Download Ibogaine

Ibogaine
Dr.Moshe Zer-Zion
Beer-Yaacov Mental Health Center
Israel
Ibogaine
Ibogaine
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Ibogaine is a naturally occurring plant alkaloid in the
West Central Africa’s shrub Tabernante Iboga
The plant is used for religious and medical purposes
by the Bwiti culture. (Gabon)
NIDA has given significant support to animal
research and the FDA has approved Phase I studies
in humans
Evidence for Ibogaine’s effectiveness includes
reduced drug use and less withdrawal signs in
animals and humans .
Ibogaine
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Is the most abundant alkaloid in the root bark
of the shrub Tabernanthe iboga .
In the dried root bark total alkaloid content is
reportedly 5% to 6%
It undergoes demethylation to form it’s principal
metabolite noribogaine .
18 MC is an Ibogaine congener.It seems to have
efficacy similar to I.with less potential toxicity
Forms in Current Use
• Botanical - root bark
Forms in Current Use
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Total alkaloid extract
Large piece 2cm x 2cm, approx 4 grams
Estimate 15% Ibogaine
Forms in Current Use
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Purified Ibogaine HCl (Endabuse)
99.4% purity
Brief Historical Time Line
Brief Historical Time Line
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1864-A first description of T.Iboga is published
1885- A published description of the ceremonial use of
the T.Iboga in Gabon appears.
1901- I. Is isolated and crystallized from T.Iboga root
bark
1939-1970 I. Is sold in France as Lambarene ,”a
neuromuscular stimulant” for fatigue,depression and
recovery from infectious disease
Brief Historical Time Line
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1962-1963 In the USA Howard Lotsof administered I. to
19 individuals at dosages of 6 to 19 mg/kg including 7
with Opioid dependency who noted an apparent effect on
acute withdrawal symptoms
1969-Claudio Naranjo ,a psychiatrist, received a French
patent for the psychotherapeutic use of I. at a a dosage of
4 to 5 mg/kg
1967-1970 The WHA classifies I. With hallucinogens and
stimulants .The FDA: assigns I. Schedule I classification
Brief Historical Time Line
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1985- Howard Lotsof received a US patent for use of I. To treat
Opioid withdrawal(additional patents for indications of
dependency on cocaine,alcohol,nicotine and poly-substance abuse)
1988-1994-US and Dutch researchers published initial findings in
animals:diminished Opioid self administration and withdrawal +
diminished cocaine self administration
1991-NIDA :I. Project.(pre-clinical toxicological evaluation and
development of a human protocol)
Brief Historical Time Line
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1993-Dr Deborah Mash got approval for human trials.The
dosage:1,2,5 mg/kg.Activity is eventually suspended
NIDA ends its I.project:opinions of the industry mostly critical
1997 begins the I. Mailing List
Brief Historical Time Line
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1990-2001 I. Becomes increasingly available in
alternative settings in view of the lack of approval in
the USA and Europe.(Panama- St.Kitts)
Mechanisms of Action
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I. Appears to have a novel mechanism of action
I.effects may result from complex interactions
between multiple neurotransmitter systems
I.reaches high concentrations in the brain after
injection of 40 mg/kg intra-peritoneal.
Glutamate
Glutamate
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There’s evidence that antagonists of the NMDA subtype of
Glutamate receptors are a potentially promising class of agents
for the development of medications for addiction
I.apparent activity as a noncompetitive NMDA antagonist has
been suggested to be a possible mechanism of anti-addictive
action
Glutamate
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Ibogaine
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Competitively inhibits the binding of the NMDA antagonist MK
801
Reduced Glutamate induced cell death in neuronal cultures
Reduction of NMDA-activated currents in hippocampal
cultures
Prevention of NMDA-mediated depolarization in frog motoneurons
Protection against NMDA-induced seizures
Glycine attenuates I.effect
I.lowered the concentration of Dopamine and its metabolites
but MK 801 did not
Glutamate
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Learning ,memory and neurophysiology
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Da and Glutamate are involved in
neuroplastic modulation of normal and
pathological learning (hippocampus)
It is apparent that Ibogaine influences the
neurological processes involved in learning
addictive behavior
Through NMDA receptors, Ibogaine
influences the process of LTP
(learning,memory and neuroplasticity)
Opioid
Opioid
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Ibogaine and noribogaine are Mu and Kappa receptor
agonists
But Ibogaine and Noribogaine have not antinociceptive effects .
I. May act at the second messenger level
Ibogaine and Noribogaine potentiated Morphine
induced inhibition of adenylyl cyclase in the Mo.
occupied receptors
Opioid
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Kappa stimulants imitate the action of
Ibogaine at reducing cocaine and morphine
self administration
Serotonin
Serotonin
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Ibogaine binds to Serotonin transporter and increases
Serotonin levels in the NAc
Noribogaine binds x 10 strongly than Ibogaine .
Some suggest I. May reduced Dopamine secretion
through Serotonin activity in the NAc
Dopamine
Dopamine
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Ibogaine is a competitive dopamine
transporter blocker
I.reduces dopamine levels and increases
dopamine metabolites levels
I. decreases Prolactin levels
Acetylcholine
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Ibogaine is a nonselective and weak inhibitor of
binding to muscarinic receptor subtypes.
Functional evidence of muscarinic agonistic
effect:decrease heart rate and effects on the
EEG (dyssynchrony)
Ganglionic nicotinic blockade with reduced
secretion of Catecholamines in cultures
Sigma Receptors
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There are not known natural endogenous
ligands for them
Sigma2 receptors binding is relatively strong in
the CNS
The I. Toxic effects are attributed to mediation
through sigma2receptors.
They increase the NMDA receptors activity.
Sigma Receptors
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Sigma 2 receptors contribute to motoric behavior
regulation.Some attribute them a role in the
mechanism of side effects like TD and dysthonia
Their activation causes cell death through
apoptosis.
Iboga alkaloids selectively bind sigma 2
receptors.They increase the [Ca] and activate
apoptosis.
Glial cell line-derived neurotrophic
factor (GDNF)
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A molecular mechanism that mediates the desirable
activities of Ibogaine on ethanol intake.
Microinjection of Ibogaine into the ventral
tegmental area (VTA) reduced self-administration
of ethanol
Systemic administration of Ibogaine increased the
expression of glial cell line-derived neurotrophic
factor (GDNF) in a midbrain region that includes
the VTA.
Summary of Mechanisms of
Action of Ibogaine
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Kappa agonist
 Opioid (morphine) and stimulant (cocaine) selfadministration
NMDA antagonist
 Opioid self-administration
 Opioid physical dependence (withdrawal)
Nicotinic antagonist
 Nicotine self-administration (smoking)
Summary of Mechanisms of
Action of Ibogaine
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Serotonin uptake inhibitor
 Alcohol intake
 Hallucinations
Sigma-2 agonist
 Cerebellar neurotoxicity
Lipid solubility and metabolism
 Long -term effects
Possible effects on Neuroadaptations
Related to Drug Sensitization or
Tolerance
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Ibogaine treatment might result in the “resetting”or
“normalization”of neuro-adaptations related to drug
sensitization or tolerance.
Ibogaine pretreatment blocked the expression of
sensitization-induced increases in the release of dopamine
in the Nac shell.
Opposition or reversal of effects on second messenger
(adenylyl cyclase)
Evidence of efficacy in
Animal models
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Drug Self-administration
Acute Opioid withdrawal
Conditioned place preference
Locomotor activity
Dopamine efflux .
Drug Self-Administration
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Reduction in morphine,heroine,cocaine,alcohol and
nicotine self-administration.
The effects are apparently persistent (five days in rats) but
water intake stopped just for a day.
The results improved with repeated treatments.
Noribogaine has also been reported to reduce |Mo,Cocaine
and Heroine self administration
Some of the Iboga alkaloids tested produce tremors.
18-MC reduces drugs intake but not water intake.
Acute Opioid withdrawal
Acute Opioid withdrawal
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Dose-dependent attenuation of Naloxone
precipitated Opioid withdrawal symptoms.
Similar results were evident in monkeys.
Conditioned place preference
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Ibogaine is reported to prevent the acquisition of place
preference when given 24 h previous to amphetamine or
Morphine.
Locomotor activity
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Diminishes Locomotor activation in
response to Morphine.
Dopamine efflux .
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In Ibogaine,Noribogaine or 18-MC treated animals t
was shown a reduction of Da secretion in the Nac.
The effects on the Nac’s shell explain the motivational
effects and those on the Nac’s core explain the motor
actions.
This action is supposed to be related to the effect on Da
secretion through NMDA and kappa receptors.
Evidence of efficacy and
subjective effects in humans
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Acute Opioid withdrawal
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Accounts of the addicts themselves,whose demand
has led to an informal treatment network in Europe
and the US.
Opioid dependence is the most common indication
Common reported features are reduction in drug
craving and opiate withdrawal signs and symptoms
within 1 to 2 hours and sustained effects
Acute Opioid withdrawal
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Alper et al. summarized 33 cases treated for the
indication of Opioid detoxification :
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Resolution of the withdrawal signs and symptoms without
further drug seeking behavior in 25 patients.
Significantly reduced craving
Mash et al .reported having treated more than 150
patients in St.Kitts,West Indies. (2001)
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Reduction of measures of craving and depression were stable
till one month
Ibogaine showed equally effective in methadone and heroine
detoxification
Long-TermOutcomes
Lotsof presented at a NIDA Ibogaine Review Meeting
Held in March 1995 a summary of patients treated between
1962 – 1993
:
 38 reported some use of Opioid
 10 of them were additionally dependent on other
drugs(cocaine,alcohol or sedative-hypnotics)
 Total of 52 treatments
 15 (29%) Cessation of use for less than 2 months
 15 (29%)Cessation of use for more than 2 months but less
than 6 months.
 7 (13% )for at least 6 months but less than a year.
 10 (19%) for a period greater than a year.
 5 (10% )of outcomes could not be determined
Subjective Effects
Subjective Effects
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Acute :
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The onset of this phase is within 1 to 3 hours
of ingestion with a duration of 4 to 8 hours
The predominant reported experiences
appear to be a panoramic readout of longterm memory(“visit to the ancestors
,archetype”)
“Oneiric experience”
Subjective Effects
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Evaluative or visualization:
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Onset after 4 to 8 hours after ingestion with a
duration of 8 to 20 hours
The volume of material recalled slows
Attention is still focused on inner subjective
experience rather than external environment.
Patients are easily distracted and annoyed and
prefer little environmental stimulation
Subjective Effects
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Residual stimulation
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The onset of this phase is approximately 12 to 24
hours after ingestion with a duration in the
range of 24 to 72 hours.
Allocation of attention to the external
environment
Less subjective psychoactive experience
Mild residual subjective arousal or vigilance
Some patients report reduced need for sleep for
several days to weeks
Pharmacokinetics
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Absorption:
 Dose dependent oral bio-availability
 Greater bio-availability in females because of gender related
differences in absorption kinetics.
 High hepatic first pass effect
Distribution:
 High hepatic extraction
 Highly lipophilic
 [Ibogaine] 100 times grater in fat and 30 times greater in brain
 Platelets might sequester Ibogaine
Pharmacokinetics
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Metabolism
 The main metabolite is Noribogaine.It’s formed through
demethylation via CYP2D6 isoform.
 Noribogaine is a more polar substance
Because Pharmacokinetics differences, poor,good and
intermediate metabolizers were identified.
Excretion
 Half- life on the order of 7.5 hours in humans .I. And
Noribogaine are excreted through the kidneys and GI system.
 In humans’ 90% of a single 20mg/kg oral dose are eliminated
in 24 hours
 Noribogaine is eliminated much slower.(“high half life”)
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Each form has
1. Different onset
2. Different duration of action
3. And significant diversity across
the patient population
Forms in Current Use
Onset of Effects (min)
160
140
120
100
80
60
40
20
0
Full Effect
Onset
HCl
Extract
Forms in Current Use
Period of visuaization (hours)
16
14
12
10
8
6
4
2
0
Extended
Visualization
Onset
HCl
Extract
Forms in Current Use
Duration of Action (days)
10
9
8
7
6
5
4
3
2
1
0
Residual
Principal
HCl
Extract
Forms in Current Use
Effect on sleep (weeks)
10
9
8
7
6
5
4
3
2
1
0
Residual
Principal
HCl
Dose and Dose Regimen
1. Single dose
2. Multiple
1. Escalating
2. Deescalating
3. Linear
Dose and Dose Regimen
All doses are representative.
Doses, including single administration doses are
determined on a patient by patient basis.
The graphs of dose regimens and information that
follow should not be used by persons without
experience to self-administer or administer to others
any dose of Ibogaine or total alkaloid extract of
Tabernanthe iboga.
Dose and Dose Regimen
Single dose regimens usually fall between 10mg/kg and
22mg/kg depending on type of therapy offered:
Opioid dependency, stimulant dependency, psycho
spiritual, etc.
Most doses fall in the 15mg/kg - 20mg/kg dose range
to reach full therapeutic effects.
Dose and Dose Regimen
ibogaine HCl (mg/hour)
20mg methadone
total - 1000mg
400
350
300
250
200
150
100
50
0
350
175
175
HCl
175
125
0
h1
h2
h3
h4
Dose and Dose Regimen
ibogaine HCl (mg/kg/hour)
heroin therapy
total 21.5mg.kg
courtesy Eric Taub
16
14
12
10
8
6
4
2
14
HCl
5
2,5
0
1h
h12
Dose and Dose Regimen
ibogaine HCl (mg/kg/hour)
methadone therapy
total 36.5 mg/kg
courtesy Eric Taub
16
14
12
10
8
6
4
2
12
HCl
2,5 2,5 2,5 2,5 2,5
3
3
3
3
0 13 23 30 34 36 59 68 77 89 100
Frequent side effects of Ibogaine
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Coordination disturbances
(unstable gait and tendency to fall)
Hallucinations-like experiences
Sleep disturbances
Concentration and speech troubles
Heart rate and blood pressure
changes
Nausea and vomiting
Dizziness
Light sensitivity
Tiredness
Muscles soreness
Safety
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Neurotoxicity
Tremor
Cardiovascular effects
Fatalities
Abuse liability
Safety
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Neurotoxicity
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Multiple laboratories have reported on the degeneration of
Cerebellar Purkinje cells in rats given 100mg/kg I.p.
This neurotoxicity is mediated through NMDA receptors
activated by sigma 2 agonists in the Olivo-Cerebellar
projection .
Safety
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Tremor
 Positive with Ibogaine
 Negative with Noribogaine which lacks a
methoxy group at position 10 or 11
 Negative with 18-MC which lacks methoxy
group at position 10 but in position 16
 LD50 145 mg-kg ip and 327 mg kg po in Rats
Observations in Humans
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Postural stability
Body and appendicular tremor
Cardiovascular effects
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Mash et al .:intensive cardiac monitoring in 39 human subjects
dependent on cocaine and/or heroine who received fixed p.o. doses of
500 mg, 600mg, 800mg ,1000mg
Six of them exhibited some significant decrease of resting pulse rate
relative to baseline
One of them experienced a decrease in BP because vasovagal reflex.
No EKG change was identified
Possible hypotensive response in some cocaine dependent subjects
(responsive to volume repletion)
Observations in Humans
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Fatalities: between 1990-1994 a few patients
previously treated with Ibogaine died in
Holland,France,G.Britain and the US
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In France :a woman age 44 died 4 hours after receiving a
dose of 4.5 mg/kg p.o.
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Autopsy revealed an old MI and severe IHD
The possibility of a direct toxic effect of Ibogaine was excluded.
In Holland : a patient aged 24 died as a result of
respiratory arrest.
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The PM was not revealing and they were evidences of surreptitious
heroine use
Observations in Humans
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There are evidences of increase toxicity of opiates
while using them with Ibogaine
This incident call the attention to the need for adequate
monitoring and for the completition of dose escalation
studies
In the US : a patient died 25 days after treatment.
The cause was an aortic clott.
It was established that Ibogaine had no causal
relationshiop to death
The patient got 4 Ibogaine treatments in the year and
a half previous to death
Abuse liability
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The available evidence does not appear to suggest a
significant potential for abuse
I. Is reportedly neither rewarding or aversive in the
Conditioned place preference paradigm
Rats given Ibogaine for 6 days showed no withdrawal
symptoms after interruption.
Animals do not self administer 18-MC
None of the consultants to NIDA in the 1995 Ibogaine
Review Meeting identified the possible abuse as a possible
safety concern
According to Kaplan and Sadock:there’s little concern about
Ibogaine liability to abuse because users do not like the
physical side effects at a hallucinogenic dose of 1500mg
Ibogaine Testing