Does Vyvanse (lisdexamfetamine) increase dopamine release or block its reuptake in the brain?

Vyvanse Mechanism: Both Dopamine Release Enhancement 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 space, making it more potent than medications that only block reuptake. 1, 2

Primary Mechanisms of Action

Reuptake Inhibition

• Dextroamphetamine (the active metabolite of lisdexamfetamine) competitively inhibits the dopamine transporter (DAT), preventing dopamine from being taken back into the presynaptic neuron 2
• This reuptake blockade also applies to norepinephrine via inhibition of the noradrenaline transporter (NAT) 2, 3
• The FDA label explicitly states that "amphetamines block the reuptake of norepinephrine and dopamine into the presynaptic neuron" 1

Enhanced Neurotransmitter Release

• Beyond blocking reuptake, dextroamphetamine actively promotes the release of dopamine and norepinephrine into the extraneuronal space 1, 2, 3
• This occurs through a specific mechanism: dextroamphetamine is taken up into neuronal cells where it acts on the vesicular monoamine transporter (VMAT2), triggering neurotransmitter release 2
• The American Academy of Child and Adolescent Psychiatry emphasizes that amphetamines increase the release of dopamine and norepinephrine into the extraneuronal space, providing an additional mechanism beyond reuptake blockade alone 4

Clinical Significance of the Dual Mechanism

Why Both Mechanisms Matter

• The combination of reuptake inhibition and enhanced release results in a substantial increase in synaptic dopamine and norepinephrine concentrations, which improves executive function, impulse control, and working memory deficits characteristic of ADHD 4
• This dual action distinguishes amphetamines from medications like methylphenidate, which primarily work through reuptake inhibition with less direct effect on neurotransmitter release 5
• Enhanced monoamine signaling in the prefrontal cortex and striatum is associated with improved ADHD symptoms 4

Prodrug Characteristics

• Lisdexamfetamine itself is pharmacologically inactive and does not bind to dopamine or norepinephrine reuptake sites 1, 6
• The parent drug must be enzymatically hydrolyzed in the blood to release active dextroamphetamine, which then exerts both the reuptake blockade and release-enhancing effects 2, 7
• This prodrug design provides gradual, sustained release of active dextroamphetamine through rate-limited hydrolysis 7, 3

Common Misconceptions to Avoid

• Do not assume Vyvanse works only through reuptake blockade like some other ADHD medications—the release-enhancing mechanism is equally important for its therapeutic effect 1, 2
• Do not confuse the inactive prodrug lisdexamfetamine with its active metabolite dextroamphetamine—only the metabolite has the dual dopaminergic effects 1, 6
• The dual mechanism (both blocking reuptake AND increasing release) is what makes amphetamines particularly effective for ADHD, with 70-80% response rates when properly titrated 5, 8