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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, p.o.) for cocaine dependence was conducted that incorporated abstinence-contingent voucher incentives. 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 (mean of 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.

Background:

The dopamine precursor levodopa has shown some, albeit relatively weak, promise in treating cocaine dependence. This study sought to identify the most appropriate behavioral therapy platform for levodopa pharmacotherapy by evaluating its effect when administered in combination with behavioral platforms of varying intensities.

Method:

A total of 161 treatment-seeking cocaine dependent subjects received sustained release levodopa/carbidopa (400/100 mg bid, Sinemet) or placebo delivered in combination with Clinical Management (ClinMan); ClinMan+Cognitive Behavioral Therapy (CBT); or ClinMan+CBT+Voucher-Based Reinforcement Therapy (VBRT) in a 12-week randomized, placebo-controlled, double-blind (for medication condition) trial. Medication compliance was monitored with riboflavin (100 mg/capsule) and the Medication Event Monitoring System. Protocol compliance was addressed in weekly, 10-minute nurse-delivered ClinMan sessions. Weekly, 1-hour CBT sessions focused on coping skills training. VBRT (with escalating reinforcer value) provided cash-valued vouchers contingent on cocaine-negative urine toxicology results. Urine benzoylecgonine assays collected thrice-weekly were analyzed by intention-to-treat criteria using generalized linear mixed models.

Results:

Levodopa main effects were found on all outcome measures of cocaine use. Contrasts testing the levodopa-placebo difference within each behavioral platform found reliable effects, favoring levodopa, only in the VBRT platform. Levodopa treatment with vouchers produced higher proportions of cocaine-negative urines and longer periods of consecutive abstinence compared to other treatment combinations.

Conclusion:

This is the first study to find a significant treatment effect for levodopa and, in doing so, to demonstrate that the magnitude of this effect is dependent upon conditions of the behavioral therapy platform. The data support use of levodopa with abstinence-based reinforcement therapy as one efficacious combination in cocaine dependence disorder treatment.

Cocaine is a stimulant that leads to the rapid accumulation of catecholamines and serotonin in the brain due to prevention of their re-uptake into the neuron that released the neurotransmitter. Cocaine dependence is a public health concern and cause of significant morbidity and mortality worldwide. At present, there are no approved medications for the treatment of this devastating illness, and behavioral interventions have proven to be of limited use. However, there have been a number of recent trials testing promising agents including dopamine agonists, GABAergic medications and the cocaine vaccine. Here we discuss the most recent human clinical trials of potential medications for treatment of cocaine dependence, as well as pre-clinical studies for another promising agent, levo tetrahydropalmatine. Examination of these recent findings shows promise for GABAergic medications and the cocaine vaccine, as well as unique medications such as disulfiram, whose mechanism remains to be determined. Future work may also confirm specific subgroups of patients for treatment response based on clinical characteristics, biomarkers and pharmacogenetics. This review highlights the need for further, bigger studies in order to determine optimal clinical usage.

When pharmacologic agents are considered in the treatment of cocaine addiction, the objective of such treatment--sustained abstinence--must be considered. Medication and medical approaches have been disappointing in the treatment of cocaine overdose. The central neurobiologic mechanism(s) involved in cocaine toxicity are poorly understood. Without a cocaine antagonist, pharmacologic approaches have been less than promising in preventing relapse. Various psychoactive medications have been tried in early cocaine abstinence, with some success.

Background

Cocaine users not seeking treatment have increased regional brain mu-opioid receptor (mOR) binding that correlates with cocaine craving and tendency to relapse. In cocaine-abusing outpatients in treatment, the relationship of mOR binding and treatment outcome is unknown.

Methods

We determined whether regional brain mOR binding before treatment correlates with outcome and compared it to standard clinical predictors of outcome. Twenty-five individuals seeking outpatient treatment for cocaine abuse or dependence (DSM-IV) received up to 12 weeks of cognitive-behavioral therapy and cocaine-abstinence reinforcement whereby each cocaine-free urine was reinforced with vouchers redeemable for goods. Regional brain mOR binding was measured before treatment using positron emission tomography (PET) with [11C] carfentanil (a selective mOR agonist). Main outcome measures were: 1) overall percentage of urines positive for cocaine during first month of treatment, 2) longest duration (weeks) of abstinence from cocaine during treatment, all verified by urine toxicology.

Results

Elevated mOR binding in the medial frontal and middle frontal gyri before treatment correlated with greater cocaine use during treatment. Elevated mOR binding in the anterior cingulate, medial frontal, middle frontal, middle temporal, and sub-lobar insular gyri correlated with shorter duration of cocaine abstinence during treatment. Regional mOR binding contributed significant predictive power for treatment outcome beyond that of standard clinical variables such as baseline drug and alcohol use.

Conclusions

Elevated mOR binding in brain regions associated with reward sensitivity is a significant independent predictor of treatment outcome in cocaine-abusing outpatients, suggesting a key role for the brain endogenous opioid system in cocaine addiction.

Methamphetamine dependence is a serious public health problem worldwide for which there are no approved pharmacological treatments. Psychotherapy is still the mainstay of treatment; however, relapse rates are high. The search for effective pharmacological treatment has intensified in the last decade. This review will highlight progress in pharmacological interventions to treat methamphetamine dependence as well as explore new pharmacological targets. Published data from clinical trials for stimulant addiction were searched using PubMed and summarized, as well as highlights from a recent symposium on methamphetamine pharmacotherapy presented at the ISAM 2006 meeting, including interim analysis data from an ongoing D-amphetamine study in Australia. Early pilot data are encouraging for administering D-amphetamine and methylphenidate as treatment for heavy amphetamine users. Abilify at 15 mg/day dose increased amphetamine use in an outpatient pilot study. Sertraline, ondansetron, baclofen, tyrosine, and imipramine were ineffective in proof-of-concept studies. Development of pharmacotherapy for methamphetamine dependence is still in an early stage. Data suggesting D-amphetamine and methylphenidate as effective pharmacotherapy for methamphetamine addiction will need to be confirmed by larger trials. Preclinical data suggest that use of GVG, CB1 antagonist, and lobeline are also promising therapeutic strategies.

Purpose of review

The aim is to compare and contrast psychological treatments for amphetamine and cocaine dependence.

Recent findings

Stimulant dependence, in the form of cocaine or amphetamine/methamphetamine dependence, is prevalent worldwide, and their ratio may vary across different countries and regions of countries. The treatment of stimulant disorders has greatly advanced in recent years, and scientific evaluation of behavioral therapies, using randomized clinical trials designs and a stage-wise approach, have demonstrated the safety and efficacy of interventions. Psychological interventions such as cognitive behavioral therapy and contingency management for cocaine and methamphetamines use disorders are well tolerated and moderately effective in achieving drug abstinence. There is evidence that contingency management interventions can help to improve retention in treatment and, in turn, other treatment outcomes. Although there are important differences in the neuropsychiatric and medical consequences of cocaine and amphetamine use disorders, there is currently no evidence for a differential treatment effect of any psychosocial treatment in the management of these disorders.

Summary

As there are no Food and Drug Administration-approved medications for the treatment of these disorders, psychological interventions form the basis of their treatment. More research is needed to address the specific psychosocial needs of cocaine and amphetamine-dependent individuals in order to improve their treatment outcomes.

We evaluated the efficacy of an interactive, computer-based behavioral therapy intervention, grounded in the community reinforcement approach (CRA) plus voucher-based contingency management model of behavior therapy. Our randomized, controlled trial was conducted at a university-based research clinic. Participants comprised 135 volunteer adult outpatients who met DSM-IV criteria for opioid dependence. All participants received maintenance treatment with buprenorphine and were randomly assigned to one of three treatments: (1) therapist-delivered CRA treatment with vouchers, (2) computer-assisted CRA treatment with vouchers, or (3) standard treatment. The therapist-delivered and computer-assisted CRA plus vouchers interventions produced comparable weeks of continuous opioid and cocaine abstinence (mean = 7.98 and 7.78, respectively) and significantly greater weeks of abstinence than the standard intervention (mean = 4.69; p<.05), yet participants in the computer-assisted CRA condition had over 80% of their intervention delivered by an interactive computer program. The comparable efficacy obtained with computer-assisted and therapist-delivered therapy may enable more widespread dissemination of the evidence-based CRA plus vouchers intervention in a manner that is cost-effective and ensures treatment fidelity.

Addiction is a chronic relapsing brain disease and treatment of relapse to drug-seeking is considered the most challenging part of treating addictive disorders. Relapse can be modeled in laboratory animals using reinstatement paradigms, whereby behavioral responding for a drug is extinguished and then reinstated by different trigger factors, such as environmental cues or stress. In this review, we first describe currently used animal models of relapse, different relapse triggering factors, and the validity of this model to assess relapse in humans. We further summarize the growing body of pharmacological interventions that have shown some promise in treating relapse to psychostimulant addiction. Moreover, we present an overview on the drugs tested in cocaine or methamphetamine addicts and examine the overlap of existing preclinical and clinical data. Finally, based on recent advances in our understanding of the neurobiology of relapse and published preclinical data, we highlight the most promising areas for future anti-relapse medication development.

Background

Telephone-based monitoring is a promising approach to continuing care of substance use disorders, but patients often do not engage or participate enough to benefit. Voucher incentives can increase retention in outpatient treatment and continuing care, but may be less effective when reinforcement is delayed, as in telephone-based care. We compared treatment utilization rates among cocaine-dependent patients enrolled in telephone continuing care with and without voucher incentives to determine whether incentives increase participation in telephone-based care.

Method

Participants were 195 cocaine-dependent patients who completed two weeks of community-based intensive outpatient treatment for substance use disorders and were randomly assigned to receive telephone continuing care with or without voucher incentives for participation as part of a larger clinical trial. The 12-month intervention included 2 in-person orientation sessions followed by up to 30 telephone sessions. Incentivized patients could receive up to $400 worth of gift cards.

Results

Patients who received incentives were not more likely to complete their initial orientation to continuing care. Incentivized patients who completed orientation completed 67% of possible continuing care sessions, as compared to 39% among non-incentivized patients who completed orientation. Among all patients randomized to receive incentives, the average number of completed sessions was 15.5, versus 7.2 for patients who did not receive incentives, and average voucher earnings were $200.

Conclusions

Voucher incentives can have a large effect on telephone continuing care participation, even when reinforcement is delayed. Further research will determine whether increased participation leads to better outcome among patients who received incentives.

New data support use of levodopa pharmacotherapy with behavioral contingency management (CM) as one efficacious combination in cocaine dependence disorder treatment. A potential mechanism of the combined treatment effects may be related to dopamine-induced enhancement of the saliency of contingently delivered reinforcers. Evidence to support this mechanism was sought by evaluating levodopa-enhancing effects across distinct CM conditions that varied in behavioral targets. A total of 136 treatment-seeking, cocaine dependent subjects participated in this 12-week, randomized, placebo-controlled trial of levodopa (vs. placebo) administered in combination with one of three behavioral CM conditions. In the CM-URINE condition, subjects received cash-valued vouchers contingent on cocaine-negative urine toxicology results. In the CM-ATTEND condition, the same voucher schedule was contingent on attending thrice weekly clinic visits. In the CM-MEDICATION condition, the same voucher schedule was contingent on Medication Event Monitoring Systems- and riboflavin-based evidence of pill-taking behavior. Primary outcomes associated with each CM target behavior were analyzed using generalized linear mixed models for repeated outcomes. CM responding in the CM-ATTENDANCE and CM-MEDICATION conditions showed orderly effects, with each condition producing corresponding changes in targeted behaviors, regardless of medication condition. In contrast, CM responding in the CM-URINE condition was moderated by medication, with levodopa-treated subjects more likely to submit cocaine-negative urines. These findings specify the optimal target behavior for CM when used in combination with levodopa pharmacotherapy.

Background

No medication is currently approved for the treatment of cocaine dependence, but several preclinical and clinical reports suggest agonist-like medications, e.g. amphetamine analogues, may be a productive strategy for medication development.

Objective

This current proof-of-concept study sought to evaluate the safety, tolerability, and effectiveness of methamphetamine as a candidate treatment for cocaine dependence.

Methods

A randomized, double-blind, placebo-controlled study served to evaluate three treatment conditions in 82 cocaine-dependent individuals: (1) placebo (0 mg, 6×/day; n = 27), (2) immediate release (IR) methamphetamine (5 mg, 6×/day; n = 30), (3) sustained release (SR) methamphetamine (30 mg first pill, 1×/day; 0 mg 5×/day; n = 25). The study employed a sequential, two-phase design (i.e., 4 weeks of medication and counseling followed by 4 weeks of medication/counseling plus a contingency management procedure).

Results

Both preparation forms of methamphetamine were well tolerated, with similar retention to placebo (0 mg, 33%; 30 mg IR, 30%, 30 mg SR, 32%). Methamphetamine SR was associated with decreased sleep and increased weight loss. Medication adherence rates were high for the first dose of the day (95%), while adherence for subsequent capsules was lower. Those in the SR condition exhibited consistently lower rates of cocaine-positive urine samples (0 mg, 60%; 30 mg IR, 66%, 30 mg SR, 29%), p<0.0001, and reported the greatest reduction in craving for cocaine, p<0.05.

Conclusions

SR methamphetamine significantly reduced cocaine use and craving. Additional research is warranted to develop and evaluate agonist-like medications that may effectively treat cocaine dependence.

Cocaine dependence is an enduring problem and years of research and drug development has yet to produce an efficacious pharmacotherapy. Recent clinical research suggests that chronic treatment with amphetamine-like medications produces tolerance to cocaine’s reinforcing effects and may offer a viable pharmacotherapy. Three methamphetamine-dependent participants that had been in our clinical laboratory experiments and previously addicted to cocaine are reviewed. Data obtained from initial screen and informal conversation suggested that all participants considered methamphetamine to have helped them stop using cocaine and eliminate cocaine craving. Methamphetamine also significantly decreased their alcohol consumption but did not alter cannabis or nicotine use.

Preclinical findings suggest that the inhibition of NMDA glutamatergic neurotransmission may have beneficial effects in the treatment of cocaine dependence. We hypothesized that memantine, a low potency, uncompetitive NMDA receptor antagonist, would be safe and effective in the treatment of cocaine dependence, particularly in preventing relapse to cocaine use in abstinent individuals.

Cocaine dependent patients (N =112) were enrolled. The trial began with a 2-week placebo lead-in period during which patients received high-value voucher contingency management to induce abstinence. Participants were then randomized to receive either memantine 20 mg bid (N=39) or placebo (N=42) for 12-weeks in combination with individual relapse-prevention therapy. The randomization was stratified by abstinence status during the lead-in period. The primary outcome was the weekly proportion of days of cocaine use.

There were no significant differences in cocaine use outcome between the groups treated with memantine versus placebo. Thus, the efficacy of memantine 40 mg/d for the treatment of cocaine dependence was not supported. Urine-confirmed abstinence during the lead-in period was achieved by 44% of participants, and was a strong predictor of subsequent cocaine abstinence during the trial. This suggests that this clinical trial design, an intensive behavioral intervention during a lead-in period, resolves cocaine dependent patients into two subgroups, one that rapidly achieves sustained abstinence and may not need a medication, and another that displays persistent cocaine use and would most likely benefit from a medication to help induce abstinence. Targeting the latter subgroup may advance medication development efforts.

Background

No medications have been proven to be effective for cocaine and methamphetamine addiction. Attenuation of drug reward has been the main strategy for medications development, but this approach has not led to effective treatments. Thus, there is a need to identify novel treatment targets in addition to the brain reward system.

Aim

To propose a novel treatment strategy for stimulant addiction that will focus on medications enhancing cognitive function and attenuating drug reward.

Methods

Preclinical and clinical literature on potential use of cognitive enhancers for stimulant addiction pharmacotherapy was reviewed.

Results and conclusions

Cocaine and methamphetamine users show significant cognitive impairments, especially in attention, working memory and response inhibition functions. The cognitive impairments seem to be predictive of poor treatment retention and outcome. Medications targeting acetylcholine (Ach) and norepinephrine (NE) are particularly well-suited for enhancing cognitive function in stimulant users. Many cholinergic and noradrenergic medications are on the market, have a good safety profile, and low abuse potential. These include galantamine, donepezil, and rivastigmine (cholinesterase inhibitors), varenicline (partial nicotine agonist), guanfacine (alpha2-adrenergic agonist), and atomoxetine (norepinephrine transporter inhibitor). Future clinical studies optimally designed to measure cognitive function as well as drug use behavior would be needed to test the efficacy of these cognitive enhancers for stimulant addiction.

Rationale

Delay discounting (DD) describes the rate at which reinforcers lose value as the temporal delay to their receipt increases. Steeper discounting has been positively associated with vulnerability to substance use disorders, including cocaine use disorders.

Objectives

In the present study, we examined whether DD of hypothetical monetary reinforcers is associated with the duration of cocaine abstinence achieved among cocaine-dependent outpatients.

Methods

Participants were 36 adults who were participating in a randomized controlled trial examining the efficacy of voucher-based contingency management (CM) using low-magnitude (N = 18) or high-magnitude (N = 18) voucher monetary values.

Results

DD was associated with the number of continuous weeks of cocaine abstinence achieved, even after adjusting for treatment condition during the initial 12-week (t(33) = 2.48, p = .045) and entire recommended 24-week of treatment (t(33) = 2.40, p = .022). Participants who exhibited steeper discounting functions achieved shorter periods of abstinence in the Low-magnitude voucher condition (12-week: t(16) = 2.48, p = .025; 24-week: t(16) = 2.68, p = .017), but not in the High-magnitude voucher condition (12-week: t(16) = 0.51, p = .618; 24-week: t(16) = 1.08, p = .298), although the interaction between DD and treatment condition was not significant (12-week: t(32) = −1.12, p = .271; 24-week: t(32) = −0.37, p = .712).

Conclusions

These results provide further evidence on associations between DD and treatment response and extend those observations to a new clinical population (i.e., cocaine-dependent outpatients), while also suggesting that a more intensive intervention like the High-magnitude CM condition may diminish this negative relationship between DD and treatment response.

Immunotherapies in the form of vaccines (active immunization) or monoclonal antibodies (passive immunization) appear safe and a promising treatment approaches for some substance-related disorders. The mechanism of action of the antibody therapy is by preventing the rapid entry of drugs of abuse into the central nervous system. In theory, immunotherapies could have several clinical applications. Monoclonal antibodies may be useful to treat drug overdoses and prevent the neurotoxic effects of drugs by blocking the access of drugs to the brain. Vaccines may help to prevent the development of addiction, initiate drug abstinence in those already addicted to drugs, or prevent drug use relapse by reducing the pharmacological effects and rewarding properties of the drugs of abuse on the brain. Passive immunization with monoclonal antibodies has been investigated for cocaine, methamphetamine, nicotine, and phencyclidine (PCP). Active immunization with vaccines has been studied for cocaine, heroin, methamphetamine, and nicotine. These immunotherapies seem promising therapeutic tools and are at different stages in their development before they can be approved by regulatory agencies for the treatment of substance-related disorders. The purpose of this article is to review the current immunotherapy approaches with emphasis on the risks and benefits for the treatment of these disorders.

Objective

To evaluate the cost-effectiveness of using prize-based and voucher-based contingency management (CM) as additions to standard treatment for cocaine- or heroin-dependent outpatients in community treatment centers.

Methods

This cost-effectiveness analysis is based on a randomized clinical trial conducted at three community-based outpatient psychosocial substance abuse treatment clinics. A total of 142 cocaine- or heroin-dependent outpatients were randomly assigned to one of three treatment conditions: standard treatment (ST), ST with prizes (prize CM), or ST with vouchers (voucher CM) for 12 weeks. The primary patient outcome was the longest duration of confirmed abstinence (LDA) from cocaine, opioids and alcohol during treatment. Unit costs were collected from the three participating clinics. Resource utilizations and patient outcomes were obtained from the clinical trial. Incremental cost-effectiveness ratios (ICERs) and acceptability curves were used to evaluate the relative cost-effectiveness of the interventions.

Results

Based on the ICERs and acceptability curves, ST is likely to be the most cost-effective intervention when the threshold value to decision makers of lengthening the LDA during treatment by 1 week is less than approximately $166, and prize CM is likely to be the most cost-effective intervention when the threshold value is greater than approximately $166.

Conclusions

Prize CM was found likely to be the most cost-effective intervention over a comparatively wide range of threshold values for lengthening the LDA during treatment by 1 week. However, additional studies with alternative incentive parameters are required to determine the generalizability of our results.

Acamprosate, a medication that has been used in Europe for years, is the newest drug to be approved by the US Federal Drug Administration for the treatment of alcohol dependence. It has been shown to assist in the maintenance of abstinence in recently detoxified alcohol-dependent individuals. The following review delineates the proposed mechanism of action and pharmacokinetics of the drug. Findings of clinical trials are outlined and topics such as cost effectiveness, comparison with other medications used for the treatment of alcohol dependences as well as combination pharmacotherapy are discussed. In combination with psychosocial treatment, acamprosate is a promising tool for the maintenance of abstinence in alcohol-dependent patients after alcohol withdrawal. This review also illustrates the continued need to search for more effective treatments, as the overall effectiveness of our currently available pharmacotherapies remains limited in the long-term maintenance of recovery from alcohol dependence.

Two males diagnosed with cocaine dependence received a behavioral intervention comprised of contingency management and the community reinforcement approach. During the initial phase of treatment, reinforcement was delivered contingent on submitting cocaine-free urine specimens. The community reinforcement approach involved two behavior therapy sessions each week. Almost complete cocaine abstinence was achieved, but regular marijuana use continued. During a second phase, reinforcement magnitude was reduced, but remained contingent on submitting cocaine-free specimens. Behavior therapy was reduced to once per week. Cocaine abstinence and regular marijuana use continued. Next, reinforcement was delivered contingent on submitting cocaine- and marijuana-free specimens. This modified contingency resulted in an abrupt increase in marijuana abstinence and maintenance of cocaine abstinence. One- and 5-month follow-ups indicated that cocaine abstinence continued, but marijuana smoking resumed. These results indicate that the behavioral intervention was efficacious in achieving abstinence from cocaine and marijuana; maintenance, however, was achieved for cocaine only.

A variety of neuropharmacological strategies are being pursued in the search for an effective treatment for methamphetamine addiction. In this study, we investigated the safety and potential efficacy of aripiprazole, an antipsychotic agent acting on both dopamine and serotonin systems. We conducted a double-blind inpatient clinical pharmacology study to assess potential interactions between intravenous (IV) methamphetamine (15mg and 30mg) and oral aripiprazole (15mg). In addition, the effects of aripiprazole treatment on abstinence related craving and cue-induced craving were evaluated. Participants included non-treatment seeking, methamphetamine dependent patients (N=16), 18-45 years of age, currently using methamphetamine. Following baseline methamphetamine dosing (15mg and 30mg), participants received 2 weeks of treatment with aripiprazole (n=8) or placebo (n=8). Participants then completed cue exposure sessions using neutral and methamphetamine-related cues. Methamphetamine dosing (15mg and 30mg) was then repeated. Aripiprazole treatment had no effect on cue-induced methamphetamine craving, or on daily baseline craving assessed over the course of medication treatment, though aripiprazole treatment was associated with increased craving independent of methamphetamine dosing. Aripiprazole treatment was associated with significantly higher ratings on ARCI subscales reflecting euphoria and amphetamine-like effects following methamphetamine dosing. Aripiprazole was treatment was also associated with significant reductions in ratings of “bad effects” and reductions on the ARCI subscale for sedation effects following methamphetamine dosing. Aripiprazole treatment reduced the increase in systolic blood pressure following methamphetamine dosing, but had no other effects on cardiovascular responses to methamphetamine. Aripiprazole treatment did not alter the pharmacokinetics of methamphetamine. These findings indicate that aripiprazole treatment appears to be safe in volunteers with methamphetamine dependence, though the finding that aripiprazole increased some of the rewarding and stimulatory effects produced by acute methamphetamine suggests that 15mg aripiprazole is unlikely to be efficacious for the treatment of methamphetamine dependence. Further research with lower doses of aripiprazole, possibly using study designs aimed at evaluating efficacy for relapse prevention, are needed before ruling out aripiprazole as a treatment for methamphetamine dependence.

Cocaine dependence continues to be a significant public health concern. Contingency management, wherein alternative reinforcers are made available upon cocaine abstinence, has shown promise for decreasing cocaine use. Other research has modeled this effect and demonstrated that alternative reinforcers also reduce cocaine self-administration in the laboratory. Results from both clinical and laboratory studies suggest that the type and value of alternative reinforcers influences their ability to decrease drug choice. The purpose of the present experiment was to determine the effect of money or food alternative reinforcers, valued at $0.01, 0.25, 0.50 and 1.00, on intranasal cocaine (4 [placebo] and 30 mg) choice. Cocaine was chosen to a greater extent than placebo across alternative reinforcer types and values, but the monetary alternative reinforcer suppressed drug choice to a greater degree than the food reinforcer. These results are concordant with previous findings and suggest that money may be a more effective alternative reinforcer for decreasing cocaine use. Future research should determine the sensitivity of this model to specific behavioral aspects of contingency management and whether food could compete with drugs as reinforcers in humans under laboratory conditions.

This 6-month randomized clinical trial (with three month follow-up) used a 2 × 2 design to compare the independent and combined effectiveness of two interventions designed to improve outcomes in treatment-seeking opioid dependent patients (n = 236): Motivated Stepped Care (MSC) and Contingent Voucher Incentives (CVI). MSC is an adaptive treatment strategy that uses principles of negative reinforcement and avoidance to motivate both attendance to varying levels of counseling services and brief periods of abstinence (Brooner and Kidorf, 2002, Brooner et al., 2004). In contrast, CVI (Higgins et al., 1991) relies on positive reinforcement to motivate drug abstinence. The results showed that the combined approach (MSC+CVI) was associated with the highest proportion of drug-negative urine samples during both the randomized and three-month follow-up arms of the evaluation. The CVI-only and the MSC-only conditions evidenced similar proportions of drug-negative urine samples that were both significantly greater than the standard care (SC) comparison group. Voucher-based reinforcement was associated with better retention, while adaptive stepped-based care was associated with better adherence to scheduled counseling sessions. These results suggest that both CVI and MSC are more effective than routine care for reducing drug use in opioid dependent outpatients, and that the overall benefits of MSC are enhanced further by adding positive reinforcement.

This study assessed a 26-week voucher-based intervention to reinforce abstinence and participation in treatment-related activities among substance-abusing offenders court referred to outpatient treatment under drug diversion legislation (California's Substance Abuse and Crime Prevention Act). Standard treatment consisted of criminal justice supervision and an evidence-based model for treating stimulant abuse. Participants were randomly assigned to four groups, standard treatment (ST) only, ST plus vouchers for testing negative, ST plus vouchers for performing treatment plan activities, and ST plus vouchers for testing negative and/or performing treatment plan activities. Results indicate that voucher-based reinforcement of negative urines and of treatment plan tasks (using a flat reinforcement schedule) showed no statistically significant effects on measures of retention or drug use relative to the standard treatment protocol. It is likely that criminal justice contingencies had a stronger impact on participants' treatment retention and drug use than the relatively low-value vouchers awarded as part of the treatment protocol.

“Agonist therapy” for cocaine and methamphetamine addiction involves administration of stimulant-like medications (e.g., monoamine releasers) to reduce withdrawal symptoms and prevent relapse. A significant problem with this strategy is that many candidate medications possess abuse liability because of activation of mesolimbic dopamine (DA) neurons in the brain. One way to reduce DA-mediated abuse liability of candidate drugs is to add in serotonin (5-HT) releasing properties, since substantial evidence shows that 5-HT neurons provide an inhibitory influence over mesolimbic DA neurons. This article addresses several key issues related to the development of dual DA/5-HT releasers for the treatment of substance use disorders. First, the authors briefly summarize the evidence supporting a dual deficit in DA and 5-HT function during withdrawal from chronic cocaine or alcohol abuse. Second, the authors discuss data demonstrating that 5HT release can dampen DA-mediated stimulant effects, and the “antistimulant” role of 5-HT2C receptors is considered. Next, the mechanisms underlying potential adverse effects of 5-HT releasers are described. Finally, the authors discuss recently published data with PAL-287, a novel nonamphetamine DA/5-HT releasing agent that suppresses cocaine self-administration but lacks positive reinforcing properties. It is concluded that DA/5-HT releasers could be useful therapeutic adjuncts for the treatment of cocaine and alcohol addictions, as well as for obesity, attention-deficit disorder, and depression.