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