What Drugs Are Metabolized by CYP2D6? A Detailed List

CYP2D6 is one of the most clinically important drug-metabolizing enzymes in the human body, responsible for breaking down roughly 20 to 25 percent of all medications on the market.¹ That fraction is striking when you consider that CYP2D6 makes up only a small share of the liver’s total cytochrome P450 protein. The drugs it handles span psychiatry, cardiology, oncology, pain management, and more, and the enzyme is famously variable from person to person. Understanding which medications pass through CYP2D6 matters because your genetic version of this enzyme can make a standard dose feel like too much, too little, or just right.

Antidepressants

Antidepressants are the single largest therapeutic category processed by CYP2D6, and they cut across nearly every subclass. Among selective serotonin reuptake inhibitors, fluoxetine, paroxetine, fluvoxamine, and to a lesser extent sertraline all rely on CYP2D6 for at least part of their clearance. The serotonin-norepinephrine reuptake inhibitors venlafaxine and duloxetine are also metabolized substantially through this pathway, along with newer agents like vortioxetine and vilazodone.² For someone who is a poor metabolizer of CYP2D6, paroxetine can accumulate to higher-than-expected blood levels, which has been linked to measurably higher glycated hemoglobin in people with diabetes, suggesting broader metabolic consequences beyond the drug’s intended effect.³

Older tricyclic antidepressants are even more dependent on CYP2D6. Nortriptyline’s main metabolic route, hydroxylation, is handled exclusively by CYP2D6, making this enzyme the rate-limiting step for clearing the drug.⁴ Amitriptyline, which the body converts into nortriptyline, shows a similarly tight relationship: in one population study, the metabolic ratio of amitriptyline to its hydroxylated product correlated strongly with CYP2D6 activity.⁵ Other tricyclics in the CYP2D6 family include imipramine, desipramine, and clomipramine. Because these drugs have narrow therapeutic windows, where the gap between an effective dose and a toxic one is small, knowing your CYP2D6 status can be genuinely protective.

Opioids and Pain Medications

Several commonly prescribed opioids are prodrugs, meaning they need CYP2D6 to convert them into their active, pain-relieving forms. Codeine is the most well-known example: the enzyme transforms it into morphine, and the active metabolite has roughly 200-fold greater affinity for the mu-opioid receptor than codeine itself. Tramadol follows the same logic, requiring CYP2D6 to produce its active metabolite O-desmethyltramadol.⁶ If you are a poor metabolizer, codeine and tramadol essentially do not work, because your body cannot produce enough of the active compound. Guidelines from the Clinical Pharmacogenetics Implementation Consortium (CPIC) recommend using an alternative analgesic in these patients.⁷

The flip side is equally dangerous. Ultrarapid metabolizers convert codeine to morphine so quickly that a standard dose can cause respiratory depression, sedation, and in rare cases death. Several pediatric fatalities prompted the U.S. FDA to restrict codeine use in children. Hydrocodone and oxycodone also pass through CYP2D6, which converts them to their more potent metabolites hydromorphone and oxymorphone, respectively.⁶ The clinical significance is somewhat less dramatic with these two because they retain meaningful activity as parent compounds, but CYP2D6 status still shifts the balance of pain relief and side effects.

Beta-Blockers and Other Cardiovascular Drugs

Metoprolol is the poster child for CYP2D6 metabolism in cardiology. Roughly 70 to 80 percent of its breakdown depends on CYP2D6, and this dependency has clear clinical consequences.⁸ Poor metabolizers experience significantly higher metoprolol exposure and lower heart rates compared to normal metabolizers. In a large retrospective study, poor metabolizers had notably more episodes of bradycardia, an abnormally slow heartbeat, than normal metabolizers.⁸ CPIC now provides formal therapeutic recommendations for adjusting metoprolol based on CYP2D6 genotype.⁹

Other beta-blockers metabolized through this pathway include carvedilol, propranolol, and timolol. Interestingly, not all beta-blockers are CYP2D6-dependent, and that distinction matters. In patients undergoing coronary artery bypass surgery, preoperative use of beta-blockers that do not rely on CYP2D6 was associated with lower operative mortality compared to both CYP2D6-dependent beta-blockers and no beta-blocker use at all.¹⁰ That finding suggests that the unpredictable blood levels created by CYP2D6 variability can blunt the protective effects of these drugs in high-stakes settings.

Beyond beta-blockers, CYP2D6 also handles several antiarrhythmic drugs, including propafenone, flecainide, and quinidine. These medications have notoriously narrow therapeutic ranges, and serum levels can vary widely at standard doses due largely to CYP2D6 variability.¹¹ A poor metabolizer taking propafenone at a standard dose could end up with drug levels high enough to cause dangerous heart rhythm disturbances rather than prevent them.

Tamoxifen in Breast Cancer Treatment

Tamoxifen occupies a unique place on this list because CYP2D6 does not just clear it from the body. Instead, CYP2D6 activates it. Tamoxifen is a prodrug with modest anti-estrogen activity on its own, but the enzyme converts it into endoxifen, which has far superior antiestrogenic potency.¹² Women who are poor metabolizers produce significantly less endoxifen, and studies in premenopausal breast cancer patients have confirmed that carrying reduced-function CYP2D6 alleles impairs endoxifen formation.¹³

Whether this lower endoxifen exposure translates to worse breast cancer outcomes has been debated for years. Some oncology teams now genotype patients before starting tamoxifen and consider aromatase inhibitors as alternatives for poor metabolizers. At a minimum, clinicians are advised to avoid prescribing strong CYP2D6 inhibitors like fluoxetine or paroxetine alongside tamoxifen, since that combination can pharmacologically reproduce the poor-metabolizer state even in someone with normal genetics.

Antipsychotics and ADHD Medications

Many first- and second-generation antipsychotics go through CYP2D6. Risperidone, aripiprazole, haloperidol, thioridazine, and perphenazine are all substrates. In cohort studies, genetic variation leading to reduced CYP2D6 function has been associated with greater antipsychotic-induced weight gain, although the picture is mixed when cross-sectional studies are included.¹⁴ The inconsistency may reflect the difficulty of capturing long-term weight trends in a single snapshot, but the cohort data at least raises a flag worth watching if you are on one of these medications and gain weight unexpectedly.

Atomoxetine, the most widely used nonstimulant ADHD medication, is another clear CYP2D6 substrate. CPIC has published specific guidelines for adjusting atomoxetine doses based on CYP2D6 genotype, because poor metabolizers can have plasma levels several times higher than normal metabolizers at the same dose.¹⁵ This often manifests as nausea, appetite loss, and insomnia at doses that work fine for others.

Why Metabolizer Status Matters So Much

CYP2D6 is one of the most genetically variable enzymes humans carry. More than 70 allelic variants have been identified, and over 15 of those encode an enzyme that is either completely inactive or never produced at all.¹⁶ The gene can also be duplicated or deleted entirely, and recombination events with the neighboring CYP2D7 pseudogene create further complexity.¹⁷ This variation sorts people into four broad metabolizer categories: poor, intermediate, normal (sometimes called extensive), and ultrarapid. About 7 percent of people of European descent are poor metabolizers, while the rate drops to around 1 percent in East Asian populations.¹⁶

Those population-level numbers mask important subtlety. In Europeans, nonfunctional alleles account for about 26 percent of all CYP2D6 alleles, dominated by the CYP2D6*4 variant. In East Asian populations, functional alleles make up only about half the total, with the reduced-function allele CYP2D6*10 present at a median frequency of 41 percent, shifting the overall population toward slower metabolism. African and African American populations carry their own distinctive pattern, with CYP2D6*17, a reduced-function allele, representing roughly 35 percent of allele variation.¹⁸ Clinical studies confirm these allele frequency differences translate to real differences in enzyme activity. Among people genotyped as normal metabolizers, African Americans demonstrated lower measured CYP2D6 activity compared to Asians and Whites when tested with multiple substrates.¹⁹

Phenoconversion and Drug-Drug Interactions

Genetics is not the only thing that determines your effective CYP2D6 status. CYP2D6 is susceptible to inhibition by other drugs, which can shift a genetically normal metabolizer to a functional poor metabolizer. This process, called phenoconversion, is one of the most clinically underappreciated sources of adverse drug reactions.²⁰ Strong CYP2D6 inhibitors include fluoxetine, paroxetine, bupropion, quinidine, and terbinafine (an antifungal). If you are taking metoprolol for your heart and your doctor adds fluoxetine for depression, your effective CYP2D6 activity may drop dramatically, potentially causing the bradycardia that would normally concern only a genetic poor metabolizer.

Even some herbal supplements can shift the picture. A clinical trial testing six commonly used botanical supplements found that goldenseal inhibited CYP2D6 activity by approximately 50 percent, while milk thistle, black cohosh, kava kava, St. John’s wort, and echinacea did not produce significant inhibition.²¹ If you are on a CYP2D6 substrate and taking goldenseal, you could experience the equivalent of a genetic downgrade in enzyme function without anyone suspecting the supplement as the cause.

When the Body Changes Its Own CYP2D6 Activity

For decades, CYP2D6 was considered noninducible, meaning that unlike other liver enzymes, nothing seemed to make the body produce more of it. That belief turns out to have been an artifact of how scientists grew liver cells in the lab. Standard cell culture conditions include a synthetic corticosteroid called dexamethasone, and researchers discovered that dexamethasone actually masks CYP2D6 induction. When cells were cultured without supplemental dexamethasone, CYP2D6 activity increased more than tenfold in response to corticosteroids.²²

The most familiar real-world example of this is pregnancy. Cortisol levels rise substantially during the third trimester, and studies have demonstrated that CYP2D6 activity increases measurably during late pregnancy. Phenotyping with the probe drug dextromethorphan showed a significant reduction in the metabolic ratio among pregnant women who carried functional CYP2D6 alleles, indicating faster metabolism.²³ This finding has been replicated in CYP2D6-humanized mice, where hepatic CYP2D6 expression increased during pregnancy alongside decreased levels of a transcriptional repressor.²⁴ For pregnant patients taking CYP2D6 substrates like SSRIs or metoprolol, this means a previously effective dose could become insufficient in the third trimester, potentially requiring temporary adjustments.

Real-World Consequences of Getting It Wrong

The clinical stakes of CYP2D6 variability go beyond individual drug side effects. In a study of patients with major depressive disorder, having reduced function in both CYP2D6 and the related enzyme CYP2C19 together increased the risk of adverse drug reactions substantially. Patients who were intermediate metabolizers for both enzymes experienced about three times the odds of side effects compared to normal metabolizers for both.²⁵ The worst combinations, such as CYP2C19 intermediate / CYP2D6 poor metabolizers, saw odds ratios above 9, meaning these patients were roughly nine times more likely to experience adverse reactions than people with normal function in both enzymes.

Ultrarapid metabolizers face their own set of problems. In one study, ultrarapid metabolizers of CYP2D6 were about 70 percent more likely to be hospitalized compared to normal metabolizers, and about 50 percent more likely to visit an emergency department.²⁶ This increased risk likely reflects both treatment failure (drugs being cleared too fast to work) and the consequences of rapid prodrug activation (too much active metabolite produced too quickly).

CYP2D6 in the Brain

Most drug metabolism discussions focus on the liver, but CYP2D6 is also expressed in the brain, and this local activity has implications beyond just clearing drugs from the bloodstream. Brain CYP2D6 participates in the metabolism of neurotransmitters like serotonin and neurosteroids, and mice engineered to express human CYP2D6 show higher baseline brain serotonin levels along with differences in anxiety-related behavior compared to normal mice.²⁷ CYP2D6 variation has been linked to the incidence of several neurological conditions, and the enzyme’s endogenous substrates in the brain include compounds involved in pain modulation and mood regulation.²⁸

This dual role complicates pharmacogenomics in psychiatry and neurology. A person’s CYP2D6 genotype does not just affect how fast a drug leaves their body. It may also influence baseline neurotransmitter tone in the brain, which could shape both the underlying condition and the response to treatment in ways that current dosing guidelines do not fully capture.

How CYP2D6 Activity Is Tested

Two approaches exist for determining your CYP2D6 status. Genotyping uses a DNA sample, typically from saliva or blood, to identify which allele variants you carry. An activity score is then calculated from the combination of your two alleles to predict your metabolizer phenotype.²⁹ This is the method used in most clinical pharmacogenomic panels and is what CPIC guidelines are built around.

The alternative is phenotyping, where you take a probe drug and the rate at which your body converts it is measured. Dextromethorphan, the cough suppressant, is the most commonly used probe: the ratio of dextromethorphan to its metabolite dextrorphan in urine reveals how fast CYP2D6 is working in real time.³⁰ Debrisoquine, an older blood-pressure medication, was historically the original probe drug used to discover CYP2D6 polymorphism, and it is still used in some research settings.³¹ Phenotyping has the advantage of capturing drug interactions and pregnancy-related induction that genotyping alone would miss, since it measures what the enzyme is actually doing at that moment, not just what the DNA says it could do.

A Quick-Reference Drug List by Category

For easy scanning, here are the major CYP2D6 substrates organized by therapeutic use. Some drugs depend on CYP2D6 as their primary metabolic route, while others use it as one pathway among several.

SSRIs and SNRIs: fluoxetine, paroxetine, fluvoxamine, sertraline, venlafaxine, duloxetine, vortioxetine
Tricyclic antidepressants: amitriptyline, nortriptyline, imipramine, desipramine, clomipramine
Opioid analgesics: codeine, tramadol, hydrocodone, oxycodone
Antipsychotics: risperidone, aripiprazole, haloperidol, thioridazine, perphenazine
Beta-blockers: metoprolol, carvedilol, propranolol, timolol
Antiarrhythmics: propafenone, flecainide, quinidine (also a strong CYP2D6 inhibitor)
Oncology: tamoxifen (bioactivation to endoxifen)
ADHD: atomoxetine
Antiemetics: ondansetron
Cough suppressants: dextromethorphan

Keep in mind that a drug appearing on this list does not automatically mean your CYP2D6 genotype will change your experience with it. Clinical significance depends on how much of the drug’s overall clearance runs through CYP2D6 versus other enzymes, whether the drug has a narrow or wide therapeutic window, and whether CYP2D6 activates or deactivates it. Codeine in a poor metabolizer and metoprolol in a poor metabolizer both involve the same enzyme, but the clinical problems are opposite: one stops working and the other works too well.

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