1. Iboga & Ibogaine: From the forest to the laboratory Howard S. Lotsof Dora Weiner Foundation Staten Island, NY Les Journees Gabonaises aux USA Tacoma, MD August 15, 2008

2. Ibogaine Found in a West African plant Tabernanthe iboga. Used in Bwiti religion

3. Gabon’s first President, Leon Mba was Bwitist and defended T. iboga use in French colonial courts.

4. Scientific literature for fifty years described the plant as 1m - 2m in height but, examples exist in the forest 5m in height (Omboue)

5. Iboga alkaloids are concentrated in the bark of the root

6. Usable forms include scraped or ground root bark 2% - 4%

7. Total Alkaloid extract 15%

8. Purified Chemical 95% - 99%

9. Proposed as an approved regulated drug

10. Physical Characteristics of ibogaine base Source Merck Index Chemical formula C 20 H 26 N 2 O Mol. Wt.310.42 Melting Point152-153° Practically insoluble in water. Soluble in ethanol, ether, chloroform Molecular structure

11. Three dimensional ibogaine molecule Blue = Nitrogen, Red = Oxygen, Black = Carbon, White = Hydrogen

12. Botanical source Tabernanthe iboga. Used for 100s of years in African medicine and religion, particularly in Gabon by Bwiti 1901 ibogaine isolated by Dybowski and Landrin 1958 molecular structure determined Bartlett et al. 1962 Lotsof discovers Antiaddictive effects 1967 Claudio Naranjo’s and Leo Zeff’s work with ibogaine in psychotherapy 1991 National Institute on Drug Abuse (NIDA) initiates evaluation of ibogaine 1993 Food and Drug Administration (FDA) approves clinical study of ibogaine Background: Ibogaine

13. 1994 Clinical studies in hospitals Republic of Panama. 1996 St. Kitts facility initiates treatment of 400 patients with ibogaine. 2000 Iboga declared national treasure by government of Gabon. 2004 Israeli Ministry of Health approval of ibogaine clinical studies Background: Ibogaine (cont.)

14. Lotsof patents advanced development 1.Rapid method for interrupting the narcotic addiction syndrome, US 4,499,096 (1985) 2.Rapid method for interrupting the cocaine and amphetamine abuse syndrome US 4,587,243 (1986) 3.Rapid method for attenuating the alcohol dependency syndrome, US 4,957,523 (1989) 4.Rapid method for interrupting or attenuating the nicotine/tobacco dependency syndrome, US 5,026,697 (1991) 5.Rapid method for interrupting or attenuating poly- drug dependency syndromes, US 5, 124,994 (1992)

15. Ibogaine: A Broad Spectrum Anti-Addictive 1.Opioids 1.Heroin 2.Morphine 3.Opium 4.Methadone 2.Cocaine 3.Methamphetamine 4.Alcohol 5.Nicotine 6.Polydrug dependence

16. Ibogaine: Other uses 1.Antibacterial 2.Antifungal 3.Possible antiviral 4.Psychotherapy

17. Preclinical Studies Rats, mice, dogs, primates Oral or IP

18. Self-Administration studies

19. Drug effects may differ Across sexes - male to female From strain Fawn-hooded rat Webster rat Species Rat Mouse Dog Monkey Man

20. First scientific publication of ibogaine antiaddictive effects - Dzoljic et al. -

21. Additional research supports Dr. Dzoljic’s findings. Dr. Stanley D. Glick at Albany Medical College begins the publication of what will become dozens of research papers showing reduction in drug use and withdrawal.

22. Ibogaine effects on cocaine

23. Ibogaine effects on cocaine Dose and regimen (Cappendijk & Dzoljic)

24. Ibogaine effects on alcohol

25. Ibogaine effects on alcohol “Dose effect” (Rezvani et al. 1995)

26. Tissue distribution and availability

27. Return to preaddictive state?

28. Neurotoxicity questions

29. Xu et al. eventually produce research showing no neurotoxicity at clinical doses (2000)

30. Xu et al. accomplished research in part at the National Center for Toxicological Research an FDA laboratory. The research demonstrated no neurotoxicity in rats at 25 mg/kg. Other research indicated no evidence of neurotoxicity in the primate and mouse, and postmortem neuropathological examination in a woman treated with up to 30 mg/kg.

31. Antibacterial studies tuberculosis

32. Antifungal studies Candida albicans

33. Ibogaine: Multiple mechanisms of action & receptor system effects where drugs of abuse also show activity Dopamine Opiate Serotonin NMDA (N-methyl-D- aspartic acid) Nicotinic GDNF ( Glial cell derived neurotrophic factor) Signal transduction independent of receptor binding

34. These systems define the pharmacology of human behavior, affecting pain, pleasure, anxiety and depression as well as, neuron growth with an inherent impact on memory and learning.

35. Clinical Studies “Safety and Efficacy”

36. In 2004, in support of clinical studies NIDA makes available a Drug Master File (DMF) provided to FDA comprising 16 volumes of data of approximately 4,000 pages.

37. Partial list of broad-ranging studies in FDA Drug Master File (DMF) included in the 16 volumes of data submitted by US National Institute on Drug Abuse (NIDA) for ibogaine. Acute Oral Toxicity Study of Ibogaine HCl in Rats. 32 Day Range-Finding Study of Ibogaine in Rats. Dose Response Neurotoxicity Study of Ibogaine in Rats. Dose Response Effect of Ibogaine on Analgesia and Mortality in Morphine-Dependent Rats. Pharmacokinetic Studies of Treatment Drugs Ibogaine. 14 Day Dose Range-Finding Toxicity Study of Ibogaine HCl in Dogs. Acute Neurotoxicity Study of Ibogaine HCl in Dogs. Salmonella/Mammalian-Microsome Plate Incorporation Mutagenicity Assay (AMES Test). L5178Y/TK +/- Moue Lymphoma Mutagenesis Assay

38. Comparative safety perspectives Drug-related fatalities (d-rf) Ibogaine/iboga (1989-2006) 11 d-rf d-rfMethadone (2004) (USA) 3965 d-rf FDA approved drugs in US hospitals (1999) 112,000 d-rf

39. Ibogaine Advantages 1.Ibogaine significantly reduces withdrawal 2. Interrupts drug craving 3.Interrupts drug self-administration 4.Returning patients to a preaddictive state 5.Eliminates stigma 6.Returns free choice 7.Antibacterial

40. Ibogaine: Stages of effect 1.Visualization or waking dream-like experience 3 - 6 hours 2.Cognitive evaluation 8 - 20 hours 3.Residual stimulation 12 - 72 hours

41. Ibogaine: Side-effects 1.Nausea or vomiting 2.Ataxia

42. Opioid withdrawal in human subjects

43. Objective Opioid Withdrawal Signs

44. Claudio Naranjo, MD use in psychotherapy Clinical Toxicology, 2(2):209-224, 1969 Copyright 1973

45. Outside of Africa, Naranjo was first to describe: 1.The waking dreamstate 2.Retrieval of early memories 3.Motion related nausea

46. Stigma A mark of disgrace associated with a particular circumstance, quality or person: for instance the stigma of chemical dependence.

47. Ibogaine Effects on Stigma Ibogaine has the ability to remove the stigmatized condition, transforming the patient to a state often described as a preaddictive. The transformation of a stigmatized person into one who is not stigmatized will affect the individual, allowing a greater contribution to self and society, improving quality of life issues.

48. Growth in number of ibogaine treated patients

49. Countries included in paper 1.USA 2.Chile 3.Switzerland 4.Panama 5.Brazil 6.St. Kitts 7.Mexico 8.Czech Republic 9.UK 10.Canada 11.Netherlands 12.Slovenia 13. Gabon* 14.France *Initiation of foreign nationals including drug treatment - limited

50. Typology of ibogaine providers and #s of patients treated (ca. 2006) TOTAL = 3414 1.Medical model (824) 2.Lay provider/treatment guide (1213) 3. Activist/self-help (200) 4.Religious/spiritual (1177)

51. Reasons for treatment 1.Total = 3414 (ca. 2006) 2.Substance-related disorders = 68% 3.Opioid withdrawal = 53%

52. Taking the hidden population estimates (20% - 30%) into account allow an estimated range of approximately 4300-4900 individuals who took ibogaine or iboga alkaloids outside of Africa as of February 2006.

53. Ibogaine science continues to grow providing 100s of peer reviewed scientific papers