, Responder rate (%) N/A +22.9 (P = 0.027) +26.5 (P = 0.029) PDA treatment period (%), CfB in TAC (g/day)

, CfB in HDD (HDD/month)

L. F. Eghorn, I. S. Villumsen, N. Karim, T. Bay, J. V. Olsen et al., GABA (A) receptors are high-affinity targets for ?-hydroxybutyric acid (GHB), Three patients had unknown DRL at baseline and were not included in this table. References Absalom N, vol.109, pp.13404-13409, 2012.

J. A. Aldrete and D. P. Barnes, 4-Hydroxybutyrate anaesthesia for cardiovascular surgery. A comparison with halothane, Anaesthesia, vol.23, pp.558-565, 1968.

I. Bazov, D. Sarkisyan, O. Kononenko, H. Watanabe, T. Yakovleva et al., Dynorphin and ?-opioid receptor dysregulation in the dopaminergic reward system of human alcoholics, Mol Neurobiol, 2018.

T. Bay, L. F. Eghorn, A. B. Klein, and P. Wellendorph, GHB receptor targets in the CNS: focus on high-affinity binding sites, vol.87, pp.220-228, 2014.

F. Caputo, G. Addolorato, M. Stoppo, S. Francini, T. Vignoli et al., Comparing and combining gammahydroxybutyric acid (GHB) and naltrexone in maintaining abstinence form alcohol: an open randomized comparative study, Eur Neuropsychopharmacol, vol.17, pp.781-789, 2007.

F. Caputo and M. Bernardi, Sodium oxybate to treat alcohol dependence: 20 years of clinical experience, Addict Biol, vol.18, pp.901-903, 2013.

F. Caputo, K. Skala, H. Walter, M. Ceccanti, M. Djurkowski et al., Sodium oxybate in the prevention of alcohol relapses in alcohol dependent patients (GATE 2 study), Alcohol Alcohol, vol.48, pp.33-34, 2013.

F. Caputo, K. Skala, A. Mirijello, A. Ferrulli, H. Walter et al., Sodium oxybate in the treatment of alcohol withdrawal syndrome: a randomized double-blind comparative study versus oxazepam. The GATE 1 trial, CNS Drugs, vol.28, pp.743-752, 2014.

F. Caputo, M. Stoppo, T. Vignoli, S. Francini, F. Lorenzini et al., Gamma-hydroxybutyric acid versus naltrexone in maintaining alcohol abstinence: an open randomized comparative study, Drug Alcohol Depend, vol.70, pp.85-91, 2003.

L. P. Carter, W. Koek, and C. P. France, Behavioral analyses of GHB: receptor mechanisms, Pharmacol Therap, vol.121, pp.100-114, 2009.

W. M. Connelly, A. C. Errington, and V. Crunelli, ) ?Hydroxybutyric acid (GHB) is not an agonist of extrasynaptic GABAA receptors, PLoS One, vol.8, p.79062, 2013.

J. Connor and S. Casswell, Alcohol-related harm to others in New Zealand: evidence of the burden and gaps in knowledge, N Z Med J, vol.125, pp.11-27, 2012.

D. Bello, M. G. Gambassi, F. Mugnai, L. Masini, E. Mannaioni et al., Gamma-hydroxybutyric acid induced suppression and prevention of alcohol withdrawal syndrome and relief of craving in alcohol dependent patients, Alcologia, vol.7, pp.111-118, 1995.

, Guideline on the development of medicinal products for the treatment of alcohol dependence, European Medicines Agency, 2010.

A. Erol, A. M. Ho, S. J. Winham, and V. M. Karpyak, Sex hormones in alcohol consumption: a systematic review of evidence, Addict Biol, 2017.

L. Gallimberti, G. Canton, N. Gentile, M. Ferri, M. Cibin et al., Gamma-hydroxybutyric acid for the treatment of alcohol withdrawal syndrome, The Lancet, vol.2, pp.787-789, 1989.

L. Gallimberti, M. Ferri, S. D. Ferrara, F. Fadda, and G. L. Gessa, ) ?Hydroxybutyric acid in the treatment of alcohol dependence: a double-blind study, Alcohol Clin Exp Res, vol.16, pp.673-676, 1992.

A. Gual, Y. He, L. Torup, W. Van-den-brink, and K. Mann, A randomised, double-blind, placebo-controlled, efficacy study of nalmefene, as-needed use, in patients with alcohol dependence, Eur Neuropsychopharmacol, vol.23, pp.1432-1442, 2013.

R. Gueorguieva, R. Wu, D. Donovan, B. J. Rounsaville, D. Couper et al., Baseline trajectories of drinking moderate acamprosate and naltrexone effects in the COMBINE study, Alcohol Clin Exp Res, vol.35, issue.3, pp.523-531, 2011.

R. Gueorguieva, R. Wu, D. Donovan, B. J. Rounsaville, D. Couper et al., Baseline trajectories of heavy drinking and their effects on post-randomization drinking in the COMBINE Study: empirically derived predictors of drinking outcomes during treatment, Alcohol, vol.46, pp.121-131, 2012.

R. Gueorguieva, R. Wu, O. Connor, P. G. Weisner, C. Fucito et al., Predictors of abstinence from heavy drinking during treatment in COMBINE and external validation in PREDICT, Alcohol Clin Exp Res, vol.38, pp.2647-2656, 2014.

D. S. Hasin, M. Wall, K. Witkiewitz, H. R. Kranzler, D. Falk et al., Alcohol Clinical Trials Initiative (ACTIVE) Workgroup (2017) Change in non-abstinent WHO drinking risk levels and alcohol dependence: a 3 year follow-up study in the US general population, Lancet Psychiatry, vol.4, pp.469-476

H. F. Hendriks and A. Van-tol, Alcohol. Handb Exp Pharmacol, vol.170, pp.3393-3461, 2005.

D. E. Jonas, H. R. Amick, C. Feltner, G. Bobashev, K. Thomas et al., Pharmacotherapy for adults with alcohol use disorders in outpatient settings: a systematic review and meta-analysis, JAMA, vol.311, pp.1889-1900, 2014.

S. Kleinschmidt, Total intravenous anaesthesia using propofol, gamma-hydroxybutyrate or midazolam in combination with sufentanil for patients undergoing coronary artery bypass surgery, Eur J Anaesthesiol, vol.14, pp.590-599, 1997.

S. Kleinschmidt, Total intravenous anaesthesia with gamma-hydroxybutyrate (GHB) and sufentanil in patients undergoing coronary artery bypass graft surgery: a comparison in patients with unimpaired and impaired left ventricular function, Eur J Anaesthesiol, vol.15, pp.559-564, 1998.

R. Kohn, S. Saxena, I. Levav, and B. Saraceno, The treatment gap in mental health care, Bull World Health Organ, vol.82, pp.858-866, 2004.

F. Kiefer and R. Spanagel, Measuring alcohol consumption in man-it is time for a change, Addiction, vol.101, pp.1215-1216, 2006.

P. Laramée, T. H. Brodtkorb, N. Rahhali, C. Knight, C. Barbosa et al., The costeffectiveness and public health benefit of Nalmefene added to psychosocial support for the reduction of alcohol consumption in alcohol-dependent patients with high/very high drinking risk levels: a Markov model, BMJ Open, vol.4, pp.259-269, 2014.

M. A. Leone, F. Vigna-taglianti, G. Avanzy, R. Brambilla, and F. Faggiano, Gamma-hydroxybutyrate (GHB) for treatment of alcohol withdrawal and prevention of relapses (Review), The Cochrane Collaboration, vol.2, pp.1-160, 2010.

R. Z. Litten, M. Egli, M. Heilig, C. Cui, J. B. Fertig et al., Medications development to treat alcohol dependence: a vision for the next decade, Addict Biol, vol.17, pp.513-527, 2012.

R. Z. Litten, I. J. Castle, D. Falk, M. Ryan, J. Fertig et al., The placebo effect in clinical trials for alcohol dependence: an exploratory analysis of 51 naltrexone and acamprosate studies, Alcohol Clin Exp Res, vol.37, pp.2128-2137, 2013.

R. Z. Litten, D. E. Falk, M. L. Ryan, J. Fertig, and L. Leggio, Advances in Pharmacotherapy Development: Human Clinical Studies, Handb Exp Pharmacol, 2018.

M. Mamelak, J. M. Escriu, and O. Stokan, The effects of ?hydroxybutyrate on sleep, Biol Psychiatry, vol.12, pp.273-288, 1977.

M. Mamelak, M. B. Scharf, and M. Woods, Treatment of narcolepsy with gammahydroxybutyrate. A review of clinical and sleep laboratory findings, Sleep, vol.9, pp.285-289, 1986.

K. Mann, A. Bladström, L. Torup, A. Gual, and W. Van-den-brink, Extending the treatment options in alcohol dependence: a randomized controlled study of as-needed nalmefene, Biol Psychiatry, vol.73, pp.706-713, 2013.

K. Mann, T. Lemenager, S. Hoffmann, R. I. Hermann, D. Batra et al., PREDICT Study Team (2012) Results of a double-blind, placebocontrolled pharmacotherapy trial in alcoholism conducted in Germany and comparison with the US COMBINE study, Addict Biol, vol.18, pp.937-946

K. Mann, L. Torup, P. Sørensen, A. Gual, R. Swift et al., Nalmefene for the management of alcohol dependence: review on its pharmacology, mechanism of action and meta-analysis on its clinical efficacy, Eur Neuropsychopharmacol, vol.26, pp.1941-1949, 2016.

K. Mann, H. J. Aubin, and K. Witkiewitz, Reduced drinking in alcohol dependence treatment, what is the evidence?, Eur Addict Res, vol.23, pp.219-230, 2017.

F. Nava, S. Premi, E. Manzato, and A. Luccini, Comparing treatments of alcoholism on craving and biochemical measures of alcohol consumptions, J Psychoactive Drugs, vol.38, pp.211-217, 2006.

, Alcohol-use disorders: diagnosis, assessment and management of harmful drinking and alcohol dependenceAppendix 17d Pharmacological Interventions Forest Plots, NICE, vol.115, p.17, 2011.

D. R. Quelch, M. I. Mcgonigle, J. Ramos, A. C. Flechais, R. Bolstridge et al., Nalmefene reduces reward anticipation in alcohol dependence: an experimental functional magnetic resonance imaging study, Biol Psychiatry, vol.81, pp.941-948, 2017.

M. Pierce, A. Sutterland, E. Beraha, and K. Morley, Van den Brink W (2018) Efficacy, tolerability and safety of low dose and high dose baclofen in the treatment of alcohol dependence: a systematic review and meta-analysis, Eur Neurpsychopharamcol, vol.26, pp.1950-1959

J. Rehm, J. Guiraud, R. Poulnais, and K. D. Shield, Alcohol dependence with a very high drinking risk level, a life threatening and seriously debilitating disease, Addict Biol, vol.23, pp.961-968, 2018.

J. Rehm, K. D. Shield, G. Gmel, M. X. Rehm, and U. Frick, Modeling the impact of alcohol dependence on mortality burden and the effect of available treatment interventions in the European Union, Eur Neuropsychopharmacol, vol.23, pp.89-97, 2013.

J. Rehm, P. Anderson, J. Barry, P. Dimitrov, Z. Elekes et al., Prevalence of and potential influencing factors for alcohol dependence in Europe, European Addiction Research, vol.21, pp.6-18, 2015.

M. Roerecke, A. Gual, and J. Rehm, Reduction of alcohol consumption and subsequent mortality in alcohol use disorders: systematic review and meta-analyses, J Clin Psychiatry, vol.74, pp.1181-1189, 2013.

S. Rösner, A. Hackl-herrwerth, S. Leucht, P. Lehert, S. Vecchi et al., Acamprosate for alcohol dependence, Cochrane Database Syst Rev, vol.9, p.4332, 2010.

S. Rösner, A. Hackl-herrwerth, S. Leucht, S. Vecchi, M. Srisurapanont et al., Opioid antagonists for alcohol dependence, Cochrane Database Syst Rev, vol.12, p.1867, 2010.

C. Sanchis-segura and J. B. Becker, Why we should consider sex (and study sex differences) in addiction research, Addict Biol, vol.21, pp.995-1006, 2016.

K. D. Shield and J. Rehm, Russia-specific relative risks and their effects on the estimated alcohol-attributable burden of disease, BMC Public Health, vol.15, p.482, 2015.

K. Skala, F. Caputo, A. Mirijello, G. Vassallo, M. Antonelli et al., Sodium oxybate in the treatment of alcohol dependence: from the alcohol withdrawal syndrome to the alcohol relapse prevention, Expert Opin Pharmacother, vol.15, pp.245-257, 2014.

M. D. Skinner, P. Lahmek, H. Pham, and H. J. Aubin, Disulfiram efficacy in the treatment of alcohol dependence: a metaanalysis, PLoS One, vol.9, p.87366, 2014.

R. Spanagel, Alcoholism: a systems approach from molecular physiology to addictive behavior, Physiol Rev, vol.89, pp.649-705, 2009.

R. Spanagel, G. Pendyala, C. Abarca, T. Zghoul, C. Sanchis-segura et al., The clock gene Per2 influences the glutamatergic system and modulates alcohol consumption, Nat Med, vol.11, pp.35-42, 2005.

R. Spanagel and V. Vengeliene, New pharmacological treatment strategies for relapse prevention, Curr Top Behav Neurosci, vol.13, pp.583-609, 2013.

R. Spanagel, V. Vengeliene, B. Jandeleit, W. N. Fischer, K. Grindstaff et al., Acamprosate produces its anti-relapse effects via calcium, Neuropsychopharmacology, vol.39, pp.783-791, 2014.

M. Tuithof, M. Ten-have, W. Van-den-brink, W. Vollebergh, and R. De-graaf, Treatment seeking for alcohol use disorders: treatment gap or adequate self-selection?, Eur Addict Res, vol.22, pp.277-285, 2016.

J. C. Umhau, R. Momenan, M. L. Schwandt, E. Singley, M. Lifshitz et al., Effect of acamprosate on magnetic resonance spectroscopy measures of central glutamate in detoxified alcohol-dependent individuals: a randomized controlled experimental medicine study, Arch Gen Psychiatry, vol.67, pp.733-744, 2010.

K. Witkiewitz, K. A. Hallgren, H. R. Kranzler, K. F. Mann, D. S. Hasin et al., Clinical Validation of Reduced Alcohol Consumption After Treatment for Alcohol Dependence Using the World Health Organization Risk Drinking Levels, Alcohol Clin Exp Res, vol.41, pp.179-186, 2017.

S. Geneva, . Who-;-geneva, . Switzerland, A. M. Wood, S. Kaptoge et al., WHO (2000) International guide for monitoring alcohol consumption and related harm, 2014.