How strong is the evidence supporting the use of amphetamine‑based stimulants (e.g., mixed amphetamine salts [Adderall], dextroamphetamine [Dexedrine, Vyvanse]) for treating attention‑deficit/hyperactivity disorder?

Evidence Quality for Amphetamine Treatment of ADHD

The evidence supporting amphetamine-based stimulants for ADHD is extremely strong, with a robust effect size of 1.0 and over 160 randomized controlled trials demonstrating efficacy in reducing core ADHD symptoms across all age groups. 1, 2

Strength of Evidence by Age Group

School-Age Children and Adolescents (6-18 years)

• Amphetamines demonstrate a large effect size of 1.0 for reducing ADHD core symptoms, which is the highest among all ADHD medications and represents the gold standard of treatment. 1, 2

• The American Academy of Pediatrics (AAP) guidelines report that more than 90% of children respond when both methylphenidate and amphetamine classes are tried, with approximately 40% responding to both and 40% responding to only one class. 1, 3

• A 2018 network meta-analysis including over 10,000 children and adolescents found large effect sizes for psychostimulants in reducing clinician-rated ADHD core symptoms. 1

• The evidence base includes more than 160 randomized controlled trials supporting stimulant efficacy, making this one of the most extensively studied pediatric treatments. 2

• Amphetamines improve not only core ADHD symptoms but also overall quality of life, functional impairment, and reduce risks of emergency trauma admissions, suicidal events, substance abuse, criminality, and unintentional injuries. 1

Preschool-Age Children (4-5 years)

• The evidence for amphetamines in preschool children is inadequate and they are NOT recommended as initial treatment, despite FDA approval granted under less stringent historical criteria. 1

• Methylphenidate is the recommended first-line stimulant for preschoolers with moderate-to-severe ADHD who fail behavioral interventions, though even methylphenidate evidence remains insufficient for FDA approval in this age group. 1

Adults

• A 2018 Cochrane review of 19 studies (2,521 adults) found amphetamines reduced ADHD symptom severity with moderate effect sizes (clinician-rated SMD -0.90; patient-rated SMD -0.51). 4

• Lisdexamfetamine (SMD -1.06) and mixed amphetamine salts (SMD -0.80) both demonstrated efficacy in adults, though the evidence quality was rated as low due to short study durations (mean 5.3 weeks) and high industry funding. 4

• A controlled trial of mixed amphetamine salts in 27 adults showed 42% reduction in ADHD Rating Scale scores (p<0.001) at an average dose of 54 mg/day, with 70% of subjects improving versus 7% on placebo. 5

Comparative Evidence: Amphetamine vs. Methylphenidate

• Both amphetamine and methylphenidate have equivalent effect sizes of approximately 1.0, making them equally effective first-line options. 1

• Individual response is idiosyncratic and unpredictable: approximately 40% respond to both classes, 40% to only one class, and the remaining 20% to neither, necessitating trials of both if the first fails. 1, 3

• The AAP strongly recommends trying both stimulant classes before moving to non-stimulants (atomoxetine, guanfacine, clonidine), which have lower effect sizes of 0.7. 1, 2

Evidence Quality Limitations and Caveats

Short-Term vs. Long-Term Evidence

• The robust evidence is primarily short-term (weeks to months); long-term efficacy beyond 2 years is less well-established. 1

• The MTA study follow-up found that children continuing stimulants for over 10 years showed no better outcomes than those who discontinued, though this observational finding cannot establish causality. 1

• A 7-week methylphenidate discontinuation study in children treated for over 2 years found significant symptom worsening when medication was stopped, supporting continued benefit with long-term use. 1

• Guidelines recommend periodic reassessment, potentially including medication-free intervals, to determine ongoing need for treatment. 1

Risk of Bias Concerns

• Most amphetamine studies have high or unclear risk of bias, primarily because amphetamines produce powerful subjective effects that can unmask treatment assignment, compromising blinding. 6, 4

• The 2016 Cochrane review of amphetamines in children rated evidence quality as "low to very low" for most outcomes due to bias concerns, though efficacy signals remained robust. 6

• Industry funding is pervasive: 16 of 19 adult studies were industry-funded, raising concerns about publication bias and outcome reporting. 4

Safety Profile

• Common adverse events include decreased appetite (RR 6.31), insomnia (RR 3.80), and abdominal pain (RR 1.44), with 30% higher overall adverse event rates versus placebo. 6

• Amphetamines increase treatment discontinuation due to adverse events (RR 2.69) but do not reduce overall retention in treatment. 4

• Preschool-aged children experience increased mood lability and dysphoria with stimulants, requiring careful monitoring. 1

• Growth delays occur in the first 1-2 years of treatment but typically normalize by 2-3 years, though long-term effects on height remain unclear. 1

• Concerns about sudden death and suicidality remain controversial and not definitively established as causal based on large registry studies. 1

Hierarchy of Evidence-Based Recommendations

The AAP and major guidelines establish the following treatment hierarchy based on evidence strength: 1, 3, 2

1. First-line: Stimulants (methylphenidate or amphetamine) – Effect size 1.0, >90% response rate when both classes tried
2. Second-line: Atomoxetine – Effect size 0.7,24-hour coverage, no abuse potential
3. Third-line: Extended-release guanfacine – Effect size 0.7
4. Fourth-line: Extended-release clonidine – Effect size 0.7

Clinical Decision-Making Framework

• For adolescents with prior amphetamine intolerance (shakiness, emotional lability), switch to methylphenidate-based stimulants first before abandoning the stimulant class entirely, as >90% respond to at least one class. 3

• Use long-acting formulations preferentially to provide stable symptom control, reduce rebound effects, and improve adherence. 1, 3

• Titrate weekly to the lowest effective dose over 3-4 weeks; dose response does not correlate with body weight. 3

• Screen adolescents for substance use before initiating stimulants and monitor for diversion risk. 1, 3

• Frame discussions around the risks of untreated ADHD (academic failure, accidents, substance abuse, criminality) rather than focusing solely on medication risks. 3