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

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Dose-Related Ethanol-Like Effects of the NMDA Antagonist, Ketamine, in Recently Detoxified Alcoholics ORIGINAL ARTICLE Dose-Related Ethanol-like Effects of the NMDA Antagonist, Ketamine, in Recently Detoxified Alcoholics 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 Background: This study evaluated the dose-related etha- Results: Ketamine produced dose-related ethanol-like ef- nol-like subjective effects of the N-methyl-D-aspartate fects on each scale measuring its similarity to ethanol. Its (NMDA) glutamate receptor antagonist ketamine hydro- effects were more similar to the sedative or descending limb chloride in recently detoxified alcoholics. effects of ethanol than to the stimulant or ascending limb effects. Ketamine effects also were more like ethanol than Methods: Twenty male inpatients meeting DSM-III-R cri- marijuana or cocaine. Ethanol-like effects were more promi- teria for alcohol dependence and who had not consumed nent at the higher ketamine dose, a dose rated as similar alcohol for 10 to 27 days prior to the study completed 3 test to greater levels of ethanol intoxication. However, ket- days that involved the intravenous infusion of ketamine hy- amine did not increase craving for ethanol. drochloride (0.1 mg/kg or 0.5 mg/kg) or saline solution un- der randomized double-blind conditions. Ethanol-like sub- Conclusion: The production of ethanol-like subjective jective effects were assessed using the Sensation Scale; the effects by ketamine supports the potential clinical im- Biphasic Alcohol Effects Scale; visual analog scales to mea- portance of NMDA receptor antagonism among the sure “high” and degree of similarity to ethanol, cocaine, and mechanisms underlying the subjective effects of etha- marijuana; a scale assessing the number of standard alco- nol in humans. hol drinks producing similar subjective effects; and visual analog scales measuring ethanol craving. Arch Gen Psychiatry. 1998;55:354-360 GROWING body of research paradigms.14-17 In these studies, the capac- indicates that the capacity ity of NMDA antagonists to substitute for of ethanol to block gluta- ethanol was greater with increasing refer- mateeffectsattheN-methyl- ence doses of ethanol. This finding sug- D-aspartate (NMDA) recep- gested that NMDA receptor blockade con- tor contributes to its acute behavioral effects tributed more prominently to the subjective A 15 and to the natural history and neuropa- effects of higher ethanol doses. thology of alcoholism.1 Ethanol reduces Our study evaluated whether ket- NMDA-stimulated ion currents in a non- amine produced ethanol-like subjective ef- competitive and concentration-depen- fects in recently detoxified alcoholic pa- dent fashion across the range of ethanol tients. To our knowledge, there are no concentrations (5-100 mmol/L) associ- previous clinical studies evaluating the ated with human ethanol intoxication.2-7 contributions of NMDA receptors to the Long-term ethanol administration in- behavioral effects of ethanol in humans. From the Department of creases the levels of NMDA receptor sub- Psychiatry, Yale University units, up-regulates NMDA receptor- School of Medicine and the related binding, and produces cross- RESULTS Veterans Affairs–Yale tolerance with other noncompetitive University Alcoholism Research NMDA antagonists.8-12 Increased NMDA re- EVIDENCE OF ETHANOL-LIKE Center, West Haven, Conn ceptor function produced by long-term EFFECTS (Drs Krystal, Petrakis, Cooney, ethanol administration contributes to with- Karper, Trevisan, and Charney drawal-related seizures10 and neurotoxic ef- Sensation Scale and Mss Webb and 13 Namanworth); and the Upjohn fects. Research Institute, Department The NMDA antagonists ketamine hy- Ketamine produced significant dose- of Pharmacology, University of drochloride, phencyclidine (PCP), and related ethanol-like effects as assessed by the Michigan Medical School, Ann dizocilpine maleate (MK-801) substitute for Sensation Scale (Figure 1; RMANOVA, Arbor (Dr Stetson). ethanol in preclinical drug discrimination dose 3 time interaction: F12,228=12.1; ARCH GEN PSYCHIATRY/ VOL 55, APR 1998 354 ©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 PATIENTS AND METHODS Subjects were inpatients at the Substance Abuse Treat- ment Research Unit of the Veterans Affairs Connecticut Healthcare System, West Haven. They participated in test- PATIENTS ing for a mean±SD of 17.6±4.2 days (range, 10-27 days) af- ter consuming their last alcoholic beverage. Fourteen patients Twentymaleinpatients(mean±SDage,44.0±10.5years;weight, completed detoxification with pharmacologic supports prior 74.7±9.0 kg) who met criteria for alcohol dependence18 as de- to study entry (benzodiazepines, n=10; nimodipine, n=4). termined by the Structured Clinical Interview for DSM-III-R 19 The mean±SD period between the administration of the last participated in testing. Patients began drinking at a mean±SD benzodiazepine dose and the first pharmacologic test day of 15.3±2.9 years of age, began regular drinking at 17.8±5.5 was 15.7±5.9 days (range, 7-26 days). On their first test day, years of age, began regular drinking to intoxication at 21.1±7.1 patients received placebo (n=5), 0.1 mg/kg ketamine hydro- yearsofage,andtheirheaviestlevelofdrinkingwasat32.7±13.8 chloride (n=9), or 0.5 mg/kg ketamine hydrochloride (n=6). years of age. Patients had a 23.0±10.1-year history of alcohol- ism. They had undergone a mean±SD of 5.8±9.7 inpatient al- TESTING PROCEDURE coholdetoxifications(range,0-40).Theirmeandailyconsump- This research protocol was approved by the Human Sub- tion of alcohol was equivalent to 391.5±170 mL of absolute jects Subcommittee of the Veterans Affairs Connecticut Health- alcohol per day. The mean±SD Michigan Alcoholism Screen- care System and the Human Investigations Committee of the ing Test score20 was 38.7±6.5. Sixteen (80%) of the 20 patients Yale University School of Medicine, New Haven, Conn. Af- in this study met the von Knorring et al21 criteria for type 2 al- ter giving informed consent for human investigation, each coholism, defined as age of onset before 25 years of age and 2 patient completed 3 test days separated by 48 to 96 hours in or more social consequences of alcoholism. Twelve (60%) of a randomized order under double-blind conditions. The in- the 20 patients had a first-degree relative with a history of al- formation presented to patients while obtaining consent in- coholism. Patients were medically stable at study entry based cluded a warning that the effects of ketamine might re- on medical history, physical examination, and routine labo- semble ethanol intoxication and might stimulate craving for ratory testing. alcohol. On each test day, patients received a 40-minute in- Patients were excluded if they met the criteria for another travenous infusion containing either saline solution, 0.1 mg/kg substance use disorder other than nicotine dependence in the ketamine hydrochloride, or 0.5 mg/kg ketamine hydrochlo- year prior to testing. Fifteen patients (75%) reported lifetime ride (Ketalar, Parke-Davis, Kalamazoo, Mich). This method marijuana use, but no use occurred in the year prior to test- of administration was similar to that reported previously in ing. Ten patients (50%) had lifetime cocaine use. Of these pa- healthy subjects.22 For each test session, participants fasted tients, 1 used cocaine 6 months prior to testing at a subabuse overnight and remained in a fasting state during the test ses- level and the remainder had not used cocaine for at least 1 year sion. They presented for testing at approximately 8:30 AM and prior to testing. The absence of other current substance abuse an intravenous line was placed at that time. Blood was drawn wassupportedbynegativeresultsofurinetoxicologicalscreens to determine ketamine levels at 10 and 80 minutes after the prior to testing. Subjects were also excluded if they had an- initiation of ketamine infusion. other DSM-III-R Axis I diagnosis during a period that was free of alcohol consumption. Continued on next page P,.001). Post hoc RMANOVAs revealed that 0.5 mg/kg (Figure 2;RMANOVA,dose3timeinteraction:F12,228=13.1; ketamine hydrochloride produced greater Sensation Score P,.001). Post hoc RMANOVAs revealed that 0.5 mg/kg ket- increases than both 0.1 mg/kg ketamine hydrochloride (dose amine hydrochloride was perceived as similar to a greater 3 time interaction: F6,114=13.1; P,.001) and saline solu- number of standard ethanol drinks than were both 0.1 mg/ tion (dose 3 time interaction: F6,114=12.4; P,.001). How- kg ketamine hydrochloride (dose 3 time interaction: ever, 0.1 mg/kg ketamine hydrochloride effects were not F6,114=12.4; P,.001) and saline solution (dose 3 time in- significantly different from saline solution. teraction: F6,114=14.3; P,.001). There was also a nonsignifi- cant trend for 0.1 mg/kg ketamine hydrochloride effects to Self-reported High be rated as similar to more ethanol drinks than saline so- lution (dose 3 time interaction: F6,114=3.4; P=.06). As depicted in Figure 1, ketamine increased self-rated high in a dose-related manner (RMANOVA, dose 3 time inter- SPECIFICITY OF ETHANOL-LIKE EFFECTS action: F12,228=8.6; P,.001). Post hoc RMANOVAs re- vealed that 0.5 mg/kg ketamine hydrochloride produced Differential Similarity to the Ascending and greater euphoria than both 0.1 mg/kg ketamine hydrochlo- Descending Limbs of Ethanol Intoxication ride (dose 3 time interaction: F6,114=7.3; P,.001) and sa- line
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