Does Adderall (amphetamine and dextroamphetamine) block neurotransmitter uptake at the presynaptic nerve terminal?

From the Guidelines

Adderall (amphetamine and dextroamphetamine) does indeed block neurotransmitter uptake at the presynaptic nerve terminal, specifically by inhibiting the dopamine and norepinephrine transporters, as well as the vesicular monoamine transporter 2 and monoamine oxidase activity. This mechanism of action is crucial in understanding how Adderall exerts its therapeutic effects in conditions like Attention Deficit Hyperactivity Disorder (ADHD) 1. By blocking the reuptake of dopamine and norepinephrine, Adderall increases the concentration of these neurotransmitters in the synaptic cleft, thereby enhancing neurotransmission in brain regions associated with attention, focus, and executive function.

The primary mechanism of action of Adderall involves the inhibition of dopamine and norepinephrine transporters, which prevents the reabsorption of these neurotransmitters back into the presynaptic neuron, leading to an increase in their availability for synaptic transmission 1. Additionally, Adderall's ability to inhibit monoamine oxidase (MAO) contributes to its overall effect by reducing the breakdown of these neurotransmitters. This combined mechanism of action leads to increased concentrations of dopamine and norepinephrine in the synaptic cleft, which is thought to be responsible for Adderall's therapeutic effects in ADHD.

It's worth noting that while the reuptake inhibition aspect of Adderall's mechanism of action is important, it is not the only mechanism by which the medication exerts its effects. Adderall also increases the release of neurotransmitters from their storage vesicles, which contributes to its overall therapeutic effect 1. The exact mechanisms by which Adderall exerts its effects are complex and multifaceted, and continued research is needed to fully understand the medication's effects on the brain. However, the inhibition of neurotransmitter uptake at the presynaptic nerve terminal is a key component of Adderall's mechanism of action, and is thought to be responsible for its therapeutic effects in conditions like ADHD.

Key points to consider when prescribing Adderall include:

• The medication's potential to increase blood pressure and heart rate, which may be clinically relevant for patients with preexisting cardiovascular diseases 1
• The potential for reduced appetite, sleep disturbances, and other adverse effects, which are generally mild and/or temporary 1
• The importance of monitoring pulse and blood pressure when prescribing Adderall, as recommended by clinical guidelines 1
• The potential for long-term effects on height and weight gain, which may be dose-related and require careful monitoring 1

From the FDA Drug Label

CLINICAL PHARMACOLOGY Amphetamines are non-catecholamine, sympathomimetic amines with CNS stimulant activity. The FDA drug label does not answer the question.

From the Research

Adderall's Mechanism of Action

• Adderall, a combination of amphetamine and dextroamphetamine, is used to treat Attention-Deficit/Hyperactivity Disorder (ADHD) and narcolepsy 2.
• The medication works by stimulating the release of norepinephrine, affecting both α- and β-adrenergic receptor sites 2.
• Studies have shown that Adderall increases brain catecholamine levels, including dopamine and noradrenaline, which play important roles in high-level executive functions often impaired in ADHD 3.

Neurotransmitter Uptake and Release

• Research suggests that amphetamine, a component of Adderall, inhibits the accumulation of dopamine and noradrenaline in synaptosomes and vesicles, leading to increased release of these neurotransmitters 4.
• The D-isomer of amphetamine is more potent than the L-isomer at inhibiting accumulation of dopamine and noradrenaline in synaptosomes and vesicles 4.
• Adderall has been shown to produce increased striatal dopamine release and a prolonged time course compared to amphetamine isomers 5.

Blockage of Neurotransmitter Uptake

• While the exact mechanism of Adderall's blockage of neurotransmitter uptake is not fully understood, studies suggest that it may involve the inhibition of dopamine and noradrenaline reuptake 4, 6.
• The dopamine transporter gene has been implicated in ADHD, and dysfunction of this gene may contribute to the depleted levels of dopamine seen in patients with ADHD 6.
• Adderall's ability to increase dopamine release and block reuptake may contribute to its therapeutic effects in the treatment of ADHD 5, 4.