MANAGEMENT OF INSOMNIA IN AGING POPULATIONS: COMPARING THE INFLUENCE OF BENZODIAZEPINES AND Z-DRUGS ON COGNITIVE HEALTH AND NEURODEGENERATIVE RISK - A REVIEW OF THE LITERATURE

Bartosz Piech; Magdalena  Dubaj; Alicja  Judzińska; Emilia  Trojanowska; Julia  Osipowska; Justyna  Ignarska; Kamila  Sobczyńska; Magda  Terbosh; Marlena  Kwolek; Sabina Kubicz Mzabi

doi:10.31435/ijitss.2(50).2026.5601

Authors

Bartosz Piech University Clinical Hospital No. 1 in Lublin (USK1), Lublin, Poland https://orcid.org/0009-0003-4621-5226
Magdalena Dubaj University Clinical Hospital No. 1 in Lublin (USK1), Lublin, Poland https://orcid.org/0009-0005-4429-2679
Alicja Judzińska University Clinical Hospital No. 1 in Lublin (USK1), Lublin, Poland https://orcid.org/0009-0007-7525-4012
Emilia Trojanowska SP ZOZ MSWiA, Grenadierów 3, 20-331, Lublin, Poland https://orcid.org/0009-0009-7331-6624
Julia Osipowska University Clinical Hospital No. 1 in Lublin (USK1) Lublin, Poland https://orcid.org/0009-0007-9024-9908
Justyna Ignarska University Clinical Hospital No. 4 in Lublin, Doktora Kazimierza Jaczewskiego 8, 20-954 Lublin, Poland https://orcid.org/0009-0009-0340-8240
Kamila Sobczyńska Stefan Cardinal Wyszyński Provincial Specialist Hospital in Lublin, Lublin, Poland https://orcid.org/0009-0002-0938-1711
Magda Terbosh University Clinical Hospital No. 1 in Lublin (USK1), Lublin, Poland https://orcid.org/0009-0006-3756-3394
Marlena Kwolek University Clinical Hospital No. 4 in Lublin, Poland https://orcid.org/0009-0004-1428-1103
Sabina Kubicz Mzabi University Clinical Hospital No. 4 in Lublin Doktora Kazimierza Jaczewskiego 8, 20-954 Lublin, Poland https://orcid.org/0009-0008-2788-5538

DOI:

https://doi.org/10.31435/ijitss.2(50).2026.5601

Keywords:

Insomnia, Benzodiazepines, Z-drugs, Cognitive Impairment, Neurodegeneration, Elderly

Abstract

Background: Insomnia is a prevalent sleep disorder among older adults and is associated with impaired cognitive function and increased risk of neurodegenerative diseases. Pharmacological management commonly involves benzodiazepines and non-benzodiazepine “Z-drugs” (zolpidem, zaleplon, zopiclone), which act as sedative-hypnotics through modulation of GABAA receptors. Although cognitive-behavioral therapy is the first-line treatment, hypnotic medications remain widely prescribed.

Aim: This review evaluates the mechanisms linking benzodiazepines and Z-drugs to neurodegeneration and summarizes the clinical and epidemiological evidence regarding their long-term impact on cognitive function in older adults.

Methods: A literature review was conducted using PubMed, PMC, and Google Scholar databases, focusing on full-text, English-language publications from 2013–2025. Search terms included “benzodiazepines and dementia risk,” “Z-drugs and cognitive impairment,” and drug-specific names such as zolpidem, zopiclone, zaleplon, and diazepam. Both observational and mechanistic studies were considered.

Results: Long-term benzodiazepine use is consistently associated with an increased risk of cognitive decline and dementia, particularly with higher cumulative doses and long-acting compounds. Evidence for Z-drugs suggests a generally more favorable cognitive profile at low doses or short-term use, although high-dose or long-term exposure may similarly increase dementia risk and adverse events such as falls and fractures. The underlying mechanisms involve modulation of GABAergic neurotransmission, potentially altering hippocampal and cortical network activity, synaptic plasticity and memory consolidation. The interpretation of causality is complicated by potential confounding factors, such as underlying insomnia or anxiety.

Conclusion: Benzodiazepines and Z-drugs are effective for insomnia management in older adults but may carry long-term cognitive risks. Minimizing dose, limiting treatment duration, and prioritizing non-pharmacological interventions such as cognitive-behavioral therapy are essential strategies to mitigate potential neurodegenerative outcomes. Future studies should aim to optimize dose–response regimens, incorporate long-term follow-up assessments, clarify the biological mechanisms through which these drugs affect cognitive function and include randomized controlled trials as well as long-term observational studies to more precisely evaluate the effects on specific cognitive domains, such as memory, attention and executive function.

References

Patel, D., Steinberg, J., & Patel, P. (2018). Insomnia in the elderly: A review. Journal of Clinical Sleep Medicine, 14(6), 1017–1024. https://doi.org/10.5664/jcsm.7172

Van Someren, E. J. W. (2021). Brain mechanisms of insomnia: New perspectives on causes and consequences. Physiological Reviews, 101(3), 995–1046. https://doi.org/10.1152/physrev.00046.2019

Yu, X., Qian, Y., Zhang, Y., Chen, Y., & Wang, M. (2024). Association between polypharmacy and cognitive impairment in older adults: A systematic review and meta-analysis. Geriatric Nursing, 59, 330–337. https://doi.org/10.1016/j.gerinurse.2024.07.005

Zhang, J., Ou, J., Lu, X., Wang, T., Dang, W., Ding, L., Liu, Y., Xu, J., Yan, B., & Yu, H. (2025). Sleep disorders and the risk of cognitive decline or dementia: An updated systematic review and meta-analysis of longitudinal studies. Journal of Neurology, 272(10), Article 689. https://doi.org/10.1007/s00415-025-13372-x

Matheson, E., & Hainer, B. L. (2017). Insomnia: Pharmacologic therapy. American Family Physician, 96(1), 29–35.

Biggio, G., & Mencacci, C. (2026). Insomnia in seasonal affective disorder: Considering the use of benzodiazepines with a focus on lormetazepam. Frontiers in Psychiatry, 16, Article 1667086. https://doi.org/10.3389/fpsyt.2025.1667086

Torres-Bondia, F., Dakterzada, F., Galván, L., Buti, M., Besanson, G., Grill, E., Buil, R., de Batlle, J., & Piñol-Ripoll, G. (2022). Benzodiazepine and Z-drug use and the risk of developing dementia. International Journal of Neuropsychopharmacology, 25(4), 261–268. https://doi.org/10.1093/ijnp/pyab073

Chapman, C. A., Povysheva, N., Tarr, T. B., Nuwer, J. L., Meriney, S. D., Johnson, J. W., & Jacob, T. C. (2025). Chronic benzodiazepine treatment triggers gephyrin scaffold destabilization and GABAAR subsynaptic reorganization. Frontiers in Cellular Neuroscience, 19, Article 1624813. https://doi.org/10.3389/fncel.2025.1624813

Zaric Kontic, M., Dragic, M., Martinovic, J., Mihajlovic, K., Brkic, Z., Mitrovic, N., & Grkovic, I. (2023). Prolonged alprazolam treatment alters components of glutamatergic neurotransmission in the hippocampus of male Wistar rats—The neuroadaptive changes following long-term benzodiazepine (mis)use. Pharmaceuticals, 16(3), Article 331. https://doi.org/10.3390/ph16030331

Lissek, S., Golisch, A., Glaubitz, B., et al. (2017). The GABAergic system in prefrontal cortex and hippocampus modulates context-related extinction learning and renewal in humans. Brain Imaging and Behavior, 11, 1885–1900. https://doi.org/10.1007/s11682-016-9662-y

Richter, G., Liao, V. W. Y., Ahring, P. K., & Chebib, M. (2020). The Z-drugs zolpidem, zaleplon, and eszopiclone have varying actions on human GABAA receptors containing γ1, γ2, and γ3 subunits. Frontiers in Neuroscience, 14, Article 599812. https://doi.org/10.3389/fnins.2020.599812

Billioti de Gage, S., Moride, Y., Ducruet, T., Kurth, T., Verdoux, H., Tournier, M., Pariente, A., & Bégaud, B. (2014). Benzodiazepine use and risk of Alzheimer’s disease: Case-control study. BMJ, 349, Article g5205. https://doi.org/10.1136/bmj.g5205

Kersanté, F., Purple, R. J., & Jones, M. W. (2023). The GABAA receptor modulator zolpidem augments hippocampal-prefrontal coupling during non-REM sleep. Neuropsychopharmacology, 48, 594–604. https://doi.org/10.1038/s41386-022-01355-9

Wu, C. C., Liao, M. H., Su, C. H., Poly, T. N., & Lin, M. C. (2023). Benzodiazepine use and the risk of dementia in the elderly population: An umbrella review of meta-analyses. Journal of Personalized Medicine, 13(10), Article 1485. https://doi.org/10.3390/jpm13101485

Shih, H. I., Lin, C. C., Tu, Y. F., Chang, C. M., Hsu, H. C., Chi, C. H., & Kao, C. H. (2015). An increased risk of reversible dementia may occur after zolpidem derivative use in the elderly population: A population-based case-control study. Medicine, 94(17), Article e809. https://doi.org/10.1097/MD.0000000000000809

Guo, F., Yi, L., Zhang, W., Bian, Z. J., & Zhang, Y. B. (2021). Association between Z drugs use and risk of cognitive impairment in middle-aged and older patients with chronic insomnia. Frontiers in Human Neuroscience, 15, Article 775144. https://doi.org/10.3389/fnhum.2021.775144

Stranks, E. K., & Crowe, S. F. (2014). The acute cognitive effects of zopiclone, zolpidem, zaleplon, and eszopiclone: A systematic review and meta-analysis. Journal of Clinical and Experimental Neuropsychology, 36(7), 691–700. https://doi.org/10.1080/13803395.2014.928268

Harbourt, K., Nevo, O. N., Zhang, R., Chan, V., & Croteau, D. (2020). Association of eszopiclone, zaleplon, or zolpidem with complex sleep behaviors resulting in serious injuries, including death. Pharmacoepidemiology and Drug Safety, 29(6), 684–691. https://doi.org/10.1002/pds.5004

Richardson, K., Loke, Y. K., Fox, C., Maidment, I., Howard, R., Steel, N., Arthur, A., Boyd, P. J., Aldus, C., Ballard, C., & Savva, G. M. (2020). Adverse effects of Z-drugs for sleep disturbance in people living with dementia: A population-based cohort study. BMC Medicine, 18, Article 351. https://doi.org/10.1186/s12916-020-01821-5