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Melatonin is a neurohormone known to modulate a wide range of circadian functions, including sleep. The synthesis and release of melatonin from the pineal gland is heavily influenced by light stimulation of the retina, particularly through the intrinsically photosensitive retinal ganglion cells. Melatonin is also synthesised within the eye, although to a much lesser extent than in the pineal gland. Melatonin acts directly on ocular structures to mediate a variety of diurnal rhythms and physiological processes within the eye. The interactions between melatonin, the eye, and visual function have been the subject of a considerable body of recent research. This review is intended to provide a broad introduction for eye-care practitioners and researchers to the topic of melatonin and the eye. The first half of the review describes the anatomy and physiology of melatonin production: how visual inputs affect the pineal production of melatonin; how melatonin is involved in a variety of diurnal rhythms within the eye, including photoreceptor disc shedding, neuronal sensitivity, and intraocular pressure control; and melatonin production and physiological roles in retina, ciliary body, lens and cornea. The second half of the review describes clinical implications of light/melatonin interactions. These include light exposure and photoreceptor contributions in melatonin suppression, leading to consideration of how blue blockers, cataract, and light therapy might affect sleep and mood in patients. Additionally, the interactions between melatonin, sleep and refractive error development are discussed. A better understanding of environmental factors that affect melatonin and subsequent effects on physiological processes will allow clinicians to develop treatments and recommend modifiable behaviours to improve sleep, increase daytime alertness, and regulate ocular and systemic processes related to melatonin.…

PMID: 30074278

Visible light synchronizes the human biological clock in the suprachiasmatic nuclei of the hypothalamus to the solar 24-hour cycle. Short wavelengths, perceived as blue color, are the strongest synchronizing agent for the circadian system that keeps most biological and psychological rhythms internally synchronized. Circadian rhythm is important for optimum function of organisms and circadian sleep-wake disruptions or chronic misalignment often may lead to psychiatric and neurodegenerative illness. The beneficial effect on circadian synchronization, sleep quality, mood, and cognitive performance depends not only on the light spectral composition but also on the timing of exposure and its intensity. Exposure to blue light during the day is important to suppress melatonin secretion, the hormone that is produced by the pineal gland and plays crucial role in circadian rhythm entrainment. While the exposure to blue is important for keeping organism's wellbeing, alertness, and cognitive performance during the day, chronic exposure to low-intensity blue light directly before bedtime, may have serious implications on sleep quality, circadian phase and cycle durations. This rises inevitably the need for solutions to improve wellbeing, alertness, and cognitive performance in today's modern society where exposure to blue light emitting devices is ever increasing.…

PMID: 31433569

Light suppresses melatonin in humans, with the strongest response occurring in the short-wavelength portion of the spectrum between 446 and 477 nm that appears blue. Blue monochromatic light has also been shown to be more effective than longer-wavelength light for enhancing alertness. Disturbed circadian rhythms and sleep loss have been described as risk factors for astronauts and NASA ground control workers, as well as civilians. Such disturbances can result in impaired alertness and diminished performance. Prior to exposing subjects to short-wavelength light from light-emitting diodes (LEDs) (peak λ = 469 nm; 1/2 peak bandwidth = 26 nm), the ocular safety exposure to the blue LED light was confirmed by an independent hazard analysis using the American Conference of Governmental Industrial Hygienists exposure limits. Subsequently, a fluence-response curve was developed for plasma melatonin suppression in healthy subjects (n = 8; mean age of 23.9 ± 0.5 years) exposed to a range of irradiances of blue LED light. Subjects with freely reactive pupils were exposed to light between 2:00 and 3:30 AM. Blood samples were collected before and after light exposures and quantified for melatonin. The results demonstrate that increasing irradiances of narrowband blue-appearing light can elicit increasing plasma melatonin suppression in healthy subjects (P < 0.0001). The data were fit to a sigmoidal fluence-response curve (R(2) = 0.99; ED(50) = 14.19 μW/cm(2)). A comparison of mean melatonin suppression with 40 μW/cm(2) from 4,000 K broadband white fluorescent light, currently used in most general lighting fixtures, suggests that narrow bandwidth blue LED light may be stronger than 4,000 K white fluorescent light for suppressing melatonin.…

PMID: 21164152

The pharmacokinetics, tissue distribution and metabolism of caffeine were studied in male New Zealand White rabbits after an i.v. dose of 4 mg/kg. The mean (n = 4) distribution half-life was 0.2 hr and the mean elimination half-life was 3.8 hr. The mean clearance was 0.20 liters/kg/hr and the mean volume of distribution was 0.82 liters/kg. Concurrent samples of blood and semen from three rabbits, trained to ejaculate into an artificial vagina, were analyzed. The mean semen/blood concentration ratio of caffeine was 1.0. The concentrations of caffeine in the tissues of three rabbits were examined at 1 hr after an i.v. dose of 4 mg/kg. Most tissues exhibited a tissue/blood concentration ratio of approximately 1.0. Exceptions to this included fat, adrenals, liver and bile in which the ratios were 0.2, 0.6, 1.5 and 2.7, respectively. Urinary metabolites were investigated after an i.v. dose of 4 mg/kg of [14C]caffeine. The metabolites of caffeine were separated by high-pressure liquid chromatography and quantified by liquid scintillation counting. The major urinary metabolites of caffeine in the rabbit were 1-methylxanthine (22%), 1-methyluric acid (19%), 7-methylxanthine (16%) and 1,7-dimethylxanthine (14%).…

PMID: 3981454

To study the pharmacokinetics of fluvoxamine when given in increasing doses to healthy volunteers. Ten healthy, non-smoking men were given maintenance treatment with fluvoxamine for 4 weeks. Eight subjects were CYP2D6 extensive metabolisers (EMs) and two were CYP2D6 poor metabolisers (PMs). As a measure of the CYP1A2 phenotype, the paraxanthine/caffeine ratio in saliva after intake of caffeine was studied. The fluvoxamine doses given were 25 mg day(-1) the first week, 50 mg day(-1) the second week, 100 mg day(-1) the third week and 200 mg day(-1) the fourth week, divided in two daily doses. On the seventh day every week, serum concentrations of fluvoxamine were followed for a dose interval of 12 h. After discontinuation of treatment, fluvoxamine concentrations were followed for 1 week. For each of the three two-fold increases in given dose, the mean AUC increased 3.25-fold, 3.17-fold and 3.14-fold, respectively (P < 0.0001), indicating a decrease in oral clearance with increasing dose. The elimination half-life based upon the serum concentrations 12-48 h after discontinuation of fluvoxamine was 32.1 +/- 11.0 h whereas the half-life based upon the concentrations 3-7 days after discontinuation was significantly shorter, 15.8 +/- 4.2h (means +/- s.d.; P < 0.001). There were no significant correlations between the CYP1A2 phenotype and fluvoxamine AUCs at different doses (r = -0.56; P = 0.095 for the correlation between the paraxanthine/caffeine ratio in saliva and fluvoxamine AUC at a dose of 50 mg day[-1]). The two CYP2D6 PMs had AUC values in the same range as the EMs. The present study conclusively demonstrates that fluvoxamine exhibits non-linear kinetics within the therapeutic dose interval. The reason for non-linearity is not Michaelis-Menten saturation kinetics of a single metabolic pathway, but rather a complex involvement of multiple parallel pathways.…

PMID: 9517369

Consuming coffee, a widely enjoyed beverage with caffeine, can impact the central nervous system and disturb sleep if taken too close to bedtime. Caffeine impacts sleep by slowing the onset, blocking adenosine receptors, lowering deep sleep levels, disrupting sleep patterns, and lessening rapid eye movement sleep. Although coffee can help with alertness in the morning, it may disturb sleep in the evening, particularly for individuals who are sensitive to caffeine. To enhance the quality of sleep, reduce the consumption of caffeine in the afternoon and evening, refrain from drinking caffeine before going to bed, and choose decaffeinated drinks instead. Variables such as personal reactions, ability to handle caffeine, and engagement with other compounds also influence the impact of coffee on sleep. Keeping track of how much caffeine you consume and your sleeping habits can assist in recognizing any disturbances and making needed changes. Furthermore, taking into account variables such as metabolism, age, and the timing of coffee consumption can assist in lessening the effects of coffee on sleep. In general, paying attention to the amount of caffeine consumed from different sources and consuming it at the right times can assist in preserving healthy sleep patterns even while enjoying coffee.…

PMID: 39168560

To investigate the effect of a typical dose of caffeine and a high dose of caffeine consumed in the morning, afternoon, and evening on subsequent sleep. Using a placebo-controlled, double-blind, randomized crossover design, 23 males (25.3 ± 5.0 years) with a moderate habitual caffeine intake (<300 mg∙day-1) completed seven conditions: placebo, and 100 and 400 mg of caffeine consumed 12, 8, and 4 hours prior to bedtime, with a 48-hour washout. In-home partial polysomnography and sleep diaries were used to assess sleep. Linear mixed models estimated the effect of each condition. No significant effect on objective or subjective sleep occurred with the 100 mg dose of caffeine compared with the placebo (p > .05), but significant effects occurred with the 400 mg dose (p < .05). Significant delays in sleep initiation and alterations to sleep architecture were observed when 400 mg was consumed within 12 hours of bedtime (p < .05), and significantly greater sleep fragmentation occurred when 400 mg was consumed within 8 hours of bedtime (p < .05). Additionally, perceived sleep quality was significantly reduced when 400 mg was consumed 4 hours prior to bedtime (-34.02%, p = .006) but not at 8 or 12 hours. A 100 mg dose of caffeine can be consumed up to 4 hours prior to bedtime, but 400 mg may negatively impact sleep when consumed as one dose within 12 hours of bedtime, with the adverse influence on sleep increasing the closer consumption occurs to bedtime. The discrepancy between objective and subjective sleep quality suggests that individuals may have difficulty accurately perceiving the influence of caffeine on sleep quality. Australian and New Zealand Clinical Trials Registry, registration number: ACTRN12621001625864, https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12621001625864.…

PMID: 39377163

Circadian and sleep-homeostatic mechanisms regulate timing and quality of wakefulness. To enhance wakefulness, daily consumption of caffeine in the morning and afternoon is highly common. However, the effects of such a regular intake pattern on circadian sleep-wake regulation are unknown. Thus, we investigated if daily daytime caffeine intake and caffeine withdrawal affect circadian rhythms and wake-promotion in habitual consumers. Twenty male young volunteers participated in a randomised, double-blind, within-subject study with three conditions: i) caffeine (150 mg 3 x daily for 10 days), ii) placebo (3 x daily for 10 days) and iii) withdrawal (150 mg caffeine 3 x daily for eight days, followed by a switch to placebo for two days). Starting on day nine of treatment, salivary melatonin and cortisol, evening nap sleep as well as sleepiness and vigilance performance throughout day and night were quantified during 43 h in an in-laboratory, light and posture-controlled protocol. Neither the time course of melatonin (i.e. onset, amplitude or area under the curve) nor the time course of cortisol was significantly affected by caffeine or withdrawal. During withdrawal, however, volunteers reported increased sleepiness, showed more attentional lapses as well as polysomnography-derived markers of elevated sleep propensity in the late evening compared to both the placebo and caffeine condition. The typical pattern of caffeine intake with consumption in both the morning and afternoon hours may not necessarily result in a circadian phase shift in the evening nor lead to clear-cut benefits in alertness. The time-of-day independent effects of caffeine withdrawal on evening nap sleep, sleepiness and performance suggest an adaptation to the substance, presumably in the homeostatic aspect of sleep-wake regulation.…

PMID: 31866308

Consuming coffee, a widely enjoyed beverage with caffeine, can impact the central nervous system and disturb sleep if taken too close to bedtime. Caffeine impacts sleep by slowing the onset, blocking adenosine receptors, lowering deep sleep levels, disrupting sleep patterns, and lessening rapid eye movement sleep. Although coffee can help with alertness in the morning, it may disturb sleep in the evening, particularly for individuals who are sensitive to caffeine. To enhance the quality of sleep, reduce the consumption of caffeine in the afternoon and evening, refrain from drinking caffeine before going to bed, and choose decaffeinated drinks instead. Variables such as personal reactions, ability to handle caffeine, and engagement with other compounds also influence the impact of coffee on sleep. Keeping track of how much caffeine you consume and your sleeping habits can assist in recognizing any disturbances and making needed changes. Furthermore, taking into account variables such as metabolism, age, and the timing of coffee consumption can assist in lessening the effects of coffee on sleep. In general, paying attention to the amount of caffeine consumed from different sources and consuming it at the right times can assist in preserving healthy sleep patterns even while enjoying coffee.…

PMID: 39168560

Caffeine is the world's most popular stimulant and is known to disrupt sleep. Administration of caffeine can therefore be used in healthy volunteers to mimic the effects of insomnia and thus to test the hypnotic effects of medication. This study assessed the effects of caffeine on sleep architecture and electroencephalography (EEG) spectrum alone and in combination with two different sleep-promoting medications. Home polysomnography was performed in 12 healthy male volunteers in a double-blind study whereby subjects received placebo, caffeine (150 mg), caffeine plus zolpidem (10 mg) and caffeine plus trazodone (100 mg) at bedtime in a randomised crossover design. In addition to delaying sleep onset, caffeine decreased total sleep time (TST), sleep efficiency (SE) and stage 2 sleep without significantly altering wake after sleep onset or the number of awakenings. Zolpidem attenuated the caffeine-induced decrease in SE and increased spindle density in the caffeine plus zolpidem combination compared with placebo. Trazodone attenuated the decrease in SE and TST, and it also increased stage 3 sleep, decreased the number of awakenings and decreased the spindle density. No significant changes in rapid eye movement (REM) sleep were observed, neither was any significant alteration in slow wave activity nor other EEG spectral measures, although the direction of change was similar to that previously reported for caffeine and appeared to 'normalise' after trazodone. These data suggest that caffeine mimics some, but not all of the sleep disruption seen in insomnia and that its disruptive effects are differentially attenuated by the actions of sleep-promoting compounds with distinct mechanisms of action.…

PMID: 19351801

There are large inter-individual differences in slow wave sleep, which constitute a trait or phenotype. We investigated whether the manifestation of this trait is impacted by daytime sleeping after sleep deprivation, and to what extent it is robust to prior caffeine intake. N = 12 subjects underwent three 48 h periods of total sleep deprivation with different caffeine dosing regimens. There were significant, considerable, and robust inter-individual differences in slow wave sleep across nighttime sleep opportunities before, and daytime sleep after, total sleep deprivation, regardless of caffeine dosing. The robustness of this phenotype may have functional implications for individuals in around-the-clock operational settings.…

PMID: 32954864