Psychopharmacology (2004) 173:88–97 DOI 10.1007/s00213-003-1695-4 ORIGINAL INVESTIGATION J. B. Deakin · M. R. F. Aitken · J. H. Dowson · T. W. Robbins · B. J. Sahakian Diazepam produces disinhibitory cognitive effects in male volunteers Received: 29 May 2003 / Accepted: 30 October 2003 / Published online: 19 December 2003  Springer-Verlag 2003 Abstract Rationale: Diazepam has well known amnestic and sedative effects but effects on fronto-executive function remain largely uninvestigated, especially on neuropsychologically validated tests of risk taking and orbitofrontal cortex function. Objectives: We aimed to determine the impact of diazepam on a variety of executive tasks. Methods: The effects of 5, 10 and 20 mg of diazepam on a battery of neuropsychological tests were investigated using a randomised, double blind, placebo-controlled design. Seventy-five adult men were recruited. The Rogers et al. (1999b) test of risk-taking was given along with tasks from the CANTAB battery. Results: Diazepam impaired performance on the Tower of London test of planning, without influencing visual pattern recognition memory. Subjects who had taken diazepam made more risky choices on the risk-taking task. On two speeded reaction time tasks diazepam impaired discrimination sensitivity and increased the bias to respond. Conclusions: In contrast to the well-known sedative effects of diazepam, we demonstrate disinhibito- ry effects on two speeded reaction time tasks. Our results show that diazepam can impair performance on reaction time tasks both by impairing sensitivity and by increasing the bias to respond. Furthermore diazepam impaired performance on tests of planning and risky decision making that depend predominantly on dorsolateral and orbitofrontal regions of the prefrontal cortex, respectively. Keywords Diazepam · Decision-making · Prefrontal cortex · Gambling · Inhibition · Impulsivity · Response bias Introduction The ability of human subjects to make decisions enabling them to select optimal responses and strategies in a complex and changing environment is clearly of funda- mental importance to people’s lives, and is the subject of a good deal of recent research both in the laboratory and within the clinical setting (see Rahman et al. 2001, for review). Much of this research has implicated a central role for specific regions of the orbital prefrontal cortex (PFC) and its connections with other brain structures in supporting these abilities (Bechara et al. 1994; Rahman et al. 1999). Diazepam, a benzodiazepine receptor agonist, is in wide clinical use as an anxiolytic, and has well- understood GABA-ergic effects (Feldman et al. 1996). In recent years, it has been implicated in effects on functions associated with processing within the orbital PFC (e.g. Blair and Curran 1999); however, there have been few, if any, studies of its effects on decision-making cognition. In a series of studies, Coull et al. (1995a, 1995b) showed that diazepam influenced performance on a range of tasks sensitive to frontal lobe dysfunction including tests of planning, extra-dimensional attentional shifting and spatial working memory (Dias et al. 1996; Owen et al. 1990, 1995b). We used a more sensitive variant of the planning task used by Coull et al. (1995b) namely the One-touch Tower of London test (OTToL; Owen et al. 1990). This task has similar planning demands, but is designed to be less susceptible to premature initial moves, as may have occurred in previous studies of diazepam (Coull et al. 1995b). We tested the influence of diazepam on responding on the OTToL task in order to investigate any possible effects of the drug on planning when the opportunity of impulsive first moves was reduced. A variant on the intra-dimensional/extra-dimensional (3D ID/ED) set-shifting task using three concurrent stimulus J. B. Deakin · J. H. Dowson · B. J. Sahakian ( ) ) University of Cambridge School of Clinical Medicine, Department of Psychiatry, Addenbrooke’s Hospital, Box 189, Cambridge, CB2 2QQ, UK e-mail: jenny.hall@addenbrookes.nhs.uk Tel.: +44-1223-331209 M. R. F. Aitken · T. W. Robbins Department of Experimental Psychology, University of Cambridge, Cambridge, CB2 3EB, UK