Psychopharmacology (1999) 145 : 193–204 © Springer-Verlag 1999 ORIGINAL INVESTIGATION John H. Krystal · D. Cyril D’Souza Laurence P. Karper · Alexandre Bennett Anissa Abi-Dargham · Danielle Abi-Saab Karyn Cassello · Malcolm B. Bowers Jr Sally Vegso · George R. Heninger · Dennis S. Charney Interactive effects of subanesthetic ketamine and haloperidol in healthy humans Received : 10 November 1998 / Final version : 23 February 1999 Abstract Ketamine is an N-methyl-D-aspartate (NM- DA) receptor antagonist with prominent psychoactive effects in humans. This study evaluated whether the oral administration of haloperidol 5 mg would block the effects of an intravenous ketamine infusion (bolus of 0.26 mg/kg followed by 0.65 mg/kg per hour). Twenty healthy subjects completed 4 test days involving the oral administration of haloperidol or matched placebo 2 h prior to the intravenous infusion of ketamine or saline. Ketamine produced cognitive, behavioral, neu- roendocrine, and physiologic effects in the healthy sub- jects that were similar to previous reports. Haloperidol pretreatment reduced impairments in executive cogni- tive functions produced by ketamine as measured by proverb interpretations and the Wisconsin Card Sorting Test. However, it failed to block the capacity of ketamine to produce psychosis, perceptual changes, negative symptoms, or euphoria in healthy subjects. These data outline an important, but functionally delineaeted modulation of ketamine effects by dopa- mine 2 receptors and other sites of haloperidol action. Key words Ketamine · N-Methyl-D-asparate · Glutamate · Psychosis · Dissociation · Addiction · Dopamine · Neuroleptic · Memory · Attention · Frontal cortex · Extrapyramidal symptom · Wisconsin Card Sorting Test Introduction The behavioral, cognitive, and electrophysiological effects of antagonists to the N-methyl-D-asparate (NMDA) receptor subclass of glutamate receptors in healthy subjects resemble some aspects of the signs and symptoms of schizophrenia and dissociative disorders (Luby et al. 1959; Domino et al. 1965; Øye et al. 1992; Krystal et al. 1994; Malhotra et al. 1996). The NMDA receptor subclass is the site of action of phencyclidine (PCP) and ketamine (Anis et al. 1983). These drugs bind non-selectively to NMDA receptor subtypes (Yamakura et al. 1993; Bresink et al. 1995). Ketamine is 10–50 times less potent than PCP at NMDA recep- tors, but it has similar effects in preclinical paradigms (Hampton et al. 1982; Byrd 1987; Rothman and Olney 1987; Willetts et al. 1990; Javitt and Zukin 1991). It is available clinically as a racemic mixture of two enan- tiomers. Its S-isomer has 2–4 times greater affinity and selectivity for the NMDA receptor and greater clinical potency than the R-isomer (Øye et al. 1991, 1992; Zeilhofer et al. 1992). Ketamine has greatest affinity for NMDA receptors, but it binds to other receptor sites with lower potency (see Krystal et al. 1994). The similarity between ketamine effects and endoge- nous psychoses created interest in the capacity of antipsychotic medications to block ketamine effects in healthy humans. Co-administration of typical neu- roleptics has been reported to attenuate the psychosis J.H. Krystal · D.C. D’Souza · L.P. Karper · A. Bennett A. Abi-Dargham · M.B. Bowers Jr · G.R. Heninger · D.S. Charney Department of Psychiatry, Yale University School of Medicine, Connecticut, USA J.H. Krystal (*) · D.C. D’Souza · L.P. Karper · A. Bennett A. Abi-Dargham · D. Abi-Saab · K. Cassello · D.S. Charney VA Medical Center, West Haven, CT 06516, USA Fax: +1-203-937-3468, e-mail : john.krystal@yale.edu J.H. Krystal · S. Vegso · G.R. Heninger Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, 34 Park St, New Haven, CT 06519, USA A. Bennett Department of Neurology, Cornell University Medical Center, New York, USA M.B. Bowers Grace Education Building, 25 Park St, New Haven, CT 06510, USA A. Abi-Dargham New York State Psychiatric Institute, 722 W, 168th St, New York, NY 10032, USA