Abstract 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 1960's, 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.
Content
1. Introduction
Ibogaine is an indole alkaloid that has been used as a botanical preparation for over 100 years both as a crude preparation and as semisynthetic ibogaine. Ibogaine was marketed in France under the tradename Lambarene as a mental and physical stimulant in 8 mg tablets until 1970 [1]. In parts of Africa where Tabernanthe iboga grows, the bark of the root is chewed for various pharmacological or ritualistic purposes and ceremonial initiation practices of the Fang Bwiti religion [2], [3], [4]. Ibogaine’s beneficial effects as an addiction treatment were discovered by heroin users, who observed that single oral doses of ibogaine rapidly alleviated opioid withdrawal symptoms and many claimed that they remained drug-free after the treatment [5], [6], [7]. Observations from the 1970's to the present have suggested that ibogaine in doses up to 1400 mg was useful for thousands of patients seeking acute drug detoxification as a means to break free from their intractable cycle of substance abuse.
In the 1990′s, NDA International was formed to advance ibogaine to the clinic based on a series of use patents describing a method for treating narcotic, psychostimulant, nicotine, alcohol and polydrug dependence with ibogaine (US Patents 4499,096; 4587,243; 4857,523). In 1993, the United States Food and Drug Administration (FDA) approved an investigator-initiated Phase 1 trial in ibogaine-experienced patients to study the pharmacokinetics (PK) and safety effects of ibogaine (IND39,680; University of Miami). This study enrolled a small number of patients before being placed on voluntary hold due to a non-study-related death that was reported following ibogaine administration in Amsterdam, Netherlands. This academic study was amended following a second in-person meeting with the FDA in 1995 to include cocaine-dependent patients. However, the United States National Institute on Drug Abuse (NIDA) opted not to fund the human Phase 1 study of ibogaine in 1995. This landmark FDA-approved clinical trial from the University of Miami was discontinued due to a lack of public or private funding [8].
The United States Drug Enforcement Administration (DEA) classified ibogaine as a hallucinogen with abuse potential and added it to Schedule I (C-1) of the Controlled Substances Act in 1967. While ibogaine is illegal in a number of other countries, its salts and metabolite were added to the New Zealand list of prescribed drugs in 2009. Health Canada added ibogaine to their Prescription Drug List in 2017 to mitigate the potential harms associated with the use of unauthorized ibogaine products. The use of ibogaine is unregulated in several countries including Mexico, Costa Rica, Panama, the Netherlands and Portugal, making these countries attractive places for clinics offering medically supported ibogaine treatments. Because of ibogaine’s Schedule 1 drug status, its clinical development as a treatment for substance use disorders (SUD) has taken place outside conventional industry and academic medical settings. Rekindled interest in ibogaine for opioid and other substance use disorders is supported by the renaissance of clinical development and therapeutic use of classical psychedelics and ketamine for the treatment of depression and anxiety among other mental health disorders.
2. Drug properties
The chemical name for the compound is ibogaine HCl. Ibogaine is also known as 12-methoxyibogamine (Fig. 1). 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 C20H26N2O. 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 C19H25N2OCl 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[13.3.1.02,10.04,9.013,18]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 1. 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[9], [10]. Ibogaine was shown to inhibit transport by SERT and DAT with IC50 values in the low micromolar range [11], [12], [13]. The significance of micromolar interactions of ibogaine in radioligand binding assays has been correlated with the concentrations of parent drug and metabolite in brain (10,14,15). Ibogaine demonstrated high micromolar binding (e.g., low affinity) or was reported inactive at 5-HT2 receptors [16], [17].
Table 1. Binding Site Affinities of Ibogaine and Noribogaine
Target
IbogaineKi; IC50 (µM)
Noribogaine Ki; IC50 (µM)
Pharmacodynamics
Monoamines
SERT ([3H]5-HT reuptake; rat)
0.5
0.3
Serotonin reuptake blocker
SERT (Paroxetine binding; human)
2.0
0.9
Serotonin reuptake blocker
SERT (RTI-55-cocaine analog binding; human)
0.5
0.04
Serotonin reuptake blocker
SERT (RTI-55-cocaine analog; rat)
0.2
0.2
Serotonin reuptake blocker
SERT (RTI-55-cocaine analog: Hela cells)
2.5
Serotonin reuptake blocker, non- competitive
5-HT2 (Ketanserin binding; rat cortex)
4.8; > 100
Inactive
Unknown
5-HT3 (GR65630; N1 E-115 cells; area postrema)
3.8; > 100
Inactive
Unknown
DAT (RTI-55-cocaine analog; human) DAT (RTI-55-cocaine analog; rat)
1.5 – 4.0
3.4
Dopamine reuptake blocker
Opioid Receptors
MU (Naloxone binding, mouse forebrain; rat thalamus)
Inhibitor, non-competitive antagonist (desensitized and resting state)
NMDA Receptor
MK-801 (rat cortex; rat forebrain)
1.0; 2.3; 3.2
Channel blocker
MK-801 (human caudate; frog spinal cord)
5.2; 9.8
31.4
Channel blocker
Voltage-dependent (rat hippocampal cells)
3.2
Channel blocker
DAT=dopamine transporter; IC50 =half-maximal inhibitory concentration; Ki=inhibitory constant; nAChR=nicotinic acetylcholine receptors; SERT=serotonin transporter. The Ki or IC50 values from ligand binding and functional assays and the agonist/antagonist classifications are taken from DemerRx Laboratory studies, Caliper Safety Pharmacology screen for binding site activity, and published references cited in the text.
More recent mechanistic studies have demonstrated that ibogaine inhibits SERT noncompetitively, in contrast to all other known inhibitors, which are competitive with substrate [18]. Notably, ibogaine is a non-competitive inhibitor of transport but displays competitive binding towards selective serotonin reuptake inhibitors[19]. 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 equilibrium with the occluded conformation, dependent on ionic conditions.
Ibogaine is active in displacement assays at MK-801 binding sites on the NMDA receptor [10], [20], [21], [22] and at kappa opioid receptors[10], [15], [23]. The rapid antidepressant efficacy of ibogaine is likely mediated in part through its ketamine-like antagonism of NMDA receptors [[20], [22], [24]). 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 [25], [26], [27], [28], [29], [30]. Ibogaine binds with high affinity to sigma-2 receptors [31], [32]. 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 (12-hydroxyibogamine). These studies demonstrate that the response varies between parent drug and metabolite [10], [33], [34], [35]. 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 [10]. 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 1). In contrast to ibogaine, noribogaine does not have significant dwell time in the NMDA channel [20] and, in keeping with this observation, the drug lacks ketamine-like psychotomimetic effects when administered to humans [36], [37], [38]. Noribogaine is a dual ligand at both mu (weak agonist/antagonist) and kappa (biased agonist) [15]. 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 [39, US Patent 5616,575]. 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 anti-addictive 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-substituted-hexahydroazepino [4,5-b]indole analogs of ibogaine [39]. 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 Davis [40], [41] has 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 [42].
3.2. In vivo pharmacology
Although face validity of animal models in addiction research has been recently questioned [43, for review], in vivo pharmacology studies demonstrate translational relevance for ibogaine, since the drug decreases the rewarding effects of opioids following single dose administration [44], [45], [46] and it reduces naloxone-precipitated opioid withdrawal signs [47], [48], [49], [50], [51]. However, two reports suggested that ibogaine was not effective for blocking withdrawal signs in animals [52], [53]. 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 [53]. 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 [33]. 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 [38], [54].
Ibogaine not only decreases the rewarding effects of opioids, but also demonstrates dose-dependent decreases in stimulant-induced locomotion and self-administration [46], [55], [56], [57], [58]. Studies have shown that ibogaine reduces ethanol self-administration in rats [59]. 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 [59]. 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 [60]. 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 [61]. 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 [62]. Noribogaine dose-dependently blocks nicotine self-administration in rats equi-effective to varenicline, a drug approved for smoking cessation in humans [63]. This study supports a role of noribogaine at neuronal nAChRs as a common substrate for treatment of both nicotine and ethanol dependence [60]. 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 colleagues [64] conducted 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 [64]. The rapid clearance of ibogaine to noribogaine [65], [66] suggests ibogaine is a prodrug and its bioactivation to noribogaine contributes to the in vivo pharmacology observed in humans [14], [33]. 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 ibogaine treatment.
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 agonists [67] or mu antagonists[33], [68]. 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 [34], [69]. The discriminative stimulus properties of ibogaine have been investigated in rats trained to discriminate phencyclidine (PCP; 2.0 mg/kg, I.P.) [70]. 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 glutamatechannel blocker[20] the 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 [10], [20], [71], 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 [34]. 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 [72]. This study provides novel biological evidence for a possible association between ibogaine’s psychedelic effects and REM sleep.
4. Pharmacokinetics
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 [73]. 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 [73]. In monkeys, the oral BA of ibogaine was reported to be < 10% in both males and females [74]. The volume of distribution (Vd) decreased with increasing oral doses of ibogaine [74]. The tmax 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 [66], [75], [76], consistent with its lipophilic nature [77]. These observations have led to the suggestion that partitioning of ibogaine in fatty tissue may serve as a slow release storage “depot” [66]. 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 [74]. Distribution studies have also shown that both ibogaine and noribogaine readily enter the CNS [10], [34], [76], [77]. 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 [78]. 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 [79].
Ibogaine is subject to extensive first-pass metabolism in the gut wall and liver [74], [80] and is metabolized primarily to the major metabolite, noribogaine, via O-demethylation by CYP2D6[14], [54], [80]. 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 [80]. 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 [79], [81].
Based on the available scientific literature, only a small fraction of parenterally administered ibogaine ([75]. 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 t½ of approximately 0.9–3.8 h in rats, depending on route of administration [75], [82], [83], and approximately 2 h in mice following intragastric administration [79]. 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) [83].
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 [38]. 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 tmax values ranging from 1.75 to 4 h across all dose levels. Extensive and intermediate metabolizers did not show consistent differences for mean Cmax, while the mean area under the curve (AUC) values were appreciably greater in intermediate metabolizers. Both Cmax and AUC0–24 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 Cmax values for noribogaine were in a similar range as the parent drug except in the CYP2D6 deficient (poor) metabolizers [14], [54], [74]. The median tmax values for noribogaine ranged from 4 to 10 h in the overall sample, indicating moderately rapid biotransformation of the parent compound. In general, noribogaine Cmax 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 Cmax and AUC values in keeping with this observation. Estimates of t½ 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 [36]. 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 Cmax in paroxetine-pretreated subjects was approximately 26-fold greater than in placebo-pretreated subjects, mean AUC0−t was approximately 66-fold greater, and mean t½ was approximately 4-fold longer (t1/2 = 10.2 vs. 2.5 h; p < 0.05). Although mean noribogaine AUC0−t values were similar in both the paroxetine- and placebo-pretreated groups, mean Cmax was numerically lower (p = 0.05) and t½ 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.
5. Drug-drug interactions
No drug interaction studies have been reported in the published literature. Drugs that are CYP2D6 substrates are subject to drug interactions [80]. 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.
6. Human clinical experience
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” [6], [38]. 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 [38], [84]. 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 [6], [14], [38], [85].
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 [86], [87], New Zealand [88], Mexico [89], [90], [91], [92], Panama [93], [94] and the West Indies (14,38,54]. 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 [14], [38], [84], [85], [86], [87], [88], [89], [90], [91], [92], [93], [94], [95], [96]. Table 2 summarizes 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 [85], [88], [89], 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.
Table 2. Overview of Open-Label Clinical Experience
Stable
Title
Study Design and Dose Range
(n)
Clinical Endpoints
Reference
University of Miami General Clinical Research Center
Pharmacokinetics and Safety Adverse Events, Neurochecks, Posturography
Mash, unpublished data; IND reporting to FDA
New Zealand Physician administered, Private Practice Setting, Addiction Counselor Referrals
Ibogaine Treatment Providers Outcomes Study
Twelve‐month open label follow‐up observational study, Ibogaine HCl 25–55 mg/kg (mean 31.4, s.d. 7.6); staggered dosing regimen, patient based; EU Drug Manufacturer and Canadian company, Phytostan Enterprises, Inc. Remogen Drug Product
Ibogaine in Patients seeking Opioid Detoxification under Medical Monitor
Open label observational study in DSM‐IV opioid dependent patients, 12–month follow up assessments, mean dose Ibogaine HCl 1540 ± 920 mg; extract of T. iboga root bark (mean dose 1610 ± 1650 mg)
30
SOWS, ASI Composite and Drug Use Scores
Brown and Alper, 2018
Mexico Residential Ibogaine Treatment Center
Changes in Withdrawal and Craving Scores in Participants Undergoing Opioid Detoxification Utilizing Ibogaine
Open‐label retrospective analysis of 50 patients diagnosed with OUD by DSM‐5 criteria that were admitted to a residential Ibogaine treatment center in Mexico for a week‐long detoxification period. Assessment scales were collected at 48 and 24 h prior to ibogaine administration and repeated at 24 and 48 h after ibogaine administration. Ibogaine HCl total dose 18–20 mg/kg given orally
40
Safety and efficacy. Opioid withdrawal and drug craving scores: ASI, COWS, SOWS
Malcolm et al., 2018
Mexico Crossroads Treatment Centre Physician‐ administered
Ibogaine‐assisted Detoxification Program for Individuals with Opioid Use Disorders
IRB approved open label online anonymous, web‐ based survey regarding patient experiences with, and effectiveness of, Ibogaine treatment; Canadian company, Phytostan Enterprises, Inc. Remogen Product
88
Questionnaires, Subjective Effectiveness; Opioid use before and after treatment; Depression, Anxiety, and Stress Scale; Satisfaction With Life Survey
Davis et al., 2018
St Kitts WI Ibogaine Healing Visions Clinic, Physician‐ administered
Ibogaine‐assisted Detoxification of Opioid and Cocaine Dependent Patients; Other Substance Use Disorders
Open label safety, pharmacokinetics and pharmacodynamics of oral Ibogaine HCl (8-12 mg/kg) in patients with DSM‐IV opioid or cocaine dependence (N = 191). Post dose at day 5 and 1–month follow up assessments where available; IRB approved retrospective chart reviews
191
Adverse Events, CYP2D6 Genotyping, Pharmacokinetics, OWS, BDI, POMS, SCL‐90, ASI, Heroin Craving Questionnaire‐ Now (HCQN), Cocaine Craving-NOW (CCQN) and Minnesota Cocaine Craving Scales, Elicitation Narrative with content coding
Mash et al., 2018
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 [38], [84], [85], [86], [87], [88], [89], [91], [92]. 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 [38].
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 [38]. 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 1-month 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 [38]. 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 [14], [85], [88], [89], [91], [92]. 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 [38]. 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[97], intravenous administration of allopregnanolone[98] and repeat intravenous treatments of ketamine [99]. 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 [100]. 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 [101]. 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 [15], [33], [38].
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[102]. Psychedelic medicines action on 5-HT2A 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 [103]. 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 [40], [61], [62]. Reward hyposensitivity and anhedonia are associated with substance use disorders, and their severity is especially prominent in SUDs comorbid with depression [104]. 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.
7. Risks and risk management
Common adverse events following ibogaine treatment included dizziness, confusion, and lack of coordination due to ataxia (38). 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[105], [106]. Ibogaine has been reported to induce QT interval prolongation[107], but systematic studies of ibogaine’s electrocardiographic effects have not been conducted to date [108]. 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 [8], recognizing that changes in heart rate play are important for estimating the magnitude of the effect [109]. 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 [110].
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 [111]. 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+) [8]. Furthermore, impure, crude alkaloidal extracts or adulterated drug product were used in many cases [112].
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 [113], [114]. 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 [115]. 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 [38], 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 [8]. 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.
8. Conclusions
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 [116]. The claimed therapeutic benefits of ibogaine as a “psychoplastogen” which treat the underlying disease instead of targeting symptoms to prevent relapse [40] provide support for the clinical development of ibogaine for inpatient use [8]. 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 [40], [41], [42].
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 [117]. 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.
Funding
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.
CRediT authorship contribution statement
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.
Declaration of Interest
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).
Acknowledgements
The author acknowledges the contributions of the many clinicians and scientists who participated in the ibogaine research program conducted over three decades (1992 – 2022). A few of the key collaborators are recognized by name. W. Lee Hearn PhD developed the GC-MS method and oversaw the original analytical work which led to the identification of noribogaine. Rachel Tyndale PhD (Univ. Toronto) and Scott Obach PhD (Pfizer) identified Cytochrome P450 family 2 subfamily D member 6 (CYP2D6) as the metabolic pathway for ibogaine. Frank Ervin MD (deceased; Professor of Psychiatry, McGill University), the clinician scientist who oversaw the offshore investigation, performed psychiatric assessments for the human clinical study conducted in St. Kitts WI. Julie Staley PhD (deceased), Postdoctoral Fellow in the author’s laboratory at the University of Miami (1991–1995) and Michael Baumann PhD (NIDA-IRP) contributed to the original nonclinical research which advanced the characterization of noribogaine as an active metabolite of ibogaine.
Conclusion: A single ibogaine treatment reduced opioid withdrawal symptoms and achieved opioid cessation or sustained reduced use in dependent individuals as measured over 12 months. Ibogaine’s legal availability in New Zealand may offer improved outcomes where legislation supports treatment providers to work closely with other health professionals.
Opioid dependence is a debilitating condition associated with increased morbidity and mortality, limited treatment response, and high relapse rate (Citation1). Patients suffer from fractured relationships, depression, inability to maintain employment, diminished cognitive and psychosocial functioning, and high healthcare costs (Citation2). Annual prevalence of opioid dependence was estimated in 2007 to be 0.4% of the world population and 0.325% of the New Zealand population aged 15–64 (Citation3). Overprescribing and insufficient monitoring of opioids, including those approved to treat substance use disorders, have contributed to increased prevalence in recent years in the United States (U.S.) (Citation4). Reducing opioid-related overdoses and deaths requires a comprehensive effort combining detoxification, behavioral, psychoanalytic, and counseling therapies with all available pharmacotherapies (Citation5). Nonetheless even with combined medication-assisted therapies, consistently achieving remission is difficult due to lack of adherence, underutilization, and limited or ineffective adoption by treatment providers (Citation5,Citation6). Collectively these phenomena add urgency to the search for solutions to opioid dependence and its accompanying risks.
The present epidemic of opioid dependence justifies consideration of novel therapeutic options. Ibogaine treatment, associated with reduced opioid use, attenuation of withdrawal symptoms, and cessation of cravings (Citation7), offers an underutilized yet promising option in response to the limitations of available treatments. Ibogaine is a psychoactive indole alkaloid with stimulatory and hallucinogenic effects that is derived from the root bark of the West African shrub Tabernanthe iboga. Iboga’s powerful psychedelic properties remain a central component of ceremonial use in the Bwiti religion among the Gabonese Fang people of West Africa, who still incorporate iboga in religious ritual, with lower doses of the root bark used as a stimulant and appetite suppressant (Citation8). Purified ibogaine hydrochloride (HCl) was previously marketed, at 5–8 mg doses used 3–4 times per day, under the trade name Lambarene in France (1939–1970) as an antidepressant and enhancer of mental and physical ability (Citation9).
Ibogaine’s potential for treating opioid dependence was discovered in 1962 by Howard Lotsof, based on personal experience and anecdotal reports. Doses up to 19 mg/kg were associated with attenuation of opioid withdrawal and craving, as well as cessation of use (Citation10,Citation11). In contrast to most pharmacotherapies which require ongoing maintenance doses, ibogaine is typically administered as a single-dose treatment on a few occasions as an adjunct to a detoxification treatment model. This treatment regimen helps to mitigate risk of adverse events associated with ibogaine. In two Phase 1 studies using very low doses, single 20 mg doses of ibogaine were well tolerated (N = 21), with no effect on vital signs and no adverse effects (Citation9,Citation12); however, typical doses used for opioid dependence treatment in New Zealand are much higher. Based on in vitro studies and one case report, the principle risk associated with ibogaine is cardiotoxicity resulting from blockade of repolarizing potassium channels and retarded repolarization of the ventricular action potential simultaneous with QT interval prolongation (Citation13). This sequence may lead to life-threatening torsades de pointes (TdP) arrhythmias and sudden death in rare instances.
Putative anti-addiction properties of ibogaine led to extensive studies of acute effects in dependent human volunteers with hazardous opioid use to explore the risk/benefit profile, summarized in . These studies support reproducible indications of effectiveness and an acceptable risk/benefit profile of ibogaine in the treatment of opioid dependence and withdrawal, as opioid dependence has a pooled relative mortality risk (RR) of 2.38 (95% CI: 1.79–3.17) even while in treatment. Out of treatment mortality risk was much greater (Citation14). Ibogaine and its active metabolite noribogaine were found to have numerous direct and indirect functional targets with complex pharmacology in studies aiming to elucidate mechanism of action (Citation15). Most recently, noribogaine was found to be the principal active moeity responsible for interrupting psychological and physiological effects of opiate dependence in rats, with profound implications for effects in humans (Citation16).
Table 1. Published reports of Ibogaine administrations to opioid-dependent patients.
The present study describes a prospective observational case series of 14 participants seeking ibogaine treatment for opioid dependence. The study aimed to contribute information on durability of ibogaine treatment outcomes covering 12-month post-treatment, which was lacking from prior studies. Undertaking this research in New Zealand received further impetus with the 2009 scheduling of ibogaine, by New Zealand’s medical regulatory body Medsafe, as a non-approved medicine (Citation17). Thus, unlike many other regulatory environments, ibogaine is available via legal prescription in New Zealand. The location of the study was chosen to encourage participants to honestly report outcomes without concern of legal consequence and to take advantage of the ability of treatment providers to share information about the patient when covered by appropriate release forms. This study evaluated durable effects of ibogaine on severity of opioid dependence. Acute withdrawal symptoms and long-term depression symptoms were also evaluated as potential contributors to treatment response. Evaluation of safety was beyond the scope of this non-interventional study. Results are intended to support design of future studies on prevention of relapse of opioid dependence after single-dose ibogaine treatment.
Methods
Ethical review, treatment providers, and participants
All participants were treated in accordance with ethical guidelines for health and disability research in New Zealand to ensure it met or exceeded established ethical standards. The study was evaluated and approved by the Health and Disabilities Multi-region Ethics Committee in February 2012 (Ethics Reference # MEC/11/11/095). Per the International Conference of Harmonization (ICH) definition, this was a non-interventional/observational study on the effects of ibogaine prescribed in accordance with regulatory authorization in a manner clearly separated from the decision of including participants in the study.
Participants who independently sought treatment were recruited through two ibogaine providers offering treatments on a fee-for-service basis (hereafter Provider 1 and Provider 2). Provider 1 offered ibogaine treatment at a clinic located in the far north of New Zealand’s North Island utilizing a medically qualified physician. Provider 2 was a registered addictions counselor who offered ibogaine treatment in a private practice setting, in collaboration with the treating physician of each client and a community health psychiatrist. Both providers offered a period of post-treatment supervision extending beyond the typical three days of treatment, during which food intake, exercise, and sleep was monitored. Patients of Provider 1 remained in care for periods extending beyond a week post-treatment. Provider 2’s patients usually left their direct care within four days post-treatment. Despite Provider 1’s greater treatment volume, they contributed only one participant due to limited engagement with this study. Although Provider 2 treated fewer patients concurrent with the study period, they ultimately contributed 13 of the 14 participants described in the present study.
Study participants were required to meet the following inclusion criteria: They had to voluntarily seek treatment without coercion; had independently contacted treatment providers seeking treatment; were over the age of 18 years; able to communicate in English; provided contact information for a close affiliate whom the researcher would contact for corroborating data; and committed to regular contact for twelve-month post-treatment via phone or Skype. Prospective participants meeting any of the following criteria were excluded: those seeking ibogaine treatment for any reason other than opioid dependence; had received ibogaine treatment on a previous occasion; in the opinion of the investigators participants had any personal, situational, health, social, or other issue that would prevent full adherence to study requirements; and those unable to give informed consent.
Drug
All participants were orally administered staggered doses of ibogaine HCL (200 mg capsules). Initially, both providers imported ibogaine HCL (98.5%) from a European manufacturer through a registered New Zealand pharmaceutical importer. Subsequently Provider 2 switched to using Remogen™, a Canadian product, assessed by HPLC as 99.5% pure ibogaine HCl. Of 14 participants, 42.9% received Remogen™.
Participants ingested their last dose of opioids between 12 and 33 hours (mean 20.2, s.d. 9.6) before ibogaine treatment. All participants were fasted prior to dosing. Participants received 25–55 mg/kg (mean 31.4, s.d. 7.6) of ibogaine with concomitant benzodiazepine and sleep aids in most cases. Treatments typically commenced in the early evening and involved multiple doses over 24–96 hours (mean 57 hours). Initial dosage was selected based on patient characteristics (psychological and physical health, age, fitness, drug use) and provider experience. Dosage was adjusted based on patient response and provider assessment through observation and questioning (SOWS scores, changes in proprioception, interoception, mood). A “test” dose of 200 mg, administered when the provider determined the patient was sufficiently in withdrawal, was followed between 1 and 4 hours by a larger dose (typically 400–600 mg), then more rapidly by smaller doses (e.g., 200 mg at 20 minute intervals) until the provider determined the appropriate level of dosing had been achieved. Administration of ibogaine was within the purview of the providers, as the investigator (GN) was solely involved in an observational capacity and was not present during treatments. Per New Zealand regulations, providers were responsible for selection and determining medical eligibility of participants. All aspects of medical care were documented in provider medical records.
Data collection and outcome measures
Data were collected over 14 interviews. These included pretreatment baseline (interview 1); an interview immediately post-treatment (interview 2); and twelve-month interviews (interviews 3–14, corresponding to post-treatment months 1–12). lists the schedule of interviews, along with the outcome measures administered during each interview.
Table 2. Schedule of subject interviews (Citation14) and data collection, with outcome measures to 12-months post-tx.
The New Zealand-based investigator (GN), who was trained in administration of the Addiction Severity Index Lite (ASI-Lite) and Beck Depression Inventory-II (BDI-II), conducted all the interviews at treatment sites in person, at baseline and immediately post-treatment. Baseline data were collected as close to the treatment time as feasible, typically either the preceding day or on the day of treatment. For subsequent visits, the same investigator collected data in person for 28.6% of participants, with the remaining participants assessed during Skype or phone call interviews. Two participants preferred to complete mailed responses.Footnote1 Verification interviews with affiliates were conducted by phone. At baseline and post-treatment interviews (except interview 2), the investigator would attempt contact with participants’ affiliates to independently verify responses, for example, for current substance use, aftercare, mood, and level of social support. Additional interviews where the outcome measures were not administered comprised brief conversations between the investigator and participants at interviews 4, 6, 7, 9, 10, and 13. Attempts were also made to contact participants’ affiliates at these times.
The primary outcome measure was the ASI-Lite (Citation18). This was administered pretreatment at baseline and at months 1, 3, 6, 9, and 12 post-treatment. The instrument uses a 40-minute clinical interview to indicate problem severity in seven life areas commonly affected by substance use disorders: medical status, employment, alcohol use, other drug use, legal status, family and social relationships, and psychiatric status. Symptoms and problems are measured over the preceding 30 days, with higher scores representing greater severity (Citation19).
The BDI-II was administered for the assessment of depression symptoms (Citation20) at baseline, immediately post-treatment, and at 3-month intervals, generally corresponding with administration of the ASI. The Subjective Opioid Withdrawal Scale (SOWS) was administered as close as feasible pre- and post-treatment by the investigator to determine participants’ experience of withdrawal symptoms (Citation21). It was also administered by each provider subsequent to the baseline data collection, to determine level of subject withdrawal immediately prior to administration of ibogaine, and up to 72 hours post-initial dosing to assess subject response during treatment.
Biological verification of drug use data post-treatment involved two random urine screens during the follow-up period, with a third final screen at the time of their last interview (interview 14). Participants were asked to complete screens within 24 hours of administration of the ASI-Lite. Arrangements were made with various testing facilities and laboratories accessible to participants, and all expenses associated with testing were met. Participants received a $10 gift voucher for each follow-up interview they participated in, up to a maximum of $120 for all twelve post-treatment interviews. Study oversight was provided on behalf of the Multidisciplinary Association for Psychedelic Studies by the third author (BY).
Statistical methods
Descriptive statistics including means, standard deviations, ranges, frequencies, and percentages were used to summarize data. Friedman’s nonparametric ANOVA was used to test for significant patterns of change over time for the ASI-Lite subscales, BDI-II, and SOWS scores. Where significant effects were identified with these analyses incorporating all assessment times, these were further explored using Wilcoxon signed rank tests to compare individual assessment times with those at baseline. The sample size was too small to usefully explore any differential sub-group effects by site. An alpha level of 0.05 was used for all tests. Statistical analysis was performed by the statistician and second author (CF) using IBM SPSS v23.
Results
Twenty people who sought ibogaine treatment with the two providers indicated interest during the enrollment period (Figure 1). Three declined to participate in the study, and one person was declined treatment by their provider due to concerns about post-treatment safety. Sixteen participants signed the study Information and Consent Form and 15 were enrolled into the study. One person died during their treatment, and a second person was disqualified from the study upon review of their treatment, due to leaving the treatment before it had been completed to the satisfaction of the Provider. The data reported here describes post-treatment outcomes for 14 participants administered ibogaine for opioid dependence.
Figure 1. CONSORT diagram showing participant flow through observational study.
Participants’ age ranged between 28 and 47 years (mean 38; s.d. 4.8), 50% were female, and all identified as Caucasian. Participants had moderate comorbid depression symptoms at baseline (mean 22.1; s.d. 10.8). They had previously received an average of 4.7 treatments for substance dependence (range 0–20), with 58% of these being detoxification. At the time of treatment, 71% (n = 10) were receiving methadone maintenance treatment (MMT; see Supplementary Table S1). Data from the ASI-Lite show that in the thirty-day period prior to baseline interviews participants had on average used opioids for approximately 28.8 days. Methadone was most commonly reported as the primary drug of dependence (n = 10), followed by codeine (dihydrocodeine) (n = 3) and poppy seeds (n = 1). Despite all those receiving MMT considering methadone as their most problematic drug, six also reported using other opioids in the preceding thirty days, that is, morphine sulfate (n = 3),Footnote2 dihydrocodeine (n = 2), and buprenorphine (n = 1).
During treatment 10 of Provider 2’s 13, subjects were administered ondansetron (4–8 mg); 5 received diazepam 5–25 mg; and 1 received zopiclone (7.5 mg). Provider 1 also administered diazepam (30 mg) and zopiclone (15 mg) to their single participant in the study during treatment. Overall, two participants were enrolled via Provider 1, with one subsequently lost to treatment at 11-months and a second disqualified from the study immediately following treatment as their Provider revealed they had not completed treatment. A third patient of Provider 1 died during treatment before they were formally enrolled. Of 13 participants enrolled through Provider 2, one voluntarily left the study at eight months and a second was lost to follow up at 11 months post-treatment. The fatality was the subject of two investigations, a coronial inquiry and the second involving New Zealand’s Health and Disability Commissioner (HDC). The latter, completed first, described the treatment provider as being in breach of their duty of care but did not offer a medical explanation for the death (Citation22). The coroner’s ruling generally supported the HDC’s findings.
SOWS assessments showed a significant reduction in withdrawal symptoms from baseline, that is, pre-administration up to 24 hours post-administration assessment (p = 0.015). Although this reduction was slightly greater at the second post-administration SOWS assessment (≥ 42 hours), it did not reach statistical significance, likely due to sample size limitations (). The SOWS was administered multiple times by providers during treatment to determine the need for further dosing of patients.
Table 3. SOWS scores comparing pre-administration baseline with post-administration 12–24 hours, and baseline with post-administration 42–84 hours.
Of the seven ASI-Lite subscales, only the Drug component showed a statistically significant decrease over time (p = 0.002). As seen in , there was a decrease in excess of 80% in the score from 0.32 to 0.06 from baseline to 12 months (p = 0.004). Of the remaining composite score categories, the majority show nonsignificant decreases over twelve months, with the notable exception of the Medical component, which actually increased significantly from 0.00 to 0.34 (p < 0.05), suggesting an increase in participants’ reported health problems or motivation to seek medical care.
Table 4. ASI summary statistics at baseline and 12-month follow-up.
The BDI-II scores decreased significantly over time (p < 0.001) with a significant reduction seen at 1-month post-treatment (mean = 22.1 v 9.3) and continuing to the final 12-month assessment (mean = 4.4) (), indicating a reduction in depression severity.
Table 5. BDI-II scores at baseline; immediately post-treatment; and at 1-, 3-, 6-, 9-, and 12-month follow-up.
Researchers were unable to consistently collect urine drug test data corroborating ASI-Lite reported drug use. For participants providing samples testing negative for opioids, percentages were recorded for some participants at three months (n = 8), six months (n = 7), and 12 months (n = 8) post-treatment. Over these periods only small percentages of participants tested positive for opioids: one subject each at three and six months (12.5% and 14.3% of observed cases, respectively), and two participants (25.0% of observed cases) at 12 months. ASI-Lite data for participants reporting positive opioid use in the preceding 30 days exceeded the incidence of positive urine drug findings and were 43% (three months; n = 14), 50% (six months; n = 14) and 45% (12 months; n = 11). Reductions both in other drug use and alcohol use were reported by 21% of participants (n = 14) each, at three and six months. Of the 11 participants remaining at twelve months, 55% reported reduced other drug use and 36% reduced alcohol use.
Discussion
The present study reports treatment outcomes for opioid dependent participants during 12 months following single-dose ibogaine administration and extends earlier work identifying ibogaine’s effectiveness in treating opioid dependence. Consistent with preceding studies, evidence showed significant attenuation of withdrawal, sustained reduction in drug craving/use, and cessation of use in some cases.
These outcomes, particularly the sustained reduction and/or cessation of opioid use reported by 12 of 14 participants, are comparable with the success of currently accepted treatments, including those reported from wide-ranging analyses and combined interventions reviewed previously (Citation6). This analysis, covering 28 trials (n = 2945 participants) of 12 psychosocial interventions combined with the pharmacological treatments, showed an advantage for treatments in combination for abstinence only (RR 1.15, 95% CI [1.01–1.32]). Measures showing nonsignificant outcomes included retention in treatment, adherence, psychiatric symptoms, and depression.
Where interventions aim for detoxification and cessation (i.e., as with ibogaine), outcomes are even more modest. This was evident in a multi-site US study measuring buprenorphine stabilization and tapering to cessation of opioids, by opioid-free urine tests for two outpatient groups, a 7-day taper group (n = 255) and a 28-day taper group (n = 261) (Citation23). There were no differences in abstinence rates between 7- and 28-day taper groups at 1-month (18% both groups) and 3-month follow-ups (12% 7-day vs. 13% 28-day taper). While the present study’s small numbers preclude conclusive comparison, by contrast, outcomes described above in , indicating that a consistently higher proportion of participants returned negative urine drug screens at three (87.5%), six (85.7%), and 12 months (75%), respectively.
Table 6. Percentages of participants in observed cases reporting urine screen data for opioid use at 3, 6, and 12 months post-ibogaine treatment.
Evidence from the current study showing attenuation of withdrawal substantiates earlier experimental research referencing ibogaine’s “significant pharmacologically mediated effect” on opioid withdrawal (Citation24). This is particularly relevant in a country like New Zealand, where methadone, a long acting synthetic opioid with a correspondingly lengthy withdrawal period, is the most commonly injected opioid (Citation25). That 71% of the present study’s participants sought ibogaine treatment for dependence on methadone perhaps also explains the increase observed in the ASI-Lite Medical composite score from baseline to 12-months (0.00 to 0.34, p < 0.05) described in . This reflects higher reporting of physical discomfort post-treatment, with methadone cessation likely exacerbating preexisting medical conditions such as chronic pain, a phenomenon described elsewhere (Citation26). The observed significant effect may also act as a proxy measure further substantiating cessation of opioid use in lieu of some participants’ missing drug test data.
The significant, sustained reductions in BDI-II scores (; p < 0.001), similarly supports earlier research identifying reductions in depressive symptoms post-ibogaine treatment (Citation27). These results are interesting as they incorporate all available data from 12 months (n = 11) and not only the eight completers (). Thus, it was notable during follow-up that even participants who did not cease opioid use entirely described their ibogaine experience in positive terms. A typical comment was that treatment had provided participants with insight into their situation. Baseline BDI-II data suggested that eight participants would have met criteria for moderate or worse depression and four participants for mild depression. Nonetheless, at baseline, only three participants were taking prescribed antidepressants (Venlafaxine, Citalopram). Of these, two ceased use post-treatment. Following treatment four participants intermittently reported antidepressant use (prescribed), with three of these ultimately being unsuccessfully treated for their opioid use. Future studies should include a measure of anxiety in addition to depression to assess the contributions of these symptoms to treatment response, remission, and relapse.
Finally, with five participants reporting benzodiazepine use in the 30 days preceding treatment (one prescribed), the research team considered the possibility that pretreatment anxiety might have inflated baseline BDI-II scores. This concern was mitigated, however, by the understanding that analyses of the BDI-II suggest it is capable of differentiating between depression and anxiety (Citation28,Citation29). Interestingly, at one month, post-treatment six participants (43%) reported benzodiazepine use (five prescribed), while at 12 months, only one of the remaining 11 participants reported this.
Despite the study’s evidence of positive outcomes, it remains that there are also specific risks associated with ibogaine. The most salient of these concerns is mortality temporally associated with treatment. Given the death during treatment of one subject pre-enrolled in the present study, this issue is of particular significance. As described above, the New Zealand death was the subject of two investigations, with a coronial inquiry supporting the earlier ruling of a failed duty of care by the treatment provider (Citation22). The coroner, however, also noted a lack of Post-Mortem and forensic evidence indicating any significant cardiac pathology or history, or other definable cause of death. Consequently, report suggests that the death was very likely “related to ibogaine ingestion and most probably related to a cardiac arrhythmia.” Nonetheless, given the positive outcomes reported in this study and in a recent study of treatments in Mexico that both suggest that treatments are likely to continue (Citation30), it is appropriate to discuss what is clearly a risk.
Ibogaine-related fatalities in treatment have been reported in detail for 19 individuals from 1990 to 2008, known to have died within 1.5–76 hours of taking ibogaine (Citation31). This thorough review of all available autopsy, toxicological, and investigative reports did not suggest a characteristic syndrome of neurotoxicity. Rather, it suggested that advanced preexisting medical comorbidities, primarily cardiovascular, and/or the misuse of a range of substances explained or contributed to 12 of the 14 cases for which there was adequate postmortem data. Seizures from alcohol and benzodiazepine withdrawal and the uninformed use of ethnopharmacological forms of ibogaine were considered other apparent risk factors.
The metabolism of ibogaine by cytochrome P450 enzyme CYP2D6 into noribogaine through the first-pass process has implications for clinical safety (Citation12), with 5–10% of Caucasians lacking the gene required for the enzyme’s synthesis (Citation32). In poor CYP2D6 metabolizers, active moiety (ibogaine plus noribogaine) is projected to be approximately two-fold higher than in individuals having standard metabolic function. Noribogaine’s long half-life, recently reported as 28–49 hours (Citation9), also suggests the potential for high plasma levels of noribogaine with multiple ibogaine treatments over a period of several days as observed in the present study. Although clinical pharmacology studies in patients with impaired hepatic function are yet to be conducted, it may be prudent to genotype potential ibogaine patients and to reduce the intended dose in cases of hepatic impairment or concomitant medications with CYP2D6 inhibition (Citation12).
Regarding New Zealand treatments, inquiries subsequent to the conclusion of the study revealed that although official reporting on New Zealand treatments is voluntary and, therefore, data are incomplete, the two providers collectively reported treating 83 patients (Provider 1, 53 patients; Provider 2, 30 patients). It seems likely, however, that more than 100 treatments occurred during the time of the study, that is, between 2012 and 2015. Notwithstanding the death reported here, in New Zealand ibogaine treatment currently, remains legal and has not been subject to any specific sanctions as a response to the fatality.
Despite the fatality, due to ibogaine being available by prescription in New Zealand, structural mechanisms within the treatment context exist to reduce ibogaine’s potential risks in that country. These are promoted through the legal availability of ibogaine, for example, where patients, ibogaine providers, and other health professionals are all able to openly engage with the treatment process. This process is clearly facilitated by legal access to ibogaine, an approach emphasized by Provider 2 in their treatment of participants in the present study. The possibility of improved treatment safety through regulation, however, is most likely to occur where there is a will amongst all stakeholders to develop a set of robust clinical guidelines or preferably national standards. These must apply to and be adhered to by all treatment providers, regardless of putative experience, skill, or qualification. In this regard, it is interesting to note that the New Zealand fatality occurred at a clinic run by a qualified medical practitioner with considerable emergency medicine experience who nonetheless was adjudged to have failed in their duty of care.
While this study has provided further evidence supporting ibogaine’s effectiveness in reducing opioid withdrawal, cravings and use over an extended period, it nonetheless has a number of weaknesses. Chief among these is the study’s method, with its reliance on a small (n = 14) convenience sample already intending treatment. Additionally, this group was also filtered by the treatment providers prior to indicating interest in participation to the investigator. The small sample size further decreased with attrition and partial datasets. Finally, while attempts were made to ensure accuracy of drug use data through random testing and interviewing significant others, these efforts were not achieved consistently with all participants. Consequently, the sample is not representative, which limits generalizability.
Despite noted limitations, this study has demonstrated that for some opioid-dependent individuals, ibogaine treatment can be effective in significantly reducing opioid withdrawal, craving and depressed mood, and reducing or ceasing opioid use. Given the modest success of existing treatments, some of which involve extensive, repeated administration and considerable risk, and the significant increase in opioid dependence globally, it seems prudent to more seriously examine the place of ibogaine in the context of treating this intractable problem. Therefore, support for further research into non-traditional options such as ibogaine is urgently needed to improve clinical outcomes of opioid dependence.
Supplemental material
Ibogaine treatment outcomes for opioid dependence from a twelve-month follow-up observational study
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ID
Age
(Year)
Sex
Weight
(kg)
Opioid
Ibogaine
Dose
(mg/kg)
Dosing
Time
(Hours)
Follow-up
Post-tx
(Months)
1
40
F
70.0
Methadone
31.4
17
12
2
45
F
120.0
Methadone
25.3
72
11*
3
39
F
88.0
Methadone
29.5
42
12
4
33
F
73.0
Methadone
35.6
21
11*
5
39
M
88.0
Methadone
25.0
19
12
6
42
M
81.0
Methadone
24.6
72
7**
7
47
F
57.0
Methadone
38.5
54
12
8
33
M
74.0
Methadone
27.0
41
12
9
29
F
92.0
Methadone
28.2
38
12
10
40
M
56.0
Dihydrocodein
e
25.0
65
12
11
34
F
54.5
Methadone
55.0
81
12
12
36
M
70.0
Poppy seed
34.2
77
12
13
41
M
75.0
Dihydrocodein
e
26.6
51
12
14
39
M
79.5
Dihydrocodein
e
25.1
71
12
S1: Demographics, drug of dependence, ibogaine dose and period of administration, and
follow-up period for each participant (n=14) receiving ibogaine treatment for opioid
The authors wish to acknowledge Kenneth Alper, M.D., Associate Professor of Psychiatry and Neurology New York University School of Medicine New York; Professor Paul Glue, Chair of Psychological Medicine, School of Medical Sciences, University of Otago, Dunedin, New Zealand; and Allison Feduccia, Ph.D., MAPS Clinical Trial Leader, for comments on earlier drafts of the manuscript. Ben Shechet and Colin Hennigan (MAPS) provided data management support.
Financial disclosures
Geoffrey E. Noller: Independent researcher receiving payment for study conduct over three years from funding sources listed below.
Chris M. Frampton: Reports no relevant financial conflicts
Berra Yazar-Klosinski: Employee receiving full time salary support from MAPS over three years, a tax-exempt charity funding research and education
Funding
Research was supported by grants from the Multidisciplinary Association of Psychedelic Studies (MAPS; a tax-exempt charity funding research and education) and The Star Trust.
