What are the first‑line ADHD medications for children, adolescents, and adults, including stimulant and non‑stimulant options, their typical dosing, mechanisms of action, and common side effects?

ADHD Medications: First-Line Options, Mechanisms, Dosing, and Side Effects

First-Line Treatment: Stimulant Medications

Stimulant medications—specifically methylphenidate and amphetamines—are the gold standard first-line treatment for ADHD across all age groups (children, adolescents, and adults), achieving 70-80% response rates with the largest effect sizes from over 161 randomized controlled trials. 1, 2

Methylphenidate Formulations

Mechanism of Action:

• Methylphenidate inhibits the reuptake of dopamine and norepinephrine in the prefrontal cortex, enhancing executive function and attention networks. 1, 3

Dosing:

• Children/Adolescents: Start at 5 mg twice daily, titrate by 5-10 mg weekly up to maximum 60 mg/day total. 1, 2
• Adults: Start at 5-20 mg three times daily for immediate-release, or use extended-release formulations for once-daily dosing with maximum 60 mg/day. 1, 2
• Long-acting formulations (Concerta, OROS-MPH): Start at 18 mg once daily, increase by 18 mg weekly up to 54-72 mg/day maximum. 1

Common Side Effects:

• Appetite suppression and weight loss 1, 2
• Insomnia (less pronounced than amphetamines due to shorter half-life) 1
• Headache 1
• Cardiovascular effects: average increases of 1-2 beats/min heart rate and 1-4 mmHg blood pressure 2

Amphetamine Formulations

Mechanism of Action:

• Amphetamines increase presynaptic release of dopamine, norepinephrine, and other biogenic amines while also blocking reuptake. 3

Dosing:

• Mixed amphetamine salts (Adderall): Start at 5-10 mg once or twice daily, titrate by 5-10 mg weekly up to 40 mg/day maximum in children/adolescents; adults typically require 10-50 mg/day. 1, 2
• Adderall XR: Start at 10 mg once daily in morning, titrate by 5 mg weekly up to 50 mg maximum (some patients may require up to 65 mg with documentation). 2
• Lisdexamfetamine (Vyvanse): Start at 20-30 mg once daily, increase by 10-20 mg weekly up to 70 mg/day maximum. 1, 2

Common Side Effects:

• Greater appetite suppression than methylphenidate due to longer elimination half-life 1, 2
• More pronounced sleep disturbances compared to methylphenidate 1, 2
• Cardiovascular effects similar to methylphenidate 2
• Headache, anxiety 1

Key Advantage of Amphetamines:

• Amphetamine-based stimulants demonstrate superior efficacy compared to methylphenidate in adults, with larger effect sizes (SMD -0.79 vs -0.49). 1

Long-Acting vs. Immediate-Release Formulations

Long-acting formulations are strongly preferred over immediate-release preparations due to:

• Better medication adherence 1, 2
• More consistent symptom control throughout the day (8-12 hours coverage) 1, 4
• Lower risk of rebound effects 1
• Reduced diversion potential and abuse risk 1, 2
• Elimination of midday school dosing 5

Prodrug Formulations with Lower Abuse Potential

• Lisdexamfetamine (Vyvanse): Prodrug formulation that requires enzymatic conversion to active dextroamphetamine, reducing abuse potential while providing once-daily dosing. 1, 2
• Serdexmethylphenidate (KP415): FDA-approved prodrug of d-methylphenidate combined with immediate-release d-methylphenidate, designed to avoid rapid plasma spikes and lower abuse potential. 6, 2

---

Second-Line Treatment: Non-Stimulant Medications

Non-stimulants should be considered when two or more stimulants have failed, caused intolerable side effects, or when active substance abuse disorder is present. 1, 2

Atomoxetine (Strattera)

Mechanism of Action:

• Selective norepinephrine reuptake inhibitor with moderate effects on noradrenergic systems. 6, 7

Dosing:

• Children/Adolescents: Start at 0.5 mg/kg/day, increase after minimum 3 days to target of 1.2 mg/kg/day (maximum 1.4 mg/kg/day or 100 mg/day, whichever is lower). 1, 2
• Adults: Start at 40 mg daily, titrate every 7-14 days to 60 mg, then 80 mg daily; target dose 60-100 mg/day. 1, 2

Key Characteristics:

• Requires 6-12 weeks to achieve full therapeutic effect (median time to response 3.7 weeks), significantly longer than stimulants which work within days. 1, 2
• Medium-range effect size of approximately 0.7 compared to stimulants (1.0). 1, 2
• Provides 24-hour "around-the-clock" symptom coverage. 1, 2
• Non-controlled substance with no abuse potential—preferred for patients with substance use history. 1, 2

Common Side Effects:

• Somnolence and fatigue (most common) 1, 2
• Decreased appetite (less pronounced than stimulants) 1
• Nausea 1
• Modest cardiovascular effects (less than stimulants) 2
• FDA Black Box Warning: Increased risk of suicidal ideation in children and adolescents—requires close monitoring during first few months and at dose changes. 2

Alpha-2 Adrenergic Agonists

Guanfacine Extended-Release (Intuniv):

Mechanism of Action:

• Selective alpha-2A adrenergic agonist that modulates prefrontal cortex function. 1, 7

Dosing:

• Start at 1 mg once daily (preferably evening), titrate by 1 mg weekly based on response and tolerability. 1, 2
• Target dose: 0.05-0.12 mg/kg/day or maximum 7 mg/day. 1
• Rule of thumb: approximately 0.1 mg/kg. 1

Key Characteristics:

• Effect size around 0.7 6, 1
• Requires 2-4 weeks for full therapeutic effect 1, 2
• FDA-approved as monotherapy or adjunctive therapy with stimulants 1, 2
• Higher specificity for alpha-2A receptors than clonidine, resulting in less sedation 1, 8
• Unique advantage: Actually decreases heart rate and blood pressure—beneficial for patients with cardiovascular concerns 2

Common Side Effects:

• Somnolence/fatigue (administer in evening to leverage sedative effects) 1, 2
• Hypotension 1
• Critical warning: Never abruptly discontinue—taper by 1 mg every 3-7 days to avoid rebound hypertension. 1

Clonidine Extended-Release (Kapvay):

Mechanism of Action:

• Non-selective alpha-2 adrenergic agonist. 1, 7

Dosing:

• Similar titration approach to guanfacine, administered in evening due to sedation. 1

Key Characteristics:

• Effect size around 0.7 6, 1
• Requires 2-4 weeks for full effect 1
• More sedating than guanfacine due to lower receptor selectivity 1
• Also decreases heart rate and blood pressure 2

Specific Indications for Alpha-2 Agonists:

• Comorbid tics or Tourette's syndrome 1, 2
• Disruptive behavior disorders or oppositional symptoms 1, 8
• Sleep disturbances 1, 2
• Comorbid anxiety or agitation 1, 2
• Substance use disorders 1

Viloxazine Extended-Release (Qelbree)

Mechanism of Action:

• Serotonin-norepinephrine modulating agent with moderate norepinephrine transporter inhibition and moderate activity at noradrenergic and dopaminergic systems; serotonin modulation is considered the predominant component. 6

Key Characteristics:

• Repurposed antidepressant (withdrawn from market in 2002, now FDA-approved for ADHD) 6
• Pivotal clinical trials in children showed favorable efficacy and tolerability 6, 1
• Demonstrated efficacy in adults with ADHD 1
• Non-controlled substance with no abuse potential 2

---

Treatment Algorithm by Clinical Scenario

Standard ADHD (No Comorbidities)

1. First-line: Long-acting stimulant (methylphenidate or amphetamine) 1, 2
2. If inadequate response to one stimulant class: Trial the other class (approximately 40% respond to both, 40% respond to only one) 1
3. If two stimulants fail: Atomoxetine 1, 2
4. If atomoxetine insufficient: Extended-release guanfacine or clonidine 1

ADHD with Substance Use Disorder

1. First-line: Atomoxetine (non-controlled substance) 1, 2
2. Alternative: Long-acting stimulant formulations with lower abuse potential (lisdexamfetamine, OROS-methylphenidate, serdexmethylphenidate) 1, 2
3. Adjunctive: Alpha-2 agonists 1

ADHD with Comorbid Anxiety

1. First-line: Stimulants (do NOT exacerbate anxiety; MTA study showed higher response rates in anxious subgroup) 1, 2
2. If anxiety persists after ADHD improvement: Add SSRI to stimulant regimen 1, 2
3. Alternative: Atomoxetine (has evidence for comorbid anxiety) 1, 2

ADHD with Tics or Tourette's

1. First-line: Extended-release guanfacine or clonidine 1, 2
2. Alternative: Atomoxetine 1
3. Stimulants can be used cautiously if alpha-2 agonists insufficient 1

ADHD with Cardiovascular Concerns

1. First-line: Atomoxetine (lowest cardiovascular impact) 2
2. Alternative: Extended-release guanfacine or clonidine (actually decrease heart rate and blood pressure) 2
3. If stimulants necessary: Methylphenidate has slightly lower cardiovascular effects than amphetamines 2

---

Critical Monitoring Parameters

Baseline Assessment (All Medications):

• Blood pressure and pulse (seated and standing if indicated) 1, 2
• Height and weight 1, 2
• Personal and family cardiac history (sudden death, arrhythmias, structural heart disease) 2
• Substance use screening in adolescents/adults 2

During Titration:

• Blood pressure and pulse at each dose adjustment 1, 2
• Weekly ADHD symptom ratings 1, 2
• Sleep quality and appetite changes 1, 2

Maintenance Phase:

• Blood pressure and pulse quarterly in adults, at each visit in children 2
• Height and weight at every visit in children/adolescents 1, 2
• Functional improvement across home, school/work, and social settings 1, 2
• Suicidality screening (especially with atomoxetine or when comorbid depression present) 2

---

Absolute Contraindications

All Stimulants:

• MAO inhibitor use within 14 days (risk of hypertensive crisis) 1, 2
• Symptomatic cardiovascular disease or uncontrolled hypertension 1, 2
• Active psychosis or mania 2
• Hyperthyroidism 2
• Glaucoma 2
• Known hypersensitivity to stimulants 2

---

Common Pitfalls to Avoid

• Do not underdose stimulants: 70% of patients respond optimally when proper titration protocols are followed to maximum therapeutic doses. 1, 8
• Do not assume tolerance develops: Little evidence exists for tolerance to stimulant effects on ADHD symptoms; most children continue responding to the same dose over prolonged treatment. 2
• Do not use immediate-release stimulants for "as-needed" dosing: ADHD requires consistent daily symptom control; sporadic dosing fundamentally misunderstands ADHD pathophysiology. 1
• Do not discontinue effective treatment due to "taking medication forever" concerns: Untreated ADHD is associated with increased risk of accidents, substance abuse, criminality, and functional impairment. 1
• Do not combine with MAO inhibitors: At least 14 days must elapse between MAOI discontinuation and stimulant/atomoxetine initiation. 1, 2
• Do not abruptly stop guanfacine or clonidine: Taper to avoid rebound hypertension. 1

---

Multimodal Treatment Integration

Pharmacotherapy must be combined with evidence-based behavioral interventions:

• Parent training in behavior management (Grade A recommendation for preschool and school-age children) 1, 2
• Behavioral classroom interventions 1, 2
• ADHD-specific Cognitive Behavioral Therapy (most effective psychotherapy for adults) 1, 2
• Mindfulness-Based Interventions (help with inattention, emotion regulation, executive function) 1

Combined treatment (medication plus behavioral therapy) provides superior functional outcomes compared to medication alone, particularly in patients with comorbid conditions. 1, 2, 8