Harry J. Lynch

Bioavailability of Oral Melatonin in Humans

We administered crystalline melatonin (80 mg) in gelatin capsules to 5 young male volunteers and measured serum and urinary melatonin levels at intervals. Changes in serum melatonin levels were best described by a biexponential equation with an absorption constant (ka) of 1.72 h-1 (half-life = 0.40 h) and an elimination constant (ke1) of 0.87 h-1 (half-life = 0.80 h). Peak serum melatonin levels, ranging from 350 to 10,000 times those occurring physiologically at nighttime, were observed 60-150 min after its administration, remaining stable for approximately 1.5 h. The fraction of ingested melatonin that was absorbed, estimated from the area under the curve describing serum melatonin concentrations as a function of time after melatonin administration (the concentration-time curve), varied by 25-fold among subjects. 3 additional volunteers received three melatonin-containing capsules (80 mg each) at 60-min intervals. This regimen extended the duration of elevated serum melatonin levels to 4-6 h. Melatonin excretion closely paralleled serum melatonin levels until 9 h after the hormones administration, after which urinary levels tended to be higher than those predicted from serum levels. However, the area under the concentration-time curve for serum melatonin correlated well (r = 0.96) with the cumulative melatonin excretion during the initial 15 h after melatonins administration, indicating that either approach can be used to estimate the absorption of orally administered melatonin.

Sleep‐inducing effects of low doses of melatonin ingested in the evening

We previously observed that low oral doses of melatonin given at noon increase blood melatonin concentrations to those normally occurring nocturnally and facilitate sleep onset, as assessed using an involuntary muscle relaxation test. In this study we examined the induction of polysomnographically recorded sleep by similar doses given later in the evening, close to the times of endogenous melatonin release and habitual sleep onset. Volunteers received the hormone (oral doses of 0.3 or 1.0 mg) or placebo at 6, 8, or 9 PM. Latencies to sleep onset, to stage 2 sleep, and to rapid eye movement (REM) sleep were measured polysomnographically. Either dose given at any of the three time points decreased sleep onset latency and latency to stage 2 sleep. Melatonin did not suppress REM sleep or delay its onset. Most volunteers could clearly distinguish between the effects of melatonin and those of placebo when the hormone was tested at 6 or 8 PM. Neither melatonin dose induced “hangover” effects, as assessed with mood and performance tests administered on the morning after treatment. These data provide new evidence that nocturnal melatonin secretion may be involved in physiologic sleep onset and that exogenous melatonin may be useful in treating insomnia.

Effects of melatonin on human mood and performance

The function of melatonin, a hormone secreted by the pineal gland primarily at night, has not been definitively established in humans. To determine if pharmacologic doses of melatonin had any behavioral effects it was administered acutely to 14 healthy men. Their mood, performance, memory and visual sensitivity were assessed. Plasma melatonin concentration was assayed as well. Melatonin significantly decreased self-reported alertness and increased sleepiness as measured by the Profile of Mood States and the Stanford Sleepiness Scale self-report mood questionnaires. The effects were brief. Melatonin also affected performance, slowing choice-reaction time but concurrently decreasing errors of commission. Sustained fine motor performance was not impaired after melatonin administration nor were the tests of memory and visual sensitivity that were administered. It is concluded that melatonin, administered orally in pharmacological quantities, has significant but short acting sedative-like properties.

Effect of pharmacological daytime doses of melatonin on human mood and performance

Melatonin (10, 20, 40, or 80 mg, PO) or placebo was administered at 1145 hours on five separate occasions to 20 healthy male volunteers and the effects on serum melatonin levels, mood, performance, and oral temperature were monitored. Subjects were studied between 0930 and 1700 hours. A battery of interactive computer tasks designed to assess performance and mood was completed, oral temperature was measured, and blood samples were taken for serum melatonin radioimmunoassay. The areas under the time-melatonin concentration curve (AUC) varied significantly in proportion to the various melatonin doses. Compared with placebo treatment, all melatonin doses significantly decreased oral temperature, number of correct responses in auditory vigilance, response latency in reaction time, and self-reported vigor. Melatonin also increased self-reported fatigue, confusion, and sleepiness.

Urinary melatonin rhythms during sleep deprivation in depressed patients and normals

Abstract Melatonin excretion was measured in 8 hour urine aliquots for eight healthy controls and six depressed patients. Both groups had similar diurnal rhythms, with increased melatonin excretion during the night. When subjects were sleep deprived, remaining awake and active in continuous light from 7 a.m. one morning until 11 p.m. the following day, the diurnal rhythm in melatonin excretion remained unchanged. These data in man appear to be inconsistent with previous studies in rats showing rapid light-induced suppression of the nocturnal rise in pineal melatonin synthesis.

Entrainment of rhythmic melatonin secretion in man to a 12-hour phase shift in the light/dark cycle

Abstract Daily rhythms in melatonin secretion were monitored in four healthy adult males by measuring the melatonin contents of sequential 4-hour urine specimens and of plasma samples collected at 12-hour intervals, or, in one subject, continuously for 24 hours. All subjects exhibited similar diurnal rhythms, with peak urinary melatonin excretion rates and blood melatonin levels occurring during the daily period of darkness and sleep. When the daily light/dark regimen was phase-shifted by 180°, the plasma and urinary melatonin rhythms required 5–7 days (depending on the subject) to re-entrain to the new schedule. Simultaneous measurements of plasma melatonin levels and melatonin excretion rates indicate that urinary melatonin reflects, with remarkable fidelity, circulating melatonin levels.

A Pharmacological Dose of Melatonin Increases PRL Levels in Males without Altering Those of GH, LH, FSH, TSH, Testosterone or Cortisol

Since reports on the influence of melatonin (aMT) on the human endocrine system are scant and inconsistent, the effect of an acute, pharmacological dose of aMT on various hormone levels in healthy males was examined in 3 different experiments. Experiment I: 80 or 240 mg of crystalline aMT were administered per os to 8 volunteers. Before, during and after this treatment, serum levels of aMT, PRL, LH, FSH and testosterone were examined. Although aMT increased at least 1,500-fold over basal levels, only PRL was significantly and consistently elevated after aMT treatment, whereas serum levels of the other hormones were not altered. Experiment II: in 2 subjects, the pulsatile secretion pattern of LH was monitored for 6 h before and 6 h after aMT administration (240 mg p.o.). Neither the amplitude nor the frequency of LH pulses was influenced by the pineal hormone. Experiment III: in 14 volunteers, serum PRL, GH, TSH and cortisol concentrations were examined, once after oral administration of 240 mg aMT and once after placebo. Serum PRL levels were significantly higher after aMT than after placebo; GH showed a slight but not significant trend towards elevation after aMT, whereas other hormones were not altered. An acute pharmacological dose of aMT causes isolated elevation of serum PRL levels and may slightly increase GH. Hormones of the pituitary gonadal axis as well as TSH and cortisol are not altered by aMT.

Relationship between environmental light intensity and retina-mediated suppression of rat pineal serotonin-N-acetyl-transferase.

Abstract The dose-response relationship between intensity of ambient lighting and pineal biosynthetic activity was characterized by measuring serotonin-N-acetyl-transferase activity in pineals from rats exposed to strong light for two days, and then to darkness or to various light intensities for three hours. As little as 0.5 μwatts/cm2 caused a greater than 50% suppression of serotonin-N-acetyl-transferase activity; maximum inhibition was obtained with 15 μwatts/cm2.

Effects of illumination on human nocturnal serum melatonin levels and performance

In humans, exposure to bright light at night suppresses the normal nocturnal elevation in circulating melatonin. Oral administration of pharmacological doses of melatonin during the day, when melatonin levels are normally minimal, induces fatigue. To examine the relationship between illumination, human pineal function, and behavior, we monitored the overnight serum melatonin profiles and behavioral performance of 24 healthy male subjects. On each of three separate occasions subjects participated in 13.5 h (1630-0800 h) testing sessions. Each subject was assigned to an individually illuminated workstation that was maintained throughout the night at an illumination level of approximately 300, 1500, or 3000 lux. Melatonin levels were significantly diminished by light treatment, F(2, 36) = 12.77, p < 0.001, in a dose-dependent manner. Performance on vigilance, reaction time, and other tasks deteriorated throughout the night, consistent with known circadian variations in these parameters, but independent of ambient light intensity and circulating melatonin levels.

Light Intensity and the Control of Melatonin Secretion in Rats

The effect of varying ambient light intensity on the phase and amplitude of urinary melatonin rhythms was studied in rats housed individually in metabolism cages. For 17 days one group (D) was exposed to alternating 12-hour periods of dim light (0.1-0.3 micro/cm2) and total darkness; a second group (L) was exposed alternately to dim light and bright ligh (45-110 micro/cm2). All animals were then exposed to constant dim light for 15 days, after which they were returned to their original lighting regimens (D or L). 18 days later, half of each group was killed at the midpoint of the dim light phase, and the other half 12 h later. Both groups excreted melatonin rhythmically when exposed to daily cycles in light intensity; the L animals excreted 69% of the total daily melatonin output during the dim light phase and the D group of rats excreted 70% during the dark phase. When placed under continuous dim light, L animals continued to excrete melatonin as before, but D rats excreted significantly less, and the melatonin rhythm was dampened. When returned to a diurnal light cycle, both groups again exhibited rhythms in melatonin excretion that were entrained to the light cycle. Animals killed at the time of day coinciding with diminished melatonin excretion had lower pineal and serum melatonin levels (0.2 +/- 0.1 ng/pineal; 30 +/- 8 pg/ml serum) than those killed 12 h later (2.0 +/- 0.4 ng/pineal; 57 +/- 20 pg/ml serum). These observations provide additional evidence that measurement of urinary melatonin levels gives an accurate index of melatonin secretion from the rat pineal. They also show that a given light intensity presented for a part of the 24-hour day (e.g., dim light; 0.1-0.3 micro/cm2) can be interpreted by the mammalian pineal as light or dark, depending on the light intensity available during the rest of the day.