Experimental and Clinical Psychopharmacology 2006, Vol. 14, No. 4, 439 – 449
Copyright 2006 by the American Psychological Association 1064-1297/06/$12.00 DOI: 10.1037/1064-1297.14.4.439
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 purported 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, placebocontrolled, 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 substitution 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, doseand time-related effects. In conjunction with previous studies of drugs with different mechanisms 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, amnestic, 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 believed 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 longterm potentiation, the effects of ketamine on memory are of particular interest. It is well established that ketamine impairs working memory (short-term memory that enables the temporary maintenance and online manipulation of information 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, associated 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; Parwani et al., 2005; Rowland et al., 2005). However, little is known about the time course of working memory impairment 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 Psychiatry 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 analysis. 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 Parkway, Lexington, KY 40509. E-mail:
[email protected] 439
440
LOFWALL, GRIFFITHS, AND MINTZER
needed regarding the specific types of episodic memory processes that are impaired by ketamine. Thus, the primary purpose of the current within-subject, dose-effect study of acute ketamine dosing in healthy volunteers was to further understand the effects of NMDA antagonism on memory. Working memory was evaluated using a paradigm that enables the differentiation of effects on memory versus attention. Three different types of episodic memory were evaluated: recognition memory (recognizing the previous occurrence of an event when presented with the event again), free recall (remembering without the assistance of cues), and source memory (remembering contextual information surrounding an event, such as who, how, where, and when). Effects on encoding and retrieval were evaluated. Encoding processes are engaged during the initial event and lead to the creation of a representation or trace of the event, whereas retrieval processes are engaged to access or bring back into consciousness the memory representation associated with a previously encoded event. To date, only one study of ketamine has assessed episodic memory encoding processes independent of retrieval processes; the results demonstrated selective encoding deficits (Honey, Honey, Sharar, et al., 2005). Metamemory (awareness and knowledge of one’s own memory; Flavell, 1971; Metcalfe & Shimamura, 1994) was also assessed, because subjective reports of ketamine’s effects in healthy volunteers suggest that such volunteers are aware of memory impairment (Dillon et al., 2003; Krystal et al., 1994); however, metamemory has never been systematically evaluated. In addition to specific memory tasks, a wide range of psychomotor, subjective, and cognitive measures were included in the study so as 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. Ketamine’s hallucinogenic and spiritual effects were of particular interest, because these are subjective effects for which ketamine is sometimes abused and used therapeutically (Krupitsky et al., 2002; Krupitsky & Grinenko, 1997). Although the psychotomimetic-type subjective effects of ketamine have been demonstrated using traditional schizophrenia test measures, little research has systematically evaluated ketamine’s effects in healthy volunteers with subjective measures typically used with other hallucinogenic drugs.
Method Participants Eighteen adult volunteers (8 male, 10 female) completed this study. Participants ranged in age from 18 to 47 years (M ⫽ 24 years) and in weight from 53 to 84 kg (M ⫽ 65 kg). They reported having completed 12–22 years of education (M ⫽ 15 years). Nine participants reported consuming 0.5–24.0 alcoholic beverages per week (M ⫽ 5 alcoholic beverages), whereas the other 9 reported not drinking any alcoholic beverages. Twelve participants reported consuming caffeinated beverages delivering 6 –186 mg of caffeine per day (M ⫽ 58 mg), whereas the other 6 reported not drinking caffeinated beverages. Two participants reported smoking less than one pack of cigarettes per day, whereas the other 16 reported not smoking.
Volunteers were excluded if they reported any prior use of ketamine or hallucinogens, past or current substance- or nonsubstance-use psychiatric disorders, histories of suicide attempts, or first-degree relatives with histories of suicide attempts or psychotic mental illnesses (Weissman et al., 2000). Volunteers with positive urine pregnancy tests or significant chronic medical problems (e.g., diabetes) were also excluded. The Johns Hopkins University School of Medicine Institutional Review Board approved this study. Participants gave their written informed consent before beginning the study and were paid for their participation. Participants were told to refrain from using all psychoactive drugs except tobacco and caffeinated products while enrolled in the study. On each session before drug administration, participants were tested for the presence of common illicit drugs in urine with an EMIT system (Syva, Palo Alto, CA) and for the presence of alcohol in expired air with a breathalyzer test; all test results were negative.
General Procedures Three drug conditions (placebo, ketamine 0.2 mg/kg, and ketamine 0.4 mg/kg) were tested across three outpatient experimental sessions at the Johns Hopkins University School of Medicine Behavioral Pharmacology Research Unit in a double-blind, placebo-controlled, crossover design. The order of drug conditions across the three sessions was determined by two Latin squares, with the Williams method used to achieve balance in presentation order and in the order of drug conditions relative to one another (Williams, 1949). Successive sessions were separated by at least 48 hr (e.g., Monday, Wednesday, and Friday). Participants were informed that they could receive placebo, various sedatives, anxiolytics, stimulants, and weight-loss medications. They were told they would receive ketamine at least once, and they were informed of ketamine side effects, including dissociative, hallucinatory, and spiritual experiences (e.g., gaining new insights into their lives and the world). Participants were told that the purpose of the study was to see how different drugs affect performance. Prior to the first session, participants practiced all experimental measures to become familiar with the procedures. During each session, an intramuscular (IM) injection was administered; data were collected before and after drug administration on a range of study measures, as described below. All computerized measures were administered on an Apple Macintosh microcomputer. Vital signs were monitored throughout sessions, and there were no clinically significant vital-sign abnormalities.
Drug Administration Single 1.0-ml IM injections of racemic ketamine (0.2 and 0.4 mg/kg; Bedford Laboratories, Bedford, OH) and 0.9% saline placebo (Abbott Laboratories, Abbott Park, IL) were administered in the participant’s nondominant arm. Ketamine doses were prepared from commercially available ketamine HCl with a base weight of 50 mg/ml and diluted with 0.9% saline for injection to achieve the desired concentration based on weight. Both placebo and ketamine solutions were filtered through a sterile pyrogen-free 0.2um-Millex-GS Millipore filter unit (Millipore Products Division, Bedford, MA) and packaged in a sterilized vial (American Pharmaceutical Partners, Los Angeles, CA) for injection.
Experimental Measures Episodic memory and metamemory. Episodic memory tasks included free recall, recognition memory, and source memory.
ACUTE DOSE EFFECTS OF INTRAMUSCULAR KETAMINE Stimuli for these tasks were three words sets (one for each session), each with four subsets of 40 words (i.e., 160 words presented each session, 480 words across three sessions). All subsets contained concrete nouns (half representing artificial or man-made objects, half representing natural objects) selected from the Thorndike and Lorge (1944) word corpus and were equated on word length and frequency of use. The four subsets within each set were counterbalanced with a Latin square such that each subset appeared equally often in pre- and postinjection study lists and new lists within recognition memory (see below). During each session, participants studied two word lists (subsets of 40 words each): one list, studied approximately 30 min before drug administration (preinjection study list), that was tested for free recall during peak drug effects (to measure ketamine’s effects on retrieval); and one list, studied approximately 35 min after drug administration (postinjection study list), during anticipated peak drug effects, that was tested after drug effects dissipated (to measure ketamine’s effects on encoding). For each list, we had participants categorize the concrete noun represented by each word as “artificial” or “natural” so as to ensure that each word was attended to, because memory for these words would be tested later. Words in both lists were correctly categorized 95%–97% of the time, and there were no differences among drug conditions in categorization accuracy. Free recall was assessed twice each session by giving participants 5 min to write down all the words they could remember on a sheet of lined paper. Approximately 1 hr after the preinjection study list, and immediately prior to presentation of the postinjection study list, free recall for words presented in the preinjection study list was assessed (Free Recall 1). Likewise, approximately 1 hr after the postinjection study list, free recall for words presented in both study lists was assessed (Free Recall 2). The number of correct words from each list was the outcome measure. Immediately after Free Recall 2, source memory was assessed. Participants had 5 min to record next to each word on the Free Recall 2 sheet whether it was from the pre- or postinjection study list. Measures were the proportion of correct source memory identifications from each study list (e.g., number of words correctly identified as being from the preinjection study list divided by the total number of words recalled from the preinjection study list). Subsequently, recognition memory was tested. In this task, words from both study lists (total of 80 old words) were presented randomly intermixed with words from two new lists (total of 80 new words). Words appeared one at a time on the computer screen, and participants indicated the degree to which they recognized (old) or did not recognize (new) the word using a 6-point confidence scale (definitely old, probably old, maybe old, maybe new, probably new, definitely new). Dependent measures for each study list included proportion of old words correctly identified as old (hit rate; collapsed across definitely old, probably old, and maybe old), proportion of new words incorrectly identified as old (false alarm rate), and signal detection measures of sensitivity in distinguishing between old and new words (d⬘) and response bias (C; Snodgrass & Corwin, 1988). Metamemory was assessed by calculating the Goodman– Kruskal gamma correlation (a correlation between confidence and correctness in recognition; Goodman & Kruskal, 1954) in the recognition memory task. Presumably, if one is aware of the state of one’s memory, one will be more confident in correct versus incorrect responses. Gamma values can range from 1 (complete concordance between confidence ratings and recognition memory accuracy) to ⫺1 (complete discordance between confidence ratings and recognition memory accuracy). Dependent measures were gamma scores from both study lists and the new word lists.
441
Working memory. Working memory was assessed with the n-back task (0-, 1-, 2-, and 3-back). By varying the number of positions (n) back, the experimenter manipulates memory load (Jonides et al., 1997). For each n-back, 60 consonant letters (excluding letters l, w, and y) were presented consecutively on the screen, and participants were instructed to make a response to each letter as follows. They were instructed to click yes whenever the current letter on the screen matched (target) the letter n positions back in the sequence and to click no when there was not a match (nontarget). The 0-back is a control condition that involves minimal memory and provides a measure of focused attention only; participants were told to click yes when the letter on the screen matched a predetermined target letter and to click no when there was not a match. Dependent measures were the proportion of yes responses made to target letters (hit rate), the proportion of yes responses made to nontarget letters (false alarm rate), signal detection measures of sensitivity in distinguishing between target and nontarget letters (d⬘) and response bias (C), and median reaction times to correct trials. The order of the four n-back conditions (0-, 1-, 2-, and 3-back) was randomly determined for each participant but was consistent across sessions within a participant. This task took approximately 20 min and was completed prior to drug administration and at approximately 10, 130, and 220 min after drug administration. In addition, immediately prior to and after each n-back, participants rated how well they thought they would perform on the task compared with normal (preperformance estimate) and how well they thought they had performed compared with normal (postperformance estimate), respectively. Participants made these ratings on a visual analog scale (VAS) labeled much worse at the left extreme and much better at the right extreme, with normal labeled in the middle. Scores range from ⫺50 (much worse) to 50 (much better). These ratings measured participants’ cognitive awareness of their performance. Psychomotor performance. Psychomotor performance was measured via circular lights (Griffiths, Bigelow, & Liebson, 1983), a standing balance task, and a computerized version of the digit symbol substitution task (DSST; McLeod, Griffiths, Bigelow, & Yingling, 1982). The dependent measure for circular lights was the number of correct buttons pressed during a 60-s trial. The balance task dependent measure was the sum of the time balanced on each foot (maximum of 30 s on each foot). For the DSST, dependent measures were the number of attempted trials and the proportion of attempted trials correctly replicated during a 90-s trial. In addition, awareness of performance was assessed before (preperformance estimate) and after (postperformance estimate) the DSST, as described above for working memory. All measures were completed prior to drug administration. Circular lights and balance were completed at approximately 5, 160, 215, and 290 min after drug administration. The DSST was completed at approximately 35, 130, and 200 min after drug administration.
Subjective Measures Participants rated (a) strength of drug effect by clicking on one of five options (no drug effect at all, possible mild effect but not sure, definite mild effect, moderately strong effect, or very strong effect), scored from 0 (no drug effect at all) to 4 (very strong effect); (b) drug liking– disliking by clicking on one of nine options (like very much, like quite a bit, like somewhat, like but not very much, feel neutral or no effect, dislike but not very much, dislike somewhat, dislike quite a bit, dislike very much), scored from ⫺4 (dislike very much) to 4 (like very much); and (c) feeling of alertness–sleepiness by clicking along a VAS line labeled very alert at the left extreme and very sleepy at the right extreme, scored
442
LOFWALL, GRIFFITHS, AND MINTZER
from 0 (very alert) to 100 (very sleepy). These measures were completed prior to drug administration and at approximately 45, 150, and 235 min after drug administration. Participants listened to music through headphones while wearing eyeshades (to promote relaxation and to reduce external environmental stimulation) for approximately 15 min twice during each session. After participants listened to music the first time (approximately 70 min after drug administration), they completed the Hallucinogen Rating Scale (HRS; Strassman 1992; Strassman, Qualls, Uhlenhuth, & Kellner, 1994) and the Mysticism Scale (M-Scale; Hood, 1975) on paper. These questionnaires were answered with reference to participants’ experiences since the injection. The HRS is a 100-item questionnaire initially designed to show sensitivity to the hallucinogen N,N-dimethyltryptamine. Items cluster into six subscales assessing various aspects of hallucinogen effects: somaethesia (interoceptive, visceral, and cutaneous–tactile effects), affect (emotional–affective responses), perception (visual, auditory, gustatory, and olfactory experiences), cognition (alterations in thought processes or content), volition (changes in capacity to willfully interact with themselves, the environment, or certain aspects of the experience), and intensity (strength of various aspects of the experience; Strassman et al., 1994). Most items are scored from 0 (not at all) to 4 (extremely), and all subscale scores range from 0 to 4 except for the intensity subscale (range: 0 – 4.25). Higher values indicate endorsement of more hallucinogenic effects. The M-Scale is a 32-item questionnaire providing an empirically based measure of mystical experience that demonstrates cross-cultural generalizability, is well regarded in the field of the psychology of religion (Hood et al., 2001; Hood & Williamson, 2000; Spilka, Hood, Hunsberger, & Gorsuch, 2003; Stace, 1960), and is sensitive to drug-induced experiences (Griffiths et al., 2006). A total score and three empirically derived factor scores are measured: Interpretation (noetic feelings, deeply felt positive mood, and sacredness), Introvertive Mysticism (internal unity, transcendence of time and space, and ineffability), Extrovertive Mysticism (unity of all things/all things are alive). Category scores range from 12 to 108 for all categories except Extrovertive Mysticism (range: 8 –72), with higher scores indicating higher levels of mysticism.
Time Estimation This computerized task assessed the participant’s ability to accurately estimate the duration of 5-, 20-, and 80-s time intervals (Mintzer, Frey, Yingling, & Griffiths, 1997). The dependent measure was the duration (in seconds) of the time interval produced by the participant following the presentation of each time interval. It was completed immediately after the repeatedly administered subjective measures at each time point.
Statistical Analysis Less than 1% of all data was missing (missing data were results of research assistant errors and brief periods of time when 2 participants vomited after receiving 0.4 mg/kg ketamine). All data were analyzed in an analysis of variance (ANOVA) model using PROC MIXED (SAS Version 9.1). For the episodic memory, metamemory, HRS, and M-Scale data that were collected at a single time point, drug condition and list (list was only relevant for episodic memory and metamemory tasks) were factors in the ANOVA. For working memory, time estimation, psychomotor performance, and subjective measures administered repeatedly, drug condition, time, and memory load (0-, 1-, 2-, and 3-back;
relevant only for working memory measures) were factors in the analysis. Because drug effects consistently peaked at the first postinjection assessment time point for all repeated measures, ANOVA analyses at this time point were conducted with drug condition (and memory load) as factors. For all ANOVA analyses, if there were significant main effects or interactions ( p ⱕ .05), simple-effects tests were completed as appropriate (Keppel, 1991). Modified Bonferroni corrections were used if the number of simple-effects tests exceeded the degrees of freedom. Raw means plus or minus standard deviations are presented below.
Results Time Course Analyses Time course analyses for repeated measures demonstrated that when there was a significant drug effect or Drug ⫻ Time interaction, ketamine effects always peaked at the first postinjection assessment time point (see Method section for specific time relative to injection for each measure) and then typically dissipated, as shown in Figure 1, with balance as a representative measure (left panel). Thus, in the following sections, results are presented only for the first postinjection assessment. However, four measures also demonstrated significant differences between ketamine and placebo at later time points: drug liking– disliking, drug strength (see Figure 1, right panel), alertness–sleepiness, and circular lights.
Episodic Memory and Metamemory Table 1 shows the results from all episodic memory and metamemory measures. There was no significant effect of drug on Free Recall 1, suggesting that retrieval processes were not impaired by ketamine. For Free Recall 2, there was a significant main effect of list and a significant Drug ⫻ List interaction. Fewer postinjection study list words (encoded after drug administration) were recalled in the 0.4 mg/kg ketamine condition than in the placebo condition. In addition, there were fewer words recalled from the postinjection study list than from the preinjection study list in the 0.4 mg/kg ketamine condition. Together, these free recall results suggest that 0.4 mg/kg ketamine selectively disrupts encoding processes. There were no significant effects on source memory. Recognition memory results for hit rate, d⬘, and C revealed significant Drug ⫻ List interactions, but there were no significant simple effects except for a lower hit rate for postinjection study list words encoded after 0.4 mg/kg ketamine compared with 0.2 mg/kg ketamine. There were no significant main effects or interactions for false alarm rate or metamemory.
Working Memory (First Postinjection Time Point) For working memory accuracy measures (hit rate, false alarm rate, d⬘, and C), there was a significant drug effect such that 0.4 mg/kg ketamine was significantly different from placebo. There was also a significant memory load effect such that performance worsened as working memory
ACUTE DOSE EFFECTS OF INTRAMUSCULAR KETAMINE
443
Figure 1. Time course effects for total balance and drug strength. Darkened symbols indicate a significant difference from placebo at that time point. Asterisks indicate a significant difference from 0.2 mg/kg ketamine at that time point. Error bars represent ⫹1 standard error of the mean.
load increased. Figure 2 shows results for hit rate and d⬘, which additionally showed a significant Drug ⫻ Memory Load interaction. Hit rate and d⬘ were significantly lower for 0.4 mg/kg ketamine relative to placebo and 0.2 mg/kg ketamine for all memory loads except 0-back. Because 0-back is primarily a measure of attention, ketamine’s working memory effects are likely not secondary to impaired attention. False alarm rate was significantly higher for 0.4 mg/kg ketamine (0.032 ⫾ 0.038) relative to placebo (0.027 ⫾ 0.029) and 0.2 mg/kg ketamine (0.026 ⫾ 0.025). Likewise, C was significantly higher (indicating a more conservative response bias) for 0.4 mg/kg ketamine (0.322 ⫾ 0.033) relative to placebo (0.258 ⫾ 0.231) and 0.2 mg/kg ketamine (0.278 ⫾ 0.281). For reaction time (see Figure 2, bottom panel), there was a significant main effect of memory load such that participants responded more slowly with increasing memory load, but there was no significant drug effect. Preperformance estimates (shown in Table 2 collapsed across memory load) demonstrated a significant doserelated drug effect (0.4 mg/kg ketamine ⬍ 0.2 mg/kg ketamine ⬍ placebo), whereas postperformance estimates (shown in Table 2 as a function of drug condition and memory load) demonstrated both a significant drug effect and a Drug ⫻ Memory Load interaction. Postperformance estimates were significantly lower for 0.4 mg/kg ketamine compared with 0.2 mg/kg ketamine and placebo across all memory loads, whereas estimates were significantly lower in the 0.2 mg/kg ketamine condition compared with placebo only for 2- and 3-back. Given that working memory accuracy was significantly reduced with 0.4 mg/kg ketamine compared with placebo (see Figure 2), the significantly
lower pre- and postperformance estimates in this condition relative to placebo are consistent with actual working memory performance. Although actual working memory accuracy measures were also numerically lower in the 0.2 mg/kg ketamine condition compared with placebo (see Figure 2), these differences were not statistically significant. Thus, the finding of significantly lower pre-and postperformance estimates in the 0.2 mg/kg ketamine condition relative to placebo suggests that participants may have been sensitive to subtle drug effects.
Psychomotor Performance (First Postinjection Time Point) Results for these tasks are shown in Table 2. There was a significant drug effect for circular lights, balance, and DSST (number of trials attempted and performance estimates). Performance on these tasks was significantly worse with 0.4 mg/kg ketamine compared with 0.2 mg/kg ketamine and placebo. The only task that also showed a significant effect of 0.2 mg/kg ketamine relative to placebo was balance. Notably, for the DSST, the proportion correct (a measure of accuracy) did not differ across drug conditions, whereas the number of trials attempted was significantly lower for 0.4 mg/kg ketamine compared with placebo. This pattern suggests that this ketamine dose slowed psychomotor speed while sparing accuracy. The finding of significantly lower pre- and postperformance estimates for the DSST also in the higher dose ketamine condition is consistent with the finding of a significantly lower number of attempted trials in this condition.
444
LOFWALL, GRIFFITHS, AND MINTZER
Table 1 Episodic Memory and Metamemory Measures Ketamine Placebo Measure Free Recall 1 No. words from preinjection study list Free Recall 2 No. words from preinjection study list No. words from postinjection study list Source memory Proportion correct from preinjection study list Proportion correct from postinjection study list Recognition memory Hit rate Preinjection study list Postinjection study list False alarm rate d⬘ Preinjection study list Postinjection study list C Preinjection study list Postinjection study list Metamemory (gamma) Preinjection study list Postinjection study list New word list
0.2 mg/kg
0.4 mg/kg
M
SD
M
SD
M
SD
9.0
3.6
8.7
6.1
8.8
3.7
8.1 8.0
3.5 4.1
9.0 6.4
5.8 5.1
9.3 4.7
3.7 3.8a
.86 .96
.17 .12
.89 .89
.24 .25
.88 .86
.15 .33
.74 .81 .17
.17 .22 .18
.78 .86 .15
.11 .08 .09
.83 .74 .16
.12 .17* .09
1.82 2.14
0.99 1.36
1.99 2.32
0.56 0.60
.20 .04
.37 .39
.14 ⫺.02
.32 .29
.02 .17
.36 .42
.31 .68 .61
.69 .54 .32
.70 .69 .54
.25 .51 .41
.68 .53 .71
.40 .56 .32
2.12 0.53 1.82 0.55
Note. Boldface indicates a significant difference from placebo. An asterisk indicates a significant difference from 0.2 mg/kg ketamine. a Significant difference from preinjection study list in that drug condition.
Subjective Measures (First Postinjection Time Point) Results for these measures are shown in Table 2. There were significant drug effects for all subjective measures except the M-Scale Interpretation factor. Ratings were significantly different from those for placebo in both ketamine conditions for several measures. For example, ratings of drug strength and hallucinogenic experiences (as measured by the HRS subscales of somaethesia, perception, cognition, volition, and intensity) were higher for both ketamine doses relative to placebo. In addition, results from the M-Scale total score and Introvertive Mysticism and Extrovertive Mysticism factors showed that ratings of mystical experiences were lower in both ketamine conditions relative to placebo. Several of these subjective measures also showed graded dose effects such that 0.4 mg/kg ketamine was significantly different from 0.2 mg/kg ketamine. Specifically, ratings of drug effect strength and hallucinogenic experiences (as measured by the HRS subscales of somaethesia, perception, cognition, and intensity) were higher for 0.4 mg/kg than for 0.2 mg/kg of ketamine, and ratings on the M-Scale total score and Introvertive Mysticism factor were lower for 0.4 mg/kg than for 0.2 mg/kg of ketamine. In addition, individual items concerning perceptual experiences were reviewed for all participants in all sessions, and no participant reported a hallucination (perception without stimulus; Jaspers, 1913/1997).
Time Estimation There were no significant effects on time estimation.
Discussion The present study was designed to further understand the effects of NMDA antagonism on memory, 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. There were several important findings. First, 0.4 mg/kg ketamine significantly and selectively impaired free recall encoding processes while sparing retrieval processes; however, there were no significant drug effects on other episodic memory tasks (recognition and source memory), nor were there significant effects on metamemory. Second, there was a higher dose-related threshold for demonstrating memory impairment compared with subjective effects and psychomotor impairment. That is, only the 0.4 mg/kg dose of ketamine produced memory impairment (free recall and working memory), whereas both 0.2 and 0.4 mg/kg doses produced graded dose-related subjective effects and impaired balance relative to placebo. Third, although peak effects for all experimental measures occurred within the first 45 min after drug administration, consistent with previous studies using IM ketamine (Ghoneim et al., 1985; Harborne, Watson, Healy, & Groves, 1996), repeated mea-
ACUTE DOSE EFFECTS OF INTRAMUSCULAR KETAMINE
445
sures results demonstrated a longer duration of subjective effects (at least 2.5 hr) compared with working memory and most psychomotor effects (less than 2 hr). The finding of selective impairment of free recall encoding processes in the present study is important for several reasons. First, it replicates the selective encoding impairment in episodic memory reported by Honey, Honey, Sharar, et al. (2005), who administered a continuous IV ketamine infusion and studied episodic memory with a recognition memory task. Second, because we, in contrast, used single IM ketamine doses and a free recall task to differentiate ketamine’s effects on encoding and retrieval processes, this study now extends the selective encoding impairment in episodic memory to free recall and also demonstrates that this impairment can be produced with single IM bolus doses of ketamine. There were no significant effects of ketamine on the other two episodic memory measures (recognition and source memory) in this study. Although the lack of any ketamine effect on source memory accuracy is not surprising (Honey, Honey, Sharar, et al. 2005; Honey, O’Loughlin, et al., 2005), several studies have reported ketamine-induced recognition impairment (Hetem et al., 2000; Honey, Honey, Sharar, et al., 2005; Honey, O’Loughlin, et al., 2005; Morgan et al., 2004; Oye, Paulsen, & Maurset, 1992). However, the degree to which this impairment is observed appears to be in part modulated by the level of processing engaged during encoding (Honey, Honey, Sharar, et al., 2005; Honey, O’Loughlin, et al., 2005; Morgan et al., 2004). Thus, it is possible that the lack of impairment in the current study is related to the task performed on the words during encoding (artificial–natural categorization). Further studies in which level of processing is specifically manipulated are needed to explore this possibility. Another possibility is that because the recognition memory task was conducted after the second free recall task, participants may have benefited from the act of retrieving words during that task. However, given that free recall for the postinjection study list was impaired with 0.4 mg/kg ketamine relative to placebo, we believe it is unlikely that any retrieval practice made a significant contribution to recognition memory performance in that condition. Overall, the episodic memory data presented here suggest that acute NMDA antagonism, as produced by ketamine, causes a dose-dependent impairment of episodic memory encoding, specifically as measured by free recall. Notably, drugs with different mechanisms of action from ketamine— such as alcohol, benzodiazepines, and anticholinergics— also selectively impair encoding processes in episodic memory tasks (Birnbaum, Parker, Hartley, & Noble, 1978; Curran, 1991; Duka, Curran, Rusted, & Weingartner, 1996;
Figure 2. Working memory hit rate, d⬘, and reaction time as a function of memory load at the first postinjection time point. Darkened symbols indicate a significant difference from placebo. Asterisks indicate a significant difference from 0.2 mg/kg ketamine. Error bars represent ⫹1 standard error of the mean.
446
LOFWALL, GRIFFITHS, AND MINTZER
Table 2 Psychomotor and Subjective Measures (First Postinjection Time Point) Ketamine Placebo Estimate or measure
M
0.2mg/kg SD
M
0.4mg/kg SD
M
SD
Performance estimates WM preperformance WM postperformance 0-back 1-back 2-back 3-back DSST preperformance DSST postperformance
0.09 ⫺1.6 ⫺3.1 ⫺3.0 ⫺3.5 ⫺0.9 0.1
5.8
⫺3.4
8.5
⫺6.6
13.1*
10.5 9.0 8.7 6.8 4.4 3.9
⫺7.1 ⫺9.7 ⫺12.7 ⫺19.2 ⫺6.9 ⫺8.8
13.4 10.3 13.4 15.1 7.2 10.1
⫺14.9 ⫺22.0 ⫺30.9 ⫺36.3 ⫺18.6 ⫺21.2
14.5* 13.8* 13.2* 11.9* 15.1* 15.8*
11.4 18.2
51.0 7.8
10.8* 9.6*
45.4 0.89
13.3* 0.14
Psychomotor measures Circular lights Balance DSST No. trials attempted Proportion correct
65.4 53.7 53.2 0.95
10.3 11.5 9.7 0.04
60.3 20.6 51.2 0.92
9.6 0.13
Subjective measures Alertness/sleepiness Drug strength Drug liking HRS Somaethesia Affect Perception Cognition Volition Intensity M-Scale Total Interpretation Introvertive Mysticism Extrovertive Mysticism
35.4 0.6 ⫺0.1
27.0 0.9 0.9
50.3 2.6 ⫺1.0
25.6 1.0 2.4
62.3 3.3 ⫺2.3
23.2 0.8* 2.4
0.1 0.4 0.0 0.2 1.7 0.3
0.2 0.2 0.1 0.3 0.7 0.5
0.8 0.5 0.5 0.6 2.1 1.1
0.6 0.4 0.6 0.6 0.5 0.7
1.6 0.7 0.9 1.2 2.4 1.6
0.7* 0.5 0.8* 0.7* 0.5 0.8*
266.3 97.0 100.2 69.1
33.7 13.8 13.7 7.7
236.7 92.8 79.8 64.1
53.5 21.2 25.7 13.1
216.6 93.8 58.7 64.1
43.3* 16.5 24.9* 11.7
Note. Boldface indicates a significant difference from placebo. An asterisk indicates a significant difference from 0.2 mg/kg ketamine. WM ⫽ working memory; DSST ⫽ digit symbol substitution task; HRS ⫽ Hallucinogen Rating Scale; M-Scale ⫽ Mysticism Scale.
Kopelman, 1986; Lister, Gorenstein, Fisher-Flowers, Weingartner, & Eckardt, 1991). However, ketamine preserved metamemory and was sometimes associated with sensitivity to subtle performance impairment. This is in contrast to benzodiazepines, which impair both episodic memory and metamemory and are often associated with underestimates of performance impairment (Bacon et al., 1998; Mintzer & Griffiths, 2003). Further studies directly comparing ketamine with benzodiazepines, alcohol, and/or scopolamine would be helpful to determine how these drugs may affect memory, awareness of memory, and performance impairment in similar and dissimilar ways given their distinct mechanisms of action. Working memory also showed dose-related ketamine impairment that appeared to be independent of changes in attention (as reflected by the lack of effects on the 0-back) and unaccompanied by significant increases in reaction times, consistent with previous studies (Adler et al., 1998;
Morgan et al., 2004). Time estimation was also not impaired; however, this task evaluated relatively short time intervals, so deficits in the perception of time passing over longer periods cannot be ruled out. Psychomotor and subjective measure results demonstrated dose-related effects of ketamine. Balance was markedly impaired with both ketamine doses, consistent with ketamine’s action in the cerebellum (Avila, Weiler, Lahti, Tamminga, & Thaker, 2002; Holcomb, Lahti, Medoff, Weiler, & Tamminga, 2001). Ketamine’s effects on psychomotor performance showed selectivity such that ketamine slowed psychomotor speed (number of trials attempted on the DSST) while sparing accuracy (proportion correct). It is interesting to note that whereas impairment on most of the psychomotor measures dissipated within 2 hr of injection, performance on the circular lights task and subjective feelings of alertness, drug liking– disliking, and drug strength persisted 2.5 hr after injection. Although there were
ACUTE DOSE EFFECTS OF INTRAMUSCULAR KETAMINE
no overt behavioral changes noted by observers in participants by the time participants left the session 5 hr after drug administration, there were longer lasting subjective effects. Participants reported still feeling like they were possibly under the influence of drug 4 hr after injection, underscoring the importance of participants being monitored for an extended period of time after drug administration and not being allowed to drive themselves home on session days. Notably, robust subjective ratings of drug effect and impaired psychomotor performance (as measured by the balance task) were observed at a ketamine dose (0.2 mg/kg) that did not produce significant episodic memory or working memory impairment. This pattern of effects appears to differ from that observed with benzodiazepines, which produce memory impairment even at relatively low doses (Mintzer et al., 1997). Not surprisingly, psychological and perceptual phenomena produced by ketamine, as measured by the HRS, were similar to those in other ketamine studies in healthy adults in that the predominant hallucinogenic-like effects were perceptual distortions/illusions and dissociative effects (Bowdle et al., 1998; Honey et al., 2003; Krystal et al., 1994; Malhotra et al., 1997). These effects contrast with hallucinations (perceptions without stimuli; Jaspers, 1959/ 1997) and delusions (fixed, false, idiosyncratic beliefs), which are often features of schizophrenia and that ketamine can induce in people with schizophrenia (Lahti, Weiler, Michaelidis, Parwani, & Tamminga, 2000; Malhotra et al., 1997). Although previous studies have reported that ketamine can produce mystical–spiritual experiences (Krupitsky et al., 2002; Krupitsky & Grinenko, 1997), in the present study, ketamine produced significant decreases in a measure of mystical experience (M-Scale). The absence of mystical experience occurred despite the fact that participants had been instructed that ketamine might induce such effects and that assessment of such effects occurred under conditions that were believed to be conducive to such effects (following a 15-min period of relaxation with eyeshades, headphones through which music was played, and the instruction/suggestion that during this period the drug effects might result in new insights about oneself and the world). Despite these efforts, it seems likely that the conditions of the set and setting of the present study (which also included nondrug-abusing adults, intensive cognitive testing, blinded doses, and discussion of possible negative side effects of ketamine during the informed consent process) were not adequate for facilitating such experiences. Indeed, ketamine was significantly disliked compared with placebo. There are limitations to this study. Ketamine plasma levels were not measured, and drug administration was IM in contrast to most previous cognitive studies in healthy volunteers, which have used continuous IV dosing. Although IM dosing does not produce constant steady-state concentrations of ketamine, the reliable pharmacokinetic and pharmacodynamic profile of IM ketamine allows for some comparison of peak drug levels across dosing routes.
447
Two studies, both administering 0.5 mg/kg IM ketamine, reported similar mean peak ketamine serum concentrations (240 and 243 ng/mL) occurring between 5 and 30 min after dosing, and although there was variability between participants, the minimum peak concentration was 100 ng/mL (Clements, Nimmo, & Grant, 1982; Grant, Nimmo, & Clements, 1981), which is at the maximum of the 50 –100 ng/mL concentration range targeted by many continuousinfusion IV ketamine studies (Honey, Honey, O’Loughlin, et al., 2005; Honey, Honey, Sharar, et al., 2005; Honey, O’Loughlin, et al., 2005; Honey, Turner, et al., 2003; Newcomer et al., 1999; Parwani et al., 2005; Rowland et al., 2005). Given these data, the lack of effects on some measures in the present study, at least in the 0.4 mg/kg ketamine dose condition, is likely not attributable to use of low ketamine doses. In addition, the presence of significant dose-related ketamine subjective and psychomotor effects suggests that any potential ketamine serum concentration variability among participants was not so wide as to prevent detectable effects. Furthermore, the effects of a single-bolus ketamine dose are clinically interesting, because ketamine is used in bolus doses as a “date rape” drug and is also recreationally abused in single-bolus doses, not uncommonly by the IM route (Jansen, 2001; Kelly, 1999; National Drug Intelligence Center, 2006; U.S. Department of Justice, National Drug Intelligence Center, 2004; Weiner et al., 2000). In summary, ketamine selectively impaired free recall while sparing recognition memory, source memory, and metamemory; disrupted encoding while sparing retrieval processes; impaired working memory performance while sparing attention; and slowed DSST performance while sparing accuracy. Subjective and psychomotor effects were present at a dose (0.2 mg/kg) that did not produce significant memory impairment, and the time course of ketamine’s effects was longer for subjective effects (e.g., drug strength, sleepiness, drug disliking) compared with working memory and most psychomotor performance tasks. These results provide important new information about the selective pattern of effects of NMDA antagonism. Furthermore, in conjunction with previous studies of drugs with different mechanisms of actions, the observed selectivity of effects enhances understanding of the pharmacological mechanisms underlying memory, attention, psychomotor performance, and subjective experience.
References Abraham, W. C., & Mason, S. E. (1988). Effects of the NMDA receptor/channel antagonists CPP and MK801 on hippocampal field potentials and long-term potentiation in anesthetized rats. Brain Research, 462, 40 – 46. Adler, C. M., Goldberg, T. E., Malhotra, A. K., Pickar, D., & Breier, A. (1998). Effects of ketamine on thought disorder, working memory, and semantic memory in healthy volunteers. Biological Psychiatry, 43, 811– 816. Anand, A., Charney, D. S., Oren, D. A., Berman, R. M., Hu, X. S., Cappiello, A., & Krystal, J. H. (2000). Attenuation of the neuropsychiatric effects of ketamine with lamotrigine: Support
448
LOFWALL, GRIFFITHS, AND MINTZER
for hyperglutamatergic effects of N-methyl-D-aspartate receptor antagonists. Archives of General Psychiatry, 57, 270 –276. Avila, M. T., Weiler, M. A., Lahti, A. C., Tamminga, C. A., & Thaker, G. K. (2002). Effects of ketamine on leading saccades during smooth-pursuit eye movements may implicate cerebellar dysfunction in schizophrenia. American Journal of Psychiatry, 159, 1490 –1496. Bacon, E., Danion, J. M., Kauffmann-Muller, F., Schelstraete, M. A., Bruant, A., Sellal, F., & Grange, D. (1998). Confidence level and feeling of knowing for episodic and semantic memory: An investigation of lorazepam effects on metamemory. Psychopharmacology, 138, 318 –325. Baddeley, A. (1992, January 31). Working memory. Science, 255, 556 –559. Birnbaum, I. M., Parker, E. S., Hartley, J. T., & Noble, E. P. (1978). Alcohol and memory: Retrieval processes. Journal of Verbal Learning and Verbal Behavior, 17, 325–335. Bowdle, T. A., Radant, A. D., Cowley, D. S., Kharasch, E. D., Strassman, R. J., & Roy-Byrne, P. P. (1998). Psychedelic effects of ketamine in healthy volunteers: Relationship to steady-state plasma concentrations. Anesthesiology, 88, 82– 88. Clements, J. A., Nimmo, W. S., & Grant, I. S. (1982). Bioavailability, pharmacokinetics, and analgesic activity of ketamine in humans. Journal of Pharmaceutical Sciences, 71, 539 –542. Curran, H. V. (1991). Benzodiazepines, memory and mood: A review. Psychopharmacology, 105, 1– 8. Dalgarno, P. J., & Shewan, D. (1996). Illicit use of ketamine in Scotland. Journal of Psychoactive Drugs, 28, 191–199. Dillon, P., Copeland, J., & Jansen, K. (2003). Patterns of use and harms associated with non-medical ketamine use. Drug and Alcohol Dependence, 69, 23–28. Duka, T., Curran, H. V., Rusted, J. M., & Weingartner, H. J. (1996). Perspectives on cognitive psychopharmacology research. Behavioural Pharmacology, 7, 401– 410. Flavell, J. H. (1971). First discussant’s comments: What is memory development the development of? Human Development, 14, 272–278. Ghoneim, M. M., Hinrichs, J. V., Mewaldt, S. P., & Petersen, R. C. (1985). Ketamine: Behavioral effects of subanesthetic doses. Journal of Clinical Psychopharmacology, 5, 70 –77. Goodman, L. A., & Kruskal, W. H. (1954). Measures of association for cross-classifications. Journal of the American Statistical Association, 49, 732–764. Grant, I. S., Nimmo, W. S., & Clements, J. A. (1981). Pharmacokinetics and analgesic effects of i.m. and oral ketamine. British Journal of Anaesthesia, 53, 805– 810. Griffiths, R. R., Bigelow, G. E., & Liebson, I. (1983). Differential effects of diazepam and pentobarbital on mood and behavior. Archives of General Psychiatry, 40, 865– 873. Griffiths, R. R., Richards, W. A., McCann, U., & Jesse, R. (2006). Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance. Psychopharmacology, 187, 268 –283. Haas, D. A., & Harper, D. G. (1992). Ketamine: A review of its pharmacologic properties and use in ambulatory anesthesia. Anesthesia Progress, 39, 61– 68. Harborne, G. C., Watson, F. L., Healy, D. T., & Groves, L. (1996). The effects of sub-anaesthetic doses of ketamine on memory, cognitive performance and subjective experience in healthy volunteers. Journal of Psychopharmacology, 10, 134 –140. Harris, E. W., Ganong, A. H., & Cotman, C. W. (1984). Long-term potentiation in the hippocampus involves activation of N-methyl-D-aspartate receptors. Brain Research, 323, 132–137.
Hetem, L. A., Danion, J. M., Diemunsch, P., & Brandt, C. (2000). Effect of a subanesthetic dose of ketamine on memory and conscious awareness in healthy volunteers. Psychopharmacology, 152, 283–288. Holcomb, H. H., Lahti, A. C., Medoff, D. R., Weiler, M., & Tamminga, C. A. (2001). Sequential regional cerebral blood flow brain scans using PET with H215O demonstrate ketamine actions on CNS dynamically. Neuropsychopharmacology, 25, 165–172. Honey, G. D., Honey, R. A., O’Loughlin, C., Sharar, S. R., Kumaran, D., Suckling, J., et al. (2005). Ketamine disrupts frontal and hippocampal contribution to encoding and retrieval of episodic memory: An fMRI study. Cerebral Cortex, 15, 749 –759. Honey, G. D., Honey, R. A., Sharar, S. R., Turner, D. C., PomarolClotet, E., Kumaran, D., et al. (2005). Impairment of specific episodic memory processes by sub-psychotic doses of ketamine: The effects of levels of processing at encoding and of the subsequent retrieval task. Psychopharmacology, 181, 445– 457. Honey, G. D., O’Loughlin, C., Turner, D. C., Pomarol-Clotet, E., Corlett, P. R., & Fletcher, P. C. (2005). The effects of a subpsychotic dose of ketamine on recognition and source memory for agency: Implications for pharmacological modelling of core symptoms of schizophrenia. Neuropsychopharmacology, 31, 413– 423. Honey, R. A., Turner, D. C., Honey, G. D., Sharar, S. R., Kumaran, D., Pomarol-Clotet, E., et al. (2003). Subdissociative dose ketamine produces a deficit in manipulation but not maintenance of the contents of working memory. Neuropsychopharmacology, 28, 2037–2044. Hood, R. W. (1975). The construction and preliminary validation of a measure of reported mystical experience. Journal for the Scientific Study of Religion, 14, 29 – 41. Hood, R. W., Jr., Ghorbani, N., Watson, P. J., Ghramaleki, A. F., Bing, M. N., Davison, H. K., et al. (2001). Dimensions of the Mysticism Scale: Confirming the three-factor structure in the United States and Iran. Journal for the Scientific Study of Religion, 40, 691–705. Hood, R. W., Jr., & Williamson, W. P. (2000). An empirical test of the unity thesis: The structure of mystical descriptors in various faith samples. Journal of Psychology and Christianity, 19, 232–244. Jansen, K. (2001). Ketamine: Dreams and realities. Sarasota, FL: Multidisciplinary Association for Psychedelic Studies. Jaspers, K. (1997). General psychopathology (J. Hoenig & M. W. Hamilton, Trans.). Baltimore: Johns Hopkins University Press. (Original work published 1913) Jentsch, J. D., & Roth, R. H. (1999). The neuropsychopharmacology of phencyclidine: From NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia. Neuropsychopharmacology, 20, 201–225. Jonides, J., Schumacher, E. H., Smith, E. E., Lauber, E. J., Awh, E., Minoshima, S., & Koeppe, R. A. (1997). Verbal working memory load affects regional brain activation as measured by PET. Journal of Cognitive Neuroscience, 9, 462– 475. Kelly, K. (1999). The little book of ketamine. Berkeley, CA: Ronin. Keppel, G. (1991). Design and analysis: A researcher’s handbook (3rd ed.). Englewood Cliffs, NJ: Prentice Hall. Kopelman, M. D. (1986). The cholinergic neurotransmitter system in human memory and dementia: A review. Quarterly Journal of Experimental Psychology: Human Experimental Psychology, 38(A), 535–573.
ACUTE DOSE EFFECTS OF INTRAMUSCULAR KETAMINE Krupitsky, E., Burakov, A., Romanova, T., Dunaevsky, I., Strassman, R., & Grinenko, A. (2002). Ketamine psychotherapy for heroin addiction: Immediate effects and two-year follow-up. Journal of Substance Abuse Treat, 23, 273–283. Krupitsky, E. M., & Grinenko, A. Y. (1997). Ketamine psychedelic therapy (KPT): A review of the results of ten years of research. Journal of Psychoactive Drugs, 29, 165–183. Krystal, J. H., D’Souza, D. C., Petrakis, I. L., Belger, A., Berman, R. M., Charney, D. S., et al. (1999). NMDA agonists and antagonists as probes of glutamatergic dysfunction and pharmacotherapies in neuropsychiatric disorders. Harvard Review of Psychiatry, 7, 125–143. Krystal, J. H., Karper, L. P., Seibyl, J. P., Freeman, G. K., Delaney, R., Bremner, J. D., et al. (1994). Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans: Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Archives of General Psychiatry, 51, 199 –214. Lahti, A. C., Weiler, M. A., Michaelidis, B. A., Parwani, A., & Tamminga, C. A. (2001). Effects of ketamine in normal and schizophrenic volunteers. Neuropsychopharmacology, 25, 455– 467. Lister, R. G., Gorenstein, C., Fisher-Flowers, D., Weingartner, H. J., & Eckardt, M. J. (1991). Dissociation of the acute effects of alcohol on implicit and explicit memory processes. Neuropsychologia, 29, 1205–1212. Malhotra, A. K., Pinals, D. A., Adler, C. M., Elman, I., Clifton, A., Pickar, D., & Breier, A. (1997). Ketamine-induced exacerbation of psychotic symptoms and cognitive impairment in neuroleptic-free schizophrenics. Neuropsychopharmacology, 17, 141– 150. Malhotra, A. K., Pinals, D. A., Weingartner, H., Sirocco, K., Missar, C. D., Pickar, D., & Breier, A. (1996). NMDA receptor function and human cognition: The effects of ketamine in healthy volunteers. Neuropsychopharmacology, 14, 301–307. McLeod, D. R., Griffiths, R. R., Bigelow, G. E., & Yingling, J. (1982). An automated version of the digit symbol substitution test (DSST). Behavior Research Methods & Instrumentation, 14, 463– 466. Metcalfe, J., & Shimamura, A. P. (Eds.). (1994). Metacognition: Knowing about knowing. Cambridge, MA: MIT Press. Mintzer, M. Z., Frey, J. M., Yingling, J. E., & Griffiths, R. R. (1997). Triazolam and zolpidem: A comparison of their psychomotor, cognitive, and subjective effects in healthy volunteers. Behavioural Pharmacology, 8, 561–574. Mintzer, M. Z., & Griffiths, R. R. (2003). Triazolam–amphetamine interaction: Dissociation of effects on memory versus arousal. Journal of Psychopharmacology, 17, 17–29. Morgan, C. J., Mofeez, A., Brandner, B., Bromley, L., & Curran, H. V. (2004). Acute effects of ketamine on memory systems and psychotic symptoms in healthy volunteers. Neuropsychopharmacology, 29, 208 –218. National Drug Intelligence Center. (2006). Ketamine fast facts: Questions and answers. Available from U.S. Department of Justice Web site: http://www.usdoj.gov/ndic/pubs4/4769/4769p.pdf
449
Newcomer, J. W., Farber, N. B., Jevtovic-Todorovic, V., Selke, G., Melson, A. K., Hershey, T., et al. (1999). Ketamine-induced NMDA receptor hypofunction as a model of memory impairment and psychosis. Neuropsychopharmacology, 20, 106 –118. Oye, I., Paulsen, O., & Maurset, A. (1992). Effects of ketamine on sensory perception: Evidence for a role of N-methyl-D-aspartate receptors. Journal of Pharmacology and Experimental Therapeutics, 260, 1209 –1213. Parwani, A., Weiler, M. A., Blaxton, T. A., Warfel, D., Hardin, M., Frey, K., & Lahti, A. C. (2005). The effects of a subanesthetic dose of ketamine on verbal memory in normal volunteers. Psychopharmacology, 183, 265–274. Rowland, L. M., Astur, R. S., Jung, R. E., Bustillo, J. R., Lauriello, J., & Yeo, R. A. (2005). Selective cognitive impairments associated with NMDA receptor blockade in humans. Neuropsychopharmacology, 30, 633– 639. Snodgrass, J. G., & Corwin, J. (1988). Pragmatics of measuring recognition memory: Applications to dementia and amnesia. Journal of Experimental Psychology: General, 117, 34 –50. Spilka, B., Hood, R. W., Jr., Hunsberger, B., & Gorsuch, R. (2003). The psychology of religion: An empirical approach (3rd ed.). New York: Guilford Press. Stace, W. T. (1960). Mysticism and philosophy. Philadelphia: Lippincott. Strassman, R. (1992). Subjective effects of DMT and the development of the Hallucinogen Rating Scale. Newsletter of the Multidisciplinary Association for Psychedelic Studies, 3(2). Strassman, R. J., Qualls, C. R., Uhlenhuth, E. H., & Kellner, R. (1994). Dose-response study of N,N-dimethyltryptamine in humans: II. Subjective effects and preliminary results of a new rating scale. Archives of General Psychiatry, 51, 98 –108. Thorndike, E. L., & Lorge, I. (1944). The teacher’s word book of 30,000 words. New York: Teachers College, Columbia University. U.S. Department of Justice, National Drug Intelligence Center. (2004, July). Intelligence bulletin: Ketamine. Available from U.S. Department of Justice Web site: http://justice.gov/ndic/ pubs10/10255/10255p.pdf Weiner, A. L., Vieira, L., McKay, C. A., & Bayer, M. J. (2000). Ketamine abusers presenting to the emergency department: A case series. Journal of Emergency Medicine, 18, 447– 451. Weissman, M. M., Wickramaratne, P., Adams, P., Wolk, S., Verdeli, H., & Olfson, M. (2000). Brief screening for family psychiatric history: The family history screen. Archives of General Psychiatry, 57, 675– 682. White, P. F., Way, W. L., & Trevor, A. J. (1982). Ketamine—Its pharmacology and therapeutic uses. Anesthesiology, 56, 119 – 136. Williams, E. J. (1949). Experimental designs balanced for the estimation of residual effects of treatments. Australian Journal of Scientific Research, 2, 149 –168.
Received April 4, 2006 Revision received July 17, 2006 Accepted July 19, 2006 䡲
