A pilot trial of olanzapine for the treatment of cocaine dependence

Background: Multiple lines of evidence suggest both dopaminergic and serotonergic involvement in the reinforcing effects of cocaine. Medications such as olanzapine, which block dopamine D2 receptors, as well as serotonin receptors 5HT2A and 5HT2C may be able to reduce cocaine use in cocaine dependent patients by reducing the euphoric effects of cocaine and attenuating cocaine craving. Methods: This was a 12-week, double blind, placebo controlled, pilot trial involving 30 cocaine dependent subjects. Subjects received either olanzapine (10 mg/day) or identical placebo. Outcome measures included treatment retention, qualitative urine benzoylecgonine tests, cocaine craving, clinical global impression scores, and results from the addiction severity index. Results: Treatment retention was slightly, but significantly, better in the placebo-treated subjects. Placebo-treated subjects were more likely to be abstinent from cocaine during the trial compared to olanzapine-treated subjects, based on urine benzoylecgonine results. Olanzapine was not superior to placebo in any outcome measure. Conclusions: The results of this trial do not support the usefulness of olanzapine for the treatment of cocaine dependence. In fact, olanzapine may worsen cocaine treatment outcome.     

A comparison of thrice weekly LAAM and daily methadone in employed heroin addicts

Forty-eight employed heroin addicts were maintained on daily doses of methadone for four months and then randomly assigned to continue methadone maintenance or be switched to thrice weekly levo-alpha-acetylmethadol (LAAM). LAAM patients had significantly less illicit drug use and longer treatment retention times than those remaining on methadone. They also preferred LAAM to methadone on nine of 15 criteria such as the dosage schedule, feeling ‘normal’, and reduction of craving for heroin. LAAM may be particularly useful with employed patients owing to the reduced frequency of clinic visits.     

A pilot trial of piracetam and ginkgo biloba for the treatment of cocaine dependence

BACKGROUND: Chronic cocaine use is associated with cognitive deficits that may reduce the effectiveness of psychosocial treatment and promote relapse in newly abstinent cocaine-dependent patients. Nootropic agents, such as piracetam and ginkgo biloba, may improve cognitive function and reduce the incidence of relapse in these patients. METHODS: This was a 10-week, double-blind, placebo-controlled pilot trial involving 44 cocaine-dependent subjects. Subjects received either piracetam (4.8 g/day), ginkgo biloba (120 mg/day), or placebo. Subjects were required to attain abstinence from cocaine during a 2-week baseline phase demonstrated by providing at least one benzoylecgonine (BE)-negative urine toxicology screen. Outcome measures included treatment retention, urine toxicology screens, Clinical Global Impression (CGI) scores, and results from the Addiction Severity Index (ASI). RESULTS: Ginkgo biloba was not superior to placebo in any outcome measure. Piracetam was associated with more cocaine use and lower CGI scores compared to placebo. CONCLUSIONS: Neither piracetam nor ginkgo biloba appears to be a promising medication for the treatment of cocaine dependence.     

Effects of the combination of metyrapone and oxazepam on cocaine craving and cocaine taking: a double-blind, randomized, placebo-controlled pilot study

Although cocaine dependence affects an estimated 1.6 million people in the USA, there are currently no medications approved for the treatment of this disorder. Experiments performed in animal models have demonstrated that inhibitors of the stress response effectively reduce intravenous cocaine self-administration. This exploratory, double-blind, placebo-controlled study was designed to assess the safety and efficacy of combinations of the cortisol synthesis inhibitor metyrapone, and the benzodiazepine oxazepam, in 45 cocaine-dependent individuals. The subjects were randomized to a total daily dose of 500 mg metyrapone/20 mg oxazepam (low dose), a total daily dose of 1500 mg metyrapone/20 mg oxazepam (high dose), or placebo for 6 weeks of treatment. The outcome measures were a reduction in cocaine craving and associated cocaine use as determined by quantitative measurements of the cocaine metabolite benzoylecgonine (BE) in urine at all visits. Of the randomized subjects, 49% completed the study. The combination of metyrapone and oxazepam was well tolerated and tended to reduce cocaine craving and cocaine use, with significant reductions at several time points when controlling for baseline scores. These data suggest that further assessments of the ability of the metyrapone and oxazepam combination to support cocaine abstinence in cocaine-dependent subjects are warranted.     

A double-blind, placebo-controlled trial of tiagabine for the treatment of cocaine dependence

BACKGROUND: The potential efficacy of tiagabine for treating cocaine dependence is suggested by both pre-clinical research and two small clinical trials. METHOD: One hundred and forty one participants who met DSM-IV criteria for cocaine dependence were enrolled into this 12-week, double blind, placebo controlled outpatient trial. Participants received either tiagabine (20 mg/day) or matching placebo. All participants received 1h of manualized individual cognitive behavioral therapy on a weekly basis. Outcome measures included cocaine use as determined by self-report confirmed with urine benzoylecgonine (BE) results, and qualitative and quantitative urine toxicology measures. Safety measures included adverse events, EKGs, vital signs, and laboratory tests. RESULTS: Seventy-nine participants (i.e., 56%) completed the 12-week trial. The safety results suggest that tiagabine was safe and generally well tolerated by the participants. Participants in both groups improved significantly on cocaine craving and global functioning, with no significant differences between the groups. There were no significant changes in cocaine use as measured by self-report confirmed by urine BE or by quantitative urine toxicology results. Qualitative urine toxicology results suggest a possible weak effect for tiagabine in reducing cocaine use. CONCLUSION: These results suggest that tiagabine, at a dose of 20 mg/day, did not have a robust effect in decreasing cocaine use.     

A double-blind, placebo-controlled trial of modafinil for cocaine dependence

This is a randomized, double-blind, placebo-controlled study of modafinil treatment for cocaine dependence. Patients (N = 210) who were actively using cocaine at baseline were randomized to 8 weeks of modafinil (0 mg/day, 200 mg/day, or 400 mg/day) combined with once-weekly cognitive-behavioral therapy. Our primary efficacy measure was cocaine abstinence, based on urine benzoylecgonine (BE) levels, with secondary measures of craving, cocaine withdrawal, retention, and tolerability. We found no significant differences between modafinil and placebo patients on any of these measures. However, there was a significant gender difference in that male patients treated with 400 mg/day tended to be more abstinent than their placebo-treated counterparts (p = .06). Our negative findings might be explained by gender differences and/or inadequate psychosocial treatment intensity in patients with severe cocaine dependence.     

Participants receiving dehydroepiandrosterone during treatment for cocaine dependence show high rates of cocaine use in a placebo-controlled pilot study

Twenty-three cocaine-dependent participants were randomly assigned to receive either dehydroepiandrosterone (DHEA; n = 11; 100 mg/day) or placebo (n = 12) in the context of 12 weeks of thrice weekly cognitive-behavioral group counseling. Outcomes were retention, urine drug screening, cocaine craving, adverse experiences, and medication compliance. DHEA-treated participants averaged 45.8 (SD = 28.8) days in treatment, compared with 70.7 (SD = 20.6) days for placebo, r(21) = -2.4, p =.03, and provided 26.8% (SD = 29.3) of urine samples free of cocaine metabolite compared with 70.6% (SD = 39.9) for the placebo condition, r(21) = -3.0, p =.01. No differences were detected between conditions for cocaine craving or adverse experiences. High levels of medication compliance were documented. Results argue against using high doses of DHEA as a pharmacotherapy for cocaine dependence.     

Intimate relationship characteristics associated with condom use among drug users and their sex partners: a multilevel analysis

This study compared the safety and efficacy of sublingual buprenorphine tablets with oral methadone in a population of opioid-dependent individuals in a double-blind, randomized, 6-week trial using a flexible dosing procedure. Fifty-eight patients seeking treatment for opioid dependence were recruited in three outpatient facilities and randomly assigned to substitution with buprenorphine or methadone. The retention rate was significantly better in the methadone maintained group (90 vs. 56%; P<0.001). Subjects completing the study in both the treatment groups had similar proportions of opioid positive urine samples (buprenorphine 62%; methadone 59%) and positive urine specimens, as well as mean heroin craving scores decreased significantly over time (P=0.035 and P<0.001). The proportion of cocaine-positive toxicology results did not differ between groups. At week six mean stabilization doses were 10.5 mg per day for the sublingual buprenorphine tablet, and 69.8 mg per day for methadone, respectively. Patient performance during maintenance was similar in both the groups. The high attrition rate in the buprenorphine group during the induction phase might reflect inadequate induction doses. Thus, buprenorphine is a viable alternative for methadone in short-term maintenance treatment for heroin dependence if treatment induction is done with adequate dosages.     

A randomized controlled trial of fluoxetine in the treatment of cocaine dependence among methadone-maintained patients

Background

Cocaine abuse and dependence continue to be widespread. Currently, there are no pharmacotherapies shown to be effective in the treatment of cocaine dependence.

Methods

A 33-week outpatient clinical trial of fluoxetine (60 mg/day, po) for cocaine dependence that incorporated abstinence-contingent voucher incentives was conducted. Participants (N = 145) were both cocaine and opioid dependent and treated with methadone. A stratified randomization procedure assigned subjects to one of four conditions: fluoxetine plus voucher incentives (FV), placebo plus voucher incentives (PV), fluoxetine without vouchers (F), and placebo without vouchers (P). Dosing of fluoxetine/placebo was double blind. Primary outcomes were treatment retention and cocaine use based on thrice-weekly urine testing.

Results

The PV group had the longest treatment retention (M = 165 days) and lowest probability of cocaine use. The adjusted predicted probabilities of cocaine use were 65% in the P group, 60% in the F group, 56% in the FV group, and 31% in the PV group.

Conclusions

Fluoxetine was not efficacious in reducing cocaine use in patients dually dependent on cocaine and opioids.     

Predictors of outcome in LAAM, buprenorphine, and methadone treatment for opioid dependence

This study examined (1) predictors of treatment outcome for opioid-dependent participants in a single-site controlled trial comparing methadone, buprenorphine, and LAAM treatments and (2) the extent to which various subpopulations of patients may have more successful outcomes with each medication. The relationships between patient demographics, drug use history, and psychological status and outcome measures of treatment retention, opiate use, and cocaine use were assessed. We believe this study to be the first to demonstrate that predictors of treatment success appear to be largely similar in LAAM, buprenorphine, and methadone treatment for opioid dependence. We did not find any factors that would strongly guide selection of one medication over others.     

Clinical efficacy of gabapentin versus tiagabine for reducing cocaine use among cocaine dependent methadone-treated patients

BACKGROUND: GABAergic medications appear to reduce the reinforcing effects of cocaine by attenuating cocaine-induced dopamine release. This study evaluated gabapentin and tiagabine compared to placebo in reducing cocaine taking behavior. METHODS: A total of 76 treatment seeking, cocaine dependent, methadone-treated, predominately Caucasian male subjects were randomly assigned to tiagabine 24 mg/day (N=25), gabapentin 2400 mg/day (N=26) or placebo (N=25) in a 10-week double-blind placebo-controlled trial. Study medications were slowly increased to their full dosages by the end of week 5 and maintained through week 10. The primary outcome measure was thrice-weekly drug free urine samples. RESULTS: Treatment retention was significantly less for the gabapentin group relative to the other groups (log rank=5.29, d.f.=1, p=0.02). The proportion of cocaine-free urine samples during weeks 6-10 was significantly larger in the tiagabine treated group (p<0.05). The longitudinal data showed significant change in thrice-weekly cocaine free urines that reached a greater abstinent rate for the tiagabine treated group (22%) compared to gabapentin (5%) or placebo (13%) treated groups. Mixed-effects ordinal regression models showed a significant tiagabine by time interaction compared to gabapentin (Z=2.48, d.f.=1, p=0.01) and placebo (Z=3.90, d.f.=1, p=0.0001). The gabapentin group did not differ from placebo. CONCLUSION: Gabapentin showed poor treatment retention and ineffectiveness in reducing cocaine use. Tiagabine significantly reduced cocaine taking behavior compared to placebo or gabapentin among methadone-stabilized cocaine abusers.     

Agonist-like or antagonist-like treatment for cocaine dependence with methadone for heroin dependence: two double-blind randomized clinical trials.

Concurrent abuse of cocaine and heroin is a common problem. Methadone is effective for opioid dependence. The question arises as to whether combining agonist-like or antagonist-like medication for cocaine with methadone for opioid dependence might be efficacious. Two parallel studies were conducted. One examined sustained release d-amphetamine and the other risperidone for cocaine dependence, each in combination with methadone. In total, 240 subjects (120/study) were recruited, who were both cocaine and heroin dependent and not currently receiving medication. All provided consent. Both studies were carried out for 26 weeks, randomized, double-blind and placebo controlled. Study I compared sustained release d-amphetamine (escalating 15-30 or 30-60 mg) and placebo. Study II examined risperidone (2 or 4 mg) and placebo. All subjects underwent methadone induction and were stabilized at 1.1 mg/kg. Subjects attended clinic twice/week, provided urine samples, obtained medication take-home doses for intervening days, and completed self-report measures. Each had one behavioral therapy session/week. In Study I, reduction in cocaine use was significant for the 30/60 mg dose compared to the 15/30 mg and placebo. Opioid use was reduced in all groups with a trend toward greater reduction in the 30/60 mg d-amphetamine group. In Study II, methadone reduced illicit opioid use but cocaine use did not change in the risperidone or placebo groups. There were no adverse medication interactions in either study. The results provide support for the agonist-like (d-amphetamine) model in cocaine dependence treatment but not for antagonist-like (risperidone) treatment. They coincide with our previous reports of amphetamine or risperidone administered singly in cocaine-dependent individuals.     

A double-blind, placebo-controlled pilot trial of acamprosate for the treatment of cocaine dependence

Background

Acamprosate is a medication shown to be effective for the treatment of alcohol dependence. Although the exact mechanism of action of acamprosate is unknown, evidence suggests that it decreases excitatory amino acid activity by post-synaptic inhibition of the NMDA subtype of glutamate receptors. It is possible that the activity of acamprosate via modulating glutamatergic activity could also reduce craving for cocaine and impact abstinence in cocaine dependence. Therefore, we conducted a double-blind placebo-controlled pilot trial of acamprosate for the treatment of cocaine dependence.

Methods

Sixty male and female cocaine dependent patients were included in a nine week double-blind, placebo-controlled trial. After a one-week baseline, patients were randomized to receive acamprosate 666 mg three times daily or identical placebo tablets for eight weeks. The primary outcome measure was cocaine use as determined by twice weekly urine drug screens.

Results

Thirty-six patients (60%) completed the trial, with no significant between-group difference in treatment retention. Percent cocaine positive urine drug screens did not differ between the two groups. Acamprosate was no better than placebo in reducing cocaine craving, reducing cocaine withdrawal symptoms, or improving measures of drug use severity from the Addiction Severity Index. Adverse events in this trial were generally mild and were evenly distributed between the two groups.

Discussion

Acamprosate was well tolerated but was no more efficacious than placebo in promoting abstinence from cocaine in cocaine dependent patients. Acamprosate does not appear to be a promising medication for the treatment of cocaine dependence.     

A randomized placebo-controlled trial of gabapentin for cocaine dependence

BACKGROUND: In laboratory animals, augmentation of GABA neurotransmission results in inhibition of cocaine self-administration and inhibition of reinstatement to cocaine-seeking behaviors. If parallel effects were observed in humans, GABA-ergic medication should be effective both in the abstinence-induction as well as in the relapse-prevention phase of cocaine dependence treatment. Gabapentin is an anticonvulsant medication that increases human brain GABA levels. We evaluated the safety and efficacy of gabapentin combined with relapse-prevention therapy in the treatment of cocaine-dependent individuals. DESIGN: The study involved 129 individuals with cocaine dependence. Of the 99 participants, who were randomized into a double-blind trial 88% were males, 66% were minorities and with an average age of 39 years (range 22-58 years). After 2 weeks of placebo lead-in, participants were randomized to receive either gabapentin 3200 mg (1600 mg bid) or placebo for 12 weeks, followed by 2 weeks of placebo lead-out. Prior to randomization, participants were stratified into four groups based on the principal route of cocaine use (smokers versus intranasal users) and the level of cocaine use during the 2 weeks of lead-in (high level versus low level). Throughout the 16 weeks study, participants received weekly individual relapse-prevention therapy. The outcome measures included: days of cocaine use and a binary indicator of abstinence based on urine toxicology test, self-reported cocaine craving and retention in treatment. RESULTS: Forty-nine percent of randomized patients completed 12 weeks of the trial. Retention did not differ by treatment group but cocaine-smokers dropped out of treatment at a significantly faster rate than intranasal users. For the entire sample, odds of cocaine use over the course of the study did not differ between gabapentin- and placebo-treated individuals. There was a significant difference in the odds of cocaine use between high and low-use groups, with the odds in high-use groups decreasing over time and odds in the low-use groups gradually increasing over the course of the study, such that by the end of the study low and high users were similarly likely to use cocaine. In the low-use group, there was a non-significant trend suggesting that gabapentin-treated subjects had more favorable outcome compared to placebo-treated individuals. There was no treatment effect on abstinence rates, craving or other substance use. Gabapentin at 3200 mg/day was very well tolerated in this group of cocaine-dependent participants. CONCLUSIONS: When combined with weekly individual relapse-prevention therapy, gabapentin 1600 mg bid was no more effective than placebo in the treatment of cocaine dependence. When reviewed in conjunction with other published studies, gabapentin and other GABA enhancing anticonvulsant medications may deserve further study as relapse-preventive agents in cocaine-dependent individuals who achieve abstinence early in treatment.     

A double-blind,placebo-controlled trial of topiramate for the treatment of comorbid cocaine and alcohol dependence

Background

Topiramate increases GABAergic activity and antagonizes the AMPA/kainate subtype of glutamate receptors. Through these mechanisms of action, topiramate may reduce alcohol and cocaine reward and may reduce alcohol and cocaine craving. Topiramate has been shown to reduce drinking in persons with alcohol dependence, and reduce relapse in stimulant-dependent patients. The current trial was intended to test the ability of topiramate to promote cocaine and alcohol abstinence among patients addicted to both drugs.

Methods

The study was a double-blind, placebo-controlled, 13-week trial involving 170 cocaine and alcohol dependent subjects. After achieving a period of cocaine and alcohol abstinence, subjects were randomized to topiramate, 300 mg daily, or identical placebo capsules. In addition, subjects received weekly individual psychotherapy. Primary outcome measures included self-reported alcohol and cocaine use, and thrice weekly urine drug screens. Secondary outcome measures included cocaine and alcohol craving, Addiction Severity Index results, cocaine withdrawal symptoms, and clinical global improvement ratings.

Results

Topiramate was not better than placebo in reducing cocaine use on the a priori primary outcome measure, or in reducing alcohol use. Topiramate was not better than placebo in reducing cocaine craving. Topiramate-treated subjects, compared to placebo-treated subjects, were more likely to be retained in treatment and more likely to be abstinent from cocaine during the last three weeks of the trial. Subjects who entered treatment with more severe cocaine withdrawal symptoms responded better to topiramate.

Discussion

Topiramate plus cognitive behavioral therapy may reduce cocaine use for some patients with comorbid cocaine and alcohol dependence.     

Antipsychotic drugs in cocaine dependence: A systematic review and meta-analysis

A systematic review and meta-analysis to evaluate the efficacy of antipsychotic drugs in subjects with cocaine dependence is presented. Twelve randomized, double-blind, placebo-controlled clinical trials involving 681 patients were included. Five outcome measures were evaluated: number of dropouts, cocaine use assessed by means of urine benzoylecgonine tests, self-reported cocaine use, craving and Addiction Severity Index. On average, 48% of the enrolled participants were lost to follow-up. In comparison to placebo, antipsychotics did not significantly reduce cocaine use (WMD = 0.01, 95%CI = − 0.12 to 0.13) or improve retention in treatment (RR 0.91, 95%CI = 0.82–1.02). Risperidone reduced slightly dropouts in comparison to placebo (RR = 0.87; 95%CI = 0.79–0.97). To date there is insufficient evidence to justify the use of antipsychotic drugs for cocaine dependence.     

A double-blind, placebo-controlled trial of reserpine for the treatment of cocaine dependence

BACKGROUND: Cocaine's increase of dopamine is strongly associated with its reinforcing properties and, thus, agents that reduce dopamine have received much attention as candidate cocaine-dependence treatments. The potential efficacy of reserpine, a dopamine depletor, for treating cocaine dependence is suggested by both pre-clinical research and a small clinical trial. METHOD: One hundred and nineteen participants who met DSM-IV criteria for cocaine dependence were enrolled into this 12-week, double-blind, placebo-controlled outpatient trial. Participants received either reserpine (0.5 mg/day) or matching placebo. All participants received 1h of manualized individual cognitive behavioral therapy on a weekly basis. Outcome measures included cocaine use as determined by self-report confirmed with urine benzoylecgonine results, cocaine craving, addiction severity index scores, and clinical global impression scores. Safety measures included adverse events, EKGs, vital signs, laboratory tests, and the Hamilton Depression Inventory. RESULTS: Seventy-nine participants (i.e., 66%) completed the 12-week trial. The safety results suggest that reserpine was safe and well tolerated by the participants. The efficacy measures indicated no significant differences between reserpine and placebo. CONCLUSION: These results do not support the efficacy of reserpine as a cocaine-dependence treatment.     

Psychosocial functioning and cocaine use during treatment: strength of relationship depends on type of urine-testing method

Although improvement in psychosocial functioning is a common goal in substance-abuse treatment, the primary outcome measure in most cocaine trials is urinalysis-verified cocaine use. However, the relationship between cocaine use and psychosocial outcomes is not well documented. To investigate this relationship and identify the optimal urine-screen method, we retrospectively analyzed data from two 25-week randomized controlled trials of abstinence reinforcement (AR) in 368 cocaine/heroin users maintained on methadone. Cocaine use was measured thrice weekly by qualitative urinalysis, benzoylecgonine concentration (BE), and an estimate of New Uses of cocaine by application of an algorithm to BE. Social adjustment (SAS-SR), current diagnosis of cocaine dependence (DSM-IV criteria), and depression symptoms (Beck Depression Inventory) were determined at study exit. Cocaine use was significantly lower in AR groups than in controls. Across groups, in-treatment cocaine use was significantly associated with worse social adjustment, current cocaine dependence, and depression at exit. Significant differences were detected more frequently with New Uses than qualitative urinalysis or BE. Nevertheless, the amount of variance accounted for by the urine screens was typically <15%. Cocaine use during treatment, especially when measured with New Uses criteria, can predict psychosocial functioning, but cannot substitute for direct measures of psychosocial functioning.     

A two-week pilot study of intranasal oxytocin for cocaine-dependent individuals receiving methadone maintenance treatment for opioid use disorder

About 30–60% of the patients receiving methadone for opioid use disorder (OUD) actively use cocaine. Cocaine use disorder (CUD) has no FDA-approved pharmacological treatment; existing psychosocial treatments are inadequate. Oxytocin (OT), a social neuropeptide, has preclinical promise as an adjunctive treatment for both OUD and CUD. Twenty-two individuals receiving methadone for OUD with co-occurring CUD were randomized to receive OT or placebo intranasally 40?IU twice daily for two weeks. A priori aims were feasibility and safety. Exploratory effectiveness aims included laboratory-based measures of drug craving, drug-related implicit cognition, and drug use. High retention rates (93.5%), the absence of study-related adverse events, and the fact that OT was well tolerated in this population support the feasibility of larger trials. Two weeks of OT (but not placebo) significantly reduced cocaine craving at day 15 compared to baseline (mean change?±?SD: OT?=??0.23?±?0.19, p?=?0.004; PL?=??0.16?±?0.29, p?=?0.114). For heroin craving, the placebo group reported a trend-level increase over time while the OT group remained unchanged – with medium to large effect sizes between the groups (Cohen’s d?=?0.71–0.90). OT led to a significant switch from implicit self-association with drugs to implicitly associating drugs with others (mean change?±?SD: 0.25?±?0.35, p?=?0.037) and a trend-level reduction in self-reported cocaine use over time (Z?=??1.78, p?=?0.075). Furthermore, OT significantly increased the accuracy of self-reported cocaine use when correlated with quantitative urine levels of cocaine metabolite. This proof-of-concept study provides promising early evidence that OT may be an effective adjunct to the treatment of co-occurring CUD and OUD. Further investigation with larger trials is warranted.     

Effectiveness of propranolol for cocaine dependence treatment may depend on cocaine withdrawal symptom severity

Propranolol may reduce symptoms of autonomic arousal associated with early cocaine abstinence and improve treatment outcome. This trial was an 8-week, double-blind, placebo-controlled trial of propranolol in 108 cocaine dependent subjects. The primary outcome measure was quantitative urinary benzoylecgonine levels. Secondary outcome measures included treatment retention, addiction severity index results, cocaine craving, mood and anxiety symptoms, cocaine withdrawal symptoms, and adverse events. Propranolol treated subjects had lower cocaine withdrawal symptom severity but otherwise did not differ from placebo treated subjects in any outcome measure. However, in a secondary, exploratory analysis, subjects with more severe cocaine withdrawal symptoms responded better to propranolol in comparison to placebo. In these subjects, propranolol treatment was associated with better treatment retention and lower urinary benzoylecgonine levels as compared with the placebo treatment. Propranolol may be useful only for the treatment of cocaine dependent patients with severe cocaine withdrawal symptoms.