What is the mechanism of action of stimulant medications such as methylphenidate and mixed‑amphetamine salts used to treat attention‑deficit/hyperactivity disorder?

Mechanism of Action of Stimulant Medications for ADHD

Stimulant medications for ADHD work primarily by blocking the reuptake of dopamine and norepinephrine at presynaptic transporters in the striatum and prefrontal cortex, with amphetamines additionally releasing these neurotransmitters directly from presynaptic terminals, resulting in increased synaptic concentrations that enhance executive function and impulse control. 1

Core Pharmacological Mechanisms

Methylphenidate (e.g., Ritalin, Concerta)

Methylphenidate acts as a pure reuptake blocker without directly stimulating neurotransmitter release 2, 3:

• Blocks dopamine and norepinephrine transporters at the presynaptic neuron, preventing reuptake and increasing synaptic availability 4, 5
• Binds to dopamine transporters in the striatum, occupying a high proportion of these sites when given orally 1
• Increases dopamine release into extraneuronal space through transporter blockade 4
• Reduces neuronal "noise" in prefrontal pyramidal neurons via D1 receptor effects, improving signal-to-noise ratio 2

Amphetamines (e.g., Adderall, Vyvanse)

Amphetamines have a dual mechanism that makes them more potent than methylphenidate 6, 7:

• Block reuptake of dopamine and norepinephrine similar to methylphenidate 2, 3
• Directly stimulate presynaptic release of dopamine, norepinephrine, and serotonin from storage vesicles 6, 7, 3
• Inhibit vesicular monoamine transporter 2 (VMAT2) and monoamine oxidase activity 6
• Produce the most robust increases in synaptic dopamine regardless of baseline neuronal activity levels 2
• Have agonist activity at serotonin 1A receptors 6

Anatomical Sites of Action

Prefrontal Cortex Effects

The prefrontal cortex is the primary therapeutic target, where executive dysfunction in ADHD originates 1:

• Enhances executive control processes including planning, impulse control, and working memory 1
• Norepinephrine reuptake blockade may indirectly increase prefrontal dopamine levels 2
• Alpha-2A noradrenergic receptor activation mediates additional therapeutic effects 2
• Improves deficits in inhibitory control characteristic of ADHD 1

Striatal Effects

Stimulants act in the striatum where dopamine transporter binding occurs 1:

• Increased synaptic dopamine enhances functioning of neural circuits connecting striatum to prefrontal cortex 1
• Modulates motor activity and reinforcement processes through nucleus accumbens effects 8

Clinical Pharmacokinetics

Onset and Duration

Rapid absorption produces quick therapeutic effects 1:

• Methylphenidate acts within 30 minutes after oral ingestion with effects lasting 3-4 hours for immediate-release formulations 1, 6
• Plasma half-life is 3 hours for methylphenidate and up to 11 hours for dextroamphetamine 1, 6
• Therapeutic effects occur during the absorption phase, not necessarily at peak plasma levels 1
• "Clockwise hysteresis" phenomenon: behavioral effects can disappear before medication leaves plasma 1

Route-Dependent Effects

Oral administration differs significantly from intravenous 1:

• Oral methylphenidate occupies high proportions of dopamine transporters without producing euphoria 1
• Intravenous administration produces euphoria due to rapid delivery to brain 1
• Slower oral absorption may trigger compensatory mechanisms that are not yet fully understood 1

Important Clinical Caveats

Metabolic Considerations

Metabolism varies between stimulant types 4:

• Methylphenidate undergoes de-esterification in plasma to ritalinic acid (inactive metabolite) 4
• Up to 80% of amphetamines may be excreted unchanged in urine 1
• Food increases methylphenidate absorption: high-fat meals increase Cmax by 13% and AUC by 25%, delaying Tmax by 1 hour 4

Neuroimaging Findings

PET scan studies reveal complex brain effects 1:

• Untreated ADHD adults show 8.1% lower cerebral glucose metabolism than controls, particularly in superior prefrontal cortex 1
• No consistent changes in glucose metabolism were found in treated patients despite significant behavioral improvements 1
• This suggests therapeutic effects involve neurotransmitter modulation rather than gross metabolic changes 1

Comparative Efficacy

Amphetamines produce stronger effects than methylphenidate 6, 7:

• Dual mechanism (reuptake blockade plus direct release) results in 70-80% response rates when properly titrated 7
• Methylphenidate's single mechanism (reuptake blockade only) may be less robust 2, 3
• Both medications improve attention, hyperactivity, and impulsivity through catecholaminergic modulation 5