Mechanism of Action of Stimulant Medications for ADHD
Stimulant medications work primarily by blocking the reuptake of dopamine and norepinephrine in the brain, with amphetamines having additional mechanisms that make them pharmacologically more potent than methylphenidate at comparable doses. 1
Methylphenidate (Ritalin) Mechanism
Methylphenidate blocks the reuptake of norepinephrine and dopamine into the presynaptic neuron and increases the release of these monoamines into the extraneuronal space. 2 This is a pure reuptake blockade mechanism that prevents these neurotransmitters from being removed from the synaptic cleft. 3
Additional Methylphenidate Actions:
- Shows agonist activity at serotonin type 1A receptors 1
- Redistributes vesicular monoamine transporter 2 (VMAT-2) 1
- Primarily acts by binding to dopamine transporters in the striatum 1
- The d-threo enantiomer is more pharmacologically active than the l-threo enantiomer 2
Amphetamine (Adderall) Mechanism
Amphetamines have a more complex mechanism than methylphenidate, including dopamine and norepinephrine transporter inhibition, vesicular monoamine transporter 2 (VMAT-2) inhibition, and monoamine oxidase activity inhibition. 1 This multi-pronged approach makes amphetamines the most robust agents in increasing synaptic dopamine levels, since they do so regardless of the endogenous level of the relevant neurons. 3
Amphetamine's Multiple Mechanisms:
- Blocks reuptake of both norepinephrine and dopamine 1, 3
- Releases all three monoamines (norepinephrine, dopamine, and serotonin) from presynaptic vesicles 3, 4
- Inhibits monoamine oxidase activity, which further increases monoamine levels 1
- Inhibits vesicular monoamine transporter 2 (VMAT-2) 1
Clinical Implications of These Mechanisms
Both medications enhance dopamine and norepinephrine activity in the prefrontal cortex, improving executive function and attention. 1 The therapeutic effects occur through increased efficiency of prefrontal cortex activity and optimization of executive and attentional function. 1
Regional Effects:
- Stimulant-evoked synaptic increases of dopamine have been demonstrated in the striatum in humans 3
- Pharmacologic effects are likely relevant to therapeutic action in other regions, particularly the prefrontal cortex 3
- Blockade of noradrenergic reuptake in the prefrontal cortex may also indirectly increase prefrontal dopamine levels 3
Functional Improvements:
- Both medications improve symptoms of inattention, hyperactivity, and impulsivity through their effects on frontal lobe function 1
- They enhance functioning of executive control processes, ameliorating deficits in inhibitory control and working memory 1
Key Mechanistic Differences Between the Two Medications
The critical distinction is that methylphenidate is a pure reuptake blocker, while amphetamines also cause active release of monoamines from presynaptic vesicles. 3, 4 This explains why amphetamines are pharmacologically more potent at comparable doses. 1
Pharmacokinetic Considerations:
- Methylphenidate peak plasma concentration occurs within 1-3 hours with an average half-life of 2 hours for immediate-release formulations 1, 2
- Amphetamines have a significantly prolonged plasma half-life compared to methylphenidate 4
Clinical Response Implications:
- Individual patients may respond preferentially to either medication, with overall very high response rates when both are tried sequentially 1
- Approximately 40% of patients respond to both medications and 40% respond to only one 5
Important Clinical Caveat
Neither medication's exact central mechanism of action for treating ADHD is fully understood, despite their established efficacy. 1 The mode of therapeutic action in ADHD is not known with certainty. 2 However, the clinical efficacy and tolerability of both amphetamines and methylphenidate are well-established and comparable. 4