inhibitory hormone in quail (980) and inhibit gonadotropin-releasing-hormone-receptor-mediated oxytocin release in rats (981). In human research, exogenous melatonin enhanced the stimulatory effect of hypothalamic gonadotropin-releasing hormone on pituitary luteinizing hormone in women (375;​376;​377;​378). This response to melatonin may become distorted in patients with menstrual abnormalities (849;​982), may be absent in postmenopausal women (983;​984), and may not be observed in men (617;​985;​986), in whom only a decrease in basal luteinizing hormone level was noted (373;​379;​987).
• Melatonin decreased progesterone and estradiol plasma levels in healthy women (414) and enhanced the stimulatory effect of chorionic gonadotropin on progesterone production in cell culture (988). Research has suggested that melatonin may mimic the effect of drugs that act through the estrogen receptor interfering with the effects of endogenous estrogens, as well as those that interfere with the synthesis of estrogens by inhibiting the enzymes controlling the interconversion from their androgenic precursors (386). In contrast, melatonin has also been shown to significantly increase progesterone and androstenedione synthesis in bats (989). Melatonin is also involved in the control of testosterone secretion (990).
• Melatonin enhanced basal levels of growth hormone and its stimulation by hypothalamic-releasing hormone or exercise (383;​384;​991;​992;​993). This result may be mediated via the serotonin pathway (994;​995;​996) or through naloxone-sensitive opioid-mediation (997;​998). However, this effect has not been confirmed in other studies (618;​999). Exogenous melatonin has been reported to generate dopamine circadian rhythms in mice (1000).
• Both endogenous (1001) and exogenous melatonin appeared to elevate plasma concentrations of prolactin without affecting the temporal pattern of its pulsatile secretion (616;​1002;​1003;​1004;​1005).
• Melatonin did not affect basal levels of cortisol in young men (1005;​1006). Cortisol increases are reported in older women, but not young women (380). However, melatonin was found to decrease circulating cortisol in goldfish (765).
• In rats, melatonin significantly affected vasopressin secretion (1007). It suppressed plasma arginine vasopressin in a rat model of hyperthyroidism (1008). In humans, melatonin may not directly alter basal and angiotensin-2-stimulated arginine-vasopressin levels (1009).
• Gastrointestinal effects: Research has been conducted concerning the effects of melatonin in patients with duodenal ulcers, dyspepsia, gastroesophageal reflux disease (GERD), and irritable bowel syndrome (IBS). In patients with GERD, melatonin inhibited gastric acid secretion and synthesis of nitric oxide; nitric oxide affects lower esophageal sphincter relaxation, a major mechanism. Melatonin also influenced gastrointestinal motility (620), regulated pancreatic secretion and maintained the integrity of the pancreas (1010), affected bowel functions, reduced gut contractions induced by serotonin, and inhibited proliferation of epithelium (622). High doses of melatonin have been shown to inhibit motility by interacting with serotonin and CCK2 (620). Protective effects of melatonin in the gastrointestinal tract may be due to its effects on prostaglandins and cytoprotection from its free radical-scavenging activity (156;​227;​789;​1011;​1012;​1013).
• Melatonin has also been shown to be beneficial in models of gastric ulcer by downregulating matrix metalloproteinases-9 and -3 (162). Melatonin showed similar benefit in a model of NSAID-induced gastropathy by preventing activation of the mitochondrially mediated apoptosis (by mitigating oxidative stress) (1014).
• Immune effects: Researchers have conducted studies concerning the effects of melatonin as they relate to cachexia, chemotherapy side effects, HIV/AIDS, ischemia-reperfusion injury, and sepsis. Researchers noted increased platelet counts after melatonin use in patients with decreased platelets due to cancer chemotherapy (428;​700;​702;​708;​711;​725;​728). Although not clearly demonstrated, studies have indicated possible stimulation of platelet production (thrombopoiesis). Based on a review, activation of melatonin receptors was associated with the release of cytokines by type 1 T-helper cells (Th1), including gamma-interferon (gamma-IFN) and IL-2, as well as novel opioid cytokines (1015). There is indirect evidence that melatonin may amplify the immunostimulatory effect of IL-2, as measured by an increase in the number of T-lymphocytes, natural killer cells, and eosinophils in cancer patients (628;​1016;​1017;​1018;​1019). In animal research, inhibition of the circadian synthesis of melatonin has been associated with reversible immunosuppression (1020)and elicited T cell autoimmunity in mice (43;​1021). Melatonin has been reported to promote neutrophil apoptosis in patients receiving hepatectomy involving ischemia and reperfusion of the liver (7;​8;​9;​10). A combination hormone therapy including melatonin was found to improve leucocyte function in ovariectomized aged rats (904).
• Preliminary clinical studies suggest that combined therapy with low-dose subcutaneous IL-2 and melatonin may improve the immune status in AIDS patients with CD4 cell counts below 200/mm³, who generally do not respond to IL-2 alone. The mean number of lymphocytes, eosinophils, T lymphocytes, natural killer (NK) cells, and CD25- and DR-positive lymphocytes increased with the treatment. An increase in the subjects' CD4:CD8 mean ratio was noted (1022).
• Based on a review, administration of melatonin agonists has reportedly reduced neophobia, and treatment with a melatonin antagonist during the dark period has reportedly reversed the anxiolytic-like effect of endogenous melatonin (179). A study in rats showed that melatonin may attenuate kainic acid (KA)-induced neuronal death, lipid peroxidation, and microglial activation, and the number of DNA breaks (1023).
• Other mechanisms through which melatonin may modulate the immune system include the following: suppression of TNF-alpha, IL-1 beta, and IL-6 (157); inhibition of Th1 cells (176); stimulation of humoral activity/antibody production (766;​1024;​1025); inhibition of NF-kappaB (1026), IKK, and JNK pathways (194); prevention of T cell apoptosis (1027); and stimulation of mononuclear cell production (1028).
• Neurologic effects: It has been proposed that melatonin may reduce the amount of neurologic damage patients experience after stroke, based on its antioxidant properties (5;​14;​18;​961;​962;​963;​964;​965). Melatonin levels have been found to be decreased in both migraine and cluster headaches. Melatonin mechanisms are related to headache pathophysiology in many ways, including its anti-inflammatory effect, toxic free radical scavenging, reduction of proinflammatory cytokine upregulation, nitric oxide synthase activity and dopamine release inhibition, membrane stabilization, GABA and opioid analgesia potentiation, glutamate neurotoxicity protection, neurovascular regulation, 5-HT modulation, and its similarity in chemical structure to indomethacin (1029).
• A significant body of basic research has indicated melatonin may possess neuroprotective properties (69;​124;​235;​235;​236;​237;​238;​238;​239;​240;​241;​242;​243;​244;​245;​246;​247;​249;​250;​251;​252;​253;​254), meriting reviews in the contexts of neurodegenerative diseases (1030), the peripheral nervous system (1031), and traumatic nervous system injury (125). One possible mechanism may be the prevention of FGF9 downregulation (1032). Other possibilities, as revealed in experimental models of Parkinson's disease in mice, may involve the prevention of the induction of mitochondrial NO synthase (1033) or the inhibition of 6-hydroxydopamine production (1034). However, in an alternate rodent model of Parkinson's disease, melatonin was found to potentiate neurodegeneration (1035). A number of preliminary animal studies have also suggested that melatonin may aid in recovery from or mitigate spinal cord injury (310;​311;​312); however, not all findings have been positive (1036).
• Melatonin has also been suggested as a possible therapeutic strategy for Alzheimer's disease, having been shown to attenuate amyloid-beta-induced phosphorylation of tau-protein and prevent GSK-3beta activation and neuroinflammation (73), and mitigate amyloid-beta-mediated mitochondrial dysfunction (71) and amyloid-beta load (72).
• Other research has indicated that melatonin may preserve hippocampal cytochrome oxidase and sirtuin-1 expression following sleep deprivation (1037).
• Opioid tolerance: In animals, researchers have concluded that melatonin acutely reversed and prevented tolerance to and dependence on morphine (1038;​1039), and reduced the incidence of naloxone-induced withdrawal (1039); however, the exact mechanism is not well understood.
• Optic/Ocular effects: Based on limited human research, melatonin may be effective in stabilizing vision in patients suffering from age-related macular degeneration (420). Preliminary evidence suggests that melatonin may decrease intraocular pressure in the eye (389;​390). However, high doses of melatonin may increase intraocular pressure and the risk of glaucoma, age-related maculopathy, and myopia (368), as well as retinal damage (358).
• Protective effects: A number of studies have established melatonin's ability to prevent or mitigate damage from a number of chemical sources, including (but not limited to) methamphetamines (109;​735), organophosphorus compounds (260;​261;​262), alcohol (289;​736), nicotine (129), beta-cyfluthrin (737), and benzo(a)pyrene (738).
• Radioprotective effects: Due to its well-known antioxidant properties, it has been suggested that melatonin possesses a protective effect against damage caused by ionizing radiation, a hypothesis borne out by preliminary animal and in vitro research (275;​276;​293;​294;​295;​297;​1040). The specific mechanisms may involve downregulation of apoptotic pathways via control of oxidative load (1041).
• Reproductive effects: Due to its low toxicity, antioxidant potential, and role in determining sexual status in certain mammals, melatonin has been suggested as a means of improving reproductive success in a variety of conditions (1042). Exposure to exogenous melatonin increased sperm motility, ejaculate volume, sperm concentration, total sperm output, total function sperm fraction, and blood testosterone concentration, and decreased means of reaction time, dead sperm, abnormal sperm, and blood triiodothyronine concentration in Damascus goats (1043). Melatonin implants have also been shown to improve semen characteristics in sheep (1044). Melatonin treatment has been shown to regulate follicular development and oocyte competence in sheep (1045) and goats (1046). Additional veterinary research has indicated that melatonin may increase reproductive success (1047;​1048;​1049) or activity (307). Similarly, melatonin has been shown to improve viability of sperm (1050) and embryos (159;​1051;​1052;​1053;​1054) produced with in vitro fertilization. In vitro, melatonin has been shown to decrease kisspeptin gene expression, while increasing that of RFRP-3 in cell lines from rat hypothalamus (1055). In other research, melatonin had no effect on luteal blood flow or function in humans (1056). In a rat model of endometriosis, melatonin was shown to induce regression of endometriotic foci (154). Other reproductive applications of melatonin include the suppression of estrus (in cats) (1057), induction of estrus (in goats) (1058), and inhibition of gonad function (in fish) (1059).
• Sleep effects: Melatonin, administered in the day or night in doses beyond the physiological range, appears to elicit a hypnotic effect. Exogenous melatonin exerted hypnotic effects primarily when circulating levels of endogenous melatonin were low (528). Even very low doses may cause sleep when ingested before endogenous melatonin onset (397;​523;​530;​536;​537), although some studies have failed to confirm this finding (525). Melatonin has been shown to decrease the amount of anesthesia required during surgery (502;​504;​585;​1060). Melatonin seems to potentiate the effects of gamma-amino butyric acid (GABA) and benzodiazepines; the quality of sleep may be improved with a combination of melatonin and benzodiazepines (1061). Melatonin may interact directly with the GABA-benzodiazepine-chloride ion channel (648;​1062), but not with the benzodiazepine receptor (1063). As seen in functional magnetic resonance imaging, melatonin may play a role in priming sleep-associated brain activation patterns in anticipation of sleep (1064).
• Randomized clinical trials have demonstrated some effect of melatonin on circadian rhythm entraining (1065;​1066;​1067). Endogenous circadian rhythmicity influences autonomic control of heart rate, and the timing of these endogenous rhythms may be altered by extended sleep/rest episodes and associated changes in the photoperiod, as well as by melatonin treatment (1068), with no evidence of changes in the duration of endogenous melatonin secretion or pituitary or gonadal hormones (1069). In blind individuals, disturbances of sleep and sleep-related neuroendocrine patterns may be caused by the absence of light cues. In individuals who are completely blind, a single administration of a pharmacological dose of melatonin may improve sleep function by synchronizing the inhibition of pituitary-adrenal activity with central nervous sleep processes (438).
• Exogenous melatonin is able to shift circadian rhythms, as well as endogenous melatonin secretion and core body temperature (1070;​1071;​1072;​1073). Light appears to be a stronger regulator of circadian rhythm than melatonin itself (419;​832;​1074;​1075;​1076;​1077;​1078;​1079). The time of administration of melatonin is of critical importance, since it may cause both phase delay and phase advance. For phase delay, melatonin should be administered in the early morning; for phase advance, melatonin should be administered 1-2 hours before 9 p.m. (419).
• Thermoregulating effects: The central thermoregulatory centers, including the preoptic area of the anterior hypothalamus, are likely to be involved with the regulation of core temperature following melatonin administration (1080). Hypothermic effects of melatonin have been reported with doses from 15mg (532;​1070;​1081). Ingestion of 1.6mg of melatonin was reported to result in approximately 0.4ºC decrease of body temperature in humans (1070;​1071;​1072;​1073). The hypothermic effects may be mediated by GABA receptor activity (1082). Melatonin may also influence chloride flux or other intracellular actions via a different mechanism that is not well understood (1063). Melatonin did not appear to exert hypothermic effects by central benzodiazepine receptors (1063). Melatonin appeared to increase heat loss and decrease heat production when taken during the day (1082). A parallel relationship was found between rectal core body temperature and the decline in sleep onset latency following melatonin administration (1082).
• Vasodilating effects: In healthy male volunteers, melatonin significantly increased peripheral blood flow, as measured by distal to proximal skin temperature gradient and finger pulse volume, which demonstrates that melatonin does not have an acute regulatory effect on cerebral blood flow in humans (772).
• Other: There was a reduction (p<0.05) of malondialdehyde and 4-hydroxylalkenals to normal levels (p<0.05) in septic newborns treated with melatonin (305). In models of experimental ischemia-reperfusion, melatonin reduced damage to tissues and limited cardiac pathophysiology (180).

Pharmacodynamics/Kinetics:

• Antioxidant activity: Melatonin was reported as having an IC₅₀ of 1.46mcM and an inhibition constant of 0.82 ± 0.28mcM vs. lactoperoxidase in vitro (1083).
• Drug concentration levels: When administered in gelatin capsules, melatonin reached peak levels after 60-150 minutes (350-10,000 times higher than nighttime concentration) (817;​1084).
• Melatonin may be monitored by its serum metabolite, 6-sulphatoxymelatonin by radioimmunoassay (884;​1085), and in saliva (1086;​1087), although melatonin concentrations measured in saliva did not consistently reflect absolute concentrations in blood (1086).
• Time to peak: Melatonin secretion increased after the onset of darkness, peaked in the middle of the night (between 2 and 4 a.m.), and then gradually decreased (1). Pharmacological effects appeared to depend on the time of administration. Research shows that the time delay between administration and maximal effect varied linearly from 220 minutes at noon, to 60 minutes at 9 p.m. (566).
• Absorption: The calculated oral bioavailability of melatonin was 3-76% (816;​817;​824). Some foods, such as oats, sweet corn, rice, ginger, tomatoes, bananas, and barley, contain small amounts of melatonin and may increase melatonin levels (816;​817). Melatonin may be delivered transdermally in humans (1088;​1089), or transmucosally to mimic physiological activity (156) and readily passes through the blood-brain barrier (227;​1090). In human research, the peak value following a 2.5mg dose was 2,630pg/mL (returning to baseline within seven hours) and the peak value following a 75mg dose was 64,730pg/mL (not at baseline at last testing period) (534).
• Metabolism: Melatonin was primarily inactivated by 6-hydroxylation in the liver, followed by conjugation and excretion as the sulfate or glucuronide. First-pass hepatic metabolism was extensive (up to 60% of the oral dose) (816;​817;​824). 6-Sulphatoxymelatonin is an inactive metabolite of melatonin (884;​1085). In patients with liver cirrhosis, melatonin levels were elevated compared to controls (756;​1091).
• Excretion: Up to 85% of 6-hydroxymelatonin sulfate was excreted in urine; 6-sulphatoxymelatonin levels during melatonin treatment correlated with a normal circadian rhythm of excretion (200). In normal children, total 6-sulfatoxymelatonin excretion ranged from 11.1 to 40.2mcg (19.0 ± 7.4mcg) (551).
• Half-life: The physiologic half-life of melatonin was approximately 30-60 minutes(345;​473;​817;​824;​1092;​1093). Nutritional supplements did not appear to mimic the physiologic release of melatonin, as dissolution testing has ranged from four to 12 hours (1094), with controlled-release formulations available (1095).

History

• Originally believed to be the seat of the soul by Descartes (1096), it was only in the early 1900s that physicians identified the pineal gland as belonging to the endocrine system. Aaron Lerner, a dermatologist from Yale, and his team of researchers discovered melatonin in 1958 when investigating a potential treatment for vitiligo (1097).
• According to secondary sources, melatonin's sedative properties emerged from research in the 1970s and 1980s, leading to its widespread use in the treatment of sleep disorders.
• According to secondary sources, melatonin's popularity grew dramatically in the United States following reports in 1995 of its ability to promote sleep and alleviate jet lag, perhaps its best known application.
• Synthetic melatonin is sold in the United States as a food supplement due to small amounts found in some foods such as bananas and rice. Some authors suggest that this categorization interferes with the standardization and quality improvement of melatonin.

Evidence Table

Condition	Study Design	Author, Year	N	Statistically Significant?	Quality of Study 0-2=poor 3-4=good 5=excellent	Magnitude of Benefit	ARR	NNT	Comments
Jet lag	Systematic review	Buscemi, 2006	Nine trials (efficacy)	NA	NA	NA	NA	NA	Outcomes were similar for melatonin and placebo.
Jet lag	Systematic review	Herxheimer, 2001; Herxheimer, 2002	10 trials	NA	NA	NA	NA	2	Nine out of 10 trials suggested a benefit of melatonin.
Jet lag	Randomized controlled trial	Spitzer, 1999	257	No	2	NA	NA	NA	Melatonin 5mg, 0.5mg, or placebo.
Jet lag	Placebo controlled trial (nonrandomized)	Paul, 2004	30	Yes	3	Medium	NA	NA	Melatonin and zopiclone were equal facilitators of sleep. No randomization.
Delayed sleep phase syndrome (DSPS)	Meta-analysis	Buscemi, 2005	279 (14 trials)	Varied	NA	Small	NA	NA	Melatonin was not effective in treating most primary sleep disorders with short-term use.
Delayed sleep phase syndrome (DSPS)	Randomized controlled trial, crossover	Kayumov, 2001	22	Yes	4	Medium	NA	NA	Melatonin 5mg or placebo.
Delayed sleep phase syndrome (DSPS)	Randomized controlled trial, crossover	Rahman, 2010	20	Yes	3	Large	NA	NA	Melatonin 5mg or placebo.
Delayed sleep phase syndrome (DSPS)	Randomized controlled trial	Mundey, 2005	22	Yes	3	Small	NA	NA	No between-group comparison.
Delayed sleep phase syndrome (DSPS)	Placebo controlled study, crossover (nonrandomized)	Nagtegaal, 1998	30	Yes	1	Medium (sleep onset latency)	NA	NA	Melatonin 5mg vs. placebo.
Insomnia (elderly)	Randomized controlled trial, crossover	Baskett, 2003	40	No	5	NA	NA	NA	Melatonin 5mg, fast-release.
Insomnia (elderly)	Randomized controlled trial, crossover	Garfinkel, 1995	15	Yes	4	Medium	NA	NA	Crossover study.
Insomnia (elderly)	Randomized controlled trial	Luthringer, 2009	40	Yes	3	Small	NA	NA	2mg of prolonged-release melatonin or placebo.
Insomnia (elderly)	Randomized controlled trial	Lemoine, 2007	170	Yes	3	Large	NA	NA	Melatonin PR 2mg or placebo for three weeks.
Insomnia (elderly)	Randomized controlled trial	Wade, 2007	354	Yes	3	Small	NA	NA	Melatonin PR 2mg vs. placebo for three weeks.
Insomnia (elderly)	Randomized controlled trial	Zhdanova, 2001	30 completers	Yes	2	Medium	NA	NA	Three melatonin doses (0.1, 0.3, and 3.0 mg) orally 30 minutes before bedtime for a week.
Insomnia (elderly)	Double-blind clinical trial	Haimov, 1995	Not reported	Not reported	2	NA	NA	NA	2mg of melatonin.
Insomnia (elderly)	Double blind trial (two trials)	Valtonen, 2005	70; 81	Varied (no overall)	1	NA	NA	NA	Two studies investigating effects of night milk with melatonin.
Insomnia (elderly)	Double-blind clinical trial	Dawson, 1998	12	No	1	NA	NA	NA	Patch containing 0.5mg of melatonin or placebo placed on gums.
Sleep disorders (children with behavioral, developmental, or intellectual disorders)	Systematic review	Bendz, 2010	Four trials	Yes	NA	Medium	NA	NA	Twenty pieces of literature evaluated. Melatonin suggested to be safe and effective in children with ADHD.
Sleep disorders (children with behavioral, developmental, or intellectual disorders)	Systematic review	Phillips, 2004	Three trials	NA	NA	NA	NA	NA	Possibly effective in reducing sleep latency.
Sleep disorders (children with behavioral, developmental, or intellectual disorders)	Randomized controlled trial, crossover, followed by open-label study	Wasdell, 2008	51	Yes	5	Medium	NA	NA	Melatonin 5mg vs. placebo.
Sleep disorders (children with behavioral, developmental, or intellectual disorders)	Randomized controlled trial, crossover	Weiss, 2006	27	Yes	5	Medium	NA	NA	Two-phase treatment study; melatonin 5mg or placebo.
Sleep disorders (children with behavioral, developmental, or intellectual disorders)	Randomized controlled trial	Braam, 2008	58	Yes	4	Medium	NA	NA	Melatonin or placebo in intellectually disabled subjects.
Sleep disorders (children with behavioral, developmental, or intellectual disorders)	Randomized controlled trial, crossover	Garstang, 2006	11	Yes	4	Large	NA	NA	Melatonin 5mg vs. placebo; children with autism.
Sleep disorders (children with behavioral, developmental, or intellectual disorders)	Randomized controlled trial, crossover	Wirojanan, 2009	18	Yes	3	Small	NA	NA	3mg at bedtime. Only sleep onset time significantly changed, though other measures showed tendencies toward improvement.
Sleep disorders (children with behavioral, developmental, or intellectual disorders)	Randomized controlled trial, crossover, followed by open-trial	Coppola, 2004	25	No	3	NA	NA	NA	Melatonin 3mg vs. placebo in children with mental retardation.
Sleep disorders (children with behavioral, developmental, or intellectual disorders)	Randomized controlled trial, crossover trial	Niederhofer, 2003	20	Yes	2	Medium	NA	NA	Melatonin vs. placebo in mentally retarded children.
Sleep disorders (children with behavioral, developmental, or intellectual disorders)	Randomized controlled trial; open label (two trials)	Jan, 2000	16; 42	No	2	NA	NA	NA	Compared fast-release melatonin and controlled-release melatonin.
Sleep disorders (children with behavioral, developmental, or intellectual disorders)	Randomized controlled trial	Van der Heijden, 2007	105	Yes	P	P	P	P	Melatonin 3 or 6mg or placebo.
Sleep enhancement in healthy people	Meta-analysis	Brzezinski, 2005	17 studies; 284 participants	Yes	NA	Small	NA	NA	Rigorous criteria for inclusion/exclusion. Limited by meta-analytic nature.
Sleep enhancement in healthy people	Systematic review	Morera, 2000	111	NA	NA	NA	NA	NA	Reviewed eight trials.
Sleep enhancement in healthy people	Randomized controlled trial, crossover	Tzischinsky, 1994	8	Yes	5	Large	NA	NA	Limited by male-only population.
Sleep enhancement in healthy people	Randomized controlled trial	Wyatt, 2006	26	Yes	4	Medium	NA	NA	Limited to healthy adults. Well-characterized study.
Sleep enhancement in healthy people	Randomized controlled trial (two parallel trials)	Kunz, 2004	16	Yes	4	Medium	NA	NA	Crossover design.
Sleep enhancement in healthy people	Randomized controlled trial	Paul, 2004	23	Yes	3	Small	NA	NA	Magnitude of benefit for total sleep time and latency in melatonin compared to placebo.
Sleep enhancement in healthy people	Randomized controlled trial	Pinto, 2004	40	Yes	3	Medium	N/A	N/A	Male-only test population.
Sleep enhancement in healthy people	Randomized controlled trial, crossover	Almeida Montes, 2003	10	No	3	NA	NA	NA	Melatonin 0.3 or 1mg or placebo.
Sleep enhancement in healthy people	Randomized controlled trial	Cajochen, 1996	Eight (in each of two experiments)	Yes	3	NA	NA	NA	Limited by homogeneity of subject population (all males of similar age).
Sleep enhancement in healthy people	Randomized controlled trial, single-blind, equivalence trial	Satomura, 2001	7	Yes	2	Small	NA	NA	Melatonin vs. triazolam vs. placebo.
Sleep enhancement in healthy people	Randomized controlled trial	Ellis, 1996	15	No	2	None	NA	NA	Melatonin 5mg or placebo.
Sleep enhancement in healthy people	Double-blind placebo controlled trial	Nave, 1995	12	Yes	2	Medium	NA	NA	Narrow age range of subject population.
Sleep enhancement in healthy people	Double-blind, crossover trial	MacFarlane, 1991	13	Yes	1	Small	NA	NA	Melatonin 75 mg orally vs. placebo.
Aging (thermoregulation)	Randomized controlled trial	Gubin, 2006	97	Yes	2	Small	NA	NA	1.5mg melatonin daily or placebo for two weeks.
Anti-inflammatory	Randomized controlled trial	Forrest, 2007	75	Mixed results	3	None	NA	NA	Melatonin group suggested proinflammatory action in individuals with rheumatoid arthritis.
Anti-inflammatory	Randomized controlled trial	Gitto, 2004	40	Yes	1	Medium-large	NA	NA	IL-6, IL-8, and TNF-alpha levels lower in melatonin group (in preterm infants with respiratory distress).
Benzodiazepine tapering	Randomized controlled trial, crossover	Garfinkel, 1997	21	Yes	4	Medium	NA	NA	Elderly subjects received controlled release melatonin or placebo.
Benzodiazepine tapering	Randomized controlled trial	Cardinali, 2002	45	No	3	NA	NA	NA	Patients received 3mg of fast-release melatonin or placebo for six weeks.
Benzodiazepine tapering	Randomized controlled trial	Garfinkel, 1999	34	Yes	3	Large	53%	2	Patients received 2mg of CR melatonin or placebo for six weeks.
Benzodiazepine tapering	Randomized controlled trial, crossover	Peles, 2007	80	No	2	NA	NA	NA	Patients received 5mg daily of melatonin or placebo for six weeks.
Benzodiazepine tapering	Placebo controlled trial	Vissers, 2007	38	No	0	NA	NA	NA	Not randomized or blinded.
Cancer treatment	Systematic review	Block, 2007	Four trials of melatonin	NA	NA	NA	NA	NA	No individual effects of melatonin.
Cancer treatment	Systematic review	Ernst, 2006,	13 trials	NA	NA	NA	NA	NA	Authors mentioned encouraging but not conclusive results.
Cancer treatment	Systematic review	Mills, 2005	10 trials; 643 patients	NA	NA	NA	NA	NA	Authors suggested great potential for melatonin in treating cancer.
Circadian rhythm entraining (in blind persons)	Double-blind crossover trial	Fischer, 2003	12	Yes	1	Large	NA	NA	Totally blind subjects received 5mg of melatonin one hour prior to bedtime.
Circadian rhythm entraining (in blind persons)	Placebo controlled single-blind trial	Hack, 2003	10	Yes	0	Small	NA	NA	0.5mg of melatonin or placebo daily at bedtime.
Cognitive disorders	Systematic review	Jansen, 2006	Three trials	NA	NA	NA	NA	NA	Insufficient evidence to support the use of melatonin in managing cognitive and noncognitive sequelae of dementia.
Cognitive disorders	Randomized controlled study	Peck, 2004	30	Yes	4	Small	NA	NA	Melatonin 1mg or placebo each night for four weeks.
Depression	Randomized controlled trial	Serfaty, 2010	33	No	5	NA	NA	NA	6mg of slow-release melatonin or placebo for four weeks.
Exercise performance	Randomized controlled trial, crossover	Mero, 2006	10	No	2	NA	NA	NA	Oral ingestion of melatonin (6mg) during daytime with heavy resistance exercise. No effect was observed on strength capacity.
Exercise performance	Double-blind clinical trial, crossover	Atkinson, 2001	12	No	1	NA	NA	NA	5mg had no effect on physical performance in athletes. Crossover design.
Gastrointestinal disorders	Randomized controlled trial, crossover	Lu, 2009	32	No	4	NA	NA	NA	3mg of melatonin or placebo. A significant effect was observed in normal, but not IBS patients.
Gastrointestinal disorders	Randomized controlled trial	Saha, 2007	18	Yes	3	Medium	NA	NA	3mg of melatonin or placebo at bedtime for eight weeks.
Gastrointestinal disorders	Randomized controlled trial, crossover	Lu, 2005	24	Yes	3	Medium	41%	3	Female patients received 3mg of melatonin or placebo for eight weeks. Incorrect method of randomization.
Gastrointestinal disorders	Randomized controlled trial	Song, 2005	40	Yes (abdominal pain)	3	Large	NA	NA	Female patients received 3mg melatonin or placebo at bedtime for two weeks.
Gastrointestinal disorders	Placebo controlled trial	Klupińska, 2007	60	Yes	P	P	50%	2	5mg of melatonin or placebo for 12 weeks.
Gastrointestinal disorders	Equivalence trial (nonrandomized and nonblinded)	Kandil, 2010	36	Yes	0	NA	NA	NA	3mg of melatonin daily, with and without omeprazole. All treatment groups showed improvement.
Headache (prevention)	Randomized controlled trial	Leone, 1996	20	Yes	2	Medium	NA	NA	Melatonin 10mg.
High blood pressure (hypertension)	Randomized controlled trial	Grossman, 2006	38	Yes	3	Small	NA	NA	Patients with controlled hypertension.
High blood pressure (hypertension)	Randomized controlled trial	Cagnacci, 2005	22	Yes	3	Medium	NA	NA	No effects on diurnal BP but did reduce systolic, diastolic, and mean BP.
High blood pressure (hypertension)	Randomized controlled trial	Rechciński, 2010	62	Yes	2	Small	20%	5	5mg of melatonin or placebo for 90 days.
High blood pressure (hypertension)	Randomized controlled trial, crossover	Scheer, 2004	16	Yes	2	Small	NA	NA	Male patients with essential hypertension.
High blood pressure (hypertension)	Randomized controlled trial	Cagnacci, 2000	31	Yes	2	Small	NA	NA	Effect was only observed in HRT-treated women (not in those not on HRT).
High blood pressure (hypertension)	Randomized controlled trial	Cagnacci, 1997	12	Yes	2	Large	NA	NA	Melatonin 1mg.
Insomnia (children)	Randomized controlled trials	van der Heijden, 2005	110	Yes	4	Medium	NA	NA	Melatonin 5mg or placebo. Study combined two previously published studies (Smits, 2001 and Smits, 2003).
Insomnia (children)	Randomized controlled trial	Smits, 2003	70	Yes	4	Medium	NA	NA	5mg melatonin or placebo for four weeks.
Insomnia (children)	Randomized controlled trial	Smits, 2001	40	Yes	4	Medium	NA	NA	Melatonin 5mg.
Memory	Randomized controlled trial	Rimmele, 2009	50	Yes	0	Small	NA	NA	3mg of melatonin or placebo one hour prior to stress test.
Menopause	Randomized controlled trial	Secreto, 2004	262	NA	5	NA	NA	NA	Soy isoflavones (80mg) + melatonin (3mg), soy isoflavones alone, melatonin alone, or placebo for three months. Statistical analysis not done due to high placebo effect.
Menopause	Randomized controlled trial	Bellipanni, 2001	79	Yes	3	Mixed	NA	NA	3mg of melatonin or placebo at bedtime.
Preoperative sedation / anxiolysis	Randomized controlled trial	Caumo, 2009	63	Yes	5	Medium	66%	2; 16 (depending on anxiety level)	5mg following total abdominal hysterectomy. Melatonin as effective as standard treatment.
Preoperative sedation / anxiolysis	Randomized controlled trial	Capuzzo, 2006	150	No	5	NA	NA	NA	Elderly patients.
Preoperative sedation / anxiolysis	Randomized controlled trial	Borazan, 2010	52	Yes	4	Medium	NA	NA	6mg of melatonin or placebo the evening before and one hour prior to surgery.
Preoperative sedation / anxiolysis	Randomized controlled trial	Ismail, 2009	40	Yes	4	Medium	NA	NA	10mg of melatonin or placebo 90 minutes prior to surgery.
Preoperative sedation / anxiolysis	Randomized controlled trial	Caumo, 2007	35	Yes	4	Medium	Unknown	3	Melatonin or placebo the night before and one hour prior to surgery.
Preoperative sedation / anxiolysis	Randomized controlled trial	Samarkandi, 2005	105	Yes	3	Small	NA	NA	Children.
Preoperative sedation / anxiolysis	Randomized dosing and equivalence trial	Kain, 2009	148	No	2	NA	NA	NA	Melatonin vs midazolam. Midazolam was significantly more effective than melatonin.
Preoperative sedation / anxiolysis	Randomized controlled trial	Acil, 2004	66	Yes	2	Medium	NA	NA	No effects on postoperative psychomotor performance.
Seasonal affective disorder (SAD)	Randomized controlled trial	Leppämäki, 2003	58	Yes	3	Medium	NA	NA	Healthy adults with SAD.
Seasonal affective disorder (SAD)	Randomized controlled trial	Danilenko, 2005	16 (SAD) + 17 (healthy controls)	No	2	NA	NA	NA	Female patients with SAD.
Seizure disorder (children)	Randomized controlled trial	Gupta, 2004	31	P	P	P	P	P	Primary outcome was subjective change in quality of life of add-on melatonin in children on valproate monotherapy via questionnaire.
Sleep disturbance	Meta-analysis	Braam, 2009	Nine trials	Yes	NA	Medium	NA	NA	Patients with intellectual disabilities.
Sleep disturbance	Systematic review	Rossignol, 2009	13 trials	Yes	NA	Medium	NA	NA	Melatonin suggested as a novel treatment for symptoms associated with autism.
Sleep disturbance	Randomized controlled trial	Serfaty, 2010	33	No	5	NA	NA	NA	6mg of slow-release melatonin or placebo for four weeks.
Sleep disturbance	Randomized controlled trial	Gögenur, 2009	121	No	5	NA	NA	NA	In postoperative patients.
Sleep disturbance	Randomized controlled trial	Ibrahim, 2006	32	No	5	NA	NA	NA	Patients with tracheostomy.
Sleep disturbance	Randomized controlled trial	Gupta, 2005	31	Yes	5	Medium	NA	NA	Sleep parameters were affected by administration of melatonin in combination with valproate. Study in children with seizures.
Sleep disturbance	Randomized controlled trial, crossover	Garzón, 2009	22	Yes	4	Medium	NA	NA	In elderly patients with sleep or behavioral problems.
Sleep disturbance	Randomized controlled trial	Medeiros, 2007	20	Yes	4	Small	NA	NA	Sleep quality was improved according to a sleep index.
Sleep disturbance	Randomized controlled trial, crossover	Dowling, 2005	43	Yes	4	Small	NA	NA	Small improvements were observed.
Sleep disturbance	Randomized controlled trial	Campos, 2004	22	Yes	4	Medium	NA	NA	Improved sleep; no effects on asthma symptoms.
Sleep disturbance	Randomized controlled trial	Andrade, 2001	33	Yes (specific days)	4	Unclear	NA	NA	Melatonin average dose: 5.4mg.
Sleep disturbance	Randomized controlled trial	de Castro-Silva, 2010	19	Yes	3	Small	NA	NA	Patients with cystic fibrosis.
Sleep disturbance	Randomized controlled trial	Gehrman, 2009	41	No	3	NA	NA	NA	Patients with Alzheimer's disease.
Sleep disturbance	Randomized controlled trial, crossover	Koch, 2009	20	Yes	3	Small	NA	NA	3mg of melatonin or placebo over 18 weeks.
Sleep disturbance	Randomized controlled trial	Suresh, 2007	40	Yes	3	Medium	NA	NA	Patients with schizophrenia.
Sleep disturbance	Randomized controlled trial, crossover	Coppola, 2004	25	No	3	NA	NA	NA	Melatonin appears to have negative effects on seizure frequency. Study in children with seizures.
Sleep disturbance	Randomized controlled trial, crossover	Shamir, 2000	19	No	3	NA	NA	NA	Melatonin 2mg in patients with tardive dyskinesia.
Sleep disturbance	Randomized controlled trial, crossover	Shamir, 2000	14	Yes	3	Medium	NA	NA	2mg of melatonin improved alertness test.
Sleep disturbance	Randomized controlled trial	Dolberg, 1998	19	Yes	3	Medium	NA	NA	Melatonin patients with depression.
Sleep disturbance	Randomized controlled trial	Leibenluft, 1997	5	No	3	NA	NA	NA	Melatonin 10mg had negative effects in patients with bipolar disorder.
Sleep disturbance	Randomized controlled trial	Braam, 2010	66	Yes	2	Medium	NA	NA	Patients with intellectual disabilities.
Sleep disturbance	Randomized controlled trial	Dowling, 2008	50 completers	No	2	NA	NA	NA	No effects of melatonin on nighttime sleep but improvement in daytime somnolence.
Sleep disturbance	Randomized equivalence trial, crossover	Kemp, 2004	7	No	2	NA	NA	NA	No differences between melatonin and amitriptyline compared to baseline.
Sleep disturbance	Randomized controlled trial	O'Callaghan, 1999	7	Yes	P	Small	NA	NA	Small but clinically significant improvement.
Sleep quality	Double-blind clinical trial	Atkinson, 2001	12	No	1	NA	NA	NA	5mg had no effect on physical performance in athletes. Crossover design.
Smoking cessation	Randomized, controlled trial, crossover	Zhdanova, 2000	12	Yes (self-ratings); No (performance tests)	3	Small	NA	NA	Only self-ratings of mood were significantly affected.
Tardive dyskinesia	Randomized, controlled crossover trial	Shamir, 2001	24	Yes	4	Small	NA	NA	Patients with schizophrenia and TD.
Tardive dyskinesia	Randomized, controlled crossover trial	Shamir, 2000	19	No	4	NA	NA	NA	2mg of melatonin daily or placebo for four weeks.
Tinnitus	Randomized controlled trial	Lopez-Bonzalez, 2007	120	Unclear	3	NA	NA	NA	Melatonin alone better than placebo; melatonin plus sulpiride most effective. Significance of results unclear.
Tinnitus	Randomized controlled trial	Neri, 2009	102	No	2	NA	NA	NA	Of three subject groups (melatonin, melatonin plus sulodexide, and no treatment), only the combination group showed significant improvement.
Urination (nocturia)	Randomized, placebo controlled trial, crossover	Drake, 2004	20	Yes	3	Small	NA	NA	Men received 2mg of melatonin or placebo for four weeks.
UV-induced erythema prevention/sunburn	Randomized controlled trial	Fischer, 1999	20	Yes	2	Large	NA	NA	Melatonin 0.6mg/cm2 skin reduced erythema when applied before UV but not after.
UV-induced erythema prevention/sunburn	Randomized controlled trial	Bangha, 1996	20	Yes	2	Medium	NA	NA	Melatonin 0.05, 0.1, 0.5% in gel. 0.5% reduced erythema eight hours after UV.
UV-induced erythema prevention/sunburn	Double-blind trial	Howes, 2006	16, 19	No	2	NA	NA	NA	Melatonin (5%) and its vehicle showed no effect.
Work shift sleep disorder	Systematic review	Buscemi, 2006	Nine trials (427 subjects)	NA	NA	NA	NA	NA	No evidence that melatonin is effective in treating secondary sleep disorders.
Work shift sleep disorder	Randomized controlled trial, crossover	Bjorvatn, 2007	Unclear	Yes	4	Moderate	NA	NA	Modest increases in sleep were reported (15-20 minutes).
Work shift sleep disorder	Randomized controlled trial, crossover	Cavallo, 2005	45	No	3	NA	NA	NA	Melatonin 3mg before bedtime in the morning after the night shift.
Work shift sleep disorder	Randomized controlled trial (not double-blind)	Dawson, 1995	36	No	1	NA	NA	NA	Melatonin 2mg may have had small effect on sleep quality but most endpoints were not significantly changed.
Work shift sleep disorder	Double-blind trial (nonrandomized)	Smith, 2005	36	No	3	NA	NA	NA	Small nonsignificant improvements in sleep were reported.
Work shift sleep disorder	Double-blind trial, crossover (nonrandomized)	Sharkey, 2001	21 completers	Yes (daytime sleep on day 1)	1	Small	NA	NA	Melatonin 1.8mg.
Work shift sleep disorder	Placebo controlled trial	Crowley, 2003	67	No	P	NA	NA	NA	Participants wore sunglasses during the day and melatonin (1.8mg, sustained-release) at night.

Evidence Discussion

Note

• Due to the popularity of melatonin research, the evidence discussion paragraphs are limited to melatonin clinical trials. Conditions lacking high-quality human evidence (i.e., only case reports) are included in the Historical or Theoretical Indications section.

Jet lag

• Summary: Several randomized, placebo controlled human trials suggest that melatonin taken by mouth, started on the day of travel (close to the target bedtime at the destination) and continued for several days, reduces the number of days required to establish a normal sleep pattern, diminishes the time it takes to fall asleep ("sleep latency"), improves alertness, and reduces daytime fatigue. Melatonin has been used in combination with zaleplon, zopiclone, and temazepam to compare the drugs' hypnotic effects and to observe drowsiness levels (493). Other research has attempted to determine optimal formulations in preparation for travel (1098). Further well-designed trials are necessary to confirm these findings, to determine optimal dosing, and to evaluate use in combination with prescription sleep aids.
• Systematic reviews: Buscemi et al. conducted a systematic review of the efficacy and safety of exogenous melatonin in managing secondary sleep disorders and sleep disorders accompanying sleep restriction, such as jet lag and shift work disorder (612). Thirteen electronic databases were searched. Reference lists of relevant reviews, as well as a random sample of included studies, were reviewed. Abstracts of meetings of Associated Professional Sleep Society abstracts (1999-2003) were also searched. MEDLINE and Embase were searched again in 2004 to identify more recent published studies. Randomized controlled trials were assessed using the Jadad Scale and criteria by Schulz et al., and nonrandomized controlled trials were assessed by the Downs and Black checklist. One reviewer extracted data and another reviewer verified the data extracted. The inverse variance method was used to weigh studies, and the random effects model was used to analyze data. A range of doses were used in the various studies. The duration of administration varied from days to weeks. Dosage and duration of melatonin administration described a considerable amount of heterogeneity across studies. Efficacy: Nine trials (427 participants) (4;​485;​488;​491;​530;​567;​568;​569;​572) were included in the efficacy analysis for secondary sleep disorders. The median quality score was 4 out of 5 (Jadad score). There was no evidence that melatonin had an effect on sleep onset latency in people who had sleep disorders accompanying sleep restriction (-1.0 minutes (-2.3 to 0.3)). Sleep onset latency: Six randomized controlled trials with 97 participants showed no evidence that melatonin had an effect on sleep onset latency in people with secondary sleep disorders (weighted mean difference: -13.2 minutes (95% confidence interval, -27.3 to 0.9)). Safety: Ten studies (487 participants) were included in the safety analysis. The most commonly reported adverse events were headaches, dizziness, nausea, and drowsiness. The occurrence of these outcomes was similar for melatonin and placebo. The effect of melatonin specifically for jet lag is not clear from this study.
• Herxheimer et al. conducted a systematic review to assess the effectiveness of oral melatonin taken in different dosage regimens for alleviating jet lag after air travel across several time zones (357;​613). Cochrane Controlled Trials Register, MEDLINE, Embase, PsychLit, and Science Citation Index electronically, and the journals Aviation, Space and Environmental Medicine and Sleep were searched by hand. Citation lists of relevant studies for other relevant trials were also searched. Principal authors of relevant studies were asked about unpublished trials. Randomized trials on airline passengers, airline staff, or military personnel given oral melatonin, compared with placebo or other medication, were included. Outcome measures consisted of subjective ratings of jet lag or related components, such as subjective well-being, daytime tiredness, onset and quality of sleep, psychological functioning, duration of return to normal, or indicators of circadian rhythms. Ten trials met the inclusion criteria (392;​412;​485;​487;​489;​490;​492;​494;​1099;​1100). All compared melatonin with placebo; in addition, one compared it with a hypnotic, zolpidem. Nine of the trials were of adequate quality to contribute to the assessment; one had a design fault and could not be used in the assessment. Reports of adverse events outside trials were found through MEDLINE, Reactions Weekly, and in the WHO UMC database. Nine of the 10 trials found that melatonin, taken close to the target bedtime at the destination (10 p.m. to midnight), decreased jet lag from flights crossing five or more time zones. Daily doses of melatonin between 0.5 and 5mg were similarly effective, except that people fell asleep faster and slept better after 5mg than 0.5mg. Doses above 5mg appeared to be no more effective. The relative ineffectiveness of 2mg of slow-release melatonin suggests that a short-lived higher peak concentration of melatonin works better. Based on the review, the number needed to treat (NNT) is 2. The benefit is likely to be greater the more time zones are crossed, and less for westward flights. The timing of the melatonin dose is important: if it is taken at the wrong time, or early in the day, it may cause sleepiness and delay adaptation to local time. The incidence of other side effects was reportedly low. Case reports suggest that people with epilepsy and patients taking warfarin may experience harm from melatonin.
• Evidence: Spitzer et al. conducted a randomized, double-blind, placebo controlled trial to validate a new rating scale for measuring severity of jet lag and to compare the efficacy of contrasting melatonin regimens to alleviate jet lag (484). The subjects were 257 Norwegian physicians who had visited New York for five days. Subjects were randomly assigned to placebo (N=60) or one of three alternative regimens of melatonin administration beginning on the day of travel and continuing daily for the five days after travel. On the sixth day after travel, the subjects made ratings but did not take any study capsules. The first experimental group (N=64) took 5mg of melatonin at bedtime. The second group (N=70) took 0.5mg at bedtime. This small dose produced total blood levels similar to those secreted endogenously over the entire night (although there was a distinctly higher initial peak concentration 30 minutes after administration, followed for at least nine hours by an exponential decline). The third group (N=63) also received 0.5mg of melatonin, but capsules were taken one hour earlier each day beginning in the early evening. The timing of the first dose (on the day of travel) was 11 hours after the subject's usual wake-up time. Jet lag ratings were made on the day of travel from New York back to Oslo (six hours eastward) and for the next six days in Norway. The main outcome measures were scale and item scores from a new, syndrome-specific instrument, the Columbia Jet Lag Scale, which identifies prominent daytime symptoms of jet lag distress. There was a marked increase in total jet lag score in all four treatment groups on the first day at home, followed by progressive improvement over the next five days. However, there were no significant group differences or group-by-time interactions. In addition, there was no group effect for sleep onset, time of awakening, hours slept, or hours napping. Ratings on a summary jet lag item were highly correlated with total jet lag scores (from a low of r=0.54 on the day of travel to a high of r=0.80 on day 3). The internal consistency of the total jet lag score was high on each day of the study. Randomization and dropouts were not described.
• Paul et al. conducted a repeated-measures, controlled crossover trial of 30 subjects to explore the effectiveness of lower doses of zopiclone and melatonin in inducing early circadian sleep and how the treatments affect the performance of air crew (495). The subjects were given capsules of a placebo, 2mg of sustained-release melatonin (Circadin®, a pharmaceutical-grade time-released formulation of melatonin made by Neurim Pharmaceuticals, Tel Aviv, Israel), or zopiclone 5mg, all with an identical appearance. Objective measures included: sleep latency, wake after sleep time, total sleep time, time taken to get to sleep, number of awakenings, and time spent awake after having fallen sleep, using wrist actigraphy (Precision Control Design, Fort Walton Beach, FL). Fatigue, sleep quality and mood, drug effects/side effects, and amount of alcohol ingested were measured subjectively using a self-reported questionnaire (using seven-point Likert scales). According to the actigraphic data, subjects slept longer while using melatonin (p<0.02) and zopiclone (p<0.005) compared to placebo. Melatonin (p<0.01) and zopiclone (p<0.003) decreased sleep latency. Compared to placebo, subjects woke up less after having fallen asleep when taking melatonin (p<0.004) and zopiclone (p<0.01). Relative to placebo, subjects spent less time awake after sleep onset while taking melatonin (p<0.01) and zopiclone (p<0.05). There was no statistically significant difference between melatonin and zopiclone in total sleep time, time taken to get to sleep (latency), number of awakenings, or time spent awake after having fallen sleep. Subjects found it easier to fall asleep on melatonin (p<0.0001) and zopiclone (p<0.001) when compared to placebo. Relative to the placebo group, subjects woke up less and reported it easier to fall back asleep after awakening when using melatonin (p<0.005 and p<0.0003, respectively) and zopiclone (p<0.001 and p<0.0003, respectively). The quality of sleep was improved in the melatonin (p<0.0003) and zopiclone (p<0.0004) groups compared to placebo. All of these findings were statistically significant. However, no statistically significant difference was shown between the zopiclone and melatonin groups in difficulty getting to sleep, reported number of awakenings, difficulty returning to sleep after awakening, or quality of sleep. Limitations of this study include a lack of a power calculation, randomization, adequate description of blinding process, and intention-to-treat analysis, as well as the suboptimal study design, length of study (just one dose, one day), and statistical interpretation. Generalizability is questionable, as the sample was from an air crew and predominantly male. Standardization, allergies, adverse effects, toxic effects, and interactions were not discussed.

Delayed sleep phase syndrome (DSPS)

• Summary: Delayed sleep phase syndrome is a condition that results in delayed sleep onset, despite normal sleep architecture and sleep duration. Several randomized controlled studies have reported improvements in sleep latency. Nonrandomized clinical trials have also been conducted (446;​451) and, overall, the results agree with those observed in the RCTs. Further well-designed study is required before conclusions can be drawn.
• Systematic review: Buscemi et al. conducted a systematic review to evaluate the efficacy and safety of exogenous melatonin in the management of primary sleep disorders (611). A number of electronic databases were searched. Bibliographies of included studies and relevant reviews were reviewed, and hand-searching was conducted. Randomized controlled trials were eligible for the efficacy review, and controlled trials were eligible for the safety review. One reviewer extracted data, while the other verified the extracted data. The Random Effects Model was used to analyze data. Fourteen randomized controlled trials were relevant to the efficacy review, encompassing 279 participants (350;​425;​447;​453;​471;​472;​473;​474;​483;​516;​522;​524;​526;​582). Melatonin decreased sleep onset latency (weighted mean difference [WMD]: -11.7 minutes; 95% confidence interval [CI], -18.2, -5.2); it was decreased to a greater extent in people with delayed sleep phase syndrome (WMD: -38.8 minutes; 95% CI, -50.3, -27.3; N=2) compared with people with insomnia (WMD: -7.2 minutes; 95% CI, -12.0, -2.4; N=12). There was no evidence of adverse effects from melatonin. The researchers concluded that there was evidence to suggest that melatonin is not effective in treating most primary sleep disorders with short-term use (four weeks or less); however, additional large-scale randomized controlled trials are needed before firm conclusions can be drawn. There is some evidence to suggest that melatonin is effective in treating delayed sleep phase syndrome with short-term use.
• Evidence: Kayumov et al. conducted a randomized, double-blind, placebo controlled crossover trial to investigate the effects of exogenous melatonin on delayed sleep phase syndrome (453). Patients with DSPS were included if they were over age 15 and did not do shift work, and had no presence of other sleep disorders, alcohol or drug abuse, use of psychotropic medications, active behavioral treatment, or severe psychiatric or neurological disorders. Twenty-two patients with delayed sleep phase syndrome received placebo or melatonin (5mg) daily for four weeks; these patients underwent a one-week washout period, and then were given the other treatment for an additional four weeks. Two consecutive overnight polysomnographic recordings were performed on three occasions: at baseline (before treatment), after four weeks of melatonin treatment, and after four weeks of placebo treatment. Twenty patients completed the study, with two subjects withdrawing (one subject moved and the other refused to sleep in the clinic). Sleep onset latency was reduced (20.2 minutes vs. 58.9 minutes for placebo vs. 35.8 minutes at baseline, p<0.05) while subjects were taking melatonin. Melatonin had no effect on total sleep time vs. baseline, but total sleep time was decreased in the placebo group vs. baseline. Melatonin had no effect on scores on subjective measures of sleepiness, fatigue, and alertness, which were administered at different times of the day. After an imposed conventional sleep period (from midnight to 8 a.m.), subjects taking melatonin reported being less sleepy and fatigued than they did while taking placebo. No adverse effects of melatonin were noted. The method of randomization was not indicated in this study. Otherwise, this study was well designed.
• Rahman et al. conducted a randomized, double-blind, placebo controlled crossover trial to examine the hypothesis that exogenous melatonin (5mg) may attenuate depressive symptomatology in delayed sleep phase syndrome patients (452). A total of 20 patients (13 males aged 35.6 ± 14.0 years and seven females aged 30.8 ± 12.4 years) with an established diagnosis of DSPS participated in the study. Subjects were excluded if they had other sleep disorders, did shift work, were under 16 years old, were alcohol or drug abusers, were current users of psychotropic medications or any other form of medication affecting melatonin secretion, were receiving active behavioral treatment, or had severe psychiatric or neurological disorders. Subjects were randomly allocated to the melatonin treatment group or placebo group. Each subject was given 5mg of melatonin or placebo capsule daily between 7 and 9 p.m. The total duration of the study was nine weeks. Before the randomization, a two-night sleep study was conducted to establish the baseline. After the second night of study and randomization, treatment continued for four weeks, followed by a one-week washout period before treatment crossover. Two-night sleep studies were later conducted again on days 27 and 28 (the first four-week treatment) and on days 62 and 63 (the second four-week treatment). Each group received the treatment of melatonin or placebo capsule between 7 and 9 p.m. daily. Subjects were primarily assessed by clinical interviews, psychometric evaluation for depression (Center for Epidemiologic Studies Depression Scale and Hamilton Depression Rating Scale-17), and overnight polysomnographic sleep studies (carried out at baseline and at the end of melatonin and placebo treatments). Melatonin secretion rhythm was measured by urinary 6-sulphatoxymelatonin level to determine circadian phase. Significant decreases (p<0.05) in HDRS-17 and CES-D scores after melatonin treatment were observed in group I (DSPS patients with comorbid depressive symptoms; N=8) while placebo treatment had no effect on either score. Changes in group II (DSPS patients without comorbid depressive symptoms; N=12) were not significant. The sleep onset latency was significantly reduced (p=0.03) in the melatonin treatment arm compared to both placebo and baseline in group I. Polysomnographic findings in group II indicated significant advance (p=0.03) in sleep onset latency in the melatonin treatment arm compared to placebo and baseline. The circadian profile of DSPS patients with marked depressive symptoms showed an abnormal pattern of endogenous melatonin secretion on placebo treatment; however, DSPS patients without depression showed normal melatonin production. This was a well-designed study; however, it should be noted that the study population was small.
• Mundey et al. conducted a randomized double-blind placebo controlled trial to test the effectiveness of melatonin to advance the timing of sleep and circadian phase in individuals with delayed sleep phase syndrome (DSPS) (448). Twenty-two subjects were included. Subjects received 0.3 (N=5) or 3mg (N=4) melatonin or placebo (N=4) capsules taken for a period of four weeks, between 1.5 and 6.5 hours before dim light melatonin onset. The primary outcomes included the circadian phase shift markers dim-light melatonin onset (DLMO) and timing of the fitted nocturnal temperature minimum, measured both objectively and subjectively. Actigraphs (Actiware-Sleep, Mini Mitter Co., Inc., Bend, OR) measured objective sleep outcomes. Subjective outcomes (bed/lights-out times from sleep-diary) were compared to actigraphy data to calculate secondary outcome sleep latency. During the baseline week and on the fourth week of treatment, sleep onset, sleep offset, sleep efficiency, and sleep latency averages were calculated. The circadian phase of endogenous melatonin progressed in the groups after taking both doses of melatonin. Compared to baseline, advances (average time in hours ± SD) in dim-light melatonin onset (1.75 ± 0.89; p<0.001) and timing of the fitted nocturnal temperature minimum (1.63 ± 1.79; p<0.05) were noted in the melatonin groups. There was a strong correlation between the size of the phase advance in dim-light melatonin onset and the time that the subjects took the melatonin. The earlier the time of melatonin administration, the more effective it was (r2=0.94; p<0.0001). There was a correlation, although weak, between the time at which the subjects took the melatonin and change in sleep time. Limitations of this study include a lack of a power calculation, intent-to-treat analysis, and between-groups comparison. This study was supported by the Northwestern Drug Discovery Program and by AG00810. Standardization, adverse effects, toxic effects, and interactions were not discussed.
• Nagtegaal et al. conducted a double-blind, placebo controlled, crossover trial to determine the importance of dim-light melatonin onset in patients suffering from DSPS (449). Patients were excluded if they were under 12 years of age, or had prior use of melatonin, liver diseases, renal failure, or psychiatric disorders. Thirty patients with DSPS received melatonin 5mg for two weeks in a double-blind setting and two weeks in an open setting, successively or interrupted by two weeks of placebo. Endpoints included measurements of the 24-hour curves of endogenous melatonin production and rectal temperature (N=14), polysomnography (N=22), actigraphy (N=13), sleep log (N=22), and subjective sleep quality (N=25). Mean dim light melatonin onset (± SD), before treatment, occurred at 23.17 hours (± 138 minutes). Melatonin was administered five hours before the individual dim-light melatonin onset. After melatonin treatment, the onset of the nocturnal melatonin profile was significantly advanced by approximately 1.5 hours. Melatonin use resulted in a significant reduction in sleep onset latency (15.3 minutes with melatonin vs. 25.3 minutes with placebo). Otherwise, sleep architecture was not influenced. During melatonin treatment, patients reported feeling more refreshed in the morning. This study was not randomized, and the identical nature of supplements was not discussed.

Insomnia (elderly)

• Summary: Mean excretion of 6-sulfatoxymelatonin (a metabolite of melatonin) has been found to be lower in patients aged 55 years or older with insomnia than patients of the same age or younger (1101). Several randomized controlled studies have reported improvements in insomnia in the elderly with melatonin supplementation. Nonrandomized clinical trials have reported similar results (478;​481). Further well-designed study is required before firm conclusions can be drawn.
• Evidence: Baskett et al. conducted a randomized, double-blind, placebo controlled, crossover trial to determine the effect of melatonin on quality of sleep in healthy older people with age-related sleep maintenance problems (471). Patients were excluded if they were aged under 65 years with a score below 26 (out of 30) points on the mini-mental status examination (MMSE) or a score >6 on the geriatric depression score (GDS). Other exclusions included non-age-related sleep problems, advanced or delayed sleep phase syndrome, poor sleep hygiene, medical conditions significantly interfering with sleep (including sleep apnea), changes in medication during the study, use of hypnosedatives, or creatinine clearance <0.41mL per second. Twenty normal and 20 problem sleepers were included in the study from a larger sample of 60 normal and 60 problem sleepers. Twenty-four-hour urine 6-sulphatoxymelatonin was measured to estimate melatonin secretion in each participant. Patients were randomized to 5mg of melatonin, or matching placebo, at bedtime for four weeks, separated by a four-week washout period. Endpoints included sleep quality (sleep diaries), the Leeds Sleep Evaluation Questionnaire, and actigraphy. There was a significant difference between the groups in self-reported sleep quality indicators at entry, but no difference in melatonin secretion. Melatonin did not significantly improve any sleep parameter measured in either group. This study was well designed and well reported.
• Garfinkel et al. conducted a randomized, controlled crossover trial of 15 elderly subjects who complained of long-term insomnia and were receiving different medications at baseline to measure 6-sulphatoxymelatonin levels and to assess the effect of controlled-release melatonin on sleep hygiene (473). Participants received tablets of 2mg of controlled-release melatonin (Circadin®, Neurim Pharmaceuticals, Tel Aviv, Israel) or a placebo. Sleep variables were measured for three consecutive nights at the end of the three-week treatment periods, and averages were taken. Wrist actigraphs (Somnitor®, Neurim Pharmaceuticals, Tel Aviv, Israel) assessed sleep-wake patterns. Indicators for sleep quality were assessed in the subjects for three nights in a row. The authors did not specifically state the primary outcome; latency is assumed. Latency (time between bedtime and sleep onset), efficiency (total time asleep as a percentage of total time in bed), total sleep time (time spent asleep after sleep onset), and wake after sleep onset (WASO; accumulated time awake after sleep onset) were assessed. 6-Sulphatoxymelatonin excretion, onset, and peak time were also measured. Compared to the melatonin group, the placebo group exhibited a longer latency period. The mean sleep latency was 19 minutes [SE: 5; range: 3-49] in the melatonin group compared to the placebo period 33 minutes [SE: 7], but the decrease was not statistically significant (p=0.088). Sleep efficiency in the melatonin period showed an increase (83% [SE: 4]), when compared to the placebo period (75% [SE 3]) (p<0.001). Wake after sleep onset in the melatonin period was 49 minutes [SE: 14], and 73 minutes [SE: 13] in the placebo group (p<0.001). Melatonin did not significantly affect total sleep time (p=0.49). It was hypothesized that, due to the short half-life of melatonin, the controlled-release melatonin is helpful for sleep maintenance. Limitations of this study include a lack of a power calculation and explanation of randomization. Toxic effects, standardization, and interactions were not discussed.
• Luthringer et al. conducted a randomized, double-blind, sleep laboratory phase II study to investigate the effects of prolonged-release melatonin (PRM) on sleep and daytime performance in patients with insomnia (479). Subjects were 40 patients aged 55 years or older with primary insomnia, as defined by the fourth revision of the Diagnostic and Statistical Manual of Mental Disorders of the American Psychiatric Association. Patients with other sleeping disorders (related to breathing disorders or restless leg/periodic leg movements), a history of severe cardiac or neurologic disorders, or those who took sedative hypnotics in the preceding month were excluded from this study. Patients were treated with a nightly single-blinded placebo for two weeks. They were then randomized in a double-blind fashion to prolonged-release melatonin (PRM) 2mg or placebo two hours before bedtime for three weeks. Following the double-blind randomization, a withdrawal period in which no drugs were given was conducted for three weeks. Eleven patients in each treatment group reported adverse events; however, none were considered to be treatment related. Sleep was assessed objectively using polysomnography, all-night electroencephalography spectral analysis, and subjective questionnaires (the Leeds Sleep Evaluation Questionnaire, LSEQ). Daytime psychomotor performance was objectively assessed using the Leeds Psychomotor Tests battery. At the end of the double-blind treatment period, the PRM treatment group had significantly shorter sleep onset latency (nine minutes; p=0.02) compared to placebo group. The PRM group also had significantly better Critical Flicker Fusion scores (p=0.008), without negative effects on sleep structure and architecture. Based on the LSEQ questionnaire, quality of sleep was significantly improved in the PRM group (p=0.004), but not in the placebo group. More patients in the PRM group also reported substantial improvement in sleep quality at home compared to placebo (50% vs. 15%; p=0.018). However, there was no significant difference in objective measures of sleep quality between the groups. The authors concluded that nightly treatment with PRM effectively induced sleep and improved perceived quality of sleep. It should be noted that this study was funded by the manufacturer of the melatonin supplement used in this study.
• Lemoine et al. conducted a randomized, double-blind, placebo controlled, parallel study to assess the efficacy and safety of melatonin in improving quality of sleep and morning alertness in 170 patients aged 55 years or older (476). Patients had primary insomnia for at least one month and had consistent complaints of poor sleep quality during the single-blind placebo run-in period. Patients with breathing-related sleep disorder, circadian rhythm sleep disorder, dyssomnia not otherwise specified, sleep disorder because of a general medical condition, significant psychiatric or neurological disorders (anxiety, depression, dementia), or use of any medications that affected the central nervous system or sleep-wake function within two weeks prior to the first day of the placebo run-in period were excluded. The study began with a two-week, single-blind, run-in phase with placebo treatment followed by an evaluation. Eligible patients were randomized to placebo or prolonged-release (PR) melatonin 2mg (Circadin®; Neurim Pharmaceuticals Ltd., Tel Aviv, Israel) for three weeks. Subjects were instructed to take the medication daily after the evening meal, between one and two hours before bedtime, preferably between 9 and 10 p.m. Prolonged-release melatonin significantly improved quality of sleep (p=0.047), quality-of-sleep ratings (p=0.003), and morning alertness (p=0.002) compared with placebo. The authors suggested that the improvements in quality of sleep and morning alertness were linked, indicating a beneficial treatment effect on the restorative value of sleep. Rebound insomnia or withdrawal effects were not found upon treatment discontinuation. Adverse effects were mild and did not occur more often in the melatonin group. Randomization and blinding were not described.
• Wade et al. conducted a randomized, double-blind, placebo controlled study to evaluate whether or not treatment with prolonged release (PR)-melatonin would improve quality of sleep and next day alertness in 354 older patients with primary insomnia (477). Patients with primary insomnia were included following exclusion of neuropsychiatric disorders and other potential reasons for development of insomnia. Patients were randomized to receive 2mg of melatonin (N=177; Circadin®, Neurim Pharmaceuticals Ltd., Tel Aviv, Israel) or placebo (N=177) for three weeks, one tablet two hours before bedtime. Twenty patients failed to complete visit 3 (eight in the melatonin group; 12 in the placebo group), with 334 patients comprising the full analysis set. This treatment period was preceded by a two-week run-in period. Endpoints included quality of sleep and morning alertness. Improvements were noted in quality of sleep and morning alertness (26% vs. 15%; p=0.014). A statistically significant and clinically relevant shortening of sleep latency to the same extent as most frequently used sleep medications was also found (-24.3 vs.-12.9 minutes; p=0.028). Quality of life also improved (p=0.034). Blinding was not described.
• Zhdanova et al. conducted a randomized, double-blind, placebo controlled trial to determine if melatonin at various doses could restore sleep in elderly subjects, 30 of which completed the study (483). Inclusion criteria included chronic insomnia and increased daytime sleepiness (or frequent napping), which gradually developed with advancing age (after subjects reached 40 years of age) and were present for at least one year before the recruitment. Subjective symptoms (International Classification of Sleep Disorders) consistent with psychophysiological insomnia as well as objective symptoms (polysomnographic (PSG) criteria showing latency to sleep onset of more than 30 minutes) also had to be present. Exclusion criteria included major psychiatric diagnosis on Axis I of the DSM-IV; regular use (once a week or more) of hypnotics, melatonin, stimulants, or other medications that may affect melatonin levels, and unwillingness or inability to discontinue the occasional use of these medications for at least four weeks before beginning the protocol; and acute or unstable chronic conditions (e.g., diabetes, uncontrolled thyroid disease; kidney, prostate, or bladder conditions; congestive heart failure, angina, or other severe cardiovascular disorders; hepatitis; asthma or severe respiratory allergies; stroke; cancer if less than one year since the end of treatment; conditions associated with chronic pain; neurological disorders; more than "moderate" alcohol use; unwillingness or inability to maintain a regular sleep-wake cycle during the entire period of the study; sleep apnea/hypopnea index >10,; and periodic (more than 10) limb movements in sleep per hour). Thirty subjects completed the study, but the number starting the study is not clear. Subjects received a placebo on alternate (odd-numbered) weeks throughout the study, starting with the first "run-in" week, thus providing washout periods between and after active treatments. During the second week and thereafter on each even-numbered treatment week, subjects received melatonin (0.1, 0.3, or 3.0mg) mixed with microcrystalline cellulose or the placebo (cellulose) daily, administered for four days at home and then for three days as inpatients in a research center. Melatonin or placebo capsules were ingested half an hour before each subject's fixed bedtime. Treatments were separated by one-week washout periods. Sleep data were obtained by polysomnography on the last three nights of each treatment period. The physiologic melatonin dose (0.3mg) restored sleep efficiency (p<0.0001), acting principally in the middle third of the night; it also elevated plasma melatonin levels (p<0.0008) to normal. The highest dose (3.0mg) was also effective in improving sleep; however, it also induced hypothermia and caused plasma melatonin to remain elevated into the daylight hours. Melatonin did not affect the sleep of the control subjects, even though they also had low melatonin levels. Description of randomization, blinding, and withdrawals is lacking.
• Haimov et al. conducted a double-blind clinical trial to investigate the effects of melatonin replacement therapy on melatonin-deficient elderly insomniacs (474;​475). The study comprised a running-in, no-treatment period and four experimental periods. During the second, third, and fourth periods, subjects were administered tablets for seven consecutive days, two hours before desired bedtime. The tablets were 2mg of melatonin administered as sustained-release or fast-release formulations, or an identical-looking placebo. The fifth period, which concluded the study, was a two-month period of daily administration of 1mg of sustained-release melatonin two hours before desired bedtime. During each of these five experimental periods, sleep-wake patterns were monitored by wrist-worn actigraphs. Analysis of the first three one-week periods revealed that a one-week treatment with 2mg of sustained-release melatonin was effective for sleep maintenance (i.e., sleep efficiency and activity level) of elderly insomniacs, while sleep initiation was improved by the fast-release melatonin treatment. The authors stated that sleep maintenance and initiation were further improved following the two-month, 1mg sustained-release melatonin treatment, indicating that tolerance had not developed. After cessation of treatment, sleep quality deteriorated. This study was not randomized.
• Valtonen et al. conducted two long-term, randomized, double-blind, placebo controlled studies to investigate the effects of a melatonin-rich nighttime milk on sleep and activity in institutionalized elderly patients (482). Inclusion and exclusion criteria were not clearly provided. In study 1, 70 patients receiving various medications for chronic illnesses participated in a crossover study. The subjects were divided into two groups (I and II). Group I (N=31) used night milk (experimental) for eight weeks and normal commercial milk (placebo) for eight weeks, with a washout period of one week in between. Group II (N=31) started with normal daytime milk for eight weeks and switched to night milk after the washout period. Each subject drank about 0.5L of milk daily. The study was performed between March and July. Based on subjective evaluation, quality of sleep was good during the whole study, with almost all scores between 8 and 10 (10=most restful). There was no difference in sleep quality between night milk and normal milk periods for group I, but for group II, which consumed night milk second, sleep quality decreased during the later period (p<0.01). Sleep quality was reduced towards the summer, indicating a seasonal effect that was more evident in subjects with severe dementia. This seasonal effect was statistically significant. In study 2, the design was changed slightly, since the subjective evaluation in study 1 was considered to be too limited. Also, the parameter most strongly related to season (light and melatonin) was nocturnal activity. Eighty-one subjects participated in this study, and all subjects consumed milk regularly. The participants were divided into three groups. Group III (N=23) started by consuming night milk for eight weeks and then, after a washout period of one week, consumed normal daytime milk for another eight weeks. Group IV (N=26) started with normal milk for eight weeks and changed to night milk after the washout period. Group V (N=32), living in another rest home, consumed normal daytime milk during the whole experiment and served as a control group for evaluating the effect of season. The study was performed between October and February. For Group III, sleep quality was rated significantly (p<0.001) higher during the normal milk period. There were no changes in morning or evening activity, and no effect of night milk. In Group IV, sleep quality, morning activity, and evening activity increased (p<0.001) when night milk was consumed. In Group V, sleep quality was slightly better (p</0.05) when night milk was consumed. There was no difference between the periods in morning or evening activity, which may indicate no seasonal effect in activity. Randomization, blinding, and dropouts were not described.
• Dawson et al. conducted a double-blind, placebo controlled, crossover trial of 12 elderly patients to assess the effect of exogenous melatonin on age-related sleep maintenance insomnia (472). Subjects were over 55 years of age (mean=65.67 years, SEM=1.68) and had all been suffering from sleep maintenance insomnia for at least six months. Subjects were treated with 0.5mg of transbuccal (delivered via a patch placed on the gums) melatonin or a placebo at 7 p.m. for two sessions of four consecutive nights, at least three days apart. Nightly urine samples were assayed for the melatonin metabolite 6-sulfatoxy-melatonin. Body temperature was measured continually from 9 p.m. to 7 a.m. Subjects self-selected lights-out times, and sleep was assessed using standard polysomnographic (PSG) measures. Outcome measures included polysomnographic recordings (EEG, EMG, EOG) and associated variables (total sleep time, sleep onset latency, REM onset latency, early morning awake, percentage time awake, sleep efficiency, stage changes in sleep period, time of sleep onset, and wake after sleep onset), and body temperature (rectal probe). Analysis revealed that, compared to the placebo, transbuccal melatonin administration significantly reduced core body temperature (p<0.05), but had no positive, statistically significant effect on any PSG measure of sleep quality. This study found no statistically significant effect of 0.5mg of transbuccal melatonin in treating age-related sleep maintenance insomnia. The authors speculated that both the dose size and timing may have influenced the negative result. Interactions, allergies and adverse effects, as well as dropouts, were not discussed.
• Studies of lesser methodological rigor (not included in the Evidence Table): Wurtman et al. reported the results of a small controlled study, in a letter to the editor, investigating melatonin's ability to improve sleep quality in aged insomniacs (478). Using a Latin square design, nine subjects (ages 51-78) were given melatonin (0.3mg) or placebo for three consecutive days, 30 minutes before bedtime. Core temperature and motor activity were recorded every minute for six days. Subjects also completed questionnaires about their previous night's sleep. Melatonin administration reduced the number of movements per night (480 ± 96 to 240 ± 55), latency to sleep onset (49 ± 8.9 to 27 ± 4.5), and awakenings per night (2.56 ± 0.32 to 0.88 ± 0.26). Subjects also reported that melatonin improved subjective sleep quality and did not increase morning sleepiness. Core body temperature was unaffected. Due to the nature of the article, it is difficult to evaluate the rigor of the study. Statistical findings were not reported.

Sleep disorders (children with behavioral, developmental, or intellectual disorders)

• Summary: Several randomized controlled studies have reported melatonin use in children with various neuropsychiatric disorders, including mental retardation, autism, psychiatric disorders, visual impairment, or epilepsy. Nonrandomized clinical trials have also been conducted (394;​584;​592;​593;​594;​595;​603;​605;​1102;​1103;​1104;​1105;​1106;​1107) and, overall, the results agree with those observed in the RCTs. Well-designed controlled trials in select patient populations are needed before a conclusion can be made.
• Systematic review: Bendz et al. conducted a systematic review of the safety and efficacy of melatonin for the alleviation of insomnia in children with attention-deficit hyperactivity disorder (ADHD) (597). Criteria for inclusion were English-language articles and human studies conducted in children with ADHD and administering melatonin for the treatment of insomnia. Databases searched included MEDLINE (1948-August 2009), EMBASE (1950-August 2009), and Scopus (1960-August 2009). Search terms were "melatonin," "attention-deficit/hyperactivity disorder (ADHD)," "pediatric," "insomnia," "sleep disorder," and "sleep." A total of four studies were found (394;​408;​624;​1108). Doses ranged from 3mg to 6mg of oral melatonin. Tjon Pian Gi et al. conducted a one-year open-label study (N=120). Van der Heijden et al. conducted a four-week randomized controlled trial (N=105). Hoebert et al. conducted a three-year follow-up to the van der Heijden trial (N=94). Weiss et al. conducted a six-month crossover study (N=28). Tjon Pian Gi et al. reported one case of restless sleep. Van der Heijden et al. reported mild adverse effects including headache, hyperactivity, dizziness, and abdominal pain. Also, a two-year safety follow-up showed bedwetting, abnormal feces, and drowsiness. Hoebert et al. had 20% of patients (N=19) report adverse effects, all of which were not serious and did not involve new cases of epilepsy. After discontinuation, there were no reports of withdrawal symptoms or dependence. Weiss et al. reported mild-to-moderate adverse effects, except for one report of severe migraine. Tjon Pian Gi et al. examined sleep onset. Van der Heijden et al. measured sleep parameters including sleep onset, total sleep time, and sleep latency as well as specific core problems, including anger, sleep, and attention. Hoebert et al. measured relapse rates of sleep onset insomnia after discontinuation of melatonin using subjective questionnaires filled out by parents. Weiss et al. measured sleep latency and also implemented a sleep hygiene regimen using actigraphy and somnolog measures. Tjon Pian Gi et al. concluded that, at short-term evaluation, sleep onset was significantly improved (median increase: 135 minutes, N=24), which was then sustained at the long-term evaluation (N=13). Van der Heijden et al. reported significant improvements in sleep parameters (sleep onset, total sleep time, sleep latency, DLMO) and specific core problems (anger, sleep, attention). Hoebert et al. reported that 92% (N=60) of subjects experienced a delay in sleep onset, although, overall, 90% (N=85) of parents believed melatonin to be an effective treatment for SOI in their children with ADHD, 71% (N=67) thought daytime behavior improved, and 61% (N=57) thought mood improved. Weiss et al. determined that those who responded well to melatonin therapy did not have a significant improvement with continued treatment. In most studies, sleep onset was improved by 0.5-2 hours, sleep duration was improved by 0.33-1 hour, and sleep latency was improved by approximately 20 minutes. The review was well conducted; however, there is an overall lack of well-designed studies related to melatonin use. The available studies were limited by small sample sizes and variable outcome measures.
• Phillips et al. conducted a systematic review to assess randomized control trial evidence for the use of melatonin in children with neurological and developmental problems (1109). Randomized clinical trials of children (up to 18 years of age) with any type of neurological disorder or neurodevelopmental disability and associated sleep disturbance, where oral melatonin was used and compared to placebo, were identified. Sustained-release formulations were excluded. Three studies (N=35 children) met inclusion criteria (418;​584;​1110). Two studies reported time to sleep onset and showed a decrease (p<0.05) in this specific outcome where melatonin was compared with a placebo (584;​1110). There was no significant effect of melatonin compared with a placebo on the other outcome measures of total sleep time, nighttime awakenings, and parental opinions.
• Evidence: Wasdell et al. conducted a randomized, double-blind, placebo controlled, crossover trial to determine the efficacy of controlled-release (CR) melatonin in the treatment of delayed sleep phase syndrome and impaired sleep maintenance of 51 children with neurodevelopmental disabilities, including autistic spectrum disorders (450). Children (age range: 2-18 years) who did not respond to sleep hygiene intervention were enrolled. Participants received a pharmaceutical grade controlled release (CR) melatonin 5mg followed by a three-month open-label study, during which the dose was gradually increased until the therapy showed optimal beneficial effects. Endpoints included sleep characteristics measured by a caregiver (somnologs and wrist actigraphs), as well as clinician ratings of severity of sleep disorder and improvement from baseline, and caregiver ratings of global functioning and family stress. Fifty patients completed the crossover trial (one withdrew due to illness) and 47 completed the open-label phase. Recordings of total nighttime sleep and sleep latency showed an improvement (p<0.001) with melatonin. Improvement was observed in both clinician and parent ratings (p<0.05). There were no adverse effects related to melatonin. This study was well designed; however, some patients had previous experience with melatonin therapy and were only asked to withdraw two weeks prior to the study.
• Weiss et al. conducted a randomized, double-blind, placebo controlled, crossover trial to evaluate the efficacy of sleep hygiene and melatonin treatment for initial insomnia in children with attention-deficit hyperactivity disorder (ADHD) (596). Twenty-seven stimulant-treated children (6-14 years of age) with ADHD and initial insomnia (>60 minutes) received sleep hygiene intervention and were administered melatonin 5mg and placebo. Each treatment period was 10 days, followed by a five-day washout period with placebo. Sleep hygiene reduced initial insomnia to less than 60 minutes in five cases, with an overall effect size in the group of 0.67. A reduction in initial insomnia of 16 minutes with melatonin relative to placebo was observed (p<0.01), with an effect size of 0.6. The effect size of the combined sleep hygiene and melatonin intervention from baseline to 90 days' post-trial was 1.7, with a mean decrease in initial insomnia of 60 minutes. Improved sleep had no demonstrable effect on ADHD symptoms. This trial was well designed.
• Braam et al. conducted a randomized, double-blind, placebo controlled trial to evaluate the effectiveness of melatonin in 58 patients with intellectual disabilities (598). Patients were included with sleep disturbances not due to somatic and psychiatric causes. Standard behavioral treatment and sleep hygiene measures had been previously unsuccessful. Individuals with sleep latency of more than 30 minutes, two or more periods of night awakenings lasting more than 45 minutes each night, or five or more night awakenings lasting more than 15 minutes for at least five nights each week were included. Sleep disturbance was to have been present for at least one year. Exclusion criteria included prior use of melatonin, restless leg syndrome, sleep apnea syndrome, liver disease, renal failure, chronic pain, age less than 24 months, and Smith-Magenis syndrome. The trial consisted of a baseline and qualification period followed by a four-week treatment period. During the treatment period, subjects received melatonin 5mg or placebo at bedtime. Individuals younger than six years received 2.5mg of melatonin. Compared with placebo treatment, mean sleep latency decreased by 29 minutes (p<0.01), mean sleep onset increased by 34 minutes (p<0.01), and mean total sleep time increased by 48 minutes (p<0.05) during melatonin treatment. The mean number of night awakenings per night decreased (p<0.05). There was no change in lights-out time, number of nights with night wakings per week, and sleep offset time compared with baseline. There was a correlation between baseline dim-light melatonin onset and the change in dim-light melatonin onset between baseline and week 4 in the melatonin group (p<0.001). Adverse effects were reported as few and minor. No specifics were provided. This trial was well designed.
• Garstang et al. conducted a randomized, double-blind, placebo controlled, crossover trial to evaluate the effects of melatonin in 11 autistic children with sleep disorders (591). Children who had used melatonin previously were excluded, and all children were aged 4-16. The children received melatonin 5mg or placebo for four weeks. There was a washout period of one week between each of the treatment periods. Seven children completed the trial. Four children did not complete the trial; reasons were moving, a child protection enquiry, and difficulty with the placebo capsules, necessitating a recall. Melatonin significantly reduced sleep latency and the number of night wakings, and increased the total sleep time. Sleep latency was 2.6 hours (95% CI, 2.28-2.93) at baseline, 1.91 hours (95% CI, 1.78-2.03) with placebo, and 1.06 hours (95% CI, 0.98-1.13) with melatonin. Wakings per night were 0.35 (95% CI, 0.18-0.53) at baseline, 0.26 (95% CI, 0.20-0.34) with placebo, and 0.08 (95% CI, 0.04-0.12) with melatonin. Total sleep duration was 8.05 hours (95% CI, 7.65-8.44) at baseline, 8.75 hours (95% CI, 8.56-8.98) with placebo, and 9.84 hours (95% CI, 9.68-9.99) with melatonin. Adverse effects were not discussed. Blinding was not described in this study, but otherwise it was well designed.
• Wirojanan et al. conducted a four-week, randomized, double-blind, placebo controlled, crossover trial to determine the efficacy of melatonin on sleep problems in children with autistic spectrum disorder (ASD) and fragile X syndrome (FXS) (599). The experiment was conducted on eighteen subjects (16 boys, two girls) between two and 15.3 years of age who were diagnosed with ASD (either autism or pervasive developmental disorder [PDD-NOS]), fragile X syndrome (FXS), or a combination of both. Participants were given 3mg of melatonin or placebo to take orally at bedtime. The placebo was provided by the Twinlab Corporation to look similar to the melatonin capsule. The study medication was given 30 minutes prior to bedtime over the two-week treatment arm followed by a one-week washout period. Lastly, the participants crossed over to the alternate treatment for an additional two weeks. There were six dropouts from a total of 18 enrolled. Three participants were excluded, even though they finished the study, because their caregivers did not complete the sleep diary or because the Actiwatch data were unreadable. Two participants were excluded since they failed to wear the Actiwatch during one of the treatment arms. Also, a family was excluded due to study protocol violation and an incomplete sleep diary. Objective sleep variables, including sleep onset time (actual time participant fell asleep), total length of sleep duration, sleep onset latency time (time from bedtime to sleep onset time), as well as the number of times the participant woke, were obtained from actigraphy and the subjective daily sleep diary that was completed by the parents or caregivers. A small device worn around the wrist or ankle, the Actiwatch, measured gross motor activity in one-minute intervals. Total night sleep duration tended to be longer (mean increase: 21 minutes) in the melatonin arm, but was not statistically significant (p=0.057). Sleep latency time tended to be shorter (mean decrease: 28 minutes, 5 seconds) in the melatonin arm, but was not significant (p=0.10). Sleep onset time was significantly earlier (mean decrease of 42 minutes) for participants (p=0.0017) during melatonin treatment compared with placebo when using a parametric test. The number of nighttime awakenings was not significantly lower in the melatonin group (p=0.73). The study was well designed, albeit with a small participant size.
• Coppola et al. conducted a randomized, double-blind, placebo controlled crossover trial to assess the efficacy of melatonin in children, adolescents, and young adults with wake-sleep disorder and mental retardation (590). Patients had mental retardation with or without seizures, were aged more than 12 months, and were diagnosed as having a sleep disorder. Medical issues causing sleep disorders were excluded. Some of the patients were on chronic anticonvulsant therapy for epileptic seizures. Twenty-five patients (16 males, nine females), aged from 3.6 to 26 years (mean: 10.5 years) were included. Patients received fast-release melatonin (3mg at bedtime) or placebo in phase 1 of the study for four weeks. After a crossover period of one week, each patient entered the four-week second phase of the study. Electroencephalography (EEG), side effects, and blood levels of concomitant adverse effects were monitored in all patients at baseline and at the end of each melatonin or placebo one-month phase of the study. At the end of the second phase, responders to melatonin entered an open-label phase of two months. Endpoints included sleep latency, time of sleep, and quality of sleep. According to sleep logs, melatonin improved sleep latency (p=0.019), but did not significantly alter the number of nocturnal awakenings (p=0.768) or total time of diurnal sleep (p=1). Melatonin was well tolerated in all patients, and no side effects were reported. Seven patients did not complete the study, due to illness, lack of interest, and loss to follow-up. Randomization and blinding were not described.
• Niederhofer et al. conducted a randomized, double-blind, placebo controlled trial to determine whether depressed nocturnal melatonin levels and insomnia are associated, and whether various melatonin doses restore sleep in 20 mentally retarded subjects (602). Patients with insomnia of at least one year (latency of sleep of 30 minutes or more, two or more nighttime awakenings, or total period of nighttime sleep less than six hours) were included if self-reports were confirmed by continuous one-week recordings of the motor activity (<85% sleep efficiency) and reasons for insomnia (disease, medications) were excluded. The patients received a placebo on alternate (odd-numbered) weeks throughout the study, starting with the first "run-in" week, thus providing washout periods between and after active treatments. During the second week and thereafter on each even-numbered treatment week, subjects received melatonin (0.1mg or 0.3mg) or the placebo daily (a half-hour before bedtime) for seven days. Sleep was improved by all three melatonin doses, with the 0.3mg dose causing the greatest effect (p<0.0001). The authors reported that melatonin had no behavioral, dose-related effects on total sleep time and number of awakenings. Randomization, blinding, and withdrawals were not adequately described.
• Jan et al. conducted a randomized, double-blind crossover trial to compare the effectiveness of fast-release and controlled-release melatonin and to establish the most effective dose in children with chronic and severe sleep disorders (348). In the initial study, 16 multidisabled children (4-21 years of age) with severe sleep-wake cycle disorders were included. These patients were already being treated with fast-release melatonin for more than three months. Then the 16 subjects were randomized to receive controlled- or fast-release melatonin, each for 11 days, and then the drugs were crossed over. A washout period was not utilized. The fast-release dose was the same as before the study. The controlled-release formulation was 50% of the fast-release dose. Improvements in sleep patterns were noted in 11 of the children, but the controlled-release formulation had no clear advantage over the fast-release melatonin in five children. Following this initial study, 42 other patients on fast-release melatonin were permitted to change to controlled-release preparation in an open-study design. The average final controlled-release melatonin dose in the 42 patients was 5.7mg (2-12mg). Fast-release melatonin was found to be most effective for delayed sleep onset; controlled-release formulations were more beneficial for sleep maintenance. Randomization was not described, and no placebo was used in this study.
• Van der Heijden et al. conducted a randomized, double-blind, placebo controlled trial to investigate the effects of melatonin treatment on sleep, behavior, cognitive performance, and quality of life in children with attention-deficit hyperactivity disorder (ADHD) and chronic sleep onset insomnia (408). A total of 105 medication-free children, aged 6-12 years, received melatonin 3mg or 6mg fast-release tablets (depending on body weight) or placebo for four weeks. Primary outcome parameters were actigraphy-derived sleep onset, total time asleep, and salivary dim-light melatonin onset. Sleep onset advanced by 26.9 ± 47.8 minutes with melatonin and delayed by 10.5 ± 37.4 minutes with placebo (p<0.0001). There was an advance in dim-light melatonin onset of 44.4 ± 67.9 minutes in melatonin and a delay of 12.8 ± 60.0 minutes in placebo (p<0.0001). Total time asleep increased with melatonin (19.8 ± 61.9 minutes) compared to placebo (-13.6 ± 50.6 minutes; p=0.01). There was no statistically significant effect on behavior, cognition, and quality of life, and significant adverse events did not occur. Randomization and blinding were not described.
• Studies of lesser methodological rigor (not included in the Evidence Table): Hoebert et al. conducted a long-term follow-up of melatonin therapy in pediatric patients with ADHD and chronic sleep onset insomnia (1108). Subjects were 101 patients (aged 6-12 years with confirmed diagnosis of ADHD, total IQ higher than 80, and chronic sleep onset insomnia) who had previously taken part in a randomized clinical trial of melatonin treatment. The mean time to follow-up was 3.7 years. Assessment was effected via questionnaires consisting of 19 questions addressing use, dose, frequency, discontinuation, and adverse events. Of responding subjects (94/101), long-term melatonin therapy was judged to be effective against sleep onset problems in 88% and to improve behavior and mood in 71 and 61% of respondents, respectively. Sixty five percent still used melatonin daily and 12% occasionally. No serious adverse events or melatonin-related comorbidities were reported. The authors concluded that melatonin was an effective long-term treatment for chronic sleep onset insomnia in children with ADHD.

Sleep enhancement in healthy people

• Summary: Patients with insomnia appear to have decreased melatonin secretion, and treatment with exogenous melatonin may offer some benefit (1111). Most human trials have been small and brief in duration (often single-dose studies). However, the weight of scientific evidence does suggest that melatonin decreases the time it takes to fall asleep ("sleep latency"), increases the feeling of "sleepiness," and may increase the duration of sleep. Melatonin may also aid in inducing daytime sleep (1112). Further well-designed study is required before firm conclusions can be drawn.
• Meta-analysis: Brzezinski et al. conducted a meta-analysis of randomized, double-blinded trials of varying design to assess the effects of exogenous melatonin on sleep (535). A total of 17 studies were included (445;​447;​473;​475;​478;​483;​523;​525;​526;​530;​532;​533;​538;​1113;​1114;​1115;​1116). Subjects included varied widely, representing insomniacs (naturally occurring and artificially induced), schizophrenics, Alzheimer's disease patients, and healthy volunteers. Age and sex distributions also varied from study to study. Authors reported that dosages ranged from 0.3 to 80mg of melatonin delivered orally. One study administered melatonin intravenously (50mg). The therapy schedule also varied from study to study, ranging from multiple times over one experimental session to one treatment daily for up to two months. Included studies employed only adult subjects. Allergies, adverse and toxic effects, and interactions were not discussed. Dropouts were also not discussed. Outcome measures included sleep onset latency, total sleep duration, and sleep efficiency. Analysis revealed that melatonin treatment significantly reduced sleep onset latency by 4.0 minutes (95% CI, 2.5-5.4), increased sleep efficiency by 2.2% (95% CI, 0.2-4.2), and increased total sleep duration by 12.8 minutes (95% CI, 2.9-22.8). Since 15 of the 17 studies included enrolled healthy subjects or people with no relevant medical condition other than insomnia, the analysis was also done including only these 15 studies. The sleep onset results were changed to 3.9 minutes (95% CI, 2.5-5.4), sleep efficiency increased to 3.1% (95% CI, 0.7-5.5), and sleep duration increased by 13.7 minutes (95% CI, 3.1-24.3). This study suggests a small but statistically significant increase in sleep onset latency, sleep efficiency, and total sleep duration in response to melatonin treatment as measured via meta-analysis of a number of studies of varying design; however, the disparate nature of the included research makes pooling of data and objective comparison of results somewhat difficult.
• Systematic review: Morera et al. conducted a review to evaluate whether melatonin may be considered as an alternative for the treatment of insomnia (1117). A computerized search spanning a 33-year period was performed, and 93 articles were collected. "Melatonin," "pineal gland," and "insomnia" were used as key words. Of the 93 articles collected, 85 were excluded because they were reviews or were not directly related to the research topic. A total of 111 insomniac patients were treated with melatonin in eight articles. 60% of the patients reported an improvement in sleep quality. Objective sleep measures also improved; there was a decrease in the sleep latency time and the number of awakenings (62% and 50% of patients, respectively) after melatonin treatment.
• Evidence: Tzischinsky and Lavie conducted a crossover, placebo controlled, double-blind trial of eight men in a 7/13 ultrashort sleep-wake paradigm (following an overnight sleep deprivation) to assess the efficacy of melatonin on inducing sleep (537). All subjects were men, with an average age of 27.06 ± 3.7 years. Subjects were administered the Technion Sleep questionnaire and the Horne and Ostberg questionnaire prior to experimentation to exclude sleep disturbances and/or extreme morning or evening types. During the sessions, subjects were administered a pill at four different times (noon, 5 p.m., 7 p.m., and 9 p.m.). In four of the sessions, three of the pills were placebo and one contained 5mg of melatonin. Melatonin administration was varied according to a Latin square design. During a fifth session, all pills administered were placebo. Four of the subjects received the all-placebo trial during the first experimental session, while the other four received it in the last. Outcome measures included polysomnographic recordings (EEG), oral temperature, and subjective reports of sleepiness. Subjects receiving melatonin at noon, 5 p.m., 7 p.m., and 9 p.m. experienced significant effects of treatment (p<0.1, p<0.003, p<0.0001, p<0.004, respectively), trial (p<0.0001, p<0.008, p<0.0001, p<0.0001, respectively), and a significant interaction trial x treatment (p<0.03, p<0.01, p<0.0001, p<0.001, respectively). Wilcoxon tests revealed significant drops in oral temperature following administration of melatonin at all times except 9 p.m. This study suggests an increase in sleep propensity in subjects ingesting melatonin prior to the desired rest period; however, it is somewhat limited by the homogeneity of the population used (adult males of a narrow age range).
• Wyatt et al. conducted a randomized, double-blind, placebo controlled, parallel-group design trial to investigate the effects of melatonin on sleep latency and sleep efficiency in sleep episodes initiated across a full range of circadian phases (531). Subjects (N=26) were healthy young adults aged 18-30 (male, N=15; female, N=11). Treatment consisted of pharmaceutical-grade melatonin obtained from Regis Technologies (Morton Grove, IL); dose was either 0.3 or 5mg delivered orally and administered 30 minutes prior to each 6.67-hour sleep episode during forced desynchrony from endogenous circadian rhythm. All subjects received placebo capsules during the first and last three days of the protocol. Outcome measures included polysomnographic recordings (EEG), sleep time and latency, core body temperature, and stage-distribution of sleep. Analysis revealed both doses of melatonin improved polysomnographically determined sleep efficiency from 77% in the placebo group (0.3mg=84%, 5.0mg=83%; all p<0.05) for sleep episodes occurring during circadian phases when endogenous melatonin was absent (EM-). However, this remained below the average sleep efficiency of 88% observed during sleep episodes scheduled during the circadian night, when endogenous melatonin was present (EM+). Comparisons within the three drug groups showed that all had statistically significant, lower sleep efficiency during EM- vs. EM+ (all p<0.05). Melatonin did not affect sleep initiation, core body temperature, or relative stage-distribution of sleep in a statistically significant manner. This study reported an increase in sleep efficiency in response to melatonin treatment when administered outside of the increased endogenous melatonin phase of the body's natural circadian rhythm. Although no children or elderly were included, this study was thorough and well characterized.
• Kunz et al. conducted two randomized, double-blind, placebo controlled trials to determine the effects of exogenous melatonin on disturbed REM sleep in healthy adults (527). The patients included in the study had contacted the interdisciplinary sleep clinic voluntarily and were seeking treatment for neuropsychiatric sleep-related disturbances (International Classification of Sleep Disorders criteria). Polysomnography (PSG) was performed in relevant subjects. Patients were included in the study if they were found to have a quantitative reduction in REM sleep duration 25% or more below their age norm. Exclusion criteria included age less than 18 or more than 80, pregnancy, current or recent shift work (during the last year), poor sleep hygiene (sleep log or actigraphic proof of a more than two-hour variation in bedtime during a 14-day recruitment period), definite morning or evening types (regular bedtime outside 10-12 p.m.), transmeridian travel (during or within one month of the study), psychiatric disorders (except mood disorders in remission, Diagnostic and Statistical Manual of Mental Disorders-IV), pathological findings in brain imaging, recent changes in medication (within one month of the study), and the intake of any medication that might interfere with melatonin production or secretion or REM sleep. Sixteen subjects were included, but two were excluded from analysis due to compliance issues. In study 1, subjects were assigned to be treated with melatonin 3mg daily for four weeks. After a 3-5-day washout period, patients treated with melatonin received placebo in study 2, and patients treated with placebo in study 1 received melatonin in study 2 for four weeks. Melatonin was found to be more effective than placebo in terms of significant increases in REM sleep percentage (baseline/melatonin, 14.7/17.8 vs. baseline/placebo, 14.3/12.0, p<0.010) and improvements in subjective measures of daytime dysfunction, as well as clinical global impression score. Melatonin did not shift circadian phase or suppress temperature but did increase REM sleep continuity and promote decline in rectal temperature during sleep. Dropouts were not described. Otherwise, the study was well designed.
• Paul et al. conducted a double-blind, placebo controlled, crossover study to compare the sleep-inducing power of four medications (zopiclone, zaleplon, melatonin, and temazepam) (493). Nine men and 14 women, aged 21-53 years, were assessed for psychomotor performance before and for seven hours after ingestion of a single dose of placebo, zaleplon 10mg, zopiclone 7.5mg, temazepam 15mg, or time-released melatonin 6mg. Subjects wore polysomnographic electrodes to record total sleep and sleep latency during four-minute periods with eyes closed immediately before and after each psychomotor test sequence. Subjective drowsiness was assessed by questionnaire. There were drug x trial interactions for zaleplon, zopiclone, and temazepam for total sleep, sleep latency, and subjective drowsiness. More sleep, shorter sleep latency, and more drowsiness occurred immediately after psychomotor testing compared to before testing for all medications. Melatonin did not cause any sleep prior to psychomotor testing sessions, but caused sleep and reduced sleep latency after psychomotor test sessions from 1.75 hours to 4.75 hours postingestion. The authors reported the sleep-inducing power of the medications before psychomotor testing as zopiclone > zaleplon > melatonin > temazepam. The corresponding effect after psychomotor testing was reported to be zopiclone > melatonin > zaleplon > temazepam.
• Pinto et al. conducted a placebo controlled, double-blind trial of 40 young adult males using two different criteria for sleep onset (10 minutes of uninterrupted sleep and first three epochs of uninterrupted stage 1 sleep) to assess the effect of melatonin on inducing the onset of sleep (539). All subjects were men, with an average age of 28 ± 5 years. Subjects were administered 10mg of melatonin or a placebo every day for 28 days one hour prior to sleep (10 p.m.). Outcome measures included polysomnographic recordings (EEG, EOG in both eyes, and EMG in both legs). Analysis revealed a statistically significant decrease in sleep latency (p<0.05) using one criterion (10 minutes of uninterrupted sleep). The study is also somewhat limited by the homogeneity of the population used (adult males of a narrow age range).
• Almeida Montes et al. conducted a randomized, double-blind, placebo controlled, crossover trial to assess the efficacy and safety of melatonin in 10 patients with primary insomnia (522). Patients with circadian rhythm sleep disorders were excluded, as were various diseases and medications (four-week washout was acceptable). Patients (mean age: 50 years, range: 30-72 years) met the DSM-IV criteria for primary insomnia. Patients were administered 0.3mg of melatonin, 1mg of melatonin, or placebo 60 minutes before bedtime. Each patient received each of the three treatments for a seven-day period (with a five-day washout period in between) by crossover method. After each seven-day treatment, nighttime electroencephalographic (EEG) records were collected. Each morning, subjects completed sleep logs and analog-visual scales to document the amount and subjective quality of sleep. There were no differences noted between placebo and the two doses of melatonin in sleep EEG or subjective measures of sleep (time, quality, or latency, REM sleep). There were no differences in adverse effects between groups. Randomization and dropouts were not described.
• Cajochen et al. conducted a randomized, placebo controlled, double-blind crossover trial of eight healthy young men to assess the effect of melatonin on subjective and objective measures of sleepiness (536). Eight male students (average age in experiment 1: 27 ± 4 years old; in experiment 2: 24.8 ± 3.5 years old) were paid to participate in the study. The study comprised two separate experiments during which melatonin was administered at 6 p.m. or 1 p.m. Each subject participated in two consecutive treatment periods made up of one day with placebo and one day of treatment with melatonin, in randomized order. Volunteers reported to the chronobiology laboratory at 3 p.m. (exp. 1) or 9 a.m. (exp. 2) each day for the eight-hour experimental period. Subjects remained awake throughout experimentation. Toxic or interaction effects were not discussed. Dropouts were also not specifically addressed; however, data were reported for all eight subjects in both experiments. Outcome measures included half-hourly self-ratings of fatigue and mood obtained on 100mm visual analogue scales (VAS), as well as subject-completed Åkerstedt Sleepiness Symptoms Check Lists (ASSC) and Åkerstedt Sleepiness Scales (ASS). Furthermore, EEG, EOG, EMG, and ECG recordings were also made. Saliva was collected in parallel for analysis of melatonin. Analysis revealed a significant increase in subjective sleepiness as rated on the VAS, ASSC, and ASS in experiment 1. The ANOVAs for all three scales separately revealed a significant interaction term "treatment x time" (VAS, p<0.02; ASSC, p<0.04; ASS, p<0.001). Following treatment, self-rated sleepiness on the ASS remained higher than after placebo from 7:30 p.m. for the remainder of the evening (p<0.05). In experiment 2, melatonin administration increased subjective sleepiness as rated on the ASS (p<0.05) but not on the other two scales (VAS and ASSC). Statistical analysis of EEG data showed that the theta/alpha-band (5.25-9Hz) was significantly higher following melatonin treatment compared to placebo (p<0.05). Further analysis of the temporal relationship between melatonin concentrations, subjective sleepiness, and theta/alpha-activity in the waking EEG revealed both subjective sleepiness and EEG power center points significantly different from the melatonin center point (p<0.002). In addition, the subjective sleepiness center point occurred 23.4 minutes later than the EEG power center point (p<0.002). Testing of the relationship between melatonin levels and the amount of increase in subjective and objective fatigue as measure in the waking EEG showed no statistically significant correlations between subjective fatigue and the area under the melatonin curve (AUC), but statistically significant, negative correlations between the center point of subjective sleepiness and melatonin AUC (p<0.05). The authors concluded that this study presented evidence that daytime administration of melatonin had an acute and strong effect on subjective and objective measures of sleepiness, though these findings are somewhat limited by the homogeneity of the subject population.
• Satomura et al. conducted a randomized, single-blind, placebo controlled, equivalence trial to assess the presence or absence of hypnotic action by administering exogenous melatonin during the day when secreted levels of melatonin are low, compared to triazolam (529). Seven male college students were included in the study. Hypnotic action, effects on rectal temperature, and dose dependency by daytime administration were assessed. Melatonin (1mg, 3mg, 6mg), triazolam 0.125mg, or placebo (lactose) was administered at 1:30 p.m.; however, the duration and frequency were not described. Exogenous melatonin (1mg, 3mg, and 6mg) significantly increased total sleep time and sleep efficiency compared to placebo (p<0.05). Melatonin 6mg was observed to demonstrate hypnotic effects that were nearly equal to those of triazolam at 0.125mg. Rectal temperature was decreased at melatonin 1mg and 3mg; however, the hypothermic action of triazolam and melatonin 6mg were not observed to be different in a statistically significant manner. Dropouts, randomization, and blinding were not described.
• Ellis et al. conducted a randomized, double-blind, placebo controlled trial to evaluate the hypnotic action of melatonin in 15 subjects with psychophysiological insomnia (524). Inclusion and exclusion criteria were not clearly provided. Melatonin 5mg or placebo was taken at 8 p.m. for a one-week period. Endpoints included the effects on sleep and wakefulness (visual analog scale and interview). Melatonin had no effect on bedtime, sleep onset time, estimated total sleep and wake time, estimates of next-day function, or self-rated sleep quality. The period of melatonin treatment was retrospectively correctly identified by eight of 15 subjects. Seven of 15 subjects reported that sleep had subjectively improved with active treatment. Possible adverse effects to melatonin included mild headache, poor sleep quality, odd taste in mouth, and "muzziness." Limitations include the lack of description of randomization, blinding, and withdrawals.
• Nave et al. conducted a placebo controlled, double-blind trial of 12 young adults to assess the combined effect of melatonin of two different dosages and presleep dosage intervals on the onset and length of sleep of an early-evening nap (528). Subjects were all students, with an average age of 24.6 ±2.7 years, following more or less the same daily schedule. None had used drugs or medications for at least three months prior to the start of the study. Patients were given one of the following treatments: placebo and placebo, placebo and 3mg of melatonin (or in the reverse order), placebo and 6mg of melatonin (or in the reverse order). There was to be no daytime sleep during the study. Outcome measures included polysomnographic recordings, sleep time and latency, and questionnaires probing subjective sleep experience. All subjects completed the study. Analysis revealed a decrease in sleep latency (p<0.0054) and an increase in sleep time (p<0.0001) in all drug conditions. Additionally, all conditions exhibited an increase in stage 2 sleep time (p<0.0054). The authors neglected to discuss their particular methodology for polysomnographic recording and how they determined sleep time and onset latency from these recordings. Adverse effects were not discussed. Randomization was not discussed.
• MacFarlane et al. conducted a conducted a double-blind, placebo controlled, crossover study to evaluate the effects of melatonin on total sleep time and daytime alertness in 13 patients with chronic insomnia (534). Patients were otherwise healthy and free of neuroactive medications for at least four weeks. Patients were also prescreened by polysomnogram and subjective ratings of sleep quality and daytime alertness for one week. Patients were administered melatonin 75mg per night or placebo at 10 p.m. daily for 14 consecutive days. The dose was based on a preliminary dosing study in two patients in which 100mg was associated with headaches. An increase in the subjective assessment of total sleep time and daytime alertness (p<0.05) was demonstrated with melatonin but not with placebo. However, seven of the 13 patients reported that the active treatment had no effect on subjective feelings of well-being. This study is limited by the lack of randomization and inadequate description of blinding and withdrawals.

Age-related macular degeneration

• Summary: Melatonin may exert antioxidant effects, which may contribute to its beneficial effects on the eyes. According to clinical research, melatonin may play a role in protecting the retina to delay macular degeneration. Well-designed clinical trials are needed before a conclusion can be made.
• Studies of lesser design quality (not included in the Evidence Table): Yi et al. conducted a case control study to evaluate the effects of melatonin in age-related macular degeneration (420). Subjects with dry or wet forms of age-related macular degeneration were included. One hundred patients with age-related macular degeneration were given melatonin 3mg each night at bedtime for at least three months. Fifty-five patients were able to be followed for more than six months. Visual acuity was stable at six months of treatment. Eight eyes showed more retinal bleeding and six eyes more retinal exudates.

Aging (thermoregulation)

• Summary: Melatonin may be helpful in regulating age-dependent changes in body temperature rhythm. More well-designed trials are needed before a conclusion can be made.
• Evidence: Gubin et al. conducted a randomized controlled trial to examine the effects of melatonin in 97 patients involved in a larger study dedicated to the study and treatment of age-dependent changes or disturbances in the circadian system in humans (421). Those with mental disorders and alcohol abuse were excluded. Both genders were included. Patients were aged 63-91 years. Patients lived a self-chosen sleep-wake regimen. After one control week, part of the group (N=63) received 1.5mg of melatonin (Melaxen®) daily at 10:30 p.m. for two weeks. The other 34 subjects were given placebo. Younger subjects (58 young adults, both genders, 17-39 years of age) were used as controls. Endpoints included rhythm characteristics of body temperature. The MESOR (36.38 ± 0.19 degrees C vs. 36.17 ± 0.21 degrees C) and circadian amplitude (0.33 ± 0.01 degrees C vs. 0.26 ± 0.01 degrees C) were slightly decreased in the elderly compared to the young adult subjects (p<0.001) at baseline; however, the mean circadian acrophase was similar in both age groups (17.19 ± 1.66 vs. 16.93 ± 3.08 hours). Interindividual differences were higher in the older group (varying between 10 a.m. and 11 p.m.). With melatonin treatment, the MESOR was lower by 0.1 degrees C, and the amplitude increased to 0.34 ± 0.01 degrees C (similar to that found in young adults). There was no significant effect on the change in the mean acrophase. This study is limited by a lack of description of randomization, blinding, and withdrawals.

Anti-inflammatory

• Summary: Melatonin has been reported to decrease upregulation of proinflammatory cytokines (677). Other anti-inflammatory effects may be related to inhibition of nitric oxide (NO) and malondialdehyde (MDA) production, or increase of glutathione levels (678;​679). Use in inflammatory conditions has been proposed (959). Based on limited human research, melatonin may be an effective anti-inflammatory (47), decreasing concentrations of interleukin-6, interleukin-8, and tumor necrosis factor-alpha. However, there is conflicting evidence that melatonin may actually induce a proinflammatory response and may increase plasma kynurenine concentrations in certain populations (39). Further well-designed study is required.
• Evidence: Forrest, et al. conducted a randomized controlled trial to investigate the anti-inflammatory effect of melatonin in 75 patients with rheumatoid arthritis (39). Patients were allocated randomly to receive melatonin 10mg at night, in addition to ongoing medication, or placebo, for six months. Blood samples were drawn monthly for endpoints that included the following: disease severity by analysis of inflammatory indicators [C-reactive protein, erythrocyte sedimentation rate (ESR), neopterin], proinflammatory cytokines [interleukin (IL)-1beta, IL-6, tumor necrosis factor (TNF)-alpha], lipid peroxidation products, and the kynurenine pathway metabolites of tryptophan. The authors reported an increase of the erythrocyte sedimentation rate (ESR) (two-way ANOVA F(1,127)=5.24, p=0.024) and neopterin concentrations (F(1,136)=4.64, p=0.033) in patients treated with melatonin compared with controls. In the placebo group, peroxidation products showed a statistically significant decrease, but no decrease was noted in melatonin-treated patients. The authors reported that these results suggested a proinflammatory response. Although over time, concentrations of proinflammatory cytokines, IL-1beta, IL-6, and TNF-alpha were elevated in the melatonin group compared to placebo, in a majority of measurements taken at specific intervals, these findings were not shown to be statistically significant. The melatonin group also demonstrated increased plasma kynurenine concentrations (F(1,124)=4.24, p= 0.041), again suggesting proinflammatory activity. This finding was statistically significant. The authors concluded that a daily dose of 10mg of melatonin showed a slowly developing antioxidant profile in patients with arthritis and increased the concentrations of some inflammatory indicators, but these effects were not associated with changes in clinical symptoms. Dropouts and double-blinding procedures were unclear.
• Gitto et al. conducted a randomized controlled trial to determine if treatment with melatonin would influence proinflammatory cytokines (interleukin-6, interleukin-8, tumor necrosis factor-alpha), and nitrite/nitrate levels in 40 newborns with grade III or IV respiratory distress syndrome (47). Patients with radiographically confirmed respiratory distress syndrome, diagnosed within the first six hours of life, were included. Compared with the melatonin-treated respiratory distress syndrome newborns, in the untreated infants, the concentrations of interleukin-6, interleukin-8, and tumor necrosis factor-alpha were significantly higher at 24 hours, 72 hours, and seven days after the onset of treatment. In addition, the authors noted that nitrite/nitrate levels at all time points were higher in the untreated respiratory distress syndrome newborns than in the melatonin-treated babies. Following melatonin administration, nitrite/nitrate levels decreased significantly, whereas they remained high and increased further in the respiratory distress syndrome infants not given melatonin. Dropouts, blinding, and randomization procedures were unclear.

Benzodiazepine tapering

• Summary: A small amount of research has examined the use of melatonin to assist with tapering or cessation of benzodiazepines such as diazepam (Valium®) or lorazepam (Ativan®). Nonrandomized clinical trials have also been conducted (424) and, overall, the results agree with those observed in the randomized controlled trials. Although preliminary results are promising, due to weaknesses in the design and reporting of this research, further research is necessary before a firm conclusion can be reached.
• Evidence: Garfinkel et al. conducted a randomized, double-blind crossover trial to investigate the efficacy of melatonin replacement therapy in improving sleep in 21 elderly subjects taking benzodiazepines for insomnia (425). Inclusion and exclusion criteria were not specifically provided. Subjects were treated for three weeks with 2mg per night of controlled-release melatonin (Circadin®; Neurim Pharmaceuticals Ltd., Tel Aviv, Israel) and for three weeks with placebo, two hours before desired bedtime, with a one-week washout period between treatment periods. Subjects' sleep was assessed by wrist actigraphy. All subjects completed the study. No adverse effects were reported by the subjects. Melatonin treatment significantly increased sleep efficiency and total sleep time and decreased wake after sleep onset, sleep latency, number of awakenings, and fragmental index, compared to placebo (p<0.05). This study is limited by the lack of description of randomization.
• Cardinali et al. conducted a randomized, double-blind, placebo controlled study to assess whether melatonin (3mg in fast-release form) could be useful to reduce benzodiazepine dosage in 45 older patients with minor sleep disturbances (423). Patients with organic or psychiatric disorders, past neurological disorders, past abuse of drugs or alcohol, or heavy smoking habits were excluded. The patients (36 females, 70.5 ± 13.1 years old) regularly taking anxiolytic benzodiazepines in low doses received 3mg of melatonin (Melatol®, Elisium S.A., Buenos Aires, Argentina) or placebo 30 minutes before anticipated sleep time for six weeks. Overall quality of morning freshness, daily alertness, sleep quality, and sleep onset and offset time were assessed from structured clinical interviews and from logs completed by the patients. The possible correlation of urinary excretion of 6-sulphatoxymelatonin (aMT6s) before starting treatment and outcome of treatment was also examined. On day 14 of treatment, the benzodiazepine dose was reduced by half and on day 28, it was halted. Twenty-one patients were excluded from the analysis for incomplete compliance. There was a general lack of changes in quality of wakefulness or sleep in patients taking melatonin or placebo vs. baseline. During the first two weeks, sleep quality of patients taking melatonin was lower than that of placebo. Melatonin advanced sleep onset by 27.9 ± 11.9 minutes and decreased the variability of sleep onset time (p=0.03). The urinary concentration of aMT6s prior to the study did not correlate with any parameter examined. This study is limited by the lack of description of randomization and blinding.
• Garfinkel et al. conducted a randomized, double-blind, placebo controlled trial to assess whether the administration of melatonin could facilitate the discontinuation of benzodiazepine therapy in 34 patients with insomnia (426). Patients had expressed willingness to discontinue therapy and were considered healthy. Patients received melatonin (2mg in a controlled-release formulation; Circadin®; Neurim Pharmaceuticals Ltd., Tel Aviv, Israel) or a placebo nightly for six weeks (period 1). Patients were encouraged to reduce their benzodiazepine dosage 50% during week 2 and 75% during weeks 3 and 4, and to discontinue benzodiazepine therapy completely during weeks 5 and 6. In period 2, melatonin was administered (single-blinded) for six weeks to all subjects, and attempts to discontinue benzodiazepine therapy were resumed. Benzodiazepine consumption and subjective sleep-quality scores were reported daily by all patients. All subjects were then allowed to continue melatonin therapy, and follow-up reassessments were performed six months later. Adverse effects were similar between groups. By the end of period 1, 14 of 18 subjects who had received melatonin therapy, and four of 16 in the placebo group, discontinued benzodiazepine therapy (p=0.006). Sleep-quality scores were higher in the melatonin therapy group (p=0.04). All patients finished the first phase of the study, and 30 agreed to take part in the second phase. Six additional subjects in the placebo group discontinued benzodiazepine therapy when given melatonin in period 2. The six-month follow-up assessments revealed that of the 24 patients who discontinued benzodiazepine and received melatonin therapy, 19 maintained good sleep quality. This study is limited by lack of description of randomization and withdrawals.
• Peles et al. conducted a randomized, double-blind crossover trial to evaluate the effectiveness of melatonin in attenuating sleep difficulties during benzodiazepine (BDZ) withdrawal in 80 patients (427). All patients who were admitted to the clinic between July 1993 and July 2004 were eligible for inclusion. Patients received melatonin (5mg daily) or placebo with the following schedule: six weeks in one arm, a one-week washout, six weeks in other arm. Outcome measures included urine BDZ, self-reported Pittsburgh Sleep Quality Index (PSQI), and the Center for Epidemiologic Studies Depression (CES-D) questionnaires administered at baseline, and at six, seven, and 13 weeks. Adverse effects were not discussed. PSQI scores were significantly lower (indicating better sleep quality) in the 22 patients who discontinued BDZ (8.9 ± 0.9) than in 39 with urine BDZ (11.2 ± 0.7, p=0.04). Sleep quality in patients who continued abusing BDZ improved slightly but significantly more in the "melatonin first" group than in the "placebo first" group, with no differences in sleep quality improvement in patients who stopped BDZ. There were no group differences in phase 2 of the study. Melatonin had no effect on BDZ withdrawal. Limitations include lack of description of randomization and blinding. Reasons for withdrawals were not discussed.
• Vissers et al. conducted a placebo controlled trial to examine whether administration of melatonin facilitates discontinuation of benzodiazepine (BD) therapy in patients with insomnia (428). Long-term users of benzodiazepines were asked by their general practitioner (GP) to participate in a discontinuation program in combination with melatonin or placebo. The intervention and follow-up period lasted one year. During this period participants received four questionnaires about their use of sleeping medication and several health instruments. The urine of all participants was tested for the presence of benzodiazepines, as proof of the discontinuation. The main outcome measures were discontinuation of benzodiazepine use, measured by questionnaires and urine samples at three assessment points. A total of 503 long-term users were selected by the GPs, of whom 38 patients (16 males and 22 females) participated. After one year, 40% had stopped their benzodiazepine use, both in the intervention group on melatonin and in the placebo control group. Comparing stoppers and nonstoppers did not reveal differences in benzodiazepine use, or awareness of problematic use. The authors concluded that these results did not conclusively indicate that melatonin was helpful for the discontinuation of the use of benzodiazepines, but the average dose of benzodiazepines in the group was low. This study is limited by the lack of randomization and double-blinding.

Cancer treatment

• Summary: There are several early-phase and controlled human trials of melatonin in patients with various advanced stage malignancies, including brain, breast, colorectal, gastric, liver, lung, pancreatic, and testicular cancers, as well as lymphoma, melanoma, renal cell carcinoma, and soft-tissue sarcomas. Many of these studies have been conducted by the same research group. Melatonin has been used in combination with somatostatin, retinoids, other pineal hormones, and vitamin D (434;​621;​683;​702;​1118), in addition to other types of treatment, including radiation therapy (430;​694), chemotherapies (such as cisplatin, etoposide, or irinotecan) (344;​431;​433;​435;​436;​697;​700;​707;​708;​709;​710;​710;​711), hormonal treatments (such as tamoxifen) (628;​629;​630), or immune therapies, such as interferon (714), interleukin-2 (429;​691;​715;​716;​717;​718;​719;​720;​721;​722;​723;​724;​725;​726;​727;​728;​729;​730;​731;​732), or tumor necrosis factor (730;​733;​734). Most of these trials have been published by the same research group and have involved giving melatonin orally, intravenously, or injected into muscle. Results have been mixed, with some patients stabilizing and others progressing. Animal studies with melatonin note reduced severity of heart damage from anthracycline drugs (223;​224;​225;​1119;​1120) or lung damage from bleomycin (291;​1121). There are some promising reported results, including small significant improvements in the survival of patients with non-small-cell lung cancer given oral melatonin with chemotherapy (cisplatin and etoposide). A review of the use of antioxidant supplements during breast cancer treatment noted a possible enhancement of tumor response associated with melatonin; however, the included trials were described as underpowered (1122). Furthermore, it has been suggested that the use of antioxidants, such as melatonin, may mitigate some of the side effects of chemotherapy, although research remains scant (133). Despite these findings, as well as those from an array of basic, nonclincal studies, which have indicated a possible role of melatonin in the prevention or suppression of cancer (59;​914;​915;​916;​917;​918;​920;​921;​926;​928;​1123;​1124;​1125;​1126;​1127), the evidence remains insufficient to recommend the use of melatonin in cancer patients. High-quality follow-up trials are necessary to confirm these preliminary results.
• Systematic reviews: Block et al. conducted a systematic review to examine the literature in order to compile results from randomized trials that evaluate concurrent use of antioxidants with chemotherapy (681). MEDLINE, Cochrane, CINAHL, AMED, AltHealthWatch, and Embase databases were searched. Only randomized, controlled clinical trials that reported survival or tumor response were included in the final tally. The literature searches were performed in duplicate following a standardized protocol. Of 845 articles considered, 19 trials met the inclusion criteria. Antioxidants evaluated were glutathione (7), melatonin (4), vitamin A (2), an antioxidant mixture (2), vitamin C (1), N-acetylcysteine (1), vitamin E (1), and ellagic acid (1). Subjects of most studies had advanced or relapsed disease. The authors concluded that none of the trials reported evidence of significant decreases in efficacy from antioxidant supplementation during chemotherapy. Many of the studies indicated that antioxidant supplementation resulted in either increased survival times, increased tumor responses, or both, as well as fewer toxicities than controls; however, lack of adequate statistical power was a consistent limitation. Large, well-designed studies of antioxidant supplementation concurrent with chemotherapy are warranted.
• Ernst et al. conducted a systematic review to evaluate and critically analyze all randomized clinical trials (RCTs) of "'alternative cancer cures" (ACCs) for breast cancer (1128). The electronic databases Cochrane Central Register of Controlled Trials, MEDLINE, Embase, Allied and Complementary Medicine, Scirus, BIOSIS, CancerLit, and CINAHL were searched; for ongoing trials, the MetaRegister at http://www.controlled-trials.com/ and the National Research Register at http://www.update-software.com/national/ were searched from their inception. Bibliographies of located studies were scanned. Unpublished or ongoing trials were identified through correspondence with experts in the field. The authors' personal files were hand-searched for further RCTs. Review methods included a systematic review of RCTs involving breast cancer patients treated with ACCs, survival, parameters indicative of tumor burden, disease progression, cancer recurrence, and cancer cure. Thirteen RCTs met the inclusion criteria. In most cases, their methodological quality was low, with only two RCTs scoring 4 and four RCTs scoring 3 out of 5 possible points for methodological quality. The treatments tested included various methods of psychosocial support, such as group support therapy, cognitive behavioral therapy cognitive existential group therapy, a combination of muscle relaxation training and guided imagery, the Chinese herbal remedy Shi Quan Da Bu Tang, thymus extract, transfer factor, melatonin, and factor AF2. For melatonin, results were encouraging but not fully convincing. Further study is required.
• Mills et al. conducted a systematic review to examine the effects of melatonin in solid tumor cancer patients and its effect on survival at one year (704). Ten electronic databases from inception to October 2004 (unspecified) were covered. Trials using melatonin as either sole treatment or as adjunct treatment were included. Prespecified criteria guided our assessment of trial quality. A meta-analysis using a random effects model was conducted. Ten RCTs published between 1992 and 2003 with a total of 643 patients were included. All trials included solid tumor cancers. All trials were conducted at the same hospital network and were unblinded. Melatonin reduced the risk of death at one year (relative risk: 0.66, 95% CI, 0.59-0.73, I2=0%, heterogeneity p≤0.56). Effects were consistent across melatonin dose and type of cancer. No severe adverse events were reported. The authors concluded that the reduction in risk of death, low adverse events reported, and low costs related to this intervention suggest great potential for melatonin in treating cancer.

Chronic fatigue syndrome

• Summary: Nonrandomized clinical trials have been conducted to examine the effects of melatonin on chronic fatigue syndrome with possible benefits (437). More well-designed trials are needed before a conclusion can be made.

Circadian rhythm entraining (in blind persons)

• Summary: In blind individuals, light and dark stimuli are not received by the eye to trigger melatonin release and the onset of sleep. In these patients, natural melatonin levels peak at a different hour every night to the point where individuals may sleep during the day and awake at night. This is commonly referred to as "free-running" circadian rhythm. There are multiple published small case series and case reports in the literature, yet limited controlled trials in this population (625;​1129;​1130;​1131;​1132;​1133;​1134;​1135;​1136;​1137;​1138;​1139;​1140;​1141;​1142) to date. At present, studies and individual cases suggest that melatonin, administered in the evening, may correct circadian rhythm. Large, well-designed controlled trials are needed before a conclusion can be made.
• Evidence: Fischer et al. conducted a double-blind crossover trial to examine whether a single administration of melatonin improves sleep and associated neuroendocrine patterns in 12 blind individuals (438). All subjects were totally blind and were in good health, based on a physical examination. The patients were not on any medications. All reported insomnia and daytime sleepiness. Twelve totally blind subjects received 5mg of melatonin and placebo orally one hour before bedtime starting at 11 p.m. Adverse effects were not discussed. Endpoints included sleep quality, including time and efficiency, as well as levels of plasma hormones involved in sleep. Melatonin increased total sleep time and sleep efficiency (p<0.05) and reduced time awake (p<0.05). The increment in total sleep time was primarily due to an increase in stage 2 sleep (p<0.01) and a slight increase in rapid eye movement sleep (p<0.06). Melatonin normalized in parallel the temporal pattern of adrenocorticotropic hormone (ACTH) and cortisol plasma concentration. Placebo had no effect on the difference in ACTH and cortisol levels between early and late sleep. However, melatonin induced the typical suppression of pituitary-adrenal activity during early sleep and induced a rise during late sleep (p<0.01, respectively). Melatonin also decreased cortisol nadir values (p<0.05). It was concluded that melatonin could improve sleep function in blind persons by synchronizing in time the inhibition of pituitary-adrenal activity with central nervous sleep processes. Limitations to this study include the lack of randomization and description of blinding and withdrawals.
• Hack et al. conducted a placebo controlled, single-blind trial to examine the entraining effects of melatonin on the cortisol rhythm and its acute effects on subjective sleep in 10 blind subjects (439). Subjects (nine adult males) had free-running 6-sulphatoxymelatonin (aMT6s) rhythms (circadian period [tau]: 24.23-24.95 hours). Inclusion and exclusion criteria were not provided. The subjects had no conscious light perception (NPL). Subjects received 0.5mg of melatonin or placebo daily at 9 p.m. (treatment duration: 26-81 days, depending on individuals' circadian period). Subjective sleep was assessed from daily sleep and nap diaries. Urinary cortisol and aMT6s were assessed for 24-48 hours weekly and measured by radioimmunoassay. While on melatonin, six of the 10 subjects had an entrained cortisol period. In four of these, the period was indistinguishable from 24 hours and in the other two subjects, the rhythm continued to free run for up to 25 days before entrainment. One subject exhibited a shortened cortisol period throughout melatonin treatment. Rhythms returned to prestudy levels after melatonin was ceased. Melatonin resulted in a significant increase in nighttime sleep duration and a significant reduction in the number and duration of daytime naps (p<0.001). The authors suggested that a daily dose of 0.5mg of melatonin was effective at entraining the free-running circadian systems in most of the blind subjects studied. This study is limited by the lack of randomization and double-blinding.

Cognitive disorders

• Summary: Limited research has been conducted to examine the effects of melatonin on cognitive disorders. Some randomized controlled trials suggest a possible benefit. Nonrandomized clinical trials have also been conducted (440;​441) and, overall, results agree with those of the RCTs. More well-designed trials are needed before a conclusion can be made.
• Systematic review: Jansen et al. conducted a systematic review to assess the clinical efficacy and safety of melatonin in the treatment of manifestations of dementia or cognitive impairment (1143). The Cochrane Dementia and Cognitive Improvement Group's Specialized Register was searched on 5 October 2005 for trials involving melatonin. The search terms used were "melatonin" and "n-acetyl-5-methoxytryptamine." All relevant randomized controlled trials in which orally administered melatonin in any dosage was compared with a control group for the effect on managing cognitive, behavioral (excluding sleep), and/or affective disturbances of people with dementia of any degree of severity were included. Two or three reviewers independently assessed the retrieved articles for relevance and methodological quality and extracted data from the selected studies. Statistically significant differences in changes in outcomes from baseline to end of treatment between the melatonin and control groups were examined. Each study was summarized using a measure of effect (e.g., mean difference), and meta-analyses were conducted when appropriate. Three studies met the inclusion criteria (442;​444;​445). This review revealed statistically nonsignificant effects from the pooled estimates of MMSE cognitive and ADAS cognitive change scores. Individual study estimates for treatment effect demonstrated a statistically significant improvement for melatonin compared with placebo in behavioral and affective symptoms as measured by the ADAS noncognitive scale in a study of 20 patients, and the Neuropsychiatric Inventory (NPI) following treatment with 2.5mg of slow-release melatonin daily, but not with 10mg of immediate-release melatonin daily in a larger study of 157 patients. The remainder of the treatment effects for affect, behavior, and activities of daily living were statistically nonsignificant. Further research is required.
• Evidence: Peck et al. conducted a randomized, double-blind, placebo controlled trial to determine if exogenous melatonin would improve cognitive function in 30 healthy elderly subjects (443). Patients with psychiatric or cognitive problems were excluded, as were those with unstable medical problems or drug concerns. Subjects received melatonin 1mg or placebo each night for four weeks. Subjects completed a sleep questionnaire and a battery of cognitive tests at baseline and after four weeks. Results were included for 26 subjects, because of benzodiazepine use or findings of dementia. Significant improvements were noted in morning restedness in the melatonin group (p<0.04). Melatonin administration also improved scores on the California Verbal Learning Test (p<0.02). Randomization was not adequately described in this study.

Depression

• Summary: Melatonin has been suggested as playing a role in and serving as a possible treatment for depression (115;​1144), a hypothesis which has garnered some support in animal research (1145;​1146). However, human research remains scant and inconclusive. Further research is required.
• Evidence: Serfaty et al. conducted a randomized, double-blind, placebo controlled trial to determine if exogenous melatonin may act as a sleep promoter and antidepressant in 33 patients with major depressive disorder (MDD) (454). Patients aged 18-65 years were included in the trial if they were diagnosed with major depressive disorder (MDD) and experienced early-morning wakings. Patients were excluded if they had delusions, hallucinations, suicidal ideation, or a recent change in psychotropic medication within the last four weeks. The subjects were administered melatonin (6mg of slow-release at bedtime) or placebo for four weeks in addition to any pre-existing treatment for depression. Actigraphy, sleep diaries, and the Leeds Sleep Evaluation Questionnaire were used as measures of sleep quality. Two subjective questionnaires, the Beck Depression Inventory (BDI) and the 21-item Hamilton Depression Rating Scale (HDRS), were used to measure depression. Of the 33 participants, 31 completed the trial; two dropped out immediately because they felt better. Improvements were noted with time in terms of sleep diary data, HDRS scores, and LSEQ scores, but changes were not associated with melatonin use. BDI scores were not significantly different between melatonin and placebo (2.03, 95% CI, -6.30 to 2.25). Adverse effects were similar between the two groups. The study was conducted over a three-year, three-month period, with different patients undergoing the four-week randomization throughout this time. The trial stated that 17 people would be required in each group (for a total of 34) in order to power the trial adequately; however, this standard was not met. It should also be noted that participants were allowed to continue any current antidepressive medication, whose effects on these findings are difficult to quantify. This study was well conducted.

Diabetes (adjunct therapy)

• Summary: Melatonin in combination with zinc has been found to improve postprandial glycemic control in patients with type 2 diabetes (673;​674). However, in other research, melatonin supplementation was found to have no significant effect upon measures of glucose homeostasis (372). More well-designed trials, using melatonin as a monotherapy, are needed before a conclusion can be made.

Exercise performance

• Summary: One randomized controlled trial determined that daytime administration of melatonin had no effects on maximal jumping ability or on maximal strength (455). More well-designed trials are needed before a conclusion can be made.
• Evidence: Mero et al. conducted a randomized, double-blind trial to investigate the effects of a heavy resistance exercise session (RES) with the oral daytime ingestion of melatonin on the physiological responses and acute performance in 10 healthy males (455). The men were resistance trained and not using medication or sport supplement. Subjects undertook an 80-minute intensive hypertrophic RES for major muscles of the lower and upper extremities. The subjects were studied on two occasions, receiving melatonin (6mg) or placebo (6mg) in random order 60 minutes before each RES. Blood samples were taken from an antecubital vein, both in fasting conditions in the morning and before RES (60 minutes and 0 minutes before), during RES (middle) and after RES (0, 15, 30, and 60 minutes after). Maximal jumping ability and maximal strength in bench press and squat were measured before and immediately after RES. Melatonin had no effect on maximal jumping ability of strength. Serum melatonin concentration increased significantly (p<0.05-0.001) in the melatonin group at all time points. The concentration reached a peak value of 1,171.3 ± 235.2pg/mL in 60 minutes at pre 0. Serum melatonin also increased slightly but significantly (p<0.05) in the placebo group just before RES, in the middle of RES, and after RES (0 and 15 minutes after). There were large differences (p<0.01-0.001) in the serum melatonin concentration between the groups at all time points. There were no differences in the growth hormone (GH), testosterone, and cortisol peak concentrations at any time points between the groups, but the area under the curve of GH during RES (p<0.01) and 60 minutes after RES (p<0.05) was higher in the placebo condition. Adverse effects were not discussed. The authors concluded that oral ingestion of melatonin (6mg) during daytime with heavy-resistance exercise may slightly decrease GH concentrations; however, melatonin administration during daytime did not have any acute (1-2 hours) effects, either on the maximal jumping ability or on the maximal strength. This study is limited by the lack of description of randomization, blinding, and withdrawals.
• Atkinson et al. conducted a controlled trial of 12 subjects to examine the effects of melatonin on the subjective quality of sleep in athletes and residual effects on physical performance the morning after treatment (456). Exclusion and inclusion criteria were not specifically discussed; however, the subjects included were described as being healthy, physically active sports science undergraduates, ages 19-30 years. The subjects were given 5mg of melatonin or a placebo; a single dose of one capsule was taken at 11 p.m., 30 minutes before retiring. The authors did not specifically state the primary outcome, although subjective measure of sleep quality (maintenance and latency) is assumed. Secondary measures included objectively measured intra-aural temperature, left and right grip strength, and time taken to complete a 4km stationary bike ride. Secondary subjective measures include perceived exertion. ANOVA was used to analyze grip strength and cycle time data. There was little difference between the means of the placebo vs. melatonin groups in right [t11=-0.15(p=0.88)] or left [t11=0.35(p=0.74)] hand grip strength, or cycle times [t11=0.44(p=0.67)]. Sleep latency [W=25.5 (p=0.33)] and maintenance [W=12.5 (p=0.87)] showed no difference between the melatonin and placebo group median values (Wilcoxon tests, p>0.5). Limitations of this study include a lack of randomization, inclusion and exclusion criteria, and adequate description of the blinding process, as well as the short study duration and overall suboptimal study design. Standardization, allergies and adverse effects, toxic effects, dropouts, and interactions were not discussed.

Gastrointestinal disorders

• Summary: Preliminary research has indicated that, in patients with functional dyspepsia, treatment with melatonin may mitigate or eliminate symptoms (457), a finding possibly corroborated by observed reductions in oxidative damage to cells of the gastric lining (1147). Other research has shown that melatonin supplementation may also be effective as a treatment or adjuvant in gastroesophageal reflux disease (GERD) (462). It has also been suggested as a possible therapy for irritable bowel syndrome (1148), although findings have been mixed (458;​459;​460;​461). Further clinical trials are required before a conclusion can be made.
• Evidence: Lu et al. conducted a randomized, double-blind, placebo controlled, crossover clinical trial to evaluate the efficacy of exogenous melatonin on gut motility in both healthy subjects and those with irritable bowel syndrome (IBS) (461). Subjects were 17 healthy controls and 17 matched IBS patients (all female). Participants were included if they had active IBS symptoms (a minimum period of more than one month prior to the study and whose IBS symptom score indicated at least a moderate severity), normal hematological and biochemical indices, and no abnormalities on barium enema or colonoscopy. Subjects who were pregnant, breastfeeding, or lactose intolerant, or who had gastrointestinal, anal, hepatic, or other systemic disorders, such as diabetes mellitus or previous gastrointestinal surgery (except appendectomy), were excluded. Subjects were treated with 3mg of melatonin or placebo daily for 16 weeks (two eight-week treatment periods reversed following a four-week washout period). All participants were asked to avoid long-distance travel and any drugs known to change gastrointestinal function, during the study and for one month preceding, as well as to follow a normal diet. Colonic transit time (CTT) measurements including Radio-Opaque, Blue Dye, and Bristol Stool Form Score (BSFS) were used to evaluate outcome. A significant increase on mean CTT measured by the radio-opaque method (p=0.04), but not the Blue Dye (p=0.65) or BSFS (p=0.43), was observed in healthy controls compared to baseline CTT. No significant differences were observed in mean CTT, measured by either the Blue Dye or BSFS methods, in IBS patients after melatonin and placebo treatment. Although CTT measured by the Blue Dye method in IBS patients was not significant (p=0.08), it appeared to be prolonged after melatonin treatment. Within the IBS subgroup, constipation-predominant patients showed slower CTT than their respective normal controls (p=0.03 for the Blue Dye method and p=0.048 for the BSFS method) after melatonin treatment, but no significant differences were found in diarrhea-predominant patients. This study was well designed.
• Saha et al. conducted a randomized, placebo controlled trial to determine if melatonin was effective in improving bowel symptoms, extracolonic symptoms, and quality of life (QOL) in 18 irritable bowel syndrome (IBS) patients (460). Adult patients with IBS symptoms (Rome II criteria) for more than three months were included. Cerebral disease, previous history of gastrointestinal surgery, and other systemic disorders were excluded. Patients (aged 18-65 years; six females) were randomly assigned to receive melatonin 3mg (N=9) or matching placebo (N=9) at bed time for eight weeks. The overall IBS scores, extracolonic IBS scores, and QOL scores were assessed at two, four, six, and eight weeks during treatment and at 16, 24, and 48 weeks during follow-up. Compared with placebo, melatonin taken for eight weeks significantly improved overall IBS score (45% vs. 16.66%, p<0.05). The posttreatment overall extracolonic IBS score was significantly lower (49.16% to 13.88%, p<0.05) when compared with the placebo group. The overall improvement in QOL score was 43.63% in the melatonin group and 14.64% in the placebo group, which was statistically significant. Decreased libido was reported as an adverse event in the melatonin group. Drowsiness was reported in both groups. This study is limited by the lack of description of randomization and withdrawals.
• Lu et al. conducted a placebo controlled, crossover trial to examine the effects of melatonin on irritable bowel syndrome in 24 patients (459). The patients satisfied the Rome II criteria for IBS, with diagnosis at least one month prior to study. Patients with previously diagnosed organic gastrointestinal diseases such as inflammatory bowel disease, previous gastrointestinal surgery, and concurrent severe systemic diseases, including diabetes mellitus, were excluded. Patients received melatonin 3mg or an identically appearing placebo for eight weeks, followed by a four-week washout period, and placebo or melatonin in the reverse order for another eight weeks. Three validated questionnaires (GI symptoms, sleep questionnaires, and the Hospital Anxiety and Depression Scale) were used to assess symptom severity and to compute the IBS, sleep, and anxiety/depression scores, respectively. Results for 17 patients were included in the analysis; withdrawals were not due to adverse events. Improvements in mean IBS scores were significantly greater after treatment with melatonin (3.9 ± 2.6) than with placebo (1.3 ± 4.0, p=0.037). Percent response rate, defined as percentage of subjects achieving mild-to-excellent improvement in IBS symptoms, was also greater in the melatonin-treated arm (88% vs. 47%, p=0.04). The changes in mean sleep, anxiety, and depression scores were similar with either melatonin or placebo treatment. This study is limited by the method of randomization; patients were randomized by tossing a coin.
• Song et al. conducted a randomized, placebo controlled trial to examine the effects of melatonin on symptoms associated with IBS in 40 patients (458). Patients with a diagnosis of IBS (Rome II criteria) who suffered sleep difficulty (defined as experiencing difficulty getting to sleep, awakening during the night, and/or early-morning awakening), with a Pittsburgh sleep quality index score of greater than 5 and sleep disturbance occurring at least two nights per week in the preceding 12 weeks, were included. Patients were asked not to take any medications known to alter gastrointestinal function or sleep conditions within a month before and during the study. Medication history was recorded. Exclusions included pregnancy; breastfeeding; organic gastrointestinal, anal, hepatic, or other systemic disorders; previous gastrointestinal surgery history except appendectomy; or history of cerebral disease or surgery. The IBS patients (aged 20-64 years; 24 female) received melatonin 3mg (N=20) or placebo (N=20) at bedtime for two weeks. Immediately before and after the treatment, subjects completed bowel, sleep, and psychological questionnaires, and underwent rectal manometry and overnight polysomnography. Compared with placebo, melatonin taken for two weeks significantly decreased mean abdominal pain score (2.35 vs. 0.70; p<0.001) and increased mean rectal pain threshold (8.9 vs. -1.2mmHg; p<0.01). Bloating, stool type, stool frequency, and anxiety and depression scores did not differ in a statistically significant manner after treatment in both groups. Data from sleep questionnaires and polysomnography showed that the two-week course of melatonin did not influence sleep parameters. Randomization and withdrawals were not adequately described.
• Klupińska et al. conducted a placebo controlled trial to assess the potential protective action of melatonin in ulcer-like dyspepsia (457). Sixty patients, aged 19-39 years, with a diagnosis of functional dyspepsia according to the Rome Criteria II and no Helicobacter pylori infection, received melatonin at a dose of 5mg (N=30) or placebo (N=30) in the evening for a period of 12 weeks. At this time, patients were on an equivalent diet and were to take only an alkaline drug in the case of abdominal pain. After 12 weeks, the dyspeptic symptoms completely subsided in 17 patients in the melatonin-treatment group (56.6%). In nine other individuals (30.0%), a partial improvement in health was achieved, especially in the frequency and intensity of nocturnal pain. After placebo, the majority of patients (93.3%) did not experience any improvement in symptoms. Multivariate analyses indicated that melatonin (odds ratio: 95.86, 95% CI, 3.72-2,469.37, p<0.01) correlated independently with improvements in patients' health. H. pylori past infection decreased the positive effect of melatonin in ulcer-like dyspepsia.
• Kandil et al. conducted a nonblinded equivalence trial to determine the effects of melatonin treatment on gastroesophageal reflux disease (GERD) in 27 patients (462). Sixty patients were initially selected for the study. After undergoing tests, 27 subjects with GERD were selected and compared with nine healthy volunteers (age and sex matched) who served as controls. Subjects with duodenal or gastric ulcers or functional dyspepsia were excluded. Group I (control) did not receive any treatment. Group II received melatonin 3mg daily at bedtime. Group III received omeprazole 20mg twice daily. Group IV received melatonin 3mg daily at bedtime and omeprazole 20mg twice daily. All medications were administered for eight weeks, with results examined at weeks 4 and 8. The study assessed heartburn, epigastric pain, and lower esophageal sphincter (LES) pressure, residual pressure, relaxation percentage, pH, serum gastrin and mean melatonin level, relaxation duration, and basal acid output (BAO). Results showed a significant decrease in LES pressure, residual pressure, relaxation percentage, pH, serum gastrin and mean melatonin level, and a significant increase in relaxation duration and basal acid output (BAO) relative to the control group. Treatment with melatonin alone (Group II) for four and eight weeks elicited an improvement in GERD symptoms, such as heartburn and epigastric pain, as well significant changes in all other measured criteria (p<0.05). Treatment with omeprazole alone (group III) for four and eight weeks led to improvement of GERD symptoms. Significant changes in BAO and serum gastrin (p<0.05), as well as nonsignificant changes in other measured criteria, were also observed. Treatment with melatonin and omeprazole for four and eight weeks also showed improvement in GERD symptoms, as well as significant (p<0.05) changes in all other criteria. It should be noted that this study was not placebo controlled or blinded.

Glaucoma

• Summary: It has been theorized that due to effects on photoreceptor renewal in the eye, high doses of melatonin may increase intraocular pressure and the risk of glaucoma, age-related maculopathy, myopia (368), or retinal damage (358). 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 (389;​390). Additional study is necessary in this area. Patients with glaucoma taking melatonin should be monitored by a healthcare professional.

Headache (prevention)

• Summary: Melatonin has gained some notoriety as an alternative therapy for the prevention of headaches (1149). Several small studies have examined the possible role of melatonin in preventing various forms of headache, including migraine, primary stabbing headache, and cluster and tension-type headache (in people who suffer from regular headaches) (213;​463;​464;​1150;​1151;​1152;​1153;​1154;​1155;​1156). Limited initial research suggests possible benefits in these types of headache, although well-designed controlled studies are needed before a firm conclusion can be drawn.
• Evidence: Leone et al. conducted a randomized, double-blind, placebo controlled trial to examine the role of melatonin in cluster headaches in 20 patients (464). Patients with cluster headaches diagnosed using the International Headache Society criteria were included. Patients had to have had at least one cluster period, and all cluster periods had to have lasted at least one month. Exclusions included drug and alcohol abuse, liver or kidney disease, psychiatric disorders, and certain medications. During a cluster period, 20 cluster headache patients (two primary chronic, 18 episodic) received oral melatonin 10mg (N=10) or placebo (N=10) for 14 days, taken in a single evening dose. Endpoints included headache frequency and analgesic use. Headache frequency was reduced (ANOVA, p<0.03), and there were strong trends towards reduced analgesic consumption (ANOVA, p<0.06) in the treatment group. Five of the 10 treated patients were responders whose attack frequency declined 3-5 days after treatment, and they experienced no further attacks until melatonin was discontinued. The chronic cluster patients did not respond. No patient in the placebo group responded. There were no side effects in either group. Limitations include lack of description of randomization, blinding, and withdrawals.

High blood pressure (hypertension)

• Summary: Several controlled studies in patients with high blood pressure (BP) report small reductions in diastolic and systolic blood pressure when taking melatonin by mouth (orally) or inhaled through the nose (intranasally) (1157;​1158;​1159;​1160). Most trials have been small and not well designed or well reported. Better-designed research is necessary before a firm conclusion can be reached.
• Evidence: Grossman et al. conducted a randomized, double-blind trial to examine the efficacy of melatonin in reduction of nighttime blood pressure (BP) in 38 treated hypertensive patients with nocturnal hypertension (466). Treated hypertensive patients (22 males, mean age: 64 ± 11 years) with confirmed nocturnal hypertension (mean nighttime systolic BP >125mmHg), according to repeated 24-hour ambulatory blood pressure monitoring (ABPM), were included. There was a two-week placebo run-in period before randomization. Patients were randomized to receive controlled release (CR)-melatonin 2mg (Circadin®; Neurim Pharmaceuticals Ltd., Tel Aviv, Israel) or placebo two hours before bedtime for four weeks. A 24-hour ABPM was then performed. The main endpoint was nocturnal blood pressure. Melatonin treatment reduced nocturnal systolic BP from 136 ± 9 to 130 ± 10mmHg (p=0.011) and diastolic BP from 72 ± 11 to 69 ± 9mmHg (p=0.002), whereas placebo had no effect on nocturnal BP. There was no effect of melatonin on daytime blood pressure measurements. Following treatment or placebo, there was a two-week washout period. All subjects completed the study. There were no adverse effects. The reduction in nocturnal systolic BP was greater with melatonin than with placebo (p=0.01) and was most prominent between 2 a.m. and 5 a.m. (p=0.002). Limitations include the lack of description of randomization and blinding.
• Cagnacci et al. conducted a randomized, double-blind trial to determine whether prolonged nocturnal administration of melatonin could influence the daily rhythm of BP in 22 women (465). Patients were normotensive or had essential hypertension controlled by diuretics or angiotensin-converting enzyme (ACE) inhibitors, or both. Treatments were kept constant throughout the study. Women who were receiving beta-blockers or calcium antagonists were excluded from the study. The women (47-63 years of age and with normal BP (N=9) or treated essential hypertension (N=9)), received a three-week course of a slow-release melatonin pill (3mg) (Armonia Retard, Nathura s.r.l., Montecchio Emila RE, Italy) or placebo one hour before going to bed. They were then crossed over to the other treatment for another three weeks. In each woman, ambulatory BP was recorded for 41 hours at baseline at the end of each treatment period. In comparison with placebo, melatonin administration did not influence diurnal BP but did decrease nocturnal systolic (-3.77 ± 1.7mmHg, p=0.0423), diastolic (-3.63 ± 1.3mmHg, p=0.0153), and mean (-3.71 ± 1.3mmHg, p=0.013) BP without modifying heart rate. The effect was inversely related to the day-night difference in BP. Two women were excluded due to insufficient blood pressure readings, and two women did not complete the study (reasons not provided). It is unclear as to whether the placebo was identical to the melatonin; otherwise, the study was well designed.
• Rechciński et al. conducted a randomized controlled trial to assess the effects of melatonin before sleep in patients with coronary artery disease (CAD) and with an abnormal circadian pattern of blood pressure (BP) (470). Subjects were sixty patients with coronary artery disease (CAD), who were "nondippers" (having an abnormal circadian pattern of blood pressure on changes in circadian blood pressure profile and heart rate variability (HRV)) between the ages of 48 and 80 (75% male). Subjects received 5mg of melatonin or placebo daily for 90 days. In three patients, the mean arterial BP at nighttime decreased by more than 20% during melatonin treatment. Two dropouts were reported prior to the 30th day of study. All patients in this study were receiving beta-adrenolytics. A potential interaction between melatonin and calcium channel blockers was noted; however, the authors found this interaction to be insignificant (p>0.05). The outcome measures for this study were as follows: the individual mean systolic (SBP) and diastolic BP (DBP) during sleep, the so-called mean pressure at night (SBPnight, DBPnight), and during waking hours, the so-called mean pressure at daytime (SBPday, DBPday), as well as the mean circadian SBP and DBP (SBP24 and DBP24). Two American Board of Preventative Medicine (ABPM) examinations were conducted for each patient, the first one at baseline and the second one on the last day of the 90-day-long treatment. Pulse wave velocity (PWV) was measured by means of an automatic device for measuring carotid-femoral transit or propagation of the pulse pressure wave (the COMPLIOR system). Thirty five percent of patients treated with melatonin and 15% taking placebo experienced a change in the circadian profile of their arterial BP (considered to be the beneficial effect of melatonin treatment). The patients in the study group also experienced a 6.4% drop in mean systolic pressure. Also, after 90 days of treatment, those in the study group experienced a significant acceleration of mean 24-hour heart rate (p=0.018), increases in daily systolic and diastolic blood pressures (p=0.05, and p=0.012, respectively), a significant change in the day to night systolic blood pressure ratio (p<0.01), and a decrease in the nightly systolic blood pressure (p=0.049). While there was no significant difference between the responder and the nonresponder groups prior to treatment, after 90 days of melatonin treatment, patients in the responder group had a higher standard deviation of normal-to-normal intervals (SDNN), and the patients in the nonresponder group had a significant increase in their mean heart rate during 24 hours (p=0.06). Responders were defined as patients exhibiting a nocturnal decrease in averaged systolic pressure in comparison with daytime values >20% or a nocturnal increase in SBP. Limitations of the study included a small sample.
• Scheer et al. conducted a randomized, double-blind crossover trial to determine whether enhancement of the functioning of the biological clock by repeated nighttime melatonin intake might reduce ambulatory blood pressure in 16 men with essential hypertension (467). Patients had mild or moderate, uncomplicated, essential hypertension. The men were treated with an acute (single) and repeated (daily for three weeks) controlled-release oral melatonin (2.5mg; 100% dissolved in water in 60 minutes; Terafarm, Katwijk, the Netherlands) intake one hour before sleep. Endpoints included 24-hour ambulatory blood pressure and actigraphic estimates of sleep quality. Repeated melatonin intake significantly reduced systolic and diastolic blood pressure during sleep by 6 and 4mmHg, respectively (p<0.05). The treatment did not affect heart rate or blood pressure during the day. The day-night amplitudes of the rhythms in systolic and diastolic blood pressures were increased by 15% and 25%, respectively (approximate p=0.03). A single dose of melatonin had no effect on blood pressure. Repeated (but not acute) melatonin also improved sleep, but there was no relationship between changes in blood pressure and benefits on sleep. Adverse effects were not reported. This study is limited by the lack of description of randomization, blinding, and control.
• Cagnacci et al. conducted a randomized, double-blind, placebo controlled trial to examine melatonin-induced vascular reactivity and reductions in blood pressure and norepinephrine levels in 31 postmenopausal women (468). Women with high blood pressure, blood lipids, or blood sugar were excluded. The women were confirmed using hormone levels and history as being 1-4 years postmenopausal. Eighteen women were not receiving HRT, and 13 women were treated continuously with transdermal estradiol (50mcg daily) plus cyclic medroxyprogesterone acetate (5mg daily x 12 days every 28 days), oral melatonin (1mg), or placebo. Endpoints included internal carotid artery pulsatility index (PI), an index of downstream resistance to blood flow, blood pressure, and catecholamine levels. In the untreated postmenopausal women, melatonin had no effect on blood pressure. In the HRT-treated women, studied during the only estrogenic phase, melatonin reduced systolic (-8.1 ± 9.9mmHg; p=0.054), diastolic (-5.0 ± 7.0mmHg; p=0.049), and mean (-6.0 ± 6.6mmHg; p=0.037) blood pressure within 90 minutes. Norepinephrine (-50.1 ± 66.7pg/mL; p=0.019), but not epinephrine levels, were also reduced. Similarly, resistance to blood flow in the internal carotid artery, as evaluated by the PI, decreased (-0.190 ± 0.15; p=0.0006) in a way that was linearly related to pre-existing PI values (r2=0.5; p=0.0059). Adverse effects were not discussed. The authors concluded that the circulatory response to melatonin was conserved in postmenopausal women on HRT but not in untreated postmenopausal women. This study is limited by the lack of description of randomization, blinding, and withdrawals.
• Cagnacci et al. conducted a placebo controlled trial to examine the cardiovascular effects induced by the daytime administration of melatonin in 12 young women (469). The women were considered young and healthy and were all asked to take a fixed dose estrogen-progestin birth control pill to remove hormonal flux. Patients received melatonin (1mg) or placebo as a single dose. Endpoints included blood pressure and the pulsatility index of the internal carotid artery. Melatonin reduced the pulsatility index of the internal carotid artery (p<0.01), as well as both systolic and diastolic blood pressure (in supine position; p<0.01), within 90 minutes vs. placebo. Supine catecholamine levels were not significantly modified, but norepinephrine levels evaluated after five minutes of standing position were significantly reduced (p<0.02). This study is limited by the lack of description of blinding, randomization, and withdrawals. Also, the use of hormones may have affected melatonin's effect on blood pressure.

High cholesterol (diabetes-related complication, adjunct therapy)

• Summary: One clinical trial found that melatonin, when used with zinc and the diabetes drug metformin, may improve diabetes-related complications, such as impaired lipid profile (674). However, there is also preliminary evidence in human and animal research that melatonin increases cholesterol levels (403;​404;​405;​406). More research is needed to clarify these mixed results.

HIV/AIDS

• Summary: There is a lack of well-designed scientific evidence to recommend for or against the use of melatonin as a treatment for AIDS (1022). 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.

Insomnia (children)

• Summary: Several randomized clinical trials have shown benefits of melatonin in children with insomnia. Nonrandomized clinical trials have also been conducted (581;​1161), and, overall, the results agree with those of randomized controlled trials (RCTs). A review of the effects of melatonin on sleep-wake disorders in children and adolescents was published by Jan et al. in 1999 (1162). More well-designed studies are needed before a conclusion can be made.
• Evidence: Van der Heijden combined the data of two randomized controlled trials (N=110, ages 6-12 years) (350;​582) to investigate the efficacy of melatonin on pretreatment dim-light melatonin onset in children with chronic sleep onset insomnia (583). Inclusion and exclusion criteria were described previously with these references. The methodology was previously described separately for each study. The primary outcome measures for this study were pre- to post-treatment changes in dim-light melatonin onset (DeltaDLMO), sleep onset (DeltaSO), sleep latency (DeltaSL), and total sleep duration (DeltaTSD). Melatonin improved dim-light melatonin onset (+1:12 hours; p<0.001), sleep onset +0:42 hours; p=0.004), and sleep latency (25 minutes; p=0.019). Melatonin had no significant effect on total sleep duration vs. placebo. In the melatonin-treated group, but not in the placebo-treated group, the pretreatment dim-light melatonin onset was related to the DeltaDLMO [F(1, 29)=7.28, p=0.012] and the DeltaSO [F(1, 25)=7.72, p=0.010]. The time interval between treatment administration and pretreatment dim-light melatonin onset (INT) was only related to the DeltaSO [F(1,26)=5.40, p=0.028]. This study is limited by the republication of data. Otherwise, the study was well designed.
• Smits et al. conducted a randomized, placebo controlled, double-blind trial to investigate the effect of melatonin treatment on health status and sleep in 70 children with idiopathic sleep-onset insomnia (582). The children, 6-12 years of age, suffered more than one year from idiopathic chronic sleep onset insomnia. They received 5mg of melatonin or placebo at 7 p.m. The study consisted of a one-week baseline period, followed by a four-week treatment. Eight patients in the melatonin group withdrew consent in the baseline period upon getting information on melatonin. There was also missing information from various patients in both groups (e.g., questionnaires, diaries). Health status was measured with the RAND General Health Rating Index (RAND-GHRI) and Functional Status II (FS-II) questionnaires. Lights-off time, sleep onset, and wake-up time were recorded in a diary, and endogenous dim-light melatonin onset was measured in saliva. The total scores of the RAND-GHRI and FS-II improved significantly more during melatonin treatment compared to placebo. The magnitude of change was much higher in the melatonin group than in the placebo group, with standardized response means for the RAND-GHRI of 0.69 vs. 0.07 and for the FS-II of 1.61 vs. 0.64. Compared with baseline, melatonin treatment significantly advanced sleep onset by 57 minutes, sleep offset by nine minutes, and melatonin onset by 82 minutes, and decreased sleep latency by 17 minutes. Lights-off time and total sleep time did not change. Adverse effects in the melatonin group included a cold feeling, decreased appetite, dizziness, and reduced mood. The method of randomization was not clear. Also, some of the children used medication, such as methylphenidates.
• Smits et al. conducted a randomized, double-blind, placebo controlled trial to establish the efficacy of melatonin treatment in childhood sleep onset insomnia in 40 children (350). Elementary school children, 6-12 years of age, who suffered more than one year from chronic sleep onset insomnia were included. Children were excluded if they had severe learning disabilities, prior use of melatonin, liver or kidney disease, pain, use of various medications, and other sleep concerns (e.g., sleep maintenance concerns). Following a one-week baseline period, the children received 5mg of melatonin or placebo for four weeks. Endpoints included lights-off time, sleep onset, and wake-up time, recorded in a diary (N=33 due to missing diaries in some patients), sleep onset (actigraph) (N=25), endogenous dim-light melatonin onset in saliva (N=27), and sustained attention (Bourdon-Vos reaction time test; N=36). Melatonin resulted in significant advancement in lights-off time by 34 (6-63) minutes, diary sleep onset time by 63 (32-94) minutes, actigraphic sleep onset by 75 (36-114) minutes, and melatonin onset by 57 (24-89) minutes. The total sleep time increased 41 (19-62) minutes. There were no statistically significant differences between the treatment groups in the change of sleep latency, wake-up time, and sustained attention reaction times. Adverse effects occurred in two children during the first two days of the melatonin treatment. Of the 38 children who finished the study and continued with open-label melatonin use, 13 stopped melatonin because their sleep problem was solved and one because sleep was not improved. One child developed mild generalized epilepsy four months after the start of the trial. Although he was initiated on valproate, the parents did not want to stop use of melatonin due to benefit in terms of sleep. Thus, he continued to use both valproate and melatonin with no further seizures. The method of randomization was not clear. Also, some of the children used medication, such as methylphenidates.

Memory

• Summary: Preliminary research has suggested that melatonin may improve memory acquisition in certain stressful contexts. However, findings in this field are preliminary; further research is required.
• Evidence: Rimmele et al. conducted a placebo controlled, single-blind trial to evaluate the effects of melatonin on memory processing while under stress (496). Subjects were 50 healthy men, 20-35 years of age. Exclusion criteria included acute or chronic illnesses, smoking, alcohol and illicit drug use, as well as regular strenuous exercise. Patients received 3mg of oral melatonin (N=27) or placebo (N=23) one hour prior to the initiation of stress testing. The study assessed stress responses, memory encoding under stress, and memory retrieval stress responses via the stress Trier Social Stress Test (TSST), as well as blood and saliva before and after the TSST to determine stress hormone levels. To examine the influence of melatonin on memory encoding under stress, the subjects encoded objects distributed in the test room during the TSST, the memories of which were evaluated the next day. Fifteen minutes after stress, retrieval of words memorized the day prior were also tested. The influence of melatonin on attention, concentration, wakefulness, and state anxiety were assessed before and after the stressor using the d2 letter cancellation test of attention, the wakefulness scale of the Multidimensional Mood Questionnaire, and the state scale of the State-Trait-Anxiety-Inventory (STAI). Baseline measures for attention, wakefulness, and state anxiety were obtained before melatonin or placebo administration. Melatonin was observed to enhance spatial memory encoded during stress (p<0.001); however, no change was observed in recall of words to which subjects had been exposed the day before. The melatonin and placebo groups did not differ in their responses to stress as indicated by cortisol, norepinephrine, and epinephrine levels (p=0.47, p=0.18, and p=0.14, respectively). Wakefulness significantly decreased throughout the experiment (p<0.001), with a stronger decrease in the melatonin group (p<0.01). Attentional levels did not differ between the two groups (p=0.48). Limitations of this study include the lack of double-blinding and randomization.

Menopause

• Summary: Melatonin has shown some beneficial effects for symptoms associated with menopause. Further study using a larger number of patients is needed before a recommendation can be made.
• Evidence: Secreto et al. conducted a double-blind, randomized, placebo controlled trial to evaluate the individual and additive effects of soy isoflavones and melatonin in relieving menopausal symptoms in 262 women (497). Postmenopausal women aged ≥35 years with the last menstrual flow at least six months before recruitment, with any condition for which classic HRT is not recommended, were included unless they were using breast cancer therapy or HRT during the previous three months, had overt endocrinopathy (diabetes mellitus, hyperthyroidism, etc.), or intolerance to soy. The women were randomized to receive (1) soy isoflavones + melatonin; (2) soy isoflavones alone (80mg); (3) melatonin alone (3mg); or (4) placebo, for three months. Endpoints included the severity of menopausal symptoms using the Greene Climacteric Scale. Although no statistical test was performed, there were no differences in the median percent differences between basal and final scores. It was stated that the placebo response was much higher than planned, and therefore it was meaningless to perform any statistical test. Somatic and vasomotor symptoms were also similar between the four groups. Improvement of psychological symptoms was higher in the isoflavones + melatonin group vs. the other three. Melatonin had no effect on menstrual flow. Twelve women withdrew from the study due to adverse events; however, it was even between groups. No specific adverse events were stated as being related to melatonin. This study was well designed. Randomization was done using a computer program, and the supplements were identical. The study was double-dummy.
• Bellipanni et al. conducted a randomized, placebo controlled, double-blind trial to examine the effects in 79 women of evening administration of melatonin on the level of hormones which are known to be involved in the genesis and progression of menopause (385). Perimenopausal and menopausal women from 42 to 62 years of age with no pathology or medication were selected. There were premenopausal women (N=25), perimenopausal women (N=36), and postmenopausal women (N=18). The women were divided into two age groups (42-49 and 50-62), as well as on menopausal status. Melatonin was measured in saliva to divide them into low-, medium- and high-melatonin patients. Half of the patients took 3mg of melatonin and half took placebo at bedtime (10-12 p.m.) for six months. At three and six months, blood was taken for determination of pituitary (LH, FSH), ovarian, and thyroid hormones I (T3 and T4). Thyroid hormone levels significantly increased in all women with low basal melatonin taking melatonin (p<0.05). Before initiation of the study, there was a negative correlation in all women between LH, FSH, and basal melatonin levels. However, after six months of melatonin use, melatonin resulted in a significant reduction of LH in the younger women (43-49 year-olds), with no effect in the older women (50-62 years old). Also, in women with low basal melatonin levels, melatonin resulted in a significant decrease in FSH. Mood and depression were generally improved with melatonin use. Adverse effects were investigated but not discussed. None of the women were using hormonal agents, so it is not clear if there would be interactions in women using these medications. Randomization and blinding were not adequately described in this study.

Parkinson's disease

• Summary: There is very limited study to date for the use of melatonin as a treatment in Parkinson's disease. Papavasiliou et al. conducted a single-blind study to examine the effects of melatonin in addition to levodopa in patients with Parkinson's disease (498). All patients (N=11) were treated with melatonin (3.0-6.6g daily), and seven of these were also treated with levodopa (0.36-5.0g daily). Ten of the 11 patients had idiopathic parkinsonism. Melatonin was indicated as being well tolerated, but side effects may have included skin flushing, diarrhea, abdominal cramps, somnolence during the day, scotoma lucidum, and headaches. Melatonin had no effect on signs of parkinsonism or levodopa effects. This topic has been reviewed (1163). Further research of higher methodological strength is needed before a recommendation can be made in this area

Periodic limb movement disorder

• Summary: There is very limited study to date for the use of melatonin as a treatment in periodic limb movement disorder. Kunz et al. conducted a study to determine if exogenous melatonin would decrease periodic limb movement and thereby improve symptoms in patients with this disorder (499). Nine patients with a first-time diagnosis of periodic limb movement disorder without restless leg syndrome were treated over a six-week period with 3mg of melatonin, taken between 10 p.m. and 11 p.m. Melatonin improved well-being in seven of the nine patients. Further research of higher methodological strength is needed before a recommendation can be made in this area.

Preoperative sedation / anxiolysis

• Summary: A small number of studies have compared melatonin with placebo and standard drugs (benzodiazepines) for sedation and anxiety reduction prior to general anesthesia for surgery. Melatonin has also been suggested as a treatment for delirium following surgery (149). Nonrandomized clinical trials have also been conducted (1164), and, overall, the results agree with those observed in the randomized controlled trials (RCT). However, due to weaknesses in the design and reporting of the available research, better studies are needed before a clear conclusion can be drawn.
• Evidence: Caumo et al. conducted a randomized, double-blind, placebo controlled study to test whether premedication with melatonin is as effective as clonidine premedication, and if both are more effective than placebo, in reducing postoperative pain and anxiety and enhancing postoperative clinical recovery (505). Patients were included if they were 19-60 years old, classified as class I or II (normal healthy patient or mild systemic disease) according to the American Society of Anesthesiologists (ASA) grading system, and scheduled to undergo total abdominal hysterectomy for myomatosis. Patients were excluded if they had contraindications to regional anesthesia, history of congestive heart failure or valvular heart disease, renal or hepatic disease, body mass index (BMI) greater than 25kg/m², or a history of or positive screening for current psychiatric disorder. Depending on the treatment group, patients received 5mg oral melatonin (N=20), 100mcg oral clonidine (N=19), or an oral placebo tablet (N=20). During the first 72 hours after the total abdominal hysterectomy, all participants received 2.5mg morphine, with a 10-minute lockout, and a maximum dose of 30mg per four hours via a patient controlled analgesia (PCA) pump. If the pain was unrelieved, then the dose was increased by 0.8mg until pain control was achieved. The night before and one hour before total abdominal hysterectomy, participants received 5mg melatonin tablet, 100mcg clonidine tablet, or a placebo tablet. Thirty-six hours after surgery, melatonin and placebo groups received a dose of placebo while the clonidine group received another dose of 100mcg oral clonidine. Sixty-three patients were originally randomly assigned to one of three groups and received preoperative intervention, but four were excluded from analysis. One patient's surgery was cancelled, one withdrew for an unknown reason, one submitted to myomectomy, and one failed epidural anesthesia. There was a reduction in morphine consumption in the melatonin-treated subjects, which authors stated may be explained by evidence from animal studies that show interactions between opioid peptides and the analgesic effects of melatonin. The primary outcomes were intensity of postoperative pain up to 72 hours after surgery, assessed using the subjective 10cm visual analog scale (VAS), and analgesic consumption, measured by morphine consumption objectively registered using a patient controlled analgesia (PCA) pump. A statistically significant difference was observed between the treatment groups (melatonin and clonidine) and placebo groups on the levels of postoperative pain (p<0.05) during the first 48 hours after surgery. There was no statistical difference (p>0.05) between VAS scores in the melatonin and clonidine treatment groups. Morphine consumption showed a significant reduction over time, independent of treatment group (p=0.00), and was not affected by the interaction between time and treatment (p=0.07). Beneficial reductions in postoperative morphine consumption from the anxiolytic effect of melatonin and clonidine were more evident in highly anxious patients than those only mildly anxious. There was a significant decrease of postoperative anxiolysis (p=0.03) in the melatonin and clonidine group from 6, 24, and 48 hours. In patients experiencing high anxiety six hours after surgery (high anxiety subgroup), the incidence of postoperative moderate to intense pain was lower in both melatonin and clonidine groups than in placebo. However, the incidence of postoperative pain in the low anxiety group was similar in the melatonin, clonidine, and placebo groups. For patients with higher levels of anxiety, the NNT to prevent moderate to intense pain during the first 24 hours postoperatively was 1.52 (95% CI, 1.14 to 6.02) and 1.64 (95% CI, 1.29 to 5.93) in the melatonin and clonidine groups, respectively, compared with the placebo. For the participants with mild levels of anxiety, the NNT to prevent moderate to intense pain during the first 24 hours postoperatively in the melatonin and clonidine groups compared with placebo-treated was 15.71(95% CI, 2.53 to 8) and 63 (95% CI, 2.28 to 8), respectively. The authors acknowledged that pharmacological response to sedatives is related to gender, age, and surgery type. Therefore, data obtained in this study cannot be extrapolated to other surgeries or different populations easily. The study was very well designed.
• Capuzzo et al. conducted a randomized, double-blind, placebo controlled study to evaluate the effects of preoperative melatonin in 150 elderly individuals (501). Inclusion and exclusion criteria were not provided although patients were older than 65 years. Patients received melatonin 10mg or placebo approximately 90 minutes before surgery. The level of anxiety was measured using a numerical rating scale ranging from 0 to 10 (0=no anxiety, 10=maximum anxiety possible). Depression was also measured using a similar numerical rating scale. The authors concluded that the effects of melatonin were similar to placebo. There was no effect of melatonin on anxiety or depression. Twelve subjects did not complete the study due to unplanned intensive care admission, surgery postponed, or refusal to take the medication. Adverse effects were not discussed. This study was well designed.
• Borazan et al. conducted a randomized, placebo-controlled trial to evaluate the effect of preoperative treatment with melatonin on postoperative analgesia, sleep quality, and sedation in patients undergoing elective prostatectomy (508). Subjects were 52 ASA I-II patients undergoing elective prostatectomy (50-65 years old) divided into two groups: receiving placebo (N=26) or 6mg melatonin (N=26) the evening prior and one hour before surgery. Patients were excluded from the study if they had taken drugs that had analgesic properties within 24 hours of surgery and those who had a history of congestive heart failure, valvular heart disease, hepatic or renal failure, psychiatric disorders, sleep disorders, chronic pain syndromes, mental impairment, and drug or alcohol abuse. Outcome measures included extubation time, intraoperative fentanyl, recovery time, pain and sedation scores, and tramadol consumption. Extubation and recovery time were significantly longer in the melatonin group (p<0.05); however, fentanyl usage, pain and sleep scores, and tramadol consumption were all significantly lower (p<0.05). This study was very well designed.
• Ismail et al. conducted a prospective, randomized, placebo controlled, double-blind study on patients undergoing cataract surgery to assess the effects of oral melatonin on pain, anxiety, and intraocular pressure (IOP) (507). Subjects were 40 patients (all aged greater than 60) with an American Society of Anesthesiologists (ASA) physical status I-III, scheduled to undergo cataract surgery with intraocular lens implantation using topical anesthesia for the procedure. The exclusion criteria included any of the following: autoimmune disease, diabetes, epilepsy, depression, leukemia, nystagmus, deafness, concurrent use of analgesic or sedative drugs regularly, allergy to study medications, and those unable to tolerate Shioetz tonometer measurements. Subjects received a one time dose of melatonin 10mg tablet (N=20) or placebo tablet (N=20) by mouth 90 minutes prior to cataract surgery. Mean arterial pressure (MAP) decreased significantly after melatonin premedication. No hypotension or bradycardia requiring intervention was reported in either group. However, after melatonin administration, IOP decreased significantly; this drop was maintained to the end of surgery. No incidence of hypoxia or intraoperative complications was noted. One individual taking melatonin complained of dizziness, and another patient taking placebo suffered nausea. Primary subjective outcomes were reduction in anxiety and pain scores measured using the verbal anxiety score (VAS) and the verbal pain score (VPS), respectively. Secondary objective outcomes included intraocular pressure, mean arterial blood pressures, heart rate, and peripheral oxygen saturation values (measured before medication administration, three times during the operation, three times after surgery had commenced, and once before discharge). Anxiety scores decreased significantly in the melatonin treatment arm preoperatively (p=0.04), and intraoperatively (p=0.005), compared to the placebo group. Pain scores and analgesia administration were also significantly lower in the melatonin group (p=0.007). Subjects treated with melatonin had significantly decreased IOP which was maintained until the end of surgery (p<0.001). MAP was also decreased significantly in the melatonin group. This study was well designed.
• Caumo et al. conducted a randomized, placebo controlled trial to determine the impact of oral melatonin premedication on anxiolysis, analgesia, and the potency of the rest/activity circadian rhythm in 35 patients (40). Patients were included if they were 30 to 55 years old, classified as class I or II (normal healthy patient or mild systemic disease) according to the American Society of Anesthesiologists (ASA) grading system, and scheduled to undergo total abdominal hysterectomy. Patients were excluded if they had contraindications to regional anesthesia, history of congestive heart failure or valvular heart disease, renal or hepatic disease, body mass index (BMI) greater than 25kg/m², or a history of or positive screening for current psychiatric disorder. Patients received oral melatonin 5mg (N=17) or placebo (N=16) the night before and one hour before surgery. The primary endpoint was postoperative pain (pain scores and analgesic consumption). Secondary endpoints were rest-activity cycles and anxiety. The analysis instruments were the Visual Analog Scale, the State-Trait Anxiety Inventory, and the actigraphy. The number of patients that needed to be treated to prevent one additional patient reporting high postoperative anxiety and moderate to intense pain in the first 24 postoperative hours was 2.53 (95% CI, 1.41-12.22) and 2.20 (95% CI, 1.26-8.58), respectively. The number-needed-to-treat was 3 (95% CI, 1.35-5.0) to prevent high postoperative anxiety in patients with moderate-to-intense pain, when compared with 7.5 (95% CI, 1.36-infinity) in the absence of pain or mild pain. Patients in the melatonin group required less morphine by patient-controlled analgesia (p=0.02). In the first week after discharge, the rest/activity cycle as assessed by actigraphy showed that the rhythmicity percentual of 24 hours was higher in the intervention group vs. placebo (p=0.02). Two patients were not included in the analysis due to major noncompliance. This study was well designed.
• Samarkandi et al. conducted a randomized, double-blind, placebo controlled trial to compare the perioperative effects of different doses of melatonin and midazolam in 105 children (503). Patients aged 2-5 years, with an American Society of Anesthesiologist physical status of I and undergoing minor elective surgery for inguinal hernia, undescended testis, hydrocele, or hypospadias under general anesthesia, were included. Exclusions included medication use within two weeks before surgery, history of prematurity, prior surgery or hospital admission, or any stressful life experience (e.g., death in the family, divorce, etc.). Seven groups of children (N=15 in each) received one of the following: midazolam (0.1, 0.25, or 0.5mg/kg orally), melatonin (0.1, 0.25, or 0.5mg/kg orally), each mixed in 15mg/kg acetaminophen, or placebo only (acetaminophen 15mg/kg). The main endpoints were anxiety and temperament, evaluated before and after administration of the study drug, on separation from parents, and on the introduction of the anesthesia mask. Following hospitalization, (week 2), the behavior of the children was measured using the Post-Hospitalization Behavior Questionnaire. Melatonin or midazolam at doses of 0.25 or 0.5mg/kg were equally effective in alleviating separation anxiety and anxiety associated with the introduction of the anesthesia mask. The use of melatonin was associated with a lower incidence (p=0.049) of excitement at 10 minutes postoperatively and a lower incidence (p=0.046) of sleep disturbance at week 2 postoperatively vs. midazolam or placebo. This study is limited by the lack of description of withdrawals and the identical nature of the study products. Postoperative nausea and vomiting was equivalent between groups. Adverse effects were not discussed.
• Kain et al. conducted a randomized dosing and equivalence trial to compare the beneficial effect of oral melatonin administered before general anesthesia and outpatient surgery (506). The study recruited a total of 148 subjects between the ages of two and eight who had an American Society of Anesthesiologist physical status of I or II and were scheduled for general anesthesia and outpatient elective surgery. Subjects were excluded from the study if there was a history of chronic illness, prematurity, or developmental delay. Participants were assigned into one of four groups: midazolam (0.5mg/kg orally), or one of three doses of melatonin (0.05, 0.2, or 0.4mg/kg, with a minimum dose of 0.05mg/kg and maximum 20mg for all doses). Participants received their designated intervention about 45 minutes before the induction of anesthesia. The preoperative anxiety (Yale Preoperative Anxiety Scale) was the primary outcome measurement, and compliance with induction (Induction Compliance Checklist), emergence behavior (Keegan scale), and parental anxiety (State-Trait Anxiety Inventory) were the secondary outcome measurements. Participants who received midazolam showed significantly less anxiety than those who received any dose of melatonin (p<0.01); however, there were no significant differences among the melatonin doses at induction of anesthesia. The proportion of high compliance rating (ICC score of 0) was significantly greater in the midazolam group when compared with the melatonin groups (73.3% vs. 49.5%, p<0.001). The occurrence of emergence delirium (Keegan score of 3) among the treatment groups showed a significant difference (p<0.05). The incidence of emergence delirium was greatest in the midazolam group (25.6%). Melatonin treatment groups demonstrated a dose-response effect on emergence, and the incidence of emergence delirium was greatest after melatonin 0.05mg/kg (25.0%), followed by 0.2mg/kg (8.3%) and 0.4mg/kg (5.4%). This is a very well designed study, with a pilot study to determine the appropriate dosing and the baseline characteristics of the participants; however, the study lacked blinding as well as a placebo control group. It should be noted that adverse reactions were also not discussed.
• Acil et al. conducted a randomized, double-blind, placebo controlled trial to compare the perioperative effects of melatonin and midazolam given in premedication on sedation, orientation, anxiety scores, and psychomotor performance (500). Sixty-six patients undergoing laparoscopic cholecystectomy were included. Patients received melatonin 5mg, midazolam 15mg, or placebo, 90 minutes before anesthesia, sublingually. The patients held it under their tongues for at least 180 seconds. The main endpoints were sedation, orientation, neurocognitive performance, and anxiety. These were examined before, as well as 10, 30, 60, and 90 minutes after, premedication, and 15, 30, 60, and 90 minutes after admission to the recovery room. Sedation significantly increased and anxiety significantly decreased in patients who received premedication with melatonin or midazolam vs. controls (p<0.05). After the operation, sedation was similar between groups. The increase in sedation prior to the surgery was associated with a poorer performance in Trail Making A and B tests vs. placebo. After surgery, results were similar between groups. Amnesia was notable only in the midazolam group for one preoperative event. Thus, the authors concluded that melatonin premedication was associated with preoperative anxiolysis and sedation without postoperative impairment of psychomotor performance. This study is limited by the lack of description of randomization, blinding, and withdrawals.

REM sleep behavior disorder

• Summary: Melatonin has been suggested as a possible treatment for REM sleep behavior disorder (1165). Limited case reports describe benefits in patients with this condition (509;​510;​1166); however, more rigorous research is needed before a clear conclusion can be drawn.

Restless leg syndrome

• Summary: Preliminary research has suggested that melatonin may have a detrimental effect on motor symptoms associated with restless leg syndrome (511); however, evidence remains inconclusive. Further study is required in this field.
• Combination studies or studies of lesser methodological rigor (not included in the Evidence Table): Whittom et al. conducted an open-label, observational study to examine whether the onset of melatonin secretion may play a role in genesis of restless leg syndrome (RLS) and worsening of the symptoms (511). Patients were included if they were drug naïve (free from any drug known to affect sleep, sensory or motor functions, or melatonin secretion), were diagnosed with primary RLS, had a severity score >20 on the International RLS Study Group Severity Scale, and had a habitual bedtime between 9 p.m. and midnight. Patients were excluded if they had a medical condition with known association to RLS (anemia, renal failure) or if another sleep disorder was present (narcolepsy, sleep apnea). Also, patients with clinical signs or a history of a psychiatric, affective, or other neurological disorder within six months preceding the study were excluded. Patients were given 3mg of oral melatonin tablet and were exposed to 3,000 lux of bright light from a light lamp. Each of the eight subjects were studied at three different times: baseline (to assess symptom severity without intervention), after oral administration of 3mg of melatonin tablet (at 7 p.m.), and during exposure to light lamp delivering 3,000 lux of bright light (7 p.m. to midnight). The dose of melatonin and bright-light exposure were separated by one week, and their order was reversed in four of the subjects. Dropouts were not specifically discussed; however, there was mention of one subject who was not included in SIT-PLM analysis, because she could not tolerate the testing during baseline and melatonin conditions. Severity of RLS symptoms were measured using the suggested immobilization test (SIT). SIT consisted of two parts: a subjective measure of motor manifestations (SIT-PLM) and a subjective mean discomfort score (SIT-MDS). The SIT PLM used surface electromyograms (EMG) on both legs to measure periodic leg movements. The SIT-MDS averaged 12 readings on a 10cm visual analog scale (VAS). SIT was administered two times at baseline, two times before oral melatonin administration, and twice for bright-light exposure. Saliva samples were also taken before and after each SIT to assess melatonin concentration. There was a statistically significant increase of the SIT-PLM index when subjects received exogenous oral melatonin compared to baseline (p=0.038) and bright-light conditions (p=0.011), but bright-light exposure had no effect on leg movements compared to the baseline condition. When exposed to bright light, there was a significant decrease in MDS compared to baseline (p = 0.032), but no difference was found in MDS with oral melatonin administration when compared to both bright-light exposure and baseline condition. Also, there was a small but statistically significant (p<0.05) decrease in sensory symptoms with bright-light exposure compared to baseline. After oral melatonin administration, there was a statistically significant increase noted from baseline condition during the first and second SIT (5pg/mL at baseline to 70pg/mL, and 12pg/mL at baseline to 60pg/mL, p<0.001 for both). After exposure to bright light, there was a statistically significant suppression in melatonin secretion (mean <5pg/mL for both SIT 1 and 2, p<0.001). In addition to a small sample size, only patients who were severely affected by RLS were included in this study. It is possible that those who had more mild presentations might experience more noticeable affects than those included in the study.

Rett's syndrome

• Summary: Rett's syndrome is a presumed genetic disorder that affects female children, characterized by decelerated head growth and global developmental regression. There is limited research on the possible role of melatonin in improving sleep disturbance associated with Rett's syndrome (343;​584;​1167). Further research is needed before a recommendation can be made in this area.

Sarcoidosis

• Summary: One case series has examined the effects of melatonin on symptoms associated with chronic sarcoidosis (CS) and determined that it may be an effective and safe therapy for CS when other treatments fail or cause side effects. More well-designed studies are needed before a conclusion can be made.
• Studies of lesser methodological rigor (not included in the Evidence Table): Pignone et al. conducted a clinical trial to examine the effects of melatonin in CS patients in whom usual treatments were ineffective or caused serious side effects (512). Eighteen patients with CS received melatonin for two years (20mg daily in the first year, 10mg daily in the second year). Pulmonary function tests, chest X-rays, pulmonary computed tomography, Ga(67) scintigraphy, and angiotensin-converting enzyme (ACE) were assayed at baseline and in the follow-up. Normalization of ACE, improvement of pulmonary parameters, and resolution of skin involvement were found in the patients given melatonin. After 24 months of melatonin therapy, hylar adenopathy completely resolved in eight patients, and parenchymal lesions were markedly improved in all patients; in the five patients with reduced diffusion capacity of the lung for carbon monoxide, the values normalized after six months of therapy and remained stable until month 24. After 24 months, Ga(67) pulmonary and extrapulmonary uptake was normalized in seven patients and, at month 12, ACE was normalized in six patients, in which the values were high at the baseline. Skin lesions, present in three patients, completely disappeared at 24 months. No side effects were experienced and no disease relapse was observed during melatonin treatment.

Seasonal affective disorder (SAD)

• Summary: There are several small brief studies of melatonin in patients with SAD (513;​1168;​1169;​1170;​1171;​1172;​1173;​1174;​1175;​1176;​1177;​1178). This research is not well designed or well reported, and further research is necessary before a clear conclusion can be reached.
• Evidence: Leppämäki et al. conducted a randomized, placebo controlled trial to examine the effects of melatonin on sleep, waking up, and well-being in 58 subjects with varying degrees of seasonal or weather-associated changes in mood and behavior (513). The adults exhibited subsyndromal seasonal affective disorder (s-SAD) and/or the negative or positive type of weather-associated syndrome (WAS). Patients with known hypersensitivity to melatonin, severe depression, or substance abuse were excluded. Patients were randomized to 2mg of sustained-release melatonin (Circadin®, Neurim Pharmaceuticals, Tel Aviv, Israel) or placebo tablets 1-2 hours before a desired bedtime for three weeks. Outcome measures were changes from baseline in sleep quality, sleepiness after waking, atypical depressive symptoms, and health-related quality of life by week 3. Early-morning salivary melatonin concentrations were measured at baseline and treatment cessation in all subjects. Melatonin administration significantly improved the quality of sleep (p=0.03) and vitality (p=0.02) in the subjects with s-SAD, but attenuated the improvement of atypical symptoms and physical parameters of quality of life compared to placebo in the subjects with WAS, positive type. Limitations include a lack of description of randomization and blinding.
• Danilenko et al. conducted a randomized, double-blind, placebo controlled trial to examine the effects of melatonin on sleep patterns in 16 women with seasonal affective disorder (SAD) and compared results with 17 healthy controls (514). Patients were unmedicated, in good general health, free of major sleep disorders, and were not engaged in shift work or long-distance travel in the prior two months. The women with SAD were diagnosed according to DSM-IV criteria. Baseline waking electroencephalogram (EEG) measurements were done in all patients over 30 hours of sleep deprivation. At 5 p.m., at completion of the 30-hour baseline, patients were randomized to placebo or 0.5g of sublingual melatonin (California Health®). The dose was repeated over a six-day period. Sixteen SAD patients and 13 controls finished the study. Endpoints included sleep duration, mid-sleep time, waking EEG power density, and subjective scores of mood. At baseline, the increase in EEG power density in a narrow theta-band (5-5.99 Hz, derivation Fz-Cz) during the 30-hour protocol was attenuated in patients compared with controls (p=0.037), with sleepiness (p=0.092) and energy (p=0.045) self-ratings following a similar pattern. After sleep deprivation, six patients improved (≥50% reduction on the 29-item Structured Interview Guide for the Hamilton Depression Rating Scale-Seasonal Affective Disorder Version (SIGH-SAD) score). There was no differential effect of melatonin or placebo on any measure; both treatments stabilized the improvement. This study is limited by a lack of description of randomization, withdrawals, and blinding. Adverse effects were not discussed.

Seizure disorder (children)

• Summary: The role of melatonin in seizure disorder is controversial. There are several reported cases of children with intractable seizures or neurologic damage whose seizure-related symptoms improved with regular melatonin administration (351;​352;​352;​353;​353;​354;​354;​355;​356;​587;​588). Exogenous melatonin has also been suggested as a promising treatment for children with epilepsy or febrile seizures, as low serum levels of melatonin were observed in such patients (1179). Melatonin administration resulted in an increase in the activity of antioxidant enzymes, glutathione peroxidase, and glutathione reductase in epileptic children receiving valproate (586;​670); it has been suggested that such activity may help protect neurons from oxidatative stress and damage. Limited animal research has supported possible antiseizure effects (786;​950;​1180). However, there has also been a report that melatonin may actually lower seizure threshold and increase the risk of seizures (346). Melatonin has also been suggested as a superior means (vs. chloral hydrate) of encouraging compliance with sleep EEG for the measurement of seizure activity (1181). Better evidence is needed in this area before a clear conclusion can be drawn regarding the safety or effectiveness of melatonin in seizure disorder.
• Evidence: Gupta et al. conducted a randomized, double-blind, placebo controlled study in epileptic children aged 3-12 years old to evaluate the effects of add-on melatonin administration on the quality of life of these children on sodium valproate (VPA) monotherapy, using a parental questionnaire (1182). The Quality of Life in Childhood Epilepsy questionnaire used was designed to assess a variety of age-relevant domains, such as physical function, emotional well-being, cognitive function, social function, behavior, and general health. Of the 31 patients, 16 randomly received add-on melatonin (MEL), whereas 15 received add-on placebo (P). The authors stated that the questionnaire had good internal consistency reliability, because for most of the multi-item scales, Cronbach's alpha reliability exceeded 0.5 (range: 0.59-0.94). The authors claimed that the study suggests a potential use of melatonin as an adjunct to antiepileptic therapy and that the beneficial effects of melatonin on sleep, its wide safety window, and its ability to cross the blood-brain barrier have the potential to improve quality of life in pediatric epilepsy. Measurements of improvements in quality of life were subjective.
• Studies of lesser methodological rigor (not included in the Evidence Table): Elkhayat et al. conducted a prospective study of 37 patients (N=23 with intractable epilepsy), to investigate melatonin levels, the impact of melatonin levels on sleeping patterns, and the clinical effects of melatonin therapy (589). Patients included in the study had intractable epilepsy that was uncontrolled despite treatment with antiepileptic drugs for at least two years. Patients were excluded if they had progressive neurologic or systemic disease, inborn errors of metabolism, or visual impairment. Patients received 1.5mg of oral melatonin tablets half an hour before bedtime for three months, in addition to their antiepileptic drug treatment. Patients were initiated on a dose of 3mg, but two patients experienced increased seizure frequency, leading to a decrease in dose to 1.5mg. Patients were reassessed at the end of the treatment period in terms of the frequency and severity of seizures, sleep pattern assessment, serum melatonin levels, and interictal EEG recording. Two patients experienced minor adverse effects, including an unexplained persistent headache, papular skin rash, and abdominal pain. Three patients discontinued melatonin due to increased seizure frequency. The Chalfont Seizure Severity Scale determined severity of patients' seizures and measures components of seizures, such as falling to the ground, dropping of a held object, incontinence, and injury. Children's Sleep Habits Questionnaire and the Epworth Sleepiness Scale (pediatric version) were used to assess psychometric sleep. Patients were instructed to keep sleep diaries, which were regularly checked at follow-up visits. A significant improvement in bedtime resistance, sleep duration, sleep latency, frequent nocturnal arousals, sleep walking, excessive daytime sleepiness, and Epworth sleepiness score was observed in patients with intractable seizures receiving melatonin (as compared to values prior to therapy). Nocturnal enuresis, forcible teeth grinding, and sleep apnea were also improved. No significant effect on sleep talking, body jerks, night terrors, or nightmares was observed. In addition, of the patients on oral melatonin (e.g., the 23 with intractable epilepsy), 20 (87%) reported some degree of improvement in seizure frequency, seizure severity, or both. However, in the remaining three patients (13%), seizure frequency worsened, such that melatonin therapy was discontinued. Limitations of this study include the lack of a placebo control. It should also be noted that some results relied on subjective reports.

Sleep disturbance

• Summary: Melatonin may improve sleep disturbances in a wide range of patients, including those in the intensive care unit (ICU) and those with Alzheimer's disease (440;​441;​515;​1183;​1184), as well as those with psychiatric disorders (1185) and end-stage renal disease (1186). Several published cases reported improvements in sleep patterns in young people with damage to the pineal gland area of the brain due to tumors or surgery (374;​606;​1187;​1188). Melatonin has also been proposed as a possible therapy for asynchronization, a disease condition produced by exposure to light during nighttime hours (1189), and melatonin in combination with clomethiazole in circadian rhythm sleep disorder in elderly patients with dementia (1190). Based on preliminary research, melatonin may improve sleep in patients with asthma. Melatonin has been suggested for the improvement of sleep patterns in patients with depression, although research is limited in this area (515;​520;​521;​1191;​1192). Due to very limited research to date, a recommendation cannot be made for or against the use of melatonin in parkinsonism (498) or Parkinson's disease (878;​1090;​1193). There is limited research on melatonin given to patients with sleep disturbances associated with bipolar disorder (such as insomnia or irregular sleep patterns) (546;​547;​1194). A review of the use of alternative treatments (including melatonin) in pediatric bipolar disorder concluded that more research is warranted and necessary (1195). There is limited study of melatonin for improving sleep latency (time to fall asleep) in patients with schizophrenia (549;​1116). Sleep disturbances in blind children have been associated with delays in nocturnal secretion of melatonin (1196). Although melatonin has been shown to improve sleep in a number of contexts, not all trials have been positive. Depending on the particular condition, melatonin may or may not be an effective sleep aid.
• Meta-analysis (patients with intellectual disability): Braam et al. conducted a meta-analysis to investigate whether melatonin is effective for sleep problems in individuals with intellectual disabilities (542). The databases PubMed, MEDLINE, and Embase were searched for randomized controlled trials, written in English, that used melatonin as a treatment intervention for individuals with a diagnosis of intellectual disabilities. Search criteria under the heading of developmental problems included "intellectual disability," "developmental disability," "learning disorder," "mental retardation," and "neurodevelopmental disability." Furthermore, for inclusion, studies had to contain quantitative data on one of the following measures: sleep latency, total sleep time, or number of wakes per night. Nine studies were found to meet inclusion criteria (450;​584;​590;​591;​598;​600;​1197;​1198). Doses used ranged from 0.5mg to 9mg, with regimens lasting from 32 to 73 days (inclusive of washout periods). Of the nine included studies, only four specified the formulation of melatonin used. McArthur et al. and both studies by Braam et al. used immediate-release melatonin, whereas the Wasdell et al. study used a combination immediate-release (1mg)/extended-release (4mg) melatonin product. Analysis of the included trials revealed that melatonin treatment was found to decrease median time to sleep by 34 minutes (p<0.001), increase median length of sleep by 50 minutes (p<0.001), and decrease median nighttime wakes (p=0.024). The mean quality of included studies was 25.28 out of 32. The two reviewers had an intraclass correlation of 0.90. No substantial effect on publication bias was observed. Overall, most adverse effects were small, with rates comparable to placebo. It should be noted that, of the nine included trials, five had less than 10 subjects. Also, none of the studies compared the same developmental disabilities.
• Systematic review (in patients with autism): Rossignol et al. conducted a systematic review of the literature for novel and emerging treatments for autism spectrum disorders (ASD), among which melatonin was identified (407) in a number of studies (450;​591;​594;​599;​1105;​1199;​1200;​1201;​1202;​1203;​1204;​1205;​1206). Studies were gathered via a systematic search through PubMed and Google Scholar (1966 to April 2009), using the search terms "autism," "autistic," "pervasive," and "PDD" in all languages, in combination with a list of identified treatments. The list of treatments was developed by drawing on the Autism Research Institute, review articles, and the author's knowledge of the relevant literature. Regimens from the included studies ranged from 0.75mg to 10mg administered over two weeks to two months. Reported adverse effects included morning drowsiness, nighttime awakening, increased enuresis, and excitement before going to sleep. Experimental measures consisted of blood melatonin concentrations, nighttime urinary excretion of 6-sulphatoxymelatonin, total night sleep, length of sleep, sleep-wake rhythm, sleep pattern, sleep latency, nighttime awaking, sleep onset time, and seizure occurrences. The Jan et al. study reported that fast-release melatonin improved sleep in over 80% of the children, without any adverse effects or tolerance observed in the retrospective study that recruited children with chronic sleep disorders and a neurologic or developmental disability (including an unspecified number with autism). Hayashi et al. observed prolonged total night sleep and improved the sleep-wake rhythm in a case study. Ishiyaki et al. reported that melatonin administered at bedtime led to improvements in sleep in 84% of participants. Paavonen et al. stated that melatonin significantly improved sleep patterns and decreased sleep latency (p<0.002) in children with Asperger's syndrome. Giannotti et al. stated that melatonin significantly improved sleep (p<0.001) without any adverse effects in autistic children with a sleep disorder, although sleep problems returned when melatonin therapy was stopped (and improved again when melatonin was reintroduced). These improvements were still present at both 12- and 24-month follow-ups. In a retrospective study, Andersen et al. reported that 85% of participating children experienced improvements in sleep. In the same study, only one child had worsening of sleep with melatonin, and three other children had mild adverse effects. Wasdel et al. stated that melatonin therapy improved the length of sleep (p<0.01) and sleep latency (p<0.01) in children with a neurodevelopmental disorder and sleep problems. Garstang et al. reported significant improvement on sleep latency, by nearly 0.9 hours (p<0.05), decreased nighttime awakenings (p<0.05), and increased sleep duration, by 1.1 hours (p<0.05) in 11 ASD children. Finally, Wirojanan et al. stated that the use of melatonin in children with autism and/or fragile X syndrome increased mean sleep duration (p=0.02), sleep latency (p=0.0001), and sleep onset time (p=0.02). The authors concluded that promising treatments for ASD include melatonin, antioxidants, acetylcholinesterase inhibitors, naltrexone, and music therapy, which all received a grade of A according to their evidence-based guideline (based on the availability of two or more randomized controlled trials or one or more systematic reviews).
• Evidence (patients with depression): Serfaty et al. conducted a randomized double-blind, placebo controlled trial to determine if exogenous melatonin could act as a sleep promoter and antidepressant in 33 patients with major depressive disorder (MDD) (454). Patients aged 18-65 years were included in the trial if they were diagnosed with major depressive disorder (MDD) and experienced early-morning wakings. Patients were excluded if they had delusions, hallucinations, suicidal ideation, or a recent change in psychotropic medication within the last four weeks. The subjects were administered melatonin (6mg of slow-release at bedtime) or placebo for four weeks in addition to any pre-existing treatment for depression. Actigraphy, sleep diaries, and the Leeds Sleep Evaluation Questionnaire were used as measures of sleep quality. Two subjective questionnaires, the Beck Depression Inventory (BDI) and the 21-item Hamilton Depression Rating Scale (HDRS), were used to measure depression. Of the 33 participants, 31 completed the trial; two dropped out immediately because they felt better. Improvements were noted with time in terms of sleep diary data, HDRS scores, or LSEQ scores, but changes were not associated with melatonin use. BDI scores were not significantly different between melatonin and placebo (2.03, 95% CI, -6.30 to 2.25). Adverse effects were similar between the two groups. The study was conducted over a three-year, three-month period, with different patients undergoing the four-week randomization throughout this time. The trial stated that 17 people would be required in each group (for a total of 34) in order to power the trial adequately; however, this standard was not met. It should also be noted that participants were allowed to continue any current antidepressive medication, whose effects on these findings are difficult to quantify. This study was well conducted.
• Evidence (postoperative): Gögenur et al. conducted a placebo controlled, randomized clinical trial to determine whether postoperative melatonin administration would improve sleep quality, fatigue, and general well-being in patients undergoing elective ambulatory laparoscopic cholecystectomy (545). Subjects were patients scheduled for elective outpatient laparoscopic cholecystectomy with an American Society of Anesthesiologists (ASA) physical status classification of I-III. Exclusion criteria were as follows: pre-existing sleep disorders, treatment with hypnotics or psychotropic drugs (including opioids) within a week of admission, daily analgesic treatment, treatment with beta-blockers, or ongoing treatment with Coumadin® derivates. Patients were instructed to take treatment (a 5mg melatonin capsule or placebo) at bedtime for three nights following discharge. Five patients were excluded from the study after enrollment. Patients who experienced a complicated recovery or were changed to an open procedure were dropped. Self-reported sleep quality was assessed by questionnaire and sleep diary. The time and duration of daytime naps were also recorded. Self-reported discomfort was evaluated using questions concerning level of fatigue, general well-being, and pain. These parameters were also measured on a visual analog scale (VAS). Assessments were made preoperatively and for three days postoperatively. No significant differences between the melatonin group and the placebo group were observed when comparing postoperative sleep quality, total sleep duration, number of night awakenings, night awakening duration, number of daytime naps, and nap duration. Sleep latency in the melatonin group was significantly reduced compared to placebo on postoperative night 1 (p<0.05), but was not significantly reduced on other postoperative nights. This was a well developed and well executed study. The authors acknowledged the possibility of suboptimal dosing.
• Evidence (hospitalized and medically ill patients): Ibrahim et al. conducted a randomized double-blind, placebo controlled trial to examine the effects of nocturnal melatonin on nocturnal sleep in 32 tracheostomized patients (541). ICU patients with tracheostomy who were not receiving continuous sedation, with a Glasgow Coma Score >9, were included if they were aged 16 and over, were not pregnant or breastfeeding, had no known allergy to melatonin, and had no intestinal obstruction, ileus, gastroparesis, or other conditions likely to affect enteral absorption of melatonin. Patients with a likelihood of death within 24 hours were not included. Patients were administered oral melatonin (3mg) or placebo at 8 p.m. Pre- and postdosage blood samples on days 1 and 3 were collected to confirm drug delivery. The primary outcome measure was the number of hours of observed sleep at night, assessed by the bedside nurse. Secondary outcome measures included comparison of the incidence of agitation, assessed by score on the Riker Sedation-Agitation Scale, and requirement for sedatives or haloperidol to settle agitation. Pretreatment melatonin levels in the two groups were low (4.8pg/mL for melatonin vs. 2.4pg/mL for placebo; p=0.13). Post-treatment melatonin levels increased in the melatonin group compared with the placebo group (3,543pg/mL vs. 3pg/mL; p<0.0001). Subsequent observed nocturnal sleep was similar in the two groups: 240 minutes (range: 75-331.3) for melatonin vs. 243.4 minutes (range: 0-344.1) for placebo (p=0.98). Observed diurnal sleep was also similar (138.7 minutes vs. 104 minutes; p=0.42). The incidence of agitation was not significantly higher in the melatonin group vs. placebo (31% vs. 7%; p=0.11). The requirement for extra sedation or use of haloperidol was slightly, but insignificantly, higher in the placebo group compared to the melatonin group (57% vs. 46%; p=0.56). Five patients were excluded from analysis (missed medication, deteriorated condition and death, and development of bowel leak). This study was well designed, with appropriate randomization and blinding.
• Evidence (in children with neuropsychiatric disorders): Gupta et al. conducted a double-blind, randomized, placebo controlled study in 31 epileptic children, aged 3-12 years, to evaluate the effect of add-on melatonin on the sleep behavior in epileptic children on sodium valproate monotherapy (607). Of the 31 patients, 16 randomly received add-on melatonin (6-9mg of fast-release, depending on age or size of child), whereas 15 received add-on placebo, one hour before bedtime, for four weeks. The main endpoint was results on the Sleep Behavior Questionnaire. The authors reported that the questionnaire showed good internal consistency in the patient population (Cronbach's alpha=0.83). The percentage decrease in the median total sleep score was 24.4 (range: 0.0-34.9) in the valproate + melatonin group compared with 14.0 (range: -2.2 to 18.8) in the valproate + placebo group (p<0.005). The median percentage decrease in the parasomnias score was 60 (range: 0.0-70.8) in the valproate + melatonin group compared with 36.4 (range: 0.0-63.2) in the valproate + placebo group (p<0.05). There was no statistically significant difference between the percent decrease in the daytime drowsiness scores and sleep fragmentation scores. Parent-child interaction subscale scores were not significantly different between age groups. The age at onset of seizures and the type of seizures did not correlate significantly to the total sleep scores. There were no adverse effects observed; however, increased appetite was reported in 13 of the 16 subjects in the melatonin group. This study was well designed.
• Evidence (elderly with sleep or behavioral disorders): Garzon et al. conducted a prospective randomized, double-blind, placebo controlled, crossover trial to examine the efficacy of melatonin on sleep and behavioral disorders in the elderly (480). A total of 22 participants (seven men and 15 women) were recruited from several community health centers in Seville, Spain. Subjects were included if they were healthy, aged 65 or older, and diagnosed with insomnia or transient sleep disorders related to emotional stress. Subjects were excluded if they had secondary sleep disorders, autoimmune diseases, tumors, dementia, psychosis or other severe mental disorders, or advanced, severe, or unstable medical diseases, or were currently enrolled in another experimental protocol. Subjects receiving hypnotic drug therapy were not excluded. Melatonin (5mg) or placebo (lactose) was given at bedtime (around 11 p.m.) seven days per week for eight weeks. Subjects then underwent a two-week washout period before crossover treatment for another eight weeks. The overall study duration was 18 weeks. Four participants did not complete the study. The causes for dropouts included missing more than two days of participation, an adverse event that was determined to be unrelated to the study, and diagnosis of a severe disease. Participants were assessed throughout the two phases (eight weeks each) with the Northside Hospital Sleep Medicine Institute (NHSMI) test for sleep disorder. The Yesavege Geriatric Depression Scale (GDS) and Goldberg Anxiety Scale (GAS) were also used. Subjects' ability to discontinue hypnotic drugs was evaluated as well. NHSMI test results showed improved sleep quality in the melatonin group (p<0.005) compared to both baseline and placebo. Nine out of 14 subjects were able to discontinue hypnotic drug therapy (benzodiazepine) during both the melatonin and placebo treatment period. The GDS and GAS also revealed significant improvements in depression (p=0.043) and anxiety (p=0.009) measurements after melatonin therapy compared to baseline or placebo. It should be noted that concomitant use of other sedatives may have affected the results of this study.
• Evidence (patients with Parkinson's disease): Medeiros et al. conducted a randomized placebo controlled trial to evaluate the effect of melatonin on sleep and motor dysfunction in 20 Parkinson's disease (PD) patients (544). Patients with diagnosed Parkinson's disease (Hoehn & Yahr I to III) were included if they were on stable medication for a month. Other neurological diseases were excluded. Patients were then randomized to receive melatonin (3mg) or placebo one hour before bedtime for four weeks. Eighteen patients completed the study (data exclusions were due to noncompliance with medication and disease diagnosis). On initial assessment, 14 patients (70%) showed poor-quality sleep (PSQI >6) and eight (40%) excessive daytime sleepiness (ESS >10). Increased sleep latency (50%), REM sleep without atonia (66%), and reduced sleep efficiency (72%) were found on polysomnography (PSG). Melatonin improved subjective quality of sleep (p=0.03) as evaluated by the PSQI index; however, PSG abnormalities were not changed. Also, motor dysfunction was not improved. There were no adverse effects. Undetected differences in motor scores and PSG findings may have been due to a small sample size and a type II error.
• Dowling et al. conducted a randomized double-blind, placebo controlled trial to compare the effects of two doses of melatonin to placebo on sleep, daytime sleepiness, and level of function in 43 patients with PD who complained of sleep disturbances (543). Patients with idiopathic parkinsonism with unsatisfactory nighttime sleep were included. The patients had age-normal scores on the mini-mental status examination and the Geriatric Depression Scale. Inclusion and exclusion criteria were examined over three study phases, such that ability to wear an actigraph, to complete questionnaires and diaries, and to provide biochemical endpoints were also considered. Patients were excluded along the way; however, 43 patients were eligible based on all criteria, and 40 patients completed the protocol. There was a two-week screening period, two-week treatment periods, and a one-week washout between treatments. Patients received 50mg of melatonin and placebo. Nocturnal sleep was assessed by actigraphy and diaries, whereas daytime sleepiness and function were assessed by the Epworth Sleepiness Scale (ESS), Stanford Sleepiness Scale (SSS), and General Sleep Disturbance Scale (GSDS). Repeated-measures analysis of variance revealed an improvement in total nighttime sleep time during treatment compared to placebo (p<0.05). There was an improvement in subjective sleep disturbance, sleep quantity, and daytime sleepiness during the 5mg melatonin treatment compared to placebo, as assessed by the GSDS. One patient in the melatonin group complained of daytime sleepiness. Limitations include the lack of description of randomization.
• Evidence (patients with asthma): Campos et al. conducted a randomized, double-blind, placebo controlled study to examine the effects of melatonin on sleep disturbances in 22 women with asthma (422). Women were excluded if they had a history of asthma exacerbation within the previous four weeks, respiratory diseases other than asthma, sleep disorders, or use of hypnotic-sedative drugs; or were smokers or ex-smokers, pregnant or breastfeeding, or shift workers. Women were randomized to receive melatonin 3mg (N=12) or placebo (N=10) for four weeks. The primary outcome measure was global sleep quality, evaluated by the Pittsburgh Sleep Quality Index. Other endpoints included the Epworth Sleepiness Scale, pulmonary function (by spirometry), and use of relief medication, asthma symptoms, and morning and evening peak expiratory flow rate. Melatonin treatment improved subjective sleep quality, compared with placebo (p=0.04). There was no statistically significant difference in asthma symptoms, use of relief medication, or daily peak expiratory flow rate. Eight patients complained of headache in the study; five were in the melatonin group. The method of randomization was not described.
• Evidence (medically ill patients): Andrade et al. conducted a randomized, double-blind, placebo controlled trial to assess the effects of melatonin in 33 medically ill patients with insomnia (516). Consecutive patients with insomnia were recruited. Patients were administered melatonin (N=18) or placebo (N=15) in a flexible-dose regimen. The mean stable dose of melatonin was found to be 5.4mg. Melatonin significantly improved sleep onset, quality and depth of sleep, and increased sleep duration without producing drowsiness, early-morning "hangover" symptoms, or daytime adverse effects (p<0.05). Melatonin also contributed to freshness in the morning and during the day and improved overall daytime functioning (0.05<p<0.10). However, these improvements occurred on specific days only, and overall, there appeared to be little significance between groups. It was indicated that benefits were most apparent during the first week of treatment. There were no adverse effects. Limitations included lack of description of randomization, lack of inclusion and exclusion criteria, and the way the statistics were conducted.
• Evidence (patients with cystic fibrosis): De Castro-Silva et al. conducted a randomized, double-blind, placebo controlled study to evaluate the effects of exogenous melatonin on sleep and inflammation in 19 patients with cystic fibrosis (519). The subjects were clinically stable patients with a confirmed diagnosis of cystic fibrosis, free of infection or hospitalization in the last 30 days. Subjects were excluded for comorbidities (including diabetes mellitus), or use of hypnotic-sedative drugs. Patients were monitored to acquire baseline (day 0 to day 6) objective and subjective measures (via questionnaire) of sleep. They were then randomized into the melatonin (3mg) or placebo groups; treatment was received two hours before bedtime for three weeks. The primary outcome measures were nitrite and isoprostane levels (to test stress and inflammation on lung tissue), measured from exhaled breath condensate (EBC) using spirometry, and sleep-wake patterns measured using actigraphy. Secondary outcome measures included subjective sleep questionnaires to evaluate global sleep quality (Pittsburgh Sleep Quality Index) and excessive daytime sleepiness (Epworth Sleepiness Scale). After treatment, patients in the melatonin group showed significant improvements in sleep efficiency (SE) (p=0.01) and a trend toward shorter sleep latency (p=0.08). Nitrite levels were significantly reduced after treatment with melatonin (p=0.01); a significant reduction was not seen in the placebo group (p=0.43). It should be noted that data from one patient were excluded from analysis without explanation.
• Evidence (patients with Alzheimer's disease): Gehrman et al. conducted a randomized, double-blind, placebo controlled trial to evaluate the effect of melatonin therapy on sleep and agitation in 41 patients with Alzheimer's disease (1207). Patients in nursing homes in the San Diego metropolitan area with probable Alzheimer's disease based on the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Related Disorders Association (NINCDS-ADRDA) diagnostic criteria were included. The subjects were given melatonin capsules (8.5mg of immediate-release and 1.5mg of sustained-release) (N=24) or identical placebo capsules (N=17). Experimentation consisted of a three-day baseline, a 10-day treatment period, and a five-day post-treatment phase. Melatonin or placebo was administered at 10 p.m. for 10 consecutive nights during the treatment period. Sleep patterns of the patients were measured using actigraphy. Agitation was measured with the Agitated Behavior Rating Scale (ABRS) and Cohen-Mansfield Agitation Inventory (CMAI). There were no significant differences in treatment effects of melatonin vs. placebo on any actigraphic sleep parameters or circadian rhythms parameters (during the day or night). Also, there were no significant differences (p>0.05) in treatment effects on observed physical or verbal agitation between the two groups, or in CMAI ratings. However, there were small but significant differences in CMAI ratings of agitation independent of treatment group (p=0.011) depending on the nursing shifts. It should be noted that the timing of the melatonin dose (10 p.m.) may have affected results, as it was not tailored to each individual's rhythms.
• Evidence (in hemodialysis patients): Koch et al. conducted a randomized, double-blind, placebo controlled, crossover study in 20 patients to investigate the effects of melatonin on sleep-wake rhythm in patients on hemodialysis (540). Patients included in this study were between 18 and 85 years of age and on stable hemodialysis for more than three months. Patients were excluded if they had previously used melatonin, were currently using hypnotics that could not be discontinued, or had severe psychological or neurological disease. Patients received 3mg of melatonin or placebo daily at 10 p.m. for six weeks. In the second six weeks, treatments were reversed. All patients received 3mg tablets for the final six weeks (no washout was included due to the short half-life of melatonin). Four patients dropped out of the original 24 patients enrolled. Two patients died, one terminated his dialysis, and one was excluded due to noncompliance. The Dutch sleep disorders questionnaire was used to determine sleep-wake characteristics, and patients kept a log of their sleep-wake schedule for one week at baseline, as well as after five and after eleven weeks. Patients needed a median of 44.5 minutes (CI, 50 ± 78 minutes) to fall asleep with placebo treatment and 15.5 minutes (CI, 33.6 ± 66 minutes, p=0.002) after melatonin treatment. Sleep efficiency increased from 67.3% with placebo to 73.1% with melatonin (p=0.01). Actual sleep time increased from 377 minutes with placebo to 388 minutes with melatonin (p=0.003), and sleep fragmentation decreased from 4.5 to 3.1 (p=0.007). Patients reported less time needed to fall asleep on nights of daytime dialysis (p=0.003) and the nights without daytime dialysis (p=0.04) when using melatonin instead of placebo. An increase in sleep time was seen on nights after daytime dialysis (p=0.01) with melatonin. Wake periods during the nights were significantly fewer on nights after dialysis (p=0.03) and nights without daytime dialysis (p=0.03). Limitations of this study include the reliance on subjective reporting.
• Evidence (patients with psychiatric disorders): Suresh et al. conducted a randomized placebo controlled trial to examine the effects of melatonin on insomnia in 40 patients with schizophrenia (550). Stable DSM-IV schizophrenic outpatients with initial insomnia of at least two weeks' duration were included. Patients were clinically stable, receiving the same dose of psychotropic medication. Patients were randomly assigned to augment their current medications with flexibly dosed melatonin (3-12mg nightly; N=20) or placebo (N=20). Aspects of sleep functioning were obtained daily across the next 15 days by questionnaire. The modal stable dose of melatonin was 3mg. Relative to placebo, melatonin improved the quality and depth of nighttime sleep, reduced the number of nighttime awakenings, and increased the duration of sleep without producing a morning hangover (p<0.05). Subjectively, melatonin also reduced sleep onset latency, heightened freshness on awakening, improved mood, and improved daytime functioning (p<0.05). Drowsiness was not experienced to a greater extent the following day in the melatonin group. Adverse effects were not specifically discussed. Randomization and withdrawal were not described adequately.
• Evidence (patients with mental retardation with or without epilepsy): Coppola et al. conducted a randomized placebo controlled trial to examine the effects of melatonin on sleep disturbance in 32 patients with mental retardation with or without epileptic seizures (590). Patients more than 12 months old with mental retardation with or without epileptic seizures, with a diagnosis of a circadian rhythm sleep disorder (including delayed onset of sleep, multiple night awakenings, and short duration of night sleep through a baseline period of six months), and exclusion of medical issues such as gastroesophageal reflux, pain, or epileptic seizures mimicking sleep disorders, with persisting sleep disturbances despite maintaining appropriate sleep hygiene, were included if there was no progressive neurological or systemic diseases. Patients were 3.6-26 years old (mean: 10.5 years). Patients received oral synthetic fast-release melatonin (3mg at bedtime) or placebo. However, in case of inefficacy, the dose could be titrated up to 9mg the following two weeks at increments of 3mg per week, unless the patient was unable to tolerate it. Twenty-five patients completed the study; withdrawals were not due to adverse effects. Endpoints included data available from sleep logs, such as sleep latency and total time of sleep, and night awakenings. The analysis of all the sleep logs disclosed a significant treatment effect of melatonin on sleep latency (p=0.019). Melatonin was well tolerated in all patients, and no side effects were reported. The authors concluded that melatonin may be effective in young patients with mental disabilities and epileptic seizures in improving the wake-sleep disorders, such as time to fall asleep. Randomization and blinding were not adequately described.
• Evidence (patients with tardive dyskinesia): Shamir et al. conducted a randomized placebo controlled, double-blind crossover trial to evaluate the effect of melatonin on tardive dyskinesia in 19 patients with chronic schizophrenia (548). Patients had tardive dyskinesia for a minimum of five years and antipsychotic treatment for at least 10 years, past or present. Central nervous system disorders were excluded. Patients (eight men, 11 women; aged 74.0 ± 9.5 years) received slow-release melatonin 2mg daily or placebo for four weeks. After a two-week washout period, the patients were switched to the other treatment arm for an additional four weeks. The Abnormal Involuntary Movement Scale (AIMS) was administered at baseline, four weeks, six weeks, and 10 weeks. Regular administration of antipsychotic and other medications was kept unchanged throughout the study. Mean AIMS scores did not change significantly from baseline in either treatment arm. All patients completed the study. There were no adverse events. Limitations included lack of description of randomization and blinding.
• Evidence (patients with schizophrenia): Shamir et al. conducted a randomized, double-blind crossover trial to explore the neurobehavioral responses of 14 patients with chronic schizophrenia to melatonin treatment using the first-night effect (FNE) as a marker (549). Patients with liver or renal diseases (serum creatinine >1.1mg/dL) or suffering from other psychiatric or other severe diseases were excluded. Patients were administered melatonin (2mg in a controlled-release formulation; Circadin®, Neurim Pharmaceuticals, Tel Aviv, Israel) or placebo for three weeks each, with a one-week washout between treatment periods. Polysomnography was performed during the last two consecutive nights of each treatment period. Significant first-night effects were found with respect to rapid eye movement sleep latency (longer), sleep efficiency (lower), and duration of wakefulness during sleep (lower on the first night vs. the second night) when subjects were using melatonin (p<0.05). These results were compared with baseline, and these effects were not found when the patients received a placebo. The FNE manifested regardless of whether melatonin was administered before or after the placebo treatment period. Adverse effects were not discussed. Limitations include the lack of description of randomization and withdrawals.
• Evidence (patients with depression): Dolberg et al. conducted a randomized, placebo controlled, double-blind trial to examine the hypnotic effects of slow-release melatonin during the initial four weeks of treatment with fluoxetine in 24 patients with major depressive disorder (521). The minimal 21-item Hamilton Depression Rating Scale score on recruitment was 16 points. Patients with psychotic depression, bipolar disorder, schizoaffective disorder, or primary sleep disorders were excluded. Patients had no other substantial physical illnesses and were not taking any other hypnotic medications. Nineteen subjects completed the study; failure to improve and side effects to fluoxetine were the main reasons for withdrawal. Patients were treated with fluoxetine plus slow-release melatonin (5mg but could be increased to 7.5 or 10mg) or fluoxetine plus placebo, for four weeks. Response to melatonin was assessed by using rating scales for depression and sleep. The 10 patient completers given slow-release melatonin reported better scores on the Pittsburgh Sleep Quality Index than the nine patients given placebo. There were no statistically significant differences in the rate of improvement in depressive symptoms between the two groups. Side effects were considered related to fluoxetine, with no differences between groups. Limitations included the lack of description of randomization and blinding.
• Evidence (patients with bipolar disorder): Leibenluft et al. conducted a randomized, double-blind, placebo controlled trial examining the effects of melatonin in five patients with rapid cycling bipolar disorder (547). Substance abuse was excluded. Patients were treated with melatonin 10mg daily or placebo at 10 p.m. for 12 weeks. After a one-month washout period, the patients used the other product. Melatonin was added to a stable regimen of medication. Melatonin administration had no positive effects. Following melatonin withdrawal, one patient developed a free-running (unentrained) sleep-wake cycle. In both this and a second patient, there was evidence that the administration of exogenous melatonin may have suppressed the secretion of endogenous melatonin. Overall, the results do not support the use of melatonin in this population.
• Evidence (patients with intellectual disability): Braam et al. combined data from a pair of randomized controlled trials (598;​600) to examine the efficacy of melatonin in improving sleep and decreasing behavioral problems in 66 persons with intellectual disabilities (ID) and chronic insomnia (601). Patients had chronic insomnia with comorbid ID who had been referred to the investigators' sleep center by local general practitioners. Insomnia was defined as difficulty falling asleep (30 minutes or greater), waking up twice or more during the night for more than 45 minutes, or waking up five times for no less than 15 minutes each time, with these difficulties persisting for one year or longer. Patients with somatic or psychiatric causes of insomnia, previous use of melatonin, restless legs syndrome, liver or renal disease, chronic pain, or sleep apnea, and those younger than two years of age were excluded. Subjects received melatonin (5mg for those six years of age and older and 2.5mg for those younger) or placebo (N=27 and 22, respectively) for four weeks (younger patients at 6 p.m., older patients at 7 p.m.). Subjective outcome measures that were used to quantify challenging behavior included the Storend Gedragsschaal voor Zwakzinnigen (SGZ; Maladaptive Behavior Scale for the Mentally Retarded). Subjective measures which were used to quantify sleep problems included times lights went out, time to actual sleep, total sleep time and number, and duration of nighttime wakes as logged by a sleep diary. Objective outcome measures included dim-light melatonin onset (DLMO), which was set when salivary melatonin reached 4pg/mL. Out of the initial subject pool, one child was withdrawn due to unwillingness to submit to saliva sampling, and nine children in the placebo group and seven in the melatonin group were excluded due to incomplete sleep logs or SGZ scales. Melatonin therapy was found to significantly reduce mean SGZ-T (p<0.003) and M (p<0.005) scores, though V subscale scores were not (p=0.0617). Though clinical improvement was noted in individual items of the SGZ-A subscale, the mean score was not significantly changed (p=0.076). Melatonin treatment was also found to significantly improve a number of sleep parameters including sleep latency, number of wakes, duration of wakes, and total sleep time (p<0.001, 0.002, 0.034, and 0.043, respectively), as well as significantly advance DLMO (p<0.001). Time of lights-out, however, was not significantly changed (p=0.697). Limitations of this study include reliance upon subjective measures of sleep and a small subject population. It should also be noted that although specific mention of an identical placebo was made, it is unclear if the study was double-blinded.
• Evidence (patients with Alzheimer's disease): Dowling et al. conducted a randomized, controlled trial to examine whether the addition of melatonin to bright-light therapy enhances the efficacy in treating rest-activity (circadian) disruption in 50 institutionalized patients with Alzheimer's disease (AD) (517). Patients had a diagnosis of probable AD according to the National Institute of Neurological and Communication Disorders and Stroke/Alzheimer's Disease and Related Disorders Association criteria, the ability to perceive light, and a stable medication regimen. Subjects were excluded if they had other neurological diagnoses or were regularly taking valerian, melatonin, or sleeping pills. Patients received one hour of morning light exposure (≥2,500 lux in gaze direction) Monday to Friday for 10 weeks and 5mg of melatonin (LM, N=16) or placebo (LP, N=17) in the evening. Control subjects (N=17) received usual indoor light (150-200 lux). Nighttime sleep variables, day sleep time, day activity, the day:night sleep ratio, and rest-activity parameters were determined using actigraphy. It was indicated that 50 subjects completed the study, but the actual number that started was unclear. There were no statistically significant differences in nighttime sleep variables between groups. The melatonin group showed improvement in daytime somnolence (reduction in the duration of daytime sleep, an increase in daytime activity, and an improvement in the day:night sleep ratio). There was also an increase in rest-activity rhythm amplitude in this group. Randomization, blinding, and withdrawals were not adequately described in this study.
• Evidence (patients with head injury): Kemp et al. conducted a randomized, double-blind, equivalence crossover trial to compare melatonin and amitriptyline in a small sample of traumatic brain injury (TBI) patients presenting with chronic sleep disturbance (560). Patients had a traumatic brain injury at least six months previously, with no history of previous neurological insults or drug dependence. Patients were not already using amitriptyline. Patients were randomized to order of melatonin (5mg) and amitriptyline (25mg) for one month, with a two-week washout in between. Endpoints included sleep latency, duration, and quality of daytime alertness. There were no statistical differences in these endpoints compared to baseline. However, the authors reported that the effect sizes revealed some encouraging changes. Patients on melatonin reported improved daytime alertness compared to baseline. On amitriptyline, patients reported increased sleep duration compared to baseline. Specific adverse effects were not discussed. This study is limited by lack of description of randomization, blinding, and withdrawals.
• O'Callaghan et al. conducted a randomized, placebo controlled, double-blind trial to examine the use of melatonin in patients with tuberous sclerosis complex who also have severe sleep problems (1208). Seven patients with confirmed diagnoses of tuberous sclerosis and significant sleep disorder were recruited. Three outcome measures were employed: total sleep time, time to sleep onset, and number of awakenings. Patients treated with melatonin had a small improvement in total sleep time (mean improvement: 0.55 hours, p<0.05). They also tended to have an improvement in sleep onset time, but this did not reach statistical significance. Melatonin, in this trial, had no effect on sleep fragmentation. The authors concluded that melatonin had a beneficial effect in prolonging the total sleep time of patients with tuberous sclerosis and sleep disorder, and that further trials are necessary to investigate the issues of optimal dosage, tolerance, and possible interactions with other medications.
• Evidence (in patients with autism) (not included in the Evidence Table due to lower level of methodological rigor): Galli-Carminati et al. conducted a retrospective study of six patients to determine the use of melatonin in adults with autism and sleep disorders (518). Included patients were all followed in a psychiatric unit for patients with intellectual deficiencies. Patients presented with autism associated with mental retardation diagnosed according to the International Classification of Diseases and exhibiting accompanying behavioral problems. including severe psychomotor agitation, autoaggressive behavior (including minor and severe automutilation), and violent behavior directed towards objects and others. Melatonin was initiated at a daily dose of 3mg before bedtime. After four weeks of treatment, if the dose was ineffective, it was increased by increments of 3mg every two weeks, with a maximum of 9mg. Both before and after the six-month treatment period, patients' global severity and global improvement of sleep disorders were evaluated. Improvement in sleep disorders were evaluated using the Clinical Global Impression scale severity and improvement scales. All of the patients' sleep disorders were significantly improved, with a median score of 5.5 before treatment and 1.0 after treatment (p=0.031). Limitations of this study include a small sample size, and lack of a control group.
• Evidence (patients with tuberous sclerosis) (not included in the Evidence Table due to dosing study with no placebo): Hancock et al. conducted a randomized, double-blind, controlled crossover trial to investigate the response to oral melatonin using two dose regimens in eight children with sleep disorders associated with tuberous sclerosis complex (552). Children with behavioral sleep problems were excluded. The outpatients received 5mg or 10mg of melatonin for two weeks each, with a two-week washout period in between. Sleep latency, total sleep time, number of awakenings, and seizure frequency were recorded in sleep and seizure diaries. There was no evidence of a dose effect between 5mg and 10mg of melatonin for any outcome measure. This study is limited due to the lack of a placebo group.
• Evidence (combination study not included in the Evidence Table): A case report penned by Nierenberg describes how a new treatment program for a patient with severe treatment-resistant bipolar depression that consisted of melatonin administered in combination with low-dose bupropion and mood stabilizers led to a significant improvement in her depression (116). The patient was a 35 year-old woman with bipolar I disorder. Following unsuccessful treatment with Selegiline (seven weeks), the patient was prescribed lamotrigine, controlled-release lithium carbonate (900mg), buspirone (5mg), and melatonin (3mg), with bupropion (75mg) added after 10 days. The Quick Inventory of Depressive Symptomology-Self-Rated (QIDS-SR) served as the index of improvement. The patient's QIDS-SR scores gradually fell over 19 weeks of treatment, eventually reaching a value of 2 (in the normal range), without any symptoms of depression, mania, hypomania, anxiety, or irritability. After three months, melatonin was discontinued due to complaints of daytime sleepiness. Remission was sustained at 10-month follow-up.

Sleep quality

• Summary: A small amount of research has examined the use of melatonin to improve sleep quality. Further study is necessary before firm conclusions can be reached.
• Evidence: Atkinson et al. conducted a controlled trial of 12 subjects to examine the effects of melatonin on the subjective quality of sleep in athletes and any residual effects on physical performance the morning after treatment (456). Exclusion and inclusion criteria were not specifically discussed; however, the subjects included were described as being healthy, physically active sports science undergraduates, ages 19-30 years. The subjects were given 5mg of melatonin or a placebo; a single dose of one capsule was taken at 11:30 p.m., 30 minutes before retiring. The authors did not specifically state the primary outcome, although subjective measure of sleep quality (maintenance and latency) is assumed. Secondary measures included objectively measured intra-aural temperature, left and right grip strength, and time taken to complete a 4km stationary bike ride. Secondary, subjective measures include perceived exertion. ANOVA was used to analyze grip strength and cycle time data. There were no significant differences between the placebo and melatonin groups for right [t11=-0.15(p=0.88)] or left [t11=0.35(p=0.74)] hand grip strength, cycle times [t11=0.44(p=0.67)], or sleep latency [W=25.5 (p=0.33)] and maintenance [W=12.5 (p=0.87)] (Wilcoxon tests, p>0.5). Limitations of this study include a lack of randomization, inclusion and exclusion criteria, and adequate description of the blinding process, as well as the short study duration and overall suboptimal study design. Standardization, allergies and adverse effects, toxic effects, dropouts, and interactions were not discussed.

Smoking cessation

• Summary: A small amount of research has examined the use of melatonin to reduce symptoms associated with smoking cessation, such as anxiousness, restlessness, irritability, and cigarette craving. Although preliminary results are promising, due to weaknesses in the design and reporting of this research, further research is necessary before a firm conclusion can be reached.
• Evidence: Zhdanova et al. conducted a randomized controlled trial to determine the effect of melatonin on nicotine withdrawal in 12 smokers (553). Subjects reported that they smoked cigarettes for a period of 3-27 years, and had smoked at least 20 cigarettes daily in the past year. All of the subjects described several unsuccessful attempts to quit smoking. During these attempts they reported experiencing at least two of the following withdrawal symptoms: cigarette craving, increase in irritability, anxiety, daytime drowsiness, or nighttime sleep disturbances. Patients were randomized to an oral 0.3mg dose of melatonin administered 3.5 hours after the nicotine withdrawal, or placebo. The effects of increasing circulating melatonin concentrations on nicotine withdrawal were examined. Self-reported ratings of mood, sleepiness, and cigarette craving were assessed hourly, using 17 visual analog scales (VAS). Computerized Four-Choice Reaction Time (FCRT) and Simple Auditory Reaction Time (SART) tests were used to assess performance every two hours. Saliva samples were collected hourly and salivary melatonin levels were measured using supersensitive radioimmunoassay. Compared with the placebo, melatonin treatment significantly reduced self-ratings of "anxious," "restless," "tense," "irritable," "angry," "depressed," "impatient," and "craving for cigarettes" (p<0.05). Melatonin treatment did not change the responses on the performance tests used. It was indicated that the computer test was only done by eight subjects, because the other subjects did not feel comfortable. It is not clear if this may have affected the outcome of this endpoint.

Stroke

• Summary: It has been proposed that melatonin may reduce the amount of neurologic damage patients experience after stroke, based on antioxidant properties (5;​14;​18;​961;​962;​963;​964;​965). In addition, melatonin levels may be altered in people immediately after stroke (196;​966), and therefore it has been suggested that melatonin supplementation may be beneficial. This has not been shown in humans. At this time, the effects of melatonin supplements immediately after stroke are not clear.

Tardive dyskinesia

• Summary: Tardive dyskinesia (TD) is a serious potential side effect of antipsychotic medications, characterized by involuntary muscle movements. Limited small studies of melatonin use in patients with TD report mixed findings (548;​554;​743;​744;​745;​746;​747;​1209). Additional research is necessary before a clear conclusion can be drawn.
• Evidence: Shamir et al. conducted a double-blind, placebo controlled, crossover trial to examine the potential benefits of melatonin for the treatment of TD in 24 patients (554). Patients were diagnosed with schizophrenia and antipsychotic-induced TD. Patients with comorbid neurological illness, substance abuse, or concurrent participation in another study were excluded. Most patients were on other medications, in addition to their antipsychotics. Medication use remained unchanged during the study. Patients received 10mg daily of melatonin (Circadin®; Neurim Pharmaceuticals Ltd., Tel Aviv, Israel) and placebo, for six weeks, with a washout period of four weeks in between. The primary outcome measure was the change from baseline in Abnormal Involuntary Movement Scale (AIMS) score. Two patients were discharged from hospital before initiation and were not included in the analysis. The decrease (mean ± SD) in AIMS score was 2.45 ± 1.92 for the melatonin and 0.77 ± 1.11 for the placebo treatment groups (p<0.001). Of the 22 patients, 17 improved more with melatonin. No adverse events or side effects were noted. This study was well designed, although the method of randomization was not clear.
• Shamir et al. conducted a randomized, placebo controlled, double-blind crossover trial to evaluate the effect of melatonin on tardive dyskinesia in patients with chronic schizophrenia (548). Nineteen patients (eight men, 11 women), with a mean age ± SD of 74.0 ± 9.5 years, with chronic DSM-IV schizophrenia of 31.3 ± 7.0 years' duration, were included. All patients had received antipsychotic medication for at least 10 years. Patients with DSM Axis III disorders of the central nervous system were excluded. Regular administration of antipsychotic and other medications was kept unchanged throughout the study. Patients received slow-release melatonin 2mg daily, and placebo, for four weeks, with a two-week washout period in between. The Abnormal Involuntary Movement Scale (AIMS) was the main endpoint and it was administered at baseline, four weeks, six weeks, and 10 weeks. Mean AIMS scores did not change from baseline in either treatment arm. Nine of 19 patients had mild improvement in both arms of the study. All patients completed the study, and there were no side effects or adverse events. This study was well designed, although the method of randomization was unclear.

Thrombocytopenia (low platelets)

• Summary: Increased platelet counts after melatonin use have been observed in patients with decreased platelets due to cancer therapies (several studies reported by the same author) (700;​702;​707;​708;​711;​725;​728). Stimulation of platelet production (thrombopoiesis) has been suggested but not clearly demonstrated. Additional research is necessary in this area before a clear conclusion can be drawn. Cases of idiopathic thrombocytopenic purpura (ITP) treated with melatonin have been reported (972;​973).

Tinnitus

• Summary: Melatonin supplementation has been suggested as a means for improving tinnitus (1210), a hypothesis supported by some preliminary research (557). However, additional research is needed before a conclusion can be made.
• Evidence: Lopez-Bonzalez et al. conducted a randomized, placebo controlled, double-blind trial to examine the effects of sulpiride, a D2 antagonist of dopamine receptors, and melatonin, which has antidopaminergic action, on tinnitus perception in tinnitus patients (556). One hundred twenty patients consulted for subjective tinnitus were included randomly in four groups of 30. Inclusion and exclusion criteria were not provided. One group took sulpiride (50mg every eight hours) alone, the second group took melatonin (3mg every 24 hours), the third group took the same doses of sulpiride (50mg every eight hours) plus melatonin (3mg every 24 hours), and the fourth group took placebo (lactose 50mg every eight hours), all for one month. Ninety-nine patients completed the study. Reasons for withdrawal were provided and did include adverse effects; however, it was not indicated which groups experienced the adverse effects. The main outcome measures included clinical history, tonal audiometry, tympanometry, and tinnitometry, and were assessed at the beginning and end of the study. Brainstem auditory-evoked potential and images were also done. Subjective grading of tinnitus perception and a visual analog scale (0-10) were done for evaluation of results. Based on the subjective grading, tinnitus perception diminished by 56% in patients treated with sulpiride, by 40% in patients treated with melatonin, by 81% in patients treated with sulpiride plus melatonin, and by 22% in patients treated with placebo. The statistical significance of these results was unclear. Based on the visual analog scale, tinnitus perception diminished from 7.7 to 6.3 in patients treated with sulpiride, to 6.5 in those treated with melatonin, to 4.8 in patients treated with sulpiride plus melatonin, and to 7.0 in those treated with placebo.
• Neri et al. conducted a prospective randomized controlled study to evaluate the efficacy of melatonin alone and in combination with sulodexide in alleviating tinnitus (558;​559). Subjects were 102 patients (45 men and 57 women, 29-79 years of age, with a mean age of 54.8) suffering from tinnitus for a minimum of one year, who did not have any psychiatric or neurological diseases. Participants were divided into three groups. For the first 40 days, group A, which included 34 patients, were given sulodexide 250mg twice daily with melatonin 3mg once daily before sleep (after 40 days, the dose of sulodexide was reduced to 250mg capsule once daily with melatonin before sleep to avoid adverse effects such as epigastric pain, for an additional 40 days). Group B included 34 patients who were given a 3mg melatonin capsule daily. The control group included 34 patients who did not receive any therapy in order to evaluate spontaneous variations in time-related in tinnitus perception. All groups received their respective treatments (or no treatment) for 80 days. The study also included a follow-up period of 40 days. The quality of life and subjective perception of tinnitus was evaluated using the Tinnitus Handicap Inventory (THI). Acufenometry was used to provide an instrumental and objective quantification of tinnitus. All participants were examined at baseline, and at the end of 40 and 80 days. Audiological investigations, including THI, acufenometry, Pure Tone Audiogram (PTA), and Speech Discrimination Score (SDS), were used to assess participants on auditory function during the follow-up period. Among the 34 participants in group A, 27 patients showed improvement (79.4%), while six patients exhibited no change (17.6%) in THI and acufenometry. Overall, results in THI and acufenometry showed significant improvement at the end of therapy for group A (p<0.05). Twenty participants in group B showed improvement (58.8%) after 40 and 80 days, although without improvements in acufenometry. However, these differences were not statistically significant. The control group did not show any statistical deviation from baseline. Limitations of this study include the lack of blinding, a placebo group, and power calculations. Furthermore, it should be noted that the lack of a sulodexide-alone group precludes any conclusions concerning melatonin's contribution to the improvements seen in the combination treatment group.

Urination (nocturia)

• Summary: Melatonin may have beneficial effects for nocturia in the elderly. Nonrandomized trials have also been conducted (562), producing conflicting results (1211). Further research is needed before a recommendation can be made.
• Evidence: Drake et al. conducted a randomized, placebo controlled, double-blind crossover trial to investigate melatonin as a potential treatment for nocturia associated with bladder outflow obstruction in 20 older men (561). Inclusion criteria were men with palpable benign prostate enlargement on digital rectal examination and videourodynamic confirmed bladder outflow obstruction. Exclusion criteria included evidence of alternative lower urinary tract pathology, renal or hepatic impairment, history of surgical treatment for bladder outflow obstruction, and use within the preceding month of diuretics, beta-adrenergic antagonists, 5-alpha-reductase inhibitors, antidepressants, or sedatives. The men received 2mg of controlled-release melatonin or placebo each night for four weeks, with a seven-day washout in between. Symptoms were assessed using a frequency volume chart, the International Prostate Symptom Score, and symptom problem index. Maximum urinary flow rate and postvoid residual urine volume were also assessed. Baseline frequency of nocturia was 3.1 episodes per night. There were seven men (35%) with detrusor overactivity, and 10 (50%) had nocturnal polyuria. Melatonin and placebo caused a decrease in nocturia of 0.32 and 0.05 episodes per night (p=0.07), respectively, and a decrease in the nocturia bother score of 0.51 and 0.05, respectively (p=0.008). Nocturia responder rates (a reduction from baseline of at least -0.5 episodes per night) differed between the active medication and placebo groups (p=0.04). Daytime urinary frequency, International Prostate Symptom Score, relative nocturnal urine volume, maximum urinary flow rate, and postvoid residual were reported to be unaffected by melatonin treatment. No adverse effects were detected. This study is limited by the lack of description of randomization and blinding.

UV-induced erythema prevention/sunburn

• Summary: Of the several small trials in healthy humans that have examined the use of melatonin in protecting human skin against UV-light damage, some clinical and in vivo studies suggest a dose-response relationship (577;​579), while other clinical trials do not (580). Although this preliminary research reported reductions in erythema (skin redness) with the use of melatonin, further research is necessary before a clear conclusion can be drawn about clinical effectiveness in humans.
• Evidence: Fischer et al. conducted a double-blind, randomized clinical trial to assess the effects of topical melatonin on UV-suppressive effect in 20 healthy volunteers (578). Volunteers were 15 males and five females with skin types II or III (often burn and rarely tan). They were free of acute and chronic disease at study time. The lower back of the volunteers was treated with 0.6mg/cm² of melatonin or vehicle at various time points: 15 minutes before or 1, 30, or 240 minutes after UV irradiation. The main endpoint was erythema, which was evaluated visually and measured by chromometry 24 hours after irradiation. Application of melatonin 15 minutes before irradiation resulted in a significant suppression of erythema vs. vehicle alone, when assessed visually (p<0.001). Similar results were found by chromometry (p<0.001). Treatment after irradiation had no UV suppressive effect. Adverse effects were not discussed. Radical scavenging was suggested as a mechanism of action. Limitations of this study include lack of description of randomization, blinding, and withdrawals.
• Bangha et al. conducted a randomized, double-blind trial to assess the efficacy of topically applied melatonin in the suppression of UV-induced erythema in 20 healthy volunteers (577). Volunteers were 12 males and eight females with skin types II or III (often burn and rarely tan). They were free of skin disease. Volunteers were irradiated with 0.099J/cm² of UV-B on the lower back. Patients were treated with melatonin (0.05, 0.1, 0.5%) in a nanocolloid gel (0.12mL) as carrier or with carrier alone immediately after irradiation. The UV-induced erythema was examined eight and 24 hours after irradiation by visual scoring and chromometry. The authors reported a dose-response relationship observed between the topical dose of melatonin and the degree of UV-induced erythema. However, statistically significant differences (p<0.05) were found in redness (chromometer a-value and visual scoring) eight hours after irradiation between the areas treated with melatonin at 0.5% only vs. melatonin at 0.05% or with the carrier. Adverse effects were not discussed. Limitations of this study include lack of description of randomization, blinding, and withdrawals.
• Howes et al. conducted a double-blind study to assess the effects of topical melatonin on solar-simulated UV-induced suppression of Mantoux reactions in 16 healthy, Mantoux-positive volunteers (580). Volunteers had no sun exposure to the back in the four weeks preceding or during the study. Inclusion and exclusion criteria were not provided. Following an initial minimal erythema dose (MED) test (upper back; no lotions applied) and initial Mantoux tests (mid-back) to determine appropriate dosing, melatonin (5%) or its ethanol, propylene glycol, and water vehicle (2:1:1) were applied to separate areas on the lower back, immediately after each of three consecutive daily UV exposures. Mantoux testing was performed at each site 24 hours after the final irradiation. The authors also conducted a separate study of 19 volunteers to assess the effect of melatonin on minimal erythema dose. All subjects completed the study. Adverse effects were not discussed. There were no significant effects of melatonin on immune suppression or sunburn in this population. This study was not indicated as randomized, and the method of blinding was not described.

Work shift sleep disorder

• Summary: Chronic circadian disturbance is thought to cause many of the health and social problems reported by shift workers. There are several studies of melatonin use in people who work irregular shifts, such as emergency room personnel (4;​566;​567;​568;​569;​572;​1212). Results are mixed, with some studies finding no statistically significant benefits, and others reporting benefits in sleep quality compared to placebo. Because most published trials are small, with incomplete reporting of design or results, additional research is necessary before a clear conclusion can be drawn.
• Systematic review: Buscemi et al. conducted a systematic review to review the efficacy and safety of exogenous melatonin in managing secondary sleep disorders and sleep disorders accompanying sleep restriction, such as jet lag and shift work disorder (612). Searches were conducted from 1999 to 2003, with additional MEDLINE and Embase searches in 2004. Randomized controlled trials were assessed by using the Jadad Scale and criteria by Schulz et al., and nonrandomized controlled trials by the Downs and Black checklist. The inverse variance method was used to weight studies, and the random-effects model was used to analyze data. There was considerable heterogeneity across studies with respect to dosage and duration (days to weeks) of melatonin administration. Nine trials (with 427 participants) (4;​485;​488;​491;​530;​567;​568;​569;​572) were included in the efficacy analysis for secondary sleep disorders. The median quality score was 4 out of 5 (Jadad score). The authors reported that there was no evidence that melatonin had an effect on sleep onset latency in people who had sleep disorders accompanying sleep restriction (-1.0 minutes (-2.3 to 0.3)). For analysis of melatonin for sleep onset latency, six randomized controlled trials with 97 participants showed no evidence of benefit of melatonin (weighted mean difference: -13.2 minutes (95% confidence interval, -27.3 to 0.9)). Ten studies (with 487 participants) were included in the safety analysis. The most commonly reported adverse events were headaches, dizziness, nausea, and drowsiness. The occurrence of these outcomes was similar for melatonin and placebo.
• Evidence: Bjorvatn et al. conducted a randomized, controlled crossover trial to evaluate the effects of bright light and melatonin on adaptation to night work on an oil rig in the North Sea in 38 volunteers (563). Inclusion criteria included problems adjusting to shift work (more than three days needed to adapt or readapt) and overall rating of sleep problems as more than moderate. It was indicated that 17 completed the study; reasons for noncompletion included not being interested in taking part. Thus, the actual number randomized was not clear. The volunteers worked a schedule of two weeks on a 12-hour shift, with the first week on night shift and the second week on day shift (swing shift schedule). The shift workers received a placebo, melatonin (3mg, one hour before bedtime), or bright light (30-minute exposure, individually scheduled) during the first four days on the night shift and during the first four days on the day shift. Subjective and objective measures of sleepiness (Karolinska Sleepiness Scale and a simple serial reaction-time test) and sleep (diary and actigraphy) were recorded. Melatonin significantly reduced irresistible sleepiness, fighting sleep, and quality of day vs. placebo. Sleep time and sleep efficiency also modestly improved. Side effects were low, although one subject in the melatonin group had more intense dreams. Given the number of endpoints in this study, it is not surprising that there were some significant changes. Limitations include the unclear number of subjects randomized and the lack of description of randomization.
• Cavallo et al. conducted a double-blind, randomized, placebo controlled, crossover study to test whether melatonin reduces the deleterious effects of night shift work on sleep, mood, and attention in pediatric residents during night float rotation (564). Volunteers had to have been willing to abstain from alcoholic beverages and sedative or hypnotic drugs during each period of the study. Exclusion criteria were presence of infants or toddlers in the household, chronic illness, pregnancy, present or past depression, use of sedatives or hypnotic drugs during the two weeks preceding each period of the study, use of exogenous melatonin, and use of light treatment devices. The volunteers were generally healthy second-year pediatric residents working two night float rotations. They took melatonin (3mg) or a placebo before bedtime in the morning after a night shift, completed a sleep diary and an adverse-effects questionnaire daily, and completed the Profile of Mood States and the Conners Continuous Performance Test three times in each study week to test mood and attention, respectively. Outcomes measures included standardized measures of sleep, mood, and attention. Twenty-eight residents completed both treatments; 17 completed one treatment (10 placebo, seven melatonin) (no reason provided for completing only one test). Only one test for attention (the number of omission errors) was significantly lower on melatonin (3.0 ± 9.6) than on placebo (4.5 ± -17.5) (z=-2.12, p=0.03). There were no statistically significant differences in measures of sleep, mood, and five of six measures of attention during melatonin and placebo treatment. Adverse effects were minimal, although one resident complained of five days of nightmares while sleeping. Limitations include the unclear method of randomization (although simple randomization was indicated). Also, it was indicated that some of the residences completed two treatment arms, whereas others completed one, but it was not indicated why this occurred.
• Dawson et al. conducted a randomized placebo controlled study to compare adaptation to a night shift in three groups of subjects (566). Inclusion and exclusion criteria were not provided. Patients received timed exposure to bright light (4-7,000 lux between midnight and 4 a.m. on each of three night shifts), exogenous melatonin by capsule (2mg at 8 a.m., then 1mg at 11 a.m. and 2 p.m.), dim red light at less than 50 lux, or placebo (sucrose) in identical capsules. Results indicated that all groups shifted from baseline in a statistically significant manner; however, melatonin did not show statistically significant differences from placebo on most outcomes measures. Sleep quality was significantly improved in the melatonin group, but movement index (sleep efficiency) was not. Melatonin had no effect on cognitive performance. Core temperature decreased on the third day in the melatonin group. This study was indicated as randomized; however, the bright-light part of the study was run at a separate time of year than the melatonin study, suggesting it was not truly randomized. Also, the study was not indicated as double-blind, although placebo was indicated as identical.
• Smith et al. conducted a placebo controlled trial to determine whether melatonin had a soporific effect (571). It was indicated that the methods were described in more detail in another article (565). Participants were included if they were free of medical and psychiatric disorders. Patients were excluded if they had disturbed nighttime sleep, excessive daytime sleepiness, or irregular sleep habits. People taking prescription medications other than oral contraceptives were excluded. Patients were given melatonin (1.8mg of sustained-release) in a double-blind manner. They took the capsule at 8:30 a.m., prior to daytime sleep. Saliva samples were taken upon awakening at 3:30 p.m. The melatonin volunteers in this study were matched with subjects given placebo in the previous study. It was possible to match N=18 of the 20 patients given melatonin with placebo subjects, so the final N=36. Matching was based on similar baseline and final dim-light melatonin onset (DLMO) (±1 hour). Endpoints included sleep log measurements of total sleep time (TST) and actigraphic measurements of sleep latency, TST, and three movement indices. Melatonin was associated with small improvements in sleep quality and quantity; however, the differences were not statistically significant by analysis of variance. Binomial analysis indicated that melatonin participants were more likely to sleep better than their placebo counterparts on some days with some measures. The placebo was indicated as identical. However, the study was not randomized.
• Sharkey et al. conducted a placebo controlled, double-blind, crossover study to assess the effects of melatonin on shift work (570). Subjects (mean age: 27.0 ± 5.0 years) with no obvious medical, psychiatric, or sleep disorders were included if they were free from prescription medications, including oral contraceptives, and had not worked a night shift job during the three months prior to the study or had travelled across more than two time zones during the month prior to the study. The volunteers participated in two six-day laboratory sessions. A half-hour before each session, they took 1.8mg of sustained-release melatonin or placebo, in a crossover manner. Polysomnography recorded sleep; the multiple sleep latency test (MSLT) and a computerized neurobehavioral testing battery evaluated sleepiness, performance, and mood during the night shifts. Melatonin significantly prevented the decrease in sleep time during daytime sleep relative to baseline, but only on the first day of melatonin administration. Total sleep time, sleep latency, movement, and other endpoints were not significantly affected. Melatonin had no effect on alertness on the MSLT, or performance and mood during the night shift. There were no hangover effects from melatonin administration. Adverse effects were not discussed. It was indicated that 21 subjects completed the study; however, the number of studies starting the study is not clear. This study was not randomized, and identical nature of capsules was not described.
• Crowley et al. conducted a placebo controlled trial to examine the effects of melatonin on correcting the misalignment associated with night work and day sleep (565). Participants (median age: 22, N=67) participated in five consecutive simulated night shifts (11 p.m. to 7 a.m.) and then slept at home (8:30 a.m. to 3:30 p.m.) in darkened bedrooms. Participants wore sunglasses with normal or dark lenses (transmission 15% or 2%) when outside during the day. Participants took placebo or melatonin (1.8mg of sustained-release) before daytime sleep. During the night shifts, participants were exposed to a moving (delaying) pattern of intermittent bright light (approximately 5000 lux, 20 minutes on, 40 minutes off, 4-5 light pulses/night) or remained in dim light (approximately 150 lux). There were six intervention groups, ranging from the least complex (normal sunglasses) to the most complex (dark sunglasses + bright light + melatonin). Dim-light melatonin onset (DLMO) was assessed before and after the night shifts (baseline and final), and seven hours was added to estimate the temperature minimum (Tmin). Participants were categorized by their amount of re-entrainment based on their final Tmin: not re-entrained (Tmin before the daytime dark/sleep period), partially re-entrained (Tmin during the first half of dark/sleep), or completely re-entrained (Tmin during the second half of dark/sleep). The sample was split into earlier participants (baseline Tmin ≤0700, sunlight during the commute home fell after the Tmin) and later participants (baseline Tmin >0700). The authors reported that the later participants were completely re-entrained regardless of intervention group, whereas the degree of re-entrainment for the earlier participants depended on the interventions. With bright light during the night shift, almost all of the earlier participants achieved complete re-entrainment, and the phase delay shift was so large that darker sunglasses and melatonin could not increase its magnitude. With only room light during the night shift, darker sunglasses helped the earlier participants' phase-delay more than normal sunglasses, but melatonin did not increase the phase delay. The authors recommended the combination of intermittent bright light during the night shift, sunglasses (as dark as possible) during the commute home, and a regular, early daytime dark/sleep period if the goal is complete circadian adaptation to night-shift work.

Products Studied

Brands used in clinical trials:

• Melatonin® (Penn Pharmaceuticals Ltd., United States) (1208); Circadin® (Neurim Pharmaceuticals Ltd., Tel Aviv, Israel) (426;​466;​476;​477;​513;​975); Melaxen® (421); Armonia Retard, Nathura s.r.l., Montecchio Emila RE, Italy (465); Duchefa Farma BV, Haarlem, the Netherlands (598).

Brands shown to contain claimed ingredients through third-party testing:

• Consumer Lab: In 2002, ConsumerLab.com evaluated 18 melatonin-containing supplements (15 quick-release and three time-release products), of which 12 were melatonin-only products. It was reported that 16 of the 18 products contained 100-135% of the claimed amount of melatonin, one rapid-release product contained only 83% of the claimed amount of melatonin, and another rapid-release product contained a small amount of lead (slightly more than 0.5mcg per daily recommended serving size). Among the 12 melatonin-only products that "passed" these standards are: Nature's Bounty® Melatonin 1mg and 3mg tablets, Puritan's Pride® Inspired by Nature® Melatonin 3mg tablets, and Twinlab® Melatonin Caps, Highest Quality, Quick Acting 3mg tablets.
• Consumer Reports: Not applicable.
• Natural Products Association: Not applicable.
• NSF International: Not applicable.
• U.S. Pharmacopeia: Not applicable.

Select patents within the United States:

• US5071875 - Substituted 2-amidotetralins as melatonin agonists and antagonists
• US4746674 - Melatonin compositions and uses thereof
• US4855305 - Compositions and methods of effecting contraception utilizing melatonin
• US5700828 - Treatment or prevention of anoxic or ischemic brain injury with melatonin
• US5885976 - Methods useful for the treatment of neurological and mental disorders

Select patents outside the United States:

• EP2034988 - Preparation for preventing ageing symptoms containing phytoestrogens and melatonin
• EP2028937 - Hair treatment compositions with alcohol(s) and melatonin/agomelatine
• WO2009024361 - Hair treatment compositions with surfactant(s) and melatonin/agomelatin
• WO2009024360 - Hair treatment agent with conditioner(s) and melatonin/agomelatin
• WO2009024359 - Preventive of magnetic storms effect on patients suffering from with ischemic heart disease and essential hypertension and method of application thereof

Author Information

• Authors/Editors: Ethan Basch, MD (Memorial Sloan-Kettering Cancer Center); Heather Boon, BScPhm, PhD (University of Toronto); Michelle Corrado, PharmD (Harvard Vanguard Medical Association); Dawn Costa, BA, BS (Natural Standard Research Collaboration); Samantha Culwell, PharmD (Natural Standard Research Collaboration); Cynthia Dacey, PharmD (Natural Standard Research Collaboration); Paul Hammerness, MD (Harvard Medical School); Elizabeth R.B. Higdon, PharmD (Natural Standard Research Collaboration); Ramon Iovin, PhD (Natural Standard Research Collaboration); Margaret Lynch, PhD (Natural Standard Research Collaboration); Jill M. Grimes Serrano, PhD (Natural Standard Research Collaboration); Michael Shaffer, MA (University of Florida); Toni Schaeffer, PhD, PharmD (Albany College of Pharmacy); Candy Tsourounis, PharmD (University of California, San Francisco); Catherine Ulbricht, PharmD (Massachusetts General Hospital); Mamta Vora, PharmD (Northeastern University); Regina C. Windsor, MPH (Natural Standard Research Collaboration); Sara Zhou, PharmD (Natural Standard Research Collaboration).
• Blinded Peer-Review: Natural Standard Editorial Board.

References

Natural Standard developed the above evidence-based information based on a thorough systematic review of the available scientific articles. For comprehensive information about alternative and complementary therapies on the professional level, go to www.naturalstandard.com. Selected references are listed below.

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83. Cruz, A., Tasset, I., Ramirez, L. M., Arjona, A., Segura, J., Tunez, I., Montilla, P., Muntane, J., and Padillo, F. J. Effect of melatonin on myocardial oxidative stress induced by experimental obstructive jaundice. Rev.Esp.Enferm.Dig. 2009;101(7):460-463. View Abstract
84. Kaur, C., Sivakumar, V., and Ling, E. A. Melatonin protects periventricular white matter from damage due to hypoxia. J.Pineal Res. 2010;48(3):185-193. View Abstract
85. Malekinejad, H., Farshid, A. A., and Mirzakhani, N. Liquorice plant extract reduces ochratoxin A-induced nephrotoxicity in rats. Exp.Toxicol.Pathol. 11-20-2009;0. View Abstract
86. Akmali, M., Ahmadi, R., and Vessal, M. Pre- and post-treatment of streptozocin administered rats with melatonin: effects on some hepatic enzymes of carbohydrate metabolism. Arch.Iran Med. 2010;13(2):105-110. View Abstract
87. Millan-Plano, S., Piedrafita, E., Miana-Mena, F. J., Fuentes-Broto, L., Martinez-Ballarin, E., Lopez-Pingarron, L., Saenz, M. A., and Garcia, J. J. Melatonin and structurally-related compounds protect synaptosomal membranes from free radical damage. Int.J.Mol.Sci. 2010;11(1):312-328. View Abstract
88. Espino, J., Bejarano, I., Ortiz, A., Lozano, G. M., Garcia, J. F., Pariente, J. A., and Rodriguez, A. B. Melatonin as a potential tool against oxidative damage and apoptosis in ejaculated human spermatozoa. Fertil.Steril. 2010;94(5):1915-1917. View Abstract
89. Wiktorska, J. A., Lewinski, A., Stuss, M., Nowak, D., Pietras, T., and Sewerynek, E. Effects of certain antioxidants on lipid peroxidation process in lung homogenates of L thyroxine-receiving rats. Neuro.Endocrinol.Lett. 2010;31(1):137-146. View Abstract
90. Dilek, M., Naziroglu, M., Baha, Oral H., Suat, Ovey, I, Kucukayaz, M., Mungan, M. T., Kara, H. Y., and Sutcu, R. Melatonin modulates hippocampus NMDA receptors, blood and brain oxidative stress levels in ovariectomized rats. J.Membr.Biol. 2010;233(1-3):135-142. View Abstract
91. Yurtcu, M., Abasiyanik, A., Bicer, S., and Avunduk, M. C. Efficacy of antioxidant treatment in the prevention of testicular atrophy in experimental testicular torsion. J.Pediatr.Surg. 2009;44(9):1754-1758. View Abstract
92. Jung, K. H., Hong, S. W., Zheng, H. M., Lee, D. H., and Hong, S. S. Melatonin downregulates nuclear erythroid 2-related factor 2 and nuclear factor-kappaB during prevention of oxidative liver injury in a dimethylnitrosamine model. J.Pineal Res. 2009;47(2):173-183. View Abstract
93. Kaji, H., Inukai, Y., Maiguma, T., Ono, H., Teshima, D., Hiramoto, K., and Makino, K. Radical scavenging activity of bisbenzylisoquinoline alkaloids and traditional prophylactics against chemotherapy-induced oral mucositis. J.Clin.Pharm.Ther. 2009;34(2):197-205. View Abstract
94. Bharti, V. K. and Srivastava, R. S. Fluoride-induced oxidative stress in rat's brain and its amelioration by buffalo (Bubalus bubalis) pineal proteins and melatonin. Biol.Trace Elem.Res. 2009;130(2):131-140. View Abstract
95. Pan, L., Fu, J. H., Xue, X. D., Xu, W., Zhou, P., and Wei, B. Melatonin protects against oxidative damage in a neonatal rat model of bronchopulmonary dysplasia. World J.Pediatr. 2009;5(3):216-221. View Abstract
96. Gomez-Moreno, G., Guardia, J., Ferrera, M. J., Cutando, A., and Reiter, R. J. Melatonin in diseases of the oral cavity. Oral Dis. 2010;16(3):242-247. View Abstract
97. Bekyarova, G., Galunska, B., Ivanova, D., and Yankova, T. Effect of melatonin on burn-induced gastric mucosal injury in rats. Burns 2009;35(6):863-868. View Abstract
98. Bekyarova, G., Tancheva, S., and Hristova, M. Protective effect of melatonin against oxidative hepatic injury after experimental thermal trauma. Methods Find.Exp.Clin.Pharmacol. 2009;31(1):11-14. View Abstract
99. Makay, B., Makay, O., Yenisey, C., Icoz, G., Ozgen, G., Unsal, E., Akyildiz, M., and Yetkin, E. The interaction of oxidative stress response with cytokines in the thyrotoxic rat: is there a link? Mediators.Inflamm. 2009;2009:391682. View Abstract
100. Huang, L. T., Tiao, M. M., Tain, Y. L., Chen, C. C., and Hsieh, C. S. Melatonin ameliorates bile duct ligation-induced systemic oxidative stress and spatial memory deficits in developing rats. Pediatr.Res. 2009;65(2):176-180. View Abstract
101. Pan, L., Xu, W., Fu, J. H., and Xue, X. D. [Effect of melatonin on hyperoxia-induced oxidant/antioxidant imbalance in the lung of neonatal rats with chronic lung disease]. Zhongguo Dang.Dai Er.Ke.Za Zhi. 2009;11(7):581-584. View Abstract
102. Xu, S., Zhou, Z., Zhang, L., Yu, Z., Zhang, W., Wang, Y., Wang, X., Li, M., Chen, Y., Chen, C., He, M., Zhang, G., and Zhong, M. Exposure to 1800 MHz radiofrequency radiation induces oxidative damage to mitochondrial DNA in primary cultured neurons. Brain Res. 1-22-2010;1311:189-196. View Abstract
103. Venkataraman, P., Selvakumar, K., Krishnamoorthy, G., Muthusami, S., Rameshkumar, R., Prakash, S., and Arunakaran, J. Effect of melatonin on PCB (Aroclor 1254) induced neuronal damage and changes in Cu/Zn superoxide dismutase and glutathione peroxidase-4 mRNA expression in cerebral cortex, cerebellum and hippocampus of adult rats. Neurosci.Res. 2010;66(2):189-197. View Abstract
104. Uluocak, N., Atilgan, D., Erdemir, F., Parlaktas, B. S., Yasar, A., Erkorkmaz, U., and Akbas, A. An animal model of ischemic priapism and the effects of melatonin on antioxidant enzymes and oxidative injury parameters in rat penis. Int.Urol.Nephrol. 1-30-2010;0. View Abstract
105. Ortega-Gutierrez, S., Lopez-Vicente, M., Lostale, F., Fuentes-Broto, L., Martinez-Ballarin, E., and Garcia, J. J. Protective effect of melatonin against mitomycin C-induced genotoxic damage in peripheral blood of rats. J.Biomed.Biotechnol. 2009;2009:791432. View Abstract
106. Kumar, A. and Singh, A. Possible involvement of GABAergic mechanism in protective effect of melatonin against sleep deprivation-induced behaviour modification and oxidative damage in mice. Fundam.Clin.Pharmacol. 2009;23(4):439-448. View Abstract
107. Yoo, Y. M. and Jeung, E. B. Melatonin-induced estrogen receptor alpha-mediated calbindin-D9k expression plays a role in H2O2-mediated cell death in rat pituitary GH3 cells. J.Pineal Res. 2009;47(4):301-307. View Abstract
108. Venkataraman, P., Krishnamoorthy, G., Selvakumar, K., and Arunakaran, J. Oxidative stress alters creatine kinase system in serum and brain regions of polychlorinated biphenyl (Aroclor 1254)-exposed rats: protective role of melatonin. Basic Clin.Pharmacol.Toxicol. 2009;105(2):92-97. View Abstract
109. Wisessmith, W., Phansuwan-Pujito, P., Govitrapong, P., and Chetsawang, B. Melatonin reduces induction of Bax, caspase and cell death in methamphetamine-treated human neuroblastoma SH-SY5Y cultured cells. J.Pineal Res. 2009;46(4):433-440. View Abstract
110. Takei, A., Okawa, M., Sasaki, H., Hamada, T., and Tashiro, K. [Effective melatonin therapy in a case of Machado-Joseph disease with insomnia]. Rinsho Shinkeigaku 2000;40(7):736-740. View Abstract
111. Kim, T. H., Jung, J. A., Kim, G. D., Jang, A. H., Ahn, H. J., Park, Y. S., and Park, C. S. Melatonin inhibits the development of 2,4-dinitrofluorobenzene-induced atopic dermatitis-like skin lesions in NC/Nga mice. J.Pineal Res. 2009;47(4):324-329. View Abstract
112. Hassler, F., Duck, A., Reis, O., and Buchmann, J. [Alternative agents used in ADHD]. Z.Kinder Jugendpsychiatr.Psychother. 2009;37(1):13-24, quiz. View Abstract
113. van den Heuvel, C. J., Reid, K. J., and Dawson, D. Effect of atenolol on nocturnal sleep and temperature in young men: reversal by pharmacological doses of melatonin. Physiol Behav. 1997;61(6):795-802. View Abstract
114. Mayeda, A., Mannon, S., Hofstetter, J., Adkins, M., Baker, R., Hu, K., and Nurnberger, J., Jr. Effects of indirect light and propranolol on melatonin levels in normal human subjects. Psychiatry Res 10-19-1998;81(1):9-17. View Abstract
115. Maldonado, M. D., Perez-San-Gregorio, M. A., and Reiter, R. J. The role of melatonin in the immuno-neuro-psychology of mental disorders. Recent Pat CNS.Drug Discov. 2009;4(1):61-69. View Abstract
116. Nierenberg, A. A. Low-dose buspirone, melatonin and low-dose bupropion added to mood stabilizers for severe treatment-resistant bipolar depression. Psychother.Psychosom. 2009;78(6):391-393. View Abstract
117. Onur, R., Ozcan, M., Tuygun, U., Ozan, T., Ayar, A., and Orhan, I. Effects of combined use of trospium chloride and melatonin on in vitro contractility of rat urinary bladder. Urology 2010;75(4):873-877. View Abstract
118. Abdel-Wanis, M. E. and Tsuchiya, H. Melatonin deficiency and fibrous dysplasia: might a relation exist? Med Hypotheses 2002;59(5):552-554. View Abstract
119. Munoz, F., Lopez-Pena, M., Mino, N., Gomez-Moreno, G., Guardia, J., and Cutando, A. Topical Application of Melatonin and Growth Hormone Accelerates Bone Healing around Dental Implants in Dogs. Clin.Implant.Dent.Relat Res. 9-29-2009;0. View Abstract
120. Guardia, J., Gomez-Moreno, G., Ferrera, M. J., and Cutando, A. Evaluation of Effects of Topic Melatonin on Implant Surface at 5 and 8 Weeks in Beagle Dogs. Clin.Implant.Dent.Relat Res. 8-3-2009;0. View Abstract
121. Calvo-Guirado, J. L., Gomez-Moreno, G., Barone, A., Cutando, A., Alcaraz-Banos, M., Chiva, F., Lopez-Mari, L., and Guardia, J. Melatonin plus porcine bone on discrete calcium deposit implant surface stimulates osteointegration in dental implants. J.Pineal Res. 2009;47(2):164-172. View Abstract
122. Arushanian, E. B., Naumov, S. S., and Ponomareva, V. A. [Protective effect of melatonin on behavioral and morphological disturbances induced by cerebrocranial trauma in different daytime in rats]. Eksp.Klin.Farmakol. 2009;72(5):18-21. View Abstract
123. Li, Z. Q., Liang, G. B., Xue, Y. X., and Liu, Y. H. Effects of combination treatment of dexamethasone and melatonin on brain injury in intracerebral hemorrhage model in rats. Brain Res. 4-6-2009;1264:98-103. View Abstract
124. Lee, S., Jadhav, V., Ayer, R. E., Rojas, H., Hyong, A., Lekic, T., Tang, J., and Zhang, J. H. Dual effects of melatonin on oxidative stress after surgical brain injury in rats. J.Pineal Res. 2009;46(1):43-48. View Abstract
125. Samantaray, S., Das, A., Thakore, N. P., Matzelle, D. D., Reiter, R. J., Ray, S. K., and Banik, N. L. Therapeutic potential of melatonin in traumatic central nervous system injury. J.Pineal Res. 2009;47(2):134-142. View Abstract
126. Persson, C., Glimelius, B., Ronnelid, J., and Nygren, P. Impact of fish oil and melatonin on cachexia in patients with advanced gastrointestinal cancer: a randomized pilot study. Nutrition 2005;21(2):170-178. View Abstract
127. Mattox, T. W. Treatment of unintentional weight loss in patients with cancer. Nutr Clin Pract. 2005;20(4):400-410. View Abstract
128. Dominguez-Rodriguez, A., Abreu-Gonzalez, P., and Reiter, R. J. Clinical aspects of melatonin in the acute coronary syndrome. Curr.Vasc.Pharmacol. 2009;7(3):367-373. View Abstract
129. Rodella, L. F., Filippini, F., Bonomini, F., Bresciani, R., Reiter, R. J., and Rezzani, R. Beneficial effects of melatonin on nicotine-induced vasculopathy. J.Pineal Res. 2010;48(2):126-132. View Abstract
130. Simko, F., Pechanova, O., Pelouch, V., Krajcirovicova, K., Mullerova, M., Bednarova, K., Adamcova, M., and Paulis, L. Effect of melatonin, captopril, spironolactone and simvastatin on blood pressure and left ventricular remodelling in spontaneously hypertensive rats. J.Hypertens.Suppl 2009;27(6):S5-10. View Abstract
131. Paulis, L., Pechanova, O., Zicha, J., Krajcirovicova, K., Barta, A., Pelouch, V., Adamcova, M., and Simko, F. Melatonin prevents fibrosis but not hypertrophy development in the left ventricle of NG-nitro-L-arginine-methyl ester hypertensive rats. J.Hypertens.Suppl 2009;27(6):S11-S16. View Abstract
132. Bonilla, E., Valero, N., Chacin-Bonilla, L., Pons, H., Larreal, Y., Medina-Leendertz, S., and Espina, L. M. Melatonin increases interleukin-1beta and decreases tumor necrosis factor alpha in the brain of mice infected with the Venezuelan equine encephalomyelitis virus. Neurochem.Res 2003;28(5):681-686. View Abstract
133. Piasek, A., Bartoszek, A., and Namiesnik, J. [Phytochemicals that counteract the cardiotoxic side effects of cancer chemotherapy]. Postepy Hig.Med.Dosw.(Online.) 2009;63:142-158. View Abstract
134. Zupancic, D., Vidmar, G., and Jezernik, K. Melatonin prevents the development of hyperplastic urothelium induced by repeated doses of cyclophosphamide. Virchows Arch. 2009;454(6):657-666. View Abstract
135. Pacini, N. and Borziani, F. Action of melatonin on bone marrow depression induced by cyclophosphamide in acute toxicity phase. Neuro.Endocrinol.Lett. 2009;30(5):582-591. View Abstract
136. Ilbey, Y. O., Ozbek, E., Simsek, A., Otunctemur, A., Cekmen, M., and Somay, A. Potential chemoprotective effect of melatonin in cyclophosphamide- and cisplatin-induced testicular damage in rats. Fertil.Steril. 2009;92(3):1124-1132. View Abstract
137. Ohta, Y., Kongo, M., and Kishikawa, T. Melatonin exerts a therapeutic effect on cholestatic liver injury in rats with bile duct ligation. J Pineal Res 2003;34(2):119-126. View Abstract
138. Bubenik, G. A. Gastrointestinal melatonin: localization, function, and clinical relevance. Dig.Dis.Sci. 2002;47(10):2336-2348. View Abstract
139. Dong, W. G., Mei, Q., Yu, J. P., Xu, J. M., Xiang, L., and Xu, Y. Effects of melatonin on the expression of iNOS and COX-2 in rat models of colitis. World J Gastroenterol. 2003;9(6):1307-1311. View Abstract
140. Jan, J. E. and Freeman, R. D. Re: Mann--melatonin for ulcerative colitis? Am.J Gastroenterol. 2003;98(6):1446. View Abstract
141. Mann, S. Melatonin for ulcerative colitis? Am.J Gastroenterol. 2003;98(1):232-233. View Abstract
142. Lisitsa, G. V., Zaslavskaia, R. M., and Kalinina, E. V. [Effectiveness of metabolic preparations in complex treatment of elderly patients with postinfarction cardiosclerosis and circulatory insufficiency]. Klin.Med (Mosk) 2005;83(3):54-57. View Abstract
143. Yoo, Y. M. and Jeung, E. B. Melatonin suppresses cyclosporine A-induced autophagy in rat pituitary GH3 cells. J.Pineal Res. 2010;48(3):204-211. View Abstract
144. Kurus, M., Esrefoglu, M., Sogutlu, G., and Atasever, A. Melatonin prevents cyclosporine-induced hepatotoxicity in rats. Med.Princ.Pract. 2009;18(5):407-410. View Abstract
145. Rezzani, R., Rodella, L. F., Fraschini, F., Gasco, M. R., Demartini, G., Musicanti, C., and Reiter, R. J. Melatonin delivery in solid lipid nanoparticles: prevention of cyclosporine A induced cardiac damage. J.Pineal Res. 2009;46(3):255-261. View Abstract
146. Esrefoglu, M., Kurus, M., and Sahna, E. The beneficial effect of melatonin on chronic cyclosporin A nephrotoxicity in rats. J Int Med Res 2003;31(1):42-44. View Abstract
147. Longoni, B., Migliori, M., Ferretti, A., Origlia, N., Panichi, V., Boggi, U., Filippi, C., Cuttano, M. G., Giovannini, L., and Mosca, F. Melatonin prevents cyclosporine-induced nephrotoxicity in isolated and perfused rat kidney. Free Radic.Res 2002;36(3):357-363. View Abstract
148. Tabet, N. and Howard, R. Pharmacological treatment for the prevention of delirium: review of current evidence. Int.J.Geriatr.Psychiatry 2009;24(10):1037-1044. View Abstract
149. Hanania, M. and Kitain, E. Melatonin for treatment and prevention of postoperative delirium. Anesth.Analg. 2002;94(2):338-9, table. View Abstract
150. Chahbouni, M., Escames, G., Venegas, C., Sevilla, B., Garcia, J. A., Lopez, L. C., Munoz-Hoyos, A., Molina-Carballo, A., and Acuna-Castroviejo, D. Melatonin treatment normalizes plasma pro-inflammatory cytokines and nitrosative/oxidative stress in patients suffering from Duchenne muscular dystrophy. J.Pineal Res. 2010;48(3):282-289. View Abstract
151. Papezova, H., Yamamotova, A., and Nedvidkova, J. Pain modulation role of melatonin in eating disorders. Eur Psychiatry 2001;16(1):68-70. View Abstract
152. Tortosa, F., Puig-Domingo, M., Peinado, M. A., Oriola, J., Webb, S. M., and de Leiva, A. Enhanced circadian rhythm of melatonin in anorexia nervosa. Acta Endocrinol (Copenh) 1989;120(5):574-578. View Abstract
153. Arushanian, E. B., Al Absi, J. M., and Chebotarev, V. V. [The therapeutic activity of melatonin and its effect on immunological parameters of patients with eczema]. Eksp.Klin.Farmakol. 2003;66(3):59-61. View Abstract
154. Yildirim, G., Attar, R., Ozkan, F., Kumbak, B., Ficicioglu, C., and Yesildaglar, N. The effects of letrozole and melatonin on surgically induced endometriosis in a rat model: a preliminary study. Fertil.Steril. 2010;93(6):1787-1792. View Abstract
155. Gur, S., Kadowitz, P. J., and Hellstrom, W. J. A critical appraisal of erectile function in animal models of diabetes mellitus. Int.J.Androl 2009;32(2):93-114. View Abstract
156. Konturek, S. J., Konturek, P. C., Brzozowski, T., and Bubenik, G. A. Role of melatonin in upper gastrointestinal tract. J Physiol Pharmacol 2007;58 Suppl 6:23-52. View Abstract
157. Lahiri, S., Singh, P., Singh, S., Rasheed, N., Palit, G., and Pant, K. K. Melatonin protects against experimental reflux esophagitis. J.Pineal Res. 2009;46(2):207-213. View Abstract
158. Ayaz, M. and Okudan, N. Effects of melatonin supplementation on exercise-induced changes in conduction velocity distributions. Methods Find.Exp.Clin.Pharmacol. 2009;31(3):151-156. View Abstract
159. Tian, X. Z., Wen, Q., Shi, J. M., Liang, Wang, Zeng, S. M., Tian, J. H., Zhou, G. B., Zhu, S. E., and Liu, G. S. Effects of melatonin on in vitro development of mouse two-cell embryos cultured in HTF medium. Endocr.Res. 2010;35(1):17-23. View Abstract
160. Romero-Zerbo, Y., Decara, J., el, Bekay R., Sanchez-Salido, L., Del Arco-Herrera, I., de Fonseca, F. R., and de Diego-Otero, Y. Protective effects of melatonin against oxidative stress in Fmr1 knockout mice: a therapeutic research model for the fragile X syndrome. J.Pineal Res. 2009;46(2):224-234. View Abstract
161. Moezi, L., Nasiripoor, S., Mohajer, V., Maghsoodi, M., Samini, M., and Dehpour, A. R. Gastric healing effect of melatonin against different gastroinvasive agents in cholestatic rats. Pathophysiology. 2010;17(1):65-70. View Abstract
162. Ganguly, K. and Swarnakar, S. Induction of matrix metalloproteinase-9 and -3 in nonsteroidal anti-inflammatory drug-induced acute gastric ulcers in mice: regulation by melatonin. J.Pineal Res. 2009;47(1):43-55. View Abstract
163. Jaworek, J., Brzozowski, T., and Konturek, S. J. Melatonin as an organoprotector in the stomach and the pancreas. J Pineal Res 2005;38(2):73-83. View Abstract
164. Thor, P. J., Krolczyk, G., Gil, K., Zurowski, D., and Nowak, L. Melatonin and serotonin effects on gastrointestinal motility. J Physiol Pharmacol 2007;58 Suppl 6:97-103. View Abstract
165. Pereira, Rde S. Regression of gastroesophageal reflux disease symptoms using dietary supplementation with melatonin, vitamins and aminoacids: comparison with omeprazole. J Pineal Res 2006;41(3):195-200. View Abstract
166. Kim, J. B., Jung, J. Y., Ahn, J. C., Rhee, C. K., and Hwang, H. J. Antioxidant and anti-apoptotic effect of melatonin on the vestibular hair cells of rat utricles. Clin.Exp.Otorhinolaryngol. 2009;2(1):6-12. View Abstract
167. Ye, L. F., Tao, Z. Z., Hua, Q. Q., Xiao, B. K., Zhou, X. H., Li, J., and Yuan, Y. L. Protective effect of melatonin against gentamicin ototoxicity. J.Laryngol.Otol. 2009;123(6):598-602. View Abstract
168. Makay, B. Is there a role of melatonin in the development of growing pains? Med.Hypotheses 2009;72(2):225. View Abstract
169. El Sokkary, G. H., Omar, H. M., Hassanein, A. F., Cuzzocrea, S., and Reiter, R. J. Melatonin reduces oxidative damage and increases survival of mice infected with Schistosoma mansoni. Free Radic.Biol.Med 2-15-2002;32(4):319-332. View Abstract
170. Wu, W., Zhang, G., Wang, Y., and He, C. [The change of serum melatonin and diagnosis value in hepatic encephalopathy]. Zhonghua Gan Zang.Bing.Za Zhi 2000;8(5):272-273. View Abstract
171. Hong, R. T., Xu, J. M., and Mei, Q. Melatonin ameliorates experimental hepatic fibrosis induced by carbon tetrachloride in rats. World J.Gastroenterol. 3-28-2009;15(12):1452-1458. View Abstract
172. Shaker, M. E., Houssen, M. E., Abo-Hashem, E. M., and Ibrahim, T. M. Comparison of vitamin E, L-carnitine and melatonin in ameliorating carbon tetrachloride and diabetes induced hepatic oxidative stress. J.Physiol Biochem. 2009;65(3):225-233. View Abstract
173. Tahan, V., Atug, O., Akin, H., Eren, F., Tahan, G., Tarcin, O., Uzun, H., Ozdogan, O., Tarcin, O., Imeryuz, N., Ozguner, F., Celikel, C., Avsar, E., and Tozun, N. Melatonin ameliorates methionine- and choline-deficient diet-induced nonalcoholic steatohepatitis in rats. J.Pineal Res. 2009;46(4):401-407. View Abstract
174. Imashuku, S., Morimoto, Y., Morimoto, A., Yamamoto, T., Hibi, S., and Todo, S. Pineal dysfunction (low melatonin production) as a cause of sudden death in a long-term survivor of Langerhans cell histiocytosis? Med Pediatr.Oncol. 2003;41(2):151-153. View Abstract
175. Maldonado, M. D., Mora-Santos, M., Naji, L., Carrascosa-Salmoral, M. P., Naranjo, M. C., and Calvo, J. R. Evidence of melatonin synthesis and release by mast cells. Possible modulatory role on inflammation. Pharmacol.Res. 2010;62(3):282-287. View Abstract
176. Lin, G. J., Huang, S. H., Chen, Y. W., Hueng, D. Y., Chien, M. W., Chia, W. T., Chang, D. M., and Sytwu, H. K. Melatonin prolongs islet graft survival in diabetic NOD mice. J.Pineal Res. 2009;47(3):284-292. View Abstract
177. Yang, F. L., Subeq, Y. M., Lee, C. J., Lee, R. P., Peng, T. C., and Hsu, B. G. Melatonin Ameliorates Hemorrhagic Shock-Induced Organ Damage in Rats. J.Surg.Res. 8-15-2009;View Abstract
178. Gitto, E., Pellegrino, S., Gitto, P., Barberi, I., and Reiter, R. J. Oxidative stress of the newborn in the pre- and postnatal period and the clinical utility of melatonin. J.Pineal Res. 2009;46(2):128-139. View Abstract
179. Delagrange, P., Atkinson, J., Boutin, J. A., Casteilla, L., Lesieur, D., Misslin, R., Pellissier, S., Penicaud, L., and Renard, P. Therapeutic perspectives for melatonin agonists and antagonists. J Neuroendocrinol. 2003;15(4):442-448. View Abstract
180. Dominguez-Rodriguez, A., Abreu-Gonzalez, P., Garcia-Gonzalez, M. J., Kaski, J. C., Reiter, R. J., and Jimenez-Sosa, A. A unicenter, randomized, double-blind, parallel-group, placebo-controlled study of Melatonin as an Adjunct in patients with acute myocaRdial Infarction undergoing primary Angioplasty The Melatonin Adjunct in the acute myocaRdial Infarction treated with Angioplasty (MARIA) trial: study design and rationale. Contemp.Clin Trials 2007;28(4):532-539. View Abstract
181. Zaouali, M. A., Ben, Abdennebi H., Padrissa-Altes, S., Mahfoudh-Boussaid, A., and Rosello-Catafau, J. Pharmacological strategies against cold ischemia reperfusion injury. Expert.Opin.Pharmacother. 2010;11(4):537-555. View Abstract
182. Guo, Y., Wang, J., Wang, Z., Yang, Y., Wang, X., and Duan, Q. Melatonin protects N2a against ischemia/reperfusion injury through autophagy enhancement. J.Huazhong.Univ Sci.Technolog.Med.Sci. 2010;30(1):1-7. View Abstract
183. Ersoz, N., Guven, A., Cayci, T., Uysal, B., Turk, E., Oztas, E., Akgul, E. O., Korkmaz, A., and Cetiner, S. Comparison of the efficacy of melatonin and 1400W on renal ischemia/reperfusion injury: a role for inhibiting iNOS. Ren Fail. 2009;31(8):704-710. View Abstract
184. Petrosillo, G., Colantuono, G., Moro, N., Ruggiero, F. M., Tiravanti, E., Di, Venosa N., Fiore, T., and Paradies, G. Melatonin protects against heart ischemia-reperfusion injury by inhibiting mitochondrial permeability transition pore opening. Am.J.Physiol Heart Circ.Physiol 2009;297(4):H1487-H1493. View Abstract
185. Li, Z., Nickkholgh, A., Yi, X., Bruns, H., Gross, M. L., Hoffmann, K., Mohr, E., Zorn, M., Buchler, M. W., and Schemmer, P. Melatonin protects kidney grafts from ischemia/reperfusion injury through inhibition of NF-kB and apoptosis after experimental kidney transplantation. J.Pineal Res. 2009;46(4):365-372. View Abstract
186. Kesik, V., Guven, A., Vurucu, S., Tunc, T., Uysal, B., Gundogdu, G., Oztas, E., and Korkmaz, A. Melatonin and 1400 W ameliorate both intestinal and remote organ injury following mesenteric ischemia/reperfusion. J.Surg.Res. 2009;157(1):e97-e105. View Abstract
187. Sokullu, O., Sanioglu, S., Kurc, E., Sargin, M., Deniz, H., Tartan, Z., Aka, S. A., and Bilgen, F. Does the circadian rhythm of melatonin affect ischemia-reperfusion injury after coronary artery bypass grafting? Heart Surg.Forum 2009;12(2):E95-E99. View Abstract
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191. Diez, E. R., Prados, L. V., Carrion, A., Ponce, Z. A., and Miatello, R. M. A novel electrophysiologic effect of melatonin on ischemia/reperfusion-induced arrhythmias in isolated rat hearts. J.Pineal Res. 2009;46(2):155-160. View Abstract
192. Chen, Z., Chua, C. C., Gao, J., Chua, K. W., Ho, Y. S., Hamdy, R. C., and Chua, B. H. Prevention of ischemia/reperfusion-induced cardiac apoptosis and injury by melatonin is independent of glutathione peroxdiase. J.Pineal Res. 2009;46(2):235-241. View Abstract
193. Baykara, B., Tekmen, I., Pekcetin, C., Ulukus, C., Tuncel, P., Sagol, O., Ormen, M., and Ozogul, C. The protective effects of carnosine and melatonin in ischemia-reperfusion injury in the rat liver. Acta Histochem. 2009;111(1):42-51. View Abstract
194. Liang, R., Nickkholgh, A., Hoffmann, K., Kern, M., Schneider, H., Sobirey, M., Zorn, M., Buchler, M. W., and Schemmer, P. Melatonin protects from hepatic reperfusion injury through inhibition of IKK and JNK pathways and modification of cell proliferation. J.Pineal Res. 2009;46(1):8-14. View Abstract
195. Hamada, F., Watanabe, K., Wakatsuki, A., Nagai, R., Shinohara, K., Hayashi, Y., Imamura, R., and Fukaya, T. Therapeutic effects of maternal melatonin administration on ischemia/reperfusion-induced oxidative cerebral damage in neonatal rats. Neonatology. 2010;98(1):33-40. View Abstract
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197. Kondoh, T., Uneyama, H., Nishino, H., and Torii, K. Melatonin reduces cerebral edema formation caused by transient forebrain ischemia in rats. Life Sci. 12-20-2002;72(4-5):583-590. View Abstract
198. Bulbuller, N., Akkus, M. A., Cetinkaya, Z., Ilhan, Y. S., Ozercan, I., Kirkil, C., and Dogru, O. Effects of melatonin and lactulose on the liver and kidneys in rats with obstructive jaundice. Pediatr.Surg Int 2002;18(8):677-680. View Abstract
199. Marino, A., Di, Paola R., Crisafulli, C., Mazzon, E., Morabito, R., Paterniti, I., Galuppo, M., Genovese, T., La, Spada G., and Cuzzocrea, S. Protective effect of melatonin against the inflammatory response elicited by crude venom from isolated nematocysts of Pelagia noctiluca (Cnidaria, Scyphozoa). J.Pineal Res. 2009;47(1):56-69. View Abstract
200. Tain, Y. L., Hsieh, C. S., Chen, C. C., Sheen, J. M., Lee, C. T., and Huang, L. T. Melatonin prevents increased asymmetric dimethylarginine in young rats with bile duct ligation. J.Pineal Res. 2010;48(3):212-221. View Abstract
201. Wang, Z., Zhang, J., Liu, H., Huang, H., Wang, C., Shen, Y., Li, D., and Jing, H. Melatonin, a potent regulator of hemeoxygenase-1, reduces cardiopulmonary bypass-induced renal damage in rats. J.Pineal Res. 2009;46(3):248-254. View Abstract
202. Ozbek, E., Ilbey, Y. O., Ozbek, M., Simsek, A., Cekmen, M., and Somay, A. Melatonin attenuates unilateral ureteral obstruction-induced renal injury by reducing oxidative stress, iNOS, MAPK, and NF-kB expression. J.Endourol. 2009;23(7):1165-1173. View Abstract
203. Ersahin, M., Sehirli, O., Toklu, H. Z., Suleymanoglu, S., Emekli-Alturfan, E., Yarat, A., Tatlidede, E., Yegen, B. C., and Sener, G. Melatonin improves cardiovascular function and ameliorates renal, cardiac and cerebral damage in rats with renovascular hypertension. J.Pineal Res. 2009;47(1):97-106. View Abstract
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207. Claustrat, B., Chazot, G., Brun, J., Jordan, D., and Sassolas, G. A chronobiological study of melatonin and cortisol secretion in depressed subjects: plasma melatonin, a biochemical marker in major depression. Biol Psychiatry 1984;19(8):1215-1228. View Abstract
208. Beck-Friis, J., Kjellman, B. F., Aperia, B., Unden, F., von Rosen, D., Ljunggren, J. G., and Wetterberg, L. Serum melatonin in relation to clinical variables in patients with major depressive disorder and a hypothesis of a low melatonin syndrome. Acta Psychiatr Scand 1985;71(4):319-330. View Abstract
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210. Srinivasan, V., Spence, D. W., Moscovitch, A., Pandi-Perumal, S. R., Trakht, I., Brown, G. M., and Cardinali, D. P. Malaria: therapeutic implications of melatonin. J.Pineal Res. 2010;48(1):1-8. View Abstract
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214. Murialdo, G., Fonzi, S., Costelli, P., Solinas, G. P., Parodi, C., Marabini, S., Fanciullacci, M., and Polleri, A. Urinary melatonin excretion throughout the ovarian cycle in menstrually related migraine. Cephalalgia 1994;14(3):205-209. View Abstract
215. Salvesen, R. and Bekkelund, S. I. Migraine, as compared to other headaches, is worse during midnight-sun summer than during polar night. A questionnaire study in an Arctic population. Headache 2000;40(10):824-829. View Abstract
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220. Sandyk, R. and Awerbuch, G. I. Relationship of nocturnal melatonin levels to duration and course of multiple sclerosis. Int J Neurosci. 1994;75(3-4):229-237. View Abstract
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222. Acikel, M., Buyukokuroglu, M. E., Aksoy, H., Erdogan, F., and Erol, M. K. Protective effects of melatonin against myocardial injury induced by isoproterenol in rats. J Pineal Res 2003;35(2):75-79. View Abstract
223. Dziegiel, P., Suder, E., Surowiak, P., Jethon, Z., Rabczynski, J., Januszewska, L., Sopel, M., and Zabel, M. Role of exogenous melatonin in reducing the nephrotoxic effect of daunorubicin and doxorubicin in the rat. J Pineal Res 2002;33(2):95-100. View Abstract
224. Dziegiel, P., Jethon, Z., Suder, E., Sopel, M., Rabczynski, J., Surowiak, P., and Zabel, M. Role of exogenous melatonin in reducing the cardiotoxic effect of daunorubicin and doxorubicin in the rat. Exp.Toxicol.Pathol. 2002;53(6):433-439. View Abstract
225. Dziegiel, P., Surowiak, P., Rabczynski, J., and Zabel, M. Effect of melatonin on cytotoxic effects of daunorubicin on myocardium and on transplantable Morris hepatoma in rats. Pol.J Pathol. 2002;53(4):201-204. View Abstract
226. Atik, B., Erkutlu, I., Tercan, M., Buyukhatipoglu, H., Bekerecioglu, M., and Pence, S. The Effects of Exogenous Melatonin on Peripheral Nerve Regeneration and Collagen Formation in Rats. J.Surg.Res. 7-10-2009;0. View Abstract
227. Reiter, R. J., Tan, D. X., Manchester, L. C., and Tamura, H. Melatonin defeats neurally-derived free radicals and reduces the associated neuromorphological and neurobehavioral damage. J Physiol Pharmacol 2007;58 Suppl 6:5-22. View Abstract
228. Lauterbach, E. C., Victoroff, J., Coburn, K. L., Shillcutt, S. D., Doonan, S. M., and Mendez, M. F. Psychopharmacological neuroprotection in neurodegenerative disease: assessing the preclinical data. J.Neuropsychiatry Clin.Neurosci. 2010;22(1):8-18. View Abstract
229. Tasset, I., Espinola, C., Medina, F. J., Feijoo, M., Ruiz, C., Moreno, E., Gomez, M. M., Collado, J. A., Munoz, C., Muntane, J., Montilla, P., and Tunez, I. Neuroprotective effect of carvedilol and melatonin on 3-nitropropionic acid-induced neurotoxicity in neuroblastoma. J.Physiol Biochem. 2009;65(3):291-296. View Abstract
230. Hou, J. W. Smith-Magenis syndrome: report of one case. Acta Paediatr.Taiwan. 2003;44(3):161-164. View Abstract
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232. Lin, A. M., Feng, S. F., Chao, P. L., and Yang, C. H. Melatonin inhibits arsenite-induced peripheral neurotoxicity. J.Pineal Res. 2009;46(1):64-70. View Abstract
233. Negi, G., Kumar, A., Kaundal, R. K., Gulati, A., and Sharma, S. S. Functional and biochemical evidence indicating beneficial effect of Melatonin and Nicotinamide alone and in combination in experimental diabetic neuropathy. Neuropharmacology 2010;58(3):585-592. View Abstract
234. Grandgirard, D. and Leib, S. L. Strategies to prevent neuronal damage in paediatric bacterial meningitis. Curr.Opin.Pediatr. 2006;18(2):112-118. View Abstract
235. Daglioglu, E., Serdar, Dike M., Kilinc, K., Erdogan, D., Take, G., Ergungor, F., Okay, O., and Biyikli, Z. Neuroprotective effect of melatonin on experimental peripheral nerve injury: an electron microscopic and biochemical study. Cen.Eur.Neurosurg. 2009;70(3):109-114. View Abstract
236. Tajes, M., Gutierrez-Cuesta, J., Ortuno-Sahagun, D., Camins, A., and Pallas, M. Anti-aging properties of melatonin in an in vitro murine senescence model: involvement of the sirtuin 1 pathway. J.Pineal Res. 2009;47(3):228-237. View Abstract
237. Olivier, P., Fontaine, R. H., Loron, G., Van, Steenwinckel J., Biran, V., Massonneau, V., Kaindl, A., Dalous, J., Charriaut-Marlangue, C., Aigrot, M. S., Pansiot, J., Verney, C., Gressens, P., and Baud, O. Melatonin promotes oligodendroglial maturation of injured white matter in neonatal rats. PLoS.One. 2009;4(9):e7128. View Abstract
238. Das, A., McDowell, M., Pava, M. J., Smith, J. A., Reiter, R. J., Woodward, J. J., Varma, A. K., Ray, S. K., and Banik, N. L. The inhibition of apoptosis by melatonin in VSC4.1 motoneurons exposed to oxidative stress, glutamate excitotoxicity, or TNF-alpha toxicity involves membrane melatonin receptors. J.Pineal Res. 2010;48(2):157-169. View Abstract
239. Radogna, F., Nuccitelli, S., Mengoni, F., and Ghibelli, L. Neuroprotection by melatonin on astrocytoma cell death. Ann.N.Y.Acad.Sci. 2009;1171:509-513. View Abstract
240. Cilio, M. R. and Ferriero, D. M. Synergistic neuroprotective therapies with hypothermia. Semin.Fetal Neonatal Med. 2010;15(5):293-298. View Abstract
241. Manda, K. and Reiter, R. J. Melatonin maintains adult hippocampal neurogenesis and cognitive functions after irradiation. Prog.Neurobiol. 1-11-2010;90(1):60-68. View Abstract
242. Ozacmak, V. H., Barut, F., and Ozacmak, H. S. Melatonin provides neuroprotection by reducing oxidative stress and HSP70 expression during chronic cerebral hypoperfusion in ovariectomized rats. J.Pineal Res. 2009;47(2):156-163. View Abstract
243. Sheth, D. S., Tajuddin, N. F., and Druse, M. J. Antioxidant neuroprotection against ethanol-induced apoptosis in HN2-5 cells. Brain Res. 8-18-2009;1285:14-21. View Abstract
244. Ramirez-Rodriguez, G., Klempin, F., Babu, H., Benitez-King, G., and Kempermann, G. Melatonin modulates cell survival of new neurons in the hippocampus of adult mice. Neuropsychopharmacology 2009;34(9):2180-2191. View Abstract
245. Ritzenthaler, T., Nighoghossian, N., Berthiller, J., Schott, A. M., Cho, T. H., Derex, L., Brun, J., Trouillas, P., and Claustrat, B. Nocturnal urine melatonin and 6-sulphatoxymelatonin excretion at the acute stage of ischaemic stroke. J.Pineal Res. 2009;46(3):349-352. View Abstract
246. Ersahin, M., Toklu, H. Z., Cetinel, S., Yuksel, M., Yegen, B. C., and Sener, G. Melatonin reduces experimental subarachnoid hemorrhage-induced oxidative brain damage and neurological symptoms. J.Pineal Res. 2009;46(3):324-332. View Abstract
247. Signorini, C., Ciccoli, L., Leoncini, S., Carloni, S., Perrone, S., Comporti, M., Balduini, W., and Buonocore, G. Free iron, total F-isoprostanes and total F-neuroprostanes in a model of neonatal hypoxic-ischemic encephalopathy: neuroprotective effect of melatonin. J.Pineal Res. 2009;46(2):148-154. View Abstract
248. Chen, H. Y., Hung, Y. C., Chen, T. Y., Huang, S. Y., Wang, Y. H., Lee, W. T., Wu, T. S., and Lee, E. J. Melatonin improves presynaptic protein, SNAP-25, expression and dendritic spine density and enhances functional and electrophysiological recovery following transient focal cerebral ischemia in rats. J.Pineal Res. 2009;47(3):260-270. View Abstract
249. Hutton, L. C., Abbass, M., Dickinson, H., Ireland, Z., and Walker, D. W. Neuroprotective properties of melatonin in a model of birth asphyxia in the spiny mouse (Acomys cahirinus). Dev.Neurosci. 2009;31(5):437-451. View Abstract
250. Kongsuphol, P., Mukda, S., Nopparat, C., Villarroel, A., and Govitrapong, P. Melatonin attenuates methamphetamine-induced deactivation of the mammalian target of rapamycin signaling to induce autophagy in SK-N-SH cells. J.Pineal Res. 2009;46(2):199-206. View Abstract
251. Saxena, G., Bharti, S., Kamat, P. K., Sharma, S., and Nath, C. Melatonin alleviates memory deficits and neuronal degeneration induced by intracerebroventricular administration of streptozotocin in rats. Pharmacol.Biochem.Behav. 2010;94(3):397-403. View Abstract
252. Agrawal, R., Tyagi, E., Shukla, R., and Nath, C. A study of brain insulin receptors, AChE activity and oxidative stress in rat model of ICV STZ induced dementia. Neuropharmacology 2009;56(4):779-787. View Abstract
253. Ma, J., Shaw, V. E., and Mitrofanis, J. Does melatonin help save dopaminergic cells in MPTP-treated mice? Parkinsonism.Relat Disord. 2009;15(4):307-314. View Abstract
254. Chetsawang, B., Chetsawang, J., and Govitrapong, P. Protection against cell death and sustained tyrosine hydroxylase phosphorylation in hydrogen peroxide- and MPP-treated human neuroblastoma cells with melatonin. J.Pineal Res. 2009;46(1):36-42. View Abstract
255. O'Rourke, S. T., Hammad, H., Delagrange, P., Scalbert, E., and Vanhoutte, P. M. Melatonin inhibits nitrate tolerance in isolated coronary arteries. Br.J Pharmacol. 2003;139(7):1326-1332. View Abstract
256. Bas, E., Martinez-Soriano, F., Lainez, J. M., and Marco, J. An experimental comparative study of dexamethasone, melatonin and tacrolimus in noise-induced hearing loss. Acta Otolaryngol. 2009;129(4):385-389. View Abstract
257. Song, Y. M. and Chen, M. D. Effects of melatonin administration on plasma leptin concentration and adipose tissue leptin secretion in mice. Acta Biol.Hung. 2009;60(4):399-407. View Abstract
258. Alonso-Vale, M. I., Peres, S. B., Vernochet, C., Farmer, S. R., and Lima, F. B. Adipocyte differentiation is inhibited by melatonin through the regulation of C/EBPbeta transcriptional activity. J.Pineal Res. 2009;47(3):221-227. View Abstract
259. Bertuglia, S. and Reiter, R. J. Melatonin reduces microvascular damage and insulin resistance in hamsters due to chronic intermittent hypoxia. J.Pineal Res. 2009;46(3):307-313. View Abstract
260. Cemek, M., Emin, Buyukokuroglu M., Yurumez, Y., Yavuz, Y., Aslan, A., Buyukben, A., and Aymelek, F. Tissue trace and major element levels in organophosphate insecticide fenthion (Lebaycid) toxicity in rats: prophylactic and therapeutic effect of exogenous melatonin. Ecotoxicol.Environ.Saf 2010;73(2):206-212. View Abstract
261. Sarabia, L., Maurer, I., and Bustos-Obregon, E. Melatonin prevents damage elicited by the organophosphorous pesticide diazinon on mouse sperm DNA. Ecotoxicol.Environ.Saf 2009;72(2):663-668. View Abstract
262. Sarabia, L., Maurer, I., and Bustos-Obregon, E. Melatonin prevents damage elicited by the organophosphorous pesticide diazinon on the mouse testis. Ecotoxicol.Environ.Saf 2009;72(3):938-942. View Abstract
263. Pei, M., He, F., Wei, L., and Rawson, A. Melatonin enhances cartilage matrix synthesis by porcine articular chondrocytes. J.Pineal Res. 2009;46(2):181-187. View Abstract
264. Tamura, H., Nakamura, Y., Korkmaz, A., Manchester, L. C., Tan, D. X., Sugino, N., and Reiter, R. J. Melatonin and the ovary: physiological and pathophysiological implications. Fertil.Steril. 2009;92(1):328-343. View Abstract
265. Wang, S., Zhang, L., Lim, G., Sung, B., Tian, Y., Chou, C. W., Hernstadt, H., Rusanescu, G., Ma, Y., and Mao, J. A combined effect of dextromethorphan and melatonin on neuropathic pain behavior in rats. Brain Res. 9-8-2009;1288:42-49. View Abstract
266. Col, C., Dinler, K., Hasdemir, O., Buyukasik, O., and Bugdayci, G. Oxidative stress and lipid peroxidation products: effect of pinealectomy or exogenous melatonin injections on biomarkers of tissue damage during acute pancreatitis. Hepatobiliary.Pancreat.Dis.Int. 2010;9(1):78-82. View Abstract
267. Jung, K. H., Hong, S. W., Zheng, H. M., Lee, H. S., Lee, H., Lee, D. H., Lee, S. Y., and Hong, S. S. Melatonin ameliorates cerulein-induced pancreatitis by the modulation of nuclear erythroid 2-related factor 2 and nuclear factor-kappaB in rats. J.Pineal Res. 2010;48(3):239-250. View Abstract
268. Col, C., Dinler, K., Hasdemir, A. O., and Bugdayci, G. The effect of an intraperitoneal injection of melatonin on serum amylase levels in acute pancreatitis. JOP. 2009;10(3):306-309. View Abstract
269. Gomez-Pinilla, P. J., Camello, P. J., and Pozo, M. J. Pancreatic calcium signaling: role in health and disease. Pancreatology. 2009;9(4):329-333. View Abstract
270. Gulben, K., Ozdemir, H., Berberoglu, U., Mersin, H., Yrkin, F., Cakyr, E., and Aksaray, S. Melatonin modulates the severity of taurocholate-induced acute pancreatitis in the rat. Dig.Dis.Sci. 2010;55(4):941-946. View Abstract
271. Sidhu, S., Pandhi, P., Malhotra, S., Vaiphei, K., and Khanduja, K. L. Melatonin treatment is beneficial in pancreatic repair process after experimental acute pancreatitis. Eur.J.Pharmacol. 2-25-2010;628(1-3):282-289. View Abstract
272. Santello, F. H., Del Vecchio, Filipin M., Caetano, L. C., Brazao, V., Caetano, L. N., Dos Santos, C. D., Alonso Toldo, M. P., and do Prado, J. C. J. Influence of melatonin therapy and orchiectomy on T cell subsets in male Wistar rats infected with Trypanosoma cruzi. J.Pineal Res. 2009;47(3):271-276. View Abstract
273. Martinez-Cruz, F., Pozo, D., Osuna, C., Espinar, A., Marchante, C., and Guerrero, J. M. Oxidative stress induced by phenylketonuria in the rat: Prevention by melatonin, vitamin E, and vitamin C. J Neurosci.Res 8-15-2002;69(4):550-558. View Abstract
274. Zhu, H., Chen, S., Yao, S., and Wang, W. Protective effect of melatonin on photo-damage to lysozyme. J.Photochem.Photobiol.B 2-9-2009;94(2):125-130. View Abstract
275. Izykowska, I., Cegielski, M., Gebarowska, E., Podhorska-Okolow, M., Piotrowska, A., Zabel, M., and Dziegiel, P. Effect of melatonin on human keratinocytes and fibroblasts subjected to UVA and UVB radiation In vitro. In Vivo 2009;23(5):739-745. View Abstract
276. Izykowska, I., Gebarowska, E., Cegielski, M., Podhorska-Okolow, M., Piotrowska, A., Zabel, M., and Dziegiel, P. Effect of melatonin on melanoma cells subjected to UVA and UVB radiation in In vitro studies. In Vivo 2009;23(5):733-738. View Abstract
277. Cagnacci, A. and Volpe, A. A role for melatonin in PCOS? Fertil.Steril. 2002;77(5):1089. View Abstract
278. Leardi, S., Tavone, E., Cianca, G., Barnabei, R., Necozione, S., Citone, G., and Simi, M. [The role of melatonin in the immediate postoperative period in elderly patients]. Minerva Chir 2000;55(11):745-750. View Abstract
279. Ersoz, N., Ozler, M., Altinel, O., Sadir, S., Ozerhan, I. H., Uysal, B., Topal, T., Guven, A., and Korkmaz, A. Melatonin prevents peritoneal adhesions in rats. J.Gastroenterol.Hepatol. 2009;24(11):1763-1767. View Abstract
280. Kucukakin, B., Gogenur, I., Reiter, R. J., and Rosenberg, J. Oxidative stress in relation to surgery: is there a role for the antioxidant melatonin? J.Surg.Res. 2009;152(2):338-347. View Abstract
281. Saeidi, M., Sobhani, R., Movahedi, M., Alsaeidi, S., and Samani, R. E. Effect of melatonin in the prevention of postoperative pericardial adhesion formation. Interact.Cardiovasc.Thorac.Surg. 2009;9(1):26-28. View Abstract
282. Tasset, I., Medina, F. J., Pena, J., Jimena, I., Del Carmen, Munoz M., Salcedo, M., Ruiz, C., Feijoo, M., Montilla, P., and Tunez, I. Olfactory bulbectomy induced oxidative and cell damage in rat: protective effect of melatonin. Physiol Res. 2010;59(1):105-112. View Abstract
283. Aritas, Y., Akcan, A., Erdogan, A. R., Akgun, H., Saraymen, R., and Akyildiz, H. Effects of melatonin and phospholipid on adhesion formation and correlation with vascular endothelial growth factor expression in rats. Ulus.Travma.Acil.Cerrahi.Derg. 2009;15(5):416-422. View Abstract
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648. Norman, T. R., Piccolo, J., Voudouris, N., and Burrows, G. D. 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. View Abstract
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650. Savaskan, E., Olivieri, G., Brydon, L., Jockers, R., Krauchi, K., Wirz-Justice, A., and Muller-Spahn, F. Cerebrovascular melatonin MT1-receptor alterations in patients with Alzheimer's disease. Neurosci Lett 7-27-2001;308(1):9-12. View Abstract
651. Savaskan, E., Olivieri, G., Meier, F., Brydon, L., Jockers, R., Ravid, R., Wirz-Justice, A., and Muller-Spahn, F. Increased melatonin 1a-receptor immunoreactivity in the hippocampus of Alzheimer's disease patients. J Pineal Res 2002;32(1):59-62. View Abstract
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655. Zhou, J. N., Liu, R. Y., Kamphorst, W., Hofman, M. A., and Swaab, D. F. Early neuropathological Alzheimer's changes in aged individuals are accompanied by decreased cerebrospinal fluid melatonin levels. J Pineal Res 2003;35(2):125-130. View Abstract
656. Rodriguez-Franco, M. I., Fernandez-Bachiller, M. I., Perez, C., Hernandez-Ledesma, B., and Bartolome, B. Novel tacrine-melatonin hybrids as dual-acting drugs for Alzheimer disease, with improved acetylcholinesterase inhibitory and antioxidant properties. J Med Chem. 1-26-2006;49(2):459-462. View Abstract
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660. Naguib, M., Schmid, P. G., III, and Baker, M. T. The electroencephalographic effects of IV anesthetic doses of melatonin: comparative studies with thiopental and propofol. Anesth.Analg. 2003;97(1):238-43, table. View Abstract
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668. Regodon, S., del Prado, Miguez M., Jardin, I., Lopez, J. J., Ramos, A., Paredes, S. D., and Rosado, J. A. Melatonin, as an adjuvant-like agent, enhances platelet responsiveness. J.Pineal Res. 2009;46(3):275-285. View Abstract
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670. Gupta, M., Gupta, Y. K., Agarwal, S., Aneja, S., and Kohli, K. A randomized, double-blind, placebo controlled trial of melatonin add-on therapy in epileptic children on valproate monotherapy: effect on glutathione peroxidase and glutathione reductase enzymes. Br.J.Clin.Pharmacol. 2004;58(5):542-547. View Abstract
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676. Zeman, M., Szantoova, K., Stebelova, K., Mravec, B., and Herichova, I. Effect of rhythmic melatonin administration on clock gene expression in the suprachiasmatic nucleus and the heart of hypertensive TGR(mRen2)27 rats. J.Hypertens.Suppl 2009;27(6):S21-S26. View Abstract
677. Reiter, R. J., Calvo, J. R., Karbownik, M., Qi, W., and Tan, D. X. Melatonin and its relation to the immune system and inflammation. Ann N.Y.Acad Sci 2000;917:376-386. View Abstract
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679. Bilici, D., Suleyman, H., Banoglu, Z. N., Kiziltunc, A., Avci, B., Ciftcioglu, A., and Bilici, S. Melatonin prevents ethanol-induced gastric mucosal damage possibly due to its antioxidant effect. Dig.Dis.Sci. 2002;47(4):856-861. View Abstract
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686. Lissoni, P., Barni, S., Crispino, S., Tancini, G., and Fraschini, F. Endocrine and immune effects of melatonin therapy in metastatic cancer patients. Eur J Cancer Clin Oncol. 1989;25(5):789-795. View Abstract
687. Lissoni, P., Barni, S., Cattaneo, G., Tancini, G., Esposti, G., Esposti, D., and Fraschini, F. Clinical results with the pineal hormone melatonin in advanced cancer resistant to standard antitumor therapies. Oncology 1991;48(6):448-450. View Abstract
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689. Lissoni, P., Tisi, E., Barni, S., Ardizzoia, A., Rovelli, F., Rescaldani, R., Ballabio, D., Benenti, C., Angeli, M., Tancini, G., and . Biological and clinical results of a neuroimmunotherapy with interleukin-2 and the pineal hormone melatonin as a first line treatment in advanced non-small cell lung cancer. Br J Cancer 1992;66(1):155-158. View Abstract
690. Lissoni, P., Barni, S., Ardizzoia, A., Tancini, G., Conti, A., and Maestroni, G. A randomized study with the pineal hormone melatonin versus supportive care alone in patients with brain metastases due to solid neoplasms. Cancer 2-1-1994;73(3):699-701. View Abstract
691. Lissoni, P., Barni, S., Tancini, G., Ardizzoia, A., Ricci, G., Aldeghi, R., Brivio, F., Tisi, E., Rovelli, F., Rescaldani, R., and . A randomised study with subcutaneous low-dose interleukin 2 alone vs interleukin 2 plus the pineal neurohormone melatonin in advanced solid neoplasms other than renal cancer and melanoma. Br J Cancer 1994;69(1):196-199. View Abstract
692. Lissoni, P., Meregalli, S., Fossati, V., Paolorossi, F., Barni, S., Tancini, G., and Frigerio, F. A randomized study of immunotherapy with low-dose subcutaneous interleukin-2 plus melatonin vs chemotherapy with cisplatin and etoposide as first-line therapy for advanced non-small cell lung cancer. Tumori 12-31-1994;80(6):464-467. View Abstract
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694. Lissoni, P., Meregalli, S., Nosetto, L., Barni, S., Tancini, G., Fossati, V., and Maestroni, G. Increased survival time in brain glioblastomas by a radioneuroendocrine strategy with radiotherapy plus melatonin compared to radiotherapy alone. Oncology 1996;53(1):43-46. View Abstract
695. Lissoni, P., Paolorossi, F., Tancini, G., Barni, S., Ardizzoia, A., Brivio, F., Zubelewicz, B., and Chatikhine, V. Is there a role for melatonin in the treatment of neoplastic cachexia? Eur.J Cancer 1996;32A(8):1340-1343. View Abstract
696. Lissoni, P., Brivio, O., Brivio, F., Barni, S., Tancini, G., Crippa, D., and Meregalli, S. Adjuvant therapy with the pineal hormone melatonin in patients with lymph node relapse due to malignant melanoma. J Pineal Res 1996;21(4):239-242. View Abstract
697. Lissoni, P., Paolorossi, F., Ardizzoia, A., Barni, S., Chilelli, M., Mancuso, M., Tancini, G., Conti, A., and Maestroni, G. J. A randomized study of chemotherapy with cisplatin plus etoposide versus chemoendocrine therapy with cisplatin, etoposide and the pineal hormone melatonin as a first-line treatment of advanced non-small cell lung cancer patients in a poor clinical state. J Pineal Res 1997;23(1):15-19. View Abstract
698. Lissoni, P., Rovelli, F., Meregalli, S., Fumagalli, L., Musco, F., Brivio, F., Brivio, O., and Esposti, G. Melatonin as a new possible anti-inflammatory agent. J Biol Regul.Homeost.Agents 1997;11(4):157-159. View Abstract
699. Lissoni, P., Giani, L., Zerbini, S., Trabattoni, P., and Rovelli, F. Biotherapy with the pineal immunomodulating hormone melatonin versus melatonin plus aloe vera in untreatable advanced solid neoplasms. Nat Immun. 1998;16(1):27-33. View Abstract
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702. Lissoni, P., Bucovec, R., Bonfanti, A., Giani, L., Mandelli, A., Roselli, M. G., Rovelli, F., and Fumagalli, L. 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. View Abstract
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706. Todisco, M., Casaccia, P., and Rossi, N. Cyclophosphamide plus somatostatin, bromocriptin, retinoids, melatonin and ACTH in the treatment of low-grade non-Hodgkin's lymphomas at advanced stage: results of a phase II trial. Cancer Biother.Radiopharm. 2001;16(2):171-177. View Abstract
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708. Lissoni, P., Cazzaniga, M., Tancini, G., Scardino, E., Musci, R., Barni, S., Maffezzini, M., Meroni, T., Rocco, F., Conti, A., and Maestroni, G. Reversal of clinical resistance to LHRH analogue in metastatic prostate cancer by the pineal hormone melatonin: efficacy of LHRH analogue plus melatonin in patients progressing on LHRH analogue alone. Eur Urol. 1997;31(2):178-181. View Abstract
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738. Murawska-Cialowicz, E., Jethon, Z., Magdalan, J., Januszewska, L., Podhorska-Okolow, M., Zawadzki, M., Sozanski, T., and Dziegiel, P. Effects of melatonin on lipid peroxidation and antioxidative enzyme activities in the liver, kidneys and brain of rats administered with benzo(a)pyrene. Exp.Toxicol.Pathol. 11-25-2009;View Abstract
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749. Valero, N., Nery, A., Bonilla, E., Espina, L. M., Chacin-Bonilla, L., Anez, F., Maldonado, M., and Melean, E. Antagonistic effect of luzindole in mice treated with melatonin during the infection with the venezuelan equine encephalomyelitis virus. Neurochem.Res. 2009;34(2):268-273. View Abstract
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792. Wakatsuki, A., Okatani, Y., Ikenoue, N., Shinohara, K., Watanabe, K., and Fukaya, T. Melatonin protects against oxidized low-density lipoprotein-induced inhibition of nitric oxide production in human umbilical artery. J Pineal Res 2001;31(3):281-288. View Abstract
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