Table 1.
Randomized Controlled Trials of Pharmacotherapy for Adolescent Substance Use Disorders
| Medication | Clinical trial | Sample characteristics | Design | Intervention and comparator dosing (mg/day) | Results | Limitations |
|---|---|---|---|---|---|---|
| Alcohol use disorder | ||||||
| Naltrexone | Miranda et al. (2014) |
N = 22 nontreatment-seeking adolescents who consumed alcohol two or more times in 30 days before recruitment. Mean age = 18.36 ± 0.95 (range 15–19) Gender: 45% male Race: 72% white 18% Asian/Pacific Islander |
Randomized, double-blind crossover study. Participants randomized to each condition for 8–10 days (mean 9.93 ± 0.34) in counterbalanced order, with a 4- to 11-day washout period. |
Intervention: 50 mg naltrexone daily Control: placebo Platform intervention: none |
Naltrexone (relative to placebo): ↓ Drinking and heavy drinking (ps < 0.003) ↓ Craving in the laboratory and natural environment (ps < 0.04) ↓ Subjective responses to alcohol consumption (ps < 0.01) |
Brief treatment period (8–10 days). Small sample size. Excluded treatment-seeking adolescents and co-occurring substance use or disorders. |
| O'Malley et al. (2015) |
N = 128 nontreatment-seeking youth who reported ≥4 heavy drinking days (≥4 drinks women and ≥5 drinks men) in the 4 weeks before study enrollment. Mean age = 21.5 ± 2.15 (range 18–25) Gender: 68.8% male Race: 77% white, 8% African American |
Randomized (1:1), double-blind, two-group, parallel placebo-controlled study, 8-week treatment period. | Intervention: 25 mg +25 mg targeted naltrexone daily Control: placebo Platform intervention: all participants received psychosocial intervention |
Naltrexone (relative to placebo): No group differences between heavy drinking days and percent days abstinent. ↓ Number of drinks per drinking day and percentage of drinking days with estimated BAC ≥0.08. |
Adult/transitional age (18–25). Relatively brief treatment duration. Nontreatment-seeking youth compensated for appointments and adherence, limits generalizability. Measures of estimated BAC among participants likely much more variable than variability in individuals. |
|
| Cannabis use disorder | ||||||
| N-Acetylcysteine | Gray et al. (2012a) |
N = 116 treatment-seeking youth who met criteria for DSM-IV (American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th ed. 1994) cannabis dependence Mean age = 18.9 ± 1.5 (range 13–21) Gender: 72.4% male Race: 83% white |
Randomized (1:1), double-blind, two-group, parallel, placebo-controlled study, 8-week treatment period. | Intervention: N-acetylcysteine (1200 mg) twice daily Control: placebo twice daily Platform intervention: all participants received contingency management and individual weekly cessation counseling |
N-acetylcysteine (relative to placebo): Twice the odds of submitting negative urine cannabinoid tests during treatment (OR 2.4, 1.1–5.2, p = 0.029), with detectable differences within the first week of treatment. Time to first negative urine cannabinoid test and end-of-treatment abstinence favored N-acetylcysteine, but nonsignificant. |
Single university-based research clinic. Relatively small sample size. Older adolescent patient population. Minimal racial diversity in sample. Study not powered to detect end-of-treatment abstinence or sustained posttreatment effects. |
| Topiramate | Miranda et al. (2017) |
N = 66 treatment-seeking youth using cannabis at least twice weekly in 30 days before study participation and experienced ≥1 symptoms of cannabis abuse or dependence (DSM-IV). Mean Age = 18.81 ± 2.08 (range 15–24) Gender: 46% male Race: 50% white |
Randomized (2:1), double-blind, two-group, parallel, placebo-controlled study, 6-week treatment period. | Intervention: 25mg topiramate a day, then titrated by 25–50 mg over 4 weeks to 200 mg/day for the final 2 weeks of study. Control: placebo Platform intervention: all participants received biweekly motivational enhancement therapy for treating cannabis use among adolescents |
Topiramate (relative to placebo): No improvement in abstinence rates. ↓ the number of grams of marijuana smoked per use day. |
Significant side effects. Topiramate group had cognitive side effects: ↓ retrieval fluency and ↓ memory during treatment, in addition to difficulty with concentration, attention, dizziness, depression, anxiety, balance/coordination, and reaction time. High attrition (only 48% of topiramate group completed trial, compared to 77% of placebo). Small sample size, relatively short treatment period. |
| Tobacco use disorder | ||||||
| Nicotine replacement therapy (NRT) | Hanson et al. (2003) |
N = 100 treatment-seeking youth who smoked ≥10 cigarettes per day for ≥6 months and motivated to quit (≥7 on a scale of 1–10 assessing motivation to quit). Mean age = 16.8 ± 1.5 (range 13–19) Gender: 43% male Race: 87% white |
Randomized (1:1), double-blind, two-group, parallel, placebo-controlled study, 13-week treatment period. | Intervention: nicotine patch Control: placebo patch Platform intervention: individual cognitive-behavioral therapy and contingency management |
NRT (relative to placebo): ↓ craving scores and overall withdrawal symptoms |
Small sample size, minimal racial diversity. High attrition (53%). Compliance with NRT not objectively confirmed and often participants failed to return unused patches to help confirm compliance. Large incentives from contingency program, unclear if participants were motivated for contingencies or smoking cessation. |
| Moolchan et al. (2005) |
N = 120 treatment-seeking adolescents who smoked ≥10 cigarettes per day for ≥6 months, and were motivated to quit smoking. Mean age = 15.2 ± 1.33 (range 13–17) Gender: 30% male Race: 73% white |
Randomized, double-blind, double-dummy, three-arm trial, 12-week treatment period. | Intervention: (1) active patch and placebo gum or (2) active gum and placebo patch Control: placebo gum and placebo patch Platform intervention: All participants received group cognitive-behavioral therapy at each visit |
Carbon monoxide-confirmed prolonged abstinence rates of active-patch group (18%) vs. placebo (2.5%). Abstinence rates for the active gum condition (6.5%) did not differ from either condition. |
Participants deterred from gum use due to aversive taste, and participants had limited instruction in proper use of nicotine gum. | |
| Roddy et al. (2006) |
N = 98 treatment-seeking youth in an open-access youth project in a socioeconomically disadvantaged region. Mean age = 14.0 (range 11–21) Gender: 42% male Race: not reported |
Randomized (1:1), double-blind, two-group, parallel, placebo-controlled study, 6-week treatment period. | Intervention: nicotine patch Control: placebo patch Platform intervention: weekly individual or small group counseling |
NRT (relative to placebo): At 4 weeks, 5% patch group was abstinent vs. 2% placebo At 13 weeks, 0% patch and placebo were abstinent |
Small sample size; too small to detect an effect of NRT on smoking. Younger smokers with lighter smoking levels and lower CO levels compared to other studies examining NRT effectiveness in adolescents and young adults. |
|
| Rubinstein et al. (2008) |
N = 40 adolescent smokers who smoked ≥5 cigarettes daily for ≥6 months. Mean age = 16.7 ± 0.99 (range 15–18) Gender: 46% male Race: not reported other than “less than half being white” |
Randomized, open-label, 12-week trial, adolescent smokers were assigned on a 1:1.5 ratio to receive either weekly counseling alone (control) for 8 weeks, or 8 weeks of counseling along with 6 weeks of nicotine nasal spray. | Intervention: Nicotrol nasal spray (1 mg total) for 6 weeks Control: none Platform intervention: 8 sessions of American Lung Association's Not On Tobacco curriculum |
No group difference in cessation rates (p = 0.16), number of cigarettes smoked per day (p = 0.22), or cotinine levels at 12 weeks (p = 0.16). | 57% participants stopped using nicotine nasal spray after only one week, with 39% of participants stating that the nasal sprayer had “lots of side effects.” Lack of placebo spray arm. Lack of association between self-reported smoking and cotinine levels suggests potential measurement bias. |
|
| Scherphof et al. (2014) |
N = 257 treatment-seeking Dutch adolescents who smoked ≥7 cigarettes a day. Mean age = 16.7 ± 1.13 (range 12–18) Gender: 47% male Race: not reported |
Randomized (1:1), double-blind, two-group, parallel, placebo-controlled study, 6- or 9-week treatment period. | Intervention: 21, 14, or 7 mg nicotine patch based on number of cigarettes smoked per day at time of enrollment Control: placebo patch Platform intervention: none |
NRT (relative to placebo): Doubled abstinence rates after 2 weeks (OR = 2.02, 95% CI = 1.11–3.69), but no differences at end of treatment. End-of-treatment abstinence rates significantly ↑ in high-compliant (OR = 1.09, 95% CI = 1.01–1.17) and not in low compliant participants. |
NRT compliance was assessed using online self-report measures, which may have elicited socially desirable answers. | |
| Bupropion | Killen et al. (2004) |
N = 211 treatment-seeking adolescents (1) who reported smoking ≥10 cigarettes daily, (2) had smoked for ≥6 months, and (3) had one or more failed attempts to quit smoking. Mean age = 17.3 ± 0.8 (range 15–18) Gender: 69% male Race/ethnicity: 50% white, 12% Hispanic, 7% Asian |
Randomized, double-blind, placebo-controlled, 10-week study | Intervention: nicotine patch plus bupropion SR (sustained release; 150 mg per day) Control: nicotine patch plus placebo group Platform intervention: weekly group skills training sessions |
No difference between abstinence rates at weeks 10 and 26: (1) patch plus bupropion 23% and 8%, (2) patch plus placebo 28% and 7%. | Low dosing of bupropion: 150 mg per day (recommended dose for adult smokers is 300 mg per day). Limited patch and medication compliance. |
| Niederhofer and Huber (2004) |
N = 22 adolescents who met DSM-IV criteria for nicotine dependence. Mean age = 17.3 ± 0.7 (range 16–19) Gender: 50% male Race: not reported |
Randomized (1:1), double-blind, two-group, parallel, placebo-controlled study, 90-day treatment period. | Intervention: bupropion 150 mg daily Control: placebo Platform intervention: psychosocial or behavioral intervention (no details provided on type or duration) |
Bupropion (relative to placebo): Higher abstinence (55%, 6/11) compared to placebo group (18%, 2/11) throughout the 90 days of treatment. Mean cumulative abstinence duration was significantly ↑ in bupropion group than in the placebo group (78.4 ± 39.6 vs. 30.2 ± 19.2, p = 0.004). |
Small study size. Study used a lower bupropion dose (150 mg) than now suggested. Some subjectivity as investigators determined judgments of whether self-reported tobacco use was likely to be true. |
|
| Muramoto et al. (2007) |
N = 312 treatment-seeking adolescents who smoke ≥6 cigarettes per day, had an exhaled carbon monoxide level of ≥10 ppm, and had at least two previous quit attempts. Median age: 16 (range 14–17) Gender: 54% male Race/ethnicity: 74% white, 15% Hispanic |
Randomized, double-blind, placebo-controlled, parallel-group, dose-ranging trial, 6-week treatment period. | Intervention: (1) Bupropion SR 150 mg per day or (2) 300 mg per day Control: placebo Platform intervention: all participants received weekly brief interventional counseling |
6 weeks: Cotinine-confirmed 7-day point prevalence abstinence rates: placebo, 5.6%; 150 mg, 10.7%; and 300 mg, 14.5% (p = 0.03, 300 mg vs placebo). 26 weeks: Confirmed point prevalence abstinence rates: placebo, 10.3%; 150 mg, 3.1%; and 300 mg, 13.9% (p = 0.049). |
Study shortened the follow-up from 52 weeks to 26 weeks due to recruitment difficulties. Compensation for study participation may have influenced motivation for enrollment and continued participation more so than overall motivation to quit. |
|
| Gray et al. (2011) |
N = 134 treatment-seeking youth who smoke ≥5 cigarettes per day with baseline urine cotinine >100 ng/mL. Mean age = (range 12–21) Gender: 58% male Race: 89% Caucasian |
Randomized, double-blind, four-group, parallel, placebo-controlled study, 6-week treatment period. | Intervention: (1) bupropion SR + with contingency management (2) bupropion SR without contingency management Control: (3) placebo with contingency management or (4) placebo without contingency management |
Combined bupropion SR + contingency management yielded significantly superior abstinence rates during active treatment when compared with placebo and no contingency management treatment: bupropion SR and contingency management 27%, bupropion SR without contingency management 8%, placebo and contingency management 10%, and placebo and noncontingency management 9%. | Reported abstinences may be underestimated, as those who missed appointments were considered to be nonabstinent at all missed visits. Low treatment completion rate (30%) was lower than other larger scale studies. Minimal racial diversity in sample. |
|
| Varenicline | Gray et al. (2012b) |
N = 29 treatment-seeking youth who smoke ≥5 cigarettes per day, with one previous unsuccessful quit attempt. Mean age = 18.9 ± 1.0 (range 15–20) Gender: 58% male Race: not reported |
Randomized, double-blind, 8-week treatment period. | Interventions: Varenicline (≤2mg) vs. bupropion sustained release (150–300 mg) Control: none Platform intervention: none |
Varenicline (relative to bupropion): ↓ cigarettes smoked per day from 14.1 ± 6.3 to 0.9 ± 2.1 and those receiving bupropion XL reduced from 15.8 ± 4.4 to 3.1 ± 4.0. |
No placebo control group. Poor participant retention. |
| Opioid use disorder | ||||||
| Buprenorphine | Marsch et al. (2005) |
N = 36 self-referred treatment-seeking adolescents who met DSM-IV criteria for opioid dependence. Mean age: 17.4 ± 0.7 (range 13–18) Gender: 39% male Race: 97% white |
Randomized, double-blind, double-dummy, parallel groups, 28-day trial. | Interventions: Outpatient detox with buprenorphine (≤8 mg) + placebo patch vs. clonidine (≤3 mg) patch + placebo tablets Control: none Platform intervention: behavioral counseling thrice weekly |
↑ Retention in buprenorphine group (72%) vs. clonidine (39%) (p < 0.05). ↑ Percentage of opioid negative urine tests (64% vs. 32%, p = 0.01). |
Study focused primarily on treatment outcomes during treatment, without any posttreatment follow-up. Minimal racial diversity in sample. Medication doses were in the low-moderate range relative to adult doses. |
| Buprenorphine/Naloxone | Woody et al. (2008) |
N = 152 treatment-seeking adolescents who met DSM-IV criteria for opioid dependence. Multisite, national sample from community programs that used methadone or buprenorphine/naloxone. Mean age: 19.4 ± 1.5 (range 15–21) Gender: 59% male Race/ethnicity: 74% white, 25% Hispanic |
Randomized, nonblinded 12-week trial. | Interventions: 14-day outpatient detoxification (≤14 mg of buprenorphine) vs. 12-week buprenorphine/naloxone (≤24 mg) Control: none Platform intervention: all participants received weekly individual and group counseling |
Compared to the detoxification group, participants in the 12-week buprenorphine/naloxone group showed the following: ↓ Opioid-positive urine tests at week 4 (26% vs. 61%) and 8 (23% vs. 54%), but not at week 12 (43% vs. 51%). ↓ reported opioid use before week 6 (p < 0.001) ↓ reported injections before week 6 (p = 0.01 ↓ cocaine and marijuana use |
Small proportion of patients younger than 18 was not sufficient to meaningfully analyze outcomes. Lack of blinding by evaluators. Buprenorphine dosing was typically observed, which strengthens internal validity, but may not parallel real-world conditions. Low follow-up rate. |
| Marsch et al. (2016) |
N = 53 youth who met DSM-IV opioid dependence criteria Mean age: 20.5 ± 2.6 (Range 16–24) Gender: 58% male Race: 70% white |
Randomized, double-blind, placebo-controlled, multicenter randomized controlled trial, 63 days in length. | Intervention: 28-day or 56-day buprenorphine/naloxone detoxification and followed over a 63-day study period. | Participants who received a 56-day buprenorphine taper were retained in treatment 11 days longer on average than participants who received a 28-day buprenorphine taper. Participants who received a 56-day buprenorphine taper had a significantly ↑ percentage of opioid-negative scheduled urine tests compared with participants who received a 28-day buprenorphine taper (35 vs. 17%). |
Small sample size. Less than half of participants enrolled in both conditions completed the entire 63 days of study. |
|
| Methamphetamine use disorder | ||||||
| Bupropion | Heinzerling et al. (2013) |
N = 19 youth with DSM-IV methamphetamine abuse or dependence and low frequency of methamphetamine use (use on ≤18/30 days). Mean age: 17.6 ± 1.4 (Range 14–21) Gender: 47% male Race: 70% white |
Randomized, double-blind, placebo-controlled, 2:1 ratio to bupropion or placebo during outpatient treatment (substance use counseling) for 8 weeks. | Intervention: Bupropion SR 150 mg twice daily Control: placebo Platform intervention: group drug counseling |
Adolescents receiving bupropion and females provided significantly fewer methamphetamine-free urine tests compared to participants receiving placebo (p = 0.043) and males (p = 0.005) respectively, compared to placebo. | Small sample size. Difficulties recruiting and retaining participants. |
OD, odds ratio; CI, confidence interval; BAC, blood alcohol content.