What are the alternatives to Adderall (amphetamine and dextroamphetamine) for a patient with Attention Deficit Hyperactivity Disorder (ADHD)?

Adderall Alternatives for ADHD Treatment

First-Line Stimulant Alternatives

Methylphenidate (including long-acting formulations like Concerta) is the strongest evidence-based alternative to Adderall, with the most robust clinical trial data and highest response rates among all ADHD medications. 1

• Long-acting methylphenidate formulations are strongly preferred over immediate-release preparations due to better medication adherence, lower risk of rebound effects, more consistent symptom control throughout the day, and reduced diversion potential 1
• Response to methylphenidate versus amphetamine is idiosyncratic—approximately 40% of patients respond to both classes, while 40% respond to only one, making it essential to trial the other stimulant class if the first fails 1
• Methylphenidate demonstrates response rates of 78% versus 4% with placebo when dosed appropriately at approximately 1 mg/kg total daily dose 1
• For adults, methylphenidate should be administered at 5-20 mg three times daily for immediate-release, or use extended-release formulations for once-daily dosing with a maximum daily dose of 60 mg 1

Lisdexamfetamine (Vyvanse) provides once-daily dosing with a prodrug formulation that reduces abuse potential, making it particularly suitable for patients with substance use concerns 1

• Amphetamine-based stimulants like lisdexamfetamine are preferred for adults based on comparative efficacy studies, achieving 70-80% response rates 1
• The prodrug formulation is resistant to tampering, making it appropriate for adolescents and those at risk for substance misuse 1

Second-Line Non-Stimulant Options

Atomoxetine is the only FDA-approved non-stimulant for adult ADHD and serves as the primary second-line option when stimulants are contraindicated or not tolerated. 2, 3

• Atomoxetine provides 24-hour coverage as a non-controlled substance with no abuse potential, making it first-line for patients with substance use history 1
• Target dose is 60-100 mg daily for adults, with a maximum of 1.4 mg/kg/day or 100 mg/day, whichever is lower 1
• Requires 6-12 weeks to achieve full therapeutic effect, with median time to response of 3.7 weeks, and probability of improvement may continue increasing up to 52 weeks 1, 3
• Effect sizes are medium-range at approximately 0.7 compared to stimulants which have effect sizes of 1.0 1
• Common adverse effects include initial somnolence, gastrointestinal symptoms (particularly if dosage is increased too rapidly), and decreased appetite 4
• FDA black box warning for increased risk of suicidal ideation in children and adolescents requires close monitoring of suicidality, clinical worsening, and unusual behavioral changes 1

Extended-release guanfacine and extended-release clonidine (alpha-2 adrenergic agonists) demonstrate effect sizes around 0.7 and can be used as monotherapy or adjunctive therapy with stimulants. 1

• Guanfacine dosing uses 0.1 mg/kg as a rule of thumb, with typical adult doses of 1-4 mg daily 1
• These medications are particularly useful when sleep disturbances, tics, or disruptive behavior disorders are present 1, 5
• Administration in the evening is generally preferable due to somnolence/fatigue as adverse effects 1
• Adverse effects include somnolence, dry mouth, dizziness, irritability, headache, bradycardia, hypotension, and abdominal pain 4
• Must be tapered rather than abruptly discontinued to avoid rebound hypertension 4, 5
• Require 2-4 weeks for treatment effects to manifest 1

Third-Line and Emerging Options

Bupropion is positioned as a second-line agent for ADHD, to be considered when two or more stimulants have failed or caused intolerable side effects, or when active substance abuse disorder is present. 1

• Bupropion has shown anecdotal benefits in adults with ADHD and may be particularly useful when depression is comorbid 1
• Works more rapidly than atomoxetine, though effect sizes are smaller than stimulants 1
• Bupropion is inherently activating and can exacerbate anxiety or agitation, making it potentially problematic for patients who are already hyperactive 6
• Maximum recommended dose is 450 mg per day, with typical starting doses of 100-150 mg daily for SR formulation or 150 mg daily for XL formulation 6

Viloxazine, a serotonin norepinephrine modulating agent, has demonstrated efficacy in adults with ADHD in several pivotal clinical trials. 1

• This is an emerging option with favorable efficacy and tolerability profiles 1
• Limited data available compared to other non-stimulant options 1

Treatment Algorithm

If response to one stimulant class (amphetamine) is inadequate, trial the other class (methylphenidate) before considering non-stimulants. 1

• Start with long-acting methylphenidate formulations (Concerta, extended-release methylphenidate) as the first alternative 1
• If methylphenidate is insufficient or not tolerated, trial atomoxetine as the primary non-stimulant option 1
• If atomoxetine is insufficient or not tolerated, trial extended-release guanfacine or clonidine, allowing 2-4 weeks for treatment effects 1
• Consider bupropion when comorbid depression is present or after multiple stimulant and non-stimulant failures 1

Special Populations

For preschool-aged children (ages 4-5), methylphenidate is the recommended first-line pharmacologic treatment due to lack of sufficient rigorous study in this population for nonstimulant ADHD medications and dextroamphetamine 4

For patients with comorbid anxiety, the presence of anxiety does not contraindicate stimulant use but requires careful monitoring. 1

• Extended-release guanfacine or clonidine are particularly useful as adjunctive therapy with stimulants if monotherapy is insufficient 1
• Atomoxetine has evidence supporting use in ADHD with comorbid anxiety 6

For patients with substance use history, prioritize non-controlled substances: atomoxetine as first-line, or long-acting stimulant formulations with lower abuse potential like lisdexamfetamine or Concerta 1

Critical Monitoring Parameters

• Regular vital sign monitoring (blood pressure, pulse) is necessary with all ADHD medications at baseline and during treatment 1
• Height and weight tracking is essential, particularly in younger patients 1
• Monitor for sleep disturbances and appetite changes as common adverse effects 1
• With atomoxetine, monitor for suicidality and clinical worsening, especially during the first few months or at dose changes 1