What is the difference between prescribing amphetamine salts (e.g. Adderall) and dextroamphetamine (e.g. Dexedrine) for conditions like Attention Deficit Hyperactivity Disorder (ADHD) or narcolepsy?

Amphetamine Salts vs Dextroamphetamine: Key Prescribing Differences

Both amphetamine salts (mixed amphetamine salts/Adderall) and dextroamphetamine are highly effective first-line treatments with comparable efficacy for ADHD, but dextroamphetamine is the preferred choice for narcolepsy with cataplexy because it demonstrates clinically significant improvements in BOTH excessive daytime sleepiness AND cataplexy control. 1

Composition and Pharmacological Differences

Mixed amphetamine salts contain a 3:1 ratio of dextroamphetamine to levoamphetamine, while dextroamphetamine products contain only the dextro-isomer. 1 Both medications work through identical mechanisms: inhibiting dopamine and norepinephrine transporters, vesicular monoamine transporter 2, and monoamine oxidase activity. 2

The key clinical implication is that approximately 40% of patients respond equally to both formulations, while 40% respond preferentially to only one, making individual response idiosyncratic and unpredictable. 1 This means you cannot assume both will work identically in a given patient.

Efficacy Comparison by Indication

For ADHD Treatment

• Both medications demonstrate 70-80% response rates with large effect sizes (SMD -0.80 for mixed amphetamine salts, effect sizes of 1.0 for amphetamines generally), significantly superior to non-stimulant alternatives. 1, 3

• Mixed amphetamine salts reduced ADHD symptom severity as rated by clinicians (SMD -0.80,95% CI -0.93 to -0.66) in controlled trials. 3

• Dextroamphetamine also reduced ADHD symptom severity, though evidence quality is lower (SMD -0.24 to -0.77 depending on rater). 3

• The American Academy of Child and Adolescent Psychiatry confirms that choosing between methylphenidate and amphetamine formulations is idiosyncratic, with no reliable predictors of which patient will respond to which medication. 4

For Narcolepsy Treatment

Dextroamphetamine is specifically recommended for narcolepsy by the American Academy of Sleep Medicine (CONDITIONAL recommendation), demonstrating clinically significant improvements in excessive daytime sleepiness AND cataplexy. 4

• Total daily doses of 60 mg dextroamphetamine have been shown to significantly reduce daytime sleepiness in narcolepsy patients. 4

• The evidence base for dextroamphetamine in narcolepsy includes 1 double-blind RCT, 1 single-blind RCT, and 1 retrospective observational case series, though overall quality of evidence was rated very low due to imprecision. 4

• While mixed amphetamine salts are FDA-approved for narcolepsy 5, the guideline literature specifically highlights dextroamphetamine for its dual benefit on sleepiness and cataplexy. 4

Dosing Protocols

Mixed Amphetamine Salts (Adderall/Adderall XR)

• Start at 10 mg once daily in the morning for adults, titrating by 5 mg weekly. 1

• Maximum recommended dose: 40-50 mg daily for ADHD, though some sources cite up to 60 mg. 1, 6

• Immediate-release formulations require dosing 2-3 times daily with effects lasting 4-6 hours. 2

Dextroamphetamine

• Recommended dosing for adults: 5 mg three times daily to 20 mg twice daily. 1

• Maximum dose: 60 mg daily, particularly for narcolepsy treatment. 4, 1

• FDA-approved for use in children as young as 3 years old for ADHD, though controlled safety data in this age group are lacking. 4

Adverse Effect Profile

Common Side Effects

Both medications cause similar adverse effects, but amphetamines typically produce greater effects on appetite and sleep compared to methylphenidate due to longer excretion half-lives. 1

• Mixed amphetamine salts: appetite suppression, sleep disturbances, cardiovascular effects (increased blood pressure and heart rate), and acute anxiety symptoms in vulnerable individuals. 1

• Dextroamphetamine: sweatiness, edginess, weight gain (paradoxically), loss of appetite, and irritability. 4

Cardiovascular Effects

Amphetamines increase systolic blood pressure by 1.93 mmHg (95% CI 1.54 to 2.31) and diastolic blood pressure by 1.84 mmHg (95% CI 1.51 to 2.16), with heart rate increasing by 3.71 beats per minute (95% CI 3.27 to 4.14). 7 These effects persist with long-term use (≥8 weeks). 7

• Rare but serious: myocardial infarction has been reported with Adderall XR, particularly when combined with alcohol. 8

Withdrawal Due to Adverse Effects

Patients taking amphetamines are 2.69 times more likely to withdraw from treatment due to adverse effects compared to placebo (95% CI 2.13 to 3.40), representing an absolute risk increase of 4.3%. 7

Critical Safety Warnings

Black Box Warnings

Both medications are FDA Schedule II controlled substances with BLACK BOX WARNINGS stating high potential for abuse and that prolonged administration may lead to dependence. 4, 1

Absolute Contraindications

• Active stimulant abuse 1
• Symptomatic cardiovascular disease 1
• Uncontrolled hypertension 1
• Concurrent use with MAO inhibitors or within 14 days of MAOI discontinuation 1, 9

Pregnancy and Lactation

• Based on animal data, both medications may cause fetal harm, though human data are insufficient to determine risk. 4

• Therapeutic use of mixed amphetamine salts during pregnancy does not appear associated with major congenital malformations, though possible small increased risks for cardiac malformations and preeclampsia have been reported. 1

• Amphetamines are excreted in human milk; mothers should refrain from nursing. 9

• Infants born to mothers dependent on amphetamines have increased risk of premature delivery, low birth weight, and withdrawal symptoms (dysphoria, agitation, lassitude). 9

Clinical Decision Algorithm

Choose Mixed Amphetamine Salts When:

• Primary indication is ADHD (not narcolepsy with cataplexy) 1
• Patient has no history of preferential response to dextroamphetamine alone 1
• Once-daily extended-release dosing is desired for medication adherence 1

Choose Dextroamphetamine When:

• Patient has narcolepsy with cataplexy as the primary indication 1
• Patient requires multiple daily doses for symptom coverage throughout the day 1
• Patient has previously demonstrated preferential response to dextroamphetamine over mixed salts 1

If Initial Choice Fails:

Trial the alternative amphetamine formulation, as 40% of patients respond preferentially to only one formulation despite identical mechanisms of action. 1 This idiosyncratic response pattern means treatment failure with one amphetamine does not predict failure with the other.

Special Population Considerations

Comorbid Anxiety

The presence of anxiety does not contraindicate stimulant use but requires careful monitoring. 1 Stimulants can improve executive function deficits, which may indirectly reduce anxiety related to functional impairment. 1

Substance Use History

Exercise particular caution when prescribing to adults with comorbid substance abuse disorder—consider long-acting formulations with lower abuse potential or non-stimulant alternatives as first-line. 1 However, daily stimulant treatment can reduce ADHD symptoms and risk for relapse to substance use in patients with comorbid substance dependence. 4

Pediatric Patients

• Amphetamines are not recommended for children under 3 years of age with ADHD. 9

• Amphetamines may exacerbate motor and phonic tics and Tourette's syndrome; clinical evaluation for tics should precede use. 9

• Growth should be monitored during treatment, as data are inadequate to determine whether chronic administration may be associated with growth inhibition. 9

Common Prescribing Pitfalls to Avoid

• Do NOT assume both formulations will produce identical responses—individual pharmacogenetic differences mean some patients respond preferentially to one formulation despite identical mechanisms. 1

• Do NOT underdose—many treatment failures result from inadequate titration rather than true medication resistance; 70-80% respond when properly titrated. 1

• Do NOT prescribe immediate-release formulations for once-daily use—they provide only 3-5 hours of coverage and require multiple daily doses. 1

• Do NOT combine with MAO inhibitors—wait at least 14 days after MAOI discontinuation before initiating amphetamines. 1, 9

• Do NOT discontinue effective treatment solely due to concerns about long-term stimulant use—untreated ADHD is associated with increased risk of accidents, substance abuse, criminality, and functional impairment. 1

Drug Interactions Requiring Dose Adjustments

• Acidifying agents (ascorbic acid, methenamine therapy): increase urinary excretion of amphetamines, reducing efficacy and requiring dose adjustments. 2, 9

• Alkalinizing agents: decrease urinary excretion, potentially increasing amphetamine levels. 9

• Chlorpromazine and haloperidol: block dopamine and norepinephrine reuptake, inhibiting central stimulant effects of amphetamines. 9

• Lithium carbonate: may inhibit stimulatory effects of amphetamines. 9