Nocturnal plasma melatonin concentrations in healthy volunteers: Effect of single doses of d-fenfluramine, paroxetine, and ipsapirone (original) (raw)
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.