What is the mechanism of action of Adderall (mixed amphetamine salts)?

Mechanism of Action of Adderall

Adderall works by directly blocking dopamine and norepinephrine transporters in the brain while simultaneously stimulating the release of these neurotransmitters from presynaptic nerve terminals, resulting in a substantial and prolonged increase in synaptic dopamine and norepinephrine that enhances executive function and attention. 1, 2

Primary Pharmacologic Mechanisms

Dopamine System Effects

• Adderall acts directly on the dopamine transporter (DAT) in the striatum, causing a significant increase in synaptic dopamine concentrations that far exceed those produced by other stimulants 1, 2
• When administered orally at therapeutic doses, Adderall occupies a high proportion of dopamine transporter sites in the striatum, blocking reuptake of dopamine back into presynaptic terminals 2
• The unique 3:1 mixture of dextroamphetamine (76%) to levoamphetamine (24%) salts in Adderall produces significantly greater dopamine release with a prolonged time course compared to single-enantiomer amphetamine preparations 3
• This enhanced dopamine release significantly improves executive function, working memory, and inhibitory control in the prefrontal cortex 2

Norepinephrine System Effects

• Adderall inhibits norepinephrine transporters (NET), preventing reuptake and increasing synaptic norepinephrine availability 2
• The medication directly stimulates the release of norepinephrine from presynaptic terminals, producing both α- and β-adrenergic receptor stimulation 2, 4
• α-Adrenergic stimulation causes vasoconstriction and increases total peripheral resistance, while β-adrenergic receptor stimulation increases heart rate, stroke volume, and skeletal muscle blood flow 4

Additional Mechanisms

• Adderall inhibits vesicular monoamine transporter 2 (VMAT2), which packages dopamine and norepinephrine into synaptic vesicles 2
• The medication inhibits monoamine oxidase (MAO) activity, reducing the breakdown of dopamine and norepinephrine 2
• Adderall has agonist activity at serotonin type 1A receptors, contributing to its overall neurotransmitter effects 2

Pharmacokinetic Profile

Absorption and Onset

• Immediate-release Adderall acts within 30 minutes of oral administration, with effects lasting 3-4 hours 2
• Extended-release formulations (Adderall XR) contain immediate-release pellets that deliver the first half of the dose upon ingestion and delayed-release pellets that begin releasing active drug approximately 4 hours later 5
• Adderall XR has a rapid onset of action within 1.5 hours and provides 12 hours of symptom coverage 5
• Following administration of three 5 mg immediate-release tablets, average maximal dextroamphetamine plasma concentrations (Cmax) of 36.6 ng/mL are achieved at approximately 3 hours 6

Metabolism and Duration

• The plasma half-life of amphetamine ranges from 3 to 12 hours, depending on urinary pH and individual metabolism 2, 6
• The average plasma half-life is approximately 12 hours for both immediate-release tablets and sustained-release capsules 6
• The bioavailability of sustained-release capsules is similar to immediate-release tablets, though the time to peak concentration is delayed to approximately 8 hours 6
• Food intake (58 to 75 gm fat) does not significantly alter the rate or extent of dextroamphetamine absorption from extended-release formulations 6

Clinical Implications of Mechanism

Therapeutic Effects

• The controlled elevation of dopamine and norepinephrine in the synaptic cleft enhances executive control processes in the prefrontal cortex without causing toxic accumulation when used at therapeutic doses 7
• Adderall produces stronger stimulant effects with greater impact on neurotransmitter systems compared to other stimulants like caffeine 2
• The unique enantiomer composition (3:1 ratio of d- to l-amphetamine) results in increased and prolonged dopamine release compared to single-enantiomer preparations 3, 5

Peripheral Sympathomimetic Actions

• As a non-catecholamine sympathomimetic amine, Adderall produces peripheral actions including elevations of systolic and diastolic blood pressures 6
• The medication has weak bronchodilator and respiratory stimulant action through its sympathomimetic properties 6

Distinguishing Features

• The presence of the l-enantiomer in Adderall separates it from other amphetamine preparations composed only of the d-enantiomer (such as dexedrine), allowing differentiation in drug testing 8
• Peak amphetamine concentrations following a 20 mg dose range from 2645 to 5948 ng/mL, with detectable levels (≥500 ng/mL) persisting up to 47.5 hours post-dose 8