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Medication development of ibogaine as a pharmacotherapy for drug dependence

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D.C. Mash
D.C. Mash
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C.A. Kovera
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B.E. Buck
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B.E. Buck
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Michael Norenberg at University of Miami Miller School of Medicine
Michael Norenberg
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Abstract

The potential for deriving new psychotherapeutic medications from natural sources has led to renewal interest in rain forest plants as a source of lead compounds for the development of antiaddiction medications. Ibogaine is an indole alkaloid found in the roots of Tabernanthe iboga (Apocynaceae family), a rain forest shrub that is native to equatorial Africa. Ibogaine is used by indigenous peoples in low doses to combat fatigue, hunger and in higher doses as a sacrament in religious rituals. Members of American and European addict self-help groups have claimed that ibogaine promotes long-term drug abstinence from addictive substances, including psychostimulants and cocaine. Anecdotal reports attest that a single dose of ibogaine eliminates withdrawal symptoms and reduces drug cravings for extended periods of time. The purported antiaddictive properties of ibogaine require rigorous validation in humans. We have initiated a rising tolerance study using single administration to assess the safety of ibogaine for treatment of cocaine dependency. The primary objectives of the study are to determine safety, pharmacokinetics and dose effects, and to identify relevant parameters of efficacy in cocaine-dependent patients. Pharmacokinetic and pharmacodynamic characteristics of ibogaine in humans are assessed by analyzing the concentration-time data of ibogaine and its desmethyl metabolite (noribogaine) from the Phase I trial, and by conducting in vitro experiments to elucidate the specific disposition processes involved in the metabolism of both parent drug and metabolite. The development of clinical safety studies of ibogaine in humans will help to determine whether there is a rationale for conducting efficacy trials in the future.
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284
ANNALS NEW YORK ACADEMY OF SCIENCES
months. Ibogaine had been administered to opiate and cocaine addicts in Europe and
Central America through an informal self-help net~ork.~ Although promising, these
anecdotal reports from addict self-help groups have not been verified in controlled
clinical trials by established investigators. Although the precise neurochemical mecha-
nism(~) of action for ibogaine have only begun to be studied, it is important to em-
phasize that many therapeutic successes have arisen empirically. The anecdotal reports
of the effectiveness of ibogaine for the treatment of opioid and cocaine dependence
provide a basis for further studies of ibogaine as a pharmacotherapy for drug depen-
dence.
SAFETY CONSIDERATIONS
Ibogaine has a variety of dose-dependent pharmacological actions that may not be
relevant to its effectiveness for opiate detoxification and psychostimulant and opiate de-
pendence, but may influence considerations for safety. However, toxicological studies
conducted in primates have demonstrated that oral ibogaine administrations, given at
doses (5
x
25
mg kg-') recommended for the treatment of cocaine and opiate depen-
dence, appear to be safe and free of behavioral or cerebellar toxicity.60 The development
of ibogaine as an antiaddiction drug has been hindered due to uncertainties over po-
tential cerebellar neurotoxicity demonstrated in rat studie~.~~.~~ O'Hearn and MolliveP
showed that high doses of ibogaine (100 mg kg-' or
3
x
100 mg kg1) causes degenera-
tion of the cerebellar purkinje cells in rats. Molinari
et
~1.~'
reevaluated the dose effects
of ibogaine. In this study, a lower dose (40 mglkg) of ibogaine, one effective in reduc-
ing morphine and cocaine self-administration, displayed no degeneration above the
level seen in saline-treated controls. These observations suggested that the degenerative
and 'antiaddictive' properties of ibogaine reflect different actions of the drug.
Although the Phase I investigations by our group have not advanced recently, we
have had the opportunity to obtain additional safety data in persons receiving ibogaine
treatments abroad under controlled conditions. Baseline screening in these subjects in-
cluded a medical evaluation, physical examination, electrocardiogram (ECG), blood
chemistries, and hematological workup, as well as psychiatric and chemical depen-
dency evaluations. A total of thirty
(23
male,
7
female) drug-dependent subjects were
assigned to one of three fixed-dose treatments under open label conditions: 500 mg, 600
mg, and 800 mg ibogaine. Adverse effects were assessed by clinician side-effect ratings
and open-ended query. No significant adverse events were seen under these study con-
ditions. The most frequent side effects observed were nausea and mild tremor at early
time points after drug administration. Random regression of vital signs (respiration
rate, systolic and diastolic blood pressures and pulse) revealed no significant changes
across time or by treatment condition. White blood cell count, neurotrophil levels,
sodium or potassium levels were in the normal range. No significant changes from
baseline were seen for alanine aminotransferase (ALT), serum aspartate aminotrans-
ferase (AST) alkaline phosphatase (ALP), and y-glutamyl transpeptidase (GGT). In-
tensive cardiac monitoring demonstrated that no electrocardiographic abnormalities
were produced or exaggerated following ibogaine administration. These preliminary re-
sults demonstrate that single oral doses of ibogaine were well tolerated in drug-
dependent subjects, and that there were no significant problems with safety within this
dose range.
Concern over potential cerebellar toxicity6' compelled us to examine ibogaine's ef-
fects on postural stability, body tremor and appendicular tremor
(FIG.
4).
In the FDA
pharmacokinetic and safety trial studies, two doses of ibogaine (1 and
2
mg kg-') were
administered to
9
volunteers with histories of recent cocaine abuse. Static posturogra-
286
ANNALS NEW YORK ACADEMY OF SCIENCES
Static Posturography
(n=6)
=Eyes Open
a~yes Closed
Heel-to-toe, Open
m~eel-to-toe, Closed
Time (hrs)
D
Tremor (Arms Extended)
a
-,
Hz
(n=4)
75
I
11-2
Hz
h
m3-7
HZ
8
-
-8-15Hz
$
50
0
a
a,
.=
C
25
m
-
a,
c
0
0
2
4
6
Time (hrs)
phy with a portable bedside computerized platform was used to quantify body sway
while standing normally and in a heel-to-toe position with eyes opened and eyes closed.
Measurements were taken at baseline and every two hours following oral administra-
tions of ibogaine. Dynamic posturography measured functional limits of stability over
6
hr. Accelerometry was used to measure tremor of the hands at rest and with arms ex-
tended over the same time period. Whole body tremor, akinesia, and retropulsion were
measured with the NeurotestTM apparatus at baseline and
48
hr after drug administra-
tion. Both doses of ibogaine produced no clinically visible effects, but static posturog-
raphy revealed a trend (albeit not significant) toward increased body sway when sub-
jects stood in the heel-to-toe posture with eyes closed. Dynamic posturography and the
Neurotest measurements revealed no changes from baseline. Hand accelerometry did
MASH
et
al.:
IBOGAINE AS PHARMACOTHERAPY
287
not show any effects of ibogaine on tremor (at rest or with arms extended). However,
baseline measurements of tremor revealed quantitative differences between cocaine-
dependent patients and age-matched and drug-free control subjects. Power spectrum
analysis of these data revealed an increase in the 3-7-Hz range, supporting the hy-
pothesis that early cocaine abstinence may reflect a hypodopaminergic state." Similar
observations on patients receiving oral doses of ibogaine in a range of 10 to 30 mgtkg
in offshore clinical settings, failed to demonstrate any effects with Neurotest measure-
ments taken at 5 to
7
days post dose
(n
=
10; 8 male, 2 female; data not shown). In ad-
dition to the lack of posturographic abnormalities, clinical neurologic exams demon-
strated no evidence of permanent cerebellar ataxia in these subjects.
Our research group had the opportunity to conduct a neuropathological evaluation
on a female subject who had received 4 doses of ibogaine ranging from 10 to 30 mg kg-
over a period of 15 months. The last two administrations occurred in a Panamanian
hospital, approximately 25 days prior to her death from natural causes. Before receiv-
ing these last ibogaine treatments, the subject received a series of clinical evaluations
at the University of Miami School of Medicine. Her diagnoses at that time included:
1) opiate and cocaine dependence; 2) amenorrhea for 11 months;
3)
a history of
asthma; 4)
a
history of peptic ulcer disease; and 5) a history of hypertension. The gen-
eral physical exam was normal. Neurological examination (including magnetic reso-
nance imaging (MRI), electroencephalogram (EEG) and a Neurotest gait analysis for
cerebellar signs were normal. Urine toxicology was positive for cocaine, opiates, and
marijuana. She received two doses of ibogaine three days apart (10 mglkg and 20
mgtkg). Approximately one week later, she returned to Miami for follow-up neurolog-
ical evaluations. At that time, the patient was admitted to the hospital for the evalua-
tion of tremors. The examination revealed temperature 98, pulse 92, respirations 22,
and blood pressure 1601108. General physical exam was notable for "an ulcerative le-
sion on her right anterior thigh with
3
to 4 cm erythmatous area surrounding it and par-
tially healed." Repeat neurological exam at that time was grossly normal. She was
treated with clonidine and discharged. The patient went back to New York where she
was treated with diazepam for anxiety and poor sleep. She returned to Miami three
weeks later, where she complained to a friend that she had been having diarrhea and
vomiting since eating raw fish the previous night. Her vomiting progressively wors-
ened, but she did not seek medical attention. The subject died thereafter and was au-
topsied. The toxicology screen was positive for benzodiazepines only. Postmortem an-
tinuclear antibody (ANA) and rheumatoid factor were negative. The postmortem
autopsy revealed mesenteric artery thrombosis with small bowel infarction as the cause
of death, left renal cortical hemorrhagic infarcts, splenic infarct, a capsular hemorrhage
of the right ovary, and agonal aspiration of gastric contents. Comprehensive evalua-
tions of the histopathology revealed multiple microscopic arterial thrombi in several tis-
sues, although there was no evidence of arteritis whatsoever. These observations led to
the conclusion that the pathological picture was that of a generalized hypercoaguable
state. The pathological picture was most consistent with an infectious source (the leg
ulcer) producing a thrombotic process resulting in mesenteric artery occlusion and
death. This cause of death was more likely than an acute drug toxicity (which would
have occurred at 25 days after ibogaine administration).
Neuropathological evaluation revealed slight medullary neuroaxonal dystrophy and
an old focal meningeal fibrosis. There were no degenerative changes seen in the cere-
bellum; cerebellar Purkinje cells were normal and there was no evidence of any signif-
icant cytopathology or neurodegeneration in any other brain area
(FIG.
5). There was
no evidence of astrocytosis or microglial activation. The neuropathological analysis for
a human subject (NH) was important in light of the observations of O'Hearn and
M~lliver,~~ which demonstrated that at high doses, ibogaine administrations result in the
... Alper et al. [6] reported that a subset of 33 individuals was treated for the indication of opioid withdrawal with a single dose of ibogaine averaging 19.3 mg/kg. The U.S. Food and Drug Administration (FDA) Advisory Panel formally approved human trials with 1, 2, and 5 mg/kg of ibogaine, and clinical trial (also approved by the FDA) in 1995 recommended similar doses [7]. Based on existing animal data, Schep et al. [8] suggested that appropriate safety factors should be applied, including a maximum oral dosage limit of less than 1 mg/kg. ...
... Therefore, in our experiments we measured the activities of the antioxidant enzymes, SOD1, mitochondrial manganese superoxide dismutase (SOD2), CAT, glutathione peroxidase (GSH-Px) and GR after ibogaine in vivo, per os (p.o.) application (1 or 20 mg/kg b.w.) after 6 and 24 h. Ibogaine has a blood half-life in humans ranging between 4-8 h, and the elimination half-life of ibogaine in humans is from 4-7 h [7,[16][17][18]. Thus, the time point of 6 h in our experiments was the mean time of its half-life used to examine the expression of antioxidant enzymes in yeast (5 h). ...
... However, ibogaine metabolism in the rat is different when compared to the human. Ibogaine is eliminated faster than noribogaine [1] and 24 h after p.o. administration about 65% of the ibogaine in rats [19], and even 90% in humans [7], can be eliminated via the urine and feces. According to Bauman et al., 24 h after intravenous (i.v.) administration of ibogaine, noribogaine still persists in rat blood, unlike ibogaine, which can no longer be detected [20]. ...
Effects of ibogaine per os application on redox homeostasis in rat liver and erythrocytes
Article
Full-text available
Ibogaine, administered as a single oral dose (1-25 mg/kg body weight), has been used as an addiction-interrupting agent. Its effects persist for up to 72 h. Ex vivo results showed that ibogaine induced cellular energy consumption and restitution, followed by increased reactive oxygen species production and antioxidant activity. Therefore, the aim of this work was to explore the effect of a single oral dose of ibogaine (1 or 20 mg/kg body weight) on antioxidative defenses in rat liver and erythrocytes. Six and 24 h after ibogaine administration, histological examination showed glycogenolytic activity in hepatocytes, which was highest after 24 h in animals that received 20 mg/kg ibogaine. There were no changes in the activities of superoxide dismutases, catalase, glutathione peroxidase, glutathione reductase and glutathione-S-transferase in the liver and erythrocytes after ibogaine treatment, regardless of the dose. Hepatic xanthine oxidase activity was elevated in rats that received 20 mg/kg compared to the controls (p<0.01), suggesting faster adenosine turnover. TBARS concentration was elevated in the group treated with 1 mg/kg after 24 h compared to the controls (p<0.01), suggesting mild oxidative stress. Our results show that ibogaine treatment influenced hepatic redox homeostasis, but not sufficiently to remodel antioxidant enzyme activities at 6 and 24 h post-ibogaine application.
... In the early 20th century, this preparation was marketed as a neuromuscular stimulant at a dose of 2-4 tablets/day ( Goutarel et al., 1993). Several groups reported on the potential benefit of ibogaine for the treatment of drug dependence (Lotsof, 1985;Sheppard, 1994;Luciano, 1998;Mash et al., 1998;Alper et al., 1999). Academic researchers reported descriptions of robust effects of the drug in preclinical animal models and in vitro data were obtained which identified possible mechanism(s) of action ( Glick et al., 1994Glick et al., , 2000Popik et al., 1995;Mash et al., 1995;Staley et al., 1996;Baumann et al., 2001; for review, Belgers et al., 2016;Mash et al., 2016). ...
... Also, there have yet to be any clinical trials to demonstrate efficacy of the drug for opioid dependence. Like most CNS drugs, ibogaine is a highly lipophilic compound that is subject to complex biotransformation and variable half-life due to genetic polymorphisms ( Obach et al., 1998;Mash et al., 1998Mash et al., , 2000Mash et al., , 2001). This issue among other lingering concerns for patient safety continue to hinder the drug development of ibogaine in the US or elsewhere. ...
... The study was conducted in a 12-bed freestanding facility in St. Kitts, West Indies. The treatment program had a planned duration of 12 days and stated goals of: (1) safe physical detoxification from opioids or cocaine, (2) motivational counseling, and (3) referral to aftercare programs and community support groups (12-step programs) ( Mash et al., 1998Mash et al., , 2000). Subjects were self-referred for inpatient detoxification and met inclusion/exclusion criteria. ...
Ibogaine Detoxification Transitions Opioid and Cocaine Abusers Between Dependence and Abstinence: Clinical Observations and Treatment Outcomes
Article
Full-text available
  • Jun 2018
Ibogaine may be effective for transitioning opioid and cocaine dependent individuals to sobriety. American and European self-help groups provided public testimonials that ibogaine alleviated drug craving and opioid withdrawal symptoms after only a single dose administration. Preclinical studies in animal models of addiction have provided proof-of-concept evidence in support of these claims. However, the purported therapeutic benefits of ibogaine are based on anecdotal reports from a small series of case reports that used retrospective recruitment procedures. We reviewed clinical results from an open label case series (N = 191) of human volunteers seeking to detoxify from opioids or cocaine with medical monitoring during inpatient treatment. Whole blood was assayed to obtain pharmacokinetic measures to determine the metabolism and clearance of ibogaine. Clinical safety data and adverse events (AEs) were studied in male and female subjects. There were no significant adverse events following administration of ibogaine in a dose range that was shown to be effective for blocking opioid withdrawal symptoms in this study. We used multi-dimensional craving questionnaires during inpatient detoxification to test if ibogaine was effective in diminishing heroin and cocaine cravings. Participants also completed standardized questionnaires about their health and mood before and after ibogaine treatment, and at program discharge. One-month follow-up data were reviewed where available to determine if ibogaine’s effects on drug craving would persist outside of an inpatient setting. We report here that ibogaine therapy administered in a safe dose range diminishes opioid withdrawal symptoms and reduces drug cravings. Pharmacological treatments for opioid dependence include detoxification, narcotic antagonists and long-term opioid maintenance therapy. Our results support product development of single oral dose administration of ibogaine for the treatment of opioid withdrawal during medically supervised detoxification to transition drug dependent individuals to abstinence.
... Ces effets, qui s'opposent aux symptômes du syndrome de sevrage aux opiacés, peuvent être mis à profit dans le traitement de patients pharmacodépendants. Lors des premiers essais cliniques réalisés sur l'homme (Mash et al., 1998(Mash et al., -2000, aucun des patients dépendants aux morphiniques et traités par des doses fixes de 8 à 12 mg/kg d'ibogaïne per os ne présenta de modifications cardiovasculaires significatives (pouls et pression artérielle). Quelques réponses hypotensives furent observées chez six patients cocaïnomanes, accompagnées pour l'un d'entre-eux d'une chute sévère de pression artérielle traitée avec succès par l'administration de soluté de remplissage. ...
... Plus récemment, l'équipe de Stanley Glick montre qu'aux doses préconisées dans le traitement des dépendances aux morphiniques (2 à 80 mg/kg chez le rat), l'ibogaïne ne présente pas d'activité trémorigène (Glick et al., 1994), contrairement à la tabernanthine, la déséthylcoronaridine et l'harmaline (de structures très voisines). En pratique, une légère agitation de l'extrémité des doigts peut être observée chez certains toxicomanes (Mash et al., 1998(Mash et al., , 2001). ...
... 2.3.3.7.4.2. Implication des récepteurs morphiniques L'hypothèse selon laquelle l'activité de l'ibogaïne et de la noribogaïne sur le syndrome de manque serait liée à leur propriété agoniste morphinique Il (Mash et al., 1998) L'implication de l'activité agoniste K de l'ibogaïne est plus convaincante puisque les agonistes K reproduisent certains de ses effets, notamment la réduction de l'auto-administration de morphine ou de cocaïne, et l'inhibition de l'hyperactivité motrice induite par l'injection de morphine (Alper, 2001). 2.3.3.7.4.3. ...
Contribution à l'étude de Tabernanthe Iboga H. Bn
Thesis
  • Apr 2007
L'emploi de substances psycho actives, à des fins thérapeutique, initiatique ou magico religieuse, est une constante dans l'Histoire de l'Humanité. En Afrique équatoriale, une plante dénommée Tabernanthe iboga (H. Bn) et un culte sont étroitement associés. L'écorce de la racine est tout particulièrement employée dans l'initiation au Bwiti qui constitue le principal rite traditionnel des peuples gabonais. Elle y révèle ses vertus visionnaires et divinatoires. Afin de mieux comprendre le sens de ces pratiques, nous nous intéresserons tout d'abord à la conception de l'homme dans l'univers bantu et aux théories subjectives sur la santé et la maladie, ainsi qu'aux médecines mises en ?uvre.Ensuite, à travers plus d'un siècle de recherches biomédicales, nous aborderons l'évaluation scientifique des principes actifs chimiques de Tabernanthe iboga. Nous évoquerons notamment les propriétés intéressantes de son alcaloïde principal, l'ibogaïne, dans le traitement de certaines addictions (opiacés, cocaïne, nicotine, éthanol). Enfin, à la lumière des écueils conceptuels et méthodologiques rencontrés par la médecine occidentale, nous tenterons d'appréhender ce qui détermine l'efficacité rituelle associée à une plante psycho active telle que l iboga. Nous montrerons qu'il faut en passer par une approche pluridisciplinaire et par un déplacement du regard des substances bioactives vers les dispositifs rituels qui sont les véritables cadres de contrôle de l'expérience.
... A remarkable example, ibogaine, addressed by Corkery and , demonstrates novel pharmacological mechanisms of action to be considered in the potential treatment of substance use disorders and depression ; through simultaneous activation of multiple neurotransmitter systems (Baumann et al., 2001a,b). This alkaloid has low micromolar affinity for mu and kappa opioid receptors, SIGMA-1 and SIGMA-2 receptors (SIGMAR1; SIGMAR2), serotonin reuptake transporter (SERT) and dopamine transporter (DAT), is an antagonist to NMDA and α3β4 nicotinic acetylcholine (nAChR) receptors and a weak 5HT 2A receptor agonist (Alburges et al., 2000;Brown and Alper, 2017;Jacobs et al., 2007;Lavaud and Massiot, 2017;Mash et al., 1998). Drugs with similar NMDA affinity (e.g., such as ketamine and memantine) or NMDA regulators (e.g., such as acamprosate) have shown promise in reducing symptoms of substance use disorders and depression Corkery, 2018;Gass et al., 2018;Ron and Wang, 2009). ...
... Ibogaine demonstrates complex, broad, and novel pharmacological mechanisms of action to consider in the potential treatment of alcohol use disorders . The alkaloid has low micromolar affinity for μ and κ opioid receptors, σ 1 and σ 2 receptors, serotonin reuptake transporter (SERT) and dopamine transporter (DAT), and is an N-methyl-D-aspartate (NMDA) and α3β4 nicotinic acetylcholine receptor (nAChR) antagonist that increases glial-derived neurotrophic factor (GDNF) expression and substance P immunoreactivity (Alburges et al., 2000;Brown and Alper, 2017;Jacobs et al., 2007;Lavaud and Massiot, 2017;Mash et al., 1998). Ibogaine is hepatically metabolized by CYP2D6 to an active metabolite, noribogaine, which has a longer duration of action with a documented half-life of 28-49 h in CYP2D6 extensive metabolizers (Glue et al., 2015). ...
An introduction to psychedelic neuroscience
Chapter
This chapter is an introduction to the volume “Psychedelic Neuroscience” of Elsevier's Progress in Brain Research addressing the neurobiological mechanisms of psychedelic drugs, the resulting changes in brain activity and integration of traditional viewpoints. As the field is relatively new, there are discrepancies in the literature related to classification, composition and effects of the various psychedelics. Currently, psychedelics are grouped according to their neuro-receptor affinities into classic and atypical psychedelics, each with individual treatment potentials and abilities to elicit potent acute experiences and long-lasting changes in neurobiology through concurrent activation of several neuromodulatory systems. There is disparity in psychedelic brain imaging studies, delineating what is neural activity and hemodynamic needs further investigation for us to understand the brain “state” changes that are apparent. The psychedelic brain “state” is often compared to acute psychosis and we review the psychedelic animal models of psychosis and human brain imaging studies and contrast these to psychosis. The term “psychedelic” means mind-revealing and psychedelics have exceptional anti-amnesic effects and are able to “make conscious” that which was previously unconscious through changes in brain “state,” but also there is growing evidence which demonstrates the role of epigenetic mechanisms. This supports traditional therapeutic use of psychedelics to heal ancestral trauma. Details of these mechanisms are provided along with suggestions for further research.
... This may be because the vermis is closer to the CSF, in which toxins may enter [55]. A human autopsy report on a woman receiving multiple doses of ibogaine did not show cerebellar damage [56]. There are no reports of long lasting neurologic effects of ibogaine treatment. ...
Safety of ibogaine administration in detoxification of opioid dependent individuals: a descriptive open‐label observational study
Article
Full-text available
  • Feb 2021
Background and aims Ibogaine is an indole alkaloid used in rituals of the Bwiti tribes of Africa. It is also used in non‐medical settings to treat addiction. However, ibogaine has been linked to several deaths, mostly due to cardiac events called torsades des pointes preceded by QTc prolongation as well as other safety concerns. This study aimed to evaluate the cardiac, cerebellar and psychomimetic safety of ibogaine in patients with opioid use disorder. Design A descriptive open‐label observational study. Setting Department of psychiatry in university medical center, The Netherlands. Participants Patients with opioid use disorder (n=14) on opioid maintenance treatment with a lasting wish for abstinence, who failed to reach abstinence with standard care. Intervention and measurements After conversion to morphine‐sulphate, a single dose of ibogaine‐HCl 10mg/kg was administered and patients were monitored at regular intervals for at least 24 hours assessing QTc, blood pressure and heart rate, Scale for the Assessment and Rating of Ataxia (SARA, to assess cerebellar side effects) and the Delirium Observation Scale (DOS, to assess psychomimetic effects). Findings The maximum QTc prolongation was on average 100ms (range 40‐168ms). Fifty percent of subjects reached a QTc of over 500ms during the observation period. In six out 14 subjects prolongation above 450ms lasted beyond 24 hours after ingestion of ibogaine. No torsades des pointes were observed. Severe transient ataxia with inability to walk without support was seen in all patients. Withdrawal and psychomimetic effects were mostly well‐tolerated and manageable (11/14 did not return to morphine within 24 hours, DOS scores remained below threshold). Conclusions An open‐label observation study found that ibogaine treatment of patients with opioid use disorder can induce a clinically relevant but reversible QTc prolongation, bradycardia, and severe ataxia.
... These are influenced by potential disparities in CYP2D6 metabolism of the parent drug into noribogaine, demonstrated by both phenotyping ( Glue et al. 2015) and genotyping ( Mash et al. 2001) of participants dosed with ibogaine. Indeed, Mash et al. (2018Mash et al. ( , 1998 reported an absence of oneiric effects in two CYP2D6 ultra-rapid metabolizers. This variability suggests that ibogaine's psychotropic effects may be less consistent than those commonly reported for what are sometimes referred to as the classical hallucinogens (MacLean, Johnson, and Griffiths 2011;Nichols 2004). ...
Ibogaine and Subjective Experience: Transformative States and Psychopharmacotherapy in the Treatment of Opioid Use Disorder
Article
  • Apr 2019
This article examines the therapeutic potential of ibogaine, a powerful oneiric alkaloid derived from Tabernanthe iboga, through exploring the subjective experiences of 44 participants from two observational treatment studies for opioid use disorder. Following treatment with ibogaine HCl, the participants (Mexico, n = 30; New Zealand, n = 14) completed the States of Consciousness Questionnaire (SCQ) to quantify the magnitude of their psychotropic experience. Participants were asked to provide written transcripts of their experiences, with those supplied being analyzed thematically through an iterative process, to produce a set of coded themes. Mean SCQ scores in many domains exceeded 0.6, the cutoff score for a “complete mystical experience,” with 43% of participants achieving this in more than five of seven domains. Qualitative data described multiple phenomenological themes, including auditory and visual phenomena. Ibogaine’s strong oneiric action promoted cyclic visions leading to confronting realizations involving remorse and regret for participants’ actions towards others, but also release from feelings of guilt and worthlessness. Many participants reported feeling a sense of spiritual transformation. We propose that the reported experiences support the meaningfulness of ibogaine’s oneiric effects as a discrete element in its capacity for healing, which is distinct from pharmacological actions associated with reduced withdrawal and craving.
... In the 1990s, academic researchers provided proof of concept that ibogaine stops drug taking in animal models of addiction (5, for review). In 1993, the FDA approved a Phase I clinical trial of ibogaine in recently abstinent patient volunteers (6). Unfortunately, these studies did not advance in the United States with government or industry support due to lingering concerns for safety (7). ...
Breaking the cycle of opioid use disorder with Ibogaine
Article
  • Dec 2017
... The subjective psychoactive experience decreases, and a residual mild subjective arousal or alertness may persist for a few days. The decreased need to sleep for several days to weeks is also reported (Maciulaitis et al., 2008;Mash et al., 1998). Some patients with addiction report that after their controlled use of ibogaine, their drug-craving symptoms disappeared, and other patients also reported quitting drug use after a single dose of ibogaine. ...
Natural Products in Addiction Treatment: A Brief Survey
Chapter
  • Jun 2017
Addiction is a psychiatric disorder characterized by loss of control over the consumption of psychotropic drugs despite adverse consequences. Nature has been a great source of metabolites of medicinal interest. Indeed, Nature has been a source of inspiration to scientists devoted to find pharmaceutics to treat drug addiction. Ibogaine, a natural tropane alkaloid, is one of the most natural products explored with respect to the antiaddiction properties. In this chapter, we primarily address the synthesis of ibogaine as well as its potential for the treatment of drug addiction. The antiaddiction properties of other natural products and related molecules are also discussed.
Ibogaine Has Sex-Specific Plasma Bioavailability, Histopathological and Redox/Antioxidant Effects in Rat Liver and Kidneys: A Study on Females
Article
Full-text available
  • Dec 2021
Ibogaine induces rapid changes in cellular energetics followed by the elevation of antioxidant activities. As shown earlier in male rats, ibogaine treatment with both 1 and 20 mg/kg b.w. per os led to significant glycogenolytic activity in the liver. In this work, female rats treated with the same doses of ibogaine per os displayed lower liver glycogenolytic activity relative to males, dilatation of the central vein and branches of the portal vein, and increased concentration of thiols 6 h after treatment. These changes were followed by increased catalase activity and lipid peroxidation, and decreased xanthine oxidase activity after 24 h. In kidneys, mild histopathological changes were found in all treated animals, accompanied by a decrease of glutathione reductase (after 6 and 24 h at both doses) and an increase of catalase (6 h) and xanthine oxidase activity (6 and 24 h). Ibogaine did not affect antioxidant enzymes activity in erythrocytes. Bioavailability of ibogaine was two to three times higher in females than males, with similar kinetic profiles. Compared to previous results in males, ibogaine showed sex specific effect at the level of antioxidant cellular system. Effects of ibogaine in rats are sex- and tissue-specific, and also dose- and time-dependent.
État des lieux de la recherche sur les capacités thérapeutiques des « substances hallucinogènes » au 21e siècle
Article
Full-text available
  • Jan 2017
Mechanisms of action of ibogaine and harmaline congeners based on radioligand binding sites
Article
Full-text available
Assays using radioligands were used to assess the actions of ibogaine and harmaline on various receptor types. Ibogaine congeners showed affinity for opiate receptors whereas harmaline and harmine did not. The Ki for coronaridine was 2.0 microM at mu-opiate receptors. The Kis for coronaridine and tabernanthine at the delta-opiate receptors were 8.1 and 3.1 microM, respectively. Ibogaine, ibogamine, coronaridine and tabernanthine had Ki values of 2.08, 2.6, 4.3 and 0.15 microM, respectively, for kappa-opiate receptors. Long-lasting, dose-dependent behavioral effects of ibogaine have been reported. The possibility that these effects were due to irreversible binding properties of ibogaine at kappa-receptors was considered; however, radioligand wash experiments showed a rapid recovery of radioligand binding after one wash. A voltage-dependent sodium channel radioligand demonstrated Ki values in the microM range for all drugs tested. Using radioligand binding assays and/or 36Cl- uptake studies, no interaction of ibogaine or harmaline with the GABA receptor-ionophore was found. The kappa-activity of ibogaine (or an active metabolite) may be responsible for its putative anti-addictive properties whereas the tremorigenic properties of ibogaine and harmaline may be due to their effects on sodium channels.
Effects of ibogaine on acute signs of morphine withdrawal in rats: Independence from tremor
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Because of the claim that ibogaine suppresses the symptoms of "narcotic withdrawal" in humans, the effect of ibogaine on naltrexone-precipitated withdrawal signs in morphine-dependent rats was assessed. Morphine was administered subcutaneously through implanted silicone reservoirs for 5 days. Ibogaine (20, 40 or 80 mg/kg, i.p.) or saline was administered 30 min prior to challenge with naltrexone (1 mg/kg, i.p.) and withdrawal signs were counted for the following 2 hr. Ibogaine (40 and 80 mg/kg) significantly reduced the occurrence of four signs (wet-dog shakes, grooming, teeth chattering and diarrhea) during naltrexone-precipitated withdrawal; three other signs (weight loss, burying and flinching) were unaffected. Ibogaine induces head and body tremors lasting for 2-3 hr and the tremors might have interfered with the expression of opioid withdrawal. To examine this issue, another experiment was conducted in which ibogaine (40 mg/kg) or saline was administered 4 hr prior to challenge with naltrexone. Although there was a complete absence of tremors, ibogaine still significantly reduced the occurrence of the same four signs of withdrawal.
Effects and after effects of Ibogaine on morphine self-administration in rats
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Ibogaine, a naturally occurring alkaloid, has been claimed to be effective in treating addition to opiate and stimulant drugs. As a preclinical test of this claim, the present study sought to determine if ibogaine would reduce the intravenous self-administration of morphine in rats. Ibogaine dose dependently (2.5-80 mg/kg) decreased morphine intake in the hour after ibogaine treatment (acute effect) and, to a lesser extent, a day later (aftereffect); while the acute effect could be attributed to abnormal motor behavior (whole body tremors), the aftereffect occurred at a time when ibogaine should have been entirely eliminated from the body and when there was no obvious indication of ibogaine exposure. In some rats, there was a persistent decrease in morphine intake for several days or weeks after a single injection of ibogaine; other rats began to show such persistent changes only after two or three weekly injections whereas a few rats were apparently resistant to prolonged aftereffects. Aftereffects could not be attributed to a conditioned aversion. Although ibogaine also depressed responding acutely in rats trained to bar-press for water, there was no evidence of any aftereffect a day or more later; the interaction between ibogaine and morphine reinforcement was therefore somewhat specific. Further studies are needed to characterize the nature of the ibogaine-morphine interaction as well as to determine if ibogaine also affects the self-administration of other drugs.
Gawin FH. Cocaine addiction: psychology and neurophysiology. Science 251: 1580-1586
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  • Apr 1991
Cocaine was considered incapable of producing dependence in 1980 but was recently proclaimed the drug of greatest national health concern. Recent clinical and preclinical investigations demonstrate that cocaine produces unique abuse and withdrawal patterns that differ from those of other major abused drugs and suggest that long-term cocaine abuse produces neurophysiological alterations in specific systems in the central nervous system that regulate the capacity to experience pleasure. It will be necessary to develop clinically pertinent research models before these findings can be considered definitive, but these evolving ideas have already led to applications of promising experimental treatments for cocaine abuse.
Ibogaine reduces preference for cocaine consumption in C57BL/6By mice
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After a period of forced exposure to 300 mg/l cocaine HCl in drinking water for a period of one week, followed by forced exposure to 200 mg/l cocaine for an additional week, male C57BL/6By mice developed a preference for cocaine when given a choice of drinking either water or a solution containing cocaine (200 mg/l). The mean daily intake of cocaine during the choice period was 26 ± 1 mg/kg or, when expressed as the ratio of cocaine over total fluid intake, represented a cocaine preference of 71 ± 2%. Administration of ibogaine HCl (40 mg/kg, two injections 6 h apart) two weeks after the beginning of the choice period reduced the cocaine preference for at least five days; the mean daily intake of cocaine was reduced by 38% (to 16 ± 1 mg/kg per day; p < 0.05) and cocaine preference was reduced to 41 ± 2% (cocaine fluid consumption/total fluid intake). An acute challenge injection of cocaine (25 mg/kg SC) produced a significant increase in cocaine-induced locomotor activity and stereotypy in mice previously exposed to cocaine in their drinking water (cocaine choice group). Five days after ibogaine administration, locomotor and stereotypy activity were significantly lower after a challenge injection of cocaine (25 mg/kg SC). Brain levels of cocaine 35 min after the challenge injection of cocaine were approimately 25% higher in ibogaine-treated mice (7.2 ± 0.5 and 9.3 ± 0.8 μg/g wet wt for water vs. mice treated with water plus ibogaine and 9.3 ± 0.2 and 11.8 ± 0.7 μg/g wet wt for cocaine drinking vs. cocaine drinking plus ibogaine treatment). Neither the reduction in cocaine preference nor attenuation in cocaine-induced ambulatory and stereotypy activity by ibogaine was accounted for by changes in brain levels of cocaine.
Ibogaine antagonizes cocaine-induced locomotor stimulation in mice
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Ibogaine (40 mg/kg i.p.), when given 2 hours before an acute injection of cocaine (25 mg/kg s.c.) to C57BL/6 mice, reduced the cocaine-induced locomotor stimulation. Such stimulation was also reduced in the ibogaine-treated mice when a second injection of cocaine was given 24 hr later. Thus, the reduction in locomotor activity was not just the short-term depression of locomotor activity seen after ibogaine administration. When mice were given a daily injection of cocaine for 3 days and ibogaine was given after the cocaine injection on day 3, and again on day 4, cocaine-induced locomotor activity was reduced three hours later on day 4. On days 5 and 9 of the cocaine administration, with no further ibogaine treatment ambulatory counts were still lower in the ibogaine-pretreated mice. Locomotor stimulation induced by amphetamine (10 mg/kg) was not affected by ibogaine. An acute injection of ibogaine resulted in a transient increase in turnover of dopamine, as indicated by the increase in the ratio of metabolites of the dopamine to dopamine, followed by a decrease in the metabolites in striatum and frontal cortex 24 hr later. In vivo treatment with ibogaine did not affect the binding of [3H]WIN 35,248 to the cocaine binding site in striatal tissue measured in vitro. In addition, ibogaine added in vitro had a weak affinity to the WIN 35,248 binding site (IC50 for cocaine = 120 nM and for ibogaine = 1,500 nM). The results suggest that ibogaine may have induced a selective change in the dopaminergic system that results in a decrease in responsiveness to cocaine that persisted for at least 1 week.
Spanagel R, Herz A, Shippenberg TS. Opposing tonically active endogenous opioid systems modulate the mesolimbic dopaminergic pathway. Proc Natl Acad Sci USA 89: 2046-2050
Article
  • Apr 1992
The mesolimbic dopaminergic system has been implicated in mediating the motivational effects of opioids and other drugs of abuse. The site of action of opioids within this system and the role of endogenous opioid peptides in modulating dopamine activity therein remain unknown. Employing the technique of in vivo microdialysis and the administration of highly selective opioid ligands, the present study demonstrates the existence of tonically active and functionally opposing mu and kappa opioid systems that regulate dopamine release in the nucleus accumbens, the major terminal area of A10 dopaminergic neurons. Thus, stimulation of mu-type receptors in the ventral tegmental area, the site of origin of A10 dopaminergic neurons, increases dopamine release whereas the selective blockade of this opioid receptor type results in a significant decrease in basal dopamine release. In contrast, stimulation of kappa-type receptors within the nucleus accumbens decreases dopamine release whereas their selective blockade markedly increases basal dopamine release. These data show that tonic activation of mu and kappa receptors is required for the maintenance of basal dopamine release in the nucleus accumbens. In view of the postulated role of the mesolimbic system in the mediation of drug-induced alterations in mood and affect, such findings may have implications for the treatment of opiate dependence and affective disorders.
Acute and prolonged effects of ibogaine on brain dopamine metabolism and morphine-induced locomotor activity in rats
Article
Ibogaine, an indolalkylamine, proposed for use in treating opiate and stimulant addiction, has been shown to modulate the dopaminergic system acutely and one day later. In the present study we sought to systematically determine the effects of ibogaine on the levels of dopamine (DA) and the dopamine metabolites 3,4 dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in tissue at several time points, between 1 h and 1 month post-injection. One hour after ibogaine-administration (40 mg/kg i.p.) a 50% decrease in DA along with a 37-100% increase in HVA were observed in all 3 brain regions studied: striatum, nucleus accumbens and prefrontal cortex. Nineteen hours after ibogaine-administration a decrease in DOPAC was seen in the nucleus accumbens and in the striatum. A week after administration of ibogaine striatal DOPAC levels were still reduced. A month after ibogaine injection there were no significant neurochemical changes in any region. We also investigated the effects of ibogaine pretreatment on morphine-induced locomotor activity, which is thought to depend on DA release. Using photocell activity cages we found that ibogaine pretreatment decreased the stimulatory motor effects induced by a wide range of morphine doses (0.5-20 mg/kg, i.p.) administered 19 h later; a similar effect was observed when morphine (5 mg/kg) was administered a week after ibogaine pretreatment. No significant changes in morphine-induced locomotion were seen a month after ibogaine pretreatment. The present findings indicate that ibogaine produces both acute and delayed effects on the tissue content of DA and its metabolites, and these changes coincide with a sustained depression of morphine-induced locomotor activity.
Interactions between ibogaine and cocaine in rats: In vivo microdialysis and motor behavior
Article
To investigate a possible basis for the proposed anti-addictive property of ibogaine, the effects of an ibogaine (40 mg/kg i.p.) pretreatment on in vivo neurochemical and motor effects induced by cocaine (20 mg/kg i.p.) were studied. Ibogaine, administered 19 h earlier, potentiated the increase in extracellular dopamine levels in striatum and nucleus accumbens as well as the stimulated motor activity induced by cocaine. Although high doses of cocaine can become aversive by producing an anxiogenic reaction, it is unknown whether the potentiation of cocaine's effects by ibogaine would also cause aversion and lead to a decrease in cocaine addiction.
Inhibition of Morphine Tolerance and Dependence by the NMDA Receptor Antagonist MK-801
Article
  • Feb 1991
The N-methyl-D-aspartate (NMDA) subtype of the glutamate receptor is an important mediator of several forms of neural and behavioral plasticity. The present studies examined whether NMDA receptors might be involved in the development of opiate tolerance and dependence, two examples of behavioral plasticity. The noncompetitive NMDA receptor antagonist MK-801 attenuated the development of tolerance to the analgesic effect of morphine without affecting acute morphine analgesia. In addition, MK-801 attenuated the development of morphine dependence as assessed by naloxone-precipitated withdrawal. These results suggest that NMDA receptors may be important in the development of opiate tolerance and dependence.