Blunted opioid regulation of the HPA stress response during nicotine withdrawal: therapeutic implications.

Endogenous opioids regulate pain, drug reward, and stress responses. We have previously shown reduced hypothalamic-pituitary-adrenal (HPA) responses to psychological stress and to opioid blockade among dependent smokers. In this study, we examined the extent to which biologically confirmed nicotine withdrawal alters endogenous opioid regulation of HPA axis functioning during rest and in response to acute stress. Smokers were randomly assigned to one of two conditions; 24 h withdrawal from all nicotine-containing products (n = 62) or smoking ad libitum (n = 44). A nonsmoking comparison group (n = 43) was also included. Participants (85 males and 64 females) completed two acute stress sessions during which a placebo or 50 mg of naltrexone (opioid antagonist) were administered using a double-blind design. Blood and saliva samples (assayed for cortisol and adrenocorticotropic hormone, i.e. ACTH) and mood measures were obtained during a resting absorption period, after acute stress (public speaking, mental arithmetic, and cold pressor tasks), and during an extended recovery period. Results indicated that opioid blockade (naltrexone) was associated with increased ACTH and cortisol responses to stress, and tobacco withdrawal was associated with blunted hormonal responses. A pattern of sex differences also emerged, with women exhibiting reduced ACTH responses to stress and higher ACTH and plasma cortisol responses to opioid blockade. These results indicated that compared to ad libitum smoking, nicotine withdrawal is associated with blunted opioid modulation of the HPA axis. Sex may modulate these effects. Blunted endogenous opioid regulation may underlie an incentive process that reinforces smoking behavior and may warrant therapeutic attention.

Open-label pilot study of lisdexamfetamine for cocaine use disorder.

Background: Cocaine use disorder (CUD) is a substantial public health problem with no FDA-approved medication treatments. Psychostimulants have shown promise as pharmacotherapy for CUD. Lisdexamfetamine, a novel prodrug psychostimulant, is roughly 40-50% as potent as dextroamphetamine.Objectives: To evaluate the safety, tolerability, and optimal dosing of lisdexamfetamine for treating CUD.Methods: Open-label, 8-week trial of 17 CUD adults. Participants were titrated to the maximum tolerated dose of 140 mg over 2-week period and maintained for 4 weeks, followed by a two-week taper period. The primary outcome measures were the maximum daily dose achieved during the study period and tolerability as measured by medication-related study drop-out.Results: Among the 16 participants with post-enrollment data, the mean dose of lisdexamfetamine achieved was 118.1 mg (standard deviation (SD) = 40.4), mean retention was 6.5 weeks (SD = 2.0), and no participants discontinued study medication due to adverse effects. Four participants had dose reductions due to adverse effects and continued in the trial. Six participants (37.5%) were abstinent for the last 3 weeks of their study participation. Mean dollars of cocaine spent per day significantly decreased from $19.72 at baseline to $7.57 during the last 3 weeks of study participation (t15 = 3.60, p = .003). The mean percent of using days significantly decreased from 25% at baseline to 12% during the last 3 weeks of study participation (t15 = 3.33, p = .005).Conclusion: The use of lisdexamfetamine for CUD in doses ranging to 140 mg daily was safe and generally well tolerated.

Mixed-amphetamine salts increase abstinence from marijuana in patients with co-occurring attention-deficit/hyperactivity disorder and cocaine dependence.

BACKGROUND AND OBJECTIVES: The prevalence of ADHD is greater in substance use disorders than the general population, and ADHD and substance use disorders share neurobiological features such as dysregulation of reward circuitry. We tested the hypothesis that stimulants would decrease marijuana use in a randomized controlled trial of extended release mixed amphetamine salts (MAS-XR) for treatment of co-occurring ADHD and cocaine use disorders. METHODS: Marijuana users were defined as participants reporting use in the 30 days before study initiation, collected with timeline follow-back. The original 14-week trial utilized a 3-arm randomized design, comparing placebo, MAS-XR 60 mg, and MAS-XR 80 mg. For this analysis, both MAS-XR groups were combined, leaving n = 20 in the placebo group and n = 37 in the MAS-XR group. The primary outcome was proportion of subjects reporting any marijuana use per study week. Comparisons between groups were made using a logistic mixed effects model incorporating multiple predictors and modeling time-by-treatment interactions. RESULTS: There were no significant baseline differences in marijuana use frequency and quantity. There was a significant decrease in the proportion of participants using marijuana over time in the MAS-XR group, but no difference in the proportion of marijuana-use days over time. DISCUSSION AND CONCLUSIONS: Treatment of ADHD and comorbid cocaine use disorders with MAS-XR is associated with increased weekly abstinence from marijuana but not with a decrease in the proportion of marijuana using days per week. SCIENTIFIC SIGNIFICANCE: Stimulant treatment of ADHD and cocaine use disorders may diminish co-occurring cannabis use. (Am J Addict 2016;25:666-672).

The Proposal Preparation Program: A Group Mentoring, Faculty Development Model to Facilitate the Submission and Funding of NIH Grant Applications.

This article describes the University of Minnesota Medical School Proposal Preparation Program (P3). P3 is designed to develop grant-writing skills for assistant professors preparing their first K- or R-series application to the National Institutes of Health (NIH). Three 4-month P3 cycles are conducted annually. For each cycle, a cohort of around 10 assistant professor participants and 5 regular faculty mentors meet for ten ~2-hour group sessions. Participants receive iterative oral and written feedback on their proposals in development within a small, interdisciplinary, group mentoring setting providing structure, accountability, guidance, and support. Between sessions, 1 peer and 1 mentor are assigned (on a rotating basis) to critique each participant's developing application. The sessions include a brief mentor-led presentation on a particular grant section followed by discussion of each participant's application conducted by the assigned reviewers. The cycle concludes with a mock NIH review session, in which each participant is matched with a University of Minnesota faculty content expert who critiques their completed application using NIH guidelines. In a survey sent to all past P3 participants as of 2018 (n = 194), 88% of respondents reported having submitted their P3-developed NIH grant, and 35% of these submitters reported funding success. A separate analysis of institutional data for all past P3 participants as of 2016 (n = 165) showed that 73% submitted at least 1 NIH proposal since completing P3 and that 43% of these had acquired NIH funding, for a combined total of $193 million in funding awarded. The estimated rate at which participants obtained funding for their P3-developed grant application (~35%) exceeds the national annual NIH grant funding rates (~20%) by approximately 50%. This article provides the practical information needed for other institutions to implement a P3-like program and presents a cost-benefit analysis showing the advantages of doing so.

Impulsiveness as a moderator of amphetamine treatment response for cocaine use disorder among ADHD patients.

BACKGROUND: Amphetamines are a first-line treatment for ADHD and have shown promise for the treatment of cocaine use disorder (CUD), both alone and with comorbid ADHD. Impulsiveness is a key aspect of both ADHD and substance use disorders. We sought to understand the role of baseline impulsiveness in the treatment of comorbid CUD and ADHD. METHODS: In a post hoc analysis (N = 76) of a 14-week, double-blind, randomized, placebo-controlled trial of mixed amphetamine salts-extended release (MAS-ER) for comorbid ADHD and CUD, we examined the relationship between treatment response and participants' baseline Barratt Impulsiveness Scale (BIS-11) score by comparing those with scores below versus above the median. In the original trial, participants received daily 60 mg MAS-ER, 80 mg MAS-ER, or placebo, in conjunction with cognitive behavioral therapy. RESULTS: The odds of a cocaine-abstinent week over time were significantly greater in the high BIS group compared to the low BIS group, both when missing data was treated as missing (p = .0155; OR = 1.23, 95% CI: 1.13, 1.35 versus OR = 1.04, 95% CI: 0.95, 1.15) and when missing data was treated as cocaine-positive (p = .003; OR = 1.15, 95% CI: 1.06, 1.24 versus OR = 0.96, 95% CI: 0.88, 1.05). CONCLUSIONS: The results show an association between higher within-group trait impulsiveness, as measured by the BIS-11, and response to MAS-ER for CUD in a cohort with comorbid ADHD. This result further demonstrates that impulsiveness is an important factor when considering treatment options for patients with CUD and that higher baseline impulsiveness may predict response to treatment with psychostimulants for CUD.

Parents as interventionists: Addressing adolescent substance use.

Much research and attention has focused on addressing the extremes of the adolescent substance use spectrum: either the prevention of substance use prior to its onset or the treatment of those with a substance use disorder (SUD). Little research has looked at adolescents who fall mid-continuum. Adolescents who use substances in this mild-to-moderate range may be efficiently and cost-effectively treated using brief interventions based on cognitive-behavioral (CB) and motivational interviewing (MI) strategies. Accessibility and feasibility of providing interventions may also be enhanced by training parents in application of CB and MI principles. An innovative home-based brief intervention for parents whose children engaged in mild to moderate drug abuse was developed and evaluated using a quasi-experimental design. Participants were parents and their adolescent child from the 7-county metro area of Minneapolis-St. Paul, Minnesota. Decreased substance use and increased family cohesion were the predicted outcomes of the Home Base intervention. Results suggest decreased adolescent marijuana use frequency, decreased alcohol use disorder symptomology, and increased parental happiness with their adolescent child. Alcohol and tobacco use frequency were statistically unchanged. Baseline levels of drug use severity moderated the relation between intervention and outcomes. These findings support the potential utility of this approach and also indicate the need to further develop accessible and efficient interventions for mild to moderate SUD.

Levodopa pharmacotherapy for cocaine dependence: choosing the optimal behavioral therapy platform.

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 (400/100mg 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 (100mg/capsule) and the Medication Event Monitoring System. Protocol compliance was addressed in weekly, 10-min nurse-delivered ClinMan sessions. Weekly, 1-h 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.

Efficacy, Safety, and Durability of Repeated Ketamine Infusions for Comorbid Posttraumatic Stress Disorder and Treatment-Resistant Depression.

OBJECTIVE: The present study examined the efficacy, safety, and durability of repeated ketamine infusions for the treatment of comorbid posttraumatic stress disorder (PTSD) and treatment-resistant depression (TRD) in a sample of veterans. METHODS: Individuals with comorbid DSM-5-defined PTSD and DSM-IV-defined major depressive disorder (N = 15) received 6 intravenous ketamine infusions (0.5 mg/kg) on a Monday-Wednesday-Friday schedule over a 12-day period from May 2015 to June 2016. Data from outcome measures were collected before and 24 hours after each infusion and weekly for 8 weeks following the final infusion. RESULTS: Continuous measures of symptom change were significant for both disorders and were associated with large effect sizes (mean decrease in PTSD Checklist for DSM-5 score = 33.3 points [95% CI, 23.0-43.5 points], P < .0005, sample size-adjusted Cohen d [d'] = 2.17; mean decrease in Montgomery-Asberg Depression Rating Scale score = 26.6 points [95% CI, 23.0-30.2 points], P < .0005, d' = 4.64). The remission rate for PTSD was 80.0%, and the response rate for TRD was 93.3%. Participants in remission from PTSD after the infusion series (n = 12) had a median time to relapse of 41 days. Similarly, participants whose depression symptoms responded to the infusion series (n = 14) had a median time to relapse of 20 days. Repeated ketamine infusions were associated with transient increases in dissociative symptoms. No participant reported worsening of PTSD symptoms over the study duration. CONCLUSIONS: This study, the first open-label study of repeated ketamine infusions in a comorbid population, found rapid and sustained improvement in PTSD and depression symptoms. This report suggests that repeated ketamine treatments are safe and may represent an efficacious treatment for individuals with comorbid PTSD and TRD. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02577250.

How treatment improvement in ADHD and cocaine dependence are related to one another: A secondary analysis.

BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) is overrepresented among individuals seeking treatment for substance use disorders. We previously reported that treatment with extended release mixed amphetamine salts (MAS-XR) increased abstinence, compared to placebo, among patients with co-occurring ADHD and cocaine dependence. This secondary analysis investigates the temporal relationship between ADHD improvement and cocaine abstinence in the first six weeks of the trial. METHODS: The study was a three-arm, randomized, double-blinded, placebo-controlled, 14-week trial comparing MAS-XR (60 mg or 80 mg daily) versus placebo among 126 participants with ADHD and cocaine dependence. An autoregressive cross-lagged structural equation model was fit and evaluated weekly ADHD improvement (defined as ≥30% reduction in the Adult ADHD Investigator Symptom Rating Scale) and urine-confirmed abstinence over the first six weeks. RESULTS: The proportion of patients with each of the possible overall patterns of response was: ADHD improves before cocaine abstinence: 24%; Cocaine abstinence occurs before ADHD improvement: 12%; ADHD improvement and abstinence occur during the same week: 6%; ADHD improves but abstinence never achieved: 34%; Abstinence achieved but ADHD never improves: 6%; Neither ADHD improvement nor abstinence: 18%. A significant cross-lagged association was found; subjects with ADHD improvement at week 2 had significantly higher odds of cocaine abstinence at week 3 (p = .014). CONCLUSION: When treating co-occurring ADHD and cocaine dependence with stimulant medication, abstinence is most likely preceded by improvement in ADHD, which tends to occur early with medication treatment. Other observed temporal patterns suggest the potential complexity of the relationship between ADHD and cocaine dependence.

Safety, tolerability and efficacy of levodopa-carbidopa treatment for cocaine dependence: two double-blind, randomized, clinical trials.

RATIONALE: The role of dopamine in cocaine abuse has been long recognized. Cocaine use can profoundly alter dopaminergic functioning through depletion of this monoamine and changes in receptor functioning. Based on these facts, levodopa (L-dopa) pharmacotherapy may be helpful in reducing or abolishing cocaine use. OBJECTIVE: The current studies sought to evaluate the safety, tolerability and efficacy of L-dopa as a treatment for cocaine dependence. METHODS: In Study 1, 67 cocaine-dependent subjects were randomized in a 5-week, double-blind, placebo-controlled safety trial. Subjects received either placebo, or 400 mg L-dopa plus 100 mg of the peripheral decarboxylase inhibitor, carbidopa, in a sustained-release preparation (Sinemet CR). In Study 2, 122 cocaine-dependent subjects were enrolled in a 9-week, randomized, double-blind, placebo-controlled trial to compare placebo to 400/100 mg and 800/200 mg L-dopa/carbidopa treatments. Placebo or L-dopa were administered twice daily in both studies. RESULTS: L-dopa was well tolerated with similar retention and medication adherence rates compared to placebo. Only two side effects occurred more often in L-dopa-treated patients: nausea and dizziness. L-dopa lowered diastolic blood pressure in a dose-dependent fashion. In these trials, L-dopa had no effect on cocaine use, cocaine craving, or mood. CONCLUSION: These two studies demonstrate the safety and tolerability of L-dopa pharmacotherapy in cocaine-dependent patients. No evidence for greater efficacy of L-dopa compared to placebo was observed. The possibility of enhancing treatment effects by combining L-dopa with other behavioral or pharmacological interventions is discussed.

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

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

Using pharmacy data on partial adherence to inform clinical care of patients with serious mental illness.

OBJECTIVE: Low adherence to antipsychotic medications is a risk factor for poor outcomes for people with serious mental illness. Pharmacy data might be used by health systems to identify partially adherent patients for interventions. This study assessed whether using pharmacy data is an accurate screening method for identifying at-risk patients. METHODS: Administrative data were used to identify 1,712 veterans as having schizophrenia or a schizoaffective or bipolar disorder and who had 12-month antipsychotic medication possession ratios (MPRs) of less than .80. Patients' charts were reviewed for alternative explanations for low rates of filling prescriptions for antipsychotic medication. RESULTS: Of 1,712 patients whose pharmacy data indicated partial adherence (MPRs less than .80), 17% (N=297) may have been adherent. Patients with bipolar disorder had higher odds of receiving a false-positive designation (adjusted odds ratio of 1.8, 95% confidence interval of 1.31-2.39). CONCLUSIONS: MPRs constructed from pharmacy data can be a useful first screen for identifying patients who need assistance with medication adherence.

Moderators of delay tolerance in treatment-seeking cocaine users.

A substantial amount of attrition in cocaine dependence treatment studies occurs between the initial telephone contact and the first evaluative clinic visit. While decreasing the wait to first visit can significantly reduce pre-intake attrition (PIA), little is known about other factors that moderate delay tolerance for first clinic visit. The current report uses data from 833 subjects who completed a first-contact telephone interview prior to an intake evaluation visit for cocaine use treatment research. Hierarchical logistic regression was used to assess three successive models to predict PIA, with the most inclusive model testing interactions between delay interval and seven predictors: age, gender, treatment motivation, recency of cocaine, alcohol, and tobacco use, and self-reported depression. Consistent with previous reports, greater delay to first clinic visit predicted PIA. However, no evidence for the moderating role of the selected factors was found. Overall, the utility of the logistic models, built on basic demographic and psychiatric factors, was poor, as evaluated using receiver-operator characteristic curves. Alternative factors must be examined to identify predictors that will increase probability of initial enrolment in cocaine-dependence clinical trials.

Illusory predictors: Generalizability of findings in cocaine treatment retention research.

Treatment retention is of paramount importance in cocaine treatment research as treatment completion rates are often 50% or less. Failure to retain cocaine patients in treatment has both significant research and clinical implications. In this paper we qualitatively and quantitatively demonstrate the inconsistency found across analyses of retention predictors in order to highlight the problem. First, a qualitative review of the published literature was undertaken to identify the frequency of predictors studied and their relations to treatment retention. Second, an empirical demonstration of predictor stability was conducted by testing a common set of variables across three similar 12-week cocaine clinical trials conducted by the same investigators in the same research clinic within a five-year period. Results of the literature review indicated inconsistently selected variables of convenience, widely varying statistical procedures, and discrepant findings of significance. Further, quantitative analyses resulted in discrepancies in variables identified as significant predictors of retention among the three studies. Potential sources of heterogeneity affecting the consistency of findings across studies and recommendations to improve the validity and generalizability of predictor findings in future studies are proposed.

Pilot study of the effects of lisdexamfetamine on cocaine use: A randomized, double-blind, placebo-controlled trial.

BACKGROUND: Amphetamine analogs have been demonstrated to have some efficacy in reducing use in cocaine dependent individuals. However, these agents also have potential for abuse. Lisdexamfetamine (LDX), a lysine+dextroamphetamine formulation, has been approved for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) and as a prodrug, has less abuse potential. OBJECTIVE: This pilot study sought to evaluate the safety, tolerability, and efficacy of LDX as a candidate treatment for cocaine dependence. METHODS: A randomized, double-blind, placebo-controlled parallel group study served to evaluate LDX in 43 cocaine-dependent individuals: (1) placebo (PBO; 0mg, n=21), (2) LDX (70mg, n=22). Participants received medication for 14 weeks. Cocaine use was determined based on urine analysis for benzoylecgonine (BE; a cocaine metabolite). RESULTS: Retention rates were higher though not significantly different in the PBO (71.4%) than the LDX condition (57.1%). Compared to those in the PBO condition, those receiving LDX were more likely to report experiencing (ps<0.05) diarrhea (45.5% vs. 14.3%), headaches (45.5% vs. 9.5%), and anxiety (31.8% vs. 4.8%). No differences in medication conditions were observed for blood pressure, heart rate, or body weight. In the randomized sample, no differences in cocaine use were seen. Those receiving LDX reported significantly less craving for cocaine than participants receiving PBO. CONCLUSIONS: LDX did not significantly reduce cocaine use compared to PBO in the randomized sample.

Extended-Release Mixed Amphetamine Salts vs Placebo for Comorbid Adult Attention-Deficit/Hyperactivity Disorder and Cocaine Use Disorder: A Randomized Clinical Trial.

IMPORTANCE: Adult attention-deficit/hyperactivity disorder (ADHD) is prevalent but often unrecognized, in part because it tends to co-occur with other disorders such as substance use disorders. Cocaine use disorder is one such disorder with high co-occurrence of ADHD. OBJECTIVE: To examine whether treatment of co-occurring ADHD and cocaine use disorder with extended-release mixed amphetamine salts is effective at both improving ADHD symptoms and reducing cocaine use. DESIGN, SETTING, AND PARTICIPANTS: Thirteen-week, randomized, double-blind, 3-arm, placebo-controlled trial of participants meeting DSM-IV-TR criteria for both ADHD and cocaine use disorder conducted between December 1, 2007, and April 15, 2013, at 2 academic health center substance abuse treatment research sites. One hundred twenty-six adults diagnosed as having comorbid ADHD and cocaine use disorder were randomized to extended-release mixed amphetamine salts or placebo. Analysis was by intent-to-treat population. INTERVENTIONS: Participants received extended-release mixed amphetamine salts (60 or 80 mg) or placebo daily for 13 weeks and participated in weekly individual cognitive behavioral therapy. MAIN OUTCOMES AND MEASURES: For ADHD, percentage of participants achieving at least a 30% reduction in ADHD symptom severity, measured by the Adult ADHD Investigator Symptom Rating Scale; for cocaine use, cocaine-negative weeks (by self-report of no cocaine use and weekly benzoylecgonine urine screens) during maintenance medication (weeks 2-13) and percentage of participants achieving abstinence for the last 3 weeks. RESULTS: More patients achieved at least a 30% reduction in ADHD symptom severity in the medication groups (60 mg: 30 of 40 participants [75.0%]; odds ratio [OR] = 5.23; 95% CI, 1.98-13.85; P < .001; and 80 mg: 25 of 43 participants [58.1%]; OR = 2.27; 95% CI, 0.94-5.49; P = .07) compared with placebo (17 of 43 participants [39.5%]). The odds of a cocaine-negative week were higher in the 80-mg group (OR = 5.46; 95% CI, 2.25-13.27; P < .001) and 60-mg group (OR = 2.92; 95% CI, 1.15-7.42; P = .02) compared with placebo. Rates of continuous abstinence in the last 3 weeks were greater for the medication groups than the placebo group: 30.2% for the 80-mg group (OR = 11.87; 95% CI, 2.25-62.62; P = .004) and 17.5% for the 60-mg group (OR = 5.85; 95% CI, 1.04-33.04; P = .04) vs 7.0% for placebo. CONCLUSIONS AND RELEVANCE: Extended-release mixed amphetamine salts in robust doses along with cognitive behavioral therapy are effective for treatment of co-occurring ADHD and cocaine use disorder, both improving ADHD symptoms and reducing cocaine use. The data suggest the importance of screening and treatment of ADHD in adults presenting with cocaine use disorder. TRIAL REGISTRATION: clinicaltrials.gov Identifier:NCT00553319.

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

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

Concurrent treatment for alcohol and tobacco dependence: are patients ready to quit both?

The prevalence of smoking among alcohol abusers is high, yet little is known about this dual-dependency. This study examines mechanisms involved in changing both alcohol and tobacco use concurrently using the transtheoretical model (TTM) measures of change. Alcohol and tobacco dependent outpatients (N=115) entering a dual-substance dependence program were compared on baseline measures of motivation, self-initiated change activities, and self-efficacy associated with each substance use behavior. Differences on these measures were expected for drinking versus smoking. Motivation to change each behavior was also examined as a potential predictor of retention in treatment. Results indicated that patients reported higher self-efficacy to abstain and lower temptation to use alcohol relative to cigarettes. Change activities were also initiated at higher levels for drinking compared with smoking. An interaction between drinking and smoking motivation for change was found in the prediction of treatment retention; those with higher motivation for changing their alcohol use and lower motivation to quit smoking remained longer in treatment, while those who were higher in motivation for changing both behaviors dropped out the earliest. Overall, participants in this dual-dependence program were more confident and active in changing their alcohol use. Initiating cessation of both behaviors equally and simultaneously may prove difficult for this population. This study initiates an understanding of the mechanisms involved in changing alcohol-tobacco dependence and may provide guidance for developing dual cessation interventions.

Predictors of internalizing and externalizing problems among children of cocaine and opiate dependent parents.

We tested associations in structural models among parent individual problems (severity of drug problems, medical problems, psychiatric symptoms), family problems, and children's internalizing and externalizing problems. Results were compared for cocaine versus opiate dependent parents, mothers versus fathers, boys versus girls, and older versus younger children. Cocaine and opiate dependent parents in treatment (N=211) were interviewed about their substance use, psychiatric symptoms, and interpersonal problems and completed a measure of family problems. Parents also rated children's internalizing and externalizing problems. In structural models controlling for the significant correlations between parent and family problems and between children's internalizing and externalizing problems, family problems but not individual parent problems predicted children's internalizing and externalizing symptoms. Models were similar across all groups compared with the exception of parent gender, with significant relations between parent and family problems for mothers but not for fathers. In addition, older girls were more deviant relative to their same-age and gender peers than the younger girls and boys. These results suggest that the personal problems of drug dependent mothers may influence children's problems indirectly by increasing family problems. For drug dependent fathers, family problems were an independent predictor of children's problems.

Agonist-like, replacement pharmacotherapy for stimulant abuse and dependence.

Stimulant abuse and dependence are disproportionately problematic due to the combination of legal and social issues added to the serious behavioural and biological features of the disorders. These problems are compounded by adverse consequences for families and society. Illegality and stigma multiply the consequences of use and difficulties in providing treatment. Specific behavioural interventions have been demonstrated as useful in treatment of substance use disorders (SUDs). Medications also have an important role in treatment. Effective agonist and antagonist pharmacotherapies as well as symptomatic treatments exist for opioid and nicotine dependence. Neither agonists nor antagonists have been approved as uniquely effective for treatment of stimulant abuse or dependence. Still, promising results are emerging for an agonist-like or 'replacement' strategy paralleling that for nicotine and opioid dependence. Supporting data have emerged from both preclinical and clinical research environments. There are scientific, clinical, social, and legal impediments to application of an agonist-like approach to stimulant abuse and dependence. Some resemble past and current concerns about opioid replacement. Others are unique to the stimulant agents, effects, and clinical features. Here, the authors consider (1) agonist and antagonist pharmacotherapy strategies; (2) preclinical research, including methodological approaches, opioid and nicotine replacement, and agonists for stimulant dependence; (3) clinical reports with stimulant medications in cocaine dependence, and the amphetamine replacement strategy for amphetamine dependence; (4) application of agonist-like/replacement strategies, including clinical requirements and risks; and (5) directions for research.