N-acetyl-5-methoxytryptamine
Melatonin/Drug Interactions:
NoteNote: 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?) (776; 777); beta-blocker blood pressure medications, such as propranolol (Inderal?) (778), atenolol (Tenormin?) and metoprolol (Lopressor?, Toprol?) (779; 780); and medications that reduce levels of vitamin B6 in the body, such as oral contraceptives, hormone replacement therapy, loop diuretics, hydralazine, and theophylline (781; 782; 783; 784). Anesthesia using 7% sevoflurane decreased melatonin blood concentrations (785). However, using 5% isoflurane, blood levels of melatonin increased (785). 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 (786; 787), with a more pronounced effect in nonsmokers (788), diazepam (782; 783), estradiol (789), vitamin B12 (790), verapamil (791), temazepam (792), and somatostatin (793). AlcoholAlcohol: In human research, alcohol consumption lacked effects on urinary levels of 6-sulfatoxymelatonin, a marker of melatonin (794). Alzheimer's agentsAlzheimer's agents: Melatonin levels are often lower in patients with Alzheimer's disease (795; 796; 797; 798; 799; 800). Some randomized controlled trials suggest a possible benefit of melatonin in patients with dementia (558; 561). In vitro studies suggest a synergy between tacrine, a cholinesterase inhibitor, and melatonin (801). AnalgesicsAnalgesics: In humans, melatonin use decreased the need for analgesics (605; 681; 682; 366; 683) and reduced levels of pain (596; 552; 683; 682). However, compared to baseline, participants with chronic fatigue syndrome treated with melatonin showed a significant worsening of bodily pain (579). AnestheticsAnesthetics: In human research melatonin augmented standard general anesthetics (677; 802; 803; 804; 805; 806; 679; 680). However, not all trials have been positive (807). In vitro studies indicate that some anesthetics have also been found to alter blood melatonin concentrations in humans (isoflurane increasing and sevoflurane decreasing) (785). Plasma levels of melatonin increased during administration of propofol in humans (802) as well as in rats (808). In humans, melatonin premedication significantly decreased the doses of both propofol and thiopental required to induce anesthesia (679; 680). Angiotensin-converting enzyme (ACE) inhibitorsAngiotensin-converting enzyme (ACE) inhibitors: In human research, melatonin normalized ACE in six patients with high levels at baseline (531). Antiaging agentsAntiaging agents: Melatonin has been identified as countering some of the deleterious effects of aging in human, animal, and in vitro research (14; 15; 16; 17; 18; 19; 20; 21; 22; 23). AntiarthriticsAntiarthritics: Based on mechanisms of action in vitro, melatonin has been suggested as possibly playing a beneficial role in osteoarthritis (60) and other rheumatic diseases (59). AntiasthmaticsAntiasthmatics: Asthmatics were found to have lower levels of endogenous melatonin (809; 810); however, elevated levels at night were associated with worsening of symptoms (811; 812). Anticoagulants and antiplateletsAnticoagulants and antiplatelets: According to experts, melatonin may decrease prothrombin time (a measurement of blood clotting ability) (400; 372). 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 (399). In animal research, melatonin enhanced platelet responsiveness (401). Increased platelet counts after melatonin use have been observed in patients with decreased platelets due to cancer therapies (402; 403; 404; 405; 406; 407; 408), and cases of idiopathic thrombocytopenic purpura (ITP) treated with melatonin have been reported (409; 410). AnticonvulsantsAnticonvulsants: It has been suggested that melatonin may act as a proconvulsant (449) and may lower seizure threshold and increase the risk of seizure, particularly in children with severe neurologic disorders (452; 451; 372). In a 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; the child was initiated on valproate, and although melatonin was not discontinued, further seizures were lacking (431). In contrast, several case reports indicated reduced incidence of seizure with regular melatonin use (453; 454; 455; 456; 457; 458). Both anticonvulsant (458; 813; 814; 815) and proconvulsant (449) properties have been associated with melatonin in preclinical studies. This remains an area of controversy (449). Increases in the anticonvulsant effects of valproate have been observed in mice (458; 813). In human research, add-on melatonin administration in epileptic children did not alter valproate serum concentrations (816); however, treatment with valproate and carbamazepine increased urinary 6-sulfatoxymelatonin, a marker of melatonin, which had decreased during the period of epileptic seizures (817). In one human study, valproate decreased the sensitivity of melatonin to light in patients with bipolar disorder (818). AntidepressantsAntidepressants: In human research, antidepressants (fluoxetine, fluvoxamine, duloxetine, and Hypericum perforatum) increased melatonin and 6-hydroxymelatonin (metabolite) levels, and fluvoxamine both increased melatonin bioavailability and decreased melatonin metabolism (819; 820; 821; 822; 823). 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 (465; 466; 467). Venlafaxine lacked effects on nocturnal melatonin concentrations in a human study (824). Commonly reported adverse effects of melatonin in clinical trials include fatigue, dizziness, headache (including migraine), irritability, drowsiness, weakness, fogginess, yawning, nighttime awakening, poor sleep quality, vertigo, insomnia, and sleepiness (426; 424; 430; 421; 381; 419; 431; 388; 416; 372; 393; 366; 358; 417; 438; 435; 396; 380; 443; 390; 354; 355; 356; 440; 367; 441; 445; 391; 392; 429; 371; 357; 353; 598; 764). These symptoms are also indications of jet lag, and in some cases, causality may be unclear. In human research, mood changes have been reported, including giddiness, dysphoria (sadness), mood dip, nervousness, hyperactivity, irritability, and transient depression (463; 419; 390; 440; 391; 392; 358; 357; 427). Psychotic symptoms have also been reported in human research, including hallucinations, delusions, and paranoia, possibly due to overdose (371; 462; 441). AntidiabeticsAntidiabetics: Elevated blood sugar levels (hyperglycemia) have been reported in patients with type 1 diabetes (insulin-dependent diabetes) (382; 383), and low doses of melatonin have reduced glucose tolerance and insulin sensitivity (384; 385). In patients with type 2 diabetes mellitus who had a 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 (386; 387). However, in other research, melatonin supplementation was found to lack an effect on measures of glucose homeostasis (763). AntihypertensivesAntihypertensives: In animal and human research, hypotension, blood-pressure lowering effects, and hypertension have been reported (756; 825; 359; 360; 361; 362; 363; 364; 365; 366; 367; 826; 827; 828; 829; 443; 609; 506; 369), although melatonin did not alter blood pressure in some animal or human research (830; 376) or had mixed effects on night and day blood pressure, with decreases at night (377; 375; 378; 608). 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 (64). Serum melatonin levels decreased noticeably with propranolol treatment (778). In animals, melatonin reduced the effects of the alpha-adrenergic agonist clonidine (756). 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 (368; 465). 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 (791). Anti-inflammatoriesAnti-inflammatories: In human research, melatonin had anti-inflammatory effects in infants with respiratory distress (11), decreased the upregulation of proinflammatory cytokines in laboratory and human research (831; 101; 47; 109; 832; 761; 115; 62), and inhibited nitric oxide (NO) and malondialdehyde (MDA) production and increased glutathione levels (833; 834). 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 (464). Also, in human research, melatonin lacked effects on C-reactive protein (CRP) levels (835). AntilipemicsAntilipemics: There is some evidence of increases in cholesterol levels and atherosclerotic plaque buildup in human research (757) and animal research (759; 760). In contrast, there are also reports of decreases in cholesterol levels in animal research (758) and decreased triglyceride and LDL cholesterol levels in human research (761; 762; 609). AntineoplasticsAntineoplastics: 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 (836). Based on theoretical antioxidant mechanisms and in human research, melatonin has anticarcinogenic effects (837; 838; 571; 351; 839; 840; 841; 841; 842; 843; 844; 845; 846; 847; 521; 848; 849; 850; 851; 852; 853; 854; 855; 856; 403; 857; 402; 858; 573; 575; 859; 860; 861). Melatonin has been combined with other types of treatment, including chemotherapies (such as cisplatin, etoposide, or irinotecan) (405; 351; 862; 863; 850; 404; 854; 864; 528; 403; 406; 865; 866), COX-2 inhibitors (867), or immune therapies, such as interferon (509), interleukin (IL)-2 or IL-12 (510; 511; 512; 513; 514; 515; 516; 517; 518; 519; 520; 521; 407; 522; 523; 408; 524; 525; 526; 527; 868), or tumor necrosis factor (529; 530; 525). 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 (869; 57), organophosphorus compounds (259; 260; 258), alcohol (870; 261), nicotine (300), beta-cyfluthrin (871), and benzo(a)pyrene (872). Results of a meta-analysis of clinical trials suggested that melatonin had a significant effect on tumor remission and the one-year survival rate, as well as an ability to decrease side effects related to radiochemotherapy, including thrombocytopenia, fatigue, and neurotoxicity (577). Antiobesity agentsAntiobesity agents: In laboratory research, melatonin inhibited adipocyte differentiation (193) and reduced gut motility (873). Other animal research has indicated that exogenous melatonin, however, lacks effect on leptin secretion (192). In patients with type 2 diabetes, nocturnal plasma melatonin levels were higher in obese subjects vs. nonobese subjects and lean nondiabetic controls (874). AntiparasiticsAntiparasitics: In animal research, melatonin therapy controlled Trypanosoma cruzi proliferation by stimulating the host's immune response (203; 875). Antiparkinson agentsAntiparkinson agents: In human research, melatonin lacked an effect on signs of parkinsonism or levodopa effects, although it was well tolerated, but with side effects such as skin flushing, diarrhea, abdominal cramps, somnolence during the day, scotoma lucidum, and headaches (381). AntipsychoticsAntipsychotics: Chronic treatment with antipsychotic drugs significantly improved psychotic symptomatology in schizophrenics, but did not change the secretory pattern of melatonin (876). 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 (877). Preliminary human and laboratory reports suggest that melatonin had mixed effects on mood, sleep, and tardive dyskinesia in patients with schizophrenia, often treated with haloperidol (878; 879; 880; 881; 684; 882; 671; 634; 673). In human research, quetiapine did not appear to alter melatonin levels (883). Anti-ulcer agentsAnti-ulcer agents: In human research, melatonin improved the healing of ulcers (693; 692). AntiviralsAntivirals: In animal research, the protective effect of melatonin against Venezuelan equine encephalomyelitis virus was likely mediated by melatonin receptor activation (884). AnxiolyticsAnxiolytics: In humans, melatonin has been widely reported as having general and synergistic anxiolytic effects (677; 563; 803; 804; 806; 805; 679; 680); however, evidence is mixed from a systematic review and well-designed clinical trials with respect to melatonin for anxiety prevention during surgery (683; 681; 678). BenzodiazepinesBenzodiazepines: 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?), and in general, results are promising (567; 565; 568; 569). Although melatonin has demonstrated effectiveness in reducing benzodiazepine consumption in older patients with established insomnia (565), low doses of immediate release melatonin (3mg) lacked usefulness for benzodiazepine tapering in older patients with minor sleep disturbances (565). In human research, melatonin was found to improve the quality of sleep in combination with benzodiazepines (885). CaffeineCaffeine: Caffeine is reported to raise natural melatonin levels in the body (787) with a more pronounced effect in nonsmokers (788), possibly due to effects on the liver enzyme cytochrome P450 1A2 (886). It has been proposed that caffeine may increase the bioavailability of endogenous melatonin (887). Caffeine may also alter circadian rhythms in humans, with effects on melatonin secretion (788). It has been reported that caffeine reduced the onset of nighttime melatonin levels for women in the luteal phase, but had little effect on melatonin levels for oral contraceptive users (888). Another human study has shown that a single dose of 200mg of caffeine reduced natural melatonin levels (786), though a more recent human study using a twice-daily dose of 200mg of caffeine over seven days found a lack of effect on nighttime salivary melatonin (889). Calcium channel blockersCalcium channel blockers: In human research, melatonin increased blood pressure in patients treated with the calcium channel blocker nifedipine (368). 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 (791). 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 (890). Cardiovascular agentsCardiovascular agents: In human research, low levels of platelet melatonin was found to be associated with angiographic no-reflow after primary percutaneous coronary intervention in patients with ST-segment elevation myocardial infarction (891). It has been proposed that melatonin acts directly on the cardiovascular system rather than modulating cardiac autonomic activity (892). In a poor-quality study, the inclusion of melatonin in the combined treatment of cardiovascular disease resulted in anti-ischemic, antianginal, antioxidant, and hypotensive effects (369). There is some evidence of increases in cholesterol levels and atherosclerotic plaque buildup in human research (757) and animal research (759; 760). In contrast, there are also reports of decreases in cholesterol levels in animal research (758) and decreased triglyceride and LDL cholesterol levels in human research (761; 762; 609). In animal and human research, hypotension, blood pressure-lowering effects, and hypertension have been reported (756; 825; 359; 360; 361; 362; 363; 364; 365; 366; 367; 826; 827; 828; 829; 443; 609; 506; 369), although melatonin did not alter blood pressure in some animal or human research (830; 376) or had mixed effects on night and day blood pressure, with decreases at night (377; 375; 378; 608). CNS depressantsCNS depressants: In theory, based on possible risk of daytime sleepiness (411; 415; 421; 418; 422; 354; 667; 435; 67) and reported negative effects on certain cognitive tasks in humans in some, but not all, studies (428; 412; 413; 767; 893; 894), 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 (114). In human research, an effect of remifentanil on melatonin concentration and an effect of melatonin on remifentanil-induced sleep disturbance were lacking (439). CNS stimulantsCNS stimulants: In human research, there was an isolated case of aggression in a child diagnosed with ADHD and taking prescribed methylphenidate (433). In animal research, melatonin increased the adverse effects of methamphetamine on the nervous system (895). Melatonin has been implicated as having dosing time-dependent effects on the action of psychostimulant drugs such as cocaine and amphetamines (896). Cognitive agentsCognitive agents: In human research, exogenous melatonin caused decrements in performance, including a slowing of choice-reaction time (412; 428) or learning (413); however, some studies have failed to confirm a decrement in performance (767; 893; 894), including a study of high-dose melatonin (50mg) in elderly persons (mean age: 84.5 years) (897). ContraceptivesContraceptives: In patients undergoing in vitro fertilization embryo transfer (IVF-ET), although melatonin benefited oocyte maturation, effects on fertilization and pregnancy were lacking (594; 898). Similarly, melatonin has been shown to improve viability of sperm (899) and embryos (900; 901; 118; 902; 903) produced with in vitro fertilization. In animal research, reproductive effects of melatonin have also been found (904; 487; 905; 906; 907; 908; 909; 910; 280). Cytochrome P450metabolized agentsCytochrome 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) (911; 912) and possibly CYP2C9. It appears to inhibit CYP1A2 (465; 466; 467) and induce CYP3A. 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 (465; 466; 467). Caffeine is reported to raise natural melatonin levels in the body (787) with a more pronounced effect in nonsmokers (788), possibly due to effects on the liver enzyme cytochrome P450 1A2 (788). This effect was more pronounced in nonsmokers (788). Other human studies suggest that interactions between exogenous melatonin and substrates metabolized by CYP1A2 may differ in individuals before and after smoking abstinence (913). In animal research, melatonin inhibited the activity of cytochrome P450 2E1, but to a lesser extent than taurine (468). Dental agentsDental agents: In human research, salivary and gingival crevicular fluid melatonin levels were lower in individuals with periodontal disease (914). Dermatologic agentsDermatologic agents: Dermatologic use of melatonin has been proposed because of its immunomodulatory and antioxidant abilities. Research findings indicate that melatonin accumulates in the stratum corneum (709). In human research, free radical scavenging was suggested as a possible mechanism of action in the protection against UV-induced erythema (711). DextromethorphanDextromethorphan: In animal research, dextromethorphan interacted synergistically with melatonin in relieving neuropathic pain (188). DiureticsDiuretics: In clinical trials, an adverse effect associated with melatonin was increased enuresis (353; 354; 355; 356; 357). A study in children with ADHD suffering from insomnia noted bedwetting at a long-term follow-up (358). Drugs that affect GABADrugs that affect GABA: In animal research, results suggested a possible role of the GABAergic system in melatonin's effects (915). In human research, melatonin was found to potentiate the effects of gamma-amino butyric acid (GABA) (885). Drugs that may lower seizure thresholdDrugs that may lower seizure threshold: It has been suggested that melatonin may act as a proconvulsant (449) and may lower seizure threshold and increase the risk of seizure, particularly in children with severe neurologic disorders (452; 451; 372). In a 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; the child was initiated on valproate, and although melatonin was not discontinued, further seizures were lacking (431). In contrast, several case reports indicated reduced incidence of seizure with regular melatonin use (453; 454; 455; 456; 457; 458). Both anticonvulsant (458; 813; 814; 815) and proconvulsant (449) properties have been associated with melatonin in preclinical studies. This remains an area of controversy (449). Drugs used for osteoporosisDrugs used for osteoporosis: In laboratory research, melatonin impaired osteoclast activity and bone resorption (916; 917; 918). In human research, melatonin lacked effects on bone density, N-terminal telopeptide (NTX), or osteocalcin (OC), although the NTX:OC ratio in the melatonin group was reduced (628). EpithalaminEpithalamin: In human research, epithalamin normalized the circadian rhythm of melatonin (919). EstrogensEstrogens: Human and laboratory 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 (920). Mechanisms of melatonin's oncostatic action may include regulation of estrogen receptor expression and transactivation (921) and antiestrogenic effects (922; 923; 924). MCF-7 human breast cancer cultured cells have been reported as melatonin sensitive, as well as estrogen receptor positive and estrogen responsive (925), although this finding was not confirmed in a subsequent study (926). Melatonin has been reported to elicit an increase in estrogen receptor activity in breast tumors (927). Low plasma melatonin concentrations were associated with greater amounts of estrogen or progesterone receptors on primary tumors (928). In a review on the anticarcinogenic role of melatonin, potential mechanisms included the inhibition of initiation and growth of hormone-dependent tumors by decreasing the expression of estrogen receptors, as well as aromatase activity, resulting in the inhibition of cancer cell proliferation, a decrease in oxidative stress, and an increase in the activity of the immune system (929). Exercise performance agentsExercise performance agents: In human research, during a heavy-resistance exercise session, melatonin increased the area under the curve of growth hormone (508) and protected against the overexpression of inflammatory mediators and inhibited the expression of proinflammatory cytokines in exercising individuals (930). Fertility agentsFertility agents: In patients undergoing in vitro fertilization embryo transfer (IVF-ET), although melatonin benefited oocyte maturation, effects on fertilization and pregnancy were lacking (594; 898). Similarly, melatonin has been shown to improve viability of sperm (899) and embryos (900; 901; 118; 902; 903) produced with in vitro fertilization. In animal research, reproductive effects of melatonin have also been found (904; 487; 905; 906; 907; 908; 909; 910; 280). FlumazenilFlumazenil: In hamsters, the administration of the benzodiazepine antagonist flumazenil blunted the activity of melatonin in these behaviors (931). Gastrointestinal agentsGastrointestinal agents: Preliminary research has indicated that melatonin aids symptoms of functional dyspepsia (598), gastroesophageal reflux disease (GERD) (602), Crohn's disease and ulcerative colitis (932), and irritable bowel syndrome (mixed evidence) (933; 438; 600; 599; 601; 603). Genitourinary tract agentsGenitourinary tract agents: In clinical trials, an adverse effect associated with melatonin was increased enuresis (353; 354; 355; 356; 357). A study in children with ADHD suffering from insomnia noted bedwetting at a long-term follow-up (358). Glaucoma agentsGlaucoma agents: Preliminary human evidence suggests that melatonin may decrease intraocular pressure in the eye (460; 461; 366); however, according to reviews, high doses of melatonin may increase intraocular pressure and the risk of glaucoma, age-related maculopathy, and myopia (382), as well as retinal damage (400). Headache agentsHeadache agents: Evidence is mixed from human research with respect to preventive effects of melatonin on headaches, including migraines (934; 935; 146; 605; 936; 604; 937; 938; 939; 940; 440). Heart rate regulating agentsHeart rate regulating agents: Melatonin has been shown to increase heart rate when administered in patients taking nifedipine (a calcium channel blocker antihypertensive) (368) and in other studies (375); however, effects were lacking in other human research (376; 377; 378). When measured in the morning, the relationship between salivary melatonin and exercise-induced heart rate changes was steeper than when measured in the evening (941). Clinical significance is unclear. There are several rare or poorly described reports of abnormal heart rhythms, palpitations, fast heart rate, or chest pain, although in most cases, patients were taking other drugs that may account for these symptoms (370; 371; 372; 373; 374). HepatotoxinsHepatotoxins: In patients with nonalcoholic steatohepatitis (NASH), use of melatonin resulted in improvements in liver function (445). In patients with steatohepatitis, melatonin decreased levels of proinflammatory cytokines, triglycerides, and GGTP (761). In human research, melatonin resulted in stable renal and liver function parameters after six weeks of use (755). Decreased transaminases have been shown in other human research (754). However, in one participant, treatment with melatonin resulted in increased alkaline phosphatase levels (390). Hormonal agentsHormonal agents: In humans, hormone replacement therapy (HRT) is reported to cause a decrease in daily melatonin secretion without disturbing circadian rhythm (942; 943). In clinical and laboratory studies, melatonin has also been reported as producing varying hormonal effects. Such reports include changes in levels of luteinizing hormone (469; 470; 471; 472; 473; 474; 475; 476), cortisol (477; 478; 481; 479; 480), progesterone (481; 482; 483; 484; 485), estradiol (482), thyroid hormone (T4 and T3) (486; 487; 488), testosterone (489; 487), growth hormone (411; 490; 476; 491; 492; 493; 494), prolactin (411; 495; 496; 497; 498; 499; 500), oxytocin and vasopressin (490; 501; 502; 503), adrenocorticotrophic hormone (478), and gonadotropin-inhibitory hormone (504). Melatonin has further been shown to alter pituitary hormone (LH and FSH) profiles in menopausal women to more "juvenile" profiles (488). In clinical trials, melatonin affected hormone levels in patients with hormonal-related cancers and had synergistic effects with tamoxifen (862; 850; 863). Other human studies report a lack of significant hormonal effects (617; 496; 944; 945). Gynecomastia (increased breast size) has been reported in men, as well as decreased sperm count (both which resolved with cessation of melatonin) (400). Decreased sperm motility has also been reported in rats (548) and humans (549). Other human and laboratory 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 (920). In females, blood pressure decreased only in hormone replacement therapy or birth control users and not nonusers (507; 506). In human research, progesterone modulated melatonin secretion in postmenopausal women (946). In human research, in combination with estradiol treatment, melatonin reduced peak values of norepinephrine and increased epinephrine levels in some, but not all, stimulus situations (505; 506; 507). In human research, during a heavy-resistance exercise session, melatonin increased the area under the curve of growth hormone (508). ImmunosuppressantsImmunosuppressants: In human research, melatonin was found to interact positively with immune therapies, such as interferon (509), interleukin-2 (510; 511; 512; 513; 514; 515; 516; 517; 518; 519; 520; 521; 407; 522; 523; 408; 524; 525; 526; 527; 528), or tumor necrosis factor (529; 530; 525). Based on limited human research, researchers concluded that melatonin may be an effective treatment for sarcoidosis (531). Exogenous melatonin has been shown to enhance immune response following veterinary vaccination (532). Researchers noted increased platelet counts after melatonin use in patients with decreased platelets due to cancer chemotherapy (402; 403; 404; 533; 406; 407; 408). According to 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 (534). Melatonin has been reported to promote neutrophil apoptosis in patients receiving hepatectomy involving ischemia and reperfusion of the liver (535; 536; 537; 283). A combination hormone therapy including melatonin was found to improve leucocyte function in ovariectomized aged rats (538). In laboratory research, melatonin suppressed TNF-alpha, IL-1 beta, and IL-6 (101); inhibited Th1 cells (114); stimulated humoral activity and antibody production (539; 532; 540); inhibited NF-kappaB (541), as well as IKK, and JNK pathways (133); prevented T cell apoptosis (542); and stimulated mononuclear cell production (543). In human research, combined therapy with low-dose subcutaneous IL-2 and melatonin improved the mean number of lymphocytes, eosinophils, T lymphocytes, natural killer (NK) cells, and CD25- and DR-positive lymphocytes, and increased the mean CD4:CD8 ratio (544). In cancer patients who achieved disease control, melatonin induced a decrease in the number of regulatory T lymphocytes; this change was lacking in individuals with progressed disease (545). IsoniazidIsoniazid: In vitro, melatonin increased the effects of isoniazid against Mycobacterium tuberculosis (263). LithiumLithium: In human research, lithium had a significant effect on sensitivity to light but not on overall melatonin synthesis (947). Magnetic fieldsMagnetic 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 (948; 949; 950; 951). Melatonin was shown to reduce the effects of lipid peroxidation, less effectively than vitamin E, in rats exposed to static magnetic fields under laboratory conditions (952). MethamphetaminesMethamphetamines: In human research, there was an isolated case of aggression in a child diagnosed with ADHD and taking prescribed methylphenidate (433). In animal research, melatonin increased the adverse effects of methamphetamine on the nervous system (895). MethoxamineMethoxamine: In animals, melatonin reduced the effects of the alpha-adrenergic agonist methoxamine (756). Musculoskeletal agentsMusculoskeletal agents: According to case reports, ataxia (difficulties with walking and balance) may occur following melatonin overdose (372). In human research, melatonin lacked negative effects on postural stability (367). Compared to baseline, participants with chronic fatigue syndrome treated with melatonin showed a significant worsening of bodily pain (579). Weakened muscle power was reported in a clinical trial (598). Neurologic agentsNeurologic agents: It has been proposed that melatonin may reduce the amount of neurologic damage patients experience after stroke, based on antioxidant properties (953; 954; 955; 956; 957; 958; 959; 960). A significant body of basic research has indicated that melatonin may possess neuroprotective properties (184; 167; 168; 169; 170; 171; 172; 173; 174; 175; 176; 177; 179; 180; 181; 182; 183; 185; 79; 186; 187), meriting reviews in the contexts of neurodegenerative diseases (961), the peripheral nervous system (962), and traumatic nervous system injury (80). However, commonly reported adverse effects of melatonin in clinical trials include fatigue, dizziness, headache (including migraine), irritability, drowsiness, weakness, fogginess, yawning, nighttime awakening, poor sleep quality, vertigo, insomnia, and sleepiness (426; 424; 430; 421; 381; 419; 431; 388; 416; 372; 393; 366; 358; 417; 438; 435; 396; 380; 443; 390; 354; 355; 356; 440; 367; 441; 445; 391; 392; 429; 371; 357; 353; 598; 764). These symptoms are also indications of jet lag, and in some cases, causality may be unclear. In human research, mood changes have been reported, including giddiness, dysphoria (sadness), mood dip, nervousness, hyperactivity, irritability, and transient depression (463; 419; 390; 440; 391; 392; 358; 357; 427). Psychotic symptoms have also been reported in human research, including hallucinations, delusions, and paranoia, possibly due to overdose (371; 462; 441). Neuromuscular blockersNeuromuscular blockers: In laboratory research, melatonin increased the neuromuscular blocking effect of the muscle relaxant succinylcholine, but not vecuronium (963). Ophthalmic agentsOphthalmic agents: In limited human research, melatonin stabilized vision in patients suffering from age-related macular degeneration (459). Preliminary human evidence also suggests that melatonin may decrease intraocular pressure in the eye (460; 461; 366); however, according to reviews, high doses of melatonin may increase intraocular pressure and the risk of glaucoma, age-related maculopathy, and myopia (382), as well as retinal damage (400). Use of transitions lenses as part of chromotherapy for macular degeneration were found to maintain the physiological balance of melatonin (964). In human research, use of eye masks increased melatonin levels (965). OpioidsOpioids: In animals, researchers have concluded that melatonin acutely reversed and prevented tolerance to and dependence on morphine (966; 967) and reduced the incidence of naloxone-induced withdrawal (967). In human research, melatonin reduced the need for morphine (563; 681). Otic agentsOtic agents: In human research, melatonin attenuated the muscle sympathetic nerve activity (vestibulosympathetic reflex) response to baroreceptor unloading while lacking effects on the vestibulocollic reflexes (968). In human research, use of ear plugs increased melatonin levels (965). Radioprotective drugsRadioprotective drugs: 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 of preliminary animal and in vitro research (969; 215; 216; 206; 207; 217; 219). Melatonin has been shown to ameliorate oxidative injury due to ionizing radiation in vitro (970; 971; 214). The specific mechanisms may involve downregulation of apoptotic pathways via control of oxidative load (972). RemifentanilRemifentanil: In human research, remifentanil did not decrease melatonin concentration (439). Melatonin administration also did not prevent remifentanil-induced sleep disturbance. Renally eliminated agentsRenally eliminated agents: In human research, melatonin resulted in decreased renal blood flow velocity and conductance (376). In human research, melatonin resulted in stable renal function parameters after six weeks of use (755). Respiratory agentsRespiratory agents: In a clinical trial, melatonin reduced dyspnea; however, changes in lung function were lacking (580). SedativesSedatives: In human research, melatonin has been shown to decrease sleep latency (390; 752) and benefit sleep quality and duration in children, older and younger adults, individuals with disabilities, and visually impaired individuals (356; 392; 431; 373; 379; 615; 389; 446; 613; 374; 357; 355; 734; 354; 638; 322; 659; 391; 581). In human research, exogenous melatonin exerted hypnotic effects primarily when circulating levels of endogenous melatonin were low (653), and even very low doses caused sleep in some studies when ingested before endogenous melatonin onset (418; 662; 655; 661; 649). Also, in human research, melatonin has been shown to decrease the amount of anesthesia required during surgery (679; 973; 680; 719). SevofluraneSevoflurane: In human research, sevoflurane resulted in a reduction of postoperative plasma melatonin levels (974). TacrineTacrine: In vitro studies suggest the possibility of a synergy between tacrine, a cholinesterase inhibitor, and melatonin, based on mechanism of action (801). Thermoregulating agentsThermoregulating agents: In human research, hypothermic effects of melatonin have been reported with doses from 15mg (975; 657; 976; 427), and ingestion of 1.6mg of melatonin was reported to result in approximately 0.4?C decrease of body temperature in humans (975; 977; 978; 979). Reports of feeling cold or hypothermia exist in other clinical literature (390; 356; 445; 392), but not in all studies (614). Thyroid hormonesThyroid hormones: In human research, thyroid-stimulating hormone (TSH) serum levels were lower and those of free thyroxine (FT4) were increased at night when endogenous melatonin levels were higher (980). In clinical and laboratory studies, melatonin has also been reported to change levels of thyroid hormone (T4 and T3) (486; 487; 488). Valproic acidValproic acid: It has been suggested that melatonin may act as a proconvulsant (449) and may lower seizure threshold and increase the risk of seizure, particularly in children with severe neurologic disorders (452; 451; 372). In a 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; the child was initiated on valproate, and although melatonin was not discontinued, further seizures were lacking (431). In contrast, several case reports indicated reduced incidence of seizure with regular melatonin use (453; 454; 455; 456; 457; 458). Both anticonvulsant (458; 813; 814; 815) and proconvulsant (449) properties have been associated with melatonin in preclinical studies. This remains an area of controversy (449). Increases in the anticonvulsant effects of valproate have been observed in mice (458; 813). In human research, add-on melatonin administration in epileptic children did not alter valproate serum concentrations (816); however, treatment with valproate and carbamazepine increased urinary 6-sulfatoxymelatonin, a marker of melatonin, which had been decreased during the period of epileptic seizures (817). In one human study, valproate decreased the sensitivity of melatonin to light in patients with bipolar disorder (818). VaccinesVaccines: Exogenous melatonin has been shown to enhance immune response following veterinary vaccination (532). VasodilatorsVasodilators: In healthy male volunteers, melatonin significantly increased peripheral blood flow, as measured by distal to proximal skin temperature gradient and finger pulse volume (981). In human research, melatonin resulted in decreased renal blood flow velocity and conductance , increased forearm blood flow and vascular conductance, and lacked an effect on cerebral blood flow (376). Melatonin/Herb/Supplement Interactions:
NoteNote: 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?) (776; 777); beta-blocker blood pressure medications, such as propranolol (Inderal?) (778), atenolol (Tenormin?) and metoprolol (Lopressor?, Toprol?) (779; 780); and medications that reduce levels of vitamin B6 in the body, such as oral contraceptives, hormone replacement therapy, loop diuretics, hydralazine, and theophylline (781; 782; 783; 784). Anesthesia using 7% sevoflurane decreased melatonin blood concentrations (785). However, using 5% isoflurane, blood levels of melatonin increased (785). 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 (786; 787), with a more pronounced effect in nonsmokers (788), diazepam (782; 783), estradiol (789), vitamin B12 (790), verapamil (791), temazepam (792), and somatostatin (793). 5-Hydroxytryptophan(5-HTP)5-Hydroxytryptophan(5-HTP): In a case report, treatment with 5-HTP was found to normalize the melatonin profile (982). Alzheimer's agentsAlzheimer's agents: Melatonin levels are often lower in patients with Alzheimer's disease (795; 796; 797; 798; 799; 800). Some randomized controlled trials suggest a possible benefit of melatonin in patients with dementia (558; 561). In vitro studies suggest a synergy between tacrine, a cholinesterase inhibitor, and melatonin (801). AnalgesicsAnalgesics: In humans, melatonin use decreased the need for analgesics (605; 681; 682; 366; 683) and reduced levels of pain (596; 552; 683; 682). However, compared to baseline, participants with chronic fatigue syndrome treated with melatonin showed a significant worsening of bodily pain (579). AnestheticsAnesthetics: In human research, melatonin augmented standard general anesthetics (677; 802; 803; 804; 805; 806; 679; 680). However, not all trials have been positive (807). Angiotensin-converting enzyme (ACE) inhibitorsAngiotensin-converting enzyme (ACE) inhibitors: In human research, melatonin normalized ACE in six patients with high levels at baseline (531). Antiaging agentsAntiaging agents: Melatonin has been identified as countering some of the deleterious effects of aging in human, animal, and in vitro research (14; 15; 16; 17; 18; 19; 20; 21; 22; 23). Antianxiety herbs and supplementsAntianxiety herbs and supplements: In humans, melatonin has been widely reported as having general and synergistic anxiolytic effects (677; 563; 803; 804; 806; 805; 679; 680); however, evidence is mixed from a systematic review and well-designed clinical trials with respect to melatonin for anxiety prevention during surgery (683; 681; 678). AntiarthriticsAntiarthritics: Based on mechanisms of action in vitro, melatonin has been suggested as possibly playing a beneficial role in osteoarthritis (60) and other rheumatic diseases (59). AntiasthmaticsAntiasthmatics: Asthmatics were found to have lower levels of endogenous melatonin (809; 810); however, elevated levels at night were associated with worsening of symptoms (811; 812). Anticoagulants and antiplateletsAnticoagulants and antiplatelets: According to experts, melatonin may decrease prothrombin time (a measurement of blood clotting ability) (400; 372). 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 (399). In animal research, melatonin enhanced platelet responsiveness (401). Increased platelet counts after melatonin use have been observed in patients, with decreased platelets due to cancer therapies (402; 403; 404; 405; 406; 407; 408), and cases of idiopathic thrombocytopenic purpura (ITP) treated with melatonin have been reported (409; 410). AnticonvulsantsAnticonvulsants: It has been suggested that melatonin may act as a proconvulsant (449) and may lower seizure threshold and increase the risk of seizure, particularly in children with severe neurologic disorders (452; 451; 372). In a 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; the child was initiated on valproate, and although melatonin was not discontinued, further seizures were lacking (431). In contrast, several case reports indicated reduced incidence of seizure with regular melatonin use (453; 454; 455; 456; 457; 458). Both anticonvulsant (458; 813; 814; 815) and proconvulsant (449) properties have been associated with melatonin in preclinical studies. This remains an area of controversy (449). AntidepressantsAntidepressants: In human research, antidepressants increased melatonin and 6-hydroxymelatonin (metabolite) levels, and increased melatonin bioavailability and decreased melatonin metabolism (819; 820; 821; 822; 823). Commonly reported adverse effects of melatonin in clinical trials include fatigue, dizziness, headache (including migraine), irritability, drowsiness, weakness, fogginess, yawning, nighttime awakening, poor sleep quality, vertigo, insomnia, and sleepiness (426; 424; 430; 421; 381; 419; 431; 388; 416; 372; 393; 366; 358; 417; 438; 435; 396; 380; 443; 390; 354; 355; 356; 440; 367; 441; 445; 391; 392; 429; 371; 357; 353; 598; 764). These symptoms are also indications of jet lag, and in some cases, causality may be unclear. In human research, mood changes have been reported, including giddiness, dysphoria (sadness), mood dip, nervousness, hyperactivity, irritability, and transient depression (463; 419; 390; 440; 391; 392; 358; 357; 427). Psychotic symptoms have also been reported in human research, including hallucinations, delusions, and paranoia, possibly due to overdose (371; 462; 441). Anti-inflammatoriesAnti-inflammatories: In human research, melatonin had anti-inflammatory effects in infants with respiratory distress (11), decreased the upregulation of proinflammatory cytokines in laboratory and human research (831; 101; 47; 109; 832; 761; 115; 62), and inhibited NO and MDA production and increased glutathione levels (833; 834). 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 (464). Also, in human research, melatonin lacked effects on CRP levels (835). AntilipemicsAntilipemics: There is some evidence of increases in cholesterol levels and atherosclerotic plaque buildup in human research (757) and animal research (759; 760). In contrast, there are also reports of decreases in cholesterol levels in animal research (758) and decreased triglyceride and LDL cholesterol levels in human research (761; 762; 609). AntineoplasticsAntineoplastics: 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 (836). Based on theoretical antioxidant mechanisms and in human research, melatonin has anticarcinogenic effects (837; 838; 571; 351; 839; 840; 841; 841; 842; 843; 844; 845; 846; 847; 521; 848; 849; 850; 851; 852; 853; 854; 855; 856; 403; 857; 402; 858; 573; 575; 859; 860; 861). Results of a meta-analysis of clinical trials suggested that melatonin had a significant effect on tumor remission and the one year survival rate, as well as an ability to decrease side effects related to radiochemotherapy, including thrombocytopenia, fatigue, and neurotoxicity (577). Antiobesity agentsAntiobesity agents: In laboratory research, melatonin inhibited adipocyte differentiation (193) and reduced gut motility (873). Other animal research has indicated that exogenous melatonin, however, lacks effect on leptin secretion (192). In patients with type 2 diabetes, nocturnal plasma melatonin levels were higher in obese subjects vs. nonobese subjects and lean nondiabetic controls (874). AntiparasiticsAntiparasitics: In animal research, melatonin therapy controlled Trypanosoma cruzi proliferation by stimulating the host's immune response (203; 875). AntiparkinsoniansAntiparkinsonians: In human research, melatonin lacked an effect on signs of parkinsonism or levodopa effects, although it was well tolerated, but with side effects such as skin flushing, diarrhea, abdominal cramps, somnolence during the day, scotoma lucidum, and headaches (381). AntipsychoticsAntipsychotics: Chronic treatment with antipsychotic drugs significantly improved psychotic symptomatology in schizophrenics, but did not change the secretory pattern of melatonin (876). 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 (877). Preliminary human and laboratory reports suggest that melatonin had mixed effects on mood, sleep, and tardive dyskinesia in patients with schizophrenia, often treated with haloperidol (878; 879; 880; 881; 684; 882; 671; 634; 673). Anti-ulcer agentsAnti-ulcer agents: In human research, melatonin improved the healing of ulcers (693; 692). AntiviralsAntivirals: In animal research, the protective effect of melatonin against Venezuelan equine encephalomyelitis virus was likely mediated by melatonin receptor activation (884). Caffeine-containing agentsCaffeine-containing agents: Caffeine is reported to raise natural melatonin levels in the body (787) with a more pronounced effect in nonsmokers (788), possibly due to effects on the liver enzyme cytochrome P450 1A2 (886). It has been proposed that caffeine may increase the bioavailability of endogenous melatonin (887). Caffeine may also alter circadian rhythms in humans, with effects on melatonin secretion (788). It has been reported that caffeine reduced the onset of nighttime melatonin levels for women in the luteal phase, but had little effect on melatonin levels for oral contraceptive users (888). Another human study has shown that a single dose of 200mg of caffeine reduced natural melatonin levels (786), though a more recent human study using a twice-daily dose of 200mg of caffeine over seven days found a lack of effect on nighttime salivary melatonin (889). Cardiovascular agentsCardiovascular agents: In human research, low levels of platelet melatonin were found to be associated with angiographic no-reflow after primary percutaneous coronary intervention in patients with ST-segment elevation myocardial infarction (891). It has been proposed that melatonin acts directly on the cardiovascular system rather than modulating cardiac autonomic activity (892). In a poor-quality study, the inclusion of melatonin in the combined treatment of cardiovascular disease resulted in anti-ischemic, antianginal, antioxidant, and hypotensive effects (369). There is some evidence of increases in cholesterol levels and atherosclerotic plaque buildup in human research (757) and animal research (759; 760). In contrast, there are also reports of decreases in cholesterol levels in animal research (758) and decreased triglyceride and LDL cholesterol levels in human research (761; 762; 609). In animal and human research, hypotension, blood pressure-lowering effects, and hypertension have been reported (756; 825; 359; 360; 361; 362; 363; 364; 365; 366; 367; 826; 827; 828; 829; 443; 609; 506; 369), although melatonin did not alter blood pressure in some animal or human research (830; 376) or had mixed effects on night and day blood pressure, with decreases at night (377; 375; 378; 608). ChasteberryChasteberry: In human research, chasteberry increased the natural secretion of melatonin (1038). CNS depressantsCNS depressants: In theory, based on possible risk of daytime sleepiness (411; 415; 421; 418; 422; 354; 667; 435; 67) and reported negative effects on certain cognitive tasks in humans in some, but not all, studies (428; 412; 413; 767; 893; 894), 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 (114). In human research, an effect of remifentanil on melatonin concentration and an effect of melatonin on remifentanil-induced sleep disturbance were lacking (439). CNS stimulantsCNS stimulants: In human research, there was an isolated case of aggression in a child diagnosed with ADHD and taking prescribed methylphenidate (433). In animal research, melatonin increased the adverse effects of methamphetamine on the nervous system (895). Melatonin has been implicated as having dosing time-dependent effects on the action of psychostimulant drugs such as cocaine and amphetamines (896). Cognitive agentsCognitive agents: In human research, exogenous melatonin caused decrements in performance, including a slowing of choice-reaction time (412; 428) or learning (413); however, some studies have failed to confirm a decrement in performance (767; 893; 894), including a study of high-dose melatonin (50mg) in elderly persons (mean age: 84.5 years) (897). ContraceptivesContraceptives: In patients undergoing in vitro fertilization embryo transfer (IVF-ET), although melatonin benefited oocyte maturation, effects on fertilization and pregnancy were lacking (594; 898). Similarly, melatonin has been shown to improve viability of sperm (899) and embryos (900; 901; 118; 902; 903) produced with in vitro fertilization. In animal research, reproductive effects of melatonin have also been found (904; 487; 905; 906; 907; 908; 909; 910; 280). Cytochrome P450-metabolized herbs and supplementsCytochrome 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) (911; 912) and possibly CYP2C9. It appears to inhibit CYP1A2 (465; 466; 467) and induce CYP3A. 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 (465; 466; 467). Caffeine is reported to raise natural melatonin levels in the body (787), with a more pronounced effect in nonsmokers (788), possibly due to effects on the liver enzyme cytochrome P450 1A2 (788). This effect was more pronounced in nonsmokers (788). Other human studies suggest that interactions between exogenous melatonin and substrates metabolized by CYP1A2 may differ in individuals before and after smoking abstinence (913). In animal research, melatonin inhibited the activity of cytochrome P450 2E1, but to a lesser extent than taurine (468). Dental agentsDental agents: In human research, salivary and gingival crevicular fluid melatonin levels were lower in individuals with periodontal disease (914). Dermatologic agentsDermatologic agents: Dermatologic use of melatonin has been proposed because of its immunomodulatory and antioxidant abilities. Study findings indicate that melatonin accumulates in the stratum corneum (709). In human research, free radical scavenging was suggested as a possible mechanism of action in the protection against UV-induced erythema (711). DHEADHEA: In mice, DHEA and melatonin have been noted to stimulate immune function, with slight additive effects when used together (1039). DiureticsDiuretics: In clinical trials, an adverse effect associated with melatonin was increased enuresis (353; 354; 355; 356; 357). A study in children with ADHD suffering from insomnia noted bedwetting at a long-term follow-up (358). EchinaceaEchinacea: 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 (1040). Exercise performance agentsExercise performance agents: In human research, during a heavy-resistance exercise session, melatonin increased the area under the curve of growth hormone (508), protected against the overexpression of inflammatory mediators, and inhibited the expression of proinflammatory cytokines in exercising individuals (930). Fertility agentsFertility agents: In patients undergoing in vitro fertilization embryo transfer (IVF-ET), although melatonin benefited oocyte maturation, effects on fertilization and pregnancy were lacking (594; 898). Similarly, melatonin has been shown to improve viability of sperm (899) and embryos (900; 901; 118; 902; 903) produced with in vitro fertilization. In animal research, reproductive effects of melatonin have also been found (904; 487; 905; 906; 907; 908; 909; 910; 280). FolateFolate: In animal research, severe folate deficiency reduced the body's natural levels of melatonin (1041). Gamma-aminobutyric acid (GABA)Gamma-aminobutyric acid (GABA): In animal research, results suggested a possible role of the GABAergic system in melatonin's effects (915). In human research, melatonin was found to potentiate the effects of gamma-amino butyric acid (GABA) (885). Gastrointestinal agentsGastrointestinal agents: Preliminary research has indicated that melatonin aids symptoms of functional dyspepsia (598), gastroesophageal reflux disease (GERD) (602), Crohn's disease and ulcerative colitis (932), and irritable bowel syndrome (mixed evidence) (933; 438; 600; 599; 601; 603). Genitourinary tract agentsGenitourinary tract agents: In clinical trials, an adverse effect associated with melatonin was increased enuresis (353; 354; 355; 356; 357). A study in children with ADHD suffering from insomnia noted bedwetting at a long-term follow-up (358). Glaucoma agentsGlaucoma agents: Preliminary human evidence suggests that melatonin may decrease intraocular pressure in the eye (460; 461; 366); however, according to reviews, high doses of melatonin may increase intraocular pressure and the risk of glaucoma, age-related maculopathy, and myopia (382), as well as retinal damage (400). Headache agentsHeadache agents: Evidence is mixed from human research with respect to preventive effects of melatonin on headaches, including migraines (934; 935; 146; 605; 936; 604; 937; 938; 939; 940; 440) Heart rate regulating agentsHeart rate regulating agents: Melatonin has been shown to increase heart rate when administered in patients taking nifedipine (a calcium channel blocker antihypertensive) (368) and in other studies (375); however, effects were lacking in other human research (376; 377; 378). When measured in the morning, the relationship between salivary melatonin and exercise-induced heart rate changes was steeper than when measured in the evening (941). Clinical significance is unclear. There are several rare or poorly described reports of abnormal heart rhythms, palpitations, fast heart rate, or chest pain, although in most cases, patients were taking other drugs that may account for these symptoms (370; 371; 372; 373; 374). HepaticsHepatics: In patients with nonalcoholic steatohepatitis (NASH), use of melatonin resulted in improvements in liver function (445). In patients with steatohepatitis, melatonin decreased levels of proinflammatory cytokines, triglycerides, and GGTP (761). In human research, melatonin resulted in stable renal and liver function parameters after six weeks of use (755). Decreased transaminases have been shown in other human research (754). However, in one participant, treatment with melatonin resulted in increased alkaline phosphatase levels (390). Herbs/supplements that affect GABAHerbs/supplements that affect GABA: In animal research, results suggested a possible role of the GABAergic system in melatonin's effects (915). In human research, melatonin was found to potentiate the effects of gamma-amino butyric acid (GABA) (885). Hormonal agentsHormonal agents: In humans, hormone replacement therapy (HRT) is reported to cause a decrease in daily melatonin secretion without disturbing circadian rhythm (942; 943). In clinical and laboratory studies, melatonin has also been reported as producing varying hormonal effects. Such reports include changes in levels of luteinizing hormone (469; 470; 471; 472; 473; 474; 475; 476), cortisol (477; 478; 481; 479; 480), progesterone (481; 482; 483; 484; 485), estradiol (482), thyroid hormone (T4 and T3) (486; 487; 488), testosterone (489; 487), growth hormone (411; 490; 476; 491; 492; 493; 494), prolactin (411; 495; 496; 497; 498; 499; 500), oxytocin and vasopressin (490; 501; 502; 503), adrenocorticotrophic hormone (478), and gonadotropin-inhibitory hormone (504). Melatonin has further been shown to alter pituitary hormone (LH and FSH) profiles in menopausal women to more "juvenile" profiles (488). In clinical trials, melatonin affected hormone levels in patients with hormonal-related cancers and had synergistic effects with tamoxifen (862; 850; 863). Other human studies reported a lack of significant hormonal effects (617; 496; 944; 945). Gynecomastia (increased breast size) has been reported in men, as has decreased sperm count (both which resolved with cessation of melatonin) (400). Decreased sperm motility has also been reported in rats (548) and humans (549). Other human and laboratory 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 (920). In females, blood pressure decreased only in hormone replacement therapy or birth control users and not nonusers (507; 506). In human research, progesterone modulated melatonin secretion in postmenopausal women (946). In human research, in combination with estradiol treatment, melatonin reduced peak values of norepinephrine and increased epinephrine levels in some, but not all, stimulus situations (505; 506; 507). In human research, during a heavy-resistance exercise session, melatonin increased the area under the curve of growth hormone (508). HypoglycemicsHypoglycemics: Elevated blood sugar levels (hyperglycemia) have been reported in patients with type 1 diabetes (insulin-dependent diabetes) (382; 383), and low doses of melatonin have reduced glucose tolerance and insulin sensitivity (384; 385). In patients with type 2 diabetes mellitus who had a 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 (386; 387). However, in other research, melatonin supplementation was found to lack an effect on measures of glucose homeostasis (763). HypotensivesHypotensives: In animal and human research, hypotension, blood pressure-lowering effects, and hypertension have been reported (756; 825; 359; 360; 361; 362; 363; 364; 365; 366; 367; 826; 827; 828; 829; 443; 609; 506; 369), although melatonin did not alter blood pressure in some animal or human research (830; 376) or had mixed effects on night and day blood pressure, with decreases at night (377; 375; 378; 608). 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 (64). Serum melatonin levels decreased noticeably with propranolol treatment (778). In animals, melatonin reduced the effects of the alpha-adrenergic agonist clonidine (756). 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 (368; 465). 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 (791). ImmunomodulatorsImmunomodulators: In human research, melatonin was found to interact positively with immune therapies, such as interferon (509), interleukin-2 (510; 511; 512; 513; 514; 515; 516; 517; 518; 519; 520; 521; 407; 522; 523; 408; 524; 525; 526; 527; 528), or tumor necrosis factor (529; 530; 525). Based on limited human research, researchers concluded that melatonin may be an effective treatment for sarcoidosis (531). Exogenous melatonin has been shown to enhance immune response following veterinary vaccination (532). Researchers noted increased platelet counts after melatonin use in patients with decreased platelets due to cancer chemotherapy (402; 403; 404; 533; 406; 407; 408). According to 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 (534). Melatonin has been reported to promote neutrophil apoptosis in patients receiving hepatectomy involving ischemia and reperfusion of the liver (535; 536; 537; 283). A combination hormone therapy including melatonin was found to improve leucocyte function in ovariectomized aged rats (538). In laboratory research, melatonin suppressed TNF-alpha, IL-1 beta, and IL-6 (101); inhibited Th1 cells (114); stimulated humoral activity and antibody production (539; 532; 540); inhibited NF-kappaB (541), as well as IKK, and JNK pathways (133); prevented T cell apoptosis (542); and stimulated mononuclear cell production (543). In human research, combined therapy with low-dose subcutaneous IL-2 and melatonin improved the mean number of lymphocytes, eosinophils, T lymphocytes, natural killer (NK) cells, and CD25- and DR-positive lymphocytes, and increased the mean CD4:CD8 ratio (544). In cancer patients who achieved disease control, melatonin induced a decrease in the number of regulatory T lymphocytes; this change was lacking in individuals with progressed disease (545) Light therapyLight therapy: Melatonin and light treatment have been used in combination in various human studies for illnesses such as depression (1042). In human research, bright light therapy increased the steepness of night melatonin levels (1043). In human research, use of an eyeglass LED delivery system suppressed melatonin secretion (1044). Nonvisual light for mood and cognitive enhancement decreased melatonin (1045). The effect of evening phototherapy for insomnia on melatonin was investigated; further details are lacking (1046). In a review, the effect of bright light therapy for mood disorders and melatonin levels was discussed; futher details are lacking (1047). LithiumLithium: In human research, lithium had a significant effect on sensitivity to light but not on overall melatonin synthesis (947). Magnetic fieldsMagnetic 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 (948; 949; 950; 951). Melatonin was shown to reduce the effects of lipid peroxidation, less effectively than vitamin E, in rats exposed to static magnetic fields under laboratory conditions (952). MeditationMeditation: In human research, meditation increased nighttime plasma melatonin levels (1048). Musculoskeletal agentsMusculoskeletal agents: According to case reports, ataxia (difficulties with walking and balance) may occur following melatonin overdose (372). In human research, melatonin lacked negative effects on postural stability (367). Compared to baseline, participants with chronic fatigue syndrome treated with melatonin showed a significant worsening of bodily pain (579). Weakened muscle power was reported in a clinical trial (598). Music therapyMusic therapy: In patients with Alzheimer's disease, music therapy increased serum melatonin levels (1049). Neurologic agentsNeurologic agents: It has been proposed that melatonin may reduce the amount of neurologic damage patients experience after stroke, based on antioxidant properties (953; 954; 955; 956; 957; 958; 959; 960). A significant body of basic research has indicated that melatonin may possess neuroprotective properties (184; 167; 168; 187; 169; 170; 171; 172; 173; 174; 175; 176; 177; 179; 180; 181; 182; 183; 184; 185; 79; 186; 187), meriting reviews in the contexts of neurodegenerative diseases (961), the peripheral nervous system (962), and traumatic nervous system injury (80). However, commonly reported adverse effects of melatonin in clinical trials include fatigue, dizziness, headache (including migraine), irritability, drowsiness, weakness, fogginess, yawning, nighttime awakening, poor sleep quality, vertigo, insomnia, and sleepiness (426; 424; 430; 421; 381; 419; 431; 388; 416; 372; 393; 366; 358; 417; 438; 435; 396; 380; 443; 390; 354; 355; 356; 440; 367; 441; 445; 391; 392; 429; 371; 357; 353; 598; 764). These symptoms are also indications of jet lag, and in some cases, causality may be unclear. In human research, mood changes have been reported, including giddiness, dysphoria (sadness), mood dip, nervousness, hyperactivity, irritability, and transient depression (463; 419; 390; 440; 391; 392; 358; 357; 427). Psychotic symptoms have also been reported in human research, including hallucinations, delusions, and paranoia, possibly due to overdose (371; 462; 441). Neuromuscular blockersNeuromuscular blockers: In laboratory research, melatonin increased the neuromuscular blocking effect of the muscle relaxant succinylcholine, but not vecuronium (963). Ocular agentsOcular agents: In limited human research, melatonin stabilized vision in patients suffering from age-related macular degeneration (459). Preliminary human evidence also suggests that melatonin may decrease intraocular pressure in the eye (460; 461; 366); however, according to reviews, high doses of melatonin may increase intraocular pressure and the risk of glaucoma, age-related maculopathy, and myopia (382), as well as retinal damage (400). Use of transition lenses as part of chromotherapy for macular degeneration was found to maintain the physiological balance of melatonin (964). In human research, use of eye masks increased melatonin levels (965). Osteoporosis agentsOsteoporosis agents: In laboratory research, melatonin impaired osteoclast activity and bone resorption (916; 917; 918). In human research, melatonin lacked effects on bone density, NTX, or OC, although the NTX:OC ratio in the melatonin group was reduced (628). Otic agentsOtic agents: In human research, melatonin attenuated the muscle sympathetic nerve activity (vestibulosympathetic reflex) response to baroreceptor unloading while lacking effects on the vestibulocollic reflexes (968). In human research, use of ear plugs increased melatonin levels (965). PhytoestrogensPhytoestrogens: Human and laboratory 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 (920). Mechanisms of melatonin's oncostatic action may include regulation of estrogen receptor expression and transactivation (921) and antiestrogenic effects (922; 923; 924). MCF-7 human breast cancer cultured cells have been reported as melatonin sensitive, as well as estrogen receptor positive and estrogen responsive (925), although this finding was not confirmed in a subsequent study (926). Melatonin has been reported to elicit an increase in estrogen receptor activity in breast tumors (927). Low plasma melatonin concentrations were associated with greater amounts of estrogen or progesterone receptors on primary tumors (928). In a review on the anticarcinogenic role of melatonin, potential mechanisms included the inhibition of initiation and growth of hormone-dependent tumors by decreasing the expression of estrogen receptors, as well as aromatase activity, resulting in the inhibition of cancer cell proliferation, a decrease in oxidative stress, and an increase in the activity of the immune system (929). Radioprotective agentsRadioprotective agents: 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 of preliminary animal and in vitro research (969; 215; 216; 206; 207; 217; 219). Melatonin has been shown to ameliorate oxidative injury due to ionizing radiation in vitro (970; 971; 214). The specific mechanisms may involve downregulation of apoptotic pathways via control of oxidative load (972). Renally eliminated agentsRenally eliminated agents: In human research, melatonin resulted in decreased renal blood flow velocity and conductance (376). In human research, melatonin resulted in stable renal function parameters after six weeks of use (755). Respiratory agentsRespiratory agents: In a clinical trial, melatonin reduced dyspnea; however, changes in lung function were lacking (580). SedativesSedatives: In theory, based on possible risk of daytime sleepiness (411; 415; 421; 418; 422; 354; 667; 435; 67) and reported negative effects on certain cognitive tasks in humans in some, but not all, studies (428; 412; 413; 767; 893; 894), melatonin may exacerbate the amount of drowsiness and reduced mental acuity caused by CNS depressants. In human research, melatonin has been shown to decrease sleep latency (390; 752) and benefit sleep quality and duration in children, older and younger adults, individuals with disabilities, and visually impaired individuals (356; 392; 431; 373; 379; 615; 389; 446; 613; 374; 357; 355; 734; 354; 638; 322; 659; 391; 581). In human research, exogenous melatonin exerted hypnotic effects, primarily when circulating levels of endogenous melatonin were low (653), and even very low doses caused sleep in some studies when ingested before endogenous melatonin onset (418; 662; 655; 661; 649). Also, in human research, melatonin has been shown to decrease the amount of anesthesia required during surgery (679; 973; 680; 719). Seizure threshold-lowering agentsSeizure threshold-lowering agents: It has been suggested that melatonin may act as a proconvulsant (449) and may lower seizure threshold and increase the risk of seizure, particularly in children with severe neurologic disorders (452; 451; 372). In a 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; the child was initiated on valproate, and although melatonin was not discontinued, further seizures were lacking (431). In contrast, several case reports indicated reduced incidence of seizure with regular melatonin use (453; 454; 455; 456; 457; 458). Both anticonvulsant (458; 813; 814; 815) and proconvulsant (449) properties have been associated with melatonin in preclinical studies. This remains an area of controversy (449). Thermoregulating agentsThermoregulating agents: In human research, hypothermic effects of melatonin have been reported with doses from 15mg (975; 657; 976; 427), and ingestion of 1.6mg of melatonin was reported to result in approximately 0.4?C decrease of body temperature in humans (975; 977; 978; 979). Reports of feeling cold or hypothermia exist in other clinical literature (390; 356; 445; 392; 448), but not in all studies (614). Thyroid agentsThyroid agents: In human research, thyroid-stimulating hormone (TSH) serum levels were lower and those of free thyroxine (FT4) were increased at night when endogenous melatonin levels were higher (980). In clinical and laboratory studies, melatonin has also been reported to change levels of thyroid hormone (T4 and T3) (486; 487; 488). VasodilatorsVasodilators: In healthy male volunteers, melatonin significantly increased peripheral blood flow, as measured by distal to proximal skin temperature gradient and finger pulse volume (981). In human research, melatonin resulted in decreased renal blood flow velocity and conductance, increased forearm blood flow and vascular conductance, and lacked an effect on cerebral blood flow (376). Melatonin/Food Interactions:
GeneralGeneral: The gastrointestinal effects of melatonin are likely dependent on food intake (1050; 1051). Food deprivation was found to impair daily rhythms of melatonin content by altering the activity of melatonin-synthesizing enzymes (1051). According to a review, in animal research, fasting lacked effects on melatonin-induced intestinal bicarbonate secretion (1052). Melatonin-containing foodsMelatonin-containing foods: Some foods, such as oats, sweet corn, rice, ginger, tomatoes, bananas, and barley, contain small amounts of melatonin and may increase melatonin levels (1053; 1054). In human research, consumption of diets enriched with Jerte Valley cherry (a food source of melatonin (1055)) increased urinary levels of 6-sulfatoxymelatonin (1056). VegetablesVegetables: Increased consumption of vegetables raised circulatory melatonin concentrations (1057). Melatonin/Lab Interactions:
8-isoprostanes8-isoprostanes: In human research, melatonin resulted in decreased 8-isoprostane levels (580). Blood glucoseBlood glucose: Elevated blood sugar levels (hyperglycemia) have been reported in patients with type 1 diabetes (insulin-dependent diabetes) (382; 383), and low doses of melatonin have reduced glucose tolerance and insulin sensitivity (384; 385). In patients with type 2 diabetes mellitus who had a 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 (386; 387). However, in other research, melatonin supplementation was found to lack an effect on measures of glucose homeostasis (763). Blood pressureBlood pressure: In animal and human research, hypotension, blood pressure-lowering effects, and hypertension have been reported (756; 825; 359; 360; 361; 362; 363; 364; 365; 366; 367; 826; 827; 828; 829; 443; 609; 506; 369), although melatonin did not alter blood pressure in some animal or human research (830; 376) or had mixed effects on night and day blood pressure, with decreases at night (377; 375; 378; 608). 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 (64). Serum melatonin levels decreased noticeably with propranolol treatment (778). In animals, melatonin reduced the effects of the alpha-adrenergic agonist clonidine (756). 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 (368; 465). 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 (791). Body temperatureBody temperature: In human research, hypothermic effects of melatonin have been reported with doses from 15mg (975; 657; 976; 427), and ingestion of 1.6mg of melatonin was reported to result in approximately 0.4?C decrease of body temperature in humans (975; 977; 978; 979). Reports of feeling cold or hypothermia exist in other clinical literature (390; 356; 445; 392; 448). Bone markersBone markers: In laboratory research, melatonin impaired osteoclast activity and bone resorption (916; 917; 918). In human research, melatonin lacked effects on bone density, NTX, or OC, although the NTX:OC ratio in the melatonin group was reduced (628). CatecholaminesCatecholamines: In human research, effects of melatonin levels on catecholamines were lacking (506). Coagulation panelCoagulation panel: According to experts, melatonin may decrease prothrombin time (a measurement of blood clotting ability) (400; 372). 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 (399). In animal research, melatonin enhanced platelet responsiveness (401). Increased platelet counts after melatonin use have been observed in patients with decreased platelets due to cancer therapies (402; 403; 404; 533; 405; 406; 407; 408), and cases of idiopathic thrombocytopenic purpura (ITP) treated with melatonin have been reported (409; 410). Electroencephalogram (EEG)Electroencephalogram (EEG): In human research, effects of melatonin on EEG characteristics were lacking (1058). Glycated hemoglobin (HA1c)Glycated hemoglobin (HA1c): In patients with type 2 diabetes mellitus who had a 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 (386; 387). Heart rateHeart rate: Melatonin has been shown to increase heart rate when administered in patients taking nifedipine (a calcium channel blocker antihypertensive) (368) and in other studies (375); however, effects were lacking in other human research (376; 377; 378). When measured in the morning, the relationship between salivary melatonin and exercise-induced heart rate changes was steeper than when measured in the evening (941). Clinical significance is unclear. There are several rare or poorly described reports of abnormal heart rhythms, palpitations, fast heart rate, or chest pain, although in most cases, patients were taking other drugs that may account for these symptoms (370; 371; 372; 373; 374). Hormone panelHormone panel: In clinical and laboratory studies, melatonin has been reported as producing varying hormonal effects. Such reports include changes in levels of luteinizing hormone (469; 470; 471; 472; 473; 474; 475; 476), cortisol (477; 478; 481; 479; 480), progesterone (481; 482; 483; 484; 485), estradiol (482), thyroid hormone (T4 and T3) (486; 487; 488), testosterone (489; 487), growth hormone (411; 490; 476; 491; 492; 493; 494), prolactin (411; 495; 496; 497; 498; 499; 500), oxytocin and vasopressin (490; 501; 502; 503), adrenocorticotrophic hormone (478), and gonadotropin-inhibitory hormone (504). Melatonin has further been shown to alter pituitary hormone (LH and FSH) profiles in menopausal women to more "juvenile" profiles (488). In human research, in combination with estradiol treatment, melatonin reduced peak values of norepinephrine and increased epinephrine levels in some, but not all, stimulus situations (505; 506; 507). Effects on cortisol, norepinephrine, and epinephrine were lacking in some human research (625). In human research, during a heavy-resistance exercise session, melatonin increased the area under the curve of growth hormone (508). Immune panelImmune panel: In human research, combined therapy with low-dose subcutaneous IL-2 and melatonin improved the mean number of lymphocytes, eosinophils, T lymphocytes, natural killer (NK) cells, and CD25- and DR-positive lymphocytes, and increased the mean CD4:CD8 ratio (544). In cancer patients who achieved disease control, melatonin induced a decrease in the number of regulatory T lymphocytes; this change was lacking in individuals with progressed disease (545). In human research, melatonin enhanced IL-2-, with or without IL-12, induced lymphocytosis, and reversed lymphcytopenia induced by IL-12 (868). In laboratory research, melatonin suppressed TNF-alpha, IL-1 beta, and IL-6 (101). In human research, melatonin reduced levels of IL-6, IL-8, IL-10, and IL-12 (552). Inflammatory markersInflammatory markers: In human research, melatonin had anti-inflammatory effects in infants with respiratory distress (11), decreased the upregulation of proinflammatory cytokines in laboratory and human research (831; 101; 47; 109; 832; 761; 115; 62), and inhibited NO and MDA production and increased glutathione levels (833; 834). In exercising individuals, melatonin protected against the overexpression of inflammatory mediators and inhibited the expression of proinflammatory cytokines in exercising individuals (930). 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 (464). Also, in human research, melatonin lacked effects on CRP levels (835). Insulin-like growth factorInsulin-like growth factor: In human research, melatonin lacked effects on insulin-like growth factor I (IGF-1) or insulin-like growth factor-binding protein 3 (IGFBP-3), or their ratio (747). Intraocular pressureIntraocular pressure: Preliminary human evidence also suggests that melatonin may decrease intraocular pressure in the eye (460; 461; 366); however, according to reviews, high doses of melatonin may increase intraocular pressure and the risk of glaucoma, age-related maculopathy, and myopia (382), as well as retinal damage (400). Lipid profileLipid profile: There is some evidence of increases in cholesterol levels and atherosclerotic plaque buildup in human research (757) and animal research (759; 760). In contrast, there are also reports of decreases in cholesterol levels in animal research (758) and decreased triglyceride and LDL cholesterol levels in human research (761; 762; 609). Liver functionLiver function: In patients with nonalcoholic steatohepatitis (NASH), use of melatonin resulted in improvements in liver function (445). In patients with steatohepatitis, melatonin decreased levels of proinflammatory cytokines, triglycerides, and GGTP (761). In human research, melatonin resulted in stable renal and liver function parameters after six weeks of use (755). Decreased transaminases have been shown in other human research (754). However, in one participant, treatment with melatonin resulted in increased alkaline phosphatase levels (390). Melatonin levelsMelatonin levels: In human research, melatonin supplementation was found to increase plasma levels of melatonin, occasionally into the daylight hours (761; 508; 754; 446; 1053; 1054; 1059; 692; 665). Nitric oxideNitric oxide: In human research, the production of NO was suggested to be regulated by melatonin; however, further details are lacking (1060). Nitrate/nitriteNitrate/nitrite: In human research, melatonin decreased nitrite and nitrate levels (645; 11). PigmentsPigments: In human research, melatonin induced and augmented lentigines and nevi (1061). This report was commented on (1062). Plasma kynurenine concentrationsPlasma kynurenine concentrations: In human research, melatonin induced an increase in plasma kynurenine concentrations in individuals with rheumatoid arthritis (464). Renal functionRenal function: In human research, melatonin resulted in decreased renal blood flow velocity and conductance (376). In human research, melatonin resulted in stable renal function parameters after six weeks of use (755). Seizure thresholdSeizure threshold: It has been suggested that melatonin may act as a proconvulsant (449) and may lower seizure threshold and increase the risk of seizure, particularly in children with severe neurologic disorders (452; 451; 372). In a 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; the child was initiated on valproate, and although melatonin was not discontinued, further seizures were lacking (431). In contrast, several case reports indicated reduced incidence of seizure with regular melatonin use (453; 454; 455; 456; 457; 458). Both anticonvulsant (458; 813; 814; 815) and proconvulsant (449) properties have been associated with melatonin in preclinical studies. This remains an area of controversy (449). Sperm functionSperm function: In animal research, exposure to exogenous melatonin increased sperm motility, ejaculate volume, sperm concentration, total sperm output, and total function sperm fraction, and decreased means of reaction time, dead sperm, and abnormal sperm (487). Melatonin implants have also been shown to improve semen characteristics in sheep (905).