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Medication Development for Alcohol Use Disorder: A Focus on Clinical Studies

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Substance Use Disorders

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 258))

Abstract

Compared to other medical disorders, including other brain diseases, the number of medications approved for alcohol use disorder (AUD) is very small. Disulfiram, naltrexone (oral and long-acting), and acamprosate are approved by the US Food and Drug Administration (FDA) to treat patients with AUD. These medications are also approved in other countries, including in Europe, where the European Medicines Agency (EMA) also approved nalmefene for AUD. Furthermore, baclofen was recently approved for AUD in France. These approved medications have small effect sizes, which are probably the consequence of the fact that they only work for some patients, yet a personalized approach to match the right medication with the right patient is still in its infancy. Therefore, research is needed to expand the armamentarium of medications that clinicians can use to treat their patients, as well as to better develop personalized approaches. This book chapter reviews other medications, beyond those approved by the FDA, that have shown efficacy in clinical trials, as well as medications which are still in the early stages of evaluation in human studies.

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Notes

  1. 1.

    Listed in alphabetical order.

References

  • Addolorato G, Caputo F, Capristo E, Domenicali M, Bernardi M, Janiri L, Agabio R, Colombo G, Gessa GL, Gasbarrini G (2002) Baclofen efficacy in reducing alcohol craving and intake: a preliminary double-blind randomized controlled study. Alcohol Alcohol 37:504–508

    Article  CAS  PubMed  Google Scholar 

  • Addolorato G, Leggio L, Ferrulli A, Cardone S, Vonghia L, Mirijello A, Abenavoli L, D’Angelo C, Caputo F, Zambon A, Haber PS, Gasbarrini G (2007) Effectiveness and safety of baclofen for maintenance of alcohol abstinence in alcohol-dependent patients with liver cirrhosis: randomised, double-blind controlled study. Lancet 370:1915–1922

    Article  CAS  PubMed  Google Scholar 

  • Agabio R, Sinclair JMA, Addolorato G, Aubin HJ, Beraha EM, Caputo F, Chick JD, de La Selle P, Franchitto N, Garbutt JC, Haber PS, Heydtman M, Jaury P, Lingford-Hughes AR, Morley KC, Müller CA, Owens L, Pastor A, Paterson L, Pélissier F, Rolland B, Stafford A, Thompson A, van den Brink W, de Beaurepaire R, Leggio L (2018) The use of baclofen to treat patients with alcohol use disorder: the Cagliari statement. Lancet Psychiatry 5:957–960

    Article  PubMed  Google Scholar 

  • Ameisen O (2005) Complete and prolonged suppression of symptoms and consequences of alcohol-dependence using high-dose baclofen: a self-case report of a physician. Alcohol Alcohol 40:147–150

    Article  CAS  PubMed  Google Scholar 

  • Anthenelli RM, Heffner JL, Wong E, Tibbs J, Russell K, Isgro M, Dinh E, Wehrle C, Worley MJ, Doran N (2017) A randomized trial evaluating whether topiramate aids smoking cessation and prevents alcohol relapse in recovering alcohol-dependent men. Alcohol Clin Exp Res 41:197–206

    Article  CAS  PubMed  Google Scholar 

  • Anton RF, Kranzler H, Breder C, Marcus RN, Carson WH, Han J (2008) A randomized, multicenter, double-blind, placebo-controlled study of the efficacy and safety of aripiprazole for the treatment of alcohol dependence. J Clin Psychopharmacol 28:5–12

    Article  CAS  PubMed  Google Scholar 

  • Anton RF, Myrick H, Baros AM, Latham PK, Randall PK, Wright TM, Stewart SH, Waid R, Malcolm R (2009) Efficacy of a combination of flumazenil and gabapentin in the treatment of alcohol dependence: relationship to alcohol withdrawal symptoms. J Clin Psychopharmacol 29:334–342

    Article  CAS  PubMed  Google Scholar 

  • Anton RF, Myrick H, Wright TM, Latham PK, Baros AM, Waid LR, Randall PK (2011) Gabapentin combined with naltrexone for the treatment of alcohol dependence. Am J Psychiatry 168:709–717

    Article  PubMed  PubMed Central  Google Scholar 

  • Anton RF, Schacht JP, Voronin KE, Randall PK (2017) Aripiprazole suppression of drinking in a clinical laboratory paradigm: influence of impulsivity and self-control. Alcohol Clin Exp Res 41:1370–1380

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Arias A, Feinn R, Oncken C, Covault J, Kranzler HR (2010) Placebo-controlled trial of zonisamide for the treatment of alcohol dependence. J Clin Psychopharmacol 30:318–322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Arnone D (2005) Review of the use of topiramate for treatment of psychiatric disorders. Ann Gen Psychiatry 4:5

    Article  PubMed  PubMed Central  Google Scholar 

  • Asghari V, Sanyal S, Buchwaldt S, Paterson A, Jovanovic V, van Tol HH (1995) Modulation of intracellular cyclic AMP levels by different human dopamine D4 receptor variants. J Neurochem 65:1157–1165

    Article  CAS  PubMed  Google Scholar 

  • Bell RL, Lopez MF, Cui C, Egli M, Johnson KW, Franklin KM, Becker HC (2013) Ibudilast reduces alcohol drinking in multiple animal models of alcohol dependence. Addict Biol 20:38–42

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Beraha EM, Salemink E, Goudriaan AE, Bakker A, de Jong D, Smits N, Zwart JW, van Geest D, Bodewits P, Schiphof T, Defourny H, van Tricht M, van den Brink W, Wiers RW (2016) Efficacy and safety of high-dose baclofen for the treatment of alcohol dependence: a multicenter, randomized, double-blind controlled trial. Eur Neuorpsychopharmacol 26:1950–1959

    Article  CAS  Google Scholar 

  • Brower KJ, Myra Kim H, Strobbe S, Karam-Hage MA, Consens F, Zucker RA (2008) A randomized double-blind pilot trial of gabapentin versus placebo to treat alcohol dependence and comorbid insomnia. Alcohol Clin Exp Res 32(8):1429–1438

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bucknam W (2007) Suppression of symptoms of alcohol dependence and craving using high-dose baclofen. Alcohol Alcohol 42:158–160

    Article  CAS  PubMed  Google Scholar 

  • Chompookham P, Rukngan W, Nilaban S, Suwanmajo S, Yoosom P, Kalayasiri R (2018) A randomized trial of low-dose gabapentin for post hospitalization relapse prevention in a Thai clinical sample of alcohol dependence. Psychiatry Res 270:34–40

    Article  CAS  PubMed  Google Scholar 

  • Colombo G, Gessa GL (2018) Suppressing effect of baclofen on multiple alcohol-related behaviors in laboratory animals. Front Psych 9:475

    Article  Google Scholar 

  • Daurio AM, Deschaine SL, Modabbernia A, Leggio L (2019) Parsing out the role of dopamine D4 receptor gene (DRD4) on alcohol-related phenotypes: a meta-analysis and systematic review. Addict Biol:e12770. https://doi.org/10.1111/adb.12770

  • de Bejczy A, Lof E, Walther L, Gutertstam J, Hammarbeg A, Ansanovska G, Franck J, Isaksson A, Soderpalm B (2015) Varenicline for treatment of alcohol dependence: a randomized, placebo-controlled trial. Alcohol Clin Exp Res 39:2189–2199

    Article  PubMed  CAS  Google Scholar 

  • Edwards S, Guerrero M, Ghoneim OM, Roberts E, Koob GF (2011) Evidence that vasopressin V1b receptors mediate the transition to excessive drinking in ethanol-dependent rats. Addict Biol 17:76–85

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Evans SM, Bisaga A (2009) Acute interaction of baclofen in combination with alcohol in heavy social drinkers. Alcohol Clin Exp Res 33:19–30

    Article  CAS  PubMed  Google Scholar 

  • Falk D, Wang XQ, Liu L, Fertig J, Mattson M, Ryan M, Johnson B, Stout R, Litten RZ (2010) Percentage of subjects with no heavy drinking days: evaluation as an efficacy endpoint for alcohol clinical trials. Alcohol Clin Exp Res 34:2022–2034

    Article  PubMed  Google Scholar 

  • Falk DE, Castle IJP, Ryan M, Fertig J, Litten RZ (2015) Moderators of varenicline treatment effects in a double-blind, placebo-controlled trial for alcohol dependence: an exploratory analysis. J Addict Med 9:296–303

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Falk DE, Ryan ML, Fertig JB, Devine EG, Cruz R, Brown ES, Burns H, Salloum IM, Newport DJ, Mendelson J, Galloway G, Grant T, Kampman K, Brooks C, Green AI, Brunette MF, Rosenthal RN, Dunn KE, Strain EC, Ray L, Shoptaw S, Ait-Daoud Tiouririne N, Gunderson EW, Random J, Scott C, Leggio L, Caras S, Mason B, Litten RZ, The National Institute on Alcohol Abuse and Alcoholism Clinical Investigations Group (NCIG) Study Group (2019a) Gabapentin enacarbil extended-release for alcohol use disorder: a randomized, double-blind, placebo-controlled, multisite trial assessing efficacy and safety. Alcohol Clin Exp Res 43:158–169

    CAS  PubMed  Google Scholar 

  • Falk DE, O’Malley SS, Witkiewitz K, Anton RF, Litten RZ, Slater M, Kranzler HR, Mann KF, Hasin DS, Johnson B, Meulien D, Ryan M, Fertig J, Alcohol Clinical Trials Initiative (ACTIVE) Workgroup (2019b) Evaluation of drinking risk levels as outcomes in alcohol pharmacotherapy trials: a secondary analysis of 3 randomized clinical trials. JAMA Psychiatry 76:374–381

    Article  PubMed  PubMed Central  Google Scholar 

  • Farokhnia M, Schwandt ML, Lee MR, Bollinger JW, Farinelli LA, Amodio JP, Sewell L, Lionetti TA, Spero DE, Leggio L (2017) Biobehavioral effects of baclofen in anxious alcohol-dependent individuals: a randomized, double-blind, placebo-controlled, laboratory study. Transl Psychiatry 7:e1108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Farokhnia M, Deschaine SL, Sadighi A, Farinelli LA, Lee MR, Akhlaghi F, Leggio L (2018) A deeper insight into how GABA-B receptor agonism via baclofen may affect alcohol seeking and consumption: lessons learned from a human laboratory investigation. Mol Psychiatry. https://doi.org/10.1038/s41380-018-0287-y

  • Farokhnia M, Faulkner ML, Piacentino D, Lee MR, Leggio L (2019) Ghrelin: from a gut hormone to a potential therapeutic target for alcohol use disorder. Physiol Behav 204:49–57

    Article  CAS  PubMed  Google Scholar 

  • Fleischhacker WW (2005) Aripiprazole. Expert Opin Pharmacother 6:2091–2101

    Article  CAS  PubMed  Google Scholar 

  • Fox HC, Anderson GM, Tuit K, Hansen J, Kimmerling A, Siedlarz KM, Morgan PT, Sinha R (2012) Prazosin effects on stress-and cue-induced craving and stress response in alcohol-dependent individuals: preliminary findings. Alcohol Clin Exp Res 36:351–360

    Article  CAS  PubMed  Google Scholar 

  • Fucito LM, Toll BA, Wu R, Romano DM, Tek E, O’Malley SS (2011) A preliminary investigation of varenicline for heavy drinking smokers. Psychopharmacology 215:655–663

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Furieri FA, Nakamura-Palacios EM (2007) Gabapentin reduces alcohol consumption and craving: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 68(11):1691–1700

    Article  CAS  PubMed  Google Scholar 

  • Garbutt JC, Kampov-Polevoy AB, Gallop R, Kalka-Juhl L, Flannery BA (2010) Efficacy and safety of baclofen for alcohol dependence: a randomized, double-blind, placebo-controlled trial. Alcohol Clin Exp Res 34(11):1849–1857

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Garbutt JC, Greenblatt AM, West SL, Morgan LC, Kampov-Polevoy A, Jordan HS, Bobashev GV (2014) Clinical and biological moderators of response to naltrexone in alcohol dependence: a systematic review of the evidence. Addiction 109(8):1274–1284

    Article  PubMed  Google Scholar 

  • Haass-Koffler CL, Goodyear K, Zywiak WH, Magill M, Eltinge SE, Wallace PM, Long VM, Jayaram-Lindstrom N, Swift RM, Kenna GA, Leggio L (2017) Higher pressure in associated with greater alcohol drinking reduction in alcohol-dependent individuals treated with doxazosin. Drug Alcohol Depend 177:23–28

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Haass-Koffler CL, Goodyear K, Zywiak WH, Leggio L, Kenna GA, Swift RM (2018a) Comparing and combining topiramate and aripiprazole on alcohol-related outcomes in a human laboratory study. Alcohol Alcohol 53(3):268–276

    Article  CAS  PubMed  Google Scholar 

  • Haass-Koffler CL, Swift RM, Leggio L (2018b) Noradrenergic targets for the treatment of alcohol use disorder. Psychopharmacology 235(6):1625–1634

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hauser P, Fuller B, Ho SB, Thuras P, Kern S, Dieperink E (2017) The safety and efficacy of baclofen to reduce alcohol use in veterans with chronic hepatitis C: a randomized controlled trial. Addiction 112(7):1173–1183

    Article  PubMed  Google Scholar 

  • Heilig M, Leggio L (2016) What the alcohol doctor ordered from the neuroscientist: theragnostic biomarkers for personalized treatments. Prog Brain Res 224:401–418

    Article  PubMed  Google Scholar 

  • Hofmann SG, Huweler R, MacKillop JM, Kantak K (2012) Effects of D-cycloserine on craving to alcohol cues in problem drinkers: preliminary findings. Am J Drug Alcohol Abuse 38:101–107

    Article  PubMed  Google Scholar 

  • Javors MA, Seneviratne C, Roache JD, Ait-Daoud N, Bergeson SE, Walss-Bass MC, Akhtar FZ, Johnson BA (2005) Platelet serotonin uptake and paroxetine binding among allelic genotypes of the serotonin transporter in alcoholics. Prog Neuro-Psychopharmacol Biol Psychiatry 29:7–13

    Article  CAS  Google Scholar 

  • Johnson BA, Campling GM, Griffiths P, Cowen PJ (1993) Attention of some alcohol-induced mood changes and the desire to drink by 5-HT3 receptor blockade: a preliminary study I healthy male volunteers. Psychopharmacology 112:142–144

    Article  CAS  PubMed  Google Scholar 

  • Johnson BA, Roache JD, Javors MA, DiClemente CC, Cloninger CR, Prihoda TJ, Bordnick PS, Ait-Daoud N, Hensler J (2000) Ondansetron for reduction of drinking among biologically predisposed alcoholic patients: a randomized controlled trial. JAMA 284(8):963–971

    Article  CAS  PubMed  Google Scholar 

  • Johnson BA, Ait-Daoud N, Bowden CL, DiClemente CC, Roache JD, Lawson K, Javors MA, Ma JZ (2003) Oral topiramate for treatment of alcohol dependence: a randomised controlled trial. Lancet 361:1677–1685

    Article  CAS  PubMed  Google Scholar 

  • Johnson BA, Rosenthal N, Capece JA, Wiegund F, Mao L, Beyers K, McKay A, Ait-Daoud N, Anton RF, Ciraulo DA, Kranzler HR, Mann K, O’Malley SS, Swift RM (2007) Topiramate for treating alcohol dependence: a randomized controlled trial. JAMA 198(14):1641–1651

    Article  Google Scholar 

  • Johnson BA, Javors MA, Roache JD, Seneviratne C, Bergeson SE, Ait-Daoud N, Dawes MA, Ma JZ (2008) Can serotonin transporter genotype predict serotonergic function, chronicity, and severity of drinking? Prog Neuro-Psychopharmacol Biol Psychiatry 32:209–216

    Article  CAS  Google Scholar 

  • Johnson BA, Ait-Daoud N, Seneviratne C, Roach JD, Javors MA, Wang XQ, Liu L, Penberthy JK, Di Clemente CC, Li MD (2011) Pharmacogenetic approach at the serotonin transporter gene as a method of reducing the severity of alcohol drinking. Am J Psychiatry 168:265–275

    Article  PubMed  PubMed Central  Google Scholar 

  • Johnson BA, Seneviratne C, Wang XQ, Ait-Daoud N, Li MD (2013) Determination of genotype combinations that can predict the outcome of the treatment of alcohol dependence using the 5-HT3 antagonist ondansetron. Am J Psychiatry 170:1020–1031

    Article  PubMed  Google Scholar 

  • Jonas DE, Amick HR, Feltner C, Bobashev G, Thomas K, Wines R, Kim MM, Shanahan E, Gass CE, Rowe CJ, Garbutt JC (2014) Pharmacotherapy for adults with alcohol use disorders in outpatient settings: a systematic review and meta-analysis. JAMA 311(18):889–900

    Article  CAS  Google Scholar 

  • Kenna GA, Zywiak WH, McGeary JE, Leggio L, McGeary C, Wang S, Grenga A, Swift RM (2009) A within-group design of nontreatment seeking 5-HTTLPR genotyped alcohol-dependent subjects receiving ondansetron and sertraline. Alcohol Clin Exp Res 33:315–323

    Article  CAS  PubMed  Google Scholar 

  • Kenna GA, Swift RM, Hillemacher T, Leggio L (2012) The relationship of appetitive, reproductive and posterior pituitary hormones to alcoholism and craving in humans. Neuropsychol Rev 22(3):211–228

    Article  PubMed  PubMed Central  Google Scholar 

  • Kenna GA, Zywiak WH, Swiftt RM, McGeary JE, Cliifford JS, Shoaff JR, Vuittonet C, Fricchione S, Brickley M, Beaucage K, Haass-Koffler CL, Leggio L (2014a) Ondansetron reduces naturalistic drinking in nontreatment-seeking alcohol-dependent individuals with the LL 5/-HTTLPR genotype: a laboratory study. Alcohol Clin Exp Res 38:1567–1574

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kenna GA, Zwiak WH, Swift RM, McGeary JE, Clifford JS, Shoaff JR, Fricchione S, Brickley M, Beaucage K, Haass-Koffler CL, Leggio L (2014b) Ondansetron and sertraline may interact with 5-HTTLPR and DRD4 polymorphisms to reduce drinking in non-treatment seeking alcohol-dependent women: exploratory findings. Alcohol 48:515–522

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kenna GA, Haass-Koffler CL, Zywiak WH, Edwards SM, Brickley MB, Swift RM, Leggio L (2015) Role of the α1 blocker doxazosin in alcoholism: a proof-of-concept randomized controlled trial. Addict Biol 21:904–914

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kiefer F, Kirsch M, Bach P, Hoffmann S, Reinhard I, Jorde A, von der Goltz C, Spanagel R, Mann K, Loeber S, Vollstadt-Klein S (2015) Effects of D-cycloserine on extinction of mesolimbic cue reactivity in alcoholism: a randomized placebo-controlled trial. Psychopharmacology 232(13):2353–2362

    Article  CAS  PubMed  Google Scholar 

  • Knapp CM, Ciraulo DA, Sarid-Segal O, Richardson MA, Devine E, Streeter CC, Oscar-Berman M, Surprise C, Colaneri L, Putnam M, Waters M, Richambault C (2015) Zonisamide, topiramate, and levetiracetam: efficacy and neuropsychological effects in alcohol use disorders. J Clin Psychopharmacol 35:1–9

    Article  CAS  Google Scholar 

  • Kothare S, Kaleyias J (2008) Zonisamide: review of pharmacology, clinical efficacy, tolerability, and safety. Expert Opin Drug Metab Toxicol 4:493–506

    Article  CAS  PubMed  Google Scholar 

  • Kranzler HR, Covault J, Pierucci-Lagha A, Chan G, Douglas K, Arias AJ, Oncken C (2008) Effects of aripiprazole on subjective and physiological responses to alcohol. Alcohol Clin Exp Res 32:1–7

    Article  CAS  Google Scholar 

  • Kranzler HR, Covault J, Feinn R, Armeli S, Tennen H, Arias AJ, Gelernter J, Pond T, Oncken C, Kampman KM (2014) Topiramate treatment for heavy drinkers: moderation by a GRIK1 polymorphism. Am J Psychiatry 171:445–452

    Article  PubMed  PubMed Central  Google Scholar 

  • Lee MR, Rohn MCH, Tanda G, Leggio L (2016) Targeting the oxytocin system to treat addictive disorders: rationale and progress to date. CNS Drugs 30(2):109–123

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee MR, Tapocik JD, Ghareeb M, Schwandt ML, Dias AA, Le AN, Cobbina E, Farinelli LA, Bouhlal S, Farokhnia M, Heilig M, Akhlaghi F, Leggio L (2018) The novel ghrelin receptor inverse agonist PF-5190457 administered with alcohol: preclinical safety experiments and a phase 1b human laboratory study. Mol Psychiatry. https://doi.org/10.1038/s41380-018-0064-y

    Article  PubMed  CAS  Google Scholar 

  • Leggio L, Kenna GA (2013) Commentary: doxazosin for alcoholism. Alcohol Clin Exp Res 37:191–193

    Article  CAS  PubMed  Google Scholar 

  • Leggio L, Garbutt JC, Addolorato G (2010) Effectiveness and safety of baclofen in the treatment of alcohol dependent patients. CNS Neurol Disord 9:33–44

    Article  CAS  Google Scholar 

  • Leggio L, Ferrulli A, Zambon A, Caputo F, Kenna GA, Swift RM, Addolorato G (2012) Baclofen promotes alcohol abstinence in alcohol dependent cirrhotic patients with hepatitis C virus (HCV) infection. Addict Behav 37(4):561–564

    Article  CAS  PubMed  Google Scholar 

  • Leggio L, Zywiak WH, McGeary JE, Edwards S, Fricchione SR, Shoaff JR, Addolorato G, Swift RM, Kenna GA (2013) A human laboratory pilot study with baclofen in alcoholic individuals. Pharmacol Biochem Behav 103:784–791

    Article  CAS  PubMed  Google Scholar 

  • Leggio L, Zywiak WH, Edwards SM, Tidey JW, Swift RM, Kenna G (2015) A preliminary double-blind, placebo-controlled randomized study of baclofen effects in alcoholic smokers. Psychopharmacology 232:233–243

    Article  CAS  PubMed  Google Scholar 

  • Litten RZ, Ryan ML, Fertig JB, Falk DE, Johnson B, Dunn KE, Green AI, Pettinati HM, Ciraulo DA, Sarid-Segal O, Kampman K, Brunette MF, Strain EC, Tiouririne NA, Ransom J, Scott C, Stout R (2013) A double-blind, placebo-controlled trial assessing the efficacy of varenicline tartrate for alcohol dependence. J Addict Med 7:277–286

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Litten RZ, Ryan ML, Falk DE, Reilly M, Fertig JB, Koob GF (2015) Heterogeneity of alcohol use disorder: understanding mechanisms to advance personalized treatment. Alcohol Clin Exp Res 39:579–584

    Article  PubMed  Google Scholar 

  • Litten RZ, Falk DE, Ryan ML, Fertig JB (2016) Discovery, development, and adoption of medications to treat alcohol use disorder: goals for the phases of medications development. Alcohol Clin Exp Res 40:1368–1379

    Article  PubMed  PubMed Central  Google Scholar 

  • Litten RZ, Falk DE, Ryan ML, Fertig J, Leggio L (2018) Advances in pharmacotherapy development: human clinical studies. Handb Exp Pharmacol 248:579–613

    Article  PubMed  CAS  Google Scholar 

  • MacKillop J, Few LR, Stojek MK, Murphy CM, Malutinok SF, Johnson FT, Hofmann SG, McGeary JE, Swift RM, Monti PM (2015) D-cycloserine to enhance extinction of cue-elicited craving for alcohol: a translational approach. Transl Psychiatry 5(4):e544

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Martinotti G, DiNicola M, De Vita O, Hatzigiakoumis DS, Guglielmo R, Santucci B, Aliotta F, Romanelli R, Verrastro V, Petruccelli F, Di Giannantonio M, Janiri L (2014) Low-dose topiramate in alcohol dependence: a single-blind, placebo-controlled study. J Clin Psychopharmacol 34:709–715

    Article  CAS  PubMed  Google Scholar 

  • Mason BJ, Light JM, Williams LD, Drobes DJ (2009) Proof-of-concept human laboratory study for protracted abstinence in alcohol dependence: effects of gabapentin. Addict Biol 14(1):73–83

    Article  CAS  PubMed  Google Scholar 

  • Mason BJ, Quello S, Goodell V, Shadan F, Kyle M, Begovic A (2014) Gabapentin treatment for alcohol dependence: a randomized clinical trial. JAMA Intern Med 174:70

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McCool BA, McGinnis MM (2019) Adolescent vulnerability to alcohol use disorder: neurophysiological mechanisms from preclinical studies. Handb Exp Pharmacol. https://doi.org/10.1007/164_2019_296

  • McKee SA, Harrison ELR, O’Malley SS, Krishnan-Sarin S, Shi J, Tetrault JM, Picciotto MR, Petrakis IL, Estevez N, Balchunas E (2009) Varenicline reduces alcohol self-administration in heavy-drinking smokers. Biol Psychiatry 66:185–195

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Medical Press (2018) France clears use of anti-spasm drug to treat alcoholism. https://medicalxpress.com/news/2018-10-france-anti-spasm-drug-alcoholism.html. Accessed 31 May 2019

  • Mihalak KB, Carroll FI, Luetje CW (2006) Varenicline is a partial agonist at α4β2 and a full agonist at α7 neuronal nicotinic receptors. Mol Pharmacol 70:801–805

    Article  CAS  PubMed  Google Scholar 

  • Miranda R, MacKillop J, Monti PM, Rohsenow DJ, Tidey J, Gwaltney C, Swift R, Ray L, McGeary J (2008) Effects of topiramate on urge to drink and the subjective effects of alcohol: a preliminary laboratory study. Alcohol Clin Exp Res 32:489–497

    Article  CAS  PubMed  Google Scholar 

  • Miranda R, MacKillop J, Treloar H, Blanchard A, Tidey JW, Swift R, Chun T, Rohsenow DJ, Monti PM (2016) Biobehavioral mechanisms of topiramate’s effects on alcohol use: an investigation pairing laboratory and ecological momentary assessments. Addict Biol 21:171–182

    Article  CAS  PubMed  Google Scholar 

  • Mitchell JM, Teague CH, Kayser AS, Bartlett SE, Fields HL (2012) Varenicline decreases alcohol consumption in heavy-drinking smokers. Psychopharmacology 223:299–306

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Morley KC, Baillie A, Fraser I, Furneaux-Bate A, Dore G, Roberts M, Abdalla A, Phung N, Haber PS (2018a) Baclofen in the treatment of alcohol dependence with or without liver disease: multisite, randomised, double-blind, placebo-controlled trial. Br J Psychiatry 212(6):362–369

    Article  PubMed  Google Scholar 

  • Morley KC, Baillie A, van den Brink W, Chitty KE, Brady K, Back SE, Seth D, Sutherland G, Leggio L, Haber PS (2018b) N-acetyl cysteine in the treatment of alcohol use disorder in patients with liver disease: rationale for further research. Expert Opin Investig Drugs 27(8):667–675

    Article  CAS  PubMed  Google Scholar 

  • Morris LS, Voon V, Leggio L (2018) Stress, motivation, and the gut-brain axis: a focus on the ghrelin system and alcohol use disorder. Alcohol Clin Exp Res 42:1378

    Article  Google Scholar 

  • Muller CA, Geisel O, Petz P, Higl V, Kruger J, Stickel A, Beck A, Wernecke KD, Hellweg R, Heinz A (2015) High-dose baclofen for the treatment of alcohol dependence (BACLAD study): a randomized, placebo-controlled trial. Eur Neuropsychopharmacol 25:1167–1177

    Article  PubMed  CAS  Google Scholar 

  • Myrick H, Li X, Randall PK, Henderson S, Voronin K, Anton RF (2010) The effect of aripiprazole in cue-induced brain activation and drinking parameters in alcoholics. J Clin Psychopharmacol 30:365–372

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Oak JN, Oldenhof J, van Tol HH (2000) The dopamine D4 receptor: one decade of research. Eur J Pharmacol 405:303–327

    Article  CAS  PubMed  Google Scholar 

  • O’Malley SS, Zweben A, Fucito LM, Wu R, Piepmeier ME, Ockert DM, Bold KW, Petrakis I, Muvvala S, Jatlow P, Gueorguieva R (2018) Effect of varenicline combined with medical management on alcohol use disorder with comorbid cigarette smoking: a randomized clinical trial. JAMA Psychiat 75:129–138

    Article  Google Scholar 

  • Petrakis IL, Desai N, Gueorguieva R, Arias A, O’Brien E, Jane JS, Sevarino K, Southwick S, Ralevski E (2016) Prazosin for veterans with posttraumatic stress disorder and comorbid alcohol dependence: a clinical trial. Alcohol Clin Exp Res 40:178–186

    Article  CAS  PubMed  Google Scholar 

  • Plebani JG, Lynch KG, Rennert L, Pettinati HM, O’Brien CP, Kampman KM (2013) Results from a pilot clinical trial of varenicline for the treatment of alcohol dependence. Drug Alcohol Depend 133(2):754–758

    Article  CAS  PubMed  Google Scholar 

  • Ray LA, Miranda R, MacKillop J, McGeary J, Tidey JW, Rohsenow DJ, Gwaltney C, Swift RW, Monti PM (2009) A preliminary pharmacogenetic investigation of adverse events from topiramate in heavy drinkers. Exp Clin Psychopharmacol 17:122–129

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ray LA, Courtney KE, Ghahremani DG, Miotto K, Brody A, London ED (2014) Varenicline, low dose naltrexone, and their combination for heavy-drinking smokers: human laboratory findings. Psychopharmacology 231:3843–3853

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ray LA, Bujarski S, Shoptaw S, Roche DJ, Heinzerling K, Miotto K (2017) Development of the neuroimmune modulator ibudilast for the treatment of alcoholism: a randomized, placebo-controlled, human laboratory trial. Neuropsychopharmacology 42(9):1776–1788

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reynaud M, Aubin HJ, Trinquet F, Zakine B, Dano C, Dematteis M, Trojak B, Paille F, Detilleux M (2017) A randomized, placebo-controlled study of high-dose baclofen in alcohol-dependent patients – the ALPADIR study. Alcohol Alcohol 52(4):439–446

    Article  CAS  PubMed  Google Scholar 

  • Richardson HN, Lee SY, O’Dell LE, Koob GF, Rivier CL (2008) Alcohol self-administration acutely stimulates the hypothalamic-pituitary-adrenal axis, but alcohol dependence leads to a dampened neuroendocrine state. Eur J Neurosci 28:1641–1653

    Article  PubMed  PubMed Central  Google Scholar 

  • Roberts W, Harrison ELR, McKee SA (2017a) Effects of varenicline on alcohol cue reactivity in heavy drinkers. Psychopharmacology 234(18):2737–2745

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Roberts W, Verplaetse TL, Moore K, Oberleitner L, Picciotto MR, McKee SA (2017b) Effects of varenicline on alcohol self-administration and craving in drinkers with depressive symptoms. J Psychopharmacol 31:906–914

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ryan ML, Falk DE, Fertig JB, Rendenbach-Mueller B, Katz DA, Tracy KA, Strain EC, Dunn KE, Kampman K, Mahoney E, Ciraulo DA, Sickles-Colaneri L, Ait-Daoud N, Johnson BA, Ransom J, Scott C, Koob GF, Litten RZ (2017) A phase2, double-blind, placebo-controlled randomized trial assessing the efficacy of ABT-436, a novel V1b receptor antagonist, for alcohol dependence. Neuropsychopharmacology 42:1012–1023

    Article  CAS  PubMed  Google Scholar 

  • Sarid-Segal O, Knapp CM, Burch W, Richardson MA, Bahtia S, DeQuattro K, Afshar M, Richambault C, Sickels L, Devine E, Ciraulo D (2009) The anticonvulsant zonisamide reduces ethanol self-administration by risky drinkers. Am J Drug Alcohol Abuse 35:316–319

    Article  PubMed  PubMed Central  Google Scholar 

  • Schacht JP, Anton RF, Randall PK, Li X, Henderson S, Myrick H (2014) Varenicline effects on drinking, craving and neural reward processing among non-treatment-seeking alcohol-dependent individuals. Psychopharmacology 231:3799–3807

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schacht JP, Voronin KE, Randall PK, Anton RF (2018) Dopaminergic genetic variation influences Aripiprazole effects on alcohol self-administration and the neural response to alcohol cues in a randomized trial. Neuropsychopharmacology 43:1247–1256

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Seif T, Simms JA, Lei K, Wegner S, Bonci A, Messing RO, Hopf FW (2015) D-serine and D-cycloserine reduce compulsive alcohol intake in rats. Neuropyschopharmacology 40(10):2357–2367

    Article  CAS  Google Scholar 

  • Sellers EM, Toneatto T, Romach MK, Somer GR, Sobell LC, Sobell MB (1994) Clinical efficacy of the 5-HT3 antagonist ondansetron in alcohol abuse and dependence. Alcohol Clin Exp Res 18(4):879–885

    Article  CAS  PubMed  Google Scholar 

  • Sills GJ (2006) The mechanisms of action of gabapentin and pregabalin. Curr Opin Pharmacol 6:108–113

    Article  CAS  PubMed  Google Scholar 

  • Simms JA, Haass-Koffler CL, Bito-Onon J, Li R, Bartlett SE (2012) Mifepristone in the central nucleus of the amygdala reduces yohimbine stress-induced reinstatement of ethanol-seeking. Neuropsychopharmacology 37:906–918

    Article  CAS  PubMed  Google Scholar 

  • Simpson TL, Saxon AJ, Meredith CW, Malte CA, McBride B, Ferguson LC, Gross CA, Hart KL, Raskind M (2009) A pilot trial of the alpha-1 adrenergic antagonist, prazosin for alcohol dependence. Alcohol Clin Exp Res 33:255–263

    Article  CAS  PubMed  Google Scholar 

  • Simpson TL, Malte CA, Dietel B, Tell D, Pocock I, Lyons R, Varon D, Raskind M, Saxon AJ (2015) A pilot trial of prazosin, an alpha-1 adrenergic antagonist, for comorbid alcohol dependence and posttraumatic stress disorder. Alcohol Clin Exp Res 39:808–817

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Simpson TL, Saxon AJ, Stappenbeck C, Malte CA, Lyons R, Tell D, Millard SP, Raskind M (2018) Double-blind randomized clinical trial of prazosin for alcohol use disorder. Am J Psychiatry 175:1216

    Article  PubMed  PubMed Central  Google Scholar 

  • Smith RV, Havens JR, Walsh SL (2016) Gabapentin misuse, abuse and diversion: a systematic review. Addiction 111:1160–1174

    Article  PubMed  PubMed Central  Google Scholar 

  • Swift RM (2003) Topiramate for the treatment of alcohol dependence: initiating abstinence. Lancet 361(9370):1666–1667

    Article  PubMed  Google Scholar 

  • Swift RM, Davidson D, Whelihan W, Kuznetsov O (1996) Ondansetron alters human alcohol intoxication. Biol Psychiatry 40:514–521

    Article  CAS  PubMed  Google Scholar 

  • Vendruscolo LF, Barbier E, Schlosburg JE, Misra KK, Whitfield TW, Logrip ML, Rivier C, Repunte-Canonigo V, Zorrilla EP, Sanna PP, Heilig M, Koob GF (2012) Corticosteroid-dependent plasticity medicates compulsive alcohol drinking in rats. J Neurosci 32:7563–7571

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vendruscolo LF, Estey D, Goodell V, Macshane LG, Logrip ML, Schlosburg JE, McGinn MA, Zamora-Martinez ER, Belanoff JK, Hunt HJ, Sanna PP, George O, Koob GF, Edwards S, Mason BJ (2015) J Clin Invest 125:3193–3197

    Article  PubMed  PubMed Central  Google Scholar 

  • Voronin K, Randall P, Myrick H, Anton R (2008) Aripiprazole effects on alcohol consumption and subjective reports in a clinical laboratory paradigm–possible influence of self-control. Alcohol Clin Exp Res 32:1954–1961

    CAS  PubMed  PubMed Central  Google Scholar 

  • Watson BJ, Wilson S, Griffin L, Kalk NJ, Taylor LG, Munafo MR, Lingford-Hughes AR, Nutt DJ (2011) A pilot study of the effectiveness of D-cycloserine during cue-exposure therapy in abstinent alcohol-dependent subjects. Psychopharmacology 216:121–129

    Article  CAS  PubMed  Google Scholar 

  • Wilcox CE, Tonigan JS, Bogenschutz MP, Clifford J, Bigelow R, Simpson T (2018) A randomized, placebo-controlled, clinical trial of prazosin for the treatment of alcohol use disorder. J Addict Med 12(5):339–345

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zallar LJ, Farokhnia M, Tunstall BJ, Vendruscolo LF, Leggio L (2017) The role of the ghrelin system in drug addiction. Int Rev Neurobiol 136:89–119

    Article  PubMed  Google Scholar 

  • Zhou Y, Colombo G, Carai MAM, Ho A, Gessa GL, Kreek MJ (2011) Involvement of arginine vasopressin and V1b receptor in alcohol drinking in Sardinian alcohol-preferring rats. Alcohol Clin Exp Res 35:1876–1883

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

The authors would like to thank the support of the National Institute on Alcohol Abuse and Alcoholism (LL, DEF, MLR, JF, RZL) and of the National Institute on Drug Abuse (LL). The authors would also like to thank Brittney Browning, B.Sc. (Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, National Institute on Alcohol Abuse and Alcoholism and National Institute on Drug Abuse), for providing support with the preparation of the manuscript.

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Authors and Affiliations

  1. Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, National Institute on Alcohol Abuse and Alcoholism, Division of Intramural Clinical and Biological Research and National Institute on Drug Abuse Intramural Research Program, Bethesda, MD, USA

    Lorenzo Leggio

  2. Medication Development Program, National Institute on Drug Abuse Intramural Research Program , Baltimore, MD, USA

    Lorenzo Leggio

  3. Center for Alcohol and Addiction Studies, Brown University, Providence, RI, USA

    Lorenzo Leggio

  4. Division of Medications Development, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA

    Daniel E. Falk, Megan L. Ryan, Joanne Fertig & Raye Z. Litten

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  1. Lorenzo Leggio
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  2. Daniel E. Falk
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  3. Megan L. Ryan
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  4. Joanne Fertig
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  5. Raye Z. Litten
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Correspondence to Lorenzo Leggio .

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Editors and Affiliations

  1. Wake Forest School of Medicine, Winston-Salem, NC, USA

    Michael A. Nader

  2. Addiction Institute of Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Yasmin L. Hurd

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Leggio, L., Falk, D.E., Ryan, M.L., Fertig, J., Litten, R.Z. (2019). Medication Development for Alcohol Use Disorder: A Focus on Clinical Studies. In: Nader, M., Hurd, Y. (eds) Substance Use Disorders. Handbook of Experimental Pharmacology, vol 258. Springer, Cham. https://doi.org/10.1007/164_2019_295

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