Ramelteon, sold under the brand name Rozerem among others, is a melatonin agonist medication which is used in the treatment of insomnia.
[3][5] It is indicated specifically for the treatment of insomnia characterized by difficulties with sleep onset.
[3] Side effects of ramelteon include somnolence, dizziness, fatigue, nausea, exacerbated insomnia, and changes in hormone levels.
[7] Ramelteon is not a benzodiazepine or Z-drug and does not interact with GABA receptors, instead having a distinct mechanism of action.
[10] Unlike certain other sleep medications, ramelteon is not a controlled substance in nearly every country and has no known potential for misuse.
[3] Ramelteon is approved for the treatment of insomnia characterized by difficulty with sleep onset in adults.
[3][5] In regulatory clinical trials, it was found to significantly reduce latency to persistent sleep (LPS).
[3] A 2009 pooled analysis of four clinical trials found that ramelteon at a dose of 8 mg reduced sleep onset by 13 minutes (30% decrease) relative to placebo on the first and second nights of use.
[11] Subsequent meta-analyses of longer-duration use have found that ramelteon decreases subjective sleep latency by about 4 to 7 minutes.
[8] The American Academy of Sleep Medicine's 2017 clinical practice guidelines recommended the use of ramelteon in the treatment of sleep-onset insomnia.
[16] A systematic review, published in 2014, concluded "ramelteon was found to be beneficial in preventing delirium in medically ill individuals when compared to placebo.
[18] Ramelteon has received attention in psychiatry as a possible add-on treatment for mania in bipolar disorder.
[3] The withdrawal and rebound insomnia that is typical with GABAA receptor positive modulators like benzodiazepines and Z-drugs is not present in ramelteon.
[3] Ramelteon has been evaluated for potential drug interactions with the following medications and showed no significant effects: omeprazole, theophylline, dextromethorphan, and midazolam, digoxin and warfarin.
[medical citation needed] A drug interaction study showed that there were no clinically meaningful effects or an increase in adverse events when ramelteon and the SSRI Prozac (fluoxetine) were coadministered.
[8][23] Remelteon has a clinically irrelevant affinity for the serotonin 5-HT1A receptor (Ki = 5.6 μM).
[medical citation needed] The activity of ramelteon at the MT1 and MT2 receptors in the suprachiasmatic nucleus of the hypothalamus is believed to contribute to its sleep-promoting properties, as these receptors, acted upon by endogenous melatonin, are thought to be involved in the maintenance of the circadian rhythm underlying the normal sleep–wake cycle.
[3][7] The half-lives of ramelteon and M-II are substantially longer than that of melatonin, which has a half-life in the range of 20 to 45 minutes.
[19] Nonetheless, meta-analytic evidence is based on very few trials and does not allow supporting the use of melatonin receptor agonists as adjunctive options for mania in clinical practice, although the small sample size do not allow ruling out their beneficial effect.