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OPEN
REVIEW
Ibogaine and addiction in the animal model, a systematic
review and meta-analysis
M Belgers
1,2,3
, M Leenaars
4
, JR Homberg
5
, M Ritskes-Hoitinga
4
, AFA Schellekens
2,3
and CR Hooijmans
4
Ibogaine is a naturally occurring substance which has been increasingly used in the lay-scene to reduce craving and relapse in
patients with substance use disorders (SUDs). Although human clinical trials on the safety and efficacy of ibogaine are lacking,
animal studies do support the efficacy of ibogaine. In this systematic review and meta-analysis (MA), we summarise these animal
findings, addressing three questions: (1) does ibogaine reduce addictive behaviour in animal models of SUDs?; (2) what are the
toxic effects of ibogaine on motor functioning, cerebellum and heart rhythm?; (3) what are neuropharmacological working
mechanisms of ibogaine treatment in animal models of SUDs? MA of 27 studies showed that ibogaine reduced drug self-
administration, particularly during the first 24 h after administration. Ibogaine had no effect on drug-induced conditioned place
preference. Ibogaine administration resulted in motor impairment in the first 24 h after supplementation, and cerebral cell loss even
weeks after administration. Data on ibogaines effect on cardiac rhythm, as well as on its neuropharmacological working
mechanisms are limited. Our results warrant further studies into the clinical efficacy of ibogaine in SUD patients in reducing craving
and substance use, but close monitoring of the patients is recommended because of the possible toxic effects. In addition, more
work is needed to unravel the neuropharmacological working mechanisms of ibogaine and to investigate its effects on heart
rhythm.
Translational Psychiatry (2016) 6, e826; doi:10.1038/tp.2016.71; published online 31 May 2016
INTRODUCTION
Substance use disorders (SUDs) account for a large share of the total
global burden of disease. Nearly 5% of all disability-adjusted life
years and 4% of overall mortality appear to be attributed to SUDs.
1–3
SUDs are often characterized by chronicity and frequent relapse.
Despite treatment, 5-year relapse rates are as high as 70% for alcohol
dependence, 78% for cocaine dependence and 97% for opioid
dependence.
4–6
Moreover, for opioid dependence, pharmacological
treatment mainly consists of harm reduction strategies, using opioid
substitution with opioid agonists
7,8
and for cocaine dependence no
effective pharmacological treatment is available at all.
9
As a consequence, new and more effective pharmacological
treatment modalities are needed. Several new treatments have
been investigated, with some more promising than others. One
promising compound is ibogaine, a naturally occurring substance
in an African shrub. This compound has been claimed to reduce
craving and relapse rates in patients with SUDs.
10
Indeed, case
reports mention a reduction of withdrawal symptoms and relapse
after a single dose of ibogaine with a sustainability of this effect of
several months.
11
Ibogaine has increasingly been used for this
purpose over the last decades, mainly in a lay-scene.
12,13
However,
human clinical trials on the safety and efficacy of ibogaine for
patients with SUDs are lacking.
Various animal studies seem to support the claim that ibogaine
could have anti-addictive effects. The use of even a single dose of
ibogaine appears to be effective in a variety of well-validated
animal models for SUDs.
10,14
Other animal studies describe
neurobiological effects of ibogaine.
15,16
These findings fit well
with current insight into the pathophysiology of SUDs and its
pharmacological targets, assigning a dominant role to dysfunction
in the brain dopamine, serotonin and stress systems in SUDs.
17,18
However, a major concern in the use of ibogaine is its potential
cerebellar and cardiac toxicity, which has been described in both
animal studies and human case reports.
19–21
In order to create an overview of possible therapeutic and
adverse effects, and further our understanding of the neurophar-
macological working mechanism of ibogaine, we conducted a
systematic review (SR) and meta-analysis (MA) of animal studies
regarding this topic. We propose that SR and MA of animal studies
will increase our insight into the possible therapeutic effects,
toxicity and potential mechanism of action of ibogaine. In addition,
the results of this review might guide the design of future clinical
trials.
22
Therefore, three research questions will be addressed: (1)
Does ibogaine reduce addictive behaviour in animal models of
SUDs?; (2) Does ibogaine supplementation to animals cause
adverse toxic effects?; and (3) Does ibogaine influence addiction-
related neurobiological response in animal models of SUDs?
MATERIALS AND METHODS
The present review was based on published results of the
therapeutic, toxic and neurobiological effects of ibogaine in
1
IrisZorg, Department of Addiction Health Care, Arnhem, The Netherlands;
2
Department of Psychiatry, Radboud University Medical Center, Nijmegen, The Netherlands;
3
Nijmegen Institute for Scientist-Practitioners in Addiction (NISPA), Nijmegen, The Netherlands;
4
Departments of SYstematic Review Centre for Laboratory animal
Experimentation (SYRCLE), Central Animal Laboratory, Radboud University Medical Center, Nijmegen, The Netherlands and
5
Behavioural Neurogenetics group at the Department
of Cognitive Neuroscience, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands. Correspondence: M Belgers,
IrisZorg, Department of Addiction Health Care, Kronenburgsingel 545, Arnhem 6831 GM, The Netherlands.
E-mail: m.belgers@iriszorg.nl
Received 8 October 2015; revised 4 March 2016; accepted 17 March 2016
Citation: Transl Psychiatry (2016) 6, e826; doi:10.1038/tp.2016.71
www.nature.com/tp
animal studies. The inclusion criteria and methods of analysis were
specified in advance and documented in a protocol and published
on the SYRCLE website (https://www.radboudumc.nl/Research/
Organisationofresearch/Departments/cdl/SYRCLE/Pages/Protocols.
aspx).
For our first research question (does ibogaine reduce addictive
behaviour in animal models of SUDs?) we focused on the two
main behavioural paradigms to measure features of SUDs: the
drug self-administration (SA) and drug-induced conditioned place
preference (CPP) paradigms. The drug SA paradigm measures the
reinforcing effects of drugs of abuse, and—depending on the
schedule of reinforcement used—the pattern, as well as motiva-
tion of animals to self-administer or seek drugs of abuse. The CPP
paradigm measures the rewarding value of drugs of abuse and the
ability of the animals to link this to the context in which they
experience the reward.
23
For our second research question (does
ibogaine supplementation to animals cause adverse toxic
effects?), we focused on the effect of ibogaine on motor
functioning, cerebellar cell loss and cardiac rhythm effects, since
tremors, ataxia and cardiac fatalities (due to cardiac arrhythmias)
are the most commonly reported toxic effects of ibogaine in
human case reports.
20
For our third research question (does
ibogaine influence addiction-related neurobiological response in
animal models of SUDs?), we focused on studies reporting on
dopaminergic and serotonergic effects of ibogaine, since these
neurotransmitters have been reported to play a pivotal role in
SUDs and relapse.
24,25
In this context, we defined an ‘animal
model of SUD’with the animals having experienced the same
drug chronically, which means for at least two times.
Search strategy and selection of the papers
We identified published manuscripts regarding the effects of
ibogaine in animal models for SUDs in Medline via the PubMed
interface, Embase, Psychinfo, CINAHL and Web of Science, until 1
November 2014. To minimise the risk of overlooking any studies,
we applied a broad search strategy using the following five search
terms:
26,27
‘Ibogaine’,‘noribogaine’,‘12-Methoxyibogamine’,‘NIH-
-10567’and ‘Endabuse’(for the complete search strategy see
Supplementary Table 1). Reference lists of the selected papers
were screened by hand for additional relevant papers.
Experimental animal studies were included in the SR if they
fulfilled one of the following criteria: (a) the study employs
ibogaine in a drug SA and/or drug-induced CPP paradigm; (b) the
study is about the effect of ibogaine on cerebellar cell structure,
motor functioning or cardiac rhythm; (c) the study is about the
effect of ibogaine on dopaminergic or serotonergic neurotrans-
mission in an animal with chronic drug use. Studies were
excluded: (a) when they appeared to be a duplicate publication,
review, letter or commentary; (b) when no control group was
included in the experiment; (c) ibogaine treatment was combined
with other drugs and (d) when the study was not an animal
in vivo model.
Using Early Review Organizing Software (EROS; Institute of
Clinical Effectiveness and Health Policy, Buenos Aires, Argentina),
each reference was randomly allocated to two independent
reviewers (MB and ML) who screened it for inclusion on the basis
of title and abstract. In case of doubt, the whole publication was
evaluated. Full-text copies of all publications eligible for inclusion
were subsequently assessed by the same two reviewers and
included if they met our pre-specified inclusion criteria. Disagree-
ments were solved by discussion with a third investigator (CRH).
Study characteristics and data extraction
From the included studies, bibliographic data such as authors,
year of publication, journal of publication and language were
registered. We also extracted data on study design (number of
animals in the experimental and control groups), animal model
characteristics (animal species, strain, age, body weight, and age
at the beginning of the study and gender), intervention
characteristics (description of addiction model, used drug in
addiction model and its dosage regimen, ibogaine dosage
regimen and administration route) and outcome measures. For
our first research question (does ibogaine reduce addictive
behaviour in animal models of SUDs?) outcome measures were
SA of a drug (as quantised by number of active/inactive nose
pokes, lever responses or drug infusions) or drug-induced CPP (as
quantised by time spent in one compartment of a two-
compartment chamber) of an animal. For our second research
question (does ibogaine supplementation to animals cause
adverse toxic effects?) outcome measures were occurrence and
severity of motor impairment (including tremors and ataxia as
measured by uphill orientation on, or falling off a tilted platform),
cerebellar cell loss and cardiac toxicity. For our third research
question (does ibogaine influence addiction-related neurobiolo-
gical response in animal models of SUDs?) outcome measures
were any proxies of dopamine and/or serotonin function in
different brain regions.
If available, raw data or group averages (mean, median or
incidence) were extracted, as well as s.d., s.e. or ranges and
number of animals per group (n). If more than one experiment
was reported on the same outcome measure in a manuscript, the
experiments were only included separately in the analyses when
other animals were used. Multiple experiments on the same group
of animals were pooled. If the number of animals was reported as
a range, the lowest number of animals was included in the
analyses. If data were presented only graphically, we applied
Universal Desktop Ruler software (http://avpsoft.com/products/
udruler/), to come to an adequate estimation of the outcome
measurements. In case of missing outcome measure data, we
contacted the authors for additional information. If no adequate
estimation could be made or data were missing, the results were
excluded from the analyses. If multiple experimental groups were
compared with the same control group, the group size of the
control group was corrected for the number of comparisons made
(n/number of comparisons).
Assessment of methodological quality and risk of bias
The risk of bias was assessed for each of the included studies by
two authors independently (MB and ML) using SYRCLE’s risk of
bias tool.
28
A‘yes’score indicates low risk of bias; a ‘no’score
indicates high risk of bias; and a ‘?’score indicates unknown risk of
bias. In case of disagreement, a third author was consulted (CRH).
Concerning the number of excluded animals, we assumed that
there had been no exclusion if the number of animals per group
mentioned in the Materials and methods section was identical to
the number stated in the Results section or figure legends.
Reporting of experimental details on animals, methods and
materials is often limited
29
and to overcome the problem of
judging too many items as ‘unclear risk of bias’we added two
items: reporting of any measure of randomisation; and reporting
of any measure of blinding. For these two items, a ‘yes’score
indicates ‘reported’, and a ‘no’score indicates ‘unreported’.
Data synthesis and statistical analyses
MA was performed using Comprehensive Meta-Analysis software
(version 2.2, Biostat, Englewood, NJ, USA). For all the continuous
outcome measures, the s.d. was calculated if only the s.e. was
reported (s.d. = s.e. × √n). In case, data were presented as median
and percentiles, these data were converted to mean and s.d.
30
In
the data set on ibogaine toxicology, both continuous and
dichotomous data were reported, which were analysed separately.
When one of the cells to calculate a risk ratio (RR) contained a
zero-value or the risk in either the control or experimental group
was 100%, we added 0.5 to each cell to calculate the RR. Despite
Ibogaine and addiction, a meta-analysis
M Belgers et al
2
Translational Psychiatry (2016), 1 –11
anticipated heterogeneity, individual effect sizes were pooled
to obtain an overall standardized mean difference (SMD)
for continuous outcome measures and a RR for dichotomous
outcome measures, with their 95% confidence intervals. A random
effects model
31
was used, which takes the precision of individual
studies and the variation between studies into account and
weights each study accordingly.
Explorative subgroup analyses were performed for different
dosages of ibogaine, different time frames for the effect, different
animal species, gender and type of drug used, only if at least four
studies were available per subgroup. These subgroups were
specified in advance and documented in the protocol (www.
syrcle.nl). Because dosing regimens varied considerably among
studies, we also grouped studies into low, medium and high dose
studies, corresponding with 0–40 mg kg
−1
,40–80 mg kg
−1
and
480 mg kg
−1
, respectively. Dosages used by humans are typically
between 10 and 25 mg kg
−1
orally.
12
When translating these
dosages to animal studies according body surface area
32
and
taking into account differences in effects after oral and i.p. dosing
regimens
33
they correspond with 40–80 mg kg
−1
. Because the
starting point of measurements after the ibogaine supplementa-
tion varied considerably between studies, we grouped these in to
three time frames, corresponding with 0–24 h, 24–72 h and 472 h
after ibogaine supplementation, respectively. Since motor impair-
ment is most often reported during the first 24 h after ibogaine
administration, this could influence measurements. It is relevant to
explore the effects beyond the acute phase of 24 h, since human
reports claim ibogaine has a lasting effect for several months even
after a single dose.
34
Morphine and heroine (di-acetyl morphine)
were grouped together under opioids since their working
mechanism are almost identical. We assumed that the variance
was comparable within the subgroups; therefore, we assumed a
common among-study variance across subgroups. For subgroup
analyses, we applied a Bonferroni correction for multiple testing
(p* number of comparisons). However, differences between
subgroups should be interpreted with caution and should only
be used for constructing new hypotheses rather than for drawing
final conclusions.
Sensitivity analyses and publication bias analyses
We performed sensitivity analyses to assess the robustness of our
findings, by changing the boundaries of dosage regimen and time
frames. We also assessed whether analysing morphine and heroin
separately would change the results for this group. Furthermore,
we assessed the possibility of publication bias by evaluating
symmetry in the funnel plot for the outcome measure SA,
performing Duval and Tweedie's trim and fill analysis, and Egger's
regression analysis for small study effects. Heterogeneity was
assessed using I
2
.
RESULTS
Study selection process and search results
Our search yielded 361 records from PubMed, 532 articles from
EMBASE, 107 from Psychinfo, 10 from CHINAHL and 373 of Web of
Science. About 660 articles appeared to be unique (see Figure 1
for a consort flow chart). Ultimately, 30 articles (all in English
language) matched the inclusion criteria (Supplementary Table 2).
These 30 articles contained 32 studies, which were included for
SR (see Supplementary Table 3 for study characteristics). Eleven
studies described the drug SA or CPP paradigms. Nineteen studies
were on ibogaine toxicity. From four of these studies data could
not be retrieved. There were no in vivo studies on the cardiac
effects of ibogaine, which matched our inclusion criteria. Only two
papers reported dopaminergic and/or serotonergic effects of
ibogaine in animals that had chronic contact with drugs. The
remaining 28 studies were analysed in MA. Most comparisons
were conducted in rats (87%), and the remaining in mice. In the
majority of comparisons, male animals were used (73%). Weight of
the animals was reported in 21 studies (70%) and half of the
studies reported the age of the animals. From the behavioural
effect studies, four studies reported on the effect on cocaine use,
four on morphine, one on heroin, one on amphetamine and one
on alcohol use.
Description of characteristics and MA of the effects of ibogaine in
animals
Effect of ibogaine on drug SA. From 8 studies, 29 independent
comparisons about the effect of ibogaine on drug SA could be
included in MA. The data of 10 independent comparisons from 3
studies could not be retrieved for MA.
35–37
MA indicates that
ibogaine reduced drug SA (SMD = −1.54 [ −1.93; −1.14] n=29;
I
2
= 64%), (Figure 2). In none of the comparisons, ibogaine
enhanced drug SA.
Subgroup analyses revealed a larger reduction of SA in the first
24 h after ibogaine dosing (SMD = −2.42 [ −3.05; −1.78] n=25;
I
2
= 71%), compared with measurements after this time point (24–
78 h: SMD = −1.14 [ −1.60; −0.68] n=13; I
2
= 46%; P=0.003,
472 h: SMD = −0.92 [ −1.50; −0.34] n=9; I
2
= 65%; P=0.002)
(Figure 3.).
There was no difference in the effect of ibogaine on SA between
other subgroups, with different types of drugs being used
(cocaine, opioids and ethanol), gender or dosing levels. There
was also no difference between these subgroups if we analysed
the prolonged effect of ibogaine on SA (measurements 424 h
after ibogaine dosing) (Table 1). We could not analyse for species
subgroup because the number of comparisons was o4. The
overall in-between study heterogeneity was large (I
2
= 64%).
Effect of ibogaine on drug-induced CPP. Fourteen independent
comparisons from 3 studies reported about the effect of ibogaine
on drug-induced CPP, 4 using amphetamine and 10 using
morphine. Ibogaine did not reduce drug-induced CPP (SMD =
−0.22 [ −0.53; 0.08] n=14; I
2
= 39%; see Figure 4). Subgroup
analyses were not performed for gender, strain and species, as all
comparisons were done with male Sprague–Dawley rats. There
were no differences in effects of ibogaine on drug-induced CPP in
the comparison of subgroups, with different types of drugs being
used (amphetamine and opioids), different time frames of
measurement after ibogaine supplementation and dosing levels
(Supplementary Table 5). There was also no difference between
the subgroups of one cycle of CPP learning or two or more cycles.
The overall in-between study heterogeneity was moderate
(I
2
= 39%).
Toxic effects of ibogaine
The effect of ibogaine on motor functioning: Eight studies
reported on toxic effects of ibogaine on motor functioning, from
which three study data could not be retrieved.
37–39
From the 5
other studies, 10 independent comparisons with continuous
outcome measures and 6 with dichotomous outcome measures
reported about the effect of ibogaine on motor functioning. Both
the continuous and dichotomous outcome measures showed that
the administration of ibogaine caused motor impairment (con-
tinuous: SMD = 0.82 [0.46; 1.17] n=10; I
2
= 0%, dichotomous:
RR = 6.20 [2.20; 17.44] n=6; I
2
= 15; see Figure 5). All measure-
ments were obtained within 24 h after ibogaine administration. In
all comparisons male animals were used. Eight comparisons used
rats, and the other eight used mice.
There was no difference in the occurrence of motor symptoms
after ibogaine between different dosing regimens (continuous
measurements: o40 mg kg
−1
: SMD = 1.11 [0.44; 1.78] n=5;
I
2
= 0%; 40–80 mg kg
−1
: SMD = 0.61 [0.07; 1.15] n=4I
2
= 0%;
dichotomous measurements: o40 mg kg
−1
: RR = 5.61 [1,15;
Ibogaine and addiction, a meta-analysis
M Belgers et al
3
Translational Psychiatry (2016), 1 –11
17.44] n=4; I
2
= 46%; see Supplementary Table 6). However,
subgroups on dosages of 480 mg kg
−1
were too small to analyse,
as well as the subgroup of medium dosage in the group of
dichotomous measurements. The in-between study heterogeneity
was low for both the continuous and dichotomous outcome
measures (I
2
= 0% and 15%, respectively).
The effect of ibogaine on cerebellar cell loss: Eleven studies
reported on toxic effects of ibogaine on cerebellar cell loss. From
the 11 studies, 1 study data could not be retrieved.
40
From the 10
other, 28 comparisons reported on the effects of ibogaine
administration on cerebellar degeneration. Indicators of cerebellar
degeneration applied were the Nadler–Evenson method, glial
fibrillary acidic protein immunocytochemical, fluoro-jade or
anti-calbinidin staining or according to immune reactivity with
antibodies against calcium-calmodulin-dependent protein kinase
II (Cam KII). Both the continuous and dichotomous outcome
measures showed that administration of ibogaine causes cere-
bellar cell loss (continuous: SMD = 0.78 [0.32; 1.23] n=13; I
2
= 42%,
dichotomous: RR = 2.60 [1.35; 5.01] n=15; I
2
= 0; see Figure 6).
In the group with continuous measurements, six comparisons
applied oral ibogaine administration. In the dichotomous group,
ibogaine was administered i.p. The effect of ibogaine on cerebral
cell loss was only observed in comparisons with i.p. administra-
tion, but not after oral administration (i.p.: SMD = 1.27 [0.87; 1.66]
n=7; I
2
= 4%; oral: SMD = −0.22 [ −0.89; 0.45] n=6I
2
= 0%).
There was no effect of gender on the results, nor was there a
difference between mice and rats (analysed in the dichotomous
studies). In the group of continuous measurements, all animals
were rats, and in this group we could not analyse potential
differences between dosing groups because the number of
comparisons was o4. However, in the group with dichotomous
measurements no effect was found in the medium dosing groups
in contrast with the high dosing group (Supplementary Table 7). In
the group with continuous measurements only, cell loss was
observed when measured 472 h after ibogaine supplementation.
The overall in-between study heterogeneity was moderate in the
group with continuous measurements (I
2
= 42%) and zero in the
group with dichotomous measurements.
The effect of ibogaine on heart rhythm: No studies were found
on cardiovascular effects of ibogaine that matched our inclusion
criteria.
Neuropharmacological effects of ibogaine in animal models of
SUDs. Only two studies matched our inclusion criteria.
15,16
These
studies showed that ibogaine treatment lowered drug-induced
dopamine efflux in rats, as measured with dialysate levels in the
nucleus accumbens and striatum after chronic cocaine or
morphine use (SMD = −1.14 [ −2.03; −0,26] n=2; I
2
= 0%).
Summary of results. See Table 2 for a summary of the results.
Figure 1. Flow chart of the study selection.
Ibogaine and addiction, a meta-analysis
M Belgers et al
4
Translational Psychiatry (2016), 1 –11
Risk of bias, quality of reporting and publication bias
Of the 30 studies included in this SR, only few applied methods to
avoid bias. Five studies (17%) reported randomisation of
treatment in some way. However, none of these studies
mentioned the methods of randomisation applied. None of the
papers stated that the experiments were blinded, described the
allocation sequence or concealing during the randomisation
process. Measures to reduce performance bias (random housing
and blinding of the caregivers) were reported in only one study.
None of the studies reported that the outcome assessor was
blinded for the allocation of the animals. Only one study reported
random outcome assessment. In 27% of the studies, the baseline
characteristics varied between the control group and experimen-
tal group at the start of the experiment. Most potential sources of
bias had to be scored as unclear risk of bias, as a consequence of
poor reporting (Supplementary Figure 1).
Inspection of the funnel plots suggested some asymmetry due
to an underrepresentation of studies with moderate to low
precision and increased drug SA after ibogaine use. Duval and
Tweedie's trimm and fill analysis for the data set on drug SA
resulted in 4 extra data points of the total of 29 comparisons,
indicating slight overestimation of the summary effect size
(Supplementary Figure 2). Sensitivity analysis revealed that
changing the boundaries of our inclusion criteria and the
classification of our subgroups did not alter our results
significantly.
DISCUSSION
The current MA on the effect of ibogaine treatment in animal
models of SUDs is, to the best of our knowledge, the first of its
kind. Ibogaine was found to reduce SA of cocaine, ethanol and
opioids in animals, but lacked an effect on CPP learning
paradigms. The effect on SA lasted for over 72 h after ibogaine
administration, indicating potentially long-term beneficial effects.
Ibogaine treatment also induced motor impairment during the
first 24 h after ibogaine administration, independent of the
dosage used. Dose-dependent cerebellar cell loss was observed
even weeks after ibogaine administration. No animal studies
regarding cardiac toxicity of ibogaine treatment were identified.
Figure 2. Forest plot of the impact of ibogaine on drug self-administration (SA). A negative outcome means reduction of SA; a positive
outcome means an enhancement. Data are presented as standardized mean differences (SMD) and 95% confidence intervals (CI).
Figure 3. Effect (standard mean difference (SMD)) of ibogaine on
drug self-administration (column, effect size; line, confidence
interval (CI)) as function in three time frames (0–24 h, 24–
72 h,472 h) after ibogaine dosing.
Ibogaine and addiction, a meta-analysis
M Belgers et al
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Translational Psychiatry (2016), 1 –11
Table 1. Effects of ibogaine on drug self-administration in different subgroups for all comparisons (blue, n=29) and for all comparisons 24 h after
ibogaine dosing (green, n=13)
Upper limit
Abbreviation: SMD, standard mean difference. (Low dose: 0–40 mg kg
−1
(not present in 424 h subgroup); Medium dose: 40–80 mg kg
−1
; High dose:
480 mg kg
−1
). None of the subgroups showed a significant difference. Subgroup analyses were conducted when the subgroups contained at least four
comparisons.
Figure 4. Forest plot of the impact of ibogaine on drug-induced conditioned place preference (CPP). A negative outcome means reduction of
CPP; a positive outcome means an enhancement. Data are presented as standardized mean differences (SMD) and 95% coincidence intervals.
Ibogaine and addiction, a meta-analysis
M Belgers et al
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Translational Psychiatry (2016), 1 –11
Similarly, studies on the neuropharmacology of ibogaine treat-
ment in animal models of SUDs are limited as well.
The observation that ibogaine reduces SA of cocaine, ethanol
and opioids is consistent with clinical observations in humans and
previous narrative reviews of animal studies.
10,12,14,41
Though the
beneficial effects of ibogaine were most prominent in the first 24 h
after administration, the beneficial effects lasted for over 72 h. This
is in line with human case reports, describing long-lasting effects
of ibogaine on craving in patients with cocaine and opiate
dependence, for several months.
42,43
While ibogaine decreases drug SA, it is not effective in reducing
drug-induced CPP. One difference between the two paradigms is
that CPP measures aspects of Pavlovian conditioning of an animal
experiencing rewarding or salient effects of a substance in a given
context. Pavlovian conditioning is an automatic, involuntarily
reflex-like process. The drug SA paradigm, on the other hand,
involves a combination of Pavlovian and operant conditioning. A
cue presented in the test cage signals the availability of the
substance through Pavlovian conditioning, serving as a condi-
tioned reinforcer. In addition, based on both the conditioned
reinforcer and the rewarding effects of the substance itself the
animals are reinforced to press on a lever or to poke into a nose-
poke-hole to obtain the substance. Hence, active behaviour is
required in the drug SA paradigm, which may eventually develop
as a habit. Because of the voluntarily nature of the drug SA
paradigm, this paradigm has greater translational value compared
with the CPP paradigm. It is tempting to speculate that ibogaine
reduces drug SA, reflecting an effect on the reinforcing properties
of a substance as measured by operant conditioning, but not
Pavlovian conditioning that is linked to the rewarding effects
of drugs.
We found that ibogaine causes acute motor impairment in
animals, even in low dosages. No studies published results on
whether these effects last over time, although three of the five
studies described that tremors and ataxia disappeared within
24 h.
44–46
This would be consistent with human studies, where
these effects also disappeared within 24 h.
47
It is hypothesised
that these effects on motor functioning are caused by ibogaines’
exciting effect on neurons in the inferior olivary nucleus, within
the medulla oblongata. Sustained release of glutamate in neurons
of the olivary nucleus triggered by ibogaine may contribute to
excitotoxic degeneration of cells within the cerebellum.
48
Indeed,
high doses of ibogaine were associated with reduced cerebellar
cell counts. It has been suggested that the motor effects of
ibogaine mediate the beneficial effects of ibogaine on drug SA.
However, some studies report an absence of the effect of ibogaine
on water-intake, making this hypothesis less likely.
49
We did not encounter animal studies focussing on the effects of
ibogaine on the heart rhythm, matching our inclusion criteria.
However, we found one study showing a decrease in heart rate,
blood pressure and cardiac output in four anaesthetised dogs
receiving 5 mg kg
−1
of ibogaine besides barbital.
50
We also found
some animal studies about the cardiovascular effect of taber-
nanthine (an isomer of ibogaine, different in the position of a
methoxyl group) reporting bradycardia and hypotension.
51–53
Mash et al.
47
reported that no electrocardiographic abnormalities
were seen in 150 patients treated with ibogaine. Notably, in this
study it is unclear which exact methods were used for monitoring.
Other human studies do report potentially life-threatening effects
of ibogaine on heart rhythm.
21
Some in vitro studies report an
effect of ibogaine on the human Ether-à-go-go-Related Gene
potassium channel, potentially contributing to prolonged QT
intervals on the electrocardiogram and eventually cardiac
arrhythmias.
54
This is particularly relevant, since SUD patients
often use other QT prolonging medication (like methadone and
SSRI’s). Moreover, studies reported bradycardia, hypotension and a
diminished cardiac output after use of an ibogaine-isomer, which
the authors attributed to an effect on calcium mobilisation.
50,51
Since cardiac effects of ibogaine could be related to previously
Figure 5. Forest plots for continuous (upper) and dichotomous (lower) effect measures of ibogaine on motor functioning. In the upper plot
(continuous measurements), a negative outcome means enhancement of motor functioning; a positive outcome means an impairment. In this
plot, data are presented as standardized mean differences (SMD) and 95% coincidence intervals. In the lower plot (dichotomous
measurements), an outcome o1 means enhancement of motor functioning; an outcome 41 means an impairment of motor functioning. In
this plot, data are presented as risk ratios and 95% coincidence intervals.
Ibogaine and addiction, a meta-analysis
M Belgers et al
7
Translational Psychiatry (2016), 1 –11
reported fatalities after ibogaine ingestion
20
and intoxications,
55
there is a great need for animal studies addressing this issue.
Although we conducted a very comprehensive search on the
neuropharmacology of ibogaines’effects in animal models of
addiction, only two articles matched our inclusion criteria. This
clearly points out that there is a gap of knowledge regarding the
neuropharmacological mechanisms of action of ibogaine in
addiction. Nevertheless, these two studies showed that ibogaine
treatment lowered drug-induced dopamine efflux in rats chroni-
cally exposed to drugs. Consistent with the theoretical role of
dopamine in addiction, this could explain why ibogaine is capable
of reducing drug SA in animals and why it may reduce craving and
relapse in patients with SUDs.
Because of the well-established role of specifically dopaminer-
gic and serotonergic signalling in drug craving, risk-related
decision making, impulse control and relapse in addiction
research,
56,57
we decided to explore the pharmacological effects
of ibogaine on these pathways only. However, several other
neurotransmitter systems are relevant in the context of addiction,
particularly for alcohol given its effects on a variety of brain
receptors. Given the limited number of studies identified in our
search, we conducted retrospective analyses on our search results
to identify studies that investigated (1) other neuropharmacolo-
gical effects of ibogaine and (2) other animal models of substance
use, including single dose studies.
The first retrospective analysis identified one extra article on
cerebral glucose utilisation, indicating ibogaine reduces cerebral
glucose utilisation in morphine-dependent rats.
58
This paper did
not report on any effect on specific neurotransmitter systems. The
second retrospective analysis identified 14 additional articles
(summarised in Supplementary Table 4). In these articles, 11
studies were about the effect of ibogaine on drug-induced
dopamine efflux. Different drugs of abuse were used and
measurements focused on different brain areas. Five studies
showed ibogaine reduced this drug-induced efflux of dopamine,
three studies showed an enhancement and three showed no
effect. This lack of a clear direction of effect when animals received
a drug only once is in contrast with our finding of ibogaines
positive effect in reducing dopamine efflux in the animal forced
with more than one drug-suppletion. This could be due to the
limited amount of studies we found, but it would also be
consistent with our findings that ibogaine affects drug-induced
reinforcement learning (as seen in drug SA) but not Pavlovian
conditioning (as seen in drug-induced CPP).
Studies on the acute effects of ibogaine in animals not exposed
to any drug of abuse show that ibogaine can block N-Methyl-D-
aspartate-type glutamatergic neurotransmission
59
and inhibit glial
glutamate re-uptake.
60
Other potential neuropharmacological
mechanisms of ibogaine proposed in the literature include
antagonism on the α3β4 nicotinic acetylcholine receptor
61
and
serotonin transporter,
62
effects on gene expression including some
transcription factors involved in SUDs (like Fos family protein
(ΔFosB) and cAMP response element binding protein)
63
and the
enhancement of glial cell line-derived neurotrophic factor.
64,65
However, the exact neuropharmacological mechanism of ibogaine
in the treatment of SUDs remains to be elucidated.
Figure 6. Forest plots for continuous (upper) and dichotomous (lower) effect measures of ibogaine on cerebellar cell loss. In the upper plot
(continuous measurements), a negative outcome means reduction of cerebellar cell loss; a positive outcome means an enhancement. In this
plot, data are presented as standardized mean differences (SMD) and 95% confidence intervals. In the lower plot (dichotomous
measurements), an outcome o1 means that no cerebellar cell loss has occurred, an outcome 41 means cerebellar cell loss has occurred. In
this plot, data are presented as risk ratios and 95% coincidence intervals.
Ibogaine and addiction, a meta-analysis
M Belgers et al
8
Translational Psychiatry (2016), 1 –11
STRENGTHS AND LIMITATIONS OF THE REVIEW
The findings of this MA should be seen in the light of its strengths
and limitations. A particularly strong point is the systematic and
meta-analytic approach to summarise all available animal
evidence regarding the effects of ibogaine for addiction. Such
an evidence-based approach maximises the changes of successful
translation from bench to bedside.
66
However, there are also some limitations to our study. First, the
risk of bias analysis showed poor reporting in most studies
concerning essential methodological details. As a consequence
most items in the risk of bias tool for animal studies
28
had to be
scored as unclear risk of bias. It is unclear whether this insufficiency
in reporting truly reflects hampered methodological rigour, con-
tributing to bias, confounding or skewed findings.
67
Nevertheless, for
both scientific and ethical reasons methodological reporting of
individual animal studies urgently needs to be improved.
22,68,69
Second, this SR/MA contains a relatively low number of studies
and revealed generally moderate to large levels of heterogeneity.
This combination may diminish the certainty in the effect
estimates. Nevertheless, to account for the observed heterogene-
ity we used a random (rather than fixed) effects model in the MA
and conducted subgroup analyses. In addition, one needs to bear
in mind that animal studies are often explorative and hetero-
geneous with respect to species, design and intervention
Table 2. Summary of results
An arrow means an effect was found with a significance of Po0.05 or less. Double arrow: effect size 42. Direction arrow up: positive effect, direction down:
negative effect. A hyphen means no effect was found (P≥0.05). A question mark means insufficient or no data was available.
Ibogaine and addiction, a meta-analysis
M Belgers et al
9
Translational Psychiatry (2016), 1 –11
protocols and so on, as compared with clinical trials, and
moderate levels of heterogeneity might therefore be expected.
Third, several limitations of the SA and the CPP models of SUDs
should be taken into account. Though the SA model is the best
behavioural paradigm for predicting medication effects for the
treatment of cocaine and opioid dependence,
70
and is increas-
ingly used in animal studies on SUDs,
71
treatments which are
effective in SA and CPP do not always translate to humans. For
example, not all aspects of SUDs in humans, like socioeconomics,
peer group, and co-morbidity can be modelled in animal models.
In addition, we did not find studies on the effect of ibogaine on SA
of other drugs of abuse than opioids, cocaine and ethanol.
Therefore, the current findings with ibogaine cannot be general-
ised to all SUDs. Yet, studies with 18-Methoxycoronaridine (a
synthetic analogue of ibogaine) and noribogaine (a metabolite of
ibogaine) did also show reduced SA for amphetamine and
nicotine.
65,72–76
Finally, no studies took phenotypic animal variation into
account, although this may be highly relevant in the context of
SUDs. For example, some rats are more attracted to conditioned
stimuli predicting reward rather than to the reward (goal) itself.
These so-called sign-trackers are more motivated to self-
administer cocaine,
77
and are highly dependent on dopamine.
Dopamine release increases on presentation of a conditioned
stimulus predicting reward in these sign-trackers.
78
Since ibogaine
blocks dopamine release in the NAc,
15
it is tempting to speculate
that sign-trackers are more responsive to ibogaine than goal-
trackers (attracted to reward delivery). Similarly, trait anxiety and
impulsivity differentially contribute to the liability to SA and CPP,
79
and could influence the efficacy of ibogaine.
RECOMMENDATIONS AND CLINICAL RELEVANCE
Our SR clearly indicates that ibogaine has potentially strong and
long-lasting reducing effects on the amount of drug SA in animals.
However, administration of ibogaine to animals also causes
negative effects, as impaired motor function and cerebellar cell
loss in high dosages given i.p. are observed. In addition, although
we did not find clear evidence regarding cardiac toxic effects of
ibogaine, clinical experiences with ibogaine do suggest that
ibogaine can cause potentially fatal cardiac arrhythmias. Given the
great clinical need for effective treatment modalities for addiction,
translational studies on the effects of ibogaine on drug craving
and relapse in humans are urgently needed. To minimise risks of
heart arrhythmias and cerebellar cell loss, we recommend oral and
low dosages of ibogaine to be applied in human studies, only
under close medical monitoring, and after thorough medical
screening.
Last but not least, with this SR, we identified several gaps of
knowledge in the preclinical literature on the effects of ibogaine.
Animal studies should further unravel the neuropharmacological
mechanisms mediating the effects of ibogaine on substance use.
Further, there is an urgent need for improving methodological
reporting of animal studies, to improve the successful translation
of animal research outcomes into the human clinical setting.
CONFLICT OF INTEREST
The authors declare no conflict of interest.
ACKNOWLEDGMENTS
We are grateful for the support of ZonMw (Netherlands) who provided SYRCLE, a
grant to promote Synthesis of Evidence of animal studies.
REFERENCES
1 Rehm J. Global alcohol-attributab le deaths from cancer, liver cirrhosis, and injury
in 2010. Alcohol Res 2014; 35: 174–183.
2 Whiteford HA, Degenhardt L, Rehm J, Baxter AJ, Ferrari AJ, Erskine HE et al. Global
burden of disease attributable to mental and substance use disorders: findings
from the Global Burden of Disease Study 2010. Lancet 2013; 382: 1575–1586.
3 Wittchen HU, Jacobi F, Rehm J, Gustavsson A, Svensson M, Jonsson B et al. The
size and burden of mental disorders and other disorders of the brain in Eur-
ope 2010. Eur Neuropsychopharmacol 2011; 21:655–679.
4 Duvall HJ, Locke BZ, Brill L. Followup study of narcotic drug addicts five years after
hospitalization. Public Health Rep 1963; 78: 185–194.
5 Finney JW, Hahn AC, Moos RH. The effectiveness of inpatient and outpatient
treatment for alcohol abuse: the need to focus on mediators and moderators of
setting effects. Addiction 1996; 91: 1773–1796, discussion 1803-1720.
6 Schoenthaler SJ, Blum K, Braverman ER, Giordano J, Thompson B, Oscar-Berman
Met al. NIDA-Drug Addiction Treatment Outcome Study (DATOS) relapse as a
function of spirituality/religiosity. J Reward Defic Syndr 2015; 1:36–45.
7 Jerry JM, Collins GB. Medication-assisted treatment of opiate dependence is
gaining favor. Clev Clin J Med 2013; 80:345–349.
8 Larney S, Gowing L, Mattick RP, Farrell M, Hall W, Degenhardt L. A systematic
review and meta-analysis of naltrexone implants for the treatment of opioid
dependence. Drug Alcohol Rev 2014; 33:115–128.
9 Shorter D, Domingo CB, Kosten TR. Emerging drugs for the treatment of cocaine
use disorder: a review of neurobiological targets and pharmacotherapy. Exp Opin
Emerg Drugs 2015; 20:15–29.
10 Brown TK. Ibogaine in the treatment of substance dependence. Curr Drug Abuse
Rev 2013; 6:3–16.
11 Alper KR, Lotsof HS, Frenken GM, Luciano DJ, Bastiaans J. Treatment of acute
opioid withdrawal with ibogaine. Am J Addict 1999; 8:234–242.
12 Alper KR, Lotsof HS, Kaplan CD. The ibogaine medical subculture. J Ethno-
pharmacol 2008; 115:9–24.
13 Alper KR, Lotsof HS. The use of ibogaine in the treatment of addictions.
In: Winkelman M, Roberts TB (eds). Psychedelic medicine: new evidence for hallu-
cinogenic substances as treatments. Vol 2. Praeger Perspectives: Westport, CT,
2007, pp 43–66.
14 Maciulaitis R, Kontrimaviciute V, Bressolle FM, Briedis V. Ibogaine, an anti-
addictive drug: pharmacology and time to go further in development. A
narrative review. Hum Exp Toxicol 2008; 27:181–194.
15 Szumlinski KK, Maisonneuve IM, Glick SD. Differential effects of ibogaine on
behavioural and dopamine sensitization to cocaine. Eur J Pharmacol 2000; 398:
259–262.
16 Pearl SM, Maisonneuve IM, Glick SD. Prior morphine exposure enhances ibogaine
antagonism of morphine-induced dopamine release in rats. Neuropharmacology
1996; 35: 1779–1784.
17 Volkow ND, Baler RD. Addiction science: uncovering neurobiological complexity.
Neuropharmacology 2014; 76 Pt B: 235–249.
18 Glick SD, Maisonneuve IM, Szumlinski KK. Mechanisms of action of ibogaine:
relevance to putative therapeutic effects and development of a safer iboga
alkaloid congener. Alkaloid Chem Biol 2001; 56:39–53.
19 Xu Z, Chang LW, Slikker W Jr, Ali SF, Rountree RL, Scallet AC. A dose-respo nse
study of ibogaine-induced neuropathology in the rat cerebellum. Toxicol Sci 2000;
57:95–101.
20 Alper KR, Stajic M, Gill JR. Fatalities temporally associated with the ingestion of
ibogaine. J Forensic Sci 2012; 57:398–412.
21 Koenig X, Hilber K. The anti-addiction drug ibogaine and the heart: a delicate
relation. Molecules 2015; 20: 2208–2228.
22 Wever KE, Menting TP, Rovers M, van der Vliet JA, Rongen GA, Masereeuw R et al.
Ischemic preconditioning in the animal kidney, a systematic review and
meta-analysis. PLoS One 2012; 7: e32296.
23 George O, Koob GF. Individual differences in prefrontal cortex function and the
transition from drug use to drug dependence. Neurosci Biobehav Rev 2010; 35:
232–247.
24 Budygin EA, Weiner JL. Exploring the neurochemical basis of alcohol addiction-
related behaviors: translational research. Transl Biomed 2015; 6(Suppl Spec): pii;
PMID: 26770883.
25 Müller CP, Homberg JR. The role of serotonin in drug use and addiction. Behav
Brain Res 2015; 277: 146–192.
26 de Vries RB, Hooijmans CR, Tillema A, Leenaars M, Ritskes-Hoitinga M. Updated
version of the Embase search filter for animal studies. Lab Anim 2014; 48:88.
27 Hooijmans CR, Tillema A, Leenaars M, Ritskes-Hoitinga M. Enhancing search effi-
ciency by means of a search filter for finding all studies on animal experi-
mentation in PubMed. Lab Anim 2010; 44: 170–175.
28 Hooijmans CR, Rovers MM, de Vries RB, Leenaars M, Ritskes-Hoitinga M, Lan-
gendam MW. SYRCLE's risk of bias tool for animal studies. BMC Med Res Methodol
2014; 14: 43.
Ibogaine and addiction, a meta-analysis
M Belgers et al
10
Translational Psychiatry (2016), 1 –11
29 Kilkenny C, Parsons N, Kadyszewski E, Festing MF, Cuthill IC, Fry D et al. Survey of
the quality of experimental design, statistical analysis and reporting of research
using animals. PLoS One 2009; 4: e7824.
30 Hozo SP, Djulbegovic B, Hozo I. Estimating the mean and variance from the
median, range, and the size of a sample. BMC Med Res Methodol 2005; 5:13.
31 DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986; 7:
177–188.
32 Reagan-Shaw S, Nihal M, Ahmad N. Dose translation from animal to human
studies revisited. FASEB J 2008; 22:659–661.
33 Kubiliene A, Marksiene R, Kazlauskas S, Sadauskiene I, Razukas A, Ivanov L. Acute
toxicity of ibogaine and noribogaine. Medicina (Kaunas) 2008; 44:984–988.
34 Sheppard SG. A preliminary investigation of ibogaine: case reports and recom-
mendations for further study. J Subst Abuse Treat 1994; 11:379–385.
35 Cappendijk SL, Dzoljic MR. Inhibitory effects of ibogaine on cocaine self-
administration in rats. Eur J Pharmacol 1993; 241:261–265.
36 Dworkin SI, Gleeson S, Meloni D, Koves TR, Martin TJ. Effects of ibogaine on
responding maintained by food, cocaine and heroin reinforcement in rats.
Psychopharmacology 1995; 117:257–261.
37 Glick SD, Kuehne ME, Raucci J, Wilson TE, Larson D, Keller RW Jr et al. Effects of
iboga alkaloids on morphine and cocaine self-administration in rats: relationship
to tremorigenic effects and to effects on dopamine release in nucleus accumbens
and striatum. Brain Res 1994; 657:14–22.
38 Chen K, Kokate TG, Donevan SD, Carroll FI, Rogawski MA. Ibogaine block of the
NMDA receptor: In vitro and in vivo studies. Neuropharmacology 1996; 35:423–431.
39 Trouvin JH, Jacqmin P, Rouch C, Lesne M, Jacquot C. Benzodiazepine receptors
are involved in tabernanthine-induced tremor: in vitro and in vivo evidence. Eur J
Pharmacol 1987; 140: 303–309.
40 O'Hearn E, Molliver ME. Degeneration of Purkinje cells in parasagittal zones of the
cerebellar vermis after treatment with ibogaine or harmaline. Neuroscience 1993;
55: 303–310.
41 Alper KR. Ibogaine: a review. Alkaloid Chem Biol 2001; 56:1–38.
42 Mash DC, Kovera CA, Pablo J, Tyndale RF, Ervin FD, Williams IC et al. Ibogaine:
complex pharmacokinetics, concerns for safety, and preliminary efficacy mea-
sures. Ann N Y Acad Sci 2000; 914: 394–401.
43 Schenberg EE, de Castro Comis MA, Chaves BR, da Silveira DX. Treating drug
dependence with the aid of ibogaine: a retrospective study. J Psychopharmacol
2014; 28: 993–1000.
44 Baumann MH, Rothman RB, Pablo JP, Mash DC. In vivo neurobiological effects of
ibogaine and its O-desmethyl metabolite, 12-hydroxyibogamine (noribogaine),
in rats. J Pharmacol Exp Ther 2001; 297:531–539.
45 Kesner RP, Jackson-Smith P, Henry C, Amann K. Effects of ibogaine on sensory-
motor function, activity, and spatial learning in rats. Pharmacol Biochem Behav
1995; 51: 103–109.
46 Leal MB, de Souza DO, Elisabetsky E. Long-lasting ibogaine protection against
NMDA-induced convulsions in mice. Neurochem Res 2000; 25: 1083–1087.
47 Mash DC, Kovera CA, Pablo J, Tyndale R, Ervin FR, Kamlet JD et al. Ibogaine in the
treatment of heroin withdrawal. Alkaloid Chem Biol 2001; 56:155–171.
48 O'Hearn E, Molliver ME. The olivocerebellar projection mediates ibogaine-induced
degeneration of Purkinje cells: a model of indirect, trans-synaptic excitotoxicity. J
Neurosci 1997; 17: 8828–8841.
49 Glick SD, Pearl SM, Cai J, Maisonneuve IM. Ibogaine-like effects of noribogaine
in rats. Brain Res 1996; 713:294–297.
50 Schneider JA, Rinehart RK. Analysis of the cardiovascular action of ibogaine
hydrochloride. Arch Int Pharmacodyn Ther 1957; 110:92–102.
51 Hamon G, Castillon A, Gaignault JC, Worcel M. Peripheral cardiovascular effects of
tabernanthine tartrate in anaesthetized rats. Arch Int Pharmacodyn Ther 1985;
276:60–72.
52 Zetler G, Lenschow E, Prenger-Berninghoff W. ?Die wirkung von 11 indol alka-
loiden auf das Meerschweinchenherz in vivo und in vitro, verglichen met 2
synthetischen Azepinoindolen, chinidin und quindonium. Naunyn Schmiedebergs
Arch Pharmakol Exp Pathol 1968; 260: 226–249.
53 Hajo N, Dupont C, Wepierre J. [Effects of tabernanthine on various cardiovascular
parameters in the rat and dog (author's transl)]. J Pharmacol 1981; 12:441–453.
54 Koenig X, Kovar M, Boehm S, Sandtner W, Hilber K. Anti-addiction drug ibogaine
inhibits hERG channels: a cardiac arrhythmia risk. Addict Biol 2014; 19: 237–239.
55 Vlaanderen L, Martial LC, Franssen EJ, van der Voort PH, Oosterwerff E, Somsen
GA. Cardiac arrest after ibogaine ingestion. Clin Toxicol 2014; 52: 642–643.
56 Orsini CA, Moorman DE, Young JW, Setlow B, Floresco SB. Neural mechanisms
regulating different forms of risk-related decision-making: Insights from
animal models. Neurosci Biobehav Rev 2015; 58:147–167.
57 Garbusow M, Sebold M, Beck A, Heinz A. Too difficult to stop: mechanisms
facilitating relapse in alcohol dependence. Neuropsychobiology 2014; 70:103–110.
58 Levant B, Pazdernik TL. Differential effects of ibogaine on local cerebral glucose
utilization in drug-naive and morphine-dependent rats. Brain Res 2004; 1003:
159–167.
59 Skolnick P. Ibogaine as a glutamate antagonist: relevance to its putative anti-
addictive properties. Alkaloid Chem Biol 2001; 56:55–62.
60 Leal MB, Emanuelli T, Porciuncula LD, Souza DO, Elisabetsky E. Ibogaine alters
synaptosomal and glial glutamate release and uptake. Neuroreport 2001; 12:
263–267.
61 Glick SD, Maisonneuve IM, Kitchen BA, Fleck MW. Antagonism of alpha 3
beta 4 nicotinic receptors as a strategy to reduce opioid and stimulant
self-administration. Eur J Pharmacol 2002; 438:99–105.
62 Bulling S, Schicker K, Zhang YW, Steinkellner T, Stockner T, Gruber CW et al. The
mechanistic basis for noncompetitive ibogaine inhibition of serotonin and
dopamine transporters. J Biol Chem 2012; 287: 18524–18534.
63 Nestler EJ. Transcriptional mechanisms of drug addiction. Clin Psychopharmacol
Neurosci 2012; 10:136–143.
64 He DY, McGough NN, Ravindranathan A, Jeanblanc J, Logrip ML, Phamluong K
et al. Glial cell line-derived neurotrophic factor mediates the desirable actions of
the anti-addiction drug ibogaine against alcohol consumption. J Neurosci 2005;
25:619–628.
65 Carnicella S, He DY, Yowell QV, Glick SD, Ron D. Noribogaine, but not 18-MC,
exhibits similar actions as ibogaine on GDNF expression and ethanol self--
administration. Addict Biol 2010; 15: 424–433.
66 Lau J, Ioannidis JP, Schmid CH. Quantitative synthesis in systematic reviews. Ann
Int Med 1997; 127: 820–826.
67 Hirst JA, Howick J, Aronson JK, Roberts N, Perera R, Koshiaris C et al. The need for
randomization in animal trials: an overview of systematic reviews. PLoS One 2014;
9: e98856.
68 Hooijmans CR, de Vries RB, Rovers MM, Gooszen HG, Ritskes-Hoitinga M. The
effects of probiotic supplementation on experimental acute pancreatitis: a sys-
tematic review and meta-analysis. PLoS One 2012; 7: e48811.
69 Macleod MR, van der Worp HB, Sena ES, Howells DW, Dirnagl U, Donnan GA.
Evidence for the efficacy of NXY-059 in experimental focal cerebral ischaemia is
confounded by study quality. Stroke 2008; 39: 2824–2829.
70 Haney M, Spealman R. Controversies in translational research: drug self--
administration. Psychopharmacology 2008; 199: 403–419.
71 Bossert JM, Marchant NJ, Calu DJ, Shaham Y. The reinstatement model of drug
relapse: recent neurobiological findings, emerging research topics, and transla-
tional research. Psychopharmacology 2013; 229: 453–476.
72 Glick SD, Maisonneuve IM, Dickinson HA. 18-MC reduces methamphe tamine and
nicotine self-administration in rats. Neuroreport 2000; 11: 2013–2015.
73 Polston JE, Pritchett CE, Sell EM, Glick SD. 18-Methoxycoronaridine blocks context-
induced reinstatement following cocaine self-administration in rats. Pharmacol
Biochem Behav 2012; 103:83–94.
74 Glick SD, Sell EM, McCallum SE, Maisonneuve IM. Brain regions mediating
alpha3beta4 nicotinic antagonist effects of 18-MC on nicotine self-administration.
Eur J Pharmacol 2011; 669:71–75.
75 Maisonneuve IM, Glick SD. Anti-addictive actions of an iboga alkaloid congener: a
novel mechanism for a novel treatment. Pharmacol Biochem Behav 2003; 75:
607–618.
76 King CH, Meckler H, Herr RJ, Trova MP, Glick SD, Maisonneuve IM. Synthesis of
enantiomerically pure (+)- and (-)-18-methoxycoronaridine hydrochloride and
their preliminary assessment as anti-addictive agents. Bioorg Med Chem Lett 2000;
10:473–476.
77 Saunders BT, Robinson TE. Individual variation in the motivational properties of
cocaine. Neuropsychopharmacology 2011; 36: 1668–1676.
78 Flagel SB, Clark JJ, Robinson TE, Mayo L, Czuj A, Willuhn I et al. A selective role for
dopamine in stimulus-reward learning. Nature 2011; 469:53–57.
79 Homberg JR, Karel P, Verheij MM. Individual differences in cocaine addiction:
maladaptive behavioural traits. Addict Biol 2014; 19:517–528.
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