Lunghi C, Valetto MR, Caracciolo AB, Bramke I, Caroli S, Bottoni P, et al. Call to action: pharmaceutical residues in the environment: threats to ecosystems and human health. Drug Saf. 2024;48:315–20. https://doi.org/10.1007/s40264-024-01497-3.

Article  PubMed  Google Scholar 

Abdel-Gawad SA, Alamri MA. Selective simultaneous ultra-performance liquid chromatographic quantification of some benzodiazepines drug residues in pharmaceutical industrial wastewater. Trop J Pharm Res. 2022;21:1951–7. https://doi.org/10.4314/tjpr.v21i9.19.

Article  Google Scholar 

Fick J, Brodin T, Heynen M, Klaminder J, Jonsson M, Grabicova K, et al. Screening of benzodiazepines in thirty European rivers. Chemosphere. 2017;176:324–32. https://doi.org/10.1016/j.chemosphere.2017.02.126.

Article  PubMed  Google Scholar 

Wilkinson JL, Boxall ABA, Kolpin DW, Leung KMY, Lai RWS, Galbán-Malagón C, et al. Pharmaceutical pollution of the world’s rivers. Proc Natl Acad Sci USA. 2022;119:e2113947119. https://doi.org/10.1073/pnas.2113947119.

Article  PubMed  Google Scholar 

Directive (EU) 2024/3019 of the European Parliament and of the Council of 27 November 2024 concerning urban wastewater treatment.

Wang A, Zhang J, Hu L, Yu Z, Lai S, Liu Y, et al. Trace analysis of 47 psychotropic medications in environmental samples by ultra-performance liquid chromatography tandem mass spectrometry (UPLC–MS/MS). J Chromatogr A. 2024;1715:464627. https://doi.org/10.1016/j.chroma.2023.464627.

Article  PubMed  Google Scholar 

Griffin CE, Kaye AM, Bueno FR, Kaye AD. Benzodiazepine pharmacology and central nervous system-mediated effects. Ochsner J. 2013;13:214–23.

PubMed  PubMed Central  Google Scholar 

Ma T-T, Wang Z, Qin X, Ju C, Lau WCY, Man KKC, et al. Global trends in the consumption of benzodiazepines and Z-drugs in 67 countries and regions from 2008 to 2018: a sales data analysis. Sleep. 2008;46:zsad124. https://doi.org/10.1093/sleep/zsad124.

Article  Google Scholar 

Möhler H, Fritschy JM, Rudolph U. A new benzodiazepine pharmacology. J Pharmacol Exp Ther. 2002;300:2–8. https://doi.org/10.1124/jpet.300.1.2.

Article  PubMed  Google Scholar 

Dionne P-A, Vasiliadis H-M, Latimer E, Berbiche D, Preville M. Economic impact of inappropriate benzodiazepine prescribing and related drug interactions among elderly persons. Psychiatr Serv. 2013;64:331–8. https://doi.org/10.1176/appi.ps.201200089.

Article  PubMed  Google Scholar 

Corral-Tuesta C, Rodríguez Díaz-Pavón A, Montero-Errasquín B, Álvarez-Pinheiro CG, Lavilla-Gracia V, Cruz-Jentoft AJ. Chronic benzodiazepine usage among older people: prevalence, indications, and treatment modifications in patients admitted to an acute geriatric unit. Eur Geriatr Med. 2024;15:539–43. https://doi.org/10.1007/s41999-023-00918-3.

Article  PubMed  Google Scholar 

Panes A, Verdoux H, Fourrier-Réglat A, Berdaï D, Pariente A, Tournier M. Use of benzodiazepines non-compliant with guidelines in patients with psychiatric and non-psychiatric chronic disorders. Gen Hosp Psychiatry. 2020;65:21–7. https://doi.org/10.1016/j.genhosppsych.2020.03.006.

Article  PubMed  Google Scholar 

Adhikari S, Kumar R, Driver EM, Bowes DA, Ng KT, Sosa-Hernandez JE, et al. Occurrence of Z-drugs, benzodiazepines, and ketamine in wastewater in the United States and Mexico during the Covid-19 pandemic. Sci Total Environ. 2023;857:159351. https://doi.org/10.1016/j.scitotenv.2022.159351.

Article  PubMed  Google Scholar 

Genario R, Giacomini ACVV, De Abreu MS, Marcon L, Demin KA, Kalueff AV. Sex differences in adult zebrafish anxiolytic-like responses to diazepam and melatonin. Neurosci Lett. 2020;714:134548. https://doi.org/10.1016/j.neulet.2019.134548.

Article  PubMed  Google Scholar 

Jin H, Yang D, Wu P, Zhao M. Environmental occurrence and ecological risks of psychoactive substances. Environ Int. 2022;158:106970. https://doi.org/10.1016/j.envint.2021.106970.

Article  PubMed  Google Scholar 

Grisotto J, Tavakolian Haghighi S, Moretti U, Paolone G. Short-term, high-end environmentally-relevant diazepam exposure induces sex-specific behavioral and molecular alterations in adult zebrafish. Sci Total Environ. 2026;1041:181918. https://doi.org/10.1016/j.scitotenv.2026.181918.

Article  PubMed  Google Scholar 

Wang W, Wang Z, Chen F, Yang F. Basin-scale exposure risk of psychiatric pharmaceuticals and illicit drugs in tap water in Eastern China. Emerg Contam. 2024;10:100330. https://doi.org/10.1016/j.emcon.2024.100330.

Article  Google Scholar 

Directive 2000/60/EC, 2014. Directive 2000/60/EC of the European Parliament and of the Council of 23 October 2000 establishing a framework for Community action in the field of water policy.

Gomez CL, Porcel RE, Marinov D, Sanseverino I, Lettieri T. Selection of substances for the 5th Watch List under the Water Framework Directive [Internet]. 2025 [cited 2025 Nov 10]. https://doi.org/10.2760/956398.

Bertram MG, Martin JM, McCallum ES, Alton LA, Brand JA, Brooks BW, et al. Frontiers in quantifying wildlife behavioural responses to chemical pollution. Biol Rev. 2022;97:1346–64. https://doi.org/10.1111/brv.12844.

Article  PubMed  PubMed Central  Google Scholar 

Bertram MG, Ågerstrand M, Balshine S, Brand JA, Brooks BW, Dang Z, et al. Are behavioral ecotoxicity endpoints relevant at the population level? Evidence-based insights for environmental protection. Environ Sci Technol. 2026;60:86–95. https://doi.org/10.1021/acs.est.5c07777.

Article  PubMed  Google Scholar 

Ford AT, Ågerstrand M, Brooks BW, Allen J, Bertram MG, Brodin T, et al. The role of behavioral ecotoxicology in environmental protection. Environ Sci Technol. 2021;55:5620–8. https://doi.org/10.1021/acs.est.0c06493.

Article  PubMed  PubMed Central  Google Scholar 

Cunha DL, De Araujo FG, Marques M. Psychoactive drugs: occurrence in aquatic environment, analytical methods, and ecotoxicity—a review. Environ Sci Pollut Res. 2017;24:24076–91. https://doi.org/10.1007/s11356-017-0170-4.

Article  Google Scholar 

Yuan X, Luo L, Li X, Lu Y, Chen S, Luan T. Recent advances in the removal of psychoactive substances from aquatic environments: a review. Sci Total Environ. 2024;953:176156. https://doi.org/10.1016/j.scitotenv.2024.176156.

Article  PubMed  Google Scholar 

Ogunbanwo OM, Kay P, Boxall AB, Wilkinson J, Sinclair CJ, Shabi RA, et al. High concentrations of pharmaceuticals in a Nigerian river catchment. Environ Toxicol Chem. 2022;41:551–8. https://doi.org/10.1002/etc.4879.

Article  PubMed  Google Scholar 

Wang Z, Gao S, Dai Q, Zhao M, Yang F. Occurrence and risk assessment of psychoactive substances in tap water from China. Environ Pollut, Barking, Essex: 1987. 2020;261:114163. https://doi.org/10.1016/j.envpol.2020.114163.

Article  Google Scholar 

Van Der Ven K, Van Dongen W, Maes BUW, Esmans EL, Blust R, De Coen WM. Determination of diazepam in aquatic samples by capillary liquid chromatography–electrospray tandem mass spectrometry. Chemosphere. 2004;57:967–73. https://doi.org/10.1016/j.chemosphere.2004.08.062.

Article  PubMed  Google Scholar 

Moreno-González R, Rodríguez-Mozaz S, Gros M, Pérez-Cánovas E, Barceló D, León VM. Input of pharmaceuticals through coastal surface watercourses into a Mediterranean lagoon (Mar Menor, SE Spain): sources and seasonal variations. Sci Total Environ. 2014;490:59–72. https://doi.org/10.1016/j.scitotenv.2014.04.097.

Article  PubMed  Google Scholar 

Esteban S, Valcárcel Y, Catalá M, Castromil MG. Psychoactive pharmaceutical residues in the watersheds of Galicia (Spain). Gac Sanit. 2012;26:457–9. https://doi.org/10.1016/j.gaceta.2012.01.018.

Article  PubMed  Google Scholar 

Yuan S, Jiang X, Xia X, Zhang H, Zheng S. Detection, occurrence and fate of 22 psychiatric pharmaceuticals in psychiatric hospital and municipal wastewater treatment plants in Beijing, China. Chemosphere. 2013;90:2520–5. https://doi.org/10.1016/j.chemosphere.2012.10.089.

Article  PubMed  Google Scholar 

Leiviskä T, Risteelä S. Analysis of pharmaceuticals, hormones and bacterial communities in a municipal wastewater treatment plant—comparison of parallel full-scale membrane bioreactor and activated sludge systems. Environ Pollut. 2022;292:118433. https://doi.org/10.1016/j.envpol.2021.118433.

Article  PubMed  Google Scholar 

Butkovskyi A, Hernandez Leal L, Rijnaarts HHM, Zeeman G. Fate of pharmaceuticals in full-scale source separated sanitation system. Water Res. 2015;85:384–92. https://doi.org/10.1016/j.watres.2015.08.045.

Article  PubMed  Google Scholar 

Gracia-Lor E, Pérez-Valenciano A, De Oro-Carretero P, Ramírez-García L, Sanz-Landaluze J, Martín-Gutiérrez MJ. Consumption of illicit drugs and benzodiazepines in six Spanish cities during different periods of the COVID-19 pandemic. Sci Total Environ. 2024;935:173356. https://doi.org/10.1016/j.scitotenv.2024.173356.

Article  PubMed  Google Scholar 

Bijlsma L, Emke E, Hernández F, De Voogt P. Investigation of drugs of abuse and relevant metabolites in Dutch sewage water by liquid chromatography coupled to high resolution mass spectrometry. Chemosphere. 2012;89:1399–406. https://doi.org/10.1016/j.chemosphere.2012.05.110.

Article