CYP2D6 controls how your body experiences ibogaine.
Genotype, phenotype, and the CYP2D6 inhibitor list explain why two patients on the same milligram-per-kilogram dose can have very different experiences — and why our protocol is built around individual metabolizer status.
CYP2D6
A liver-expressed cytochrome P450 isoenzyme responsible for metabolising approximately 25% of clinically used drugs — including ibogaine, codeine, tramadol, many antidepressants, antipsychotics, beta-blockers, and tamoxifen. Genetic variation in CYP2D6 is the single most important pharmacogenomic factor in modern psychiatric and addiction medicine.
The Two-Step Pharmacology
Ibogaine and noribogaine are not the same drug.
Step 1: Ibogaine itself. Following oral or sublingual administration, ibogaine peaks in plasma within 2-4 hours. It binds with moderate affinity at sigma-2, NMDA, kappa-opioid, mu-opioid (low affinity), nicotinic acetylcholine, and serotonin transporter sites. The acute experiential phase — visions, motor ataxia, autonomic activation — is driven primarily by parent ibogaine over the first 4-8 hours.
Step 2: Noribogaine, the active metabolite. CYP2D6 demethylates ibogaine to noribogaine. Noribogaine has a longer half-life (28-49 hours in humans), is a potent serotonin reuptake inhibitor, a kappa-opioid agonist, and a mu-opioid partial agonist. The longer anti-craving and antidepressant arc — felt in the days and weeks after dosing — is driven primarily by noribogaine.
Why the kinetics matter. A poor CYP2D6 metabolizer accumulates higher and longer-lasting ibogaine plasma levels and produces less noribogaine. The acute experience is more intense and the QTc effect is larger. An ultrarapid metabolizer clears ibogaine quickly, with shorter and lower peaks but a higher noribogaine ceiling. Both phenotypes can have safe, productive treatments — but only when the dosing protocol is matched to the kinetics.
Read the full noribogaine pharmacology brief at /noribogaine, the cardiac mechanism at /ibogaine-cardiac-screening, and the QTc pre-screen tool at /tools/qtc-risk.
How CYP2D6 status reshapes the dosing protocol.
| Phenotype | Population frequency | Genotype basis | Ibogaine kinetics | Protocol implication |
|---|---|---|---|---|
| Poor Metabolizer (PM) | ~7% of European populations; up to 19% in some Asian populations | Two non-functional CYP2D6 alleles | Higher peak ibogaine; longer half-life; lower noribogaine peak | Lower starting dose, longer telemetry, conservative QTc threshold |
| Intermediate Metabolizer (IM) | ~10-15% of most populations | One reduced-function and one non-functional or two reduced-function alleles | Modestly elevated peak ibogaine compared with normal | Standard or slightly reduced dose; close monitoring |
| Normal (Extensive) Metabolizer (NM/EM) | ~70-80% of most populations | Two functional CYP2D6 alleles | Reference ibogaine and noribogaine kinetics | Standard mg/kg dosing |
| Ultrarapid Metabolizer (UM) | ~1-3% globally; up to 25% in North African populations | Gene duplication or high-activity alleles | Faster conversion; shorter ibogaine peak; faster-rising noribogaine | Standard dose; protocol may use a small booster if experience is short |
The Inhibitor Problem
A CYP2D6 inhibitor turns a normal metabolizer into a functional poor metabolizer.
Phenoconversion. Pharmacology has a name for it: phenoconversion. A patient with a normal CYP2D6 genotype who takes a strong inhibitor produces a poor-metabolizer plasma profile while the inhibitor is on board. For ibogaine, this means higher peaks, longer clearance, and amplified QTc — exactly the kinetics we work hardest to avoid.
The big four. Paroxetine, fluoxetine, bupropion, and quinidine are the strongest CYP2D6 inhibitors in routine clinical use. Each requires washout before ibogaine. Fluoxetine carries the longest washout in the protocol (35 days) because its metabolite norfluoxetine is itself a long-lived CYP2D6 inhibitor.
The hidden inhibitors. Patients sometimes underestimate inhibitors that are not psychiatric drugs — terbinafine (Lamisil) for fungal infections, cinacalcet (Sensipar) for hyperparathyroidism, ritonavir for HIV. Our intake screens every prescription, OTC, and supplement.
Common CYP2D6 inhibitors and their washout windows for ibogaine.
| Medication | Inhibition strength | Standard washout | Notes |
|---|---|---|---|
| Paroxetine (Paxil) | Strong inhibitor | 14 days | SSRI; also serotonergic risk |
| Fluoxetine (Prozac) | Strong inhibitor | 35 days | Long half-life metabolite (norfluoxetine 4-16 days) |
| Bupropion (Wellbutrin) | Strong inhibitor | 14 days | Threshold-lowering; taper supervised |
| Quinidine | Strong inhibitor | Physician-directed | Antiarrhythmic; also QTc — usually contraindicated |
| Duloxetine (Cymbalta) | Moderate inhibitor | 7-14 days | SNRI; serotonergic |
| Sertraline (Zoloft) | Mild-to-moderate (dose-dependent) | 7 days | Inhibitor effect rises at doses ≥ 150 mg |
| Terbinafine (Lamisil) | Moderate inhibitor | Physician-directed | Long tissue half-life — case-by-case |
| Cinacalcet (Sensipar) | Moderate inhibitor | 7 days | Calcium-sensing receptor agonist |
When We Recommend Phenotyping
Genetic testing is not mandatory — but here is when we strongly recommend it.
Known opioid sensitivity. If codeine has ever made you violently nauseated, sedated beyond expectation, or unusually pain-free, you are a candidate for CYP2D6 phenotyping. Codeine is metabolised to morphine by CYP2D6 — poor metabolizers feel little effect, ultrarapid metabolizers can develop respiratory depression at standard doses.
Recent or current CYP2D6 inhibitor. Anyone on paroxetine, fluoxetine, bupropion, or quinidine within the last six weeks should be screened, even after washout, because residual phenoconversion can persist past nominal half-life calculations.
Past psychiatric drug intolerance. Patients who have failed multiple antidepressants because of side effects, or who developed pronounced nausea, sedation, or QTc changes on antipsychotics, often turn out to be poor metabolizers of CYP2D6 or CYP2C19.
Family history. Pharmacogenomic phenotype is heritable. If a first-degree relative is a documented poor metabolizer, your prior probability is elevated.
How testing works. We coordinate buccal-swab or blood-draw testing through accredited labs (typically the GeneSight, OneOme RightMed, or equivalent panels). Results return in 5-10 days and feed directly into the medical director's dosing plan.
Phenotype-Aware Dosing
What changes in the protocol based on metabolizer status.
Poor metabolizers begin at the lower end of the standard mg/kg range, with extended cardiac telemetry windows that capture the slower clearance tail. Booster doses are avoided unless the experience plateaus prematurely. Pre-dose QTc tolerance is set conservatively (≤ 440 ms men, ≤ 460 ms women).
Normal metabolizers follow the reference dosing protocol with standard telemetry. The QTc tier targets in our calculator are calibrated to this group.
Ultrarapid metabolizers follow the reference dose; if the active phase is unusually short, a low-dose booster may be administered under continuous telemetry. The noribogaine ceiling is reached more quickly, so the post-acute phase often delivers strong anti-craving signal.
Functional poor metabolizers (anyone on a strong CYP2D6 inhibitor that has not been washed out) are not eligible for treatment until washout is documented. This is non-negotiable. The protocol exists to reduce risk; ignoring it eliminates the protocol's protective value.
Cross-reference with the full A-Z drug interaction directory, the QTc risk calculator, and the medical team page for who reviews each plan.
Pharmacogenomics FAQ