Pharmacotherapy of Cocaine Addiction

Strategies for Selecting Candidate Medications for Testing

Bottom–Up Approach: Modulation of Appetitive Drives

Preclinical animal models of cocaine addiction, self-administration, reinstatement, and cue reactivity are commonly used to screen compounds for their potential as medications for treating cocaine dependence. These models, although helpful in selecting compounds, have very limited predictive validity. This issue is a critical one and will not be resolved fully until an effective medication is found that can be tested in animals for model validation. Until then, these limitations need to be factored in any go-no-go decision for advancing compounds for further development.

Preclinical Data

The role of corticotropin-releasing factor in drug addiction is very important, especially for relapse (which has been reviewed extensively. Corticotropin-releasing factor appears to be a mediator of stress-induced reinstatement in rodent models. This effect was found not to be unique to cocaine in the rat models of stress-induced relapse but also has been shown in heroin and alcohol. These data support the well-known notion that stress is a major precipitator of relapse in abstaining individuals. Modulating the stress circuitry will be beneficial not only for cocaine but also for other substances. Multiple corticotropin-releasing factor-1 antagonists are currently in development for the treatment of depression and anxiety. One that is being developed in collaboration between the National Institute on Drug Abuse and the National Institute of Mental Health will be tested for addiction as well.

† Deceased.

Dopamine D3 receptors, cloned in 1990, are located mainly in the accumbens. This dopamine receptor subtype was found to be upregulated in postmortem brains of individuals with cocaine addiction who died of cocaine overdose. D3 receptor levels, measured by the positron emission tomography (PET) ligand [11C]-+-PHNO, have been reported to be elevated in cocaine users by two independent groups. D3 agonists exhibit cocaine-like effects in rodents and primates and increased cocaine’s subjective effects in human subjects ; see Table 53.1 . D3 partial agonists have been shown to block cue-induced cocaine reinstatement, cocaine-primed cocaine seeking, and footshock-induced reinstatement of cocaine self-administration in rats, suggesting overall a potential role for D3 antagonists in preventing the three triggers of relapse. However, the D3 antagonist GSK598809 increased blood pressure in dogs, suggesting caution in advancing novel D3 antagonists to clinical studies.

Table 53.1

Summary of Data on Published Medication Trials for Cocaine Dependence.

	Study	Outcome	Results
Dackis et al., 2005	A double-blind, placebo-controlled trial of modafinil for cocaine dependence. 62 randomized subjects received a single morning dose of modafinil (400 mg) or matched placebo.	The primary efficacy measure was cocaine abstinence based on urine BE levels. Secondary measures were craving, cocaine withdrawal, retention and adverse events.	Subjects treated with modafinil provided significantly more cocaine-negative urine samples when compared with that of the placebo group.
Kaleschstein et al., 2013	Modafinil, but not escitalopram, improves working memory and sustained attention in long term-term, high-dose cocaine users . 61 subjects were randomized to placebo ( n = 14), escitalopram ( n = 16), modafinil (200 mg, n = 16) or modafinil (200 mg) plus escitalopram ( n = 15).	Measures included attention/information processing, episodic memory, working memory run at baseline and after 5 days of dosing.	Subjects treated with modafinil showed improved performance on two measures of working memory (mean n-back span, max n-back span), and trends toward improvement in visual working memory and sustained attention. Escitalopram did not improve cognitive measures.
Verrico et al., 2014	Treatment with modafinil and escitalopram, alone or in combination, on cocaine-induced effects: a randomized, double-blind, placebo-controlled study. 64 subjects randomized to placebo ( n = 16), modafinil (200 mg, n = 16), escitalopram, and modafinil (200 mg) plus escitalopram ( n = 15).	Study participants were given a choice of cocaine or keeping money after 5 days of dosing. Participants rated the subjective effects of cocaine.	Modafinil attenuated many of the positive effects of cocaine. Escitalopram did not alter cocaine’s subjective effects nor intensify the inhibitory effect of modafinil.
Anderson et al., 2009	Modafinil for the treatment of cocaine dependence. Multicenter ( n = 6) trial of 210 subjects randomized to placebo ( n = 72), modafinil (200 mg, n = 69), or modafinil (400 mg, n = 69) and treated for 12 weeks.	Primary outcome measure was the weekly percentage of cocaine nonuse days. Secondary measure included maximum consecutive nonuse days and craving.	No significant difference was noted in the primary outcome measure, although the 200-mg modafinil group showed significant effects on the maximum number of nonuse days ( P = 0.02) and craving ( P = 0.04). Modafinil increased the weekly percentage of nonuse days in subjects without a history of alcohol dependence.
Dackis et al., 2012	A double-blind, placebo-controlled trial of modafinil for cocaine dependence. 210 subjects were randomized to placebo, 200 mg, or 400 mg of modafinil and treated for 8 weeks .	Primary outcome measure was cocaine abstinence. Secondary measures included craving, cocaine withdrawal, retention, and tolerability.	No significant differences were seen on any measures although male subjects in the 400-mg group tended to be more abstinent than the placebo group ( P = 0.06).
Kampman et al., 2015	A double-blind, placebo-controlled trial of modafinil for the treatment of cocaine dependence without comorbid alcohol dependence. 94 cocaine-dependent men and women were evenly randomized to modafinil (300 mg) or placebo for 8 weeks.	Primary outcome measure was cocaine use by self-report, verified by twice-weekly urinalysis of benzoylecgonine. Secondary measures included cocaine craving (BSCS) and global improvement (CGI scale).	OR favored abstinence in the modafinil group (2.54; P = 0.03). Modafinil-treated subjects were more likely to be abstinent the last 3 weeks of the trial (23 vs 9 %, P < 0.05) and more likely to report low levels of craving intensity ( P = 0.03) and duration ( P = 0.03). Modafinil-treated subjects also were more likely to rate themselves much improved on the CGI ( P = 0.03)
Nuijten et al., 2015	Modafinil in the treatment of crack cocaine dependence in The Netherlands: Results of an open-label randomized controlled feasibility study. 65 crack-cocaine–dependent outpatients were randomized to receive either 12 weeks of CBT alone or CBT plus modafinil (400 mg/day) for 12 weeks.	The primary outcome measure was CBT retention. Secondary measure included modafinil adherence, tolerability, and safety; use of cocaine and other substances; cocaine craving/ health; social functioning; and patient satisfaction.	Modafinil had no effect on treatment retention, although adherence was low (10% completers). Post hoc exploratory analyses showed greater reduction in baseline use among highly adherent modafinil-treated subjects.
Morgan et al., 2016	Modafinil and sleep architecture in an inpatient-outpatient treatment study of cocaine dependence . 57 cocaine-dependent subjects received either modafinil (400 mg) or placebo as inpatients followed by 6 weeks of outpatient treatment.	Primary outcome measure was the percentage of urine toxicology screens that were negative for cocaine. Polysomnographic sleep recordings were made prior to and after starting modafinil.	Modafinil was associated with a higher percentage of cocaine-free urine specimens (52% vs 26%, P = 0.02), an increase in N3 (stage 3) sleep time, more consecutive days abstinent and greater survival of abstinence.
Karila et al., 2016	Dopamine transporter correlates and occupancy by modafinil in cocaine-dependent patients: A controlled study with high-resolution PET and [11C] - PE2I. 29 cocaine-dependent male subjects were randomized to modafinil or placebo. Modafinil was given as 400 mg/day for 26 days, 300 mg/day for 30 days, and 200 mg/day for 31 days. Dopamine transporter availability was measured with [11C]- PE2I prior to and after modafinil dosing.	Primary outcome measure was cocaine abstinence. Secondary measures included dopamine transporter occupancy, craving, depression, and decision making.	There were more therapeutic failures in the modafinil group. The dopamine transporter occupancy was reduced by 65.6% in patients receiving modafinil for 2 weeks.
Kampman et al., 2001	Effectiveness of propranolol for cocaine-dependence treatment may depend on cocaine withdrawal symptom severity. 108 randomized subjects received 100 mg propranolol or matched placebo.	Quantitative urinary BE levels was the primary outcome measure. Secondary included treatment retention, ASI results, cocaine craving, mood and anxiety symptoms, cocaine withdrawal symptoms, and adverse events.	No comparison overall between the two groups with the exception of cocaine withdrawal symptoms in the propranolol subjects. However, propranolol-treated subjects with more severe cocaine withdrawal symptoms responded better than their placebo counterparts.
Kampman et al., 2006	A double-blind, placebo-controlled trial of amantadine, propranolol, and their combination for the treatment of cocaine dependence in patients with severe cocaine withdrawal symptoms. 199 randomized patients received 300 mg/day of amantadine, 100 mg/day of propranolol, a combination of 300 mg/day or matching placebo.	Cocaine abstinence was the primary outcome measure.	The odds of cocaine abstinence improved significantly over time in propranolol-treated subjects who were highly adherent to study medication but not in placebo-treated subjects.
Brodie et al., 2003	Treating cocaine addiction: from preclinical to clinical trial experience with gamma-vinyl GABA (GVG). 20 randomized subjects with a titration dose (1, 1.5, 2 g) of GVG.	Measuring 28 consecutive days clean (negative for cocaine).	Eight subjects successfully completed the program and were drug-free for periods ranging from 46–58 days.
Brodie et al., 2005	Safety and efficacy of gamma-vinyl GABA (GVG) for the treatment of methamphetamine and/or cocaine addiction. 30 randomized.	Designed to include extensive visual field monitoring as well as outcome measures of therapeutic efficacy.	Sixteen of 18 subjects who completed the trial tested negative for methamphetamine and cocaine during the last 6 weeks of the trial. GVG did not produce any visual field defects or alterations in visual acuity.
Brodie et al., 2009	Randomized, double-blind, placebo-controlled trial of vigabatrin for the treatment of cocaine dependence in Mexican parolees. Participants were randomly assigned to vigabatrin ( n = 50) or placebo ( n = 53) for 9 weeks. Maximum vigabatrin dose was 3000 mg/day and then the dose was tapered.	Cocaine use was measured twice weekly in urine samples. Primary outcome variable was 3 weeks of abstinence at the end of the trial. Secondary endpoints included alcohol use, craving, and CGI scores.	The vigabatrin group had a 28% abstinence rate vs 7.5% for placebo ( P = 0.01). Retention was 62% in the vigabatrin group vs 41.5% for the placebo group. The alcohol abstinence rate was 43.5% vs. 6.3% in the placebo group.
Somoza et al., 2013	A multisite, double-blind, placebo-controlled clinical trial to evaluate the safety and efficacy of vigabatrin for treating cocaine dependence. 186 subjects were randomized to vigabatrin (3000 mg/day) or placebo and dosed for 12 weeks.	The primary outcome variable was the proportion of participants with 2- week abstinence during the last 2 weeks of the trial.	No significant differences in the primary or secondary variables were observed across the groups. The vigabatrin group’s adherence was marginal; urine measurement of vigabatrin suggested that 40% to 60% of the subjects may not have been dose adherent.
Kampman et al., 2004	A pilot trial of topiramate for the treatment of cocaine dependence. 40 randomized titrating up to 200 mg/day of topiramate.	Cocaine abstinence was the primary outcome measure verified by twice weekly urine BE.	The topiramate-treated subjects were more likely to be abstinent from cocaine compared with placebo-treated subjects.
Kampman et al., 2013	A double-blind, placebo-controlled trial of topiramate for the treatment of comorbid cocaine and alcohol dependence. 170 cocaine- and alcohol-dependent subjects were randomized to 300 mg topiramate or placebo for 13 weeks.	Primary outcome measures were self-reported cocaine and alcohol use with thrice weekly urine screens. Secondary measures included craving, Addiction Severity Index, cocaine withdrawal, and CGI improvement.	No significant difference on the primary outcome measure or in reducing alcohol use. Topiramate-treated subjects were more likely to be abstinent for the last 3 weeks of the trial. Subjects with more severe cocaine withdrawal symptoms fared better on topiramate.
Johnson et al., 2013	Topiramate for the treatment of cocaine addiction: a randomized clinical trial. 142 subjects were randomized to topiramate (300 mg/day maximum dose in weeks 6–12) or placebo.	Primary outcome measure was the weekly difference from baseline in the proportion of cocaine nonuse days. Secondary measures included urinary cocaine-free weeks, craving, and CGI improvement.	Topiramate was associated with an increased number of cocaine nonuse days relative to placebo ( P = 0.02) and increased the likelihood of cocaine-free weeks (OR 3.21; P = 0.02).
Umbricht et al., 2014	Topiramate for cocaine dependence during methadone maintenance treatment: a randomized controlled trial. 171 patients were randomized to topiramate (max dose 300 mg/day for weeks 8–15) or placebo and contingent or noncontingent vouchers for drug abstinence in a 2 × 2 design .	Primary outcome measures were cocaine abstinence measured by thrice weekly urinalysis, and retention. Voucher incentives were provided over 12 weeks. The analyses were conducted for the 12-week period in which vouchers were provided.	No significant differences emerged across the groups in terms of cocaine use or retention in the trial.
Nuijten et al., 2014	Treatment of crack cocaine dependence with topiramate; a randomized-controlled feasibility trial in The Netherlands. 74 patients were randomized to receive CBT or topiramate (200 mg per day) plus CBT for 12 weeks.	Primary outcome measure was retention. Secondary outcome measures were medication adherence, safety, other substance use, health, social functioning, and patient satisfaction.	No differences were seen in retention or cocaine use, although adherence to topiramate was low. A post hoc analysis revealed a reduction in cocaine use only in patients with comorbid opioid dependence.
Gonzalez et al., 2003	Tiagabine increases cocaine-free urines in cocaine-dependent methadone-treated patients: results of a randomized pilot study. 45 randomized to 12 or 24 mg of tiagabine or matched placebo.	Reduction of use as measured by cocaine-free urines.	In weeks 9 and 10, cocaine-free urine samples increased from baseline by 33% in subjects taking 24 mg/day and by 14% in those taking 12 mg/day and decreased by 10% with placebo-treated subjects.
Carroll et al., 1998	Treatment of cocaine and alcohol dependence with psychotherapy and disulfiram. 122 randomized with 250–500 mg of disulfiram vs psychotherapy control (1 of 5 treatments).	Duration of continuous abstinence from cocaine or alcohol; frequency and quantity of cocaine and alcohol use by week, verified by urine toxicology and breathalyzer screens.	Disulfiram treatment was associated with better retention in treatment as well as longer duration of abstinence from alcohol and cocaine use. Two active psychotherapies (CBT and 12-step facilitation [TSF]) reduced cocaine use over time compared with the supportive treatment (clinical management).
George et al., 2000	Disulfiram vs placebo for cocaine dependence in buprenorphine-maintained subjects: a preliminary trial. 20 randomized to 250 mg of disulfiram vs matched placebo.	Duration of abstinence from cocaine verified by urine test.	The total number of weeks abstinent from cocaine was higher in the disulfiram group versus placebo-treated subjects.
Petrakis et al., 2000	Disulfiram treatment for cocaine dependence in methadone-maintained opioid addicts. 67 randomized to 250 mg disulfiram vs matched placebo.	Weekly assessments of the frequency and quantity of drug and alcohol use, weekly urine toxicology screens and breathalyzer readings.	Cocaine use was significantly decreased in quantity and frequency in subjects treated with disulfiram as compared with placebo-treated subjects.
Carroll et al., 2004	Efficacy of disulfiram and cognitive behavior therapy in cocaine-dependent outpatients: a randomized placebo-controlled trial. 121 randomized to 250 mg/day of disulfiram or matched placebo.	Random regression analyses of self-reported frequency of cocaine use and results of urine toxicology screens.	Disulfiram-treated subjects reduced their cocaine use more than placebo-treated subjects.
Oliveto et al., 2011	Randomized, double- blind, placebo-controlled trial of disulfiram for the treatment of cocaine dependence in methadone-stabilized patients. 161 cocaine- and opioid-dependent patients were randomized to 0, 62.5, 125, and 250 mg of disulfiram for weeks 3–14 of the trial.	The primary outcome measures were thrice weekly urine samples and weekly self-reported drug use.	Cocaine-positive urines increased in the 62.5 and 125-mg groups and decreased in the placebo and 250-mg dose groups ( P = 0.0001). Self-reported cocaine use increased in the 125-mg group relative to the other dose groups ( P = 0.04).
Carroll et al., 2012	Efficacy of disulfiram and 12-step facilitation in cocaine-dependent individuals maintained on methadone: a randomized placebo-controlled trial. 112 study participants received either disulfiram (250 mg/day) or placebo and 12-step facilitation (TSF) or standard counseling in a 2 x 2 factorial design.	Primary outcome measure was urine benzoylecgonine levels.	The TSF group has fewer cocaine-positive urines throughout the trial. Disulfiram did not reduce cocaine use relative to placebo assignment, although a subgroup of disulfiram subjects without an alcohol use disorder showed greater reductions in cocaine use over time.
Kosten et al., 2013	Pharmacogenetic randomized trial for cocaine abuse: disulfiram and dopamine β-hydroxylase . 74 cocaine- and opioid-dependent subjects received disulfiram (250 mg/day) or placebo and followed for 10 weeks.	Primary outcome measure was cocaine-positive urines. Participants were genotyped for the DβH gene polymorphism (rs1611115).	Disulfiram treatment reduced cocaine-positive urines relative to placebo (80% to 62%, respectively, P = 0.001). When stratified by DβH genotype, those subjects with the normal variant (CC) reduced their cocaine-positive urines from 84% to 56% ( P = 0.001).
Schottenfeld et al., 2014	Randomized clinical trial of disulfiram for cocaine dependence or abuse during buprenorphine treatment. 177 buprenorphine-treated subjects with cocaine dependence or abuse were randomized to disulfiram ( n = 91, 250 mg/day) or placebo ( n = 86).	Primary outcomes included days per week of cocaine use, number of cocaine-negative tests, and maximum consecutive weeks of cocaine abstinence. Participants were genotyped for the DβH gene polymorphism (84 CC homozygous, 71 CT or TT) and medication by genotype results were analyzed.	Self-reported use of cocaine was lowest in the CT or TT carriers, although there were no significant differences across the four groups in terms of cocaine-negative urine tests or consecutive weeks of cocaine abstinence.
Carroll et al., 2016	A randomized factorial trial of disulfiram and contingency management to enhance cognitive behavioral therapy for cocaine dependence. 99 cocaine-dependent outpatients receiving CBT were assigned to disulfiram (250 mg/day) or placebo and contingency management (CM) or no CM in a 2 x 2 factorial design.	Primary outcome was percent days abstinent by self-report. Secondary outcome was cocaine use measured by three times weekly urinalysis.	There was no effect of disulfiram to reduce cocaine use. The order of effect in achieving self-reported 3 weeks continuous abstinence was CM + placebo > disulfiram with or without CM > placebo without CM.
Martell et al., 2005	Vaccine pharmacotherapy for the treatment of cocaine dependence. 18 total randomized (10 received TA-DC 400 μg and 8 received 2000 μg) vs matched placebo.	Cocaine abstinence as verified by urine test.	The likelihood of using cocaine decreased in subjects who received the more intense vaccination schedule.
Martell et al., 2009	Cocaine vaccine for the treatment of cocaine dependence in methadone-maintained patients: a randomized, double-blind, placebo-controlled efficacy trial. 115 patients were randomized to vaccine or placebo and followed for 12 weeks (weeks 8–20 of the trial).	The primary outcome measure was urinary benzoylecgonine measured three times weekly. Serum IgG levels of anti-cocaine antibodies were measured. Trials results were compared in those attaining a serum level of IgG anti-cocaine antibodies greater or less than 43 μg/mL.	Patients who had a serum level >43 μg/mL used less cocaine than those with levels <43 μg/mL. A higher proportion of patients with a serum level >43 μg/mL achieved a 50% reduction in cocaine use vs. those with a lower antibody level ( P = 0.048).
Kosten et al., 2014	Vaccine for cocaine dependence: a randomized double-blind placebo-controlled efficacy trial. 300 cocaine smokers were randomized to vaccine or placebo in this 16-week trial.	Primary outcome measure was urinary benzoylecgonine, collected thrice weekly. Analyses were conducted in the vaccine group dichotomized for serum IgG anti cocaine antibody levels ≥42 μg/mL and placebo group.	After week 8, more vaccinated than placebo-treated subjects had 2 weeks abstinence and the vaccine subgroup with IgG levels ≥42 μg/mL had the most cocaine-free urines for the last 2 weeks of the trial (OR = 3.02)
Kosten et al., 2003	Desipramine and contingency management for cocaine and opiate dependence in buprenorphine-maintained patients. 160 randomized to 150 mg/day or matched placebo (with and without contingency management).	Cocaine abstinence as verified by urine test.	Cocaine-free and combined opiate and cocaine-free urines increased over time in those treated with either desipramine or contingency management and those receiving both had more drug-free urines (50%).
Poling et al., 2006	Six-month trial of bupropion with contingency management for cocaine dependence in a methadone-maintained population. 106 randomized to 300 mg/day of bupropion or matched placebo (with and without voucher control and contingency management).	Reduction of cocaine use as tested by thrice-weekly urine toxicologic test results for cocaine and heroin.	Overall, voucher-based control and bupropion had fewer cocaine-positive urine drug screens than the other groups.
Ciraulo et al., 2005	Nefazodone treatment of cocaine dependence with comorbid depressive symptoms. 69 randomized to 200 mg (bid) of nefazodone or matching placebo.	Cocaine use measured by urine BE and self-report.	Median weekly BE declined in the nefazodone group and scores for strength of cocaine craving decreased compared with placebo.
Winhusen et al., 2007	A double-blind, placebo-controlled trial of reserpine for the treatment of cocaine dependence. 119 randomized to 0.5 mg/day of reserpine or matching placebo.	Cocaine use as determined by self-report confirmed with urine BE, cocaine craving, ASI and CGI scores.	No significant differences between reserpine and placebo.
Winhusen et al., 2007	A double-blind, placebo-controlled trial of tiagabine for the treatment of cocaine dependence. 140 randomized to 20 mg/day of tiagabine or matching placebo.	Cocaine use as determined by self-report confirmed with urine BE, qualitative and quantitative urine toxicology measures.	Qualitative urine toxicology results suggest a possible weak signal for tiagabine in reducing cocaine use.
Kahn et al., 2009	Multicenter trial of baclofen for abstinence initiation for severe cocaine dependence. 160 randomized to 60 mg of baclofen (max dose).	Cocaine use as determined by self-report confirmed by urine BE.	No significant effect between baclofen over placebo-treated subjects.
Elkashef A et al., 2006	Double-blind, placebo-controlled trial of selegiline transdermal system (STS) for the treatment of cocaine dependence. 300 subjects to 20 mg of selegiline or placebo.	Self-reported cocaine use substantiated by urine BE.	There was no effect of selegiline over placebo-treated subjects.
Moeller et al., 2007	Citalopram combined with behavioral therapy reduces cocaine use: a double-blind, placebo-controlled trial. 76 randomized to 20 mg/day of citalopram or matched placebo (with cognitive management and cognitive behavioral therapy).	Reduction in cocaine positive urines.	Cocaine treated subjects showed a significant reduction in positive urines during treatment as compared with placebo-treated subjects.
Johnson et al., 2006	A preliminary randomized double-blind placebo-controlled study of the safety and efficacy of ondansetron in the treatment of cocaine dependence. 63 cocaine-dependent men and women were randomized to 0, 0.5, 2, and 8 mg/day of ondansetron and followed for 10 weeks.	Cocaine use by urine BE.	The 8 mg/day group had the lowest drop out and greater rate of negative urine BE ( P = 0.02) compared with placebo. Ondansetron was well tolerated with no serious adverse events.
Mariani et al., 2012	Extended-release mixed amphetamine salts and topiramate for cocaine dependence: a randomized controlled trial. 81 cocaine-dependent adult patients were randomized to mixed amphetamine salts plus topiramate or matching placebos .	The primary outcome measure was the proportion of subjects per group who achieved self-reported 3 weeks consecutive abstinence that was confirmed by self-report.	Participants in the mixed amphetamine salts plus topiramate group had a 33 % abstinence rate vs 16.7 % for placebo. There was a moderating effect of baseline cocaine use, suggesting the medication combination was more effective in those with high baseline cocaine use ( P = 0.05).
Levin et al., 2015	Extended-release mixed amphetamine salts vs placebo for comorbid adult attention deficit/hyperactivity disorder and cocaine use disorder: A randomized clinical trial. 126 adults diagnosed with comorbid adult attention deficit/hyperactivity disorder and cocaine use disorder were randomized to mixed amphetamine salts (60 or 80 mg) or placebo for 13 weeks.	ADHD symptomatology was measured by the Adult ADHD Investigator Symptom Rating Scale. Cocaine use was measured by self-report and weekly urine screens. The percentage of participants achieving three weeks abstinence was determined.	Seventy five percent of those in the 60 mg group ( P < 0.001) and 58 % ( P = 0.07) in the 80-mg group achieved a 30 % reduction in ADHD symptoms compared with 39.5 % in the placebo group. Rates of continuous abstinence for the last three weeks of the trial were 30.2 % in the 80-mg group ( P = 0.004), 17.5 % in the 60 mg group ( P = 0.04) vs a 7% rate for placebo.
Mooney et al., 2015	Pilot study of effects of lisdexamfetamine in cocaine use: A randomized, double-blind, placebo-controlled trial. 43 cocaine-dependent participants were randomized to lisdexamfetamine ( n = 22, 70 mg/day) or placebo ( n = 21) and followed for 14 weeks.	Primary outcome measure was cocaine use, determined by twice weekly urinalysis.	No difference in cocaine use was noted between the two groups. Craving was lower in the lisdexamfetamine group.
Kampman et al., 2011	A double-blind, placebo-controlled pilot trial of acamprosate for the treatment of cocaine dependence. 66 cocaine-dependent patients were enrolled in a 9-week trial where they received acamprosate (666 mg tid) or placebo for 8 weeks.	Primary outcome measure was cocaine use detected by twice weekly urinalysis.	The percent cocaine positive urines did not differ between the drug and placebo groups.
LaRowe et al., 2013	A double-blind placebo-controlled trial of N-acetylcysteine in the treatment of cocaine dependence. 111 cocaine-dependent participants were randomized to N-acetylcysteine or placebo for 8 weeks.	Primary outcome measure was cocaine use, determined by thrice weekly urine collections.	No difference in cocaine use was noted between the N-acetylcysteine and placebo groups although N-acetylcysteine participants abstinent at randomization were less likely to relapse.
Pettinati et al., 2014	A pilot trial of injectable, extended-release naltrexone for the treatment of co-occurring cocaine and alcohol dependence. 80 cocaine- and alcohol-dependent participants were randomized to two monthly injections of extended-release naltrexone or placebo injections.	Cocaine and alcohol use	No differences in either cocaine or alcohol use were seen in this pilot study.
Plebani et al., 2012	Results of an initial trial of varenicline for the treatment of cocaine dependence. 37 cocaine-dependent participants were administered varenicline (1 mg bid) or placebo for 9 weeks.	Primary outcome measure was cocaine use, determined by thrice weekly urinalysis. Cocaine rewards was measured by the multiple-choice procedure (MCP).	Varenicline was associated with less cocaine use than placebo (OR = 2.02, P = 0.08). Varenicline deceased cocaine reward as measured in the MCP ( P = 0.02).
Fox and Sinha, 2014	The role of guanfacine as a therapeutic agent to address stress-related pathophysiology in cocaine-dependent individuals.	Laboratory challenge studies of stress and stress and cocaine cues.	Guanfacine, in doses of up to 3 mg/day, reduces cocaine craving, alcohol craving, anxiety, and negative emotion in women compared with women administered placebo.
Mooney et al., 2009	Effects of oral methamphetamine on cocaine use: A randomized, double-blind, placebo-controlled trial. 82 cocaine-dependent participants were randomized to three medication treatment conditions 30-mg immediate-release methamphetamine, 30-mg sustained-release methamphetamine or matched placebo.	Cocaine use measured by urine BE; Medical adherence measured by pill count, urine riboflavin, methamphetamine and medication event monitoring system; craving by visual analogue scale, mood measured by BDI; adverse events and vital signs.	Participants who received sustained-release methamphetamines showed lower rates of cocaine positive urine samples (29%, P < 0.0001) and a greater reduction in craving ( P < 0.05). BDI scores declined over the course of the trial. Similar retention rates between both forms of methamphetamines.
Schmitz et al., 2012	Combination of modafinil and d-amphetamine for the treatment of cocaine dependence: a preliminary investigation. 73 participants were randomized to 400 mg modafinil, 60 mg d-amphetamine, 200 mg modafinil plus 30 mg d-amphetamine or matched placebo.	Primary outcome variables were retention and cocaine use by self-report and urine BE	No difference in retention rates between groups; Participants who received modafinil and d-amphetamine showed an increase in cocaine use over time with a low Bayesian probability of benefit (33%). Reduction in cocaine positive results in placebo and d-amphetamine only group.

ADHD, Attention-deficit/hyperactivity disorder; ASI, Addiction Severity Index; BSCS , Brief Substance Craving Scale; BDI, Beck Depression Inventory; BE, benzylecgonine; CBT, cognitive behavioral therapy; CGI, Clinical Global Impression; OR, odds ratio.

Buspirone has recently emerged as a potential D3/D4 antagonist medication candidate. In self-administration studies in rhesus monkeys, the D3/D4 dopamine antagonist buspirone (intramuscular) reduced intravenous cocaine self-administration and intravenous buspirone reduced intravenous cocaine self-administration in dominant rhesus monkeys, whereas it was ineffective in subordinate monkeys. Buspirone (0.032 – 0.056 mg/kg/administered intravenously 20 minutes per hour for 23 hours) also reduced self-administration of the combination of cocaine and nicotine in rhesus monkeys. PET studies in rhesus monkeys showed that buspirone, at intramuscular doses of 0.19 and 0.5 mg/kg and oral dose of 3 mg/kg, was extensively bound to D3 receptors in globus pallidum and midbrain. These researchers also suggested that higher doses, approximately three times the 60 mg dose limit used to treat anxiety, would be needed to provide >80% sustained receptor occupancy. This has implications for the study reported by Winhusen et al. as this trial may have used insufficient doses of buspirone (see Table 53.1 ).

The cannabinoid-1 receptor (CB-1) antagonists have been shown in different animal models to have potential to treat multiple addictions. CB-1 antagonists act either by blocking the subjective/rewarding effects of drugs such as tetrahydrocannabinol or by blocking the ability of conditioned cues to promote reinstatement of drug-seeking behavior in animals, presumably through the endocannabinoid system. Taken together, results suggest a role for the cannabinoid system for polysubstance addiction. However, the failure to gain marketing approval for rimonabant due to adverse events must be seen as a caution for advancing other CB-1 antagonists to clinical studies.

Vigabatrin is a γ-aminobutyric acid (GABA) transaminase inhibitor, which leads to marked elevation of GABA levels in the brain. It has been shown to be very effective in animal models to block cocaine self-administration, and to block dopamine release in a primate PET imaging study. Early open-label pilot data in cocaine- and methamphetamine-addicted individuals showed promising results in facilitating abstinence. Vigabatrin has been reported to cause visual field defects following prolonged use. In a 12-week study of vigabatrin (3000 mg/day) in cocaine users, no changes in visual acuity or peripheral field changes were noted (see Table 53.1 ).

Dopamine β-hydroxylase (DβH) inhibitors have been studied in preclinical studies, clinical pharmacology studies, and clinical trials. Both disulfiram and nepicastat, another DβH inhibitor, were reported to attenuate cocaine-primed reinstatement in a rodent model, but neither medication altered cocaine priming in the squirrel monkey. In a placebo-controlled clinical pharmacology study, disulfiram dose was negatively correlated with cocaine choices. In a second clinical pharmacology study with disulfiram, cocaine, and ethanol, disulfiram (0, 250, and 500 mg) doses were tested. Disulfiram (250 mg dose) did not enhance the cardiovascular effects of cocaine and may have reduced the subjective effects of cocaine. A disulfiram-ethanol response was seen with alcohol administration in disulfiram-treated participants. Cocaine did not exacerbate the response; in fact, it may have counteracted the hypotension but it increased tachycardia in two of seven participants. Clinical trial results with disulfiram are reported in Table 53.1 . Nepicastat was reported to reduce the breakpoint in a progressive ratio model and attenuated cue-, cocaine prime-, footshock-, and yohimbine-induced reinstatement of cocaine-seeking behavior in the rodent. In a clinical pharmacology study, nepicastat reduced the subjective effects of cocaine in non–treatment-seeking volunteers with cocaine use disorder. A multicenter trial of nepicastat (120 mg per day or placebo) in cocaine-dependent study participants has been completed. The primary outcome measure is 2 weeks of abstinence at weeks 11 and 12 of the trial. Results are expected within the year.

Other compounds with interesting preclinical data include metabotropic glutamate receptor 5, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor antagonists, orexin-A receptor antagonists, opioid receptor-like 1 agonists, N -acetylated-alpha-linked-acidic dipeptidase inhibitors, and muscarinic M5 receptor ligands. The partial mGluR5-negative allosteric modulators (NAMs) 5MPEP and Br-5MPEPy as well as MTEP, the full mGluR5 NAM, dose-dependently reduced cocaine self-administration and attenuated the discriminative stimulus properties of cocaine. The mGluR5 NAM fenobam, which has been administered to human subjects in clinical trials, reduced intravenous cocaine self-administration, and cue-induced and cocaine-primed reinstatement behavior in rats. Thus an mGluR5 compound could be tested in clinical studies in patients with cocaine use disorder.

Bottom–Up Approach: Pharmacotherapy of Reversal Learning/Cognitive Targets

Another pharmacotherapy target that has been discovered by basic neuroscience researchers is cocaine-induced deficits in reversal learning. Reversal learning, a test of cognitive flexibility, involves an organism’s ability to determine that reward contingencies have changed and act accordingly. Cocaine has been shown to produce reversal learning deficits in an odor-discriminating task in rats trained to self-administer cocaine. Lesions of the orbitofrontal cortex in rats also have been shown to cause reversal learning deficits in the odor discrimination model and a serial discrimination reversal learning model. Cocaine administered for 14 days can cause a failure to signal adverse outcomes in rats that also fail to reverse their cue selectivity, suggesting a failure of plasticity mechanisms in this brain region caused by the drug. Cocaine administered to vervet monkeys for 14 days produced a reversal learning deficit of learned object discrimination. Chronic cocaine users, but not amphetamine users, demonstrated reversal learning deficits in a probabilistic reversal learning task.

Pharmacological modulation of reversal learning is in the early stages of testing. The serotonin-6 receptor antagonist Ro 04-6790 improved reversal learning in isolation-reared rats in the Morris water maze spatial discrimination task. Several serotonin-6 receptor antagonists are in clinical testing, suggesting that medications with this mechanism could be tested in chronic cocaine users in the probabilistic reversal learning task. The noradrenergic medications atomoxetine, desipramine, and methylphenidate improved reversal learning in a four-position discrimination task in rats and a three-choice visual discrimination task in Vervet monkeys, whereas the dopamine transporter inhibitor GBR-12909 did not alter reversal learning. The authors noted that methylphenidate impaired retention in both rats and monkeys. Because it has been demonstrated that cocaine can produce reversal learning deficits, the obvious next studies that should be performed would be to test serotonin-6 receptor antagonists and norepinephrine transporter inhibitors in cocaine-affected animals. Positive results would provide a rationale for testing these medications in human subjects in the probabilistic reversal learning task mentioned above.

Prefrontal cortex (PFC) modulation of dopamine is largely influenced by serotonin (5-HT) in the frontal cortex. Serotonin receptor 2A (5-HT _2A R) receptors are found in their highest density on layer V cortical pyramidal glutamatergic cells that project to subcortical structures. Serotonin 2C (5-HT _2C R) receptors are located mainly on GABA interneurons with the prefrontal cortex as well as dopaminergic and GABAergic neurons in the ventral tegmental area (VTA). Elevation of 5-HT _2A R receptors in the VTA following injection of a plasmid containing the gene for 5-HT _2A R produced an enhanced response to cocaine-induced locomotor activity and rearing, suggesting a role for the 5-HT _2A R system in response to cocaine. M100907, a 5-HT _2A R antagonist, administered intraperitoneally or within the ventral medial PFC, significantly attenuated cocaine cue-induced reinstatement behavior in rats. M100907 also attenuated cocaine-induced impulsivity in the differential reinforcement of low rate task and the one-choice serial reaction time task. M100907 attenuated both cue- and cocaine-induced reinstatement behavior in rhesus monkeys, although cocaine self-administration was unaffected. The 5-HT _2C R agonist Ro 60-0175 has been reported to attenuate cocaine-induced locomotor activity and cocaine self-administration in rats. The dose of the 5-HT _2C R agonist WAY 163909 needed to suppress the reinforcing efficacy of cocaine and cocaine-associated cues was 5–12-fold lower than that needed to suppress horizontal locomotor activity, suggesting a differential sensitivity to modulation of incentive salience of cocaine. The 5-HT _2C R agonist MK 212 has been reported to attenuate the discriminative stimulus effects of cocaine. Infusions of MK212 into the medial PFC attenuated the cue-induced and cocaine-prime induced reinstatement of self-administration behavior in rats. In squirrel monkeys, the 5-HT _2C R agonist Ro 60-0175 was reported to attenuate the stimulant, reinforcing, and cocaine-priming effect on reinstatement of self-administration behavior. The 5-HT _2C R system has also been studied for its effects on impulsivity and cocaine cue reactivity. Experiments in rats that had their 5-HT _2C R receptor population knocked down had an increase in impulsivity and reactivity to cocaine cues, suggesting that the 5-HT _2C R system modulates both of these behaviors. Parallel studies in cocaine-dependent subjects with a single nucleotide polymorphism in the HTR2C gene noted that males with the Ser23 variant had greater attentional bias to cocaine cues in the Stroop test. The recently approved 5-HT _2C R agonist lorcaserin will allow assessment of the possible efficacy of 5-HT _2C R agonism in the treatment of cocaine dependence.

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