Cognitive and Subjective Acute Dose Effects of Intramuscular Ketamine in Healthy Adults Michelle R. Lofwall, Roland R. Griffiths, and Miriam Z. Mintzer Johns Hopkins University School of Medicine Ketamine is a noncompetitive N-methyl-D-aspartate (NMDA) antagonist. Given the pur- ported role of the NMDA receptor in long-term potentiation, the primary purpose of the present study was to further understand the dose-related effects of ketamine on memory. The study was also designed to provide information about the relative effects of ketamine on memory versus nonmemory effects and to more fully characterize ketamine’s overall pattern and time course of effects. Single intramuscular injections of ketamine (0.2 mg/kg, 0.4 mg/kg) were administered to 18 healthy adult volunteers using a double-blind, placebo- controlled, crossover design. Word lists were used to evaluate episodic memory (free recall, recognition memory, source memory) and metamemory. Working memory, time estimation, psychomotor performance, and subjective effects were assessed repeatedly for 5 hours after drug administration. Ketamine selectively impaired encoding (as measured by free recall) while sparing retrieval, working memory while sparing attention, and digit symbol substitu- tion task speed while sparing accuracy. Ketamine did not significantly impair recognition or source memory, metamemory, or time estimation. There were no hallucinations or increases in mystical experiences with ketamine. Memory measures were less sensitive to ketamine effects than subjective or psychomotor measures. Subjective effects lasted longer than memory and most psychomotor impairments. Ketamine produces selective, transient, dose- and time-related effects. In conjunction with previous studies of drugs with different mech- anisms of actions, the observed selectivity of effects enhances the understanding of the pharmacological mechanisms underlying memory, attention, psychomotor performance, and subjective experience. Keywords: ketamine, human, memory, psychomotor, subjective Ketamine is an injectable, short-duration sedative, am- nestic, analgesic, “dissociative” anesthetic drug used in a variety of human and veterinary anesthesia and emergency care situations in the United States and abroad (Haas & Harper, 1992; White, Way, & Trevor, 1982). Because of its psychoactive effects, it has also been abused recreationally (Dalgarno & Shewan, 1996; Dillon, Copeland, & Jansen, 2003; Weiner, Vieira, McKay, & Bayer, 1999) and used in drug-assisted psychotherapy studies for the treatment of alcohol- and drug-dependent adults (Krupitsky et al. 2002; Krupitsky & Grinenko, 1997). Pharmacologically, ketamine acts predominantly as a noncompetitive antagonist at N-methyl-D-aspartic acid (NMDA) glutamate-type receptors. These receptors are widely distributed in the brain—with high densities in the cerebral cortex, including hippocampus—and they are be- lieved to play a key role in learning and memory via long-term potentiation (Abraham & Mason, 1988; Harris, Ganong, & Cotman, 1984) and in the etiology and treatment of several neuropsychiatric disorders (e.g., schizophrenia, epilepsy, dementia of the Alzheimer’s type; Jentsch & Roth, 1999; Krystal et al. 1999). Given the purported role of NMDA receptors in long- term potentiation, the effects of ketamine on memory are of particular interest. It is well established that ketamine im- pairs working memory (short-term memory that enables the temporary maintenance and online manipulation of infor- mation in the service of behavioral goals; Adler, Goldberg, Malhotra, Pickar, & Breier, 1998; Baddeley, 1992; Morgan, Mofeez, Brandner, Bromley, & Curran, 2004) and episodic memory (memory for a personally experienced event, asso- ciated with a specific spatial and temporal context; Anand et al., 2000; Ghoneim, Hinrichs, Mewaldt, & Petersen, 1985; Hetem, Danion, Diemunsch, & Brandt, 2000; Krystal et al., 1994; Malhotra et al., 1996; Newcomer et al., 1999; Par- wani et al., 2005; Rowland et al., 2005). However, little is known about the time course of working memory impair- ment produced by ketamine, and additional clarification is Michelle R. Lofwall and Miriam Z. Mintzer, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine; Roland R. Griffiths, Departments of Psychi- atry and Behavioral Sciences and Neuroscience, Johns Hopkins University School of Medicine. This study was supported by National Institute on Drug Abuse Research Grants R01 DA03889 and T32 DA07209. We thank Jeanene Pope and Eva Costlow for protocol management, John Yingling for technical assistance, and Paul Nuzzo for data analy- sis. The study was conducted in compliance with United States laws. Correspondence concerning this article should be addressed to Michelle R. Lofwall, who is now at the Department of Psychiatry, University of Kentucky College of Medicine, 3470 Blazer Park- way, Lexington, KY 40509. E-mail: mlofw2@email.uky.edu Experimental and Clinical Psychopharmacology Copyright 2006 by the American Psychological Association 2006, Vol. 14, No. 4, 439 – 449 1064-1297/06/$12.00 DOI: 10.1037/1064-1297.14.4.439 439