ZOLPIDEM AND COGNITIVE IMPAIRMENT: PHARMACODYNAMIC IMPLICATIONS ON GABA-A RECEPTORS

Abstract

Zolpidem hemitartrate, a hypnotic from the imidazopyridine class, was developed as an alternative to benzodiazepines, aiming to reduce adverse effects such as dependence and cognitive impairment. It acts selectively on the α1 subunit of GABA-A (gamma-aminobutyric acid) receptors, promoting sedative effects with a lower incidence of anxiolytic and muscle relaxant actions. Despite its effectiveness in treating short-term insomnia, prolonged use has been associated with tolerance, dependence, and cognitive deficits. Objective: To conduct a systematic review investigating the pharmacodynamic implications of zolpidem on GABA-A receptors that may be linked to cognitive impairment in users, contributing to the understanding of the neuropsychiatric risks associated with its use. Methodology: This systematic review followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Inclusion criteria comprised original research articles published between 2015 and 2025, in English, Spanish, or Portuguese, from databases including PubMed, SciELO, LILACS, MEDLINE, and Google Scholar. Studies had to specifically address the pharmacodynamic action of zolpidem on GABA-A receptors, with relevant clinical data and cognitive impact. Excluded were review articles, academic works (such as undergraduate theses, dissertations, and theses), e-books, paywalled articles, and duplicated reviews. Results: After screening, five studies were included for directly addressing the relationship between zolpidem, GABA-A receptors, and cognition. Over time, these studies converge on the understanding that the pharmacodynamic effects of zolpidem—particularly due to its affinity for α1 subunits—are strongly associated with cognitive and behavioral impairments. These effects are supported by experimental, observational, and clinical evidence, indicating that prolonged or inappropriate use of zolpidem poses a considerable neuropsychiatric risk. Conclusion: Given the increasing use of zolpidem, especially in prolonged contexts, and reports of cognition-related adverse effects, it is crucial to deepen the understanding of the mechanisms involved. While zolpidem's efficacy as a short-acting hypnotic is well established, the neurocognitive impacts resulting from its pharmacodynamic action on GABA-A receptors still require further investigation.