1 / 69

Ibogaine

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

salena
Download Presentation

Ibogaine

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  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 reduction of 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 2% to 6% • It undergoes demethylation to form it’s principal metabolitenoribogaine. • 18 MC is an Ibogaine congener. It seems to have efficacy similar to Ibogaine with less potential toxicity

  5. Ibogaine

  6. Forms in Current Use • Botanical - root bark

  7. Forms in Current Use • Total alkaloid extract • Large piece 2cm x 2cm, approx 4 gramsEstimate 15% Ibogaine

  8. Forms in Current Use • Purified Ibogaine HCl(Endabuse) • 99.4% purity

  9. Brief Historical Time Line

  10. 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

  11. 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

  12. 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 animals:diminished Opioid self administration and withdrawal + diminished cocaine self administration • 1991-NIDA :Ibogaine Project.(pre-clinical toxicological evaluation and development of a human protocol)

  13. Brief Historical Time Line • 1993-Dr Deborah Mash got approval for human trials.The dosage:1,2,5 mg/kg.Activity is eventually abandoned • NIDA ends its Ibogaine project:opinions of the industry mostly critical • 1997 begins the Ibogaine Mailing List

  14. 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)

  15. 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.

  16. Glutamate

  17. 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 • Ibogaine apparent activity as a noncompetitive NMDA antagonist has been suggested to be a possible mechanism of anti-addictive action

  18. 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

  19. 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)

  20. Opioid

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

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

  23. Serotonin

  24. Serotonin • Ibogainebinds 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

  25. Dopamine

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

  27. 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

  28. 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.

  29. 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.

  30. 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.

  31. 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)

  32. 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

  33. 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)

  34. Evidence of efficacy in Animal models • Drug Self-administration • Acute Opioid withdrawal • Conditioned place preference • Locomotor activity • Dopamine efflux.

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

  36. Acute Opioid withdrawal

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

  38. Conditioned place preference • Ibogaineis reported to prevent the acquisition of place preference when given 24 h previous to amphetamine or Morphine.

  39. Locomotor activity • Diminishes Locomotor activation in response to Morphine.

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

  41. 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

  42. 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

  43. 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

  44. Subjective Effects

  45. 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”

  46. 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

  47. 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

  48. 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

  49. 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”)

  50. Each form has • Different onset • Different duration of action • And significant diversity across the patient population

More Related