How is Adderall (amphetamine and dextroamphetamine) metabolized?

Metabolism of Adderall (Amphetamine and Dextroamphetamine)

Adderall is primarily metabolized through hepatic pathways, with the CYP2D6 enzyme playing a significant role in its metabolism, though the majority of amphetamine metabolism occurs through other mechanisms including deamination and hydroxylation.1, 2

Primary Metabolic Pathways

Adderall, a combination of amphetamine salts containing a 3:1 ratio of d-enantiomer (dextroamphetamine) to l-enantiomer (levoamphetamine), undergoes several metabolic processes:

1. Hepatic Metabolism:

   • CYP2D6 Pathway: While CYP2D6 is involved in amphetamine metabolism, it is not the primary pathway 3
   • Deamination: A major metabolic pathway resulting in the formation of phenylacetone
   • Hydroxylation: Formation of hydroxyamphetamine
   • N-Dealkylation: Conversion to phenylethylamine

2. Excretion Characteristics:

   • The d-enantiomer is excreted in higher proportions initially, with the l-enantiomer proportion increasing over time 4
   • Peak urinary concentrations can range from 2,645 to 5,948 ng/mL 4
   • Detectable levels (≥500 ng/mL) can persist for up to 47.5 hours after dosing 4

Factors Affecting Metabolism

Several factors can significantly alter the metabolism of Adderall:

Genetic Variations

• CYP2D6 Polymorphisms: About 5-8% of Caucasians are poor metabolizers (PMs) and 1-7% are ultrarapid metabolizers (UMs) 5
• Recent research suggests CYP2D6 poor metabolizers may have higher odds of symptom improvement with amphetamine treatment 6

Drug Interactions

1. Acidifying Agents:

   • Gastrointestinal acidifiers (guanethidine, reserpine, ascorbic acid, fruit juices): Lower absorption of amphetamines 1, 2
   • Urinary acidifiers (ammonium chloride, sodium acid phosphate): Increase ionized species concentration, enhancing urinary excretion 1, 2

2. Alkalinizing Agents:

   • Gastrointestinal alkalinizers (sodium bicarbonate): Increase absorption 1, 2
   • Urinary alkalinizers (acetazolamide, some thiazides): Decrease urinary excretion by increasing non-ionized species concentration 1, 2

3. Critical Drug Interactions:

   • MAO Inhibitors: Can cause hypertensive crisis and potentially fatal reactions 5, 1, 2
   • Tricyclic Antidepressants: Amphetamines may enhance TCA activity; can cause sustained increases in d-amphetamine brain concentration 1, 2
   • SSRIs: May elevate amphetamine levels and increase risk of serotonin syndrome 2, 7
   • CYP2D6 Inhibitors: May increase amphetamine exposure 2, 7

Clinical Implications

Understanding Adderall's metabolism has important clinical implications:

1. Dosing Considerations:

   • Genetic variations in CYP2D6 may necessitate dose adjustments 5, 6
   • Drug interactions may require dose modifications to maintain efficacy and safety 7

2. Monitoring:

   • Patients taking medications that affect urinary pH may experience altered drug effects 1, 2
   • Patients on multiple medications should be monitored for potential interactions 7

3. Safety Concerns:

   • Long-term use has been associated with cardiovascular effects including potential cardiomyopathy 8
   • Genetic poor metabolizers may experience more side effects due to higher drug concentrations 5

Common Pitfalls and Caveats

• Misinterpreting Drug Tests: The presence of both d- and l-enantiomers in varying ratios can help differentiate prescribed Adderall use from illicit amphetamine use 4
• Overlooking pH Effects: Changes in urinary pH can dramatically alter excretion rates and drug effectiveness 1, 2
• Ignoring Genetic Factors: Failure to consider CYP2D6 status may result in unexpected treatment responses or side effects 6
• Underestimating Drug Interactions: Complex interactions with other medications can significantly alter amphetamine metabolism and effects 7

Understanding these metabolic pathways is crucial for optimizing treatment efficacy while minimizing adverse effects in patients prescribed Adderall.