one death and several cases of liver transplantation. As a result, alpidem was soon withdrawn from the market. The liver toxicity of alpidem was subsequently characterized in preclinical research. It may be related to interactions of alpidem with the translocator protein (TSPO), which is present in high amounts in the liver and which may mediate toxic effects in this tissue. Overdose Little information is available on overdose with alpidem. Doses of as high as 300mg/day, which is 2 to 4times the recommended total daily dose, were assessed in clinical trials. Interactions Alpidem may interact with alcohol, but to a lesser extent than benzodiazepines. Pharmacology Pharmacodynamics Alpidem is a GABAA receptor positive allosteric modulator (GABAkine), specifically acting as an agonist of the benzodiazepine site of the receptor complex (formerly known as the central benzodiazepine receptor (CBR)). In addition to its affinity for the benzodiazepine site of the GABAA receptor (Ki = 1–28nM), alpidem has similarly high affinity for the translocator protein (TSPO) (formerly the peripheral benzodiazepine receptor (PBR)) (Ki = 0.5–7nM). Alpidem shows more than 500-fold selectivity for α1 subunit-containing GABAA receptors over α5 subunit-containing GABAA receptors and 80-fold selectivity for α1 subunit-containing GABAA receptors over α3 subunit-containing GABAA receptors. However, alpidem has also been described as potently modulating α1, α2, and α3 subunit-containing GABAA receptors with no effect on α5 subunit-containing GABAA receptors. Findings appear to be mixed on whether alpidem is a partial agonist or a full agonist of the benzodiazepine site of the GABAA receptor. In animals, alpidem has anxiolytic-like effects in some but not all models, weak anticonvulsant effects, and weak or no sedative, amnesic, ataxic, or muscle relaxant effects. High doses of alpidem antagonize the sedative and muscle relaxant effects of diazepam in animals. Flumazenil has been shown to antagonize the anxiolytic and anticonvulsant effects of alpidem in animals. Besides acting directly via the GABAA receptor, interactions with the TSPO might also contribute to the anxiolytic effects of alpidem. This protein mediates promotion of neurosteroidogenesis in the brain, for instance of allopregnanolone. Alpidem is structurally related to zolpidem, and both alpidem and zolpidem are GABAA receptor positive allosteric modulators of the benzodiazepine site with preference for α1 subunit-containing receptors. Both alpidem and zolpidem have very low affinity for α5 subunit-containing GABAA receptors, in contrast to benzodiazepines. Similarly, both alpidem and zolpidem are selective for γ2 subunit-containing GABAA receptors, with very low affinity for γ1 and γ3