What evidence supports the use of amphetamine‑based stimulants as first‑line therapy for adults with attention‑deficit/hyperactivity disorder (ADHD)?

Evidence for Amphetamine-Based Stimulants in Adult ADHD

Amphetamine-based stimulants demonstrate robust efficacy as first-line therapy for adult ADHD, with response rates of 70-80% and the largest effect sizes among all ADHD medications. 1, 2

Efficacy Data from Clinical Trials

Response Rates and Effect Sizes

• Lisdexamfetamine produces the highest effect size (SMD -0.89) among stimulants for reducing ADHD symptoms in adults, significantly outperforming placebo and demonstrating superior efficacy compared to other psychostimulants. 3
• Mixed amphetamine salts (Adderall) achieve a 42% reduction in ADHD Rating Scale scores at an average dose of 54 mg/day (administered in two divided doses), with 70% of adults showing clinically meaningful improvement (≥30% symptom reduction) versus only 7% with placebo. 4
• Mixed amphetamine salts demonstrate a moderate effect size (SMD -0.64) for ADHD symptom reduction in adults, which is substantially larger than non-stimulant alternatives. 3
• Amphetamines as a class produce effect sizes of approximately 1.0, compared to non-stimulants like atomoxetine (effect size ~0.7), establishing them as the most potent pharmacologic option for adult ADHD. 1, 2

Comparative Efficacy

• Approximately 40% of adults respond to both methylphenidate and amphetamine, while another 40% respond to only one stimulant class, making it essential to trial amphetamines when methylphenidate fails or vice versa. 2
• Amphetamine-based stimulants are preferred over methylphenidate for adults based on comparative efficacy studies, though both classes remain first-line options. 1, 2
• When compared head-to-head with other drug interventions (guanfacine, modafinil, paroxetine), amphetamines showed no significant differences in efficacy, though these comparisons are limited by small sample sizes. 5

Onset and Duration of Action

• Stimulants produce therapeutic effects within days, allowing rapid assessment of ADHD symptom response, in stark contrast to non-stimulants like atomoxetine which require 6-12 weeks for full effect. 1, 2
• Long-acting amphetamine formulations provide 8-14 hours of continuous symptom coverage, addressing functional impairment across work, home, and social settings throughout the day. 1

FDA-Approved Indications

• Lisdexamfetamine is FDA-approved for the treatment of ADHD in adults and pediatric patients 6 years and older, with established efficacy in controlled clinical trials. 6
• Mixed amphetamine salts (Adderall) are widely used for adult ADHD treatment, with dosing typically ranging from 10-50 mg daily in divided doses or extended-release formulations. 1, 2

Safety and Tolerability Profile

Common Adverse Effects

• Amphetamines are associated with higher attrition due to adverse events (RR 2.69-3.03 for dropout due to side effects), with the most common being decreased appetite, insomnia, headache, and modest cardiovascular effects. 5, 7
• Appetite suppression and weight loss occur more frequently with amphetamines than methylphenidate due to longer elimination half-lives, requiring monitoring of weight and nutritional status. 2

Cardiovascular Monitoring

• Baseline blood pressure and pulse measurement are mandatory before initiating amphetamine therapy, with regular monitoring at each dose adjustment and quarterly during maintenance treatment. 1, 2
• Amphetamines cause statistically significant but generally clinically modest increases in blood pressure (1-4 mm Hg) and heart rate (1-2 bpm) in most patients. 2
• Amphetamines are contraindicated in patients with symptomatic cardiovascular disease, uncontrolled hypertension, or active substance use disorders. 1, 2

Dosing and Titration Protocols

Lisdexamfetamine (Vyvanse)

• Start at 20-30 mg once daily in the morning, titrating by 10-20 mg weekly based on response and tolerability, with a maximum dose of 70 mg daily. 1, 2
• Lisdexamfetamine's prodrug formulation reduces abuse potential compared to immediate-release amphetamines while maintaining high efficacy. 8

Mixed Amphetamine Salts (Adderall/Adderall XR)

• Initiate at 10 mg once daily (extended-release) or 5 mg twice daily (immediate-release), increasing by 5-10 mg weekly until optimal symptom control is achieved. 1, 2
• Therapeutic range is typically 10-50 mg daily, with some patients requiring up to 60-65 mg when lower doses prove insufficient and no dose-limiting side effects occur. 1
• Adderall XR provides approximately 8-9 hours of symptom coverage with once-daily dosing, improving medication adherence compared to immediate-release formulations. 9

Dexamphetamine

• Recommended dosing is 5 mg three times daily to 20 mg twice daily for adults, with systematic titration to the lowest effective dose that achieves symptom control. 1

Evidence Quality and Study Limitations

• Most adult ADHD amphetamine trials have short-term follow-up (mean 5.3-8.1 weeks), limiting conclusions about long-term efficacy and safety. 5, 7
• The majority of studies were industry-funded (16 of 19 in the most recent Cochrane review), raising potential concerns about publication bias, though funnel plot analyses have not consistently demonstrated this. 7
• No studies achieved low risk of bias across all domains, primarily because amphetamines produce powerful subjective effects that may unmask treatment assignment in double-blind trials. 5, 7
• Despite methodological limitations, the consistency of findings across multiple trials and meta-analyses supports the robust efficacy of amphetamines for adult ADHD. 3, 5, 7

Clinical Recommendations Based on Evidence

• Begin with a long-acting amphetamine formulation (lisdexamfetamine or Adderall XR) as first-line therapy to maximize adherence, provide consistent all-day coverage, and reduce abuse potential compared to immediate-release products. 1, 2
• If response to one stimulant class is inadequate after proper titration to maximum tolerated doses, switch to the other stimulant class (amphetamine to methylphenidate or vice versa) before considering non-stimulant alternatives. 2
• Reserve non-stimulant medications for patients who fail ≥2 stimulant trials, experience intolerable side effects, or have active substance use disorders. 1, 2
• Combine pharmacotherapy with evidence-based psychosocial interventions (particularly ADHD-specific CBT) to achieve optimal functional outcomes beyond core symptom reduction. 1, 2