18 Treatment of Substance Use Disorders

The high rate of adolescent substance abuse in the United States (Forrester 2012; Jones et al., 2015; Substance Abuse and Mental Health Services Administration, 2014) makes the identification of effective treatment approaches a significant priority. Effective early intervention is crucial. Adolescents who initiate alcohol use by age 14 are significantly more likely to develop alcohol dependence as adults than those who initiate by age 20, with significant reductions in the odds of developing dependence for each year of delayed initiation (Barry et al., 2016; Grant, 1997; Von Diemen et al., 2008). Effective early intervention is also crucial with substance-abusing adolescents because it can play a preventive role in later years (Borduin, 1995; Kazdin, 1991, 1993; Pianca et al., 2016; Santisteban, 2003; Winters, Botzet, & Fahnhorst, 2011).

Alcohol remains the most commonly used age-restricted substance among adolescents in several countries (Brown et al., 2015; Kandel, 1993). However, a marked trend in recent years is the increased use of cannabis among adolescents, which has led to an increased demand for cannabis treatment. According to United Nations Office of Drugs and Crime (UNODC, 2012), North America has one of the highest prevalences of cannabis use (10.8%) worldwide. However, recent surveys indicate small decreases in cannabis use. One study examined time trends in tobacco and cannabis use among 15-year-olds in Europe and North America between 2002 and 2010 (Hublet et al., 2015). The authors included 28 countries, with 142,796 adolescents divided into “non-users,” “tobacco and cannabis users,” “tobacco-only users,” and “cannabis-only users.” Tobacco use and concurrent tobacco and cannabis use decreased by 3% and 3.7%, respectively, but prevalence rates varied by region. In the United States, there was an interaction between time and gender for tobacco and cannabis use. This is in agreement with the “Monitoring the Future Study: Trends in Prevalence of Various Drugs for 8th Graders, 10th Graders, and 12th Graders; 2012–2015,” where there was a reduction in the prevalence of cannabis use in the past month and daily use among students in 12th grade between 2012 and 2015. In Brazil, in 2012, 4.3% of the adolescents in a national survey reported lifetime use of cannabis, and 3.4% in the last month (Abdalla et al., 2014).

Despite the tendency for a decrease in cannabis prevalence among North American adolescents since the 1970s, there is a significant number of youth in need of marijuana treatment. From 1992 to 1998, the number of adolescents with primary, secondary, or tertiary problems related to cannabis who presented to the U.S. public treatment system grew from 51,081 to 109,875 (a 115% increase) (Dennis, Dawud-Noursi, Muck, & McDermeit, 2002). In 1998, over 80% of these adolescents received treatment in an outpatient setting. The bulk of treatment evaluation studies and clinical trials report that the most prevalent types of substance use in clinical populations are alcohol and marijuana, with some cocaine, heroin, methamphetamine, hallucinogen, and polysubstance use as well, based on setting and sample. The perception of the risks of marijuana use have steadily declined over the past decade among adolescents, possibly related to public debate about legalizing for medicinal and recreational use (Johnston et al., 2014). Medical emergencies possibly related to marijuana use have also increased. The Drug Abuse Warning Network (DAWN) estimated that in 2011, there were 456,000 drug-related emergency department visits in the United States in which marijuana use was mentioned in the medical record (a 21% increase over 2009) (Substance Abuse and Mental Health Services Administration, 2013).

Treatment of substance-abusing adolescents is complicated by a number of factors that appear to be particularly prevalent or problematic among adolescents (although they complicate treatment for adults as well). First, as noted above, adolescents in treatment or community samples use multiple substances, typically alcohol and marijuana, with occasional cocaine use (Kaminer, 2002; Szobot et al., 2007; Winters, 2000) and, increasingly, heroin as well. This reality is also seen among adolescents who use prescription stimulants (McCabe et al., 2014).

Second, as highlighted at several points throughout this volume, substance-using adolescents have very high rates of comorbid psychiatric disorders, which can greatly complicate treatment delivery and outcome. For example, Henggeler (1996) reported that 35% of participants in a clinical trial of family approaches (described in more detail below) met criteria for conduct disorder (CD), 19% for social phobia, 12% for oppositional defiant disorder (ODD), and 9% for major depression. In Waldron’s sample (Waldron, 2001), 89.8% had a history of significant delinquent behavior, 29.7% met criteria for anxiety and depressive disorders, and 27.3% had attention problems. Kaminer et al. (Kaminer, 2002) reported that 55% met criteria for an externalizing disorder, 39% for CD, 18% for attention-deficit/hyperactivity disorder (ADHD), 22% for major depression, and 26% for an anxiety disorder. Recently, Pianca et al. (2016) evaluated the comorbidity profile in adolescents hospitalized for crack cocaine use (n = 88) compared to community controls (n = 81). Based on DSM-IV-TR, the authors found a high lifetime prevalence (98.9%) of comorbidity, with 81.8% of CD, 52.3% of ODD, and 44.3% of ADHD; 46.6% had any anxiety disorder. For current comorbidities, the prevalence was also high: 74% for CD, 51.1% for ODD, and 39.8% for ADHD; 15.2% had any current mood disorder and 27.2% had any anxiety disorder. As discussed in more detail below, the presence of a comorbid disorder often indicates the need for evaluation for pharmacotherapy as well and, with it, the need to coordinate treatment to include close monitoring of treatment adherence and response. The presence of CD is particularly significant among substance-abusing adolescents as it is often associated with poor long-term treatment outcome and persistence of antisocial behavior in this population (Myers, 1998). Moreover, in some circumstances (e.g., deviant adolescents assigned to interactional groups), having a high proportion of adolescents with CD in unstructured treatment groups may lead to poor outcomes (Arnold, 1999; Dishion, 1999).

Third, treatment of substance-abusing adolescents is complicated by high rates of substance abuse in their immediate families. Henggeler (1996) reported that a substance abuse problem was present in 18% of birth mothers and 56% of the fathers of youth in his treatment sample. Winters (2000) reported that 66% of participants had at least one parent with substance use disorder. According to the 2009 National Survey on Drug Use and Health (NSDUH), approximately 8.3 million children under the age of 18 years have lived with at least one parent who abused alcohol or illicit drugs during the 12 months prior to the interview (Substance Abuse and Mental Health Services Administration, 2009). This is significant because parental substance use is associated with poor parenting practices and low levels of parent monitoring, which can exacerbate adolescent substance use (Chilcoat, 1995). Furthermore, exposure to drug use and drug-related cues within the household is likely to provoke craving in established adolescent substance abusers.

Fourth, adolescents rarely seek treatment voluntarily but are usually coerced at some level after experiencing school, legal, or medical problems (Brown, 1993). Treatment is also complicated by adolescents’ involvement in multiple systems and points of entry, as many have legal problems, school problems, and medical problems that may be identified prior to recognition of the presence of a substance use disorder (Henggeler, 1991). Thus, multiple treatment systems are simultaneously involved with a given individual. In this sense, ethical issues deserve more attention in future studies, as it is often difficult to distinguish between coercion and protection in these systems.

Finally, high attrition in treatment is also a particular problem among adolescents, with treatment completion rates for adolescents in therapeutic communities estimated at less than 20%; completion rates for outpatient programs are generally estimated at 50% (Henggeler, 1996).

Based on all these premises, treatment programs must be designed specifically for adolescents. There has been a lot of progress in recent decades concerning adolescent approaches, and treatment choice should consider, for instance, the severity of drug use and environmental factors, such as family conditions. The American Society of Addiction Medicine (2001) suggests the following patient placement levels, from least to most intensive:

Psychosocial approaches are essential when making a treatment plan. The most frequent treatment psychosocial approaches offered in adolescent drug addiction services are family-based therapy (FBT), with several theoretical orientations, and individual and group therapy (Becker & Cury, 2008; Winters, Botzet, & Fahnhorst, 2011). For individual and group therapy, despite the several theoretical available approaches, the most evaluated are cognitive-behavioral therapy (CBT), brief motivational interviewing (MI), and behavioral therapy, where contingency management (CM) reinforcement approaches are included. Some of these studies will be described later in this chapter.

There are rigorous evaluations of the efficacy and effectiveness of standard treatment approaches for adolescents. As of 2001, two major reviews identified between 32 and 53 published studies (Dennis & White, 2003; Williams et al., 2000). Overall, most of these were program evaluation studies of inpatient services, and only about 15 were randomized clinical trials (RCTs) in outpatient settings. Although the older studies tended to suffer from a range of methodological problems, a number of newer studies have provided more methodologically sound conclusions. These are reviewed by Waldron and Turner (2008) and more recently by Hogue and colleagues (2014). The newer studies are more likely to have high inclusion rates (>80%), experimental designs, manualized protocols, standardized measures, validation substudies, repeated measures, long-term follow-up (12 or more months), high follow-up rates (80%–90% or more), and an economic analysis of the cost and benefits to society.

Until about 2001, the three more intensive programs (inpatient, residential, and Outward Bound) had received the most attention from investigators. Roughly 30 to 40 studies existed, which primarily involved uncontrolled evaluations of a single treatment program (Williams et al., 2000). In these studies, it was difficult to determine the relative effectiveness of the approaches because few included any type of comparison or control group; however, in some studies, patients who dropped out of treatment served as a quasi-experimental control group (although this is clearly not an ideal comparison because of the possibility of selection bias). The primary outcome measures used in these studies were typically abstinence, drug use reduction, and treatment retention, although different studies tended to define these differently. Outcomes were almost always measured by self-report and often taken from clinical records rather than assessed by an independent evaluator. The use of validated outcome measures or biological indicators of substance use was rare. Thus, the highly positive outcomes typically reported by these studies should be tempered by an understanding of the substantial limitations of their designs. On average about 50% of patients reported significant decreases in substance use, typically measured as number of days with any drug use (Williams et al., 2000). Given that most of these programs emphasized complete abstinence, on average only 38% of those followed reported complete abstinence at 6 months.

A substantial number of studies have been conducted, including two important literature reviews on outpatient treatments for adolescents with substance use disorder. Waldron and Turner (2008), in an empirical review and meta-analysis of 17 RCTs, identified 46 different interventions: 17 with FBT, 13 with group CBT, seven with individual CBT, and nine with minimal treatment controls. Later, Hogue et al. (2014) updated Waldron and Turner´s revision; they included findings from literature reviews and meta-analyses for adolescent substance use disorder treatment from 2009 to 2013. One of the conclusions was the confirmation that protocol-driven interventions were more effective than treatment as usual; also, FBT had the strongest support and several manualized options; CBT (group or individual) and MI interventions also received empirical support. Besides these reviews, the authors selected 19 comparative studies and evaluated them according to sample characteristics, methodological quality, and substance use outcomes (based on Journal of Clinical and Adolescent Psychology Levels of Support Evaluation Criteria). One important point is that in this publication, effect size (ES) estimates were noted when available. The studies were evaluated according to the presence/mention of the following: random assignment; blind assessment; clear inclusion and exclusion criteria and sampling process; strong and reliable measures of substance use; sample size; follow-up duration of 6 months or longer; and statistical analysis using intent-to-treat, reporting between-group ESs for substance use disorder. Of the 19 included studies, 11 were considered to have effectiveness (three FBT, five MI, and the remaining integrating treatments such as CBT and MI). The effectiveness for the intervention was based on intra-group comparisons, mostly on ES at follow-up. For instance, in a study comparing Multidimensional Family Therapy (MDFT) versus CBT, an ES of 0.77 for substance frequency favoring MDFT intervention was reported (Liddle et al., 2009). In another study, considered not effective, MDFT was compared to individual CBT; the main outcome variable was self-reported delinquency and the ES was small (Hendriks et al., 2011). This review suggested some topics to improve adolescent substance abuse treatment, since despite the existence of effective interventions, only 7% of the adolescents in the United States meeting the diagnostic criteria for substance abuse receive specific treatment (U.S. Department of Mental Health, 2011). Thus, treatment delivery is an important issue. Some suggestions to make progress in this area are strategies like pursuing partnerships with influential governmental systems in order to achieve great market penetration and to use web-based technology (see Chapter 31 in this volume).

Despite the progress in more recent research, much more evidence is needed, such as longitudinal studies accounting for gene–environment interactions with treatment. For instance, an elegant study by Chung et al. (2014) evaluating 142 adolescents receiving substance use treatment found that the serotonin transporter linked polymorphic region (5-HTTLPR) genotype was associated with externalizing behaviors (S and L_G > L_AL_A), and externalizing behaviors predicted alcohol and marijuana problem severity at follow-up. This finding might have treatment implications. Adolescents with substance use disorder and with low-expressing (S and L_G) 5-HTTLPR alleles plus externalizing behavior could benefit from interventions targeting serotonergic functioning and externalizing behaviors, besides drug use–specific treatment. This article points toward integrative goals for further studies.

Also, some outcomes could be added in light of the current knowledge about drug use and its effects on the body. For instance, although most of the abused drugs have a systemic effect on body functions (de Jong et al., 2015; Spring et al., 2014), few studies include clinical data as participant description or as outcome measures, which is especially important for a population, such as adolescents, who are still in a growth period. It would be interesting to have clinical outcomes, like vascular or liver tests, besides infections, in these longitudinal studies, since drug addiction should be understood as a health issue.

Although residential and inpatient treatments warrant more research, focus on improving the effectiveness of outpatient services seems more promising, given that nearly 80% of adolescents with substance abuse at least initially receive outpatient treatment. In addition, outpatient services have many benefits (e.g., ability to characterize or dictate specific treatments, potential use of randomized designs, larger sample size).

Although few well-designed treatment evaluations of outpatient services exist, some of the most important large-scale studies involve primarily cannabis use and are summarized here. These multisite studies of existing practice generally defined minimal or no treatment as less than 90 days (13 weeks) of outpatient service, even though nearly 80% met that criteria. Changes in days of marijuana use were assessed in most of these studies, allowing some cross-study comparison. Among the 111 to 158 youths (under age 21) followed through the Drug Abuse Reporting Program (DARP; Sells & Simpson, 1979; Simpson et al., 1978) in the early 1970s, cannabis use rose from 3% to 10% in the 3 years following their discharge. Among the 87 adolescents receiving outpatient treatment in the Treatment Outcome Prospective Study (TOPS; Hubbard et al., 1985) in the early 1980s, the change in daily cannabis use from the year before to the year after treatment varied from a decrease of 42% (for those with less than 3 months of treatment) to an increase of 13% (for those with 3 or more months of treatment). Among the 156 adolescents receiving treatment (predominantly outpatient) in the Services Research Outcome Study during the late 1980s to early 1990s (SROS; OAS, 2000), cannabis use rose from 2% to 9% between the year before and the 5 years after treatment. Among the 236 adolescents in the National Treatment Improvement Evaluation Study (NTIES; CSAT, 1999; Gerstein, & Johnson, 1999) during the early 1990s, there was a 10% to 18% reduction in use between the year before and year after treatment. Among the 445 adolescents followed up after outpatient treatment in the Drug Abuse Treatment Outcome Study, Adolescents (DATOS-A; Grella et al., 2001; Hser et al., 2001) in the middle to late 1990s, there was a 21% to 25% reduction in cannabis use between the years before and after treatment. These findings are important, since cannabis is the most used illicit drug. However, a significant number of adolescents use more than one drug (polydrug users), usually alcohol, so evaluation in this context is strongly needed.

In recent decades, more outpatient follow-up studies became available, endorsing the idea that development-appropriate approaches are fundamental. One intervention is the Adolescent-Community Reinforcement Approach (A-CRA; Godley et al., 2001). A-CRA takes into account differences in adolescents’ patterns of use, addresses life areas that are developmentally appropriate for adolescents, and adds procedures for working with parents/caregivers (Godley et al., 2001). An individually based standalone treatment intervention, A-CRA is generally delivered with 10 individual sessions for adolescents, two with caregivers alone, and two with adolescents and caregivers combined. It has been shown to be among the most effective and cost-effective approaches for the treatment of adolescent substance abuse (Dennis et al., 2004). The treatment also allows polydrug users. Data from 399 adolescents, from one of four RCTs of A-CRA, were used to examine the extent to which exposure to A-CRA procedures mediated the relationship between treatment retention and outcomes. Participants were primarily male (68%), Caucasian (65%), and 15 or 16 years of age (55%). With regard to alcohol and other drug use, 72% reported weekly use of any other drug at intake, with nearly all participants self-reporting DSM-IV criteria for abuse (30%) or dependence (64%) in the year prior to intake. The authors concluded that there was a significant relationship between treatment exposure and reductions in any other drug use and related problems (Bryan et al., 2009). Besides treatment exposure, therapeutic alliance also had an association with cannabis reduction in adolescents. In a longitudinal study (12 months), patient-rated alliance predicted a reduction in cannabis use at 3 and 6 months and a reduction in substance-related problem behaviors at 6 months (Diamond et al., 2006).

RCTs are the gold standard for establishing the efficacy of a given approach, as they are the most rigorous approach that clinical investigators have for evaluating the effectiveness of a given treatment, in comparison with a well-defined control treatment, and while controlling for multiple threats to internal validity. While the number of well-designed controlled clinical trials of well-defined treatment approaches for substance-abusing adolescents is steadily increasing, the knowledge base regarding effective treatments continues to lag well behind that for adult substance use disorders. Drawing firm conclusions about treatment outcome and the relative benefits of different approaches is difficult, as few controlled clinical trials meet the rigorous standards required for determining that a treatment can be called “empirically supported” (Chambless, 1998). Many of the studies reviewed here are characterized by several threats to internal validity, including differential attrition, lack of validated independent outcome measures with objective evaluation of drug use, small sample sizes, lack of specification and evaluation of treatment fidelity and quality, dilution of interventions, and limited follow-up (Cottrell, 2002; Deas, 2001; Kaminer, 2002; Waldron, 1997). Thus, with only a few exceptions, caution must be used in drawing conclusions about the effectiveness of these approaches.

Becker and Curry (2008) conducted a literature review to assess the interventions for adolescent substance abuse. They rated each study (n = 31, published up to 2007) according to methodological issues: objective, sample size, power, outcome measures, sequence, allocation, active comparison, baseline measures, manualized treatment, treatment adherence, collateral report, objective measure, intention-to-treat analysis, treated case analysis, and blind assessment. From the 31 studies, just 16% had blind assessment of the outcome, indicating that this is a point that needs improvement. Eighty-one percent, on the other hand, had manualized interventions. FBT was the most frequently tested approach, with 22 models evaluated across 17 studies. “Brief motivational interventions” was the second most frequently investigated outpatient intervention, and three (out of four) methodologically stronger studies found good results for this modality. CBT was tested by four studies and was the intervention that was supported by the greatest proportion of methodologically stronger studies (100%). CBT models explicitly aimed to modify cognitive processes, beliefs, individual behaviors, or environmental reinforcers associated with the adolescent’s substance use.

Since the need for developmentally appropriate approaches became a consensus, much effort has been engaged toward this goal. The release of the Cannabis Youth Treatment (CYT) interventions was a significant advance for better-designed research on adolescent treatment follow-up (Diamond et al., 2002). Briefly, these five manual-guided treatment models were (a) a 6-week intervention consisting of two sessions of individual motivational enhancement therapy (MET) plus three sessions of group CBT (MET/CBT5); (b) a 12-week intervention of two sessions of MET plus 10 sessions of group CBT (MET/CBT12); (c) a 12-week intervention consisting of MET/CBT12 plus the family support network (FSN), a multicomponent intervention that includes parent education, family therapy, and case management; (d) a 12-week intervention based on A-CRA; and (e) MDFT. Dennis et al. (2004) presented the main outcome findings from two interrelated randomized trials conducted at four sites (n = 600 cannabis users, age 15 or 16) to evaluate the effectiveness and cost-effectiveness of five short-term outpatient interventions for adolescents with cannabis use disorders according to CYT. The five CYT interventions demonstrated significant pre–post treatment effects after 12 months in two main outcomes: days of abstinence and the percentage of adolescents in recovery (no use or abuse/dependence problems and living in the community). The outcomes were similar across sites and conditions; however, after controlling for initial severity, the most cost-effective interventions were MET/CBT5 and MET/CBT12 in Trial 1 and A-CRA and MET/CBT5 in Trial 2 (Dennis et al., 2004). The MET/CBT5 (CYT) intervention (n = 174) was tested with community-based outpatient treatment among 323 adolescents with marijuana problems. The outcome measures, over 12 months, were substance use problems, substance use frequency, emotional problems, illegal activities, recovery, and institutionalization. Youth who received MET/CBT5 exhibited greater reductions in substance use frequency, substance use problems, and illegal behaviors 12 months after treatment entry than those who entered community-based outpatient programs (Ramchand et al., 2011).

Another approach, with a manual for outpatient adolescents with substance abuse, thus allowing clinical studies, is Assertive Continuing Care (ACC; Godley et al., 2006). ACC sessions are conducted either with the adolescent individually, the caregiver alone, or the two together. This format is in part dictated by the setting of the intervention: in the adolescent’s home or community. ACC led to significantly greater continuing care linkage and retention and longer-term abstinence from marijuana in comparison to usual continuing care. ACC also resulted in better adherence to continuing care (Godley et al., 2007). An RCT including 320 adolescents evaluated the effectiveness and cost-effectiveness of two types of outpatient treatment, with and without ACC. Participants were randomly assigned to one of four conditions: (a) Chestnut’s Bloomington Outpatient Treatment without ACC; (b) Chestnut’s Bloomington Outpatient Treatment with ACC; (c) MET/CBT, seven-session model (MET/CBT7) without ACC; and (d) MET/CBT7 with ACC. Analysis of the costs of each intervention combined with its outcomes revealed that the most cost-effective condition was MET/CBT7 without ACC (Godley et al., 2010).

An RCT compared the efficacy of individual CBT and MDFT among 224 youth, primarily male (81%), from low-income single-parent homes (58%) with an average age of 15 years. The outcomes were substance use problem severity; 30-day frequency of cannabis use; 30-day frequency of alcohol use; 30-day frequency of other drug use; and 30-day abstinence. Both treatments produced significant decreases in cannabis use and slightly significant reductions in alcohol use, without differences in reducing the frequency of cannabis and alcohol use. Significant treatment effects were found favoring MDFT on substance use problem severity, among other outcomes. MDFT is notable for the sustainability of treatment effects (Liddle et al., 2008).

Another RCT allowed conclusions about treatment predictors. Hendriks et al. (2011) compared MDFT and CBT among 109 adolescents (13–18 years) and found that both approaches were equally effective in reducing cannabis use (ES = 0.14). In a secondary analysis of the trial data, there was an age-specific effect: older adolescents (17 or 18) benefited considerably more from CBT, and younger adolescents benefited considerably more from MDFT (p < .01). Similarly, adolescents with a past-year comorbid CD or ODD and those with internalizing problems achieved considerably better results in MDFT, while those without these coexisting psychiatric problems benefited much more from CBT (p < .01 and p = .02, respectively), again favoring the idea that MDFT is a good approach for more impaired youths (Hendriks et al., 2012).

A key defining feature of family and multisystem approaches is that they treat adolescents in the context of the family and social systems in which substance use develops and may be maintained. Thus, inclusion of family members in treatment (often with the provision of home visits) is seen as a critical strategy for reducing attrition and addressing multiple issues simultaneously (Henggeler, 1996; Liddle, 2001). Because they are grounded solidly in the knowledge base on adolescence and development and thus are well suited to the specific problems of this population, family-based approaches have been among the most widely studied approaches for adolescents in controlled trials and also have, to date, the highest levels of empirical support (Deas, 2001; Liddle, 1995; Waldron, 1997):

Reviews of formal clinical trials of family-based treatments have consistently found that more drug-abusing adolescents enter, engage in, and remain in family therapy than in other treatments and that family therapy produces significant reductions in substance use from pre- to post-treatment … in seven of eight studies comparing family therapy with a non-family-based intervention, adolescents receiving family therapy showed greater reductions in substance use than did those receiving adolescent group therapy, family education, and individual therapy, individual tracking through schools, or juvenile justice system interventions. (Waldron, 2001)

Moreover, the high level of support for family and multisystem approaches parallels findings from large meta-analyses pointing to the effectiveness of family therapies for adult substance users (Stanton, 1997). Family-based approaches are diverse, and many combine a variety of techniques, including family and individual therapies and skills and communication training, which may broaden the benefits of treatment by allowing greater individualization and enabling clinicians to address multiple factors in treatment (Waldron, 2001). The family-based approaches with the highest level of support with this population include Multisystemic Therapy (MST; Henggeler, 1990), Brief Strategic Family Therapy (BSFT; Szapocznik, 2012), and MDFT (Liddle, 2001).

MST is a manualized approach that addresses the multiple determinants of drug use and antisocial behavior. It is intended to promote fuller family involvement through engaging family members as collaborators in treatment, stressing the strength of the youth and their families, and addressing a broad and comprehensive array of barriers to attaining treatment goals. Therapists must be familiar with several empirically based therapies (including structural family therapy and CBT) and make frequent visits to the home and be available on a full-time basis to families. Henggeler et al. (1996) conducted a controlled trial with 118 substance-abusing or -dependent juvenile offenders (mean age 16) in which participants were randomly assigned to home-based MST and compared with usual community treatment services. The comparison condition involved referral by the youth’s probation officer to outpatient adolescent group meetings. Ninety-eight percent of families completed a full course of treatment (an average of 130 days and 40 hours of service provision), compared with very little service access among the youth assigned to the control group (78% of youths received no substance abuse or mental health services, and only 5% received both substance use and mental health services). Other studies showed that MST reduced re-arrest rates by up to 64% and was associated with significantly lower rates of substance-related arrests (Henggeler, 1991, 1997). In a later study, the authors evaluated 80 of the 118 original participants for a 4-year follow-up. A multimethod assessment battery was used to measure the criminal behavior, illicit drug use, and psychiatric symptoms of the participating young adults. In this follow-up, there was a significant long-term treatment effect for aggressive criminal activity, and biological measures indicated higher rates of marijuana abstinence for MST participants (Henggeler et al., 2002).

BSFT (Szapocznik, 2012) is a somewhat less intensive approach (it targets fewer systems and can be delivered in a once-per-week office-based format) that has also achieved an impressive level of empirical support. BSFT targets patterns of interaction in the family system that have been shown to influence adolescent drug abuse and consists of three classes of interventions: engaging all family members in treatment, identifying family strengths as well as roles and relationships linked to adolescent problems, and developing new family interactions (e.g., improved parenting skills and conflict resolution) to protect the adolescent. Home visits and use of specific engagement strategies are encouraged. In a comparison of 126 drug-abusing adolescents and their families that compared BSFT to a group control condition, 75% of those assigned to BSFT showed reliable improvement and 56% could be classified as recovered. In the control condition, only 14% showed reliable improvement, while 43% showed reliable deterioration in marijuana use (Santisteban, 2003). BSFT has also been shown to be associated with improved retention (Santisteban, 1996; Szapocznik, 1988) as well as significant reductions in the frequency of externalizing behaviors (aggression, delinquency) (Szapocznik, 1986).

A multisite randomized trial was designed to evaluate the effectiveness of BSFT compared to treatment as usual as provided in community-based adolescent outpatient drug abuse programs. Family participants were 480 adolescents and their family members. The primary outcome was adolescent drug use, assessed monthly via adolescent self-report and urinalysis for up to 1 year after randomization. BSFT was significantly more effective than treatment as usual in engaging and retaining family members in treatment and in improving parent reports of family functioning (effect size [EF] = 0.4), but differences in adolescent drug use were weak (Robbins et al., 2011).

MDFT is a multicomponent, staged family therapy that targets substance-abusing adolescents, their families, and their interactions. Liddle et al. (2001) assigned 182 substance-abusing adolescents who were referred by the criminal justice system or the schools to either MDFT, group therapy, or multifamily education. Treatment was delivered in weekly sessions over 6 months, with roughly 70% of participants completing treatment across conditions. Superior outcomes for the adolescents assigned to MDFT relative to other approaches were seen at termination and 1-year follow-up. At termination, 42% of those assigned to MDFT, 25% of those in group therapy, and 32% of those in family education had clinically significant reductions in their drug use. Positive outcomes have also been reported for other models of family therapy, including Family System Therapy (Joanning, 1992) and Functional Family Therapy (Friedman, 1989).

Henderson et al. (2010) analyzed two clinical trials on the effectiveness of MDFT with higher-severity substance-abusing adolescents. The first study compared individually focused CBT and MDFT in a sample of 224 ethnic-minority youths (average age 15 years). The second compared a cross-systems version of MDFT with enhanced services as usual for 154 youths (average age 15 years) who were incarcerated. Results favored MDFT, especially in youths with more severe drug use and greater psychiatric comorbidity. It seems, in fact, that this approach is of special interest when dealing with externalizing symptoms among adolescents with drug use (Schaub et al., 2014). Like any other clinical trial, it is always important to evaluate the context in which the intervention is evaluated, especially regarding the comparison intervention (Treatment as usual, or other family therapy approach, or other individual/group technique). In this sense, Hendriks et al. (2011) investigated whether MDFT was more effective than CBT in treatment-seeking adolescents with a DSM-IV cannabis use disorder in the Netherlands. Sample size was 109 adolescents. MDFT was not superior to CBT in terms of cannabis use, delinquent behavior, treatment response, and recovery at 1-year follow-up. Treatment intensity and retention were significantly higher in MDFT than in CBT. Post hoc subgroup analyses suggested that subgroups with high problem severity at baseline may benefit more from MDFT than from CBT, again favoring the idea that the most severely affected adolescents might benefit from MDFT

A wide range of individual behavioral interventions, including those that seek to provide alternative reinforcers to drugs or reduce reinforcing aspects of abused substances, are based on operant conditioning theory and recognition of the reinforcing properties of abused substances (Aigner, 1978; Bigelow, 1984; Thompson, 1971). For adult substance users, these approaches have among the highest empirical support (Griffith, 2000; NIDA, 2000). Examples include the work of Stitzer et al., which has demonstrated that persons with methadone-maintained opioid addiction will reduce illicit drug use when incentives such as take-home methadone are offered for abstinence (Stitzer, 1978, 1992, 1993), as well as contingency management (CM) incentive systems (Higgins, 1991, 1999; Kirby, 1998; Petry, 2000; Silverman, 1996; Stanger & Budney, 2010), which offer incentives for targeted treatment goals (e.g., retention, drug-free urine samples) on an escalating schedule of reinforcement.

Behavioral approaches have begun to be evaluated among substance-abusing adolescents. Azrin et al. (1994) assigned 26 substance-using adolescents to supportive counseling or behavior therapy, which consisted of therapist modeling and rehearsal, self-monitoring, and written assignments. After 6 months, urine toxicology screens as well as self-reports suggested significantly less substance abuse among the group assigned to behavioral therapy relative to supportive counseling, as well as better school and family functioning.

CM has started to be evaluated in adolescents. In a feasibility study that involved adolescent smokers as a model for drug use, Corby et al. (2000) found that providing cash incentives to adolescents enrolled in a smoking cessation project for not smoking (as assessed by twice-daily carbon monoxide levels) reduced adolescent smoking and also appeared to improve their mood. In a pilot study involving young-adult marijuana users referred by the criminal justice system, Sinha et al. (Sinha, in press) studied the use of vouchers that could be used to purchase items in neighborhood stores. By providing these vouchers as rewards contingent on session attendance, treatment retention improved significantly. Kaminer et al. (2014) investigated the efficacy of a voucher-based reinforcement therapy rewarding drug-free urine samples for adolescents with cannabis use disorder. It was a controlled 10-week study (n = 59; age 14–18 years) in which adolescents were assigned into groups of either integrated CBT and voucher-based reinforcement or CBT with an attendance-based reward program. There was no difference for cannabis use either from sessions 1 to 10 or between end-of-treatment to 3-month follow-up. Good results with CM were achieved when adolescents in the experimental condition (plus CBT, vs. a group without the CM, but just CBT) participated in an abstinence-based CM program based on previous trials for adult marijuana dependence with modification (Stanger, Budney, Kamon, & Thostensen, 2009).

In another study, adolescents received incentives only if they provided a urine specimen and breath specimen that tested negative for all substances and parent and self-reports indicated no substance use (including alcohol). For each substance-negative specimen and report during weeks 3 to 14, participants earned vouchers starting at $1.50 and escalating by $1.50 with each consecutive negative specimen. A $10 bonus was earned for each two consecutive negative results. Vouchers were reset back to their initial value if results were positive. Voucher earnings were redeemed for retail goods selected by the teen (e.g., a movie pass). There were two groups, both with Motivational Enhancement and CBT, plus FBT. The experimental group received the above-mentioned intervention and earned a mean of $312 (SD = $237) or $22.28 per week. The control group could earn $5 vouchers twice per week (maximum earnings of $140; average actual earnings = $113). The experimental group had fewer positive urine specimens (ES = 0.48) (Stanger et al., 2009). Another recent study with CM in adolescents and cannabis use demonstrated the effectiveness of this approach (Stanger et al., 2015).

Cognitive-behavioral approaches, based on social learning theory, are among the approaches with highest levels of empirical support for the treatment of adult substance use disorders. Key defining features of most cognitive-behavioral approaches for substance use disorders are (1) an emphasis on functional analysis of drug use—that is, understanding instances of substance use with respect to their antecedents and consequences, and (2) emphasis on skills training and self-regulation. CBT has been shown to be effective across a wide range of substance use disorders (Carroll, 1996; Irvin, 1999), including alcohol dependence (Morgenstern, 2000; Miller, 2002), marijuana dependence (MTP Research Group, 2001; Stephens, 2000), cocaine dependence (Carroll, 1994, 1998; McKay, 1997; Rohsenow, 2000), and nicotine dependence (Fiore, 1994; Hall, 1998; Patten, 1998). These findings are consistent with evidence supporting the effectiveness of CBT across a number of other psychiatric disorders as well, including depression, ADs, and eating disorders (DeRubeis, 1998).

CBT has also been evaluated as a treatment for adolescent substance use disorders. In an extremely well-done study, Waldron et al. (Waldron, 2001) randomly assigned 120 adolescents who were abusers of illicit drugs (primarily marijuana) to one of four treatment conditions: family therapy alone (Functional Family Therapy), individual CBT alone, a combination of individual and family therapy, and a psychoeducational group. Completion rates were high (70%–80% across groups). In general, while there were meaningful reductions in drug use in all conditions, there were larger and more durable reductions in substance use for the combined and family conditions relative to the individual CBT and group conditions. Treatment effects were strongest immediately after treatment but persisted through a 7-month follow-up.

Kaminer et al. (Kaminer, 2002) compared group CBT to psychoeducational substance abuse treatment for 88 adolescents referred for treatment of a substance abuse problem. Eighty-six percent of the sample completed treatment and 9-month follow-up data were available for 65% of the sample. The presence of a CD was associated with treatment dropout. CBT was significantly more effective than the psychoeducational group only for male subjects; females appeared to improve regardless of treatment condition. Nevertheless, there were no significant differences between the two conditions at the 9-month follow-up. The relatively high rates of relapse in this sample (52% had a urinalysis that was positive for marijuana at the 9-month follow-up evaluation) suggest that an eight-session standalone approach may not be adequately intensive or structured for this population.

Since many CBT studies have an RCT design, some of them have already been addressed in this chapter (Dennis et al., 2004; Liddle et al., 2008; Ramchand et al., 2011). Cornelius et al. (2011) compared the long-term (2-year) efficacy of an acute-phase trial of CBT/MET versus naturalistic treatment among adolescents with both major depressive disorder and an alcohol use disorder who had signed consent for a treatment study involving fluoxetine and CBT/MET. Outcomes measures were levels of depressive symptoms and alcohol-related symptoms at a 2-year follow-up evaluation. CBT/MET demonstrated superior outcomes compared to those who had not received protocol CBT/MET therapy. No significant difference was noted between those receiving fluoxetine versus those receiving placebo on any outcome at any time point. Other pharmacological studies also included CBT, and sometimes one of the explanations for the lack of effect, or small pharmacological effect, seen in these adolescents with substance abuse is that receiving CBT reduced the ability to detect the effects of the pharmacological agent (Riggs et al., 2007; Cornelius et al., 2009).

Much attention has been given to meditation and mindfulness interventions, since they may enhance the individual skills of children and adolescents by helping them feel more relaxed, focused, and creative. There are different techniques, and one is closely related to CBT: mindfulness-based cognitive therapy (MBCT) (Simkin & Black, 2014). MBCT aims to relieve negative feelings by targeting negative thoughts or emotions (Gilpin, 2009). Up to now, few studies have evaluated MBCT in adolescents with substance abuse. One of the first studies in this field investigated how to effectively teach mindfulness to 10 incarcerated adolescent substance users in an urban California detention setting (Himelstein et al., 2014). In another study, with 1,051 students, mindfulness-based strategies toward impulsivity and positive and negative urgency were evaluated cross-sectionally. Mindfulness was associated with a lower likelihood of lifetime alcohol or marijuana use. Interactions between urgency and mindfulness were not supported (Robinson et al., 2014). More studies in this field are recommended, especially because RCTs have demonstrated the effectiveness of diverse psychotherapeutic approaches (CBT, family, behavioral).

Motivational approaches are brief treatment approaches that are designed to produce rapid, internally motivated change in addictive behavior and other problem behaviors. Grounded in principles of motivational psychology and patient-centered counseling, MI (Miller, 1991, 2002) arose out of several theoretical and empirical advances (Miller, 2000). MI has high levels of empirical support in the adult substance abuse treatment literature (Burke, 2003; Dunn, 2001; Miller, 2002; Wilk, 1997). The core principles of MI are as follows: (1) express empathy; (2) develop discrepancy; (3) avoid argumentation; (4) roll with resistance; and (5) support self-efficacy. MI makes the important assumption that ambivalence and fluctuating motivations define substance abuse recovery and need to be thoroughly explored rather than confronted harshly. Ambivalence is considered a normal event, not something that indicates the patient is unsuitable for treatment or needs vigorous confrontation in hopes of forcing a sudden change. The patient’s point of view is respected, which in some cases may mean accepting that major change, or even any change, is not what the patient wants, at least at the present time (Carroll, in press). Thus, while the bulk of research on the efficacy of MI is in the adult literature, this nonconfrontational approach appears quite well suited for application to adolescents and young adults, given its flexibility around goals and recognition of abstinence as part of the change process.

Another distinct advantage of using MI with adolescent populations is that it can be implemented in a range of settings, given that adolescents with substance abuse problems rarely seek treatment of their own volition in traditional substance abuse settings. Monti et al. (1999) studied 94 adolescents treated at an emergency room for a problem related to alcohol use (e.g., injuries related to drinking, drunk driving). They were randomly assigned to MI or standard care, with all interventions and assessments conducted in the emergency room. At a 6-month follow-up, there were significantly fewer incidents of drunk driving, traffic violations, and alcohol-related problems in the group assigned to receive MI. Not only does this study suggest the promise of brief motivational approaches for this population, but it also underlines the importance of intervening with adolescents in nontraditional settings.

Kohler and Hofmann (2015), in a systematic review and meta-analysis, investigated the effect of MI delivered in a brief intervention during an emergency care contact on the alcohol consumption of young people who screen positively for risky alcohol consumption. Six trials with 1,433 participants, ages 13 to 25 years, were included. MI was never less efficacious than a control intervention. Two trials found significantly more reduction in one or more measures of alcohol consumption in the MI group. One trial indicated that MI may be used most effectively in young people with high-volume alcohol consumption. MI was effective in reducing the drinking quantity more than control interventions in a meta-analysis of the subset of trials that were implemented in the United States (standardized mean differences [SMD] = −0.12, p = .04). The authors concluded that MI is effective and possibly more effective than other brief interventions in emergency care to reduce alcohol consumption in young people. Similar results for alcohol consumption were not confirmed by a Cochrane Review, when studies selected were not limited to emergency department samples (Foxcroft et al., 2014).

MI was tested against brief advice for smoking cessation among adolescent (13–17 years old) smokers hospitalized for psychiatric and substance use disorders. After 12 months, there was no difference between groups regarding quit attempt. Given that MI was associated with greater increases in self-efficacy compared to brief advice, the authors examined whether self-efficacy at discharge was associated with better smoking outcomes when controlling for self-efficacy before treatment. In fact, there was an association between MI, better self-efficacy, and more abstinence (Brown et al., 2003).

Adolescents (n = 48) presenting for treatment intake assessments were randomized to MI (n = 22) or MI plus normative feedback (n = 26) (Smith et al., 2015). Three-month outcomes included the percentage of youth engaged in treatment, the percentage of youth reporting past-month binge drinking, and the percentage of days of abstinence. There were no differences between groups for abstinence rate. MI was also evaluated among adolescents with cannabis use, with positive results when considering, at the 3-month follow-up, number of days of cannabis use and negative consequences of drug use. Reductions in use and problems were sustained at 12 months (Walker et al., 2011).

Overall, MI seems a very interesting approach for adolescents and has been tested in different settings and with different drugs. More studies are recommended, especially to test its efficacy for polydrug use.

While disease model treatments and other approaches associated with the 12 steps of Alcoholics Anonymous dominate the treatment system for both adults and adolescents, there are no RCTs evaluating the effectiveness of these approaches in adolescents. Reports from RCTs evaluating the efficacy of manualized 12-step approaches have found evidence to suggest their effectiveness with adult substance users (Carroll, 1998; Crits-Christoph, 1999; Project MATCH Research Group, 1997). It is important to note, however, that these manual-guided approaches are highly structured, are delivered as individual (rather than group) therapy, and might be quite different from the nonmanualized group approaches typically delivered in community settings with adolescents. In addition, since individual drug counseling emphasizes and encourages frequent 12-step group attendance, its effectiveness might reflect increased patient involvement in rehabilitative groups. It is important to note that the absence of sufficient research on 12-step treatment should not lead one to conclude that this widespread and popular approach is ineffective; up to now, however, there are no data on those who are younger than 18 years.

Data on the effectiveness of more traditional programs are beginning to emerge, but no data from randomized trials comparing these approaches to alternatives are available. Winters et al. (Winters, 2000) reported on a large nonrandomized evaluation comparing a group of substance-abusing youth who completed the 12-step Minnesota Model Treatment to similar individuals who did not complete treatment and to a group on a waiting list for treatment. The treatment was multimodal, based on the principles of the 12 steps of Alcoholics Anonymous, and included group therapy and individual counseling, family therapy, lectures about the 12 steps, and reading assignments. Better substance-use outcomes and psychosocial outcomes at 6 and 12 months were reported for those who completed treatment compared with those who did not complete or who did not receive treatment. While a high rate of abstinence was reported among treatment completers, it is difficult to interpret these findings, given the self-selection due to lack of randomization and lack of measurement of treatment delivery or process.

As new effective therapies for adolescents are identified, the field must move toward evaluating how these treatments exert their effects by looking at mediators and moderators of outcome. Several investigations have examined these variables. In terms of retention and engagement, Szapocznik’s (1983) impressive work on engaging teens and families in treatment has been replicated and further developed (e.g., Coates et al., 2001; Santisteban et al., 1996). Henggeler (1996) demonstrated a 98% treatment completion rate for home-based MST. Henggeler has also demonstrated that adherence to the treatment was significantly associated with better treatment outcome. Liddle has conducted several process studies looking at mechanisms of change, including in-session patterns of change associated with the resolution of parent–adolescent conflict (G. S. Diamond & Liddle, 1996, 1996) and the link between improvement in parenting and better substance use outcome (Schmidt, Liddle, & Dakof, 1996). These kinds of studies will help identify key treatment ingredients hopefully leading to increased treatment potency.

The treatment process in Therapeutic Community (TC) is also a matter of interest. This psychotherapeutic technique emphasizes socioenvironmental and interpersonal influences in the resocialization and rehabilitation of the patient. The setting is usually a hospital unit or ward in which professional and nonprofessional staff interact with the patients. Five points have been considered in this setting: treatment motivation, personal development, problem recognition, family relations, and social network. Stucky et al. (2014) evaluated the validity of the short form of the Dimensions of Change in Therapeutic Communities Treatment Instrument-Adolescent (DCI-A; DCI-A-SF) by examining its associations with demographic and pretreatment characteristics as well as program completion status. The study sample consisted of 442 adolescents in residential treatment at one of seven TC treatment programs in the United States. The majority of participants were referred to treatment by the criminal justice system (62%). Other referral reasons included self/family (18%), social services (9%), transfer (6%), and referral by a medical professional (2%). At the time of the survey administration, 21.7% of respondents had been in treatment for 30 days or less, 19.2% for 31 to 60 days, 14.5% for 61 to 90 days, 29.9% for 91 to 180 days, and 14.7% for more than 180 days. In this study, DCI-A-SF demonstrated correlated with treatment outcomes. It might contribute to further studies on therapeutic process in TC for adolescents.

Another area relevant to treatment research that may be influenced by the developmental perspective concerns assessment. While self-report of substance use by adolescents has been confirmed as fairly reliable (Buchan et al., 2002), analysis from the Cannabis Youth Treatment Study suggests that parent reports provide information not given by the adolescent. In terms of substance use symptoms, although adolescents and parents reported about the same number of symptoms, there was a very low concordance in terms of which symptoms were endorsed. Parents tended to report more symptoms related to role failure, tolerance, and substance-induced psychological problems (Dennis et al., 2002). Similar findings were discovered regarding mental health symptoms; specifically, parents tended to endorse more symptoms of depression and attention problems (Diamond et al., in press). This was particularly true for African-American adolescents, suggesting that parent report may have a unique contribution when working with a minority population, a community that has been characterized as suspicious of the research community.

Based on the authors’ clinical experience, it seems that parents are good informants for reporting some conduct problems, such as staying out overnight, skipping medications, or school refusal. However, adolescent drug use is usually a hidden behavior, especially at the beginning of the disorder, or when moving toward a new drug (e.g., starts treatment due to alcohol abuse and, under treatment, starts on marijuana). By using the Adolescent Diagnostic Interview (ADI) in 109 adolescents (14–18 years), providers’ impressions of adolescents’ level of substance use were compared with the resultant diagnostic classifications. Of 50 participants who were classified with a diagnosis of alcohol or drug abuse, providers correctly identified only 10. These data confirm the idea that parents underestimate adolescents’ alcohol/drug involvement. According to the Practice Parameter for the Assessment and Treatment of Children and Adolescents with Substance Use Disorders (Bukstein et al., 2005), toxicology tests of bodily fluids should be part of the evaluation and the ongoing assessment of substance use in adolescents. It is important to establish rules regarding the confidentiality of the results before testing, since maintaining the therapeutic alliance is always a matter of concern.

One area that has received strikingly little research with adolescents is the integration of substance use and other mental health services that can treat adolescents with both kinds of disorders. Historically there has been a divide between treatment systems for substance abuse and mental health disorders, where substance abuse counselors often have little or no training in mental health issues and programs either ignore co-occurring problems or refer patients to other systems during (parallel) or after (sequential) substance abuse treatment. There is emerging consensus that lack of integration leads to poor coordination of services, interagency miscommunication, and funding conflicts that contribute to attrition and poor outcomes for patients (Osher & Drake, 1996; Report to Congress, 2003). This is particularly troubling since co-occurring mental health distress is associated with more severe substance use, greater psychosocial impairment, treatment resistance, and poorer long-term prognosis (Diamond et al., 2005; Drake et al., 1996; Shane et al., 2006). Consequently, the most severe and chronic patients often receive the poorest care, leading to repeated visits to hospital emergency rooms and inpatient and residential facilities (Richardson et al., 1995). The end result is that patients with comorbidities in need of care are consuming a major portion of treatment funding (Ridgely et al.,1990).

The gap between substance abuse and mental health dates back to the 1930s (Rosenthal & Westreich, 1999). At that time, psychodynamic therapists, who dominated the treatment world, believed that persons with substance use disorder had a personality structure that was not amenable to the analytic method, and therefore were not treatable. This attitude may persist today in the mental health community, who tend to view addiction as inhibiting treatment of other “underlying” problems (Blanchard, 2000). Simultaneously, the self-help movement developed independent of the mental health community, and as the self-help philosophies and programs matured, educational and professional licensure pathways emerged that legitimized and strengthened these approaches (Rosenthal et al., 1999). As often happens, then, these ideological differences became institutionalized and perpetuated a division that does not reflect the clinical realities of patients.

Recognition of this schism has inspired many attempts to integrate substance abuse and mental health treatment programs for adult dual-diagnosis populations (Drake et al., 1993; Lehman & Dixon, 1995; Miller, 1994; Minkoff & Drake, 199; Ziedonis & Fisher, 1994). At least 36 studies have evaluated different versions of integrated programs, at all levels of care (e.g., outpatient, day treatment, inpatient, residential). Some studies added a substance abuse group to outpatient mental health services, resulting in reduced dropout, decreased hospitalization, and increased abstinence (e.g., Hellerstein, 1995; Kofoed et al., 1989). Studies that combine substance abuse services with inpatient, day treatment, and residential care have also shown some benefits as long as patients remained in the program. Unfortunately, attrition rates were often high and, once discharged, relapse rates were high as well (e.g., Rahay et al., 1995).

A major contribution to this area was the 1987 funding of 13 dual-diagnosis demonstration projects (National Institute of Mental Health, 1989). These studies demonstrated that integrated programs could be implemented in a number of settings, resulting in increased engagement and services utilization and reduced drug use. Another five studies were conducted on comprehensive integrated systems using more sophisticated treatment programs and quasi- or true experimental designs (e.g., Drake et al., 1997, 1998; Godley,1994; Jerrell & Ridgely, 1995; Ridgely & Jerrell, 1996). These studies showed significant reductions in substance use, program readmission, and hospital admission, and improvement in other functional outcomes (Drake et al., 1998). However, there has been little or no comparable research on the effectiveness of integrated programs for adolescent substance users.

In a multicenter study, 992 adolescents were evaluated considering the presence of some comorbidity (positive in 64% of the sample). The presence of comorbidity was associated with more severe pretreatment condition and poorer outcomes, such as more use of marijuana and hallucinogens and engaging in illegal acts in the 12 months after treatment (Grella et al., 2001).

A review of the literature was conducted to evaluate the effects of comorbid depression on treatment retention and outcomes across 13 adolescent substance use treatment studies. Depression had a mixed relationship with treatment retention and other outcomes, depending on aspects of the study: it could increase or decrease retention (Hersh et al., 2014).

As stated by the American Society of Addiction Medicine (2001), intensive inpatient treatment might be appropriate for adolescents whose substance use, biomedical, and emotional problems are so severe that they require 24-hour primary medical care. The length of the intervention should depend on the adolescent’s progress. Usually, there are few possibilities, up to now not well studied, ranging from inpatient treatment for detoxification inside general or psychiatric hospitals, to residential programs. Tripodi (2009) reviewed eight studies regarding the effectiveness of residential treatment centers for substance-abusing adolescents, and only three of them used a strong quasi-experimental design. Of the four most rigorous studies reviewed, two found significant differences in substance use reduction between the treatment and comparison groups. In other words, there are important methodological flaws and a small number of studies, limiting more robust conclusions on their long-term effectiveness. However, based on clinical experience, this is an important resource when dealing with risky situations. More studies are needed, since it is a reality in clinical practice.

Clinical research during the past 20 years has identified a number of effective treatments for adolescent substance users. Although the field is still young, this growing body of work has yielded several important findings that support the effectiveness of carefully implemented, structured behavioral approaches for adolescent substance use (Liddle & Rowe, 2001; Stanton & Shaddish, 1997; Williams, 2000). These can be summarized as follows:

Pharmacotherapy for substance dependence is a relatively young field of medicine, and the proven treatments for adults have not been adequately researched in adolescents. Therefore, few conclusions regarding this modality can be stated conclusively at this time. However, the actual usage of pharmacotherapy for psychiatric syndromes has been steadily increasing among adolescents and children, despite lack of data. Prescribing for these young patients between 1987 and 1996 rose 300% overall (Magno Zito, 2003). By 1996 stimulants and antidepressants were ranked first and second in terms of total prescriptions. These two medications also had the greatest increase in prescribing (400% each): stimulant prescribing rose from 10 per 1,000 youth to 40 per 1,000 youth, and antidepressants rose from 3 per 1,000 to 13 per 1,000.

Regarding prescription patterns of antipsychotic use among patients aged 1 to 24 in the United States based on calendar years 2006 (n = 765,829), 2008 (n = 858,216), and 2010 (n = 851,874), the percentages of young people using antipsychotics in 2006 and 2010, respectively, were 1.10% and 1.19% for adolescents and 0.69% and 0.84% for young adults. The authors concluded that antipsychotic use increased from 2006 to 2010 for adolescents and young adults, especially among boys (Olfson, King, & Schoenbaum, 2015). Comer, Olfson, and Mojtabai (2010) examined the patterns and trends in multiclass psychotropic treatment among youth visits to office-based physicians in the United States from 1996 to 2007. There was an increase in the percentage of child visits in which psychotropic medications were prescribed that included at least two psychotropic classes. Across the 12-year period, multiclass psychotropic treatment rose from 14.3% of child psychotropic visits (1996–1999) to 20.2% (2004–2007). In the presence of a current mental disorder, the percentage of multiclass psychotropic treatment increased from 22.2% (1996–1999) to 32.2% (2004–2007). Over time, there were significant increases in multiclass psychotropic visits in which ADHD medications, antidepressants, or antipsychotics were prescribed, and a decrease in those visits in which mood stabilizers were prescribed. Specific increases were found for co-prescription of ADHD and antipsychotic medications (adjusted odds ratio [AOR] = 6.22, 95% CI 2.82–13.70, p < .001) and for co-prescription of antidepressant and antipsychotic medications (AOR = 5.77, 95% CI 2.88–11.60, p < .001).

In a cross-sectional survey in United States, the prevalence of specific classes of psychotropic medications indicated for mental disorders was evaluated between February 2001 and January 2004. Participants were adolescents ages 13 to 18 years who participated in the National Comorbidity Survey Adolescent Supplement (n = 9,244; response rate 74.7%). Among adolescents with substance use disorder based on DSM-IV criteria (n = 854), 9.2% were on antidepressants, 4.1% on stimulants, 1.1% on antipsychotics, 1.0% on mood stabilizers, 2.7% on anxiolytics, and 14.4% on any medication (Merikangas et al., 2013).

This last publication corroborates the association of behavioral problems and substance use disorders in adolescents, since adolescents who abuse drugs and have substance use disorders typically have deviant behavior, skills deficits, academic difficulties, family problems, and mental health problems (Peeters et al., 2014; Rao, 2006; Ridenour et al., 2013; Tarter, 2002; Tims, 2002). While these problems usually reflect more than neurochemical defects that may be reversed with medications, adolescents with substance dependence and comorbid psychiatric disorders can benefit from pharmacotherapy, but pharmacotherapy should be justified by careful evaluations of the diagnoses in these young patients. These medical and psychiatric evaluations can be informed by structured interviews for common comorbid disorders such as depression and bipolar disorders, ADHD, and substance dependence. Medical disorders including infections, endocrine problems, and various developmental disorders also need consideration but are beyond the scope of this review. However, based on Merikangas et al. (2013), comorbidity may not be as treated as it should, perhaps reflecting the lack of studies in this area, or even the lack of positive results, as will be reviewed

Adolescents who enter substance abuse treatment programs are more likely than non-drug-abusing peers to have experienced abuse or neglect, to have significant family problems, and to have developed a psychiatric disorder during childhood such as ADHD and mood disorder. These behavioral, psychosocial, and mental health problems are coupled with the neurohormonal changes of puberty and lead to poor adjustment in the school environment, thereby increasing the risk for school failure (Riggs, 1999; Tarter, 2002). These school experiences also may lead to the early onset of substance abuse (Crowley, 1995; Rutter, 1998). Substance abuse exacerbates preexisting psychiatric disorders such as ADHD, as well as mood disorders and AD (Kruesi, 1990; Markou, 1998; Rutter, 1998).

The multidimensionality of the problems that substance-abusing youth typically bring to treatment underscores their need for multimodal treatment that addresses a broad range of mental health and psychosocial problems integrated with treatment for drug abuse. The role of pharmacotherapy targeted specifically to substance abuse may therefore be relatively limited, and there is no research base to provide guidance on the dosing or duration of treatment for adolescents with dependence on alcohol, nicotine, opiates, or other addictions for which we have pharmacotherapies. Furthermore, the other most commonly abused drug—cannabis—has no specific pharmacotherapy. Pharmacotherapies are also entirely lacking for “club drugs” such as MDMA, GHB, and various hallucinogens.

Given the clinical importance of drug euphoria and drug craving, most pharmacological strategies for addiction target these primary reinforcers. Drug-induced reward is attenuated in animal models by a number of agents, depending on the drug in question. These medications act on dopamine, opioid, glutamate, or GABA systems. These reward-blocking medications have been tested in human substance abusers to determine whether they reduce drug euphoria under controlled settings, or promote abstinence in clinical trials. Other means of reducing reward have also been tested, including vaccines that block the entry of an addictive substance into the brain, and agents like disulfiram that produce aversive symptoms when alcohol is consumed. In addition to strategies that reduce drug euphoria, strategies that reduce craving have also been tested and prescribed. Agonist treatment (prescribing a substance that replaces the addictive drug) has been used in opioid (e.g., methadone, buprenorphine) and nicotine (e.g., nicotine gum) dependence with considerable success, providing a means of bypassing dangerous routes of administration or hazards associated with drug procurement. Reversing clinically relevant neuroadaptations associated with chronic exposure to addictive substances has the theoretical ability to reduce craving and other aversive aspects of addiction.

Unfortunately, there has been little research directed toward the pharmacological treatment of substance dependence in adolescents. For a number of reasons, there are not enough controlled trials evaluating the effectiveness of substitution/replacement therapies (e.g., methadone, buprenorphine), antagonists (e.g., naltrexone), aversive therapies (e.g., disulfiram), or anticraving medications (e.g., bupropion, naltrexone) in this subpopulation. Therefore, if such medications are used in adolescents, they must be used with caution, careful monitoring, and consideration of the developmental characteristics that distinguish adult patients from adolescents (e.g., greater impulsivity and polydrug use) (Solhkhah, 1998). More research is clearly needed in this area. In most of the available controlled trials, strength of the therapeutic benefit (number needed to treat) is lacking.

Since the most commonly abused substances by adolescents are nicotine, alcohol, and cannabis, these are the most likely drugs for which pharmacotherapy questions might arise. A few specific relapse-prevention pharmacotherapies are approved by the U.S. Food and Drug Administration (FDA) for nicotine and alcohol dependence in adults, and some of them have started to be evaluated in adolescents in the past decade. For nicotine the medications are nicotine replacement, bupropion, and varenicline, and for alcohol the medications are disulfiram, naltrexone, and acamprosate. We will review these medications briefly, starting with those used in detoxification. Advances in our understanding of the mechanisms of drug craving and drug-induced euphoria should guide future research and shed light on more effective pharmacological treatments for addiction in adolescents.

Medical detoxification is required for alcohol, sedatives, and opiates but not for other abused drugs. In adolescents with alcohol use disorder, withdrawal symptoms occur in only between 5% and 10% of cases (Chung et al., 2002; Langenbucher et al., 2000), and only a small percentage will require pharmacotherapy. Detoxification from alcohol dependence can be effectively attained in adults by using benzodiazepines or barbiturates and anticonvulsants such as valproate and carbamazepine to block or reverse withdrawal symptoms (Kosten, 2003). These medications have not been tested in adolescents with withdrawal symptoms, but detoxification medications should be used in adolescents if withdrawal symptoms are significant, particularly because alcohol withdrawal is potentially life-threatening. Since the combination of alcohol and benzodiazepines is potentially lethal, this approach should only be undertaken in supervised settings (Clarck, 2012).

Detoxification from sedative-hypnotic dependence can be accomplished by prescribing descending doses of benzodiazepines. However, there is currently no approved pharmacotherapy for benzodiazepine use disorder treatment even in adults (Sabioni, Bertram, & Le Foll, 2015).

For opioid dependence, the most common means of detoxification involves prescribing descending doses of methadone for a period of 2 to 4 days while carefully monitoring the patient’s response. Methadone is a long-acting opioid agonist that reverses heroin withdrawal by replacing heroin at the opioid receptor. Since methadone has the potential to cause lethal opioid overdose, and opioid withdrawal is not medically dangerous, it is imperative to avoid prescribing an excessive dose of methadone to adolescents. The appropriate dose is best selected by closely monitoring the signs of opioid withdrawal, which should be given more weight than reported symptoms that might be exaggerated or feigned by drug-seeking patients.

A new treatment for detoxification and maintenance was made available in the United States in 2003. This is buprenorphine, a partial μ-opioid receptor agonist. It may be ideally suited to adolescents and is currently in clinical trials in this population. Detoxification with this medication is simple because overdose is almost impossible. The patient can be transferred from the opiate of abuse to buprenorphine, and then the dose is gradually reduced with minimal or absent withdrawal symptoms. Yet another option is the nonopioid clonidine, an antihypertensive medication that blocks many of the opiate withdrawal symptoms (Gold, 1984). Most patients prefer methadone or buprenorphine because of greater comfort. However, up to now, neither methadone nor buprenorphine has been sufficiently evaluated in adolescents.

One of the first studies on adolescent opioid detoxification tested buprenorphine versus clonidine. A significantly greater percentage of adolescents who received buprenorphine stayed in treatment (72%) relative to those who received clonidine (39%) (Marsch et al., 2005). Later, a naturalistic study, conducted in Dublin by Smyth et al. (2012), described the detoxification process safely used in 100 adolescents with opioid dependence (mean age 16.6 years). Induction onto methadone started with a dose of 20 mg, increasing by 10 mg every 2 to 4 days, titrated against withdrawal symptoms, cravings, and ongoing heroin use while also monitoring for evidence of sedation. Stabilization doses were generally between 40 and 70 mg. For buprenorphine, induction usually involved provision of 2 mg during the morning of day 1, with a further 2 to 6 mg later that afternoon. Single daily doses of up to 8 to12 mg were administered from day 2. Stabilization doses were typically in the region of 6 to 12 mg. There were no deaths during treatment among these 100 patients.

Recently, Minozzi et al. (2014a, 2014b) assessed the effectiveness of any opioid detoxification treatment alone or in combination with psychosocial intervention compared with no intervention, other pharmacological intervention, or psychosocial interventions on completion of treatment, reducing the use of substances, and improving health and social status. Two trials involving 190 participants were included in this study. One trial compared buprenorphine with clonidine for detoxification. No difference was found in terms of the dropout rate, and more participants in the buprenorphine group initiated naltrexone treatment. The other trial compared maintenance treatment (buprenorphine/naloxone) versus detoxification (buprenorphine) treatment: in terms of the dropout rate, the results were in favor of buprenorphine/naloxone. In this Cochrane Review, the authors emphasized that it is difficult to draw conclusions on the basis of only two trials and a small sample size. Furthermore, the two studies included did not consider the efficacy of methadone. Thus, there is a need for more studies on adolescent opioid detoxification.

Despite the benefits of pharmacological approaches in the detoxification process, inpatient detoxification treatment should not be restricted merely to the medical management of heroin withdrawal. This intensive intervention provides the physician with an ideal opportunity to establish a therapeutic alliance with adolescent patients by concomitantly addressing the critical treatment issues of honesty, openness, trust, denial, and engagement. Inpatient detoxification also provides an opportunity to fully evaluate patients, assess their readiness for change, and provide critical family therapy. Since families require education, support, and guidance throughout the process, clinicians should be familiar with the psychosocial as well as medical aspects of heroin addiction. It is essential to emphasize that detoxification, in and by itself, is not sufficient treatment for heroin dependence and must therefore be followed by ongoing outpatient drug rehabilitation. The recent fad of very rapid detoxification using general anesthesia has not been shown to produce better outcomes than standard detoxification.

Because detoxification in and by itself is usually insufficient treatment for addiction, medications for relapse prevention are more likely to be useful in promoting abstinence. However, before medicating adolescents, it is imperative to determine that they will be cooperative, that parental consent has been obtained, and that the adolescents and parents have the same understanding of treatment goals and approaches.

The nature of addiction requires that complete abstinence be the treatment goal for addicted adolescents rather than the mere reduction of drug and alcohol use. Indeed, even the use of other addictive agents, such as alcohol by a cocaine-dependent adolescent, often leads to relapse to the drug of choice. Thus, total abstinence from all addicting drugs should be the goal when treating adolescents. Furthermore, since both alcohol purchase and illicit drug use are illegal activities in adolescents, it is hard to argue with a goal of total abstinence. After attaining abstinence, preventing relapse to drug dependence is the primary clinical target in adolescents. The following sections review proven treatments for both initiation of abstinence and relapse prevention for nicotine, alcohol, and opiates.

Despite the prevalence of adolescent tobacco use and nicotine dependence, there have been relatively fewer studies that evaluate adolescent smoking treatment programs. The settings for and approaches to the treatment of adolescent tobacco use are similar to those described for adolescent smoking prevention, with the addition of pharmacological approaches. However, the challenges inherent in adolescent smoking treatment appear to be greater than those for prevention. Another challenge is the role of comorbidity in adolescent nicotine dependence (Goodwin et al., 2014). Recruitment to adolescent smoking treatment programs is difficult, in part because of adolescents’ desires to keep their smoking practices confidential. Moreover, among those adolescents who enroll in treatment programs, attrition rates are very high (Mermelstein, 2003).

For the most part, available data on the effectiveness of adolescent smoking treatment have been disappointing. Quit rates for adolescents receiving behavioral smoking cessation treatment are roughly 10% to 15%, compared with 5% to 10% in control conditions (Pomerleau, 1998). The results of pharmacological trials using nicotine replacement therapy (e.g., nicotine patch) have also been disappointing, yielding 6-month quit rates of only 5% (Hurt, 2000; Smith, 1996). While not yet thoroughly investigated, interventions delivered by pediatricians and family physicians may have great promise for assisting youth to quit smoking (Pbert, 2003). E-cigarette use in adolescents is also a matter of interest. It is not clear, up to now, if it might have a protective or a harmful effect, for instance (Rennie, Bazillier-Bruneau, & Rouëssé, 2016; Kinnunen et al., 2015; Schneider & Diehl, 2015; Glasser et al., 2017). Adolescents with comorbid psychiatric conditions are an important target group for treatment, given their greater predisposition to tobacco use (Dune et al., 2014; Moolchan, 2000). The prevalence of anxiety disorders and dysthymia among current smokers appears to have increased from 1990 to 2001. Tobacco cessation interventions should address comorbidities as well, and attention should be paid to this trend in the increase of comorbidity among smokers (Goodwin et al., 2014).

Nicotine replacement therapy (NRT), varenicline (a partial agonist at the nicotinic receptors) and bupropion (a nicotinic acetylcholine-receptor antagonist that is a dopamine and norepinephrine reuptake inhibitor) are FDA-approved smoking cessation medications for adult smokers. Their role in the adolescent population needs more evidence.

It is unclear if the interventions that are effective for adults can also help adolescents to quit. The forms of NRT include patches, gum, inhalers (oral absorptions), nasal spray, and lozenges (McCance, 1998). NRT might be a reasonable treatment for adolescents who want to quit smoking and are experiencing acute withdrawal symptoms that interfere with abstinence.

A Cochrane Review on tobacco cessation interventions for young people included 28 trials, with 6,000 adolescents (both pharmacological and psychotherapy, together or separately). A small trial testing NRT did not detect a statistically significant effect. Two trials of bupropion, one testing two doses and one testing it as an adjunct to NRT, did not detect significant effects (Stanton & Grimshaw, 2013). Despite the few trials included in this review, there was no evidence for pharmacological interventions (NRT and bupropion) for adolescent smokers.

Scherphof et al. (2014a) conducted a randomized, double-blind, placebo-controlled trial in 257 adolescents (mean age 16.7 years); 136 received NRT and 129 received placebo. The duration was 6 to 9 weeks of treatment. In the NRT group, participants smoking more than 20 cigarettes per day received a higher transdermal nicotine patch dose (3 weeks 21 mg/day, 3 weeks 14 mg/day, and 3 weeks 7 mg/day) to use daily for 9 weeks; those who smoked less than 20 cigarettes per day received a lower dose (3 weeks 14 mg/day and 3 weeks 7 mg/day) to use daily for 6 weeks. Intent-to-treat analyses showed that independent of compliance, NRT was effective in promoting abstinence rates after 2 weeks (OR = 2.02, 95% CI 1.11–3.69) but not end-of-treatment abstinence. However, end-of-treatment abstinence rates were significantly increased in highly compliant participants (OR = 1.09, 95% CI 1.01–1.17) but not in low-compliant ones. The authors tested NRT’s long-term effectiveness in the same sample of adolescents, concluding that NRT fails to help patients to quit smoking at 6- and 12-month follow-ups (Scherphof et al., 2014b).

The safety and efficacy of sustained-release bupropion hydrochloride for adolescent smoking cessation was evaluated by and prospective, randomized, double-blind, placebo-controlled, dose-ranging trial. Adolescents (aged from 14–17 years, n = 312), received sustained-release bupropion hydrochloride, 150 mg/d (n = 105) or 300 mg/d (n = 104), or placebo (n = 103) for 6 weeks, plus weekly brief individual counseling for 12 weeks and then 26 weeks. There was a difference, in terms of nicotine abstinence, between placebo and medication at 300 mg (6 weeks: 5.6% vs. 14.5%, p = 0.03; 26 weeks: 10.3% for placebo and 13.9% for bupropion, p = 0.049) (Muramoto et al., 2007). Gray et al. (2011) studied the effects of bupropion for smoking cessation. The study had four arms: bupropion SR alone; bupropion SR + contingency management (CM ); Placebo + CM, or just placebo. Combined bupropion SR and CM was efficacious in the short term, and more effective than other study arms (Gray et al., 2011). Varenicline also needs more clinical trials in adolescents. The multiple-dose pharmacokinetics, safety, and tolerability of varenicline in adolescent smokers was tested by Faessel and colleagues (2009). Varenicline was generally well tolerated during the 14-day treatment period. Later, varenicline (n = 15) was compared to bupropion XL (n = 14) in a randomized double-blind study with adolescents (age from 15–20 years). Participants receiving varenicline reduced from 14.1 ± 6.3 to 0.9 ± 2.1 cigarettes/day (CPD), and four participants achieved abstinence, without adverse-event-related discontinuation from the study. In the bupropion XL group, participants reduced from 15.8 ± 4.4 to 3.1 ± 4.0 CPD (two achieved abstinence; two discontinued the study due to adverse events) (Gray et al., 2012).

Discussion has considered vaccines for nicotine dependence (Kosten, 2002; Fahim et al., 2011). These immunotherapies can attenuate the rewarding effects of nicotine and have been considered as a potential prophylactic for preventing nicotine dependence. Immunotherapies might also be used as a secondary prevention for adolescents who have begun to smoke (Kosten, 2002). However, this type of invasive and long-lasting intervention has potential ethical problems, particularly in adolescents who do not want to stop smoking (Feldman, 2013; Lieber & Millum, 2013).

One of the actions of alcohol in the body is to release endogenous opioids. Thus, a drug such as naltrexone that blocks opiate receptors will reduce the reward of alcohol and help to prevent relapse. The majority of controlled studies in adults have shown that naltrexone increases abstinence. Although there are case reports in adolescents (Lifrak et al., 1997), we were able to identify only one controlled study of naltrexone in adolescents with alcohol use disorder. Side effects of naltrexone in adults have generally been minimal at usual doses. Naltrexone also has substantial hormonal effects that include raising cortisol and various sex hormone levels (e.g., luteinizing hormone), and these actions could interfere with growth and development in adolescents (Morgan, 1990). Miranda et al. (2014) conducted a randomized, double-blind, placebo-controlled crossover study comparing naltrexone (50 mg/daily) and placebo in 22 adolescents with drinking problems (mean age 18.36 years, SD = 0.95; 12 were women). The primary outcome measures were alcohol use, subjective responses to alcohol consumption, and alcohol-cue-elicited craving. In this study, naltrexone significantly reduced the likelihood of drinking and heavy drinking (p’s ≤ .03), reduced craving in the laboratory and in the natural environment (p’s ≤ .04), and altered subjective responses to alcohol consumption (p’s ≤ .01). The only ES mentioned in this study was related to the naltrexone-reduced likelihood of drinking on a study day (OR = 0.69, 95% CI 0.50–0.97, p = .03, ES d = 0.17 [a small ES]). The medication was well tolerated by the research subjects. The comparison of adverse events between placebo and naltrexone groups became nonsignificant in all analyses, considering neurocognitive, gastrointestinal, and ear, nose, and throat symptoms. These results encourage larger clinical trials with long-term follow-up.

Disulfiram promotes abstinence by blocking the metabolism of alcohol, resulting in the production of acetaldehyde, a noxious compound. It can produce severe reactions when mixed with alcohol, including death, and there is significant risk associated with prescribing this medication to impulsive adolescent alcohol abusers. Thus, disulfiram is rarely used for younger patients. We could identify only one study of disulfiram use in adolescents with alcohol use disorder (Niederhofer & Staffen, 2003a); its efficacy and long-term safety were evaluated in a double-blind, placebo-controlled study (n = 26, ages 16–19 years). Patients were randomly allocated to treatment with disulfiram (200 mg/day) or placebo for 90 days. At the end of treatment, seven disulfiram-treated and two placebo-treated patients had been abstinent continuously (p = .0063). Mean cumulative abstinence duration was significantly greater in the disulfiram group than in the placebo group (68.5 vs. 29.7 days; p = .012). In this pioneering study, the authors concluded that in some cases, disulfiram may be an effective and well-tolerated pharmacological adjunct to psychosocial and behavioral interventions for adolescents with alcohol use disorder.

Other medications such as acamprosate and topiramate are have been found effective in relapse prevention in clinical trials in adult populations but have not yet received FDA approval. There have been few studies of these medications in adolescents. Niederhofer and Staffen (2003b) assessed the efficacy and safety of long-term acamprosate treatment in alcohol dependence of adolescents by a double-blind, placebo-controlled study. Participants were 26 youth, ages 16 to 19 years, with alcohol use disorder. Patients were randomly allocated to treatment with acamprosate (1,332 mg/day) or placebo for 90 days. Thirteen acamprosate-treated and 13 placebo-treated patients completed the treatment phase (50% loss). At the end of treatment, seven acamprosate-treated and two placebo-treated patients had been continuously abstinent (p = .0076). Mean cumulative abstinence duration was significantly greater in the acamprosate group than in the placebo group (79.8 days vs. 32.8 days; p = .012). Despite the limits of the study (small sample size, short follow-up, sampling loss), results indicate that acamprosate was well tolerated and might be an effective pharmacological adjunct to psychosocial treatment programs.

Opioid dependence is relatively uncommon in adolescents, particularly those seeking treatment. However, many regions of the United States have experienced a rise in opioid addiction, particularly with the available of potent, smokeable heroin. Naltrexone, by blocking opiate receptors, can absolutely prevent relapse to opioid dependence as long as it is ingested. Adolescents, however, are not likely to take this medication regularly. Several naltrexone depot preparations are currently in clinical trials. When these become available, a monthly injection will effectively prevent relapse.

Extended-release naltrexone was evaluated on a convenience sample of 16 adolescents and young adults (mean age 18.5 years) treated for opioid dependence by Fishman et al. (2010). The medication was well tolerated over a period of 4 months and its use was feasible in a community-based treatment setting.

Agonist maintenance using methadone or buprenorphine is the most generally effective treatment for adolescent opioid addiction currently available (Gonzalez, 2002).

A recent Cochrane Review that included randomized and controlled clinical trials of any maintenance pharmacological interventions, either alone or associated with psychosocial intervention compared with no intervention, placebo, other pharmacological intervention, pharmacological detoxification, or psychosocial intervention in adolescents (13–18 years), selected two studies involving 189 participants. One study (n = 35) compared methadone with levo-alpha-acetylmethadol (LAAM) for maintenance treatment lasting 16 weeks, after which patients were detoxified. In this trial, the authors concluded that there was no difference in the use of a substance of abuse or social functioning. The other trial (n = 154) compared maintenance treatment with buprenorphine/naloxone and detoxification with buprenorphine. In this second study, maintenance treatment appeared to be more efficacious in retaining patients in treatment but not in reducing the number of patients with a positive urine test at the end of the study. Self-reported opioid use at 1-year follow-up was significantly lower in the maintenance group, even though both groups reported a high level of opioid use (Minozzi et al., 2014a, 2014b).

There has been little research on the treatment of adolescent stimulant dependence, and most regions of the United States do not provide adequate treatment options for the large population of afflicted adolescents. Unfortunately, no pharmacological treatments with proven efficacy have been identified for cocaine dependence in general, and few clinical trials have even included adolescents. Similarly, psychosocial treatments have been minimally researched in stimulant-addicted adolescents. Group-based treatments, following the principles of Alcoholics Anonymous and Narcotics Anonymous, are commonly employed in specialized adolescent treatment programs in the United States. Adolescents will naturally resist treatment approaches that ignore normal developmental issues, including their need for peer acceptance, autonomy, and individualization. In addition, they cannot be treated in a vacuum, and it is important to address maladaptive family patterns with family therapy. Parents should also receive education about cocaine addiction that includes the warning signs of relapse and specific behavioral guidance.

Treatment approaches have limited effectiveness when adolescent patients do not view their use as problematic, or are not sufficiently motivated to quit using cocaine. It is even more difficult to establish a therapeutic alliance when adolescents have been pressured into treatment by their parents, the legal system, or school authorities. Even internally motivated adolescents are often difficult to engage, and treatment facilities should be staffed with practitioners who are familiar with the dynamics of addiction, normal adolescent development, and the nuances of treating adolescent patients.

A large number of medications have been examined, in adults, for reducing cocaine craving and euphoria or helping to promote abstinence, including disulfiram, without promising results, and several agents that enhance GABA activity, such as baclofen, topiramate, and tiagabine, have also been evaluated (Kosten, in press). Some experimental agents include immunotherapies such as a cocaine vaccine (Kosten, 2002) and glutamatergic agents such as modafinil (Dackis, 2003), but these are still waiting for more robust effectiveness evidence. According to a recent Cochrane Review, no current evidence supports the clinical use of anticonvulsant medications in the treatment of patients with cocaine dependence (Minozzi et al., 2015). At present, no medication has been consistently beneficial in preventing relapse to stimulant abuse and dependence in adolescents.

Current research provides fairly solid support favoring integrated pharmacotherapy of co-occurring psychiatric disorders and substance dependence in adolescents. The first consideration is that comorbid psychiatric disorders in adolescents with substance dependence are associated with poorer treatment outcomes compared to those with single disorders; if the comorbid condition goes untreated, the likelihood of successful engagement, retention, and completion of substance treatment will be reduced (Grella, 2001; Lohman, 2002; Whitmore, 1997; Wise, 2001). Second, pharmacotherapy of comorbid disorders, alone, is not likely to reduce substance use or “treat” substance abuse in the absence of specific substance treatment interventions in adolescents with substance dependence. This has been demonstrated in controlled trials for comorbid ADHD, bipolar disorder, and depression (Deas, 2001; Geller, 1998; Lohman, 2002; Riggs, 2001). Third, treatment of substance dependence (or achievement of abstinence), alone, does not “treat” comorbid psychiatric disorders, such as ADHD, bipolar disorder, or major depression, in the absence of specific pharmacotherapy for the comorbid disorder. Even depression is much less likely to remit with abstinence in adolescents compared to findings in depressed adults with chronic alcohol or drug dependence (Bukstein, 1992; Riggs, 1996). Fourth, controlled trials indicate that some medications commonly used to treat psychiatric disorders in children and adolescents may be safe and effective in treating comorbid disorders in adolescents with substance dependence, even if the adolescent is nonabstinent. Specific studies have examined fluoxetine for depression (Lohman, 2002), lithium for bipolar disorder (Geller, 1998), and bupropion and methylphenidate (MPH) for ADHD (Riggs, 2001).

Taken together, current research supports integrated, concurrent treatment of comorbid psychiatric disorders and substance abuse in adolescents. Sequential treatment models requiring adolescents to first complete substance treatment and achieve abstinence as a prerequisite for medicating comorbidity are much less effective and are probably contraindicated. Although research now supports integrated treatment models, it is understandable why sequential models evolved and have been perpetuated. Some of these reasons include a shortage of child and adolescent psychiatrists with training in addictions; shortages of addiction clinicians with substantial psychiatric training; separate provider networks for mental health and substance treatment services; and poor third-party payer coverage for integrated treatment services. Although coordinated treatment of co-occurring disorders in adolescents provides significant clinical advantages, it is often unavailable due to inadequacies in the health delivery system.

The dearth of research related to pharmacological treatment of addiction in adolescents results, in part, from the traditional exclusion of addicted adolescents from clinical trials evaluating the safety and efficacy of medications, even when prescribed for psychiatric illnesses. Until very recently, virtually nothing was known about the safety and effectiveness of these medications in adolescents with substance dependence or the potential for adverse interactions of medications with drugs of abuse. Clinicians were therefore understandably reluctant to use medications to treat psychiatric disorders in substance-abusing adolescents, often referring such youth for substance treatment before considering treatment of comorbidity. This reluctance to use pharmacotherapy is often cited as one reason for the poorer treatment outcomes in dually diagnosed adolescents, since untreated psychiatric illness significantly diminishes the likelihood of successful substance treatment. The risks of treatment must be balanced with the risks associated with not treating psychiatric comorbidity. Some controlled clinical trials have begun to extricate clinicians from this therapeutic conundrum by demonstrating the safety and efficacy of some medications used to treat the most common psychiatric comorbidities, including bipolar disorder, ADHD, and depression (Geller, 1998; Lohman, 2002; Riggs, 2001). When evaluating such studies, it is important to take into account what is considered the outcome measure, which in this case can be complex if we consider, for instance, the self-medication theory for addiction. Usually, studies present multiple outcome variables, including substance use measures (e.g., retention rate, days of abstinence, time to relapse), and comorbidity symptoms (e.g., reduction in depressive symptoms). For the purpose of this section, we will only consider studies specifically treating adolescents.

ADHD is highly prevalent among adolescents with addiction (Horner & Scheibe, 1997; Kuperman et al., 2001). The comorbidity is clinically relevant, since ADHD is associated with both earlier and more frequent alcohol relapses (Ercan et al., 2003) and a lower likelihood of cannabis treatment completion (White et al., 2004) in adolescents. Several evidence-based guidelines have suggested that stimulants such as methylphenidate (MPH) should be the first option for treatment of ADHD (see, for instance, Pliszka et al., 2006). However, ADHD treatment studies typically exclude individuals with drug use/misuse or addiction. Given that most abused drugs act on the dopaminergic system (Volkow, Fowler, & Wang, 2004), as does MPH (Volkow, Wang, Fowler, & Ding, 2005), pharmacological studies of subjects with ADHD and addiction are crucial. That is, data from adolescents with ADHD without addiction can not necessarily be generalized to those with comorbid addiction. Pharmacotherapy with psychostimulants is considered the first-line treatment for ADHD in children and adolescents without substance dependence. The stimulants used for ADHD have good efficacy but a relatively high abuse potential and have been grouped with Schedule II psychostimulants (e.g., MPH, dextroamphetamine) (Klein-Schwartz, 2003). This is of special concern for short-action formulations, and some data suggest that long-acting formulations might be safer, such as osmotic-release oral system methylphenidate (OROS-MPH), even despite drug abstinence (Winhusen et al., 2011). Given the lack of evidence-based guidelines for the concurrent treatment of ADHD and substance use disorder, evidence suggests that stimulant medications should not necessarily be avoided for those with both ADHD and substance use disorder; indeed, concurrent treatment may be a successful approach to improve ADHD outcomes without worsening substance use symptoms (Klassen et al., 2012).

Recently, it was described that “medication for ADHD did not protect from, or contribute to, visible risk of substance use or [substance use disorder] by adolescents,” based on the multimodal treatment study ADHD (MTA), in an 8-year follow-up. Substance use or substance use disorder rates were greater in the ADHD than in the non-ADHD samples, regardless of sex (Molina et al., 2013). These data do not agree with a previous finding indicating a protective effect of ADHD medication and further substance abuse development. Mannuzza et al. (2008), for instance, found a positive relationship between age at MPH initiation and non-alcohol substance use disorder later on. However, this study excluded children with CD, limiting its external validity. While a protective role for the use of ADHD medication since childhood on adolescent and adult substance use disorder remains an open question, studies have begun on the pharmacological effects of first-line ADHD medications in patients with both ADHD and substance use disorder, specifically in adolescents. An RCT of OROS-MPH, together with CBT, in adolescents with ADHD and substance use disorder showed no group differences in terms of reducing ADHD-RS scores or days of substance use; that is, there were no differences in either ADHD or substance use disorder outcome measures (Riggs et al., 2011). It is interesting to note that in this study, parent ADHD-RS scores was considered a secondary outcome measure, and it favored OROS-MPH at 8 weeks (mean difference = 4.4, 95% CI 0.8–7.9) and 16 weeks (mean difference = 6.9; 95% CI 2.9–10.9). This multicenter study recruited 303 adolescents with ADHD and substance use disorder (ages 13–18 years), and the medication dosage was from 18 to 72 mg/day, or to the highest dose tolerated. Later on, the authors intended to find significant treatment predictors in this sample, which included (1) substance use severity, associated with poorer ADHD and substance use disorder outcomes, (2) ADHD severity, associated with better ADHD and substance use disorder outcomes, (3) comorbid CD, associated with poorer ADHD outcomes, and (4) court-mandated status, associated with better substance use disorder outcomes but poorer treatment completion (Tamm, 2013).

In a less robust study, the authors evaluated the effects of a long-acting formulation of MPH (Spheroidal Oral Drug Absorption System [MPH-SODAS]) on ADHD symptoms in an outpatient sample of adolescents with ADHD and substance use disorder. In this 6-week, single-blind, placebo-controlled crossover study assessing the efficacy of escalated doses of MPH-SODAS, participants were randomly allocated to either group A (weeks 1–3 on MPH-SODAS, weeks 4–6 on placebo) or group B (reverse order). The primary outcome measures were the Swanson, Nolan, and Pelham Scale, version IV (SNAP-IV) and the Clinical Global Impression Scale (CGI). The sample consisted of 16 marijuana users, 7 of whom also used cocaine (43.8%). Subjects had a significantly greater reduction in SNAP-IV and CGI scores (p < .001 for all analyses) during MPH-SODAS treatment compared to placebo (Szobot et al., 2008).

Despite a few reports of the use of lisdexamfetamine in adults with ADHD and substance use disorder, we were not able to find studies on adolescent samples.

To date, just one study is available assessing the use of atomoxetine in adolescents with comorbid ADHD and substance use disorder (Thurstone et al., 2010). In this placebo-randomized, controlled trial, change in ADHD scores did not differ between the atomoxetine + MI/CBT and placebo + MI/CBT groups (F4,191 = 1.23, p = .2975). Change in days in which non-nicotine substances were used in the last 28 days did not differ between the groups (F3,100 = 2.06, p = .1103).

Bupropion has a low effect size in children and adolescents with ADHD (0.32 vs. 0.80 for MPH, for instance, and 0.72 for atomoxetine) (Faraone at al., 2006). Thus, it should not be considered as a first option unless there is a contraindication for other medications. Moreover, although several questions remain open, it seems reasonable to state that the use of long-acting formulations of MPH will not worsen substance use disorder. Its effects on ADHD, and in what dosages, need better understanding. It is also interesting to note that the above-mentioned pharmacological protocols did not require drug abstinence for treating ADHD. ADHD diagnoses usually can be made retrospectively, based on the anamnesis (it is difficult to have 12 years as the age of onset for substance use disorder, and it is the upper limit for diagnosing ADHD, based on DSM-5). Thus, we can assume that, in the presence of substance use disorder, ADHD should be investigated, given the high prevalence. No abstinence period is needed to establish an ADHD diagnosis. If present, a long-acting stimulant could be considered, with use closely monitored by the parents, together with a substance use intervention.

Pharmacotherapy with mood stabilizers (e.g., lithium, valproic acid, carbamazepine) is the first-line treatment for bipolar disorder in adolescents without substance dependence. Only one controlled trial (lithium vs. placebo) has been conducted in adolescents with bipolar disorder and substance dependence (Geller, 1998). In this study, lithium had a relatively good safety profile and was shown to be effective in stabilizing mania or hypomania in adolescents with substance dependence, many of whom were not abstinent during the trial (Geller, 1998). Although there was a somewhat greater decline in substance use in the lithium-treated group compared to those who received placebo, the pharmacological treatment of bipolar disorder did not effectively treat substance dependence in the absence of specific substance treatment. The available data would support treating bipolar disorder only in the context of concurrent treatment for substance dependence in dually diagnosed adolescents. No data are yet available from controlled trials about the safety or efficacy of other mood stabilizers in dually diagnosed adolescents.

Studies have suggested that the second-generation antipsychotics may be more efficacious than the traditional mood stabilizers in the acute phase, and they appear to yield a quicker response (Liu et al., 2011). The FDA has approved several second-generation antipsychotics for the acute treatment of manic/mixed episodes in children and adolescents: risperidone for 10- to 17-year-olds, olanzapine for 13- to 17-year-olds, aripiprazole for 10- to 17-year-olds, and quetiapine for 10- to 17-year-olds. However, up to now, there are no reports on their use in adolescents with a concomitant substance use disorder. Thus, despite the clinical relevance of this comorbidity, there is a lack of studies on this topic.

In standard practice, adolescents with major (severe) depression would receive both psychotherapy and pharmacotherapy, while those with mild or moderate symptoms might be given a trial of psychotherapy alone before considering medications. When medications are used, selective serotonin reuptake inhibitors (SSRIs) are considered first-line medication choices for adolescent depression without comorbid substance dependence (Emslie, 1997). Fluoxetine is the best studied and has the best evidence of effectiveness. It is approved by the FDA and the European Medicines Agency (EMEA) for those aged 8 years or older. Sertraline, citalopram, and escitalopram have less robust evidence of effectiveness, though they may be effective in patients who did not respond to fluoxetine (Joseph et al., 2015). Escitalopram has been approved by the FDA for adolescents with depression. Paroxetine appears not to be effective in youth and shows more side effects than the other SSRIs. Monoamine oxidase inhibitors and tricyclic antidepressants should be avoided in children and adolescents (Rey, Bella-Awusah, & Liu, 2015).

No adequately powered controlled trials of SSRIs have yet been completed in depressed adolescents with substance dependence. Preliminary data from an ongoing RCT of fluoxetine for depression in 120 depressed and addicted adolescents indicates that it appears to have a very good safety profile even in nonabstinent adolescents with polydrug abuse (Lohman, 2002). A protocol of fluoxetine (20 mg/day) or placebo, both with CBT, for 16 weeks was tested in 126 adolescents (ages 13–19) meeting DSM-5 diagnostic criteria for current major depressive disorder, lifetime CD, and at least one nontobacco substance use disorder. Fluoxetine combined with CBT produced greater changes on the Childhood Depression Rating Scale-Revised (ES = 0.78) but not on the Clinical Global Impression Improvement treatment response (76% and 67%, respectively; relative risk, 1.08). There was an overall decrease in self-reported substance use, without a difference between the groups (Riggs et al., 2007). In a double-blind controlled trial to test the efficacy of fluoxetine over placebo in 50 adolescents with alcohol use disorder and comorbid major depression, concomitant with CBT and MET, there was no significant difference between groups for both depressive symptoms and alcohol use. In this study, alcohol abstinence was not required (Cornelius et al., 2009). Fluoxetine was also evaluated in 70 adolescents and young adults with depression and current cannabis use in a 12-week study, concomitant with CBT and MET. Again, no difference between the fluoxetine (up to 20 mg/day) and the placebo groups was described for either depressive symptoms or cannabis use (Cornelius et al., 2010). This cohort was followed and, after 1 year, 68 of the participants (97%) were retained. Most of the clinical improvements in depressive symptoms and for cannabis-related symptoms persisted at the 1-year follow-up evaluation, despite the study arm (fluoxetine or placebo). The authors suggest that the persistence of the efficacy of the acute-phase treatment might be attributed to the CBT/MET psychotherapy (Cornelius et el., 2012).

It seems that the good results for the SSRIs in nonaddicted youths have not been replicated in adolescents with comorbid substance use disorder. Whether it is a matter of low medication dosage, for instance, or whether there really is no effect in adolescent who are currently using drugs remains to be better understood. Studies demonstrated, however, that fluoxetine was well tolerated. Moreover, there is currently a controversy over whether SSRIs may increase the risk of suicide in adolescents; this issue is thoroughly discussed in Chapter 2 of this volume.

CBT, often used in combination with SSRIs, are considered standard treatment for a variety of anxiety disorders (including social anxiety disorder, generalized anxiety disorder, and posttraumatic stress disorder) in adolescents without substance dependence. While the use of SSRIs in adolescent anxiety disorders that are comorbid with substance dependence has not yet been well studied, the data support their relatively good safety profile in treating depression in adolescents with substance dependence, as mentioned above. Furthermore, the high rates of co-occurring depression and anxiety disorders suggest that clinicians may wish to consider SSRIs in dually diagnosed adolescents with anxiety disorders. Good target symptoms for SSRIs include the management of sleep problems, depressive symptoms, intrusive memories, and hyperarousal symptoms often associated with posttraumatic stress disorder (Davies, 2001; Lohman, 2002). There is a strong need for studies on this comorbidity.

Benzodiazepines are contraindicated for anxiety disorders in patients with substance dependence because of their well-known abuse potential.

In CD, the most common comorbidity in adolescents with substance abuse, the results of pharmacological treatment in adolescents without substance abuse have been poor, but there is some evidence that medications might help, together with an integrative approach. The impulsive/aggressive symptoms of CD seem to be responsive, for instance, to divalproex sodium (Padhy et al., 2011; Saxena et al., 2010; Steiner et al., 2003), aripiprazole (Ercan et al., 2012; Kuperman et al., 2011), and risperidone (Loy et al., 2012). Although most pharmacotherapy studies in adolescent substance abuse enroll adolescents with CD, studies specifically on the pharmacological approach to this common comorbidity are missing.

Eating disorder is another comorbidity that needs more attention. In adolescents with eating disorders, rates of substance use and abuse have also been found to be 20% to 40% greater than that of normal-weight peers (Denoth et al., 2011). Studies evaluating the role of medication in this complex clinical situation, which requires a multidisciplinary team, are needed.

Polypharmacy has become increasingly common in the adolescent population over the past two decades (Jureidini, Tonkin, & Jureidini, 2013). In the United States, among adolescents with mental disorder, polypharmacy increased from 22.2% (1996–1999) to 32.2% (2004–2007), despite the lack of studies on its safety and effectiveness (Comer, Olfson, & Moitabai, 2010). In clinical practice, adolescents with substance abuse usually present with more than one comorbidity (e.g., CD plus ADHD), and there are no studies, up to now, evaluating multiclass drug treatment in adolescents with substance abuse. This is of special interest and concern given the higher rates of psychotropic drug interactions expected when in the presence of a drug of abuse.

Another open question is the best moment to introduce medication in the presence of a comorbidity. Some studies, for instance, did not require abstinence to start comorbidity treatment (like most ADHD studies). If the adolescent has a comorbid disorder for which medication is being considered (e.g., ADHD, major depression), abstinence should be considered before initiating medication for comorbidity. However, abstinence is not a realistic goal for many adolescent patients. Clinicians must therefore weigh the risk of potential interactions between the drug and the medication against the risk that the untreated psychiatric illness will thwart treatment engagement or precipitate early dropout. Once the adolescent is engaged in substance abuse treatment, both urine drug screening and self-report should indicate either abstinence or significant reduction in substance use, although it is often necessary to tolerate some ongoing alcohol or cannabis use. The mental health professional or psychiatrist then should develop a plan for regular drug abuse monitoring (e.g., urine toxicology, breath alcohol) and for information exchange regarding compliance with substance treatment, urine toxicology results, target symptom response, and emergence of adverse side effects. When initiating medications, the patient should be compliant with at least weekly therapy sessions. Our clinical experience suggests benefit from MET coupled with CBT and an empathic, encouraging therapeutic style. Such an approach typically leads to successful medication stabilization for comorbidity during the first month of treatment. Early treatment of a psychiatric disorder can be critically important in facilitating treatment engagement and retention during the initial months of substance abuse treatment.

The following principles also may be helpful when using medications to treat comorbid disorders concurrently with substance dependence:

Following these principles should facilitate pharmacotherapy in adolescents who frequently have comorbid psychiatric disorders with their substance dependence. Medications primarily targeted at the substance dependence, such as bupropion or NRT for nicotine dependence, might also be considered, but behavioral treatments should be tried first for most adolescents with primary substance dependence and no other psychopathology.

Approximately one in seven users of prescribed adolescent medication had diverted their controlled medications in their lifetime. Medication must be closely monitored by parents/guardians and physicians, given the high rates of diversion in substance-abusing patients (trading, selling, giving away, or loaning). In a study conducted by McCabe et al. (2011), being approached to divert medications was more prevalent among adolescents who had substance use disorder. Thus, diligent prescribing and monitoring of controlled medications are recommended (McCabe at al., 2011).