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PURPOSE OF REVIEW: This review examines the neurocognitive effects of cannabis and relevant developmental factors across adolescence (age 13–21), adulthood (21–65), and older adulthood (65+). RECENT FINDINGS: Cannabis use is robustly associated with poorer neurocognitive functioning; however, studies that carefully control for confounds have often not found any evidence for impairment. Notably, the endocannabinoid system may underly how cannabis use affects neurocognitive functions, including heightened vulnerability during adolescence. In contrast, the endocannabinoid system may underlie protective neurocognitive effects of cannabis in older adults. Notably, older adults have reported sharp increases in recent cannabis use. SUMMARY: As legalization increases the accessibility, variety, and potency of cannabis, strong empirical evidence is needed to understand its neurocognitive effects across the lifespan. In particular, rigorous study designs are needed to investigate the neurocognitive effects of cannabis, including among vulnerable populations (adolescents, older adults) and mediating (e.g., endocannabinoid system) and moderating factors (e.g., alcohol use).

Importance There is a pressing need for development of novel pharmacology for the treatment of Posttraumatic Stress Disorder (PTSD). Given increasing use of medical cannabis among US military veterans to self-treat PTSD, there is strong public interest in whether cannabis may be a safe and effective treatment for PTSD. Objective The aim of the present study was to collect preliminary data on the safety and potential efficacy of three active concentrations of smoked cannabis (i.e., High THC = approximately 12% THC and < 0.05% CBD; High CBD = 11% CBD and 0.50% THC; THC+CBD = approximately 7.9% THC and 8.1% CBD, and placebo = < 0.03% THC and < 0.01% CBD) compared to placebo in the treatment of PTSD among military veterans. Methods The study used a double-blind, cross-over design, where participants were randomly assigned to receive three weeks of either active treatment or placebo in Stage 1 (N = 80), and then were re-randomized after a 2-week washout period to receive one of the other three active treatments in Stage 2 (N = 74). The primary outcome measure was change in PTSD symptom severity from baseline to end of treatment in Stage 1. Results The study did not find a significant difference in change in PTSD symptom severity between the active cannabis concentrations and placebo by the end of Stage 1. All three active concentrations of smoked cannabis were generally well tolerated. Conclusions and relevance The present study is the first randomized placebo-controlled trial of smoked cannabis for PTSD. All treatment groups, including placebo, showed good tolerability and significant improvements in PTSD symptoms during three weeks of treatment, but no active treatment statistically outperformed placebo in this brief, preliminary trial. Additional well-controlled and adequately powered studies with cannabis suitable for FDA drug development are needed to determine whether smoked cannabis improves symptoms of PTSD. Trial registration Identifier: NCT02759185; ClinicalTrials.gov.

Medical research is often designed to investigate changes in a collection of response variables that are measured repeatedly on the same subjects. The multivariate generalized linear mixed model (MGLMM) can be used to evaluate random coefficient associations (e.g. simple correlations, partial regression coefficients) among outcomes that may be non-normal and differently distributed by specifying a multivariate normal distribution for their random effects and then evaluating the latent relationship between them. Empirical Bayes predictors are readily available for each subject from any mixed model and are observable and hence, plotable. Here, we evaluate whether second-stage association analyses of empirical Bayes predictors from a MGLMM, provide a good approximation and visual representation of these latent association analyses using medical examples and simulations. Additionally, we compare these results with association analyses of empirical Bayes predictors generated from separate mixed models for each outcome, a procedure that could circumvent computational problems that arise when the dimension of the joint covariance matrix of random effects is large and prohibits estimation of latent associations. As has been shown in other analytic contexts, the p-values for all second-stage coefficients that were determined by naively assuming normality of empirical Bayes predictors provide a good approximation to p-values determined via permutation analysis. Analyzing outcomes that are interrelated with separate models in the first stage and then associating the resulting empirical Bayes predictors in a second stage results in different mean and covariance parameter estimates from the maximum likelihood estimates generated by a MGLMM. The potential for erroneous inference from using results from these separate models increases as the magnitude of the association among the outcomes increases. Thus if computable, scatterplots of the conditionally independent empirical Bayes predictors from a MGLMM are always preferable to scatterplots of empirical Bayes predictors generated by separate models, unless the true association between outcomes is zero.

Purpose We sought to describe the prevalence of the nonmedical use of prescription opioids (NMUPO) and its association with co-occurring substance use disorders in a sample of adolescents in substance treatment. Methods Adolescents in two substance treatment programs were recruited for participation between 2009 and 2013. The Composite International Diagnostic Interview—Substance Abuse Module (CIDI-SAM) was administered to assess substance use patterns and lifetime abuse or dependence. Results A total of 378 adolescents completed the CIDI-SAM (mean age 16.1 [standard deviation = 1.1], 78% male, 50% white, non-Hispanic). Of the 378 adolescents, 62 (16.4%) reported NMUPO and 59 (15.6%) were diagnosed with opioid/heroin abuse or dependence. The mean age at first NMUPO was 14.3 (standard deviation = 1.4). NMUPO was associated with a 3.31-fold (95% confidence interval: 2.83–3.79) increase in having three or more co-occurring substance use diagnoses. Conclusions NMUPO is quite prevalent among adolescents in substance use treatment. Intervention to interrupt NMUPO from progressing to heroin use or developing into a disorder is critical.

Mediation analysis evaluates the significance of an intermediate variable on the causal pathway between an exposure and an outcome. One commonly utilized test for mediation involves evaluation of counterfactual effects, estimated from separate regression models, corresponding to a composite null hypothesis. However, the “compositeness” of this null hypothesis is not commonly acknowledged and accounted for in mediation analyses. We describe a generalized multivariate approach in which these separate regression models are fit simultaneously in a single parsimonious model. This multivariate modeling approach can reproduce standard mediation analysis and has notable advantages over separate regression models, including the ability to combine distributions in the exponential family with any link functions and perform likelihood-based tests of some relevant hypotheses using existing software. We propose the use of a novel visual representation of confidence intervals of the two estimates for the indirect path with the use of a confidence ellipse. The calculation of the confidence ellipse is facilitated by the multivariate approach, can test the components of the composite null hypothesis under a single experiment-wise type I error rate, and does not require estimation of the standard error of the product of coefficients from two separate regressions. This method is illustrated using three examples. The first compares results between the multivariate method and separate regression models. The second example illustrates the proposed methods in the presence of an exposure–mediator interaction, missing data and confounding, and the third example utilizes these proposed methods for an outcome and mediator with negative binomial distributions.

Blunted: The Effects of Cannabis on Cognition and Motivation The effects of cannabis on cognition and motivation are key considerations both for clinicians and policy makers alike. The medical research on this topic shows some inconsistency in their conclusions but overall suggests that cannabis can indeed lead to reduced cognitive and motivational abilities, particularly in the areas of verbal memory and attention. Despite suggestions to the contrary, the strength of this evidence goes well beyond simple correlational studies. Fortunately, evidence suggests that at least most of the deficits can be reversed with sustained abstinence, although more research in this area needs to be done. One reason for some of the inconsistent findings in this area may be related to important variables such as amount of use, age, and perhaps THC content that can moderate the amount of risk involved in cannabis use. Research is now going beyond the question of if cannabis is related to cognitive problems and toward a greater understanding of mechanisms that may underlie this process.

In the most recent 2016 National Survey on Drug Use and Health (NSDUH),1 more than 1.3 million adolescents aged 12 to 17 years reported past-year nonmedical use of prescription drugs. About 70% started using in the past year, and about half report nonmedical use of prescription opioid medications. Misuse of prescription opioid medication is associated with 19 times greater risk of transitioning to heroin compared to no misuse.2 Although the national opioid crisis affects all age groups, the steepest rise in unintentional opioid overdose fatalities has been in young adults aged 18 to 25 years.2,3 More than 80% of young adult injection heroin users report that they started using prescription opioids, most during adolescence, before transitioning to heroin.3 While it is clear that the seeds of opioid addiction often begin during adolescence, there are many gaps in our knowledge and understanding of sources and predictive risk factors to guide development of more effective and targeted youth interventions.

Schools provide an ideal setting for screening, brief interventions, and outpatient treatment for substance use disorders (SUD). Individual treatment for SUD is effective at decreasing substance use as well as substance-related harm. In some contexts, rather than being helpful, group interventions can result in harm to participants; therefore, individual treatment may be preferred. Early interventions for adolescents who are using alcohol and other drugs (AOD) are generally effective in decreasing frequency and quantity of AOD use as well as decreasing risky behaviors.

Significant progress has been made in development and dissemination of evidence-based behavioral interventions for adolescents with substance use disorders (SUD). Medications have also shown promise in reducing substance use when used in conjunction with psychosocial treatment for adolescents with SUD, even in the context of co-occurring psychopathology. Although the efficacy or “probable efficacy” of the behavioral interventions discussed in this review have been established based on at least two randomized controlled trials, they produce relatively low abstinence rates and modest reductions in substance use that attenuate over time. Research has shown that abstinence rates may increase with the addition of abstinence-based incentives, however, post-treatment relapse rates remain high with few treated adolescents sustaining abstinence one year post-treatment. This may be due to the paucity of continuing care or post-treatment recovery support services and the lack of integrated or concurrent treatment for co-occurring psychiatric conditions that contribute to poorer treatment outcomes. Thus, despite significant progress, there is clearly room for improvement of existing treatment for adolescents with SUD. There is also critical need to increase the availability and access to substance and behavioral health treatment services for adolescents. Although 10–15% of U.S. high school students would currently meet diagnostic criteria for at least one SUD, only 10% of those who could benefit from substance treatment receive it. Five-year trends showing significant increases in the use of marijuana and nonmedical prescription drugs among U. S. high school students are evidence of the shortcomings of existing school-based interventions and poor access to community-based substance treatment for non-juvenile-justice involved youth. There is clearly a need to adapt or develop more effective prevention, early interventions, and treatment for youth who are “at risk” as well as the increasing number of adolescents who have progressed to more serious substance involvement.

The nonmedical use of prescription drugs is the fastest growing drug problem in the United States, disproportionately impacting youth. Furthermore, the population prevalence of injection drug use among youth is also on the rise. This short communication examines the association between current prescription drug misuse (PDM) and injection among runaway and homeless youth.Homeless youth were surveyed between October 2011 and February 2012 at two drop-in service agencies in Los Angeles, CA. Prevalence ratios (PR) and 95% confidence intervals (CI) for the association between current PDM and injection behavior were estimated. The outcome of interest was use of a needle to inject any illegal drug into the body during the past 30 days.Of 380 homeless youth (median age, 21; IQR, 17-25; 72% male), 84 (22%) reported current PDM and 48 (13%) reported currently injecting. PDM during the past 30 days was associated with a 7.7 (95% CI: 4.4, 13.5) fold increase in the risk of injecting during that same time. Among those reporting current PDM with concurrent heroin, cocaine, and methamphetamine use, the PR with injection was 15.1 (95% CI: 8.5, 26.8).Runaway and homeless youth are at increased risk for a myriad of negative outcomes. Our preliminary findings are among the first to show the strong association between current PDM and injection in this population. Our findings provide the basis for additional research to delineate specific patterns of PDM and factors that enable or inhibit transition to injection among homeless and runaway youth.

on DSM-5, 14 • Editor’s Note, 15 ADHD in teens is associated with a higher risk for comorbid substance use disorder (SUD), and those teens are at greater risk for negative outcomes, such as poorer academic achievement and school dropout (Barkley, Murphy, & Fischer, 2008), and may be more difficult to treat than adolescents with only one of the diagnoses. It is important to know if there are any factors that predict better or worse treatment outcomes in this difficult-to-treat population. This is particularly critical since up to half of individuals with persistent ADHD also meet criteria for an SUD (Sullivan & Rudnik-Levin, 2001). Similarly, up to 20% of individuals with an SUD also have comorbid ADHD (Wilens, 2007). Individuals with ADHD start using substances earlier (Ernst et al., 2006), use substances for longer, are more likely to progress from alcohol abuse to another drug disorder (Kousha, Shahrivar, & Alaghband-Rad, 2012; Sullivan & Rudnik-Levin, 2001), and transition more quickly between abuse and dependence diagnoses (Kousha et al., 2012; Riggs, Mikulich, Whitmore, & Crowley, 1999; Wilens, 2007) than individuals without ADHD. ADHD also poses a risk for treatment failure as disruptive behaviors may interfere with treatment adherence and compliance (Whitmore & Riggs, 2006; Wise, Cuffe, & Fischer, 2001). In the current report, we summarize results of a recent paper published in the Journal of Substance Abuse Treatment investigating treatment response to stimulant medication and cognitive behavioral therapy in adolescents diagnosed with ADHD with a co-occurring non-tobacco SUD (Tamm et al., 2013). Based on the literature, we opted to investigate whether substance use severity, ADHD severity, conduct disorder, and/or court-mandated status significantly predicted treatment outcomes.

Attention-Deficit/Hyperactivity Disorder (ADHD) frequently co-occurs with substance use disorder (SUD) and is associated with poor substance-use treatment outcomes. A trial evaluating osmotic-release oral system methylphenidate (OROS-MPH) for adolescents with ADHD and SUD, concurrently receiving behavioral therapy, revealed inconsistent medication effects on ADHD or SUD. Clinical care for this population would be advanced by knowledge of treatment outcome predictors. Data from the randomized placebo-controlled trial (n = 299) were analyzed. Significant treatment predictors included: 1) Substance use severity, associated with poorer ADHD and SUD outcomes, 2) ADHD severity, associated with better ADHD and SUD outcomes, 3) comorbid conduct disorder, associated with poorer ADHD outcomes, and 4) court-mandated status, associated with better SUD outcomes but poorer treatment completion. An interaction effect showed that OROS-MPH improved SUD outcomes in adolescents with comorbid conduct disorder compared to placebo. While severe SUD may require more intensive psychosocial treatment, OROS-MPH may improve substance treatment outcomes in adolescents with co-morbid attention and conduct problems.

Research shows that the majority of adolescents with substance use disorders also have other cooccurring psychiatric disorders, which has been associated with poorer treatment outcomes. Despite considerable consensus that treatment of cooccurring disorders should be integrated or concurrent, most such youth do not receive it. In addition to systemic and economic barriers, few studies have been conducted that inform evidence-based integrated treatment approaches. This article provides a review of current research from which empirically derived principles of integrated treatment can originate and which have informed the development of at least one evidence-based model of integrated mental health and substance treatment.

Background The intertwining prescription opioid and heroin epidemic is a major public health problem in the United States, with increasing morbidity and mortality among persons who use these substances. We examined differences between persons who reported being hooked on prescription opioids prior to injecting for the first time and those who did not by demographics, injection and non-injection characteristics, and overdose. Methods Between June and December 2015, persons who inject drugs were recruited using respondent-driven sampling as part of the National HIV Behavioral Surveillance system in Denver, Colorado. Results Of 599 participants (median age, 40: IQR, 19–69; 71% male; 58% white, non-Hispanic), 192 (32%) reported being hooked on prescription opioids before they injected for the very first time. Compared to participants who were not hooked before they injected, participants who reported being hooked were significantly more likely to be younger, more recent injectors, report a slightly older age at first injection, and report heroin as the first drug injected as well as the drug most frequently injected. Those who reported being hooked were also more likely to be more frequent users of benzodiazepines, non-injection prescription opioids, and non-injection heroin as well as report injecting on a daily or more than daily basis. Being hooked on prescription opioids prior to injection drug use was associated with a 1.55 (95% CI: 1.14, 2.10) fold increase in the risk of at least one overdose in the past 12 months. Conclusions Being hooked on prescription opioids prior to injection might result in a higher risk profile for persons who inject drugs.

Objective To evaluate the efficacy and safety of osmotic-release methylphenidate (OROS-MPH) compared with placebo for attention-deficit/hyperactivity disorder (ADHD), and the impact on substance treatment outcomes in adolescents concurrently receiving cognitive-behavioral therapy (CBT) for substance use disorders (SUD). Method This was a 16-week, randomized, controlled, multi-site trial of OROS-MPH + CBT versus placebo + CBT in 303 adolescents (aged 13 through 18 years) meeting DSM-IV diagnostic criteria for ADHD and SUD. Primary outcome measures included the following: for ADHD, clinician-administered ADHD Rating Scale (ADHD-RS), adolescent informant; for substance use, adolescent-reported days of use in the past 28 days. Secondary outcome measures included parent ADHD-RS and weekly urine drug screens (UDS). Results There were no group differences on reduction in ADHD-RS scores (OROS-MPH: −19.2, 95% confidence interval [CI], −17.1 to −21.2; placebo, −21.2, 95% CI, −19.1 to −23.2) or reduction in days of substance use (OROS-MPH: −5.7 days, 95% CI, 4.0–7.4; placebo: −5.2 days, 95% CI, 3.5–7.0). Some secondary outcomes favored OROS-MPH, including lower parent ADHD-RS scores at 8 (mean difference=4.4, 95% CI, 0.8–7.9) and 16 weeks (mean difference=6.9; 95% CI, 2.9-10.9) and more negative UDS in OROS-MPH (mean = 3.8) compared with placebo (mean = 2.8; p = .04). Conclusions OROS-MPH did not show greater efficacy than placebo for ADHD or on reduction in substance use in adolescents concurrently receiving individual CBT for co-occurring SUD. However, OROS-MPH was relatively well tolerated and was associated with modestly greater clinical improvement on some secondary ADHD and substance outcome measures. Clinical Trial Registration Information—Attention Deficit Hyperactivity Disorder (ADHD) in Adolescents with Substance Use Disorders (SUD); http://www.clinicaltrials.gov; NCT00264797.

Purpose Estimate separate and combined prevalence of depression and frequent substance use (FSU), evaluate gender differences, and compare the severity of depression and substance use across groups in a sample of youth in the U.S. child welfare system. Methods Data on youth aged 11 to 15 years from the National Survey on Child and Adolescent Well-Being were used (N = 1179). Depression was assessed using the Children's Depression Inventory. Substances assessed included tobacco, alcohol, marijuana, inhalants, hard drugs, and use of prescription medication for non-medical purposes. Descriptive statistics and chi-square tests were used to estimate and compare prevalence rates. Multinomial logistic regression was used to estimate the age-adjusted effect of gender on depression/FSU. Results Depression was more than twice as common in girls as boys (17% versus 7%, p Conclusions Although the prevalence of depression was significantly higher among girls than boys, there were no gender differences in FSU prevalence. Boys with comorbid depression and FSU had more severe depressive symptoms as those with depression only.

Background: The present article reports on recruiting strategies in a 16-week, multi-site trial of osmotic-release methylphenidate combined with cognitive-behavioral therapy in adolescents with co-occurring attention deficit hyperactivity disorder and substance use disorder. Methods: A multifaceted recruiting strategy was employed that targeted multiple referral sources, used incentives, involved numerous staff members, emphasized the therapeutic alliance during prescreening, and utilized data to modify strategies based on results. Overall, 303 adolescents were randomized from 1,333 total referrals across 11 participating sites. Results: Overall, existing treatment program sources, including treatment program staff, social services, the juvenile justice system, and mental health clinics provided a majority of referrals for pre-screening and randomization. Conclusions and Scientific Significance: These results support the feasibility of recruiting dually-diagnosed adolescents utilizing a multifaceted appro...

Psychiatric comorbidity is defined as the co-occurrence of a psychiatric disorder in a patient with a substance use disorder. Psychiatric disorders in substance abuse patients can antedate the substance use disorder or be a consequence of the substance abuse. There is emerging evidence that drug use in adolescence may alter the onset of certain psychiatric disorders in vulnerable individuals. Patients with concurrent comorbid disorders present special challenges for the substance abuse treatment system in terms of diagnosis and management because each disorder has the capability of exacerbating the other. This manuscript is a summary of an ISAM symposium that featured three speakers who discussed the following topics: 1. Etiology and treatment of comorbid psychiatric and substance use disorders in adolescents; 2. Treatment of ADHD and substance use disorders in adults; 3. Effects of substance abuse on the onset, severity, and treatment of schizophrenia. Recommendations for further research will be presented.

Substance use disorders account for approximately 6% of deaths worldwide and cost about $700 billion in the United States. Approximately 80% of drug users begin using during adolescence, underscoring the public health importance of effective substance prevention programs for youth and families. Prevention science designates 3 intervention categories: (1) universal prevention, targeting all individuals in the population, (2) selective interventions, targeting high-risk groups, and (3) indicated prevention interventions for youth with risk-taking behaviors. School-based and non-school-based interventions are reviewed, as well as the limitations of existing research, gaps in access and availability, and directions for future research and development.

It is important to correctly understand the associations among addiction to multiple drugs and between co-occurring substance use and psychiatric disorders. Substance-specific outcomes (e.g. number of days used cannabis) have distributional characteristics which range widely depending on the substance and the sample being evaluated.We recommend a four-part strategy for determining the appropriate distribution for modeling substance use data. We demonstrate this strategy by comparing the model fit and resulting inferences from applying four different distributions to model use of substances that range greatly in the prevalence and frequency of their use.Using Timeline Followback (TLFB) data from a previously-published study, we used negative binomial, beta-binomial and their zero-inflated counterparts to model proportion of days during treatment of cannabis, cigarettes, alcohol, and opioid use. The fit for each distribution was evaluated with statistical model selection criteria, visual plots and a comparison of the resulting inferences.We demonstrate the feasibility and utility of modeling each substance individually and show that no single distribution provides the best fit for all substances. Inferences regarding use of each substance and associations with important clinical variables were not consistent across models and differed by substance.Thus, the distribution chosen for modeling substance use must be carefully selected and evaluated because it may impact the resulting conclusions. Furthermore, the common procedure of aggregating use across different substances may not be ideal.

This study utilized data on a treatment cohort from a randomized clinical trial that recruited adolescents with co-occurring major depression and substance use disorder (N=126). The purpose of this study was to compare adolescents for whom the onset of depression was first versus those for whom the onset of substance use disorder was first or in the same year as depression. Intake clinical evaluations were abstracted to yield common stressors that included childhood abuse, early loss or death, exposure to violence, and attachment problems. Tobacco, alcohol, and cannabis initiation and dependence were compared for the depression first and substance use disorder first groups, and within those groups by gender. Among the substances studied, only cannabis dependence was significantly more prevalent among those with depression first. Comparisons suggest some differences in the developmental path toward comorbid depression and substance use disorders, but remarkable similarity in measures of dependence and severity. Although small samples limited statistical significance, observed differences suggest possible avenues for prevention or intervention.

The prevalence and persistence of adolescent substance use and abuse is a national health issue, and substance use among adolescents is frequently comorbid with other psychiatric disorders. Most studies in this area utilize samples of middle or high school students or from inpatient settings. Less is known about substance use and psychiatric comorbidity among delinquent adolescents. The present study examined data from two cohorts of juvenile offenders collected over a 2-year period (n = 245, n = 299). Participants reported frequency of cigarette, alcohol, marijuana, and other substance use. Participants' parents completed a measure of behavior problems. Path analyses suggested that parental reports of externalizing problems were significantly related to self-reported substance use while parental reports of internalizing problems were not. Results also suggested that smoking and alcohol use act as mediators between externalizing problems and marijuana and other drug use. Although there were some mean differences by gender, the pattern of relationships amongst the variables did not differ by gender. Implications of the findings and future directions are discussed.

Recent research has identified a cluster of standardized approaches that effectively treat adolescents with substance abuse disorders. Many of these approaches share elements that may be adopted to improve outcomes in substance treatment programs. In adolescents, treatment goals should be informed by a comprehensive assessment that includes the adolescent patient’s developmental history and evaluation of psychiatric comorbidity. Treatment for behavioral, psychosocial, and psychiatric problems should be integrated with substance abuse interventions. The author describes practical clinical guidelines, grounded in current research, for providing integrated treatment services. Special emphasis is given to strategies for integrating the treatment of comorbid psychiatric disorders with substance use disorders in adolescents.

Objective The Genes for Treatment study is an international, multisite collaboration exploring the role of genetic, demographic, and clinical predictors in response to cognitive-behavioral therapy (CBT) in pediatric anxiety disorders. The current article, the first from the study, examined demographic and clinical predictors of response to CBT. We hypothesized that the child’s gender, type of anxiety disorder, initial severity and comorbidity, and parents’ psychopathology would significantly predict outcome. Method A sample of 1,519 children 5 to 18 years of age with a primary anxiety diagnosis received CBT across 11 sites. Outcome was defined as response (change in diagnostic severity) and remission (absence of the primary diagnosis) at each time point (posttreatment, 3-, 6-, and/or 12-month follow-up) and analyzed using linear and logistic mixed models. Separate analyses were conducted using data from posttreatment and follow-up assessments to explore the relative importance of predictors at these time points. Results Individuals with social anxiety disorder (SoAD) had significantly poorer outcomes (poorer response and lower rates of remission) than those with generalized anxiety disorder (GAD). Although individuals with specific phobia (SP) also had poorer outcomes than those with GAD at posttreatment, these differences were not maintained at follow-up. Both comorbid mood and externalizing disorders significantly predicted poorer outcomes at posttreatment and follow-up, whereas self-reported parental psychopathology had little effect on posttreatment outcomes but significantly predicted response (although not remission) at follow-up. Conclusion SoAD, nonanxiety comorbidity, and parental psychopathology were associated with poorer outcomes after CBT. The results highlight the need for enhanced treatments for children at risk for poorer outcomes.

Different types of outcomes (e.g. binary, count, continuous) can be simultaneously modeled with multivariate generalized linear mixed models by assuming: (1) same or different link functions, (2) same or different conditional distributions, and (3) conditional independence given random subject effects. Others have used this approach for determining simple associations between subject-specific parameters (e.g. correlations between slopes). We demonstrate how more complex associations (e.g. partial regression coefficients between slopes adjusting for intercepts, time lags of maximum correlation) can be estimated. Reparameterizing the model to directly estimate coefficients allows us to compare standard errors based on the inverse of the Hessian matrix with more usual standard errors approximated by the delta method; a mathematical proof demonstrates their equivalence when the gradient vector approaches zero. Reparameterization also allows us to evaluate significance of coefficients with likelihood ratio tests and to compare this approach with more usual Wald-type t-tests and Fisher’s z transformations. Simulations indicate that the delta method and inverse Hessian standard errors are nearly equivalent and consistently overestimate the true standard error. Only the likelihood ratio test based on the reparameterized model has an acceptable type I error rate and is therefore recommended for testing associations between stochastic parameters. Online supplementary materials include our medical data example, annotated code, and simulation details.

Anxiety disorders frequently occur in individuals with neurologic illness. Anxiety may be a symptom of or a reaction to the neurologic disorder, a medication side effect, or a comorbid condition. The most common anxiety disorders seen in neurologic patients are panic disorder, generalized anxiety disorder, social phobia, and obsessive-compulsive disorder (OCD). Very often, these conditions go unrecognized (and therefore untreated) or are attributed to being a normal response to having a neurologic illness. However, if they are not treated, anxiety disorders can significantly increase morbidity and mortality in neurologic patients. Selective serotonin reuptake inhibitors (SSRIs) should be considered the first-line of pharmacologic treatment, because they offer a broad spectrum of efficacy in the anxiety disorders, are generally well tolerated, and are effective in treating comorbid depression. Benzodiazepines, although most effective for acute anxiety, are now considered adjunctive or second-line treatments. Cognitive behavioral therapy and other behavioral treatments are effective in the treatment of anxiety disorders. They should be considered primary treatments for patients who cannot tolerate or prefer not to take medications.

This study used standardized interviews to examine the relationship of attention deficit hyperactivity disorder (ADHD), major depression (MDD), and other illicit substance use disorders (SUD) to onset and severity of nicotine dependence in 82 female and 285 male adolescents with conduct disorder (CD) and SUD. Results indicate that both ADHD and MDD significantly contribute to severity of nicotine dependence in delinquents with SUD. ADHD is further associated with earlier onset of regular smoking in males. Severity of non-tobacco SUD also was related directly to nicotine dependence severity in both males and females, and to earlier onset of smoking in males. Our findings illuminate the contribution of comorbidity to nicotine dependence and its relationship to other SUD severity among adolescents with CD and SUD and highlight the need for coordinated assessment and treatment of smoking cessation along with concurrent treatment of other drug use and psychiatric comorbidity such as ADHD and MDD in such youths.

Objective: In adolescents, conduct disorder (CD), attention deficit hyperactivity disorder (ADHD), and depression are frequently comorbid with substance dependence (SD). We hypothesized that the prevalence and severity of CD, major depressive disorder (MDD), and ADHD would differ by gender, and that these conditions would associate differentially with severity of SD in males and females. Method: We examined these issues, using standardized diagnostic interviews, in 285 male and 82 female adolescents referred for comorbid CD and SD. Results: Males and females did not differ significantly in severity of substance involvement, MDD, or ADHD, but males had more severe CD. MDD severity was the only variable significantly associated with SD severity for females, while for males, severity of CD combined with MDD and ADHD was significantly associated with SD severity. Conclusions: Among referred adolescents, CD, MDD, and ADHD may all be important concomitants of SD in males, while in females, depression may be the primary variable related to SD.

We examined adolescents with conduct disorder (CD) and substance problems to determine if those with attention deficit hyperactivity disorder (ADHD) symptomatology had more severe delinquency and substance involvement. ADHD symptomatology was assessed in two ways: (1) by self-reports using the Diagnostic Interview Schedule for Children (DISC) and (2) by use of DISC plus reports of others (parents, program staff, and program teacher). We divided boys into three ADHD groups based on DISC: those who met criteria, those who reported at least eight current symptoms, and those who reported fewer than eight symptoms. We also divided the same boys into two groups: those with reports of ADHD by two or more sources and those without this multisource ADHD. Examining these definitions of ADHD revealed that boys with either self- or multisource ADHD had more CD symptoms, earlier age of CD onset, more substance dependence diagnoses, and more comorbid depression and anxiety.

Psychostimulants are effective treatments for attention-deficit/hyperactivity disorder (ADHD) but may be associated with euphoric effects, misuse/diversion, and adverse effects. These risks are perceived by some clinicians to be greater in substance-abusing adolescents relative to non-substance-abusing adults. The present study evaluates the subjective effects, misuse/diversion, and adverse effects associated with the use of osmotic-release oral system methylphenidate (OROS-MPH), relative to placebo, for treating ADHD in adolescents with a substance use disorder (SUD) as a function of substance use severity and compared these risks with those associated with the treatment of ADHD in adults without a non-nicotine SUD.Datasets from two randomized placebo-controlled trials of OROS-MPH for treating ADHD, one conducted with 303 adolescents (13-18) with at least one non-nicotine SUD and one with 255 adult smokers (18-55), were analyzed. Outcome measures included the Massachusetts General Hospital Liking Scale, self-reported medication compliance, pill counts, and adverse events (AEs).Euphoric effects and misuse/diversion of OROS-MPH were not significantly affected by substance use severity. The euphoric effects of OROS-MPH did not significantly differ between the adolescent and adult samples. Adults rated OROS-MPH as more effective in treating ADHD, whereas adolescents reported feeling more depressed when taking OROS-MPH. The adolescents lost more pills relative to the adults regardless of treatment condition, which suggests the importance of careful medication monitoring. Higher baseline use of alcohol and cannabis was associated with an increased risk of experiencing a treatment-related AE in OROS-MPH, but baseline use did not increase the risk of serious AEs or of any particular category of AE and the adolescents did not experience more treatment-related AEs relative to the adults.With good monitoring, and in the context of substance abuse treatment, OROS-MPH can be safely used in adolescents with an SUD despite non-abstinence.

Little is known about the relationship between attention-deficit/hyperactivity disorder (ADHD) subtypes and substance-use disorder (SUD). As there is literature suggesting different subtype phenotypes, there may be subtype differences in regard to the risk for developing SUD and substance treatment response.To characterize the sample in a Clinical Trials Network (CTN) study according to ADHD subtypes and baseline psychosocial and substance-use characteristics and to compare subtypes on response to treatment.Secondary analyses on data collected from adolescents (n = 276) diagnosed with ADHD and SUD (non-nicotine) and treated with stimulant medication or placebo and cognitive behavioral therapy (CBT) for substance use. Participants were characterized as inattentive or combined ADHD subtype and compared on baseline characteristics and treatment outcome.The combined subtype presented with more severe SUDs and higher rates of conduct disorder. There were a greater proportion of boys with inattentive subtype. The inattentive subtype appeared less ready for treatment (greater University of Rhode Island Change Assessment precontemplation scores) with poorer coping skills (poorer problem-solving and abstinence focused coping) at baseline. However, the two subtypes responded equally to treatment even after controlling for baseline differences.Findings from this large community sample indicate that there were no subtype differences in treatment response, although there were differences in terms of substance use, antisocial behavior, readiness for treatment, and gender prior to treatment.This study is the first to report on subtype differences for treatment response for non-nicotine SUD in a comorbid ADHD-SUD population. Despite some baseline differences, both subtypes responded equally to treatment, suggesting limited relevance for subtype designation on treatment planning.

Major depressive disorder (MDD) frequently co-occurs in adolescents with substance use disorders (SUDs) and attention deficit hyperactivity disorder (ADHD), but the impact of MDD on substance treatment and ADHD outcomes and implications for clinical practice are unclear.Adolescents (n=303; ages 13-18) meeting DSM-IV criteria for ADHD and SUD were randomized to osmotic release methylphenidate (OROS-MPH) or placebo and 16 weeks of cognitive behavioral therapy (CBT). Adolescents with (n=38) and without (n=265) MDD were compared on baseline demographic and clinical characteristics as well as non-nicotine substance use and ADHD treatment outcomes.Adolescents with MDD reported more non-nicotine substance use days at baseline and continued using more throughout treatment compared to those without MDD (p0.0001 based on timeline followback; p0.001 based on urine drug screens). There was no difference between adolescents with and without MDD in retention or CBT sessions attended. ADHD symptom severity (based on DSM-IV ADHD rating scale) followed a slightly different course of improvement although with no difference between groups in baseline or 16-week symptom severity or 16-week symptom reduction. There was no difference in days of substance use or ADHD symptom outcomes over time in adolescents with MDD or those without MDD treated with OROS-MPH or placebo. Depressed adolescents were more often female, older, and not court ordered.These preliminary findings suggest that compared to non-depressed adolescents with ADHD and SUD, those with co-occurring MDD have more severe substance use at baseline and throughout treatment. Such youth may require interventions targeting depression.

Background Cigarette smoking is common in adolescents with attention-deficit/hyperactivity disorder (ADHD) and substance use disorders (SUD). However, little is known about the relationship between cigarette and cannabis use trajectories in the context of treatment for both ADHD and SUD. To address this research gap, we report collateral analyses from a 16-week randomized, controlled trial (n = 303) of osmotic-release methylphenidate (OROS-MPH) in adolescents with ADHD concurrently receiving cognitive behavioral therapy (CBT) targeting non-nicotine SUD. Methods Participants completed cigarette and cannabis use self-report at baseline and throughout treatment. Analyses were performed to explore the relationships between cigarette smoking, cannabis use, and other factors, such as medication treatment assignment (OROS-MPH versus placebo). Results Baseline (pre-treatment) cigarette smoking was positively correlated with cannabis use. Negligible decline in cigarette smoking during treatment for non-nicotine SUD was observed in both medication groups. Regular cigarette and cannabis users at baseline who reduced their cannabis use by >50% also reduced cigarette smoking (from 10.8 ± 1.1 to 6.2 ± 1.1 cigarettes per day). Conclusions Findings highlight the challenging nature of concurrent cannabis and cigarette use in adolescents with ADHD, but demonstrate that changes in use of these substances during treatment may occur in parallel.

Objective To evaluate the effect of atomoxetine hydrochloride versus placebo on attention-deficit/hyperactivity disorder (ADHD) and substance use disorder (SUD) in adolescents receiving motivational interviewing/cognitive behavioral therapy (MI/CBT) for SUD. Method This single-site, randomized, controlled trial was conducted between December 2005 and February 2008. Seventy adolescents (13 through 19 years of age) with Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) (DSM-IV) ADHD, a DSM-IV ADHD checklist score greater than or equal to 22, and at least one nontobacco SUD were recruited from the community. All subjects received 12 weeks of atomoxetine hydrochloride + MI/CBT versus placebo + MI/CBT. The main outcome measure for ADHD was self-report DSM-IV ADHD checklist score. For SUD, the main outcome was self-report number of days used nontobacco substances in the past 28 days using the Timeline Followback interview. Results Change in ADHD scores did not differ between atomoxetine + MI/CBT and placebo + MI/CBT (F4,191 = 1.23, p=.2975). Change in days used nonnicotine substances in the last 28 days did not differ between groups (F3,100 = 2.06, p=.1103). Conclusions There was no significant difference between the atomoxetine + MI/CBT and placebo + MI/CBT groups in ADHD or substance use change. The MI/CBT and/or a placebo effect may have contributed to a large treatment response in the placebo group. Clinical Trials Registry Information—A Randomized, Placebo-Controlled Trial of Atomoxetine for Attention-Deficit/Hyperactivity Disorder in Adolescents with Substance Use Disorder. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00399763.

The steep escalation in non-medical use and abuse of prescription medications in recent years has begun to seriously affect public health, calling for increased clinician awareness. Effective action and collaborative efforts are required to reduce prescription drug abuse while ensuring that availability of needed prescription medications for the majority of patients who use them appropriately is not inadvertently diminished.To educate physicians, clinicians, and other healthcare providers about the scope of non-medical prescription drug abuse and effective clinical management strategies to reduce abuse and diversion of prescription medications.Articles were identified through PubMed and PsycINFO searches (January 2000 to November 2007). Search terms included combinations of 'prescription drug abuse', 'substance abuse', and 'non-medical use of prescription drugs'. Government agency Web sites were searched for additional references.Data from recent national surveys and other published reports indicate that the lifetime prevalence of non-medical prescription drug use/abuse in the United States is approximately 20% (48 million persons agedor = 12 years). Public health concern is further heightened by a significant increase in past-month use among adolescents (3.3% of 12-17 year olds) and young adults (6.4% of 18-25 year olds) and the vulnerability of a growing elderly population.Increased clinician awareness of the scope, demographics, and current trends in prescription medication abuse can be used to enhance screening and effective clinical management skills and strategies to reduce abuse and diversion of prescription drugs without compromising access to needed medications for the majority of patients who use them appropriately.

Advances in neurobiological research related to interventions in adolescents with substance use disorders: Research to practice Paula D. Riggs a,∗, Laetitia L. Thompson a, Susan F. Tapert b, Joseph Frascella c, a a a a Susan Mikulich-Gilbertson , Manish Dalwani , Mark Laudenslager , Michelle Lohman a University of Colorado, School of Medicine, CO, USA b University of California, San Diego, CA, USA ional lth, U