Transcript Iboga and Ibogaine - From Forest to Lab

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 1m - 2m in height but, examples
exist in the forest 5m 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
C20H26N2O
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 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 (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).
•L5178Y/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
100s of peer reviewed scientific papers