Is lisdexamfetamine (Vyvanse) an amphetamine?

Lisdexamfetamine Is an Amphetamine Prodrug

Yes, lisdexamfetamine (Vyvanse) is definitively an amphetamine prodrug that converts to dextroamphetamine in the body. Specifically, it consists of the active moiety d-amphetamine covalently bound to the amino acid l-lysine 1.

Pharmacological Classification and Mechanism

Lisdexamfetamine is classified as:

• A prodrug of dextroamphetamine (d-amphetamine)
• A CNS stimulant
• A non-catecholamine sympathomimetic amine 2

Conversion Process

Lisdexamfetamine itself is therapeutically inactive until metabolized. After oral administration:

• It undergoes hydrolysis in the bloodstream
• The l-lysine amino acid is cleaved from the molecule
• This process gradually releases the pharmacologically active d-amphetamine 1
• The conversion is primarily performed by peptidases associated with red blood cells 3

Pharmacokinetic Properties

The prodrug nature of lisdexamfetamine creates distinct pharmacokinetic characteristics:

• Absorption and Conversion Timeline:

  • Lisdexamfetamine peaks in plasma approximately 1-1.5 hours after administration
  • D-amphetamine levels peak approximately 3.5-4.4 hours after lisdexamfetamine administration 2, 4
  • Lisdexamfetamine levels become negligible by 6 hours post-dose 4

• Comparison with Direct D-amphetamine:

  • Lisdexamfetamine produces similar peak levels and total exposure (AUC) of d-amphetamine compared to equivalent doses of direct d-amphetamine
  • The primary difference is a delayed onset of action (approximately 1 hour later) 5

Clinical Implications

The prodrug formulation of lisdexamfetamine offers several clinical considerations:

1. Duration of Action: Clinical effects can persist up to 14 hours in ADHD treatment 4

2. Abuse Potential:

   • The rate-limited enzymatic hydrolysis may reduce abuse potential compared to immediate-release amphetamine formulations 1, 6
   • Intravenous administration studies show reduced "liking" effects compared to equivalent amounts of immediate-release d-amphetamine 6
   • However, when taken orally as prescribed, it ultimately delivers the same active compound (d-amphetamine) as other amphetamine medications 5

3. Side Effect Profile:

   • Side effects are consistent with those commonly reported with amphetamines
   • These include decreased appetite, insomnia, upper abdominal pain, headache, irritability, weight loss, and nausea 6

Important Considerations

• Despite its prodrug formulation, lisdexamfetamine is still classified as a Schedule II controlled substance due to its conversion to d-amphetamine
• Physical dependence can develop with prolonged use, with withdrawal symptoms including dysphoric mood, depression, fatigue, vivid dreams, insomnia/hypersomnia, increased appetite, and psychomotor changes 2
• Overdose risks are similar to other amphetamines, including cardiovascular effects, CNS effects, hyperthermia, and rhabdomyolysis 2

In summary, lisdexamfetamine is indeed an amphetamine, specifically a prodrug form that converts to d-amphetamine through a rate-limited enzymatic process in the bloodstream.