Review

Nature Clinical Practice Neurology (2007) 3, 221-228
doi:10.1038/ncpneuro0467  
Received 31 October 2006 | Accepted 30 January 2007

Drug Insight: the use of melatonergic agonists for the treatment of insomnia—focus on ramelteon

Seithikurippu R Pandi-Perumal*, Venkataramanujan Srinivasan, Burkhard Poeggeler, Rüdiger Hardeland and Daniel P Cardinali  About the authors

Correspondence *Comprehensive Center for Sleep Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Mount Sinai School of Medicine, 1176 5th Avenue, New York, NY 10029, USA

Email pandiperumal@gmail.com

Summary

Melatonin, a chronobiotic that participates in the control of the circadian system, is known for its sleep-promoting effects, which include shortening of sleep latency and lengthening of sleep duration. As a result of its short half-life, melatonin does not exhibit undesirable side effects, and its broad applicability for a variety of sleep problems has been the focus of numerous scientific studies. Melatonin has not, however, received regulatory approval from the US FDA as a drug, because it can be sold freely as a food supplement. Consequently, there has been an active search for patentable melatonin receptor ligands in recent years. Ramelteon, an agonist that acts solely on melatonin MT1 and MT2 receptors, is of particular interest, and preliminary research indicates that it holds considerable promise for clinical applications. Ramelteon has been shown to induce sleep initiation and maintenance in various animal models and in clinical trials. In chronic insomnia, ramelteon decreases sleep latency and increases total sleep time and sleep efficiency, without causing hangover, addiction or withdrawal effects. Ramelteon is thought to promote sleep by influencing homeostatic sleep signaling mediated by the suprachiasmatic nucleus. Although ramelteon's metabolism and pharmacokinetics differ from those of melatonin, its safety seems to be sufficient for short-term application. Its long-term effects remain to be determined.

Review criteria

PubMed was searched using Entrez for articles published up to 1 December 2006, including electronic early-release publications. Search terms included "ramelteon" and "melatonin". Full publications were obtained and references were checked for additional material where appropriate.

Keywords:

circadian rhythms, insomnia, melatonin, ramelteon, sleep

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Introduction

The natural compound melatonin promotes sleep by aiding its initiation and maintenance. Additionally, among numerous other actions, melatonin makes an important contribution to the regulation of the body's circadian rhythms.1, 2 In its role as a hormone of the pineal gland (it is also produced in other organs), melatonin is released into the circulation and is distributed throughout the body. It is also released directly into the cerebrospinal fluid, via the pineal recess, where it attains concentrations that are considerably higher than those reached in serum.3

Physiologically, melatonin has important chronobiological effects, including sleep-promoting actions, which are mediated through specific receptors located in the major circadian pacemaker, the suprachiasmatic nucleus (SCN).4 These effects are distinct from those that result from the introduction of supraphysiological amounts of melatonin from exogenous sources, some of which are not receptor-mediated and involve metabolism, either in terms of formation of new bioactive compounds or interactions with free radicals.1, 2

Melatonin has been used successfully in the treatment of insomnia in older individuals,5, 6, 7 in circadian rhythm sleep disorders—in particular, delayed sleep phase syndrome8, 9, 10—and in sleep disorders in children with various neurologic diseases.11, 12, 13 Studies of the effects of melatonin on decreasing sleep latency and on total sleep have not always produced consistent results, however, with some investigators reporting an absence of effects.14, 15 This lack of effect has been attributed mainly to the short half-life of melatonin. In addition, melatonin has not received approval from the US FDA because of regulations allowing it to be sold freely as a food supplement, and its status as a nonpatentable agent means that it has been of limited interest to the pharmaceutical industry.

In view of the fact that melatonin promotes and synchronizes sleep by acting on SCN melatonin MT1 and MT2 receptors, respectively, it has been suggested that synthesized melatonin receptor agonists with a longer duration of action might have significant clinical value for the treatment of patients with insomnia. Consequently, several melatonin receptor agonists have now been developed and tested in humans,16, 17, 18 including the nonselective MT1/MT2 agonist ramelteon, which was recently approved by the FDA for use as a hypnotic.

This Review summarizes the pharmacology and metabolism of ramelteon, with reference to current knowledge regarding the role of melatonin in sleep regulation. We discuss the actions of ramelteon in animal models, the clinical studies that support its efficacy in patients with insomnia, and the possible mechanism of action, safety, and adverse effects of this new drug.

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Melatonin and sleep regulation

Melatonin secretion not only correlates with the timing of sleep, but also participates in sleep regulation through actions exerted on the SCN.19 Neurons in the SCN express MT1 and MT2 melatonin receptors, which have different functional roles.20 Melatonin causes acute inhibition of electrical activity in SCN neurons via MT1 receptors, as shown in transgenic mice not expressing these receptors; the phase-shifting effect of melatonin was found to persist in animals in which expression of MT2 receptors was normal.21 From this and other studies, it has become clear that whereas SCN MT1 receptors mediate the inhibitory effects of melatonin, MT2-expressing neurons are essential for melatonin's rhythm-regulatory effect.21, 22

A reduction in sleep onset latency is the most consistently reported effect of melatonin administration.23, 24, 25, 26 There is evidence that exogenous melatonin treatment of sleep disorders is most effective in cases in which physiological melatonin production is deficient.6 Considerable improvements in sleep maintenance and duration have been obtained by using slow-release tablets of melatonin, a treatment that has also been found to reduce sleep latency.27 Serum melatonin has a very short half-life (approx20 min), and slow-release preparations can extend the period of elevated serum levels to 5–7 hours.27

A recent meta-analysis of the effects of melatonin in sleep disturbances, which included all age-groups (and presumably individuals with normal melatonin levels), failed to document clinically meaningful effects of exogenous melatonin on sleep quality, efficiency or latency.15 The studies reviewed had a significant heterogeneity index and a low-quality size-effect estimation (indicated by the wide 95% confidence intervals reported). Additionally, the reviewed papers showed notable variations in the route of administration of melatonin, the dose administered and the way in which outcomes were measured, and consequently the findings were difficult to interpret.15

By contrast, another meta-analysis that comprised 17 studies involving a total of 284 subjects, most of whom were older, concluded that melatonin was effective in increasing sleep efficiency and reducing sleep onset time.28 The authors of this meta-analysis proposed the utility of exogenous melatonin treatment for insomnia, particularly in aged individuals with nocturnal melatonin deficiency.

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Ramelteon, a melatonergic agonist to treat insomnia

Ramelteon (Rozerem® [Takeda Pharmaceutical Company Ltd., Osaka, Japan]; TAK-375), a tricyclic synthetic analog of melatonin with the chemical name (S)-N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propionamide (Figure 1), was approved by the FDA in July 2005 for the treatment of insomnia. Unlike other clinically relevant melatonergic agonists, such as agomelatine, ramelteon is a specific agonist that acts via MT1 and MT2 receptors without any known significant interference with other receptor systems.29, 30, 31, 32, 33, 34 According to the National Pharmacy Benefits Management Drug Monograph,35 ramelteon has no relevant affinity for the gamma-aminobutyric acid (GABA) receptor complex, or for any other receptor that binds dopamine, norepinephrine, acetylcholine, opiates or neuropeptides. Ramelteon has a very low affinity for the serotonin (5-hydroxytryptamine or 5-HT) receptor 5-HT1A (Ki = 5.6 microM),34 and the drug does not reach this concentration at clinically useful doses, so any possible interaction of ramelteon with the serotonergic system can be ruled out. Ramelteon can, therefore, be considered to act exclusively on melatonergic membrane receptors, even though it does not exhibit receptor subtype selectivity. With regard to melatonin's other molecular or non-receptor-mediated effects (e.g. antioxidant activity),2 it is presumed that these properties will not apply to ramelteon, in view of its modified indolic ring (Figure 1). The extent to which this should be considered to be an advantage or disadvantage of ramelteon, as compared with melatonin, remains to be determined.


Pharmacology and metabolism

Ramelteon, which is usually administered at a dose of 8 mg orally, is rapidly absorbed by the body and reaches peak serum concentrations of 5,700 pg/ml within 0.5–1.5 h.33 At 1.5 h, serum concentrations resulting from a comparable dose of melatonin would have decreased from peak value to less than 1,000 pg/ml.36 In serum, 82% of the ramelteon is bound to plasma proteins and, like melatonin, 70% of circulating ramelteon is bound to plasma albumin. Ramelteon doses of between 4 mg and 64 mg have been tested in humans.33 The absorption of orally administered ramelteon is at least 84%, but the absolute bioavailability is only about 1.8% because of extensive first-pass metabolism, and also, presumably, because of uptake by tissues. Intravenously administered ramelteon has been shown to reach a distribution volume of 73.6 l. Ramelteon's unique molecular structure—a propionyl group instead of an acetyl group, two hydrocarbon groups in a furan ring instead of a methoxy group, and its lack of nitrogen in the 5-atom ring (Figure 1)—are factors that particularly facilitate its tissue distribution. Compared with melatonin, which itself enters tissues with ease, ramelteon has even greater lipophilicity, and consequently superior penetration and absorption into tissue. The half-life of circulating ramelteon is in the range of 1–2 h, depending on the dose,33 which is considerably longer than that of melatonin. This might be regarded as a decisive advantage for use of ramelteon as a sleep promoter, because the relatively poor efficiency of melatonin in supporting sleep maintenance is presumed to result from its rapid decay.

The metabolism and oxidation chemistry of ramelteon are entirely different from those of melatonin. Although ramelteon and melatonin are both substrates of hepatic cytochrome P450 (CYP) monooxygenases—mainly CYP1A2 and, to a minor extent, CYP2C subforms and CYP3A4—the sites of oxidation of ramelteon are different to those of the melatonin molecule.

Four metabolites of ramelteon have been identified: M-I, M-II, M-III and M-IV.33 Of these, only M-II can be explained by a single enzymatic hydroxylation step. This compound, which represents the major metabolite, carries a hydroxyl group at the C2 position of the propionyl residue.

Metabolite M-I is formed by cleavage of the furan ring, which leads to replacement of the oxygen atom with a hydroxyl group. Ring cleavage takes place through formation of a carboxyl group, reminiscent of a dioxygenation step, so it remains to be determined whether such a reaction can be attributed to CYP activity.

The metabolites M-III and M-IV each carry a carbonyl group in a position that would be impossible for melatonin, because the relevant carbon atom in ramelteon corresponds to the indolic nitrogen atom in melatonin. Again, the introduction of the carbonyl group cannot be explained by a single hydroxylation step, but requires an additional oxidation. It might be assumed that the monohydroxylated indene formed by CYP is a reactive intermediate that readily undergoes further oxidation. The possible significance of a reactive intermediate has, however, never been addressed or discussed, either in pharmacological or toxicological terms. Metabolite M-IV differs from M-III by the presence of an aliphatic hydroxyl group similar to that of M-II, and it might be formed from either M-II or M-III.33

The M-II metabolite of ramelteon exerts selective actions on MT1 and MT2 receptors, as does the parent compound, but it is only about 10% as potent as ramelteon itself. The affinity of M-II for the melatonin receptors is not surprising given its similarity to ramelteon. M-II circulates at much higher concentrations than does ramelteon, however, resulting in a 20–100-fold greater mean systemic exposure, so it is likely to contribute to ramelteon's biological effects.33

Ramelteon is less rapidly eliminated than is melatonin, but it is still eliminated at a sufficient rate to avoid accumulation. Radiolabeling of ramelteon has revealed that less than 0.1% of the drug is excreted nonmetabolized; 84% of radioactivity appears in the urine and 4% in the feces. Total elimination is completed within 96 h. It should be noted that the half-life of M-II is 2–5 h longer than that of the parent compound.33

As ramelteon is metabolized by CYP1A2, drugs that inhibit this enzyme can considerably increase the levels of the agonist. Consequently, ramelteon should not be used in combination with fluvoxamine, ciprofloxacin, mexiletine, norfloxacin, tacrine or zileuton.34 Substantial increases in ramelteon levels were also observed when it was administered with the CYP2C9 inhibitor fluconazole and the CYP3A4 inhibitor ketoconazole, whereas compounds affecting various other P450 enzymes did not produce meaningful changes. The CYP inducer rifampin caused considerable decreases in levels of both ramelteon and its metabolite M-II. To avoid loss of efficacy, this and other strong upregulators of relevant CYP enzymes should be avoided.

Actions in animal models

In a study of freely moving cats involving electroencephalogram (EEG), electromyogram and electro-oculogram recordings, ramelteon in doses of 0.001, 0.01 and 0.1 mg/kg body weight increased slow-wave sleep and decreased wakefulness.37 The 0.1 mg/kg dose increased rapid eye movement sleep when compared with vehicle controls. Ramelteon was found to be more effective than exogenous melatonin in promoting and maintaining sleep. Ramelteon had no negative influence on motor performance of mice, as tested by rotarod.38 It has also been shown to be effective in re-entraining the circadian rhythm of rats,39 an effect that should be expected with an MT2 agonist, thereby confirming its action on the circadian pacemaker.

In a study of nocturnal sleep in freely moving monkeys (adult female Macaca fascicularis), the effects of ramelteon, melatonin and zolpidem were compared.29 Sleep parameters were recorded by EEG, using implanted electrodes, and further analyzed by fast Fourier transform and power spectra. Treatment with ramelteon (0.03 mg/kg or 0.3 mg/kg, administered orally) significantly shortened sleep onset latency and increased total duration of sleep.29 The effect was found to be superior to that of melatonin. Spectral analyses of EEG recordings revealed that the sleep patterns after treatment with either ramelteon or melatonin were indistinguishable from those of naturally occurring physiological sleep. Neither ramelteon nor melatonin affected the general behavior of the monkeys even at very high doses, whereas the highest dose of zolpidem induced apparent sedation, muscle relaxation and a moderate increase in slow-wave sleep.29

The physical dependence potential of ramelteon was further evaluated in another study undertaken in a different but related monkey species (Macaca mulatta).40 In this investigation the monkeys received ramelteon at 10 mg/kg body weight daily for 1 year. These animals showed no signs of abnormal behavior, abnormal pharmacokinetics, or alterations in operant behavior related to intermittent discontinuation of ramelteon treatment, indicating that ramelteon does not produce physical dependence, or clinical or behavioral alterations associated with withdrawal.40 These findings are important because they demonstrate that ramelteon is unlikely to have the abuse or dependence potential that is associated with benzodiazepines. This is a considerable advantage, as benzodiazepine dependency remains a significant worry for prescribing physicians worldwide.

Clinical studies

In a clinical trial of 107 patients with insomnia (mean age 37.7 years), ramelteon was administered in a variety of doses ranging from 4 mg to 32 mg.41 The drug was given 30 min before habitual bedtime and sleep was monitored polysomnographically for 8 h. Ramelteon at all doses significantly reduced sleep latency by 13 min and increased total sleep time by 12 min. No residual next-day hangover effects were noted.41

Similar results were obtained in a larger trial of 375 patients aged 35–60 years, who were given 16 mg or 64 mg of ramelteon daily.31 Sleep latency was reduced by 9–10 min, and total sleep time was increased by 11–14 min. The higher doses did not result in larger improvements. No withdrawal effects or rebound insomnia were noted.

In a randomized double-blind placebo-controlled study involving 829 elderly patients with insomnia (341 men and 488 women; ages 64–93 years), ramelteon in doses of either 4 mg or 8 mg was given at night for 5 weeks.32 Patients reported reductions in sleep latency and increases in total sleep time. Ramelteon produced approximately 13–29 min reductions in sleep latency. This effect was demonstrated from the first week onwards, and became increasingly more pronounced until week 5. These findings were similar for both dosage regimens of ramelteon. The total sleep time among elderly insomniacs was greater than the total sleep time of control subjects. The increase in dosage from 4 mg to 8 mg, however, did not significantly increase total sleep time.32 The drug did not cause any rebound insomnia or withdrawal effects. A noteworthy and clinically important finding was that ramelteon use was associated with reductions in sleep latency even during the week following treatment discontinuation, demonstrating that, unlike benzodiazepines, which tend to produce rebound insomnia and other withdrawal symptoms, the normalizing effects of ramelteon therapy might not be dependent on continued use of the drug.

Possible mechanisms of sleep control by ramelteon

The lack of rebound insomnia and withdrawal effects of ramelteon can be attributed to its mechanism of action.31 In view of the fact that ramelteon binds to MT1 and MT2 receptors without significant interaction with other CNS binding sites such as GABA-benzodiazepine, opioid, muscarinic, serotonin or dopamine receptors, its limited side effect profile is not surprising. Ramelteon's highly specific receptor agonist action and relative freedom from noteworthy side effects make it unique among all other hypnotics. Clinical evidence indicating that ramelteon does not alter sleep architecture and tends to be well tolerated is consistent with knowledge of its pharmacokinetic activity.41

MT1 and MT2 melatonin receptors are present in particularly high densities in the SCN.42 Nevertheless, the SCN is not the only site where melatonin receptors are found, and in view of the fact that sleep is not exclusively under circadian control, but is also influenced by factors such as fever, hypothermia and infections, one question that remains to be answered is whether ramelteon also acts as a chronobiotic. Indeed, ramelteon's ability to promote phase shifting—a capability that can be attributed to its action on the MT2 receptor—has been demonstrated in animals.39

The role of the SCN in the control of sleep was first indicated by the study of Edgar and co-workers on diurnally active squirrel monkeys.43 In monkeys with SCN lesions, consolidated sleep and wake periods were abolished and the animals slept more. On the basis of these findings, it was proposed that the circadian signal arising from the SCN promotes wakefulness during the day as well as consolidating sleep during the night.43

Activation of SCN MT1 receptors might attenuate the circadian wake-promoting signal, thereby prolonging the homeostatic mechanisms that underpin the sleep process. This suggestion assumes that the principal effect of MT1 receptor activation is to suppress neuronal firing in the SCN, and that phase effects make only a minor contribution to the process.21, 22 MT1 stimulation inhibits neuronal firing in the SCN of both diurnal and nocturnal animals, but suppression of wakefulness via MT1 can only take place in diurnally active species, such as primates.44

A reduction in sleep onset latency can be interpreted in various ways. In the case of melatonin, some investigators have implicated hypothermia in this process,45, 46, 47, 48 although hypothermia, in addition to circadian phasing of core body temperature, is only seen at high, pharmacological doses (e.g. 3 mg).34 It is still unknown whether ramelteon induces hypothermia. In view of the fact that the production of hypothermia via 5-HT1A receptors is potentiated by melatonin,49 it might be inferred that ramelteon has a similar action, although ramelteon's weak affinity for this 5-HT receptor subclass argues against the possibility (Ki of ramelteon for 5HT1A receptor in a competition experiment: 5.6 microM; maximal serum concentrations after 8 mg dose: approx6 ng/ml,33 slightly above 0.02 microM).

Another possible explanation for reduced sleep onset latency can be deduced from the sleep-switch model.44 This model, which is physiologically and anatomically well founded,50, 51 describes mutual inhibitions among sleep-associated activities in the hypothalamic ventrolateral preoptic nucleus and wakefulness-associated activities in locus coeruleus, dorsal raphe and tuberomammillary nuclei, a system capable of changing in a flip-flop manner.44 The SCN can influence both of these subsystems through projections via the ventral subparaventricular zone to the hypothalamic dorsomedial nucleus, from where numerous circadian functions are regulated. Projections from the dorsomedial nucleus to the ventrolateral preoptic nucleus induce sleep, whereas projections to the lateral hypothalamus are associated with activities displayed in the state of wakefulness. Both melatonin and ramelteon should be capable of influencing the switch and accelerating sleep onset via MT1 and MT2 receptors in the SCN. Whether such melatonergic actions would also support sleep maintenance is not known. This would depend on receptor availability throughout the sleep period; that is, it might be a question of duration and extent of receptor desensitization and internalization. In this respect, ramelteon's affinity for MT1 and MT2 receptors is greater than that of melatonin. Plasma levels of ramelteon after the recommended 8 mg dose are greater and longer lasting than those of melatonin. Consequently, ramelteon seems more likely to desensitize MT1 and MT2 receptors than is melatonin itself.34 More information is required concerning receptor downregulation by ramelteon.

Safety and adverse effects

According to information provided by Takeda, the FDA and several publications,41, 52 the safety of ramelteon is similar to that of placebo in all doses studied. The incidence of treatment of emerging adverse events has ranged from 8.4% to 10.7% among the ramelteon dose groups, compared with 8.7% in a placebo group. The commonly noted adverse effects with ramelteon include headache, somnolence and sore throat. Although infrequent, some serious adverse effects noted with ramelteon have included decreased libido, galactorrhea, nipple discharge, amenorrhea, extreme fatigue, sleepiness, nausea and depression.41, 52

In comparison to the safety of other newly introduced drugs, ramelteon seems to be well tolerated, at least during short-term treatment. Although the extent and duration of melatonin receptor desensitization following ramelteon therapy are unknown, these effects are probably limited, as clinical studies have shown no next-day hangover, withdrawal symptoms, or rebound insomnia with ramelteon.31, 32

Toxicological data have been sufficient for FDA approval of ramelteon in the US. Interference with other drugs—in particular, those changing CYP activities—and precautions concerning the use of alcohol, high-fat meals, hepatic and renal impairment, and pregnancy have been documented.34, 41, 52

One final point of concern relates to the possible mutagenic and carcinogenic potential of ramelteon. According to the information provided by Takeda,53 the no-effect level for induction of hepatic tumors in male mice was only three times the concentration of the metabolite M-II measured after the therapeutic dose. Moreover, micronuclei formations were observed in Chinese hamster lung cells after metabolic activation.53 The same information sheet mentions that there was no mutagenicity observed in the Ames test, but does not refer in this case to metabolic activation, which should also be routinely assessed with this assay. It seems advisable that toxicity studies of ramelteon and its metabolites should be continued, particularly of M-II, which attains concentrations more than an order of magnitude higher than the parent compound and which is much more slowly removed from the circulation.33

In summary, the suitability of ramelteon for long-term treatment requires further substantiation. With good reason, Wurtman has critically noted the paucity of available information on extended treatment with ramelteon.34 For the present, this drug should be prescribed cautiously and only for short-term treatment.

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Conclusions and perspectives

What is the advantage of ramelteon over the natural MT1/MT2 ligand, melatonin? Melatonin promotes both sleep onset and sleep maintenance, even at physiologic doses (0.1–0.3 mg). This range is much lower than the recommended dose for ramelteon (8 mg). As ramelteon has a higher affinity for MT1 and MT2 receptors than does the natural ligand, and as it acts for longer, the efficiency of ramelteon would be expected to be higher than that of melatonin at a comparable dosage. It remains to be clarified, however, whether low doses of ramelteon have hypnotic properties, in view of the possible long-term desensitization of melatonin receptors occurring after supraphysiological exposure to agonists.34

It must be noted that neither melatonin nor ramelteon are selective agonists for either of the two membrane melatonin receptors present in humans (MT1 and MT2). Selective binding could potentially give a synthetic agonist advantages over melatonin or ramelteon by activating some but not all of the targets of the natural compound. This is an important goal in the development of the next generation of melatonin receptor agonists.54

Another practical—although somewhat banal—advantage of ramelteon over melatonin is the fact that melatonin has not yet obtained regulatory approval to be marketed as a drug in the US. It should be pointed out that this is not related to any significant potential disadvantage in melatonin's actions or lack of data on its efficacy or safety, but to the regulations that allow this hormone to be sold freely as a food supplement. This makes melatonin nonpatentable and, therefore, nonprofitable for the pharmaceutical companies.

Ramelteon, as the first approved melatonergic drug for treatment of insomnia, seems to be safe for short-term treatment. A major question for future scientific investigation is whether ramelteon is safe for extended therapeutic use. Moreover, its applicability in older individuals, including those with age-related diseases, requires further investigation in our opinion. In this context, we would like to draw attention to the fact that MT1 and MT2 receptors are not only present in the SCN, but are widely distributed throughout the body. It seems important to know the consequences of desensitization of these receptors in the cerebral vascular system, in leukocytes and in peripheral organs, especially if ramelteon causes longer lasting receptor downregulation compared with melatonin. These consequences might particularly concern cerebral vascular tone and immune function, especially in elderly people following long-term application. There is clearly an urgent need for a timely investigation of these issues.

Key points

  • Ramelteon acts as an MT1 and MT2 melatonin receptor agonist, showing higher affinities for these receptors than does the natural ligand
  • Ramelteon induces sleep initiation and maintenance, as demonstrated in animal models and clinical trials
  • Ramelteon is efficient in treating chronic insomnia, without causing addiction, hangover or withdrawal effects
  • Ramelteon is assumed to promote sleep efficacy by influencing homeostatic as well as chronobiotic sleep regulation
  • A major metabolite of ramelteon, which accumulates to levels 10-fold higher than the parent drug, contributes to the drug's effects
  • Safety of ramelteon seems to be sufficient after short-term administration, but long-term treatment of elderly or unwell individuals requires further study

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Competing interests

The authors declared no competing interests.

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Subject areas under which this article appears: Sleep