Vyvanse's Mechanism of Action: Both Dopamine Release and Reuptake Blockade
Vyvanse (lisdexamfetamine) works through a dual mechanism: it both blocks the reuptake of dopamine AND increases the release of dopamine into the synaptic cleft. 1
Primary Mechanism of Action
Lisdexamfetamine is a prodrug that is enzymatically hydrolyzed to its active form, dextroamphetamine, after oral administration. 1 The active metabolite dextroamphetamine then exerts its therapeutic effects through two complementary pathways:
Reuptake Inhibition
- Amphetamines block the reuptake of both norepinephrine and dopamine into the presynaptic neuron, preventing these neurotransmitters from being cleared from the synaptic cleft. 1
- Dextroamphetamine competitively inhibits the dopamine transporter (DAT) and noradrenaline transporter (NAT), increasing dopamine and noradrenaline concentrations in the synaptic space. 2
- The parent drug lisdexamfetamine itself does not bind to dopamine or norepinephrine reuptake sites in vitro—only the active metabolite dextroamphetamine has this effect. 1, 3
Enhanced Neurotransmitter Release
- Amphetamines increase the release of dopamine and norepinephrine into the extraneuronal space, providing an additional mechanism beyond reuptake blockade alone. 1
- Dextroamphetamine is taken up into neuronal cells where it acts on the vesicular monoamine transporter, promoting the release of dopamine and noradrenaline from presynaptic neurons. 2
- This dual action—blocking reuptake while simultaneously promoting release—distinguishes amphetamines from medications like bupropion, which only block reuptake without enhancing neurotransmitter release. 4
Clinical Implications
The combination of reuptake inhibition and enhanced release results in a substantial increase in synaptic dopamine and norepinephrine concentrations. 4 This enhanced monoamine signaling in the prefrontal cortex and striatum is thought to improve executive function, impulse control, and working memory deficits characteristic of ADHD. 4
The prodrug design of lisdexamfetamine provides rate-limited conversion to active dextroamphetamine, resulting in a gradual release of the active compound with reduced abuse potential compared to immediate-release amphetamine formulations. 5, 6