Zolpidem and Alcohol: From a Dangerous Combination to the Risk of Dependence

The concomitant use of alcohol and Z-drugs, such as zolpidem, poses significant health risks that go beyond the immediate interaction with alcohol, extending to an increased vulnerability to the development of long-term substance-related problems.

So-called Z-drugs are a class of medications widely used for the short-term treatment of insomnia and other sleep disorders.¹ This term includes drugs such as zolpidem, zopiclone, and eszopiclone. They were originally developed as alternatives to benzodiazepines, with the aim of providing sedative–hypnotic effects with lower risks of dependence and side effects. However, recent evidence challenges this perception of safety, suggesting that the risk profile for the subsequent development of alcohol- and drug-related problems is comparable between individuals who initiate treatment with benzodiazepines and those who start with Z-drugs.²

The mechanism of action of Z-drugs involves the selective stimulation of GABA-A receptors in the brain. This effect amplifies the activity of the neurotransmitter GABA, inhibiting neuronal excitability and inducing sleep.³ However, studies indicate that this allosteric modulation of GABA-A receptors also affects neural circuits involved in the behavioral effects of drugs of abuse, such as reward and reinforcement systems. This mechanism is shared by alcohol, which also increases GABA-A receptor activity, helping to explain the potential transition from medical use to misuse or the dangerous combination of these substances.

The concomitant use of alcohol and Z-drugs, such as zolpidem, presents immediate and severe risks. Because alcohol potentiates the sedative effects of these medications, combined use can result in excessive sedation and respiratory depression. According to the FDA, this combination increases the occurrence of complex sleep-related behaviors, in which individuals may walk, drive, or perform other activities while unconscious (sleepwalking), with no subsequent memory of the event (amnesia). For this reason, activities requiring full alertness should be avoided, and mixing these medications with alcohol is contraindicated.⁴

Beyond the immediate dangers of the interaction, new evidence suggests that the initiation of zolpidem treatment itself may represent a turning point for a patient’s long-term health. A large study published in 2025² indicated that patients who begin using Z-drugs have an increased risk—approximately twice as high for drug-related problems and 1.5 times higher for alcohol-related problems—compared with those who do not use these medications. This risk exists even among individuals with no prior history of dependence and is associated with severe outcomes, including not only substance use disorders but also unintentional intoxications, deaths, and suspected criminal offenses related to substance use.

To minimize these risks, ANVISA changed the prescription requirements for zolpidem in 2025, implementing stricter controls due to the risk of dependence and abuse.⁵ Therefore, it is essential that the use of these medications be restricted to the short term and accompanied by continuous medical supervision. Monitoring patients’ substance-use behaviors should be ongoing, not only during the period of prescription but also after treatment initiation, in order to prevent serious health and social consequences.

References

1. FDA Label for Ambien®. Drugs@FDA. https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/019908s027lbl.pdf
2. Wang, X., Chang, Z., Molero, Y., Isomura, K., Fernández de la Cruz, L., Lichtenstein, P., Kuja-Halkola, R., D'Onofrio, B. M., Quinn, P. D., Larsson, H., Brikell, I., Hellner, C., Hasselström, J., Jayaram-Lindström, N., Mataix-Cols, D., & Sidorchuk, A. (2025). Incident benzodiazepine and Z-drug use and subsequent risk of alcohol- and drug-related problems: A nationwide matched cohort study with co-twin comparison. Journal of psychopharmacology (Oxford, England), 2698811251373069. Advance online publication. https://doi.org/10.1177/02698811251373069
3. Neumann, E., Rudolph, U., Knutson, D. E., Li, G., Cook, J. M., Hentschke, H., Antkowiak, B., & Drexler, B. (2019). Zolpidem Activation of Alpha 1-Containing GABAA Receptors Selectively Inhibits High Frequency Action Potential Firing of Cortical Neurons. Frontiers in pharmacology, 9, 1523. https://doi.org/10.3389/fphar.2018.01523
4. Taking Z-drugs for Insomnia? Know the Risks. U.S. Food and Drug Administration. September 9, 2020. https://www.fda.gov/consumers/consumer-updates/taking-z-drugs-insomnia-know-risks
5. Agência Nacional de Vigilância Sanitária. (2024, 17 de abril). Medicamento zolpidem terá alteração no tipo de receita para prescrição e venda.