What are examples of stimulant controlled substances used to treat Attention Deficit Hyperactivity Disorder (ADHD) and narcolepsy?

Stimulant Controlled Substances for ADHD and Narcolepsy

The primary stimulant controlled substances used to treat ADHD and narcolepsy are methylphenidate (MPH), dextroamphetamine (DEX), and mixed amphetamine salts (AMP), all of which are Schedule II controlled substances with proven efficacy in both conditions. 1, 2

Primary Stimulant Medications

Methylphenidate Formulations

• Methylphenidate is FDA-approved for both ADHD and narcolepsy, making it the optimal choice when treating both conditions simultaneously 3, 2
• Available in multiple formulations including immediate-release (3-5 hours duration), extended-release (8-12 hours), and OROS-methylphenidate/Concerta (12 hours) 1, 4
• Effective doses range from 30-37.5 mg/day for ADHD and up to 60 mg/day for narcolepsy 3
• Acts as a pure blocker of norepinephrine and dopamine transporters without releasing monoamines from presynaptic vesicles 5

Amphetamine Formulations

• Dextroamphetamine (DEX) is particularly effective for narcolepsy with cataplexy, demonstrating improvements in both excessive daytime sleepiness AND cataplexy at doses up to 60 mg/day 6
• Mixed amphetamine salts (Adderall) contain a combination of amphetamine enantiomers and demonstrate 70-80% response rates in ADHD 6
• Amphetamines work by blocking catecholamine reuptake AND releasing norepinephrine, dopamine, and serotonin from presynaptic vesicles, making them more robust in increasing synaptic dopamine levels 7, 5
• Maximum recommended doses are 40-50 mg/day for mixed amphetamine salts and 60 mg/day for dextroamphetamine 6

Pemoline (Historical)

• Pemoline (PEM) was previously used at doses of 112.5 mg/day for narcolepsy, though it is rarely prescribed now due to hepatotoxicity concerns 1

Comparative Efficacy

ADHD Treatment

• More than 160 controlled studies involving over 5,000 school-age children demonstrated a 70% response rate when a single stimulant is tried 1
• Effect sizes for behavioral and attention changes range from 0.8 to 1.0 standard deviations on teacher reports for both MPH and DEX 1
• Individual response is idiosyncratic—approximately 40% respond equally to both methylphenidate and amphetamines, while 40% respond preferentially to only one class 6

Narcolepsy Treatment

• Methylphenidate, dextroamphetamine, and pemoline all significantly reduce daytime sleepiness in narcolepsy 1, 3
• Dextroamphetamine receives conditional recommendation for narcolepsy with cataplexy due to effects on both sleepiness and cataplexy 6

Mechanism of Action Differences

Methylphenidate

• Decreases non-specific neuronal signals (noise) via D1 receptors in the prefrontal cortex 5
• Does not cause release of monoamines from presynaptic vesicles, only blocks reuptake 5

Amphetamines

• Most robust agents for increasing synaptic dopamine levels regardless of endogenous neuronal activity 5
• Release all three monoamines (norepinephrine, dopamine, serotonin) in addition to blocking reuptake 7, 5
• Cause greater effects on appetite and sleep compared to methylphenidate due to longer excretion half-lives 6

Critical Safety Considerations

Abuse Potential

• BLACK BOX WARNING: All stimulants carry high potential for abuse and misuse, which can lead to substance use disorder and addiction 2
• Prescribers must assess each patient's risk for abuse before prescribing and monitor throughout treatment 2
• Long-acting formulations have lower abuse potential compared to immediate-release preparations 4
• Rising prescription volumes have increased concerns about diversion and abuse 1, 8

Cardiovascular Risks

• Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmias, coronary artery disease, or other serious cardiac disease 2
• Monitor blood pressure and pulse at baseline, with each dose adjustment, and regularly during stable treatment 3, 2
• Amphetamine-like drugs cause cardiovascular side effects including tachycardia and arrhythmia 9, 7

Contraindications

• Known hypersensitivity to methylphenidate or amphetamines 2
• Concurrent treatment with MAO inhibitors or use within preceding 14 days 6, 2
• Active stimulant abuse, symptomatic cardiovascular disease, uncontrolled hypertension 6

Common Pitfalls to Avoid

• Do not underdose methylphenidate by limiting to typical ADHD doses (30-37.5 mg/day) when narcolepsy requires higher doses (60 mg/day) for adequate control 3
• Do not assume positive response to stimulants is diagnostic for ADHD—stimulants improve behavior and attention in children with other disorders and normal subjects 1
• Do not prescribe immediate-release formulations for once-daily use—they provide only 3-5 hours of coverage and require multiple daily doses 6, 4
• Do not combine with MAO inhibitors—wait at least 14 days after MAOI discontinuation before initiating stimulants 6
• 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 6

Overdose Considerations

• Overdose with ADHD stimulants can produce major morbidity requiring intensive care, though fatalities are rare with appropriate care 7
• Clinical presentation includes mydriasis, tremor, agitation, hyperreflexia, combative behavior, confusion, hallucinations, delirium, seizures, tachycardia, and hypertension 7
• Management is largely supportive with judicious use of benzodiazepines for sympathomimetic syndrome 7
• Toxic levels for methylphenidate start from approximately 500 ng/mL serum, compared to therapeutic levels of 5-60 ng/mL 9