Ibogaine Human Pharmacokinetics: Glue et al. 2015 CYP2D6 Study Explained

Definition

Definition: Primary human PK paper (distinct from the Glue noribogaine healthy-volunteer study at /blog/glue-2015-noribogaine-healthy-volunteers): Glue P. et al. (2015) *Influence of CYP2D6 activity on the pharmacokinetics and pharmacodynamics of a single 20 mg dose of ibogaine in healthy volunteers*, *Journal of Clinical Pharmacology* 55(6):680–687 (doi: 10.1002/jcph.471; PMID 25651476). Crossover-style comparison after oral ibogaine 20 mg in healthy volunteers pretreated with placebo vs the CYP2D6 inhibitor paroxetine: reduced CYP2D6 activity roughly doubled active-moiety exposure (ibogaine + noribogaine); authors advise genotyping and considering ≥50% dose reduction in poor metabolizers. Related later work: Knuijver 2024 OUD PK/PD at 10 mg/kg (doi 10.1177/02698811241237873) showing clearance tightly tied to CYP2D6 activity score and QTc better related to ibogaine than noribogaine; Mash 2018 clinical PK genotype vignettes (doi 10.3389/fphar.2018.00529). This is oral micro-/low-dose and clinical oral PK teaching—not psychoactive IV ibogaine infusion PK proof. Not a cure paper. Schedule I / not approved for any indication. Cardiac risk remains exposure-linked.

Short answer

Glue and colleagues’ 2015 Journal of Clinical Pharmacology study showed CYP2D6 activity strongly shapes ibogaine exposure after a 20 mg oral dose, roughly doubling active moiety when CYP2D6 is inhibited. That human PK signal—extended by later OUD studies—does not prove psychoactive IV ibogaine infusion dosing and heightens QTc caution in poor metabolizers.

Why this paper matters

A separate article covers Glue noribogaine ascending-dose volunteers (/blog/glue-2015-noribogaine-healthy-volunteers). This one covers the Glue ibogaine–CYP2D6 human PK paper, plus a short bridge to 2016–2024 clinical PK (see also /blog/knuijver-2024-ibogaine-pk-cyp2d6). Next steps: /safety-and-screening → /apply. Metabolism explainer: /blog/ibogaine-cyp2d6-metabolism.

What Glue 2015 CYP2D6 studied

Bridge to later human PK

• Knuijver 2024: At oral 10 mg/kg in OUD, ibogaine clearance rose steeply with CYP2D6 activity score; QTc concentration–effect related more to ibogaine than noribogaine; authors push individualized/lower dosing research.
• Mash 2018: Clinical observations linking CYP2D6 genotype to parent/metabolite levels and subjective intensity (ultra-rapid metabolizers with low parent levels noted historically).
• Glue noribogaine 2015 (/blog/glue-2015-noribogaine-healthy-volunteers): Separate molecule (noribogaine dosing)—do not conflate the two studies.

Why PK is a cardiac story

Higher parent ibogaine exposure → more QT liability in concentration–effect models. Poor metabolizers and patients on CYP2D6 inhibitors (e.g., certain antidepressants) are theoretically at higher arrhythmia risk for a given nominal mg/kg dose. PK literacy belongs inside screening—not as biohacker dose math (/blog/ibogaine-drug-interactions-qtc).

Route honesty & entity clarity

All cited human PK here is oral (and oral noribogaine elsewhere). Oral bioavailability, first-pass CYP2D6 conversion, and IV psychoactive infusion kinetics are not interchangeable. Do not copy Glue’s 20 mg volunteer curves into IV infusion dosing charts (/blog/ibogaine-oral-vs-iv).

Key findings (no hype)

• CYP2D6 is a major determinant of ibogaine→noribogaine conversion and parent exposure.
• Pharmacologic CYP2D6 inhibition approximately doubled active-moiety exposure after 20 mg oral ibogaine in Glue 2015.
• Later clinical PK at detox-range doses confirms high variability and QT links to parent concentrations.
• Genotype-guided dosing is a research/safety recommendation—not an approved companion diagnostic product claim on this site.
• Low-dose volunteer tolerability ≠ high-dose detox safety.

Limits

Practical PK questions clinicians ask

Misleading claims to watch for

“Glue proved 20 mg is the clinical dose,” “double the dose if ultra-rapid,” or “IV infusion bypasses CYP so no risk.” First-pass differences do not erase cardiac channel effects once drug is systemic.

Where this sits in the PK article cluster

Keep titles unconflated in internal links and meta descriptions.

Noribogaine glucuronide note

Knuijver 2024 also assayed noribogaine glucuronide alongside parent/metabolite—reminding readers that “active moiety” accounting can be more than a two-compound cartoon. Still, the practical screening message remains: CYP2D6 status and QT-active co-meds change risk.

Ultra-rapid metabolizers (clinical vignette class)

Mash-line observations historically noted ultra-rapid CYP2D6 metabolizers with very low parent ibogaine levels and muted oneirogenic effects while noribogaine remained detectable—another reason nominal mg/kg charts fail individuals. Genotype does not replace monitoring; it sharpens monitoring hypotheses.

Next steps

Metabolism questions belong in screening: /safety-and-screening → /apply.

FAQ

Is this the same as the Glue noribogaine study? No. This is **ibogaine 20 mg + CYP2D6/paroxetine** PK; the other study is ascending-dose **noribogaine**.

DOI? **10.1002/jcph.471** (PMID **25651476**).

Does doubling exposure matter clinically? Yes for safety planning—especially QT—though 20 mg data need cautious extrapolation to detox doses.

Was the route IV? No—oral.

Does PK prove efficacy? No. Exposure science ≠ outcome cures.

Is ibogaine approved for medical use? No. Schedule I.

Where is full OUD 10 mg/kg PK covered? /blog/knuijver-2024-ibogaine-pk-cyp2d6.

Where should screening start? /safety-and-screening → /apply.

Sources (selected)

1. Glue P. et al. *J Clin Pharmacol*. 2015. doi: 10.1002/jcph.471. PMID: 25651476.
2. Knuijver T. et al. *J Psychopharmacol*. 2024. doi: 10.1177/02698811241237873.
3. Mash D.C. et al. *Front Pharmacol*. 2018. doi: 10.3389/fphar.2018.00529.
4. Glue P. et al. *J Clin Pharmacol*. 2015. doi: 10.1002/jcph.404 (noribogaine HV; separate article).
5. 21 CFR 1308.11 — ibogaine Schedule I (United States).

Medical disclaimer

Educational research synopsis only—not medical advice and not individualized dosing instructions. Ibogaine can prolong the QTc interval and has been associated with serious cardiac events including torsades de pointes and death in some contexts. CYP2D6 variability can alter exposure. Ibogaine is Schedule I in the United States and is not approved for any indication. Our IV ibogaine programs in Mexico and Gabon are not approved U.S. clinics. Next steps: /safety-and-screening, then /apply.

Glue 2015 CYP2D6 oral ibogaine PK is not a cure claim and not psychoactive IV ibogaine infusion proof.