The antiaddictive effects of ibogaine: A systematic literature review of human studies

Abstract

Background and aims
Ibogaine is a naturally occurring hallucinogenic alkaloid with a therapeutic potential for reducing drug craving and withdrawal. To the best of our knowledge, no systematic review was previously performed assessing these effects. Thus, we conducted a systematic literature review of human studies assessing the antiaddictive effects of ibogaine.

Methods
Papers published up to July 2, 2016 were included from PubMed, LILACS, and SciELO databases following a comprehensive search strategy and a pre-determined set of criteria for article selection.

Results
Two hundred and fifty-nine studies were identified, of which eight met the established criteria. Seven studies were open-label case series with ibogaine and one study was a randomized, placebo-controlled clinical trial with noribogaine. Case series suggest that a single dose or a few treatments with ibogaine may significantly reduce drug withdrawal, craving, and self-administration in dependent individuals lasting from 24 h to weeks or months. No significant effects of noribogaine on opiate/opioid withdrawal were observed in the clinical trial.

Conclusions
Considering the necessity of new drugs that may produce fast-acting and sustained effects in opiate/opioid and cocaine dependence, the potential beneficial effects of ibogaine/noribogaine should be further investigated in controlled trials.

Full text

The antiaddictive effects of ibogaine: A systematic literature
review of human studies
RAFAEL G. DOS SANTOS
1,2,3
*, JOSÉ CARLOS BOUSO
2
and JAIME E. C. HALLAK
1,3
1
Department of Neurosciences and Behavior, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
2
International Center for Ethnobotanical Education, Research and Service, Barcelona, Spain
3
National Institute of Science and Technology –Translational Medicine, Ribeirão Preto, Brazil
(Received: August 22, 2016; revised manuscript received: October 15, 2016; accepted: October 19, 2016)
Background and aims: Ibogaine is a naturally occurring hallucinogenic alkaloid with a therapeutic potential for
reducing drug craving and withdrawal. To the best of our knowledge, no systematic review was previously performed
assessing these effects. Thus, we conducted a systematic literature review of human studies assessing the
antiaddictive effects of ibogaine. Methods: Papers published up to July 2, 2016 were included from PubMed,
LILACS, and SciELO databases following a comprehensive search strategy and a pre-determined set of criteria for
article selection. Results: Two hundred and fifty-nine studies were identified, of which eight met the established
criteria. Seven studies were open-label case series with ibogaine and one study was a randomized, placebo-controlled
clinical trial with noribogaine. Case series suggest that a single dose or a few treatments with ibogaine may
significantly reduce drug withdrawal, craving, and self-administration in dependent individuals lasting from 24 h to
weeks or months. No significant effects of noribogaine on opiate/opioid withdrawal were observed in the clinical trial.
Conclusions: Considering the necessity of new drugs that may produce fast-acting and sustained effects in opiate/
opioid and cocaine dependence, the potential beneficial effects of ibogaine/noribogaine should be further investigated
in controlled trials.
Keywords: ibogaine, noribogaine, substance use disorders, dependence, withdrawal
INTRODUCTION
Ibogaine is a naturally occurring indole alkaloid derived
from the root barks of Tabernanthe iboga, a plant native to
western Central African countries such as Gabon and
Cameroon, where it has been used traditionally by the
Pygmies and other African ethnic groups for several centu-
ries, and more recently, as a sacrament in initiatory rites and
for social cohesion in the Bwiti religion (Alper, 2001;Alper,
Lotsof, & Kaplan, 2008;Brown, 2013;Mash et al., 1998).
Although T. iboga contains several other alkaloids, ibogaine
is considered to be the main psychoactive substance present
in this plant. The mechanism of action of ibogaine –and its
O-demethylated active metabolite noribogaine –is poorly
understood and considered to involve antagonism of the
N-methyl-D-aspartate (NMDA) glutamate receptor and
α3β4 nicotinic acetylcholine receptor, inhibition of the
serotonin (5-HT) reuptake transporter and dopamine release,
agonism of the σ
2
receptor, κ- and μ-opioid receptors, M
1/2
muscarinic receptor, and 5-HT
2A
receptors [similar to classic
hallucinogens such as lysergic acid diethylamide (LSD),
psilocybin, and dimethyltryptamine (DMT)], and enhance-
ment of glial cell line-derived neurotrophic factor (GDNF)
(Alper, 2001;Alper et al., 2008;Brown, 2013;Donnelly,
2011;Lotsof & Alexander, 2001;Mash et al., 1998).
In the 1960s, Lotsof et al. showed that ibogaine could
reduce heroin withdrawal (Alper, 2001;Alper et al., 2008;
Brown, 2013;Donnelly, 2011;Lotsof & Alexander, 2001;
Mash et al., 1998). On the basis of the initial observations
and several treatments provided in non-medical contexts,
Lotsof et al. proposed ibogaine as a new method to treat
dependence to opiates/opioids (morphine, heroin, and meth-
adone), stimulants (nicotine, cocaine, amphetamine, and
methamphetamine), and ethanol and acquired several
patents for such uses (United States patents: US 4499096
1985, 4587243 1986, 4857523 1989, 5026697 1991, and
5152995 1992). It has been estimated that more than 3,400
people have been treated with ibogaine for drug dependence
in clinics around the world, mainly in countries such as The
Netherlands, the United States, Mexico, and Brazil (Alper,
2001;Alper et al., 2008;Brown, 2013;Donnelly, 2011).
In the context of drug dependence treatment, ibogaine is
usually ingested orally in the form of extracts/hydrochloride
(HCl) in doses ranging from 4 to 25 mg/kg (Alper, 2001;
Alper et al., 2008;Brown, 2013;Donnelly, 2011;Forsyth
et al., 2016;Glue, Lockhart, et al., 2015;Glue, Winter, et al.,
2015;Lotsof & Alexander, 2001;Mash et al., 1998). About
1 hr after oral administration, subjects experience decreased
muscular coordination, increased sensitivity to light and
sound, nausea and vomiting if they move, and visual effects
that the ibogaine supporters refer to them as “oneirogenics”
* Corresponding author: Rafael G. dos Santos, PhD; Departamento
de Neurociências e Ciências do Comportamento, Faculdade de
Medicina de Ribeirão Preto, Universidade de São Paulo, Hospital
das Clínicas, Terceiro Andar, Av. Bandeirantes, 3900, Ribeirão
Preto, São Paulo, Brazil; Phone/Fax: +55 16 3602 2703; E-mail:
banisteria@gmail.com
© 2016 The Author(s)
Journal of Psychedelic Studies 1(1), pp. 20–28 (2017)
DOI: 10.1556/2054.01.2016.001
First published online December 19, 2016

(similar to dreams). These visual effects are sustained for
around 4–8 hr and are followed by a contemplative state of
12–24 hr in which lucid dreaming may occur accompanied
by the emergence of autobiographical memories. Insomnia
and increased energy may be present for 72 hr following
ibogaine intake (Alper, 2001;Alper et al., 2008;Brown,
2013;Donnelly, 2011;Forsyth et al., 2016;Glue, Lockhart,
et al., 2015;Glue, Winter, et al., 2015;Lotsof & Alexander,
2001;Mash et al., 1998). Lower oral doses of ibogaine
(20 mg) and noribogaine (3–60 mg) were administered to
healthy male volunteers in recent open-label (ibogaine)
and double-blind, placebo-controlled (noribogaine) studies,
and both drugs were found to be safe and well tolerated
(Forsyth et al., 2016;Glue, Lockhart, et al., 2015;Glue,
Winter, et al., 2015). At this dose levels, subjects did not
experience the above-mentioned psychoactive effects,
reporting basically transient nausea, gastrointestinal symp-
toms, and dizziness.
Ibogaine administration has been associated with several
fatalities (>25 cases), which appear to involve increases in
cardiac arrhythmias, previous cardiovascular diseases, and
use of opiates/opioids or other drugs during the acute effects
of ibogaine (Alper, 2001;Alper, Staji´c, & Gill, 2012;
Brown, 2013;Koenig & Hilber, 2015;Litjens & Brunt,
2016;Meisner, Wilcox, & Richards, 2016). Ibogaine intake
has also been associated with psychosis (Houenou, Homri,
Leboyer, & Drancourt, 2011), mania (Marta, Ryan,
Kopelowicz, & Koek, 2015), and seizures (Breuer et al.,
2015). However, most of these cases happened in uncon-
trolled/non-medical settings, using unknown doses of
ibogaine of variable purity. When administered in more
controlled/supervised contexts, to individuals without pre-
vious cardiovascular diseases or under the acute effects of
drugs, ibogaine appears to be relatively safe (Alper, 2001;
Alper et al., 2008,2012;Brown, 2013;Donnelly, 2011;
Forsyth et al., 2016;Glue, Lockhart, et al., 2015;Glue,
Winter, et al., 2015;Koenig & Hilber, 2015;Lotsof &
Alexander, 2001;Mash et al., 1998;Meisner et al., 2016).
However, sudden deaths and fatalities with unknown causes
have also been reported, and ibogaine should be adminis-
tered only after a complete medical screening and with a
rigorous cardiovascular monitoring (Alper, 2001;Alper et al.,
2012;Brown, 2013;Koenig & Hilber, 2015;Litjens &
Brunt, 2016;Meisner et al., 2016).
Animal studies showed that ibogaine is neither reinfor-
cing nor aversive, and that this alkaloid reduces opiate/
opioid (morphine and heroin), cocaine, and ethanol self-
administration (Alper, 2001;Alper et al., 2008;Belgers
et al., 2016;Brown, 2013;Donnelly, 2011;Frenken, 2001;
Lotsof & Alexander, 2001;Mash et al., 1998). Animal
studies also reported that noribogaine reduces nicotine and
amphetamine self-administration (Alper, 2001;Alper et al.,
2008;Belgers et al., 2016;Brown, 2013;Donnelly, 2011;
Frenken, 2001;Lotsof & Alexander, 2001;Mash et al.,
1998). A recent meta-analysis of animal studies reported
that the most significant effects of ibogaine in reducing drug
self-administration were observed in the first 24 hr after its
administration, and these effects were sustained for more
than 72 hr (Belgers et al., 2016). Moreover, several case
reports described significant reductions in drug (mostly
heroin, methadone, and cocaine) craving and withdrawal
symptoms within 1–2 hr after oral administration of single
or few doses of ibogaine, followed by complete cessation of
the opiate/opioid withdrawal syndrome within 24–48 hr
and significant reductions or even total cessation of
substance use weeks to months (or longer) following
ibogaine intake (Alper, 2001;Alper et al., 2008;
Brown, 2013;Donnelly, 2011;Frenken, 2001;Lotsof &
Alexander, 2001;Mash et al., 1998). These data from
human case reports are in line with animal studies (Belgers
et al., 2016).
Although some reviews analyzing the antiaddictive
effects of ibogaine in humans were published, these were
narrative and non-systematic reviews (Alper, 2001;Alper
et al., 2008;Brown, 2013;Donnelly, 2011;Mash et al.,
1998), and the most recent of them was published 3 years
ago (Brown, 2013). To the best of our knowledge, no
systematic review analyzing the antiaddictive effects of
ibogaine in humans was previously performed. Therefore,
considering the apparent increase in ibogaine use and its
possible toxic and therapeutic effects (Alper et al., 2008),
this study aimed to conduct a systematic literature review of
human studies that investigated the antiaddictive effects of
ibogaine or of its main active metabolite, noribogaine.
METHODS
Data for this systematic review were collected in accor-
dance with the Systematic Reviews and Meta-Analyses
guidelines (Moher, Liberati, Tetzlaff, Altman, & The
PRISMA Group, 2009).
Data acquisition
We attempted to identify all human studies available to
review up to July 2, 2016 in which the antiaddictive effect of
ibogaine or noribogaine was analyzed.
Search strategy
Electronic searches were performed using PubMed, LILACS,
and SciELO databases. The following keywords were used:
ibogaine OR noribogaine AND humans OR addiction OR
dependence. References were retrieved through searching
electronic databases and manual searches through reference
lists of identified literature. All the studies published up to
July 2, 2016 were included without any language restriction.
Eligibility criteria
The following inclusion and exclusion criteria were estab-
lished prior to the literature search.
Article type
Case reports and clinical studies published in peer-reviewed
journals were included. Books and book chapters indexed in
the above-cited databases were also included. Preclinical
studies (in vitro and in vivo), reviews, abstracts and letters,
comments, and editorials were excluded.
Journal of Psychedelic Studies 1(1), pp. 20–28 (2017) |21
Antiaddictive effects of ibogaine

Study design
The review included case reports and clinical studies of
ibogaine administration that assessed dependence/abuse
symptoms.
Participants/sample
Subjects with a diagnosis of drug abuse/dependence were
included.
Interventions
All designs evaluating the effect of ibogaine on abuse/
dependence measures were included.
Comparisons
The main comparator considered was pre-treatment abuse/
dependence symptoms.
Outcomes
Studies investigating the effect of ibogaine on abuse/
dependence symptoms were included.
Data extraction
All studies were screened by two independent reviewers
with discrepancies resolved by a third reviewer. From the
articles included, we recorded the names of authors, year of
publication, study location (city and country), study design
(open label or controlled), characteristics of the participants
(sample size, age, and gender), response criteria (antiaddic-
tive effect), type of intervention (dose), and type of outcome
measure (abuse/dependence symptoms).
RESULTS
Study selection
Aflow diagram illustrating the different phases of the
systematic review is presented in Figure 1.
The literature search yielded 259 separate references, all
from PubMed. These citations were reviewed for abstract
screening, and seven potentially relevant references were
identified (Alper, 2001;Alper, Lotsof, Frenken, Luciano, &
Bastiaans, 1999;Luciano, 1998;Mash et al., 2000,2001;
Schenberg, de Castro Comis, Chaves, & Da Silveira, 2014;
Sheppard, 1994). Full-text reports of these citations were
obtained for more detailed evaluation. One more citation
(Glue, Cape, Tunnicliff, Lockhart, Lam, Hung, et al., 2016)
was found after handsearching the bibliography of one of
the references used in the Introduction section (Forsyth
et al., 2016). This citation was not indexed at any of the
databases used at the time of preparation of the manuscript,
and the paper was obtained directly from the authors.
Following detailed examination of the reports, all citations
were included. The studies included comprised seven case
series involving the administration of ibogaine (Alper, 2001;
Alper et al., 1999;Luciano, 1998;Mash et al., 2000,2001;
Schenberg et al., 2014;Sheppard, 1994) and one random-
ized, placebo-controlled clinical trial with noribogaine
(Glue, Cape, Tunnicliff, Lockhart, Lam, Hung, et al.,
2016). Table 1shows the main information of each study.
Case series
In an open-label study performed in non-medical settings in
Amsterdam, The Netherlands, seven opiate-dependent indi-
viduals (five men; mean age 29.28 years; six individuals
were dependent on heroin, two on ethanol, and one on
codeine) were treated with single oral doses of 700–1800 mg
(11.7–25.0 mg/kg) ibogaine HCl (Sheppard, 1994). Treat-
ments occurred between October 1989 and August 1990,
and the researchers documented the immediate and long-
term (up to 14 weeks) effects of ibogaine. Subjects were
administered a trial dose of 100–200 mg ibogaine, followed
1–2 hr later by the remainder of the dose. None of the
subjects showed significant opiate withdrawal symptoms
24–38 hr after ibogaine administration. Two subjects who
received the lowest dose (700 mg) relapsed to opiate usage
within 2 days after ibogaine administration, two subjects
who received >1,000 mg relapsed after a number of weeks,
one subject who received >1,000 mg reverted to intermittent
heroin use, and three subjects who received >1,000 mg
remained drug-free for >14 weeks after treatment. Ibogaine
administration was also associated with increased energy,
appetite, and reduced sleep for several weeks after drug
intake. Ibogaine was well tolerated, and adverse effects
reported included sensitivity to light and sound, ataxia,
diarrhea, and nausea and vomiting. Interestingly, ibogaine
Figure 1. Flow diagram illustrating the different phases of the
systematic review
22 |Journal of Psychedelic Studies 1(1), pp. 20–28 (2017)
dos Santos et al.

Table 1. Open-label case series and clinical trials describing the antiaddictive effects of ibogaine
References Design/setting Subjects Dose Main results Safety
Sheppard
(1994)
a
Open-label 7 (heroin, methadone,
codeine, and ethanol)
5 men, mean age
29.28 years
Single doses
11.7–25 mg/kg
Absence of withdrawal symptoms after 24–38 hr for
all subjects, two relapsed within 48 hr, two after
several weeks, one reverted to intermittent heroin
use, and three remained drug-free >14 weeks
No medical screening or monitoring
Non-medical No serious adverse reactions
Amsterdam, The Netherland
Luciano (1998) Open-label 3 (cocaine, opiates/
opioids, and ethanol)
Gender, age (?)
Single doses
20–25 mg/kg
Absence of withdrawal and craving symptoms after
24 hr for all subjects
Medical screening and monitoring
No serious adverse reactions
Setting (?) Abstinence (?)
Alper et al.
(1999)
a
Open-label 33 (heroin. methadone,
and cocaine)
22 men, mean age
27.3 years
Single doses
6–29 mg/kg
Absence of withdrawal symptoms and drug use for
25 (76%) subjects after 72 hr, four did not report
symptoms but used drugs in <72 hr, two reported
attenuated symptoms and no drug use in <72 hr, and
one reported absence of effects
Medical screening and monitoring
one fatality, probably caused by
concomitant heroin use
Non-medical
United States and The
Netherlands
Mash et al.
(2000)
b
Open-label 27 (heroin, methadone [?]
and cocaine)
23 men, mean age 34.6
(opiates/opioids) and
37.5 (cocaine) years
Single doses
500, 600, and
800 mg
Significant (p<.005) reductions in all HCQN-29
subscales
c
and in two CCQN-45 subscales
d
after
36 hr and 14 days, and significant (p<.0005)
reductions in BDI scores after one month
Abstinence (?)
Medical screening and monitoring
Private clinic
St. Kitts, West Indies
No serious adverse reactions
Mash et al.
(2001)
b
Open-label 32 (heroin and methadone)
23 men, mean age
33.6 years
Single dose
800 mg
Significant (p<.05) reductions in OOWS scores after
12–24 hr and in OP-SCL scores after <72 hr and 6–9
days, and months of abstinence in many subjects
(although data were not presented)
Medical screening and monitoring
Private clinic
St. Kitts, West Indies
No serious adverse reactions
Alper (2001)
a
Open-label 41 (heroin. methadone,
cocaine, sedatives,
ethanol)
Gender, age (?)
Single doses
6–29 mg/kg
15 (29%) subjects reported abstinence for <2 months,
15 (29%) for ≥2 months/<6 months, 7 (13%) for
≥6 months/<1 year, 10 (19%) for >1 year, and
5 (10%) the outcomes could not be determined
Medical screening and monitoring
Non-medical No serious adverse reactions
United States and The
Netherlands
Schenberg
et al. (2014)
Open-label 75 (ethanol, cannabis,
cocaine, and crack-
cocaine)
67 men and
8 women, mean age
34.16 (men) and
29.50 (women) years
Single and multiple
doses; mean
number of
sessions 3.83
(men) and
5.40 (women)
17–20 mg/kg
Significant (p<.001) increases in abstinence
duration, and 61% of subjects were abstinent after
single (median 5.5 months) and multiple (median
8.4 months) doses
Medical screening and monitoring
Private hospital No serious adverse reactions
Santa Cruz do Rio Pardo, Brazil
Glue, Cape,
Tunnicliff,
Lockhart,
Lam, Gray,
et al. (2016)
Randomized, double-blind,
placebo-controlled, single
ascending-dose clinical trial
Research unit
27 (methadone)
21 men, mean age
41.2 years
Single doses
(noribogaine)
60, 120, and
180 mg
Non-significant effects on SOWS, OOWS, COWS,
and time to resumption of MST
Medical screening and monitoring
No serious adverse reactions
Significant QT interval
prolongation
Dunedin, New Zealand
Note. BDI, Beck Depression Inventory; CCQN-45, Cocaine Craving Questionnaire; COWS, Clinical Opioid Withdrawal Scale; HCQN-29, Heroin Craving Questionnaire; OOWS, Objective Opiate
Withdrawal Scale; OP-SCL, Opiate-Symptom Checklist; MST, methadone substitution treatment; SOWS, Subjective Opioid Withdrawal Scale. Interrogation: not informed.
a
Included subjects from the same sample.
b
Included subjects from the same sample.
c
Desire to Use, Intention to Use, Anticipation of Positive Outcomes, Relief of Negative States, and Lack of Control.
d
Relief of Negative States and Lack of Control.
Journal of Psychedelic Studies 1(1), pp. 20–28 (2017) |23
Antiaddictive effects of ibogaine

administration was not associated with a reduction in can-
nabis use. Importantly, there is no control of drug use prior,
during, or after treatment was performed, and some subjects
used drugs (mostly heroin) in the days immediately before/
after treatment. Moreover, no medical or psychiatric screen-
ing was described in the report. Careful analysis of this
report, other citations, and handsearching the bibliography
of the references showed that this study described a full
sample of previous treatments published in non-scientific
reports (Frenken, 2001).
Areportfromanunidentified city/country (probably
Amsterdam, The Netherlands) and apparently of an open-
label design reported three cases of subjects treated with
ibogaine HCl (20–25 mg/kg) for cocaine dependence (one
subject was also dependent on heroin and two were also
dependent on ethanol) (Luciano, 1998). No information
regarding age or gender of the participants was given in the
report. Subjects were included after medical and psychiatric
screening, laboratory exams, electrocardiogram (ECG),
electroencephalogram (EEG), and magnetic resonance.
Medical monitoring was continuous, and neurologic/EEG
assessments were performed intermittently over 24 hr. All
subjects showed transient cerebellar dysfunction (nystagmus,
tremor, and ataxia) 2 hr after ibogaine intake, and these
symptoms improved 8 hr after drug administration. Visual
alterations with eyes closed were observed in only one
subject, reality testing remained normal in all of them, and
no anxiety symptoms or thought disorder were observed.
EEG assessments were normal in all participants during and
after treatment, and no medical or ECG abnormalities were
observed during the treatment. Twenty-four hours after
ibogaine administration, all subjects reported an absence of
subjective or objective signs of withdrawal or craving, and all
neurologic/EEG examinations were normal.
A larger retrospective report described a group of
33 subjects (22 men, mean age 27.3 ±4.7 years) that were
treated with ibogaine HCl (average dose: 19.3 ±6.9 mg/kg,
range 6–29 mg/kg) for opiate/opioid dependence (mostly
heroin, primarily by the i.v. route; all met DSM-IV criteria
for opiate/opioid dependence) in non-medical settings under
open-label conditions between 1962 and 1993 (Alper et al.,
1999). Eight subjects were also using methadone and eight
were using cocaine on a daily basis. Seven treatments were
carried out in the United States between 1962 and 1963, and
the other 26 treatments were carried out in The Netherlands
between 1989 and 1993 [including patients from a previous
report (Sheppard, 1994)]. Treatments occurred 8–10 hr after
the subjects made their last use of heroin (24 hr in the case of
the subjects using methadone), and they were monitored for
72 hr. Twenty-four hours after ibogaine administration,
25 subjects (76%) reported complete resolution of opiate/
opioid withdrawal without drug-seeking behavior, and these
effects were sustained for 72 hr. Four subjects did not report
withdrawal signs but used opiates/opioids within 72 hr after
ibogaine administration, and the other two subjects reported
attenuated signs of withdrawal but remained drug-free. Only
one participant reported an absence of effect of ibogaine on
withdrawal symptoms. But the report does not specify
whether the subjects with less effect of ibogaine on with-
drawal symptoms were the methadone users or not. One
fatality was reported: a 24-year-old female treated in The
Netherlands, in 1993, died 19 hr after ibogaine administra-
tion. Apparently, this fatality was due to heroin use in the
first few hours after treatment.
In a conventional research setting (clinic) in St. Kitts,
West Indies, more than 150 drug-dependent subjects were
treated with single doses of 500–800 mg ibogaine HCl
under open-label conditions (Mash et al., 2000,2001).
Baseline screening included physical and psychiatric exam-
inations, ECG, and blood/hematological tests, and adverse
effects were assessed by clinician ratings and self-reports.
Ibogaine was safely administered based on cardiorespiratory
measures, blood cell tests, and measures of hepatic
enzymes. The most frequent adverse effects were transient
nausea and mild tremor during the acute effects of ibogaine.
A subset of 27 opiate/opioid- and cocaine-dependent
(DSM-IV criteria) subjects (23 men, mean age 34.6 ±1.9
years for the opiate/opioid group and 37.5 ±2.9 years for
the cocaine group) participated in a 2-week inpatient Phase I
dose-escalation study to assess ibogaine safety and efficacy
for treating drug dependence symptoms (Mash et al., 2000).
Subjects were randomly assigned to receive single fixed
doses of 500, 600, or 800 mg ibogaine HCl under open-label
conditions and completed structured self-reports relating to
depression symptoms (Beck Depression Inventory, BDI)
and craving [heroin (HCQN-29) or cocaine (Craving Ques-
tionnaire, CCQN-45); 1 hr before drug intake, and 36 hr and
14 days after drug intake]. The BDI was also applied
1 month after ibogaine administration. Ibogaine administra-
tion was associated with significant reductions in all five
subscales of the HCQN-29 (Desire to Use,Intention to Use,
Anticipation of Positive Outcomes,Relief of Negative States,
and Lack of Control; for all subscales p<.0001) 36 hr and
14 days after drug intake, suggesting decreased craving for
opiates/opioids. Ibogaine intake was also associated with
significant reductions in two subscales of the CCQN-45
(Relief of Negative States,p<.0005; Lack of Control,
p<.002) 36 hr and 14 days after drug administration,
suggesting decreased craving for cocaine. Ibogaine admin-
istration was also associated with significant reductions in
BDI scores (p<.0005) 1 month after drug intake, suggest-
ing sustained reductions in depressive symptoms. Again, the
study did not clarify if (or which) the subjects were under
methadone treatment and if this interfered somehow with
the results.
Another subset of 32 patients from the original sample
(23 men, mean age 33.6 years), all opiate/opioid dependent
(heroin or methadone, DSM-IV criteria), received a single
800 mg of dose, and withdrawal and craving symptoms were
assessed with the physician-rated Objective Opiate With-
drawal Scale (OOWS) and with the Opiate-Symptom Check-
list (OP-SCL, self-rated) (Mash et al., 2001). Data were
collected 1 hr before drug intake (12 hr after last opiate/
opioid dose) and 12 and 24 hr after drug intake (24 and 36 hr
after last opiate/opioid dose, respectively). The OP-SCL was
also used 6–9 days after ibogaine intake. Compared with
baseline values, OOWS scores were significantly (p<.05)
reduced 12 and 24 hr after ibogaine administration, and
OP-SCL scores were significantly (p<.05) decreased
<72 hr and 6–9 days after drug intake. The only informa-
tion provided regarding drug abstinence stated vaguely
that many subjects “:::were able to maintain abstinence
24 |Journal of Psychedelic Studies 1(1), pp. 20–28 (2017)
dos Santos et al.

from illicit opiates and methadone over the months follow-
ing detoxification (data not shown).”Again, authors did not
differentiate subjects regarding previous methadone use.
A retrospective report assessed the long-term effects of
ibogaine in 41 individuals treated in non-medical settings
under open-label conditions between 1962 and 1993, in the
United States and in The Netherlands, mainly for opiate/
opioid or stimulant dependence (Alper, 2001), including
patients from previous studies (Alper et al., 1999;Sheppard,
1994). Fifteen (29%) reported abstinence of less than
2 months, 15 (29%) for at least 2 months and less than
6 months, seven (13%) for at least 6 months and less
than 1 year, and 10 (19%) for more than 1 year. In five
cases (10%), the outcomes could not be determined.
Again, authors failed to identify subjects under methadone
treatment.
In another retrospective study conducted in a private
hospital in Santa Cruz do Rio Pardo, Brazil, the safety and
efficacy of an open-label ibogaine treatment combining the
administration of the drug with cognitive behavioral therapy
were analyzed using data from 75 drug-dependent (DSM-IV
criteria) patients (67 males and 8 females; mean ages 34.16
±8.33 and 29.50 ±5.31 years, respectively) (Schenberg
et al., 2014). Seventy-two percent of the subjects were
Brazilian polydrug users (ethanol, cannabis, cocaine, and
crack cocaine), with only one European patient having a
history of opiate/opioid use. Subjects underwent a total of
134 ibogaine sessions (mean number of sessions for male
and female participants was 3.83 ±3.31 and 5.40 ±0.91,
respectively). Patients were required to stay abstinent for
30–60 days prior to ibogaine administration at their homes,
or for at least 24 hr as a residential patient at the clinic.
Subjects received oral doses of 17–20 mg/kg ibogaine HCl,
preceded 30–45 min before by 20 mg of the dopamine D
2/3
receptor antagonist domperidone, to reduce nausea. If a
patient reported a weak response to ibogaine after the initial
dose, an additional 100–200 mg of dose was administered.
Blood pressure, cardiac frequency, and oxygen saturation
were measured every 25–30 min for 10 hr, and subjects
were dismissed after 24–48 hr, returning for psychological
therapy/follow-up. Single and multiple doses of ibogaine
were associated with significant (p<.001) increases in
abstinence duration, and 61% of participants were abstinent
after ibogaine treatment (single dose, median 5.5 months;
multiple doses, median 8.4 months). Acute adverse effects
included transient nausea, ataxia, vomiting, tremors, head-
aches, and mental confusion. No serious adverse reactions
such as cardiac arrhythmias or fatalities were observed.
Clinical trials
In a randomized, double-blind, placebo-controlled, single
ascending-dose study, 27 patients (21 men, mean age 41.2
years) on methadone substitution therapy received noribo-
gaine doses of 60, 120, or 180 mg (Glue, Cape, Tunnicliff,
Lockhart, Lam, Hung, et al., 2016). Subjects were selected
based on medical history, physical examination, safety
laboratory tests, vital signs, ECG, and switched to morphine
treatment a week before study participation. The effects of
noribogaine on withdrawal symptoms and as a possible
agonist of μ-opioid receptors were assessed by pupillometry
(baseline to 144 hr later), and oximetry and capnography
(baseline to 72 hr later). Withdrawal symptoms were also
analyzed by measuring the time to resumption of methadone
treatment (mean time between last morphine dose given 2 hr
prior to treatment and time to resumption of methadone
treatment) and by the Subjective, Objective, and Clinical
Opioid Withdrawal Scales (SOWS, OOWS, and COWS;
baseline to 144 hr later, at the time of resumption of
methadone treatment, and 2 hr afterward). Safety and
tolerability measures (physical examinations, adverse
events, laboratory tests, vital signs, and continuous ECG
recordings) were assessed from baseline to 144 hr after
noribogaine/placebo administration, and outpatient and tele-
phone assessments were performed until 35 days later.
Noribogaine was well tolerated: no significant changes
were observed in vital signs, safety laboratory tests, oxime-
try or capnography, respiratory rate, or physical examina-
tions, and there were no deaths or serious adverse effects.
The most frequent adverse effects were transient changes
in light perception (light brighter than usual), headache, and
nausea, and no hallucinogenic effects were reported.
However, noribogaine induced significant dose- and
concentration-dependent QT interval prolongation (a risk
factor for cardiac arrhythmias and sudden death), which
reached clinically concerning levels with the 180 mg of
dose. Opiate/opioid withdrawal symptoms increased 1–2hr
before resumption of methadone treatment as well as pupil
diameter. Noribogaine did not produce significant reduc-
tions on subjective and objective rating scales measuring
opiate/opioid withdrawal symptoms (SOWS, OOWS, and
COWS) and also failed to induce significant increases in the
time to resumption of methadone treatment, which was very
similar between the placebo and noribogaine groups. Sur-
prisingly, the 120-mg dose group experienced the longest
time to resumption of methadone treatment, which was
supported with the lowest scores on opiate/opioid withdraw-
al symptoms.
DISCUSSION
In this systematic review, eight studies suitable for inclusion
regarding the investigation of the antiaddictive effects of
ibogaine in humans were identified. Despite the small
number of studies, the open-label nature of most citations
(seven), the high degree of heterogeneity among them, and
the results reported in the case series suggest that ibogaine/
noribogaine significantly reduced opiate/opioid withdrawal
symptoms and that many subjects remained drug-free for
several days after treatment. However, the only clinical trial
performed, using noribogaine, failed to find significant
reductions on opiate/opioid withdrawal symptoms. There-
fore, the antiaddictive effects of ibogaine/noribogaine
should be interpreted with caution.
The absence of effects of noribogaine could be related to
several factors. First, the equivalence between therapeutic
doses of ibogaine and noribogaine is not well known, so the
lack of effects could be related to the administration of low
doses of noribogaine, which would not be enough to achieve
anti-withdrawal effects. In fact, based on their studies
involving the administration of ibogaine and noribogaine
Journal of Psychedelic Studies 1(1), pp. 20–28 (2017) |25
Antiaddictive effects of ibogaine

to healthy volunteers (Glue, Lockhart, et al., 2015;Glue,
Winter, et al., 2015), the authors predicted that an ibogaine
dose of 286 mg would lead to noribogaine C
max
values
comparable to a 180-mg dose of noribogaine, and there are
no reports in the bibliography, where such a low dose of
ibogaine has been administered to opiate-/opioid-dependent
subjects. Second, the case series described the treatments of
subjects mostly dependent on heroin, with fewer patients
reporting the use of methadone, and most of the reports did
not differentiate between heroin/methadone users.
Methadone has a longer half-life than heroin (Argoff &
Silvershein, 2009). In another paper, Glue, Cape, Tunnicliff,
Lockhart, Lam, Gray, et al. (2016) detailed how they did the
patient’s switching from methadone to morphine in 6 days
and explained that at that time 91% of methadone was
cleared. They also found a mean elimination half-life of
59 hr. Furthermore, subjective reports of methadone depen-
dents suggest that they may suffer withdrawal symptoms for
more than a month. Thus, the absence of significant reduc-
tions in opiate/opioid withdrawal, as the authors acknowl-
edge, may need repetitive doses of ibogaine/noribogaine if
the propose is to detoxify from methadone.
The most important limitation of the reviewed studies is
that seven of the eight citations are open-label case series.
The lack of control groups and placebo in these studies does
not allow to suggest causation, especially considering that
most treatments were performed in non-medical and unsu-
pervised contexts with no standardized protocols. Therefore,
it is not possible to affirm that ibogaine/noribogaine are
effective treatments for drug dependence. Moreover, the
only clinical trial performed with noribogaine did not find
significant reductions on opiate/opioid withdrawal symp-
toms, suggesting that the results reporting antiaddictive
effects of ibogaine/noribogaine should be interpreted with
caution.
However, animal studies consistently show that ibogaine
significantly reduces opiate/opioid and cocaine self-
administration (Alper, 2001;Alper et al., 2008;Belgers
et al., 2016;Brown, 2013;Donnelly, 2011;Frenken, 2001;
Lotsof & Alexander, 2001;Mash et al., 1998), and the
pattern of results observed in all case series –including the
duration of the therapeutic effects of ibogaine –is very
similar (from 24 hr to days/weeks). However, as exposed
above, the only clinical trial found in the review reported
that noribogaine failed to reduce opiate/opioid withdrawal
symptoms (Glue, Cape, Tunnicliff, Lockhart, Lam, Hung,
et al., 2016).
Some researchers have been speculated that the thera-
peutic effects of ibogaine seem to be related to the pharma-
cokinetics of its main metabolite, noribogaine, which is
longer lasting, and to the multiple receptor profile of both
compounds (Alper, 2001;Alper et al., 2008;Brown, 2013;
Donnelly, 2011;Frenken, 2001;Kolp et al., 2007;Lotsof &
Alexander, 2001;Mash et al., 1998,2000,2001). The
neurochemical effects of ibogaine/noribogaine are not
completely understood and may include antagonism of the
NMDA glutamatergic and α3β4 adrenergic receptors, inhi-
bition of 5-HT reuptake transporter and of dopamine release
in the nucleus accumbens and other brain areas, agonism of
the σ
2
,κ-opioid, and 5-HT
2A
receptors, and enhancement of
GDNF (Alper, 2001;Alper et al., 2008;Brown, 2013;Mash
et al., 1998). Antagonism of the NMDA receptor is shared
with the anesthetic hallucinogen ketamine, which has been
reported to show anxiolytic (Kolp et al., 2007), antidepres-
sive (Luckenbaugh et al., 2014;Sos et al., 2013), and
antiaddictive (Dakwar, Levin, Foltin, Nunes, & Hart,
2014;Krupitsky et al., 2007) effects. Agonism of the
κ-opioid receptor is shared with the plant hallucinogen
salvinorin A, which has potential effects in the treatment
of stimulant-related disorders (Dos Santos, Crippa,
Machado-de-Sousa, & Hallak, 2014). Agonism of the
5-HT
2A
receptor is shared with classic serotonergic hallu-
cinogens such as LSD, psilocybin, and ayahuasca/DMT,
which has anxiolytic, antidepressive, and antiaddictive
properties (Dos Santos, Os´orio, Crippa, & Hallak, 2016;
Dos Santos, Os´orio, Crippa, Riba, et al., 2016;Nunes et al.,
2016).
An important limitation to the clinical use of ibogaine/
noribogaine is the possible toxicity of these alkaloids, which
include fatalities, cardiac arrhythmias, psychosis, mania,
and seizures (Alper, 2001;Alper et al., 2012;Breuer
et al., 2015;Brown, 2013;Forsyth et al., 2016;Glue,
Lockhart, et al., 2015;Glue, Winter, et al., 2015;Houenou
et al., 2011;Koenig & Hilber, 2015;Litjens & Brunt, 2016;
Marta et al., 2015;Meisner et al., 2016). Moreover, the
clinical trial with noribogaine reported a significant
dose-dependent increase in QT interval prolongation, which
is a risk factor for cardiac arrhythmias and sudden death.
Thus, a clear and firm warning of the cardiovascular dangers
of ibogaine/noribogaine should be provided to patients, who
must also be informed of the risks of using drugs –in
particular opiates/opioids –during or immediately after ibo-
gaine/noribogaine intake, which may potentiate the effects
of these alkaloids or of the opiates/opioids, thus increasing
the risk of an overdose. This is especially important con-
sidering that many ibogaine treatments are performed under
non-medical/unsupervised conditions using extracts of un-
known purity sold in the black market. The absence of
proper medical screening and monitoring increases the
possibility of hazardous situations (Alper, 2001;Alper
et al., 2012;Breuer et al., 2015;Brown, 2013;Forsyth
et al., 2016;Glue, Lockhart et al., 2015;Glue, Winter,
et al., 2015;Houenou et al., 2011;Koenig & Hilber, 2015;
Litjens & Brunt, 2016;Marta et al., 2015;Meisner et al.,
2016).
In summary, the results of this systematic review suggest
that ibogaine/noribogaine have antiaddictive properties.
Although these results are supported by animal studies, no
controlled clinical trials have been performed with ibogaine,
and the only clinical trial assessing the antiaddictive poten-
tials of noribogaine failed to find significant results. These
results suggest a more cautious interpretation of the anti-
addictive effects of ibogaine/noribogaine.
The use of heroin and synthetic opiates has reached an
alarming level in Europe (EMCDDA, 2016),andonlyinthe
United States, 44 people die every day from overdose of
prescription painkillers (SAMHSA, 2016). Moreover, there
are no proper medications for treating withdrawal symptoms
associated with methadone use in the case of patients that use
this drug for treating dependence on other opiates/opioids,
such as heroin. In this sense, the investigation of ibogaine/
noribogaine could provide new pharmacological treatments
26 |Journal of Psychedelic Studies 1(1), pp. 20–28 (2017)
dos Santos et al.

with fast-acting and sustained beneficial effects for patients
suffering drug dependence, especially to opiates/opioids and
cocaine. Controlled studies are needed to replicate these
findings.
Acknowledgements: RGDS is the Fellow of the Brazilian
National Post-Doctorate Program (PNPD/CAPES) and the
member of the ICEERS Advisory Board. JCB is the Scien-
tific Investigations Director of ICEERS. ICEERS is a non-
profit organization that promotes the scientific research of
ibogaine. JECH receives a CNPq (Brazil) Productivity
Fellowship Award. None of the authors received any spe-
cific funding for participating in this investigation. All
authors had full access to all the data and had final respon-
sibility for the decision to submit for publication.
Conflict of interest: The authors declare that they have no
conflict of interest.
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