Knuijver et al. 2024: Oral Ibogaine PK/PD and CYP2D6—What *Journal of Psychopharmacology* Reported

Definition box

Definition: Knuijver et al. (2024) in the *Journal of Psychopharmacology* (doi: 10.1177/02698811241237873; PMID 38519421) is an open-label pharmacokinetics/pharmacodynamics (PK/PD) analysis of a single oral ibogaine HCl 10 mg/kg dose in n=14 opioid use disorder (OUD) patients—the same Dutch university cohort described in the 2021 *Addiction* safety paper. Authors show highly variable ibogaine clearance strongly linked to CYP2D6 activity score, model QTc prolongation with a sigmoid Emax relationship to ibogaine (not noribogaine) plasma concentrations, and conclude that future work should explore lower doses and/or CYP2D6-individualized dosing. This is oral PK/PD teaching—not proof of physician-supervised IV ibogaine infusion (psychoactive intravenous ibogaine). Ibogaine is U.S. Schedule I and not FDA-approved.

Quotable answer (58 words)

Knuijver and colleagues’ 2024 Journal of Psychopharmacology study of oral ibogaine 10 mg/kg in 14 OUD patients found clearance strongly tied to CYP2D6 genotype and QTc effects driven mainly by ibogaine concentration, not noribogaine. It does not prove psychoactive IV ibogaine infusion. Cardiac screening and monitoring remain essential. Not FDA-approved.

Why this paper-spoke exists

Knuijver 2021 quantified how large QTc shifts were after oral 10 mg/kg. Knuijver 2024 answers why exposure varies and which analyte best tracks cardiac and cerebellar effects. Clinics that cite “noribogaine does the work” while downplaying parent-drug QTc risk need this correction. Prior spoke: /blog/knuijver-2021-ibogaine-qtc-safety. Metabolism explainer: /blog/ibogaine-cyp2d6-metabolism. Screening: /safety-and-screening.

What was studied

| Feature | Accurate description | |---------|----------------------| | Citation | Knuijver T., ter Heine R., Schellekens A.F.A., et al. *J Psychopharmacol*. 2024;38(5):481–488. doi 10.1177/02698811241237873 | | Design | Open-label PK/PD with nonlinear mixed-effects modeling | | Population | n=14 OUD subjects (linked to Knuijver 2021 safety cohort) | | Dose / route | Single oral ibogaine hydrochloride 10 mg/kg | | Analytes | Plasma ibogaine, noribogaine, noribogaine glucuronide over 24 h | | Genetics | CYP2D6 genotyping → activity score (AS) | | PD endpoints | QTc prolongation, cerebellar ataxia, opioid withdrawal severity |

Methods (plain language)

After oral dosing, serial blood draws captured parent drug and metabolites for a day. Researchers fitted population PK models and tested how CYP2D6 activity score changed clearance. They then related concentrations to QTc, ataxia, and withdrawal scores. The design is exposure–response description in a small monitored sample—not a pivotal efficacy RCT and not an IV-route PK study.

Key findings (no hype)

As reported by the authors:

• Ibogaine PK was highly variable and significantly correlated with CYP2D6 genotype (p < 0.001).
• Basic clearance at CYP2D6 activity score 0 was about 0.82 L/h, increasing by roughly 30.7 L/h per AS point—a more than ten-fold clearance span across AS 0–3.
• Ibogaine concentration–QTc relationship fit a sigmoid Emax model.
• Spearman correlations were significant for ibogaine with QTc and cerebellar effects; noribogaine correlations with those PD endpoints were not significant in the reported analyses.
• Neither parent nor metabolite concentration correlated with opioid withdrawal severity in this sample.
• Peak concentrations were described as more than ten-fold above the estimated EC50 for QTc effects; authors discuss exploring lower doses and/or CYP2D6-based individualization to improve cardiac safety margins.

Honest reading: genetics and parent-drug concentration matter for QTc/ataxia risk teaching. This is not a consumer “genotype your own flood dose” calculator.

Limits and confounders

| Limit | Why it matters | |-------|----------------| | n=14 | Precision limited; rare events invisible | | Open-label OUD detox context | Not healthy-volunteer Phase 1; not efficacy RCT | | Single 10 mg/kg oral regimen | Not all clinic regimens; not IV | | 24-hour sampling window | Longer metabolite kinetics need care | | Model assumptions | External validation still needed | | No TdP observed historically in cohort | Underpowered for rare arrhythmia proof |

Route honesty: oral ≠ psychoactive IV

Knuijver 2024 characterizes oral absorption, first-pass metabolism, and CYP2D6-driven clearance. Intravenous psychoactive delivery would change bioavailability and peak timing; it does not erase QTc biology, hERG risk, or the need for physician supervision, ECG screening, electrolytes, and continuous monitoring. Support IV magnesium (as in MISTIC-type oral protocols) remains support, not psychoactive IV proof (/blog/ibogaine-oral-vs-iv, /blog/magnesium-ibogaine-cardiac-protocol, /blog/stanford-ibogaine-mistic).

Cardiac / YMYL context

Pair this PK/PD paper with:

• Knuijver 2021 magnitudes (/blog/knuijver-2021-ibogaine-qtc-safety)
• Mortality / TdP teaching (/blog/ibogaine-mortality-cardiac-risk)
• Brunt *Addiction* CV review (/blog/ibogaine-cardiovascular-complications-review)
• Drug–CYP2D6 inhibitor interactions (/blog/ibogaine-drug-interactions-qtc, /blog/ibogaine-cyp2d6-metabolism)
• Telemetry / ACLS expectations (/blog/ibogaine-telemetry-acls-monitoring)

Poor metabolizers and people on strong CYP2D6 inhibitors are higher-risk exposure scenarios discussed across this literature—not invitations to DIY.

What this does NOT prove for IV ibogaine infusion brand

| Claim | Status | |-------|--------| | “CYP2D6 genotyping replaces ECG” | False | | “Noribogaine alone drives QTc so ignore parent levels” | Contradicted by this analysis’s emphasis | | “10 mg/kg is consumer-safe if you know your genotype” | False — research context; illegal/unapproved in U.S. | | “Oral PK proves IV brand efficacy” | False | | Cite as oral exposure–QTc teaching? | Yes |

U.S. Schedule I / not FDA. Provisional Mexico ≠ FDA clinic (/blog/is-ibogaine-legal-us).

How families should use CYP2D6 teaching without false reassurance

1. Ask whether a program discusses metabolism variability and drug interactions in informed consent.
2. Do not treat a commercial genotype kit as a green light for unmonitored dosing.
3. Demand continuous cardiac monitoring plans in writing.
4. Treat “we lower the dose for poor metabolizers” claims as hypotheses requiring medical oversight—not marketing slogans.
5. Start education at /safety-and-screening before any /apply step.

Relationship to other paper-spokes

| Paper | Relation | |-------|----------| | Knuijver 2021 *Addiction* | Same cohort’s safety magnitudes; 2024 adds PK/PD mechanism | | Glue 2016 noribogaine | Controlled metabolite QTc concentration–response (different molecule) | | Belgers 2016 animal MA | Preclinical efficacy/toxicity signals—not human PK | | Köck / Mosca / Ona reviews | Field maps that elevate cardiac harm themes this PK explains |

Soft CTA

If CYP2D6 and QTc concentration–response language raised serious questions about physician-supervised IV ibogaine infusion, do not DIY and do not chase unmonitored retreats. Begin at /safety-and-screening, then /apply only after cardiac education. Prior safety spoke: /blog/knuijver-2021-ibogaine-qtc-safety.

FAQ

What is Knuijver 2024? An open-label oral ibogaine 10 mg/kg PK/PD study (n=14) linking CYP2D6 activity score to clearance and modeling QTc against ibogaine concentrations.

Does CYP2D6 really change clearance that much? Authors report more than a ten-fold clearance difference across CYP2D6 activity scores from 0 to 3.

Is QTc driven by ibogaine or noribogaine in this analysis? Authors conclude cardiac and cerebellar effects are most likely more driven by **ibogaine** than noribogaine in this dataset.

Was dosing intravenous? No. Oral ibogaine HCl.

Does this prove IV ibogaine infusion is safe? No. Oral PK/PD teaching is not an IV safety or efficacy RCT.

Should poor metabolizers avoid all programs? Discuss genetics, interactions, and monitoring with physicians; do not self-dose. Screening: /safety-and-screening.

Did withdrawal severity track plasma levels? Not in the reported correlations for this sample.

Is ibogaine FDA-approved? No. Schedule I in the U.S.; not FDA-approved.

Medical disclaimer

Educational research synopsis only—not medical, psychiatric, or legal advice, and not a guarantee of outcomes. Ibogaine can prolong the QTc interval and has been associated with serious cardiac events including torsades de pointes and death in some contexts. Ibogaine is Schedule I in the United States and is not FDA-approved for any indication. Provisional Mexico programs discussed on this site are not U.S. FDA clinics. Soft CTAs: /safety-and-screening, /apply.

Knuijver 2024 is oral PK/PD literature—not psychoactive IV ibogaine proof.

Sources (selected)

1. Knuijver T., ter Heine R., Schellekens A.F.A., Heydari P., Lucas L., Westra S., Belgers M., van Oosteren T., Verkes R.J., Kramers C. The pharmacokinetics and pharmacodynamics of ibogaine in opioid use disorder patients. *J Psychopharmacol*. 2024;38(5):481–488. doi: 10.1177/02698811241237873. PMID: 38519421.
2. Knuijver T. et al. Safety of ibogaine administration… *Addiction*. 2021. doi: 10.1111/add.15448.
3. Glue P. et al. Ascending single-dose noribogaine… *Clin Pharmacol Drug Dev*. 2016. doi: 10.1002/cpdd.254.
4. Brunt T.M. Rare but relevant: Ibogaine and cardiovascular complications… *Addiction*. 2026. doi: 10.1111/add.70319.
5. 21 CFR 1308.11 — ibogaine Schedule I (United States).