Haloperidol antagonism of cue-elicited cocaine craving. Pergolide mesylate for cocaine abuse: a controlled preliminary trial. A double-blind placebo-controlled pilot study of risperidone for decreasing cue-elicited craving in recently withdrawn cocaine dependent patients. The efficacy of olanzapine for decreasing cue-elicited craving in individuals with schizophrenia and cocaine dependence: a preliminary report. Agonist-like or antagonist-like treatment for cocaine dependence with methadone for heroin dependence: two double-blind randomized clinical trials. A placebo-controlled screening trial of olanzapine, valproate, and coenzyme Q10/L-carnitine for the treatment of cocaine dependence. A pilot trial of olanzapine for the treatment of cocaine dependence.
Studies of cocaine-dependent subjects have shown that re-exposure to environmental cues previously associated with cocaine use produces a strong conditioned response characterised by autonomic hyperarousal and increases in subjective measures of cocaine craving.
                To evaluate the role of dopamine release by such cues, 20 cocaine-dependent inpatients were randomised in a single-dose, crossover, placebo-controlled design, to haloperidol (4 mg by mouth) and placebo. Plasma homovanillic acid (HVA, a dopamine metabolite), adrenocorticotropic hormone (ACTH), and cortisol were assayed before and after cue exposure. Craving and anxiety were measured before and after cues with visual analogue scales for desire to use cocaine now and for mood changes.
                Cocaine cues significantly increased anxiety, ACTH, cortisol, and HVA. Increases in anxiety and craving resulting from cue exposure were significantly antagonised by pretreatment with haloperidol.
                It has long been hypothesised that increases in extracellular concentrations of dopamine mediate the acute reinforcing effects of cocaine. Our data suggest that dopamine release may also mediate some of the conditioned responses to cocaine cues. A small, controlled study was conducted to assess whether pergolide mesylate has clinical promise as a treatment for cocaine abuse prior to embarking on a larger, randomized, double-blind, controlled trial. Fourteen individuals were placed on placebo for 2 weeks, followed by a 24-week single-blind study in which they were placed on pergolide for 12 weeks, followed by placebo for 12 weeks. Another 14 patients received single-blind placebo for two weeks and then were randomized into a 24-week double-blind, placebo-controlled, multiple baseline design. Initially, patients enrolled in the study were placed on risperidone (n = 9) or placebo (n = 5). During the first 12 weeks, retention was worse for those receiving pergolide compared to risperidone or placebo. Neither risperidone nor pergolide were more efficacious in reducing cocaine use than placebo. Although earlier open studies found pergolide to show promise as a treatment for cocaine abuse, this study did not support these earlier findings. Comparing an agent to both an active control and placebo group may better predict whether a promising new agent will have clinical utility compared to the standard open trial. Cocaine use causes an initial increase in dopamine and serotonin neurotransmission that is largely responsible for the pleasurable and reinforcing effects of the drug. Dysregulation of these neurotransmitters during withdrawal plays an important role in craving. Recent research has focused on the use of dopamine and serotonin antagonists early in recovery to reduce cocaine craving in both schizophrenic and non-schizophrenic cocaine dependent patients. This 2-week, double blind, placebo-controlled study compared risperidone vs. placebo in reducing cue-elicited cocaine craving. Thirty-four subjects with cocaine dependence were randomized to either risperidone or a placebo and underwent a weekly cue-exposure procedure. Although both groups had a reduction in craving over time, there were no significant differences among those treated with risperidone (n=19) compared to those taking a placebo (n=16) on the four craving dimensions. The results do not support the hypothesis that risperidone reduces cocaine craving among non-schizophrenic cocaine-dependent individuals. Although a growing body of research suggests that atypical neuroleptic medications are efficacious in the treatment of cocaine addiction among individuals with schizophrenia, more rigorously controlled trials are needed. To extend this research, we performed a 6-week double-blind study comparing olanzapine to haloperidol with the primary objective of reducing cue-elicited cocaine craving and the secondary aims of decreasing substance use, improving psychiatric symptoms, and determining an effect size for future studies.
                Thirty-one subjects with cocaine dependence and schizophrenia were randomized to olanzapine or haloperidol, underwent a cue-exposure procedure, and completed psychiatric and substance abuse ratings.
                Individuals in the olanzapine group who completed the study had a significant reduction on the energy subscale of the Voris Cocaine Craving Scale at study completion compared with individuals in the haloperidol group. The olanzapine-treated group also had lower, but not statistically significant, PANSS General Psychopathology Subscale scores and fewer positive urine toxicology screens compared with those in the haloperidol group.
                This small, but rigorously controlled, pilot trial provides additional evidence for the use of atypical antipsychotics for the treatment of individuals with co-occurring schizophrenia and cocaine dependence. Reductions in craving were associated with medium to large effect sizes. 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. To conduct a medication screening trial on the efficacy of olanzapine, valproate or coenzyme Q10/L-carnitine combination versus placebo for the treatment of cocaine dependence.
                A four-arm, modified blinded, parallel group study in an out-patient setting using the Cocaine Rapid Efficacy and Safety Trials (CREST) study design.
                The study was performed at the New York Medications Development Research Unit (MDRU).
                All participants met Diagnostic and Statistical Manual version IV (DSM-IV) criteria for cocaine dependence and provided at least two urine samples positive for benzoylecgonine (BE) during the 2-week screening period. Sixty-eight participants were enrolled with 39 completing the study.
                After a 2-week screening period, 68 subjects were assigned randomly to receive either olanzapine (10 mg/day), valproate (1500 mg/day), coenzyme Q10 (200 mg/day) and L-carnitine (500 mg/day) combination or placebo for an 8-week treatment period. All subjects also received individual cognitive behavioral counseling during treatment.
                Primary outcome measures included quantitative urine benzoylecgonine (BE) levels, self-report of drug use, and global impression scores. Secondary outcomes included cocaine craving, study retention and related psychosocial measures. Safety measures included adverse event monitoring, vital signs, and extrapyramidal side-effects tests.
                Study retention was similar across all treatment groups, and all groups showed improvement across most measures of treatment efficacy over the duration of the study. None of the study medications, however, were superior to placebo on any of the primary or secondary outcome measures. Cocaine use, as measured by urine BE levels and self-report, was not significantly lower than placebo in any of the drug treatment groups. All study medications were equally well tolerated, and few medication side effects were observed.
                This pilot study does not support the effectiveness of olanzapine, valproate or coenzyme Q10/L-carnitine combination for the treatment of cocaine dependence. 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.
                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.
                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.
                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.
Although caution is needed when assessing results from a limited number of small clinical trials there is no current evidence, at the present , supporting the clinical use of antipsychotic medications in the treatment of cocaine dependence. Furthermore, most of the included studies did not report useful results on important outcomes such as side effects, use of cocaine during the treatment and craving. Aiming to answer the urgent demand of clinicians, patients, families, and the community as a whole for an adequate treatment for cocaine dependence, larger randomised investigations should be designed investigating relevant outcomes and reporting data to allow comparison of results between studies. Moreover some efforts should be done also to investigate the efficacy of other type medications, like anticonvulsant, currently used in clinical practice.