What are the best non‑stimulant medications for ADHD, including recommended dosing and monitoring?

Best Non-Stimulant Medications for ADHD

Atomoxetine is the single best non-stimulant medication for ADHD, as it is the only FDA-approved non-stimulant for both children and adults, with demonstrated efficacy, 24-hour symptom coverage, and no abuse potential. 1, 2

First-Line Non-Stimulant: Atomoxetine

Atomoxetine should be your primary non-stimulant choice because it offers the most robust evidence base among non-stimulants, with medium-range effect sizes of approximately 0.7 compared to stimulants, and provides continuous "around-the-clock" symptom control without scheduling restrictions. 1, 3

Dosing Protocol

• Children and adolescents ≤70 kg: Start at 0.5 mg/kg/day, increase after minimum 3 days to target of 1.2 mg/kg/day, with maximum 1.4 mg/kg/day or 100 mg/day (whichever is lower). 2
• Children >70 kg and adults: Initiate at 40 mg daily, increase after minimum 3 days to target of 80 mg daily, may increase after 2–4 additional weeks to maximum 100 mg daily if response is inadequate. 2
• Administration: Can be given as single morning dose or divided into morning and late afternoon/early evening doses to minimize adverse effects. 1
• Time to effect: Requires 6–12 weeks to achieve full therapeutic benefit, with median response time of 3.7 weeks—significantly longer than stimulants which work within days. 1, 4

When to Choose Atomoxetine First-Line

• Active substance use disorder or high abuse risk—atomoxetine is an uncontrolled substance with zero abuse potential. 1, 5
• Comorbid anxiety or autism spectrum disorder—atomoxetine has specific evidence supporting efficacy in these populations. 1
• Patient/family preference against controlled substances or concerns about stimulant diversion. 5
• Inadequate response to two or more stimulant trials or intolerable stimulant side effects. 1

Monitoring Requirements

• Baseline: Blood pressure, pulse, height, weight, personal/family cardiac history. 1
• During titration: Blood pressure and pulse at each dose adjustment. 1
• Ongoing: Suicidality screening (FDA black box warning for increased suicidal ideation in children/adolescents), height/weight tracking, sleep and appetite assessment. 1, 2

Key Advantages Over Other Non-Stimulants

• Only FDA-approved non-stimulant for adults with ADHD. 1, 3
• Fewer cardiovascular effects, less appetite suppression, and fewer growth concerns compared to stimulants. 1
• Can be discontinued abruptly without rebound effects or discontinuation syndrome. 4
• May be co-administered with stimulants during switching periods without undue cardiovascular concern (though monitoring remains essential). 4

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Second-Line Non-Stimulants: Alpha-2 Agonists

Guanfacine extended-release and clonidine extended-release are FDA-approved as monotherapy or adjunctive therapy to stimulants, with effect sizes around 0.7. 1, 6

Guanfacine Extended-Release (Preferred Alpha-2 Agonist)

Guanfacine has higher specificity for alpha-2A receptors than clonidine, resulting in less sedation while maintaining therapeutic efficacy. 6

Dosing

• Starting dose: 1 mg once daily in the evening. 6
• Target range: 0.05–0.12 mg/kg/day or 1–7 mg/day maximum. 6
• Titration: Increase by 1 mg weekly based on response and tolerability. 6
• Time to effect: 2–4 weeks before clinical benefits are observed. 6

When to Choose Guanfacine First-Line

• Comorbid tic disorders or Tourette syndrome—guanfacine treats both ADHD and tics without worsening tic severity. 6
• Sleep disturbances—evening dosing leverages sedating properties to improve sleep onset while providing 24-hour ADHD coverage. 6
• Comorbid anxiety or agitation—guanfacine's calming effects are particularly useful. 5, 6
• Disruptive behavior disorders or oppositional symptoms. 1, 6
• Substance use risk—guanfacine is non-controlled with no abuse potential. 6

Critical Safety Warnings

• Never abruptly discontinue guanfacine—taper by 1 mg every 3–7 days to avoid rebound hypertension. 6
• Monitor blood pressure and heart rate at baseline and each dose adjustment—guanfacine decreases both by 1–4 mmHg and 1–2 bpm. 6
• Contraindicated in baseline bradycardia (<60 bpm) or hypotension (systolic <90 mmHg). 6

Clonidine Extended-Release

• Dosing: Start 0.1 mg at bedtime, titrate carefully with twice-daily administration up to 0.4 mg/day. 6
• Disadvantages vs. guanfacine: Requires twice-daily dosing (lower adherence), causes more sedation due to lower alpha-2A receptor specificity. 6
• Same indications as guanfacine but generally less preferred due to sedation profile and dosing frequency. 6

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Third-Line Non-Stimulant: Viloxazine Extended-Release

Viloxazine ER is a novel serotonin-norepinephrine modulating agent FDA-approved for children and adults with ADHD, offering a unique mechanism distinct from atomoxetine and alpha-2 agonists. 1, 7, 8

Key Features

• Mechanism: Modulates both serotonin and norepinephrine activity (not a pure reuptake inhibitor). 7
• Evidence: Pivotal Phase 2 and 3 trials demonstrated favorable efficacy and tolerability in pediatric and adult populations. 1, 7
• Common adverse effects: Somnolence, decreased appetite, headache. 7
• Potential advantage: May be beneficial for comorbid depression. 7

Clinical Positioning

• Consider viloxazine when atomoxetine and alpha-2 agonists have failed or are not tolerated. 8
• Emerging option with less long-term data compared to atomoxetine and alpha-2 agonists. 8

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Treatment Algorithm for Non-Stimulant Selection

Step 1: Identify Clinical Scenario

• Substance use disorder/abuse risk → Atomoxetine (first choice) or guanfacine (if sleep/tics present). 1, 6
• Comorbid anxiety or autism → Atomoxetine. 1
• Tics, Tourette syndrome, or sleep disturbances → Guanfacine ER. 6
• Disruptive behavior or oppositional symptoms → Guanfacine ER. 6
• Failed ≥2 stimulant trials → Atomoxetine (first choice), then guanfacine if inadequate response after 6–12 weeks. 1

Step 2: Initiate and Titrate

• Atomoxetine: Start low, titrate weekly, allow 6–12 weeks for full effect. 2, 4
• Guanfacine: Start 1 mg evening, titrate weekly, allow 2–4 weeks for effect. 6
• Clonidine: Start 0.1 mg bedtime, titrate carefully, allow 2–4 weeks for effect. 6

Step 3: Monitor and Adjust

• Cardiovascular parameters at baseline and each adjustment. 1, 6
• Suicidality screening (especially atomoxetine). 1, 2
• Functional improvement across home, school, and social settings. 1

Step 4: If Inadequate Response

• After adequate atomoxetine trial (6–12 weeks at target dose): Switch to guanfacine ER. 1
• After adequate guanfacine trial (4–6 weeks at optimal dose): Consider viloxazine ER or return to stimulant trial. 6, 8

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Common Pitfalls to Avoid

• Do not expect immediate results from non-stimulants—counsel families that atomoxetine requires 6–12 weeks and alpha-2 agonists require 2–4 weeks, unlike stimulants which work within days. 1, 6
• Do not abruptly discontinue guanfacine or clonidine—always taper to prevent rebound hypertension. 6
• Do not assume atomoxetine treats comorbid depression—despite its antidepressant origins, evidence does not support efficacy for depression. 1
• Do not underdose atomoxetine—target 1.2 mg/kg/day in children or 80–100 mg/day in adults for optimal effect. 2
• Do not overlook the need for multimodal treatment—pharmacotherapy should always be combined with behavioral interventions and psychoeducation. 1, 5