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Melatonin is produced in the pineal gland under very tight control through the influences of light and the suprachiasmatic nucleus. As such, melatonin circulates in the blood at levels <3 pg/ml during the day and is only actively secreted at night reaching levels of approximately 100 pg/ml. As a consequence of binding to plasma proteins, free melatonin appears in saliva at approximately one third the plasma concentration. Measurement of melatonin is technically challenging because of these very low concentrations and while a number of commercial immunoassay kits are available and mass spectrometry assay methods have been published, not all are fit for purpose and can lead to unreliable conclusions. In this review I discuss the aspects of pineal melatonin production that saliva melatonin reflects, the factors influencing melatonin production or metabolism, saliva collection and analysis methods. Examples are provided of the appropriate use of saliva melatonin measurements; Dim Light Melatonin Onset (DLMO) assessment, impact of light on melatonin and the monitoring of rhythms prior to specific treatments. Examples of inappropriate use of saliva melatonin measurements are also provided including the use of poorly validated assays, morning saliva collections, attempts to stimulate melatonin, and linking specific illnesses to saliva melatonin levels. [ABSTRACT FROM AUTHOR]

Background Delayed Sleep-Wake Phase Disorder (DSWPD) is characterised by sleep initiation insomnia when attempting sleep at conventional times and difficulty waking at the required time for daytime commitments. Although there are published therapeutic guidelines for the administration of melatonin for DSWPD, to our knowledge, randomised controlled trials are lacking. This trial tested the efficacy of 0.5 mg melatonin, combined with behavioural sleep-wake scheduling, for improving sleep initiation in clinically diagnosed DSWPD patients with a delayed endogenous melatonin rhythm relative to patient-desired (or -required) bedtime (DBT). Methods This randomised, placebo-controlled, double-blind clinical trial was conducted in an Australian outpatient DSWPD population. Following 1-wk baseline, clinically diagnosed DSWPD patients with delayed melatonin rhythm relative to DBT (salivary dim light melatonin onset [DLMO] after or within 30 min before DBT) were randomised to 4-wk treatment with 0.5 mg fast-release melatonin or placebo 1 h before DBT for at least 5 consecutive nights per week. All patients received behavioural sleep-wake scheduling, consisting of bedtime scheduled at DBT. The primary outcome was actigraphic sleep onset time. Secondary outcomes were sleep efficiency in the first third of time in bed (SE T1) on treatment nights, subjective sleep-related daytime impairment (Patient Reported Outcomes Measurement Information System [PROMIS]), PROMIS sleep disturbance, measures of daytime sleepiness, clinician-rated change in illness severity, and DLMO time. Findings Between September 13, 2012 and September 1, 2014, 307 participants were registered; 116 were randomised to treatment (intention-to-treat n = 116; n = 62 males; mean age, 29.0 y). Relative to baseline and compared to placebo, sleep onset occurred 34 min earlier (95% confidence interval [CI] -60 to -8) in the melatonin group. SE T1 increased; PROMIS sleep-related impairment, PROMIS sleep disturbance, insomnia severity, and functional disability decreased; and a greater proportion of patients showed more than minimal clinician-rated improvement following melatonin treatment (52.8%) compared to placebo (24.0%) (P < 0.05). The groups did not differ in the number of nights treatment was taken per protocol. Post-treatment DLMO assessed in a subset of patients (n = 43) was not significantly different between groups. Adverse events included light-headedness, daytime sleepiness, and decreased libido, although rates were similar between treatment groups. The clinical benefits or safety of melatonin with long-term treatment were not assessed, and it remains unknown whether the same treatment regime would benefit patients experiencing DSWPD sleep symptomology without a delay in the endogenous melatonin rhythm. Conclusions In this study, melatonin treatment 1 h prior to DBT combined with behavioural sleep-wake scheduling was efficacious for improving objective and subjective measures of sleep disturbances and sleep-related impairments in DSWPD patients with delayed circadian phase relative to DBT. Improvements were achieved largely through the sleep-promoting effects of melatonin, combined with behavioural sleep-wake scheduling. Trial registration This trial was registered with the Australian New Zealand Clinical Trials Registry, ACTRN12612000425897., Author(s): Tracey L. Sletten 1,2,*, Michelle Magee 1,2, Jade M. Murray 1,2, Christopher J. Gordon 2,3,4, Nicole Lovato 2,5, David J. Kennaway 6, Stella M. Gwini 7,8, Delwyn J. Bartlett [...]

The role of peripheral vs. central circadian rhythms and Clock in the maintenance of metabolic homeostasis and with aging was examined by using [Clock.sup.[DELTA]19]+MEL mice. These have preserved suprachiasmatic nucleus and pineal gland rhythmicity but arrhythmic Clock gene expression in the liver and skeletal muscle. [Clock.sup.[DELTA]19]+MEL mice showed fasting hypoglycemia in young-adult males, fasting hyperglycemia in older females, and substantially impaired glucose tolerance overall. [Clock.sup.[DELTA]19]+MEL mice had substantially reduced plasma insulin and plasma insulin/ glucose nocturnally in males and during a glucose tolerance test in females, suggesting impaired insulin secretion. [Clock.sup.[DELTA]19]+MEL mice had reduced hepatic expression and loss of rhythmicity of gck, pfkfb3, and pepck mRNA, which is likely to impair glycolysis and gluconeogenesis. [Clock.sup.[DELTA]19]+MEL mice also had reduced glut4 mRNA in skeletal muscle, and this may contribute to poor glucose tolerance. Whole body insulin tolerance was enhanced in [Clock.sup.[DELTA]19]+MEL mice, however, suggesting enhanced insulin sensitivity. These responses occurred although the [Clock.sup.[DELTA]19] mutation did not cause obesity and reduced plasma free fatty acids while increasing plasma adiponectin. These studies on clock-gene disruption in peripheral tissues and metabolic homeostasis provide compelling evidence of a relationship between circadian rhythms and the glucose/insulin and adipoinsular axes. It is, however, premature to declare that clock-gene disruption causes the full metabolic syndrome.

The circadian rhythmicity of hormone secretion, body temperature, and sleep/wakefulness results from an endogenous rhythm of neural activity generated by clock genes in the suprachiasmatic nucleus (SCN). One of these genes, Clock, has been considered essential for the generation of cellular rhythmicity centrally and in the periphery; however, melatonin-proficient [Clock.sup.[DELTA]19] + MEL mutant mice retain melatonin rhythmicity, suggesting that their central rhythmicity is intact. Here we show that melatonin production in these mutants was rhythmic in constant darkness and could be entrained by brief single daily light pulses. Under normal light-dark conditions, per2 and prokineticin2 (PK2) mRNA expression was rhythmic in the SCN of [Clock.sup.[DELTA]19] + MEL mice. Expression of Bma11 and npas2 was not altered, whereas per1 expression was arrhythmic. In contrast to the SCN, per1 and per2 expression, as well as Bmal1 expression in liver and skeletal muscle, together with plasma corticosterone, was arrhythmic in [Clock.sup.[DELTA]19] + MEL mutant mice in normal light-dark conditions. npas2 mRNA was also arrhythmic in liver but rhythmic in muscle. The Clock.sup.[DELTA]19] mutation does not abolish central rhythmicity and light entrainment, suggesting that a functional Clock homolog, possibly npas2, exists in the SCN. Nevertheless, the SCN of Clock.sup.[DELTA]19] + MEL mutant mice cannot maintain liver and muscle rhythmicity through rhythmic outputs, including melatonin secretion, in the absence of functional Clock expression in the tissues. Therefore, liver and muscle, but not SCN, have an absolute requirement for CLOCK, with as yet unknown Clock-independent factors able to generate the latter. circadian; melatonin; clock genes

Melatonin and wheel-running rhythmicity and the effects of acute and chronic light pulses on these rhythms were studied in [Clock.sup.[DELTA]19] mutant mice selectively bred to synthesize melatonin. Homozygous melatonin-proficient [Clock.sup.[DELTA]19] mutant mice ([Clock.sup.[DELTA]19/[DELTA]19]-MEL) produced melatonin rhythmically, with peak production 2 h later than the wild-type controls (i.e., just before lights on). By contrast, the time of onset of wheel-running activity occurred within a 20-min period around lights off, irrespective of the genotype. Melatonin production in the mutants spontaneously decreased within 1 h of the expected time of lights on. On placement of the mice in continuous darkness, the melatonin rhythm persisted, and the peak occurred 2 h later in each cycle over the first two cycles, consistent with the endogenous period of the mutant. This contrasted with the onset of wheel-running activity, which did not shift for several days in constant darkness. A light pulse around the time of expected lights on followed by constant darkness reduced the expected 2-h delay of the melatonin peak of the mutants to ~1 h and advanced the time of the melatonin peak in the wild-type mice. When the [Clock.sup.[DELTA]19/[DELTA]19]-MEL mice were maintained in a skeleton photoperiod of daily 15-min light pulses, a higher proportion entrained to the schedule (57%) than melatonin-deficient mutants (9%). These results provide compelling evidence that mice with the [Clock.sup.[DELTA]19] mutation express essentially normal rhythmicity, albeit with an underlying endogenous period of 26-27 h, and they can be entrained by brief exposure to light. They also raise important questions about the role of Clock in rhythmicity and the usefulness of monitoring behavioral rhythms compared with hormonal rhythms. circadian; pineal gland; Clock genes; entrainment

The rhythm of melatonin in rat milk and the capacity of pups to synthesize and metabolize melatonin were studied. Melatonin was undetectable in milk in the light ( circadian; ontogeny; pineal; metabolism; 6-sulphatoxymelatonin

Significant thermoregulatory changes without soporific effects may be generated by daytime intravenous injection of melatonin to achieve normal nocturnal levels in young adults. This was gleaned from an investigation of the effect of a rapid increase in circulating melatonin on body temperatures and sleepiness in eight young adults. The thermoregulatory effect appears to be maximal within a range of melatonin levels in plasma achieved during the night. A slight but non-significant trend for increased subjective sleepiness was noted at the highest dose.

Melatonin is a hormonal product of the pineal gland, a fact that is often forgotten. Instead it is promoted as a dietary supplement that will overcome insomnia, as an antioxidant and as a prescription only drug in most countries outside the United States of America and Canada. The aim of this review is to step back and highlight what we know about melatonin following its discovery 60 years ago. What is the role of endogenous melatonin; what does melatonin do to sleep, body temperature, circadian rhythms, the cardiovascular system, reproductive system, endocrine system and metabolism when administered to healthy subjects? When used as a drug/dietary supplement, what safety studies have been conducted? Can we really say melatonin is safe when it has not been systematically studied and many studies show interactions with a wide range of physiological processes? Finally the results of studies investigating the efficacy of melatonin as a drug to alleviate insomnia are critically evaluated. In summary, melatonin is an endogenous pineal gland hormone with specific physiological functions in animals and humans, with its primary role in humans to maintain synchrony of sleep with the day/night cycle. When administered as a drug it affects a wide range of physiological systems and has clinically important drug interactions. With respect to efficacy for treating sleep disorders, melatonin can advance the time of sleep onset but the effect is modest and variable. In children with neurodevelopmental disabilities melatonin appears to have the greatest impact on sleep onset but little effect on sleep efficiency. [ABSTRACT FROM AUTHOR]

A study was conducted to analyze the influence of physiological melatonin levels on body temperatures and subjective sleepiness in young adults. Thermistors used in the study were linked to a Mini-logger ambulatory data recorder while the cannula of the subjects were utilized to sample 10 ml of blood. Results showed that high melatonin was correlated with significant attenuation in the daytime increase in rectal temperature.