ibogaine dr.moshe zer-zion beer-yaacov mental health center israel

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Ibogaine Dr.Moshe Zer-Zion Beer-Yaacov Mental Health Center Israel Slide 2 Ibogaine Slide 3 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. Slide 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 Slide 5 Forms in Current Use Botanical - root bark Slide 6 Forms in Current Use Total alkaloid extract Large piece 2cm x 2cm, approx 4 grams Estimate 15% Ibogaine Slide 7 Forms in Current Use Purified Ibogaine HCl (Endabuse) 99.4% purity Slide 8 Brief Historical Time Line Slide 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 Slide 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 Slide 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) Slide 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 Slide 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) Slide 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. Slide 15 Glutamate Slide 16 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 Slide 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 Slide 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) Slide 19 Opioid Slide 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 Slide 21 Opioid Kappa stimulants imitate the action of Ibogaine at reducing cocaine and morphine self administration Slide 22 Serotonin Slide 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 Slide 24 Dopamine Slide 25 Ibogaine is a competitive dopamine transporter blocker I.reduces dopamine levels and increases dopamine metabolites levels I. decreases Prolactin levels Slide 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 Slide 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. Slide 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. Slide 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. Slide 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) Slide 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 Slide 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) Slide 33 Evidence of efficacy in Animal models Drug Self-administration Acute Opioid withdrawal Conditioned place preference Locomotor activity Dopamine efflux. Slide 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. Slide 35 Acute Opioid withdrawal Slide 36 Dose-dependent attenuation of Naloxone precipitated Opioid withdrawal symptoms. Similar results were evident in monkeys. Slide 37 Conditioned place preference Ibogaine is reported to prevent the acquisition of place preference when given 24 h previous to amphetamine or Morphine. Slide 38 Locomotor activity Diminishes Locomotor activation in response to Morphine. Slide 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. Slide 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 Slide 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 Slide 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%)