What is the difference between dextroamphetamine and amphetamine salts in the treatment of Attention Deficit Hyperactivity Disorder (ADHD) or narcolepsy?

Dextroamphetamine vs Amphetamine Salts: Key Differences

Dextroamphetamine and mixed amphetamine salts (Adderall) are both highly effective first-line treatments for ADHD and narcolepsy with comparable efficacy, but mixed amphetamine salts may offer superior retention in treatment. 1

Composition and Formulation

• Dextroamphetamine is a single-isomer formulation containing only the dextro (right-handed) enantiomer of amphetamine 2, 3

• Mixed amphetamine salts (Adderall) contain a 3:1 ratio of dextroamphetamine to levoamphetamine, specifically: dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine aspartate monohydrate, and amphetamine sulfate 4

• Both medications are DEA Schedule II controlled substances with high potential for abuse 5

Clinical Efficacy

• A Cochrane systematic review found that all three amphetamine derivatives (dextroamphetamine, lisdexamfetamine, and mixed amphetamine salts) significantly improved ADHD symptom severity with a standardized mean difference of -0.72 (95% CI -0.87 to -0.57) 1

• Mixed amphetamine salts demonstrated a unique advantage in increasing retention in treatment compared to dextroamphetamine alone, though the mechanism for this difference is unclear 1

• In adults with ADHD, mixed amphetamine salts at an average dose of 54 mg daily (administered in two divided doses) produced a 42% decrease in ADHD Rating Scale scores (P<0.001), with 70% of subjects achieving clinically meaningful improvement (≥30% reduction) versus 7% with placebo 4

• For narcolepsy, dextroamphetamine 30 mg daily was only slightly more potent than 10 mg daily in reducing attack frequency, with both doses roughly halving the reported frequency of narcoleptic attacks 6

Dosing Considerations

For ADHD:

• Dextroamphetamine: Start with 5 mg once or twice daily in patients ≥6 years; titrate by 5 mg weekly intervals until optimal response; rarely necessary to exceed 40 mg/day total 2

• Mixed amphetamine salts: Start with 10 mg once daily in the morning for adults; titrate by 5 mg weekly based on response and tolerability; maximum recommended daily dose is 50 mg for adults 7

For Narcolepsy:

• Both medications: Usual dose range is 5-60 mg per day in divided doses 2
• For patients aged 6-12 years: Start with 5 mg daily; increase by 5 mg weekly 2
• For patients ≥12 years: Start with 10 mg daily; increase by 10 mg weekly 2

Pharmacokinetic Profiles

• Immediate-release formulations of both medications provide 4-6 hours of clinical action, requiring multiple daily doses (typically given on awakening with additional doses at 4-6 hour intervals) 8, 2

• Extended-release mixed amphetamine salts (Adderall XR) provide approximately 8-9 hours of symptom control 9

• Dextroamphetamine extended-release (Dexedrine Spansules) similarly provides 8-9 hours of coverage 9

• Most patients could not distinguish subjective effects between immediate-release dextroamphetamine tablets and extended-release Spansules 6

Side Effect Profile

• Both medications share similar sympathomimetic side effects including hyperactivity, hyperthermia, tachycardia, tachypnea, mydriasis, tremors, and potential seizures in overdose 5

• Appetite suppression is more commonly reported with mixed amphetamine salts compared to other ADHD medications 10

• Amphetamines as a class were associated with significantly higher dropout rates due to adverse events (RR 3.03; 95% CI 1.52 to 6.05) compared to placebo 1

• Cardiovascular monitoring (blood pressure and pulse) is required at baseline and regularly during treatment with both medications 10, 7

Clinical Decision-Making Algorithm

When choosing between these medications:

1. Start with mixed amphetamine salts (Adderall) if treatment retention is a concern, as this formulation has demonstrated superior adherence in clinical trials 1

2. Consider dextroamphetamine if the patient has previously responded well to single-isomer formulations or if cost is a significant barrier (generic dextroamphetamine may be less expensive) 2

3. Use extended-release formulations (Adderall XR or Dexedrine Spansules) for once-daily dosing to improve adherence and reduce stigma associated with in-school dosing 10, 9

4. If inadequate response occurs after adequate treatment with one amphetamine formulation, approximately 40% of patients respond to both methylphenidate and amphetamines, while 40% respond to only one class—trial the other stimulant class (methylphenidate) before abandoning stimulants entirely 10

Common Pitfalls to Avoid

• Do not assume higher doses are always better: More than 70% of patients respond when a full range of doses is properly titrated, but excessive dosing can paradoxically worsen attention and cause overstimulation 7

• Avoid late evening doses of either medication due to resulting insomnia 2

• Do not use with MAO inhibitors due to risk of severe hypertension and potential cerebrovascular accidents; allow at least 14 days between discontinuation of an MAOI and initiation of amphetamines 10

• Exercise caution in patients with substance abuse disorders: Consider long-acting formulations with lower abuse potential or non-stimulant alternatives like atomoxetine 10