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Effectiveness and tolerability of melatonin and zolpidem for the alleviation of jet lag
Abstract
The aim of this study was to compare the effectiveness and tolerability of a chronobiotic (melatonin) with a hypnotic (zolpidem) and the combination of both substances to alleviate jet lag symptoms associated with eastward travel.
This double-blind, randomized, placebo-controlled study is based on 137 volunteers flying from Switzerland to the American continent and back (6-9 time zones). The participants either received melatonin 5 mg (n = 35), zolpidem 10 mg (n = 34), a combination thereof (n = 29) or placebo (n = 39) on the eastbound flight back to Switzerland and once daily at bedtime on 4 consecutive days after the flight. The test battery included daily sleep logs, symptoms questionnaires, and the Profile of Mood States (POMS). Also, on the last treatment day, Visual Analog Scales (VAS) were completed to assess overall jet lag ratings and treatment effectiveness. Baseline data were collected on 4 consecutive days 2 wk after the flight. During post-flight treatment and baseline, motor activity was assessed in a subgroup of 49 subjects using wrist-worn ambulatory monitors.
The self-rated sleep quality was significantly improved by zolpidem, especially during the night flight. Subjects taking zolpidem reported significantly less jet lag and zolpidem was rated as the most effective jet lag medication. However, zolpidem and the combination melatonin/zolpidem were less well tolerated than melatonin alone; adverse event reports included nausea, vomiting, amnesia and somnambulia to the point of incapacitation. Confusion, morning sleepiness and nausea were highest in the combination group.
All active treatments led to a decrease of jet lag severity with zolpidem being the most effective treatment, particularly in facilitating sleep on night flights. Potential individual adverse reactions to this hypnotic have to be considered.
... Wtedy to Suhner i in. [24] przedstawili w miesięczniku Aviation, Space and Enviromental Medicine efekty prowadzonego przez siebie podwójnie ślepego, randomizowanego badania, oceniającego skuteczność melatoniny i zolpidemu w uśmierzaniu objawów jet lag. Zebrano grupę 160 ochotników, których średnia wieku wynosiła 41 lat; 51% spośród uczestników stanowili przedstawiciele płci męskiej. ...
... Większa część z przeanalizowanych powyżej doniesień naukowych, wskazuje na jej efektywność w łagodzeniu objawów tegoż zespołu [3][1] [17] [7][18] [25]. Jednakże, w czterech z omówionych prac, w tym najbardziej aktualnych, autorzy nie zaobserwowali istotnego efektu terapii, w porównaniu z wynikami w grupie otrzymującej placebo [16][21][9] [24]. Autorzy są zgodni, iż znaczącą może odgrywać czas przyjmowania preparatu, ponieważ środek otrzymywany na kilka dni przed podróżą wykazywał się wyższą skutecznością, aniżeli podawany w dniu lotu lub po nim. ...
... 1][3][17][18][25][21][9][24], natomiast dwa pozostałe badania były jej pozbawione[16][7]. Najstarszy omówiony artykuł pochodzi z 1987[3], natomiast najbardziej aktualny -z roku 2001[24]. ...
Jet lag is a circadian rhythm disorder, affecting plane passengers travelling across multiple time zones. The severity of symptoms is strictly connected with the number of zones crossed. Common symptoms include: insomnia, difficulty concentrating attention, memory loss, anxiety, diarrhea, confusion, dizziness, headache, as well as malaise. Melatonin is a neurohormone, produced by the pineal gland. The hormone is released into the bloodstream and acts on MT1 and MT2 receptors, having the ability to induce sleep. Melatonin is therefore responsible for regulating the human biological clock and, consequently, the rhythm of sleep and wakefulness. Synthetic forms of melatonin have become a potential medication for various circadian rhythm disorders, including jet lag syndrome. Ten scientific reports were analyzed. The characteristics of the subjects, directions of the trips taken, the doses of melatonin, as well as the patterns of its administration, differed among studies. According to most of the reviewed trials, melatonin may have a beneficial effect on alleviating jet lag symptoms. The timing of intake plays a significant role – it has proven most effective when taken days before travel. However, several studies have not confirmed its effectiveness, compared to placebo. Further research seems to be inevitable to objectively reassess the effectiveness of melatonin preparations. Unambiguous determination of the melatonin dosage, the timing of its administration, the time of initiation, and the duration of the treatment would also be advisable. Nevertheless, all of the mentioned trials confirmed that the use of oral melatonin preparations, especially at low doses, turned out to be free of serious side effects.
... It influences the GABA-A receptor. The adverse effect is based on walking during sleep, sleep-driving, eating spontaneous food, no memory, or loss of memory, and on the other hand, it will cause drowsiness and dizziness in the morning (11). ...
... During the observation of management of sleep disorder by using zolpidem. (7)(8)(9)(10)(11). ...
... It is currently unoccupied in health stores as a supplement; these medications may have bothersome symptoms on execution and mental sharpness. In the quest for a superior tranquilizer, specialists have focused on melatonin, an ordinarily active hormone created in the cerebrum's pineal organ (11). Ground-based research shows that melatonin may encourage rest, a characteristic that is especially significant if space explorers are planned to rest during the day when their bodies are not delivering the hormone (16). ...
Since the start of civilization and even further back, humankind has been dreaming of flying. Recently, this dream has come true and reached beyond that and sends astronauts to outer space. However, by achieving this milestone, we encountered new problems that were new to humanity. One of the biggest problems is having a sleeping disorder and disruption of the biological clock. It is essential because having a sleep disorder makes astronauts unable to function at 100% capacity, and in outer space, it is dangerous. Some treatments for sleep disorders include drug therapy, such as Dexedrine, temazepam, modafinil, bupropion, melatonin, zolpidem, dextroamphetamine, light treatment, or a trickling sleep/wake schedule, according to NASA's guidelines. This study aimed to review the treatments for sleep disorders and disruption of the biological clock aimed at astronauts during space flights. We presented the different treatments and discussed and oriented the next prospect of research on sleep in space. Therefore, there will be guidelines for astronauts during their flights. Since the beginning of space travel, there have been many papers regarding space and weightlessness on the adverse effects on health. Studies have described the effect of space travel and the environment of microgravity on health. A few studies include both the short- and long-term effects of microgravity on the biological clock. With this new dawn and sending new astronauts to International Space Station (ISS) with NASA and SpaceX commercial Falcon 9 rocket, which opened a new horizon for spaceflights, it is even more important to consider the adverse effects microgravity on health. Purpose: This review aims to specifically analyze the biological clock, sleep deficiency, and circadian disorders. As we acknowledge, there is a sleep deficiency associated with complex microgravity environs and space missions before and after launch. Material and methods: Two researchers searched a thorough and detailed search of the PubMed database with the keywords mentioned below. The search was performed in November 2020 without any time limitations. We only included human studies and articles in the English language. Results: A total of 148 articles were found, and after going through titles, 77 articles were chosen for checking abstracts. Finally, only 12 manuscripts were accepted for data extraction. Conclusion: It is essential for health care involved in space travel providers to help pre-emptively identify problems that may prevent severe consequences during a microgravity environment. Sleep and circadian factors are the fundamental issues of human fatigue, and aviation schedules significantly impact both. We should admire a computerized fatigue model for having a better approach to studying the impact of scheduling.
... Por el contrario, no existe acuerdo sobre el efecto de la MLT en el jet-lag 44,46 . Mientras que Spitzer et al. 44 encontraron que ni 0,5 ni 5 mg de MLT eran útiles para tratar los síntomas del jet-lag, Shuner et al. 45 encuentran una mejoría en estos síntomas tras la administración de 5 mg de MLT. La posible explicación de estas diferencias puede ser debida a que en el trabajo de Spitzer et al. 44 la MLT se tomaba en el momento de irse a dormir, mientras que en el de Shuner et al. 45 se tomaba entre las 17 y 21 h del tiempo local, lo que permitiría resincronizar con más facilidad el NSQ con el tiempo local. ...
... Mientras que Spitzer et al. 44 encontraron que ni 0,5 ni 5 mg de MLT eran útiles para tratar los síntomas del jet-lag, Shuner et al. 45 encuentran una mejoría en estos síntomas tras la administración de 5 mg de MLT. La posible explicación de estas diferencias puede ser debida a que en el trabajo de Spitzer et al. 44 la MLT se tomaba en el momento de irse a dormir, mientras que en el de Shuner et al. 45 se tomaba entre las 17 y 21 h del tiempo local, lo que permitiría resincronizar con más facilidad el NSQ con el tiempo local. Lagarde et al. 46 estudiaron el efecto de 6 mg de MLT y 2 mg de cafeína sobre el rendimiento físico de un grupo de militares tras un viaje transoceánico con 7 h de diferencia entre el tiempo de salida y el de llegada. ...
Methods. Data source and search strategy: a 39 year period search covering a 39 year period (1966-2004) was carried out using Medline data base. The search strategy consisted in the combination of the key words «mental disorders or psychiatry» and «melatonin and therapeutic use». Two restrictive criteria were applied: a) selection of studies carried out in humans, and b) only randomized controlled trials were admitted. Results. 56 articles were found. Twelve were excluded because they were not directly related to the study aim. Melatonin was used in 44 articles related to different clinical conditions. It was used because of its hypno-tic and/or resynchronizing actions in 93.2 % of the articles , while in 4.5 % of the articles melatonin was used due to its antioxidant properties. Conclusions. The main use of melatonin as a therapeutic agent in psychiatry is in sleep disorders and its use in other psychiatric is minor. INTRODUCCIÓN El uso terapéutico de la melatonina (MLT) data, al me-nos, de 1920 1 , cuando Becker utilizó extractos de glándula pineal para tratar a pacientes con dementia praecox. No fue hasta 1958 cuando Lerner et al. 2 descubrieron la MLT, mientras buscaban la causa de la despigmentación de la piel en el vitíligo, y no es hasta el año siguiente cuando se aísla su estructura química 3. El uso terapéutico de la MLT comienza a generalizarse en la década de 1960; aunque inicialmente este uso se hizo mediante la aplicación de ex-tractos de glándula pineal 4 , posteriormente se hizo me-diante la utilización de MLT sintética 5. El espectro clínico inicial al cual se redujo su utilización fue el de la psicosis esquizofrénica 6 , para pasar más tarde a usarse en los tras-tornos afectivos 7 y posteriormente generalizarse a casi to-do el resto de la patología psiquiátrica 8-10. El objetivo del presente trabajo consiste en realizar una revisión bibliográ-Introducción. Se realiza una revisión bibliográfica so-bre el uso de la melatonina como elemento terapéutico en psiquiatría. Métodos. Como fuente de datos y estrategia de bús-queda se realizó una búsqueda bibliográfica en la base de datos Medline que cubrió un período de 39 años (1966-2004). La estrategia de la búsqueda consistió en la intersec-ción de las palabras clave mental disorders or psychiatry melatonin and therapeutic use. Se aplicaron dos criterios restrictivos: a) sólo se admitió la inclusión de investigacio-nes realizadas con seres humanos, y b) el tipo de trabajos seleccionados consistió en estudios aleatorios controlados. Resultados. Se encontraron 56 artículos, de los cuales 12 fueron excluidos por no estar directamente relacionados con el objetivo del estudio. En 44 artículos la melatonina se usó como elemento terapéutico en diferentes situaciones clínicas. En el 93,2 % de los trabajos la melatonina se utilizó por sus propiedades hipnóticas y/o resincronizantes, mien-tras que en el 4,5 % de los trabajos se usó por sus propieda-des antioxidantes. Conclusiones. El principal uso terapéutico de la mela-tonina en psiquiatría se produce en el área de los trastornos del sueño, y su uso es minoritario en otras patologías o con-diciones psiquiátricas Palabras clave: Enfermedad mental. Psiquiatría. Melatonina. Glándula pineal. Uso terapéutico.
... In contrast to previous findings, no evidence of melatonin's therapeutic effect was found in the Hansen et al 27 study, which examined the impact of a lower dose of melatonin (6 mg oral medication vs placebo for 3 months) on cognitive performance in patients undergoing breast cancer surgery. Despite the fact that a lower dose of melatonin did not have positive effects in the previous study, it appears that in addition to the dosage, other practical factors should be considered, as the dose of 20 mg of melatonin did not have a positive and statistically significant effect on physical fatigue in the study by Lund Rasmussen et al. 28 Regarding the toxicity of treatments, all cases of severe nausea in our study were observed in the melatonin group, resulting in withdrawal from the treatment (5 patients out of 29,30 On the other hand, most chemotherapeutic regimens used in the management of breast cancer are considered as moderately to highly emetogenic chemotherapy regimens. 31 It is possible that coadministration of melatonin during chemotherapy might have increased the likelihood of presence of severe nausea. ...
Objective:
Cancer related fatigue is a distressing condition and correlated with decrease in quality of life of patients with malignant conditions. In continuation of our previous research, we assessed long term anti-fatigue effects of melatonin in patients with the breast cancer.
Material and methods:
In this clinical trial, 92 breast cancer patients were randomly assigned to receive either melatonin (18 mg/day) or placebo from 1 week before the adjuvant treatments until 2 years after their completion. The levels of fatigue were assessed before and after intervention using Brief Fatigue Inventory (BFI) and were compared at a significance level of P ≤ .05.
Results:
The BFI scores were similar between the 2 groups at the baseline (placebo group: 5.56 ± 1.59 and melatonin group: 5.72 ± 1.68, P = .67). After the intervention, not only the mean fatigue score was significantly lower in melatonin group (2.93 ± 1.04 vs 1.99 ± 1.02, P < .001, P ≤ .05), but also a greater reduction in fatigue score in intervention group was evident over time (P ≤ .001).
Conclusion:
Long-term usage of melatonin even after completion of adjuvant therapies in women with breast cancer decreased the levels of fatigue associated with the malignant condition and its treatments.
The trial registry name and url, and registration number:
Iranian Registry of Clinical Trials, https://en.irct.ir/trial/62267, IRCT20180426039421N3.
... The lower dosage of 0.5 mg was almost as effective as the 5 mg dosage in reducing fatigue and subjective sleepiness whereas for the hypnotic properties (sleep quality and sleep latency) the higher dosage was more effective [37]; all studies compared MEL effect vs. placebo but two studies also compared its effects vs. zolpidem or zopiclone. The latter were as effective [38] or more effective [41] than MEL regarding the hypnotic effect (sleep latency, sleep time, sleep quality) but with more side effects; the duration of MEL intake ranged from 1 day to 7 days with three possible dosing schedules. The treatment could be initiated 1 to 3 days before departure, during the flight or only after arrival. ...
Résumé
La société française de recherche et de médecine du sommeil a mandaté un groupe d’experts au sein d’une conférence de consensus afin de définir les indications et conditions de prescription de la mélatonine exogène. Onze somnologues et chercheurs ont étudiés en sous-groupe de travail l’usage de la mélatonine dans différents domaines de la santé en rapport avec leur spécialité (troubles circadiens du rythme veille-sommeil ; troubles psychiatriques ; neurologiques ; pédiatriques et neuro-développementaux). Dans cet article nous présentons une synthèse des principales conclusions du groupe d’expert dans les troubles circadiens du rythme veille-sommeil.
... In addition, melatonin can be used to aid in entrainment. One strategy suggests evening melatonin therapy dosed at 2 mg or 5 mg upon arrival at the destination bedtime for 4-5 days [82][83][84], or some studies have recommended a more complex regimen initiating melatonin therapy 5 mg in the native time zone at the corresponding destination bedtime for 3 days prior to travel, and continued therapy for 3-4 days in the new time zone [85,86]. ...
Circadian rhythms oscillate throughout a 24-h period and impact many physiological processes and aspects of daily life, including feeding behaviors, regulation of the sleep-wake cycle, and metabolic homeostasis. Misalignment between the endogenous biological clock and exogenous light–dark cycle can cause significant distress and dysfunction, and treatment aims for resynchronization with the external clock and environment. This article begins with a brief historical context of progress in the understanding of circadian rhythms, and then provides an overview of circadian neurobiology and the endogenous molecular clock. Various tools used in the diagnosis of circadian rhythm sleep–wake disorders, including sleep diaries and actigraphy monitoring, are then discussed, as are the therapeutic applications of strategically timed light therapy, melatonin, and other behavioral and pharmacological therapies including the melatonin agonist tasimelteon. Management strategies towards each major human circadian sleep–wake rhythm disorder, as outlined in the current International Classification of Sleep Disorders – Third Edition, including jet lag and shift work disorders, delayed and advanced sleep–wake phase rhythm disorders, non-24-h sleep–wake rhythm disorder, and irregular sleep–wake rhythm disorder are summarized. Last, an overview of chronotherapies and the circadian dysregulation of neurodegenerative diseases is reviewed.
After a flight across multiple time zones, most people show a transient state of circadian misalignment causing temporary malaise known as jetlag disorder. The severity of the elicited symptoms is postulated to depend mostly on circadian factors such as the number of time zones crossed and the direction of travel. Here, we examined the influence of prior expectation on symptom severity, compared to said “classic” determinants, in order to gauge potential psychosocial effects in jetlag disorder.
To this end, we monitored jetlag symptoms in travel-inexperienced individuals (n=90, 18-37y) via detailed questionnaires twice daily for one week before and after flights crossing >3 time zones. We found pronounced differences in individual symptom load that could be grouped into 4 basic symptom trajectories. Both traditional and newly devised metrics of jetlag symptom intensity and duration (accounting for individual symptom trajectories) recapitulated previous results of jetlag prevalence at about 50-60% as well as general symptom dynamics.
Surprisingly, however, regression models showed very low predictive power for any of the jetlag outcomes. The classic circadian determinants, including number of time zones crossed and direction of travel, exhibited little to no link with jetlag symptom intensity and duration. Only expectation emerged as a parameter with systematic, albeit small, predictive value.
These results suggest expectation as a relevant factor in jetlag experience - hinting at potential placebo effects and new treatment options. Our findings also caution against jetlag recommendations based on circadian principles but insufficient evidence linking circadian re-synchronization dynamics with ensuing symptom intensity and duration.
Significance Statement
Jetlag disorder afflicts millions of travelers each year - a nuisance on holiday trips but also a danger in safety and performance-critical operations. For effective prevention and treatment, it is critical to understand what influences jetlag severity, i.e. jetlag symptom intensity and duration. In contrast to what guidelines state, in our study, we did not find that symptom severity could be explained by the number of time zones crossed or travel direction. Rather, travelers’ expectations about how long and strongly they will suffer from jetlag symptoms was the only factor systematically predicting jetlag severity. If this holds true not only for subjective but also objective symptoms, we need to revisit assumptions about how circadian desynchronization relates to experienced jetlag symptoms.
Notwithstanding technological innovation, the COVID-19 pandemic, and new communication tools, the need for travel is growing again and, in some travel segments, it is stronger than ever. Interestingly, the public health implications of traveling across time zones are still poorly understood and this is especially true for organizations that send their workers across the globe. Using data from 173 Olympic teams over 15 Olympic Games, we show that crossing multiple time zones has negative implications for human (sports) performance. More importantly, the results indicate that performance impairment is especially visible after flying east, with peak performance particularly impaired, leading to a “gold demotion effect” of gold medals to silver medals as a result. Given that Olympic sporting teams typically have dedicated medical staff and active mitigation strategies, these findings have important public health implications. For example, organizations are demanding their workers to be on “top of their game” while traveling, without providing them with the support and tools to do so. The implications for public health management and human resource management are discussed.
Nearly all biological processes exhibit circadian rhythms that are generated by circadian clocks in central and peripheral tissues. In mammals a central circadian clock, the suprachiasmatic nucleus helps to align behaviors and physiological processes, including the sleep–wake cycle with the 24-h environment. Disruption of the proper alignment of circadian clocks with the required sleep–wake time leads to development of circadian rhythm sleep–wake disorders. These disorders can develop as a result of pathology at the level of the internal clock, disruption of the ability to receive or process environmental synchronizing signals, or changes to the external environmental time. Treatment of circadian rhythm sleep–wake disorders depends on behavioral adjustments, often in conjunction with specific timing of light and/or melatonin. This chapter will highlight the six primary circadian rhythm sleep–wake disorders, focusing on what is known about their underlying pathogenic mechanisms and the currently recommended treatment strategies.KeywordsCircadianSuprachiasmatic nucleusMelatoninLightActigraphy
Growing understanding of the finely orchestrated and integrated mechanisms governing sleep and wakefulness allow for new insights into sleep disorders and their pharmacological treatments. While sleep related conditions are many and diverse, this chapter focuses on the common ailments of insomnia and circadian rhythm disorders. We provide a brief overview of these conditions followed by a review of current pathophysiologic understandings for these conditions, which provide context to the subsequent medication review. While an in-depth review of the pharmacologic options is provided, section summaries and tables are included to allow for ease of accessibility and retrieval of the information.
Home base recordings of motor activity during bedtime, and of subjective sleep parameters, were obtained from air crew members before and after the following routes with multiple flight segments: (1) south-north (SN) across 1 time zone; (2) west-east (WE) across 17 time zones; (3) east-west (EW) across 7 time zones. For the EW route, recordings were also obtained during layover. Only after return from the EW route was bedtime motor activity (measured by a wrist-worn ambulatory monitor) enhanced, was the percentage of bedtime immobility periods reduced, and were frequency and duration of self-assessed waking after sleep onset increased. The subjects rated their sleep as less quiet and felt less rested than during baseline. The various parameters gradually reverted toward baseline during the first 4 days at home. Although sleep showed only minor impairments during the EW route, the subjective jet-lag score was high during layover and after return to home base. Ambulatory activity monitoring is a useful method for assessing sleep quality after long-haul flights.
SYNOPSIS. Melatonin, a hormone of the pineal gland, exerts multiple effects upon the brain-pituitary axis of vertebrates. Among mammals, the best documented physiological roles of melatonin involve the photoperiodic induction of reproductive and other seasonal adjustments. Daylength regulates the effects of gonadal steroids upon gonadotropin secretion and sexual behavior as well as the frequency of a neural generator of GnRH pulses. In hamsters, these effects are paralleled by changes in GnRH, AVP and beta-endorphin immunoreactivity, and in opiate receptor density in the medial amygdala. Autoradiographic studies indicate a high concentration of 2[ 125I]-iodomelatonin binding sites in the suprachiasmatic nuclei of some photoperiodic mammals but not in others. In contrast, such binding sites have been found in the pars tuberalis of all seasonally breeding mammals studied to date.
A physiological dose of orally administered melatonin shifts circadian rhythms in humans according to a phase-response curve (PRC) that is nearly opposite in phase with the PRCs for light exposure: melatonin delays circadian rhythms when administered in the morning and advances them when administered in the afternoon or early evening. The human melatonin PRC provides critical information for using melatonin to treat circadian phase sleep and mood disorders, as well as maladaptation to shift work and transmeridional air travel. The human melatonin PRC also provides the strongest evidence to date for a function of endogenous melatonin and its suppression by light in augmenting entrainment of circadian rhythms by the light-dark cycle.
Seventeen healthy volunteers (10 women and 7 men, aged 29-68) were flown from London to San Francisco between 20 November 1985 and 25 January 1986 and remained there for 14 days prior to flight home. Subjects took melatonin (N = 8, 5 women, 3 men) or placebo in a double-blind design, at 18.00h local time for three days before the return flight and at bedtime (22.00-24.00h) in Great Britain for four days. For three days before departure and on days 1-7,14,15, 21 and 22 after their return subjects collected 6-hourly sequential urine samples and kept a daily sleep log. They recorded mood and oral temperature 2 hourly and performed logical reasoning and letter cancellation tests 4 hourly from 08.00h (or wake up time) to 24.00h (or bedtime) whichever was the earlier. Urine was also collected for 48 h prior to departure from the U.S.A‥ On day 7 after their return subjects rated ‘jet lag’ (10 cm visual analogue scale—VAS) from 0 (insignificant) to 100 (very bad). Melatonin significantly improved ‘jet lag’ (p= 0.009). Comparisons by ANOVA between jet-lagged placebo subjects (N = 7) and melatonin (N = 8) showed decreased sleep latency with melatonin (p= 0.0397) which correlated positively with jet lag ratings, p< 0.001. Sleep quality was significantly improved in the melatonin group and correlated negatively with jet-lag ratings (p
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.
The major inhibitory neurotransmitter, γ-aminobutyric acid (GABA) acts on a postsynaptic receptor complex which includes GABA and benzodiazepine (BZ) recognition sites and a chloride ionophore (Turner and Whittle, 1983). Pharmacological, biochemical and neurophysiological studies suggest that BZ agonists, such as diazepam, exert their central effects by enhancing lowaffinity GABA binding (DeFeudis, 1983; Olsen and Venter, 1986).
The environmental photoperiod regulates the synthesis of melatonin by the pineal gland, which in turn induces daily and seasonal adjustments in behavioral and physiological state. The mechanisms by which melatonin mediates these effects are not known, but accumulating data suggest that melatonin modulates a circadian biological clock, either directly or indirectly via neural inputs. The hypothesis that melatonin acts directly at the level of the suprachiasmatic nucleus (SCN), a central mammalian circadian pacemaker, was tested in a rat brain slice preparation maintained in vitro for 2-3 days. Exposure of the SCN to melatonin for 1 h late in the subjective day or early subjective night induced a significant advance in the SCN electrical activity rhythm; at other times melatonin was without apparent effect. These results demonstrate that melatonin can directly reset this circadian clock during the period surrounding the day-night transition.
Melatonin (MLT), a pineal hormone, has some sedative and hypnotic properties. To explore this effect further 20 young, healthy volunteers exposed to artificial insomnia participated in a double-blind, placebo controlled, parallel group design study. They slept in a sleep laboratory for several consecutive nights and were polygraphically monitored and subjected to a battery of psychometric tests and standardized self-report questionnaires each morning. One night all subjects received only placebo (21:00 hours) and on a second night half of them were subjected to placebo and half to MLT. On the later night blood MLT levels were measured. Polygraphic recordings revealed that MLT at bedtime decreased the time the subjects were awake before sleep onset (P less than 0.025), sleep latency (P less than 0.05), and the number of awakenings during the total sleep period (P less than 0.025), and increased sleep efficiency (P less than 0.05). In addition, it decreased sleep stage 1 (P less than 0.05) and increased sleep stage 2 (P less than 0.025). On the morning following the treatment most objective and subjective measures for awakening quality showed a trend towards improvement after MLT. One hour after its oral administration, serum MLT rose to a high pharmacological level (25817 pg/ml; median), but individual peak serum MLT levels varied by a factor of 300.(ABSTRACT TRUNCATED AT 250 WORDS)
In vitro autoradiography with 125I-labeled melatonin was used to examine melatonin binding sites in human hypothalamus. Specific 125I-labeled melatonin binding was localized to the suprachiasmatic nuclei, the site of a putative biological clock, and was not apparent in other hypothalamic regions. Specific 125I-labeled melatonin binding was consistently found in the suprachiasmatic nuclei of hypothalami from adults and fetuses. Densitometric analysis of competition experiments with varying concentrations of melatonin showed monophasic competition curves, with comparable half-maximal inhibition values for the suprachiasmatic nuclei of adults (150 picomolar) and fetuses (110 picomolar). Micromolar concentrations of the melatonin agonist 6-chloromelatonin completely inhibited specific 125I-labeled melatonin binding, whereas the same concentrations of serotonin and norepinephrine caused only a partial reduction in specific binding. The results suggest that putative melatonin receptors are located in a human biological clock.