IUPAC: 12-methoxyibogamine · C20H26N2O · MW 310.44 g/mol · CAS 83-74-9 · ChEMBL222287
Ibogaine. The principal psychoactive alkaloid of the West-Central African shrub Tabernanthe iboga, sacrament of the Bwiti tradition of Gabon. A dirty, promiscuous polypharmacological molecule with no single clean target — it is an allosteric serotonin-transporter (SERT) inhibitor, an NMDA open-channel blocker, a weak κ-opioid and sigma ligand, and an α3β4 nicotinic antagonist. Famous for a single property no clean drug has matched: interrupting opioid, cocaine and nicotine dependence — sometimes abolishing withdrawal after one dose. Also famous for killing people. Context names: iboga, Endabuse, "the anti-addiction molecule."
Ibogaine has no single mechanism — its clinical effects emerge from simultaneous low-micromolar engagement of a panel of unrelated targets. This is the opposite of a designed drug: nothing about ibogaine is selective. The anti-addiction effect is generally attributed to the combination — serotonergic, glutamatergic, opioid, sigma and cholinergic actions converging on the reward and habit circuitry — rather than to any one receptor. Its highest-affinity interactions in binding assays are actually at the sigma-2 receptor (Ki ≈ 201 nM) and sigma-1 (Ki ≈ 250 nM), but the transporter and channel actions below are where the pharmacology gets interesting.
Ibogaine inhibits the serotonin transporter (IC50 ≈ 0.6–6 μM) but not like an SSRI. It binds preferentially to the inward-open state from the cytoplasmic side, stabilizing an occluded conformation rather than competing at the outward orthosteric site — a genuinely allosteric mode of inhibition (Jacobs et al. 2007; Bulling et al. 2012). The 6DZV cryo-EM structure captures ibogaine wedged in the central S1 site holding SERT closed.
Ibogaine binds the MK-801/PCP site inside the open NMDA-receptor pore (IC50 ≈ 5.2 μM at [3H]MK-801 site). This use-dependent glutamatergic block is thought to disrupt the synaptic plasticity that maintains drug-conditioned associations — a shared logic with ketamine and memantine.
Direct affinity is modest: μ-opioid IC50 ≈ 3.8 μM, κ-opioid IC50 ≈ 25 μM. Ibogaine is a weak MOR modulator, but its metabolite noribogaine is a full κ-opioid agonist and a stronger μ ligand — the KOR agonism is a leading candidate mechanism for the anti-withdrawal effect (Maillet et al. 2015).
Ibogaine is a noncompetitive blocker of α3β4 neuronal nicotinic acetylcholine receptors (IC50 ≈ 1 μM; Fryer & Lukas 1999). The α3β4 subtype dominates the medial habenula–interpeduncular pathway that gates nicotine and opioid withdrawal — this is a favored explanation for the anti-addiction signal and is shared with the iboga congener 18-MC.
The tightest binding of all: sigma-2 Ki ≈ 201 nM and sigma-1 Ki ≈ 250 nM (Bowen; Mach et al.). Sigma-2 engagement has been linked to ibogaine's neurotoxic potential at high dose (Purkinje-cell degeneration in rats), while sigma-1 modulates ER-stress and calcium signaling.
Weak dopamine-transporter inhibition (IC50 ≈ 4.1 μM) plus SERT block raises synaptic monoamines. The oneirogenic "waking-dream" state — closed-eye panoramic autobiographical imagery — is distinct from classical 5-HT2A psychedelia; ibogaine has only weak, non-defining 5-HT2A activity.
Because affinities cluster in the low-micromolar range, ibogaine only "works" at the high plasma concentrations reached by the large oral doses used in addiction interruption (often 10–25 mg/kg). Those same concentrations are what put the heart in danger — the therapeutic window and the arrhythmogenic window overlap almost completely.
Ibogaine is rapidly and extensively O-demethylated by CYP2D6 to noribogaine (12-hydroxyibogamine), which is pharmacologically active and dramatically longer-lived. The parent alkaloid is highly lipophilic, sequesters into fat and brain, and clears over hours; noribogaine can persist for days. This split kinetics matters clinically: acute intensity and the peak arrhythmia risk track the parent, while the sustained anti-craving effect tracks the metabolite.
CYP2D6 is polymorphic. Poor metabolizers (~7–10% of Europeans) generate less noribogaine and accumulate parent ibogaine — potentially raising acute cardiac risk. Ultra-rapid metabolizers do the reverse. Any co-administered CYP2D6 inhibitor (many SSRIs, bupropion, quinidine) can convert a "standard" dose into an overdose. There is no such thing as a routinely safe fixed dose.
Metabolism cascade: a single dominant demethylation, then phase-II conjugation. The active metabolite is the story, not an inactivation product.
Noribogaine ★ (12-hydroxyibogamine, ChEMBL6068516) is a more potent SERT inhibitor than the parent and a full κ-opioid agonist with moderate μ-opioid affinity (Baumann et al. 2001; Maillet et al. 2015, Nat Chem Biol). Its long half-life is why a single ibogaine session can blunt opioid withdrawal for days. It also blocks hERG in its own right, so cardiac monitoring must continue well past the acute trip — the QT risk does not end when the visions do.
Ibogaine occupies a strange place: it is one of the only substances for which recreational users, underground clinics and controlled case series all report the same, near-unique effect — a marked, sometimes complete interruption of opioid, cocaine, alcohol and nicotine dependence, frequently suppressing physical withdrawal within hours of a single administration. Howard Lotsof's 1962 observation and decades of Bwiti practice seeded a real, ongoing clinical-research interest (now including MAPS/observational cohorts). The promise is not hype — the anti-craving signal is robust across sources.
Ibogaine is an "oneirogen": rather than kaleidoscopic psychedelia it produces a prolonged (up to 24–36 h with residual metabolite) waking-dream of vivid, panoramic, autobiographical imagery — often experienced as reviewing one's life and choices. Users lie still in a dark room; movement worsens ataxia and nausea. This is mechanistically distinct from 5-HT2A psychedelics and likely reflects the SERT/NMDA/sigma blend.
Across rodent models, ibogaine and 18-MC reduce self-administration of morphine, cocaine, nicotine and alcohol. Convergent candidate mechanisms: α3β4 nicotinic block in the habenulo-interpeduncular "anti-reward" pathway, NMDA-dependent disruption of drug-cue plasticity, κ-opioid agonism by noribogaine, and upregulation of GDNF in the VTA (He et al. 2005) producing lasting changes in dopaminergic tone.
Against that promise stands a real fatality record. Multiple case series (Alper et al. 2012; Koenig & Hilber 2015) document sudden cardiac deaths during and after ibogaine sessions — driven by hERG-channel blockade, QT-interval prolongation and torsades de pointes, compounded by bradycardia, electrolyte loss from vomiting, undiagnosed cardiac disease, and concurrent opioids. Deaths are not rare curiosities; ibogaine is genuinely dangerous, and most reported fatalities occurred in unmonitored, non-clinical settings.
Schedule I in the United States; unscheduled or unregulated in much of the world, which is why an underground clinic economy (Mexico, Costa Rica, the Caribbean, parts of Europe) exists. This means most real-world use happens without ECG screening, telemetry or resuscitation capability — precisely the conditions the pharmacology least forgives. Renewed formal research (e.g. Stanford/veteran cohorts) is attempting to separate the therapeutic signal from the cardiac liability, including via safer congeners.
The honest summary: ibogaine may do something no approved addiction medicine does, and it may stop your heart doing it. Those two facts are not in tension — they are the same molecule at the same dose. Everything in harm reduction below follows from that.
Non-moralizing and evidence-based. Ibogaine is not a party drug and not a solo drug. If you are going to do it anyway, the single thing that keeps people alive is continuous cardiac monitoring by someone who can respond to an arrhythmia — everything else is secondary.
| Target | Affinity | Rel. | Action |
|---|---|---|---|
|
σ2R
Sigma-2 (TMEM97)
|
Ki = 201 nM
|
Ligand | |
|
σ1R
Sigma-1 receptor
|
Ki = 250 nM
|
Ligand | |
|
SERT
Serotonin transporter (SLC6A4)
|
IC50 = 0.59 μM
uptake IC₅₀ 2.5–6.3 μM
|
Allosteric inhib. | |
|
α3β4 nAChR
Neuronal nicotinic AChR
|
IC50 ≈ 1 μM
|
Antagonist | |
|
MOR
μ-opioid receptor
|
IC50 = 3.76 μM
|
Weak mod. | |
|
DAT
Dopamine transporter
|
IC50 = 4.11 μM
|
Weak inhib. | |
|
NMDA
Glutamate NMDA (MK-801 site)
|
IC50 = 5.2 μM
|
Channel blocker | |
|
KOR
κ-opioid receptor
|
IC50 = 25 μM
noribogaine = full agonist
|
Weak (metab. ↑) | |
|
hERG
Kv11.1 · IKr (KCNH2)
|
IC50 ≈ 3–4 μM
|
Blocker · QT ↑ |
The 6DZV structure shows why ibogaine is an allosteric, not a competitive, SERT inhibitor — and it is a clean Shannon-entropy story. An empty transporter is a conformational ensemble: it samples outward-open, occluded and inward-open states, a high-entropy distribution across the transport cycle. Ibogaine wedges into the central S1 site and collapses that ensemble onto a single occluded microstate, driving the configurational Shannon entropy of the protein sharply downward. The transporter can no longer visit the states it needs to move serotonin — inhibition is the entropy collapse.
In FlexAID∆S terms this is a large negative conformational ΔS on binding — a genuine entropic penalty that must be paid out of the enthalpic contacts ibogaine makes deep in the pocket. This is the mechanistic difference from an SSRI, which competes at the outward orthosteric site and blocks a specific state; ibogaine instead pins the whole cycle, which is why its inhibition is noncompetitive and why the same rigid iboga cage that grips SERT also fits — loosely — into the unrelated pockets of NMDA channels, sigma receptors and nicotinic receptors. A conformationally locked polycyclic ligand pays a small entropy cost to bind (it is pre-organized) but extracts a large one from every flexible target it touches. That is the pharmacological signature of a promiscuous molecule: modest, similar affinities everywhere, driven by rigid-body complementarity rather than induced-fit selectivity — exactly the regime where a ∆S-aware docking model earns its keep, because the ranking is decided by entropy, not enthalpy alone.