Nocturnal plasma melatonin concentrations in healthy volunteers: Effect of single doses of d-fenfluramine, paroxetine, and ipsapirone (original) (raw)
Background. Changing lifestyles and the widespread use of artificial lighting have contributed to the disruption of circadian rhythms in modern society. As various aspects of affect and cognition are also controlled by circadian rhythms, this is of concern. Thus, circadian phase assessment is increasingly applied in the diagnostic process in clinical practice, as knowledge of circadian timing and the etiology of symptoms associated with circadianVer misalignment inform treatment choices. However, clinicians should be aware that certain psychopharmaceuticals may influence endogenous melatonin profiles. Other pharmacological agents and behaviors have shown to mask, suppress, or promote DLMO and nighttime melatonin levels (e.g. caffeine, bright light, exercise). Moreover, health and nutritional organizations are increasingly emphasizing certain foods and dietary supplements (e.g. magnesium, tryptophan) that contain melatonin or boost the body’s natural melatonin production. Although it...
Chronic Administration of Melatonin: Physiological and Clinical Considerations
Neurology International
Background: Exogenous melatonin is commonly used to treat insomnia, other sleep problems, and numerous medical illnesses, including Alzheimer’s disease, autism spectrum disorder, and mild cognitive impairment in adults and children. There is evolving information regarding issues with the use of chronic melatonin. Methods: The present investigation was a narrative review. Results: Melatonin usage has risen dramatically in recent years. Many countries only allow melatonin prescriptions. In the United States (U.S.), it is classified as a dietary supplement accessible over the counter and can be derived from animals, microorganisms, or, most commonly, made synthetically. No regulatory agency oversees its manufacturing or sale in the U.S. melatonin concentration of marketed preparations varies widely between product labels and manufacturers. Melatonin’s ability to induce sleep is detectable. However, it is modest for most people. Sleep length appears to be less important in sustained-rel...
Human Psychopharmacology: Clinical and Experimental, 2008
The secretion of the hormone melatonin is particularly robust to the effect of pharmacological agents. Medications may alter melatonin levels through either altering adrenergic activity or affecting liver enzymes involved in melatonin metabolism. The aim of this study was to investigate the effect of venlafaxine, a third generation antidepressant with known adrenergic properties on melatonin secretion. A further aim of the study was to investigate the correlation between plasma and salivary measures on this medication. Eight healthy adult participants (four males, four females) took part in this double blind placebo controlled randomised trial. Participants were tested on 3 nights after taking venlafaxine XR (75 mg), venlafaxine IR (75 mg) or placebo. Participants were placed in a darkened room between 1900 and 0300 h and regular temperature readings, blood and saliva samples were drawn to assess melatonin and cortisol secretion in each condition. There was no significant effect of venlafaxine IR or XR on melatonin concentrations in plasma or saliva and no effects on other circadian parameters including cortisol and temperature. It was notable that the correlation between plasma and salivary melatonin levels became poor after drug treatment. These results indicate that at low doses the mixed serotonergic and noradrenergic drug venlafaxine has no effect on nocturnal melatonin concentrations.
British Journal of Clinical Pharmacology, 1994
Acute administration of the specific serotonin uptake inhibitor, fluvoxamine (100 mg at 16.00 h), markedly increased nocturnal plasma melatonin concentrations, with high levels extending into the morning hours. 2 Acute administration of the noradrenaline uptake inhibitor, desipramine (DMI) (100 mg at 16.00 h), increased evening plasma melatonin concentrations. 3 Both drug treatments increased the duration of melatonin secretion, fluvoxamine significantly delaying the offset time and DMI significantly advancing the onset time. 4 The stimulatory effect of DMI on plasma melatonin was mirrored by increased urinary 6-sulphatoxymelatonin (aMT6s) excretion. 5 On the contrary, there was no correlation between plasma melatonin and urinary aMT6s concentrations following fluvoxamine treatment, suggesting that fluvoxamine may inhibit the metabolism of melatonin. 6 Treatment with DMI increased plasma cortisol concentrations in the evening and early morning, treatment with fluvoxamine increased plasma cortisol at 03.00 h, 10.00 h and 11.00 h. 7 The drug treatments affected different aspects of the nocturnal plasma melatonin profile suggesting that the amplitude of the melatonin rhythm may depend upon serotonin availability and/or melatonin metabolism whilst the onset of melatonin production depends upon noradrenaline availability.
Increased bioavailability of oral melatonin after fluvoxamine coadministration
Clinical pharmacology and therapeutics, 2000
Fluvoxamine, a selective serotonin reuptake inhibitor, is known to elevate melatonin serum concentrations. It has not been clear whether these effects might be attributed to an increased melatonin production or to an decreased elimination of melatonin. The latter hypothesis was tested by this study. Five healthy male volunteers (one CYP2D6 poor metabolizer) received 5 mg melatonin either with or without coadministration of 50 mg fluvoxamine. Serum concentrations of melatonin and fluvoxamine were assessed from 0 to 28 hours after melatonin intake. Coadministration of fluvoxamine, on average, led to an 17-fold higher (P < .05) area under concentration-time curve (AUC) and a 12-fold higher (P < .01) serum peak concentration (Cmax) of melatonin. The terminal elimination half-life was not significantly affected. The AUC and Cmax of fluvoxamine were about three times higher and the half-life was about two times higher in the poor metabolizer. There was a correlation (r = 0.63; P <...
Acute and Delayed Effects of Melatonin: Operational Significance
2000
Work Rhythms/Status of the Use of Drugs in Sleep-Wakefulness Management [les Differences entre individus concernant les facultes d' adaptation aux rythmes irreguliers activite-repos/Le point sur l'utilisation des medicaments pour la gestion des periodes veille-sommeil] To order the complete compilation report, use: ADA388183 The component part is provided here to allow users access to individually authored sections f proceedings, annals, symposia, ect. However, the component should be considered within he context of the overall compilation report and not as a stand-alone technical report.
Divergent Importance of Chronobiological Considerations in High- and Low-dose Melatonin Therapies
Diseases, 2021
Melatonin has been used preclinically and clinically for different purposes. Some applications are related to readjustment of circadian oscillators, others use doses that exceed the saturation of melatonin receptors MT1 and MT2 and are unsuitable for chronobiological purposes. Conditions are outlined for appropriately applying melatonin as a chronobiotic or for protective actions at elevated levels. Circadian readjustments require doses in the lower mg range, according to receptor affinities. However, this needs consideration of the phase response curve, which contains a silent zone, a delay part, a transition point and an advance part. Notably, the dim light melatonin onset (DLMO) is found in the silent zone. In this specific phase, melatonin can induce sleep onset, but does not shift the circadian master clock. Although sleep onset is also under circadian control, sleep and circadian susceptibility are dissociated at this point. Other limits of soporific effects concern dose, dura...
Journal of Pineal Research, 1997
TR. The effect of atenolol, a PI-adrenergic antagonist, on nocturnal plasma melatonin secretion: Evidence for a dose-response relationship in humans. J. Pineal Res. 1997; 23:13 1-135.0 Munksgaard, Copenhagen Abstract: Pineal P,-adrenergic receptors are involved in the regulation of melatonin secretion. The involvement of PI-adrenergic receptors has been demonstrated by the ability of acute administration of P-antagonists to suppress the nocturnal rise of circulating melatonin and its urinary metabolite 6-sulphatoxymelatonin (aMT6s). The present study was undertaken to examine the relationship between increasing doses of atenolol and nocturnal plasma melatonin concentrations. Six healthy subjects participated in the study for a period of 5 weeks. Subjects were administered placebo, 12.5, 25, 37.5, and 50 mg doses of atenolol in a randomized single blind design. Each dose was separated by a 1 week washout period. Blood samples were collected at regular intervals from 19.00 hr to 06.00 hr. Repeated measures analysis of variance showed a dose-dependent decrease in plasma melatonin concentrations (RO.01). A Student Newman-Keuls post hoc test indicated significant differences between placebo and all doses of atenolol (P<0.05). The results demonstrate a dose-dependent relationship between PI -receptor blockade and suppression of nocturnal plasma melatonin in humans.
Differential Effects of Fluvoxamine and Other Antidepressants on the Biotransformation of Melatonin
Journal of Clinical Psychopharmacology, 2001
Melatonin, the predominant product of the pineal gland, is involved in the maintenance of diurnal rhythms. Nocturnal blood concentrations of melatonin have been shown to be enhanced by fluvoxamine, but not by other serotonin reuptake inhibitors. Because fluvoxamine is an inhibitor of several cytochrome P450 (CYP) enzymes, the authors studied the biotransformation of melatonin and the effects of fluvoxamine on the metabolism of melatonin in vitro using human liver microsomes and recombinant human CYP isoenzymes. Melatonin was found to be almost exclusively metabolized by CYP1A2 to 6-hydroxymelatonin and Nacetylserotonin with a minimal contribution of CYP2C19. Both reactions were potently inhibited by fluvoxamine, with a K i of 0.02 M for the formation of 6-hydroxymelatonin and 0.05 M for the formation of N-acetylserotonin. Other than fluvoxamine, fluoxetine, paroxetine, citalopram, imipramine, and desipramine were also tested at 2 and 20 M. Among the other antidepressants, only paroxetine was able to affect the metabolism of melatonin at supratherapeutic concentrations of 20 M, which did not reach by far the magnitude of the inhibitory potency of fluvoxamine. The authors concluded that fluvoxamine is a potent inhibitor of melatonin degradation. Because this inhibitory action is also found in vivo, fluvoxamine might be used as an enhancer of melatonin, which might offer new therapeutic possibilities of fluvoxamine.
Journal of Pineal Research, 1989
Several studies suggest that GABAergic mechanisms may be involved in the modulation of melatonin secretion. However, conflicting results have been reported in animal studies; in humans the issue has not been widely investigated. In the present study, using a double‐blind design, six healthy men received orally, at midnight, 10 mg of diazepam, a GABAergic agent, or placebo, on two different occasions 1 week apart. Blood samples were collected, in the dark, immediately before the drug administration, and at 12:30, 1, 2, 3, and 4 AM. Serum melatonin was measured by a radioimmunological method with [125I]melatonin as a tracer. Two‐way ANOVA with repeated measurements disclosed a significant effect for treatment (P < 0.01), for time (P < 0.0004), and for treatment X time interaction (P < 0.05). Following diazepam administration, serum melatonin levels observed at 2, 3, and 4 AM were significantly lower than the corresponding values following placebo (P < 0.02 at 2 and 4 AM; P...
Prediction of nocturnal plasma melatonin from morning urinary measures
Journal of Pineal Research, 1998
A growing literature indicates that blood levels of the hormone melatonin may have important implications for human health and wellbeing. Melatonin is synthesized and released into the general circulation at night, however, and it is seldom feasible to draw blood samples at night in epidemiological studies. There is some evidence that levels of urinary melatonin and of 6-sulfatoxymelatonin (aMT6s), the major metabolite of melatonin, accurately reflect nocturnal plasma melatonin. If this is the case, urinary assays could be powerful tools for epidemiological studies. A laboratory-based study was performed to examine the relationships between nocturnal plasma melatonin, morning urinary melatonin, and morning urinary aMT6s levels in 78 men. The relationship between total nocturnal plasma melatonin and both urinary aMT6s corrected for creatinine and urinary melatonin is significant. Combining the two urinary measures accounts for 72% of the variance in total plasma melatonin. Peak nocturnal plasma melatonin also was significantly related to urinary melatonin and to aMT6s. The urinary measures show good sensitivity and specificity in identifying individual differences in nocturnal plasma melatonin levels. These results support the inclusion of morning urine samples to assess the contribution of the hormone melatonin in occupational or residential studies involving healthy, young men.
Melatonergic Drugs in Clinical Practice
Arzneimittelforschung, 2011
Melatonin (CAS 73-31-4) has both hypnotic and sleep/wake rhythm regulating properties. These sleep promoting actions, which are already demonstrable in healthy humans, have been found useful in subjects suffering from circadian rhythm sleep disorders (CRSD) like delayed sleep phase syndrome (DSPS), jet lag and shift-work sleep disorder. Low
Melatonin & the High Dose Mystery: The Yin-Yang
Research Square (Research Square), 2023
Background & Aim: Melatonin is primarily involved in the regulation of circadian rhythm and sleep and with its neuroprotective, anti-in ammatory, antihypertensive, oncostatic and immunomodulatory roles, it has become a popular supplement. However, limited literature is available regarding the side effects associated with its consumption, particularly at high dosages. Our review offers a critical insight into the adverse events of melatonin supplementation above the recommended dosage i.e., 5mg/day. Methodology: A literature search was executed using controlled vocabulary, involving Medical Subject Headings (MeSH) through electronic databases like PubMed and Clinicaltrials.gov from inception to 19 th June 2022. Additional papers were subsequently added through hand-searching citations contained within retrieved articles, relevant systemic reviews, and meta-analysis, without any restriction regarding date or language. The inclusion criteria for studies were: 1) Freely accessible, full articles 2) Original studies, observational and interventional, Randomised Controlled Trials, and 3) Published trials in peer-reviewed journals that reported any adverse events. The studies excluded were 1) irrelevant to the subject of the review, such as studies that did not use melatonin as the exposure; 2) insu cient data to report the adverse events after the dose; 3) duplicate studies or overlapping participants, and 4) reviews, editorials, conference papers, case reports or animal experiments. Articles were further excluded if melatonin was only given in combination with other interventions, whereby the independent effect of melatonin could not be assessed. Results: After the nal screening, 16 articles were retained for a full review. Various adverse events associated with the high dosage of melatonin were noticed. In the healthy population, the adverse events included reduced insulin release after the morning dose, impaired insulin release after the evening dose, suppression of Luteinizing hormone and ovulation, reduction in selective attention and visual reacting time, sleepiness or loss of sleep, exacerbation or onset of depression, anger or psychotic symptoms, weight loss, fatigue, and confusion. While in healthy sports people, a negative impact on performance and agility after morning doses in females, reduced performance in hand-grip strength, squat jump, and counter-movement jump tests were noticed, with the report of a rocking sensation among the travelling sports o cials. Multiple other side effects were also noticed in the population with a high risk for/pre-existing comorbidities. Challenges and Discussion: The use of melatonin supplementation, especially as a self-medication, has seen a signi cant rise in recent times, owing to the correction of sleep disturbances that could be linked with prevalent mental health issues, a diminished sensation of control, or insomnia associated with Page 3/22 different disorders. However, as sleep irregularities can typically be corrected with minor adjustments in lifestyle, diet, and physical activity, the excessive use of the supplements, without supervision and/or awareness regarding the adverse effects and possible drug interactions, is alarming. In addition to highlighting the adverse events related to higher dosages of Melatonin, we also discuss potential adjuncts to Melatonin supplementation for sleep irregularities and minor disturbances that lead to Melatonin use. Conclusion: Melatonin, is undoubtedly an asset to the eld, but is related to a variety of adverse effects when taken in higher doses. Thus, consideration needs to be done before its regular consumption, speci cally in individuals with pre-existing comorbidities or those with high risk, among whom the reports of adverse events were higher. Further cohorts and randomized controlled trials with a larger sample size are needed to further explore this domain. Similarly, additional emphasis should be given to the prevention of the widespread use of melatonin as a self-medication for minor disturbances and the drug should only be used when seriously needed, under strict instructions regarding dosage and consumption by healthcare o cials.
The Effect of Sleep/Wake State on Nocturnal Melatonin Excretion
Journal of Pineal Research, 1990
Twenty-four hour patterns of urinary 6-sulphatoxymelatonin excretion were monitored in eight healthy adult subjects in two bed rest constant routines, one with normal nocturnal sleep and one with continuous wakefulness. The implementation of dim light "constant routines" enabled the effect of the sleep wakehtate on melatonin to be tested without the confounding effects of body activity and normal room lighting. In both conditions 6-sulphatoxymelatonin excretion was significantly higher during the nighttime hours (2200-1000) than during the daytime hours (1000-2200) producing averages of 80% and 78.5% of the total 24 hour output in the sleep and wakeful conditions, respectively. The large differences between subjects in nocturnal melatonin excretion (38 to 150 nmol) were highly consistent between the two conditions. There were no differences between the nocturnal wakeful and sleep conditions in total nighttime melatonin excretion nor in the nighttime percentage of the 24 hour total melatonin excretions. Therefore, the sleep/wake state alone had no effect on nocturnal melatonin excretion. On the other hand, a significant correlation between the nighttime melatonin percentage and sleep length suggested the need to investigate further the relation between the amplitude of the melatonin circadian rhythm and sleep length and quality.
Melatonin and clinical application
Reproduction Nutrition Development, 1999
A review of the different publications dealing with melatonin in humans shows that this field has been very active in the last few years. Normative melatonin values have been defined. Various relationships between melatonin and other traits have been studied, such as sleep, circadian rhythm, surgical stress and anaesthesia. Age-related melatonin studies and melatonin during depression and other psychiatric disorders have been reviewed. Finally, some studies have been performed to use melatonin as a medication for sleep disturbance in depression, for jet-lag and as a skin protector for ultraviolet light. © Inra/Elsevier, Paris melatonin / clinics / depression / sleep / circadian Résumé ― Mélatonine et applications cliniques. Une revue des différentes publications traitant de la mélatonine chez l'homme montre que ce champ a été très actif au cours de ces dernières années. Des normes de concentrations de mélatonine ont été définies. Diverses relations entre la mélatonine et d'autres caractéristiques comme le sommeil, les rythmes circadiens, le stress chirurgical et l'anesthésie ont été étudiées. Des études sur la mélatonine au cours du vieillissement et sur la mélatonine pendant la dépression et au cours d'autres désordres psychiatriques ont été conduites. Enfin, plusieurs essais ont utilisé la mélatonine comme médicament pour traiter les troubles du sommeil pendant la dépression, pour atténuer le jet-lag et comme protecteur de la peau contre les UV. © Inra/
Potential drug interactions with melatonin
Physiology & Behavior, 2014
Possible interactions of melatonin with concurrently administered drugs were investigated in in vitro studies utilising human hepatic post-mitochondrial preparations; similar studies were conducted with rat preparations to ascertain whether rat is a suitable surrogate for human. Drugs were selected based on the knowledge that the 6-hydroxylation of exogenous melatonin, its principal pathway of metabolism, is mainly mediated by hepatic CYP1A2, but also on the likelihood of the drug being concurrently administered with melatonin. Hepatic preparations were incubated with either melatonin or 6-hydroxymelatonin in the presence and absence of a range of concentrations of interacting drug, and the production of 6sulphatoxymelatonin monitored using a radio-immunoassay procedure. Of the drugs screened, only the potent CYP1A2 inhibitor 5-methoxypsoralen impaired the 6-melatonin hydroxylation at pharmacologically relevant concentrations, and is likely to lead to clinical interactions; diazepam, tamoxifen and acetaminophen (paracetamol) did not impair the metabolic conversion of melatonin to 6-sulphatoxymelatonin at concentrations attained following therapeutic administration. 17-Ethinhyloestradiol appeared not to suppress the 6hydroxylation of melatonin but inhibited the sulphation of 6-hydroxymelatonin, but this is unlikely to result in an interaction following therapeutic intake of the steroid. Species differences in the inhibition of melatonin metabolism in human and rat hepatic postmitochondrial preparations were evident implying that the rat may not be an appropriate surrogate of human in such studies Introduction Melatonin (N-acetyl-5-methoxytryptamine) is a versatile pineal hormone secreted during darkness that has been implicated in a wide variety of physiological functions, including regulation of circadian rhythms [1], control of seasonal reproduction [2], modulation of insulin secretion [3], immune function [4,5], retinal function [6] and neuroprotection [7].
Melatonin: reducing the toxicity and increasing the efficacy of drugs
Journal of Pharmacy and Pharmacology, 2002
Melatonin (N-acetyl-5-methoxytryptamine) is a molecule with a very wide phylogenetic distribution from plants to man. In vertebrates, melatonin was initially thought to be exclusively of pineal origin ; recent studies have shown, however, that melatonin synthesis may occur in a variety of cells and organs. The concentration of melatonin within body uids and subcellular compartments varies widely, with blood levels of the indole being lower than those at many other sites. Thus, when de ning what constitutes a physiological level of melatonin, it must be de ned relative to a speci c compartment. Melatonin has been shown to have a variety of functions, and research in the last decade has proven the indole to be both a direct free radical scavenger and indirect antioxidant. Because of these actions, and possibly others that remain to be de ned, melatonin has been shown to reduce the toxicity and increase the ef cacy of a large number of drugs whose side effects are well documented. Herein, we summarize the bene cial effects of melatonin when combined with the following drugs: doxorubicin, cisplatin, epirubicin, cytarabine, bleomycin, gentamicin, ciclosporin, indometacin, acetylsalicylic acid, ranitidine, omeprazole, isoniazid, iron and erythropoietin, phenobarbital, carbamazepine, haloperidol, caposide-50, morphine, cyclophosphamide and L-cysteine. While the majority of these studies were conducted using animals, a number of the investigations also used man. Considering the low toxicity of melatonin and its ability to reduce the side effects and increase the ef cacy of these drugs, its use as a combination therapy with these agents seems important and worthy of pursuit.
Melatonin: Pharmacology, Functions and Therapeutic Benefits
Current Neuropharmacology, 2017
Background: Melatonin synchronizes central but also peripheral oscillators (fetal adrenal gland, pancreas, liver, kidney, heart, lung, fat, gut, etc.), allowing temporal organization of biological functions through circadian rhythms (24-hour cycles) in relation to periodic environmental changes and therefore adaptation of the individual to his/her internal and external environment. Measures of melatonin are considered the best peripheral indices of human circadian timing based on an internal 24-hour clock. Methods: First, the pharmacology of melatonin (biosynthesis and circadian rhythms, pharmacokinetics and mechanisms of action) is described, allowing a better understanding of the short and long term effects of melatonin following its immediate or prolonged release. Then, research related to the physiological effects of melatonin is reviewed. Results: The physiological effects of melatonin are various and include detoxification of free radicals and antioxidant actions, bone formation and protection, reproduction, and cardiovascular, immune or body mass regulation. Also, protective and therapeutic effects of melatonin are reported, especially with regard to brain or gastrointestinal protection, psychiatric disorders, cardiovascular diseases and oncostatic effects. Conclusion: This review highlights the high number and diversity of major melatonin effects and opens important perspectives for measuring melatonin as a biomarker (biomarker of early identification of certain disorders and also biomarker of their follow-up) and using melatonin with clinical preventive and therapeutic applications in newborns, children and adults based on its physiological regulatory effects.