Ibogaine

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Ibogaine

• Dr.Moshe Zer-Zion
• Beer-Yaacov Mental Health Center
• Israel

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Ibogaine
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Ibogaine

• Ibogaine is a naturally occurring plant alkaloid
  in the West Central Africas 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 Ibogaines effectiveness includes
  reduced drug use and reduction of withdrawal
  signs in animals and humans.

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Ibogaine

• Is the most abundant alkaloid in the root bark of
  the shrub Tabernanthe iboga.
• In the dried root bark total alkaloid content is
  reportedly 2 to 6
• It undergoes demethylation to form its principal
  metabolite noribogaine.
• 18 MC is an Ibogaine congener. It seems to have
  efficacy similar to Ibogaine with less potential
  toxicity

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Ibogaine
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Forms in Current Use

• Botanical - root bark

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Forms in Current Use

• Total alkaloid extract
• Large piece 2cm x 2cm, approx 4 grams Estimate
  15 Ibogaine

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Forms in Current Use

• Purified Ibogaine HCl (Endabuse)
• 99.4 purity

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Brief Historical Time Line
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Brief Historical Time Line

• 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

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Brief Historical Time Line

• 1962-1963 In the USA Howard Lotsof administered
  Ibogaine 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
  Ibogaine at a dosage of 4 to 5 mg/kg
• 1967-1970 The WHA classifies Ibogaine. With
  hallucinogens and stimulants .The FDA assigns
  Ibogaine Schedule I classification

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Brief Historical Time Line

• 1985- Howard Lotsof received a US patent for use
  of Ibogaine 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 animalsdiminished Opioid
  self administration and withdrawal diminished
  cocaine self administration
• 1991-NIDA Ibogaine Project.(pre-clinical
  toxicological evaluation and development of a
  human protocol)

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Brief Historical Time Line

• 1993-Dr Deborah Mash got approval for human
  trials.The dosage1,2,5 mg/kg.Activity is
  eventually abandoned
• NIDA ends its Ibogaine projectopinions of the
  industry mostly critical
• 1997 begins the Ibogaine Mailing List

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Brief Historical Time Line

• 1990-2001 I. Becomes increasingly available in
  alternative settings in view of the lack of
  approval in the USA and Europe.(Panama- St.Kitts)

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Mechanisms of Action

• Ibogaine appears to have a novel mechanism of
  action
• Ibogaine effects may result from complex
  interactions between multiple neurotransmitter
  systems
• Ibogaine reaches high concentrations in the brain
  after injection of 40 mg/kg intra-peritoneal.

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Glutamate
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Glutamate

• Theres evidence that antagonists of the NMDA
  subtype of Glutamate receptors are a potentially
  promising class of agents for the development of
  medications for addiction
• Ibogaine apparent activity as a noncompetitive
  NMDA antagonist has been suggested to be a
  possible mechanism of anti-addictive action

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Glutamate

• Ibogaine
• 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 moto-neurons
• Protection against NMDA-induced seizures
• Glycine attenuates I.effect
• Ibogaine lowered the concentration of Dopamine
  and its metabolites but MK 801 did not

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Glutamate

• Learning ,memory and neuro-physiology
• 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)

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Opioid
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Opioid

• Ibogaine and noribogaine are Mu and Kappa
  receptor agonists.
• But Ibogaine and Noribogaine have no
  anti-nociceptive effects.
• Ibogaine May act at the second messenger level.
• Ibogaine and Noribogaine potentiated Morphine
  induced inhibition of adenylyl cyclase in the
  Morphine occupied receptors.

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Opioid

• Kappa stimulants imitate the action of Ibogaine
  at reducing cocaine and morphine self
  administration

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Serotonin
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Serotonin

• Ibogaine binds to Serotonin transporter and
  increases Serotonin levels in the NAc
• Noribogaine binds x 10 strongly than Ibogaine.
  
• Some suggest Ibogaine May reduced Dopamine
  secretion through Serotonin activity in the NAc

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Dopamine
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Dopamine

• Ibogaine is a competitive dopamine transporter
  blocker
• Ibogaine reduces dopamine levels and increases
  dopamine metabolites levels
• Ibogaine decreases Prolactin levels

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Acetylcholine

• Ibogaine is a nonselective and weak inhibitor of
  binding to muscarinic receptor subtypes.
• Functional evidence of muscarinic agonistic
  effectdecrease heart rate and effects on the EEG
  (dyssynchrony)
• Ganglionic nicotinic blockade with reduced
  secretion of Catecholamines in cultures

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Sigma Receptors

• There are no known natural endogenous ligands for
  them
• Sigma2 receptor binding is relatively strong in
  the CNS
• The Ibogaine toxic effects are attributed to
  mediation through sigma2 receptors.
• They increase the NMDA receptors activity.

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Sigma Receptors

• 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 to sigma 2
  receptors. They increase Ca and activate
  apoptosis.

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Glial cell line-derived neurotrophic factor
(GDNF)

• 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.

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Summary of Mechanisms of Action of Ibogaine

• Kappa agonist
• Opioid (morphine) and stimulant (cocaine)
  self-administration
• NMDA antagonist
• Opioid self-administration
• Opioid physical dependence (withdrawal)
• Nicotinic antagonist
• Nicotine self-administration (smoking)

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Summary of Mechanisms of Action of Ibogaine

• Serotonin uptake inhibitor
• Alcohol intake
• Hallucinations
• Sigma-2 agonist
• Cerebellar neurotoxicity
• Lipid solubility and metabolism
• Long -term effects

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Possible effects on Neuroadaptations Related to
Drug Sensitization or Tolerance

• Ibogaine treatment might result in the
  resettingor normalizationof 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)

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Evidence of efficacy in Animal models

• Drug Self-administration
• Acute Opioid withdrawal
• Conditioned place preference
• Locomotor activity
• Dopamine efflux.

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Drug Self-Administration

• 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
  Morphine,Cocaine and Heroine self
  administration.
• Some of the Iboga alkaloids tested produce
  tremors.
• 18-MC reduces drugs intake but not water intake.

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Acute Opioid withdrawal
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Acute Opioid withdrawal

• Dose-dependent attenuation of Naloxone
  precipitated Opioid withdrawal symptoms.
• Similar results were evident in monkeys.

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Conditioned place preference

• Ibogaine is reported to prevent the acquisition
  of place preference when given 24 h previous to
  amphetamine or Morphine.

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Locomotor activity

• Diminishes Locomotor activation in response to
  Morphine.

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Dopamine efflux.

• In Ibogaine, Noribogaine or 18-MC treated
  animals, a reduction of Da secretion in the
  Nac.was shown.
• The effects on the Nacs shell explain the
  motivational effects and those on the Nacs core
  explain the motor actions.
• This action is supposed to be related to the
  effect on Da secretion through NMDA and kappa
  receptors.

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Evidence of efficacy and subjective effects in
humans

• Acute Opioid withdrawal
• 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

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Acute Opioid withdrawal

• Alper et al. summarized 33 cases treated for the
  indication of Opioid detoxification
• 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)
• Reduction of measures of craving and depression
  were stable till one month
• Ibogaine showed equally effective in methadone
  and heroine detoxification

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Long-TermOutcomes

• Lotsof presented at a NIDA Ibogaine Review
  Meeting
• Held in March 1995 a summary of patients treated
  between
• 1993 1962
• 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

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Subjective Effects
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Subjective Effects

• Acute
• 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 long-term memory(visit to
  the ancestors, archetype)
• Oneiric experience

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Subjective Effects

• Evaluative or visualization
• 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

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Subjective Effects

• Residual stimulation
• 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

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Pharmacokinetics

• 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

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Pharmacokinetics

• Metabolism
• The main metabolite is Noribogaine. Its 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

• Different onset
• Different duration of action
• And significant diversity across the patient
  population

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Forms in Current Use
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Forms in Current Use
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Forms in Current Use
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Forms in Current Use
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Dose and Dose Regimen

• Single dose
• Multiple
• Escalating
• Deescalating
• Linear

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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.

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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.

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Dose and Dose Regimen
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Dose and Dose Regimen
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Dose and Dose Regimen
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Frequent side effects of Ibogaine

• 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

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Safety

• Neurotoxicity
• Tremor
• Cardiovascular effects
• Fatalities
• Abuse liability

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Safety

• Neurotoxicity
• 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.

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Safety

• 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

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Observations in Humans

• Postural stability
• Body and appendicular tremor
• Cardiovascular effects
• 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)

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Observations in Humans

• Fatalities between 1990-1994 a few patients
  previously treated with Ibogaine died in
  Holland,France,G.Britain and the US
• In France a woman age 44 died 4 hours after
  receiving a dose of 4.5 mg/kg p.o.
• 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.
• The PM was not revealing and they were evidences
  of surreptitious heroine use

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Observations in Humans

• 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

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Abuse liability

• The available evidence does not appear to suggest
  a significant potential for abuse
• Ibogaine 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 Sadocktheres little
  concern about Ibogaine liability to abuse because
  users do not like the physical side effects at a
  hallucinogenic dose of 1500mg

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Ibogaine Testing