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Ibogaine, an Anti-Addictive Drug: Pharmacology and Time to Go Further in Development

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Ibogaine, an Anti-Addictive Drug: Pharmacology and Time to Go Further in Development Human & Experimental Toxicology (2008) 27: 181-194 www.het.sagepub.com Ibogaine, an anti-addictive drug: pharmacology 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 neurotransmitter 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 addiction 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, cocaine, amphetamine abuse, T. iboga and in biological matrices (brain homogenate, alcohol, and nicotine 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 opioid a derivatization procedure. A method for determining withdrawal, dependence on cocaine and other sti- opiate 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 »o. 122.1 136 Figure
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