{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T13:09:55Z","timestamp":1793106595970,"version":"4.5.0"},"reference-count":226,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2025,9,19]],"date-time":"2025-09-19T00:00:00Z","timestamp":1758240000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Insomnia is a common and complex disorder, rooted in the dysregulation of circadian rhythms, impaired neurotransmitter function, and disturbances in sleep\u2013wake homeostasis. While conventional hypnotics such as benzodiazepines and Z-drugs are effective in the short term, their use is limited by a high potential for dependence, cognitive side effects, and withdrawal symptoms. In contrast, melatonergic receptor agonists\u2014melatonin, ramelteon, tasimelteon, and agomelatine\u2014represent a pharmacologically targeted alternative that modulates MT1 and MT2 receptors, which are pivotal to the regulation of circadian timing and sleep initiation. Clinical evidence supports the efficacy of these agents in reducing sleep onset latency, extending total sleep duration, and re-aligning disrupted circadian rhythms, particularly among older individuals and patients with non-24 h sleep\u2013wake disorders. Notably, agomelatine offers additional antidepressant properties through selective antagonism of the 5-HT2C receptor in micromolar concentrations. In contrast, its agonistic activity at melatonergic receptors is observed in the low sub-nanomolar range, which illustrates the complexity of this drug\u2019s interactions with the human body. All compounds reviewed demonstrate a generally favorable safety and tolerability profile. Accumulating evidence highlights that selected medicinal plants, such as chamomilla, lemon balm, black cumin, valeriana, passionflower and lavender, may exert relevant hypnotic or anxiolytic effects, thus complementing melatonergic strategies in the management of insomnia. This structured narrative review presents a comprehensive analysis of the molecular pharmacology, receptor affinity, signaling pathways, and clinical outcomes associated with melatonergic agents. It also examines their functional interplay with serotonergic, GABAergic, dopaminergic, and orexinergic systems involved in arousal and sleep regulation. Through comparative synthesis of pharmacokinetics and neurochemical mechanisms, this work aims to inform the development of evidence-based strategies for the treatment of insomnia and circadian rhythm sleep\u2013wake disorders.<\/jats:p>","DOI":"10.3390\/molecules30183814","type":"journal-article","created":{"date-parts":[[2025,9,19]],"date-time":"2025-09-19T12:33:32Z","timestamp":1758285212000},"page":"3814","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["The Efficacy of Melatonergic Receptor Agonists Used in Clinical Practice in Insomnia Treatment: Melatonin, Tasimelteon, Ramelteon, Agomelatine, and Selected Herbs"],"prefix":"10.3390","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-1151-2332","authenticated-orcid":false,"given":"Kacper","family":"\u017be\u0142abowski","sequence":"first","affiliation":[{"name":"Scientific Society for Psychopharmacology, Department of Forensic Medicine, Wroclaw Medical University, 4 J. Mikulicza-Radeckiego Street, 50-345 Wroclaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wojciech","family":"Pichowicz","sequence":"additional","affiliation":[{"name":"Scientific Society for Psychopharmacology, Department of Forensic Medicine, Wroclaw Medical University, 4 J. Mikulicza-Radeckiego Street, 50-345 Wroclaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-2503-7473","authenticated-orcid":false,"given":"Izabela","family":"Skowron","sequence":"additional","affiliation":[{"name":"Scientific Society for Psychopharmacology, Department of Forensic Medicine, Wroclaw Medical University, 4 J. Mikulicza-Radeckiego Street, 50-345 Wroclaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9078-5830","authenticated-orcid":false,"given":"Jagoda","family":"Szwach","sequence":"additional","affiliation":[{"name":"Scientific Society for Psychopharmacology, Department of Forensic Medicine, Wroclaw Medical University, 4 J. Mikulicza-Radeckiego Street, 50-345 Wroclaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-2157-103X","authenticated-orcid":false,"given":"Kamil","family":"Biedka","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology, Division of Pathophysiology, Wroclaw Medical University, Chalubinskiego 10, 50-368 Wroclaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-8752-2321","authenticated-orcid":false,"given":"Micha\u0142","family":"Weso\u0142owski","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology, Division of Pathophysiology, Wroclaw Medical University, Chalubinskiego 10, 50-368 Wroclaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-4209-3700","authenticated-orcid":false,"given":"Katarzyna","family":"B\u0142aszczyk","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology, Division of Physiology, Wroclaw Medical University, Chalubinskiego 10, 50-368 Wroclaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-7085-0104","authenticated-orcid":false,"given":"Oliwia","family":"Ziobro","sequence":"additional","affiliation":[{"name":"Scientific Society for Psychopharmacology, Department of Forensic Medicine, Wroclaw Medical University, 4 J. Mikulicza-Radeckiego Street, 50-345 Wroclaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wiktor","family":"Petrov","sequence":"additional","affiliation":[{"name":"Scientific Society for Psychopharmacology, Department of Forensic Medicine, Wroclaw Medical University, 4 J. Mikulicza-Radeckiego Street, 50-345 Wroclaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7076-600X","authenticated-orcid":false,"given":"Wirginia","family":"Kukula-Koch","sequence":"additional","affiliation":[{"name":"Department of Pharmacognosy with Garden of Medicinal Plants, Medical University of Lublin, Chod\u017aki 1, 20-093 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnieszka","family":"Ch\u0142opa\u015b-Konowa\u0142ek","sequence":"additional","affiliation":[{"name":"Department of Forensic Medicine, Division of Molecular Techniques, Wroclaw Medical University, Sklodowskiej-Curie 52, 50-369 Wroclaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"65","DOI":"10.13078\/jsm.240014","article-title":"The Intricacies of Insomnia: A Comprehensive Exploration","volume":"21","author":"Khara","year":"2024","journal-title":"J. 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