Table 1.
Placebo-controlled studies of pharmacological treatment in adolescents with ADHD and comorbid SUD, and in adolescents without comorbid SUD.
| Author, Year | Population | SUD Diagnosis | Study Design and Treatment |
Concurrent Treatment |
Treatment Completers |
Primary Outcome Measurement: ADHD |
Primary Outcome Measurement: SUD |
Primary Outcome |
Level of Evidence (SIGN) |
|---|---|---|---|---|---|---|---|---|---|
| Adolescents with ADHD and SUD | |||||||||
| Methylphenidate | |||||||||
| Szobot, 2008 [36] | 16 adolescents aged 15–21 years (mean 17.4 years; 100% male) with ADHD and cannabis an/or cocaine use disorder (DSM-IV) | Dependence: cannabis (93.8%) or cocaine (43.8%) |
6-week, randomized, SB, PC, crossover study: 2 × 3 weeks: MPH-SODAS (0.3–1.2 mg/kg/day) or placebo | No concurrent Tx for ADHD or SUD | 87.5% in both treatment conditions combined | Mean change over time on mother-reported SNAP-IV and investigator-rated CGI by treatment condition | Mean change over time in adolescent-reported days of substance use past 1 week by treatment condition | Significant improvement in ADHD symptoms and global functioning (both: p ≤ 0.001) in MPH-SODAS condition vs. placebo; no treatment effect on substance use | 2 − |
| Riggs, 2011 [37] | 303 adolescents aged 13–18 years (mean 16.5 years; 78.9% male) with ADHD and SUD (DSM-IV) | Dependence: cannabis (66.7%), alcohol (29.7%), cocaine (7.3%), hallucinogen (5%), sedative (2.6%), amphetamine (1.3%), or other (1.2%) Abuse: alcohol (26.4%), cannabis (25.4%), opiate (12.2%), hallucinogen (7.6%), sedative (7.3%), amphetamine (3%), cocaine (2.6%), or other (4%) |
16 weeks, RCT, DB, PC; parallel groups: OROS-MPH (max. 72 mg/day, titrated fixed dose) or placebo | 16-week individual CBT/MET for SUD | OROS-MPH: 78.1%; placebo: 71.7% | Mean change over time on adolescent-reported ADHD-RS-IV by treatment group | Mean change over time in adolescent-reported days of substance use past 4 weeks (TLFB) by treatment group | No significant difference between both groups in reduction of ADHD symptoms (d = 0.22; ns) and substance use (d = 0.05; ns) | 1 + |
| Pemoline | |||||||||
| Riggs, 2004 [38] | 69 adolescents aged 13–19 years (mean 15.8 years; 84.1% male) with ADHD, SUD, and CD (DSM-IV) | Dependence: alcohol (47.8%) or cannabis (73.9%) |
12 weeks, RCT, DB, PC; parallel groups: pemoline (75–112.5 mg/day) or placebo | No concurrent Tx for ADHD, SUD or CD | Pemoline: 54.3%; placebo: 50.0% | % responders on clinician-rated CGI (ADHD-symptoms “much improved” or “very much improved”) at study endpoint and mean change over time on parent-rated CHI by treatment group | Mean change over time in adolescent-reported days of substance use past 30 days (TLFB) and total number of negative urine drug screens by treatment group | Significantly more responders in pemoline group vs. placebo (d = 0.5; p = 0.05); no treatment effect on ADHD symptoms on CHI (d = 0.34; ns) and substance use (d = 0.05; ns) | 1 − |
| Atomoxetine | |||||||||
| Thurstone, 2010 [39] | 70 adolescents aged 13–19 years (mean 16.1 years; 78.6% male) with ADHD and SUD (DSM-IV) | Alcohol (28.6%), cannabis (95.7%), cocaine (2.9%), amphetamine (1.4%), or hallucinogen (1.4%) |
12 weeks, RCT, DB, PC; parallel groups: atomoxetine (<70 kg: 1.1–1.5 mg/kg/day; ≥70 kg: max. 100 mg/day) or placebo | 12-week individual CBT/MET for SUD | Atomoxetine: 91.4%; placebo: 94.3% | Mean change over time on an adolescent-reported DSM-IV checklist by treatment group | Mean change over time in adolescent-reported days of substance use past 4 weeks (TLFB) by treatment group | No significant difference between both groups in reduction of ADHD symptoms (d = 0.10; ns) and substance use (d = 0.35; ns) | 1 + |
| Adolescents with ADHD, without SUD | |||||||||
| Methylphenidate | |||||||||
| Wilens 2006 [40] | 177 adolescents aged 13–18 years (mean 14.6 years; 80.2% male) with ADHD (DSM-IV) without a history of nonresponse to MPH, who responded favorably to OROS-MPH in an open-label titration phase | 2 weeks, RCT, DB, PC; parallel groups: OROS-MPH (18–72 mg/day, titrated fixed dose) or placebo | Subjects in behavioral treatment at study enrollment could continue their treatment | OROS-MPH: 81.6%; placebo: 68.9% | Mean change over time on adolescent-reported ADHD-RS-IV by treatment group | NA | Significant improvement in ADHD symptoms in OROS-MPH group vs. placebo (d = 0.56; p = 0.001) | 1 − | |
| Findling, 2010a [27] | 217 adolescents aged 13–17 years (mean 14.6 years; 74.4% male) with ADHD (DSM-IV-TR) | 7 weeks, RCT, DB, PC; parallel groups: MTS (10, 15, 20, or 30 mg/day, titrated fixed dose) or placebo | No concurrent Tx | MTS: 65.5%; placebo: 40.3% | Mean change over time on adolescent-reported ADHD-RS-IV by treatment group | NA | Significant improvement in ADHD symptoms in MTS group vs. placebo (d = 1.33; p < 0.001) |
1 − | |
| Pelham, 2013 [33] | 30 adolescents aged 12–17 years (mean 14.1 years; 90% male) with ADHD (DSM-III) | 12-week, randomized, DB, PC, conditions cross-over study: IR-MPH (max. 75 mg/day, titrated dose) or pemoline (max. 112.5 mg/day, titrated dose) or placebo in a naturalistic school setting | Not reported | Not reported | Mean change over time on teacher-reported inattention/overactivity subscale of IOWA-CRS by treatment condition | NA | Significant improvement in ADHD symptoms in IR-MPH condition vs. placebo (d = 0.53; p < 0.05), but not in pemoline condition vs. placebo (d = 0.21; ns) | 2 − | |
| Newcorn 2017a [34] | 464 adolescents aged 13–17 years (mean 14.7 years; 66.4% male) with ADHD (DSM-IV-TR) | 8 weeks, RCT, DB, PC; parallel groups: OROS-MPH (12–72 mg/day, titrated flexible dose) or LDX (30–70 mg/day, titrated flexible dose) or placebo | Not reported | OROS-MPH: 84.9%; LDX: 83.3%; placebo: 73.1% | Mean change over time on parent-reported ADHD-RS-IV by treatment group | NA | Significant improvement in ADHD symptoms in OROS-MPH (d = 0.97; p < 0.0001) and LDX (d = 1.16; p < 0.0001) vs. placebo. No significant difference between OROS-MPH and LDX (p = 0.07) |
1 − | |
| Newcorn 2017b [34] | 549 adolescents aged 13–17 years (mean 14.7 years; 66.0% male) with ADHD (DSM-IV-TR) | 6 weeks, RCT, DB, PC; parallel groups: OROS-MPH (72 mg/day, titrated fixed dose) or LDX (70 mg/day, titrated fixed dose) or placebo | Not reported | OROS-MPH: 84.5%; LDX: 82.6%; placebo: 88.2% | Mean change over time on parent-reported ADHD-RS-IV by treatment group | NA | Significant improvement in ADHD symptoms in OROS-MPH (d = 0.50; p < 0.0001) and LDX (d = 0.82; p < 0.0001) vs. placebo. Significant improvement in LDX vs. OROS-MPH (d = 0.33; p = 0.0013) |
1 + | |
| (Lis)dexamphetamine/mixed amphetamine salts | |||||||||
| Spencer, 2006 [41] | 287 adolescents aged 13–17 years (mean 14.2 years; 65.5% male) with ADHD (DSM-IV-TR) | 4 weeks, RCT, DB, PC; parallel groups: MAS-XR (10, 20, 30, 40 mg/day, forced dose titration) or placebo | Not reported | 92.8% in all treatment groups combined | Mean change over time on adolescent-reported ADHD-RS-IV by treatment group | NA | Significant improvement in ADHD symptoms in MAS-XR group vs. placebo (d = 0.80; p ≤ 0.001) | 1 + | |
| Findling, 2011 [42] | 314 adolescents aged 13–17 years (mean 14.6 years; 70.3% male) with ADHD (DSM-IV-TR) | 4 weeks, RCT, DB, PC; parallel groups: LDX (30, 50, 70 mg/day, forced dose titration) or placebo | Subjects in behavioral treatment at study enrollment could continue their treatment | LDX: 83.4%; placebo: 87.3% | Mean change over time on adolescent-reported ADHD-RS-IV by treatment group | NA | Significant improvement in ADHD-symptoms in LDX groups vs. placebo (30 mg: d = 0.80; 50 mg: d = 1.23; 70 mg: d = 1.09; all: p ≤ 0.0056) | 1 + | |
| Pemoline | |||||||||
| Bostic, 2000 [43] | 21 adolescents aged 12–17 years (mean 14.1 years; 85.7% male) with ADHD (DSM-IV) | 10-week, randomized, DB, PC, crossover study: 2 × 4-week: pemoline (1–3 mg/kg) or placebo | Not reported | 71.4% in both treatment groups combined | Mean change over time on adolescent-reported ADHD-RS-IV by treatment condition | NA | Significant improvement in ADHD symptoms in pemoline condition vs. placebo (d = 2.05; p = 0.001) | 2 − | |
| Atomoxetine | |||||||||
| Bangs, 2007 [44] | 142 adolescents aged 12–18 years (mean 14.5 years; 73.2% male) with ADHD and major depression (DSM-IV) | 9 weeks, RCT, DB, PC; parallel groups: atomoxetine (1.2–1.8 mg/kg/day) or placebo | No concurrent Tx | Atomoxetine: 81.9%; placebo: 87.1% | Mean change over time on parent-reported ADHD-RS-IV and CDRS-R by treatment group | NA | Significant improvement in ADHD symptoms in atomoxetine group vs. placebo (d = 0.99; p <0.001); no significant difference in reduction of depressive symptoms (d = 0.20; ns) | 1 − | |
| Guanfacine | |||||||||
| Biederman, 2008 [45] | Subgroup of 80 adolescents (gender for subset not reported) aged 13–17 years with ADHD (DSM-IV) | 8 weeks, RCT, DB, PC; parallel groups: GXR (2, 3, and 4 mg/day, fixed dose escalation) or placebo | Not reported | Not reported for the adolescent subgroup | Mean change over time on parent-reported ADHD-RS-IV by treatment group | NA | No significant difference between GXR groups and placebo in reduction of ADHD symptoms (p > 0.05) | 1 − | |
| Sallee, 2009 [46] | Subgroup of 80 adolescents (gender for subset not reported) aged 13–17 years with ADHD (DSM-IV-TR) | 9 weeks, RCT, DB, PC; parallel groups: GXR (1, 2, 3, and 4 mg/day, fixed dose escalation) or placebo | Not reported | Not reported for the adolescent subgroup | Mean change over time on parent-reported ADHD-RS-IV by treatment group | NA | No significant difference between GXR groups and placebo in reduction of ADHD symptoms (p = 0.20) | 1 − | |
| Wilens 2015 [47] | 314 adolescents aged 13–18 years (mean 14.5 years; 64.7% male) with ADHD (DSM-IV-TR) | 13 weeks, RCT, DB, PC; parallel groups: GXR (4 to 7 mg/day dependent on weight and optimal dose titration) or placebo | Subjects in behavioral treatment at study enrollment could continue their treatment | GXR: 74.5%; placebo: 70.1% | Mean change over time on adolescent-reported ADHD-RS-IV by treatment group | NA | Significant improvement in ADHD symptoms in GXR group vs. placebo (d = 0.52; p < 0.001) | 1 − | |
Note: Pelham 2013 and Newcorn 2017a and 2017b are three-armed studies that investigated two active medications and placebo. ADHD—attention deficit/hyperactivity disorder; SUD—substance use disorder; CD—conduct disorder; RCT—randomized controlled trial; DB—double blind; SB—single blind; PC—placebo controlled; Tx—treatment; OROS-MPH—osmotic-release oral system methylphenidate; MPH-SODAS—extended release formulation of methylphenidate; MTS—methylphenidate transdermal system; IR-MPH—immediate release methylphenidate; LDX—lisdexamfetamine dimesylate; MAS-XR—mixed amfetamine salts extended release; GXR—guanfacine extended release; CBT—cognitive behavioral therapy; MET—motivational enhancement therapy; DSM-IV —Diagnostic and Statistical Manual of Mental Disorders; ADHD-RS-IV—DSM-IV ADHD Rating Scale; SNAP-IV—Swanson, Nolan, and Pelham Scale, version IV; CHI —Conners Hyperactivity-Impulsivity scale; IOWA-CRS—IOWA Conners Rating Scale; CDRS-R—Children’s Depression Rating Scale-Revised; CGI—Clinical Global Impression scale; TLFB—Time Line Follow-Back calendar method; NA—not applicable; ns—not significant. Mechanisms of action for each pharmacological treatment mentioned: Methylphenidate: increases dopaminergic and noradrenergic activity in the prefrontal cortex by inhibiting dopamine and noradrenaline reuptake. Pemoline: increases dopaminergic activity by blocking dopamine reuptake. Atomoxetine: not fully known but thought to be related to increased noradrenergic activity in the prefrontal cortex via selective noradrenaline reuptake inhibition. (Lis)dexamfetamine/mixed amfetamine salts: increases monoamine neurotransmitter release (including dopamine, norepinephrine, and serotonin) and prevents their reuptake. Guanfacine: not fully known but thought to be related to the stimulation of alpha2 adrenergic receptors in the brain.