Combing Ramelteon, a Sleep Aid, with MAOIs

Using Ramelteon (Rozerem), a sleep aid, with MAOIs

If you are a provider with an usual case to report and do not plan to write a case report, please send us the appropriate de-identified medical information so we may add it to our cases.

VERY IMPORTANT: These phenomena have NOT been written up into a case report that has meet the evidentiary standards for publication. We have chosen not to write case reports for our cases below for several reasons, including that although there is value in case reports, they may sometimes do more harm than good. [1] Therefore, any findings reported on this page should not be used to guide patient care nor be cited as evidence to support guidelines for patient care.

Ramelteon is a melatonin receptor agonist used as a relatively safe drug for insomnia. [2] In clinical studies, Ramelteon has been found to be 10 times more potent than melatonin and more effective at producing somnolence than melatonin. [3, 4] However, combinations of Ramelteon and a MAO inhibitor have not been reported in the literature to our knowledge. Given that insomnia is a common and significant, although typically short-lived, side effect of MAO inhibitors, consideration for the potential use of Ramelteon to assist with MAO inhibitor-induced insomnia is warranted. [5]

Ramelteon binds weakly to serotonin receptors (5-HT2B) and thus poses a theoretical, but unreported to our knowledge, risk of serotonin syndrome. [6, 7] We have safely used Ramelteon in over a dozen patients on MAO inhibitors, none of whom displayed symptoms of serotonin syndrome. Anecdotally, we have found Ramelteon may be effective option for patients with MAO inhibitor-induced insomnia who have reported at least partial benefit from melatonin.

Providers attempting to assess response to melatonin should be mindful of the potential mild hypotensive effects of melatonin which may augment the hypotensive effects of MAO inhibitors. [8] Although melatonin is known to be more effective in its sublingual than oral form, rapid surge in serum levels of melatonin may cause a more pronounced hypotensive effect although this has not been directly assessed to our knowledge. [9, 10] Ramelteon is rarely associated with a mild orthostatic hypotension effect. [11] Additionally, unlike melatonin, Ramelteon has rarely been associated with nightmares. [12, 13]

Citations

1. Nissen T, Wynn R. The clinical case report: a review of its merits and limitations. BMC Res Notes. 2014 Apr 23;7:264. doi: 10.1186/1756-0500-7-264. PMID: 24758689; PMCID: PMC4001358.

2. Simpson D, Curran MP. Ramelteon: a review of its use in insomnia. Drugs. 2008;68(13):1901-19. doi: 10.2165/00003495-200868130-00011. PMID: 18729542.
3. Neubauer DN. A review of ramelteon in the treatment of sleep disorders. Neuropsychiatr Dis Treat. 2008;4(1):69-79. doi:10.2147/ndt.s483
4. Hardeland R. New approaches in the management of insomnia: weighing the advantages of prolonged-release melatonin and synthetic melatoninergic agonists. Neuropsychiatr Dis Treat. 2009;5:341-354. doi:10.2147/ndt.s4234
5. Mayers AG, Baldwin DS. Antidepressants and their effect on sleep. Hum Psychopharmacol. 2005 Dec;20(8):533-59. doi: 10.1002/hup.726. PMID: 16229049.
6. Pandi-Perumal SR, Srinivasan V, Poeggeler B, Hardeland R, Cardinali DP. Drug Insight: the use of melatonergic agonists for the treatment of insomnia-focus on ramelteon. Nat Clin Pract Neurol. 2007 Apr;3(4):221-8. doi: 10.1038/ncpneuro0467. PMID: 17410109.
7. Laudon M, Frydman-Marom A. Therapeutic effects of melatonin receptor agonists on sleep and comorbid disorders. Int J Mol Sci. 2014;15(9):15924-15950. Published 2014 Sep 9. doi:10.3390/ijms150915924
8. Oxenkrug GF, McCauley RB, Fontana DJ, McIntyre IM, Commissaris RL. Possible melatonin involvement in the hypotensive effect of MAO inhibitors. J Neural Transm. 1986;66(3-4):271-80. doi: 10.1007/BF01260919. PMID: 3097249.
9. Jan JE, Freeman RD, Fast DK. Melatonin treatment of sleep-wake cycle disorders in children and adolescents. Dev Med Child Neurol. 1999 Jul;41(7):491-500. PMID: 10454235.
10. Gooneratne NS, Edwards AY, Zhou C, Cuellar N, Grandner MA, Barrett JS. Melatonin pharmacokinetics following two different oral surge-sustained release doses in older adults. J Pineal Res. 2012;52(4):437-445. doi:10.1111/j.1600-079X.2011.00958.x
11. Pandi-Perumal SR, Spence DW, Verster JC, et al. Pharmacotherapy of insomnia with ramelteon: safety, efficacy and clinical applications. J Cent Nerv Syst Dis. 2011;3:51-65. Published 2011 Apr 12. doi:10.4137/JCNSD.S1611
12. Guardiola-Lemaître B. Toxicology of melatonin. J Biol Rhythms. 1997 Dec;12(6):697-706. doi: 10.1177/074873049701200627. PMID: 9406047.
13. Shah C, Kablinger A. Ramelteon-induced nightmares: A case report. Asian J Psychiatr. 2015 Dec;18:111-2. doi: 10.1016/j.ajp.2015.09.004. Epub 2015 Sep 21. PMID: 26427581.