Table 1.

Pharmacotherapy for Adolescent Substance Use Disorders

Drug	Sample(s)	Study design(s)	Intervention dosing and duration	Outcome measures	Level of Evidencea
Alcohol Withdrawal Syndrome
Benzodiazepines		Consensus Guidelines; there are no controlled treatment studies examining pharmacotherapy for adolescent AW or AWS.			Grade C (level 3 evidence) for AWS
Alcohol Use Disorder
Naltrexone (oral)	Outpatient, treatment-seeking, adolescents (mean age = 13.2 years); Non-treatment- seeking heavy drinkers (ages 15– 19); 2 studies, n= 27 total subjects	6-week, open-label, clinical study; 4-week double-blind, placebo controlled cross-over study using EMA	Naltrexone, oral, flexible dose, 25–50 mg daily; Naltrexone, oral, fixed dose, 50 mg daily	Self-report alcohol use (time-line follow-back methods and EMA); A- OCDS; alcohol craving; subjective- response to alcohol	Grade C (level 3 evidence) for AUD
Disulfiram	Post- detoxification, outpatient, treatment-seeking adolescents (ages 16–19); 1 study, n= 26 subjects	90-day, randomized double-blind, placebo controlled study	Disulfiram, oral, fixed dose, 200 mg daily	Self-report alcohol use	Grade C (level 3 evidence) for AUD
Ondansetron	Outpatient, treatment-seeking, adolescents (ages 14–20); 1 study, n= 12 subjects	8-week, open-label, clinical study	Ondansetron, oral, fixed dose, 4 micrograms/kg two times per day	Self-report alcohol use; adverse events	Grade C (level 3 evidence) for AUD
Topiramate	Non-treatment seeking, heavy drinkers (mean age = 19 years); 1 study, n= 13 subjects	5-week, randomized, placebo controlled, pilot study using EMA	Topiramate, oral, escalating dose, up to 200 mg per day	Self-report alcohol use (EMA); alcohol craving; subjective- response to alcohol	Grade C (level 3 evidence) for AUD
Tobacco Use Disorder
Nicotine Replacement Therapy (patch, gum, nasal spray)	Outpatient, treatment-seeking adolescents (ages 12–19), smoking ≥ 5 CPDb; 5 studies, n= 728 total subjects	Meta-analysis, 12-week randomized double- blind, double-placebo controlled study comparing nicotine patch to nicotine gum; 10-week randomized double-blind placebo-controlled study of nicotine patch; 6-to-9- week randomized, double-blind placebo controlled study of nicotine patch; 8-week open-label clinical study of nicotine nasal spray	Nicotine patch, fixed dose 21 mg (participants smoking ≥ 20 CPD) or 14 mg (< 20 CPD). Nicotine patch, fixed-taper dosing, starting dose 21 mg (participants smoking > 15 CPD) or 14 mg (10–14 CPD) tapered over 10-weeks. Nicotine gum, 4 mg (participants smoking ≥ 24 CPD) or 2 mg (< 24 CPD). Nicotine nasal spray, 1 mg dosing as needed.	CO–confirmed PPA at EOT; cotinine- confirmed PPA at EOT; nicotine craving; nicotine withdrawal	Nicotine patch: Grade B (level 2 evidence) for TUD Nicotine gum and nasal spray: Grade C (level 3 evidence) for TUD
Varenicline	Outpatient, treatment-seeking adolescents (ages 14–20), smoking ≥ 5 CPD; 1 study, n= 29 subjects	8-week, randomized double-blind controlled study comparing Varenicline to Buproprion XL	Varenicline, oral, 1 mg two times per day or Buproprione XL, oral, 300 mg daily	Self-report smoking reduction; cotinine confirmed PPA at EOT	Grade B (level 2 evidence) for TUD
Buproprion	Outpatient, treatment-seeking adolescents (ages 12–21), smoking ≥ 5 CPDb; 4 studies, n= 688 total subjects	Meta-analysis, 8-week, randomized, double- blind, placebo controlled add-on to nicotine patch; 6-week, randomized, double-blind, placebo controlled dose comparison study (150 mg vs. 300 mg) study; 6- week, randomized double-blind, placebo controlled study with added +/− CM; 8-week, randomized double-blind comparison to Varenicline	Buproprion SR, oral, fixed dose, 150 mg daily or 300 mg daily	Cotinine-confirmed PPA at EOT; CO- confirmed PPA at EOT; self-report smoking reduction	Grade B (level 2 evidence) for TUD
Cannabis Use Disorder
N-acetylcysteine (NAC)	Outpatient, treatment-seeking, adolescents (ages 15–21); 2 studies, n= 134 total subjects	8-week, randomized, double-blind, placebo controlled study added to brief cessation counseling and CM; 4- week open-label pilot study	NAC, oral, fixed dose, 1200 mg two times per day (2400 mg/day)	Negative urine cannabinoid test, self- report cannabis use, cravings for cannabis	Grade B (level 2 evidence) for CUD
Topiramate	Outpatient, treatment-seeking, youth (ages 15– 24); 1 study, n = 66	6-week, randomized, double-blind, placebo controlled pilot study medication added to 3 sessions of motivational enhancement therapy (MET)	Topiramate, oral, fixed dose, titrated to 200 mg daily over 4 weeks and maintained at 200 mg/day over 2 weeks	Positive urine cannabinoid test, self- report cannabis use (% days of cannabis use, grams of cannabis use per day), treatment retention, adverse events, neurocognitive functioning	Grade C (level 3 evidence) for CUD
Opioid Withdrawal Syndrome
Buprenorphine and Buprenorphine- naloxone	Outpatient detoxification, treatment-seeking, adolescents (ages 13–18); 2 studies, n= 188 total subjects	Systematic review; 28- day randomized, double- blind, double-placebo, controlled study comparing clonidine and buprenorphine detoxification regimens; 12-week randomized multisite clinical trial comparing 2-week detoxification to 12-week maintenance	Buprenorphine, sublingual, fixed-taper dosing, starting dose 8 mg or 6 mg (age based); Buprenorphine- naloxone (2 mg/0.05 mg ratio), oral, fixed-taper dosing, up to 24 mg daily	Opiate negative urine tests, treatment retention, self-report HIV-risk behavior, opiate withdrawal symptoms	Grade B (level 2 evidence) for OWS
Clonidine (patch)	Outpatient detoxification, treatment-seeking, adolescents (ages 13–18); 1 study, n= 36 subjects	28-day randomized, double-blind, double- placebo, controlled study comparing clonidine and buprenorphine detoxification regimens	Buprenorphine, sublingual, fixed-taper dosing, starting dose 8 mg or 6 mg (age based); Clonidine, transdermal patch, fixed- taper dosing, starting dose 0.1–0.3 mg daily	Opiate negative urine tests, treatment retention, self-report HIV-risk behavior, opiate withdrawal symptoms	Grade B (level 2 evidence) for OWS
Opioid Use Disorder
Methadone	Inpatient detoxification and Specialized Opioid Treatment Programs, treatment-seeking, adolescents, heroin users (ages ≤ 20); 9 studies, n= 6,263 total subjects	Systematic review; naturalistic study comparing methadone maintenance, detoxification, therapeutic community, and abstinence-based treatments; naturalistic studies of methadone maintenance or methadone detoxification treatment without comparator groups; methadone-based short- term detoxification (30- days) versus long-term detoxification (up to 6- months)	Methadone, oral, flexible dosing, for 30-day detoxification or up to 6- month maintenance treatment	Treatment retention, self-report opioid use	Grade C (level 3 evidence) for OUD
Buprenorphine- naloxone	Outpatient, treatment-seeking, adolescents (ages 15–21); 1 study, n= 152 subjects	Systematic review; 12- week, randomized, multisite, controlled study comparing 2-week buprenorphine-naloxone detoxification to 12-week buprenorphine-naloxone maintenance/extended treatment	Buprenorphine-naloxone (2 mg/0.05 mg ratio), oral, fixed-taper dosing, up to 24 mg daily	Opiate positive urine tests	Grade B (level 2 evidence) for OUD
Extended- release injectable Naltrexone (intramuscular)	Residential treatment transitioning to outpatient treatment, treatment-seeking, adolescents (ages 16–20); 1 study, n= 16 subjects	Retrospective, open- label, case series	XR-naltrexone, intramuscular injection, 380 mg once every 4 weeks	Treatment retention, abstinence, opioid use (chart abstraction of self-report and urine drug screen data)	Grade C (level 3 evidence) for OUD
Opioid Overdose
Naloxone (intranasal)		Consensus guidelines; there have been no studies examining pharmacotherapy for opioid overdose in adolescents.	Naloxone, intranasal, 2mg/2ml pre-filled luer-lock needle-less syringe		Grade C (level 3 evidence) for Opioid Overdose

Abbreviations: A-OCDS = Alcohol Obsessive Compulsive Drinking Scale, AW = alcohol withdrawal, AWS = alcohol withdrawal syndrome, AUD = alcohol use disorder, Buproprion SR – sustained release buproprion, Buproprion XL – extended release buproprion, CM = contingency management, CO = carbon monoxide, Cotinine = urine cotinine level (ng/dl), CUD = cannabis use disorder, EMA = ecological momentary assessment, EOT = end of treatment, HIV = human immunodeficiency virus, NAC = n-acetyl-cysteine, NRT = nicotine replacement therapy, OUD = Opioid Use Disorder, OWS = Opioid Withdrawal Syndrome, PPA = point prevalence abstinence, TUD = tobacco use disorder, XR-naltrexone = Extended-release injectable Naltrexone

^aLevels of evidence presented are based upon the US Preventative Services Task Force (USPSTF) Strength of Recommendation Taxonomy (SORT) approach to grading evidence in medical literature.¹⁰³ Levels of evidence include: Level 1: good-quality, patient-oriented evidence including systematic reviews, meta-analyses, and well-designed randomized controlled trials with consistent findings. Level 2: limited-quality, patient-oriented evidence including lower-quality/less consistent systematic reviews, meta-analyses, or clinical trials as well as cohort and case-control series. Level 3: other evidence in the form of consensus guidelines, disease-oriented evidence, and case series. These levels of evidence are used to determine a strength of recommendation grade, which include A (good-quality, patient-oriented evidence); B (limited-quality, patient-oriented evidence); C (other evidence); and no recommendation.

^bFor the adolescent TUD pharmacotherapy studies, and specifically the 5 NRT and 4 bupropion studies, all studies had CPD-based inclusionary criteria which ranged from ≥ 5 to ≥ 10 CPD.