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1.  A Pilot Study of Community-Friendly Manual Guided Drug Counseling 
To facilitate effectiveness testing and dissemination of treatments to community based setting, therapist training manuals that are more “community friendly” are needed. The aim of the current project was to create revised versions of individual drug counseling (IDC) and group drug counseling (GDC) treatment manuals for cocaine dependence and to conduct a preliminary study of their effectiveness. After changing the format and context of existing drug counseling manuals to have greater ease of use in the community, draft manuals were given to 23 community-based counselors for their feedback. Final versions were then used in a pilot randomized clinical trial involving 41 cocaine dependent patients who received 3 months of either IDC + GDC or GDC alone treatment. Counselors implemented the new treatment manuals with acceptable levels of adherence and competence. Outcome results indicated that substantial change in drug use was evident, but the amount of abstinence obtained was limited.
doi:10.1016/j.jsat.2008.09.004
PMCID: PMC2744318  PMID: 19038525
Cocaine dependence; drug counseling; randomized trial
2.  A double-blind, placebo-controlled trial of topiramate for the treatment of comorbid cocaine and alcohol dependence 
Drug and alcohol dependence  2013;133(1):94-99.
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.
doi:10.1016/j.drugalcdep.2013.05.026
PMCID: PMC3786029  PMID: 23810644
topiramate; cocaine; alcohol; clinical trial; placebo
3.  Achieving smoking abstinence is associated with decreased cocaine use in cocaine-dependent patients receiving smoking-cessation treatment 
Drug and alcohol dependence  2013;134:391-395.
Background
Past research suggests that a significant relationship exists between cigarette smoking and illicit-stimulant abuse. The present study evaluated the association between achieving smoking abstinence in response to smoking-cessation treatment (SCT) and illicit-stimulant abstinence in cocaine- and/or methamphetamine-dependent participants.
Methods
Secondary analysis of a randomized, 10-week trial conducted at 12 substance use disorder (SUD) treatment programs. Two hundred and sixty seven adults, meeting DSM-IV-TR criteria for cocaine and/or methamphetamine-dependence and interested in quitting smoking were randomized to SUD treatment as usual plus SCT consisting of weekly individual smoking cessation counseling, extended-release (XL) bupropion (300 mg/day), nicotine inhaler, and contingency management for smoking abstinence. Illicit-stimulant-abstinence was measured by self-report and urine drug screens. Smoking abstinence was assessed via self-report and carbon monoxide levels.
Results
A significant effect was found for the cocaine-dependent subsample (N=147) in which participants who stopped smoking were abstinent for illicit stimulants an average of 78.2% of the post-smoking-quit weeks (weeks 4-10) relative to 63.6% in participants who continued smoking (X2(1)=8.55, p<.01, d=0.36). No significant effects were found for the sample as a whole (N=249) or for the methamphetamine-dependent subsample (N=102).
Conclusions
The present results suggest that cocaine-dependent patients achieving smoking abstinence in response to SCT might evidence not only improved smoking outcomes but improved cocaine-use outcomes as well. Future research to replicate this finding appears warranted.
doi:10.1016/j.drugalcdep.2013.09.019
PMCID: PMC3889710  PMID: 24128381
cocaine; smoking cessation; methamphetamine
4.  Randomized Trial of Continuing Care Enhancements for Cocaine Dependent Patients Following Initial Engagement 
Objective
The effects of cognitive-behavioral relapse prevention (RP), contingency management (CM), and their combination (CM+RP) were evaluated in a randomized trial with 100 cocaine dependent patients (58% female, 89% African American) who were engaged in treatment for at least two weeks and had an average of 44 days of abstinence at baseline.
Method
The participants were from intensive outpatient programs (IOPs), which provide 10 hours per week of group counseling. The CM protocol provided gift certificates (maximum value of $1,150; mean received= $740) for cocaine-free urines over 12 weeks using an escalating reinforcement schedule, and weekly individual RP sessions were offered for up to 20 weeks. Average number of RP sessions attended was 3 in RP and 13 in CM+RP.
Results
GEE analyses over 18 months post-randomization showed significant effects for CM (but not RP) on urine toxicology and self-reported cocaine use (p=.05), with no significant CM × RP interactions. Secondary analyses indicated CM+RP produced better cocaine urine toxicology outcomes at 6 months than TAU [OR=3.96 (1.33,11.80), p< .01] and RP [OR=4.89 (1.51,15.86), p< .01), and better cocaine urine toxicology outcomes at 9 months than TAU [OR=4.21 (1.37,12.88), p< .01] and RP [OR=4.24 (1.32,13.65), p< .01). Trends also favored CM+RP over CM at 6 [OR=2.93 (0.94,9.07), p= .06] and 9 [OR=2.93 (0.94,9.10), p= .06) months. Differences between the conditions were not significant after 9 months.
Conclusions
These results suggest CM can improve outcomes in cocaine dependent IOP patients who have achieved initial engagement, particularly when combined with relapse prevention.
doi:10.1037/a0018139
PMCID: PMC3076098  PMID: 20099956
cocaine dependence; treatment; contingency management; relapse prevention
5.  An Adaptive Approach for Identifying Cocaine Dependent Patients Who Benefit from Extended Continuing Care 
Objective
Study tested whether cocaine dependent patients using cocaine or alcohol at intake or in the first few weeks of intensive outpatient treatment would benefit more from extended continuing care than patients abstinent during this period. The effect of incentives for continuing care attendance was also examined.
Methods
Participants (N=321) were randomized to: treatment as usual (TAU), TAU and Telephone Monitoring and Counseling (TMC), or TAU and TMC plus incentives (TMC+). The primary outcomes were: (1) abstinence from all drugs and heavy alcohol use, and (2) cocaine urine toxicology. Follow-ups were at 3, 6, 9, 12, 18, and 24 months.
Results
Cocaine and alcohol use at intake or early in treatment predicted worse outcomes on both measures (ps≤ .0002). Significant effects favoring TMC over TAU on the abstinence composite were obtained in participants who used cocaine (OR=1.95 [1.02, 3.73]) or alcohol (OR=2.47 [1.28, 4.78]) at intake or early in treatment. A significant effect favoring TMC+ over TAU on cocaine urine toxicology was obtained in those using cocaine during that period (OR= 0.55 [0.31, 0.95]). Conversely, there were no treatment effects in participants abstinent at baseline, and no overall treatment main effects. Incentives almost doubled the number of continuing care sessions received, but did not further improve outcomes.
Conclusion
An adaptive approach for cocaine dependence in which extended continuing care is provided only to patients who are using cocaine or alcohol at intake or early in treatment improves outcomes in this group while reducing burden and costs in lower risk patients.
doi:10.1037/a0034265
PMCID: PMC3938091  PMID: 24041231
cocaine dependence; continuing care; adaptive treatment; incentives; moderators
6.  Predictors of Treatment Outcome in Outpatient Cocaine and Alcohol Dependence Treatment 
We examined the ability of several baseline variables to predict treatment outcome in a pharmacotherapy trial that included 164 participants who were both cocaine- and alcohol-dependent and were selected for a randomized, double-blind, placebo-controlled study. Predictor variables included results from the baseline Addiction Severity Index (ASI), initial Urine Drug Screen results, cocaine and alcohol craving and cocaine and alcohol withdrawal symptoms at the start of treatment. Successful treatment was defined as four continuous weeks of self-reported cocaine abstinence verified by urine drug screens. In respect to demographic characteristics, there were no significant differences between patients who achieved four weeks of abstinence from cocaine and those who did not. Baseline variables that most consistently predicted cocaine abstinence included initial urine drug screen (UDS) results, the initial Cocaine Selective Severity Assessment (CSSA) scores, and initial self-reported cocaine use in past 30 days, whereas cocaine craving, cocaine composite scores, alcohol craving, alcohol withdrawal symptoms, and alcohol composite scores did not. The results of this study suggest that cocaine dependence severity in general, and initial UDS results, the CSSA scores and frequency of recent cocaine use in particular, have a significant impact on treatment outcome in the treatment of cocaine-dependent patients with comorbid alcoholism. Initial UDS results and CSSA scores are very useful predictors of treatment outcome and could be used as stratifying variables in outpatient cocaine and alcohol medication trials.
doi:10.1080/10550490802545174
PMCID: PMC3777818  PMID: 19219669
7.  Process Predictors of the Outcome of Group Drug Counseling 
Objective
This study examined the relation of process variables to the outcome of group drug counseling, a commonly used community treatment, for cocaine dependence.
Method
Videotaped group drug counseling sessions from 440 adult patients (23% female, 41% minority) were rated for member alliance, group cohesion, participation, self-disclosure, positive and non-positive feedback and advice, during the 6-month treatment of cocaine dependence. Average, session-level, and slopes of process scores were evaluated. Primary outcomes were monthly cocaine use (days using out of 30), next session cocaine use, and duration of sustained abstinence from cocaine. Secondary outcomes were endorsement of 12-step philosophy and beliefs about substance abuse.
Results
More positive alliances (with counselor) were associated with reductions in days using cocaine per month and next-session cocaine use, and increases in endorsement of 12-step philosophy. Patient self-disclosure about the past and degree of participation in the group were generally not predictive of group drug counseling outcomes. More advice from counselor and other group members were consistently associated with poorer outcomes in all categories. Individual differences in changes in process variables over time (linear slopes) were generally not predictive of treatment outcomes.
Conclusions
Some group behaviors widely believed to be associated with outcome, such as self-disclosure and participation, were not generally predictive of outcomes of group drug counseling, but alliance with the group counselor was positively associated, and advice giving negatively associated, with the outcome of treatments for cocaine dependence.
doi:10.1037/a0030101
PMCID: PMC3565014  PMID: 23106760
group drug counseling; cocaine dependence; predictors; process ratings
8.  The Role of Therapist Characteristics in Training Effects in Cognitive, Supportive-Expressive, and Drug Counseling Therapies for Cocaine Dependence 
The role of therapist characteristics in therapy training was examined for 62 therapists in a multisite psychotherapy outcome study that included cognitive therapy (CT), supportive-expressive (SE) psychodynamic therapy, and individual drug counseling (IDC) for cocaine-dependent patients. Demographic variables and experience and competence ratings prior to training were correlated with measures of change in competence during the training phase. Higher competence ratings before training were associated with greater change in competence for SE and higher average competence for IDC. More years of experience were associated with greater change in competence for CT therapists, but more hours of pre-training supervision in the CT treatment modality were associated with less change.
PMCID: PMC3330597  PMID: 10896736
Psychotherapy Training and Supervision; Therapist Characteristics; Cocaine
9.  Comparative Efficacy of Seven Psychotherapeutic Interventions for Patients with Depression: A Network Meta-Analysis 
PLoS Medicine  2013;10(5):e1001454.
Jürgen Barth and colleagues use network meta-analysis - a novel methodological approach - to reexamine the comparative efficacy of seven psychotherapeutic interventions for adults with depression.
Please see later in the article for the Editors' Summary
Background
Previous meta-analyses comparing the efficacy of psychotherapeutic interventions for depression were clouded by a limited number of within-study treatment comparisons. This study used network meta-analysis, a novel methodological approach that integrates direct and indirect evidence from randomised controlled studies, to re-examine the comparative efficacy of seven psychotherapeutic interventions for adult depression.
Methods and Findings
We conducted systematic literature searches in PubMed, PsycINFO, and Embase up to November 2012, and identified additional studies through earlier meta-analyses and the references of included studies. We identified 198 studies, including 15,118 adult patients with depression, and coded moderator variables. Each of the seven psychotherapeutic interventions was superior to a waitlist control condition with moderate to large effects (range d = −0.62 to d = −0.92). Relative effects of different psychotherapeutic interventions on depressive symptoms were absent to small (range d = 0.01 to d = −0.30). Interpersonal therapy was significantly more effective than supportive therapy (d = −0.30, 95% credibility interval [CrI] [−0.54 to −0.05]). Moderator analysis showed that patient characteristics had no influence on treatment effects, but identified aspects of study quality and sample size as effect modifiers. Smaller effects were found in studies of at least moderate (Δd = 0.29 [−0.01 to 0.58]; p = 0.063) and large size (Δd = 0.33 [0.08 to 0.61]; p = 0.012) and those that had adequate outcome assessment (Δd = 0.38 [−0.06 to 0.87]; p = 0.100). Stepwise restriction of analyses by sample size showed robust effects for cognitive-behavioural therapy, interpersonal therapy, and problem-solving therapy (all d>0.46) compared to waitlist. Empirical evidence from large studies was unavailable or limited for other psychotherapeutic interventions.
Conclusions
Overall our results are consistent with the notion that different psychotherapeutic interventions for depression have comparable benefits. However, the robustness of the evidence varies considerably between different psychotherapeutic treatments.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Depression is a very common condition. One in six people will experience depression at some time during their life. People who are depressed have recurrent feelings of sadness and hopelessness and might feel that life is no longer worth living. The condition can last for months and often includes physical symptoms such as headaches, sleeping problems, and weight gain or loss. Treatment of depression can include non-drug treatments (psychotherapy), antidepressant drugs, or a combination of the two. Especially for people with mild or intermediate depression, psychotherapy is often considered the preferred first option. Psychotherapy describes a range of different psychotherapies, and a number of established types of psychotherapies have all shown to work for at least some patients.
Why Was This Study Done?
While it is broadly accepted that psychotherapy can help people with depression, the question of which type of psychotherapy works best for most patients remains controversial. While many scientific studies have compared one psychotherapy with control conditions, there have been few studies that directly compared multiple treatments. Without such direct comparisons, it has been difficult to establish the respective merits of the different types of psychotherapy. Taking advantage of a recently developed method called “network meta-analysis,” the authors re-examine the evidence on seven different types of psychotherapy to see how well they have been shown to work and whether some work better than others.
What Did the Researchers Do and Find?
The researchers looked at seven different types of psychotherapy, which they defined as follows. “Interpersonal psychotherapy” is short and highly structured, using a manual to focus on interpersonal issues in depression. “Behavioral activation” raises the awareness of pleasant activities and seeks to increase positive interactions between the patient and his or her environment. “Cognitive behavioral therapy” focuses on a patient's current negative beliefs, evaluates how they affect current and future behavior, and attempts to restructure the beliefs and change the outlook. “Problem solving therapy” aims to define a patient's problems, propose multiple solutions for each problem, and then select, implement, and evaluate the best solution. “Psychodynamic therapy” focuses on past unresolved conflicts and relationships and the impact they have on a patient's current situation. In “social skills therapy,” patients are taught skills that help to build and maintain healthy relationships based on honesty and respect. “Supportive counseling” is a more general therapy that aims to get patients to talk about their experiences and emotions and to offer empathy without suggesting solutions or teaching new skills.
The researchers started with a systematic search of the medical literature for relevant studies. The search identified 198 articles that reported on such clinical trials. The trials included a total of 15,118 patients and compared one of the seven psychotherapies either with another one or with a common “control intervention”. In most cases, the control (no psychotherapy) was deferral of treatment by “wait-listing” patients or continuing “usual care.” With network meta-analysis they were able to summarize the results of all these trials in a meaningful way. They did this by integrating direct comparisons of several psychotherapies within the same trial (where those were available) with indirect comparisons across all trials (using no psychotherapy as a control intervention).
Based on the combined trial results, all seven psychotherapies tested were better than wait-listing or usual care, and the differences were moderate to large, meaning that the average person in the group that received therapy was better off than about half of the patients in the control group. When comparing the therapies with each other, the researchers saw small or no differences, meaning that none of them really stood out as much better or much worse than the others. They also found that the treatments worked equally well for different patient groups with depression (younger or older patients, or mothers who had depression after having given birth). Similarly, they saw no big differences when comparing individual with group therapy, or person-to-person with internet-based interactions between therapist and patient.
However, they did find that smaller and less rigorous studies generally found larger benefits of psychotherapies, and most of the studies included in the analysis were small. Only 36 of the studies had at least 50 patients who received the same treatment. When they restricted their analysis to those studies, the researchers still saw clear benefits of cognitive-behavioral therapy, interpersonal therapy, and problem-solving therapy, but not for the other four therapies.
What Do these Findings Mean?
Similar to earlier attempts to summarize and make sense of the many study results, this one finds benefits for all of the seven psychotherapies examined, and none of them stood as being much better than some or all others. The scientific support for being beneficial was stronger for some therapies, mostly because they had been tested more often and in larger studies.
Treatments with proven benefits still do not necessarily work for all patients, and which type of psychotherapy might work best for a particular patient likely depends on that individual. So overall this analysis suggests that patients with depression and their doctors should consider psychotherapies and explore which of the different types might be best suited for a particular patient.
The study also points to the need for further research. Whereas depression affects large numbers of people around the world, all of the trials identified were conducted in rich countries and Western societies. Trials in different settings are essential to inform treatment of patients worldwide. In addition, large high-quality studies should further explore the potential benefits of some of therapies for which less support currently exists. Where possible, future studies should compare psychotherapies with one another, because all of them have benefits, and it would not be ethical to withhold such beneficial treatment from patients.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001454.
The US National Institute of Mental Health provides information on all aspects of depression (in English and Spanish); information on psychotherapy includes information on its most common forms
The UK National Health Service Choices website also provides detailed information about depression and includes personal stories about depression
The UK nonprofit Mind provides information on depression, including an explanation of the most common psychotherapies in the UK
MedlinePlus provides links to other resources about depression (in English and Spanish)
The UK nonprofit healthtalkonline.org has a unique database of personal and patient experiences on depression
doi:10.1371/journal.pmed.1001454
PMCID: PMC3665892  PMID: 23723742
10.  Measuring adherence and competence of dynamic therapists in the treatment of cocaine dependence 
This article presents the development of a new 82-item rating scale of therapist adherence and competence for supportive-expressive (SE) dynamic psychotherapy for the treatment of cocaine dependence. Sixty- four items are rated for adherence, appropriateness, and quality of prescribed interventions. As part of the pilot/training phase of the National Institute on Drug Abuse Collaborative Cocaine Treatment Study, two independent expert judges rated 32 audiotapes of SE therapy sessions with cocaine-dependent patients, 10 tapes of cognitive therapy (CT) sessions, and 10 tapes of individual drug counseling (IDC) sessions. Reliability was acceptable for adherence but poor for quality and appropriateness. SE therapists used more expressive (interpretative) techniques than did either CT therapists or IDC counselors, and they used more supportive techniques than did IDC counselors.
PMCID: PMC3330446  PMID: 9058557
11.  Abstinence-Contingent Recovery Housing and Reinforcement Based Treatment Following Opioid Detoxification 
Addiction (Abingdon, England)  2012;107(5):973-982.
Aims
To conduct a randomized, controlled trial of abstinence-contingent recovery housing delivered with or without intensive day treatment among individuals exiting residential opioid detoxification.
Design
Random assignment to one of three conditions: Recovery housing alone (RH), abstinence-contingent recovery housing with RBT (RH+RBT), or usual care (UC). RH and RH+RBT participants received 12 weeks of paid recovery housing contingent upon drug abstinence. RH+RBT participants also received 26 weeks of RBT, initiated concurrently with recovery housing. Assessments were conducted at 1, 3, and 6 months after treatment enrollment.
Setting
Outpatient drug-free substance abuse treatment program in Baltimore, Maryland.
Participants
Patients (N = 243) who completed medication-assisted opioid detoxification.
Measurements
Primary outcome was drug abstinence (opioid- and cocaine-negative urine and no self-reported opioid or cocaine use in the previous 30 days). Secondary outcomes included abstinence at all time points (1, 3, and 6 months), days in recovery housing, and employment.
Findings
Overall rates of drug abstinence were 50% for RH+RBT, 37% for RH, and 13% for UC (p < .001). At 6 months, RH+RBT participants remained more likely to meet abstinence criteria than UC participants (37% vs. 20%, p = .016). Length of stay in recovery housing mediated abstinence outcomes and was longer in RH+RBT (49.5 days) than in RH (32.2 days; p < .002).
Conclusions
Abstinence-contingent recovery housing improves abstinence in opioid-dependent adults following medication-assisted detoxification. The addition of intensive ‘reinforcement-based treatment’ behavioural counseling further improves treatment outcomes in part by promoting longer recovery house stays.
doi:10.1111/j.1360-0443.2011.03750.x
PMCID: PMC3421907  PMID: 22151478
12.  A Mechanism for the Inhibition of Neural Progenitor Cell Proliferation by Cocaine 
PLoS Medicine  2008;5(6):e117.
Background
Prenatal exposure of the developing brain to cocaine causes morphological and behavioral abnormalities. Recent studies indicate that cocaine-induced proliferation inhibition and/or apoptosis in neural progenitor cells may play a pivotal role in causing these abnormalities. To understand the molecular mechanism through which cocaine inhibits cell proliferation in neural progenitors, we sought to identify the molecules that are responsible for mediating the effect of cocaine on cell cycle regulation.
Methods and Findings
Microarray analysis followed by quantitative real-time reverse transcription PCR was used to screen cocaine-responsive and cell cycle-related genes in a neural progenitor cell line where cocaine exposure caused a robust anti-proliferative effect by interfering with the G1-to-S transition. Cyclin A2, among genes related to the G1-to-S cell cycle transition, was most strongly down-regulated by cocaine. Down-regulation of cyclin A was also found in cocaine-treated human primary neural and A2B5+ progenitor cells, as well as in rat fetal brains exposed to cocaine in utero. Reversing cyclin A down-regulation by gene transfer counteracted the proliferation inhibition caused by cocaine. Further, we found that cocaine-induced accumulation of reactive oxygen species, which involves N-oxidation of cocaine via cytochrome P450, promotes cyclin A down-regulation by causing an endoplasmic reticulum (ER) stress response, as indicated by increased phosphorylation of eIF2α and expression of ATF4. In the developing rat brain, the P450 inhibitor cimetidine counteracted cocaine-induced inhibition of neural progenitor cell proliferation as well as down-regulation of cyclin A.
Conclusions
Our results demonstrate that down-regulation of cyclin A underlies cocaine-induced proliferation inhibition in neural progenitors. The down-regulation of cyclin A is initiated by N-oxidative metabolism of cocaine and consequent ER stress. Inhibition of cocaine N-oxidative metabolism by P450 inhibitors may provide a preventive strategy for counteracting the adverse effects of cocaine on fetal brain development.
Investigating the mechanism of cocaine's effect on fetal brain development, Chun-Ting Lee and colleagues find that down-regulation of cyclin A by a cocaine metabolite inhibits neural proliferation.
Editors' Summary
Background.
Every year, cocaine abuse by mothers during pregnancy exposes thousands of unborn infants (fetuses) to this powerful and addictive stimulant. Maternal cocaine abuse during early pregnancy increases the risk of miscarriage; its use during late pregnancy slows the baby's growth and can trigger premature labor. Babies exposed to cocaine shortly before birth are often irritable and have disturbed sleep patterns. They can also be very sensitive to sound and touch and consequently hard to comfort. These problems usually resolve spontaneously within the first few weeks of life but some permanent birth defects are also associated with frequent cocaine abuse during pregnancy. In particular, babies exposed to cocaine before birth sometimes have small heads—an abnormality that generally indicates a small brain—and, although they usually have normal intelligence, the development of their thinking skills and language is often delayed, and they can have behavioral problems.
Why Was This Study Done?
Exposure to cocaine before birth clearly interferes with some aspects of brain development. More specifically, it reduces the number and position of neurons (the cells that transmit information in the form of electrical impulses around the body) within the brain. All neurons develop from neural progenitor cells, and previous research suggests that cocaine exposure before birth inhibits the proliferation of these cells in the developing brain. It would be useful to understand exactly how cocaine affects neural progenitor cells, because it might then be possible to prevent the drug's adverse effects on brain development. In this study, therefore, the researchers investigate the molecular mechanism that underlies cocaine's effect on neural progenitor cells.
What Did the Researchers Do and Find?
When the researchers investigated the effects of cocaine on AF5 cells (rat neural progenitor cells that grow indefinitely in the laboratory), they found that concentrations of cocaine similar to those measured in fetal brains after maternal drug exposure inhibited the proliferation of AF5 cells by blocking the “G1-to-S transition.” This is a stage that cells have to pass through between each round of cell division (the production of two daughter cells from one parent cell). Next, the researchers showed that cocaine-treated AF5 cells made much less cyclin A2, a protein that controls the G1-to-S transition, than untreated cells. Cocaine also decreased cyclin A2 levels in neural progenitor cells freshly isolated from human fetal brains and in fetal rat brains exposed to the drug while in their mother's womb. Treatment of AF5 cells with a cyclin A2 expression vector (a piece of DNA that directs the production of cyclin A2) counteracted the down-regulation of cyclin A2 and restored AF5 proliferation in the presence of cocaine. Other experiments indicate that the reduction of cyclin A2 by cocaine in AF5 cells involves the accumulation of “reactive oxygen species,” by-products of the breakdown of cocaine by a protein that is a member of a family of proteins called cytochrome P450. Finally, treatment of pregnant rats with cimetidine (which inhibits the action of cytochrome P450) counteracted both the inhibition of neural progenitor cell proliferation and the cyclin A2 down-regulation that cocaine exposure induced in the brains of their unborn pups.
What Do These Findings Mean?
These findings show that the cocaine-induced inhibition of neural progenitor cell proliferation involves, at least in part, interfering with the production (that is, causing down-regulation) of cyclin A2. They also show that this down-regulation is induced by the breakdown of cocaine by cytochrome P450, and that in both a rat cell line and in fetal rats, the cytochrome P450 inhibitor cimetidine (a drug that is already used clinically for stomach problems) can block the adverse effects of cocaine on the proliferation of neural progenitor cells. These findings need to be confirmed in animals more closely related to people than rats, and the long-term effects of cimetidine need to be investigated, in particular its effects on cocaine toxicity. Nevertheless these results raise the possibility that giving cimetidine or other drugs with similar effects to pregnant women who are addicted to cocaine might prevent some of the harm that their drug habit does to their unborn children, although it is not clear whether there is a dosage of cimetidine that might be both safe and adequate for this purpose.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050117.
A PLoS Medicine Perspective article by Steven Hyman further discusses this study
The US National Institute on Drug Abuse provides a fact sheet on cocaine (in English and Spanish)
The UK charity Release provides information and advice to the public and professionals about the law and drugs, including information about cocaine
MedlinePlus also provides a list of links to information about cocaine (in English and Spanish)
The March of Dimes Foundation, a US nonprofit organization for the improvement of child health, provides information about illicit drug use during pregnancy (in English and Spanish)
The Organization of Teratology Information Specialists also provides a fact sheet on cocaine and pregnancy (in English, Spanish, and French)
doi:10.1371/journal.pmed.0050117
PMCID: PMC2504032  PMID: 18593214
13.  Randomized trial of buprenorphine for treatment of concurrent opiate and cocaine dependence 
Background
Buprenorphine is a partial μ-opiate agonist and κ-opiate antagonist with established efficacy in the treatment of opiate dependence. Its efficacy for cocaine dependence is uncertain. This study evaluated buprenorphine for the treatment of concomitant cocaine and opiate dependence.
Methods
Two hundred outpatients currently dependent on both cocaine and opiates were randomly assigned to double-blind groups receiving a sublingual solution of buprenorphine (2, 8, or 16 mg daily, or 16 mg on alternate days, or placebo), plus weekly individual drug abuse counseling, for 13 weeks. The chief outcome measures were urine concentrations of opiate and cocaine metabolites (quantitative) and proportion of urine samples positive for opiates or cocaine (qualitative). Group differences were assessed by use of mixed regression modeling.
Results
The target dose of buprenorphine was achieved in 179 subjects. Subjects receiving 8 or 16 mg buprenorphine daily showed statistically significant decreases in urine morphine levels (P = .0135 for 8 mg and P < .001 for 16 mg) or benzoylecgonine concentrations (P = .0277 for 8 mg and P = .006 for 16 mg) during the maintenance phase of the study. For the 16-mg group, mean benzoylecgonine concentrations fell from 3715 ng/mL during baseline to 186 ng/mL during the withdrawal phase; mean morphine concentrations fell from 3311 ng/mL during baseline to 263 ng/mL during withdrawal. For the 8-mg group, mean benzoylecgonine concentrations fell from 6761 ng/mL during baseline to 676 ng/mL during withdrawal; mean morphine concentrations fell from 3890 ng/mL during baseline to 661 ng/mL during withdrawal. Qualitative urinalysis showed a similar pattern of results. Subjects receiving the highest dose showed concomitant decreases in both urine morphine and benzoylecgonine concentrations. There were no significant group differences in treatment retention or adverse events.
Conclusions
A sublingual buprenorphine solution at 16 mg daily is well tolerated and effective in reducing concomitant opiate and cocaine use. The therapeutic effect on cocaine use appears independent of that on opiate use.
doi:10.1016/j.clpt.2003.09.004
PMCID: PMC2633656  PMID: 14749690
14.  Modafinil for the treatment of cocaine dependence✩ 
Drug and alcohol dependence  2009;104(1-2):133.
Aim
Modafinil was tested for efficacy in facilitating abstinence in cocaine-dependent patients, compared to placebo.
Methods
This was a double-blind placebo-controlled study, with 12 weeks of treatment and a 4-week follow-up. Six outpatient substance abuse treatment clinics participated in the study. There were 210 treatment-seekers randomized, having a diagnosis of cocaine dependence; 72 participants were randomized to placebo, 69 to modafinil 200 mg, and 69 to modafinil 400 mg, taken once daily on awakening. Participants came to the clinic three times per week for assessments and urine drug screens, and had one hour of individual psychotherapy weekly. The primary outcome measure was the weekly percentage of cocaine non-use days.
Results
The GEE regression analysis showed that for the total sample, there was no significant difference between either modafinil group and placebo in the change in average weekly percent of cocaine non-use days over the 12-week treatment period (p > 0.79). However, two secondary outcomes showed significant effects by modafinil 200 mg: the maximum number of consecutive non-use days for cocaine (p = 0.02), and a reduction in craving (p = 0.04). Also, a post hoc analysis showed a significant effect of modafinil that increased the weekly percentage of non-use days in the subgroup of those cocaine patients who did not have a history of alcohol dependence (p < 0.02).
Conclusions
These data suggest that modafinil, in combination with individual behavioral therapy, was effective for increasing cocaine non-use days in participants without co-morbid alcohol dependence, and in reducing cocaine craving.
doi:10.1016/j.drugalcdep.2009.04.015
PMCID: PMC2818032  PMID: 19560290
Modafinil; Cocaine-related disorders; Alcoholism; Pharmacotherapy; Risk factors
15.  Brain mu-opioid receptor binding predicts treatment outcome in cocaine-abusing outpatients 
Biological psychiatry  2010;68(8):697-703.
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.
doi:10.1016/j.biopsych.2010.05.003
PMCID: PMC2949457  PMID: 20579973
cocaine; mu-opioid receptor; PET; treatment; addiction; dependence
16.  Individual psychodynamic psychotherapy and psychoanalysis for schizophrenia and severe mental illness 
Background
People with schizophrenia and severe mental illness may require considerable support from health care professionals, in most cases over a long period of time. Research on the effects of psychotherapy for schizophrenia has shown mixed results. Although pharmacological interventions remain the treatment of choice, the effects of treatments focusing on psychosocial factors affecting schizophrenia are important.
Objectives
To review the effects of psychodynamic psychotherapy, psychoanalysis, or both, for people with schizophrenia or severe mental illness.
Search methods
For the updated review, we searched the Cochrane Schizophrenia Group Trials Register (June 2008) which is based on regular searches of BIOSIS, CENTRAL, CINAHL, EMBASE, MEDLINE and PsycINFO.
Selection criteria
We sought all randomised trials of individual psychodynamic psychotherapy or psychoanalysis for people with schizophrenia or severe mental illness.
Data collection and analysis
We extracted data independently. For dichotomous data we calculated relative risks (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis using a fixed-effect model. We calculated numbers needed to treat/harm (NNT/NNH) where appropriate. For continuous data, we calculated mean differences (MD) and weighted mean differences (WMD) using a fixed-effect model.
Main results
We included four randomised trials (total 528 participants, 5 comparisons). All used a psychodynamic approach and reported limited data.
For individual psychodynamic therapy versus medication alone we found significantly more participants in the therapy group were unable to be discharged (n=92, RR 8.35 CI 2.0 to 34.3, NNH 3 CI 2 to 6). We found no significant difference between groups in the number of participants who were re-hospitalised (n=24, RR 0.63 CI 0.3 to 1.4) during long-term analyses. At 12 months, fewer participants in the psychotherapy groups needed additional medications compared with those who did receive medication (n=74, RR 0.64 CI 0.5 to 0.8, NNT 3 CI 3 to 6), and also at three years follow up (n=87, RR 0.85 CI 0.8 to 1.0, NNT 7 CI 5 to 26).
For individual psychodynamic therapy plus medication versus medication alone we found no significant difference in suicide (n=92, RR 0.16 CI 0.01 to 2.9) or suitability for discharge (n=92, RR 1.09 CI 0.2 to 7.4). Also, we found re-hospitalisation rates in long-term analyses were equivocal (n=24, RR 1.00 CI 0.4 to 2.6). For insight-orientated psychodynamic psychotherapy versus reality adaptive psychotherapy we found no significant difference in re-hospitalisation rates (n=164, RR 1.20 CI 0.9 to 1.6), but we found study attrition favoured the insight-orientated psychodynamic psychotherapy group at 12 months (n=164, RR 0.46 CI 0.3 to 0.6, NNT 2 CI 2 to 4). For individual psychodynamic psychotherapy versus group psychotherapy we found no significant difference in global state ‘not improved’ (n=100, RR 1.27 CI 1.0 to 1.7). For individual psychodynamic therapy plus medication versus individual psychodynamic therapy we found rates of re-hospitalisation during long-term analyses were equivocal (n=24, RR 1.00 CI 0.4 to 2.6). There is no clear evidence of any positive effect of psychodynamic therapy and the possibility of adverse effects seems never to have been considered. We did not identify any trials using a psychoanalytic approach.
Authors’ conclusions
Current data do not support the use of psychodynamic psychotherapy techniques for hospitalised people with schizophrenia. If psychoanalytic therapy is being used for people with schizophrenia there is an urgent need for trials.
doi:10.1002/14651858.CD001360
PMCID: PMC4171459  PMID: 11686988
*Psychoanalytic Therapy; *Psychotherapy; Hospitalization; Mental Disorders [therapy]; Randomized Controlled Trials as Topic; Schizophrenia [*therapy]; Humans
17.  Sertraline Delays Relapse in Recently Abstinent Cocaine-Dependent Patients with Depressive Symptoms1 
Addiction (Abingdon, England)  2011;107(1):131-141.
Aims
Whether the selective serotonin reuptake inhibitor sertraline at 200 mg/day delays relapse in recently abstinent cocaine dependent individuals
Design
12-week, double blind, placebo-controlled clinical trial with 2-week residential stay followed by 10-wk outpatient participation
Setting
Veterans Affairs residential unit and outpatient treatment research program
Participants
Cocaine-dependent volunteers (N=86) with depressive symptoms (Hamilton score > 15), but otherwise no major psychiatric or medical disorder or contraindication to sertraline.
Measurements
Participants were housed on a drug-free residential unit (wks 1–2) and randomized to receive sertraline or placebo. Participants then participated on an outpatient basis during weeks 3–12 while continuing to receive study medication. Patients participated in a day substance abuse day treatment program during weeks 1–3 and underwent weekly cognitive behavioral therapy during weeks 4–12. The primary outcome measure was thrice-weekly urine results and secondary measure was Hamilton Depression scores.
Findings
Pre hoc analyses were performed on those who participated beyond week 2. Generally no group differences in retention or baseline characteristics occurred. Sertraline patients showed a trend toward longer time before their first cocaine-positive urine (“lapse,” χ2=3.67, p=0.056), went significantly longer before having two consecutive urine samples positive for cocaine (“relapse,” χ2=4.03, p=0.04) and showed significantly more days to lapse (26.1±3.2±10.5; z = 2.89, p=0.004) and relapse (21.3±10.8 vs 32.3±14.9; z=2.25, p=0.02). Depression scores decreased over time (F=43.43, p<0.0001), but did not differ between groups (F =0.09, p = 0.77).
Conclusions
Sertraline delays time to relapse relative to placebo in cocaine dependent patients who initially achieve at least two weeks of abstinence.
doi:10.1111/j.1360-0443.2011.03552.x
PMCID: PMC3237722  PMID: 21707811
cocaine dependence; randomized clinical trial; placebo control; sertraline; relapse prevention; cognitive behavioral therapy
18.  Efficacy of Disulfiram and Cognitive Behavior Therapy in Cocaine-Dependent Outpatients 
Archives of general psychiatry  2004;61(3):264-272.
Context
Disulfiram has emerged as a promising treatment for cocaine dependence, but it has not yet been evaluated in general populations of cocaine users.
Objectives
To compare the effectiveness of disulfiram therapy with that of a placebo condition in reducing cocaine use and to compare the effectiveness of 2 active behavioral therapies—cognitive behavior therapy (CBT) and interpersonal psychotherapy (IPT)—in reducing cocaine use.
Design
Randomized, placebo-controlled, double-masked (for medication condition), factorial (2×2) trial with 4 treatment conditions: disulfiram plus CBT, disulfiram plus IPT, placebo plus CBT, and placebo plus IPT.
Setting
A community-based outpatient substance abuse treatment program.
Patients
A total of 121 individuals meeting the criteria for current cocaine dependence.
Interventions
Patients received either disulfiram (250 mg/d) or placebo in identical capsules. Medication compliance was monitored using a riboflavin marker procedure. Both behavioral therapies (CBT and IPT) were manual guided and were delivered in individual sessions for 12 weeks.
Main Outcome Measures
Random regression analyses of self-reported frequency of cocaine use and results of urine toxicology screens.
Results
Participants assigned to disulfiram reduced their cocaine use significantly more than those assigned to placebo, and those assigned to CBT reduced their cocaine use significantly more than those assigned to IPT (P<.01 for both). Findings were consistent across all study samples (eg, intention to treat, treatment initiators, and treatment completers). Benefits of disulfiram use and CBT were most pronounced for participants who were not alcohol dependent at baseline or who fully abstained from drinking alcohol during treatment. Adverse effects experienced by participants who received disulfiram were mild and were not considerably different from those experienced by participants who received placebo.
Conclusions
Disulfiram and CBT are effective therapies for general populations of cocaine-dependent individuals. Disulfiram seems to exert a direct effect on cocaine use rather than through reducing concurrent alcohol use.
doi:10.1001/archpsyc.61.3.264
PMCID: PMC3675448  PMID: 14993114
19.  Alpha Synuclein Protein Levels are Increased in Serum from Recently Abstinent Cocaine Abusers 
Drug and alcohol dependence  2007;94(1-3):246-250.
Alpha synuclein is increased in dopamine neurons of cocaine abusers and in rats whose alcohol preference is inbred. Recent studies have shown increased alpha-synuclein protein expression in serum of alcoholic patients that is linked with severity of alcohol craving. The aim of this study was to analyze the serum levels of alpha synuclein in healthy subjects and in recently abstinent cocaine abusers. Alpha synuclein protein expression was measured by enzyme-linked immunosorbent assay in serum specimens obtained from 38 recently abstinent cocaine dependent patients and 14 control subjects. The presence of cocaine dependence disorder was based on the Structured Clinical Interview (DSM-IV). Drug severity was assessed by the Addiction Severity Index ratings and composite measures. Scores of the intensity and frequency of cocaine craving episodes were obtained from the Minnesota Cocaine Craving Questionnaire. The serum concentrations of alpha synuclein in cocaine dependent patients were significantly higher as compared with age-matched drug-free controls (p < 0.001). Alpha synuclein levels in blood were significantly correlated with the intensity (r = 0.60, p < 0.001) and frequency (r = 0.64. p < 0.001) of cocaine craving and with thirty days of cocaine use in the prior month before entry to treatment (r = 0.56, p < 0.005). However, there was no correlation between the serum protein levels of alpha synuclein and age in either group. This report is the first demonstration of altered alpha synuclein levels in peripheral blood from cocaine abusers. These data agree with previous reports in postmortem brain of cocaine abusers and provide support for an association between alpha synuclein and cocaine dependence.
doi:10.1016/j.drugalcdep.2007.09.020
PMCID: PMC2366137  PMID: 18055133
Cocaine; serum; dopamine; craving; synuclein
20.  A PLACEBO CONTROLLED TRIAL OF MEMANTINE FOR COCAINE DEPENDENCE WITH HIGH-VALUE VOUCHER INCENTIVES DURING A PRE-RANDOMIZATION LEAD-IN PERIOD 
Drug and alcohol dependence  2010;111(1-2):97-104.
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.
doi:10.1016/j.drugalcdep.2010.04.006
PMCID: PMC2930076  PMID: 20537812
Cocaine dependence; Pharmacotherapy trials; NMDA receptors; Placebo lead-in; High value contingency reinforcement
21.  Systematic Review of Abstinence-Plus HIV Prevention Programs in High-Income Countries 
PLoS Medicine  2007;4(9):e275.
Background
Abstinence-plus (comprehensive) interventions promote sexual abstinence as the best means of preventing HIV, but also encourage condom use and other safer-sex practices. Some critics of abstinence-plus programs have suggested that promoting safer sex along with abstinence may undermine abstinence messages or confuse program participants; conversely, others have suggested that promoting abstinence might undermine safer-sex messages. We conducted a systematic review to investigate the effectiveness of abstinence-plus interventions for HIV prevention among any participants in high-income countries as defined by the World Bank.
Methods and Findings
Cochrane Collaboration systematic review methods were used. We included randomized and quasi-randomized controlled trials of abstinence-plus programs for HIV prevention among any participants in any high-income country; trials were included if they reported behavioural or biological outcomes. We searched 30 electronic databases without linguistic or geographical restrictions to February 2007, in addition to contacting experts, hand-searching conference abstracts, and cross-referencing papers. After screening 20,070 abstracts and 325 full published and unpublished papers, we included 39 trials that included approximately 37,724 North American youth. Programs were based in schools (10), community facilities (24), both schools and community facilities (2), health care facilities (2), and family homes (1). Control groups varied. All outcomes were self-reported. Quantitative synthesis was not possible because of heterogeneity across trials in programs and evaluation designs. Results suggested that many abstinence-plus programs can reduce HIV risk as indicated by self-reported sexual behaviours. Of 39 trials, 23 found a protective program effect on at least one sexual behaviour, including abstinence, condom use, and unprotected sex (baseline n = 19,819). No trial found adverse program effects on any behavioural outcome, including incidence of sex, frequency of sex, sexual initiation, or condom use. This suggests that abstinence-plus approaches do not undermine program messages encouraging abstinence, nor do they undermine program messages encouraging safer sex. Findings consistently favoured abstinence-plus programs over controls for HIV knowledge outcomes, suggesting that abstinence-plus programs do not confuse participants. Results for biological outcomes were limited by floor effects. Three trials assessed self-reported diagnosis or treatment of sexually transmitted infection; none found significant effects. Limited evidence from seven evaluations suggested that some abstinence-plus programs can reduce pregnancy incidence. No trial observed an adverse biological program effect.
Conclusions
Many abstinence-plus programs appear to reduce short-term and long-term HIV risk behaviour among youth in high-income countries. Programs did not cause harm. Although generalisability may be somewhat limited to North American adolescents, these findings have critical implications for abstinence-based HIV prevention policies. Suggestions are provided for improving the conduct and reporting of trials of abstinence-plus and other behavioural interventions to prevent HIV.
In their systematic review, Underhill and colleagues found that abstinence-plus programs appear to reduce short-term and long-term HIV risk behavior among youth in high-income countries.
Editors' Summary
Background.
Human immunodeficiency virus (HIV), which causes AIDS, is most often spread through unprotected sex (vaginal, oral, or anal) with an infected partner. Individuals can reduce their risk of becoming infected with HIV by abstaining from sex or delaying first sex, by being faithful to one partner or having few partners, and by always using a male or female condom. Various HIV prevention programs targeted at young people encourage these protective sexual behaviors. Abstinence-only programs (for example, Project Reality in the US) present no sex before marriage as the only means of reducing the risk of catching HIV. Abstinence-plus programs (for example, the UK Apause program) also promote sexual abstinence as the safest behavior choice to prevent HIV infection. However, recognizing that not everyone will remain abstinent, and that in many locations same-sex couples are not permitted to marry, abstinence-plus programs also encourage young people who do become sexually active to use condoms and other safer-sex strategies. Safer-sex programs, a third approach, teach people how to protect themselves from pregnancy and infections and might recommend delaying first sex until they are physically and emotionally ready, but do not promote sexual abstinence over safer-sex strategies such as condom use.
Why Was This Study Done?
There is considerable controversy, particularly in the US, about the relative merits of abstinence-based programs for HIV prevention. Abstinence-only programs, which the US government supports, have been criticized because they provide no information to protect participants who do become sexually active. Critics of abstinence-plus programs contend that teaching young people about safer sex undermines the abstinence message, confuses participants, and may encourage them to become sexually active. Conversely, some people worry that the promotion of abstinence might undermine the safer-sex messages of abstinence-plus programs. Little has been done, however, to look methodically at how these programs change sexual behavior. In this study, the researchers have systematically reviewed studies of abstinence-plus interventions for HIV prevention in high-income countries to get an idea of their effect on sexual behavior.
What Did the Researchers Do and Find?
In an extensive search for existing abstinence-plus studies, the researchers identified 39 trials done in high-income countries that compared the effects on sexual behavior of various abstinence-plus programs with the effects of no intervention or of other interventions designed to prevent HIV infection. All the trials met strict preset criteria (for example, trial participants had to have an unknown or negative HIV status), and all studies meeting the criteria turned out to involve young people in the US, Canada, or the Bahamas, nearly 40,000 participants in total. In 23 of the trials, the abstinence-plus program studied was found to improve at least one self-reported protective sexual behavior (for example, it increased abstinence or condom use) when compared to the other interventions in the trial; none of the trials reported a significant negative effect on any behavioral outcome. Limited evidence from a few trials indicated that some abstinence-plus programs reduced pregnancy rates, providing a biological indicator of program effectiveness. Conversely, there were no indications of adverse biological outcomes such as an increased occurrence of sexually transmitted diseases in any of the trials.
What Do These Findings Mean?
These findings indicate that some abstinence-plus programs reduce HIV risk behavior among young people in North America. Importantly, the findings do not uncover evidence of any abstinence-plus program causing harm. That is, fears that these programs might encourage young people to become sexually active earlier or confuse them about the use of condoms for HIV prevention seem unfounded. These findings may not apply to all abstinence-plus programs in high-income countries, do not include low-income countries, do not specifically address nonheterosexual risk behavior, and are subject to limited reliability in self-reporting of sexual activity by young people. Nonetheless, this analysis provides support for the use of abstinence-plus programs, particularly in light of another systematic review by the same authors (A systematic review of abstinence-only programs for prevention of HIV infection, published in the British Medical Journal), which found that abstinence-only programs did not reduce pregnancy, sexually transmitted diseases, or sexual behaviors that increase HIV risk. Abstinence-plus programs, these findings suggest, represent a reasonable strategy for HIV prevention among young people in high-income countries.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040275.
• US National Institute of Allergy and Infectious Diseases fact sheet on HIV infection and AIDS
• Information from the UK charity AVERT on all aspects of HIV and AIDS, including HIV and AIDS prevention
• US Centers for Disease Control and Prevention fact sheet on HIV/AIDS among young people (in English and Spanish)
• Information on Project Reality, a US abstinence-only program
• Information on Reducing the Risk and on Apause, US and UK abstinence-plus programs, respectively
doi:10.1371/journal.pmed.0040275
PMCID: PMC1976624  PMID: 17880259
22.  Extended Release Mixed Amphetamine Salts and Topiramate for Cocaine Dependence: A Randomized Controlled Trial 
Biological psychiatry  2012;72(11):950-956.
Background
Cocaine dependence is a substantial public health problem, yet there are no clearly effective medication treatments. Amphetamine and topiramate have both shown promise for the treatment of cocaine dependence in preclinical and early-stage clinical studies.
Method
Eighty-one cocaine-dependent adults were randomized to receive a combination of mixed amphetamine salts extended-release (MAS-ER) and topiramate or placebo for twelve weeks under double-blind conditions. MAS-ER doses were titrated over two weeks to a maximum dose of 60 mg daily and topiramate doses were titrated over six weeks to a maximum dose of 150 mg twice daily. All participants received a supportive behavioral intervention. The primary outcome was the proportion of individuals who achieved three consecutive weeks of abstinence as measured by urine toxicology confirmed self-report.
Results
The overall proportion of participants who achieved three consecutive weeks of abstinence was larger in the extended-release mixed amphetamine salts and topiramate group (33.3%) than in placebo group (16.7%). There was a significant moderating effect of baseline total number of cocaine use days (Wald χ2=3.75, df =1, P=.05) on outcome suggesting that the combination treatment was most effective for participants with a high baseline frequency of cocaine use.
Conclusions
The results of this study supported our hypothesis that the combination of MASER and topiramate would be superior to placebo in achieving three weeks of consecutive abstinence. These findings provide evidence that the combination of MAS-ER and topiramate is efficacious in promoting abstinence in cocaine-dependent individuals.
doi:10.1016/j.biopsych.2012.05.032
PMCID: PMC3648884  PMID: 22795453
cocaine dependence; amphetamines; topiramate; treatment; clinical trial; substance dependence
23.  Increased serum brain-derived neurotrophic factor (BDNF) is predictive of cocaine relapse outcomes: A prospective study 
Biological psychiatry  2011;70(8):706-711.
Background
Cocaine dependence is associated with high relapse rates but few biological markers associated with relapse outcomes have been identified. Extending preclinical research showing a role for central Brain Derived Neurotrophic Factor (BDNF) in cocaine seeking, we examined whether serum BDNF is altered in abstinent, early recovering, cocaine-dependent individuals and if it is predictive of subsequent relapse risk.
Methods
Serum samples were collected across three consecutive mornings from 35 treatment-engaged, 3 week abstinent cocaine-dependent inpatients (17M/18F) and 34 demographically matched hospitalized healthy control participants (17M/17F). Cocaine dependent individuals were prospectively followed on days 14, 30 and 90 post-treatment discharge to assess cocaine relapse outcomes. Time to cocaine relapse, number of days of cocaine use (frequency), and amount of cocaine use (quantity) were the main outcome measures.
Results
High correlations in serum BDNF across days indicated reliable and stable serum BDNF measurements. Significantly higher mean serum BDNF levels were observed for the cocaine-dependent patients compared to healthy control participants (p<.001). Higher serum BDNF levels predicted shorter subsequent time to cocaine relapse (hazard ratio: HR: 1.09, p<.05), greater number of days (p<.05) and higher total amounts of cocaine used (p = .05).
Conclusions
High serum BDNF levels in recovering cocaine-dependent individuals are predictive of future cocaine relapse outcomes and may represent a clinically relevant marker of relapse risk. These data suggest that serum BDNF levels may provide an indication of relapse risk during early recovery from cocaine dependence.
doi:10.1016/j.biopsych.2011.05.013
PMCID: PMC3186871  PMID: 21741029
BDNF; cocaine dependence; cocaine relapse; treatment outcome
24.  Effects of Extended Cocaine Access and Cocaine Withdrawal on Choice Between Cocaine and Food in Rhesus Monkeys 
Chronic drug use may lead to sufficient drug intake to produce dependence and the emergence of abstinence signs during withdrawal. Although withdrawal can increase the reinforcing effects of some drugs (e.g. opioids), the impact of withdrawal on the reinforcing effects of stimulants like cocaine is less clear. This study used a novel cocaine-versus-food choice procedure to examine the relative reinforcing strength of cocaine before, during and after exposure to graded levels of extended cocaine access. Responding in four rhesus monkeys was maintained by cocaine (0–0.1 mg/kg/inj) and food delivery under a concurrent-choice schedule during daily 2hr sessions. Under baseline conditions, cocaine maintained a dose-dependent increase in cocaine choice. Subsequently, subjects were exposed to and withdrawn from periods of extended cocaine access, which was accomplished by implementing daily 21-hr supplemental sessions of cocaine self-administration in addition to daily choice sessions. During supplemental sessions, cocaine (0.1 mg/kg/inj) was available under a fixed-ratio 10/time out X schedule, and the duration of the time out was varied from 30 min to 7.5 min. Cocaine intake increased 10-fold to more than 11 mg/kg/day during exposure to supplemental sessions with the shortest post-injection time out. However, parameters of cocaine choice were not significantly affected either during or after extended cocaine access. These results do not support the hypothesis that cocaine withdrawal increases the reinforcing strength of cocaine. This differs from results with the opioid agonist heroin and suggests that withdrawal may play different roles in maintenance of opioid and stimulant abuse.
doi:10.1038/npp.2009.154
PMCID: PMC2913442  PMID: 19776729
Cocaine; choice procedure; nonhuman primates; dependence; withdrawal; alternative reinforcer
25.  Effects of Extended Cocaine Access and Cocaine Withdrawal on Choice Between Cocaine and Food in Rhesus Monkeys 
Neuropsychopharmacology  2009;35(2):493-504.
Chronic drug use may lead to sufficient drug intake to produce dependence and the emergence of abstinence signs during withdrawal. Although withdrawal can increase the reinforcing effects of some drugs (eg opioids), the impact of withdrawal on the reinforcing effects of stimulants like cocaine is less clear. This study used a novel cocaine vs food choice procedure to examine the relative reinforcing strength of cocaine before, during, and after exposure to graded levels of extended cocaine access. Responding in four rhesus monkeys was maintained by cocaine (0–0.1 mg/kg/injection) and food delivery under a concurrent-choice schedule during daily 2-h sessions. Under baseline conditions, cocaine maintained a dose-dependent increase in cocaine choice. Subsequently, subjects were exposed to and withdrawn from periods of extended cocaine access, which was accomplished by implementing daily 21-h supplemental sessions of cocaine self-administration in addition to daily choice sessions. During supplemental sessions, cocaine (0.1 mg/kg/injection) was available under a fixed-ratio 10/time-out X schedule, and the duration of the time-out was varied from 30 to 7.5 min. Cocaine intake increased 10-fold to >11 mg/kg/day during exposure to supplemental sessions with the shortest post-injection time-out. However, parameters of cocaine choice were not significantly affected either during or after extended cocaine access. These results do not support the hypothesis that cocaine withdrawal increases the reinforcing strength of cocaine. This differs from results with the opioid agonist heroin and suggests that withdrawal may have different functions in the maintenance of opioid and stimulant abuse.
doi:10.1038/npp.2009.154
PMCID: PMC2913442  PMID: 19776729
cocaine; choice procedure; nonhuman primates; dependence; withdrawal; alternative reinforcer

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