Conference Objectives.
Ibogaine is an indole alkaloid derived from the bark of the
root of the African shrub Tabernanthe iboga, which has
a history of use as a medicinal and ceremonial agent in West
Central Africa. which has been alleged to have anti-addictive
properties. The major published scientific evidence for ibogaine's
effectiveness includes of reduced drug self administration and
withdrawal in animals, and case reports in humans. The National
Institute on Drug Abuse (NIDA) has given significant support
to animal research, and the US Food and Drug Administration (FDA)
has approved phase 1 dose escalation studies. As a naturally
occurring plant alkaloid, on a patent that is close to expiration,
and a mechanism of action that is unknown, ibogaine has not been
attractive to the pharmaceutical industry and remains a quintessential
orphan drug development project. This leaves the academic community
in the public sector with a crucial role in research on ibogaine.
From a pharmacologic standpoint, ibogaine is interesting because
it appears to have a novel mechanism of action that is different
from other existing pharmacotherapeutic approaches to addiction.
A major objective of this proposed conference will include an
in depth series of presentations and discussions on ibogaine's
possible mechanism(s) of action, as well as a focus on safety,
toxicity and pharmacokinetic issues. The question of ibogaine's
mechanism of action is important because its ultimate significance
may not lie in clinical treatment with ibogaine per se, but as
a paradigm for understanding the neurobiology of addiction as
well as the development of new treatments.
Much research on ibogaines' mechanism of action has focused
on the modulation of glutamate transmission, which is a topic
of considerable current interest and programmatic emphasis not
only to NIDA, but across many of the Institutes and Centers of
the National Institutes of Health. Opioid dependence is the indication
for which addicts have most commonly sought ibogaine treatment,
and the focus of a large proportion of published research on
evidence of efficacy in animals. Ibogaine is not a substitution
therapy, such as methadone. Ibogaine has activity at a variety
of different receptors in the brain, and its effects may result
from complex interactions between multiple neurotransmitter systems.
The reported evidence of efficacy of ibogaine in multiple drug
dependence syndromes raises the possibility suggested by NIDA
Director Alan Leshner (Leshner, 1997) of targeting "common
effects that may underlie common properties of all addictions."
There is evidence to suggest that ibogaine treatment might result
in the "resetting" or "normalization" of
neuroadaptations related to sensitization or tolerance.
Of interest is the advent of a distinctive unofficial treatment
network involving international addict self-help movements, and
lay providers of ibogaine treatment, or "treatment guides."
The current ibogaine scene involves the use of a schedule 1 substance,
and is an appropriate topic of drug abuse research. In the present
era of growing patient driven interest in "alternative medicine",
an awareness of why individuals chose to use ibogaine could be
useful in accessing hidden populations presently unavailable
to more conventional treatment. An understanding of expectations
and cultural beliefs about the ibogaine treatment experience
could be useful in optimizing the clinical milieu and interpersonal
dynamics of present conventional treatment settings, or of future
treatment settings if ibogaine or a congener ever receive official
approval. From a social and ethnographic perspective, the present
ibogaine subculture of the US and Europe may have interesting
parallels to the centuries older, sacramental context of the
use of Eboga in Africa.
Topics and Problems to be Addressed: Background, Significance
and Questions for Discussion.
Sessions 1 and 2: Mechanisms of Action I and II:
Receptor Activities: Ibogaine may represent a new approach
to the neurobiology of addiction, and appears to have a novel
mechanism of action that is different from other existing pharmacotherapeutic
approaches to addiction. Ibogaine does not appear to be a conventional
dopamine or opioid agonist or antagonist, or an amine re-uptake
inhibitor and is not a substitution therapy, such as methadone
(Glick and Maisonneuve, 1998; Popik et al., 1995; Popik and Glick,
1996; Popik and Skolnick, 1999). Ibogaine has significant affinities
for multiple binding sites within the central nervous system,
and its effects may result from complex interactions between
multiple neurotransmitter systems. Ibogaine has apparently significant
activity at N-methyl-D-aspartate (NMDA), nicotinic, and kappa
and mu opioid, and sigma receptors (Glick and Maisonneuve, 1998;
Sershen et al., 1997). Interest has been focused on NMDA antagonism
as one possible mechanism of action with particular relevance
to a putative effect on opioid withdrawal (Chen et al., 1996;
Glick and Maisonneuve, 1998; Layer et al., 1996; Mash et al.,
1995; Popik and Glick, 1996; Popik and Skolnick, 1999; Sershen
et al., 1997). Simultaneous kappa opioid agonist and NMDA antagonist
activity is reportedly required for Ibogaine's effect on drug
self administration, dopamine efflux in the nucleus accumbens
(Nac), or locomotor activity (Glick et al., 1997; Glick and Maisonneuve,
1998).
Possible effects on neuroadaptations related to drug sensitization
or tolerance: Ibogaine appears to have persistent effects
not accounted for by a metabolite with a long biological half
life. (Glick et al., 1991; Maisonneuve et al., 1991). Ibogaine's
action could possibly involve "resetting" or "normalization"
of persistent neuroadaptive changes associated with drug tolerance
or sensitization. Such an action could be accounted for by persistent
effects on second messengers (Rabin and Winter, 1996a; Rabin
and Winter, 1996b). For example, sensitization is thought to
involve enhanced dopamine D1 stimulation of cyclic AMP (White
and Kalivas, 1998). Ibogaine has been reported to potentiate
the inhibition of adenyl cyclase by serotonin (5HT) (Rabin and
Winter, 1996a), an effect that would be expected to oppose that
associated with sensitization. Ibogaine effects are relatively
more evident in animals with prior exposure to amphetamine (Blackburn
and Szumlinski, 1997) or morphine (Pearl et al., 1995; Pearl
et al., 1996), which is also consistent with an effect of ibogaine
on neuroadaptations acquired from drug exposure.
Discrimination studies: Drug discrimination studies
offer a possible approach to the issue of ibogaine's mechanism
of action, and the question of the possible resolution of ibogaines
therapeutic from its hallucinogenic effects. The discrimnability
of the ibogaine stimulus does not appear to due to the 5HT2A
receptor, the primary mediator of responding for LSD ( Helsley
et al., 1998a ,b,c ). NMDA does not appear to be,
but sigma 2 and mu and kappa opioid activity may be involved
in the ibogaine discriminative stimulus (Helsley et al., 1998c).
A high degree of stimulus generalization is reported between
ibogaine and Harmala alkaloids, a group of hallucinogenic beta
carbolines including harmaline that are structurally related
to ibogaine (Helsley et al., 1998d, Helsley et al., 1997 ).
Sessions 1 and 2 Questions for Discussion:
Does ibogaine modify neuroadaptations thought to be associated
with substance dependence?
Is the apparent persistence of ibogaine's effect mediated by
a long acting metabolite, or a lasting effect on neural signal
transduction?
Is ibogaine's putative therapeutic effect mediated by action
at one particular receptor or at multiple receptor types simultaneously?
Session 3: Clinical Pharmacology: Efficacy and Safety.
Current Availability: Ibogaine is restricted in the
U.S., Belgium, and Switzerland, and is not regulated in the rest
of North America and Europe. Presently, treatment with ibogaine
is not available as an approved option in conventional medical
settings in the US. Presently, treatment with ibogaine can be
accessed on a severely limited basis through addict self help
networks in Europe or the US, and relatively small and expensive
private clinics in Panama and the Caribbean. A single oral dose
on the order of 20mg./kg. is given Individuals undergoing ibogaine
treatment for the objective of "addiction interruption",
most often for the specific indication of opioid dependence (Alper
et al., 1999). The other type of ibogaine treatment is the so-called
"initiatory session", which usually involves a lower
dosage on the order of 10 mg./kg., and is oriented towards non-addicted
individuals seeking out the ibogaine experience as a psychotherapeutic
paradigm oriented towards the objective of facilitating personal
growth and change.
Regulatory History: Prior to being regulated, ibogaine
was used for an apparent stimulant-like effect in single doses
in the range of 8 to 30 mg, and was sold in France as Lambarène
from 1939-1970, for indications which included fatigue, depression,
and recovery from infectious disease. Between 1967-70 ibogaine
was classified by the World Health Assembly with the hallucinogens
and stimulants as a "substance likely to cause dependency
or endanger human health", and assigned to Schedule 1 status
by the US FDA. In1993 FDA Director Curtis Wright chaired an Advisory
Panel meeting which resulted in approval of the Investigational
New Drug Application filed by D. Mash for human Phase 1 trials.
The protocol initially included only individuals with histories
of having previously received ibogaine, at dosage levels of 1,2,
and 5 mg.\kg., and was extended to include non ibogaine experienced
subjects at doses up to 8 mg./kg. in 1995. The phase I dose escalation
study was eventually suspended, reportedly due to non-clinical
issues such as finances, and Dr. Mash continued with studies
in humans undergoing ibogaine treatment at a clinic in the Caribbean
in St. Kitts(Mash et al., 1998, Kovera et al., 1998 ). In 1995
the NIDA-MDD Ibogaine Review Meeting chaired by Director F. Vocci
was held to consider the possibility of funding a human trial
of ibogaine utilizing a Phase I\II protocol developed within
NIDA. The draft protocol called for single administration of
fixed dosages of ibogaine of 150 and 300 mg. versus placebo,
for the indication of cocaine dependence, and consultants from
the pharmaceutical industry were a significant influence in the
decision reached in the Review Meeting not to fund the study.
Presently, FDA Phase1 work remains approved but not proceeding
within the US. Applications for clinical research on ibogaine
are reportedly being pursued at the present time in Israel and
Europe. NIDA is presently not involved in human studies but continues
to support basic research on ibogaine.
Evidence of Efficacy in Animal Models: Evidence for
ibogaine's effectiveness in animal models of addiction includes
observations of reductions in morphine (Dworkin et al., 1995;
Glick et al., 1991; Glick et al., 1994; Glick et al., 1996);,
cocaine (Glick et al., 1994; Glick et al., 1996) or alcohol (Rezvani
1995) self administration, and diminished locomotor activation
or dopamine efflux in the nucleus accumbens in response to cocaine
(Broderick et al., 1994; Glick et al., 1992; Sershen et al.,
1996), opioid (Glick et al., 1997; Maisonneuve et al., 1992;
Pearl et al., 1995; Pearl et al., 1996), or nicotine (Maisonneuve
et al., 1997. Ibogaine is reported to attenuate, or interfere
with the acquisition of place preference to amphetamine (Moroz
et al.,1997 ) or morphine (Parker et al.,1995).
Attenuation of morphine withdrawal has been reported in rodents
(Cappendijk et al., 1994; Dzoljic et al., 1988; Glick et al.,
1992; Popik et al., 1995) and monkeys (Aceto et al., 1990). An
ibogaine congener, 18-Methoxycoronaridine (18-MC), is reportedly
effective in animal models of morphine withdrawal (Rho and Glick,
1998), cocaine or morphine self administration (Glick et al.,
1996), and nicotine preference (Glick et al., 1998).
Evidence of Efficacy in Humans: One line of clinical
evidence suggesting ibogaine's possible efficacy are the accounts
of the addicts themselves, whose demand has led to the existence
of a historically unprecedented, unofficial treatment network
involving addict self-help movement. Opioid dependence is most
common indication for which addicts have sought ibogaine treatment.
There are some case studies in humans in the literature (Cantor,
1990; Luciano, 1998; Sheppard, 1994; Sisko, 1993) that describe
ibogaine treatment in an aggregate total of 13 patients, as well
as recent preliminary reports from a private clinic in the Caribbean
(Kovera et al., 1998; Mash et al., 1998). Common reported features
in these reports are reductions in drug craving and opiate withdrawal
signs and symptoms within 1 to 2 hours, and complete resolution
of the opioid withdrawal syndrome within 24 hours after the ingestion
of ibogaine. These case studies appear consistent with general
descriptions of ibogaine treatment (DiRienzo and Beal, 1997;
Kaplan et al., 1993; Lotsof et al., 1995).
A recent study summarizing 33 cases treated for the indication
of opioid detoxification performed in settings under open label
conditions (Alper et al.,1999). Resolution of the signs of opioid
withdrawal without further drug seeking behavior within 24 hours
was reported in 25 patients. Other outcomes included drug seeking
behavior without withdrawal signs (4 patients), drug abstinence
with attenuated withdrawal signs (2 patients), drug seeking behavior
with continued withdrawal signs (1 patient), and one fatality
possibly involving surreptitious heroin use (see "Safety"
below). In evaluating the validity of clinical reports of efficacy
from the existing informal ibogaine treatment network, a focus
on opioid withdrawal may offset some of the methodological limitations
of the informal treatment context. Opioid withdrawal, the indication
for which most addicts have sought out ibogaine, is a clinically
robust phenomenon occurring within a relatively limited time
frame yielding reasonably clear outcome measures, which contrasts
for example, with the lesser consensus regarding the clinical
syndrome of cocaine withdrawal (Gawin and Kleber, 1986; Weddington
et al., 1990). The lay "treatment guides" reporting
on the above case series might be expected to be able to assess
the presence or absence of the relatively clinically obvious
and unambiguous features opioid withdrawal, and in the majority
of reported cases had the benefit of the corroboration of Jan
Bastiaans MD, Professor and former Chairman of the Department
of Psychiatry at the State University of Leiden. The reported
effectiveness of ibogaine in this series suggests the need for
systematic investigation in a conventional clinical research
setting.
Clinical phenomenology reported by patients treated with ibogaine:
Within 1 to 3 hours of ingestion, ibogaine produces its most
intense subjective effects during a state lasting approximately
4 to 8 hours. The acute phase is characterized by the panoramic
recall of a large amount of material relating to prior life events
from long-term memory, primarily in the visual modality. Ibogaine
related visual experiences are strongly associated with eye closure,
and suppressed by eye opening. Descriptions of this state appear
more consistent with the experience of dreams than hallucinations,
and the term "oneiric" (Greek, oneiros, dream) has
been preferred to the term "hallucinogenic". Individuals
who have taken ibogaine describe an experience of being placed
in, and entering and exiting entire visual landscapes, rather
than the intrusion of visual or auditory hallucinations on an
otherwise continuous waking experience of reality. Hallucinations
have been described but do not appear to be as prominent an aspect
of the experience as the volume of images recalled from visual
long-term memory. Following the acute phase is a state lasting
approximately 8 to 20 hours in which the density of recall of
visual images is greatly reduced and attention is directed toward
evaluating the material recalled in the acute phase. The emotional
tone of this second state appears to be generally characterized
as neutral and reflective. Reduced need for sleep for several
days to weeks following treatment is commonly reported. Patients
have reported significant reductions or total cessation of substance
use and craving for weeks to months or longer following treatment,
although methodologically adequate follow-up observations are
lacking.
Safety: The safety concern that is currently most problematic
for the development of ibogaine a fatality occurring during a
heroin detoxification treatment of 24 year old female in the
Netherlands in 1993. This incident, which is currently was a
significant factor in the decision not to pursue a clinical trial
of ibogaine following the NIDA Review Meeting held in March of
1995 [F. Vocci, Director, MDD-NIDA, personal communication, 1998]
The patient received an ibogaine dose of 29 mg\kg., and then
suffered a respiratory arrest, possibly involving aspiration,
and died 19 hours post treatment. Forensic pathological examination
revealed no definitive conclusion regarding the probable cause
of death (Van Ingen 1994), and cited the general lack of information
correlating ibogaine concentrations with possible toxic effects
in humans. The potential artifact associated with a high volume
of distribution and postmortem release of drug previously sequestered
in tissue (Broderick et al., 1994; Dhahir, 1971; Hough et al.,
1996) limits the interpretability of postmortem levels of ibogaine,
or its principal metabolite noribogaine. An additional source
of uncertainty was the possibility of surreptitious opioid use,
which was suggested by the finding among the patient's effects
of charred tin foil, which is used to smoke heroin by the method
of ``chasing the dragon" which is popular in the Dutch heroin
scene (Strang et al., 1997). Analysis of gastric contents for
heroin or morphine, which might have confirmed recent heroin
smoking, and analysis of blood for 6-monoacetyl morphine, a heroin
metabolite whose presence indicates recent use (Kintz et al.,
1989) were not performed. There is evidence that suggests that
the toxicity of opioids may be relatively greater following treatment
with ibogaine (Popik et al., 1995; Schneider and McArthur, 1956).
This incident underscores the need for the security procedures
and medical supervision available in a conventional medical setting,
and completion the FDA dose escalation studies (Mash et al.,
1998) to allow systematic collection of pharmacokinetic and safety
data.
Neurotoxicity: A safety concern regarding potential
neurotoxicity was raised by the observation of cerebellar damage
in rats in the context of work in which ibogaine at a high dose
of 100 mg\kg was used as a probe of the functional anatomy of
excitatory transmission in the olivocerebellar tract (O'Hearn
and Molliver, 1993, O'Hearn and Molliver, 1997 ). However, no
evidence of toxicity was seen at the dose of 40 mg\kg demonstrated
to reduce morphine or cocaine self administration in rats (Cappendijk
et al., 1994; Glick et al., 1991; Glick et al., 1994; Molinari
et al., 1996). Helsley et. al., (1997) (Helsley et al., 1997)
treated rats with 10 mg/kg ibogaine every other day for 60 days
and observed no evidence of neurotoxicity. Likewise, Mash et
al., (1998) (Mash et al., 1998) observed no evidence of neurotoxicity
in monkeys treated for 5 days with repeated oral doses of ibogaine
of 5 to 25 mg\kg, or subcutaneously administered doses of 100
mg\kg. J. W. Olney has described the rationale for the use of
ibogaine as an actual neuroprotective agent to minimize excitotoxic
damage in stroke and anoxic brain injury (Olney, 1997). The available
evidence suggests that the neurotoxic effects of ibogaine occur
at levels higher than those observed to have effects on opioid
withdrawal and self administration. In addition, the neurotoxic
effects of ibogaine appear to be specifically mediated by activity
at the sigma type 2 opioid receptor, and to be potentially dissociable
from ibogaine's putative antiaddictive effect (Glick and Maisonneuve,
1998). Ibogaine's activity at the sigma 2 receptor may explain
the apparent paradox of possible cerebellar excitotoxicity at
high doses despite its properties as an NMDA antagonist (Glick
et al., 1998a). Ibogaine's cerebellar excitoxicity appears
to be related to excitatory effects mediated by sigma 2 receptors
in the olivocerebellar projection which excite cerebellar Purkinje
cells (Coutre and Debonnel, 1998 ), whose synaptic
redundancy makes them particularly vulnerable to excitotoxic
injury (O'Hearn and Molliver, 1997). An ibogaine congener with
relatively less sigma 2 activity, 18-methoxycoronaridine, reportedly
produces effects similar to ibogaine on morphine and cocaine
administration in rats, but has shown no evidence of neurotoxicity
even at high dosages (Glick et al. 1996, Glick et al., 1998a,b)
Session 3 Questions for Discussion:
What is a clinically efficacious dose of ibogaine?
Is ibogaine safe for treatment in humans at dosage levels thought
to be necessary for clinical efficacy?
What measures are needed to provide appropriate assurance of
safety in an ibogaine clinical trial?
Session 4: Learning, Memory, and Neurophysiology.
Rationale: Drug abusers may be viewed as having a disorder
involving excess attribution of salience to drugs and related
stimuli ( Robinson and Berridge 1993 ), which suggests the possibility
of a role of processes subserving learning and memory in the
acquisition of the pathological motivational focus in addiction
(Wickelgren, 1998). Ibogaine appears to have important activity
at the NMDA receptor (see above), and is involved in long term
potentiation (LTP), which is a process thought to be important
in learning, memory and neural plasticity. Experiences apparently
involving memory, such as panoramic recall are prominent in descriptions
by individuals who have taken ibogaine. Animal studies of ibogaine
suggest an attenuation of place preference learning for morphine
or amphetamine (Moroz et al.,1997, Parker et al.,1995
). A general effect of interference with learning has
been suggested (Kesner et al., 1995), but studies
on spatial learning show an enhancement by ibogaine (Helsley
et al., 1997 Popik, 1996). The demonstration of interference
of ibogaine with the expression of behavioral sensitization to
amphetamine but not preference acquired to taste (Blackburn and
Szumlinski, 1997) raises the interesting possibility of a specific
effect of ibogaine on the pathological encoding of drug salience,
distinguished from learning involving more appropriate non-drug
incentives.
Ibogaine and the EEG: The apparent sensitivity of the
EEG to exposure to drugs of abuse (Alper et al.,1998). suggests
that an EEG effect of ibogaine might relate to its putative therapeutic
action. Studies in animals treated acutely with ibogaine report
an apparently activated EEG state consistent with arousal, vigilance,
or REM sleep, and a decline in delta amplitude, interpreted as
similar to that reported in animals with activation of dopaminergic
receptors (Binienda, 1998). The possible involvement of ascending
cholinergic input is suggested by the observation that ibogaine
enhanced an atropine sensitive theta frequency rhythm (Depoortere,
1987). There is apparently no data on possible differences between
the pre- and post- treatment EEG, or effects persisting into
extended periods of time post treatment.
Session 4 Questions for Discussion:
Can ibogaine's effects on memory be linked to its putative therapeutic
action?
What pharmacologic activity appears to be represented in the
EEG changes reported with ibogaine?
Session 5: Ethnographic and Sociological Methods.
Rationale: Ibogaines' use appears to involve distinctive
interactions of psychopharmacologic effects with set and setting.
Some of the same interactions may be shared between the ibogaine
subculture of the US and Europe and the centuries older, sacramental
context of the use of Eboga by the Bwiti cult of West Central
Africa. In both settings the ibogaine experience has been
attributed with serving the objective of facilitating personal
growth and change.
In the present era of growing interest in "alternative medicine",
an awareness of why individuals chose to use ibogaine could be
useful in accessing hidden populations presently unavailable
to more conventional treatment. The application of ethnographic
techniques to the quantitative analysis of the phenomenologic
features of the acute treatment experience could be informative
from both a neuropsychiatric and cultural perspective. For example,
similar subjective phenomena are frequently described in both
ibogaine treatment and near death experiences (NDEs) (Roberts
and Owen, 1988) such as panoramic memory; calm, detached emotional
tone; specific experiences such as passage along a long path,
or floating; "visions" or "waking dream"
states featuring archetypal experiences such as contact with
transcendent beings; and the frequent attribution of transcendent
significance to the experience. Such shared features between
ibogaine and NDEs suggest a common transcultural phenomenoloy
of transcendent or religious experience, as well as the possibility
of a common underlying neuropsychiatric mechanism such as altered
NMDA transmission.
Session 5 Questions for Discussion:
Could ibogaine be adapted to the conventional clinical setting?
Does ethnographic evidence indicate a communality among experiences
attributed with sacred or transcendent value?
Session 6: Political, Economic, and Historical Perspectives.
Economic Incentives and Ibogaine Development: The academic
research community working in the public sector has a crucial
role in studying ibogaine as a paradigm for the development of
new treatment approaches. The strategy of relying on the pharmaceutical
industry to underwrite the cost of drug development works extremely
well in many instances, but presents some limitations with regard
to the development of ibogaine. The U.S. pharmaceutical industry
has not generally viewed addiction as an attractive area for
development. Ibogaine is particularly unattractive, because its
mechanism of action is complex and incompletely understood, and
its patent is close to expiration. US public expenditures for
the development of medications for addiction are small relative
to those of the pharmaceutical industry, or to the potential
societal return. The entire annual budget for MDD, which accounts
for about 90% of U.S. public sector spending on developing addiction
pharmacotherapy, is only the order of approximately 60 million
dollars, a fraction of the estimated $200 to $600 million average
cost of bringing a drug to market.
In the public sector the major economic incentive for the
development of addiction treatment is the saved costs associated
with preventing medical morbidity, crime, HIV, or hepatitis.
In the private sector, decisions are based on weighing the expense
of development against the expected profit, and not the magnitude
of saved costs to society. In the case of a theoretically interesting
drug with a limited profit potential and significant developmental
expense, the private sector's weighting of costs and long term
incentives can appear to be irrational from the larger standpoint
of society.
Cost Effectiveness: The experience of the addict self-help
community, which has provided ibogaine treatment in non-medical
settings such as an apartment or hotel room, provides some evidence
for ibogaine as an inexpensive and practical "low tech"
treatment approach. Ibogaine may be well adapted as a treatment
option under circumstances of severely limited resources and
a pressing need to provide clinical services to heroin addicts
such as Eastern Europe. The shrub that produces ibogaine, which
is isolated from root scrapings with a purity of over 98%, can
be easily cultivated, which favors further improvement in cost
effectiveness if ibogaine becomes a conventional treatment option.
On the other hand, the need for clinical personnel for roles
presently filled by lay providers in the existing informal treatment
network would also need to be included in a calculation of the
costs associated with ibogaine treatment in a conventional medical
setting.
Session 6 Questions for Discussion:
Would ibogaine treatment adapted to the conventional clinical
setting be cost effective?
How have political issues affected ibogaine's development?
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