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Detoxification from methadone using low, repeated, and increasing doses of ibogaine: A case report

Authors:
  • Ribeirão Preto Medical School, University of São Paulo, Brazil
  • International Center for Ethnobotanical Education, Research and Service (ICEERS)

Abstract and Figures

Background and aims: Ibogaine is a natural alkaloid that has been used in the last decades as an adjuvant for the treatment of opiate withdrawal. Despite the beneficial results suggested by animal studies and case series, there is a lack of clinical trials to assess the safety and efficacy of ibogaine. Moreover, the majority of reports described cases of heroin-dependent individuals, with and without concomitant use of methadone, using high doses of ibogaine. Therefore, it is not clear if ibogaine at low doses could be used therapeutically in people on methadone maintenance treatments (MMT). Methods: Case report of a female on MMT for 17 years who performed a self-treatment with several low and cumulative doses of ibogaine over a 6-week period. Results: The patient successfully eliminated her withdrawals from methadone with ibogaine. Each administration of ibogaine attenuated the withdrawal symptoms for several hours, and reduced the tolerance to methadone until all signs of withdrawal symptoms disappeared at the end of the treatment. No serious adverse effects were observed, and at no point did the QTc measures reach clinically significant scores. Twelve months after the treatment, she was no longer on MMT. Conclusions: To our knowledge, this is the first case report describing an ibogaine treatment using low and cumulative doses in a person on MMT. Although preliminary, this case suggests that low and cumulative doses of ibogaine may reduce withdrawal symptoms in patients undergoing MMT.
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Detoxication from methadone using low, repeated, and increasing doses
of ibogaine: A case report
CLARE WILKINS
1
, RAFAEL G. DOS SANTOS
2,3,4
, JORDI SOLÁ
2
, MARC AIXALÁ
2
, PEP CURA
2
, ESTEFANÍA MORENO
2
,
MIGUEL ÁNGEL ALCÁZAR-CÓRCOLES
5
, JAIME E. C. HALLAK
3,4
and JOSÉ CARLOS BOUSO
2
*
1
Pangea Biomedics, Nayarit, Mexico
2
International Center for Ethnobotanical Education, Research & Services, Barcelona, Spain
3
Department of Neurosciences and Behavior, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
4
National Institute of Science and Technology Translational Medicine, Ribeirão Preto, Brazil
5
Departamento de Psicología Biol´ogica y de la Salud, Facultad de Psicología, Universidad Aut´onoma de Madrid, Madrid, Spain
(Received: September 26, 2016; accepted: March 23, 2017)
Background and aims: Ibogaine is a natural alkaloid that has been used in the last decades as an adjuvant for the
treatment of opiate withdrawal. Despite the benecial results suggested by animal studies and case series, there is a
lack of clinical trials to assess the safety and efcacy of ibogaine. Moreover, the majority of reports described cases of
heroin-dependent individuals, with and without concomitant use of methadone, using high doses of ibogaine.
Therefore, it is not clear if ibogaine at low doses could be used therapeutically in people on methadone maintenance
treatments (MMT). Methods: Case report of a female on MMT for 17 years who performed a self-treatment with
several low and cumulative doses of ibogaine over a 6-week period. Results: The patient successfully eliminated her
withdrawals from methadone with ibogaine. Each administration of ibogaine attenuated the withdrawal symptoms for
several hours, and reduced the tolerance to methadone until all signs of withdrawal symptoms disappeared at the end
of the treatment. No serious adverse effects were observed, and at no point did the QTc measures reach clinically
signicant scores. Twelve months after the treatment, she was no longer on MMT. Conclusions: To our knowledge,
this is the rst case report describing an ibogaine treatment using low and cumulative doses in a person on MMT.
Although preliminary, this case suggests that low and cumulative doses of ibogaine may reduce withdrawal
symptoms in patients undergoing MMT.
Keywords: ibogaine, methadone, opioid substitution treatments (OST), methadone maintenance treatments (MMT),
methadone detoxication, drug addiction
INTRODUCTION
Opioid misuse is increasing alarmingly in both the EU and
North America. According to the US Centers for Disease
Control and Prevention, since 1999, the number of over-
dose deaths involving opioids (including prescription opioid
pain relievers and heroin) nearly quadrupled. From 2000 to
2014 nearly half a million people died from drug overdoses.
78 Americans die every day from an opioid overdose
(Centers for Disease Control and Prevention, 2016). Since
the problem has repeatedly been described as an epide-
mic,a drug abuse and treatment bill has recently been
signed into US law after passing through the House and
Senate (Spangler, 2016). Simultaneously, in the EU, and
according to the 2016 European Drug Report, Europes
opioids problem remains a central issue in the 2016 analysis,
reecting the signicant impact these drugs still have on
mortality and morbidity. We see now an increasingly com-
plex relationship between use of heroin and synthetic
opioids, accompanied by a worrying increase in overall
estimates of opioid-related deaths(European Monitoring
Centre for Drugs and Drug Addiction [EMCDDA], 2016).
The new epidemic of opioid overdoses is not only related
to heroin misuse, as it has been in the past, but also to a high
prevalence of the misuse of prescription opioids, including
methadone (Substance Abuse and Mental Health Services
Administration [SAMHSA], 2016). The Guidelines for the
Psychosocially Assisted Pharmacological Treatment of
Opioid Dependence of the World Health Organization
(WHO) state that there are two strategies to treat opioid
use disorders: (a) to progressively reduce the dose and
(b) to begin an opioid substitution treatment (OST), gen-
erally using methadone or buprenorphine (WHO, 2009).
According to those guidelines, opioid withdrawal (rather
than maintenance treatment) results in poor outcomes
over the long term (WHO, 2009). Although an OST is a
successful approach to reduce opioid misuse and crime, it
tends to become a perpetual treatment, and it has been
shown that those stabilized on high doses in methadone
maintenance treatments (MMT) have more medical, cog-
nitive, and emotional problems and a decreased quality of
life than people who terminated MMT (Pedrero-Pérez &
MethaQoL, 2016). It is clear that novel pharmacological
treatments that are effective in ceasing opioid misuse are
necessary.
* Corresponding author: José Carlos Bouso; International Center
for Ethnobotanical Education, Research & Services, c/Cendra 8,
bajos, 08012 Barcelona, Spain; Phone/Fax: +34 931 882 099;
E-mail: jcbouso@iceers.org
© 2017 The Author(s)
CASE REPORT Journal of Psychedelic Studies 1(1), pp. 2934 (2017)
DOI: 10.1556/2054.01.2017.005
Ibogaine is the principal alkaloid in Tabernanthe iboga,
an African plant used in ethnomedicine in traditional
communities (Alper, 2001). In 1956, a Ciba Pharmaceu-
ticals patent was acquired for its properties to reduce
tolerance to morphine (United States Patent Ofce,
1957). In the 1960s, Howard Lotsof serendipitously dis-
covered the anti-withdrawal properties of ibogaine (Alper,
2001). Ibogaine has demonstrated efcacy in attenuating
opioid withdrawal in animal models (Belgers et al., 2016),
but the evidence in humans is scarce (Brown, 2013).
Globally, approximately 70100 private clinics and practi-
tioners offer treatments with ibogaine, and in New Zealand
and South Africa, ibogaine is listed as a prescription
medication (Ibogaine Legal Status, 2016). The typical
doses used for treating substance use disorders are between
15 and 20 mg/kg (Brown, 2013) in a single administration.
High doses of ibogaine may induce bradycardia and pro-
long the QTc interval (Litjens & Brunt, 2016;Meisner,
Wilcox, & Richards, 2016), which can be life-threatening.
Indeed, 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 (Litjens & Brunt, 2016;
Meisner et al., 2016).
In a recent clinical trial with noribogaine (Glue, Cape,
Tunnicliff, Lockhart, Lam, Hung, et al., 2016), the main
metabolite of ibogaine and a possible candidate for explain-
ing its anti-addictive properties (Mash et al., 1998), this
compound was administered to people on MMT who were
switched to morphine. No signicant reduction in with-
drawal symptoms was observed after the administration of
60, 120, and 180 mg [the 180 mg dose of noribogaine is
equivalent in noribogaine plasma concentration to a 286 mg
dose of ibogaine (Glue, Cape, Tunnicliff, Lockhart, Lam,
Gray, et al., 2016)] but was observed a concentration-
dependent increase in QTc. The authors of that study
speculated that the dose of noribogaine administered prob-
ably was too low, and repeated dosing would be necessary
to achieve a reduction in withdrawal symptoms. A recent
report establishes the safe dose to be administered in an
ibogaine treatment in 0.87 mg/kg that is far from the 1520
mg/kg doses (Schep, Slaughter, Galea, & Newcombe,
2016).
We present here the case of a successful detoxica-
tion from long-term methadone dependence using low,
repeated, and increasing doses of ibogaine.
CASE PRESENTATION
The patient was a 47-year-old woman (58 kg), who was on
MMT for 17 years to treat her previous heroin dependence.
Three years before starting the ibogaine treatment, she
tried to abruptly end her methadone intake with non-
pharmacological support but was unsuccessful. After
3 months, she returned to the methadone program, as the
abstinence syndrome (AS) was intolerable for her. She
reinitiated the methadone treatment at a lower dose than
before (from 70 to 37 mg). Upon initiating the ibogaine
treatment, she was stabilized at 37 mg. Regarding her use of
other drugs, the patient occasionally used heroin (23 times
per month, intranasally) and amphetamine (23 times per
month, intranasally), and a limited use of ethanol (1/2
standard units per week). She was a daily cannabis user
(12 joints per day).
During the ibogaine treatment, the patient had a stable
work and partner, owned her own house, and was without
socio-familiar and legal conicts assessed by the ASI
(McLellan et al., 1992).
As a consequence of her former intravenous use of
heroin, the patient acquired the hepatitis C virus (HCV).
Before initiating this treatment, the viral count for the HCV
was 2,140,000 Ul/ml (logarithm HCV =6.33; interval of
quantication =1569,000,000 Ul/ml). An analytic exam
was performed before the treatment, including complete
blood count and biochemistry, hormones, urine biochem-
istry, coagulation, serology, and molecular biochemistry.
From over 70 parameters measured in the analytical tests,
only the following were out of the interval of reference (IR),
but only slightly, and without clinical signicance: leuko-
cytes =10.34 ×10
9
/L (IR =410); LKS-basophils =0.1%
(IR =0.22); lymphocytes =3.09 ×10
9
/L (IR =13);
basophils =0.01 ×10
9
/L (IR =0.020.1); alanine amino-
transferase; b =0.72 μkat/L (IR =0.000.55); 43.20 U/L
(IR =0.033.0); and transferrin saturation =46.18% (IR =
2045). An electrocardiogram (EKG) was also performed
before the treatment, and no abnormalities were found. Her
QTc values were 425 ms, blood pressure (BP) =120/70
mm Hg, and heart rate (HR) =85 bpm.
The psychiatric examination performed using the M.I.N.I.
(Mini-International Neuropsychiatric Interview, Version
5.0.0; Sheehan et al., 1998) did not result in any psychiatric
diagnosis.
Objectives of the treatment, procedures, and assessment
materials
The main objective of the treatment was to completely
detoxify the patient safely and with as much comfort as
possible from methadone. The Opiate Withdrawal Scale
(OWS; Bradley, Gossop, Phillips, & Legarda, 1987) and the
Short OWS (SOWS; Gossop, 1990) were used to assess
withdrawal symptoms, the Brief Psychiatric Rating Scale
(BPRS; Overall & Gorham, 1962) was used as a measure of
psychiatric safety, and the Udvalg for Kliniske Underso-
gelser Side Effects Rating Scale (UKU-SERS; Lingjaerde,
Ahlfors, Bech, Denckes, & Elgen, 1987) was used to assess
the side effects of ibogaine. The OWS was administered
once a day throughout the treatment. The SOWS was
administered before each ibogaine session and every hour
for the rst 6 hr, and at 8- and 12-hr post-ibogaine. The
BPRS was administered before each ibogaine session and
every hour for the rst 6 hr, at 8- and 12-hr post-ibogaine,
and also every morning during the treatment process. The
UKU was administered for 24 hr after each ibogaine session.
During each ibogaine administration, BP and HR were
monitored every 30 min for the rst 4 hr, then every hour
for the next 12 hr, and at 18- and 24-hr post-ibogaine. EKG
monitoring and measurement of the QTc were performed
during each ibogaine session every 60 min for the rst 8 hr
and then at 10-, 12-, 16-, 20-, and 24-hr post-administration.
30 |Journal of Psychedelic Studies 1(1), pp. 2934 (2017)
Wilkins et al.
The patient had psychological support throughout the treat-
ment. She continued with psychotherapy for 3-month post-
treatment to reorient her life.
Treatment
The patient contacted the ICEERS Support Service
(http://iceers.org/support-service.php) for advice, as she was
planning to undergo a self-treatment with ibogaine. She felt
that her methadone dependence was iatrogenic and wished
to cease the treatment utilizing ibogaine, after considerable
research. Since ICEERS is a non-prot research organiza-
tion that does not provide ibogaine treatments but has
contact with several treatment centers/providers, and after
assessing that the patient had the irreversible plan of taking
ibogaine for self-treating her methadone dependence, the
Support Service put her in contact with Pangea Biomedics, a
clinic in Mexico with 10 years of experience in treating
substance dependencies, such as MMT with ibogaine (note:
ibogaine is not scheduled in Mexico). Financial constraints
denied her from traveling to Mexico, thus she and the
clinicians at Pangea Biomedics decided to undergo the
detoxication while she was being supervised live through
Skype video in Spain, along with the ICEERS Support
Service team who offered psychological support and col-
lected the measures. The treatment consisted of low and
increasing doses of ibogaine administered in between pro-
gressively decreasing methadone dosages. The dose and
timing of dosing were chosen with the intention of nding a
new and less risky ibogaine treatment, avoiding the higher
doses. Ibogaine was donated to the patient by a private
donor from South Africa (Anwar Jeewa) and by a laboratory
based in Montreal, Canada (Phytostan Enterprises, Inc.)
(note: ibogaine is not scheduled in Canada, South Africa,
and Spain, and in South Africa, it is authorized to be used as
medicine to treat drug dependence). However, the patient
only needs to use the sample from South Africa one. The
chemical analysis (using thin layer chromatography, high
performance liquid chromatography, mass spectrometry,
and nuclear magnetic resonance) showed that it contained
96.3% ibogaine hydrochloride.
An EKG machine with QTc lecture was used for cardiac
monitoring. Ibogaine sessions were performed with medical
supervision for the rst four sessions.
The treatment consisted of alternating low but increasing
oral doses (n=5) of ibogaine with decreasing methadone
doses. With this method, she stopped taking methadone and
only when the withdrawal symptoms became physiologi-
cally evident (OWS =23; SOWS =9), she took 150 mg of
ibogaine. One hour after ibogaine administration, all with-
drawal symptoms disappeared (SOWS =0), and reappeared
21 hr afterward (OWS =24) (for a timeline of the SOWS
scores for the rst four doses of ibogaine, see Figure 1).
Then the patient took half the basal dose of methadone
(18 mg) and maintained that dose every morning for the
following 3 days. She then ceased self-administering meth-
adone, and when withdrawal symptoms became physiolog-
ically evident, she took 300 mg of ibogaine. This process
was repeated three more times, alternating ibogaine doses
(400, 500, and 600 mg) while reducing methadone doses in
half. The time frame that the patient was administering
methadone between ibogaine sessions varied between 3
and 7 days, depending on her work obligations. After the
last dose of ibogaine (600 mg), the methadone AS ceased
and never returned.
Outcome and follow-up
The patient successfully eliminated her withdrawals from
methadone with ibogaine. Each administration of ibogaine
attenuated or even eliminated the withdrawal symptoms for
many hours (see Figure 1; there are no data for the 600 mg
dose), and reduced the tolerance to methadone until all signs
of withdrawal symptoms disappeared at the end of the
treatment. The lower ibogaine doses taken by the patient
were apparently devoid of visual effects, yet repressed
memories and emotions did surface. There were no psychi-
atric effects according to the BPRS. There were few side
effects according to the UKU. In a scale of gravity from 1 to
3, fatigability, memory impairment, akathisia, and ortho-
static dizziness were rated as 1, constipation and tension
headache were rated as 2, and reduction in the duration of
sleep was rated as 3. The rest of the eventual side effects
assessed by the UKU were rated as 0, and there was no dose
effect. In fact, the most uncomfortable side effect reported
by the patient was difculty in sleeping after each ibogaine
session, so the patient decided to use a benzodiazepine
(diazepam 2 mg) after the rst ibogaine session. After the
other ibogaine sessions, she took cannabis oil orally
acquired from her Cannabis Social Club in Barcelona, Spain
(note: in Spain, the personal use and acquisition of cannabis
in these clubs is not a criminal offense). After recovering
from the last ibogaine session, she did not continue using
methadone, benzodiazepines, nor cannabis oil.
Regarding QTc and BP, there were no clinically signi-
cant decrements. HR dropped with the 400 and 500 mg
doses from 85 to 53 bpm between the rst 23 hr. However,
sitting or standing up effectively increased HR. At no point
did the QTc measures reach clinically signicant scores.
The highest score (444 ms) was reached with the 500 mg
dose at 3 hr.
The ibogaine sessions appeared to lack visionary content,
although she had psychological insights regarding bio-
graphical events with emotional, non-distressing reactions.
The patient reported feeling comfortable, relaxed, and
Figure 1. Short Opiate Withdrawal Scale (SOWS) scores for every
ibogaine dose after its administration
Journal of Psychedelic Studies 1(1), pp. 2934 (2017) |31
Detoxication from methadone using ibogaine
completely free of anxiety during the rst 68hrofthe
experience.
During this report, 12 months after the ibogaine treat-
ment, she was no longer an MMT patient, and was without
any symptoms of post-acute withdrawal syndrome (PAWS).
Her life has improved in several ways (such as beginning to
study, play music, and volunteer again), and her frequent
use of drugs has been reduced. In an analytical test that
the patient completed 7 months after the treatment, all the
parameter values were within the IRs, including those that
were not prior to the treatment. According to the patient, this
analysis was the only one in the last 17 years where all
the parameters were within the normal ranges, although the
exact HCV viral load was not measured in the analysis.
DISCUSSION
To our knowledge, this is the rst time that a protocol based
on low and multiple doses of ibogaine administered inter-
mittently between decreasing methadone doses has been
performed to detoxify from methadone for the purposes of
research and better outcomes. Standard treatments for
detoxifying from methadone require many months to com-
plete, and patients consider it signicantly more difcult,
with more protracted PAWS symptoms than that of heroin
or other short-acting opioids (Gutwinski, Bald, Gallinat,
Heinz, & Bermpohl, 2014). The protocol based on low,
multiple, ascending doses of ibogaine may provide a rela-
tively brief but successful alternative to classical methods
based on conventional detoxication. In addition, contrary
to alpha2-adrenergic drugs that reduce abstinence symptoms
but do not eliminate it, ibogaine seems to signicantly
reduce and even eliminate AS, returning the system to its
normal physiological state. Because even very low doses of
ibogaine may induce prolongations in the QTc interval and
lower HR, which may be life-threatening (Litjens & Brunt,
2016;Meisner et al., 2016), it is critical and absolutely
required that protocols based on low doses must be medi-
cally supervised.
The ibogaine literature is confusing regarding its ef-
cacy with methadone-dependent patients because authors
do not differentiate methadone-dependent from heroin-
dependent patients, making it impossible to know precisely
whether those for whom the treatment failed were depen-
dent on methadone or not. According to the experience of
the clinicians at Pangea Biomedics, a singular large dose of
ibogaine, even with supplemental doses, over a short
period of time, does not completely eliminate the with-
drawal symptoms of methadone, especially PAWS that
aresocommontoMMTdetoxication (unpublished
observations).
It is not well understood why ibogaine has withdrawal-
mitigating properties. Ibogaine and noribogaine have a
complex neuropharmacology, binding to multiple brain
receptors, among them μ- and κ-opioid receptors, and
increasing brain-derived neurotrophic factor (Maciulaitis,
Kontrimaviciute, Bressolle, & Briedis, 2008). Noribogaine,
the principal metabolite of ibogaine, has been proposed as
the molecule responsible for its anti-withdrawal effects
(Mash et al., 1998). Earlier pharmacokinetics studies
showed that the half-life of ibogaine was of 7.45 hr for
extensive metabolizers, while noribogaine levels stayed in
the 90% range of the C
max
for 24 hr after an oral adminis-
tration of 500 mg (female) and 800 mg (male) of ibogaine
(Mash et al., 2000). A recent study has found a mean plasma
elimination of 2849 hr across dose groups after adminis-
tration of doses of 3, 10, 30, and 60 mg (Glue, Cape,
Tunnicliff, Lockhart, Lam, Hung, et al., 2016). This long
action of ibogaine/noribogaine may explain the sustained
anti-withdrawal effects of only one dose of ibogaine admin-
istered to heroin and/or other short-acting opiate users.
In this case report, the withdrawal symptoms appeared
again after 6 hr with the initial lower dose, and after almost
24 hr following the incremental doses. There are several
possible explanations for that. First, although it has
generally been established that the half-life of methadone
is 24 hr (Argoff & Silvershein, 2009), a recent pharmaco-
kinetic study found a mean elimination half-life of 59 hr in
methadone-dependent patients (Glue, Cape, Tunnicliff,
Lockhart, Lam, Gray, et al., 2016), so it is possible that
one administration of ibogaine could be insufcient, in
pharmacokinetic terms, to completely counteract the
effects of methadone withdrawal symptoms. Complemen-
tarily, the former studies of Ciba Pharmaceuticals showed
that ibogaine reduced morphine tolerance (United States
Patent Ofce, 1957), so it is possible that ibogaine could
also reduce methadone tolerance. Therefore, in this case
report, progressively increasing ibogaine doses could pro-
duce an accumulation of noribogaine in the organism, and
thus the withdrawal symptoms would take longer to reap-
pear until they completely disappeared after multiple in-
creasing doses.
Finally, there is a discrepancy between this case and the
lack of signicant effects in the only clinical trial that
assessed the anti-withdrawal properties of noribogaine
(Glue, Cape, Tunnicliff, Lockhart, Lam, Hung, et al.,
2016). Noribogaine and ibogaine have a different neuro-
pharmacology. A recent study using oral doses of noribo-
gaine in rodents found that it is necessary to administer high
doses of noribogaine to reduce withdrawal symptoms (the
half-efcacious dose was 13 mg/kg) (Mash, Ameer, Prou,
Howes, & Maillet, 2016). It is possible that it may be
necessary to combine both the effects of ibogaine and
noribogaine to obtain a complete anti-withdrawal effect.
A recent study showed that noribogaine, in contrast to
ibogaine, is a weak μ-opioid receptor antagonist and an
efcient κ-opioid receptor agonist (Maillet et al., 2015).
Since ibogaine and noribogaine have different actions on the
brain, it could be speculated that both of them cooperateto
reach a nal anti-withdrawal effect, at least in patients
dependent on opioids with a long half-life. Thus, it is
possible that because of the agonist action of ibogaine at
μ-opioid receptor subjects may rst experience a relief of
withdrawal effects, and the action of noribogaine on
κ-opioid receptors may be the responsible mechanism for
reversing tolerance (Fujita-Hamabe et al., 2010). This sug-
gests that it may not be necessary to use high doses of
ibogaine to briey reverse withdrawal, and that repeated
doses of ibogaine would be necessary to reverse tolerance in
methadone-dependent patients, so that noribogaine can
32 |Journal of Psychedelic Studies 1(1), pp. 2934 (2017)
Wilkins et al.
sufciently accumulate in the brain until reaching the
necessary levels to completely reverse/eliminate withdrawal
symptoms. Because of the undesirable side effects of ibo-
gaine, including emotional and memory processing, even
at low doses, it is more tolerable for the patient to alternate
the doses of ibogaine with periods of methadone, thereby
progressively reducing the opioid dose until dependence
has denitively been eliminated, and psychological inte-
gration is achieved. The use of benzodiazepines may be
indicated to counteract insomnia and psychostimulant side
effects. Our patient preferred to use legal cannabis, which
may have anti-withdrawal properties as well (Scavone,
Sterling, Weinstein, & Van Bockstaele, 2013). Clinical
trials comparing single doses with multiple doses of ibo-
gaine are necessary to establish which approach is the
safest and most efcient in treating opioid withdrawal and
dependence.
Acknowledgements: The authors would like to thank the
patient for her kindness in allowing us to supervise her
treatment, and Sarita Wilkins and Douglas Greene for their
invaluable assistance with manuscript editing. They would
also like to thank Anwar Jeewa (South Africa) and Phyto-
stan Enterprises, Inc. (Montreal, Canada) for kindly donat-
ing the ibogaine.
Ethics: The patient signed a patient consent form giving her
permit to publish this case report.
Conict of interest: CW is the Director of Pangea Biomedics
(Nayarit, Mexico), a clinic that runs legal ibogaine treatments
in Mexico. RGdS is a Fellow of the Brazilian National
Postdoctoral Program (PNPD/CAPES) and member of the
ICEERS Advisory Board. JS, PC, EM, MAA-C, and JCB are
ICEERS employees or collaborators. ICEERS is a non-prot
organization that promotes the scientic research of ibo-
gaine. JECH received a CNPq (Brazil) Productivity Fellow-
ship Award. For the remaining authors, none were declared.
None of the authors received any specic funding for
participating in this investigation. All authors had full access
to all the data in this study and had nal responsibility for the
decision to submit for publication.
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34 |Journal of Psychedelic Studies 1(1), pp. 2934 (2017)
Wilkins et al.
... In summary, a total of 18 articles were included in the systematic review. Of the 18 selected articles, 15 were case reports or case series (Breuer et al. 2015;Marta et al. 2015;O'Connell et al. 2015;Cloutier-Gill et al. 2016;Hildyard et al. 2016;Meisner et al. 2016;Henstra et al. 2017;Wilkins et al. 2017;Knuijver et al. 2018;Mash et al. 2018;Steinberg and Deyell, 2018;Barsuglia et al. 2018;Grogan et al. 2019;Matamoros-Castillo et al. 2019;Wilson et al. 2021). There were also two randomized, double-blind clinical trials (Glue et al. 2016(Glue et al. , 2015, and one observational study (Brown and Alper, 2018). ...
... Regarding adverse events, the results obtained after analyzing the articles were divided between acute (< 24 h) and long-lasting effects (> 24 ho). Almost half of the citations (8 in 18) reported absence of effects after the first 24 h (Glue et al. 2016;O'Connell et al. 2015;Wilkins et al. 2017;Mash et al. 2018;Barsuglia et al. 2018;Wilson et al. 2021;Glue et al. 2015;Brown and Alper, 2018). In the case reports, most cases required hospital intervention, some of them being admitted to intensive care units (Breuer et al. 2015;Steinberg and Deyell 2018;Grogan et al. 2019). ...
... Only in five out of 15 case reports the presence of ibogaine could be determined (O'Connell et al. 2015;Henstra et al. 2017;Wilkins et al. 2017;Mash et al. 2018;Grogan et al. 2019), and in only one both the presence and the quantity of ibogaine were measured (O'Connell et al. 2015). Iboga root bark was supposedly used in three cases (Breuer et al. 2015;Grogan et al. 2019;Wilson et al. 2021), while the other ones supposedly used ibogaine HCl (O'Connell et al. 2015;Cloutier-Gill et al. 2016;Hildyard et al. 2016;Meisner et al. 2016;Henstra et al. 2017;Wilkins et al. 2017;Mash et al. 2018;Steinberg and Deyell, 2018;Barsuglia et al. 2018;Brown and Alper, 2018), or it was unknown (Marta et al. 2015;Matamoros-Castillo et al. 2019). ...
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Context Ibogaine is the main alkaloid of the African shrub Tabernanthe iboga. It produces hallucinogenic and psychostimulant effects, but it is currently known for the anti-addictive properties. Despite the potential therapeutic effects, several cases of fatalities and serious adverse events related to ibogaine/noribogaine use can be found in the literature. Most studies consist in case reports or were conducted under non-controlled settings, so causation cannot be clearly established. Objectives To update (2015–2020) the literature on the adverse events and fatalities associated with ibogaine/noribogaine administration. Methods Systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Results Eighteen studies were included in the final selection. Highly heterogeneous results were found in terms of kind of product used or the known dosages. The adverse events were classified in acute effects (< 24 h), mainly cardiac (the most common was QTc prolongation), gastrointestinal, neurological, and clinical alterations, and long-lasting effects (> 24 h), mainly persistent cardiac alterations, psychiatric, and neurological signs. Conclusions There is a high need of phase I clinical trials that can describe the safety of different dosages of ibogaine with standardized products. Further research should perform clinical profiling of vulnerable populations, and design effective screening methods and clinical procedures.
... She had previously undertaken various treatment modalities, including opioid-agonist-therapy (OAT) with methadone. Wilkins et al. (2017) published another case of a 47-year-old female patient treated for OUD by tapering her off methadone while increasing oral doses of ibogaine (max. 600 mg/d). ...
... In recent years, some studies evaluated the effects of microdosing of other hallucinogenic compounds like LSD, psilocybin, or ketamine (Higgins et al., 2021;Kuypers et al., 2019). The case report by Wilkins et al. (2017), which we included in this review, describes a successful treatment of OUD with repeated small doses of ibogaine. Another anecdotal article reported that three individuals with OUD benefited from repeated administration of small ibogaine doses (Kroupa & Wells, 2005). ...
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Background Iboga and its primary alkaloids, ibogaine and noribogaine, have been of interest to researchers and practitioners, mainly due to their putative efficacy in treating substance use disorders (SUDs). For many SUDs, still no effective pharmacotherapies exist. Distinct psychoactive and somatic effects of the iboga alkaloids set them apart from classic hallucinogens like LSD, mescaline, and psilocybin. Aims The study team performed this systematic review focusing on clinical data and therapeutic interventions involving ibogaine and noribogaine. Methods The team conducted a search for all publications up to December 7, 2020, using PubMed and Embase following PRISMA guidelines. Results In total, we identified 743 records. In this review, we consider 24 studies, which included 705 individuals receiving ibogaine or noribogaine. This review includes two randomized, double-blind, controlled clinical trials, one double-blind controlled clinical trial, 17 open-label studies or case series (including observational or retrospective studies), three case reports, and one retrospective survey. The published data suggest that ibogaine is an effective therapeutic intervention within the context of SUDs, reducing withdrawal symptoms and craving. Data also point toward a beneficial impact on depressive and trauma-related psychological symptoms. However, studies have reported severe medical complications and deaths, which seem to be associated with neuro- and cardiotoxic effects of ibogaine. Two of these fatalities were described in the 24 studies included in this review. Conclusion Treatment of SUDs and persisting comorbidities requires innovative treatment approaches. Rapid-onset therapies such as the application of ibogaine may offer novel treatment opportunities for specific individuals. Rigorous study designs within medical settings are necessary to warrant safe application, monitoring, and, possibly, medical intervention.
... Pre-clinical research has demonstrated the anti-addictive properties of ibogaine in different animal species with reductions in self-administered morphine, cocaine, (meth)-amphetamines, alcohol and nicotine 3 . Ibogaine was also found to reduce or eliminate drug craving and withdrawal in humans in several case series and in clinical settings, but randomized trials are lacking [4][5][6][7] . ...
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Background: Therapeutic properties of ibogaine in the treatment of addiction are attracting both clinicians and patients to its use. Since ibogaine is not an authorized medicine, the quality of these products is not always known, increasing the probability of adverse reactions. Objective: This study collects different types of iboga-derived samples from treatment providers, vendors and online buyers to analyse their content. Methods: Analysis of iboga products (n = 16) was performed using gas chromatography and mass spectrometry methods (GC/MS). Products included Iboga root bark, Total Alkaloids (TA), Purified Total Alkaloids (PTA HCl), ibogaine hydrochloride (ibogaine HCl) and one Voacanga africana root bark. Results: The content of ibogaine was highly variable, ranging from 0.6% to 11.2% for products sold as iboga root bark, from 8.2% to 32.9% for products sold as TA, 73.7% for one sample sold as PTA and from 61.5% to 73.4% for products sold as ibogaine HCl. One sample did not show any iboga alkaloids. Other alkaloids and unknown substances were found in almost all samples. Discussion: The purity of iboga products is highly variable. These results should be taken into consideration by suppliers and users, especially regarding correct dosing to avoid overdose, as well as potential interactions with other substances.
... While the effects on W and SWS were observed only in first 2 h, the effects on REM sleep lasted through the entire recording. These results may resemble observational studies in humans where ibogaine administration in multiple doses produced difficulties in sleep onset and maintenance immediately after each intake (Wilkins et al., 2017). Ibogaine's W-promoting effect, in addition, is in accordance with a previous report in cats (Schneider and Sigg, 1957), suggesting that ibogaine induces W in rats, cats, and probably in humans. ...
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p>Ibogaine is a psychedelic alkaloid which has been subject of intense scientific research due to its reported ability to attenuate drug-seeking behavior. Recent work suggested that ibogaine effects on alcohol self-administration in rats was related to the release of Glial Cell Derived Neurotrophic Factor (GDNF) in the Ventral Tegmental Area (VTA), a mesencephalic region which hosts soma of dopamine neurons. It is well known that neurotrophic factors (NFs) mediate the neuroadaptations induced in the mesocorticolimbic dopaminergic system by repeated exposure to drugs. Although previous reports have shown ibogaine´s ability to induce GDNF expression in rat midbrain, there are no studies addressing its effect on the expression of GDNF, Brain Derived Neurotrophic Factor (BDNF) or Nerve Growth Factor (NGF) in distinct regions containing dopaminergic neurons. In this work, we examined the effect of ibogaine acute administration on the expression of these NFs in the VTA, Prefrontal Cortex (PFC), Nucleus Accumbens (NAcc) and the Substantia Nigra (SN). Thus, rats were i.p. treated with ibogaine 20 mg/kg (I<sub>20</sub>), 40 mg/kg (I<sub>40</sub>) or vehicle, and NFs expression was analyzed after 3 and 24 hours. Only at 24 h an increase of the expression for the three NFs were observed in a site and dose dependent manner. Results for GDNF showed that only I<sub>40</sub> selectively upregulated its expression in the VTA and SN. Both doses of ibogaine elicited a large increase in the expression of BDNF in the NAcc, SN and PFC, while a significant effect was found in the VTA only for I<sub>40</sub>. Finally, NGF was found to be upregulated in all regions after I<sub>40</sub>, while a selective upregulation was found in PFC and VTA for the I<sub>20</sub> treatment. An increase in the content of mature GDNF was observed in the VTA but no significant increase in the mature BDNF protein content was found in all the studied areas. Interestingly, an increase in the content of proBDNF was detected in the NAcc for both treatments. Further research is needed to understand the neurochemical bases of these changes, and to confirm their contribution to the anti-addictive properties of ibogaine. </p
... While the effects on W and SWS were observed only in first 2 h, the effects on REM sleep lasted through the entire recording. These results may resemble observational studies in humans where ibogaine administration in multiple doses produced difficulties in sleep onset and maintenance immediately after each intake (Wilkins et al., 2017). Ibogaine's W-promoting effect, in addition, is in accordance with a previous report in cats (Schneider and Sigg, 1957), suggesting that ibogaine induces W in rats, cats, and probably in humans. ...
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Full-text available
Ibogaine is a potent psychedelic alkaloid that has been the focus of intense research because of its intriguing anti-addictive properties. According to anecdotic reports, ibogaine has been originally classified as an oneirogenic psychedelic; i.e., induces a dream-like cognitive activity while awake. However, the effects of ibogaine administration on wakefulness (W) and sleep have not been thoroughly assessed. The main aim of our study was to characterize the acute effects of ibogaine administration on W and sleep. For this purpose, polysomnographic recordings on chronically prepared rats were performed in the light phase during 6 h. Animals were treated with ibogaine (20 and 40 mg/kg) or vehicle, immediately before the beginning of the recordings. Furthermore, in order to evaluate associated motor behaviors during the W period, a different group of animals was tested for 2 h after ibogaine treatment on an open field with video-tracking software. Compared to control, animals treated with ibogaine showed an increase in time spent in W. This effect was accompanied by a decrease in slow wave sleep (SWS) and rapid-eye movements (REM) sleep time. REM sleep latency was significantly increased in animals treated with the higher ibogaine dose. While the effects on W and SWS were observed during the first 2 h of recordings, the decrement in REM sleep time was observed throughout the recording time. Accordingly, ibogaine treatment with the lower dose promoted an increase on locomotion, while tremor and flat body posture were observed only with the higher dose in a time-dependent manner. In contrast, head shake response, a behavior which has been associated in rats with the 5HT 2A receptor activation by hallucinogens, was not modified. We conclude that ibogaine promotes a waking state that is accompanied by a robust and long-lasting REM sleep suppression. In addition, it produces a dose-dependent unusual motor profile along with other serotonin-related behaviors. Since ibogaine is metabolized to produce noribogaine, further experiments are needed to elucidate if the metabolite and/or the parent drug produced these effects.
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Ibogaine is the most abundant alkaloid present in the African shrub Tabernanthe iboga. As a result of the lack of research on the acute subjective effects, the purpose of this study was to identify categories of the ibogaine experience and gain a better understanding of the internal processes while under its effects. We created a semistructured interview and recruited twenty individuals who had recently taken ibogaine. The interviews were analyzed according to grounded theory approach. We identified eight categories (physical, sensory, visual, cognitive, auditory, adverse, anti‐dependency agent, after‐effects) and ten subcategories (open eye visuals; closed eye visuals: ancestors and entities, sceneries and landscapes, horrific scenarios; self‐psychoanalysis enhancement; empathy, love, and prosocial behavior; catharsis; observer quality; ego dissolution; spiritual states) of the acute subjective effects of ibogaine. The study contributes to the advancement of our understanding of ibogaine and its role in personal growth, prosocial behavior, therapeutic use, and anti‐dependency treatments.
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The effectiveness of methadone maintenance treatment is beyond any doubt, but there remains some incertitude about the appropriate and effective dosage and the objectives that should be achieved by this therapy. Some authors maintain that only doses higher than 50-60 mg/day ought to be considered effective, since only these block all the opioid receptors. But others propose the use of doses adjusted to the needs of the patient, based on their recovery process. Quality of life, satisfaction with treatment, psychopathological symptoms, cognitive performance and additional intake of illegal and unprescribed drugs were evaluated in a representative sample of all patients treated with opioid agonists in the Addiction Institute of Madrid (N = 1898, n = 450) and the Junta de Extremadura (N = 100, n = 65). The results revealed a negative relationship between dose and quality of life, psychopathological symptoms and cognitive performance. Satisfaction with treatment, based on doses negotiated together by doctor and patient, was very high, regardless of the dose. To establish hypothetical causal dependencies among the studied variables structural equation modelling was performed. The results reject the need for high dosage if not required by the patient, and highlight the benefits of other psychosocial interventions that lead to recovery, despite the chronification that could imply the use of high doses. Whereas high dosage programmes provide better indicators of social control, the patient's quality of life must be one of the main indicators of a successful treatment, as in any other health problem.
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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.
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Context: Ibogaine is a psychoactive indole alkaloid found in the African rainforest shrub Tabernanthe Iboga. It is unlicensed but used in the treatment of drug and alcohol addiction. However, reports of ibogaine's toxicity are cause for concern. Objectives: To review ibogaine's pharmacokinetics and pharmacodynamics, mechanisms of action and reported toxicity. Methods: A search of the literature available on PubMed was done, using the keywords "ibogaine" and "noribogaine". The search criteria were "mechanism of action", "pharmacokinetics", "pharmacodynamics", "neurotransmitters", "toxicology", "toxicity", "cardiac", "neurotoxic", "human data", "animal data", "addiction", "anti-addictive", "withdrawal", "death" and "fatalities". The searches identified 382 unique references, of which 156 involved human data. Further research revealed 14 detailed toxicological case reports. Pharmacokinetics and pharmacodynamics: Ibogaine is metabolized mainly by CYP2D6 to the primary metabolite noribogaine (10-hydroxyibogamine). Noribogaine is present in clinically relevant concentrations for days, long after ibogaine has been cleared. Mechanisms of action: Ibogaine and noribogaine interact with multiple neurotransmitter systems. They show micromolar affinity for N-methyl-D-aspartate (NMDA), κ- and μ-opioid receptors and sigma-2 receptor sites. Furthermore, ibogaine has been shown to interact with the acetylcholine, serotonin and dopamine systems; it alters the expression of several proteins including substance P, brain-derived neurotrophic factor (BDNF), c-fos and egr-1. Neurotoxicity: Neurodegeneration was shown in rats, probably mediated by stimulation of the inferior olive, which has excitotoxic effects on Purkinje cells in the cerebellum. Neurotoxic effects of ibogaine may not be directly relevant to its anti-addictive properties, as no signs of neurotoxicity were found following doses lower than 25 mg/kg intra-peritoneal in rats. Noribogaine might be less neurotoxic than ibogaine. Cardiotoxicity: Ether-a-go-go-related gene (hERG) potassium channels in the heart might play a crucial role in ibogaine's cardiotoxicity, as hERG channels are vital in the repolarization phase of cardiac action potentials and blockade by ibogaine delays this repolarization, resulting in QT (time interval between the start of the Q wave and the end of the T wave in the electrical cycle of the heart) interval prolongation and, subsequently, in arrhythmias and sudden cardiac arrest. Twenty-seven fatalities have been reported following the ingestion of ibogaine, and pre-existing cardiovascular conditions have been implicated in the death of individuals for which post-mortem data were available. However, in this review, 8 case reports are presented which suggest that ibogaine caused ventricular tachyarrhythmias and prolongation of the QT interval in individuals without any pre-existing cardiovascular condition or family history. Noribogaine appears at least as harmful to cardiac functioning as ibogaine. Toxicity from drug-drug interaction: Polymorphism in the CYP2D6 enzyme can influence blood concentrations of both ibogaine and its primary metabolite, which may have implications when a patient is taking other medication that is subject to significant CYP2D6 metabolism. Conclusions: Alternative therapists and drug users are still using iboga extract, root scrapings, and ibogaine hydrochloride to treat drug addiction. With limited medical supervision, these are risky experiments and more ibogaine-related deaths are likely to occur, particularly in those with pre-existing cardiac conditions and those taking concurrent medications.
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A naturally occurring hallucinogenic plant alkaloid, ibogaine has been used as an adjuvant for opiate withdrawal for the past 50 years. In the setting of an escalating nationwide opiate epidemic, use of substances such as ibogaine may also increase. Therefore, familiarity with the mechanisms and potential adverse effects of ibogaine is important for clinicians. We present the case report of a man whose use of ibogaine resulted in cardiac arrest and death, complemented by a review of the literature regarding ibogaine’s clinical effects. A 40-year-old man who used ibogaine for symptoms of heroin withdrawal suffered acute cardiac arrest leading to cerebral edema and brain death. His presentation was consistent with ibogaine-induced cardiotoxicity and ibogaine-induced cardiac arrest, and a review of the literature regarding the history, mechanisms, risks and clinical outcomes associated with ibogaine is presented. The case presented underscores the significant potential clinical risks of ibogaine. It is important the healthcare community be aware of the possible effects of ibogaine such that clinicians can provide informed counseling to their patients regarding the risks of attempting detoxification with ibogaine.
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Noribogaine is the long-lived human metabolite of the anti-addictive substance ibogaine. Noribogaine efficaciously reaches the brain with concentrations up to 20 μM after acute therapeutic dose of 40 mg/kg ibogaine in animals. Noribogaine displays atypical opioid-like components in vivo, anti-addictive effects and potent modulatory properties of the tolerance to opiates for which the mode of action remained uncharacterized thus far. Our binding experiments and computational simulations indicates that noribogaine may bind to the orthosteric morphinan binding site of the opioid receptors. Functional activities of noribogaine at G-protein and non G-protein pathways of the mu and kappa opioid receptors were characterized. Noribogaine was a weak mu antagonist with a functional inhibition constants (Ke) of 20 μM at the G-protein and β-arrestin signaling pathways. Conversely, noribogaine was a G-protein biased kappa agonist 75% as efficacious as dynorphin A at stimulating GDP-GTP exchange (EC50 = 9 μM) but only 12% as efficacious at recruiting β-arrestin, which could contribute to the lack of dysphoric effects of noribogaine. In turn, noribogaine functionally inhibited dynorphin-induced kappa β-arrestin recruitment and was more potent than its G-protein agonistic activity with an IC50 of 1 μM. This biased agonist/antagonist pharmacology is unique to noribogaine in comparison to various other ligands including ibogaine, 18-MC, nalmefene, and 6'-GNTI. We predict noribogaine to promote certain analgesic effects as well as anti-addictive effects at effective concentrations >1 μM in the brain. Because elevated levels of dynorphins are commonly observed and correlated with anxiety, dysphoric effects, and decreased dopaminergic tone, a therapeutically relevant functional inhibition bias to endogenously released dynorphins by noribogaine might be worthy of consideration for treating anxiety and substance related disorders. Copyright © 2015. Published by Elsevier Ltd.
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The indole alkaloid ibogaine, present in the root bark of the West African rain forest shrub Tabernanthe iboga, has been adopted in the West as a treatment for drug dependence. Treatment of patients requires large doses of the alkaloid to cause hallucinations, an alleged integral part of the patient's treatment regime. However, case reports and case series continue to describe evidences of ataxia, gastrointestinal distress, ventricular arrhythmias and sudden and unexplained deaths of patients undergoing treatment for drug dependence. High doses of ibogaine act on several classes of neurological receptors and transporters to achieve pharmacological responses associated with drug aversion; limited toxicology research suggests that intraperitoneal doses used to successfully treat rodents, for example, have also been shown to cause neuronal injury (purkinje cells) in the rat cerebellum. Limited research suggests lethality in rodents by the oral route can be achieved at approximately 263mg/kg body weight. To consider an appropriate and safe initial dose for humans, necessary safety factors need to be applied to the animal data; these would include factors such as intra- and inter-species variability and for susceptible people in a population (such as drug users). A calculated initial dose to treat patients could be approximated at 0.87mg/kg body weight, substantially lower than those presently being administered to treat drug users. Morbidities and mortalities will continue to occur unless practitioners reconsider doses being administered to their susceptible patients.
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This study investigated the effects of noribogaine, the principal metabolite of the drug ibogaine, on substance-related disorders. In the first experiment, mice chronically treated with morphine were subjected to naloxone-precipitated withdrawal two hours after oral administration of noribogaine. Oral noribogaine dose dependently decreased the global opiate withdrawal score by up to 88% of vehicle control with an ED50of 13 mg/kg. In the second experiment, blood and brain levels of noribogaine showed a high brain penetration and a brain/blood ratio of 7±1 across all doses tested. In a third experiment, rats given oral noribogaine up to 100 mg/kg were tested for abuse liability using a standard biased conditioned place paradigm. Noribogaine-treated rats did not display place preference, suggesting that noribogaine is not perceived as a hedonic stimulus in rodents. Retrospective review of published studies assessing the efficacy of ibogaine on morphine withdrawal shows that the most likely cause of the discrepancies in the literature is the different routes of administration and time of testing following ibogaine administration. These results suggest that the metabolite noribogaine rather than the parent compound mediates the effects of ibogaine on blocking naloxone-precipitated withdrawal. Noribogaine may hold promise as a non-addicting alternative to standard opiate replacement therapies to transition patients to opiate abstinence.
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Ibogaine is a psychoactive substance that may reduce opioid withdrawal symptoms. This was the first clinical trial of noribogaine, ibogaine's active metabolite, in patients established on methadone opioid substitution therapy (OST). In this randomized, double-blind, placebo-controlled, single ascending dose study, we evaluated the safety, tolerability, and pharmacokinetics of noribogaine in 27 patients seeking to discontinue methadone OST, who had been switched to morphine during the previous week. Noribogaine doses were 60, 120 or 180mg (n = 6/dose level) or matching placebo (n = 3/dose level). Noribogaine was well tolerated. The most frequent treatment-emergent adverse events were non-euphoric changes in light perception at ∼1h post dose, headache and nausea. Noribogaine had dose-linear increases for AUC and Cmax, and was slowly eliminated (mean t1/2 range 24–30h). There was a concentration-dependent increase in QTcI (0.17msec/ng/mL) with largest observed mean effect of ∼16msec, 28msec, and 42msec in the 60mg, 120mg, and 180mg groups, respectively. Noribogaine showed a non-statistically significant trend to decrease total scores in opioid withdrawal ratings, most notably at the 120mg dose, however the study design may have confounded evaluations of time to resumption of OST. Future exposure-controlled multiple-dose noribogaine studies are planned that will address these safety and design issues. This article is protected by copyright. All rights reserved
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The aim of this study was to switch patients established on methadone opioid substitution therapy (OST) to morphine over 1 week. Subjects established on daily methadone OST (mean dose 60mg/day) were switched to morphine slow release capsules, dosed at 4x the previous total daily methadone dose, for 6 days, then given morphine syrup dosed q3h. All 27 subjects enrolled in this study completed the switch from methadone to morphine. Opioid withdrawal symptoms (OWS) peaked within 12-24h of starting morphine, and 24/27 subjects required higher daily morphine doses (mean 5.2x multiple). Pharmacokinetic evaluation showed that 91% of methadone was cleared during this time, with a mean elimination half-life of 59h. The most frequent treatment-emergent non-OWS adverse events were headache, nausea, constipation and neck pain. The method described here appears to be a safe and acceptable approach to switch subjects from methadone to morphine. This article is protected by copyright. All rights reserved.