Melatonin Ingestion Research Articles

Daily Melatonin Administration Attenuates Age-Dependent Disturbances of Cardiovascular Rhythms.

Increased blood pressure and reduced robustness of circadian rhythms are frequently reported in elderly subjects. The present study was aimed to investigate whether such changes can be reversed by daily melatonin ingestion. 97 normotensive and hypertensive volunteers of both genders and 63 to 91 years old participated. They lived in the Tyumen Elderly Veteran House on a self-chosen sleep-wake regimen to suit their personal convenience. The experiment lasted for three weeks. After one control week, part of the group (n=63) received 1.5 mg melatonin (Melaxen(TM)) each day at 22:30 h for two weeks. The other 34 subjects were placebo-treated. Systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) were measured using semi-automated devices at 03:00, 08:00, 11:00, 14:00, 17:00, 23:00 h each day of the first and the third week. Specially trained personnel made the measurements, taking care not to disturb subjects' sleep. Rhythm characteristics were estimated by means of single and population-mean cosinor analyses. Bingham test was used to compare rhythm parameters between groups and investigated physiologic variables. The 24-h HR rhythm was monophasic as described in other studies for young subjects though with a steeper increase in the morning. The daily SBP and DBP rhythms were bimodal. In reference to previously reported data of younger subjects, mean blood pressure of our cohort was elevated, particularly the nocturnal fall was less pronounced. Also, the overall SBP variability was higher as was the percentage of the 12-h component. Both values and also the SBP and DBP levels were reduced during melatonin treatment. The hypotensive effect of melatonin was most pronounced between 3:00 and 8:00 in the morning, i.e. at the time of the highest risk of adverse cardiovascular events, and in subjects with highest BP values before treatment. Moreover, the morning increase of HR was gentler what could have been of additional benefit. Melatonin has a direct hypotensive effect. Also, it stabilizes the internal temporal order enhancing the circadian component and the synchronization between rhythms of different physiological functions. This may further improve health and welfare of elderly subjects and particularly of those with hypertension. Taken together our data show the usefulness of melatonin for adjuvant medication.

Effect of nocturnal melatonin ingestion on short-term anaerobic performance in soccer players

No study has examined whether nocturnal melatonin ingestion affects short-term maximal athletic performance. Therefore, the aim of this study was to investigate the effect of nocturnal melatonin ingestion on upper and lower body anaerobic performances. Twelve professional soccer players from a Tunisian league two squad (age: 22.9 ± 1.3yrs; height: 1.8 ± 0.05 m, and body mass 72.0 ± 8.8 kg) performed three testing sessions at 21:00 h (two melatonin sessions, 5 mg or 8 mg, and one placebo session) in a double-blind, counterbalanced protocol. During each session, 30 min after melatonin or placebo ingestion, subjects performed the following tests: the squat jump, the countermovement jump, the medicine-ball throw, the five jumps, the grip strength, and agility tests. In all tests, the results showed no difference between placebo and 5 mg melatonin ingestion (p < 0.05). However, short-term maximal performances were lower after 8 mg melatonin ingestion in comparison with the placebo ingestion (p < 0.05). In conclusion, although 8 mg of melatonin has an adverse effect on physical capacities, 5 mg of melatonin ingestion does not affect short-term maximal performance.

Melatonin attenuates the skin sympathetic nerve response to mental stress

Melatonin attenuates muscle sympathetic nerve responses to sympathoexcitatory stimuli, but it is unknown whether melatonin similarly attenuates reflex changes in skin sympathetic nerve activity (SSNA). In this double-blind, placebo-controlled, crossover study, we tested the hypothesis that melatonin (3 mg) would attenuate the SSNA response to mental stress (mental arithmetic). Twelve healthy subjects underwent experimental testing on two separate days. Three minutes of mental stress occurred before and 45 min after ingestion of melatonin (3 mg) or placebo. Skin temperature was maintained at 34°C. Reflex increases in SSNA (peroneal nerve), mean arterial pressure, and heart rate (HR) to mental stress before and after melatonin were determined. Melatonin lowered HR (pre, 66 ± 3 beats/min; and post, 62 ± 3 beats/min, P = 0.046) and SSNA (pre, 14,282 ± 3,706 arbitrary units; and post, 9,571 ± 2,609 arbitrary units, P = 0.034) at rest. In response to mental stress, SSNA increases were significantly attenuated following melatonin ingestion (second minute, 114 ± 30 vs. 74 ± 14%; and third minute, 111 ± 29 vs. 54 ± 12%, both P < 0.05). The mean arterial pressure increase to mental stress was blunted in the third minute (20 ± 2 vs. 17 ± 2 mmHg, P = 0.032), and the HR increase was blunted in the first minute (33 ± 3 vs. 29 ± 3 beats/min, P = 0.034) after melatonin. In summary, exogenous melatonin attenuates the SSNA response to mental stress.

Negative impact of melatonin ingestion on the photopic electroretinogram of dogs

Melatonin follows a circadian rhythm entrained by the light/dark cycle and plays a role in promoting light sensitivity at night. It has been suggested that melatonin and dopamine reciprocal inhibition may contribute to the switch between day and night vision. The purpose of this study was to investigate the impact of a high dose of melatonin administration on the photopic and scotopic electroretinogram (ERG) of dogs in the daytime, when it is not thought to be present. Photopic and scotopic ERG luminance response functions were obtained from 7 anaesthetized beagle dogs (3 males and 4 females), once without melatonin (control) and once after oral administration of melatonin (90mg/dog). Vmax (maximal b-wave amplitude achieved) and logK (retinal sensitivity) were calculated from the derived luminance response function. Photopic flicker ERG was also recorded. In photopic condition, a-wave amplitude (control: −126.90μV; with melatonin: −49.64μV; p<0.001) and Vmax (control: 252.50μV; with melatonin: 115.40μV; p<0.001) were decreased. A significant reduction of the photopic flicker ERG amplitude was observed after melatonin ingestion. In scotopic condition, an overall difference was reported before and after melatonin ingestion for the a- and b-wave amplitude, but no change was significant for Vmax. Melatonin ingestion at a high dose during the day decreases the photopic amplitude of a- and b-wave, but has no impact on implicit time. This negative impact of melatonin on photopic system may serve to promote night vision.

Melatonin in the afternoons of a gradually advancing sleep schedule enhances the circadian rhythm phase advance

We test methods to advance (shift earlier) circadian rhythms without producing misalignment between rhythms and sleep. We previously tested (1) a gradually advancing sleep/dark schedule plus morning bright light and afternoon/evening melatonin and (2) the same sleep schedule with only morning bright light. Now we report on the same sleep schedule with only afternoon/evening melatonin. This study aims to examine phase advances, sleepiness, and performance in response to melatonin compared to placebo. Twelve adults (five female individuals) aged 20-45 years (mean ± SD = 28.3 ± 7.3 years) completed this within-subjects placebo-controlled counterbalanced study. The participants slept on fixed 8-h sleep schedules for nine days. Then, sleep/dark was advanced by 1 h/day for three consecutive days of treatment. The participants took 3 mg of melatonin or placebo 11 h before baseline sleep midpoint (the optimal time to produce phase advances) on the first treatment day and 1 h earlier on each subsequent day. We measured the dim light melatonin onset before and after treatment. The participants rated subjective symptoms throughout the study. They completed the Psychomotor Vigilance Task and rated sleepiness from 1 h before pill ingestion until bedtime on each treatment day. Melatonin produced significantly larger advances (1.3 ± 0.7 h) compared to placebo (0.7 ± 0.7 h); however, in the hours between melatonin ingestion and bed, melatonin caused sleepiness and performance decrements. Adding afternoon/evening melatonin to the gradually advancing sleep schedule increased the phase advance, but given the side effects, like sleepiness, it is better to use morning bright light and perhaps a lower dose of melatonin.

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.

Effect of melatonin on the vestibulocollic reflex in humans

Melatonin has been reported to decrease nerve activity of the medial vestibular nuclei in rats. The purpose of the present study was to determine if melatonin alters the vestibulocollic reflex (VCR) in humans. Based on our previous findings with melatonin's affect on the vestibulosympathetic reflex (VSR), we hypothesized that exogenous melatonin ingestion would attenuate the VCR. To test this hypothesis, vestibular evoked myogenic potentials (VEMP) were recorded in 10 healthy subjects (26 ± 1 yr; 4 male, 6 female) before and 45 min after ingestion of 3 mg melatonin. Additionally, we recorded VEMP in 8 healthy subjects (25 ± 1 yr; 1 male, 7 female) who underwent the same experiments but without melatonin to serve as time controls. Melatonin did not alter the timing of the first VEMP peak (13 ± 0.4 and 14 ± 0.3 ms, pre and post melatonin, respectively) nor the second VEMP peak (21 ± 0.6 and 21 ± 0.7 ms, pre and post melatonin, respectively). More importantly, VEMP interpeak amplitude was not altered by melatonin (before: 22 ± 5 vs. after: 23 ± 5 a.u.). Comparable results were observed in the control group (before: 26 ± 6 vs. after: 26 ± 7 a.u.) These data indicate that melatonin does not alter the VCR in humans. In conjunction with our previous findings demonstrating an attenuated VSR with exogenous melatonin, the present findings suggest that melatonin's affect on the VCR and VSR are different in humans.NIH HL077670, NASA Space Fellowship

La melatonina reduce la respuesta de cortisol al ACTH en humanos

Melatonin receptors are widely distributed in human tissues but they have not been reported in human adrenal gland. To assess if the human adrenal gland expresses melatonin receptors and if melatonin affects cortisol response to ACTH in dexamethasone suppressed volunteers. Adrenal glands were obtained from 4 patients undergoing unilateral nephrectomy-adrenalectomy for renal cancer. Expression of mRNA MT1 and MT2 melatonin receptors was measured by Reverse TranscriPtase Polymerase Chain Reaction (RT-PCR). The effect of melatonin on the response to intravenous (i.v.) ACTH was tested (randomized cross-over, double-blind, placebo-controlled trial) in eight young healthy males pretreated with dexamethasone (1 mg) at 23:00 h. On the next day, at 08:00 h, an i.v. line was inserted, at 08:30 h, and after a blood sample, subjects ingested 6 mg melatonin or placebo. At 09:00 h, 1-24 ACTH (Cortrosyn, 1 microg/1.73 m2 body surface area) was injected, drawing samples at 0, 15, 30, 45 and 60 minutes after. Melatonin, cortisol, cortisone, progesterone, aldosterone, DHEA-S, testosterone and prolactin were measured by immunoassay. The four adrenal glands expressed only MT1 receptor mRNA. Melatonin ingestion reduced the cortisol response to ACTH from 14.6 +/- 1.45 microg/dl at 60 min in the placebo group to 10.8 +/- 1.2 microg/dl in the melatonin group (p < 0.01 mixed model test). It did not affect other steroid hormone levels and abolished the morning physiological decline of prolactin. The expression of MT1 melatonin receptor in the human adrenal, and the melatonin reduction of ACTH-stimulated cortisol production suggest a direct melatonin action on the adrenal gland.

Coping with jet-lag: A Position Statement for the European College of Sport Science

Elite athletes and their coaches are accustomed to international travel for purposes of training or sports competition. Recreational participants are similarly, if less frequently, exposed to travel stress. Transient negative effects that constitute travel fatigue are quickly overcome, whereas longer-lasting difficulties are associated with crossing multiple time-zones. Jet-lag is linked with desynchronization of circadian rhythms, and its impact depends on the duration and direction of flight, flight schedule, and individual differences. Athletes’ performances are likely to be affected for some days until the body clock is readjusted in harmony with local time. Knowledge of the physiological characteristics of the body clock can be used to develop behavioural strategies that accelerate readjustment, in particular the timing of outdoor or bright light exposure, perhaps melatonin ingestion, meals, and exercise. Attempts to promote sleep by use of drugs that adjust the body clock, induce sleepiness or promote wakefulness are relevant but discouraged in travelling athletes. Support staff should develop appropriate education programmes for their athletes who can then make informed choices about their behaviour and minimize the transient effects of jet-lag on their well-being and performance.

멜라토닌 섭취한 쥐에 있어 운동이 연료 이용에 미치는 영향

멜라토닌 섭취한 쥐에 있어 운동이 연료 이용에 미치는 영향

Cyclic melatonin synchronises the circadian rhythm of feeding activity in Japanese quail, Coturnix c. japonica

In Japanese quail, we can observe the circadian rhythm of feeding activity in constant conditions, especially in birds from selected lines. In order to try to test the importance of melatonin as hormonal output for the circadian system, we gave a 24-h period cycle of exogenous melatonin to some of these birds when they were free running. We used castrated males firstly in order to cancel the known effect of steroids on circadian organisation. Secondly, as castrated birds generally expressed a very short periodicity, it allowed us to check induced synchronisation more easily. We maintained ten castrated males in constant dim light. We divided the experiment into five successive phases. The birds received a 24-h period cycle of melatonin (M phase) or of control solution with only the alcoholic solvent (C phase) as a drink. Before and after each one of these two phases, we gave water continually to drink (W1, W2 and W3 phases).Thus, the successive phases were W1–M–W2–C–W3. We measured intake of liquids and plasma melatonin concentrations to check melatonin ingestion. We automatically recorded individual feeding activity by infrared detectors, and analysed this by spectral analysis. At the beginning of the experiment, eight birds showed a rhythmic feeding activity, with a mean period of 22.9 ± 0.2 h, and the two others an arrhythmic circadian activity. During the 24-h period cycle of exogenous melatonin, for the rhythmic birds, the circadian period became approximately 24 h (23.9 ± 0.2 h), the inactive phase corresponding to the period of melatonin availability. During the W2 and C phases, the circadian period was similar to that expressed during the W1 phase. Moreover, when birds only drink water, we found a significant positive relationship between the clarity of the circadian rhythm and the ratio, between the melatonin level of the inactive phase and that of the active phase. These facts support the hypothesis of the role of this hormone in the regulation of the circadian system, at least for feeding activity, in quail.

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.

Time course of saliva and serum melatonin levels after ingestion of melatonin.

Salival and serum melatonin levels after melatonin ingestion were measured by gas chromatography-mass spectrometry. Ingestion of 3 mg melatonin caused a marked increase in serum melatonin (3561+/-1201 pg/mL) within 20 min, followed by a gradual decrease, but the level still remained higher than the basal level at 240 min after the ingestion. The saliva melatonin 60 min after the ingestion showed the highest level (1177+/-403 pg/mL) which was one-third of the plasma level. The saliva melatonin level was highly correlated with the serum level throughout the experimental period (r=0.82, P=0.0001). These data indicate that the measurement of saliva melatonin level may be a suitable indicator for the melatonin secretion into general circulation.

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.

Reproductive safety of melatonin: a "wonder drug" to wonder about.

By some accounts, melatonin is the wonder drug of the 1990s. This previously obscure hormone came to the public's full attention as the result of a series of popular books claiming therapeutic benefits of melatonin ingestion. Some of these claims deserve serious consideration and investigation, whereas others appear unfounded. Without waiting for the outcome of the ongoing scientific debate, however, melatonin set astounding sales records. The hormone is now ingested on a daily basis by many thousands of people. There is little information on the potential adverse effects of melatonin ingestion in humans. Melatonin, its analogs, and its metabolites are not mutagenic, and melatonin possesses remarkably low acute toxicity in animals and humans. It is more difficult to exclude toxic effects of long-term melatonin treatment. The fact that melatonin is normally secreted each night does not ensure that exogenous melatonin, taken at other times and/or in supraphysiological doses, will not have adverse effects. Despite the well-recognized role of melatonin in the regulation of reproduction in photoperiodic species, it seems unlikely that chronic ingestion of moderate melatonin doses will have a profound impact on reproductive function in humans. Evidence that melatonin modulates steroid hormone action in some steroid-responsive tissues suggests that these tissues should be carefully examined when attempting to assess whether melatonin has chronic toxicity in humans. In the absence of sufficient information regarding the longterm safety of exogenous melatonin, the conservative course of action is to restrict melatonin use to those therapeutic applications in which a significant benefit is expected. The decision to ingest melatonin should be preceded by careful consideration of the expected benefits as well as the potential costs of treatment, with recognition of the fact that there has been exaggeration of the benefits and little attention paid to the potential costs in most discussions of this issue to date.

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.

Daytime melatonin administration enhances sleepiness and theta/alpha activity in the waking EEG

It is still controversial whether the pineal hormone melatonin can be characterized as a hypnotic. We therefore measured subjective sleepiness and waking EEG power density in the range of 0.25–20 Hz after a single dose of melatonin (5 mg). During an 8 h miniconstant routine protocol, melatonin administered in a double blind cross-over design to healthy young men at 1300 h or 1800 h increased subjective sleepiness, as rated half-hourly on three different scales (Visual Analogue Scale, Åkerstedt Sleepiness Symptoms Check List, Åkerstedt Sleepiness Scale) and objective fatigue as evidenced by augmented waking EEG power density in the theta/alpha range (5.25–9 Hz). The increase in subjective sleepiness reached significance 40 min and 90 min after melatonin administration (at 1300 h and 1800 h, respectively) and lasted for 3 h (at 1300 h) and 5 h (at 1800 h). The increase in the theta/alpha frequencies of the waking EEG occurred immediately after melatonin ingestion and stayed significantly higher parallel to the higher sleepiness ratings. However, the EEG changes appeared before the subjective symptoms of sleepiness became manifest. There was a significant correlation between salivary melatonin levels and the timing of increased subjective sleepiness. Melatonin had no effects on mood.