Dexamphetamine and Lisdexamfetamine- Mechanism of Action, Side Effects and Dosing

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Amphetamine (AMPH):

Amphetamine has a d-isomer and an l-isomer.

The d-isomer is the active isomer.

Mechanism of action

Amphetamine has the following mechanisms:

  1. Competitive inhibitor at DAT competing with dopamine and noradrenaline at NAT.
  2. Competitive inhibitor of VMAT

3. High levels amphetamine will lead to the displacement of dopamine from the vesicle into the terminal

4. Reversal of DAT.


All types of AMPH are metabolised in the liver by side-chain oxidative deamination and by ring hydroxylation. Since acidification of the urine increases the urinary output of AMPH.

Therefore, taking medicine with ascorbic acid or fruit juice may decrease its absorption, while the use of alkalinising agents (e.g., sodium bicarbonate) may increase AMPH absorption

Dexamphetamine (d-amphetamine) and lisdexamfetamine:

D-amphetamine is a competitive inhibitor of DAT, NAT, and VMAT.

Lisdexamfetamine is a produg of d-amphetamine which is linked to the amino acid lysine.  It is cleaved to compounds d-amphetamine and inactive L-lysine.

Dexamphetamine (d-amphetamine)

  • Onset of action – 20 to 60 minutes.
  • Duration – 3 to 6 hours.
  • Dosing: Starting 2.5 mg to 10 mg daily titrated at weekly increments of 2.5 mg to 5 mg to a maximum of 20 mg to 40 mg daily.


  • Onset – 20 to 60 minutes.
  • Duration – 13 plus hours
  • Doses: 30 mg, 50 mg, 70 mg.

The prodrug nature of Lisdexamfetamine, its rapid uptake from the gut, and its rate-limiting hydrolysis in the blood to produce active d-amphetamine have several important clinical implications.[Sharman and Pennick, 2014]

  • The profile of d-amphetamine delivery by Lisdexamfetamine underlies its long daily duration of action in relieving ADHD symptoms
  • Low potential for pharmacokinetic interactions
  • Less ‘drug-liking’ effects
  • Product information from TGA. 

Other Extended-release dexamphetamine formulations:

An extended-release mixed amphetamine salt formulation is a dual-pulse capsule preparation that includes both immediate- and extended-release beads. This formulation is not available in Australia.

Adverse effects:

  • Common: Insomnia, decreased appetite, dysphoria, irritability, tics
  • Rare: anxiety, depression, psychosis, mania


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