Human & Experimental Toxicology (2008) 27: 181-194 www.het.sagepub.com , an anti-addictive : and time to go further in development. A narrative review R Maciulaitls', V KontrimaviÈiüté^••^ FMM BressoUe^ and V Briedis^ 'Department of Basic and Clinical Pharmacology. Kaunas University of Medicine, Lithuania; ^Clinical Pharmacokinetic Laboratory, Faculty of Pharmacy, University Montpellier L France: ''Department of Analytical and Toxicological Chemistry, Kaunas University of Medicine. Lithuania: and '^Department of Pharmaceutical Technology and Social Pharmacy, Kaunas University of Medicine, Lithuania

Ibogaine is an Índole alkaloid derived from the bark of physiological and psychological actions of ihogaine are the root of the African shrub Tabernanlhe iboga. Psycho- not completely understood. Ihogaine is rapidly melaho- active properties of ibogaine have been known for dec- lized in the hody in norihogaine. The purpose oí this arti- ades. More recently, based on experimental data from cle was to review data from the literature concerning animals and anectodal reports in human, it has been physicochemical properties, hio-analytical methods, and found that this drug has anti-addictive efFecls. Several pharmacology of ihogaine: this article will he focused on patents were published between 1969 and 1995. The the use of this drug as anti-addictive agent. pharmacology of ihogaine is quite complex, affecting many different systems simultaneously. Key words; bioanalytical nielhods: iliogaino: noribogaintí; phar- However, Ihe pharmacülogicai targets underlying the marodynamic studies: pharmacokincUcs: safety

Introduction will we forget about this novelty in addictive therapy or will we have a finalized development. The development process ofthe medicinal product is The mechanism of action of ibogaine in the treat- a system consisting of many operational aspects ment of drug appears to be distinct from designed to solve certain organizational, scientific, other existing p harm ac o therapeutic approaches. The and regulatory questions.^'^ Ideally one can have a purpose of this article was to review data from the clear view about this system, meet the needs, and literature concerning physicochemical properties, have a product on the market. The real problems bio-analytical methods, and pharmacology of ibo- are the practicalities that hinder implementation of gaine; this article will be focused on the use of this ideal principles and make product failed. Bib- drug as anti-addictive agent. liographical review of ibogaine development might be one of the learning case studies that we can To identify articles for this review, we use learn from others. Ibogaine is one ofthe psychoactive Internet-based Grateful Med to access electronic índole alkaloids naturally occurring in the West Afri- databases: MEDLINE and Currents Contents 1957- can shrub Tabernanthe iboga. The major compo- 2007. We searched, without language limitations, nents of T. iboga root bark extracts are ibogaine for the subject terms "ihogaine", "noribogaine", (approximately 80%). ibogaline (15%), and iboga- "mechanism of action", "quantification", "pharma- mine (up to 5%1. which confirms the complexity of cokinetics", and "pharmacodynamics". We further the extract.^ From the results ofthe preclinical stud- narrowed the search hy using the terms "anti- ies and anecdotal reports from American and Euro- addictive properties", "animals", "healthy volun- pean addict self-help groups, ibogaine could be a teers", and "dependent patients". We then improved promising drug in addiction therapy. Unfortunately, tlie search using the terms "withdrawal signs" and lost opportunities to confirm a positive benefit risk "drug craving". We identified additional citations balance during both preclinical and clinical develop- from the reference sections of articles retrieved and ments as well as losses of financial supports have consulted these articles. We completed this search lead to the stopping of the ibogaine development in using the website "google.com" and the engine the treatment of drug dependence. Future will show "Copernic". the strategy one will obtain and outcome thereof - History [forraspondence to: Dr Françoise Brossolle, PhD, Laboratoire de Ibogaine is a naturally occurring plant Índole alka- Phiirmacocinétique Ciiniquo. Faculté de Pharmacie Montpellier. 15 Avenue Charles Flahaull. B.P. 14491, 34093 Montpellier loid. The root bark of the Apocynaceous shrub Cedex 5, France. Email: [email protected] T. iboga is the most frequently cited source of

© 2008 SAGE Publications 10,1177/0960327107087802 Ibogaine, an anti-addictive drug R Maciulaitis, et al. 182 ibogaine. The Iboga tree is the central pillar of the thetically from nicotinamide hy way of a 13 or 14 step Bwiti religion practiced in West-Central Africa, process.^'' although extraction from the iboga root is a mainly Gabon. Cameroon, and the Republic of the simpler metliod for obtaining the compound. Ibogaine Congo, which uses the alkaloid-containing roots of has B melting point of 153 °C and a pK^. of 8,1 in 80% the plant for its psychoactive properties in a number methylcellosolve; its heptano/water partition coeffr- of ceremonies. Ibogaine is also used by indigenous cient of 28 confirms the lipophilicity of the com- peoples in low doses to combat fatigue, hunger, and pound. Recently, a stmctiiral analysis of ibogaino thirst." Other sources of ibogaine are Voacanga and of its main active metabolite, noribogaine (or 12- tbouarsii var. Ortusa.,^ Tahernnfímontana austniUs''', hydroxyibogamino. (6R. 6aS. 7S. 9R)-7-ethyl-6, 6a, 7. and Tabernaemontana orientalis7 Although known 8, 9, 10, 12, 13-octahydro-5H-6, 9-methanopyrido for many centuries for tribes in West Africa, research [l',2':1.2lazepino|4,5-/jlkidol-2-ol. Figure 1), using of ihogaino ¡itarted in late 19th century. The first Fourrier transform-infrared spectroscopy, lD and 2D description of T. iboga is published in 19B5 from spe- nuclear magnetic rnsonanco spectroscopy, and liquid cimens ofthe plant brought to France from Gabon." A chromatography-electrospray mass spectrometry publishfîd description of the ceremonial use of (LG/HSI-MS) has been published.^'' In accordance T. iboga in Gabon appears in 1885." Ibogaine was with the article of Taylor.-^ a fragmentation pattern iji first extracted and crystallized from the T. iboga root LC/ESI-MS is proposed (Figure 2). Ibogaine and nori- in 1901."*"'^ Ibogaine structure has been established bogaint! in solution suffer facile autoxidation under in 1957 through chemical studies,'^ and X-ray crys- light- and heat-exposure giving iboluteine and ibo- tallographic investigations have fixed the configura- chine. and desmethoxyiboluteine and desmetJioxyi- tion ofthe ethyl group.^"* Moreover, ^•'C nuclear mag- bochine, respectively.^'*"^'^ Recently, it has been netic resonance data'^ were reported in comparison shown that at 20 °C with daylight exposure, ibogaine with several iboga similar structures. The total syn- (22.4 ng/mL] and noribogaine (25 ng/niL) showed a thesis of ibogaine and its availability in the form of monoexponential decrease in cfrug concentrations: the racomate was reported in 1966."' the corresponding half-lives were 81,5 min for ibo- The intßrest of ibogaine to contemporary pharma- gaine and 11 min for noribogaine.^'' cology is that this drug possesses anti-addictive properties. Between 1969 and 1995, tlie anti- Analytical methods addictive properties of ibogaine and its use in the Ibogaine was determined in complex mixtures of treatment of heroin, , abuse, T. iboga and in biological matrices (brain homogenate, alcohol, and dependence, and even some urine, and plasma) by spectrophotometry.^** thin-layer drug abuse have been patented in the United States chromatography,^-' or gas chi'omatography with and in France. A French patent for the psychothera- ñame ionization,^^^"* nitrogen-specific''^ or mass- peutic use of ihogaine at a dosage of 4—5 mg/kg was spoctrometric (electron impact or chemical ioniza- published in 1969.'" US patents have been pub- tion)''^"''^ detection. Most of these methods involved lished by Lotsof for the use of ibogaine in a derivatization procedure. A method for determining withdrawal, dependence on cocaine and other sti- agonists including ibogaine by liquid mulants, alcohol, nicotine, and polysubstance chromatography-atmospheric-pressure chemical- abuse.'^"^^ These patents claim that an oral or rectal ionization mass spectrometry procedure has heen 4-25 mg/kg dose of ibogaine interrupts addictive also described (LC/APCI-MS).^*^' Recently, a high per- drug behavior for a period of 6-36 months. formance liquid cliromatography method with fluo- Chemistry Ibogaine (12-methoxyibogamine. (6R, 6aS, 7S, 9R)-7- ethyl-2-methoxy-6, 6a, 7, 8, 9, 10, 12, 13-octahydro- 5H-6, 9-methanopyrido[l',2':l,2|azepino[4,5-6iindole) has a molecular weight of 310.44 (Figure l). Extrac- tion of ibogaine from T. iboga shrub requires profes- sional training. N4ainly haloalkanes or alcohols were used for extraction. Chromatography was the method of choice for its purification. Extraction of ibogaine R = O H Noribogaïnc from T. iboga root bark using diluted vinegar and R = OCH3 Ibogaine ammonia was described. ' This drug can also he obtained semisynthetically from voacangine-' or syn- Figure 1 Molecular structurefi of ibogaine and noribogaine. [bogaine, an antj-addictive drug R Maciulaitis, ef ai. 183

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Figure 2 Kragmentation pattern of ibogaine and noribogaine. rescence detection^^ and LC-MS methods with elec- of the total T. iboga extract.^** The ibogaine hydro- trospray ionization^^'^" have been published to quan- chloride salt (98% purity) was favored for resoarch. tify ibogaine in plasma, blood, and urine. These meth- Capsules containing 100 or 200 mg of ibogaine were ods involved liquid-liquid or solid-phase extraction available.*" of the biological samples. Some of Uiem reported Most of preclinical experimentations have been simultaneous quantitation of ibogaine and its 12- reported by laboratories preparing the administered hydroxy metaboHte^^-^^-^-''-^''--^^ The main characteris- dose from the ibogaine hydrochloride acquired from tics of these methods are summarized in Table 1. Sigma Chemical Co. (compound No. 1-7003, St. Louis, Mo, USA). Future research will pormit Formulations the acquisition of ibogaine salt from the National In traditional use, ibogaine was consumed by chew- Institutti of Drug Abuse (NIDA). The use of ibogaine ing the root hark of T. iboga. Commernially available in tlie form of Endabuse®, the trademarked proce- formulations include plant extracts and crystalline dure to synthesize ibogaine for use in human drug ibogaine hydrochloride salt. From 1901 to 1905, ibo- abusors, provided another source for the compound. gaine was recommended as a treatment for "asthe- Three formulations containing ihogaine (the Sigma nia" at a dosage range of 10-30 mg/day. Tablets compound, the NIDA compound, and Endabuse®) from extracts of the roots of Tabernanthe nmnii, con- were tested in rat for their discriminative dosti- taining about 200 mg of extract or 8 mg of ibogaine response effects. Results indicated tliat these per tablet, were sold in France as a neuromuscular were equipotent.''^ stimulant between 1939 and 1970 under the ti-ade The main metabolite of ibogaine was noribogaine name of Lambarene®. This marketed formulation (Figure 1). Noribogaine may selectively mediate was recommended in the treatment of fatigue, putative anti-addictive effects that persist for pro- depression, and recovery from infectious disease.^ longed periods of time. Evaluation of pharmacoki- Another ibogaine containing preparation was Iper- netics and metabolism peculiarities of ibogaine sup- ton®, used as a tonic or stimulant, delivering 40 mg ports the possibility of development of a slow (bogaine, an anti-addictive drug R Macjulaitis, ei al. 184

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4f .g c -S .9 •a S .s o tí o et "3 •a 3 '3 d -9 OQ 00 oc oc oc'C oc o«-c 2c 00 T O 0 O O O o 9 o o o 3 o • E Ë â e XI az cSZ c a a; u Q « ^~ 'So: «I m > (Q n P ° n tal. ¡rir a tri m tri m c "^ ^ Uli Ibogaine, an anti-addictive drug R Maciulaitis, et al 185 release formulation of noribogaine as an anticraving brain following oral administration. Noribogaine medication for and psychostimulants.^ was detected at the earliest time point (15 min) con- sistent with a first pa.ss motaholism of the parent Preclinical pharmacokinetics dnig."^" After i.p. and oral administi'ations of Ihogaine in rat, maximum concentrations were 11-15 ^LM in Absorption the whole blood and tlie brain for ibogaine. and Studies in rats showed dose-dependent and gender- 21.9 ^M in the whole blood and 9,8-11.3 MM in the dependent bioavailability after oral route suggesting brain for noribogaine. In the whole blood and in the that ibogaine absorption, and/or first pass elimina- brain, area under concentration-time curve (AUC) tion, is non-linear.*^ After oral administration of Iper- values were 9- and 1.8-times higher for noribogaine ton® capsules, containing 40 mg of natural extract of than for ihogaine, respectively. The AUC ratios T. iboga, a substantial sex difference in rat brain and (brain/whole hlood) were equal to 2 for ihogaine and plasma concentrations of ibogaine was observed.^' 0.4 for noribogaine."^^ These results report that nori- These data were consistent with those of Pearl, bogaine reaches significant concentrations in brain eta}.,^^ reporting that plasma levels of ibogaine following both routes of administration in rat. Thus, after oral administration were approximately three- the concentrations of norihogaine in brain may acti- fold higher in female than in male rats, and the bio- vate processes that cause the desired effects of sup- availability of ihogaine was approximately twofold pressing opiate withdrawal signs and diminishing higher in female than in male.'*^ After oral adminis- drug craving. tration of 5 and 50 mg/kg to rat, the bioavailahility was 16% and 71% in female and 7% and 43% in Metabolism male, respectively/^ Ibogaine is metabolized by cytochrome P4502D6 (CYP2D6) into a major (active) metabolite - Distribution noribogaine.^'* An important aspect is that this iso- An intriguing property of ibogaine is its prolonged form is subjected to polymorphic expression partic- duration of action when behavioral and neurochem- ularly in Caucasians. From in-vitro study using ical effects are identified after one or more days fol- human liver microsomes, Obach, efa/.^" reported lowing oral, intraperitoneal (i.p.), or subcutaneous that two (or more) enzymes were involved in this administration. Pharmacokinetics of ibogaine in rat reaction. These authors identified two kinetically were consistent with a two-compartment model, but distinguishable ibogaine O-demethylases involved the extremely high concentrations found in adipose in this reaction corresponditig, to high [Kf^\, tissues suggests the possibility of more complex > 200 \iM] and low [KM, 0.1 ^M) values ofthe appar- pharmac o kinetics.'*'* One hundred times greater con- ent Michaelis constant. The importance ofthe route centrations in fat and 30 times greater concentra- of administration has been underlined, indicating tions in brain, than in plasma found 1 h after admin- that the noribogaine/ibogaine concentration ratio in istration were consistent with the highly lipophilic the bloodstream was higher when ibogaine is nature of ibogaine.'*^ It was proposed that prolonged injected by the i.p. route rather than by tho intrave- actions of ibogaine could be explained by adipose nous route.^' As well as, higher concentrations of tissue reservoir with release and metahoUsm to ibogaine in plasma, brain, kidney, liver, and fat active metabolite noribogaine over an extended were observed following subcutaneous versus i.p. period of time.*^'*^ administration suggesting a substantial "first pass" Another depot might be the platelets or otlier effect after i.p. administration involving hepatic blood components, as concentrations of ibogaine extraction."*^' were higher in the whole blood than in plasma.^ It seems tliat noribogaine could be a safer and The concentrations of ibogaine and noribogaine possihly more efficacious alternative to ibogaine as have been measured in rat brain following both oral a medication for the treatment of various types ot" and i.p. admimstrations [40 mg/kg i.p.. 50 mg/kg per addiction.'^* os.).^^^*^ The signitlcance of micromolar interactions of ibogaine and noribogaine with various radioligand Elimination binding sites was related to the concentration of the The half-life of ibogaine in rat was 1-3 h.^s-^s.ai xhis parent drug and its metabolite in brain. Concentra- elimination half-life could be underestimated since tions of thesü two drugs in rat cerebral cortex, stria- 3-h post-dose ibogaine conc:entrations remained tum, brainstem, and cerebellum were measured very high in fat."*'' Ibogaine and noribogaine are 15 min, 1 and 2 h following drug administration. It excreted via the renal and the gastrointestinal tract was shown that ihogaine was rapidly detected in (60-70% ofthe administered dose in 24 h in raf"^]. Ibogaine. an anti-addictive drug R Maeiulaitis, et al. 186 Pharmacodynamic studies in animals and Signal transduction pathways were examined mechanism of action during several preclinical trials. The examination of discriminative stimulus effects of ibogaino and Primary and secondary pharmacology noribogaine in rats in relation to their concentrations Several reviews have reported the pharmacological in hlood plasma and brain regions and to receptor profile of ibogaine."-^'^'-'*'''^^ It has been shown that systems suggested that norihogaine may be the ibogaine and noribogaine interact with multiple hind- major entity that produces the discriminative effect ing sites witliin the central nervous system (CNS), of ihogaine.^'' It has been reported that the observed including iV-methyl-n-aspartate (NMDA) receptor- increase in phosphoinositide hydrolysis by noribo- coupled ion channels, K-opioid (K, and K^). ^i-opioid gaine should be accompanied by an activation of and 02. (5-HT2 and 5-HT:j). muscarinic (M, protein kinase C which mediated a variety of long- and M2) receptors and monoamine uptake sites, and term changes and might be involved in the behav- nicotinic acetylcholine receptors. The pharmacologi- ioral effects of ibogaine.''" The selective increase in cal profile of noribogaine is different from that of receptor-mediated inhibition of adenyl cyclase iboga i ne.'*^'^^"''^ Ibogaine is more potent than noribo- activity caused by ibogaine and noribogaine might gaine (i) in binding to the NMDA receptor in brain also be involved in the pharmacological activity of tissue"*^ ••'•'' and (ii) as a stimulator of the these compounds.'*' Recently, it has been shown hypothalamic-pituitary-adrenal axis.^*-^^ Although that the remedial effect of ibogaine as anti- ibogaine and 5-HT display chemical similaritiüs, addictive drug is mediated, at least partially, because both molecules contain an Índole as part of through an influence on energy metabolism.'^- their structure, norihogaine is much more potent than Among the recent proposals for ibogaine mechan- ibogaine in its ability to elevate extracellular 5-HT in isms of action is the activation of the glial cell the brain.^'^ Thus, this drug is 10-times more potent in line-derived neurotrophic factor (GDNF) pathway binding to serotonin transporter and inhibiting reup- in the ventral tegmental area of the brain.®-'' This take of serotonin.^^'^^-^^"-''^ Noribogaine is also (i) work has principally been accomplished in preclin- much more potent than ibogaine for binding to \x- ical ethanol research, where 40 mg/kg of ibogaine opioid receptor and is a full p-opioid agonist'*''^-^^-^'**" caused increase of RNA expression of GDNF in ^^ and (ii) more potent binding to KI and less potent keeping with reduction of ethanol intake in the rat and absence of neurotoxicity or cell death. Short- binding to K^ opioid receptors. Affinities of ibogaine term ibogaine exposure results in a sustained and noribogaine to some of these receptors are increase in GDNF expression, resulting in an reported in Table 2.'*'' Although not apparent in bind- increase in GDNF mRNA leading to protein expres- ing studios, fimctional studies indicate significant sion and to the corresponding activation of the activity of ibogaine as a non-competitive antagonist GDNF signaling pathway.'*'' at the nicotinic acetylcholine receptor.'' It was also shown that ibogaine and noribogaine Conflicting results were reported about the alter- may stimulate the secretion of corticosterone from ation of extracellular dopamine levels in the nucleus the adrenal cortex and prolactine from the anterior accumbens. According to Baumann. etaij'^ neither pituitary.^^ These two drugs also caused similar ibogaint! nor its metabolite significantly altered increase in plasma prolactine. Relevance of these dopamine levels, whereas Glick, efa/.^*''^^ reported physiological changes for primary or secondary that these two drugs cause significant decreases in pharmacology should he elucidated more in tho dopamine levels. future.

Table 2 Affinities of ibogaine and noribogaine to some receptors (according to Mash, et al.*

¡bogaine Noribogaine Phnrmacodynamic activity

IC50.

5-HT transporter (RTI-55 DAT sites) 0.5 0.04 Reuptake blocker Opioidergic Mil (DAMGO) 11.0 0.16 Agonist Kappa 1 (lJ6959;i) 25.0 4.2 Partial agonist (?) Kappa 2 (IOXY) 23.8 92.3 Partial agunist (?) Clutaminorgic NMDA (MK-801) 5.2 ;ti.4 Channel blo(;kcr DAT. dopamine transporters; NMDA, N-methyl-oaspartatti, Ibogaine, an anti-addictive drug R Maí-iulaiíis, et ai 187 Anti-addictive activity in animals safety concerns, mainly neurotoxicity and possible NMDA, opioid, and serotonin receptors have been cardiotoxicity. targeted successfully for many years as anti- Multiple laboratories have reported on the degen- addictive treatment of opioid and/or cocaine eration of cerebellai' Purkinje cells in rat receiving addiction.®^-^^ Activities of both ibogaine and nori- i.p. administration of ibogaine at a dose of bogfiino on tliese receptors provided a biological 40-100 mg/kg,•'^^•^'^•*'" These include abnormal plausibility to expect anti-addictive efficacy for ibo- motor behavior (such as tremors, ataxia) related to gaine in human also. Initial findings, suggestive of histologically proven neurotoxicity.™ Single-dose the efficacy of ibogaine in animal models of addic- investigations showed that a 25 mg/kg i.p. dose tion, including diminished opioid self- was found to correspond to a no-observed- administration and withdrawal'''''"''^ and diminished adverse-effect-level (NOAEL)."' Helsley. et al. cocaine self-administration/'' were published in late observed no evidence of neurntoxicity in a study 1i)80s and in early 1990s. where rats received 10 mg/kg of ibogaine per day for 60 days."^ However, the neurotoxic effects of iho- Animal models of addiction were used to study gaine may occur at levels higher than those the activity of ibogaine in the treatment of drug observed to have effects on opioid withdrawal and dependence. The administration of ibogaine self-administration. The monkey appears to be less reduced self-administration of cocaine, , sensitive to potential ibogaine neurotoxicity than heroin, alcohol, and reduced nicotine preference.^ the rat.'' Mash, et al. observed no evidence of neuro- The decrease in cocaine consumption has been toxicity in monkeys treated for 5 days with repeated described in mice after L.p. administration of two oral doses of ibogaine of 5-25 mg/kg or siibcutane- 40 mg/kg dose at 6 h intervaP^ and in rat after i.p. ously administered doses of 100 mg/kg.'* Another administration of 2.5-80 mg/kg given as single or species difference in sensitivity is the mouse, repeated doses (daily or weekly, n = 3).67.70.72 which unlike the rat showed no evidence of cerebel- According to Cappendijk and Dzoljic, the maximum lar degeneration at a 100 mg/kg i.p. dose of effects were observed when ibogaine was given ibogaine."'' weekly for 3 weeks/" The decrease in opiate con- sumption has been described after administration of Animal studies showed certain cardiotoxicities. Observed cardiotoxicity could be dose dependent. 2.5-80 mg/kg ibogaine in morphine- and heroin- No changes in resting heart rate or hlood pressure dependent rat.'^^'^--^^ were found at a dose of ibogaine of 40 mg/kg i.p., Ibogaine also eliminates some of the signs of opi- which has been used in or self- ate withdrawal precipitated by or naltrex- administration studies. Higher doses of ibogaine one in morphine-dependent rats given 20, 40, or (100 and 200 mg/kg) decreased the heart rate with- 80 mg/kg ibogaine i-p.'^"-^'* and monkeys given 2 or out an effect on blood pressure.'*'' However, 8 mg/kg ibogaine subcutaneously/^-^^ However, Binienda, etal.^^^ found a significantly decreased Sharpe and Jaffe^'' failed to report that ibogaine heart rate in rats given ibogaine 50 mg/kg i.p. The administered subcutaneously attenuated naloxone- lethal dose 50% of ibogaine was 145 mg/kg i.p. and precipitated withdrawal in rat receiving 5. 10, 20, 327 mg/kg intragastrically in the rat, and 175 mg/kg and 40 mg/kg of ibogaine. Conflicting results were i.p. in the mouse.^^ observed in mice. At doses ranging from 40 to In conclusion, preclinical development showed 80 mg/kg i.p., a reduced naloxone-precipitated jump- that ihogaine is acting on several mediators in CNS ing in morphine-dependent mice was observed^^''"; that have been targeted in treatment of drug- however, opposite effects were found after a dependence. Nenrotoxiciy and cardiotoxicity are 30 mg/kg i.p. dose.'^'^ These discrepancies might be safety concerns to be investigated further. No suffi- related to ibogaine administration: before^''-^*' or cient long-term safety non-clinical studies are avail- after^^ naloxone administration. able. All these data make further investigation of Although ibogaine has diverse effects on the CNS, ibogaine's activity as potential therapeutic agent bio- the pharmacological targets underlying the physio- logically plausible. logical and psychological actions of ibogaine are not completely understood. Clinical pharmacokinetic and pharmacodynamic studies Preclinical safety studies Clinical studies Several safety studies were performed during pre- Clinical development of ibogaine has continued for clinical development. These studies raised several some decades. Development was governed by Ibogaine, an anti-addictive drug R Maeiulaitis, et ai. 188 several sponsors handed over management form one 150 and 300 mg versus placebo for the indication of hand to other. Development was carried by several cocaine dependence were proposed.""'-' The next separate academicians and companies. year, a NIDA ibogaine review meeting decided to The first phar maco dynamic studies of ibogaine end the ibogaine project but to continue to support have been performed during 1901-1905. First anti- some preclinical research on iboga alkaloids. A fatal- addictive attempts were done by Harris Isbell in ity occurred during a heroin detoxification treatment 1955, administering doses of ibogaine of up to of a 24-year-oId women in the Netherlands in ]ime 300 mg to eight already detoxified morphine addicts 1993. This incident was a significant factor in the at the United States. Addiction Research Centre in NIDA decision not to fruid a clinical trial of ibogaine Loxingfon, Kentucky." In 1962-1963, Lotsof adminis- in 1995." But the drug-addicted persons continue tered ibogaine at the dose of 6-19 mg/kg. to 19 indi- taking purified ibogaine hydrochloride powders or viduals including seven subjects with opioid depen- a whole plant extract that contains an unidentified dence who noted an apparent effect on acute number of other biologically active compounds. withdrawal symptomatology.^^-^^ In 1967-1970, the Some practically applied recommendations instruct World Health Assembly classified ibogaine with hal- taking between 2 and 6 g of powdered iboga.''" lucinogens and stimulants as a "substance likely to cause dependency or endanger human health". In Some clinical experiences were gained during 1970, the US Food and Drug Administration (FDA) mid 1990s to 2001. At that time, ibogaine was avail- classified ibogaine as a Schedule I Controlled Sub- able in alternative settings and studies based on a stance, along with other psychedelics such as LSD conventional medical model were carried out in and . The International Olympic Commit- Panama and in St Kitts. Informal protocols were tee banned ibogaine as a potential doping agent. developed in the United States, Slovenia, Britain, Thus, sales of Lambiu-ène® were stopped in France." the Netherlands, and the Czech Republic. The ibo- Since that time, several countries, including Sweden, gaine mailing Ust began in 1997 and heralded an Denmark, Belgium, Switzerland, and recently (since increasing utilization of the Internet within the ibo- March 2007) France, have bamied the sale and pos- gaine medical subculture. session of ibogaine. In early 2006, the creation of a non-profit founda- tion addressing the issue of providing ibogaine for The available data from private clinics described the purpose addiction interruption within establish- in scientific reports, where ibogaine has been used ment drug treatment care was formed in Sweden for informal addiction treatment, stated that ibo- (Stiftelsen Iboga's web site, accessed march 2007). gaine has been taken orally at an average dose of 19.3 ± 6.9 mg/kg."'^•"•^ Another study reported six Pharmacokinetics heroin-addicted individuals and one subject who Pharmacokinetic data relative to ibogaine in human were addicted to codeine treated with ibogaine at are limited."•''''•^'^'•"' Most of these studies have been doses ranging from 700 to 1800 mg."*" carried out in drug-dependent patients. Following From 1989 to 1993, treatments were conducted single oral doses of ibogaine (500-800 mg) to indi- outside of conventional medical settings in the Neth- vidual subjects, maximum ihogaine and noribogaine erlands involving the International Coalition of blood concentrations of 30-1250 ng/mL and 700- Addict Self-Help, Dutch Addict Self Help, and NDA 1200 ng/mL were obtained approximately 2 and 5 h International.*^"" In 1991, NIDA Medication Devel- after drug administration, respectively.'*-'-''^' Thereaf- opment Division began its ibogaine project. This ini- ter, ibogaine was cleared rapidly from the blood, tiative was based on case reports end preclinical evi- whereas noribogaine concentrations remained high. dence suggesting possible efficacy. The major Indeed, concentrations of noribogaine measured at objectives of the ibogaine project were preclinical 24 h post-dose were in the range of 300-800 ng/mL toxicological evaluation and development of a whereas those of ibogaine were about 100 times human protocol. In August 1993. FDA Advisory lower. From blood concentration-time profiles of ibo- Panel meeting formally considered Investigational gaine published by Mash, et ti/.,**'^-''" after an oral New Drug Application filed by Dr Deborah Mash. dose of 800 mg, the steady-state volume of distribu- Professor of at the University of Miami. tion uncorrtîcted for bioavailability was about 13 I/kg Approval for human trials was given with 1, 2, and and the half-life of the terminal part of the curves 5 mg/kg of ibogaine dosage levels. The Phase I dose was 4-7 h. Ibogaine being metabolized hy the escalation study began in December 1993, but activ- CYP2D6 into noribogaine, the pharmacokinetic pro- ity was eventually suspended.'*'* From October 1993 file of this drug was different in extensive and poor to December 1994, phase I/n protocols were dis- metabolizers. After single oral doses of ibogaine cussed by the NTDA and fixed doses of ibogaine of (10 mg/kg), maximum concentrations of noribogaine Ibogaine, an anti-addictive drug R Maciulaitis, ef al. 189 were nine times lower in poor metabolizers [n = 3) were detected in the cardiac tissue. Both ihogaine than in extensive metabolizers {n = 24). whereas and noribogaine are secreted in the bile and cross maximum concentrations of ibogaine were about the blood—brain barrier. 18% higher comparing to extensive metabolizers. Results are summarized in Table 3. This gap reflects speculation that conversion rate of the parent compound to noribogaine in CYP2D6 defi- Pliarmacodynamic effects cient subjects may reflect the metabolic contribution Some case-report studies showed that ibogaine is of other cytochromes [CYP2C9. CYP3A4J. The blood active as psycliotropic agent with possible anti- AUC vaines, poor metabolizers versus extensive addictive activity in acute opioid metabolizers, were almost three times higher for ibo- withdrawal.•*'^^"^'"^ After administration of ibo- gaine and four times lower for noribogaine. These gaine, individuals can experience (i) certain subjec- AUC levels were more representative for understand- tive new experience and (ii) reductions of drug crav- ing systemic exposures in extensive and poor meta- ing and withdrawal signs and symptoms. bolizers. In extensive metabolizers, the blood AUC ratio, noribobaine/ibogaine, was approximately 3. Subjective new experiences described bv patients Thus, the contribution of noribogaine to the total treated with ibogaine Preliminary data shows that pharmacodynamic effect of the parent drug was sig- patients experience several different phases that nificant. The calculated terminal half-Hfe of ibogaine may be categorized into acute, evaluative, and resid- in this study was 7.45 b in extensive metabolizers. ual stimulation stages [Figure 3)." In a recent study, Kontrimaviciûté, efaA"^ The first phase (acute phase) is experienced reported for the first time the tissue distribution of within flrst 1-3 h after exposure and lasts 4-8 h. ibogaine and norihogaine, in a subject dead after a During tliis phase, patients report panoramic deliv- poisoning itivolving ingestion of root hark of the ery of long-term memory, mainly visual; "visions" or shrub T. iboga. The highest concentrations of ibo- "waking dream" states experiencing contact with gaine and noribogaine were found in spleen, liver, transcendent beings, passage along a lengthy path, brain, and lung. The tissue/sub-clavian blood con- floating, etc. Although visual experiences are not centration ratios averaged 1.78, 3.75, 1.16, and 4.64 reported by all patients and seem depend of drug for ibogaine and 0.83. 2.43. 0.90, and 2.69 for nori- exposure, it is also noticed that they were associated bogaine. for spleen, liver, brain, and lung, respec- and enhanced with eye closure. Unfortunately, dif- tively. Very low concentrations of the two drugs ference between these dreams and hallucinations were found in the prostatic tissue. No compounds are not clear enough.

Table 3 Pharmacokinetic paramßters from clinical studiss

Extensive metoholizers Poor metaboHzers in = 24r (n = 5/"" ibogaine doses 500-800 mg 10 mg/kg 10 mg/kg ibogaine 2 1.7 2.5 C,,,,.x, ng/mL 30-1250 737 896 VJF, I/kg 13 — — f]/2 (last phase), h 4-7 7.5 — AiJCti..24i,, ngxh/mL — 3936 11471 Tissular distribution (tissue/blood Spleen: 1.78 — — concentration ratios) Liver: 3.75 Brain: 1.16 Lung: 4.64 Bile: 1.97 Noribogaine 5 6.2 3.2 C,nnx. ng/mL 700-1200 949 105 C241T ng/mL 300-800 — — AUCiv_24i,, ngxh/mL — 14705 3646 Tissular distribution (Ussue/blood Spleen: 0,83 — — concenlratioii ratios) Liver: 2.43 Brain: 0.90 Lung: 2,69 Bile: 0.54 /I. numliur of .subjects; C^ x. maximum concentration: /,„„«, time of C,,,,,^; C-^AU- concentration 24 h post-doso: AUCo_:.4 area under conciîntratinn-time curve; ^,, steady-state volume of distribution: Í.,,. half-life. IbogaJne, an anti-addictive drug R MaOiulaitis, et al. 190

opiate Kvductiunor Reduction ol'iimg Reduction of Repurlvd withdrawal drug craving withdrawal depression and ceAüution ul drii^ drug craving (up to uselupioniore one tnonth) than 1 year)*

Personal new Acute phase wilh Evaluative phase with Residual experience "tinL-iric" "neutral" and "rcncclivc" Stimulation ;iliiist: experiences emotional tone with rcttim uf (onset: I-.Í h. (onsci: 4'X li. duration: X- luirnial alluciilum duration: 4-Sh) 20 h) ül'aiicnlicín (unset: I2-Ü4h. diiratiun: 24-72 hi

• Reported eessal i on from thesatupleof 41 individuals nine individuals were treated (wieeandonc was treated three limes fora total of 52 treuinicnts, I'illcen (2'3''-'o) tiftlic ircutmcnts were reportedly followed by cessaliun dnig use tor less ihan 2 months. 15 (2')''«) for at least 2 months and icss thuii 6 nionths. 7 ( i }."<, ) for at leysl 6 months und less than one yctir. 10 (19%) for u period of greater thnn one year (8. H9, 93).

Figure 3 Clinical pharmacodynamic effects after ibogaine administration. The second phase [evaluative phase) starts 12 h and 24 h after ihogaine administration (i.e., 24 approximately 4-8 h after ingestion and lasts and 3fi h after the last dose of opiate, respectively) 8-20 h. During tliis phase, dreams decreased slowly was statistically lower than the rating obtained 1 h and the emotional tone is generally described as before ibogaine administration. The OOWS mean neutral and reflective. Patients reflect that their total score decreases from approximately 5.6 to 1.1 attention is focused on inner subjective experiences and 1.9, 12, and 24 h following ihogaine administra- (i.e., hy evaluating liie experiences of the acute tion, respectively. Authors noticed that objective phase). signs of opiate withdrawal were rarely seen and During these two first phases, patients tend to stay none were exacerbated at later time points. focused on their experiences and avoid any external A second measurement used was "self-reports of distraction. withdrawal symptoms according to Opiate- The third phase (residual stimulation phase) Symptom Checklist" (OP-SCL). Tbis "discanifort" starts 12-24 h after exposure and lasts 24-72 h. measurement showed statistically significant Patients regain normal attention to the external envi- decreases in mean scores: from approximately 21 ronment. Subjective psychoactive experience les- (score observed 24 h before ibogaine treatment) to sens, remaining with mild residual suhjective 12 shortly after recovery from ibogaine treatment arousal or alertness. Decrease in the need to sleep (<72 h) and down to 7 (at program discharge, for several days to weeks can he observed. approximately 6-9 days later). Reductions of withdrawal signs and symptoms, drug Impressive success of single dose of ibogaine craving and depression After administration of detoxification process was noticed as well as the fact 6-29 nig/kg dose of ibogaine, acute reduction in that many ofthe patients were able to maintain absti- drug craving and opiate withdrawal signs and symp- nence over the months following detoxification.'''' toms are observed in 1-2 h. Resolution of with- This relatively small study suggests that drawal was observed during 1 week, reduction of withdrawal was not more difficult to detoxify than craving and depression - 1 month after exposure. heroin withdrawal. Speculation that long-acting Opiate is assessed usually metabolite noribogaine may account for the efficacy by discontinuation of opiate treatment (spontaneous of ibogaine can be done. withdrawal) or by antagonist-precipitated Craving is an important symptom reported by withdrawal.'*^ Usually, acute withdrawal syndrome opiate-dependent subjects during tlie early stages of in case of heroin addiction may begin approximately withdrawal contributing to continued drug use.'*'*"^ 8 h after the last heroin dose, peaks in intensity at Craving symptoms for opiates could be evaluated by 24-28 h, and subsides within 7-10 days. In one of using the "Heroin Craving Questionnaire scales the opiate (heroin or methadone] addiction studies (HCQN-29)". Thirty-six hour post-ibogaine treat- including 32 patients, rapid detoxifications of these ment, the mean scores on five measures about spe- patients was assessed after single-dose ibogaine cific aspects of drug craving (including urges, treatment (10 mg/kg). Results are summarized in thoughts about drug of choice, or plans to use the Table 4. The post-ibogaine Objective Opiate With- drug) show significant decreases and lasted at pro- drawal Scale (OOWS) blinded rating obtained 10- gram discharge. Ibogaine, an anti-addictive drug R Maiiulailis, ef a!. 191 Evaluation of patients using Beck Depression on cocaine and/or heroin, who received fixed oral Inventory scores showed also significant reduction doses of ibogaine of 500, 600, 800, or 1000 mg, of scores both at program discharge and at 1-month were monitored. Six suhjects exhibited some signifi- follow-up assessments.''"•^'' cant decrease of resting pulse rate; one of them evi- Subjects undergoing cocaine detoxification also denced a significant decrease in blood pressure reported significant decrease in drug-craving 36 h (attributed to a transient vasovagal response). No post-ibogaine treatment and at discharge for three evidence of electrocardiogram abnormalities was of the five category scales of the Cocaine Craving showed. There were hypotensive episodes (respon- Questionnaire (CCQN)-45 (anticipation of positive sive to volume repletion) noticed during ibogaine outcomes, relief of negative states, and lack of tlierapy in some cocaine-dependent subjects.•'^ control). The safety of ibogaine was also evaluated in more Tbere is only limited retrospective experience in than 150 drug-dependent subjects receiving H, 10, or long-term outcomes (Figure a].«-»"-*»^ No clear nega- 12 mg/kg ibogaine.'^" The most frequent side-effects tive or positive conclusions could be drawn. It encountered were nausea and mild tremor, and seems that relapses could he attempted with ibo- ataxia earliest after drug administration. A hypoten- gaine re-challenge, as this was done several times sion was obsen'ed in some cocaine-dependent sub- in anecdotal cases. jects, who required close monitoring of blood pres- It seems that pharmacodynamic effects experi- sure. No other significant adverse events were seen enced by patients varied and may be related to under the study conditions; and, therefore, there are dose. bioavailability. and interindividual no clear evidences till now that there are big issues variabilities.** Sequential pattern of clinical pharma- in tolerance after single dose of ibogaine. codynamic effects could be summarized as pre- In conclusion, clinical development could be con- sented in Figure 3. sidered as started only and needs essential explor- atory program first. Clinical safety Main unanswered questions Neurotoxicity observed in animal studies was also noticed in human studies (e.g., effects on postural Experience available in public domain suggests that stability, body tremor, and appendicular tremor]. In ibogaine might have some activity in anti-addiction 1994, a fatal case of woman treated with ibogaine treatment. Although data seems quite promising, was reported. Fifteen months before her death, this several issues remain to be elucidated first before woman had undergone four separate treatments moving fiu-ther towards controlled pivotal clinical with ibogaine in rather high dosages (ranging from trials. Four major product development issues to be solved relates to the areas of pharmaceutical formu- 10 to 30 mg/kg). Death was not attributed to ibogaine lation development and starting clinical exploratory but was related to mesenteric arterial tlirombosis studies: related to chronic cellulitis.*-" Similar to the findings in animals, some cardiac 1) Is ibogaine pharmaceutical formulation devel- side-effects were also observed during clinical oped enough to ensure proper constant composi- investigations.^""* Thirty-nine patients dependent tion form certain active ingredients?

Table 4 Effects uf single-dose ibogaine (10 mg/kg) on opiate withdrawal signs

Time after Time after OOWS OP-SCL HCQN-29-' BDI the. ¡así opiate done, h tha ibogaine dose, h

Before ibogaine treatment 5.6 (1 h) 21 (24 h) 3.26-4.88 Iti,9 24 10-12 1.1* 36 24 1.9* 36 1.57-3.67 10.4 <72h 12' 6-9 days 7" Discharge 1.22-2,85*** 3.0** l-month follow-up 2.29** OOWS. Objeclivo Opiate VVitlidrawal Scale; OP-SCL. Opiate-Symptom Checklist; HCQN-29. Heroin Craving Questionnaire scales (sub- scaics: desirn to use, intention to use. anticipation of positive outcomes, relief of negative states and lack of control); BDI. Beck Depression inventory scores. "According tu the subscale. *P<0.05; **i*< 0.0005; •**P<ü.Oüül. Ibogaine, an anti-addictive drug R Maciulaitis, et al. 192 2) What is ibogaines' pharmacodynamic activity in Conclusion controlled exploratory trial in drug-dependent Experience available in public domain suggests that stabilized subjects? ibogaine might have some activity in anti-addiction 3) What is ibogaines' potential for abuse by drug- treatment, but current data are not sufficient to do dependent subjects (in both pharmacodynamic furtlier in development. Data gathered during more and economic measurements)? than 100 years of pharmaceutical, non-clinical, and 4) What is the most rational dosage range to be stud- clinical developments need to be validated. Good ied in dose-response studies in treatment of laboratory and clinical practice environment is some drug dependences [first, in opiate and/or essential for future investigations. Several major cocaine dependencies? objectives of preclinical and clinical investigations sbould focus on core-identified questions first.

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