Amphetamine

Amphetamine (sold under brand names including Adzenys ER, and as part of Adderall) is a central nervous system stimulant used to improve attention and reduce impulsivity and hyperactivity.

It's FDA-approved for ADHD and narcolepsy. The drug pushes dopamine and norepinephrine release while also blocking their reuptake, which raises levels of both neurotransmitters in the brain regions tied to attention and arousal.

The key gene affecting amphetamine metabolism is CYP2D6. This gene encodes an enzyme in the liver that helps convert amphetamine into inactive metabolites.

CYP2D6 variants can alter enzyme activity: increased function speeds clearance, while reduced function slows it. These changes may impact drug levels and the balance between efficacy and side effects. “Metabolizer” classifications group these differences into common functional categories.

Patients are classified by CYP2D6 metabolizer status—ultrarapid, normal, intermediate, or poor—which influences amphetamine plasma levels, therapeutic effect, and adverse event risk. Ultrarapid metabolizers clear the drug quickly, potentially reducing efficacy, while poor metabolizers have higher exposure, increasing toxicity risk.

Ultrarapid Metabolizer

• Effect on drug levels: Faster clearance leading to lower plasma concentrations.
• Clinical consequence: Potential reduced therapeutic effect and need for higher dose.
• Side effects: Lower risk of stimulant-related adverse effects (mild severity, less frequent).

Normal Metabolizer

• Effect on drug levels: Standard plasma concentrations.
• Clinical consequence: Typical therapeutic response at standard doses.
• Side effects: Expected incidence of adverse effects (e.g., insomnia, appetite suppression).

Intermediate Metabolizer

• Effect on drug levels: Slightly reduced clearance with modestly increased exposure.
• Clinical consequence: Possible mild increase in effects and adverse reactions.
• Side effects: Mildly increased risk of stimulant side effects (moderate severity).

Poor Metabolizer

• Effect on drug levels: Markedly reduced clearance resulting in higher plasma concentrations.
• Clinical consequence: Increased risk of excessive pharmacologic effects and toxicity.
• Side effects: Higher incidence of severe stimulant-related adverse events (e.g., tachycardia, hypertension).

Indeterminate / Not Available

• Effect: Unknown impact on drug metabolism and levels.
• Clinical consequence: No specific guidance; follow standard dosing with clinical monitoring.

CYP2D6 Dosing Guideline

Examples of alternative stimulant medications include methylphenidate and lisdexamfetamine. These are provided for illustrative purposes only and are not direct recommendations.

• FDA – Table of Pharmacogenetic Associations