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; Daniel P Cardinali


Nat Clin Pract Neurol. 2007;3(4):221-228. 

In This Article

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.


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