Zolpidem dependence case series: possible neurobiological mechanisms and clinical management

Zolpidem is a short-acting imidazopyridine hypnotic that is an agonist at the gamma-aminobutyric acid A type (GABAA) receptor. It has been suggested that it acts selectively on alpha1 subunit-containing GABAA benzodiazepine (BZ1) receptors presenting (contrary to classic benzodiazepines) low or no affinity for other subtypes. Therefore, it has been proposed that it lacks the benzodiazepines-like side-effects, having minimal abuse and dependence potential. Nevertheless, there is a considerable number of zolpidem dependence case reports in the literature. We present eight cases of zolpidem abuse and dependence without criminal record, without history of substance abuse (except for one alcohol abuser), with minor psychiatric disorders, who took zolpidem after physicians prescription in order to deal with their insomnia. However, they became zolpidem abusers not craving its sedative, but its anxiolytic and stimulating action, which helped them to cope with everyday activities. It is possible that, in the high doses that our patients used, zolpidem abandons its selectivity for BZ1 receptors and demonstrates all the actions of classic benzodiazepines. Molecular biology, via possible mutations on GABA receptors, may provide some answers as to why our eight patients (who did not differ much from the thousands of insomniacs who use zolpidem) and other zolpidem abusers, raised the dose progressively, and sought something from the drug other than hypnotic action.