agonist use causes a persistent conformational change and thus a shift in benzodiazepine receptor efficacy in the direction of inverse agonist function (Little, Nutt and Taylor, 1987) and that flumazenil resets the receptor's sensitivity (Nutt and Costello, 1988). In binding to the benzodiazepine receptor flumazenil may alter the coupling of the elements of the GABA/benzodiazepine macromolecular complex modified by benzodiazepine binding, thus restoring the GABA recognition site to its pre-drug affinity (Gonsalves and Gallager, 1985). Very little parallel work has been done in man. Healthy volunteers given lorazepam for 1 or 2 weeks developed various features of tolerance which were not affected by a small dose of flumazenil (0.2 mg) (Cittadini and Lader, 1991) but were reversed by a larger dose (3.0 mg) (Evans et al., 1990). Because we considered that flumazenil might, by displacing the benzodiazepine, induce an abrupt withdrawal in chronic users with the risk of acute anxiety, psychosis or fits, we deemed it too hazardous to attempt to prevent subsequent withdrawal by prior administration of flumazenil. Instead we studied the effects of flumazenil in patients with symptoms persisting after they had become drug free. Method Subjects The study was conducted at the maudsley Hospital over a 2 year period starting in 1989. The protocols were approved by the appropriate Ethics Committee and fully informed written consent was obtained from each patient. Since this was not a licensed use of flumazenil, the study was run on a 'named patient' basis. Patients, aged between 18 and 65 and of