CYP2D6: The Most Polymorphic Drug-Metabolizing Gene
What Is CYP2D6?
CYP2D6 is a gene that encodes one of the most clinically important drug-metabolizing enzymes in the human body. Despite accounting for only a small fraction of total liver cytochrome P450 content, CYP2D6 is responsible for metabolizing approximately 25% of all prescribed medications — making it one of the most consequential genes in pharmacogenomics.
The CYP2D6 enzyme is produced in the liver and plays a primary role in the metabolism of a wide range of drug classes, including antidepressants, opioid analgesics, antipsychotics, beta-blockers, antiemetics, and the breast cancer drug tamoxifen. What makes CYP2D6 particularly important is its extreme genetic variability — over 130 allelic variants have been identified, making it the most polymorphic of all CYP enzymes. For a general introduction, see our guide to DNA testing for medication.
Metabolizer Types (Phenotypes)
CYP2D6 phenotype assignment uses an activity score system standardized by CPIC. Each allele is assigned a value (typically 0, 0.5, or 1), and the sum of both alleles determines your phenotype. Learn more about how pharmacogenomic testing determines your phenotype or read our plain-language guide to metabolizer status.
| Phenotype | Activity Score | Enzyme Activity | What It Means | Example Drug Impact |
|---|---|---|---|---|
| Ultrarapid (UM) | >2.0 | Enhanced | Gene duplications produce excess enzyme. Drugs cleared faster than expected. | Codeine → dangerously rapid morphine formation; antidepressants may be ineffective at standard doses |
| Normal (NM) | 1.25–2.0 | Standard | Two functional alleles or one functional + one decreased. Standard dosing applies. | Standard drug labels and doses are designed for this group |
| Intermediate (IM) | 0.25–1.0 | Reduced | One or two decreased-function alleles. Slower drug clearance. | May need dose reduction for some TCAs; reduced prodrug activation for codeine |
| Poor (PM) | 0 | Absent | Two no-function alleles. No CYP2D6 enzyme activity. | Codeine/tramadol ineffective; atomoxetine toxicity risk; tamoxifen alternative recommended |
CYP2D6 poor metabolizer frequency varies by population: approximately 5–10% of European populations, 1–3% of East Asian and African populations, and up to 1–2% in some Middle Eastern populations. Ultrarapid metabolizer frequency also varies, reaching 10–29% in some North African and Middle Eastern populations.
Drug Interactions by CYP2D6 Phenotype
The following table summarizes CPIC-guided clinical implications for selected CYP2D6-dependent medications. This is not exhaustive — consult your healthcare provider or pharmacist for guidance specific to your medications.
| Drug | Class | Effect in Poor Metabolizers | Effect in Ultrarapid Metabolizers | Guideline |
|---|---|---|---|---|
| Codeine | Opioid | Reduced pain relief — codeine not converted to morphine | Toxicity risk — rapid morphine formation | CPIC: avoid in both PM and UM |
| Tramadol | Opioid | Reduced efficacy | Toxicity risk | CPIC: avoid in both PM and UM |
| Amitriptyline | TCA | Higher drug levels — reduce dose 50% | Sub-therapeutic levels — consider alternative or increase dose | CPIC Level A |
| Paroxetine | SSRI | Higher drug levels — consider alternative or reduce dose | Lower levels — consider alternative SSRI | CPIC Level A |
| Venlafaxine | SNRI | Altered metabolite ratio — monitor or consider alternative | Faster clearance of active metabolite | CPIC Level B |
| Aripiprazole | Antipsychotic | Higher levels — reduce dose | May need dose increase | FDA label + CPIC |
| Atomoxetine | ADHD | Higher levels — lower starting dose | Standard dosing typically applies | CPIC Level A |
| Tamoxifen | Breast cancer | Reduced endoxifen levels — consider alternative endocrine therapy | Standard or enhanced conversion | CPIC Level A |
| Metoprolol | Beta-blocker | Higher levels — increased beta-blockade effects | Rapid clearance — reduced efficacy possible | DPWG |
Source: CPIC Gene-Drug Pairs and FDA Table of Pharmacogenomic Biomarkers. For a broader look at pharmacogenomic testing services, see our GeneSight cost and alternatives guide.
Common CYP2D6 Variants
CYP2D6 is the most polymorphic pharmacogene, with over 130 identified star alleles. The most clinically relevant variants include:
- CYP2D6*1: The reference (wild-type) allele with normal enzyme function.
- CYP2D6*4: The most common no-function allele in European populations (~20% frequency). A splice site variant that results in a nonfunctional protein. This single allele accounts for the majority of poor metabolizer phenotypes in people of European ancestry.
- CYP2D6*5: A complete gene deletion — the entire CYP2D6 gene is absent. This results in zero enzyme production from that chromosome. Found at ~2–7% frequency across populations.
- CYP2D6*10: A decreased-function allele that is the most common variant in East Asian populations (~40–50% frequency). The enzyme is produced but has reduced stability and activity.
- CYP2D6 gene duplications: Some individuals carry multiple copies of functional CYP2D6 alleles (e.g., *1x2, *2x2), resulting in ultrarapid metabolizer status. Gene duplication frequency ranges from ~1–2% in East Asian populations to ~10–29% in some North African and Middle Eastern populations.
- CYP2D6*41: A decreased-function allele common in European (~8%) and Middle Eastern populations. Associated with reduced but not absent enzyme activity.
CYP2D6 on 23andMe: What's Detected & What's Missing
If you have 23andMe raw data, your file contains several SNPs that define common CYP2D6 star alleles. The table below shows which variants are detectable from consumer genotyping arrays and which require clinical-grade testing.
| SNP / Variant | Star Allele | Function | On 23andMe Array? | Population Frequency |
|---|---|---|---|---|
| rs1065852 | CYP2D6*4 | No function (splice defect) | Yes | ~20% European |
| rs1135840 | CYP2D6*10 | Decreased function (unstable enzyme) | Yes | ~40–50% East Asian |
| rs28371725 | CYP2D6*41 | Decreased function (reduced splicing) | Yes | ~8% European |
| Gene deletion | CYP2D6*5 | No function (entire gene absent) | No — structural variant | ~2–7% across populations |
| Gene duplication | *1x2, *2x2, etc. | Ultrarapid (excess enzyme) | No — copy number variant | 1–29% (varies by ancestry) |
| Hybrid alleles | CYP2D6/CYP2D7 | No function (gene conversion) | No — structural rearrangement | Varies |
Bottom line: 23andMe raw data covers the three most common CYP2D6 SNP-based variants (*4, *10, *41), which account for the majority of poor and intermediate metabolizer assignments in most populations. However, approximately 5–15% of individuals carry clinically significant structural variants — gene deletions (*5), duplications, or hybrid rearrangements — that consumer arrays cannot detect. A CYP2D6 result from consumer data should be considered a starting point; if critical prescribing decisions depend on your CYP2D6 status, clinical-grade testing with copy number analysis is recommended.
CYP2D6 Substrates and Inhibitors
Substrates are medications that CYP2D6 breaks down. Inhibitors are substances that reduce CYP2D6 activity — potentially shifting a normal metabolizer toward an intermediate or poor metabolizer phenotype, even without genetic variants. This matters because a drug interaction can mimic a genetic phenotype (phenoconversion).
Selected CYP2D6 Substrates
- Antidepressants: paroxetine, venlafaxine, amitriptyline, nortriptyline, desipramine, fluoxetine, fluvoxamine. See the full list of CYP2D6-affected antidepressants.
- Opioids: codeine, tramadol, hydrocodone, oxycodone (partially)
- Antipsychotics: aripiprazole, haloperidol, risperidone, thioridazine
- Other: atomoxetine (ADHD), tamoxifen (breast cancer), metoprolol (beta-blocker), ondansetron (antiemetic), eliglustat (Gaucher disease)
Common CYP2D6 Inhibitors
CYP2D6 inhibitors can reduce enzyme activity in anyone — regardless of genotype. A normal metabolizer taking a strong CYP2D6 inhibitor may effectively function as a poor metabolizer for co-administered CYP2D6 substrates.
- Strong inhibitors: fluoxetine, paroxetine, bupropion, quinidine
- Moderate inhibitors: duloxetine, sertraline (at higher doses), terbinafine
If you take a CYP2D6 inhibitor alongside a CYP2D6 substrate, the combined effect on drug levels may be greater than either factor alone. This interaction is independent of your genetic CYP2D6 status and should be evaluated by your prescriber or pharmacist.
How CYP2D6 Is Tested
CYP2D6 testing is available through several approaches, each with different strengths and limitations:
- Clinical pharmacogenomic panels: Tests like GeneSight and Genomind use clinical-grade assays that can detect both SNP-based variants and structural variants (gene deletions, duplications). These require a clinician order and are classified as diagnostic tests. See our comparison of pharmacogenomic testing options.
- Consumer raw data analysis: Services like DecodeMyBio analyze raw DNA data from 23andMe, AncestryDNA, or other consumer tests against published CPIC guidelines. This approach is informational (not diagnostic), costs significantly less, and requires no new sample — but cannot detect structural variants. See our step-by-step upload guide or learn about methylation testing for nutrient metabolism insights from the same raw data.
- Hospital-based testing: Some academic medical centers offer in-house pharmacogenomic testing through their clinical laboratories, often as part of precision medicine programs.
Structural Variant Limitations
CYP2D6 is uniquely challenging for consumer genotyping because it is one of the few pharmacogenes where structural variants — gene deletions, duplications, and hybrid gene rearrangements — are both common and clinically significant:
- Gene deletion (*5): The entire CYP2D6 gene is absent from one chromosome. Consumer arrays test individual SNPs, not whether the gene is present at all — so a *5 deletion is typically invisible in raw data.
- Gene duplications (*1x2, *2x2, etc.): Multiple copies of a functional allele on the same chromosome produce ultrarapid metabolizer status. Consumer SNP arrays cannot count gene copies, so a duplication may be missed.
- Hybrid rearrangements (CYP2D6/CYP2D7): Gene conversion events between CYP2D6 and the nearby pseudogene CYP2D7 can create non-functional hybrid alleles. These are not detectable by SNP genotyping.
A CYP2D6 result from consumer raw data should be considered a minimum assessment. If clinical decisions depend on your CYP2D6 status, clinical-grade testing with copy number analysis is recommended. See our limitations page and methodology for full details.
Limitations
CYP2D6 testing — whether clinical or consumer-grade — has important limitations that should be considered when interpreting results:
- Not diagnostic: CYP2D6 results do not diagnose any medical condition. They provide information about enzyme function that may inform medication discussions with a clinician.
- One factor among many: Drug response is influenced by age, weight, kidney and liver function, other medications, and additional genetic factors beyond CYP2D6 alone.
- Phenoconversion: Drug–drug interactions can override your genetic phenotype. A genetically normal metabolizer taking a strong CYP2D6 inhibitor may function as a poor metabolizer in practice.
- Requires clinician interpretation: CYP2D6 results should be interpreted by a healthcare provider in the context of your complete medication list, medical history, and clinical circumstances. Do not change medications based solely on genetic results.
- Consumer data gaps: As noted above, consumer genotyping cannot detect gene deletions, duplications, or hybrid rearrangements. These structural variants affect approximately 5–15% of individuals depending on ancestry.
For a comprehensive discussion of what pharmacogenomic testing can and cannot determine, see our full limitations page.
CYP2D6 and Psychiatric Medications
CYP2D6 metabolizes many commonly prescribed antidepressants, antipsychotics, and ADHD medications. If you take psychiatric medications, your CYP2D6 status may be clinically relevant. Key CYP2D6-dependent psychiatric medications include paroxetine (Paxil) and atomoxetine (Strattera) for ADHD. DecodeMyBio's Psychiatric Medication Report maps your CYP2D6 and CYP2C19 results to CPIC guidelines for SSRIs, tricyclics, antipsychotics, and atomoxetine.
Learn more about the Psychiatric Report · CYP2D6 and antidepressants · PGx for ADHD
Frequently Asked Questions
What medications should CYP2D6 poor metabolizers avoid?
CPIC guidelines recommend avoiding codeine and tramadol in CYP2D6 poor metabolizers due to reduced conversion to active metabolites. For tricyclic antidepressants, dose reductions of 25–50% are recommended. For tamoxifen, an alternative endocrine therapy may be considered. All medication changes should be discussed with a prescriber. See our CYP2D6 poor metabolizer guide for more detail.
Is CYP2D6 the same as a drug allergy?
No. CYP2D6 metabolizer status affects how quickly your body processes certain drugs — it is not an allergy. A poor metabolizer may accumulate higher drug levels, while an ultrarapid metabolizer may clear a drug too quickly. Drug allergies involve immune system reactions and are a separate phenomenon entirely.
How common is CYP2D6 poor metabolizer?
Approximately 5–10% of European populations are CYP2D6 poor metabolizers, most commonly due to the *4 allele. The frequency is lower in East Asian (1–3%) and African (1–3%) populations. Ultrarapid metabolizers are most common in North African and Middle Eastern populations (up to 29%).
Can CYP2D6 status change over time?
Your CYP2D6 genotype is fixed and does not change. However, your effective CYP2D6 activity can be altered by drug interactions — certain medications (fluoxetine, paroxetine, bupropion) strongly inhibit CYP2D6, which can shift a normal metabolizer toward poor metabolizer function. This is called phenoconversion.
Can 23andMe determine my CYP2D6 status?
23andMe's genotyping array includes SNPs that define many common CYP2D6 alleles. A dedicated raw data analysis can extract these variants, assign your diplotype and activity score, and map the result to CPIC guidelines. However, 23andMe arrays cannot detect gene deletions or duplications. See our guide to pharmacogenomic insights from raw DNA data.
Which CYP2D6 variants does 23andMe detect?
23andMe's array includes rs1065852 (defining the *4 no-function allele), rs1135840 (contributing to *10 decreased-function), and rs28371725 (defining *41 decreased-function). These three SNPs cover the most common CYP2D6 variants across populations. However, 23andMe cannot detect the *5 gene deletion (~2–7% of individuals), gene duplications that cause ultrarapid metabolizer status, or hybrid CYP2D6/CYP2D7 rearrangements. Approximately 5–15% of individuals carry clinically significant structural variants that consumer arrays miss. See the detection table above for a full breakdown.
How does CYP2D6 affect codeine?
Codeine is a prodrug that requires CYP2D6 to convert it to morphine. Poor metabolizers get little to no pain relief. Ultrarapid metabolizers may produce dangerously high morphine levels. CPIC recommends avoiding codeine in both groups. See our codeine pharmacogenomics page.
What is the difference between CYP2D6 and CYP2C19?
Both are drug-metabolizing enzymes, but they affect different medications. CYP2C19 primarily affects clopidogrel, PPIs, and some SSRIs (escitalopram, citalopram). CYP2D6 primarily affects opioids, TCAs, some SSRIs (paroxetine), antipsychotics, and tamoxifen. Both genes are included in standard pharmacogenomic panels.
Does CYP2D6 testing replace clinical judgment?
No. CYP2D6 results are one input among many. Drug response is influenced by age, weight, organ function, other medications, and environmental factors. Results should always be interpreted by a healthcare provider in the context of your complete medical history.
Get Your CYP2D6 Results
If you have raw DNA data from 23andMe, AncestryDNA, MyHeritage, or FamilyTreeDNA, you can upload it to DecodeMyBio to learn your CYP2D6 metabolizer status. Your Medication Safety Report will include your CYP2D6 diplotype, activity score, metabolizer phenotype, and any CPIC-guideline drug-gene interactions relevant to your genotype.
Upload your data · View a sample report · What to do with your 23andMe raw data
Beyond Medications: CYP2D6 and Broader Genomic Insights
If you're exploring how your DNA affects nutrition or methylation, your raw data also contains variants in genes like MTHFR, FUT2, VDR, and others that influence nutrient metabolism. See our Nutrition & Methylation Report for a nutrigenomic analysis from the same DNA data. Browse our learning center for more guides on pharmacogenomics and metabolizer status.
Last reviewed: March 2026 · DecodeMyBio Editorial Team