The effects of melatonin on sleep onset are recognized but still poorly understood.

Research has shown that melatonin is involved in regulating the circadian rhythm. Its clinical use in several rhythm disorders is recognized, and it has a chronobiotic effect in advancing sleep onset. However, while melatonin treatments are popular and new prospects are posed by the release of ramelteon—a melatonin receptor selective agonist that may become a latest generation hypnotic—the use of melatonin in insomnia is controversial since the mechanisms involved are little known.

Melatonin is the main substance produced by the pineal gland, a small structure located between the cerebral hemispheres, in front of the cerebellum, in the postdorsal position of the diencephalon. Calcification of the pineal begins early in life, but there is no evidence of this process leading to degeneration of pinealocytes or diminished metabolic activity. Humans do, however, produce less melatonin with age, particularly women.¹

The main means of synthesizing melatonin is based on the retina’s exposure to light-dark cycles. Through the retinal-suprachiasmatic tract, light pulses reach the suprachiasmatic core of the hypothalamus, which acts as a clock regulating circadian rhythm synchronized with light. The stimuli then reach the paraventricular core of the hypothalamus, spinal cord, and superior cervical ganglion, and induce melatonin synthesis by stimulating a- and in particular b- noradrenergic receptors located in the pinealocytes of the pineal gland.²

The first step in the formation of melatonin is the pineal capturing tryptophane amino acid circulating in plasma, to be converted to 5-hydroxytryptophan, which is in turn decarboxylated to 5-hydroxytryptamine or serotonin (5-HT), the precursor of melatonin. Immediately after synthesis, melatonin, or N-acetyl-5 methoxytryptamine, is released into circulation and distributed through all organs. Serum levels of melatonin are low during the day and high during the night, peaking between 2 and 4 am, remaining high during the night and falling before dawn. The physiological significance of higher melatonin levels during the night is probably related to several effects, including lower temperature, altered cerebral monoamine levels, and inducing somnolence.³

Chronobiotic effects of melatonin
Melatonin is closely related to our light-dark rhythm and so to our arousal-sleep rhythm,⁴ thus providing for regular sleep schedules. The mechanism through which melatonin induces sleep is a matter for speculation. Some authors believe that it derives from higher indolamine levels at the beginning of the sleep period and suggest that endogenous melatonin is involved in regulating the arousal-sleep cycle leading to a cascade of events that may activate somnogenic structures, or that melatonin metabolites may have a hypnotic effect.⁵

There is a consensus in most studies of melatonin and sleep that melatonin leads to reduced sleep latency.⁶ Reid et al⁷ tested multiple sleep latencies and observed that administering 5 mg at 2 pm shortened sleep latency and decreased body temperature. Similar results were observed by Dollins et al³; using melatonin doses ranging from 0.1 to 10 mg administered at 11:45 pm, they observed reduced sleep latency and temperature and emphasized that effectiveness depended on replenishment of endogenous melatonin. This was confirmed by Zhdanova et al^8,9 administering 0.3 and 1.0 mg at 9 pm, 2 to 4 hours before beginning sleep. Nave et al¹⁰ administered 3 and 6 mg melatonin at 6 pm and 8 pm and observed reduced sleep latency with longer total sleep times, and volunteers reported deeper sleep. Neurophysiological studies have also shown that 5 mg of melatonin administered during the day increases somnolence and raises the theta/alpha fraction in electroencephalograms.¹¹ Tzischinsky and Lavie¹² found that the hypnotic effect of melatonin depended on the time of administration. They used 5 mg of melatonin at noon, 5 pm, 7 pm, and 9 pm in normal volunteers, after a night of sleep deprivation, and observed reduced high and increased lower frequencies (theta and delta), and the effect peaked 3:40 hours before the noon and 1 hour before the 9 pm administrations. Ferini-Strambi et al¹³ found that melatonin improved sleep quality and potentiated the effects of g-aminobutyric acid (GABA) and benzodiazepines.

Although most publications emphasize the effectiveness of melatonin in inducing sleep, some have observed different results. James et al¹⁴ found that melatonin did not affect sleep latency. Attenburrow et al¹⁵ found no differences in sleep latency after doses of 0.3 and 1.0 mg of melatonin administered 2 hours before bedtime. Some contradictory results suggest that the effects of melatonin depend partly on dosage, time of administration, levels of endogenous melatonin, age, normal or insomniac subjects, and even individual variations.¹⁶ Nave et al¹⁰ showed that 3.0 and 6.0 mg of melatonin administered 30 or 120 minutes before starting polysomnography had the effect of reducing sleep onset time.

Sleep Onset
Different criteria may be used to determine the point of sleep onset. In 1968, Rechtschaffen and Kales¹⁷ set the criterion for sleep latency as the interval between the beginning of the polysomnographic recording and the first three stage 1 periods or first stage 2 period of sleep. Webb¹⁸ suggested 5 uninterrupted minutes of sleep after the first stage 2 of sleep, while Carskadon and Rechtschaffen¹⁹ suggested the first 10 minutes of uninterrupted sleep.

The transition from arousal to sleep may be debatable or controversial when defined from the neurophysiological point of view alone. Sleep onset is an imprecise and continuous process that is best described as a sequence of interrelated events.

Timmons et al²⁰ found different phases of respiratory activity were related with stages of cerebral electrical activity. Sleep stage 1 corresponds to a reduction in the amplitude of thoracic and abdominal movements, whereas the amplitude of thoracic movements exceeds abdominal movements at the end of stage 1 and beginning of stage 2. Naifeh and Kamiya^21,22 reached similar conclusions on measuring alveolar carbon dioxide tension, and concluded that the sleep onset process is intrinsically associated with central neuronal mechanisms controlling breathing. Olgivie et al²³ described the arousal-sleep transition as a continuous process and suggested using the term “sleep onset period.”

In a recent study, we found that melatonin led to sounder sleep.²⁴ We studied normal volunteers who took 10 mg of melatonin an hour before bedtime and compared them with placebo volunteers. We observed the effects of melatonin on sleep onset and compared the use of two criteria: the Rechtschaffen and Kales (1968) criterion of 1.5 minutes in stage 1 after starting recording, and a second criterion of 10 minutes of uninterrupted sleep after beginning the test, translating more consolidated sleep. We found that volunteers who took melatonin were quicker to reach sleep onset understood as “10 minutes without interruption” but there was no alteration in sleep latency using the “1.5 minutes of sleep” criterion. Therefore, the sleep-inducing effect of melatonin may also depend on the sleep-onset concept used.

Therapeutic Effects of Melatonin
Therapeutic effects may be seen in some disorders of arousal-sleep rhythm in night-shift workers and particularly in the phase delay syndrome,⁴ in which some individuals tend to sleep late and wake late. The standard treatment for the phase delay syndrome is to set waking time in the morning and count back 8 hours to determine bedtime. Melatonin should be administered 3 hours before. The aim is to bring forward sleep onset. Patients keep a sleep journal and are advised to do physical activity in the morning on awakening (preferably in sunlight) to inhibit melatonin production. In contrary cases, of patients with early phases, melatonin should be administered in the morning. Melatonin may be useful in other rhythm disorders affecting shift workers or for jet lag.

Although melatonin advances sleep onset, its use in treating insomnia is controversial. Insomnia is not just a question of longer time in bed before sleep onset. This characteristic, when isolated, is present in a certain type of insomnia, denominated initial insomnia. Other mechanisms are involved in triggering most insomnia, such as multiple awakenings, difficulty in getting back to sleep, and particularly the misperception of sleep that these patients present to a varying extent.

On the basis of the mechanisms involved, melatonin may be effective only in initial insomnias and we do not yet know whether it affects all aspects of insomnia and if so in what way.²⁵ Insomniacs generally may present a reduced endogenous melatonin.²⁶ Melatonin may be beneficial for insomnia in seniors or patients that also present irregular arousal-sleep rhythms.²⁷ With zolpidem and valerian, melatonin may be used as an auxiliary method in withdrawing benzodiazepines from insomnia patients who are chronic users.²⁸

Some studies have shown that melatonin may not only reduce sleep latency but also improve sleep architecture. Dijk and Cajochen²⁹ observed that a 5 mg dose not only reduced sleep latency but also increased REM sleep and the amount of spindles. Kunz et al³⁰ also found higher percentages of REM sleep with 3 mg doses of melatonin administered from 22 to 23 hours for 4 weeks. Waldhouser et al⁵ observed that melatonin reduced sleep latency and nocturnal awakenings and heightened sleep efficiency. It also shortened sleep stage 1 and lengthened sleep stage 2.

Certain mental processes may also be affected by melatonin. Acupuncture, yoga, and meditation have been reported to boost melatonin secretion and have beneficial effects on insomnia and anxiety.^31,32 Crasson et al³³ observed that nocturnal peaking of melatonin secretion was retarded in depressed patients. They found that urinary 6-sulfatoxymelatonin was higher in the morning than at night. In seniors, melatonin may improve vestibular symptoms and cognitive deficits. Wu and Swaab³⁴ suggest that the use of melatonin and treatment with light may bring clinical improvement for Alzheimer disease patients.

Cohen and Kraube³⁵ suggest that melatonin may be involved in the genesis of basilar migraine and in hypnic headache and that these types of migraine may have to do with REM-sleep-related rhythm disruption. Michaud et al³⁶ found that melatonin inhibited production of dopamine and aggravated nocturnal restless limb syndrome. Other effects that have been attributed to melatonin include oncostatic, antioxidizing effects, and activating the immunological system, since melatonin seems to be produced by lymphoid cells as well as the pineal gland. Melatonin has also been suggested as an auxiliary medicine for the treatment of epilepsy. Although much has been published, particularly in recent years, the clinical use of melatonin in the different fields of medicine is still controversial.

Comprehensive knowledge of the metabolism of melatonin and its effects on sleep has prompted research into the synthesis of pharmaceutical products for treating insomnia. Reduced sleep latency, both objective and subjective, was obtained on administering beta-methyl-6-chloromelatonin, a melatonin receptor agonist.³⁷ New prospects for pharmacological treatment of insomnia may well derive from the use of ramelteon, a selective agonist of MT1 and MT2 receptors,³⁸ thus placing melatonin, its agonists, and derivates alongside latest generation hypnotics.

Luciano Ribeiro Pinto, Jr, MD, PhD, is a professor of sleep medicine, and Sérgio Tufik, MD, PhD, is a professor and director of a sleep institute, both at the Universidade Federal de São Paulo, Brazil. Tufik is president of the Federation of Latin American Sleep Societies (FLASS) and the past president of the Sociedade Brasileira de Sono (SBS).

Acknowledgements
This work was supported by Associação Fundo Incentivo Psicofarmacologia (AFIP).

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