Ibogaine

# Research Output: Ibogaine

## Chemical Identity

**PubChem CID:** 197060 (confirmed via `get_pubchem_compound` API) [Ref 1 — PubChem database lookup]

**Molecular formula:** C₂₀H₂₆N₂O (api_verified)

**Molecular weight:** 310.4 g/mol (api_verified)

**IUPAC name:** (1R,15R,17S,18S)-17-ethyl-7-methoxy-3,13-diazapentacyclo[13.3.1.02,10.04,9.013,18]nonadeca-2(10),4(9),5,7-tetraene (api_verified; matches brief seed data exactly)

**InChIKey:** HSIBGVUMFOSJPD-CFDPKNGZSA-N (api_verified)

**CAS number:** 83-74-9 (unverified — not returned by PubChem API; appears in secondary literature; ⚠️ FLAG for editorial verification)

**Stereochemistry:** Four stereocenters — (1R,15R,17S,18S) as encoded in the IUPAC name. Ibogaine is a naturally occurring single enantiomer. The (−)-ibogaine enantiomer is the biologically active form found in *Tabernanthe iboga*. No published human data on the (+)-enantiomer was found in searches.

**Chemical class:** Indole alkaloid of the ibogamine skeleton. Classified as a monoterpenoid indole alkaloid (MIA). Structurally related to voacangine, tabernanthine, ibogamine, and coronaridine.

**SMILES:** Not returned by PubChem API; absent from brief seed data. ⚠️ FLAG: SMILES field needs manual population from PubChem CID 197060 page.

**Physical properties:** PubChem web page failed to load (JavaScript error). The following data are from secondary literature (Maciulaitis et al. 2008 [Ref 20]) and are **web_retrieved / unverifiable** status:
- Melting point: approximately 152–153°C (hydrochloride salt form); free base ~73°C — ⚠️ FLAG: not API-verified
- Solubility: sparingly soluble in water; more soluble as HCl salt; lipophilic compound
- logP: approximately 3.3–3.5 (estimated from structure) — ⚠️ FLAG: not API-verified

**Discrepancies with brief seed data:**
- PubChem CID was listed as blank in brief — confirmed as CID 197060
- Molecular formula and weight were blank in brief — confirmed C₂₀H₂₆N₂O, 310.4 g/mol
- SMILES and InChIKey were blank in brief — InChIKey confirmed; SMILES not returned by API
- IUPAC name matches brief exactly ✓

---

## Pharmacology

### Receptor Binding Profile

Ibogaine is a multi-target compound with low micromolar affinities at several receptor systems. Binding affinity data from published radioligand competition assays:

**Kappa-opioid receptor (KOR):** Ki ~2.0–2.1 µM for ibogaine; Ki 0.15 µM for tabernanthine (Deecher et al. 1992 [Ref 2]). Confirmed as KOR agonist in behavioral studies — kappa agonist and NMDA antagonist actions together account for anti-addictive effects on opioid and stimulant self-administration (Glick & Maisonneuve 1997 [Ref 6]; Glick & Maisonneuve 1998 [Ref 4]).

**NMDA receptor (open-channel antagonist):** IC50 3.1 µM (whole-cell patch clamp, rat hippocampal neurons, −60 mV); [³H]dizocilpine binding IC50 3.2 µM in rat forebrain membranes. Block is use- and voltage-dependent, consistent with open-channel mechanism (Chen et al. 1996 [Ref 3]). In vivo: ED50 31 mg/kg (i.p.) for maximal electroshock protection in mice [Ref 3].

**Serotonin transporter (SERT):** Ibogaine inhibits serotonin reuptake at low micromolar concentrations. Ibogaine (but NOT noribogaine or 18-MC) acutely increases extracellular serotonin in the nucleus accumbens (Glick et al. 2000 [Ref 51]). Serotonergic action is specifically implicated in ibogaine-induced reduction of alcohol intake (Glick & Maisonneuve 1998 [Ref 4]). Noribogaine acts as an atypical SERT modulator with pharmacochaperone-like properties (Avanes et al. 2025 [Ref 40, context]).

**Sigma-2 receptor (σ₂):** Ibogaine binds sigma-2 receptors (Sweetnam et al. 1995 [Ref 1]; Glick & Maisonneuve 1998 [Ref 4]). Sigma-2 action appears to mediate ibogaine's neurotoxicity (Purkinje cell injury) (Glick & Maisonneuve 1998 [Ref 4]).

**Sigma-1 receptor (σ₁):** Not mentioned in receptor binding profile from primary sources. Do not conflate with sigma-2. ⚠️ Brief lists "sigma-2 receptor agonist" — confirmed; sigma-1 not supported.

**Nicotinic acetylcholine receptor (nAChR):** Ibogaine binds nicotinic receptors; antagonist action implicated in reduction of nicotine intake in rats (Glick & Maisonneuve 1998 [Ref 4]). 18-MC shares this property (Glick et al. 2000 [Ref 51]).

**hERG (cardiac IKr channel):** IC50: 3.53 µM (ibogaine from *T. iboga* extraction); 4.09 µM (ibogaine from semisynthesis); noribogaine IC50 2.86 µM; voacangine 2.25 µM. Voltage-dependent low-affinity blockade. Comparator 18-MC: IC50 >50 µM (Alper et al. 2016 [Ref 14]).

**Sodium channels (voltage-gated):** Ki values in low micromolar range for ibogaine and congeners (Deecher et al. 1992 [Ref 2]; Sweetnam et al. 1995 [Ref 1]). Brief lists "Sodium channel blocker" — confirmed.

**Mu-opioid receptor (MOR):** Ibogaine, noribogaine, and 18-MC are functional MOR **antagonists** (Ke values 3–13 µM in rat thalamic membranes). None stimulate [³⁵S]GTPγS binding — no agonist action. MOR agonism does NOT account for ibogaine's effects on opioid withdrawal (Antonio et al. 2013 [Ref 9]).

**5-HT₂, 5-HT₃ receptors:** Moderate affinity reported in broad binding panel (Sweetnam et al. 1995 [Ref 1]). 18-MC shares 5-HT₃ affinity with ibogaine but not sigma-2, NMDA, or SERT (Glick et al. 2001 [Ref 37]).

**Muscarinic receptors (M1, M2):** Moderate affinity at low micromolar concentrations (Sweetnam et al. 1995 [Ref 1]).

**Dopamine transporter (DAT):** Ibogaine acutely decreases extracellular dopamine in nucleus accumbens (Glick & Maisonneuve 1998 [Ref 4]; Glick et al. 2000 [Ref 51]). However, direct DAT binding affinity is lower than SERT binding. The dopamine-reducing effect may be indirect (via kappa agonism or NMDA antagonism).

### Mechanism of Action

Ibogaine does not have a single dominant mechanism. It acts simultaneously on multiple addiction-relevant systems:

1. **Kappa-opioid agonism + NMDA antagonism:** Together account for effects on morphine and cocaine self-administration. Partial reversal by norbinaltorphimine (kappa antagonist) + NMDA (agonist) confirms both mechanisms in vivo (Glick et al. 1997 [Ref 6]).

2. **GDNF upregulation in VTA:** Ibogaine increases expression of glial cell line-derived neurotrophic factor (GDNF) in the midbrain ventral tegmental area (VTA). Intra-VTA GDNF microinjection mimics ibogaine's anti-alcohol effect; anti-GDNF antibodies block it. GDNF receptor (Ret) and ERK1 phosphorylation are increased (He et al. 2005 [Ref 36]). Noribogaine, but not 18-MC, also induces GDNF in SH-SY5Y cells and reduces alcohol self-administration when infused into VTA (Carnicella et al. 2010 [Ref 35]). This is considered a key mechanism for anti-alcohol and potentially other anti-addictive effects.

3. **Dopamine modulation:** Acutely decreases nucleus accumbens dopamine (both ibogaine and noribogaine). Blocks morphine-induced and nicotine-induced dopamine release. Counterintuitively, ibogaine **enhances** cocaine-induced dopamine increases (Glick et al. 2000 [Ref 51]) — suggesting different mechanisms operate on different drug classes.

4. **Serotonergic action:** Ibogaine-specific SERT inhibition elevates serotonin in nucleus accumbens; implicated in anti-alcohol effects (Glick & Maisonneuve 1998 [Ref 4]; Sershen et al. 1997 [Ref 7]).

5. **Neuroplasticity "reset":** Emerging hypothesis: ibogaine reopens critical periods for reward learning (via GDNF and extracellular matrix reorganization) in a manner analogous to other psychedelics (Nicolas 2025 [Ref 28]; see also Nardou et al. 2023 on general psychedelic critical period reopening).

6. **Noribogaine's long duration:** Ibogaine is rapidly converted to noribogaine (t1/2 28–49h). The long duration of ibogaine's effects is likely attributable to noribogaine's prolonged plasma and tissue presence, combined with slow release from fat stores (Glick & Maisonneuve 2000 [Ref 38]).

### Metabolite: Noribogaine

Noribogaine (12-hydroxyibogamine) is ibogaine's primary active metabolite. Formed via O-demethylation by CYP2D6. Key properties:
- hERG IC50 2.86 µM — more potent hERG blocker than ibogaine itself
- t1/2: 28–49 hours (Glue et al. 2015 [Ref 12])
- Apparent Vd: 1,417–3,086 L (very high, consistent with extensive tissue distribution including fat)
- Tmax: 2–4 hours after oral ibogaine
- Dose-linear PK between 3–180 mg doses
- GDNF inducer in VTA
- Kappa-opioid activity
- No mu-opioid agonist activity
- QTcI prolongation: 0.17 ms/ng/mL (Glue et al. 2016 [Ref 13])

### Pharmacokinetics

**Administration:** Oral (primary), consistent with brief.

**Absorption:** Rapidly absorbed after oral administration. P-glycoprotein (ABCB1) and BCRP (ABCG2) limit oral bioavailability by mediating hepatobiliary/intestinal excretion. In mice, brain-to-plasma ratio 3.4 (good CNS penetration); ABCB1 knockout increases brain penetration 1.5-fold (Martins et al. 2022 [Ref 18]).

**Metabolism:**
- Primary: CYP2D6 converts ibogaine → noribogaine (O-demethylation)
- Secondary: noribogaine → noribogaine glucuronide (conjugation)
- CYP3A4: NOT significantly involved in ibogaine or noribogaine PK (Martins et al. 2022 [Ref 18])
- CYP2D6 genotype robustly correlates with ibogaine AUC (r=0.82) and Cmax (r=0.77) (Glue et al. 2015 [Ref 11])
- CYP2D6 poor metabolizers (e.g., after paroxetine pretreatment): active moiety exposure ~2-fold higher — dose reduction recommended; genotyping advised (Glue et al. 2015 [Ref 11])

**Distribution:** High tissue distribution; sequestered in adipose tissue; slow release provides extended pharmacological effects. Brain penetration is substantial.

**Elimination:** Ibogaine itself: short half-life (~1–10 hours depending on CYP2D6 status). Noribogaine: long half-life (28–49 hours) — accounts for delayed effects and delayed cardiac risk.

**Human PK/PD in OUD:** Relationships between PK of ibogaine and metabolites and clinical effects (side effects, withdrawal severity) characterized in Dutch OUD detoxification study (Knuijver et al. 2024 [Ref 19]).

---

## History

### Ethnobotanical Origins

*Tabernanthe iboga* Baill. (family Apocynaceae) is a perennial rainforest shrub native to West and Central Africa, primarily Gabon, Cameroon, and the Republic of Congo. The root bark has been used for centuries in Bwiti religious and ceremonial practices, particularly among the Fang people of Gabon. Traditional uses include initiation rites, spiritual ceremonies, and as a stimulant at sub-hallucinogenic doses (Knuijver et al. 2022 [Ref 33]; Forsyth et al. 2016 [Ref 44]). The psychoactive properties of *iboga* root bark were documented by European explorers during 19th-century colonization of West Africa.

### First Isolation

Ibogaine was first isolated from *T. iboga* root bark by the French chemists Dybowski and Landrin in 1901. The alkaloid was independently isolated and named by Haller and Heckel in the same year. (Note: This is reported in secondary literature; primary 1901 sources are pre-digital and not programmatically verifiable.) The total synthesis of (±)-ibogamine was achieved in 1966 by Büchi et al. No efficient enantioselective total synthesis of ibogaine itself is available; the compound is currently obtained by direct extraction from *T. iboga* (low yield) or semi-synthesis from voacangine, an iboga alkaloid found in higher concentration in *Voacanga africana* root bark (González et al. 2021 [Ref 39]).

### Howard Lotsof and Anti-Addictive Discovery

Howard Lotsof discovered ibogaine's anti-addictive properties in 1962 at age 19. He and five friends, all heroin-dependent, self-administered ibogaine and noted subjective reduction of heroin craving and absence of withdrawal symptoms after ~30 hours. Lotsof subsequently dedicated decades to promoting ibogaine research. He contracted with a Belgian company to produce ibogaine in tablet form for clinical trials in the Netherlands and was awarded US Patent No. 4,499,096 in 1985 for ibogaine's anti-addictive use (web-retrieved [Ref 47]).

### Regulatory and Research History

- **1960s:** Ibogaine classified as Schedule I controlled substance in the US (effective prohibition initiated ~1967; formally codified in the Controlled Substances Act 1970)
- **Late 1980s–1990s:** Howard Lotsof and colleagues organized informal treatment sessions in the Netherlands; published first case series (Alper et al. 1999 [Ref 10])
- **1991–1995:** NIDA (US National Institute on Drug Abuse) funded preclinical ibogaine research program; NDA Investigational New Drug (IND) studies initiated under Deborah Mash at University of Miami
- **1993:** NIDA IND program opened; FDA authorized IND for ibogaine research
- **1995:** NIDA ended preclinical ibogaine program due to neurotoxicity findings in rats at high doses
- **Late 1990s–2000s:** Mash conducted open-label clinical observations at Caribbean facilities (led to Mash et al. 2018 [Ref 17])
- **2009:** New Zealand becomes first country to make ibogaine legally available by physician prescription
- **2016:** UK bans ibogaine under the Psychoactive Substances Act
- **2021–2024:** Surge of clinical trials and high-profile publications (Nature Medicine MISTIC study, atai Phase 1)
- **2024–2026:** US Veterans access becomes politically prominent; 2026 US executive order accelerating ibogaine research and reviewing scheduling; Texas allocated $50M for FDA clinical research (web-retrieved [Ref 47, 48])

---

## Subjective Effects

Published descriptions of ibogaine's subjective experience come primarily from clinical case series, patient self-reports within observational studies, and qualitative research. No double-blind placebo-controlled study of subjective effects at full psychedelic doses has been published to date.

### Character of the Experience

Ibogaine is classified as an "oneirogen" — a compound that produces waking dream states — rather than a classic serotonergic psychedelic. The experience is qualitatively distinct from psilocybin, LSD, or DMT (Köck et al. 2022 [Ref 34]; Mosca et al. 2023 [Ref 42]).

Characteristics from clinical literature:

**Oneiric/waking-dream phase:** The dominant early phase (roughly first 4–8 hours post-dose) features visual imagery described as panoramic autobiographical "life review" — patients report vivid, often narrative scenes from their personal history arising spontaneously with closed or open eyes. This is distinct from the geometric or entity-contact hallucinations of serotonergic psychedelics (Cherian et al. 2024 [Ref 23]).

**Visionary/perceptual phase:** Visual phenomena including internal hallucinations, tracers, color enhancement, and object transformations consistent with effects taxonomy in the brief. Pattern recognition enhancement and conceptual thinking are reported.

**Introspective phase:** Characterized by personal insight, emotional catharsis, existential realization, and self-reflection. Participants frequently report encounters with autobiographical memories in a "third-person" observer perspective (Cherian et al. 2024 [Ref 23]).

**Mystical experience dimension:** Measured with MEQ30, greater mystical experience intensity during ibogaine predicts larger PTSD reductions immediately and 1 month post-treatment (Brown et al. 2026 [Ref 22]).

**Somatic effects during acute phase:** Severe ataxia (inability to walk), nausea, tremor, tinnitus, dizziness, bradycardia (Knuijver et al. 2022 [Ref 33]). Patients are typically supine during the experience due to ataxia.

**Stimulation:** At sub-hallucinogenic doses, ibogaine has stimulant properties (root bark historically used as stimulant). Low-dose (20 mg) study documented non-euphoric light perception changes, headache, nausea (Forsyth et al. 2016 [Ref 44]; Glue et al. 2016 [Ref 13]).

### Duration

Per brief seed data and consistent with clinical literature:
- **Onset:** 30–180 minutes (oral)
- **Peak (psychedelic phase):** 18–36 hours (oral) — this is unusually long relative to other psychedelics
- **Aftereffects:** 24–72 hours

The prolonged peak is consistent with noribogaine's pharmacokinetics (t1/2 28–49h), though direct PK-effect correlation data are limited. Clinical literature describes two distinct phases: an initial acute psychedelic/oneiric phase and a more resolving "integration" or "afterglow" phase over days.

---

## Safety & Toxicity

### Cardiac Risk (PRIMARY SAFETY CONCERN)

Ibogaine's most serious and best-documented risk is **cardiac arrhythmia leading to death**. This is mediated by hERG channel blockade → QT interval prolongation → torsades de pointes (TdP) → ventricular fibrillation → sudden cardiac death.

**Mechanism:**
- hERG (IKr) IC50: 3.53–4.09 µM for ibogaine; 2.86 µM for noribogaine (Alper et al. 2016 [Ref 14])
- Therapeutic concentrations of ibogaine and noribogaine retard action potential repolarization in human ventricular-like iPSC-derived cardiomyocytes — first experimental proof of cardiac risk in human cardiac cells (Rubi et al. 2017 [Ref 41])
- Noribogaine's longer half-life (28–49h) means cardiac risk persists **days after** ibogaine ingestion — explaining delayed fatalities (Rubi et al. 2017 [Ref 41]; Koenig & Hilber 2015 [Ref 31])

**Clinical observations:**
- Clinically relevant but reversible QTc prolongation and bradycardia documented in Dutch OUD detoxification study (Knuijver et al. 2022 [Ref 33])
- Noribogaine dose-dependent QTcI prolongation: 0.17 ms/ng/mL; mean increases 16–42 ms across 60–180 mg dose groups (Glue et al. 2016 [Ref 13])
- Case report of prolonged multiple cardiac arrhythmias following internet-purchased ibogaine (Henstra et al. 2017 [Ref 15])

**Fatalities:** Multiple case reports of death temporally associated with ibogaine ingestion have been published. Deaths are attributed to arrhythmia, particularly TdP. The exact number of ibogaine-related fatalities in the literature is not consolidated in a single database accessible via APIs — ⚠️ FLAG: Koenig & Hilber 2015 [Ref 31] and Litjens & Brunt 2016 [Ref 16] review available fatality cases; exact count requires primary access to those reviews.

**Magnesium coadministration:** Magnesium is a physiological QTc stabilizer. The Stanford MISTIC protocol coadministers magnesium with ibogaine in veterans, with no unexpected SAEs in 30 participants (Cherian et al. 2024 [Ref 21]). Magnesium's mechanism: reduces QT-prolonging risk by stabilizing cardiac repolarization.

### Cerebellar Neurotoxicity (Rat; Dose-Dependent)

Ibogaine causes Purkinje cell degeneration in rats via an indirect, trans-synaptic excitotoxic mechanism:
- Ibogaine activates inferior olivary neurons → excessive glutamate release at climbing fiber synapses → excitotoxic Purkinje cell death (O'Hearn & Molliver 1997 [Ref 24])
- Sigma-2 receptor action mediates the neurotoxicity (Glick & Maisonneuve 1998 [Ref 4])
- Dose-response in rats: NOAEL 25 mg/kg; degeneration appears at 75–100 mg/kg (Xu et al. 2000 [Ref 25])
- **Critically:** 40 mg/kg (the anti-addictive dose used in rat models) does NOT cause Purkinje cell degeneration above saline controls (Molinari et al. 1996 [Ref 26])
- **Clinical relevance:** Human therapeutic doses (~10–25 mg/kg oral) are substantially below rodent neurotoxic doses (75–100 mg/kg i.p.). Interspecies dose extrapolation is uncertain. No human neuroimaging studies have identified cerebellar damage following clinical ibogaine use (⚠️ FLAG: absence of positive evidence is not confirmation of safety; controlled neuroimaging studies lacking)

### Other Acute Toxic Effects

- **Ataxia and tremors:** Severe, consistent, present in all clinical reports during the acute phase. Patients should remain supine (Knuijver et al. 2022 [Ref 33])
- **Nausea and vomiting:** Common during onset and early phase
- **Bradycardia:** Dose-dependent; more pronounced at higher doses; 18-MC lacks this effect (Glick et al. 2000 [Ref 51])
- **Wakefulness / sleep prevention:** Ibogaine suppresses sleep for 24–36 hours

### LD50

⚠️ **FLAG:** No published LD50 data for ibogaine in humans were found in any database searched. Animal LD50 data were not returned by PubMed or OpenAlex literature searches. The Maciulaitis 2008 review [Ref 20] discusses ibogaine toxicology but specific LD50 values from that abstract are not extracted. The therapeutic index relative to neurotoxic and lethal doses has not been formally established in humans. This is a critical data gap.

### Acute Toxicity Rating (Seed Data)

Brief states: "Acute: low; Chronic: low — Inferred from pharmacological class — not sourced from literature." This is consistent with the evidence in that ibogaine is not acutely lethal at typical doses used clinically; however, "low" acute toxicity does not capture the life-threatening cardiac risk at therapeutic doses. ⚠️ FLAG: The toxicity characterization in the brief significantly understates the cardiac safety concern. The generation agent should revise this: ibogaine carries **substantial acute cardiac risk** that has resulted in documented fatalities, even though the compound does not cause immediate systemic organ failure in the way classical toxic substances do.

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## Harm Reduction

### Pre-Treatment Screening (Critical)

Based on the literature:
- **12-lead ECG required:** Baseline QTc >450 ms (men) or >470 ms (women) is a contraindication
- **Cardiac history:** Structural heart disease, arrhythmia, and pre-existing conduction abnormalities are contraindications (Koenig & Hilber 2015 [Ref 31]; Litjens & Brunt 2016 [Ref 16])
- **Electrolyte panel:** Hypokalemia and hypomagnesemia increase TdP risk synergistically; correct before treatment
- **CYP2D6 genotyping:** Recommended before dosing; reduce dose in poor metabolizers (Glue et al. 2015 [Ref 11])
- **Drug washout:** All QT-prolonging medications, opioids, and CYP2D6 inhibitors (e.g., paroxetine, fluoxetine, bupropion) must be cleared

### Monitoring During Treatment

- Continuous cardiac monitoring (telemetry or ECG) required throughout the 24–36-hour acute phase and for 24–72 hours after (due to noribogaine's long half-life)
- Physical support: patient must be supine due to severe ataxia; fall risk

### Magnesium Protocol

The Stanford MISTIC protocol (Cherian et al. 2024 [Ref 21]) coadministers magnesium to reduce QTc risk. This has become a reference protocol for medically supervised ibogaine administration.

### Contraindications

Based on published literature (Koenig & Hilber 2015 [Ref 31]; Litjens & Brunt 2016 [Ref 16]; Knuijver et al. 2022 [Ref 33]; Cherian et al. 2024 [Ref 23]):
- Pre-existing QT prolongation
- Cardiac arrhythmia or structural heart disease
- Concurrent QT-prolonging medication
- Concurrent opioid use (interaction risk, including increased aspiration/respiratory risk during ataxic phase)
- Severe hepatic impairment (ibogaine hepatically metabolized)
- Electrolyte imbalances (hypokalemia, hypomagnesemia)
- Pregnancy (no human safety data)
- CYP2D6 inhibitor use without dose adjustment

### Emergency Guidance

Management of ibogaine-induced TdP: standard ACLS protocols; magnesium sulfate IV; cardioversion if needed. Clinicians should be aware that arrhythmia risk may persist for 48–72 hours due to noribogaine's long half-life. Do NOT administer opioids to reverse ibogaine effects (complex interaction; fatality risk).

---

## Tolerance & Dependence

### Tolerance

No published studies specifically characterizing ibogaine tolerance development were found in literature searches. The compound is not used repeatedly in clinical contexts — the treatment paradigm is typically a single dose or a small number of widely-spaced doses. The absence of tolerance literature is consistent with the single-dose treatment model.

**Cross-tolerance:** No data found on cross-tolerance with other psychedelics or kappa agonists specifically for ibogaine.

### Dependence Liability

- Ibogaine shows no evidence of positive reinforcement in animal models — it does NOT support self-administration in rats (Belgers et al. 2016 [Ref 32])
- The compound suppresses drug self-administration for multiple substances across diverse drug classes
- No human case reports of ibogaine dependence or addiction were found in literature searches
- Brief seed data ("Formation: not habit-forming") is consistent with the published evidence
- 18-MC, noribogaine, and ibogaine all lack self-administration in animal models

### Withdrawal

No withdrawal syndrome from ibogaine has been characterized in the literature. The prolonged half-life of noribogaine (28–49h) means the transition off ibogaine is gradual rather than abrupt.

---

## Interactions

### CYP2D6 Inhibitors (HIGH RISK)

CYP2D6 converts ibogaine to noribogaine. Inhibition of CYP2D6 significantly elevates ibogaine exposure:
- Paroxetine pretreatment: ~2-fold increase in active moiety AUC (Glue et al. 2015 [Ref 11])
- Other CYP2D6 inhibitors: fluoxetine, bupropion, quinidine, duloxetine — similar expected interaction
- Clinical implication: CYP2D6 poor metabolizers (genetic or drug-induced) at substantially increased cardiac risk unless dose is reduced

### QT-Prolonging Medications (HIGH RISK)

Additive QTc prolongation risk with antipsychotics (especially haloperidol, ziprasidone), antiarrhythmics (quinidine, sotalol, amiodarone), antibiotics (azithromycin, fluoroquinolones), antihistamines (terfenadine), methadone, and TCAs.

### Opioids (HIGH RISK)

Complex and potentially lethal interaction. Ibogaine blocks opioid-induced dopamine release. If opioids are used concurrent with or shortly after ibogaine:
- Risk of respiratory depression during ataxic phase (patient unable to protect airway)
- One fatality in Alper et al. 1999 [Ref 10] was attributed to possible surreptitious heroin use during ibogaine treatment
- Opioid washout period required before ibogaine administration

### Serotonergic Drugs

Theoretical serotonin syndrome risk given ibogaine's SERT inhibition. No published case reports of serotonin syndrome specifically from ibogaine found in searches. Concurrent SSRIs, MAOIs, or serotonin-releasing agents should be discontinued before treatment.

### CYP3A4

Not a significant interaction pathway — CYP3A4 does NOT substantially affect ibogaine or noribogaine PK (Martins et al. 2022 [Ref 18]).

### P-glycoprotein (ABCB1)

ABCB1 inhibitors (e.g., verapamil, cyclosporine) may increase ibogaine oral bioavailability and brain penetration (Martins et al. 2022 [Ref 18]). Clinical significance not characterized.

---

## Legal Status

### United States

Schedule I controlled substance under the Controlled Substances Act (effective ~1967; formalized 1970). Classification: "no accepted medical use" and "high potential for abuse." Possession, distribution, and manufacture are federal crimes.

**Recent developments (2025–2026):**
- Texas allocated $50 million for FDA-regulated ibogaine clinical research (2025)
- Some cities have non-binding decriminalization resolutions
- A 2026 executive order (Trump administration) instructed acceleration of ibogaine research, regulatory review, and patient access through Right to Try pathways (web-retrieved [Ref 47, 48])
- Scheduling review contingent on successful Phase 2/3 trial completion and FDA approval

### New Zealand

Available by physician prescription since 2009 as a "non-approved medicine." Requires case-by-case justification and licensed clinical supervision. De facto legal with regulatory oversight.

### Canada

Listed as a Prescription Drug under the Food and Drug Regulations. Access available theoretically through the Special Access Program, but approvals are rare in practice.

### United Kingdom

Prohibited since 2016 under the Psychoactive Substances Act (blanket prohibition on psychoactive substances not otherwise regulated). No medical exemptions.

### European Union

No EU-wide scheduling. Individual countries:
- **France, Belgium, Sweden, Switzerland, Norway, Ireland:** Prohibited; no medical exemptions
- **Portugal:** Decriminalized for personal possession since 2001; commercial treatment operations remain illegal

### Australia

Not listed on the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP) as a scheduled substance explicitly. However, regulated as a prescription-only substance via TGA oversight. Effectively not clinically available.

### Mexico, Costa Rica, The Bahamas

Unregulated or legal for clinical treatment. Mexico: treatment centers operate in a legal gray area (not explicitly prohibited, not formally approved). The Bahamas: permits clinical use; established treatment centers with US-standard protocols. Costa Rica: no legal restrictions (web-retrieved [Ref 40]).

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## Clinical Trials

Active and completed ibogaine clinical trials identified on ClinicalTrials.gov:

| NCT ID | Title | Status | Phase | Sponsor |
|--------|-------|--------|-------|---------|
| NCT05029401 | Study of Oral Ibogaine in Opioid Withdrawal | COMPLETED | Phase 1 | atai Therapeutics, Inc. |
| NCT04313712 | Pre-Post Evaluation of Ibogaine-Magnesium in Veterans (MISTIC) | ACTIVE_NOT_RECRUITING | — (observational) | Stanford University |
| NCT04003948 | Safety and Efficacy of Ibogaine-Magnesium in Methadone Detoxification | COMPLETED | Phase 2 | ICEERS |
| NCT03380728 | Ibogaine in the Treatment of Alcoholism: Open-Label Escalating-Dose | COMPLETED | Phase 2 | University of São Paulo |
| NCT07226570 | Mapping Ibogaine Neural Dynamics in Opioid Use Disorder | RECRUITING | — | University of California, Irvine |
| NCT06810765 | Trifecta Research Study (TBI/PTSD/Cognitive) | WITHDRAWN | Phase 2 | Johns Hopkins University |

### Key Published Results

**MISTIC (NCT04313712) — Nature Medicine 2024:** Prospective observational study of 30 male Special Operations Forces veterans with predominantly mild TBI receiving magnesium-ibogaine under Stanford MISTIC protocol. Significant improvements in WHO Disability Assessment at 1 month (Cohen's d = 2.20); PTSD severity (d = 2.54); depression (d = 2.80); anxiety (d = 2.13). No unexpected serious adverse events. (Cherian et al. 2024 [Ref 21])

**Mystical Experience follow-up (Brown et al. 2026 [Ref 22]):** In same cohort, higher MEQ30 scores predicted larger PTSD reductions immediately and at 1 month. Greater mystical experience also associated with decreased peak alpha frequency in EEG at 1 month.

**atai Phase 1 (NCT05029401 — COMPLETED):** Phase 1 safety study of oral ibogaine in opioid withdrawal; data not yet published in peer-reviewed literature at time of search.

**Köck et al. 2022 systematic review [Ref 34]:** Synthesizes available clinical trial literature; notes paucity of controlled trials; most data from open-label case series and observational studies.

**Weleff et al. 2025 systematic review [Ref 50]:** Most ibogaine clinical studies have high risk of bias due to lack of randomization and blinding. Ibogaine and ketamine are the most studied psychedelics for OUD, but evidence quality remains weak.

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## Community Feedback Analysis

No community feedback was submitted in Part A2 of the brief.

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## Gaps & Flags

### Safety-Critical Gaps

1. **⚠️ LD50 data not found:** No published LD50 values for ibogaine in humans or animals were retrieved by any API search. The therapeutic index relative to fatal doses has not been formally established in humans. This must be flagged for editorial review and sourced from toxicology reviews (Koenig & Hilber 2015 [Ref 31]; Litjens & Brunt 2016 [Ref 16] may contain this data — abstract-only access did not reveal specific values).

2. **⚠️ Acute toxicity rating in brief understates cardiac risk:** Brief states "Acute toxicity: low" with caveat "inferred from pharmacological class." This is misleading — ibogaine causes documented fatalities via cardiac arrhythmia at therapeutic doses. The generation agent should revise toxicity characterization to reflect documented fatalities and serious adverse events.

3. **⚠️ Cardiac contraindications not listed in brief:** The "Contraindications" field is empty in the brief. Ibogaine has clinically critical contraindications (pre-existing QT prolongation, structural heart disease, QT-prolonging medications, electrolyte imbalances) that must be populated.

4. **⚠️ Ibogaine-related fatality count not confirmed:** Multiple reviews reference ibogaine-related deaths but a consolidated, verified count was not extractable from API searches of available abstracts. The full text of Koenig & Hilber 2015 and Litjens & Brunt 2016 reviews would provide this.

### Chemical Identity Gaps

5. **CAS number (83-74-9):** Not returned by PubChem API; appears in secondary literature. Requires manual verification from PubChem CID 197060 full page.

6. **SMILES string:** Not returned by PubChem API. Must be populated from PubChem CID 197060 full page.

7. **Physical properties (melting point, logP, solubility):** Not API-verified. PubChem page failed to load.

### Pharmacology Gaps

8. **Ki values for SERT (ibogaine):** Specific Ki value for ibogaine at SERT not found in available abstracts. Qualitatively confirmed as a SERT inhibitor; quantitative Ki needed for precision.

9. **Ki values for sigma-2 receptor:** Not extracted from available abstracts. Sweetnam 1995 [Ref 1] and Glick 1998 [Ref 4] confirm the interaction but Ki not abstracted.

10. **Stereochemistry / enantiomer pharmacology:** Only the naturally-occurring (−) enantiomer has human data. Published data on the (+) enantiomer are limited to preclinical binding assays (18-MC enantiomer data referenced in Glick et al. 2001 [Ref 37]).

### Clinical Gaps

11. **atai Phase 1 (NCT05029401) results:** Trial completed but no peer-reviewed publication found. Data pending.

12. **Long-term abstinence outcomes:** No long-term (>1 year) controlled follow-up data identified in API searches. Most clinical evidence is acute (24–72 hours) or short-term (1 month).

13. **Noribogaine as standalone therapeutic:** Glue et al. clinical studies (Ref 12, 13) evaluated noribogaine directly. Development status as a drug candidate not confirmed from searches.

### Historical Gaps

14. **First isolation (1901):** Dybowski & Landrin citation is from pre-digital era; not programmatically verifiable. Reported in secondary sources.

15. **Lotsof 1985 patent:** Referenced in web sources; patent number US 4,499,096 noted but not verified via patent database API.

### Dose Notes

16. **Common dose in brief (15–22 mg/kg oral):** Consistent with published clinical literature. Mash et al. 2018 [Ref 17] reports effective dose range for opioid withdrawal; Knuijver et al. 2024 [Ref 19] provides PK/PD data in OUD patients. The dose range should be contextualized as "for addiction treatment" — not for general psychedelic use.

17. **Duration data:** Onset 30–180 min, peak 18–36h, aftereffects 24–72h from brief are consistent with published clinical descriptions. Noribogaine's t1/2 (28–49h) supports the prolonged peak duration pharmacokinetically.