Investigational drug therapies in phase I and phase II clinical trials for alcohol use disorders

References

• Koob GF, Moal Le M. Drug addiction, dysregulation of reward, and allostasis. Neuropsychopharmacology. 2001;24(2):97-129.
   PubMed Web of Science ®Google Scholar
• Grant BF, Goldstein RB, Saha TD, et al. Epidemiology of dsm-5 alcohol use disorder: results from the national epidemiologic survey on alcohol and related conditions iii. JAMA Psychiatry. 2015;72(8):757–766.
   PubMed Web of Science ®Google Scholar
• World Health Organization (WHO). Management of Substance Abuse Unit. Global status report on alcohol and health, 2014.
   Google Scholar
• Mokdad AH, Marks JS, Stroup DF, et al. Actual causes of death in the United States, 2000. JAMA. 2004;291(10):1238–1245.
   PubMed Web of Science ®Google Scholar
• Substance Abuse and Mental Health Services Administration (SAMHSA): National survey on drug use and health (nsduh) 2015 (nsduh-2015-ds0001). [cited 2018, Mar 12]. Available from: http://www.Datafiles.Samhsa.Gov/study-dataset/national-survey-drug-use-and-health-2015-nsduh-2015-ds0001-nid16894. (2015).
   Google Scholar
• Lyon J. More treatments on deck for alcohol use disorder. JAMA. 2017;317(22):2267–2269.
   PubMed Web of Science ®Google Scholar
• Edlund MJ, Booth BM, Han X. Who seeks care where? Utilization of mental health and substance use disorder treatment in two national samples of individuals with alcohol use disorders. J Stud Alcohol Drug. 2012;73(4):635–646.
   PubMed Web of Science ®Google Scholar
• Vallari RC, Pietruszko R. Human aldehyde dehydrogenase: mechanism of inhibition of disulfiram. Science. 1982;216(4546):637–639.
   PubMed Web of Science ®Google Scholar
• Niciu MJ, Arias AJ. Targeted opioid receptor antagonists in the treatment of alcohol use disorders. CNS Drugs. 2013;27(10):777–787.
   PubMed Web of Science ®Google Scholar
• Anton RF. Naltrexone for the management of alcohol dependence. N Eng J Med. 2008;359(7):715–721.
   PubMed Web of Science ®Google Scholar
• Al Qatari M, Khan S, Harris B, et al. Acamprosate is neuroprotective against glutamate‐induced excitotoxicity when enhanced by ethanol withdrawal in neocortical cultures of fetal rat brain. Alcohol Clin Exp Res. 2001;25(9):1276–1283.
   PubMed Web of Science ®Google Scholar
• Spanagel R, Vengeliene V, Jandeleit B, et al. Acamprosate produces its anti-relapse effects via calcium. Neuropsychopharmacology. 2014;39(4):783.
   PubMed Web of Science ®Google Scholar
• Jupp B, Lawrence AJ. New horizons for therapeutics in drug and alcohol abuse. Pharmacol Ther. 2010;125(1):138–168.
   PubMed Web of Science ®Google Scholar
• Gilpin NW, Koob GF. Neurobiology of alcohol dependence: focus on motivational mechanisms. Alcohol Res Health. 2008;31(3):185.
   PubMedGoogle Scholar
• Funk D, Coen K, Tamadon S, et al. Effects of prazosin and doxazosin on yohimbine-induced reinstatement of alcohol seeking in rats. Psychopharmacology. 2016;233(11):2197–2207.
   PubMed Web of Science ®Google Scholar
• Rasmussen DD, Kincaid CL, Froehlich JC. Prazosin prevents increased anxiety behavior that occurs in response to stress during alcohol deprivations. Alcohol Alcohol. 2017;52(1):5–11.
   PubMed Web of Science ®Google Scholar
• Madras BK, Xie Z, Lin Z, et al. Modafinil occupies dopamine and norepinephrine transporters in vivo and modulates the transporters and trace amine activity in vitro. J Pharmacol Exp Ther. 2006;319(2):561–569.
   PubMed Web of Science ®Google Scholar
• Mitchell HA, Bogenpohl JW, Liles LC, et al. Behavioral responses of dopamine β-hydroxylase knockout mice to modafinil suggest a dual noradrenergic–dopaminergic mechanism of action. Pharmacol Biochem Behav. 2008;91(2):217–222.
   PubMed Web of Science ®Google Scholar
• Andersen ML, Kessler E, Murnane KS, et al. Dopamine transporter-related effects of modafinil in rhesus monkeys. Psychopharmacology. 2010;210(3):439–448.
   PubMed Web of Science ®Google Scholar
• Volkow ND, Fowler JS, Logan J, et al. Effects of modafinil on dopamine and dopamine transporters in the male human brain: clinical implications. JAMA. 2009;301(11):1148–1154.
   PubMed Web of Science ®Google Scholar
• Minzenberg MJ, Carter CS. Modafinil: a review of neurochemical actions and effects on cognition. Neuropsychopharmacology. 2008;33(7):1477.
   PubMed Web of Science ®Google Scholar
• Ishizuka T, Murotani T, Yamatodani A. Modanifil activates the histaminergic system through the orexinergic neurons. Neurosci Lett. 2010;483(3):193–196.
   PubMed Web of Science ®Google Scholar
• Wong YN, King SP, Simcoe D, et al. Open‐label, single‐dose pharmacokinetic study of modafinil tablets: influence of age and gender in normal subjects. J Clin Pharmacol. 1999;39(3):281–288.
   PubMed Web of Science ®Google Scholar
• Kampman KM, Lynch KG, Pettinati HM, et al. A double blind, placebo controlled trial of modafinil for the treatment of cocaine dependence without co-morbid alcohol dependence. Drug Alcohol Depend. 2015;155:105–110.
   PubMed Web of Science ®Google Scholar
• Kim JH, Lawrence AJ. Drugs currently in phase ii clinical trials for cocaine addiction. Expert Opin Investig Drugs. 2014;23(8):1105–1122.
   PubMed Web of Science ®Google Scholar
• Morley KC, Cornish JL, Faingold A, et al. Pharmacotherapeutic agents in the treatment of methamphetamine dependence. Expert Opin Investig Drugs. 2017;26(5):563–578.
   PubMed Web of Science ®Google Scholar
• Schmaal L, Joos L, Koeleman M, et al. Effects of modafinil on neural correlates of response inhibition in alcohol-dependent patients. Biol Psychiatry. 2013;73(3):211–218.
   PubMed Web of Science ®Google Scholar
• Schmaal L, Goudriaan AE, Joos L, et al. Modafinil modulates resting-state functional network connectivity and cognitive control in alcohol-dependent patients. Biol Psychiatry. 2013;73(8):789–795.
   PubMed Web of Science ®Google Scholar
• Schmaal L, Goudriaan A, Joos L, et al. Neural substrates of impulsive decision making modulated by modafinil in alcohol-dependent patients. Psychol Med. 2014;44(13):2787–2798.
   PubMed Web of Science ®Google Scholar
• Joos L, Goudriaan AE, Schmaal L, et al. Effect of modafinil on impulsivity and relapse in alcohol dependent patients: a randomized, placebo-controlled trial. Eur Neuropsychopharmacol. 2013;23(8):948–955.
   PubMed Web of Science ®Google Scholar
• Kate N, Grover S, Ghormode D. Dependence on supratherapeutic doses of modafinil: A case report. Prim care companion CNS disord. 2012;(14): 5.
   Google Scholar
• Krishnan R, Chary KV. A rare case modafinil dependence. J Pharmacol Pharmacother. 2015;6(1):49.
   PubMed Web of Science ®Google Scholar
• Mann N, Bitsios P. Modafinil treatment of amphetamine abuse in adult adhd. J Psychopharmacol. 2009;23(4):468–471.
   PubMed Web of Science ®Google Scholar
• Carboni E, Acquas E, Frau R, et al. Differential inhibitory effects of a 5-ht3 antagonist on drug-induced stimulation of dopamine release. Eur J Pharmacol. 1989;164(3):515–519.
   PubMed Web of Science ®Google Scholar
• Roila F, Del Favero A. Ondansetron clinical pharmacokinetics. Clin Pharmacokinet. 1995;29(2):95–109.
   PubMed Web of Science ®Google Scholar
• Tomkins DM, Le AD, Sellers EM. Effect of the 5-ht3 antagonist ondansetron on voluntary ethanol intake in rats and mice maintained on a limited access procedure. Psychopharmacology. 1995;117(4):479–485.
   PubMed Web of Science ®Google Scholar
• Costall B, Jones B, Kelly M, et al. Ondansetron inhibits a behavioural consequence of withdrawing from drugs of abuse. Pharm Biochem Behav. 1990;36(2):339–344.
   PubMed Web of Science ®Google Scholar
• Lê AD, Funk D, Harding S, et al. Effects of dexfenfluramine and 5-ht3 receptor antagonists on stress-induced reinstatement of alcohol seeking in rats. Psychopharmacology. 2006;186(1):82–92.
   PubMed Web of Science ®Google Scholar
• Koulu M, Lappalainen J, Hietala J, et al. Effects of chronic administration of ondansetron (gr38032f), a selective 5-ht 3 receptor antagonist, on monoamine metabolism in mesolimbic and nigrostriatal dopaminergic neurons and on striatal d2-receptor binding. Psychopharmacology. 1990;101(2):168–171.
   PubMed Web of Science ®Google Scholar
• Johnson B, Campling G, Griffiths P, et al. Attenuation of some alcohol-induced mood changes and the desire to drink by 5-ht 3 receptor blockade: a preliminary study in healthy male volunteers. Psychopharmacology. 1993;112(1):142–144.
   PubMed Web of Science ®Google Scholar
• Swift RM, Davidson D, Whelihan W, et al. Ondansetron alters human alcohol intoxication. Biol Psychiatry. 1996;40(6):514–521.
   PubMed Web of Science ®Google Scholar
• Sellers EM, Toneatto T, Romach MK, et al. Clinical efficacy of the 5‐ht3 antagonist ondansetron in alcohol abuse and dependence. Alcohol Clin Exp Res. 1994;18(4):879–885.
   PubMed Web of Science ®Google Scholar
• George DT, Rawlings R, Eckardt MJ, et al. Buspirone treatment of alcoholism: age of onset, and cerebrospinal fluid 5‐hydroxyindolacetic acid and homovanillic acid concentrations, but not medication treatment, predict return to drinking. Alcohol Clin Exp Res. 1999;23(2):272–278.
   PubMed Web of Science ®Google Scholar
• Johnson BA, Roache JD, Javors MA, et al. Ondansetron for reduction of drinking among biologically predisposed alcoholic patients: a randomized controlled trial. JAMA. 2000;284(8):963–971.
   PubMed Web of Science ®Google Scholar
• Kenna GA, Zywiak WH, McGeary JE, et al. A within‐group design of nontreatment seeking 5‐httlpr genotyped alcohol‐dependent subjects receiving ondansetron and sertraline. Alcohol Clin Exp Res. 2009;33(2):315–323.
   PubMed Web of Science ®Google Scholar
• Johnson BA, Ait-Daoud N, Seneviratne C, et al. Pharmacogenetic approach at the serotonin transporter gene as a method of reducing the severity of alcohol drinking. Am J Psychiatry. 2011;168(3):265–275.
   PubMed Web of Science ®Google Scholar
• Johnson BA, Seneviratne C, Wang X-Q, et al. Determination of genotype combinations that can predict the outcome of the treatment of alcohol dependence using the 5-ht3 antagonist ondansetron. Am J Psychiatry. 2013;170(9):1020–1031.
   PubMed Web of Science ®Google Scholar
• Rao P, Bell RL, Engleman EA, et al. Targeting glutamate uptake to treat alcohol use disorders. Front Neurosci. 2015;9:144.
   PubMed Web of Science ®Google Scholar
• White PF. Ketamine-its pharmacology and therapeutic uses. Anesthesiology. 1982;56:119–136.
   PubMed Web of Science ®Google Scholar
• Clements J, Nimmo W, Grant I. Bioavailability, pharmacokinetics, and analgesic activity of ketamine in humans. J Pharm Sci. 1982;71(5):539–542.
   PubMed Web of Science ®Google Scholar
• Sabino V, Narayan AR, Zeric T, et al. Mtor activation is required for the anti-alcohol effect of ketamine, but not memantine, in alcohol-preferring rats. Behav Brain Res. 2013;247:9–16.
   PubMed Web of Science ®Google Scholar
• Rezvani AH, Levin ED, Cauley M, et al. Ketamine differentially attenuates alcohol intake in male versus female alcohol preferring (p) rats. J Drug Alcohol Res. 2017;6:1–6.
   Google Scholar
• Wright KN, Kabbaj M. Sex differences in sub-anesthetic ketamine’s antidepressant effects and abuse liability. Current Opin Behav Sci. 2018;23:36–41.
   PubMedGoogle Scholar
• Ezquerra-Romano II, Lawn W, Krupitsky E, et al. Ketamine for the treatment of addiction: evidence and potential mechanisms. Neuropharmacology. 2018;S0028–3908(18).
   Google Scholar
• Krupitsky E, Grinenko A. Ketamine psychedelic therapy (kpt): a review of the results of ten years of research. J Psychoactive Drugs. 1997;29(2):165–183.
   PubMed Web of Science ®Google Scholar
• McAndrew A, Lawn W, Stevens T, et al. A proof-of-concept investigation into ketamine as a pharmacological treatment for alcohol dependence: study protocol for a randomised controlled trial. Trials. 2017;18(1):159.
   PubMedGoogle Scholar
• Jansen KL, Darracot-Cankovic R. The nonmedical use of ketamlne, part two: a review of problent use and dependence. J Psychoactive Drugs. 2001;33(2):151–158.
   PubMed Web of Science ®Google Scholar
• Liu Y, Lin D, Wu B, et al. Ketamine abuse potential and use disorder. Brain Res Bull. 2016;126:68–73.
   PubMed Web of Science ®Google Scholar
• Mason BJ, Quello S, Shadan F. Gabapentin for the treatment of alcohol use disorder. Expert Opin Investig Drugs. 2018;27(1):113–124.
   PubMed Web of Science ®Google Scholar
• Gajraj NM. Pregabalin: its pharmacology and use in pain management. Anesth Analg. 2007;105(6):1805–1815.
   PubMed Web of Science ®Google Scholar
• Bockbrader HN, Wesche D, Miller R, et al. A comparison of the pharmacokinetics and pharmacodynamics of pregabalin and gabapentin. Clin Pharmacokinet. 2010;49(10):661–669.
   PubMed Web of Science ®Google Scholar
• Stopponi S, Somaini L, Cippitelli A, et al. Pregabalin reduces alcohol drinking and relapse to alcohol seeking in the rat. Psychopharmacology. 2012;220(1):87–96.
   PubMed Web of Science ®Google Scholar
• Di Nicola M, Martinotti G, Tedeschi D, et al. Pregabalin in outpatient detoxification of subjects with mild‐to‐moderate alcohol withdrawal syndrome. Hum Psychopharmacol Clin Exp. 2010;25(3):268–275.
   PubMed Web of Science ®Google Scholar
• Martinotti G, Di Nicola M, Frustaci A, et al. Pregabalin, tiapride and lorazepam in alcohol withdrawal syndrome: a multi‐centre, randomized, single‐blind comparison trial. Addiction. 2010;105(2):288–299.
   PubMed Web of Science ®Google Scholar
• Förg A, Hein J, Volkmar K, et al. Efficacy and safety of pregabalin in the treatment of alcohol withdrawal syndrome: a randomized placebo-controlled trial. Alcohol Alcohol. 2012;47(2):149–155.
   PubMed Web of Science ®Google Scholar
• Martinotti G, Di Nicola M, Tedeschi D, et al. Efficacy and safety of pregabalin in alcohol dependence. Adv Ther. 2008;25(6):608–618.
   PubMed Web of Science ®Google Scholar
• Martinotti G, Di Nicola M, Tedeschi D, et al. Pregabalin versus naltrexone in alcohol dependence: a randomised, double-blind, comparison trial. J Psychopharmacol. 2010;24(9):1367–1374.
   PubMed Web of Science ®Google Scholar
• Krupitsky E, Rybakova K, Skurat E, et al. A double blind placebo controlled randomised clinical trial of pregabalin for alcohol dependence. Eur Neuropsychopharmacol. 2017;27:S1050.
   Web of Science ®Google Scholar
• Schjerning O, Rosenzweig M, Pottegård A, et al. Abuse potential of pregabalin. CNS Drugs. 2016;30(1):9–25.
   PubMed Web of Science ®Google Scholar
• Baird CR, Fox P, Colvin LA. Gabapentinoid abuse in order to potentiate the effect of methadone: a survey among substance misusers. E Addict Res. 2014;20(3):115–118.
   PubMed Web of Science ®Google Scholar
• Schifano F, D’Offizi S, Piccione M, et al. Is there a recreational misuse potential for pregabalin? Analysis of anecdotal online reports in comparison with related gabapentin and clonazepam data. Psychother Psychosomat. 2011;80(2):118–122.
   PubMed Web of Science ®Google Scholar
• Lee MR, Tapocik JD, Ghareeb M, et al. The novel ghrelin receptor inverse agonist pf-5190457 administered with alcohol: preclinical safety experiments and a phase 1b human laboratory study. Epub ahead of print. Mol Psychiatry. 2018. doi:10.1038/s41380-018-0064-y.
   Google Scholar
• World Health Organization (WHO): Cannabidiol (cbd), pre-review report. (2017) expert committee on drug dependence, thirty-ninth meeting. [cited 2018, Mar 12]. Available from : http://www.Who.Int/medicines/access/controlled-substances/5.2_cbd.Pdf
   Google Scholar
• Soyka M, Koller G, Schmidt P, et al. Cannabinoid receptor 1 blocker rimonabant (sr 141716) for treatment of alcohol dependence: results from a placebo-controlled, double-blind trial. J Clin Psychopharmacol. 2008;28(3):317–324.
   PubMed Web of Science ®Google Scholar
• George DT, Herion DW, Jones CL, et al. Rimonabant (sr141716) has no effect on alcohol self-administration or endocrine measures in nontreatment-seeking heavy alcohol drinkers. Psychopharmacology. 2010;208(1):37.
   PubMed Web of Science ®Google Scholar
• Bowen MT, Neumann ID. The multidimensional therapeutic potential of targeting the brain oxytocin system for the treatment of substance use disorders. Curr Top Behav Neurosci. 2017. epub ahead of print. DOI:10.1007/7854_2017_17.
   Google Scholar
• Szabó G, Kovács GL, Székeli S, et al. The effects of neurohypophyseal hormones on tolerance to the hypothermic effect of ethanol. Alcohol. 1985;2(4):567–574.
   PubMed Web of Science ®Google Scholar
• Szabo G, Kovacs G, Telegdy G. Intraventricular administration of neurohypophyseal hormones interferes with the development of tolerance to ethanol. Acta Physiol Hung. 1989;73(1):97–103.
   PubMedGoogle Scholar
• Lee MR, Weerts EM. Oxytocin for the treatment of drug and alcohol use disorders. Behav Pharmacol. 2016;27(8):640–648.
   PubMed Web of Science ®Google Scholar
• Sarnyai Z, Kovács GL. Role of oxytocin in the neuroadaptation to drugs of abuse. Psychoneuroendocrinology. 1994;19(1):85–117.
   PubMed Web of Science ®Google Scholar
• McGregor IS, Bowen MT. Breaking the loop: oxytocin as a potential treatment for drug addiction. Horm Behav. 2012;61(3):331–339.
   PubMed Web of Science ®Google Scholar
• Peters S, Slattery DA, Flor PJ, et al. Differential effects of baclofen and oxytocin on the increased ethanol consumption following chronic psychosocial stress in mice. Addict Biol. 2013;18(1):66–77.
   PubMed Web of Science ®Google Scholar
• King CE, Griffin WC, Luderman LN, et al. Oxytocin reduces ethanol self‐administration in mice. Alcohol Clin Exp Res. 2017;41(5):955–964.
   PubMed Web of Science ®Google Scholar
• King C, McGinty J, Becker H. Effects of oxytocin on stress-induced reinstatement of alcohol-seeking in mice with and without a history of stress. Alcohol. 2017;60:231–232.
   Web of Science ®Google Scholar
• Peters ST, Bowen MT, Bohrer K, et al. Oxytocin inhibits ethanol consumption and ethanol‐induced dopamine release in the nucleus accumbens. Addict Biol. 2017;22(3):702–711.
   PubMed Web of Science ®Google Scholar
• Hansson AC, Koopmann A, Uhrig S, et al. Oxytocin reduces alcohol cue-reactivity in alcohol-dependent rats and humans. Neuropsychopharmacology. 2017. Epub ahead of print. DOI:10.1038/npp.2017.257.
   Web of Science ®Google Scholar
• MacFadyen K, Loveless R, DeLucca B, et al. Peripheral oxytocin administration reduces ethanol consumption in rats. Pharmacol Biochem Behav. 2016;140:27–32.
   PubMed Web of Science ®Google Scholar
• Stevenson J, Wenner S, Freestone D, et al. Oxytocin reduces alcohol consumption in prairie voles. Physiol Behav. 2017;179:411–421.
   PubMed Web of Science ®Google Scholar
• Lee M, Scheidweiler K, Diao X, et al. Oxytocin by intranasal and intravenous routes reaches the cerebrospinal fluid in rhesus macaques: determination using a novel oxytocin assay. Mol Psychiatry. 2018;23(1):115.
   PubMed Web of Science ®Google Scholar
• Marchesi C, Chiodera P, Brusamonti E, et al. Abnormal plasma oxytocin and beta-endorphin levels in alcoholics after short and long term abstinence. Prog Neuro-Psychopharmacol Biol Psychiatry. 1997;21(5):797–807.
   PubMed Web of Science ®Google Scholar
• Sivukhina E, Jirikowski G, Bernstein H, et al. Expression of corticosteroid-binding protein in the human hypothalamus, co-localization with oxytocin and vasopressin. Horm Metabol Res. 2006;38(04):253–259.
   PubMedGoogle Scholar
• Pedersen CA, Smedley KL, Leserman J, et al. Intranasal oxytocin blocks alcohol withdrawal in human subjects. Alcohol Clin Exp Res. 2013;37(3):484–489.
   PubMed Web of Science ®Google Scholar
• Mitchell JM, Arcuni PA, Weinstein D, et al. Intranasal oxytocin selectively modulates social perception, craving, and approach behavior in subjects with alcohol use disorder. J Addict Med. 2016;10(3):182–189.
   PubMed Web of Science ®Google Scholar
• Gajbhiye SV, Tripathi RK, Salve B, et al. Evaluation of effect of minocycline on rewarding potential and alcohol relapse in place preference model in mice. Neurosci Lett. 2017;649:28–33.
   PubMed Web of Science ®Google Scholar
• Gajbhiye S, Tripathi R, Petare A, et al. Minocycline in alcohol withdrawal induced anxiety and alcohol relapse in rats. Curr Clin Phamacol. 2018. Epub ahead of print. DOI:10.2174/1574884713666180228110310.
   PubMedGoogle Scholar
• McIver SR, Muccigrosso MM, Haydon PG. The effect of doxycycline on alcohol consumption and sensitivity: consideration for inducible transgenic mouse models. Exp Biol Med. 2012;237(10):1129–1133.
   Web of Science ®Google Scholar
• Karahanian E, Rivera-Meza M, Quintanilla ME, et al. Pparα agonists reduce alcohol drinking: do they act in the brain or in the liver? Alcohol and Alcoholism. 2015;50(6):717–718.
   PubMed Web of Science ®Google Scholar
• Barson JR, Karatayev O, Chang G-Q, et al. Positive relationship between dietary fat, ethanol intake, triglycerides, and hypothalamic peptides: counteraction by lipid-lowering drugs. Alcohol. 2009;43(6):433–441.
   PubMed Web of Science ®Google Scholar
• Page C, Spina D. Phosphodiesterase inhibitors in the treatment of inflammatory diseases. In: Phosphodiesterases as drug targets. Berlin, Heidelberg: Springer. 2011. Vol. 204, p. 391–414.
   Google Scholar
• Hoffmann M, Kumar G, Schafer P, et al. Disposition, metabolism and mass balance of [(14)C]apremilast following oral administration. Xenobiotica. 2011;41(12):1063–1075.
   PubMed Web of Science ®Google Scholar
• Blednov YA, Benavidez JM, Black M, et al. Inhibition of phosphodiesterase 4 reduces ethanol intake and preference in c57bl/6j mice. Front Neurosci. 2014;8:129.
   PubMed Web of Science ®Google Scholar
• Hu W, Wen R, Huang Y, et al. Yclic amp-specific phosphodiesterase-4 pde4: a novel target for alcohol dependence. Alcohol Clin Exp Res. 2011;35:182A.
   Web of Science ®Google Scholar
• Wen RT, Zhang M, Qin WJ, et al. The phosphodiesterase‐4 (pde4) inhibitor rolipram decreases ethanol seeking and consumption in alcohol‐preferring fawn‐hooded rats. Alcohol Clin Exp Res. 2012;36(12):2157–2167.
   PubMed Web of Science ®Google Scholar
• Blednov YA, Da Costa AJ, Tarbox T, et al. Apremilast alters behavioral responses to ethanol in mice: I. reduced ethanol consumption and preference. Epub ahead of print. Alcohol Clin Exp Res. 2018. doi:10.1111/acer.13616.
   Web of Science ®Google Scholar
• Blednov YA, Da Costa AJ, Harris RA, et al. Apremilast alters behavioral responses to ethanol in mice: ii. Increased sedation, intoxication and reduced acute functional tolerance. Alcohol Clin Exp Res. 2018. Epub ahead of print. DOI:10.1111/acer.13615.
   Web of Science ®Google Scholar
• Giembycz M. Can the anti‐inflammatory potential of pde4 inhibitors be realized: guarded optimism or wishful thinking? Brit J Pharmacol. 2008;155(3):288–290.
   PubMed Web of Science ®Google Scholar
• Papp K, Kaufmann R, Thaçi D, et al. Efficacy and safety of apremilast in subjects with moderate to severe plaque psoriasis: results from a phase ii, multicenter, randomized, double‐blind, placebo‐controlled, parallel‐group, dose‐comparison study. J Eur Acad Dermatol Venereol. 2013;27(3):e376–383.
   PubMed Web of Science ®Google Scholar
• Cherry JA, Davis RL. Cyclic amp phosphodiesterases are localized in regions of the mouse brain associated with reinforcement, movement, and affect. J Comp Neurol. 1999;407(2):287–301.
   PubMed Web of Science ®Google Scholar
• Clarke T-K, Adams MJ, Davies G, et al. Genome-wide association study of alcohol consumption and genetic overlap with other health-related traits in uk biobank (n= 112 117). Mol Psychiatry. 2017;22(10):1376.
   PubMed Web of Science ®Google Scholar
• Mulligan MK, Ponomarev I, Hitzemann RJ, et al. Toward understanding the genetics of alcohol drinking through transcriptome meta-analysis. Proc Nat Acad Sci. 2006;103(16):6368–6373.
   PubMed Web of Science ®Google Scholar
• Palpacuer C, Laviolle B, Boussageon R, et al. Risks and benefits of nalmefene in the treatment of adult alcohol dependence: a systematic literature review and meta-analysis of published and unpublished double-blind randomized controlled trials. PLoS Med. 2015;12(12):e1001924.
   PubMed Web of Science ®Google Scholar
• Reynolds AR, Saunders MA, Honoree’W B, et al. Acute oral administration of the novel, competitive and selective glucocorticoid receptor antagonist org 34517 reduces the severity of ethanol withdrawal and related hypothalamic–pituitary–adrenal axis activation. Drug Alcohol Depend. 2015;154:100–104.
   PubMed Web of Science ®Google Scholar
• McGregor NR. Pueraria lobata (kudzu root) hangover remedies and acetaldehyde-associated neoplasm risk. Alcohol. 2007;41(7):469–478.
   PubMed Web of Science ®Google Scholar
• Penetar DM, Toto LH, Lee DY-W, et al. A single dose of kudzu extract reduces alcohol consumption in a binge drinking paradigm. Drug Alcohol Depend. 2015;153:194–200.
   PubMed Web of Science ®Google Scholar
• Howland RH. Mifepristone as a therapeutic agent in psychiatry. J Psychosoc Nurs Ment Health Serv. 2013;51(6):11–14.
   Web of Science ®Google Scholar
• Stephens MAC, Wand G. Stress and the hpa axis: role of glucocorticoids in alcohol dependence. Alcohol Res Curr Rev. 2012;34(4):468–483.
   Web of Science ®Google Scholar
• Sharrett‐Field L, Butler TR, Berry JN, et al. Mifepristone pretreatment reduces ethanol withdrawal severity in vivo. Alcohol Clin Exp Res. 2013;37(8):1417–1423.
   PubMed Web of Science ®Google Scholar
• Koenig HN, Olive MF. The glucocorticoid receptor antagonist mifepristone reduces ethanol intake in rats under limited access conditions. Psychoneuroendocrinology. 2004;29(8):999–1003.
   PubMed Web of Science ®Google Scholar
• Vendruscolo LF, Barbier E, Schlosburg JE, et al. Corticosteroid-dependent plasticity mediates compulsive alcohol drinking in rats. J Neurosci. 2012;32(22):7563–7571.
   PubMed Web of Science ®Google Scholar
• Vendruscolo LF, Estey D, Goodell V, et al. Glucocorticoid receptor antagonism decreases alcohol seeking in alcohol-dependent individuals. J Clin Invest. 2015;125(8):3193–3197.
   PubMed Web of Science ®Google Scholar
• Fahlke C, Hård E, Hansen S, et al. Consequence of long-term exposure to corticosterone or dexamethasone on ethanol consumption in the adrenalectomized rat, and the effect of type i and type ii corticosteroid receptor antagonists. Psychopharmacology. 1995;117(2):216–224.
   PubMed Web of Science ®Google Scholar
• Simms JA, Haass-Koffler CL, Bito-Onon J, et al. Mifepristone in the central nucleus of the amygdala reduces yohimbine stress-induced reinstatement of ethanol-seeking. Neuropsychopharmacology. 2012;37(4):906.
   PubMed Web of Science ®Google Scholar
• Repunte-Canonigo V, Shin W, Vendruscolo LF, et al. Identifying candidate drivers of alcohol dependence-induced excessive drinking by assembly and interrogation of brain-specific regulatory networks. Genome Biol. 2015;16(1):68.
   PubMedGoogle Scholar
• Sinha R. How does stress increase risk of drug abuse and relapse? Psychopharmacology. 2001;158(4):343–359.
   PubMed Web of Science ®Google Scholar
• Kaitin KI, Milne CP. A dearth of new meds. Sci Am. 2011;305(1):16.
   PubMedGoogle Scholar
• Arrowsmith J, Miller P. Trial watch: phase ii and phase iii attrition rates 2011–2012. Nat Rev Drug Discov. 2013;12(8):569.
   PubMed Web of Science ®Google Scholar
• Barajaz AM, Kliethermes CL. An assessment of the utilization of the preclinical rodent model literature in clinical trials of putative therapeutics for the treatment of alcohol use disorders. Drug Alcohol Depend. 2017;181:77–84.
   PubMed Web of Science ®Google Scholar
• Perry CJ, Lawrence AJ. Hurdles in basic science translation. Front Pharmacol. 2017;8:478.
   PubMed Web of Science ®Google Scholar
• Knapp CM, Mercado M, Markley TL, et al. Zonisamide decreases ethanol intake in rats and mice. Pharmacol Biochem Behav. 2007;87(1):65–72.
   PubMed Web of Science ®Google Scholar
• Fein G, Bachman L, Fisher S, et al. Cognitive impairments in abstinent alcoholics. West J Med. 1990;152(5):531.
   PubMedGoogle Scholar
• Perry C, Lawrence A. Addiction, cognitive decline and therapy: seeking ways to escape a vicious cycle. Genes Brain Behav. 2017;16(1):205–218.
   PubMed Web of Science ®Google Scholar
• Maurage P, Grynberg D, Noël X, et al. Dissociation between affective and cognitive empathy in alcoholism: a specific deficit for the emotional dimension. Alcohol Clin Exp Res. 2011;35(9):1662–1668.
   PubMed Web of Science ®Google Scholar
• Joos L, Goudriaan AE, Schmaal L, et al. Effect of modafinil on cognitive functions in alcohol dependent patients: a randomized, placebo-controlled trial. J Psychopharmacol. 2013;27(11):998–1006.
   PubMed Web of Science ®Google Scholar
• Fernando AB, Economidou D, Theobald DE, et al. Modulation of high impulsivity and attentional performance in rats by selective direct and indirect dopaminergic and noradrenergic receptor agonists. Psychopharmacology. 2012;219(2):341–352.
   PubMed Web of Science ®Google Scholar
• Bello NT. Clinical utility of guanfacine extended release in the treatment of adhd in children and adolescents. Patient Prefer Adherence. 2015;9:877.
   PubMed Web of Science ®Google Scholar
• Fredriksson I, Jayaram-Lindström N, Wirf M, et al. Evaluation of guanfacine as a potential medication for alcohol use disorder in long-term drinking rats: behavioral and electrophysiological findings. Neuropsychopharmacology. 2015;40(5):1130.
   PubMed Web of Science ®Google Scholar
• Jacquot C, Croft AP, Prendergast MA, et al. Effects of the glucocorticoid antagonist, mifepristone, on the consequences of withdrawal from long term alcohol consumption. Alcohol Clin Exp Res. 2008;32(12):2107–2116.
   PubMed Web of Science ®Google Scholar
• Donoghue K, Rose A, Coulton S, et al. Double-blind, 12 month follow-up, placebo-controlled trial of mifepristone on cognition in alcoholics: the mifcog trial protocol. BMC Psychiatry. 2016;16(1):40.
   PubMedGoogle Scholar
• Knapp CM, Ciraulo DA, Sarid-Segal O, et al. Zonisamide, topiramate, and levetiracetam: efficacy and neuropsychological effects in alcohol use disorders. J Clin Psychopharmacol. 2015;35(1):34.
   PubMed Web of Science ®Google Scholar
• Hara Y, McKeehan N, Dacks P, et al. Evaluation of the neuroprotective potential of n-acetylcysteine for prevention and treatment of cognitive aging and dementia. Evaluation. 2017;4(3):201–206.
   Google Scholar
• Jones JD, Comer SD, Kranzler HR. The pharmacogenetics of alcohol use disorder. Alcohol Clin Exp Res. 2015;39(3):391–402.
   PubMed Web of Science ®Google Scholar
• Oslin DW, Berrettini W, Kranzler HR, et al. A functional polymorphism of the μ-opioid receptor gene is associated with naltrexone response in alcohol-dependent patients. Neuropsychopharmacology. 2003;28(8):1546.
   PubMed Web of Science ®Google Scholar
• Karpyak V, Biernacka J, Geske J, et al. Genetic markers associated with abstinence length in alcohol-dependent subjects treated with acamprosate. Transl Psychiatry. 2014;4(10):e453.
   PubMedGoogle Scholar
• Kiefer F, Witt S, Frank J, et al. Involvement of the atrial natriuretic peptide transcription factor gata4 in alcohol dependence, relapse risk and treatment response to acamprosate. Pharmacogenomics J. 2011;11(5):368.
   PubMed Web of Science ®Google Scholar
• Arias AJ, Armeli S, Gelernter J, et al. Effects of opioid receptor gene variation on targeted nalmefene treatment in heavy drinkers. Alcohol Clin Exp Res. 2008;32(7):1159–1166.
   PubMed Web of Science ®Google Scholar
• Kosaka H, Okamoto Y, Munesue T, et al. Oxytocin efficacy is modulated by dosage and oxytocin receptor genotype in young adults with high-functioning autism: A 24-week randomized clinical trial. Transl Psychiatry. 2016;6(8):e872.
   PubMed Web of Science ®Google Scholar
• Kranzler HR, Armeli S, Feinn R, et al. Grik1 genotype moderates topiramate’s effects on daily drinking level, expectations of alcohol’s positive effects and desire to drink. Int J Neuropsychopharmacol. 2014;17(10):1549–1556.
   PubMed Web of Science ®Google Scholar
• Kenna GA, Haass‐Koffler CL, Zywiak WH, et al. Role of the α1 blocker doxazosin in alcoholism: A proof‐of‐concept randomized controlled trial. Addict Biol. 2016;21(4):904–914.
   PubMed Web of Science ®Google Scholar