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

Nature Clinical Practice Neurology volume 3, pages 221–228 (2007)Cite this article

Abstract

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.

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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Figure 1: Chemical structures of melatonin and ramelteon

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Author information

Authors and Affiliations

  1. Department of Pulmonary, SR Pandi-Perumal is based at the Comprehensive Center for Sleep Disorders, Critical Care, and Sleep Medicine, Mount Sinai School of Medicine, New York, NY, USA.,

    Seithikurippu R Pandi-Perumal

  2. V Srinivasan is an Associate Professor in the Department of Physiology, School of Medical Sciences, University Sains Malaysia, Kota Bharu, Kelatan, Malaysia.,

    Venkataramanujan Srinivasan

  3. B Poeggeler is a Researcher, and R Hardeland is Professor of Zoology, at the Georg August University Göttingen, Germany.,

    Burkhard Poeggeler & Rüdiger Hardeland

  4. DP Cardinali is Professor of Physiology and Director of the Neuroscience Laboratory, Faculty of Medicine, University of Buenos Aires, Argentina.,

    Daniel P Cardinali

Authors
  1. Seithikurippu R Pandi-Perumal
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  3. Burkhard Poeggeler
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Correspondence to Seithikurippu R Pandi-Perumal.

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Pandi-Perumal, S., Srinivasan, V., Poeggeler, B. et al. Drug Insight: the use of melatonergic agonists for the treatment of insomnia—focus on ramelteon. Nat Rev Neurol 3, 221–228 (2007). https://doi.org/10.1038/ncpneuro0467

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  • DOI: https://doi.org/10.1038/ncpneuro0467

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