We ex ned effects of very low doses of melatonin (0.1-10 mg, orally) or placebo, administered at 1145 h, on sleep latency and dura , mood, pertormance, oral temperature, and chansIn serum m aI levels In 20 healthy male volunteers. A repeated-mea e doublind Latin square design was used. Subjects compleed a battery of tests designed to assess mood and performance between 0930 and 1730 h. The sedative-like effects of melatonin were ass by a simple sleep test: at 1330 h subjects were asked to hold a positie pressure switch in each hand and to relax with eyes cosed while reclining In a quiet darkened room. Latency and duration of switch release, indicators of sleep, were measured. Areas under the time-nelatonin concentration curve varied in proportion to the different meato doses ingested, and the 0.1-and 0.3-mg doses generated peak serum melatonin levels that were within the normal range of nocturnal melatonin levels in untreated people. All melatoin doses tested sgn tly increased sleep duration, as well as self-reported sleepiness and fatigne, relative to placebo. Moreover, all of the dose sigificantly decreased eep et latency, oral temperature, and the number of correct resses on the Wilkinson auditory vigilance task. These data indicate that oraily adm melatonin can be a highly potent hypnotic agent; they also suggest that the physiological increase in serum melatonin levels, which occurs around 2100 h daily, may constitute a signal initiating normal sleep onset.Serum melatonin levels in normal humans are very low during most ofthe day but increase significantly to a mean of 80 pg/ml (range, 0-200) between 0200 and 0400 h (1 pg/ml = 4.31 pmol/liter) and remain elevated during the normal hours of sleep, falling sharply to daytime values around 0900 h (1). The physiological significance of the nocturnal increase in serum melatonin could derive from acute effects of the hormone [e.g., its ability to reduce core body temperature (2), alter thermoregulation (3), modify brain levels of monoamine neurotransmitters (4), stimulate prolactin secretion (5), or induce sleepiness (6, 7) The present study was designed to determine whether much lower daytime doses, which elevate serum melatonin levels significantly but keep these levels within the normal nocturnal range, are also sufficient to produce short-term behavioral effects. If so, this would suggest a similar role for the normal nocturnal increase in serum melatonin levels. We gave the melatonin at midday (9 or more h before the nocturnal increase) and measured mood, performance, sleepiness, and (indirectly) sleep onset. METHODS AND MATERIAL

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 (k_a) of 1.72 h^-1 (half-life = 0.40 h) and an elimination constant (k_el) 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 hormone’s 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 melatonin’s administration, indicating that either approach can be used to estimate the absorption of orally administered melatonin.

Melatonin, the major hormone of the pineal gland, has antigonadotrophic activity in many mammals and may also be involved in human reproduction. Melatonin suppresses steroidogenesis by ovarian granulosa and luteal cells in vitro. To determine if melatonin is present in the human ovary, preovulatory follicular fluids (n = 32) from 15 women were assayed for melatonin by RIA after solvent extraction. The fluids were obtained by laparoscopy or sonographically controlled follicular puncture from infertile women undergoing in vitro fertilization and embryo transfer. All patients had received clomiphene citrate, human menopausal gonadotropin, and hCH to stimulate follicle formation. Blood samples were obtained by venipuncture 30 min or less after follicular aspiration. All of the follicular fluids contained melatonin, in concentrations [36.5 +/- 4.8 (+/- SEM) pg/mL] substantially higher than those in the corresponding serum (10.0 +/- 1.4 pg/mL). A positive correlation was found between follicular fluid and serum melatonin levels in each woman (r = 0.770; P less than 0.001). These observations indicate that preovulatory follicles contain substantial amounts of melatonin that may affect ovarian steroidogenesis.

We previously observed tht low oral doses of melatonin given at noon increase blood melatonin concentrations to those normally occurring nocturnally and facilitate sleep onset, as assessed using and 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.