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Pharmacologically, they act as positive allosteric modulators of the ionotropic GABAA receptor, enhancing inhibitory synaptic transmission. However, prolonged use poses a significant public health concern, risking adverse effects such as cognitive impairment, motor incoordination, tolerance, and physical dependence. The development of tolerance is mediated by complex neurobiological changes, notably the downregulation of GABAA receptor subunits and a compensatory sensitization of excitatory glutamatergic systems. Effective management of established dependence requires comprehensive psychological intervention coupled with pharmacological substitution (switching to a long-acting BZD) and gradual dose tapering. Preventive measures are complex, emphasizing short-term prescriptions, minimum effective dosing, and selecting non-pharmacological or alternative pharmacological agents, such as SSRIs\/SNRIs, to mitigate the risk of developing tolerance and dependence. This expert review aims to compile the most relevant, representative, and recent literature summarizing the pharmacology, clinical indications, adverse effects, misuse, and abuse of BZDs that ultimately lead to BZD use disorder (BUD). It also details the involved neurobiological mechanisms and discusses critical preventive and therapeutic strategies, providing readers with the main aspects to consider for addressing this global public health problem.<\/jats:p>","DOI":"10.3390\/ijms27031430","type":"journal-article","created":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T09:00:33Z","timestamp":1770022833000},"page":"1430","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Benzodiazepine Dependence: Clinical and Molecular Aspects, Preventive Strategies and Therapeutic Approaches"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1251-6357","authenticated-orcid":false,"given":"Francisco","family":"Navarrete","sequence":"first","affiliation":[{"name":"Instituto de Neurociencias, Universidad Miguel Hern\u00e1ndez-CSIC, Avda. de Ram\u00f3n y Cajal s\/n, San Juan de Alicante, 03550 Alicante, Spain"},{"name":"Red de Investigaci\u00f3n en Atenci\u00f3n Primaria de Adicciones, Instituto de Salud Carlos III, MICINN and FEDER, 28029 Madrid, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria y Biom\u00e9dica de Alicante (ISABIAL), 03010 Alicante, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8335-9382","authenticated-orcid":false,"given":"Marta","family":"Mar\u00edn-Mayor","sequence":"additional","affiliation":[{"name":"Red de Investigaci\u00f3n en Atenci\u00f3n Primaria de Adicciones, Instituto de Salud Carlos III, MICINN and FEDER, 28029 Madrid, Spain"},{"name":"Instituto de Investigaci\u00f3n (i+12), Hospital Universitario 12 de Octubre, 28041 Madrid, Spain"},{"name":"Department of Psychiatry, Complutense University of Madrid, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorena","family":"Mart\u00ednez-Hostyn","sequence":"additional","affiliation":[{"name":"Instituto de Neurociencias, Universidad Miguel Hern\u00e1ndez-CSIC, Avda. de Ram\u00f3n y Cajal s\/n, San Juan de Alicante, 03550 Alicante, Spain"},{"name":"Red de Investigaci\u00f3n en Atenci\u00f3n Primaria de Adicciones, Instituto de Salud Carlos III, MICINN and FEDER, 28029 Madrid, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria y Biom\u00e9dica de Alicante (ISABIAL), 03010 Alicante, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1171-1508","authenticated-orcid":false,"given":"Gabriel","family":"Rubio","sequence":"additional","affiliation":[{"name":"Red de Investigaci\u00f3n en Atenci\u00f3n Primaria de Adicciones, Instituto de Salud Carlos III, MICINN and FEDER, 28029 Madrid, Spain"},{"name":"Instituto de Investigaci\u00f3n (i+12), Hospital Universitario 12 de Octubre, 28041 Madrid, Spain"},{"name":"Department of Psychiatry, Complutense University of Madrid, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4681-1533","authenticated-orcid":false,"given":"Jorge","family":"Manzanares","sequence":"additional","affiliation":[{"name":"Instituto de Neurociencias, Universidad Miguel Hern\u00e1ndez-CSIC, Avda. de Ram\u00f3n y Cajal s\/n, San Juan de Alicante, 03550 Alicante, Spain"},{"name":"Red de Investigaci\u00f3n en Atenci\u00f3n Primaria de Adicciones, Instituto de Salud Carlos III, MICINN and FEDER, 28029 Madrid, Spain"},{"name":"Instituto de Investigaci\u00f3n Sanitaria y Biom\u00e9dica de Alicante (ISABIAL), 03010 Alicante, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,31]]},"reference":[{"key":"ref_1","unstructured":"International Narcotics Control Board (2020). 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