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

2. Ibogaine

3. 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.

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 it’s 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. 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 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)

12. Brief Historical Time Line 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

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. 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

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. 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. 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. 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 effect:decrease 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 “ 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)

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. 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 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.

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. 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.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”)

49. Each form has 1.Different onset 2.Different duration of action 3.And significant diversity across the patient population

50. Forms in Current Use

54. Dose and Dose Regimen 1.Single dose 2.Multiple 1.Escalating 2.Deescalating 3.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

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 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

68. Ibogaine Testing