Antiglutamatergic Strategies for Ethanol Detoxification: Comparison With Placebo and Diazepam Evgeny M. Krupitsky, Anatoly A. Rudenko, Andrey M. Burakov, Tatyana Y. Slavina, Alexander A. Grinenko, Brian Pittman, Ralitza Gueorguieva, Ismene L. Petrakis, Edwin E. Zvartau, and John H. Krystal Background: Benzodiazepines are the standard pharmacotherapies for ethanol detoxification, but concerns about their abuse potential and negative effects upon the transition to alcohol abstinence drive the search for new treatments. Glutamatergic activation and glutamate receptor up-regulation contribute to ethanol dependence and withdrawal. This study compared 3 antiglutamatergic strate- gies for ethanol detoxification with placebo and to the benzodiazepine, diazepam: the glutamate release inhibitor, lamotrigine; the N-methyl-D-aspartate glutamate receptor antagonist, memantine; and the AMPA/kainite receptor inhibitor, topiramate. Methods: This placebo-controlled randomized single-blinded psychopharmacology trial studied male alcohol-dependent inpatients (n 5 127) with clinically significant alcohol withdrawal symptoms. Subjects were assigned to 1 of 5 treatments for 7 days: placebo, diazepam 10 mg TID, lamotrigine 25 mg QID, memantine 10 mg TID, or topiramate 25 mg QID. Additional diazepam was adminis- tered when the assigned medication failed to suppress withdrawal symptoms adequately. Results: All active medications significantly reduced observer-rated and self-rated withdrawal severity, dysphoric mood, and supplementary diazepam administration compared with placebo. The active medications did not differ from diazepam. Conclusions: This study provides the first systematic clinical evidence supporting the efficacy of a number of antiglutamatergic approaches for treating alcohol withdrawal symptoms. These data support the hypothesis that glutamatergic activation contributes to human alcohol withdrawal. Definitive studies of each of these medications are now needed to further evaluate their effectiveness in treating alcohol withdrawal. Key Words: Ethanol, Alcoholism, Dependence, Withdrawal, Glutamate, Glutamate Receptors (NMDA, AMPA, Kainate), Anticonvulsant, Lamotrigine, Memantine, Topiramate. E THANOL WITHDRAWAL ACTIVATES brain glutamatergic systems. Ethanol blocks N-methyl- D-aspartate (NMDA) glutamate receptors and voltage-gated cation channels (Hoffman et al., 1990; Lovinger, 1997). It also stimulates the extrasynaptic subtypes of GABA A receptors and stimulates GABA release (Carta et al., 2004; Sundstrom-Poromaa et al., 2002; Wallner et al., 2003; Wei et al., 2004). Ethanol dependence is asso- ciated with many neurobiological adaptations including up-regulation of NMDA receptors, kainate receptors, and voltage-gated cation channels as well as alterations in GABA A receptor subunit composition that reduce the function of these receptors (Carta et al., 2002; Engberg and Hajos, 1992; Hoffman et al., 1992; Krystal et al., 2003a, 2003b, 2006; Tsai and Coyle, 1998). Upon abrupt discon- tinuation of ethanol consumption by ethanol-dependent animals, the alcohol dependence-related changes in excitato- ry and inhibitory neurotransmission combine to increase glutamate release in synapses that also have increased postsynaptic NMDA receptor-related function. The com- bination of these presynaptic and postsynaptic alterations during withdrawal contributes to withdrawal-related dysphoria, seizures, and neurotoxicity (Hoffman, 1995; Hoffman et al., 1992). Withdrawal-dependent forms of neu- roplasticity are also linked to glutamatergic activation. Thus, across episodes of withdrawal, there is evidence of progres- sive hyperreflexia (Krystal et al., 1997) and reduced seizure threshold (McCown and Breese, 1990) in animals and humans (Becker, 1996). From the St. Petersburg Regional Center of Addictions and Psycho- pharmacology, Pavlov State Medical University, St. Petersburg, Russia (EMK, AAR, AMB, TYS, AAG, EEZ); the Department of Psychiatry, NIAAA Center for the Translational Neuroscience of Alcoholism, Yale University School of Medicine, New Haven, Connecticut (BP, RG, ILP, JHK); and the Alcohol Research Center, VA Connecticut Healthcare System, West Haven, Connecticut (BP, RG, ILP, JHK). Received for publication September 27, 2006; accepted December 16, 2006. The authors acknowledge support from the Civilian Research Devel- opment Fund (CRDF), the National Institute on Alcohol Abuse and Alcoholism (R21-AA014543-01A1, KO5 AA 14906-01, I-P50 AA-12870- 04), and the U.S. Department of Veterans Affairs via their Merit Review Program and Alcohol Research Center for their support of this study. Reprint requests: John H. Krystal, MD, Alcohol Research Center (116-A), VA Connecticut Healthcare System, 950 Campbell Ave., West Haven, CT 06516; Fax: 1203-937-3468; E-mail: john.krystal@yale.edu Copyright r 2007 by the Research Society on Alcoholism. DOI: 10.1111/j.1530-0277.2007.00344.x Alcohol Clin Exp Res, Vol 31, No 4, 2007: pp 604 – 611 604 ALCOHOLISM:CLINICAL AND EXPERIMENTAL RESEARCH Vol. 31, No. 4 April 2007