Ibogaine

1
Ibogaine

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

2
Ibogaine
3
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 less withdrawal signs in
  animals and humans.

4
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 5 to 6
• It undergoes demethylation to form its principal
  metabolite noribogaine.
• 18 MC is an Ibogaine congener.It seems to have
  efficacy similar to I.with less potential
  toxicity

5
Forms in Current Use

• Botanical - root bark

6
Forms in Current Use

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

7
Forms in Current Use

• Purified Ibogaine HCl (Endabuse)
• 99.4 purity

8
Brief Historical Time Line
9
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

10
Brief Historical Time Line

• 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

11
Brief Historical Time Line

• 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 animalsdiminished Opioid
  self administration and withdrawal diminished
  cocaine self administration
• 1991-NIDA I. Project.(pre-clinical toxicological
  evaluation and development of a human protocol)

12
Brief Historical Time Line

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

13
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)

14
Mechanisms of Action

• 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.

15
Glutamate
16
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
• I.apparent activity as a noncompetitive NMDA
  antagonist has been suggested to be a possible
  mechanism of anti-addictive action

17
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
• I.lowered the concentration of Dopamine and its
  metabolites but MK 801 did not

18
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)

19
Opioid
20
Opioid

• Ibogaine and noribogaine are Mu and Kappa
  receptor agonists
• But Ibogaine and Noribogaine have not
  anti-nociceptive effects.
• I. May act at the second messenger level
• Ibogaine and Noribogaine potentiated Morphine
  induced inhibition of adenylyl cyclase in the
  Mo. occupied receptors

21
Opioid

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

22
Serotonin
23
Serotonin

• 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

24
Dopamine
25
Dopamine

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

26
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

27
Sigma Receptors

• 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.

28
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 sigma 2
  receptors.They increase the Ca and activate
  apoptosis.

29
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.

30
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)

31
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

32
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)

33
Evidence of efficacy in Animal models

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

34
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
  Mo,Cocaine and Heroine self administration
• Some of the Iboga alkaloids tested produce
  tremors.
• 18-MC reduces drugs intake but not water intake.

35
Acute Opioid withdrawal
36
Acute Opioid withdrawal

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

37
Conditioned place preference

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

38
Locomotor activity

• Diminishes Locomotor activation in response to
  Morphine.

39
Dopamine efflux.

• In Ibogaine,Noribogaine or 18-MC treated animals
  t was shown a reduction of Da secretion in the
  Nac.
• 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.

40
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

41
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

42
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

43
Subjective Effects
44
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

45
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

46
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

47
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

48
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)

49
Each form has

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

50
Forms in Current Use
51
Forms in Current Use
52
Forms in Current Use
53
Forms in Current Use
54
Dose and Dose Regimen

• Single dose
• Multiple
• Escalating
• Deescalating
• Linear

55
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.

56
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.

57
Dose and Dose Regimen
58
Dose and Dose Regimen
59
Dose and Dose Regimen
60
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

61
Safety

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

62
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.

63
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

64
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)

65
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

66
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

67
Abuse liability

• 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 Sadocktheres little
  concern about Ibogaine liability to abuse because
  users do not like the physical side effects at a
  hallucinogenic dose of 1500mg

68
Ibogaine Testing