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 Africa’s shrub Tabernante Iboga • The plant is used for religious and medical purposes by the Bwiti culture. (Gabon) • NIDAhas given significant support to animal research and the FDAhas 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 metabolitenoribogaine. • 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 gramsEstimate 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 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. Glutamate • 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. Opioid • Ibogaine and noribogaine are Mu and Kappa receptor agonists • But Ibogaineand Noribogaine have not anti-nociceptive effects. • I. May act at the second messenger level • Ibogaineand 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 • Ibogainebinds 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 • Ibogaineis 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 desirableactivities of Ibogaine on ethanol intake. • Microinjection ofIbogaine into the ventral tegmental area (VTA) reduced self-administration of ethanol • Systemic administration of Ibogaine increased the expressionof glial cell line-derived neurotrophic factor (GDNF) in a midbrainregion 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 resultsimproved 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 • Ibogaineis 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 aNIDA 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.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 • Different onset • Different duration of action • And significant diversity across the patient population

50. Forms in Current Use