This review (2023) gives an overview of research into ibogaine. It details animal studies and the human use of ibogaine in stopping addiction. Studies are few and far between, and clinical trials are only now being started.
Ibogaine is a powerful psychoactive substance that not only alters perception, mood and affect, but also stops addictive behaviors. Ibogaine has a very long history of ethnobotanical use in low doses to combat fatigue, hunger and thirst and in high doses as a sacrament in African ritual contexts. In the 1960s, American and European self-help groups provided public testimonials that a single dose of ibogaine alleviated drug craving, opioid withdrawal symptoms and prevented relapse for weeks, months and sometimes years. Ibogaine is rapidly demethylated by first-pass metabolism to a long-acting metabolite noribogaine. Ibogaine and its metabolite interact with two or more CNS targets simultaneously and both drugs have demonstrated predictive validity in animal models of addiction. Online forums endorse the benefits of ibogaine as an “addiction interrupter” and present-day estimates suggest that more than ten thousand people have sought treatment in countries where the drug is unregulated. Open label pilot studies of ibogaine-assisted drug detoxification have shown positive benefit in treating addiction. Ibogaine, granted regulatory approval for human testing in a Phase 1/2a clinical trial, joins the current landscape of psychedelic medicines in clinical development.
The paper reviews the history, pharmacology, preclinical evidence and human clinical experience of ibogaine, an indole alkaloid with longstanding ethnobotanical and medicinal uses. Earlier observational reports from the 1960s onward suggested that single large oral doses could rapidly alleviate opioid withdrawal, reduce craving and in some cases prevent relapse for extended periods. Despite these anecdotal and case-series reports, ibogaine's clinical development has been constrained by regulatory scheduling and limited controlled human data. C. and colleagues set out to synthesise available evidence relevant to the therapeutic potential and risks of ibogaine and its primary metabolite, noribogaine. The review covers chemical and receptor pharmacology, in vitro and in vivo animal studies, pharmacokinetics including the role of CYP2D6, reports of human clinical experience (largely open-label and observational), and safety concerns—particularly cardiac risk. The article also notes ongoing clinical development (a Phase I/IIa trial authorised by the UK regulator) and describes gaps that impede definitive assessment of efficacy and safety.
Papers cited by this study that are also in Blossom
Alper, K. R., Lotsof, H. S., Kaplan, C. D. · Journal of Ethnopharmacology (2007)
Sweetnam, P. M., Lancaster, J., Snowman, A. et al. · Psychopharmacology (1995)
Coleman, J. A., Yang, D., Zhao, Z. et al. · Nature (2019)
Mash, D. C., Ameer, B., Prou, D. et al. · Journal of Psychopharmacology (2016)
The extracted text does not present a dedicated Methods section or describe a systematic search strategy, inclusion criteria, or formal review methodology. The paper is therefore best characterised as a narrative, expert review that integrates historical reports, in vitro and in vivo experimental studies, case series and observational clinical cohorts, and selected meta-analytic findings from the animal literature. The authors draw on radioligand binding data, animal pharmacology experiments, pharmacokinetic studies in multiple species, and published human case series (including a large inpatient cohort from St. Kitts). Where available, specific experimental parameters (doses, routes, timing) and selected quantitative results are reported, but the paper does not report an explicit, reproducible literature search, study selection process, or risk-of-bias assessment typical of a systematic review or meta-analysis.
Chemistry and basic properties: Ibogaine HCl (12-methoxyibogamine) and its primary metabolite noribogaine are described molecularly and noted to be obtainable by plant extraction or semi-synthesis. Physical and molecular weights for parent and salt forms are provided. In vitro pharmacology: Radioligand binding screens show that ibogaine and noribogaine interact with multiple central nervous system targets. Ibogaine displaces binding at dopamine and serotonin transporters and vesicular monoamine transporter at micromolar concentrations and inhibits SERT and DAT transport with low micromolar IC50s. Mechanistic studies indicate non-competitive inhibition of SERT by ibogaine, possibly via binding to an inward transporter conformation. Ibogaine also shows activity at NMDA receptor MK-801 sites, kappa opioid receptors, nicotinic receptor subtypes (including α3β4), and sigma-2 receptors. Noribogaine has higher affinity at serotonin reuptake sites than ibogaine, negligible NMDA binding, and relevant interactions at mu and kappa opioid receptors, ionotropic nicotinic receptors and SERT in the 0.05–5 μM range. Noribogaine is described as a dual ligand at mu (weak agonist/antagonist) and kappa (G-protein biased agonist) receptors, with an EC50 ≈ 9 μM for GDP-GTP exchange and low β-arrestin recruitment. In vivo pharmacology (animal studies): Preclinical work shows that single doses of ibogaine decrease reward-related behaviours for opioids, stimulants and ethanol, and can reduce naloxone-precipitated opioid withdrawal in some models. However, results vary by species, dose and route: subcutaneous administration often yielded weaker effects than oral dosing, consistent with the importance of first-pass metabolism to noribogaine. Noribogaine dose-dependently blocked naloxone-precipitated withdrawal in mice with an approximate ED50 of 13 mg/kg orally; corresponding blood and brain concentrations were reported (≈26 ng/mL blood; 533 ng/g brain). A referenced meta-analysis of animal studies (Belgers et al.) concluded that the most significant reductions in drug self-administration occurred in the first 24 h after intraperitoneal ibogaine and persisted beyond 72 h. Conditioning and discrimination studies indicate that ibogaine does not produce classic conditioned place preference or substitute for mu agonists or PCP, and that noribogaine generalises to ibogaine in rodent discrimination assays. Pharmacokinetics: Oral bioavailability and PK parameters vary markedly by species, dose and sex. In rats, oral bioavailability increased disproportionately with dose (e.g. 7%–16% at 5 mg/kg versus 43%–71% at 50 mg/kg) and showed sex differences. Ibogaine displays rapid absorption (median tmax ≈1.75–4 h in a human case series) and extensive first-pass O-demethylation to noribogaine via CYP2D6 (and to lesser extent CYP3A4). Noribogaine has a larger volume of distribution and longer half-life than ibogaine; AUC values for noribogaine were 1.5–9-fold higher than for parent drug in the reported human subset, consistent with extensive first-pass metabolism. CYP2D6 genotype and pharmacological inhibition modify exposures: in healthy volunteers pretreated with the CYP2D6 inhibitor paroxetine, mean ibogaine Cmax increased ≈26-fold and AUC0–t ≈66-fold versus placebo, with mean ibogaine t1/2 rising from ≈2.5 to 10.2 h (p < 0.05). Noribogaine Cmax and half-life were also affected numerically. The authors note intersubject variability and that some PK parameters (e.g. noribogaine terminal half-life) were not quantifiable in the observational human dataset due to limited sampling. Drug interactions: The paper states that no formal drug interaction studies have been published. Given ibogaine’s CYP2D6-mediated metabolism, concomitant use of CYP2D6 substrates or inhibitors is a plausible safety concern. Human clinical experience (observational): Historical and contemporary case series and open-label reports suggest that single large oral doses (typically 8–25 mg/kg, though reported ranges extend much wider) can rapidly alleviate opioid withdrawal within 12–18 h and reduce craving and depressed mood for weeks to months in some patients. The largest reported observational cohort (St. Kitts, N = 191; 24.6% female) administered oral ibogaine HCl (8–12 mg/kg). In that study opioid-dependent patients (N = 102) were stabilised on oral morphine prior to ibogaine; physician-rated opioid withdrawal scores at 24 h were mild (0–2 on a 0–13 scale) and subjective measures showed significant reductions in craving and depressive symptoms up to 1 month (p ≤ 0.01). The authors note the absence of randomised, placebo-controlled efficacy trials. Safety and adverse events: Common transient adverse events included visual hallucinations, ataxia, nausea, feeling hot and headache, with frequencies reported between 18% and 48% in the St. Kitts cohort. Cardiac ion channel blockade is documented in vitro (hERG, Nav1.5, Cav1.2), and ibogaine has been associated with QT interval prolongation in case reports. The hERG IC50 is reported between 1 and 4 μM under varying assay conditions. Thirty-three deaths associated with ibogaine treatment are cited in the literature; reported cases often involved additional risk factors such as supra-therapeutic dosing, concomitant CYP2D6 inhibitors or QT-prolonging drugs, polydrug use, comorbid cardiovascular disease, electrolyte disturbances, or impure/adulterated preparations. The authors emphasise that systematic, intensified cardiac monitoring studies are ongoing (a concentration-QTc study in healthy volunteers) to better characterise these risks.
The authors interpret the assembled evidence as supportive of ibogaine’s multimodal pharmacology and its potential as an "addiction interrupter" and psychoplastogen that may act on withdrawal, negative affect and preoccupation/anticipation stages of the addiction cycle. They highlight that ibogaine’s therapeutic profile likely reflects a combination of parent drug and active metabolite (noribogaine) actions across NMDA, monoaminergic, opioid and nicotinic systems, and that noribogaine’s serotonergic and biased kappa properties could contribute to prolonged benefits without ketamine-like psychotomimetic effects. C. and colleagues place ibogaine within the broader renaissance of psychedelic and rapid-acting treatments (e.g. psilocybin, ketamine), and suggest parallels in proposed mechanisms such as promotion of neuroplasticity and modulation of prefrontal glutamate signalling. At the same time they stress major uncertainties: there are no published randomised controlled trials demonstrating efficacy for relapse prevention; human data are dominated by uncontrolled case series with heterogeneous methodologies; PK sampling in observational studies was limited; and no formal drug–drug interaction trials have been reported. Key safety concerns emphasised by the authors include cardiac electrophysiology (QT prolongation and potential proarrhythmia), the impact of CYP2D6 variability and concomitant CYP2D6 inhibitors on exposure, and the risk introduced by impure or adulterated products used in non-regulated settings. The authors note 33 reported deaths in the literature and describe multiple contributing factors in many cases. They advocate that ibogaine administration should occur under physician oversight with attention to PK, drug interactions and cardiac monitoring. Implications and next steps discussed by the authors include the need for randomised, controlled clinical trials (the gold standard for causality) to demonstrate that benefits outweigh risks; ongoing Phase I/IIa clinical development authorised by the UK regulator (with a Phase 2 randomised, placebo-controlled proof-of-concept design planned to test relapse prevention in detoxified opioid users); and parallel development of ibogaine analogues designed to retain therapeutic effects with improved cardiac safety. The authors call for expanded, rigorous clinical research to validate observational signals and to characterise safety, pharmacokinetics and drug interaction profiles more fully.
The authors conclude that ibogaine is a dissociative, oneiric psychedelic with multiple mechanisms that plausibly target stages of the addiction cycle and may produce protracted therapeutic effects through neuroplasticity-related pathways. Experimental and preclinical data support a role for noribogaine as an active metabolite contributing to therapeutic and off-target effects. Clinical development is advancing (including a UK-authorised Phase I/IIa trial and a Phase 2 proof-of-concept design), and an ibogaine analogue is being pursued to improve cardiac safety. Nonetheless, randomised clinical trials and further safety and pharmacokinetic studies are required to determine whether the benefits of ibogaine outweigh its risks.
The chemical name for the compound is ibogaine HCl. Ibogaine is also known as 12-methoxyibogamine (Fig.). The hydrochloride salt has a protonated tertiary amine in the aliphatic fused ring (e.g., nonindolic nitrogen atom). The indole nitrogen of ibogaine is a tertiary amine. Ibogaine free base has a chemical formula of C 20 H 26 N 2 O. The molecular weight of the free base is 310.4 g/mole and 346.9 for the hydrochloride salt. The molecular formula of noribogaine is C 19 H 25 N 2 OCl for the hydrochloride salt. The molecular weight is 296.4 for the free base and 332.9 for the hydrochloride salt. Ibogaine in the form of white to off-white powder has the IUPAC name (1 R,15 R,17 S,18 S)-17-ethyl-7-methoxy-3,13-diazapentacyclo[13.3.1.0 2,10 .0 4,9 .0 13,18 ]nonadeca-2(10),4(9),5,7-tetraene. Ibogaine is obtained either by extraction from the roots of the iboga plant or by semi-synthesis from the precursor compound voacangine.
The in vitro activity and in vivo pharmacology of ibogaine have been characterized at neurotransmitter receptors and monoamine transporters to evaluate selectivity and potency of ibogaine and related compounds in specific assays to predict their potential for adverse events or to provide data suggestive of therapeutic applications for psychiatric disorders. Radioligand binding screens of the potencies of ibogaine and its primary metabolite noribogaine are summarized in Table. In radioligand binding assays, 10 µM ibogaine displaced ≥ 50% of the total binding to the dopamine transporter (DAT), 5-HT transporter (SERT) and vesicular monoamine transporter. Ibogaine was shown to inhibit transport by SERT and DAT with IC 50 values in the low micromolar range. The significance of micromolar interactions of ibogaine in radioligand binding assays has been correlated with the concentrations of parent drug and metabolite in brain. Ibogaine demonstrated high micromolar binding (e.g., low affinity) or was reported inactive at 5-HT 2 receptors. More recent mechanistic studies have demonstrated that ibogaine inhibits SERT noncompetitively, in contrast to all other known inhibitors, which are competitive with substrate. Notably, ibogaine is a non-competitive inhibitor of transport but displays competitive binding towards selective serotonin reuptake inhibitors. The authors suggest that the binding of ibogaine to the inward conformation likely forms the basis for the non-competitive inhibition because serotonin does not compete for binding to this conformation (e.g., ibogaine is not a substrate) and the SERT-ibogaine complex may exist in dynamic Ibogaine is active in displacement assays at MK-801 binding sites on the NMDA receptorand at kappa opioid receptors. The rapid antidepressant efficacy of ibogaine is likely mediated in part through its ketamine-like antagonism of NMDA receptors. Beyond its blockade of NMDA channels, ibogaine also has effects on aminergic, opioid, and cholinergic systems that could contribute to the rapid behavioral changes which are observed following single dose ibogaine administrations. Ibogaine demonstrates pharmacological activity mediated by a noncompetitive inhibitory action on several nicotinic receptors, including the α3β4 subtype. Ibogaine binds with high affinity to sigma-2 receptors. The physiological relevance of sigma-2 binding site activity is unknown. In animal models of addiction, some of the behavioral effects of ibogaine may, at least in part, be attributed to noribogaine. These studies demonstrate that the response varies between parent drug and metabolite. Thus, ibogaine and noribogaine are not recognized as equivalent drugs although in vitro binding to monoamine transport and other neuronal receptor sites may partially overlap. Noribogaine binds to DAT, SERT and kappa opioid receptors. However, unlike ibogaine, noribogaine has negligible binding to the NMDA receptor channel and sigma-2 receptor, and shows 10-fold higher affinity at serotonin reuptake sites. Radioligand screens for binding site activity demonstrate that noribogaine has relevant interactions at kappa and mu opioid receptors, ionotropic nicotinic receptors, and the serotonin transporter in the range 0.05-5 μM (Table). In contrast to ibogaine, noribogaine does not have significant dwell time in the NMDA channeland, in keeping with this observation, the drug lacks ketamine-like psychotomimetic effects when administered to humans. Noribogaine is a dual ligand at both mu (weak agonist/antagonist) and kappa (biased agonist). Noribogaine as a G-protein biased kappa agonist was 75% as efficacious as dynorphin A at stimulating GDP-GTP exchange (EC50 = 9 μM) but only 12% at recruiting β-arrestin, which could explain in part, the lack of dysphoric effects when administered in humans. The identified molecular targets coupled with various drug design techniques suggested early promiscuity of ibogaine and noribogaine which led us to develop analogs with a mix of multiple targets for the treatment of drug addiction. The goal of this research program was to develop synthetic ibogaine-like compounds that might be more effective than the parent molecule. Due to the fact that ibogaine has a relatively complex structure, our immediate objective was to identify the simplest ibogaine fragment that retains antiaddictive activity. This composition of matter series derived from close inspection of the 5-methoxytryptamine and isoquinuclidine fragments led us to the discovery of novel phenyl-substitutedhexahydroazepinoindole analogs of ibogaine. Unfortunately, this research was done in an era of pharmacologic research which focused only on highly specific single target drugs. As a result, our medicinal chemistry program was not viewed to be meritorious and thus, remained unfunded research. More recently, Tabernanthalog (TBG), a novel water-soluble, non-toxic azepinoindole analog of ibogaine synthesized by David E. Olson at UC Davishas been licensed by Delix Therapeutics. Tabernanthelog has antidepressant and antiaddictive effects in rodents similar to ibogaine with the hope of similar efficacy but better safety parameters.
Although face validity of animal models in addiction research has been recently questionedfor review], in vivo pharmacology studies demonstrate translational relevance for ibogaine, since the drug decreases the rewarding effects of opioids following single dose administrationand it reduces naloxone-precipitated opioid withdrawal signs. However, two reports suggested that ibogaine was not effective for blocking withdrawal signs in animals. In morphine-dependent rhesus monkeys, s.c.injections of ibogaine (2 and 8 mg/kg) only partially suppressed the total number of withdrawal signs. Ibogaine (5, 10, 20 and 40 mg kg-1, s.c.) administered 15 min before a naloxone challenge (0.5 mg kg-1, s.c.) failed to reduce naloxone-precipitated withdrawal in the morphine-dependent rat model following s.c. administration. These observations suggests that the s.c. route of administration which avoids first pass metabolism of ibogaine to noribogaine may explain the negative results. We have demonstrated that noribogaine dose-dependently blocks naloxone precipitated withdrawal signs in opioid dependent mice. The approximate ED50 for blocking withdrawal signs following naloxone administration was 13 mg/kg following oral administration of noribogaine. At 10 mg/kg, noribogaine reached blood levels of 26 ng/mL and brain levels of 533 ng/g, which equates to approximately 0.6 μM and 5.8 μM, respectively. These observations provide further evidence that noribogaine may contribute to the potential efficacy of ibogaine for opioid withdrawal management following oral doses in humans. Ibogaine not only decreases the rewarding effects of opioids, but also demonstrates dose-dependent decreases in stimulant-induced locomotion and self-administration. Studies have shown that ibogaine reduces ethanol self-administration in rats. Ibogaine itself appeared more active at blocking ethanol consumption when administered i.p. versus s.c., consistent with first-pass metabolism of ibogaine to noribogaine. The rewarding effects of ethanol (1.8 g/kg, i.p.) or ibogaine (10 or 30 mg/kg, p. o.) has been recently investigated using the conditioned place preference (CPP) model. The results demonstrate that ethanol, but not ibogaine, induced CPP in mice. Oral gavage administration of ibogaine after conditioning with ethanol blocked the reinstatement of ethanol-induced CPP, both during a drug priming reinstatement test and during a drug-free test conducted after re-exposure to ethanol. A seminal study conducted by Dorit Ron and her collaborators at the Ernest Gallo Clinic and Research Center has shown definitively in experiments with both rats and mice that ibogaine reduces alcohol consumption. This study also demonstrated that ibogaine reduced binge drinking after a period of abstinence by increasing the level of glial cell line-derived neurotrophic factor (GDNF). The authors demonstrated that noribogaine exhibited similar actions as ibogaine on GDNF expression and ethanol self-administration. Noribogaine dose-dependently blocks nicotine self-administration in rats equi-effective to varenicline, a drug approved for smoking cessation in humans. This study supports a role of noribogaine at neuronal nAChRs as a common substrate for treatment of both nicotine and ethanol dependence. The observed effects of ibogaine and noribogaine in animal models of drug and alcohol addiction supports further investigation of this class of compounds as a pharmacotherapy to modulate brain circuits which process the encoding of natural rewards. In keeping with biological transformation of drugs and the important role of active metabolites in drug discovery, Belgers and colleaguesconducted a meta-analysis of in vivo animal studies of ibogaine, and reported that the most significant effects of ibogaine in reducing drug self-administration were observed in the first 24 h after i.p. administration, and these effects were sustained for more than 72 h. The rapid clearance of ibogaine to noribogainesuggests ibogaine is a prodrug and its bioactivation to noribogaine contributes to the in vivo pharmacology observed in humans. Noribogaine as a pharmacologically active metabolite can be significantly responsible for the therapeutic effect of ibogaine (on-target activity) or it could have off-target activities unrelated to the therapeutic action of the parent molecule. Further drug studies are needed in humans and animals using noribogaine as the sole chemical agent to dissect on-/off-target effects of DemerRx Laboratory studies, Caliper Safety Pharmacology screen for binding site activity, and published references cited in the text. Neither noribogaine or its parent drug ibogaine exhibit conditioned place preference seen with potent mu agonists or the conditioned place aversion observed following administration of kappa agonistsor mu antagonists. In keeping with results from in vitro binding studies, noribogaine does not substitute for the discriminative stimulus of morphine or the kappa agonist U50,488. The discriminative stimulus properties of ibogaine have been investigated in rats trained to discriminate phencyclidine (PCP; 2.0 mg/kg, I.P.). Ibogaine (5.6-17.6 mg/kg, I.P.) showed a lack of substitution for PCP in rats and rhesus monkeys ((0.5-4.0 mg/kg, I.M.) trained to discriminate PCP (0.1 mg/kg, I.M.) from sham injections. Interestingly, lysergic acid diethylamide (LSD), tested as a reference compound, produced only a partial substitution for PCP in rats and occasioned little responding on the PCP-associated lever in monkeys. Since noribogaine is inactive as a glutamate channel blockerthe extensive first-pass metabolism of ibogaine to noribogaine should be considered when interpreting the behavioral effects of ibogaine in animal models of addiction and reward. These findings underscore important differences between the ketamine-like behavioral effects of PCP and other hallucinogenic drugs including LSD and ibogaine. Ibogaine, despite having some affinity at the NMDA receptor channel, appears to lack ketamine's unique psychic effects which although shorter-acting are similar to PCP in humans. In rats trained to discriminate ibogaine from saline, complete generalization to noribogaine was obtained. Ibogaine is not a classical hallucinogen, although it is an "oneirogenic" substance which stimulates a "dream-like" state. Rodent models suggest that ibogaine administration causes EEG gamma band alterations and REM-like traits that are comparable to natural REM sleep. This study provides novel biological evidence for a possible association between ibogaine's psychedelic effects and REM sleep.
The route of administration and the dose of a drug have a significant impact on both the rate and magnitude of bioavailability. The oral bioavailability (BA) of ibogaine in rats was assessed at 5 mg/kg and 50 mg/kg. At 5 mg/kg, BA was 7% in males and 16% in females, yielding peak plasma levels of 10 ng/mL and 30 ng/mL, respectively. The mean AUC was 2 times higher in females than in males. At 50 mg/kg, BA was 43% in males and 71% in females, yielding peak plasma levels of 180 ng/mL and 430 ng/mL, respectively. Mean AUCs at 50 mg/kg were 45-59 times greater than at 5 mg/kg. The mean residence time was increased markedly at the high dose in females, but not males. These findings suggest that the kinetics of ibogaine absorption and/or first-pass metabolism are nonlinear and may be different between genders. In monkeys, the oral BA of ibogaine was reported to be < 10% in both males and females. The volume of distribution (Vd) decreased with increasing oral doses of ibogaine. The t max of ibogaine following oral administration was approximately 1-2.5 h in monkeys. Noribogaine has a higher Vd and longer t½ compared to ibogaine. Following IP and SC administration, ibogaine has been reported to be rapidly distributed to various organs and to accumulate in the fatty tissue of rats, consistent with its lipophilic nature. These observations have led to the suggestion that partitioning of ibogaine in fatty tissue may serve as a slow release storage "depot". In monkeys, sex differences in whole blood concentrations following oral administration may potentially be related to differences in partitioning of ibogaine into fat stores or other tissues. Distribution studies have also shown that both ibogaine and noribogaine readily enter the CNS. Ibogaine and noribogaine distribution profiles in organs such as spleen, liver, heart, kidney, brain and muscle in mice showed that the highest concentration of noribogaine occurred in spleen following intragastric ibogaine administration and in liver following intragastric noribogaine administration. Due to its high blood flow and to the characteristics of its microcirculation, the spleen appears to be significantly exposed to noribogaine, perhaps because the drug is sequestered in erythrocytes. Ibogaine is subject to extensive first-pass metabolism in the gut wall and liverand is metabolized primarily to the major metabolite, noribogaine, via O-demethylation by CYP2D6. Noribogaine is the only active metabolite of ibogaine identified to date formed from the activity of polymorphic CYP2D6 and, to a lesser degree, CYP3A4 during first-pass metabolism of orally administered ibogaine. CYP2D6-mediated metabolism in liver, kidney, and brain is dependent on protein expression levels which differ substantially between species. The conversion to noribogaine may occur in brain and kidney, and may be influenced by sex hormones. Based on the available scientific literature, only a small fraction of parenterally administered ibogaine (<5%) is excreted unchanged in urine in rats, and approximately 15% is thought to be excreted after 24 h, presumably as noribogaine. No studies have reported on the recovery of ibogaine or metabolites in urine or feces in mice, monkeys or humans. Elimination occurs rapidly, with an estimated t ½ of approximately 0.9-3.8 h in rats, depending on route of administration, and approximately 2 h in mice following intragastric administration. In rats, ibogaine pharmacokinetic (PK) parameters following IV administration could be described by a two-compartment model, which is characterized by rapid distribution (7.3 min) and elimination phases (3.3 h). In a case series of patients with substance use disorders (SUD), whole blood samples for 24 h PK analysis were collected in a subset of CYP2D6 genotyped patients who received weight-based oral doses of ibogaine HCl ranging from 500 mg to 1200 mg. The drug product was a simple powder-in-capsule. Administered doses ranged from 6.4 mg/kg to 14.3 mg/kg. The derived PK parameters were examined by dose range and CYP2D6 genotype for ibogaine and its metabolite noribogaine. Ibogaine was rapidly absorbed from the gastrointestinal tract with a median t max values ranging from 1.75 to 4 h across all dose levels. Extensive and intermediate metabolizers did not show consistent differences for mean C max , while the mean area under the curve (AUC) values were appreciably greater in intermediate metabolizers. Both C max and AUC 0-24 h values for ibogaine showed intersubject variability. Due to the nature of this observational study, the estimation of clearance and other important parameters were not conducted to the same procedural standards as an industry-sponsored study. The median terminal half-life for ibogaine ranged from 2.4 to 7.6 h depending on CYP2D6 metabolizer status. The C max values for noribogaine were in a similar range as the parent drug except in the CYP2D6 deficient (poor) metabolizers. The median t max values for noribogaine ranged from 4 to 10 h in the overall sample, indicating moderately rapid biotransformation of the parent compound. In general, noribogaine C max values were similar for intermediate and fast metabolizers. The AUC values for noribogaine were between 1.5-and 9-fold higher than for the parent drug, suggesting extensive CYP2D6-mediated first-pass metabolism after single oral dose administration of ibogaine. Poor metabolizers had markedly lower noribogaine C max and AUC values in keeping with this observation. Estimates of t ½ values for noribogaine were not quantifiable due to an insufficient length of sampling that would have been needed for modeling of the terminal concentration-time phase. The influence of CYP2D6 activity on the pharmacokinetics and pharmacodynamics of ibogaine was measured following administration of a single 20 mg dose administered in healthy volunteers. PK parameters were measured in subjects that had intrinsic CYP2D6 activity reduced by prior administration of the CYP2D6 inhibitor paroxetine. In subjects pretreated with placebo, ibogaine concentrations in plasma were barely detectable, whereas there were substantial noribogaine exposures. In subjects pretreated with paroxetine, there were more substantial ibogaine and noribogaine exposures. Mean ibogaine C max in paroxetine-pretreated subjects was approximately 26-fold greater than in placebo-pretreated subjects, mean AUC 0-t was approximately 66-fold greater, and mean t ½ was approximately 4-fold longer (t1/2 = 10.2 vs. 2.5 h; p < 0.05). Although mean noribogaine AUC 0-t values were similar in both the paroxetine-and placebo-pretreated groups, mean C max was numerically lower (p = 0.05) and t ½ numerically longer (t1/2 = 13.0 vs. 20.1 h; p = 0.07). Further research is needed to demonstrate whether the CYP2D6 phenotype is an important determinant in the clinical pharmacology of ibogaine at higher doses.
No drug interaction studies have been reported in the published literature. Drugs that are CYP2D6 substrates are subject to drug interactions. Considering that the potential patient population that would benefit from the therapeutic effects of ibogaine is likely to use other medications (prescription and/or illicit) that are CYP2D6 substrates and inhibitors, the potential for drug interactions with ibogaine is an important consideration for patient safety and product labeling.
The putative antiaddictive properties of ibogaine were first described by Howard Lotsof, who reported that ibogaine administration of 6-9 mg/kg induced an active period of visualizations described as a "waking dream state", followed by an intense phase of "deep introspection". Drug-dependent individuals report that their dream-like visions usually reflect on early childhood memories, traumas, or other significant life events. Some people recount that the experience gave them insights into their addictive and self-destructive behaviours. Opioid-and cocaine-dependent individuals report an alleviation or in some cases a complete cessation of drug craving for extended periods, and some remain drug-free for several years thereafter following a single dose of the drug. Although ibogaine is not approved as a medical treatment for SUD, a large number of uncontrolled and anecdotal case studies have been conducted in private clinics in the Netherlands, New Zealand, Mexico, Panamaand the West Indies. The general consensus taken from these observational studies is that ibogaine can be useful for opioid and other SUDs. The published case series suggest the effectiveness of single large doses of ibogaine in blocking opioid withdrawal symptoms, post withdrawal drug cravings, and the desire to continue to use drugs. Tablesummarizes representative case series which describe the human clinical experience with ibogaine. For some studies, the claims of high rates of abstinence have been made for ibogaine months after detoxification, but verification of relapse prevention obtained by random urine screens following ibogaine therapy do not currently exist and the study cohorts and clinical methodologies are not comparable. When administered to treat SUDs, ibogaine is primarily used orally as the HCl salt. The doses administered range widely from 6 to 55 mg/ kg, although typically between 8 and 25 mg/kg. Patients commonly report sustained resolution of their withdrawal symptoms within 12-18 h of dosing and a reduction in drug craving and improved mood for prolonged periods of up to several weeks or months. The claimed beneficial after effects of ibogaine for relapse prevention suggest that they persist beyond ibogaine's and noribogaine's clearance from the blood. There have been no controlled clinical efficacy trials conducted with ibogaine published to date. The largest observational clinical data supporting open-label efficacy and safety are summarized from the St. Kitts ibogaine study. This report contains results from patients who participated in a 12-day inpatient study to determine the safety and efficacy of ibogaine as a pharmacological treatment for drug detoxification. The study included self-referred, treatment-seeking opioid-and cocaine-dependent patients (N=191; 24.6% female). All opioid-dependent patients (N = 102) were switched at program entry to oral morphine for stabilization prior to ibogaine detoxification. Opioid withdrawal symptoms were recorded before ibogaine administration, approximately 12 h after the last dose of oral morphine and 24 h after ibogaine administration (e.g., 36 h after the last dose of morphine). All patients were administered oral doses of ibogaine HCl (8 -12 mg/kg). Opioid-dependent patients reported significantly decreased withdrawal symptoms and drug cravings as measured by all Heroin Craving Questionnaire (HCQ) subscales post-dose and where available at 1month follow-up. Similarly, assessments of mood states revealed significant reductions in depression symptoms and improvement in scores from baseline to post-dose and at 1-month follow-up (p ≤ 0.01). Pharmacokinetic parameters (Cmax values) and opioid withdrawal ratings by CYP2D6 genotype were reported for a subset of patients administered ibogaine HCl. The physician-rated opioid withdrawal scores (possible scores of 0 -13) demonstrated that objective signs of opioid withdrawal at 24 h were mild (0-2), and none were exacerbated at later time points. These observations are in keeping with other published case reports which demonstrate that ibogaine was effective for opioid detoxification based on physician ratings or subjective reports]. Ibogaine's rapid management of opioid withdrawal symptoms and drug cravings is a potentially important advantage compared to lofexidine and methadone, the two FDA approved drugs used to relieve acute somatic withdrawal symptoms caused by abrupt discontinuation of heroin and prescription opioids. In the St. Kitts study, patient volunteers were asked questions to obtain their interpretation of the benefit of the ibogaine experience using an open-ended elicitation narrative. A total of 92% of the subjects reported that they felt a benefit of ibogaine's "oneiric" experience and that ibogaine was useful as a treatment for drug abuse. Subjects described that they had gained insight into their self-destructive behaviors and that they were "mindful" of the need to become sober/abstinent now. These observations suggest that ibogaine's oneiric effects may engage frontal lobe function to integrate reasoning, decision-making and adaptive behaviors following detoxification from opioids and other abused substances. The multitarget actions of ibogaine and noribogaine identify molecular mechanisms that work in concert to mediate circuit-level processes within brain areas implicated in drug and alcohol dependence. Ibogaine, by targeting NMDA receptors may promote neuroplasticity and increased receptor functionality, through similar mechanisms to what is reported following single oral doses of psilocybin, intravenous administration of allopregnanoloneand repeat intravenous treatments of ketamine. Several studies have shown that drugs of abuse may induce permissive changes that subsequently affect synaptic plasticity events, through a mechanism that has been defined as "plasticity of synaptic plasticity" or metaplasticity. The metaplasticity associated with compulsive drug taking has been characterized as a maladaptive process that causes neural circuits to be more "hard wired" and less susceptible to normal patterns of synaptic remodeling. Like other classic psychedelics, NMDA receptor blockade and 5-HT circuit mechanisms may explain ibogaine's dose-related "oneiric" effects in humans. We have suggested that noribogaine may contribute to the beneficial after effects of ibogaine therapy through dynorphin-kappa and serotonergic mechanisms. Classical psychedelics promote glutamate-dependent increases in the activity of pyramidal neurons in the prefrontal cortex as demonstrated recently by proton magnetic resonance spectroscopy (MRS) in vivo assessment of glutamate. Psychedelic medicines action on 5-HT 2A receptor-mediated glutamate release is the final common pathway not only for the acute actions related to changes in thought and perception, but also a potential underlying mechanism of their therapeutic effects. Ibogaine has been described as an "addiction interrupter" by patients who have taken the drug to treat opioid and other SUDs. Ibogaine and its metabolite are '"psychoplastogens" that have specific effects on dopamine circuitry through activation of GDNF and other downstream second messenger signalling pathways. Reward hyposensitivity and anhedonia are associated with substance use disorders, and their severity is especially prominent in SUDs comorbid with depression. The polypharmacological actions of ibogaine and its active metabolite may lessen withdrawal related anhedonia and improve other dysregulated reward-related circuits by re-engaging or reversing state-dependent glutamate tone which has gone awry with continued abuse of opioids, psychostimulants and alcohol. Understanding how ibogaine produces a "reset" of reward circuitry in the brain is an area of active investigation, especially in the context of clinical development of psychedelics and ketamine for a range of mental health disorders.
Common adverse events following ibogaine treatment included dizziness, confusion, and lack of coordination due to ataxia. The ataxia was often followed by nausea, and in some cases, vomiting, and dry mouth was reported. Ibogaine has also been associated with visual hallucinations (usually with the patients' eyes closed) and perceptual disturbances. Consistent with these findings, the most common adverse events reported using the MedDRA terminology were visual hallucination, ataxia, nausea, feeling hot, and headache (frequencies between 18% and 48% of patients). The adverse events reported in the St. Kitts cohort were transient and resolved without sequelae. Ibogaine inhibits various cardiac voltage-gated ion channels, including human ether-a-go-go-related gene (hERG) potassium, Nav1.5 sodium, and Cav1.2 calcium channels. Ibogaine has been reported to induce QT interval prolongation, but systematic studies of ibogaine's electrocardiographic effects have not been conducted to date. The IC50 of ibogaine at hERG channels ranges depending on the assay conditions from 1 to 4 μM, which corresponds to an estimated therapeutic free ibogaine concentrations in plasma of approximately 1200 ng/mL. Currently, a clinical trial is underway to determine the relationship of ibogaine and noribogaine concentrations on QT intervals (concentration-QTc) in healthy volunteers using intensified cardiac monitoring, recognizing that changes in heart rate play are important for estimating the magnitude of the effect. This ongoing dose-escalation trial includes subject-specific heart rate corrections based on full profiles derived from drug-free baseline and placebo corrected measurement of the QT interval at ascending concentrations of ibogaine and noribogaine. To date, 33 deaths have been reported in the published literature of patients treated with ibogaine. Some of these reports described changes to the electrocardiogram (ECG), including prolonged QT intervals and arrhythmias, although typically in multi-drug situations. Most patients were at an increased risk for adverse events due to use of supra-therapeutic and sometimes toxic ibogaine doses, concomitant use of CYP2D6 inhibitors or QT-prolonging drugs, polydrug abuse or alcohol withdrawal, presence of cardiovascular disease and other predisposing comorbidities, and/or electrolyte dysbalances (Mg++ and K+). Furthermore, impure, crude alkaloidal extracts or adulterated drug product were used in many cases. Drug-induced long QT syndrome is unpredictable in any given individual, since the relationship between the off-target molecular action of a drug (e.g., hERG channel blockade) and the expected clinical effect is not always concordant. An example is amiodarone which markedly prolongs the QT interval but very rarely causes Torsade des Points (TdP) in patients with a normal baseline QT. In 2020, amiodarone was the 198th most commonly prescribed medication in the United States, with more than 2 million prescriptions. Although no serious adverse events of TdP or mortality related to QT prolongation were reported in the St. Kitts study, further clinical studies are needed to determine the magnitude of QT prolongation and if the benefits of single dose ibogaine administration outweigh any potential risks. Current estimates suggest that over ten thousand people have taken ibogaine in countries where it is unregulated. Despite the growing number of ibogaine clinics, it is important to emphasize that the drug should be administered to patients only by physicians who have knowledge of the pharmacokinetics, metabolism, drug-drug interactions and potential cardiac safety risks for this investigational drug product.
Ibogaine is a dissociative psychedelic with oneiric properties that has multiple aforementioned antiaddictive mechanisms which target the stages of the addiction cycle, including the withdrawal/negative affect and the preoccupation/anticipation of the rewarding effects of abused substances. The protracted negative affect which persists following drug detoxification drives an intractable cycle of compulsive drug use and relapse. The claimed therapeutic benefits of ibogaine as a "psychoplastogen" which treat the underlying disease instead of targeting symptoms to prevent relapseprovide support for the clinical development of ibogaine for inpatient use. The role of noribogaine as an active metabolite of ibogaine is supported by experimental observations from in vitro binding assays and animal pharmacology studies. These studies have identified biological activities for noribogaine which are relevant to consider in regards to the overall therapeutic benefits and adverse off-target effects associated with oral dose ibogaine administrations. An ibogaine analogue is current being advanced to the clinic, in the hope of similar efficacy to ibogaine but better cardiac safety parameters. The UK Medicines and Healthcare Products Regulatory Agency (MHRA) granted approval to start subject enrolment in a Phase 1/2a clinical trial of ibogaine. The Phase 1 part of the study will provide an assessment of safety at escalating doses of ibogaine, while the randomized, placebo-controlled Phase 2 is designed as a proof of concept study. The goal of the Phase 2 is to demonstrate if ibogaine promotes relapse prevention in detoxified opioid users. While there are no ongoing Good Clinical Practice (GCP) trials in the United States or Canada, there is a large amount of information available on the clinical use of ibogaine. A preliminary efficacy and safety study of ibogaine in the treatment of methadone detoxification is currently enrolling patients in Spain. Randomized clinical trials, the gold standard for clinical trials, are needed for obtaining causality in drug development. However, the weight of real-world evidence grows as patients continue to seek addiction treatment with ibogaine outside the USA. Researchers and drug developers need to expand the size and pace of clinical trials to demonstrate that the benefits of ibogaine outweigh the risks.
The original laboratory studies reported here were funded in part by gifts to the Addiction Research Project, University of Miami Miller School of Medicine, Department of Neurology (DM); MAPS, Multidisciplinary Association for Psychedelic Studies, and an early contract award from NIH-NIDA to conduct pharmacokinetic studies in monkeys.
Deborah C. Mash (Writing, review and editing) is solely responsible for the preparation, creation and presentation of the published writing of the initial and revised draft.
The author is an inventor on patents pertaining to the active metabolite of ibogaine. She is the CEO, founder and a shareholder in DemeRx Inc., a clinical stage drug development company. ATAI Life Sciences AG ("ATAI") has funded the joint venture with DemeRx to advance clinical trials of ibogaine for the treatment of opioid use disorder (OUD).
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