Glue et al. 2015: Ascending-Dose Oral Noribogaine in Healthy Volunteers — PK, Safety, Not IV Ibogaine

Definition box

Definition: Glue P., Lockhart M., Lam F., Hung N., Hung C.-T., Friedhoff L. (2015) in *The Journal of Clinical Pharmacology* (doi: 10.1002/jcph.404; PMID 25279818; *J Clin Pharmacol* 55(2):189–194) report a Phase I ascending single-dose, placebo-controlled, randomized, double-blind, parallel-group study of oral noribogaine—ibogaine’s primary metabolite—in n=36 healthy drug-free male volunteers. Four cohorts (n=9 each) received 3, 10, 30, or 60 mg or matching placebo, with intensive PK/safety assessments out to 216 hours plus mu-opioid–sensitive pharmacodynamic tests (pupillometry, cold-pressor). Authors reported rapid absorption (Tmax ~2–3 h), dose-linear AUC/Cmax, mean t½ ~28–49 hours, high apparent volume of distribution, no identified safety/tolerability issues in these cohorts, and no mu-opioid agonist PD effects. This is oral noribogaine in healthy volunteers, not psychoactive IV ibogaine infusion, not ibogaine HCl flood dosing, and not FDA approval. Later Glue 2016 work in opioid-dependent patients showed dose-related QTc signals at higher exposures—so “well tolerated at ≤60 mg in healthy men” must not be over-read as “cardiac risk solved.” Ibogaine remains U.S. Schedule I and not FDA-approved.

Quotable answer (58 words)

Glue and colleagues’ 2015 Journal of Clinical Pharmacology Phase 1 study found oral noribogaine 3–60 mg generally well tolerated in 36 healthy men, with long half-life and no mu-opioid agonist effects. Healthy-volunteer metabolite data are not proof of psychoactive IV ibogaine infusion. Later patient dosing showed QTc signals. Schedule I; screen cardiac risk.

Why this paper-spoke exists

Blogs sometimes cite “noribogaine was safe in Phase 1” without saying who, what dose, which molecule, or what happened at higher doses in patients. Glue 2015 is the healthy-volunteer PK/safety foundation; Glue 2016 (/blog/glue-2016-noribogaine-phase1) is the opioid-dependent follow-on where QTc became unmistakable. Families deserve both layers. Soft CTA: /safety-and-screening → /apply. Related: /blog/noribogaine-explained, /blog/noribogaine-trials-vs-iv-infusion.

What was studied

| Feature | Accurate description | |---------|----------------------| | Citation | Glue P. et al. Ascending-dose study of noribogaine in healthy volunteers: pharmacokinetics, pharmacodynamics, safety, and tolerability. *J Clin Pharmacol*. 2015;55(2):189–194. doi 10.1002/jcph.404. PMID 25279818 | | Design | Ascending single-dose DBPC parallel-group Phase 1 | | N | 36 healthy drug-free male volunteers (4 cohorts × n=9) | | Molecule | Noribogaine (metabolite)—not ibogaine | | Route | Oral | | Doses | 3 / 10 / 30 / 60 mg vs matching placebo | | Follow-up window | Intensive assessments to 216 hours | | Key PD | Pupillometry + cold-pressor (mu-opioid sensitive)—no agonist effects | | What it is not | Ibogaine flood RCT; patient efficacy proof; IV psychoactive brand proof |

Window note: Published February 2015 (online 2014)—borderline for a ≈2016–2026 inventory but included as the essential healthy-volunteer companion to Glue 2016.

Methods (plain language)

Healthy men without current drug dependence received a single oral noribogaine capsule or placebo in ascending cohorts. Investigators measured how fast and how completely the drug entered the bloodstream, how long it stayed, whether mu-opioid–like effects appeared on pupil size or cold-pain tests, and whether adverse events or safety labs flagged problems. Parallel-group ascending design means each volunteer got one dose level—not a within-subject ladder.

Why this matters:

1. Healthy ≠ SUD patient physiology — clearance, QT vulnerability, and polypharmacy differ.
2. ≤60 mg ≠ clinic flood exposures of parent ibogaine (often reported ~10–25 mg/kg oral in observational settings).
3. Metabolite ≠ parent — noribogaine PK informs, but does not replace, ibogaine cardiac literature.
4. No mu-agonist PD — important for mechanism debates; not a safety free pass at all doses.

Key findings (no hype)

As reported by the authors:

• Rapid absorption with peak concentrations ~2–3 hours after oral dosing.
• Dose-linear increases in AUC and Cmax from 3–60 mg.
• Slow elimination: mean half-life estimates ~28–49 hours across dose groups.
• High apparent volume of distribution (means roughly 1417–3086 L across groups).
• No safety or tolerability issues identified in these healthy cohorts at these doses.
• No mu-opioid agonist pharmacodynamic effects on pupillometry or cold-pressor testing.
• Conclusion thrust: single oral doses 3–60 mg were safe and well tolerated in healthy volunteers.

Honest reading: This is necessary early development science—not proof that higher-dose noribogaine, parent ibogaine, or IV psychoactive delivery is “safe for everyone.”

Bridge to Glue 2016: why QTc still matters

The same development program’s 2016 DBPC study in opioid-dependent patients (doi 10.1002/cpdd.254) used higher noribogaine doses (60 / 120 / 180 mg) and reported concentration-dependent QTcI prolongation (largest observed mean effects ~16 / 28 / 42 ms by dose). Families who only read the healthy-volunteer abstract miss the cardiac chapter. Always pair:

• Glue 2015 healthy ≤60 mg → generally well tolerated (this spoke)
• Glue 2016 patients 60–180 mg → QTc dose-related (/blog/glue-2016-noribogaine-phase1)
• Broader ibogaine QTc/hERG literature (/blog/knuijver-2021-ibogaine-qtc-safety, /blog/alper-herg-ibogaine-cardiac-mechanism)

Route honesty: oral noribogaine ≠ psychoactive IV ibogaine

| Entity | Relation to this paper | |--------|------------------------| | Oral noribogaine 3–60 mg | What was studied | | Oral ibogaine flood | Different molecule/dose tradition—not this trial | | IV magnesium / support IV | Not relevant here | | Psychoactive IV ibogaine infusion | Not studied; brand claims cannot borrow this DOI |

Entity hub: /what-is-ibogaine-infusion. Oral≠IV: /blog/ibogaine-oral-vs-iv.

Limits and confounders

| Limit | Why it matters | |-------|----------------| | Healthy males only | Sex, age, comorbidity, and drug-use physiology absent | | Max 60 mg single dose | Does not characterize higher exposures | | Single dose | Not steady-state multi-day metabolite loading | | Metabolite focus | Does not measure parent ibogaine cardiac risk directly | | 2015 snapshot | Later patient QTc data must be co-cited | | Not efficacy for SUD | PD was mu-opioid assay, not craving/withdrawal RCT endpoint |

What this does NOT prove for IV ibogaine infusion brand

| Claim | Status | |-------|--------| | “Phase 1 safe = ibogaine cures addiction” | False | | “Healthy volunteer noribogaine = IV ibogaine proof” | False | | “No issues at ≤60 mg = no QTc at any dose” | Dangerously false (see Glue 2016) | | Cite as foundational oral noribogaine PK/tolerability in healthy men? | Yes |

No cure claims. Schedule I / not FDA-approved.

Soft CTA

If metabolite Phase 1 language made development sound finished, pause. Learn how screening treats QTc and drug interactions at /safety-and-screening, then /apply only if exploring physician-supervised IV ibogaine infusion questions with molecule/route honesty. Entity: /what-is-ibogaine-infusion.

FAQ

What is Glue 2015? A *J Clin Pharmacol* Phase 1 ascending-dose study of oral noribogaine 3–60 mg in 36 healthy men (doi **10.1002/jcph.404**).

Is noribogaine the same as ibogaine? No—noribogaine is the primary metabolite. Different dosing history and development path.

Did volunteers get IV ibogaine? No—**oral noribogaine** only.

Does “well tolerated” mean no cardiac risk ever? No. Later patient work showed dose-related QTc prolongation at higher exposures.

Does this prove addiction treatment works? No—this was healthy-volunteer PK/safety/PD, not an SUD efficacy RCT.

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

Should families still demand ECG/telemetry for ibogaine-related care? Yes (/blog/ibogaine-ecg-pre-infusion-checklist, /safety-and-screening).

Where should screening start? /safety-and-screening, then /apply if appropriate.

Medical disclaimer

Educational research synopsis only—not medical, psychiatric, or legal advice, and not a guarantee of outcomes. Ibogaine and related compounds can prolong the QTc interval and have 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.

Glue 2015 is oral noribogaine healthy-volunteer Phase 1 science—not personal access, not a cure claim, and not psychoactive IV ibogaine efficacy proof.

Sources (selected)

1. Glue P. et al. Ascending-dose study of noribogaine in healthy volunteers. *J Clin Pharmacol*. 2015;55(2):189–194. doi: 10.1002/jcph.404. PMID: 25279818.
2. Glue P. et al. Ascending single-dose DBPC safety study of noribogaine in opioid-dependent patients. *Clin Pharmacol Drug Dev*. 2016;5(6):460–468. doi: 10.1002/cpdd.254.
3. Litjens R.P.W., Brunt T.M. How toxic is ibogaine? *Clin Toxicol*. 2016;54(4):297–302. doi: 10.3109/15563650.2016.1138226.
4. Alper K. et al. hERG blockade by iboga alkaloids. *Cardiovasc Toxicol*. 2016;16(1):14–22. doi: 10.1007/s12012-015-9311-5.
5. 21 CFR 1308.11 — ibogaine Schedule I (United States).