title: Assessing the efficacy of melatonin to curtail benzodiazepine/Z drug abuse.
abstract: The abuse of benzodiazepine (BZP) and Z drugs has become, due to the tolerance and dependence they produce, a serious public health problem. Thirty years ago, we demonstrated in experimental animals the interaction of melatonin with central BZD receptors, and in 1997 we published the first series of elderly patients who reduced BZP consumption after melatonin treatment. Almost every single neuron in the hypothalamic suprachiasmatic nuclei (SCN), the central pacemaker of the circadian system, contains γ-aminobutyric acid (GABA) and many results in animals point out to a melatonin interaction with GABA-containing neurons. In addition, central-type BZD antagonism, that obliterates GABAA receptor function, blunted most behavioral effects of melatonin including sleep. Melatonin is involved in the regulation of human sleep. This is supported by the temporal relationship between the rise of plasma melatonin levels and sleep propensity as well as by the sleep-promoting effects of exogenously administered melatonin. Both meta-analyses and consensus agreements give support to the therapeutic use of melatonin in sleep disorders. This action is attributed to MT1 and MT2 melatoninergic receptors localized in the SCN, as well as in other brain areas. This review discusses available data on the efficacy of melatonin to curtail chronic BZD/Z drug use in insomnia patients. A major advantage is that melatonin has a very safe profile, it is usually remarkably well tolerated and, in some studies, it has been administered to patients at very large doses and for long periods of time, without any potentiality of abuse. Further studies on this application of melatonin are warranted.
authors.affiliation: BIOMED-UCA-CONICET and Department of Teaching and Research, Faculty of Medical Sciences, Pontificia Universidad Católica Argentina, Buenos Aires, Argentina; Laboratory of Retinal Neurochemistry and Experimental Ophthalmology, Department of Human Biochemistry, School of Medicine/CEFyBO, University of Buenos Aires/CONICET, Buenos Aires, Argentina. Electronic address: danielcardinali@fibertel.com.ar.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Cardinali
authors.affiliation: Department of Science and Technology, National University of Quilmes and CONICET, Argentina; Laboratory of Retinal Neurochemistry and Experimental Ophthalmology, Department of Human Biochemistry, School of Medicine/CEFyBO, University of Buenos Aires/CONICET, Buenos Aires, Argentina.
authors.forename: Diego A
authors.initials: DA
authors.lastname: Golombek
authors.affiliation: Department of Science and Technology, National University of Quilmes and CONICET, Argentina; Laboratory of Retinal Neurochemistry and Experimental Ophthalmology, Department of Human Biochemistry, School of Medicine/CEFyBO, University of Buenos Aires/CONICET, Buenos Aires, Argentina.
authors.forename: Ruth E
authors.initials: RE
authors.lastname: Rosenstein
authors.affiliation: Centro de Neuropsiquiatría y Neurología de la Conducta, Hospital de Clínicas "José de San Martín", Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina; Laboratory of Retinal Neurochemistry and Experimental Ophthalmology, Department of Human Biochemistry, School of Medicine/CEFyBO, University of Buenos Aires/CONICET, Buenos Aires, Argentina.
authors.forename: Luis I
authors.initials: LI
authors.lastname: Brusco
authors.affiliation: BIOMED-UCA-CONICET and Department of Teaching and Research, Faculty of Medical Sciences, Pontificia Universidad Católica Argentina, Buenos Aires, Argentina; Laboratory of Retinal Neurochemistry and Experimental Ophthalmology, Department of Human Biochemistry, School of Medicine/CEFyBO, University of Buenos Aires/CONICET, Buenos Aires, Argentina.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Vigo
mesh_terms: D000818:Animals; D001569:Benzodiazepines / Q000627:therapeutic use; D059330:GABAergic Neurons / Q000502:physiology; D006801:Humans; D008550:Melatonin / Q000502:physiology / Q000627:therapeutic use*; D007319:Sleep Initiation and Maintenance Disorders / Q000188:drug therapy*; D019966:Substance-Related Disorders / Q000517:prevention & control*
chemical_list: D001569:Benzodiazepines; D008550:Melatonin
keywords: Alprazolam (PubChem CID: 2118); Benzodiazepines; Drug abuse; Flumazenil (PubChem CID: 3373); Insomnia; Melatonin; Melatonin (PubChem CID: 896); N(1)-acetyl- N(2)-formyl-5-methoxykynuramine (PubChem CID: 171161); Ramelteon (PubChem CID: 208902); Temazepam (PubChem CID: 5391); Triazolam (PubChem CID: 5556); Z drugs; Zaleplon (PubChem CID: 5719); Zolpidem (PubChem CID: 5732); Zopiclone (PubChem CID: 5735)