What is the mechanism of action of Concerta (methylphenidate) and how does it differ from Adderall (amphetamine and dextroamphetamine)?

Mechanism of Action: Concerta vs. Adderall

Both Concerta (methylphenidate) and Adderall (amphetamine salts) block dopamine and norepinephrine reuptake, but Adderall has additional mechanisms—including monoamine oxidase inhibition and vesicular monoamine transporter 2 (VMAT-2) inhibition—making it pharmacologically more potent at comparable doses. 1

Core Pharmacological Differences

Methylphenidate (Concerta)

• Primary mechanism: Blocks reuptake of dopamine and norepinephrine at presynaptic transporters and increases release of these monoamines into the extraneuronal space 2
• Additional actions:
  • Agonist activity at serotonin type 1A receptors 1
  • Redistributes VMAT-2 (does not inhibit it) 1
  • Primarily binds dopamine transporters in the striatum 1
• Pharmacokinetics: Peak plasma concentration (Tmax) occurs 1-2 hours after dosing, with mean terminal half-life of 2.7 hours 2

Amphetamine (Adderall)

• Primary mechanism: Inhibits dopamine and norepinephrine transporters 1
• Additional mechanisms (key differences):
  • Inhibits VMAT-2 (unlike methylphenidate which only redistributes it) 1
  • Inhibits monoamine oxidase activity, further increasing monoamine levels 1
  • These additional mechanisms explain why amphetamines are more potent milligram-for-milligram 1

Shared Therapeutic Pathways

Both medications enhance dopamine and norepinephrine activity in the prefrontal cortex, improving executive function and attention 1. They increase efficiency of prefrontal cortex activity and optimize executive and attentional function, enhancing inhibitory control and working memory 1. Both improve symptoms of inattention, hyperactivity, and impulsivity through their effects on frontal lobe function 1.

Clinical Implications of Mechanism Differences

Potency Considerations

The additional mechanisms of Adderall (MAO inhibition and VMAT-2 inhibition) make it pharmacologically stronger at equivalent doses 1. This means lower milligram doses of amphetamine may produce effects comparable to higher doses of methylphenidate.

Delivery System Differences

Concerta specifically uses an osmotic release oral system (OROS) that produces an ascending-pattern plasma drug level throughout the day 3. This once-daily formulation is equivalent to methylphenidate 5 mg three times daily when given as 18 mg Concerta 3. The OROS system is resistant to diversion (cannot be ground up or snorted), making it particularly suitable for adolescents 3.

Side Effect Profiles

Both medications share similar side effects including decreased appetite, sleep disturbances, and increased blood pressure and heart rate 1. However, the exact central mechanism for treating ADHD remains incompletely understood despite established efficacy 1.

Important Caveats

• Methylphenidate plasma levels do not correlate with clinical response and provide no more predictive power than teacher and parent rating forms 3
• The d-threo enantiomer of methylphenidate is more pharmacologically active than the l-threo enantiomer 2
• Both medications carry risks of abuse, dependence, and cardiovascular effects at toxic doses 3, 2
• Concerta's delayed onset (90 minutes vs. 30 minutes for immediate-release methylphenidate) may be less immediately helpful in some situations 3