Iboga Ibogaine From the forest to the laboratory

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

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

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

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

Iboga alkaloids are concentrated in the bark of the root

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

Total Alkaloid extract 15%

Purified Chemical 95% - 99%

Proposed as an approved regulated drug

Physical Characteristics of ibogaine base Source Merck Index Chemical formula C 20 H 26 N 2 O Mol. Wt. 310. 42 Melting Point 152 -153° Practically insoluble in water. Soluble in ethanol, ether, chloroform Molecular structure

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

Background: Ibogaine • Botanical source Tabernanthe iboga. Used for 100 s 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 (cont. ) • 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

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 polydrug dependency syndromes, US 5, 124, 994 (1992)

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

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

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

Self-Administration studies

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

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

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.

Ibogaine effects on cocaine

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

Ibogaine effects on alcohol

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

Tissue distribution and availability

Return to preaddictive state?

Neurotoxicity questions

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

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.

Antibacterial studies tuberculosis

Antifungal studies Candida albicans

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

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.

Clinical Studies “Safety and Efficacy”

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.

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). • L 5178 Y/TK +/- Moue Lymphoma Mutagenesis Assay

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

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

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

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

Opioid withdrawal in human subjects

Objective Opioid Withdrawal Signs

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

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

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

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.

Growth in number of ibogaine treated patients

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

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)

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

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.

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