PAPER

TOXICOLOGY

Kenneth R. Alper,1 M.D.; Marina Stajic,2 Ph.D.; and James R. Gill,3 M.D.

Fatalities Temporally Associated with theIngestion of Ibogaine

ABSTRACT: Ibogaine is a naturally occurring psychoactive plant alkaloid that is used globally in medical and nonmedical settings for opioiddetoxification and other substance use indications. All available autopsy, toxicological, and investigative reports were systematically reviewed for theconsecutive series of all known fatalities outside of West Central Africa temporally related to the use of ibogaine from 1990 through 2008. Nineteenindividuals (15 men, four women between 24 and 54 years old) are known to have died within 1.576 h of taking ibogaine. The clinical and post-mortem evidence did not suggest a characteristic syndrome of neurotoxicity. Advanced preexisting medical comorbidities, which were mainly cardio-vascular, and or one or more commonly abused substances explained or contributed to the death in 12 of the 14 cases for which adequatepostmortem data were available. Other apparent risk factors include seizures associated with withdrawal from alcohol and benzodiazepines and theuninformed use of ethnopharmacological forms of ibogaine.

KEYWORDS: forensic science, toxicology, ibogaine, iboga alkaloid, substance abuse, human, fatality, opioid, opioid detoxification,ethnopharmacology

The iboga alkaloids are a group of monoterpene indole alkaloids,some of which reportedly reduce the self-administration of drugs ofabuse and opiate withdrawal symptoms in animal models andhumans (1,2). Ibogaine (Fig. 1), the most extensively studied ibogaalkaloid, occurs in the root bark of the West African Apocynaceousshrub Tabernanthe iboga Baill. In Gabon, eboga, the scrapings ofthe root bark, has been used as a psychopharmacological sacramentin the Bwiti religion for several centuries (3,4). Elsewhere, includ-ing North America, Europe, and South Africa, ibogaine is used forthe purpose of acute opioid detoxification, and to reduce cravingand maintain abstinence from opioids and other abused substancesincluding stimulants and alcohol, as well as for psychological orspiritual purposes (5).Ibogaine is used most frequently as a single oral dose in the

range of 1025 mg kg of body weight for the specific indicationof detoxification from opioids (5,6). It is most commonly used inthe form of the hydrochloride (HCl), which certificates of analysistypically indicate is 9598% pure, with present retail prices in therange of c. $125$250 USD per gram. Ibogaine is also used in theform of alkaloid extracts or dried root bark (Fig. 2).Ibogaine is a schedule I substance in the United States, and simi-

larly is illegal in France, Denmark, Sweden, Belgium, Switzerland,and Australia. However, it is unregulated in most countries, whereit is neither illegal nor officially approved. Lay providers administeribogaine in nonmedical settings and have accounted for the

majority of treatments (5). Ibogaine is administered in medical set-tings in countries such as Mexico and South Africa, where physi-cians have the legal prerogative to prescribe unapprovedmedications.Published case series and individual accounts regarding ibogaine

for opioid detoxification tend to be consistent with regard to rapidremission of acute withdrawal symptoms following a single admin-istration that is subsequently sustained without further ibogainetreatment or the use of opioids (1,6,7). This effect of ibogaineappears to be pharmacologically mediated and not accounted forby placebo, which has clinically negligible effects in opioid detoxi-fication (810). In the naloxone-precipitated withdrawal model ofopioid detoxification, iboga alkaloids have attenuated opioid with-drawal signs in 13 of 14 independent replications in two rodentand two primate species (1124). Ibogaine administered to rats ormice as a single dose reduces the self-administration of morphine(2528), cocaine (26,29,30), and alcohol (31,32), with sustainedtreatment effects for 4872 h averaged for an entire sample, and aneven longer duration in individual animals (25,26,28,30). Theserum half-life of ibogaine in the rat is c. 12 h (33,34), indicatingthat the prolonged effect on self-administration outlasts the presenceof ibogaine itself, without compelling evidence that it is mediatedby a long-lived metabolite (35).Ibogaine does not appear to be an abused substance. The

National Institute on Drug Abuse (NIDA) did not identify potentialabuse as an issue in the context of its research program on iboga-ine, which included preclinical testing and the development of aclinical trial protocol (1). Animals do not self-administer 18-meth-oxycoronaridine (18-MC), a closely structurally related ibogainecongener with the same effects as ibogaine on self-administrationand withdrawal in preclinical models (36). Aversive side effectssuch as nausea and ataxia limit ibogaines potential for abuse.Ibogaine potentiates the lethality of opioids (33,3739). This is

apparently because of an enhancement of opioid signaling (1,40),and not because of binding at opioid receptors as an agonist (such

1Departments of Psychiatry and Neurology, New York University Schoolof Medicine, 550 First Avenue, New York, NY 10016.

2Department of Forensic Toxicology, New York City Office of ChiefMedical Examiner and Department of Forensic Medicine, New York Uni-versity School of Medicine, 520 First Avenue, New York, NY 10016.

3New York City Office of Chief Medical Examiner and Department ofForensic Medicine, New York University School of Medicine, 520 FirstAvenue, New York, NY 10016.Received 28 July 2010; and in revised form 17 Nov. 2010; accepted 20

Nov. 2010.

J Forensic Sci, March 2012, Vol. 57, No. 2doi: 10.1111/j.1556-4029.2011.02008.x

Available online at: onlinelibrary.wiley.com

398 2012 American Academy of Forensic Sciences

as methadone) or antagonist. Doses of ibogaine used in opioiddetoxification do not produce signs of overdose in individuals wholack tolerance to opioids, such as African Bwiti adepts, or individu-als in non-African contexts who take ibogaine for psychological orspiritual purposes or the treatment of addiction to substances other

than opioids. If ibogaine was acting as an opioid agonist, it wouldnot be tolerated by opioid-nave individuals because the methadonedosage of 60100 mg day that is used to stabilize withdrawalsymptoms in the maintenance treatment of opioid-dependentpatients (41) substantially exceeds the estimated LD50 of 4050 mgin humans who are not pharmacologically tolerant to opioids (42).Other evidence that ibogaine alters signaling through opioid recep-tors but is not itself an orthosteric agonist includes its potentiationof morphine analgesia in the absence of a direct analgesic effect(22,38,39,4347). Ciba Pharmaceutical patented the use of ibogaineto reduce tolerance to opioid analgesics in 1957 (47).Although ibogaine contains an indole ring and is designated as a

hallucinogen, it is pharmacologically distinct from the classi-cal hallucinogens such as LSD, mescaline, or psilocybin, whichare thought to act by binding as agonists to the serotonin type 2A(5-HT2A) receptor (48). Serotonin agonist or releasing activity doesnot appear to explain ibogaines effects in opioid withdrawal(2,49). There is no anecdotal or preclinical evidence for a signifi-cant effect of classical hallucinogens in acute opioid withdrawal,and in the animal model ablation of 90% of the raphe, the majorserotonergic nucleus of the brain does not significantly affect theexpression of opioid withdrawal (50). Descriptions of subjectiveexperiences associated with ibogaine differ from those associatedwith the classical hallucinogens (5,48,51). The visual effects ofclassical hallucinogens are typically most strongly experienced withthe eyes open and limited to alterations of colors, textures, and pat-terns. In contrast, the psychoactive state associated with ibogaine isexperienced most intensely with the eyes closed and has beendescribed as oneiric and likened to a waking dream, with

Iboga alkaloid R1 R2 R3

Ibogaine OCH3 H HNoribogaine OH H HIbogamine H H HIbogaline OCH3 OCH3 HTabernanthine H OCH3 HVoacangine OCH3 H CO2CH3

FIG. 1Chemical structures of ibogaine and its major metabolite norib-ogaine, and the alkaloids ibogamine, ibogaline, tabernanthine, and voacan-gine that co-occur with ibogaine in T. iboga. In the Chemical Abstractssystem the positions of R1, R2, and R3 on the ibogamine parent structuralskeleton are respectively numbered 12, 13 and 18, whereas in the Le Menand Taylor system these same positions are numbered 10, 11 and 16.

FIG. 2Forms of availability of ibogaine: Ibogaine is available in form of the hydrochloride (HCl) dried root bark, or alkaloid extract. The upper leftphoto shows 96% pure ibogaine HCl in the form of powder in the upper left quadrant of the photo. In the lower left quadrant of the photo are five capsules.The four lighter colored capsules contain 96% pure ibogaine HCl; the smaller two contain 120 mg and the larger two contain 250 mg respectively. The larg-est capsule is darker and contains 330 mg of 85% ibogaine HCl. In the lower right quadrant of the photo is ground dried root bark. The upper right photoshows alkaloid extract with an estimated total iboga alkaloid content of about 4050%. The lower photo shows a partially scraped dried Tabernanthe ibogaroot, with external bark layer, an inner bark layer, and wood. The alkaloid content is mainly concentrated in the inner root bark layer, which is exposedalong the lower border of the bare wood in left middle portion of the photo (photos courtesy of Robert Bovenga Payne and Rocky Caravelli).

ALPER ET AL. FATALITIES TEMPORALLY ASSOCIATED WITH THE INGESTION OF IBOGAINE 399

interrogatory verbal exchanges involving ancestral and archetypalbeings, and movement and navigation within visual landscapes.Another frequently described experience is panoramic memory, therecall of a rapid, dense succession of vivid autobiographical visualmemories. Mechanistically, these subjective experiences associatedwith ibogaine might possibly suggest functional muscarinic cholin-ergic effects, which are prominent in the mechanisms of dreamingand memory (52). In animals, ibogaine is reported to enhance spa-tial memory retrieval (53,54), and to produce an atropine-sensitiveEEG rhythm (55,56), commonly regarded as a model of REMsleep (57).Ibogaines highest affinity receptor interactions are as an agonist

at the r2 receptor, and an antagonist at the N-methyl-d-aspartate-type (NMDA) glutamate and a3b4 nicotinic acetylcholine recep-tors (1,2,58). Initially, ibogaines mechanism of action in drugself-administration and withdrawal was hypothesized to involveNMDA receptor antagonism (59); however, this hypothesis is nowviewed as unlikely because the synthetic ibogaine congener 18-MC has negligible NMDA receptor affinity but is equally effec-tive as ibogaine in reducing withdrawal and self-administration inthe animal model (2). Studies of iboga alkaloids and nicotinicagents (6064) provide some support for antagonism of the a3b4nicotinic receptor as a possible mechanism of action with regardto drug craving and self-administration but do not appear toexplain detoxification in the setting of extensive physical depen-dence on opioids. Likewise, the increased expression of glial cell-derived neurotrophic factor may mediate reduction in drug cravingand self-administration (32) but does not explain ibogaines effectin opioid detoxification.Ibogaine was administered to human subjects in a clinical Phase

I dose escalation study under a physician-initiated InvestigationalNew Drug Application approved by the FDA in 1993 (65). Thestudy was eventually discontinued because of disputes related tocontractual and intellectual property issues (66); however, the avail-able safety data indicated no adverse events (65). Most of theavailable preclinical pharmacological, toxicological, and pharmaco-kinetic data on ibogaine are derived from research supported byNIDA between 1991 and 1995. NIDA eventually ended its iboga-ine project without having initiated a clinical trial apparentlybecause of its high cost and complexity relative to NIDAs existingresources (1). Ibogaines underlying structure cannot be patentedbecause it is naturally occurring, which limits the financial incen-tive for its development. Ibogaine continues to be used in unregu-lated contexts with associated risks because of a lack of clinicaland pharmaceutical standards (5).Deaths have occurred temporally related to the use of ibogaine.

This article presents a systematic review of all available autopsy,toxicological, and investigative reports on the consecutive seriesconsisting of all known fatalities temporally related to the use of ib-ogaine that have occurred outside of West Central Africa from1990 through 2008.

Materials and Methods

The Institutional Review Board of the New York UniversitySchool of Medicine and the General Counsel of the New York CityOffice of Chief Medical Examiner (OCME) approved this research.

Identification of Cases

This series spans the time interval beginning with the firstreported fatality in 1990 (1) until December 2008. Eighteen of the19 fatalities in this series were found through contact with ibogaine

treatment providers since the mid-1990s (5,6,67,68). One of thesefatalities was also investigated by the OCME (69) as are all unex-pected, violent, and suspicious deaths in New York City. One fatal-ity was found by literature search (70). The ethnographicmethodology and access to the network of the providers of iboga-ine treatment and other participants in the ibogaine subculture aredescribed in detail elsewhere (5,67).All fatalities were followed up by contact with appropriate

medico-legal death investigation agencies to obtain all availableautopsy and toxicology reports, inquest testimony, and other inves-tigative reports. In addition to documentary evidence, in mostinstances, treatment providers and other first-hand observers of thedeath scene were interviewed. Systematic evaluation of the litera-ture included Medline searches from 1966 to June 2010 utilizingPubMed and ISI Web of Knowledge with the search terms iboga-ine combined with death or fatality in addition to searches ofperiodical and nonindexed grey literature as described elsewhere(5,67).

Analytical Toxicology

Various methodologies for toxicological analysis of ibogaine(molecular weight 310.44) have been previously described, includ-ing liquid chromatography with flourimetric detection (71), gaschromatography mass spectrometry (GC MS) (7276) liquid chro-matography mass spectrometry (LC-MS) (70,75,7780), and liquidchromatography-tandem mass spectrometry (LC-MS MS) (8183).There is a potential for confusion because of the use of two differ-ent schemes for numbering the iboga alkaloid parent ibogamineskeleton (84), the Chemical Abstracts system, which is common inthe biological and medical literature, and the Le Men and Taylorsystem, which tends to be favored by natural products and syntheticchemists and is also frequently encountered in the biologicalliterature (see Fig. 1).Ibogaine screening usually is not included in most routine foren-

sic toxicological laboratories and a suspicion of use is required foranalysis, which is typically performed by a referral laboratory. Fortwo fatalities in this series (cases #3 and #10 in Table 1), theForensic Toxicology Laboratory at the OCME performed the analy-sis. The presence of ibogaine was confirmed by GC MS and theconcentration determined using GC with a nitrogen phosphorusdetector (69).

Cause of Death

The certified cause of death is included in Table 1, entitledOfficial cause of death. The certified cause of death is that whichis indicated by the official documentation, that is, autopsy report ordeath certificate, by the local authority that investigated andrecorded the death. The available documentation varied greatly withregard to investigative rigor, level of detail, and geographic locationof the official entity that issued the report. As an approach to con-trolling for this variance, a coauthor (JRG, a board-certified foren-sic pathologist) made a determination regarding the cause of eachdeath on the basis of all available data, which in addition to theofficial documentation, included any information that was providedby treatment providers and other first-hand observers of the deathscene, or friends and acquaintances of the decedent. Table 1 pro-vides the conclusions of this systematic, critical evaluation of allavailable evidence in the far right-hand column entitled Proximatecause of death.The cause of death is defined as the original, etiologically spe-

cific, underlying medical condition that initiates the lethal sequence

400 JOURNAL OF FORENSIC SCIENCES

TABLE1

Worldwideknow

nfatalities

outsideof

WestCentral

Africatemporallyassociated

withtheingestionof

ibogaine,19902008.

Age

Gender,

Reasonfor

Ibogaine

Use

Country

Year

Circumstance

Tim

eInterval

from

Most

Recent

Ingestionof

Ibogaine

UntilDeath

Ibogaine

Form,

Dose

Ibogaine

(Blood,mgL

ormgkg)

Other

Toxicology

(mgL)

Other

Autopsy

orHistorical

Findings

OfficialCause

ofDeath

ProximateCause

ofDeath

144

FPsychological

spiritual(1)

France

1990

Witnessed

tobecome

unre-

sponsive

during

treatm

ent

4h

Ibogaine

HCl

300mg(c.

4.5mgkg)

0.24 Liver:0.17

Kidney:

0.3

Negative

Hypertension;

priorleft

ventricular

myocardialinfarct,

marked

3-vessel

coronary

artery

atherosclerosis,

inverted

Twaves

notedon

EKG

3monthspriorto

death

Acute

heart

failure

(autopsy)

Acute

ibogaine

intoxication.

Contributing

conditions:

atherosclerotic

andhypertensive

cardiovascular

disease

224

FOpioid

detoxification

(6)

Netherlands

1993

Diedduring

ibogaine

treatm

ent;

gurgling

sounds

19h

Ibogaine

HCl

29mgkg

Cardiac:0.74

Fem

oral

vein:

0.75

Morphine:

trace