Oral Dose Of Melatonin Research Articles

The impact of melatonin administration on the fertility performance and several relating parameters during the breeding season in the Arabi ewes

A total of twenty-four healthy ewes aged between 2-3 years old and weighed about 35.09 kg of body weight were divided randomly into four groups (6 animals for each group). The first group included the non-treated control group, while the other three groups were subjected to various oral doses of melatonin 9 mg, 12 mg and 15 mg/head, respectively. All treatments were applied at 6 o'clock in the morning, to investigate the effect of treatment with melatonin during breeding season on reproductive performance and levels of some biochemical parameters in Arabi ewes from 1 May to 1 October 2017. Blood samples 7ml were collected after one hour of treatment and then monthly during the pregnancy months to determine the concentrations of biochemical parameters. After Postpartum, lambed ewes/lambs number, birth weight, placenta empty weight and cotyledon number were recorded. The results showed significant (P<0.05) improvement in reproductive performance (fertility percentage, twinning rate and the number of offspring) when ewes administrated melatonin at two doses (12 and 15 mg/ head). Also, melatonin administration caused significant (P<0.05) decrease in the concentrations of thyroxin, cortisol, and cholesterol. Conversely, there was a significant increase (P<0.05) in glucose concentration after 1 hour of treatment. The concentrations of thyroxin, cortisol, cholesterol, and vitamin C increased significantly (P<0.01) in early-gestation compared with mid and late-gestation, while the concentrations progesterone and glucose increased significantly (P<0.05) in mid-gestation compared with early and late-gestation. In conclusion, melatonin administration at doses 12 and 15 mg/ head improves ewe reproductive performance (fertility percentage, twinning rate and the number of born lambs). Additionally, the gestation stage has a negative effect on the concentrations of thyroxin, cholesterol and vitamin C.

Effects of Caffeic Acid and Quercetin on In Vitro Permeability, Metabolism and In Vivo Pharmacokinetics of Melatonin in Rats: Potential for Herb-Drug Interaction.

Melatonin is a popular dietary supplement and also considered as pharmaceutical product for sleep disorders. Caffeic acid and quercetin are widely distributed in leafy vegetables, fruits, tea extract, and both are used as natural antioxidant. There is an immense concern for health researchers to study the herb/food-drug interactions of melatonin. It is mainly metabolized by CYP1A2 in human so that herbs/foods containing cytochrome P450 (CYP) inhibitors can affect pharmacokinetics of melatonin. By considering pharmacokinetic aspects, the present study was undertaken to evaluate the effects of caffeic acid and quercetin on Caco-2 cells permeability, metabolism, CYP1A inhibition in vitro assay systems and a single dose pharmacokinetics of melatonin in vivo rats. The effects of caffeic acid and quercetin on melatonin permeability were tested in Caco-2 cells. Metabolic stability and CYP1A activity were investigated in rat liver microsomes (RLMs) using probe substrates (melatonin/phenacetinin vitro). Melatonin and phenacetin were incubated in RLMs with or without caffeic acid and quercetin, and the IC50 values were determined. The pharmacokinetics of melatonin conducted in rats after a single dose (15mg/kg) pre-treatment with caffeic acid, quercetin and caffeic acid plus quercetin followed by oral dose of melatonin at 5mg/kg. Analysis of all samples was with LC-MS/MS. Caffeic acid and quercetin did not alter Caco-2 permeability of melatonin in apical to basolateral direction and vice versa. Melatonin was metabolized in rat liver microsomes, which was inhibited by both caffeic acid and quercetin through CYP1A. The concomitant oral administration of melatonin along with 15mg/kg of caffeic acid or quercetin or caffeic acid plus quercetin significantly (p<0.05) increased the AUC0-t of melatonin by 30.0, 66.7 and 114.0%, respectively. The apparent oral rat plasma clearance (CL/F) of melatonin also decreased significantly (p<0.05) by 28.78, 47.87 and 50% in presence of caffeic acid, quercetin and caffeic acid plus quercetin, respectively. These findings suggest that caffeic acid and quercetin improved oral exposure of melatonin via CYP1A inhibition pathway.

Melatonin and alpha lipoic acid attenuate lopinavir/ritonavir - induced testicular toxicity in albino rats

The use of lopinavir/ritonavir (LPV/r) could be associated with testicular toxicity as a limiting factor. The present study evaluated the effects of melatonin (MT) and alpha lipoic (ALA) acid on LPV/r–induced testicular toxicity in male albino rats. Eighty five male albino rats used for this study were randomized into 6 groups (A-F). Rats in groups A1 and A2 served as placebo and solvent control and were orally exposed to water and 1% ethanol, respectively. Rats in group B were exposed to oral doses of MT (10 mg kg-1/day), ALA (10 mg kg-1/day) and combined doses of MT and ALA, respectively. Rats in group C were exposed to oral doses of LPV/r (22.9/5.71 - 91.4/22.9 mg kg-1/ day), respectively. Rats in group D-F were exposed to oral doses of MT (10 mg kg-1/day), ALA (10 mg kg-1/day) and combined doses of MT and ALA prior to oral exposure to LPV/r (22.9/5.71 - 91.4/22.9 mg kg-1/day), respectively. At the end of 60 days of exposure to drugs, rats were sacrificed; blood was collected and serum extracted and evaluated for testosterone. Testes were collected and evaluated for sperm parameters. LPV/r-treated rats showed significant (P&lt;0.05) and dose-dependent decreases in sperm count, sperm motility, sperm viability and serum testosterone levels with increases in abnormal sperm cells, debris, and primordial sperm cells when compared to placebo control. However, LPV/r-induced changes in sperm parameters and serum testosterone levels were attenuated in rats pretreated with MT and ALA. The best effects were observed in rats pretreated with combined doses of MT and ALA. Melatonin and alpha lipoic acid have potential to reduce testicular toxicity associated with lopinavir/ritonavir treatment.

A comparison of the effect of two doses of oral melatonin with oral midazolam and placebo on pre-operative anxiety, cognition and psychomotor function in children: A randomised double-blind study.

Background and Aims:Melatonin (MT), a naturally occurring pituitary hormone has a sleep promoting effect. There are very few studies on pre-operative oral MT (0.2–0.5 mg/kg) in children. We planned a study to assess the efficacy of oral MT in two doses and compare it with oral midazolam and placebo for pre-operative anxiolysis, sedation, maintenance of cognition and psychomotor skills, parental separation behaviour and venepuncture compliance.Methods:This prospective double-blind randomised study was conducted after ethical committee approval on 100 children aged 5–15 years, American Society of Anaesthesiologists physical status I and II undergoing elective surgery at our hospital from January 1, 2014, to December 31, 2014. Mentally disordered children were excluded from the study. They were randomised into four groups of 25 each (A, B, C, D) to receive either oral MT 0.5 mg/kg or 0.75 mg/kg or oral midazolam 0.5 mg/kg or placebo 45–60 min, respectively, before induction. The child's anxiety, cognition and psychomotor function before and after pre-medication, behaviour during the parental separation and venepuncture were appropriately scored. Kruskal–Wallis analysis of variance for intergroup and Wilcoxon matched pairs tests for intragroup comparisons of data were applied.Results:The four groups were comparable regarding mean age, weight and sex. The anxiety score reductions in the three groups when compared to placebo were statistically significant. Children receiving MT 0.75 mg/kg had maximum anxiolysis and venepuncture compliance (P < 0.05). Cognition was decreased with maximum sedation, successful parental separation and psychomotor impairment in the midazolam group (P < 0.05).Conclusion:Oral MT (0.5 mg/kg and 0.75 mg/kg) in children decreases pre-operative anxiety without impairing cognitive and psychomotor functions, the 0.75 mg/kg dose being most effective.

Abstract A91: Over-the-counter melatonin supplementation in human subjects: A potentially novel chronotherapeutic approach targeting the Warburg effect and fatty acid metabolism in breast cancer therapy/prevention

Abstract Melatonin, a circadian anti-cancer hormone produced by the pineal gland during darkness at night suppresses the Warburg effect, linoleic acid (LA) uptake/metabolism and tumor cell proliferation in both estrogen receptor (ERα+) and ERα- in tissue-isolated human breast cancer xenografts. The nighttime circadian melatonin signal regulates circadian rhythms in tumor glucose and fatty acid metabolism as well as related signaling pathways that are important in controlling cell proliferative and survival mechanisms. Over-the-counter (OTC) melatonin supplements are used by millions of individuals to treat insomnia and/or jet-lag. The present study addressed the hypothesis that oral ingestion of OTC melatonin supplements by normal adult human female volunteers results in blood levels of melatonin that suppress LA uptake/metabolism, aerobic glycolysis and cell proliferative activity in human breast cancer xenografts, growing in nude female rats, directly perfused in situ with human subject donor whole-blood following melatonin intake. Twelve young, healthy premenopausal women were recruited to ingest an OTC melatonin supplement at a single dose of either 75μg, 150μg, 300μg or 1 mg during midday (low endogenous melatonin levels) resulting in low to high pharmacological blood concentrations of melatonin. A pre-supplement venous blood sample was collected from the antecubital vein of the forearm. Each subject then ingested a randomly selected oral dose of melatonin followed approximately 1 hour later by the withdrawal of a post-supplement venous blood sample. On the following day, the pre- and post-supplement whole-blood samples collected from a given subject were separately placed into a tumor perfusion reservoir. Tissue-isolated ERα- MCF-7 human breast cancer xenografts grown in female nude rats were then directly perfused in situ for 1 hour with either pre- or post-supplement oxygenated blood (37°C). Irrespective of the dose tested, melatonin induced a 50% decrease in both tumor glucose uptake and lactate release, 22% and 44% deceases in O2 uptake and CO2 production, respectively, 50% decrease in cAMP concentrations, and a 100% decrease in linoleic acid (LA) uptake and 13-hydroxyoctadecadienoic acid (13-HODE) formation. Melatonin also caused a marked decrease in the expression of phospho-AKT, GSK3β and ERK1/2, and an 85% decrease in the incorporation of [3H]thymidine into DNA. Similar results were obtained at the lowest dose of melatonin (e.g., 75μg) in ERα+ human breast cancer xenografts. The melatonin-induced suppression tumor proliferative and metabolic activity in both ERα- and ERα+ breast cancer xenografts was completely prevented by the co-perfusion with the non-selective MT1/MT22 melatonin receptor blocker S20928 consistent with the involvement of a melatonin receptor-mediated mechanism. These results indicate that oral administration of an OTC melatonin supplement at a variety of low to high doses were equally effective in suppressing the Warburg effect and key tumor proliferative and survival signaling pathways, cAMP-dependent LA uptake and metabolism to mitogenically active 13-HODE and ultimately cell proliferation in tissue-isolated human breast xenografts irrespective of ERα status via a melatonin receptor-mediated mechanism. These findings suggest that even low doses of OTC melatonin preparations may play a potentially important role as a new chronotherapeutic agent in human breast cancer treatment and/or prevention by targeting aerobic glycolysis and fatty acid signaling and metabolism. Supported by NIH Grants R21CA129875 (DEB) and R01CA54152 (SMH). Citation Format: David E. Blask, Robert T. Dauchy, Erin M. Dauchy, Steven M. Hill, Lulu Mao, Melissa M. Wren, Mary M.C. Meyaski-Schluter, Lin Yuan. Over-the-counter melatonin supplementation in human subjects: A potentially novel chronotherapeutic approach targeting the Warburg effect and fatty acid metabolism in breast cancer therapy/prevention. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr A91.

Sleep in the neurological intensive care unit: feasibility of quantifying sleep after melatonin supplementation with environmental light and noise reduction.

Sleep deprivation may be particularly detrimental to intensive care unit (ICU) patients. Polysomnography has demonstrated abnormal sleep in medical and surgical ICU populations. Both environmental factors and circadian disruption have been implicated. We hypothesized that patients in a neurologic ICU would demonstrate similar sleep disturbances and that a combination of sleep-promoting interventions would increase sleep time. Twelve patients were enrolled in this pilot-randomized, controlled, study in a neurologic ICU. For adult patients undergoing continuous EEG for clinical purposes, noise-cancelling headphones and eye masks were worn, and an oral dose of melatonin was administered for 3 days, or until EEG was stopped. Sleep was scored according to standard criteria; EEG was characterized and analyzed quantitatively. Sixty-five percent of the patients' recordings were unscorable based on accepted standardized criteria; therefore, sleep measures could not be compared. For those with sleep that could be scored, total sleep time was normal, although sleep was fragmented and time spent in slow-wave or rapid eye movement sleep was notably decreased. Patients with unscorable recordings had worse injury severity measures, absent or significantly slower posterior dominant rhythm, and less coherence of posterior faster frequencies. Clinical outcomes were similar between intervention and control groups. Although sleep-promoting interventions were feasible, sleep quantification based on currently accepted criteria limited the ability to score sleep. Similar to other ICUs, sleep in the neurologic ICU is abnormal; patients with unscorable sleep-like states have greater injury severity. This study was limited by strict enrollment criteria. A reliable method to quantify sleep and sleep-like states in the ICU is needed.

Melatonin as a potential therapy for sepsis: a phase I dose escalation study and an ex vivo whole blood model under conditions of sepsis

Sepsis is a massive inflammatory response mediated by infection, characterized by oxidative stress, release of cytokines, and mitochondrial dysfunction. Melatonin accumulates in mitochondria, and both it and its metabolites have potent antioxidant and anti-inflammatory activities and may be useful in sepsis. We undertook a phase I dose escalation study in healthy volunteers to assess the tolerability and pharmacokinetics of 20, 30, 50, and 100 mg oral doses of melatonin. In addition, we developed an ex vivo whole blood model under conditions mimicking sepsis to determine the bioactivity of melatonin and the major metabolite 6-hydroxymelatonin at relevant concentrations. For the phase I trial, oral melatonin was given to five subjects in each dose cohort (n = 20). Blood and urine were collected for measurement of melatonin and 6-hydroxymelatonin, and symptoms and physiological measures were assessed. Validated sleep scales were completed. No adverse effects after oral melatonin, other than mild transient drowsiness with no effects on sleeping patterns, were seen, and no symptoms were reported. Melatonin was rapidly cleared at all doses with a median [range] elimination half-life of 51.7 [29.5–63.2] min across all doses. There was considerable variability in maximum melatonin levels within each dose cohort, but 6-hydoxymelatonin sulfate levels were less variable and remained stable for several hours. For the ex vivo study, blood from 20 volunteers was treated with lipopolysaccharide and peptidoglycan plus a range of concentrations of melatonin/6-hydroxymelatonin. Both melatonin and 6-hydroxymelatonin had beneficial effects on sepsis-induced mitochondrial dysfunction, oxidative stress, and cytokine responses at concentrations similar to those achieved in vivo.

Abstract 4673: A randomized, double-blind, multicenter trial evaluating the chronotherapeutic role of concomitant melatonin in the treatment of stage IIIB and IV non-small cell lung carcinoma.

Abstract Background: A recently published meta-analysis suggests that melatonin administered concurrently with chemotherapy leads to significant improvements in tumor response and survival in solid tumors, however, the role of melatonin in cancer treatment still remains disputable. We investigated the impact of chronotherapeutic administration of melatonin on tumor response and overall survival in stage IIIB and IV non-small cell lung cancer (NSCLC) patients undergoing conventional chemotherapy. Methods: Veteran Affairs Medical Center (VAMC) and Cancer Treatment Centers of America® at Midwestern Regional Medical Center (MRMC), a non-VA site, entered 42 patients each. The patients were randomized to receive placebo 8 am and placebo 8 pm (arm 1; n=29), or melatonin 20 mg 8 am and placebo 8 pm (arm 2; n=27), or placebo 8 am and melatonin 20 mg 8 pm (arm 3; n=28). All study participants received treatment with cisplatin (25 mg/m2/day) followed by etoposide (100 mg/m2/day) chemotherapy. Patient survival was defined as the time between the study start date and date of death from any cause/date of last contact. Kaplan-Meier analysis with log-rank test was used to evaluate the equality of survival distributions across the three treatment arms. Tumor response was evaluated using the RECIST guidelines. Results: 64 patients had stage IV while 20 had stage IIIB disease. 65 patients were males while 19 were females. All patients had expired at the time of this analysis. Mean age at study entry was 61.3 years (57 years for MRMC versus 65.7 for VAMC). There were no significant differences in the three treatment arms with respect to age, gender, tumor stage and performance status. Median survival time in the 3 treatment arms was 10.4 (arm 1), 6.8 (arm 2) and 8.0 (arm 3) months respectively (log rank p=0.81). Similarly, there was no significant difference in the treatment arms with regard to tumor response, such that 48.3%, 37.0% and 32.1% patients had stable disease in arm 1, arm 2 and arm 3 respectively (Chi-square p=0.49). Conclusions: Contrary to the recently reported meta-analysis, we found that neither the addition nor the timing of a high oral dose of melatonin added therapeutically to the combination of cisplatin and etoposide. The melatonin dose used in this study is at least 20x the usual replacement dose and this may have resulted in melatonin being inappropriately present in the circulation during both day and night, an un-physiologic state, which might be responsible for the apparent lack of efficacy of this particular regimen. Citation Format: Robert D. Levin, James F. Grutsch, Christopher G. Lis, Digant Gupta, Patricia A. Wood, William JM Hrushesky. A randomized, double-blind, multicenter trial evaluating the chronotherapeutic role of concomitant melatonin in the treatment of stage IIIB and IV non-small cell lung carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4673. doi:10.1158/1538-7445.AM2013-4673

Melatonin does not attenuate dynamic cardiovascular and cerebrovascular reflex responses to acute hypotension in healthy men

BackgroundMelatonin has been shown to attenuate the reflex sympathetic increases that arise in response to orthostatic challenges. We tested the hypothesis that the attenuated sympathetic increase induced by melatonin premedication may weaken the arterial blood pressure (ABP) preserving the capability during acute hypotension, thereby altering dynamic cerebral autoregulation and causing a further decrease in cerebral blood flow (CBF).MethodsAcute hypotension was induced in 12 healthy subjects by releasing bilateral thigh cuffs before and after an oral dose of melatonin (0.2 mg/kg). Heart rate (HR), arterial blood pressure (ABP), Modelflow estimate of cardiac output (CO), total peripheral resistance (TPR) and cerebral blood flow velocity (CBFV) by transcranial Doppler were measured.ResultsSteady state HR, the mean arterial pressure and CBFV were not altered 60 minutes after melatonin ingestion. Reduced systolic arterial pressure (ΔSAP), changes in HR (ΔHR), CO (ΔCO), and TPR (ΔTPR), ΔHR/ΔSAP and percentage restoration of SAP were not affected after a temporal decrease in ABP induced by thigh cuff release. In the cerebral circulation, melatonin did not affect changes in CBFV, cerebrovascular resistance index, the rate of regulation and percentage restoration of CBFV following a sudden decrease in ABP.ConclusionsContrary to our hypothesis, melatonin did not affect the rapid vasodilatory and recovery responses of cardiovascular and dynamic cerebral autoregulation. These results suggest that melatonin premedication may not impair ABP and CBF preserving capability induced by sudden postural changes or hemorrhage.

Questionnaire Helps Identify Children's Sleep Disorders

Questionnaire Helps Identify Children's Sleep Disorders

Melatonin promotes sleep in three species of diurnal nonhuman primates

Nocturnal melatonin secretion is concurrent with consolidated sleep episodes in diurnal mammals and physiological melatonin levels can promote sleep onset in humans and in pigtail macaques. In order to further investigate the effects of melatonin treatment on sleep parameters in diurnal nonhuman primates, three macaque species have been studied: Macaca nemestrina, Macaca fascicularis, and Macaca mulatta. Sleep was assessed using continuous actigraphic recording of motor activity in animals maintained under 12:12-h light/dark cycle. Oral doses of melatonin (5–320 μg/kg) were administered 2 h before lights-off time, with 5- and 10-μg/kg doses resulting in physiological circulating melatonin levels (31–95 pg/ml). The effects of melatonin administration were similar in three species studied and included significantly earlier sleep onset time and longer sleep period time, with no difference in time of awakening, following administration of both physiological (5–10 μg/kg) and pharmacological (20–320 μg/kg) doses. While low melatonin doses (5–20 μg/kg) did not significantly affect nighttime sleep efficiency, higher pharmacological doses reduced sleep efficiency and increased sleep fragmentation at night, and reduced spontaneous daytime locomotor activity. Daily administration of a 5-μg/kg dose for 4 weeks or gradually escalating melatonin doses (5–320 μg/kg over a 3-week period) did not result in the development of tolerance or sensitization to the effect of melatonin on sleep initiation or sleep period. These data affirm that sleep-promoting effects of melatonin observed in humans are also typical for diurnal primates. They also suggest that physiological and pharmacological melatonin levels might produce different effects on sleep efficiency and that nonhuman primates can serve as adequate animal model for studying the mechanisms of melatonin's action on sleep and performance.

Melatonin: possible mechanisms involved in its ‘radioprotective’ effect

Peripheral blood samples were collected from four human volunteers before, and at 1 and 2 h after a single oral dose of 300 mg of melatonin. From each sample, separate aliquots of whole blood were exposed to 100–150 cGy gamma radiation in vitro to determine the extent of genetic damage. Irradiated lymphocytes from all volunteers which were collected after melatonin ingestion exhibited a significantly decreased extent of primary DNA damage and reduced frequencies of chromosomal aberrations and micronuclei, as compared with similarly irradiated cells collected before the oral dose of melatonin. The extent of the melatonin-associated decrease in primary DNA damage was less than the corresponding decrease observed in the incidence of chromosomal aberrations and micronuclei; the latter assays required an additional post-irradiation incubation of the cells at 37±1°C for 48 and 72 h, respectively. The possible mechanisms involved in the radioprotective influence of melatonin are discussed.

Melatonin reduces gamma radiation-induced primary DNA damage in human blood lymphocytes

Peripheral blood samples were collected from human volunteers 5–10 min before, and at 1 and 2 h after a single oral dose of 300 mg of melatonin. At each time point: (1) the concentration of melatonin in the serum and in the leukocytes was determined; and (2) the whole blood was exposed in vitro to 100 cGy of gamma radiation. Immediately after exposure to the radiation, the lymphocytes were examined to determine the extent of primary DNA damage, viz., single strand breaks and alkali labile lesions (determined from the length of DNA migration and fluorescence intensity of migrated DNA in the comet tail), using the alkaline comet assay. For each volunteer, the results showed a significant increase in the concentration of melatonin in the serum and in the leukocytes at 1 h after the oral dose of melatonin, as compared to the sample collected at 0 hour. The lymphocytes in the blood samples collected at 1 and 2 h after melatonin ingestion and exposed in vitro to 100 cGy gamma radiation exhibited a significant decrease in the extent of primary DNA damage, as compared with similarly irradiated lymphocytes from the blood sample collected before melatonin ingestion. The extent of the melatonin-associated decrease in primary DNA damage did not correspond with the decrease reported earlier in the incidence of chromosomal aberrations and micronuclei; the latter assays required an additional postirradiation incubation of the cells at 37±1°C for 48 and 72 h, respectively.

Melatonin and radioprotection from genetic damage: In vivo/in vitro studies with human volunteers

Peripheral blood samples were collected from human volunteers at 0 (5–10 min before), and at 1 and 2 h after a single oral dose of 300 mg of melatonin. At each time point, (i) the concentration of melatonin in the serum and in the leukocytes were cultured with mitogenic stimulation to determine the extent of radiation-induced genetic damage, viz., chromosome aberrations and micronuclei. For each volunteer, the results showed a significant increase in the concentration of melatonin in the serum and in the leukocytes at 1 h after the oral dose of melatonin, as compared to the sample collected at 0 h. The lymphocytes in the blood samples collected at 1 and 2 h after melatonin ingestion and exposed in vitro to 150 cGy gamma radiation exhibited a significant decrease in the incidence of chromosome aberrations and micronuclei, as compared with similarly irradiated lymphocytes from the blood sample collected at 0 h; the frequencies abserved in the cells sampled at 2 h after the ingestion of melatonin were consistently lower when compared with those collected at 1 h. The data may have important implications for the protection of human lymphocytes from the genetic damage induced by free radical-producing mutagens and carcinogens.

Melatonin-induced temperature suppression and its acute phase-shifting effects correlate in a dose-dependent manner in humans

Melatonin is able to phase-shift the endogenous circadian clock and can induce acute temperature suppression. It is possible that there is a direct relationship between these phenomena. In a double-blind, placebo-controlled crossover study, 6 healthy volunteers maintained a regular sleep/wake cycle in a normal environment. From dusk until 24:00 h on days (D) 1-4 subjects remained in dim artificial lighting (< 50 lux) and darkness (< 1 lux) from 24:00-08:00 h. At 17:00 h on D3 either melatonin (0.05 mg, 0.5 mg or 5 mg) or placebo was administered. Melatonin treatment induced acute, dose-dependent temperature suppression and decrements in alertness and performance efficiency. On the night of D3, earlier sleep onset, offset and better sleep quality were associated with increasing doses of melatonin. The following day, a significant dose-dependent phase-advance in the plasma melatonin onset time and temperature nadir (D4-5) was observed with a trend for the alertness rhythm to phase-advance. A significant dose-response relationship existed between the dose of oral melatonin, the magnitude of temperature suppression and the degree of advance phase shift in the endogenous melatonin and temperature rhythms, suggesting that acute changes in body temperature by melatonin may be a primary event in phase-shifting mechanisms.