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Clinical Trials for Stimulant Use Disorders: Addressing Heterogeneities That May Undermine Treatment Outcomes

  • Paul S. RegierEmail author
  • Kyle M. Kampman
  • Anna Rose Childress
Part of the Handbook of Experimental Pharmacology book series


In recent years, use of cocaine and amphetamines and deaths associated with stimulants have been on the rise, and there are still no FDA-approved medications for stimulant use disorders. One contributing factor may involve heterogeneity. At the neurobiological level, dual dopamine dysfunction may be undermining medication efficacy, suggesting a need for combination pharmacotherapies. At the population level, individual variability is expressed in a number of ways and, if left unaddressed, may interfere with medication efficacy. This chapter reviews studies investigating medications to address dopamine dysfunction, and it also identifies several prominent heterogeneities associated with stimulant (and other substance) use disorders. The chapter has implications for improving interventions to treat stimulant use disorders, and the theme of individual heterogeneity may have broader application across substance use disorders.


Amphetamines Cocaine Heterogeneity Medication-assisted treatment Relapse 


  1. Abdalla RR, Madruga CS, Ribeiro M et al (2014) Prevalence of cocaine use in Brazil: data from the II Brazilian national alcohol and drugs survey (BNADS). Addict Behav 39:297–301Google Scholar
  2. Agabio R, Colombo G (2014) GABAB receptor ligands for the treatment of alcohol use disorder: preclinical and clinical evidence. Front Neurosci 8:140. Scholar
  3. Ahmadi J, Kampman KM, Oslin DM et al (2009) Predictors of treatment outcome in outpatient cocaine and alcohol dependence treatment. Am J Addict 18:81–86. Scholar
  4. Ahmed SH (2010) Validation crisis in animal models of drug addiction: beyond non-disordered drug use toward drug addiction. Neurosci Biobehav Rev 35:172–184. Scholar
  5. Ahmed SH, Koob GF (1998) Transition from moderate to excessive drug intake: change in hedonic set point. Science 282:298–300. Scholar
  6. Al-Hasani R, McCall JG, Foshage AM, Bruchas MR (2013) Locus coeruleus kappa-opioid receptors modulate reinstatement of cocaine place preference through a noradrenergic mechanism. Neuropsychopharmacology 38:2484–2497. Scholar
  7. Anderson SM, Famous KR, Sadri-Vakili G et al (2008) CaMKII: a biochemical bridge linking accumbens dopamine and glutamate systems in cocaine seeking. Nat Neurosci 11:344–353. Scholar
  8. Anderson AL, Reid MS, Li S-H et al (2009) Modafinil for the treatment of cocaine dependence. Drug Alcohol Depend 104:133–139. Scholar
  9. Ashok AH, Mizuno Y, Volkow ND, Howes OD (2017) Association of stimulant use with dopaminergic alterations in users of cocaine, amphetamine, or methamphetamine: a systematic review and meta-analysis. JAMA Psychiat 74:511–519. Scholar
  10. Augier E, Dulman RS, Damadzic R et al (2017) The GABAB positive allosteric modulator ADX71441 attenuates alcohol self-administration and relapse to alcohol seeking in rats. Neuropsychopharmacology 42:1789–1799. Scholar
  11. Baldaçara L, Cogo-Moreira H, Parreira BL et al (2016) Efficacy of topiramate in the treatment of crack cocaine dependence: a double-blind, randomized, placebo-controlled trial. J Clin Psychiatry 77:398–406. Scholar
  12. Bazzett TJ, Becker JB (1994) Sex differences in the rapid and acute effects of estrogen on striatal D2 dopamine receptor binding. Brain Res 637:163–172. Scholar
  13. Becker JB (1990) Direct effect of 17 beta-estradiol on striatum: sex differences in dopamine release. Synapse 5:157–164. Scholar
  14. Becker JB (1999) Gender differences in dopaminergic function in striatum and nucleus accumbens. Pharmacol Biochem Behav 64:803–812. Scholar
  15. Becker JB (2016) Sex differences in addiction. Dialogues Clin Neurosci 18:395–402Google Scholar
  16. Berridge KC, Robinson TE (1998) What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience? Brain Res Rev 28:309–369. Scholar
  17. Bobzean SAM, DeNobrega AK, Perrotti LI (2014) Sex differences in the neurobiology of drug addiction. Exp Neurol 259:64–74. Scholar
  18. Bonson KR, Grant SJ, Contoreggi CS et al (2002) Neural systems and cue-induced cocaine craving. Neuropsychopharmacology 26:376–386. Scholar
  19. Brebner K, Phelan R, Roberts DC (2000a) Effect of baclofen on cocaine self-administration in rats reinforced under fixed-ratio 1 and progressive-ratio schedules. Psychopharmacology (Berl) 148:314–321Google Scholar
  20. Brebner K, Phelan R, Roberts DC (2000b) Intra-VTA baclofen attenuates cocaine self-administration on a progressive ratio schedule of reinforcement. Pharmacol Biochem Behav 66:857–862Google Scholar
  21. Brodie JD, Figueroa E, Dewey SL (2003) Treating cocaine addiction: from preclinical to clinical trial experience with gamma-vinyl GABA. Synapse 50:261–265. Scholar
  22. Brodie JD, Figueroa E, Laska EM, Dewey SL (2005) Safety and efficacy of γ-vinyl GABA (GVG) for the treatment of methamphetamine and/or cocaine addiction. Synapse 55:122–125. Scholar
  23. Brodie JD, Case BG, Figueroa E et al (2009) Randomized, double-blind, placebo-controlled trial of vigabatrin for the treatment of cocaine dependence in Mexican parolees. Am J Psychiatry 166:1269–1277. Scholar
  24. Bubar MJ, Cunningham KA (2006) Serotonin 5-HT2A and 5-HT2C receptors as potential targets for modulation of psychostimulant use and dependence. Curr Top Med Chem 6:1971–1985Google Scholar
  25. Calipari ES, Ferris MJ (2013) Amphetamine mechanisms and actions at the dopamine terminal revisited. J Neurosci 33:8923–8925. Scholar
  26. Campbell UC, Lac ST, Carroll ME (1999) Effects of baclofen on maintenance and reinstatement of intravenous cocaine self-administration in rats. Psychopharmacology (Berl) 143:209–214Google Scholar
  27. Cao D-N, Shi J-J, Hao W et al (2016) Advances and challenges in pharmacotherapeutics for amphetamine-type stimulants addiction. Eur J Pharmacol 780:129–135. Scholar
  28. Carey AN, Borozny K, Aldrich JV, McLaughlin JP (2007) Reinstatement of cocaine place-conditioning prevented by the peptide kappa-opioid receptor antagonist arodyn. Eur J Pharmacol 569:84–89. Scholar
  29. Carpentier P-J, Levin FR (2017) Pharmacological treatment of ADHD in addicted patients: what does the literature tell us? Harv Rev Psychiatry 25:50–64. Scholar
  30. Carroll KM, Kiluk BD, Nich C et al (2011) Cognitive function and treatment response in a randomized clinical trial of computer-based training in cognitive-behavioral therapy. Subst Use Misuse 46:23–34. Scholar
  31. Cepeda-Benito A, Reynoso JT, Erath S (2004) Meta-analysis of the efficacy of nicotine replacement therapy for smoking cessation: differences between men and women. J Consult Clin Psychol 72:712–722. Scholar
  32. Charney DA, Palacios-Boix J, Gill KJ (2007) Sexual abuse and the outcome of addiction treatment. Am J Addict 16:93–100. Scholar
  33. Chase HW, Eickhoff SB, Laird AR, Hogarth L (2011) The neural basis of drug stimulus processing and craving: an activation likelihood estimation meta-analysis. Biol Psychiatry 70:785–793. Scholar
  34. Chenoweth MJ, Tyndale RF (2017) Pharmacogenetic optimization of smoking cessation treatment. Trends Pharmacol Sci 38:55–66. Scholar
  35. Chien EYT, Liu W, Zhao Q et al (2010) Structure of the human dopamine D3 receptor in complex with a D2/D3 selective antagonist. Science 330:1091–1095. Scholar
  36. Childress AR, Mozley PD, McElgin W et al (1999) Limbic activation during cue-induced cocaine craving. Am J Psychiatry 156:11–18. Scholar
  37. Chiodo KA, Läck CM, Roberts DCS (2008) Cocaine self-administration reinforced on a progressive ratio schedule decreases with continuous D-amphetamine treatment in rats. Psychopharmacology (Berl) 200:465–473. Scholar
  38. Chomchai C, Chomchai S (2015) Global patterns of methamphetamine use. Curr Opin Psychiatry 28:269. Scholar
  39. Clayton LM, Stern WM, Newman WD et al (2013) Evolution of visual field loss over ten years in individuals taking vigabatrin. Epilepsy Res 105:262–271. Scholar
  40. Connolly CG, Foxe JJ, Nierenberg J et al (2012) The neurobiology of cognitive control in successful cocaine abstinence. Drug Alcohol Depend 121:45–53. Scholar
  41. Cornish JL, Kalivas PW (2000) Glutamate transmission in the nucleus accumbens mediates relapse in cocaine addiction. J Neurosci 20:RC89. Scholar
  42. Courtney KE, Schacht JP, Hutchison K et al (2016) Neural substrates of cue reactivity: association with treatment outcomes and relapse. Addict Biol 21:3–22. Scholar
  43. Crist RC, Clarke T-K, Ang A et al (2013) An intronic variant in OPRD1 predicts treatment outcome for opioid dependence in African-Americans. Neuropsychopharmacology 38:2003–2010. Scholar
  44. Crist RC, Doyle GA, Nelson EC et al (2018) A polymorphism in the OPRM1 3′ untranslated region is associated with methadone efficacy in treating opioid dependence. Pharmacogenomics J 18:173–179. Scholar
  45. Czoty PW, Martelle JL, Nader MA (2010) Effects of chronic d-amphetamine administration on the reinforcing strength of cocaine in rhesus monkeys. Psychopharmacology (Berl) 209:375–382. Scholar
  46. Czoty PW, Martelle SE, Gould RW, Nader MA (2013) Effects of chronic methylphenidate on cocaine self-administration under a progressive-ratio schedule of reinforcement in rhesus monkeys. J Pharmacol Exp Ther 345:374–382. Scholar
  47. Czoty PW, Blough BE, Fennell TR et al (2016) Attenuation of cocaine self-administration by chronic oral phendimetrazine in rhesus monkeys. Neuroscience 324:367–376. Scholar
  48. Dackis CA, Gold MS (1985) New concepts in cocaine addiction: the dopamine depletion hypothesis. Neurosci Biobehav Rev 9:469–477. Scholar
  49. Dackis C, O’Brien C (2003) Glutamatergic agents for cocaine dependence. Ann N Y Acad Sci 1003:328–345Google Scholar
  50. Dackis CA, Lynch KG, Yu E et al (2003) Modafinil and cocaine: a double-blind, placebo-controlled drug interaction study. Drug Alcohol Depend 70:29–37. Scholar
  51. Dackis CA, Kampman KM, Lynch KG et al (2005) A double-blind, placebo-controlled trial of modafinil for cocaine dependence. Neuropsychopharmacology 30:205–211. Scholar
  52. Dackis CA, Kampman KM, Lynch KG et al (2012) A double-blind, placebo-controlled trial of modafinil for cocaine dependence. J Subst Abuse Treat 43:303–312. Scholar
  53. Dean AC, Sevak RJ, Monterosso JR et al (2011) Acute modafinil effects on attention and inhibitory control in methamphetamine-dependent humans. J Stud Alcohol Drugs 72:943–953Google Scholar
  54. Deroche-Gamonet V, Belin D, Piazza PV (2004) Evidence for addiction-like behavior in the rat. Science 305:1014–1017. Scholar
  55. DeVito EE, Babuscio TA, Nich C et al (2014) Gender differences in clinical outcomes for cocaine dependence: randomized clinical trials of behavioral therapy and disulfiram. Drug Alcohol Depend 145:156–167. Scholar
  56. Dewey SL, Smith GS, Logan J et al (1992) GABAergic inhibition of endogenous dopamine release measured in vivo with 11C-raclopride and positron emission tomography. J Neurosci 12:3773–3780. Scholar
  57. Di Chiara G, Bassareo V (2007) Reward system and addiction: what dopamine does and doesn’t do. Curr Opin Pharmacol 7:69–76. Scholar
  58. Di Ciano P, Everitt BJ (2003) The GABA(B) receptor agonist baclofen attenuates cocaine- and heroin-seeking behavior by rats. Neuropsychopharmacology 28:510–518. Scholar
  59. Diana M, Raij T, Melis M et al (2017) Rehabilitating the addicted brain with transcranial magnetic stimulation. Nat Rev Neurosci 18:685–693. Scholar
  60. Ehrman RN, Robbins SJ, Cornish JW (2001) Results of a baseline urine test predict levels of cocaine use during treatment. Drug Alcohol Depend 62:1–7Google Scholar
  61. Espay AJ, Pagan FL, Walter BL et al (2017) Optimizing extended-release carbidopa/levodopa in Parkinson disease: consensus on conversion from standard therapy. Neurol Clin Pract 7:86–93. Scholar
  62. Fadda P, Scherma M, Fresu A et al (2003) Baclofen antagonizes nicotine-, cocaine-, and morphine-induced dopamine release in the nucleus accumbens of rat. Synapse 50:1–6. Scholar
  63. Felitti VJ, Anda RF, Nordenberg D et al (1998) Relationship of childhood abuse and household dysfunction to many of the leading causes of death in adults. Am J Prev Med 14:245–258. Scholar
  64. Ferland J-MN, Winstanley CA (2017) Risk-preferring rats make worse decisions and show increased incubation of craving after cocaine self-administration. Addict Biol 22:991–1001. Scholar
  65. Filip M, Frankowska M, Sadakierska-Chudy A et al (2015) GABAB receptors as a therapeutic strategy in substance use disorders: focus on positive allosteric modulators. Neuropharmacology 88:36–47. Scholar
  66. Flagel SB, Akil H, Robinson TE (2009) Individual differences in the attribution of incentive salience to reward-related cues: implications for addiction. Neuropharmacology 56(Suppl 1):139–148. Scholar
  67. Flagel SB, Robinson TE, Clark JJ et al (2010) An animal model of genetic vulnerability to behavioral disinhibition and responsiveness to reward-related cues: implications for addiction. Neuropsychopharmacology 35:388–400. Scholar
  68. Fotros A, Casey KF, Larcher K et al (2013) Cocaine cue-induced dopamine release in amygdala and hippocampus: a high-resolution PET [18F]fallypride study in cocaine dependent participants. Neuropsychopharmacology 38:1780–1788. Scholar
  69. Fox H, Sinha R (2014) The role of guanfacine as a therapeutic agent to address stress-related pathophysiology in cocaine-dependent individuals. Adv Pharmacol 69:217–265. Scholar
  70. Fox HC, Morgan PT, Sinha R (2014) Sex differences in guanfacine effects on drug craving and stress arousal in cocaine-dependent individuals. Neuropsychopharmacology 39:1527–1537. Scholar
  71. Franklin TR, Wang Z, Wang J et al (2007) Limbic activation to cigarette smoking cues independent of nicotine withdrawal: a perfusion fMRI study. Neuropsychopharmacology 32:2301–2309. Scholar
  72. Franklin TR, Lohoff FW, Wang Z et al (2008) DAT genotype modulates brain and behavioral responses elicited by cigarette cues. Neuropsychopharmacology 34:717–728. Scholar
  73. Gerasimov MR, Schiffer WK, Gardner EL et al (2001) GABAergic blockade of cocaine-associated cue-induced increases in nucleus accumbens dopamine. Eur J Pharmacol 414:205–209Google Scholar
  74. Goeders NE (2003) The impact of stress on addiction. Eur Neuropsychopharmacol 13:435–441. Scholar
  75. Goldman M, Szucs-Reed RP, Jagannathan K et al (2013) Reward-related brain response and craving correlates of marijuana cue exposure: a preliminary study in treatment-seeking marijuana-dependent subjects. J Addict Med 7:8–16. Scholar
  76. Goldstein RZ, Volkow ND (2002) Drug addiction and its underlying neurobiological basis: neuroimaging evidence for the involvement of the frontal cortex. Am J Psychiatry 159:1642–1652Google Scholar
  77. Goldstein RZ, Volkow ND (2011) Dysfunction of the prefrontal cortex in addiction: neuroimaging findings and clinical implications. Nat Rev Neurosci 12:652–669. Scholar
  78. Grabowski J, Rhoades H, Schmitz J et al (2001) Dextroamphetamine for cocaine-dependence treatment: a double-blind randomized clinical trial. J Clin Psychopharmacol 21:522Google Scholar
  79. Grabowski J, Rhoades H, Stotts A et al (2004) Agonist-like or antagonist-like treatment for cocaine dependence with methadone for heroin dependence: two double-blind randomized clinical trials. Neuropsychopharmacology 29:969–981. Scholar
  80. Greenwald MK (2018) Anti-stress neuropharmacological mechanisms and targets for addiction treatment: a translational framework. Neurobiol Stress 9:84–104. Scholar
  81. Greenwald MK, Lundahl LH, Steinmiller CL (2010) Sustained release d-amphetamine reduces cocaine but not ‘speedball’-seeking in buprenorphine-maintained volunteers: a test of dual-agonist pharmacotherapy for cocaine/heroin polydrug abusers. Neuropsychopharmacology 35:2624–2637. Scholar
  82. Hanlon CA, Dowdle LT, Austelle CW et al (2015) What goes up, can come down: novel brain stimulation paradigms may attenuate craving and craving-related neural circuitry in substance dependent individuals. Brain Res 1628:199–209. Scholar
  83. Hart CL, Haney M, Vosburg SK et al (2008) Smoked cocaine self-administration is decreased by modafinil. Neuropsychopharmacology 33:761–768. Scholar
  84. Heekin RD, Shorter D, Kosten TR (2017) Current status and future prospects for the development of substance abuse vaccines. Expert Rev Vaccines 16:1067–1077. Scholar
  85. Heidbreder CA, Newman AH (2010) Current perspectives on selective dopamine D3 receptor antagonists as pharmacotherapeutics for addictions and related disorders. Ann N Y Acad Sci 1187:4–34. Scholar
  86. Heilig M, Goldman D, Berrettini W, O’Brien CP (2011) Pharmacogenetic approaches to the treatment of alcohol addiction. Nat Rev Neurosci 12:670–684. Scholar
  87. Hester R, Garavan H (2004) Executive dysfunction in cocaine addiction: evidence for discordant frontal, cingulate, and cerebellar activity. J Neurosci 24:11017–11022. Scholar
  88. Hester R, Lee N, Pennay A et al (2010) The effects of modafinil treatment on neuropsychological and attentional bias performance during 7-day inpatient withdrawal from methamphetamine dependence. Exp Clin Psychopharmacol 18:489–497. Scholar
  89. Hwa LS, Kalinichev M, Haddouk H et al (2014) Reduction of excessive alcohol drinking by a novel GABAB receptor positive allosteric modulator ADX71441 in mice. Psychopharmacology (Berl) 231:333–343. Scholar
  90. Hyman SM, Paliwal P, Sinha R (2007) Childhood maltreatment, perceived stress, and stress-related coping in recently abstinent cocaine dependent adults. Psychol Addict Behav 21:233. Scholar
  91. Hyman SM, Paliwal P, Chaplin TM et al (2008) Severity of childhood trauma is predictive of cocaine relapse outcomes in women but not men. Drug Alcohol Depend 92:208–216. Scholar
  92. James MH, Stopper CM, Zimmer BA et al (2018) Increased number and activity of a lateral subpopulation of hypothalamic orexin/hypocretin neurons underlies the expression of an addicted state in rats. Biol Psychiatry 85(11):925–935. Scholar
  93. Jasinska AJ, Stein EA, Kaiser J et al (2014) Factors modulating neural reactivity to drug cues in addiction: a survey of human neuroimaging studies. Neurosci Biobehav Rev 38:1–16. Scholar
  94. Jentsch JD, Taylor JR (1999) Impulsivity resulting from frontostriatal dysfunction in drug abuse: implications for the control of behavior by reward-related stimuli. Psychopharmacology (Berl) 146:373–390. Scholar
  95. Johnson BA, Ait-Daoud N, Wang X-Q et al (2013) Topiramate for the treatment of cocaine addiction: a randomized clinical trial. JAMA Psychiat 70:1338–1346. Scholar
  96. Jones L, Lin L (2017) An in silico study on the isomers of pentacene: the case for air-stable and alternative C22H14 acenes for organic electronics. J Phys Chem A 121:2804–2813. Scholar
  97. Jones JD, Comer SD, Kranzler HR (2015) The pharmacogenetics of alcohol use disorder. Alcohol Clin Exp Res 39:391–402. Scholar
  98. Juncosa JI, Takaya K, Le HV et al (2018) Design and mechanism of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid, a highly potent γ-aminobutyric acid aminotransferase inactivator for the treatment of addiction. J Am Chem Soc 140:2151–2164. Scholar
  99. Kahn R, Biswas K, Childress A-R et al (2009) Multi-center trial of baclofen for abstinence initiation in severe cocaine-dependent individuals. Drug Alcohol Depend 103:59–64. Scholar
  100. Kalivas PW, Duffy P (1993a) Time course of extracellular dopamine and behavioral sensitization to cocaine. I. Dopamine axon terminals. J Neurosci 13:266–275. Scholar
  101. Kalivas PW, Duffy P (1993b) Time course of extracellular dopamine and behavioral sensitization to cocaine. II. Dopamine perikarya. J Neurosci 13:276–284. Scholar
  102. Kalivas PW, McFarland K, Bowers S et al (2003) Glutamate transmission and addiction to cocaine. Ann N Y Acad Sci 1003:169–175. Scholar
  103. Kampman KM (2010) What’s new in the treatment of cocaine addiction? Curr Psychiatry Rep 12:441–447. Scholar
  104. Kampman KM, Volpicelli JR, Mulvaney F et al (2002) Cocaine withdrawal severity and urine toxicology results from treatment entry predict outcome in medication trials for cocaine dependence. Addict Behav 27:251–260Google Scholar
  105. Kampman KM, Pettinati H, Lynch KG et al (2004) A pilot trial of topiramate for the treatment of cocaine dependence. Drug Alcohol Depend 75:233–240. Scholar
  106. Kampman KM, Pettinati HM, Lynch KG et al (2013) A double-blind, placebo-controlled trial of topiramate for the treatment of comorbid cocaine and alcohol dependence. Drug Alcohol Depend 133:94–99. Scholar
  107. Kampman KM, Lynch KG, Pettinati HM et al (2015) A double blind, placebo controlled trial of modafinil for the treatment of cocaine dependence without co-morbid alcohol dependence. Drug Alcohol Depend 155:105–110. Scholar
  108. Karkhanis AN, Beveridge TJR, Blough BE et al (2016) The individual and combined effects of phenmetrazine and mgluR2/3 agonist LY379268 on the motivation to self-administer cocaine. Drug Alcohol Depend 166:51–60. Scholar
  109. Khantzian EJ, Gawin F, Kleber HD, Riordan CE (1984) Methylphenidate (Ritalin®) treatment of cocaine dependence – a preliminary report. J Subst Abuse Treat 1:107–112. Scholar
  110. Kober H, Lacadie CM, Wexler BE et al (2016) Brain activity during cocaine craving and gambling urges: an fMRI study. Neuropsychopharmacology 41:628–637. Scholar
  111. Kosten TA, Gawin FH, Kosten TR, Rounsaville BJ (1993) Gender differences in cocaine use and treatment response. J Subst Abuse Treat 10:63–66Google Scholar
  112. Kosten TR, Scanley BE, Tucker KA et al (2006) Cue-induced brain activity changes and relapse in cocaine-dependent patients. Neuropsychopharmacology 31:644–650. Scholar
  113. Kranzler HR, Gelernter J, Anton RF et al (2009) Association of markers in the 3′ region of the GluR5 kainate receptor subunit gene to alcohol dependence. Alcohol Clin Exp Res 33:925–930. Scholar
  114. Kranzler HR, Wetherill R, Feinn R et al (2014) Posttreatment effects of topiramate treatment for heavy drinking. Alcohol Clin Exp Res 38:3017–3023. Scholar
  115. Kühn S, Gallinat J (2011) Common biology of craving across legal and illegal drugs – a quantitative meta-analysis of cue-reactivity brain response. Eur J Neurosci 33:1318–1326. Scholar
  116. Kushner SA, Dewey SL, Kornetsky C (1999) The irreversible γ-aminobutyric acid (GABA) transaminase inhibitor γ-vinyl-GABA blocks cocaine self-administration in rats. J Pharmacol Exp Ther 290:797–802Google Scholar
  117. Lal R, Sukbuntherng J, Tai EHL et al (2009) Arbaclofen placarbil, a novel r-baclofen prodrug: improved absorption, distribution, metabolism, and elimination properties compared with R-baclofen. J Pharmacol Exp Ther 330:911–921. Scholar
  118. Lam SCB, Wang Z, Li Y et al (2013) Wavelet-transformed temporal cerebral blood flow signals during attempted inhibition of cue-induced cocaine craving distinguish prognostic phenotypes. Drug Alcohol Depend 128:140–147. Scholar
  119. Langleben DD, Ruparel K, Elman I et al (2008) Acute effect of methadone maintenance dose on brain fMRI response to heroin-related cues. Am J Psychiatry 165:390–394. Scholar
  120. Le Foll B, Payer D, Di Ciano P et al (2016) Occupancy of dopamine D3 and D2 receptors by buspirone: a [11C]-(+)-PHNO PET study in humans. Neuropsychopharmacology 41:529–537. Scholar
  121. Levin FR, Evans SM, McDowell DM, Kleber HD (1998) Methylphenidate treatment for cocaine abusers with adult attention-deficit/hyperactivity disorder: a pilot study. J Clin Psychiatry 59:300–305Google Scholar
  122. Levin FR, Mariani JJ, Secora A et al (2009) Atomoxetine treatment for cocaine abuse and adult attention-deficit hyperactivity disorder (ADHD): a preliminary open trial. J Dual Diagn 5:41–56. Scholar
  123. Levin FR, Mariani JJ, Specker S et al (2015) Extended-release mixed amphetamine salts vs placebo for comorbid adult attention-deficit/hyperactivity disorder and cocaine use disorder. JAMA Psychiat 72:593–602. Scholar
  124. Levin FR, Mariani JJ, Pavlicova M, Choi CJ, Mahony AL, Brooks DJ, Bisaga A, Dakwar E, Carpenter KM, Naqvi N, Nunes EV, Kampman K (2020) Extended release mixed amphetamine salts and topiramate for cocaine dependence: A randomized clinical replication trial with frequent users. Drug Alcohol Depend 206:107700Google Scholar
  125. Li CR, Morgan PT, Matuskey D et al (2010) Biological markers of the effects of intravenous methylphenidate on improving inhibitory control in cocaine-dependent patients. Proc Natl Acad Sci U S A 107:14455–14459. Scholar
  126. Li Q, Li W, Wang H et al (2015) Predicting subsequent relapse by drug-related cue-induced brain activation in heroin addiction: an event-related functional magnetic resonance imaging study. Addict Biol 20:968–978. Scholar
  127. Ling W, Shoptaw S, Majewska D (1998) Baclofen as a cocaine anti-craving medication: a preliminary clinical study. Neuropsychopharmacology 18:403–404. Scholar
  128. Logrip ML, Koob GF, Zorrilla EP (2011) Role of corticotropin-releasing factor in drug addiction: potential for pharmacological intervention. CNS Drugs 25:271–287. Scholar
  129. Luigjes J, van den Brink W, Feenstra M et al (2012) Deep brain stimulation in addiction: a review of potential brain targets. Mol Psychiatry 17:572–583. Scholar
  130. Maccioni P, Colombo G (2019) Potential of GABAB receptor positive allosteric modulators in the treatment of alcohol use disorder. CNS Drugs 33:107–123. Scholar
  131. Mach RH, Tu Z, Xu J et al (2011) Endogenous dopamine competes with the binding of a radiolabeled D3 receptor partial agonist in vivo: a positron emission tomography study. Synapse 65:724–732. Scholar
  132. MacNiven KH, Jensen ELS, Borg N et al (2018) Association of neural responses to drug cues with subsequent relapse to stimulant use. JAMA Netw Open 1:e186466. Scholar
  133. Maguire MJ, Hemming K, Wild JM et al (2010) Prevalence of visual field loss following exposure to vigabatrin therapy: a systematic review. Epilepsia 51:2423–2431. Scholar
  134. Mann K, Vollstädt-Klein S, Reinhard I et al (2014) Predicting naltrexone response in alcohol-dependent patients: the contribution of functional magnetic resonance imaging. Alcohol Clin Exp Res 38:2754–2762. Scholar
  135. Mariani JJ, Levin FR (2012) Psychostimulant treatment of cocaine dependence. Psychiatr Clin North Am 35:425–439. Scholar
  136. Marsot A, Imbert B, Alvarez J-C et al (2014) High variability in the exposure of baclofen in alcohol-dependent patients. Alcohol Clin Exp Res 38:316–321. Scholar
  137. Martinez D, Greene K, Broft A et al (2009) Lower level of endogenous dopamine in patients with cocaine dependence: findings from PET imaging of D 2/D 3 receptors following acute dopamine depletion. Am J Psychiatry 166:1170–1177. Scholar
  138. Martinez D, Carpenter KM, Liu F et al (2011) Imaging dopamine transmission in cocaine dependence: link between neurochemistry and response to treatment. Am J Psychiatry 168:634–641. Scholar
  139. McFarland K, Kalivas PW (2001) The circuitry mediating cocaine-induced reinstatement of drug-seeking behavior. J Neurosci 21:8655–8663. Scholar
  140. Medrano MA, Hatch JP, Zule WA, Desmond DP (2002) Psychological distress in childhood trauma survivors who abuse drugs. Am J Drug Alcohol Abuse 28:1–13Google Scholar
  141. Moeller SJ, Paulus MP (2018) Toward biomarkers of the addicted human brain: using neuroimaging to predict relapse and sustained abstinence in substance use disorder. Prog Neuropsychopharmacol Biol Psychiatry 80:143–154. Scholar
  142. Mooney ME, Schmitz JM, Moeller FG, Grabowski J (2007) Safety, tolerability and efficacy of levodopa–carbidopa treatment for cocaine dependence: two double-blind, randomized, clinical trials. Drug Alcohol Depend 88:214–223. Scholar
  143. Moran-Santa Maria MM, McRae-Clark A, Baker NL, Ramakrishnan V, Brady KT (2014) Yohimbine administration and cue-reactivity in cocaine-dependent individuals. Psychopharmacology (Berl) 231:4157–4165Google Scholar
  144. Morgan AE, Dewey SL (1998) Effects of pharmacologic increases in brain GABA levels on cocaine-induced changes in extracellular dopamine. Synapse 28:60–65.<60::AID-SYN7>3.0.CO;2-ACrossRefGoogle Scholar
  145. Morgan PT, Angarita GA, Canavan S et al (2016) Modafinil and sleep architecture in an inpatient–outpatient treatment study of cocaine dependence. Drug Alcohol Depend 160:49–56. Scholar
  146. Morley KC, Luquin N, Baillie A et al (2018) Moderation of baclofen response by a GABAB receptor polymorphism: results from the BacALD randomized controlled trial. Addiction 113:2205–2213. Scholar
  147. Negus SS, Henningfield J (2015) Agonist medications for the treatment of cocaine use disorder. Neuropsychopharmacology 40:1815–1825. Scholar
  148. NETI (2018) Emerging threats report 2018: status and factors affecting the United States. National Drug Control Policy, High Intensity Drug Trafficking Areas, National Emerging Threats Initiative, WashingtonGoogle Scholar
  149. Nuijten M, Blanken P, van den Brink W, Hendriks V (2011) Cocaine addiction treatments to improve control and reduce harm (CATCH): new pharmacological treatment options for crack-cocaine dependence in the Netherlands. BMC Psychiatry 11:135. Scholar
  150. Nuijten M, Blanken P, van de Wetering B et al (2016) Sustained-release dexamfetamine in the treatment of chronic cocaine-dependent patients on heroin-assisted treatment: a randomised, double-blind, placebo-controlled trial. Lancet 387:2226–2234. Scholar
  151. Parvaz MA, Moeller SJ, Goldstein RZ (2016) Incubation of cue-induced craving in adults addicted to cocaine measured by electroencephalography. JAMA Psychiat 73:1127–1134. Scholar
  152. Patkar AA, Thornton CC, Berrettini WH et al (2002) Predicting treatment-outcome in cocaine dependence from admission urine drug screen and peripheral serotonergic measures. J Subst Abuse Treat 23:33–40Google Scholar
  153. Penberthy JK, Ait-Daoud N, Vaughan M, Fanning T (2010) Review of treatment for cocaine dependence. Curr Drug Abuse Rev 3:49–62Google Scholar
  154. Pettinati HM, Kampman KM, Lynch KG et al (2008) Gender differences with high-dose naltrexone in patients with co-occurring cocaine and alcohol dependence. J Subst Abuse Treat 34:378–390. Scholar
  155. Pitman KA, Puil E, Borgland SL (2014) GABAB modulation of dopamine release in the nucleus accumbens core. Eur J Neurosci 40:3472–3480. Scholar
  156. Prescot AP, Miller SR, Ingenito G et al (2018) In vivo detection of CPP-115 target engagement in human brain. Neuropsychopharmacology 43:646–654. Scholar
  157. Redila VA, Chavkin C (2008) Stress-induced reinstatement of cocaine seeking is mediated by the kappa opioid system. Psychopharmacology (Berl) 200:59–70. Scholar
  158. Regier PS, Monge ZA, Franklin TR et al (2016) Emotional, physical and sexual abuse are associated with a heightened limbic response to cocaine cues. Addict Biol 22(6):1768–1777. Scholar
  159. Rice C, Mohr CD, Del Boca FK et al (2001) Self-reports of physical, sexual and emotional abuse in an alcoholism treatment sample. J Stud Alcohol 62:114–123Google Scholar
  160. Roberts DC, Andrews MM, Vickers GJ (1996) Baclofen attenuates the reinforcing effects of cocaine in rats. Neuropsychopharmacology 15:417–423. Scholar
  161. Robinson TE, Berridge KC (2001) Incentive-sensitization and addiction. Addiction 96:103–114. Scholar
  162. SAMHSA (2018) Key substance use and mental health indicators in the United States: results from the 2017 National Survey on Drug Use and Health. Center for Behavioral Health Statistics and Quality, Substance Abuse and Mental Health Services Administration, RockvilleGoogle Scholar
  163. Savitz J, Hodgkinson CA, Martin-Soelch C et al (2013) DRD2/ANKK1 Taq1A polymorphism (rs1800497) has opposing effects on D2/3 receptor binding in healthy controls and patients with major depressive disorder. Int J Neuropsychopharmacol 16:2095–2101. Scholar
  164. Schiffer WK, Gerasimov M, Hofmann L et al (2001a) Gamma vinyl-GABA differentially modulates NMDA antagonist-induced increases in mesocortical versus mesolimbic DA transmission. Neuropsychopharmacology 25:704–712. Scholar
  165. Schiffer WK, Gerasimov MR, Marsteller DA et al (2001b) Topiramate selectively attenuates nicotine-induced increases in monoamine release. Synapse 42:196–198. Scholar
  166. Schmitz JM, Mooney ME, Moeller FG et al (2008) Levodopa pharmacotherapy for cocaine dependence: choosing the optimal behavioral therapy platform. Drug Alcohol Depend 94:142–150. Scholar
  167. Schmitz JM, Lindsay JA, Stotts AL et al (2010) Contingency management and levodopa-carbidopa for cocaine treatment: a comparison of three behavioral targets. Exp Clin Psychopharmacol 18:238–244. Scholar
  168. Schmitz JM, Rathnayaka N, Green CE et al (2012) Combination of modafinil and d-amphetamine for the treatment of cocaine dependence: a preliminary investigation. Front Psychiatry 3:77. Scholar
  169. Schubiner H, Saules KK, Arfken CL et al (2002) Double-blind placebo-controlled trial of methylphenidate in the treatment of adult ADHD patients with comorbid cocaine dependence. Exp Clin Psychopharmacol 10:286–294Google Scholar
  170. Segal DS, Kuczenski R (1992a) In vivo microdialysis reveals a diminished amphetamine-induced DA response corresponding to behavioral sensitization produced by repeated amphetamine pretreatment. Brain Res 571:330–337Google Scholar
  171. Segal DS, Kuczenski R (1992b) Repeated cocaine administration induces behavioral sensitization and corresponding decreased extracellular dopamine responses in caudate and accumbens. Brain Res 577:351–355Google Scholar
  172. Shearer J, Wodak A, Beek IV et al (2003) Pilot randomized double blind placebo-controlled study of dexamphetamine for cocaine dependence. Addiction 98:1137–1141. Scholar
  173. Shinn AK, Greenfield SF (2010) Topiramate in the treatment of substance related disorders: a critical review of the literature. J Clin Psychiatry 71:634–648. Scholar
  174. Shoptaw S, Yang X, Rotheram-Fuller EJ et al (2003) Randomized placebo-controlled trial of baclofen for cocaine dependence: preliminary effects for individuals with chronic patterns of cocaine use. J Clin Psychiatry 64:1440–1448Google Scholar
  175. Shoptaw S, Watson DW, Reiber C et al (2005) Randomized controlled pilot trial of cabergoline, hydergine and levodopa/carbidopa: Los Angeles Cocaine Rapid Efficacy Screening Trial (CREST). Addiction 100(Suppl 1):78–90. Scholar
  176. Shorter D, Kosten TR (2011) Novel pharmacotherapeutic treatments for cocaine addiction. BMC Med 9:119. Scholar
  177. Shorter D, Nielsen DA, Huang W et al (2013) Pharmacogenetic randomized trial for cocaine abuse: disulfiram and α1A-adrenoceptor gene variation. Eur Neuropsychopharmacol 23(11):1401–1407. Scholar
  178. Shorter D, Domingo CB, Kosten TR (2015) Emerging drugs for the treatment of cocaine use disorder: a review of neurobiological targets and pharmacotherapy. Expert Opin Emerg Drugs 20:15–29. Scholar
  179. Sinha R (2001) How does stress increase risk of drug abuse and relapse? Psychopharmacology (Berl) 158:343–359. Scholar
  180. Sinha R (2008) Chronic stress, drug use, and vulnerability to addiction. Ann N Y Acad Sci 1141:105–130. Scholar
  181. Sinha R, Lacadie C, Skudlarski P et al (2005) Neural activity associated with stress-induced cocaine craving: a functional magnetic resonance imaging study. Psychopharmacology (Berl) 183:171–180. Scholar
  182. Sinha R, Fox HC, Hong KA et al (2009) Enhanced negative emotion and alcohol craving, and altered physiological responses following stress and cue exposure in alcohol dependent individuals. Neuropsychopharmacology 34:1198–1208. Scholar
  183. Siniscalchi A, Bonci A, Biagio Mercuri N et al (2015) The role of topiramate in the management of cocaine addiction: a possible therapeutic option. Curr Neuropharmacol 13:815–818Google Scholar
  184. Somoza EC, Winship D, Gorodetzky CW et al (2013) A multisite, double-blind, placebo-controlled clinical trial to evaluate the safety and efficacy of vigabatrin for treating cocaine dependence. JAMA Psychiat 70:630–637. Scholar
  185. Stoops WW, Rush CR (2014) Combination pharmacotherapies for stimulant use disorder: a review of clinical findings and recommendations for future research. Expert Rev Clin Pharmacol 7:363–374. Scholar
  186. Suh JJ, Pettinati HM, Kampman KM, O’Brien CP (2008) Gender differences in predictors of treatment attrition with high dose naltrexone in cocaine and alcohol dependence. Am J Addict 17:463–468. Scholar
  187. UNODC (2018) World drug report 2018. United Nations Office on Drugs and Crime, ViennaGoogle Scholar
  188. Veenstra-VanderWeele J, Cook EH, King BH et al (2017) Arbaclofen in children and adolescents with autism spectrum disorder: a randomized, controlled, phase 2 trial. Neuropsychopharmacology 42:1390–1398. Scholar
  189. Verrico CD, Haile CN, Mahoney JJ et al (2014) Treatment with modafinil and escitalopram, alone and in combination, on cocaine-induced effects: a randomized, double blind, placebo-controlled human laboratory study. Drug Alcohol Depend 141:72–78. Scholar
  190. Viola TW, Tractenberg SG, Levandowski ML et al (2014) Neurotrophic factors in women with crack cocaine dependence during early abstinence: the role of early life stress. J Psychiatry Neurosci 39:206–214. Scholar
  191. Volkow ND, Wang G-J, Telang F et al (2006) Cocaine cues and dopamine in dorsal striatum: mechanism of craving in cocaine addiction. J Neurosci 26:6583–6588. Scholar
  192. Wang G, Shi J, Chen N et al (2013) Effects of length of abstinence on decision-making and craving in methamphetamine abusers. PLoS One 8:e68791. Scholar
  193. Weerts EM, Froestl W, Kaminski BJ, Griffiths RR (2007) Attenuation of cocaine-seeking by GABA B receptor agonists baclofen and CGP44532 but not the GABA reuptake inhibitor tiagabine in baboons. Drug Alcohol Depend 89:206–213. Scholar
  194. Wexler BE, Gottschalk CH, Fulbright RK et al (2001) Functional magnetic resonance imaging of cocaine craving. Am J Psychiatry 158:86–95. Scholar
  195. Willuhn I, Burgeno LM, Groblewski PA, Phillips PEM (2014) Excessive cocaine use results from decreased phasic dopamine signaling in the striatum. Nat Neurosci 17:704–709. Scholar
  196. Wolfsohn R, Angrist B (1990) A pilot trial of levodopa/carbidopa in early cocaine abstinence. J Clin Psychopharmacol 10:440–442Google Scholar
  197. Wolfsohn R, Sanfilipo M, Angrist B (1993) A placebo-controlled trial of L-dopa/carbidopa in early cocaine abstinence. Neuropsychopharmacology 9:49–53. Scholar
  198. Wong DF, Kuwabara H, Schretlen DJ et al (2006) Increased occupancy of dopamine receptors in human striatum during cue-elicited cocaine craving. Neuropsychopharmacology 31:2716–2727. Scholar
  199. Young KA, Franklin TR, Roberts DCS et al (2014) Nipping cue reactivity in the bud: baclofen prevents limbic activation elicited by subliminal drug cues. J Neurosci 34:5038–5043. Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Paul S. Regier
    • 1
    Email author
  • Kyle M. Kampman
    • 1
  • Anna Rose Childress
    • 1
  1. 1.Department of Psychiatry, Perelman School of Medicine, Center for Studies of AddictionUniversity of PennsylvaniaPhiladelphiaUSA

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