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Original Article |

Dose-Related Ethanol-like Effects of the NMDA Antagonist, Ketamine, in Recently Detoxified Alcoholics FREE

John H. Krystal, MD; Ismene L. Petrakis, MD; Elizabeth Webb; Ned L. Cooney, PhD; Laurence P. Karper, MD; Sheila Namanworth; Philip Stetson, PhD; Louis A. Trevisan, MD; Dennis S. Charney, MD
[+] Author Affiliations

From the Department of Psychiatry, Yale University School of Medicine and the Veterans Affairs–Yale University Alcoholism Research Center, West Haven, Conn (Drs Krystal, Petrakis, Cooney, Karper, Trevisan, and Charney and Mss Webb and Namanworth); and the Upjohn Research Institute, Department of Pharmacology, University of Michigan Medical School, Ann Arbor (Dr Stetson).


Arch Gen Psychiatry. 1998;55(4):354-360. doi:10.1001/archpsyc.55.4.354.
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Published online

Background  This study evaluated the dose-related ethanol-like subjective effects of the N -methyl-D-aspartate (NMDA) glutamate receptor antagonist ketamine hydrochloride in recently detoxified alcoholics.

Methods  Twenty male inpatients meeting DSM-III-R criteria for alcohol dependence and who had not consumed alcohol for 10 to 27 days prior to the study completed 3 test days that involved the intravenous infusion of ketamine hydrochloride (0.1 mg/kg or 0.5 mg/kg) or saline solution under randomized double-blind conditions. Ethanol-like subjective effects were assessed using the Sensation Scale; the Biphasic Alcohol Effects Scale; visual analog scales to measure "high" and degree of similarity to ethanol, cocaine, and marijuana; a scale assessing the number of standard alcohol drinks producing similar subjective effects; and visual analog scales measuring ethanol craving.

Results  Ketamine produced dose-related ethanol-like effects on each scale measuring its similarity to ethanol. Its effects were more similar to the sedative or descending limb effects of ethanol than to the stimulant or ascending limb effects. Ketamine effects also were more like ethanol than marijuana or cocaine. Ethanol-like effects were more prominent at the higher ketamine dose, a dose rated as similar to greater levels of ethanol intoxication. However, ketamine did not increase craving for ethanol.

Conclusion  The production of ethanol-like subjective effects by ketamine supports the potential clinical importance of NMDA receptor antagonism among the mechanisms underlying the subjective effects of ethanol in humans.

Figures in this Article

A GROWING body of research indicates that the capacity of ethanol to block glutamate effects at the N-methyl-D-aspartate (NMDA) receptor contributes to its acute behavioral effects and to the natural history and neuropathology of alcoholism.1 Ethanol reduces NMDA-stimulated ion currents in a noncompetitive and concentration-dependent fashion across the range of ethanol concentrations (5-100 mmol/L) associated with human ethanol intoxication.27 Long-term ethanol administration increases the levels of NMDA receptor subunits, up-regulates NMDA receptor-related binding, and produces cross-tolerance with other noncompetitive NMDA antagonists.812 Increased NMDA receptor function produced by long-term ethanol administration contributes to withdrawal-related seizures10 and neurotoxic effects.13

The NMDA antagonists ketamine hydrochloride, phencyclidine (PCP), and dizocilpine maleate (MK-801) substitute for ethanol in preclinical drug discrimination paradigms.1417 In these studies, the capacity of NMDA antagonists to substitute for ethanol was greater with increasing reference doses of ethanol. This finding suggested that NMDA receptor blockade contributed more prominently to the subjective effects of higher ethanol doses.15

Our study evaluated whether ketamine produced ethanol-like subjective effects in recently detoxified alcoholic patients. To our knowledge, there are no previous clinical studies evaluating the contributions of NMDA receptors to the behavioral effects of ethanol in humans.

PATIENTS

Twenty male inpatients (mean±SD age, 44.0±10.5 years; weight, 74.7±9.0 kg) who met criteria for alcohol dependence18 as determined by the Structured Clinical Interview for DSM-III-R19 participated in testing. Patients began drinking at a mean±SD of 15.3±2.9 years of age, began regular drinking at 17.8±5.5 years of age, began regular drinking to intoxication at 21.1±7.1 years of age, and their heaviest level of drinking was at 32.7±13.8 years of age. Patients had a 23.0±10.1-year history of alcoholism. They had undergone a mean±SD of 5.8±9.7 inpatient alcohol detoxifications (range, 0-40). Their mean daily consumption of alcohol was equivalent to 391.5±170 mL of absolute alcohol per day. The mean±SD Michigan Alcoholism Screening Test score20 was 38.7±6.5. Sixteen (80%) of the 20 patients in this study met the von Knorring et al21 criteria for type 2 alcoholism, defined as age of onset before 25 years of age and 2 or more social consequences of alcoholism. Twelve (60%) of the 20 patients had a first-degree relative with a history of alcoholism. Patients were medically stable at study entry based on medical history, physical examination, and routine laboratory testing.

Patients were excluded if they met the criteria for another substance use disorder other than nicotine dependence in the year prior to testing. Fifteen patients (75%) reported lifetime marijuana use, but no use occurred in the year prior to testing. Ten patients (50%) had lifetime cocaine use. Of these patients, 1 used cocaine 6 months prior to testing at a subabuse level and the remainder had not used cocaine for at least 1 year prior to testing. The absence of other current substance abuse was supported by negative results of urine toxicological screens prior to testing. Subjects were also excluded if they had another DSM-III-R Axis I diagnosis during a period that was free of alcohol consumption.

Subjects were inpatients at the Substance Abuse Treatment Research Unit of the Veterans Affairs Connecticut Healthcare System, West Haven. They participated in testing for a mean±SD of 17.6±4.2 days (range, 10-27 days) after consuming their last alcoholic beverage. Fourteen patients completed detoxification with pharmacologic supports prior to study entry (benzodiazepines, n=10; nimodipine, n=4). The mean±SD period between the administration of the last benzodiazepine dose and the first pharmacologic test day was 15.7±5.9 days (range, 7-26 days). On their first test day, patients received placebo (n=5), 0.1 mg/kg ketamine hydrochloride (n=9), or 0.5 mg/kg ketamine hydrochloride (n=6).

TESTING PROCEDURE

This research protocol was approved by the Human Subjects Subcommittee of the Veterans Affairs Connecticut Healthcare System and the Human Investigations Committee of the Yale University School of Medicine, New Haven, Conn. After giving informed consent for human investigation, each patient completed 3 test days separated by 48 to 96 hours in a randomized order under double-blind conditions. The information presented to patients while obtaining consent included a warning that the effects of ketamine might resemble ethanol intoxication and might stimulate craving for alcohol. On each test day, patients received a 40-minute intravenous infusion containing either saline solution, 0.1 mg/kg ketamine hydrochloride, or 0.5 mg/kg ketamine hydrochloride (Ketalar, Parke-Davis, Kalamazoo, Mich). This method of administration was similar to that reported previously in healthy subjects.22 For each test session, participants fasted overnight and remained in a fasting state during the test session. They presented for testing at approximately 8:30 AM and an intravenous line was placed at that time. Blood was drawn to determine ketamine levels at 10 and 80 minutes after the initiation of ketamine infusion.

Ratings were performed to characterize subjective responses to ketamine that mirrored a previous psychopharmacologic study.23 Patients completed visual analog scales of anger, anxiety, high, nervousness, and sadness.22,23 Anxiety was defined as "a mental awareness of worry." Nervousness was defined as a "physical feeling of jitteriness, tension, heart throbbing, breathlessness, or other similar symptoms." These scales consisted of 100-mm lines (0=none; 100=maximum possible) marked proportionately to the perceived intensity of the experience.

Patients completed measures of ethanol-like subjective effects: the Sensation Scale24; self-rated visual analog scales measuring similarity to acute behavioral effects of alcohol, cocaine, and marijuana (0=not at all similar; 100=identical); a scale measuring the number of standard drinks of ethanol comparable to their drug responses; and the Biphasic Alcohol Effects Scale.25 The Biphasic Alcohol Effects Scale measures stimulant effects associated with the ascending limb of ethanol intoxication and sedative effects associated with the descending limb of ethanol intoxication. Items associated with the ascending limb of ethanol intoxication include energized, excited, stimulated, talkative, "up," and vigorous. Items associated with the descending limb include difficulty concentrating, "down," heavy head, inactive, sedated, slow thoughts, and sluggish. Inspection of the data on the visual analog scales measuring similarity to ethanol, cocaine, and marijuana revealed no clear discriminative effects of ketamine beyond 80 minutes after the initiation of drug infusion. To simplify the analysis and reduce lack of sphericity, time points up to 80 minutes after the initiation of drug infusions were analyzed. For comparison purposes, standard drinks were defined as equivalents of 15 mL of absolute ethanol, approximately comparable to 12 oz of beer, 4 oz of wine, 1.25 oz of 80-proof alcohol, or 1 oz of 100-proof alcohol. Ethanol craving was assessed using a self-rated visual analog scale evaluating "desire to drink alcohol" used in a previous study.23 Assessments of ethanol-like effects, mood states, and craving were completed at 60 and 15 minutes prior to ketamine infusion and 10, 40, 80, 110, 170, and 230 minutes after the initiation of ketamine infusion.

KETAMINE LEVELS

Plasma ketamine levels were determined by gas chromatography–mass spectrometry by 1 of the authors (P.S.) according to methods reported previously.26 Triplicate quality control samples were assayed on each of 3 consecutive days. The calibration curve was calculated for ketamine concentrations ranging between 20 ng/mL and 500 ng/mL. The concentration means for seeded control samples containing 50 ng/mL and 200 ng/mL were found to be within 1.3% and 3.1% of the theoretical values. The assay was found to have coefficients of variation ranging between 3.7% and 4.9%.

DATA ANALYSIS

Data were evaluated initially using repeated-measures analysis of variance (RMANOVA) with within-subjects factors of drug (placebo, 0.1 mg/kg ketamine hydrochloride, or 0.5 mg/kg ketamine hydrochloride) and time. These RMANOVAs were tested for lack of sphericity and Huynh-Feldt adjustments were made to the degrees of freedom to reduce type I error. Significant RMANOVAs were followed with post hoc RMANOVAs comparing the responses following the low and high doses of ketamine to placebo. Significant main effects were also followed with post hoc within-subjects contrasts with significance adjusted for multiple comparisons using Bonferroni corrections. The means of the baseline values were compared between test days using paired t tests with Bonferroni correction made to decrease the effect of multiple comparisons. No significant baseline differences emerged in these analyses.

EVIDENCE OF ETHANOL-LIKE EFFECTS
Sensation Scale

Ketamine produced significant dose-related ethanol-like effects as assessed by the Sensation Scale (Figure 1; RMANOVA, dose × time interaction: F12,228=12.1; P<.001). Post hoc RMANOVAs revealed that 0.5 mg/kg ketamine hydrochloride produced greater Sensation Score increases than both 0.1 mg/kg ketamine hydrochloride (dose × time interaction: F6,114=13.1; P<.001) and saline solution (dose × time interaction: F6,114=12.4; P<.001). However, 0.1 mg/kg ketamine hydrochloride effects were not significantly different from saline solution.

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Figure 1.

Effects of placebo, 0.1 mg/kg ketamine hydrochloride, and 0.5 mg/kg ketamine hydrochloride on Sensation Scale Scores (A) and on self-rated "high" (B) in recently detoxified alcoholic patients (N=20). Values are expressed as mean±SEM. See "Patients and Methods" and "Results" sections for explanation of statistical analyses.

Graphic Jump Location
Self-reported High

As depicted in Figure 1, ketamine increased self-rated high in a dose-related manner (RMANOVA, dose × time interaction: F12,228=8.6; P<.001). Post hoc RMANOVAs revealed that 0.5 mg/kg ketamine hydrochloride produced greater euphoria than both 0.1 mg/kg ketamine hydrochloride (dose × time interaction: F6,114=7.3; P<.001) and saline solution (dose × time interaction: F6,114=15.3; P<.001). Effects of 0.1 mg/kg ketamine hydrochloride were not significantly different than saline solution.

Number of Drinks Scale

Ketamine produced a dose-dependent increase in the perceived number of standard ethanol drinks administered (Figure 2; RMANOVA, dose × time interaction: F12,228=13.1; P<.001). Post hoc RMANOVAs revealed that 0.5 mg/kg ketamine hydrochloride was perceived as similar to a greater number of standard ethanol drinks than were both 0.1 mg/kg ketamine hydrochloride (dose × time interaction: F6,114=12.4; P<.001) and saline solution (dose × time interaction: F6,114=14.3; P<.001). There was also a nonsignificant trend for 0.1 mg/kg ketamine hydrochloride effects to be rated as similar to more ethanol drinks than saline solution (dose × time interaction: F6,114=3.4; P=.06).

Place holder to copy figure label and caption
Figure 2.

The number of standard ethanol drinks that recently detoxified alcoholic patients (N=20) determined were similar to the effects of placebo, 0.1 mg/kg ketamine hydrochloride, and 0.5 mg/kg ketamine hydrochloride. Values are expressed as mean±SEM. See "Patients and Methods" and "Results" sections for explanation of statistical analyses.

Graphic Jump Location
SPECIFICITY OF ETHANOL-LIKE EFFECTS
Differential Similarity to the Ascending and Descending Limbs of Ethanol Intoxication

Ketamine increased total scores on the Biphasic Alcohol Effects Scale (RMANOVA, dose × time interaction: F12,204=6.0; P=.001). The ketamine dose effect was explored with post hoc within-subjects contrasts, which indicated that 0.5 mg/kg ketamine hydrochloride had greater ethanol-like effects relative to both 0.1 mg/kg and saline solution (F1=5.1; P=.03), but no significant difference between the 0.1 mg/kg dose and saline solution.

As depicted in Figure 3, ketamine increased scores on the sedative or descending limb items on the Biphasic Alcohol Effects Scale, but not the stimulant or ascending limb items. The overall RMANOVA performed on subjects completing the Biphasic Alcohol Effects Scale (n=18) revealed significant effects (dose × time interaction: F12,204=6.2; P<.001; limb × dose × time interaction: F12,204=4.1; P=.001). There were no significant main effects or interactions in the RMANOVA performed on ascending limb data. However, the RMANOVA conducted on descending limb data revealed highly significant ketamine effects (dose × time interaction: F12,204=8.4; P<.001). Post hoc contrasts revealed that the 0.5 mg/kg ketamine hydrochloride dose effect was greater then both 0.1 mg/kg and placebo effects (F1=7.9; P=.009) and the 0.1 mg/kg ketamine hydrochloride dose effect was greater than the placebo effect (F1=4.6; P=.04).

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Figure 3.

Effects of placebo, 0.1 mg/kg ketamine hydrochloride, and 0.5 mg/kg ketamine hydrochloride on scores for the stimulant or ascending limb of the Biphasic Alcohol Effects Scale (A) and on the sedative or descending limb of the Biphasic Alcohol Effects Scale (B) in recently detoxified alcoholic patients (N=20). Values are expressed as mean±SEM. See "Patients and Methods" and "Results" sections for explanation of statistical analyses.

Graphic Jump Location
Differential Similarity to Ethanol, Cocaine, and Marijuana

Ketamine effects were rated as more similar to those of ethanol than to marijuana or cocaine (Figure 4, visual analog scale). In the initial analysis, the 10 patients who had previous experience with the effects of ethanol, marijuana, and cocaine compared the similarity of ketamine effects with each of these drugs of abuse. The RMANOVA performed on these data revealed significant effects of the reference drug of abuse (ethanol, marijuana, or cocaine; F2,18=3.8; P=.04), ketamine dose (F2,18=7.3; P=.01), and the ketamine dose × time interaction (F6,54=6.0; P=.002). There was a nonsignificant trend toward significance for the drug of abuse × ketamine dose × time interaction (F12,108=1.9; P=.1). A post hoc within-subjects contrast revealed that ketamine effects were significantly more similar to ethanol than to both marijuana and cocaine (F1=6.7; P=.02).

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Figure 4.

Similarity of the effects of placebo, 0.1 mg/kg ketamine hydrochloride, and 0.5 mg/kg ketamine hydrochloride to ethanol (A), marijuana (B), and cocaine (C) in recently detoxified alcoholic patients (N=20). Values are expressed as mean±SEM. See "Patients and Methods" and "Results" sections for explanation of statistical analyses.

Graphic Jump Location
Ethanol

Ketamine effects showed a dose-related similarity to ethanol effects (RMANOVA, dose × time interaction: F6,114=12.1; P<.001). Post hoc RMANOVAs revealed that 0.5 mg/kg ketamine hydrochloride was more similar to ethanol than both 0.1 mg/kg ketamine hydrochloride (dose × time interaction: F6,114=12.9; P<.001) and saline solution (dose × time interaction: F6,114=16.6; P<.001). However, 0.1 mg/kg ketamine hydrochloride effects were not significantly different from saline solution.

Marijuana

In patients reporting a history of marijuana use, ketamine had dose-related marijuana-like effects. The RMANOVA performed on data from the visual analog scale assessing similarity to marijuana revealed a significant ketamine dose × time interaction (F6,84=4.6; P=.02).

Cocaine

In patients reporting a history of cocaine use, there was a trend for ketamine to produce cocaine-like effects. The RMANOVA performed on data from the visual analog scale measuring similarity to cocaine revealed a nonsignificant ketamine dose × time interaction (F6,54=3.1; P=.09).

SELF-RATED VISUAL ANALOG SCALES OF CRAVING AND MOOD STATES

There was no significant increase in self-rated desire to drink alcohol following high doses of ketamine (baseline craving [mean±SD], 19.5±7.0 mm; 10 minutes after initiating the infusion, 25.8±7.8 mm) or low doses of ketamine (baseline, 18.2±6.8 mm; 10 minutes after initiating the infusion, 23.2±7.1 mm) relative to placebo (baseline, 15.0±4.7 mm; 10 minutes after initiating the infusion, 18.9±5.6 mm). The RMANOVA performed on these data found a significant time effect (F6,114=3.9; P=.03), but no other main effects or interactions. No significant ketamine effects were found on the visual analog scales for anger, anxiety, drowsiness, nervousness, or sadness.

PLASMA KETAMINE LEVELS

Ketamine blood levels increased in a dose-dependent fashion (Figure 5; RMANOVA, dose × time interaction: F4,64=30.7; P<.001).

Place holder to copy figure label and caption
Figure 5.

Plasma ketamine levels in recently detoxified alcoholic patients (n=17) following the administration of placebo, 0.1 mg/kg ketamine hydrochloride, and 0.5 mg/kg ketamine hydrochloride. Values are expressed as mean±SEM. Asterisk indicates P<.05 by within-subjects contrasts with Bonferroni adjustments for multiple comparisons; dagger, P<.001 by within-subjects contrasts with Bonferroni adjustments for multiple comparisons. See "Patients and Methods" and "Results" sections for explanation of all other statistical analyses.

Graphic Jump Location

The principal finding of this study was that ketamine produced dose-related ethanol-like subjective effects in recently detoxified type 2 alcoholics across several response measures. Ketamine effects were rated more similar to items associated with the sedative or descending limb than the stimulant or ascending limb of the Biphasic Alcohol Effects Scale. These data suggested a possible differential contribution of NMDA receptors to the stimulant and sedative effects of ethanol. Ketamine hydrochloride produced effects similar to 1.5±2.5 standard alcohol drinks at the 0.1 mg/kg dose and 8.7±8.1 standard alcohol drinks at the 0.5 mg/kg dose. As predicted by the preclinical literature,15 ketamine doses associated with greater similarity to ethanol produced effects that were attributed to higher levels of ethanol consumption.

Ketamine effects were rated more similar to ethanol than to either marijuana or cocaine. Thus, NMDA receptor antagonism may figure more prominently in the behavioral effects of ethanol than marijuana or cocaine. In contrast, patients found m CPP effects comparably similar to ethanol, marijuana, and cocaine.23 Although more modest than its ethanol-like effects, ketamine effects did show some similarity to the effects of marijuana and cocaine in our study. The NMDA antagonists also showed cocaine-like effects in preclinical studies.27,28 However, the current study design may have biased the results in favor of finding ethanol-like effects. For example, this study evaluated a patient group who identified ethanol as their primary substance of abuse. Also, the comparisons of ketamine with cocaine were limited to a smaller subsample of alcoholics with cocaine use histories, reducing the statistical power of this analysis. In addition, the slow intravenous ketamine infusion used in the current study may have minimized the stimulant effects and enhanced the sedative or descending limb effects of ketamine. Stimulant effects in this study may have been more prominent had ketamine been administered as a rapid intravenous bolus.22,26

Ketamine did not stimulate craving relative to placebo in our study. However, both ketamine and placebo infusion briefly increased craving, suggesting that test day instructions may have created an expectancy that craving would develop. The current findings contrasted with previous studies of m CPP,23,29 in which the production of ethanol-like subjective effects was accompanied by craving. The failure to produce craving was not likely caused by the absence of rewarding effects of ketamine. In animals, NMDA antagonists produce conditioned place preference,30 enhance brain stimulation reward,31 and are usually self-administered.32,33 Further, ketamine and PCP abuse has been a significant clinical problem.34 However, ketamine may have failed to produce dysphoric emotional states that have been linked to the elicitation of craving in other studies.22,35 In addition, the lower ketamine dose may not have been sufficiently similar to ethanol to facilitate the induction of craving.3638 In contrast, the higher ketamine dose may have sated the desire for further consumption of an NMDA antagonist–like compound. It is possible that an intermediate ketamine dose might have been more effective in stimulating ethanol craving.

The inability of ketamine to prime craving in the patient group may also have been related to the similarity of its effects to the sedative effects of ethanol that emerge as blood alcohol levels plateau or decline.25 Stimulant effects associated with the ascending limb of ethanol intoxication are more closely tied to the development of craving than are the sedative or descending limb effects.39,40 Currently, there is no clear evidence implicating NMDA antagonism in the stimulant effects of ethanol. Instead, clinical studies have implicated both catecholamine41,42 and opiate43 systems in these effects.

The neuropharmacology of the ethanol-like effects of ketamine remains to be clarified. The generalization between ethanol and the other NMDA antagonists is not symmetrical, reflecting the multiplicity of mechanisms contributing to the discriminative properties of ethanol.14,23,44,45 Animals trained to discriminate ethanol from other drugs recognize the ethanol-like properties of NMDA antagonists. In contrast, ethanol effects on other systems are sufficiently prominent to animals trained to discriminate NMDA antagonists from other drugs to make ethanol seem like a different type of drug.15,46 Consistent with this view, ethanol also shows asymmetrical generalization with selective agents acting at other sites of ethanol action, such as γ-aminobutyric acid and serotonin receptors.45,47 Thus, it is possible that an appropriate combination of drugs acting at NMDA, serotonin, γ-aminobutyric acid, and other receptors might produce symmetrical generalization with ethanol.

Ketamine also appears to be a more complex stimulus in animals than the selective noncompetitive NMDA antagonist dizocilpine (MK-801),48 as suggested by the asymmetrical generalization between these drugs. Animals trained to discriminate ketamine recognize dizocilpine as ketamine-like,33 while animals trained to identify dizocilpine do not recognize ketamine as a similar agent.49 The complexity of the ketamine stimulus may arise from its differential relative affinity for NMDA receptor subunits,50 its agonism of the µ−opiate receptor, 51,52 and its blockade of dopamine transporters.53

The µ−agonist actions of ketamine may be of limited importance to its ethanol-like effects. The discriminative properties of NMDA antagonists, particularly their ethanol-like effects, are not dependent on their affinity for µ−receptors.15,54 Similarly, µ−receptor agonism does not appear to contribute to the discriminative properties of ethanol in animals.55 However, µ−antagonists reduce aspects of human ethanol intoxication.43,56 Thus, future studies will be needed to more fully assess the contributions of µ−receptors to the ethanol-like effects of ketamine.

Modulation of dopamine systems also may have contributed to the current findings. Ketamine has direct dopaminergic effects via its low affinity for dopamine reuptake sites as well as its NMDA receptor–mediated modulation of dopaminergic neuronal activity.57,58 However, ketamine effects on dopamine neurons do not correlate well with its NMDA antagonist-like discriminative properties.59 Also, the euphoric effects of ketamine in humans seem to be insensitive to haloperidol pretreatment.60

Our data support the hypothesis that the capacity of ethanol to block NMDA receptors contributes significantly to its subjective effects in humans. Future studies should explore a wider range of ketamine doses and rates of administration. Further, the similarity of ketamine to drugs of abuse should be evaluated in populations primarily dependent on cocaine or marijuana. These studies should also consider employing training doses of ethanol, cocaine, and marijuana to facilitate the accuracy of interpreting the similarity between ketamine effects and those of these other drugs. Comparisons of ketamine and sedative-hypnotic agents would also provide insights into the specificity of the similarity between ketamine effects and the sedative effects of ethanol. In addition, the dependence on subjective report is a potential limitation of our study. Physiologic measures might aid the evaluation of neurobiological contributions to the acute behavioral effects of ethanol.

The NMDA antagonist properties of ethanol may have therapeutic implications in humans. For example, acamprosate reduced ethanol consumption in clinical trials. 61,62 This drug has both NMDA agonist and antagonist-like effects, making it difficult to extrapolate a therapeutic mechanism at this time.63 One potential strategy would be to explore agents that reduce ethanol effects at the NMDA receptor. One class of candidate agents to serve this function would be agonists of the strychnine-insensitive glycine modulatory site of the NMDA receptor complex. These drugs reduce ethanol effects in some preclinical studies.64,65 Preliminary human data also suggest that the strychnine-insensitive glycine partial agonist, D-cycloserine, exacerbates ethanol intoxication at doses associated with NMDA antagonistlike amnestic and euphoric effects.62 Thus, NMDA receptors may become an important focus for future drug development in the alcoholism field.

Accepted for publication June 9, 1997.

This research was supported by grant NIAAA 1 R01 AA10121-01 from the National Institute on Alcohol Abuse and Alcoholism, Bethesda, Md (Dr Krystal), and the Department of Veterans Affairs, Washington, DC, through funding of the VA-Yale Alcoholism Research Center and a Merit Review Grant (Dr Krystal).

We wish to acknowledge the critical contributions to this research made by the clinical and research staff of the Biostudies Unit and Substance Abuse Treatment Unit of the West Haven Veterans Affairs Medical Center. We also thank Christine Boose for her assistance in data collection and analysis.

Corresponding author: John H. Krystal, MD, Department of Psychiatry, Schizophrenia Biology Research Center, Yale University, 950 Campbell Ave, VAMC 116A, West Haven, CT 06516.

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Maisto  SAConners  GJTucker  JAMcCollam  JBAddesso  VJ Validation of the Sensation Scale, a measure of subjective physiological responses to alcohol. Behav Res Ther. 1980;1837- 43
Martin  CSEarleywine  MMusty  REPerrine  MWSwift  RM Development and validation of the Biphasic Alcohol Effects Scale. Alcohol Clin Exp Res. 1993;17140- 146
Krystal  JHKarper  LPBennett  AD'Souza  DCAbi-Dargham  AMorrissey  KAbi-Saab  DBremner  JDHeninger  GRBowers  MBSuckow  RStetson  PHeninger  GRCharney  DS Interactive effects of subanesthetic ketamine and subhypnotic lorazepam in humans. Psychopharmacology (Berl). 1998;135213- 229
Colpaert  FCNiemegeers  CJEJanssen  PAJ Discriminative stimulus properties of cocaine. Pharmacol Biochem Behav. 1979;10535- 546
Koek  WColpaert  FCWoods  JHKamenka  J-M The phencyclidine (PCP) analog N-(1-[2-benzo(B)thiophenyl]cyclohexyl) piperidine shares cocaine-like but not other characteristic behavioral effects with PCP, ketamine, and MK-801. J Pharmacol Exp Ther. 1989;2501019- 1027
Benkelfat  CMurphy  DLHill  JLGeorge  DTNutt  DLinnoila  M Ethanollike properties of the serotonergic partial agonist m -chlorophenylpiperazine in chronic alcoholic patients. Arch Gen Psychiatry. 1991;48383
Layer  RTKaddis  FGWallace  L The NMDA receptor antagonist MK-801 elicits conditioned place preference in rats. Pharmacol Biochem Behav. 1993;44245- 247
Heberg  LJRose  IC The effect of MK-801 and other antagonists of NMDA-type glutamate receptors on brain-stimulation reward. Psychopharmacology. 1989;9987- 90
Young  AMWoods  JH Maintenance of behavior by ketamine and related compounds in rhesus monkeys with different self-administration histories. J Pharmacol Exp Ther. 1981;218720- 727
Koek  WWoods  JHWinger  GD MK-801, a proposed noncompetitive antagonist of excitatory amino acid neurotransmission, produces phencyclidine-like behavioral effects in pigeons, rats and rhesus monkeys. J Pharmacol Exp Ther. 1988;245969- 974
Siegel  RK Phencyclidine and ketamine intoxication: a study of four populations of recreational users. Petersen  RCStillman  RCeds.Phencyclidine (PCP) Abuse An Appraisal Rockville, Md National Institute on Drug Abuse1978;119- 147NIDA Research Monograph 21.
Litt  MDCooney  NLKadden  RMGaupp  L Reactivity to alcohol cues and induced moods in alcoholics. Addict Behav. 1990;15137- 146
Engle  KBWilliams  TK Effect of an ounce of vodka on alcoholics' desire for alcohol. Q J Stud Alcohol. 1972;331099- 1105
Ludwig  AMWikler  AStark  L The first drink. Arch Gen Psychiatry. 1974;30539- 547
Hodgson  RRankin  HStockwell  T Alcohol dependence and the priming effect. Behav Res Ther. 1979;17379- 387
Newlin  DThomson  J Alcohol challenge in sons of alcoholics: a critical review and analysis. Psychol Bull. 1990;108383- 402
Earleywine  M Confirming the factor structure of the Anticipated Biphasic Alcohol Effects Scale. Alcohol Clin Exp Res. 1994;18861- 866
Perez-Reyes  MMcDonald  SAHicks  RE Interaction between ethanol and dextroamphetamine. Alcohol Clin Exp Res. 1992;1675- 81
McDougle  CJKrystal  JHPrice  LHHeninger  GRCharney  DS Noradrenergic response to acute ethanol administration in healthy subjects: comparison with intravenous yohimbine. Psychopharmacology. 1995;118127- 135
Swift  RMWhelihan  WKuznetsov  OBuongiorno  GHsuing  H Naltrexone-induced alterations in human ethanol intoxication. Am J Psychiatry. 1994;1511463- 1467
Overton  DA Comparison of ethanol, pentobarbital, and phenobarbital using drug vs drug discrimination training. Psychopharmacology. 1977;53195- 199
Signs  SASchechter  MD The role of dopamine and serotonin receptors in the mediation of the ethanol interoceptive cue. Pharmacol Biochem Behav. 1988;3055- 64
Garcha  HSStolerman  IP Discrimination of a drug mixture in rats: role of training dose, and specificity. Behav Pharmacol. 1989;125- 31
De Vry  JSlanger  JF Effect of training dose on discrimination and cross-generalization of chlordiazepoxide, pentobarbital, and ethanol in the rat. Psychopharmacology. 1986;88341- 345
Wong  EHFKemp  JAPriestley  TKnight  ARWoodruff  GNIversen  LL The anticonvulsant MK-801 is a potent N-methyl-D-aspartate antagonist. Proc Natl Acad Sci U S A. 1986;837104- 7107
France  CPMoerschbaecher  JMWoods  JH MK-801 and related compounds in monkeys. J Pharmacol Exp Ther. 1991;257727- 773
Sucher  NJAwobuluyi  MChoi  Y-BLipton  SA NMDA receptors: from genes to channels. Trends Pharmacol Sci. 1996;17348- 355
Smith  DJWestfall  DPAdams  JD Ketamine interacts with opiate receptors as an agonist [abstract]. Anesthesiology. 1980;53S-5
Herling  SCoale  EHHein  DWWinger  GWoods  JH Similarity of the discriminative stimulus effects of ketamine, cyclazocine, and dextrorphan in the pigeon. Psychopharmacology (Berl). 1981;73286- 291
Smith  DJAzzaro  AJZaldivar  SBPalmer  SLee  HS Properties of the optical isomers and metabolites of ketamine on the high-affinity transport and catabolism of monoamines. Neuropharmacology. 1981;20391- 396
Shannon  HE Pharmacological analysis of the phencyclidine-like discriminative properties of narcotic derivatives in rats. J Pharmacol Exp Ther. 1982;222146- 151
Winter  JC The stimulus properties of morphine and ethanol. Psychopharmacologia. 1975;44209- 214
Volpicelli  JPWatson  NTKing  ACSherman  CEO'Brien  CP Effect of naltrexone on alcohol "high" in alcoholics. Am J Psychiatry. 1995;152613- 615
Javitt  DCZukin  SR Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry. 1991;1481301- 1308
Irufine  MShimizu  TNomoto  M Ketamine-induced hyperlocomotion associated with alteration of presynaptic components of dopamine neurons in the nucleus accumbens of mice. Pharmacol Biochem Behav. 1991;40399- 407
Snell  LDMueller  ZLGannon  RLSilverman  PBJonson  KM A comparison between classes of drugs having phencyclidine-like behavioral properties on dopamine efflux in vitro and dopamine metabolism in vivo. J Pharmacol Exp Ther. 1984;231261- 269
Krystal  JKarper  LBennett  AAbi-Saab  DD'Souza  CAbi-Dargham  ACharney  D Modulating ketamine-induced thought disorder with lorazepam and haloperidol in humans [abstract]. Schiz Res. 1995;15156
Sass  HSoyka  MMann  KZieglgansberger  W Relapse prevention by acamprosate: results from a placebo-controlled study on alcohol dependence. Arch Gen Psychiatry. 1996;53673- 680
Whitworth  ABFischer  FLesch  OMNimmerrichter  AOberbauer  HPlatz  TPotgieter  AWalter  HFleischhacher  WW Comparison of acamprosate and placebo in long-term treatment of alcohol dependence. Lancet. 1996;3471438- 1442
Lovinger  DMZieglgansberger  W Interactions between ethanol and drugs acting on the NMDA-type glutamate receptor. Alcohol Clin Exp Res. 1996;20(suppl)187A- 191A
Rabe  CSTabakoff  B Glycine site-directed agonists reverse the actions of ethanol at the N-methyl-D-asparate receptor. Mol Pharmacol. 1990;38753- 757
Woodward  JJGonzales  RA Ethanol inhibition of N -methyl-D-aspartate–stimulated endogenous dopamine release from rat striatal slices: reversal by glycine. J Neurochem. 1990;54712- 715

Figures

Place holder to copy figure label and caption
Figure 1.

Effects of placebo, 0.1 mg/kg ketamine hydrochloride, and 0.5 mg/kg ketamine hydrochloride on Sensation Scale Scores (A) and on self-rated "high" (B) in recently detoxified alcoholic patients (N=20). Values are expressed as mean±SEM. See "Patients and Methods" and "Results" sections for explanation of statistical analyses.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

The number of standard ethanol drinks that recently detoxified alcoholic patients (N=20) determined were similar to the effects of placebo, 0.1 mg/kg ketamine hydrochloride, and 0.5 mg/kg ketamine hydrochloride. Values are expressed as mean±SEM. See "Patients and Methods" and "Results" sections for explanation of statistical analyses.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Effects of placebo, 0.1 mg/kg ketamine hydrochloride, and 0.5 mg/kg ketamine hydrochloride on scores for the stimulant or ascending limb of the Biphasic Alcohol Effects Scale (A) and on the sedative or descending limb of the Biphasic Alcohol Effects Scale (B) in recently detoxified alcoholic patients (N=20). Values are expressed as mean±SEM. See "Patients and Methods" and "Results" sections for explanation of statistical analyses.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.

Similarity of the effects of placebo, 0.1 mg/kg ketamine hydrochloride, and 0.5 mg/kg ketamine hydrochloride to ethanol (A), marijuana (B), and cocaine (C) in recently detoxified alcoholic patients (N=20). Values are expressed as mean±SEM. See "Patients and Methods" and "Results" sections for explanation of statistical analyses.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 5.

Plasma ketamine levels in recently detoxified alcoholic patients (n=17) following the administration of placebo, 0.1 mg/kg ketamine hydrochloride, and 0.5 mg/kg ketamine hydrochloride. Values are expressed as mean±SEM. Asterisk indicates P<.05 by within-subjects contrasts with Bonferroni adjustments for multiple comparisons; dagger, P<.001 by within-subjects contrasts with Bonferroni adjustments for multiple comparisons. See "Patients and Methods" and "Results" sections for explanation of all other statistical analyses.

Graphic Jump Location

Tables

References

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Dildy-Mayfield  JELeslie  SW Mechanism of inhibition of N-methyl-D-aspartate–stimulated increases in free intracellular Ca2+ concentration by ethanol. J Neurochem. 1991;561536- 1543
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Fidecka  SLangwinski  R Interaction between ketamine and ethanol in rats and mice. Pol J Pharmacol Pharm. 1989;4123- 32
Chandler  LJNewsom  HSumner  CCrews  F Chronic ethanol exposure potentiates NMDA excitotoxicity in cerebral cortical neurons. J Neurochem. 1993;601578- 1581
Grant  KAKnisely  JSTabakoff  BBarrett  JEBalster  RL Ethanol-like discriminative stimulus effects of non-competitive N -methyl-D-aspartate antagonists. Behav Pharmacol. 1991;287- 95
Grant  KAColombo  G Discriminative stimulus effects of ethanol: effect of training dose on the substitution of N-methyl-D-aspartate antagonists. J Pharmacol Exp Ther. 1993;2641241- 1247
Butelman  ERBaron  SPWoods  JH Ethanol effects in pigeons trained to discriminate MK-801, PCP or CGS-19755. Behav Pharmacol. 1993;457- 60
Schechter  MDMeehan  SMGordon  TLMcBurney  DM The NMDA receptor antagonist MK-801 produces ethanol-like discrimination in the rat. Alcohol. 1993;10197- 201
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised.  Washington, DC American Psychiatric Association1987;
Spitzer  RIWilliams  JBWGibbon  MFirst  MB The Structured Clinical Interview for DSM-III-R, I: history, rationale, and description. Arch Gen Psychiatry. 1992;49624- 629
Selzer  ML The Michigan Alcoholism Screening Test: the quest for a new diagnostic instrument. Am J Psychiatry. 1971;1271653- 1658
von Knorring  ALBohman  Mvon Knorring  LOreland  L Platelet MAO activity as a biological marker in subgroups of alcoholism. Acta Psychiatr Scand. 1985;7251- 58
Krystal  JHKarper  LPSeibyl  JPFreeman  GKDelaney  RBremmer  JDHeninger  GRBowers  MB  JrCharney  DS Subanesthetic effects of the NMDA antagonist, ketamine, in humans. Arch Gen Psychiatry. 1994;51199- 214
Krystal  JHWebb  ECooney  NLKranzler  HCharney  DS Specificity of ethanol-like effects elicited by serotonergic and noradrenergic mechanisms. Arch Gen Psychiatry. 1994;51898- 911
Maisto  SAConners  GJTucker  JAMcCollam  JBAddesso  VJ Validation of the Sensation Scale, a measure of subjective physiological responses to alcohol. Behav Res Ther. 1980;1837- 43
Martin  CSEarleywine  MMusty  REPerrine  MWSwift  RM Development and validation of the Biphasic Alcohol Effects Scale. Alcohol Clin Exp Res. 1993;17140- 146
Krystal  JHKarper  LPBennett  AD'Souza  DCAbi-Dargham  AMorrissey  KAbi-Saab  DBremner  JDHeninger  GRBowers  MBSuckow  RStetson  PHeninger  GRCharney  DS Interactive effects of subanesthetic ketamine and subhypnotic lorazepam in humans. Psychopharmacology (Berl). 1998;135213- 229
Colpaert  FCNiemegeers  CJEJanssen  PAJ Discriminative stimulus properties of cocaine. Pharmacol Biochem Behav. 1979;10535- 546
Koek  WColpaert  FCWoods  JHKamenka  J-M The phencyclidine (PCP) analog N-(1-[2-benzo(B)thiophenyl]cyclohexyl) piperidine shares cocaine-like but not other characteristic behavioral effects with PCP, ketamine, and MK-801. J Pharmacol Exp Ther. 1989;2501019- 1027
Benkelfat  CMurphy  DLHill  JLGeorge  DTNutt  DLinnoila  M Ethanollike properties of the serotonergic partial agonist m -chlorophenylpiperazine in chronic alcoholic patients. Arch Gen Psychiatry. 1991;48383
Layer  RTKaddis  FGWallace  L The NMDA receptor antagonist MK-801 elicits conditioned place preference in rats. Pharmacol Biochem Behav. 1993;44245- 247
Heberg  LJRose  IC The effect of MK-801 and other antagonists of NMDA-type glutamate receptors on brain-stimulation reward. Psychopharmacology. 1989;9987- 90
Young  AMWoods  JH Maintenance of behavior by ketamine and related compounds in rhesus monkeys with different self-administration histories. J Pharmacol Exp Ther. 1981;218720- 727
Koek  WWoods  JHWinger  GD MK-801, a proposed noncompetitive antagonist of excitatory amino acid neurotransmission, produces phencyclidine-like behavioral effects in pigeons, rats and rhesus monkeys. J Pharmacol Exp Ther. 1988;245969- 974
Siegel  RK Phencyclidine and ketamine intoxication: a study of four populations of recreational users. Petersen  RCStillman  RCeds.Phencyclidine (PCP) Abuse An Appraisal Rockville, Md National Institute on Drug Abuse1978;119- 147NIDA Research Monograph 21.
Litt  MDCooney  NLKadden  RMGaupp  L Reactivity to alcohol cues and induced moods in alcoholics. Addict Behav. 1990;15137- 146
Engle  KBWilliams  TK Effect of an ounce of vodka on alcoholics' desire for alcohol. Q J Stud Alcohol. 1972;331099- 1105
Ludwig  AMWikler  AStark  L The first drink. Arch Gen Psychiatry. 1974;30539- 547
Hodgson  RRankin  HStockwell  T Alcohol dependence and the priming effect. Behav Res Ther. 1979;17379- 387
Newlin  DThomson  J Alcohol challenge in sons of alcoholics: a critical review and analysis. Psychol Bull. 1990;108383- 402
Earleywine  M Confirming the factor structure of the Anticipated Biphasic Alcohol Effects Scale. Alcohol Clin Exp Res. 1994;18861- 866
Perez-Reyes  MMcDonald  SAHicks  RE Interaction between ethanol and dextroamphetamine. Alcohol Clin Exp Res. 1992;1675- 81
McDougle  CJKrystal  JHPrice  LHHeninger  GRCharney  DS Noradrenergic response to acute ethanol administration in healthy subjects: comparison with intravenous yohimbine. Psychopharmacology. 1995;118127- 135
Swift  RMWhelihan  WKuznetsov  OBuongiorno  GHsuing  H Naltrexone-induced alterations in human ethanol intoxication. Am J Psychiatry. 1994;1511463- 1467
Overton  DA Comparison of ethanol, pentobarbital, and phenobarbital using drug vs drug discrimination training. Psychopharmacology. 1977;53195- 199
Signs  SASchechter  MD The role of dopamine and serotonin receptors in the mediation of the ethanol interoceptive cue. Pharmacol Biochem Behav. 1988;3055- 64
Garcha  HSStolerman  IP Discrimination of a drug mixture in rats: role of training dose, and specificity. Behav Pharmacol. 1989;125- 31
De Vry  JSlanger  JF Effect of training dose on discrimination and cross-generalization of chlordiazepoxide, pentobarbital, and ethanol in the rat. Psychopharmacology. 1986;88341- 345
Wong  EHFKemp  JAPriestley  TKnight  ARWoodruff  GNIversen  LL The anticonvulsant MK-801 is a potent N-methyl-D-aspartate antagonist. Proc Natl Acad Sci U S A. 1986;837104- 7107
France  CPMoerschbaecher  JMWoods  JH MK-801 and related compounds in monkeys. J Pharmacol Exp Ther. 1991;257727- 773
Sucher  NJAwobuluyi  MChoi  Y-BLipton  SA NMDA receptors: from genes to channels. Trends Pharmacol Sci. 1996;17348- 355
Smith  DJWestfall  DPAdams  JD Ketamine interacts with opiate receptors as an agonist [abstract]. Anesthesiology. 1980;53S-5
Herling  SCoale  EHHein  DWWinger  GWoods  JH Similarity of the discriminative stimulus effects of ketamine, cyclazocine, and dextrorphan in the pigeon. Psychopharmacology (Berl). 1981;73286- 291
Smith  DJAzzaro  AJZaldivar  SBPalmer  SLee  HS Properties of the optical isomers and metabolites of ketamine on the high-affinity transport and catabolism of monoamines. Neuropharmacology. 1981;20391- 396
Shannon  HE Pharmacological analysis of the phencyclidine-like discriminative properties of narcotic derivatives in rats. J Pharmacol Exp Ther. 1982;222146- 151
Winter  JC The stimulus properties of morphine and ethanol. Psychopharmacologia. 1975;44209- 214
Volpicelli  JPWatson  NTKing  ACSherman  CEO'Brien  CP Effect of naltrexone on alcohol "high" in alcoholics. Am J Psychiatry. 1995;152613- 615
Javitt  DCZukin  SR Recent advances in the phencyclidine model of schizophrenia. Am J Psychiatry. 1991;1481301- 1308
Irufine  MShimizu  TNomoto  M Ketamine-induced hyperlocomotion associated with alteration of presynaptic components of dopamine neurons in the nucleus accumbens of mice. Pharmacol Biochem Behav. 1991;40399- 407
Snell  LDMueller  ZLGannon  RLSilverman  PBJonson  KM A comparison between classes of drugs having phencyclidine-like behavioral properties on dopamine efflux in vitro and dopamine metabolism in vivo. J Pharmacol Exp Ther. 1984;231261- 269
Krystal  JKarper  LBennett  AAbi-Saab  DD'Souza  CAbi-Dargham  ACharney  D Modulating ketamine-induced thought disorder with lorazepam and haloperidol in humans [abstract]. Schiz Res. 1995;15156
Sass  HSoyka  MMann  KZieglgansberger  W Relapse prevention by acamprosate: results from a placebo-controlled study on alcohol dependence. Arch Gen Psychiatry. 1996;53673- 680
Whitworth  ABFischer  FLesch  OMNimmerrichter  AOberbauer  HPlatz  TPotgieter  AWalter  HFleischhacher  WW Comparison of acamprosate and placebo in long-term treatment of alcohol dependence. Lancet. 1996;3471438- 1442
Lovinger  DMZieglgansberger  W Interactions between ethanol and drugs acting on the NMDA-type glutamate receptor. Alcohol Clin Exp Res. 1996;20(suppl)187A- 191A
Rabe  CSTabakoff  B Glycine site-directed agonists reverse the actions of ethanol at the N-methyl-D-asparate receptor. Mol Pharmacol. 1990;38753- 757
Woodward  JJGonzales  RA Ethanol inhibition of N -methyl-D-aspartate–stimulated endogenous dopamine release from rat striatal slices: reversal by glycine. J Neurochem. 1990;54712- 715

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