Partly as a consequence of the growing public concern regarding dependence and possible abuse of benzodiazepine anxiolytics over the past 10 years, a number of approaches to the development of novel, non-dependence-producing anxiolytics have occurred. Knowledge of the complexity of benzodiazepine receptors has resulted in the development of a number of partial agonists ( for example, bretazenil) that show anxiolytic activity without causing excessive sedation or memory disturbance that characterizes some of the full agonist benzodiazepines such as diazepam. It is also apparent that a slight modiยฎcation of the benzodiazepine structure can produce anxiolytics that have fewer adverse side-eects than the typical 1,4-benzodiazepines such as diazepam. For example, clobazam combines the anxiolytic and anticonvulsant properties of conventional benzodiazepines without causing sedation, and has a low dependence potential. Etizolam is another unique molecule that appears to combine the anxiolytic properties of conventional benzodiazepines with noradrenaline reuptake inhibition. The triazolobenzodiazepine alprazolam, like etizolam, also modulates noradrenergic and serotonergic function which could account for its ecacy not only as a potent anxiolytic but also as an anti-panic agent. Suriclone is an example of another structurally modiยฎed benzodiazepine that lacks the sedative properties of the conventional benzodiazepines, but appears to be an eective anxiolytic that lacks dependence-producing properties, while etazolate appears to owe its anxiolytic action to an ability to enhance chloride ion conductance at the GABA-benzodiazepine receptor complex. Non-benzodiazepine anxiolytics have also been developed that appear to act by modulating the serotonergic, histaminergic and nonaminergic systems. The anxiolytic eects of drugs acting as partial agonists at 5HT1A receptors, thereby reducing the functional activity of serotonin in limbic regions of the brain, may be characterized by buspirone, gepirone, ipsapirone and tandispirone. In addition, 5HT2A antagonists such as ketanserin and 5HT3 antagonists, exempliยฎed by ondansetron, have also been shown to have anxiolytic properties, although their ecacy and cost appears to limit their clinical development. Recently attention has also been redirected towards drugs with a central antihistaminic action. For example, hydroxyzine has been shown to be a non-dependence producing anxiolytic with therapeutic ecacy in the treatment of GAD. Of the novel approaches that are currently under consideration, cholecystokinin antagonists, such as devazepride, have shown activity in the treatment of panic disorder, while the adenosine receptor agonist indosine has been shown to exert weak anxiolytic activity possibly by an indirect modulatory eect on the benzodiazepine receptor. Irrespective of the direct mechanisms of action of this diverse group of anxiolytics, it is apparent that all therapeutically eective agents ultimately enhance inhibitory neurotransmission in the brain. The main advantages of the non-benzodiazepines lies not in their ecacy, but their reduced ability to cause sedation, potentiate the eects of alcohol and cause dependence.