Treatment Of Cocaine Dependence Research Articles

Time of abstinence prior admission to a residential rehabilitation program as a predictor of cocaine dependence treatment completion in Lima, Peru

goal of this research was to characterize the behavioral effects of CP47,497 using well-established preclinical in vivo models, tetrad and drug discrimination, to evaluate cannabimimetic effects. Complementary pharmacological and genetic approaches will be used to determine whether CB1 receptors mediate the pharmacological effects of CP47,497. Methods: ICR mice (n=8) were tested in the tetrad paradigm that assesses catalepsy, antinociception, hypothermia, and decreases in spontaneous locomotor activity. In drug discrimination experiments, C57BL/6J (n=8–12) mice were trained to discriminate 5.6mg/kg THC from vehicle. Results: CP47,497 was significantly more potent than THC in each parameter of the tetrad and in drug discrimination studies. The CB1 receptor antagonist, rimonabant, blocked all effects of CP47,497 but required high doses (10mg/kg) to antagonize the antinociceptive, hypothermic and locomotor depressant effects. In accordance with these data, all cannabimimetic effects of CP47,497 were abolished in CB1 (−/−) mice. Furthermore, in drug discrimination studies, CP47,497 fully substituted for THC; demonstrating a potency 5 times that of THC. Conclusions: Collectively, these results indicate that acute administration of CP47,497 elicits markedly more potent effects (i.e. 5–7 fold) when compared to THC. Since these products are almost exclusively smoked, ongoing research is investigating inhalation exposure of CP47,497, to further address the pharmacology and bioavailability of this abused synthetic cannabinoid. Financial support: Research supported by NIDA F31DA033183 (KLS), P01DA009789 (AHL), T32DA007027 (WLD).

Multisite, randomized, double-blind, placebo-controlled pilot clinical trial to evaluate the efficacy of buspirone as a relapse-prevention treatment for cocaine dependence.

To evaluate the potential efficacy of buspirone as a relapse-prevention treatment for cocaine dependence. A randomized, double-blind, placebo-controlled, 16-week pilot trial was conducted at 6 clinical sites between August 2012 and June 2013. Adult crack cocaine users meeting DSM-IV-TR criteria for current cocaine dependence who were scheduled to be in inpatient/residential substance use disorder (SUD) treatment for 12-19 days when randomized and planning to enroll in local outpatient treatment through the end of the active treatment phase were randomized to buspirone titrated to 60 mg/d (n = 35) or placebo (n = 27). All participants received psychosocial treatment as usually provided by the SUD treatment programs in which they were enrolled. Outcome measures included maximum days of continuous cocaine abstinence (primary), proportion of cocaine use days, and days to first cocaine use during the outpatient treatment phase (study weeks 4-15) as assessed by self-report and urine drug screens. There were no significant treatment effects on maximum continuous days of cocaine abstinence or days to first cocaine use. In the female participants (n = 23), there was a significant treatment-by-time interaction effect (χ²₁ = 15.26, P < .0001), reflecting an increase in cocaine use by those receiving buspirone, relative to placebo, early in the outpatient treatment phase. A similar effect was not detected in the male participants (n = 39; χ²₁ = 0.14, P = .70). The results suggest that buspirone is unlikely to have a beneficial effect on preventing relapse to cocaine use and that buspirone for cocaine-dependent women may worsen their cocaine use outcomes. ClinicalTrials.gov identifier: NCT01641159.

Cocaine dependent individuals with attenuated striatal activation during reinforcement learning are more susceptible to relapse

Cocaine-dependent individuals show altered brain activation during decision making. It is unclear, however, whether these activation differences are related to relapse vulnerability. This study tested the hypothesis that brain-activation patterns during reinforcement learning are linked to relapse 1 year later in individuals entering treatment for cocaine dependence. Subjects performed a Paper-Scissors-Rock task during functional magnetic resonance imaging (fMRI). A year later, we examined whether subjects had remained abstinent (n=15) or relapsed (n=15). Although the groups did not differ on demographic characteristics, behavioral performance, or lifetime substance use, abstinent patients reported greater motivation to win than relapsed patients. The fMRI results indicated that compared with abstinent individuals, relapsed users exhibited lower activation in (1) bilateral inferior frontal gyrus and striatum during decision making more generally; and (2) bilateral middle frontal gyrus and anterior insula during reward contingency learning in particular. Moreover, whereas abstinent patients exhibited greater left middle frontal and striatal activation to wins than losses, relapsed users did not demonstrate modulation in these regions as a function of outcome valence. Thus, individuals at high risk for relapse relative to those who are able to abstain allocate fewer neural resources to action-outcome contingency formation and decision making, as well as having less motivation to win on a laboratory-based task.

Effects of pharmacologic dopamine β-hydroxylase inhibition on cocaine-induced reinstatement and dopamine neurochemistry in squirrel monkeys.

Disulfiram has shown promise as a pharmacotherapy for cocaine dependence in clinical settings, although it has many targets, and the behavioral and molecular mechanisms underlying its efficacy are unclear. One of many biochemical actions of disulfiram is inhibition of dopamine β-hydroxylase (DBH), the enzyme that converts dopamine (DA) to norepinephrine (NE) in noradrenergic neurons. Thus, disulfiram simultaneously reduces NE and elevates DA tissue levels in the brain. In rats, both disulfiram and the selective DBH inhibitor nepicastat block cocaine-primed reinstatement, a paradigm which is thought to model some aspects of drug relapse. This is consistent with some clinical results and supports the use of DBH inhibitors for the treatment of cocaine dependence. The present study was conducted to confirm and extend these results in nonhuman primates. Squirrel monkeys trained to self-administer cocaine were pretreated with disulfiram or nepicastat prior to cocaine-induced reinstatement sessions. Neither DBH inhibitor altered cocaine-induced reinstatement. Unexpectedly, nepicastat administered alone induced a modest reinstatement effect in squirrel monkeys, but not in rats. To investigate the neurochemical mechanisms underlying the behavioral results, the effects of DBH inhibition on extracellular DA were analyzed in the nucleus accumbens (NAc) using in vivo microdialysis in squirrel monkeys. Both DBH inhibitors attenuated cocaine-induced DA overflow in the NAc. Hence, the attenuation of cocaine-induced changes in accumbal DA neurochemistry was not associated with altered cocaine-seeking behavior. Overall, the reported behavioral effects of DBH inhibition in rodent models of relapse did not extend to nonhuman primates under the conditions used in the current studies.

(13) C magnetic resonance spectroscopic imaging of hyperpolarized [1-(13) C, U-(2) H5 ] ethanol oxidation can be used to assess aldehyde dehydrogenase activity in vivo.

Aldehyde dehydrogenase (ALDH2) is an emerging drug target for the treatment of heart disease, cocaine and alcohol dependence, and conditions caused by genetic polymorphisms in ALDH2. Noninvasive measurement of ALDH2 activity in vivo could inform the development of these drugs and accelerate their translation to the clinic. [1-(13) C, U-(2) H5 ] ethanol was hyperpolarized using dynamic nuclear polarization, injected into mice and its oxidation in the liver monitored using (13) C MR spectroscopy and spectroscopic imaging. Oxidation of [1-(13) C, U-(2) H5 ] ethanol to [1-(13) C] acetate was observed. Saturation of the acetaldehyde resonance, which was below the level of detection in vivo, demonstrated that acetate was produced via acetaldehyde. Irreversible inhibition of ALDH2 activity with disulfiram resulted in a proportional decrease in the amplitude of the acetate resonance. (13) C magnetic resonance spectroscopy measurements of hyperpolarized [1-(13) C, U-(2) H5 ] ethanol oxidation allow real-time assessment of ALDH2 activity in liver in vivo.

Topiramate for cocaine dependence during methadone maintenance treatment: A randomized controlled trial

BackgroundDual dependence on opiate and cocaine occurs in about 60% of patients admitted to methadone maintenance and negatively impacts prognosis (Kosten et al. 2003. Drug Alcohol Depend. 70, 315). Topiramate (TOP) is an antiepileptic drug that may have utility in the treatment of cocaine dependence because it enhances the GABAergic system, antagonizes the glutamatergic system, and has been identified by NIDA as one of only a few medications providing a “positive signal” warranting further clinical investigation. (Vocci and Ling, 2005. Pharmacol. Ther. 108, 94). MethodIn this double-blind controlled clinical trial, cocaine dependent methadone maintenance patients (N=171) were randomly assigned to one of four groups. Under a factorial design, participants received either TOP or placebo, and monetary voucher incentives that were either contingent (CM) or non-contingent (Non-CM) on drug abstinence. TOP participants were inducted onto TOP over 7 weeks, stabilized for 8 weeks at 300mg daily then tapered over 3 weeks. Voucher incentives were supplied for 12 weeks, starting during the fourth week of TOP induction. Primary outcome measures were cocaine abstinence (Y/N) as measured by thrice weekly urinalysis and analyzed using Generalized Estimating Equations (GEE) and treatment retention. All analyses were intent to treat and included the 12-week evaluation phase of combined TOP/P treatment and voucher intervention period. ResultsThere was no significant difference in cocaine abstinence between the TOP vs. P conditions nor between the CM vs. Non-CM conditions. There was no significant TOP/CM interaction. Retention was not significantly different between the groups. ConclusionTopiramate is not efficacious for increasing cocaine abstinence in methadone patients.

Comparative Study of the Perceived Quality of Life of Patients in Treatment for Cocaine and Heroin Dependence in Spain: Differences by Gender and Time in Treatment

This is a cross-sectional study in which we compared the perceived quality of life (QoL) of patients receiving outpatient treatment for cocaine (n = 727) and heroin dependence (n = 469), by analyzing differences by gender and time in treatment. Participants were recruited from addictive behavior centers in Spain in 2004. The World Health Organization Quality of Life Assessment Instrument (WHOQOL-Bref) was used as a measure. Analysis of covariance and multivariate linear regression were used. This study shows the relevance of considering the role of gender in QoL studies, and the need to evaluate the effectiveness of treatment in the improvement of QoL. Limitations of the study were noted.

Structural Basis for Inactivation of Giardia lamblia Carbamate Kinase by Disulfiram

Carbamate kinase from Giardia lamblia is an essential enzyme for the survival of the organism. The enzyme catalyzes the final step in the arginine dihydrolase pathway converting ADP and carbamoyl phosphate to ATP and carbamate. We previously reported that disulfiram, a drug used to treat chronic alcoholism, inhibits G. lamblia CK and kills G. lamblia trophozoites in vitro at submicromolar IC50 values. Here, we examine the structural basis for G. lamblia CK inhibition of disulfiram and its analog, thiram, their activities against both metronidazole-susceptible and metronidazole-resistant G. lamblia isolates, and their efficacy in a mouse model of giardiasis. The crystal structure of G. lamblia CK soaked with disulfiram revealed that the compound thiocarbamoylated Cys-242, a residue located at the edge of the active site. The modified Cys-242 prevents a conformational transition of a loop adjacent to the ADP/ATP binding site, which is required for the stacking of Tyr-245 side chain against the adenine moiety, an interaction seen in the structure of G. lamblia CK in complex with AMP-PNP. Mass spectrometry coupled with trypsin digestion confirmed the selective covalent thiocarbamoylation of Cys-242 in solution. The Giardia viability studies in the metronidazole-resistant strain and the G. lamblia CK irreversible inactivation mechanism show that the thiuram compounds can circumvent the resistance mechanism that renders metronidazole ineffectiveness in drug resistance cases of giardiasis. Together, the studies suggest that G. lamblia CK is an attractive drug target for development of novel antigiardial therapies and that disulfiram, an FDA-approved drug, is a promising candidate for drug repurposing.

Effect of experimental analogs of contingency management treatment on cocaine seeking behavior

BackgroundContingency management (CM) treatment is effective for treating cocaine dependence but further mechanistic studies of its efficacy are warranted. This study aimed to determine whether: (a) higher vs. lower predictable money amounts ($3 vs. $1; analogs of standard voucher-based CM) increase cocaine demand elasticity; and (b) probabilistic amounts matched for expected value with the $3-predictable amount (50% chance of $6; 25% chance of $12; and 12.5% chance of $24; analogs of prize CM) similarly affect cocaine choice. MethodsEach of 15 cocaine-dependent participants first completed a qualifying session to ensure that intranasal cocaine functioned as a reinforcer, then completed a 10-session, within-subject, randomized crossover study. During each of the 10 sessions, the participant responded on a progressive ratio schedule to earn units of cocaine (5-mg or 10-mg) and/or money (five monetary conditions above). ResultsDuring the reinforcement qualifying session (10-mg vs. 0-mg units; no money alternative), cocaine choice was high. The $3-predictable amount significantly decreased cocaine choice relative to both the $1-predictable amount and the qualifying session. Cocaine-choices in the probabilistic conditions were similar to the $3 predictable condition. ConclusionsThese findings indicate that CM interventions targeted at reducing cocaine self-administration are more likely to succeed with higher value non-drug reinforcement.

Preliminary evidence for normalization of risk taking by modafinil in chronic cocaine users

Modafinil, a wake-promoting agent used to treat sleep disorders, is thought to enhance cognition. Although modafinil has shown promise as a pharmacotherapy for the treatment of cocaine dependence, it is unknown to what extent cognitive effects may play a role in such treatment. We examined the effect of modafinil on the Balloon Analogue Risk Task (BART), a behavioral measure in which higher scores are purported to reflect a greater propensity for risk-taking. Thirty cocaine dependent individuals, enrolled in a randomized clinical trial of modafinil 400mg (n=12) versus placebo (n=18), were administered the BART during the second week of inpatient treatment for cocaine dependence. A comparison cohort of healthy participants (n=19) performed the BART under similar conditions. Modafinil treatment was associated with significantly higher BART scores (p=0.01), which were comparable to scores in healthy persons. BART scores in placebo treated participants were much lower than previously reported in healthy participants, and lower than those observed in the comparison cohort. As propensity toward risk taking is typically associated with higher BART scores as well as increased risk for substance use, our findings may reflect a novel aspect of cognitive impairment related to chronic cocaine use. Notably, the low BART scores reflect highly suboptimal performance on the task, and the observed effect of modafinil may indicate a normalization of this impairment and have implications for treatment outcome.

The Use of Neuromodulation in the Treatment of Cocaine Dependence

Cocaine related disorders are currently among the most devastating mental diseases, as they impoverish all spheres of life resulting in tremendous economic, social and moral costs. Despite multiple efforts to tackle cocaine dependence, pharmacological as well as cognitive therapies have had limited success. In this review, we discuss the use of recent neuromodulation techniques, such as conventional repetitive transcranial magnetic stimulation (rTMS), deep brain stimulation (DBS) and the use of H coils for deep rTMS for the treatment of cocaine dependence. Moreover, we discuss attempts to identify optimal brain targets underpinning cocaine craving and withdrawal for neurodisruption treatment, as well as some weaknesses in the literature, such as the absence of biomarkers for individual risk classification and the inadequacy of treatment outcome measures, which may delay progress in the field. Finally, we present some genetic markers candidates and objective outcome measures which could be applied in combination with TMS treatment of cocaine dependence. We anticipate future research in this area combining genetic and physiological markers, neurodisruption, and clinical behavioral measures.

Treatment of crack-cocaine dependence with topiramate: A randomized controlled feasibility trial in The Netherlands

BackgroundCrack-cocaine dependence is a complex disorder with limited treatment options. Topiramate is one of the promising medications with reported reductions in cocaine use and craving in former studies. The present study evaluated the acceptance and effectiveness of topiramate as an add-on to cognitive behavioral therapy (CBT) in crack-cocaine dependent patients. MethodsSeventy-four crack-cocaine dependent outpatients participated in an open-label, randomized feasibility trial. They were randomized to receive either 12-week CBT plus topiramate (200mg/day) or 12-week CBT only. The primary outcome measure was treatment retention. Secondary outcomes included medication adherence, safety, cocaine and other substance use, health, social functioning, and patient satisfaction. ResultsAdherence to topiramate treatment was low. In the intent-to-treat analyses, topiramate neither improved treatment retention nor reduced cocaine and other substance use. Post hoc, exploratory analyses suggested a moderation effect of comorbid opioid dependence, with a significant effect of topiramate on cocaine use reduction only in crack-cocaine dependent patients with comorbid opioid dependence. ConclusionsTopiramate was safe and well-tolerated in this sample of crack-cocaine dependent patients, but efficacy was not supported probably due to low acceptance of the treatment. Given the equivocal results of previous studies and the negative findings in our study, the potential of topiramate in the treatment of cocaine dependence seems limited.

Clinical differences between cocaine-induced psychotic disorder and psychotic symptoms in cocaine-dependent patients

The aim of this study is to compare the clinical characteristics of three groups of patients in treatment for cocaine dependence: patients without any psychotic symptoms (NS), patients with transient psychotic symptoms (PS) and patients with cocaine-induced psychotic disorder (CIPD). An observational and retrospective study of 150 cocaine-dependent patients undergoing treatment in the Drug Unit of the Psychiatry Department of University Hospital Vall d׳Hebron in Barcelona (Spain) using these three groups, NS, PS and CIPD, was performed. All patients were evaluated with the PRISM interview. ANOVA, χ2 tests and multivariate multinomial regression analysis were used to perform statistical analyses. Seven patients with a primary psychotic disorder were discharged. Forty-six patients (32.1%) did not report any psychotic symptoms. Ninety-seven patients (67.9%) presented with a history of any cocaine-induced psychotic symptom and were considered as the cocaine-induced psychotic (CIP) group. Among them, 39 (27.3%) were included in the PS group and 58 (40.6%) were included in the CIPD group. A history of imprisonment was found significantly more frequently in the PS group than in the NS group. The distribution of age at onset of dependence, lifetime cannabis abuse or dependence and imprisonment were significantly different between the NS and CIPD groups. We conclude that in cocaine-dependent patients, clinicians should be advised about the risk of development of psychotic symptoms. The presence of some psychotic symptoms could increase the potential risks of disturbing behaviours.

Pharmacological Evidence for an Abstinence-Induced Switch in 5-HT1B Receptor Modulation of Cocaine Self-Administration and Cocaine-Seeking Behavior

Studies examining serotonin-1B (5-HT1B) receptor manipulations on cocaine self-administration and cocaine-seeking behavior initially seemed discrepant. However, we recently suggested based on viral-mediated 5-HT1B-receptor gene transfer that the discrepancies are likely due to differences in the length of abstinence from cocaine prior to testing. To further validate our findings pharmacologically, we examined the effects of the selective 5-HT1B receptor agonist CP 94,253 (5.6 mg/kg, s.c.) on cocaine self-administration during maintenance and after a period of protracted abstinence with or without daily extinction training. We also examined agonist effects on cocaine-seeking behavior at different time points during abstinence. During maintenance, CP 94,253 shifted the cocaine self-administration dose–effect function on an FR5 schedule of reinforcement to the left, whereas following 21 days of abstinence CP 94,253 downshifted the function and also decreased responding on a progressive ratio schedule of reinforcement regardless of extinction history. CP 94,253 also attenuated cue-elicited and cocaine-primed drug-seeking behavior following 5 days, but not 1 day, of forced abstinence. The attenuating effects of CP 94,253 on the descending limb of the cocaine dose–effect function were blocked by the selective 5-HT1B receptor antagonist SB 224289 (5 mg/kg, i.p.) at both time points, indicating 5-HT1B receptor mediation. The results support a switch in 5-HT1B receptor modulation of cocaine reinforcement from facilitatory during self-administration maintenance to inhibitory during protracted abstinence. These findings suggest that the 5-HT1B receptor may be a novel target for developing medication for treating cocaine dependence.

Early Cannabis Use Is Associated With Severity of Cocaine-Induced Psychosis Among Cocaine Smokers in Martinique, French West Indies

Cocaine intoxication can induce transient psychotic symptoms. The principal aim of this study was to determine sociodemographic and clinical characteristics associated with cocaine-induced psychosis (CIP) and to identify clinical factors predicting CIP in crack cocaine smokers in Martinique. The second aim was to identify clinical factors associated with severity of CIP, assessed with the Scale for Assessment of Positive Symptoms for Cocaine-Induced Psychosis (SAPS-CIP). Fifty-three cocaine-dependent smokers (45 men and 8 women) seeking treatment for cocaine dependence were included. Patients were assessed using the Cocaine Experience Questionnaire (CEQ), an instrument for the identification of cocaine-induced paranoia, and a French version of the SAPS-CIP, for the severity of CIP. Thirty-five (66%) patients reported cocaine-induced paranoia on the CEQ (CIP(+) patients). The mean SAPS-CIP total score was 6.1 ± 3.7, with a significant difference between CIP(+) and CIP(-) patients (P < 0.0001). Age at first cannabis use was associated with occurrence of CIP on the CEQ, and adolescent-onset cannabis use was associated with severity of hallucinations score on the SAPS-CIP. Cocaine-induced psychosis is frequent in crack cocaine smokers in Martinique, and early cannabis use is associated with the occurrence and the severity of psychotic symptoms during cocaine intoxication in this population. Patients developing psychotic symptoms during cocaine use began smoking cannabis earlier during adolescence than patients without CIP. These results confirm those of previous studies, highlighting the need to better assess early cannabis use in cocaine users, because early cannabis use is associated with severity of CIP.

Phenytoin Toxicity from Cocaine Adulteration

The use of phenytoin (PHT) as a cocaine adulterant was reported decades ago; that practice is still current. Ironically PHT has also been used for the treatment of cocaine dependence. A drug smuggler developed PHT toxicity after swallowing several rocks of crack. We investigated the current trends of PHT as a cocaine adulterant and its toxicological implications. We also reviewed the clinical use of PTH in relation to cocaine. The use of PHT as cocaine cut is a current practice. This may affect the clinical manifestations and the management of the cocaine-related visits to the emergency department.

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Randomized clinical trial of disulfiram for cocaine dependence or abuse during buprenorphine treatment

BackgroundDisulfiram may be efficacious for treating cocaine dependence or abuse, possibly through inhibiting dopamine β-hydroxylase (DβH). Consequently, this randomized, placebo-controlled clinical trial of disulfiram during buprenorphine maintenance treatment evaluated the study hypothesis that disulfiram is superior to placebo and explored whether disulfiram response is greatest for participants with a single nucleotide polymorphism coding for genetically low DβH (T-allele carriers). MethodsWe randomized 177 buprenorphine-treated opioid dependent participants with cocaine dependence or abuse to 12 weeks of double-blind treatment with disulfiram 250mg daily (n=91) or placebo (n=86). Of 155 participants genotyped, 84 were CC-homozygous, and 71 CT or TT genotypes. Primary outcomes included days per week cocaine use, number of cocaine-negative urine tests, and maximum consecutive weeks of cocaine abstinence. We analyzed an intention-to-treat comparison between disulfiram and placebo. We also explored potential pharmacogenetic interactions and examined treatment responses of four participant groups based on medication (disulfiram or placebo) by genotype (CC-homozygous or T-allele carrier) classification. ResultsDisulfiram participants reported significantly less frequent cocaine use; the differences in cocaine-negative urine tests or consecutive weeks abstinence were not significant. Frequency of cocaine use was lowest in disulfiram-treated T-allele carriers; differences in cocaine-negative urine tests or consecutive weeks abstinence were not significant among the four medication-genotype groups. ConclusionsThe findings provide limited support for the efficacy of disulfiram for reducing cocaine use and suggest that its mechanism of action may involve inhibition of DβH. Further studies of its efficacy, mechanism of action, and pharmacogenetics of response are warranted.

Seizure Drug Shows Promise As Cocaine-Addiction Treatment

Back to table of contents Previous article Next article Clinical & Research NewsFull AccessSeizure Drug Shows Promise As Cocaine-Addiction TreatmentJoan Arehart-TreichelJoan Arehart-TreichelSearch for more papers by this authorPublished Online:18 Dec 2013https://doi.org/10.1176/appi.pn.2013.12a1AbstractEvery few years, a promising medication to treat cocaine dependence emerges, only to fizzle. Is the latest one—topiramate—the longed-for treatment or will it too disappoint?Despite decades of zealous scientific effort, an effective medication to treat cocaine addiction remains elusive. Hope for such a treatment is growing, however, based on results of a study published online October 16 in JAMA Psychiatry.The medication topiramate—already approved by the Food and Drug Administration (FDA) to treat seizures and prevent migraines and also used off label to treat alcohol dependence—is now looking promising as a treatment for cocaine dependence as well.The study was headed by Bankole Johnson, M.D., D.Sc., chair of psychiatry at the University of Maryland.Animal research has shown that an intact GABA neurotransmitter system in the nucleus accumbens, corpus striatum, and several other brain structures is critical for cocaine to exert its effects. Animal research has also indicated that medications that enhance GABA function can reduce cocaine’s effects. Thus Johnson and his colleagues hypothesized that topiramate, a medication known to enhance GABA function, might be effective in treating cocaine dependence. They then launched a clinical trial to test this hypothesis.A total of 142 cocaine-dependent adults were recruited to take part in their study. Half were randomized to receive topiramate, and half were randomized to receive a placebo over a 12-week period. The primary outcome variable was the weekly difference from baseline in the proportion of cocaine nonuse days during weeks 6 to 12, the period when subjects’ topiramate doses should have been optimal. Cocaine use was monitored by self-report and urine tests three times a week.Bankole Johnson, M.D., D.Sc.: “A large effectiveness study is being planned to generalize the findings to an even wider population of cocaine addicts.”Bankole Johnson, M.D., D.Sc.The second outcome variable was cocaine craving as measured by two craving scales that had been well validated in previous pharmacotherapy trials for cocaine dependence—the Cocaine Selective Severity Assessment Scale and the Brief Substance Craving Scale.Finally, global functioning was evaluated by a clinician or nurse practitioner using the Clinical Global Impression-Observer Scale and by the subjects themselves using the Clinical Global Impression–Self Scale.Topiramate was significantly more efficacious than placebo in increasing cocaine-nonuse days and urinary cocaine-free weeks, in reducing the frequency and intensity of cocaine craving, and in improving both observer-rated and self-rated global functioning.In short, “We have some great news regarding a treatment for cocaine dependence,” Johnson told Psychiatric News. As he and his colleagues asserted in their report, “Taken together, it is reasonable to propose that topiramate treatment was associated with a clinically meaningful improvement in the severity of cocaine dependence.”They did acknowledge that they could not compare topiramate’s impact with that of any other medication, since no medication has been approved by the FDA to treat cocaine dependence. “Finding a safe and effective medication (or vaccine) for the treatment of cocaine use disorder has been the holy grail of our field for decades,” Petros Levounis, M.D., chair of psychiatry at Rutgers New Jersey Medical School and an addiction psychiatrist, said during an interview. “Every few years, an exciting possibility appears on the pharmacotherapy scene, only to fizzle out a little later. For a long time, topiramate has been thought of as one of the more promising medications for the treatment of cocaine addiction, and the present study supports this notion. We hope that our current optimism for the success of topiramate is not short-lived as was the case for some other drugs. Had the study been longer than 12 weeks, our confidence in the reported encouraging results would be considerably higher.”Indeed, the next step, Johnson and his team explained, will be to undertake a trial of six months or longer to try to replicate and extend their current findings. The study was funded by the National Institutes of Health and the Agency for Healthcare Research and Quality. ■ An abstract of “Topiramate for the Treatment of Cocaine Addiction: A Randomized Clinical Trial” is posted at http://archpsyc.jamanetwork.com/article.aspx?articleid=1756816. ISSUES NewArchived

Treatment of cocaine addiction with amphetamine, a sleep-suppressant drug: associative learning, sleep patterns and clinical perspectives

Dear Editor Stimulants have shown promise as a treatment for cocaine dependence despite resistance in the field to using controlled substances as therapeutic agents for addictive disorders. Conceptually, the goal of substitution pharmacotherapy is to replace a drug of abuse with rapid onset and brief half-life with an agent that has a more gradual onset of action and long halflife to suppress withdrawal and drug craving, reducing the cycle of compulsive use (Grabowski et al. 2004; Mariani and Levin 2012). Within this context, the recent study by Zimmer and colleagues (2013) demonstrated that D-amphetamine treatment during the persistence of a previously established active cocaine self-administration, but not during passive cocaine infusions, resulted in a significant decrease in cocaine-maintained responding under a PR schedule of reinforcement. The authors discussed these findings in terms of associative processes between the drug effect and the environmental cues, culminating into drug-seeking behavior. This potential hypothesis needs to be viewed in relation to an important aspect of addiction, namely the potentiating effect of environmental cues previously paired with drug effects on the development of drug craving in humans (Carter and Tiffany 1999; Niaura et al. 1988). Because several stimuli can become conditioned to the drug for the abusers, the exposure to conditioned reinforcement may lead to relapse into drug-seeking behavior following a period of abstinence thought to play a crucial role in the addictive cycle. Despite these interesting findings by Zimmer and colleagues (2013), one cannot ignore the use of amphetamine by humans. As an alertness-enhancing and euphorigenic drug, amphetamine is frequently used when irregular work/rest patterns cause excessive sleepiness (Akersted and Ficca 1997; Parsons et al. 2006; Robinson and Becker 1986), characterizing it as a sleep deprivation-related drug. In addition, it has been repeatedly demonstrated that sleep deprivation shares similar neurobiological effects with psychostimulants (Demontis et al. 1990; Fadda et al. 1993; Nunes et al. 1994; Tufik 1981a, b). In this scenario, studies from our group have been conducted in order to investigate the relationship between sleep deprivation and addiction. Of note, we demonstrated that the sleep condition affects amphetamine-induced behavioral changes by specifically modulating its conditioned component. Context-dependent behavioral sensitization to amphetamine is potentiated by sleep deprivation procedures, and a sleep rebound period can attenuate it (Calzavara et al. 2008; Frussa-Filho et al. 2004). In the study under consideration, Zimmer et al. (2013) propose a continuous and passive infusion of amphetamine as a potential treatment to reduce the reinforcing effectiveness of cocaine. Nonetheless, this therapeutic approach would suppress the sleep pattern of addicts. Because it has been extensively demonstrated that sleep disorders, which may impair addiction treatment bymodulating the drug–environment conditioning, are concomitant features in patients with addictive disorders (Canellas and de Lecea 2012; Mahfoud et al. 2009), characterizing a vicious cycle, this prolonged substitution pharmacotherapy could be dangerous in the clinic. Indeed, regarding the authors’ findings, the role of the environment needs to be considered not only in the treatment of the contingent cocaine group but also in that of the noncontingent This letter is in memory of Dr. Roberto Frussa-Filho, who dedicated his entire life to Science, because aman is alivewhile his name is still spoken.