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Table of Contents > Interactions & Depletions > Melatonin (N-acetyl-5-methoxytryptamine) Print

Melatonin (N-acetyl-5-methoxytryptamine)



Interactions

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

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

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

Melatonin/Lab Interactions:
  • Blood glucoseBlood glucose: Elevated blood sugar levels (hyperglycemia) have been reported in patients with type 1 diabetes (insulin-dependent diabetes) (368; 369), and low doses of melatonin have reduced glucose tolerance and insulin sensitivity (370). Melatonin in combination with zinc has been found to improve postprandial glycemic control in patients with type 2 diabetes (673; 674). However, in other research, melatonin supplementation was found to have no significant effect upon measures of glucose homeostasis (372).
  • Blood pressureBlood pressure: Melatonin may cause drops in blood pressure, as observed in animals (360) and in preliminary human research (361; 362; 363; 364; 365).
  • Coagulation panelCoagulation panel: It has been suggested that there might be a dose-response relationship between the plasma concentration of melatonin and coagulation activity (359). There are at least six reported cases of alterations in prothrombin time (a measurement of blood clotting ability) in patients taking both melatonin and warfarin (349). These cases have noted decreases in prothrombin time (PT).
  • Glycated hemoglobin (HA1c)Glycated hemoglobin (HA1c): In human research, melatonin use resulted in decreases in glycated hemoglobin (673; 674).
  • Heart rateHeart rate: Melatonin has been shown to increase heart rate when administered in patients taking nifedipine (a calcium channel blocker antihypertensive) (366).
  • Hormone panelHormone panel: Melatonin has also been reported to produce varying hormonal effects. Such reports include changes in levels of luteinizing hormone (373; 374; 375; 376; 377; 378; 379), cortisol (765; 380; 438), adrenocorticotropic hormone (ACTH) (438). progesterone (380), estradiol, thyroid hormone (T4 and T3) (381), growth hormone (382; 383; 379; 384), prolactin (382), oxytocin, and vasopressin (383). Melatonin has further been shown to alter pituitary hormone (LH and FSH) profiles in menopausal women to a more "juvenile" one (385).
  • Inflammatory markersInflammatory markers: Based on limited human research, melatonin may be an effective anti-inflammatory agent (47), decreasing the upregulation of proinflammatory cytokines (677), as well as inhibiting nitric oxide (NO) and malondialdehyde (MDA) production and increasing glutathione levels (678; 679). However, there is conflicting evidence from human trials, where melatonin induced a proinflammatory response, increasing levels of certain inflammatory cytokines (p>0.05), as well as plasma kynurenine concentrations (p<0.05) in individuals with rheumatoid arthritis (39).
  • Intraocular pressureIntraocular pressure: Preliminary evidence in humans suggests that melatonin may decrease intraocular pressure in the eye (389; 390). However, high doses of melatonin may increase intraocular pressure and the risk of glaucoma, age-related maculopathy, and myopia (368), as well as retinal damage (358).
  • Lipid profileLipid profile: According to animal research, melatonin may elicit decreases in free serum cholesterol levels (406). However, research has found that regular use of melatonin may increase atherosclerotic plaque buildup in humans (403) and animals (404; 405).
  • Magnetic 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 (819; 820; 821; 822). Melatonin was seen to reduce the effects of lipid peroxidation, less effectively than vitamin E, in rats exposed to static magnetic fields under laboratory conditions (823).
  • Melatonin levelsMelatonin levels: Melatonin supplementation increased plasma melatonin levels (816; 817; 824).
  • Plasma kynurenine concentrationsPlasma kynurenine concentrations: There is evidence that melatonin may induce a proinflammatory response and increase plasma kynurenine concentrations (p<0.05) in individuals with rheumatoid arthritis (39).
  • TemperatureTemperature: Melatonin use was found to decrease body temperature in various clinical trials (483; 566).

Copyright © 2011 Natural Standard (www.naturalstandard.com)

The information in this monograph is intended for informational purposes only, and is meant to help users better understand health concerns. Information is based on review of scientific research data, historical practice patterns, and clinical experience. This information should not be interpreted as specific medical advice. Users should consult with a qualified healthcare provider for specific questions regarding therapies, diagnosis and/or health conditions, prior to making therapeutic decisions.
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