Amphetamine

Amphetamine is thought to block the reuptake of norepinephrine and dopamine into nerve endings and to increase their release; how this improves ADHD is not known [2]. Products differ in their mix of the two mirror-image forms: Adderall tablets, for example, contain d-amphetamine and l-amphetamine in a 3:1 ratio [3]. Most products are approved for ADHD, Adderall also for narcolepsy, and Evekeo for narcolepsy, ADHD and short-term use in weight reduction [3][4].

The body clears amphetamine in several ways. The label describes oxidation of the benzene ring to 4-hydroxyamphetamine, the step CYP2D6 is known to carry out, and oxidation of the side chain, which leads through several steps to benzoic and hippuric acids. With normal urine pH, about half of a dose appears in the urine as products of the side-chain route and another 30 to 40% as unchanged amphetamine. Urinary recovery of unchanged amphetamine depends heavily on urine pH and flow, and has ranged from 1% to 75% of a dose. The average half-life is about 11 hours for d-amphetamine and 14 hours for l-amphetamine in adults, a little shorter in children [2].

The labels describe the CYP2D6 link cautiously. They state that the enzymes involved in amphetamine metabolism "have not been clearly defined", that CYP2D6 forms 4-hydroxyamphetamine, and that because CYP2D6 is genetically variable, "population variations in amphetamine metabolism are a possibility" [2]. They report no studies that measured amphetamine levels or side effects by CYP2D6 genotype.

The clearer evidence concerns drugs that block CYP2D6. Current labels warn that CYP2D6 inhibitors may increase amphetamine exposure and the risk of serotonin syndrome, and advise starting with lower doses, monitoring, or choosing a drug that does not inhibit CYP2D6 [2][3]. A poor metabolizer has little or no CYP2D6 activity even without an inhibitor. The codeine page explains how CYP2D6 results are classified.

The FDA's Table of Pharmacogenetic Associations lists amphetamine in its first section, for associations where the data support management recommendations: in CYP2D6 poor metabolizers, CYP2D6 variation "may affect systemic concentrations and adverse reaction risk", and prescribers should "consider lower starting dosage or use alternative agent" [1]. The current prescribing information for Adderall and Adzenys XR-ODT does not mention poor metabolizers; it addresses CYP2D6 inhibitors instead [2][3]. CPIC has not published a guideline; its gene-drug list gives the pair only a provisional level [5].

Amphetamine doses are adjusted to response and side effects, so a poor metabolizer result mainly supports starting low and increasing carefully, as the FDA table suggests. Tell your prescriber about other medicines too. The FDA lists bupropion, fluoxetine, paroxetine, quinidine and terbinafine as strong CYP2D6 inhibitors [6]; fluoxetine and paroxetine are also serotonergic, which adds to the serotonin syndrome warning. Drugs that change urine pH also matter: acidifying agents such as vitamin C lower amphetamine levels and alkalinizing agents such as sodium bicarbonate raise them [2].

Do not start, stop or change a stimulant or any other medicine because of a genetic result without talking to your prescriber.

Consumer arrays (23andMe, AncestryDNA, MyHeritage) are not clinical-grade tests, and their raw data is labeled not for medical use. They read fixed positions, and Gene2Rx uses imputation to infer some variants that were not measured directly. A normal result means none of the assessed variants was found among the positions your data covers; it cannot rule out a variant at a position the data does not cover.

The bigger limit is the evidence. The labels report no studies of amphetamine in poor metabolizers, and urine pH, dose and individual sensitivity also affect amphetamine levels and side effects.

Does this apply to Vyvanse?

Vyvanse contains lisdexamfetamine, a prodrug that the body converts to d-amphetamine. Its label carries the same CYP2D6 inhibitor warning [7]. The FDA table has no separate entry for lisdexamfetamine; its poor metabolizer statement is listed under amphetamine [1].

I am a poor metabolizer. Should I avoid stimulants?

Not necessarily. The FDA table suggests a lower starting dose or another drug, and that choice is one to make with your prescriber (see What the FDA says).

1. FDA. Table of Pharmacogenetic Associations. Amphetamine entry for CYP2D6 poor metabolizers.
2. Adzenys XR-ODT (amphetamine) extended-release orally disintegrating tablets: prescribing information. DailyMed. Mechanism, metabolism, CYP2D6 statements, urine pH effects.
3. Adderall (mixed amphetamine salts) tablets: prescribing information (Teva). DailyMed. Indications, composition, CYP2D6 inhibitor warning.
4. Evekeo (amphetamine sulfate) tablets: prescribing information. DailyMed. Indications.
5. CPIC. Gene-drug pairs and CPIC levels (spreadsheet). Provisional level, no guideline.
6. FDA. For healthcare professionals: FDA's examples of drugs that interact with CYP enzymes and transporter systems. Strong CYP2D6 inhibitors.
7. Vyvanse (lisdexamfetamine) capsules and chewable tablets: prescribing information (Takeda). DailyMed. Prodrug conversion and CYP2D6 inhibitor warning.