Pharmacology of psychostimulants: A systematic review of the literature

Attention-deficit/hyperactivity disorder (ADHD) is a persistent condition characterized by neurobiological dysfunction in several neurotransmitter systems, most notably dopamine (DA) and norepinephrine (NE). Stimulant medications, primarily amphetamine (AMP) and methylphenidate (MPH), serve as the gold-standard first-line pharmacotherapies for managing symptoms in children, adolescents, and adults. Despite their shared clinical efficacy, these medications interact with the brain in fundamentally different ways, influencing the regulation of executive function, attention, and reward processing.

The central pharmacological effect of both AMP and MPH is the increased synaptic availability of catecholamines, specifically DA and NE. However, their cellular methods are distinct:

• Amphetamine: Acts as a potent releaser of monoamines. It inhibits the dopamine transporter (DAT) and norepinephrine transporter (NET) and also enters the cell to inhibit vesicular monoamine transporter 2 (VMAT-2), causing the release of stored neurotransmitters into the synapse via reverse transport. Additionally, it can inhibit monoamine oxidase (MAO) activity.
• Methylphenidate: Primarily functions as a reuptake inhibitor, blocking the DAT and NET to prolong the presence of catecholamines in the synaptic cleft. It also shows agonist activity at the serotonin type 1A receptor and redistributes VMAT-2, but does not induce the same profound release mechanisms as amphetamines.

ADHD is frequently accompanied by psychiatric comorbidities such as anxiety, depression, and substance use disorder. Because these conditions share common neurobiological underpinnings with ADHD, understanding how stimulants impact these circuits is critical. While stimulants have shown varying efficacy in mood disorders, clinicians must carefully navigate the potential for adverse effects—such as insomnia, cardiovascular changes, or the rare potential for misuse—when managing patients with complex psychiatric profiles. Neuroimaging studies suggest that observed symptomatic improvements correlate with changes in striatal dopamine transporter density, though the specific mechanisms underlying why some patients respond better to one drug than the other remain elusive.