Drug and Alcohol Dependence 166 (2016) 1–5
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Drug and Alcohol Dependence
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Review
Ibogaine for treating drug dependence. What is a safe dose?
a,∗ a b,c c
L.J. Schep , R.J. Slaughter , S. Galea , D. Newcombe
a
National Poisons Centre, Department of Preventive and Social Medicine, University of Otago, Dunedin, New Zealand
b
Community Alcohol and Drug Services, Waitemata DHB, New Zealand
c
Social and Community Health and Centre for Addiction Research, University of Auckland, New Zealand
a r t i c l e i n f o a b s t r a c t
Article history: The indole alkaloid ibogaine, present in the root bark of the West African rain forest shrub Tabernanthe
Received 12 May 2016
iboga, has been adopted in the West as a treatment for drug dependence. Treatment of patients requires
Received in revised form 4 July 2016
large doses of the alkaloid to cause hallucinations, an alleged integral part of the patient’s treatment
Accepted 4 July 2016
regime. However, case reports and case series continue to describe evidences of ataxia, gastrointestinal
Available online 15 July 2016
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 trans-
Keywords:
porters to achieve pharmacological responses associated with drug aversion; limited toxicology research
Ibogaine
suggests that intraperitoneal doses used to successfully treat rodents, for example, have also been shown
Drug dependence
to cause neuronal injury (purkinje cells) in the rat cerebellum. Limited research suggests lethality in
QT prolongation
Purkinje cells rodents by the oral route can be achieved at approximately 263 mg/kg body weight. To consider an
Potassium voltage gated human appropriate and safe initial dose for humans, necessary safety factors need to be applied to the animal
Ether-à-go-go-Related gene (hERG) channel 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 0.87 mg/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.
© 2016 Elsevier Ireland Ltd. All rights reserved.
1. Introduction and higher doses being hallucinogenic (Alper et al., 2008; Mash
et al., 2000). Patients undergoing treatment report oneirophrenic
The indole alkaloid ibogaine is the most abundant hallucino- effects that can endure for 4–8 h post-ingestion followed by an eval-
genic constituent present in the root bark of the West African rain uation phase, during which patients report a high level of mental
forest shrub Tabernanthe iboga. Extracts derived from this plant activity, terminating with a residual stimulation state that may last
have a long history of traditional medicinal and ceremonial use up to 72 h (Lotsof and Alexander, 2001).
by local Bwiti people (Alper et al., 2008). Since approximately However, in addition to ibogaine’s hallucinogenic properties,
1962, ibogaine has been employed in Western jurisdictions, such which allegedly contribute to its efficacy in treating drug addiction,
as Europe and the United States (Alper et al., 2001), as a treatment case reports consistently report evidences of ataxia, gastrointesti-
for drug dependence particularly to treat the cravings and with- nal distress, ventricular arrhythmias and sudden and unexplained
drawal that accompany opioid and cocaine dependence (Lotsof and deaths (Alper et al., 2012). Given the risks associated with its use,
Alexander, 2001). this paper seeks to explore the drug’s toxicity and show that doses
Nevertheless, evidence of its efficacy has been restricted to case employed in recovery clinics to treat patients are within values that
studies in patients withdrawing from drug dependence, suggest- demonstrate mammalian toxicity.
ing apparent reduction in withdrawal severity (symptoms) and
drug seeking for up to 72 h post-treatment (Alper, 2001; Alper
2. Mechanism of action
et al., 2008; Galea et al., 2011). Ibogaine appears to have a dose-
dependent effect with low doses reportedly acting as a stimulant
Ibogaine has a complex pharmacology and the underlying
mechanisms that mediate its physiological and psychological
effects are not well elucidated. Investigations of the pharmacolog-
∗
ical activity of ibogaine and its putative anti-addictive properties
Corresponding author.
E-mail address: [email protected] (L.J. Schep). suggest that its action involves mediation of several classes of neu-
2 L.J. Schep et al. / Drug and Alcohol Dependence 166 (2016) 1–5
rological receptors and transporters, including the sigma-2, kappa- 4. Correlating animal toxicity to human clinical trials
& mu-opioid, 5HT2 and 5HT3 receptors, ␣34 nicotinic receptors,
and the N-methyl-d-aspartic acid (NMDA) ion channel (Glick et al., Animal investigations can assist in assessing the toxicology of a
2002; Maciulaitis et al., 2008). drug in living systems. To establish the risk of toxicity to humans
There is some suggestion that ibogaine is a Sigma-2 selective in clinical trials, for example, animal studies that establish a NOAEL
ligand (Bowen et al., 1995); the receptor itself has a putative role in can be applied to human investigations, following the application
modulating cytotoxicity and cell death (Bowen, 2001) and the neu- of an appropriate safety factor. This is determined by converting the
rotoxic effects of ibogaine may be due, in part, to agonist action at animal NOAEL to a human equivalent dose (HED). Suggested values
this receptor (Bowen, 2001; Glick et al., 2001). Radioligand binding are derived by dividing the NOAEL by a safety factor that can range
assays have demonstrated ibogaine binding to kappa- and mu- from 10 through to 50, depending on results from the preclinical
opioid receptors at low concentrations (Sweetnam et al., 1995), and investigations, such as the gradient of the dose response curve (FDA,
it is an antagonist at nicotinic receptors and the NMDA receptor 2005).
coupled ion channel (Glick et al., 2002; Popik et al., 1994). Research There is very limited information on the animal toxicity of
has suggested the combination of these receptor site activities may ibogaine and less so by the route of ingestion. The only report
have a role in promoting anti-addictive properties in animal models that has established a NOAEL for ibogaine was determined fol-
(Glick et al., 1997). Ibogaine also acts upon 5-HT2 and 5-HT3 recep- lowing administration by the intraperitoneal route (see Table 1),
tors and binds to the serotonin transporters, thereby preventing which established a dose of 25 mg/kg. Some authors have sug-
serotinin reabsorption, similar to a serotonin-selective reabsorp- gested that on the basis of this experiment it is safe to administer
tion inhibitor (such as fluoxetine; Baumann et al., 2001). Evidence 25 mg/kg orally for the treatment of drug dependency (Mash et al.,
suggests there is a dose-related increase of extracellular 5-HT in 1998). However, there are flaws in this argument. Firstly, a dose
the nucleus accumbens (Baumann et al., 2001). administered by one route of exposure (IP) cannot be compared
Radio-ligand binding of ibogaine to these various receptor sites with another route (oral). Secondly, and more importantly, esti-
suggests IC50 concentrations necessary to achieve pharmacolog- mates of toxicity cannot solely depend on doses given to animals;
ical activity range from 1 to 10 M (Baumann et al., 2001). In there need to be, as described above, additional safety factors
comparison, oral administration of 50 mg/kg to rats has, for exam- installed into the calculation. For example, if a safety factor of 30
ple, achieved ibogaine concentrations in the brain ranging from 4 was to be applied to this value (the approximate median value
to 17 M (Staley et al., 1996), suggesting doses of ibogaine that between values ranging from 10 to 50), then a theoretical dose of
achieve drug aversions in animal models are within those values 0.83 mg/kg could be considered acceptable for a starting dose for
necessary to achieve micromolar-affinity binding in vitro (Baumann human clinical trials, if administration of the drug was by the IP
et al., 2001). route.
However, a NOAEL for ibogaine has not been established for
the oral route. The lowest reported oral dose of ibogaine that can
3. Toxicity
cause lethality in animals is 263 mg/kg (Table 1). In the absence of
any other data, this dose should be divided by several safety fac-
There is limited information available on the toxicity of ibo-
tors to estimate a considered dose by the oral route. Such factors
gaine in mammalian species. A summary of the investigations
would include dividing by 10 for intra-species variability, another
involving acute toxicity to ibogaine are presented in Table 1. Inves-
10 for inter-species variability (animal model to humans) and in
tigations have been undertaken with rats and mice, and, depending
some instances another value, such as 3, for susceptible people in a
on the route of exposure, lethal doses varied from 145 to 175 mg/kg
population (such as long-term drug users that have medical comor-
and 263 to 327 mg/kg body weight by the intraperitoneal (IP)
bidities; Alper et al., 2012) or to account for possible weaknesses in
and oral routes, respectively. The no observable adverse effect
the design and application of the animal investigation (IPCS, 1994).
level (NOAEL), defined as the highest dose of a chemical which
Based on a 263 mg/kg oral investigation in mice, an initial starting
does not cause an observable adverse effect on a test animal, was
dose, possibly acceptable for human exposure, could therefore be
25 mg/kg IP (Xu et al., 2000), where the measurable parameter of
0.87 mg/kg.
adverse effect was evidence of neuropathology (purkinje cells) in
Although this suggested dose is theoretical, it is not surprising
the rat cerebellum. The lowest observable dose to cause observ-
that the clinical trial approved by the U.S. Food and Drug Adminis-
able neuronal injury in this study was reported to be 50 mg/kg IP.
tration in 1995 recommended similar doses, to treat patients with
Other research suggests elevated acute doses (100 mg/kg, IP, rat)
a history of drug abuse; doses were initiated at 1–2 mg/kg body
of ibogaine can cause tremors with resultant degeneration of purk-
weight (Mash et al., 1998). Additionally, a recently completed con-
inje cells (O’Hearn and Molliver, 1993). Chronic administration of
trolled clinical trial employed a 20 mg dose of ibogaine (assuming
10 mg/kg IP in the rat did not show evidence of neuropathology
an 80 kg weight, this would equate to 0.25 mg/kg), which was well
(Helsley et al., 1997).
tolerated without evidence of host toxicity (Glue et al., 2015). In
Tremors are a common symptom following acute ibogaine
contrast, doses used to treat patients in unregulated treatments
administration in rodents, occurring as low as 12 mg/kg sub-
have ranged from 6 to 30 mg/kg. (Alper, 2001), within doses that
cutaneous (SC; Zetler et al., 1972), though other authors have
have shown evidence of toxicity in animal models.
reported this phenomenon at 40 and 80 mg/kg doses (IP; Glick et al.,
1992, 1991).
Mild cardiotoxicity has also been evident in animal models.
5. Human toxicity
Administration of 40 mg/kg IP in rats, showed no changes in resting
heart rate or blood pressure whereas doses of 100 and 200 mg/kg
Doses necessary to achieve efficacy in rodents are within those
demonstrated bradycardia without evidence of hypotension (Glick
that cause observable toxicity. A number of studies, such as sum-
et al., 2000). Nevertheless, another investigation demonstrated
marised by Zubaran (2000), for example, suggest aversions to
hypotension and bradycardia in the same species at 50 mg/kg by
various drugs of abuse were achieved in animal models at 40 and
the intraperitoneal route (Binienda et al., 1998). Unfortunately, the
80 mg/kg IP; these are, however, within doses that have been shown
authors had not undertaken ECG profiles to identify any evidences
to cause neuronal injury by the same route of exposure (Xu et al., of dysrhythmias. 2000).
L.J. Schep et al. / Drug and Alcohol Dependence 166 (2016) 1–5 3
Table 1
A Summary of acute toxicity to ibogaine in rats and mouse by various routes of exposure.
Toxicology end point Species Route of exposure Dose (mg/kg) Duration Author(s)
LD50 Mouse Oral 263 Acute Kubiliene et al. (2008)
LD50 Rat IP 145 Acute Dhahir, (1971)
LD50 Mouse IP 175 Acute Dhahir (1971)
LD50 Rat Oral 327 Acute Dhahir (1971)
NOAEL (neuropathology) Rat IP 25 Acute Xu et al. (2000)
Abbreviations: LD50, the dose that kills 50% of treated animals; NOAEL, No Observable Effect Level, IP, Intraperitoneal.
To achieve efficacy in patients seeking interruption from drug ticularly where some patients may be susceptible due to a history
dependency, doses administered to patients have ranged from 6 of chronic use of sympathomimetic agents such as cocaine and
to 30 mg/kg (Alper, 2001). Given the increased risks of toxicity at methamphetamine (Schep et al., 2010; Schwartz et al., 2010). Fur-
these prescribed amounts, as summarised above, it is not surprising thermore, the pharmacodynamics of ibogaine in patients who are
that there are ongoing reports of toxicity and death with patients CYP2D6 poor metabolisers, the major isoenzyme responsible for
undergoing treatment with this drug. the metabolism of ibogaine (Mash et al., 2001), may be altered, lead-
Nausea and tremors have been reported following oral doses of ing to elevated concentrations with further risks of toxicity. Indeed,
ibogaine at 500, 600 and 800 mg (Mash et al., 1998). Indeed, nau- case reports are corroborating these findings, where patients being
sea, vomiting, tremors and ataxia are the most commonly reported treated with ibogaine have suffered QT prolongation and subse-
mild to moderate signs and symptoms following administration quent cardiac dysrhythmias (Asua, 2013; Hildyard et al., 2016;
of ibogaine (Alper et al., 1999; Cienki et al., 2001; Hoelen et al., Hoelen et al., 2009; O’Connell et al., 2015; Paling et al., 2012;
2009; Jalal et al., 2013; Kontrimaviciute et al., 2006; Mash et al., Pleskovic et al., 2012; Shawn et al., 2012; Vlaanderen et al., 2014).
2001; O’Connell et al., 2015; Paling et al., 2012; Schenberg et al., In some instances, resolution of these cardiac effects can be delayed
2014; Sheppard, 1994). In a number of instances these symptoms for several days, with the patient requiring ongoing intensive sup-
have resolved without further adverse effects to the subject. Nev- portive care (Hoelen et al., 2009; Paling et al., 2012; Pleskovic et al.,
ertheless, these symptoms have also heralded the onset of more 2012; Shawn et al., 2012). Other related signs and symptoms asso-
severe and, sometimes, life-threating clinical effects. These effects ciated with cardiotoxicity have included hypotension (Mash et al.,
can include coma (Paling et al., 2012; Pleskovic et al., 2012; Shawn 2001), sinus bradycardia (Asua, 2013; Pleskovic et al., 2012; Shawn
et al., 2012; Vlaanderen et al., 2014), seizures (Alper et al., 2012; et al., 2012), hypomagnesemia (Hoelen et al., 2009), hypokalemia
Asua, 2013; Breuer et al., 2015; Hoelen et al., 2009; Vlaanderen (Hoelen et al., 2009; Paling et al., 2012; Shawn et al., 2012) and
et al., 2014), respiratory difficulties (Alper et al., 1999; Jalal et al., hypophosphatemia (Paling et al., 2012).
2013; Kontrimaviciute et al., 2006; Paling et al., 2012) and pul- In the absence of prompt resolution following presentation of
monary aspiration (Alper et al., 1999; Paling et al., 2012). moderate to severe clinical effects, deaths have ensued (Cienki
However, the major concern with ibogaine toxicity in humans et al., 2001; Jalal et al., 2013; Kontrimaviciute et al., 2006; Mazoyer
is the risk of QT prolongation with associated torsades des pointes et al., 2013; Meisner et al., 2016; Papadodima et al., 2013). Alper
(a cardiac dysrhythmia that can lead to sudden cardiac death) et al. (2012), for exmple, have carefully examined the reports of 19
and ventricular fibrillation. There is increasing evidence to sug- deaths following ibogaine treatment from the years 1990–2008.
gest ibogaine has the potential to reduce currents through the Of these, 15 occurred during detoxification, 2 were linked to spir-
Human Related Ether-à-go-go Gene (hERG) encoded subunit, that itual and/or psychoactive experiences and 2 were of unknown
contributes to the electric activity of the voltage gated cardiac origin. With an increasing number of clinics offering treatments for
potassium channels (Alper et al., 2016; Koenig et al., 2013); specif- addictions, the risks of associated toxicity and death, particularly
ically, ibogaine targets the open and inactivated conformation of ibogaine-triggered cardiac dysrhythmias and cardiac related mor-
the protein (Thurner et al., 2014). Drug-induced blockage of cardiac talities (Jalal et al., 2013; Mazoyer et al., 2013; Paling et al., 2012;
potassium channels has the risk of prolonging the cardiac QT inter- Papadodima et al., 2013; Pleskovic et al., 2012; Vlaanderen et al.,
val with subsequent risks of torsades des pointes (van Noord et al., 2014), will continue to be reported.
2010). Research suggests that plasma concentration of therapeutic
drugs that are at, or within, their IC50 values for hERG inhibition can
in some instances delay cardiac repolarisation (Redfern et al., 2003). 6. Conclusion
It is interesting that IC50 values for ibogaine, necessary to block
potassium voltage gated hERG channels in TSA-201 and HEK 293 Ibogaine, an indole alkaloid obtained from the West African rain
cells in vitro (Alper et al., 2016; Koenig et al., 2013), 3.53–4.1 M, forest shrub Tabernanthe iboga, is used as a recreational drug and as
obtained from patch clamp investigations, were within plasma an alternate therapy for drug dependence. Despite its widespread
concentrations that are anticipated for the treatment of patients popularity, there still remains very limited information on its tox-
seeking respite from drug addictions. For example, administered icity. Investigations with animal models, however, suggest doses
doses of 8 and 10 mg/kg for male and females respectively (assum- necessary to obtain dependence aversion have been shown to cause
ing 60 kg for females and 80 kg for males; Mash et al., 1998, 2000), degeneration of purkinje cells and block potassium voltage gated
resulted in peak plasma concentrations that are similar to in vitro hERG channels. High doses of ibogaine used in humans, at times
EC50 determinations (Alper et al., 2016; Koenig et al., 2013). Blood similar to those used in animal investigations, have resulted in
concentrations of 377 ng/mL [approximately one third of the peak increased risks of adverse events; reported life-threatening effects
plasma concentrations reported by Mash et al. (2000)] and approx- have included seizures and cardiac dysrhythmias that in some
imately 950 ng/mL have resulted in QT prolongations in patients instances have resulted in deaths. An appropriate and safe dose
attending emergency departments (O’Connell et al., 2015; Vlaan- for humans remains unknown. Nevertheless, based on limited ani-
deren et al., 2014). This, therefore, suggests that doses used to treat mal data, and applying appropriate safety factors, a maximum oral
patients, reported to range from 6 to 30 mg/kg (Alper, 2001), may dosage limit of less than 1 mg/kg should be adhered to. This then
increase the risk of QT prolongation, which could prove fatal, par- may be incrementally increased, using appropriate clinical trials
that closely monitor indices of human toxicity, to establish a dose
4 L.J. Schep et al. / Drug and Alcohol Dependence 166 (2016) 1–5
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often associated with long-term drug use.
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Glue, P., Winter, H., Garbe, K., Jakobi, H., Lyudin, A., Lenagh-Glue, Z., Hung, C.T.,
Conflict of interest
2015. Influence of CYP2D6 activity on the pharmacokinetics and
pharmacodynamics of a single 20 mg dose of ibogaine in healthy volunteers. J.
Clin. Pharmacol. 55, 680–687.
No conflict declared.
Helsley, S., Dlugos, C.A., Pentney, R.J., Rabin, R.A., Winter, J.C., 1997. Effects of
chronic ibogaine treatment on cerebellar Purkinje cells in the rat. Brain Res.
759, 306–308.
Role of funding source
Hildyard, C., Macklin, P., Prendergast, B., Bashir, Y., 2016. A case of QT prolongation
and Torsades de Pointes caused by ibogaine toxicity. J. Emerg. Med. 50, e83–87.
This research did not receive any specific grant from funding Hoelen, D.W., Spiering, W., Valk, G.D., 2009. Long-QT syndrome induced by the
antiaddiction drug ibogaine. N. Engl. J. Med. 360, 308–309.
agencies in the public, commercial, or not-for-profit sectors.
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Health Risks of Chemicals: Derivation of Guidance Values for Health-Based
Exposure Limits. International Programme on Chemical Safety. World Health
Contributors
Organisation, Geneva, Accessed from http://www.inchem.org/documents/ehc/
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Jalal, S., Daher, E., Hilu, R., 2013. A case of death due to ibogaine use for heroin
LS conducted the literature search and review and wrote the
addiction: case report. Am. J. Addict. 22, 302.
first draft of the manuscript. RS provided toxicological input and
Koenig, X., Kovar, M., Rubi, L., Mike, A.K., Lukacs, P., Gawali, V.S., Todt, H., Hilber, K.,
reviewed and revised subsequent drafts of the document. SG and Sandtner, W., 2013. Anti-addiction drug ibogaine inhibits voltage-gated ionic
currents: a study to assess the drug’s cardiac ion channel profile. Toxicol. Appl.
DN provide clinical and addiction input and reviewed and revised
Pharmacol. 273, 259–268.
drafts of the document. All authors have approved the final sub-
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mission. Baccino, E., Bressolle, F.M., 2006. Distribution of ibogaine and noribogaine in a
man following a poisoning involving root bark of the Tabernanthe iboga shrub.
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