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Ibogain och missuppfattningarna......

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Joined: 08 Jun 2006
Posts: 270
Topics: 45

PostPosted: Wed 28 Jun, 2006 14:11    Post subject: Ibogain och missuppfattningarna...... Reply with quote

Dags att börja rensa i mytologiträsket kanske?
Såg detta i mejlboxen ....
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Från: http://www.ens2000.nu/fragelada/fraga.php?id=58

2006-03-07 - Mats Erikssons fråga
Ibogaine

Hej
Vad vet man om Ibogaine och dess effekter på drogberoende. Har fått fram att det är en extremt stark Hallucinogen drog, fanns många tripprapporter, har dock inte hittat några vad jag betecknar som seriösa sidor om Ibogaine och att ämnet inte finns att hitta i svenska Fass!

MvhME/Mats
Mats Eriksson

Svar

Hej!
Ibogaine är en psykoaktiv alkaloid och tillhör gruppen hallucinogener. I läkemedelsverkets förteckningar är ibogaine narkotikaklassat i förteckning I vilket innebär att medlet inte har någon medicinsk användning.
Ibogaine tas från den afrikanska växten Tabermanthe iboga och dess rotbark.
Vissa forskare har prövat medlet i avsikt att få missbrukare av alkohol och andra narkotiska preparat att upphöra med missbruket, men denna metod har ingen vetenskaplig förankring. Metoden anses kontroversiell.

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Kommentar till svar
Ingen vetenskaplig förankring? Vilken planet har ni vistats på de senaste decennierna? Det finns gott om vetenskapliga förankringar och inte bara det, det finns dessutom människor som avslutat sina tunga missbruk tack vare just Ibogain! Kan det säga något måhända?

Eller är det ni skriver bara ett led i en oändligt döv stadsapparats blinda narkotikapolitik, där det varken kan förekomma någotsomhelst positivt med någon drog överhuvudtaget?

Det är tvärtom ovetenskapligt och lögnaktigt att påstå att metoden saknar vetenskapligt stöd! Vad är det egentligen ni vill åstakomma med texter som denna? Kan ni inte hålla käften och läsa på lite innan ni blåser ur er en massa skit? Eller sover ni gott när tunga narkomaner inte får tillgång till något som beviserligen fungerat för andra?

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Operator



Joined: 08 Jun 2006
Posts: 270
Topics: 45

PostPosted: Thu 29 Jun, 2006 08:38    Post subject: LMV Reply with quote

Fru-Lindgren agiterar mot LMV..............
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På vilka vetenskapliga och medicinska grunder är Ibogain narkotikaklassat i grupp I?

Diskussion:
Då ibogain enligt ett flertal vetenskapliga studier bevisats ha en antiaddiktiv effekt på både människa och djur så förefaller det ivarjefall ur logiskt synpunkt svårförklarat varför man valt att narkotikaklassa Ibogain i denna grupp. Kanhända Läkemedelsverket kan komma med en förklaring? Vidare borde väl ett narkotikum kunna gå att missbruka, men eftersom ibogainmissbruk verkar vara okänt av den vetenskapliga världen och andra världar dessutom så förefaller det minst sagt fundersamt, håller ni med?

Referenser särskilda:
Ibogain och antiaddiktion

GDNF and addiction.

Ron D, Janak PH.

Ernest Gallo Research Center, Department of Neurology, University of California, San Francisco, Emeryville, USA. dorit@itsa.ucsf.edu

Biochemical adaptations to drugs of abuse and alcohol are especially profound in midbrain dopaminergic neurons. Long-lasting molecular and structural changes in mesolimbic dopaminergic neurons that result from chronic exposure to drugs of abuse and alcohol are thought to underlie adverse behaviors such as compulsive drug seeking and relapse. Recent studies suggest that a subset of these changes is prevented/reversed by activation of the glial cell line-derived neurotrophic factor (GDNF) signaling pathway. Behavioral effects of drugs of abuse such as cocaine and alcohol are also negatively regulated by GDNF: inhibition of the endogenous GDNF pathway enhances the activity of drugs of abuse, while administration of GDNF reduces the severity of the effects. In this review, we summarize the data implicating GDNF as a negative regulator of drug and alcohol addiction. We also provide evidence to suggest that therapies that activate GDNF signaling may be useful for the treatment of drug and alcohol addiction.

Publication Types:
• Review

PMID: 16519005 [PubMed - indexed for MEDLINE]

3: Br J Psychiatry. 2006 Feb;188:109-21.
,


Complementary medicines in psychiatry: review of effectiveness and safety.

Werneke U, Turner T, Priebe S.

Division of Psychiatry, Homerton University Hospital, East Wing, Homerton Row, London E9 6SR, UK. Ursula.Werneke@elcmht.nhs.uk

BACKGROUND: The use of complementary medicines in those with mental health problems is well documented. However, their effectiveness is often not established and they may be less harmless than commonly assumed. AIMS: To review the complementary medicines routinely encountered in psychiatric practice, their effectiveness, potential adverse effects and interactions. METHOD: Electronic and manual literature search on the effectiveness and safety of psychotropic complementary medicines. RESULTS: Potentially useful substances include ginkgo and hydergine as cognitive enhancers, passion flower and valerian as sedatives, St John's wort and s-adenosylmethionine as antidepressants, and selenium and folate to complement antidepressants. The evidence is less conclusive for the use of omega-3 fatty acids as augmentation treatment in schizophrenia, melatonin for tardive dyskinesia and 18-methoxycoronaridine, an ibogaine derivative, for the treatment of cocaine and heroin addiction. CONCLUSIONS: Systematic clinical trials are needed to test promising substances. Meanwhile, those wishing to take psychotropic complementary medicines require appropriate advice.

Publication Types:
• Review

PMID: 16449696 [PubMed - indexed for MEDLINE]

4: Science. 2005 Apr 15;308(5720):345-6.
,


Erratum in:
• Science. 2005 May 27;308(5726):1260.

Addiction research. Ibogaine therapy: a 'vast, uncontrolled experiment'.

Vastag B.

Publication Types:
• News

PMID: 15831735 [PubMed - indexed for MEDLINE]

5: J Neurosci. 2005 Jan 19;25(3):619-28.
,


Glial cell line-derived neurotrophic factor mediates the desirable actions of the anti-addiction drug ibogaine against alcohol consumption.

He DY, McGough NN, Ravindranathan A, Jeanblanc J, Logrip ML, Phamluong K, Janak PH, Ron D.

Ernest Gallo Research Center, University of California, San Francisco, Emeryville, California 94608, USA.

Alcohol addiction manifests as uncontrolled drinking despite negative consequences. Few medications are available to treat the disorder. Anecdotal reports suggest that ibogaine, a natural alkaloid, reverses behaviors associated with addiction including alcoholism; however, because of side effects, ibogaine is not used clinically. In this study, we first characterized the actions of ibogaine on ethanol self-administration in rodents. Ibogaine decreased ethanol intake by rats in two-bottle choice and operant self-administration paradigms. Ibogaine also reduced operant self-administration of ethanol in a relapse model. Next, we identified a molecular mechanism that mediates the desirable activities of ibogaine on ethanol intake. Microinjection of ibogaine into the ventral tegmental area (VTA), but not the substantia nigra, reduced self-administration of ethanol, and systemic administration of ibogaine increased the expression of glial cell line-derived neurotrophic factor (GDNF) in a midbrain region that includes the VTA. In dopaminergic neuron-like SHSY5Y cells, ibogaine treatment upregulated the GDNF pathway as indicated by increases in phosphorylation of the GDNF receptor, Ret, and the downstream kinase, ERK1 (extracellular signal-regulated kinase 1). Finally, the ibogaine-mediated decrease in ethanol self-administration was mimicked by intra-VTA microinjection of GDNF and was reduced by intra-VTA delivery of anti-GDNF neutralizing antibodies. Together, these results suggest that GDNF in the VTA mediates the action of ibogaine on ethanol consumption. These findings highlight the importance of GDNF as a new target for drug development for alcoholism that may mimic the effect of ibogaine against alcohol consumption but avoid the negative side effects.

PMID: 15659598 [PubMed - indexed for MEDLINE]

6: Planta Med. 2004 Sep;70(9):808-12.
,


Anti-HIV-1 activity of the Iboga alkaloid congener 18-methoxycoronaridine.

Silva EM, Cirne-Santos CC, Frugulhetti IC, Galvao-Castro B, Saraiva EM, Kuehne ME, Bou-Habib DC.

Laboratorio Avancado de Saude Publica, Centro de Pesquisas Goncalo Moniz, Salvador, BA, Brazil.

The Iboga alkaloid congener 18-methoxycoronaridine (18-MC) exhibits in vitro leishmanicidal and in vivo anti-addiction properties. In this paper, we describe that 18-MC inhibits HIV-1 infection in human peripheral blood mononuclear cells (PBMCs) and monocyte-derived macrophages. We found that 18-MC inhibits the replication of primary isolates of HIV-1 in a dose-dependent manner, regardless of the preferential chemokine receptor usage of the isolates, at non-cell-toxic concentrations. The antiretroviral activity of 18-MC resulted in EC (50) values of 22.5 +/- 4.7 microM and 23 +/- 4.5 microM for R5 and X4 isolates, respectively, in PBMCs, and a therapeutic index (TI) of 14.5. Similar findings were observed for inhibition of HIV-1 replication in macrophages: EC (50) equal to 12.8 +/- 5 microM and 9.5 +/- 3 microM for an R5 virus after 14 and 21 days of infection, respectively, with TI equal to 25.6 and 34.5. 18-MC moderately inhibits the HIV-1 enzyme reverse transcriptase (IC (50) = 69.4 microM), which at least partially explains its antiretroviral activity.

PMID: 15386189 [PubMed - indexed for MEDLINE]

7: Neuroscience. 2004;127(2):373-83.
,


Administration of a non-NMDA antagonist, GYKI 52466, increases excitotoxic Purkinje cell degeneration caused by ibogaine.

O'Hearn E, Molliver ME.

Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. eohearn@jhmi.edu

Ibogaine is a tremorigenic hallucinogen that has been proposed for clinical use in treating addiction. We previously reported that ibogaine, administered systemically, produces degeneration of a subset of Purkinje cells in the cerebellum, primarily within the vermis. Ablation of the inferior olive affords protection against ibogaine-induced neurotoxicity leading to the interpretation that ibogaine itself is not directly toxic to Purkinje cells. We postulated that ibogaine produces sustained excitation of inferior olivary neurons that leads to excessive glutamate release at climbing fiber terminals, causing subsequent excitotoxic injury to Purkinje cells. The neuronal degeneration induced by ibogaine provides an animal model for studying excitotoxic injury in order to analyze the contribution of glutamate receptors to this injury and to evaluate neuroprotective strategies. Since non-N-methyl-D-aspartate (NMDA) receptors mediate Purkinje cell excitation by climbing fibers, we hypothesized that 1-4-aminophenyl-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI-52466), which antagonizes non-NMDA receptors, may have a neuroprotective effect by blocking glutamatergic excitation at climbing fiber synapses. To test this hypothesis, rats were administered systemic ibogaine plus GYKI-52466 and the degree of neuronal injury was analyzed in cerebellar sections. The results indicate that the AMPA antagonist GYKI-52466 (10 mg/kg i.p. x 3) does not protect against Purkinje cell injury at the doses used. Rather, co-administration of GYKI-52466 with ibogaine produces increased toxicity evidenced by more extensive Purkinje cell degeneration. Several hypotheses that may underlie this result are discussed. Although the reason for the increased toxicity found in this study is not fully explained, the present results show that a non-NMDA antagonist can produce increased excitotoxic injury under some conditions. Therefore, caution should be exercised before employing glutamate antagonists to reduce the risk of neuronal damage in human clinical disorders. Moreover, the contribution of different glutamate receptors to excitotoxic injury is complex and merits further analysis.

PMID: 15262328 [PubMed - indexed for MEDLINE]

8: Eur J Pharmacol. 2004 May 25;492(2-3):159-67.
,


Novel iboga alkaloid congeners block nicotinic receptors and reduce drug self-administration.

Pace CJ, Glick SD, Maisonneuve IM, He LW, Jokiel PA, Kuehne ME, Fleck MW.

Center for Neuropharmacology and Neuroscience, The Albany Medical College, MC-136, 47 New Scotland Avenue, Albany, NY 12208, USA.

18-Methoxycoronaridine, a novel iboga alkaloid congener, reduces drug self-administration in animal models of addiction. Previously, we proposed that these effects are mediated by the ability of 18-methoxycoronaridine to inhibit nicotinic alpha3beta4 acetylcholine receptors. In an attempt to identify more potent 18-methoxycoronaridine analogs, we have tested a series of 18-methoxycoronaridine congeners by whole-cell patch clamp recording of HEK 293 cells expressing recombinant nicotinic alpha3beta4 receptors or glutamate NR1/NR2B N-methyl-d-aspartate (NMDA) receptors. The congeners exhibited a range of inhibitory potencies at alpha3beta4 receptors. Five congeners had IC(50) values similar to 18-methoxycoronaridine, and all of these were ineffective at NMDA receptors. The congeners also retained their ability to reduce morphine and methamphetamine self-administration. These data are consistent with the importance of nicotinic alpha3beta4 receptors as a therapeutic target to modulate drug seeking. These compounds may constitute a new class of synthetic agents that act via the nicotinic alpha3beta4 mechanism to combat addiction.

PMID: 15178360 [PubMed - indexed for MEDLINE]

9: Brain Res. 2004 Apr 2;1003(1-2):159-67.
,


Differential effects of ibogaine on local cerebral glucose utilization in drug-naive and morphine-dependent rats.

Levant B, Pazdernik TL.

Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160-7417, USA. blevant@kumc.edu

Ibogaine, a hallucinogenic indole alkaloid, has been proposed as a treatment for addiction to opioids and other drugs of abuse. The mechanism for its putative anti-addictive effects is unknown. In this study, the effects of ibogaine on local cerebral glucose utilization (LCGU) were determined in freely moving, drug-naive, or morphine-dependent adult, male, Sprague-Dawley rats using the [(14)C]2-deoxyglucose (2-DG) method. Morphine-dependent rats were treated with increasing doses of morphine (5-25 mg/kg, s.c., b.i.d.) and then maintained at 25 mg/kg (b.i.d.) for 4-7 days. For the 2-DG procedure, rats were injected with saline or ibogaine (40 mg/kg, i.p.). 2-DG was administered 1 h after administration of ibogaine. The rate of LCGU was determined by quantitative autoradiography in 46 brain regions. In drug-naive animals, ibogaine produced significant increases in LCGU in the parietal, cingulate, and occipital cortices and cerebellum compared to controls consistent with its activity as a hallucinogen and a tremorogen. Morphine-dependent rats had only minor alterations in LCGU at the time assessed in this experiment. However, in morphine-dependent animals, ibogaine produced a global decrease in LCGU that was greatest in brain regions such as the lateral and medial preoptic areas, nucleus of the diagonal band, nucleus accumbens shell, inferior colliculus, locus coeruleus, and flocculus compared to morphine-dependent animals treated with saline. These findings indicate that ibogaine produces distinctly different effects on LCGU in drug-naive and morphine-dependent rats. This suggests that different mechanisms may underlie ibogaine's hallucinogenic and anti-addictive effects.

PMID: 15019575 [PubMed - indexed for MEDLINE]

10: Prog Neuropsychopharmacol Biol Psychiatry. 2003 Aug;27(5):781-5.
,


Ibogaine attenuation of morphine withdrawal in mice: role of glutamate N-methyl-D-aspartate receptors.

Leal MB, Michelin K, Souza DO, Elisabetsky E.

Faculdade de Farmacia, Pontificia Universidade Catolica do Rio Grande do Sul, Rua da Republica 580/306, Cep: 90050-320, Porto Alegre, RS, Brazil. mirnabl@pucrs.br

Ibogaine (IBO) is an alkaloid with putative antiaddictive properties, alleviating opiates dependence and withdrawal. The glutamate N-methyl-D-aspartate (NMDA) receptors have been implicated in the physiological basis of drug addiction; accordingly, IBO acts as a noncompetitive NMDA antagonist. The purpose of this study was to evaluate the effects of IBO on naloxone-induced withdrawal syndrome in morphine-dependent mice, focusing on the role of NMDA receptors. Jumping, a major behavioral expression of such withdrawal, was significantly (P<.01) inhibited by IBO (40 and 80 mg/kg, 64.2% and 96.9% inhibition, respectively) and MK-801 (0.15 and 0.30 mg/kg, 67.3% and 97.7%, respectively) given prior to naloxone. Coadministration of the lower doses of IBO (40 mg/kg) and MK-801 (0.15 mg/kg) results in 94.7% inhibition of jumping, comparable to the effects of higher doses of either IBO or MK-801. IBO and MK-801 also significantly inhibited NMDA-induced (99.0% and 71.0%, respectively) jumping when given 30 min (but not 24 h) prior to NMDA in nonaddictive mice. There were no significant differences in [3H]MK-801 binding to cortical membranes from naive animals, morphine-dependent animals, or morphine-dependent animals treated with IBO or MK-801. This study provides further evidence that IBO does have an inhibitory effect on opiate withdrawal symptoms and suggests that the complex process resulting in morphine withdrawal includes an IBO-sensitive functional and transitory alteration of NMDA receptor.

PMID: 12921910 [PubMed - indexed for MEDLINE]

11: Pharmacol Biochem Behav. 2003 Jun;75(3):607-18.
,


Anti-addictive actions of an iboga alkaloid congener: a novel mechanism for a novel treatment.

Maisonneuve IM, Glick SD.

Center for Neuropharmacology and Neuroscience, Albany Medical College, MC-136, 47 New Scotland Avenue, Albany, NY 12208, USA. maisoni@mail.amc.edu

18-Methoxycoronaridine (18-MC), a novel iboga alkaloid congener that decreases drug self-administration in several animal models, may be a potential treatment for multiple forms of drug abuse. In animal models, 18-MC reduced intravenous morphine, cocaine, methamphetamine and nicotine self-administration, oral alcohol and nicotine intake, and attenuated signs of opioid withdrawal, but had no effect on responding for a nondrug reinforcer (water) and produced no apparent toxicity [Brain Res. 719 (1996) 29; NeuroReport 11 (2000) 2013; Pharmacol. Biochem. Behav. 58 (1997) 615; Psychopharmacology (Berl.) 139 (1998) 274; NeuroReport 9 (1998) 1283; Ann. N. Y. Acad. Sci. 914 (2000) 369]. Consistent with a relationship among drug sensitization, mesolimbic dopamine, and drug-seeking behavior, 18-MC also blocked the sensitized dopamine responses to morphine and cocaine in the nucleus accumbens. An extensive series of receptor studies showed that 18-MC was most potent and somewhat selective as an antagonist at alpha3beta4 nicotinic receptors. Low-dose combinations of 18-MC with other drugs known to have this same action (e.g., mecamylamine, dextromethorphan, bupropion) decreased morphine, methamphetamine, and nicotine self-administration in rats at doses that were ineffective if administered alone. Together, the data support the hypothesis that diencephalic pathways having high densities of alpha3beta4 nicotinic receptors modulate mesocorticolimbic pathways more directly involved in drug reinforcement. Antagonists of alpha3beta4 nicotinic receptors may represent a totally novel approach to treating multiple addictive disorders, and 18-MC might be the first of a new class of synthetic agents acting via this novel mechanism and having a broad spectrum of activity.

PMID: 12895678 [PubMed - indexed for MEDLINE]

12: JAMA. 2002 Dec 25;288(24):3096, 3099-101.
,


Addiction treatment strives for legitimacy.

Vastag B.

Publication Types:
• News

PMID: 12495380 [PubMed - indexed for MEDLINE]

13: J Psychoactive Drugs. 2002 Jul-Sep;34(3):239-48.
,


Hallucinogens and redemption.

de Rios MD, Grob CS, Baker JR.

Associate Clinical Professor of Psychiatry and Human Behavior, University of Califomia, Irvine, USA.

This article examines drug substitution with regard to hallucinogens (ayahuasca, ibogaine, peyote and LSD) set within the concept of redemption. The model examines both religious and secular approaches to the contemporary use of hallucinogens in drug substitution, both by scientists and in religious settings worldwide. The redemptive model posits that the proper use of one psychoactive substance within a spiritual or clinical context helps to free an individual from the adverse effects of their addiction to another substance and thus restores them as functioning members of their community or group. Data is drawn from the U.S., Brazil, Peru, and West Africa. Two principle mechanisms for this are proposed: the psychological mechanism of suggestibility is examined in terms of the individual reaching abstinence goals from addictive substances such as alcohol and opiates. Neurophysiological and neurochemical mechanisms to understand the efficacy of such substitution are highlighted from ongoing research on hallucinogens. Research by two of the authors with the Unaio do Vegetal (UDV) Church in Brazil is examined in terms of the model.

PMID: 12422934 [PubMed - indexed for MEDLINE]

14: Curr Med Chem. 2002 Oct;9(20):1807-18.
,


A review of chemical agents in the pharmacotherapy of addiction.

Levi MS, Borne RF.

Department of Medicinal Chemistry, School of Pharmacy, The University of Mississippi, University, MS 38677, USA.

Chemical substance abuse has tormented mankind throughout history. A number of chemical approaches have been employed in an attempt to treat chemical addiction. Unfortunately, most of these have proven unsuccessful though several chemical entities have been shown to be moderately effective. The naturally occurring alkaloid ibogaine has been reported to interrupt the cravings for alcohol, cocaine and opiates. Other alkaloids from Tabernanthe iboga, such as ibogamine and tabernanthine, provide insight into the structure activity relationship at the different receptors believed to be involved in addiction. The synthetic iboga alkaloid congener, 18-MC, also shows potential as an anti-addictive agent without the hallucinogenic effects of ibogaine. Additionally, acamprosate, BP 897, GBR12909, lofexidine and memantine have shown promising results in the treatment of addiction. All of these leads provide a start for the medicinal chemist to design anti-addictive agents, since currently no drugs are approved in the U.S. for the treatment of addictions to cocaine, methamphetamine, other stimulants or PCP.

Publication Types:
• Review

PMID: 12369879 [PubMed - indexed for MEDLINE]

15: Ann N Y Acad Sci. 2002 Jun;965:28-46.
,


Ibogaine signals addiction genes and methamphetamine alteration of long-term potentiation.

Onaivi ES, Ali SF, Chirwa SS, Zwiller J, Thiriet N, Akinshola BE, Ishiguro H.

Department of Biology, William Paterson University, Wayne, New Jersey 07470, USA. OnaivaE@WPUNJ.edu

The mapping of the human genetic code will enable us to identify potential gene products involved in human addictions and diseases that have hereditary components. Thus, large-scale, parallel gene-expression studies, made possible by advances in microarray technologies, have shown insights into the connection between specific genes, or sets of genes, and human diseases. The compulsive use of addictive substances despite adverse consequences continues to affect society, and the science underlying these addictions in general is intensively studied. Pharmacological treatment of drug and alcohol addiction has largely been disappointing, and new therapeutic targets and hypotheses are needed. As the usefulness of the pharmacotherapy of addiction has been limited, an emerging potential, yet controversial, therapeutic agent is the natural alkaloid ibogaine. We have continued to investigate programs of gene expression and the putative signaling molecules used by psychostimulants such as amphetamine in in vivo and in vitro models. Our work and that of others reveal that complex but defined signal transduction pathways are associated with psychostimulant administration and that there is broad-spectrum regulation of these signals by ibogaine. We report that the actions of methamphetamine were similar to those of cocaine, including the propensity to alter long-term potentiation (LTP) in the hippocampus of the rat brain. This action suggests that there may be a "threshold" beyond which the excessive brain stimulation that probably occurs with compulsive psychostimulant use results in the occlusion of LTP. The influence of ibogaine on immediate early genes (IEGs) and other candidate genes possibly regulated by psychostimulants and other abused substances requires further evaluation in compulsive use, reward, relapse, tolerance, craving and withdrawal reactions. It is therefore tempting to suggest that ibogaine signals addiction gene products.

Publication Types:
• Review

PMID: 12105083 [PubMed - indexed for MEDLINE]

16: Nat Prod Lett. 2002 Feb;16(1):71-6.
,


Extraction studies of Tabernanthe iboga and Voacanga africana.

Jenks CW.

cwj@earthling.net

The root bark of Tabernanthe iboga contains ibogaine as its predominant alkaloid and has been an important source of it. Ibogaine is used experimentally to interrupt drug addiction and allow therapeutic intervention, but is currently unaffordable to doctors in less economically developed countries. To meet this need, an extraction of alkaloids from T. iboga root bark was optimized and simplified to use only diluted vinegar and ammonia, and was successfully applied to related alkaloids from Voacanga africana bark also. The alkaloids were converted to their hydrochlorides and purified, and the minor alkaloids were recovered.

PMID: 11942686 [PubMed - indexed for MEDLINE]

17: Alkaloids Chem Biol. 2001;56:63-77.
,


Drug discrimination studies with ibogaine.

Helsley S, Rabin RA, Winter JC.

Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USA.

The results of the studies described here support the hypothesis that ibogaine produces its effects via selective interactions with multiple receptors. It appears that 5-HT2A, 5-HT2C, and sigma 2 receptors are involved in mediating the stimulus effects of ibogaine. In addition, opiate receptors may also be involved. In contrast, sigma 1, PCP/MK-801, 5-HT3, and 5-HT1A receptors do not appear to play a major role. Ibogaine's hallucinogenic effects may be explained by its interactions with 5-HT2A and 5-HT2C receptors, while its putative antiaddictive properties may result from its interactions with sigma 2 and opiate receptors. Alternatively, the possibility that ibogaine's hallucinogenic properties underlie its antiaddictive effects, as previously suggested (34), would support a role for 5-HT2 receptors in mediating the reported therapeutic effects of ibogaine. Certainly many questions remain regarding ibogaine's mechanism of action. Although drug discrimination will be useful for answering some of those questions, the true potential of this technique is realized whin it is combined with other techniques. The next few years promise to be fruitful with respect to our understanding of this agent. Reasons supporting this belief include advances in the study of sigma receptors, interest in ibogaine's effects on second messenger systems, and the development of ibogaine congeners such as 18-methoxycoronaridine (35). In conclusion, the aforementioned studies should serve to guide further endeavors. Pertinent questions have been generated: What is the role of sigma receptors in the effects of ibogaine, especially with regard to addiction? How does ibogaine affect opiate neurotransmission? What effects, if any, do the Harmala alkaloids have on addiction phenomena? What is the mechanism of action of harmaline? Can 10-hydroxyibogamine serve as a discriminative stimulus and, if so, what receptor interactions mediate its stimulus effects? Does the ibogaine-trained stimulus generalize to novel agents, including 18-methoxycoronaridine?

Publication Types:
• Review

PMID: 11705117 [PubMed - indexed for MEDLINE]

18: Pharmacol Biochem Behav. 2001 Jul-Aug;69(3-4):485-91.
,


Iboga compounds reverse the behavioural disinhibiting and corticosterone effects of acute methamphetamine: Implications for their antiaddictive properties.

Szumlinski KK, Haskew RE, Balogun MY, Maisonneuve IM, Glick SD.

Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, NY 12208, USA. szumlink@musc.edu

This study investigated the effects of pretreatment with the putative antiaddictive compound, ibogaine (IBO), and its synthetic derivative, 18-methoxycoronaridine (18-MC), on the changes in behaviour in an elevated plus maze and the changes in corticosterone (CORT) produced by a low dose of methamphetamine (METH). In the elevated plus maze, the acute administration of METH (0.1 mg/kg ip, -20 min) produced an increase in both the number and the duration of open arm entries relative to saline (SAL)-treated controls. No effect of METH administration was observed on the total number of arm entries. These data indicated that METH alone produced either anxiolysis or behavioural disinhibition in this paradigm. More consistent with the latter possibility, the open arm behaviour of METH controls was associated with an increase in plasma levels of CORT, supporting a facilitatory role for CORT in this METH-induced effect. Pretreatment with both IBO and 18-MC (40 mg/kg ip, 19 h earlier) antagonized the behavioural disinhibiting effects of acute METH without altering locomotor activity. In addition, both iboga agents antagonized the increase in CORT produced by METH. These data provide insight into yet another potential mechanism through which iboga compounds may exert their antiaddictive effects, a reversal of the behavioural disinhibiting properties of stimulant drugs. Furthermore, these data indicate that this reversal is related to effects of iboga compounds on the stimulation of neuroendocrine systems by stimulant drugs.

PMID: 11509208 [PubMed - indexed for MEDLINE]

19: Neuroreport. 2001 Feb 12;12(2):263-7.
,


Ibogaine alters synaptosomal and glial glutamate release and uptake.

Leal MB, Emanuelli T, Porciuncula LD, Souza DO, Elisabetsky E.

Curso de Pos Graduacao em Ciencias Biologicas-Bioquimica, ICBS, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.

Ibogaine has aroused expectations as a potentially innovative medication for drug addiction. It has been proposed that antagonism of the NMDA receptor by ibogaine may be one of the mechanisms underlying its antiaddictive properties; glutamate has also been implicated in ibogaine-induced neurotoxicity. We here report the effects of ibogaine on [3H]glutamate release and uptake in cortical and cerebellar synaptosomes, as well as in cortical astrocyte cultures, from mice and rats. Ibogaine (2-1000 microM) had no effects on glutamate uptake or release by rat synaptosomes. However, ibogaine (500-1000 microM) significantly inhibited the glutamate uptake and stimulated the release of glutamate by cortical (but not cerebellar) synaptosomes of mice. In addition, ibogaine (1000 microM) nearly abolished glutamate uptake by cortical astrocyte cultures from rats and mice. The data provide direct evidence of glutamate involvement in ibogaine-induced neurotoxicity.

PMID: 11209932 [PubMed - indexed for MEDLINE]

20: Neurochem Res. 2000 Aug;25(Cool:1083-7.
,


Long-lasting ibogaine protection against NMDA-induced convulsions in mice.

Leal MB, de Souza DO, Elisabetsky E.

Departamento de Farmacologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.

Ibogaine, a putative antiaddictive drug, is remarkable in its apparent ability to downgrade withdrawal symptoms and drug craving for extended periods of time after a single dose. Ibogaine acts as a non-competitive NMDA receptor antagonist, while NMDA has been implicated in long lasting changes in neuronal function and in the physiological basis of drug addiction. The purpose of this study was to verify if persistent changes in NMDA receptors could be shown in vivo and in vitro after a single administration of ibogaine. The time course of ibogaine effects were examined on NMDA-induced seizures and [3H] MK-801 binding to cortical membranes in mice 30 min, 24, 48, and 72 h post treatment. Ibogaine (80 mg/kg, ip) was effective in inhibiting convulsions induced by NMDA at 24 and 72 hours post administration. Likewise, [3H] MK-801 binding was significantly decreased at 24 and 72 h post ibogaine. No significant differences from controls were found at 30 min or 48 h post ibogaine. This long lasting and complex pattern of modulation of NMDA receptors prompted by a single dose of ibogaine may be associated to its antiaddictive properties.

PMID: 11055745 [PubMed - indexed for MEDLINE]

21: Psychopharmacology (Berl). 2000 Aug;151(2-3):234-41.
,


Interactions between iboga agents and methamphetamine sensitization: studies of locomotion and stereotypy in rats.

Szumlinski KK, Balogun MY, Maisonneuve IM, Glick SD.

Center for Neuropharmacology and Neuroscience, Albany Medical College, NY 12208, USA. szumlik@mail.amc.edu

RATIONALE: The phenomenon of sensitization has been theoretically implicated in mediating various aspects of drug addiction. Recent dose-response studies demonstrated that pretreatment with the putative antiaddictive agent, ibogaine (IBO), and a synthetic iboga alkaloid congener, 18-methoxycoronaridine (18-MC), increase the potency of cocaine to elicit behavioral sensitization, an effect proposed to contribute, in part, to their ability to attenuate drug self-administration. OBJECTIVES: As abuse of the methylated amphetamine derivative, methamphetamine (METH), is a growing public health concern, the present study determined the interactions between IBO and 18-MC and the expression of METH-induced behavioral sensitization. METHODS: The effects of pretreatment with 18-MC (40 mg/kg, IP, 19 h earlier) on the expression of METH-induced locomotion (0, 0.25, 0.5, 1 and 2 mg/kg, IP) and the effects of pretreatment with either IBO or 18-MC on the expression of METH-induced stereotypy (2 and 4 mg/kg, IP) were assessed in rats treated chronically with either METH (4 mg/kg daily for 7 days) or saline. RESULTS: Compared to vehicle-pretreated controls, 18-MC produced an overall enhancement in METH-induced locomotion in rats treated chronically, but not acutely, with METH. In addition, both iboga agents increased the stereotypic response to METH. CONCLUSIONS: Iboga agents augment both the locomotor and stereotypic effects of METH in a manner consistent with previous reports for cocaine. Thus, it appears that iboga agents interact in a similar manner with the neural mechanisms mediating motor hyperactivity induced by the chronic administration of stimulant drugs.

PMID: 10972470 [PubMed - indexed for MEDLINE]

22: Toxicol Sci. 2000 Sep;57(1):95-101.
,


A dose-response study of ibogaine-induced neuropathology in the rat cerebellum.

Xu Z, Chang LW, Slikker W Jr, Ali SF, Rountree RL, Scallet AC.

Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.

Ibogaine (IBO) is an indole alkaloid from the West African shrub, Tabernanthe iboga. It is structurally related to harmaline, and both these compounds are rigid analogs of melatonin. IBO has both psychoactive and stimulant properties. In single-blind trials with humans, it ameliorated withdrawal symptoms and interrupted the addiction process. However, IBO also produced neurodegeneration of Purkinje cells and gliosis of Bergmann astrocytes in the cerebella of rats given even a single dose (100 mg/kg, ip). Here, we treated rats (n = 6 per group) with either a single ip injection of saline or with 25 mg/kg, 50 mg/kg, 75 mg/kg, or 100 mg/kg of IBO. As biomarkers of cerebellar neurotoxicity, we specifically labeled degenerating neurons and axons with silver, astrocytes with antisera to glial fibrillary acidic protein (GFAP), and Purkinje neurons with antisera to calbindin. All rats of the 100-mg/kg group showed the same pattern of cerebellar damage previously described: multiple bands of degenerating Purkinje neurons. All rats of the 75-mg/ kg group had neurodegeneration similar to the 100-mg/kg group, but the bands appeared to be narrower. Only 2 of 6 rats that received 50 mg/kg were affected; despite few degenerating neuronal perikarya, cerebella from these rats did contain patches of astrocytosis similar to those observed with 75 or 100 mg/kg IBO. These observations affirm the usefulness of GFAP immunohistochemistry as a sensitive biomarker of neurotoxicity. None of the sections from the 25-mg/kg rats, however stained, were distinguishable from saline controls, indicating that this dose level may be considered as a no-observable-adverse-effect level (NOAEL).

PMID: 10966515 [PubMed - indexed for MEDLINE]

23: Toxicon. 2001 Jan;39(1):75-86.
,


Iboga interactions with psychomotor stimulants: panacea in the paradox?

Szumlinski KK, Maisonneuve IM, Glick SD.

Center for Neuropharmacology and Neuroscience, MC-136, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208, USA. szumlik@mail.amc.edu

Currently, no effective therapy has been approved for the treatment of addiction to stimulant drugs (e.g., cocaine, amphetamine and its methylated derivatives). However, preclinical studies indicate that the naturally-occurring indole alkaloid, ibogaine, and a synthetic iboga alkaloid congener, 18-methoxycoronaridine (18-MC), attenuate stimulant self-administration in laboratory animals. The in vivo pharmacological interactions between iboga agents and stimulant drugs are unclear. Ibogaine enhances the increase in accumbal dopamine produced by the acute administration of stimulant drugs. Consistent with these data, both ibogaine and 18-MC potentiate the expression of stimulant-induced motor behaviors in acute and chronic stimulant-treated animals. To account for the paradox between their effects on self-administration and motor behavior, we proposed that iboga agents interfere with stimulant self-administration by increasing sensitivity to their psychomotor-activating effects. However, this interpretation is contradicted by very recent observations that 18-MC is without effect on the dopamine response to acute cocaine and that both ibogaine and 18-MC block the expression of sensitized levels of dopamine in the nucleus accumbens produced by chronic cocaine administration. Thus, a positive relationship exists between the effects of iboga pretreatment on stimulant-induced dopamine sensitization and stimulant self-administration behavior. These data indicate that iboga agents might attenuate stimulant self-administration by reversing the neuroadaptations theoretically implicated in drug craving and compulsive drug-seeking behavior.

Publication Types:
• Review

PMID: 10936624 [PubMed - indexed for MEDLINE]

24: Ann N Y Acad Sci. 2000;909:275-9.
,


18-Methoxycoronaridine differentially alters the sensitized behavioral and dopaminergic responses to repeated cocaine and morphine administration. Implications for sensitization in the mediation of drug addiction.

Szumlinski KK, Maisonneuve IM, Glick SD.

Department of Pharmacology and Neuroscience, Albany Medical College, New York 12208, USA. szumlik@mail.amc.edu

PMID: 10911941 [PubMed - indexed for MEDLINE]

25: Ann N Y Acad Sci. 2000;909:88-103.
,


Development of novel medications for drug addiction. The legacy of an African shrub.

Glick SD, Maisonneuve IM.

Department of Pharmacology and Neuroscience, Albany Medical College, New York 12208, USA. glicks@mail.amc.edu

Ibogaine, one of several alkaloids found in the root bark of the African shrub Tabernanthe iboga, has been claimed to be effective in treating multiple forms of drug abuse. Problems associated with side effects of ibogaine have spawned a search for more effective and safer structural derivatives. 18-Methoxycoronaridine (18-MC), a novel iboga alkaloid congener, appears to have substantial potential for broad use as an anti-addictive therapy. Like ibogaine (40 mg/kg), 18-MC (40 mg/kg) decreases the intravenous self-administration of morphine and cocaine and the oral self-administration of ethanol and nicotine in rats; unlike ibogaine, 18-MC does not affect responding for a non-drug reinforcer (water). Ibogaine and 18-MC appear to reduce the reinforcing efficacies, rather than the potencies, of drugs of abuse. Both ibogaine and 18-MC decreases extracellular levels of dopamine in the nucleus accumbens while only ibogaine increases serotonin levels in this brain region. Both ibogaine and 18-MC block morphine-induced and nicotine-induced dopamine release in the accumbens; only ibogaine enhances cocaine-induced increases in dopamine levels. Ibogaine produces whole body tremors and, at high doses (at least 100 mg/kg), cerebellar damage; 18-MC does not produce these effects. Ibogaine, but not 18-MC, causes bradycardia at high doses. Ibogaine and its metabolite noribogaine have low microM affinities for kappa and mu opioid receptors, NMDA receptors, 5HT-3 receptors, sigma-2 sites, sodium channels and the serotonin transporter. 18-MC has low microM affinities at all three opioid receptors and at 5HT-3 receptors but much lower or no affinities for NMDA and sigma-2 receptors, sodium channels, and the 5HT transporter. Both 18-MC and ibogaine are sequestered in fat and, like ibogaine, 18-MC probably has an active metabolite. 18-MC also has (+) and (-) enantiomers, both of which are active. Considered together, all of the data indicate that 18-MC should be safer than ibogaine and at least as efficacious as an anti-addictive medication.

PMID: 10911925 [PubMed - indexed for MEDLINE]

26: Brain Res. 2000 Jul 21;871(2):245-58.
,


Interactions between 18-methoxycoronaridine (18-MC) and cocaine: dissociation of behavioural and neurochemical sensitization.

Szumlinski KK, McCafferty CA, Maisonneuve IM, Glick SD.

Center for Neuropharmacology and Neuroscience (MC-136), Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208, USA. szumlik@mail.amc.edu

The phenomenon of sensitization has been implicated in various aspects of drug addiction. As such, the present study determined the effects of a potential anti-addictive agent, 18-methoxycoronaridine (18-MC; 40 mg/kg, IP, 19 h earlier), on the expression of sensitization following the repeated administration of cocaine (COC; five once daily injections of 15 mg/kg, IP) or saline. The effects of 18-MC on COC metabolism were also assessed. Compared to vehicle controls, 18-MC significantly enhanced the expression of COC-induced locomotion (0, 10, 20 and 40 mg/kg, IP) in chronic COC treated rats only. In both acute and chronic COC rats, 18-MC potentiated the stereotypy induced by higher COC doses (20 and 40 mg/kg, IP). In contrast, 18-MC abolished the sensitized dopamine (DA) response in the nucleus accumbens (NAC) to COC (20 mg/kg), without altering the DA response of acute COC rats. None of the interactions between 18-MC and COC appear to be related to alterations in COC metabolism as no effect of 18-MC pretreatment was observed on extracellular levels of COC or two of its metabolites, benzoylecogonine and norcocaine. From the present findings, it is concluded that the enhancement of COC-induced behaviour produced by 18-MC pretreatment is independent of effects on either COC pharmacokinetics or COC-induced alterations in DA transmission. However, given that 18-MC decreases the self-administration of COC in laboratory animals, it is proposed that the anti-addictive efficacy of 18-MC might be related to an ability to selectively block the expression of sensitized extracellular levels of DA in the NAC in rats with previous COC experience.

PMID: 10899291 [PubMed - indexed for MEDLINE]

27: Eur J Pharmacol. 2000 Feb 25;390(1-2):119-26.
,


Responses of the extrapyramidal and limbic substance P systems to ibogaine and cocaine treatments.

Alburges ME, Ramos BP, Bush L, Hanson GR.

Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, 30 S 2000 E RM 201, Salt Lake City, UT 84112, USA. m.e.alburges@m.cc.utah.edu

Ibogaine is an indolamine found in the West Africa shrub, Tabernanthe iboga, and has been proposed for the treatment of addiction to central nervous system (CNS) stimulants such as cocaine and amphetamine. The mechanism of ibogaine action and its suitability as a treatment for drug addiction still remains unclear. Since previous studies demonstrated differential effects of stimulants of abuse (amphetamines) on neuropeptide systems such as substance P, we examined the impact of ibogaine and cocaine on extrapyramidal (striatum and substantia nigra) and limbic (nucleus accumbens and frontal cortex) substance P-like immunoreactivity. Ibogaine and cocaine treatments altered substance P systems by increasing striatal and nigral substance P-like immunoreactivity concentration 12 h after the last drug treatment. However, substance P-like immunoreactivity content was not significantly increased in nucleus accumbens after treatment with either drug. The ibogaine- and cocaine-induced increases in substance P-like immunoreactivity in striatum and substantia nigra were blocked by coadministration of selective dopamine D(1) receptor antagonist (SCH 23390; R(+)-7-Chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4, 5-tetrahydro-1H-3-benzazepine hydrochloride) or dopamine D(2) receptor antagonist (eticlopride; S(-)-3-Chloro-5-ethyl-N-[(1-ethyl-2-pyrrolidinyl)methyl]-6-hydroxy-2- methoxy-benzamide hydrochloride). Most of the responses by substance P systems to ibogaine administration resembled those caused by cocaine, except in cortical tissue where multiple administration of cocaine, but not ibogaine increased substance P-like immunoreactivity. These data suggest that substance P systems may contribute to the effects of ibogaine and cocaine treatment.

PMID: 10708715 [PubMed - indexed for MEDLINE]

28: Lancet. 1999 Nov 27;354(9193):1883.
,


Data accrue on "visionary" agent to interrupt addiction.

Morris K.

Publication Types:
• News

PMID: 10584734 [PubMed - indexed for MEDLINE]

29: Brain Res. 1999 Nov 13;847(1):139-42.
,


Ibogaine pretreatment dramatically enhances the dynorphin response to cocaine.

Alburges ME, Hanson GR.

Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, 30 So. 2000 E. Room 201, Salt Lake City, UT, USA. m.e.albruges@m.cc.utah.edu

Ibogaine (Endabuse) is a psychoactive indole alkaloid found in the shrub, Tabernanthe iboga, which has been used to treat stimulant addiction. Because ibogaine influences the activity of neurotensin systems, a dopamine-linked neuropeptide, the present study investigated if ibogaine also influences dynorphin (DYN) pathways. Unlike neurotensin responses, ibogaine alone did not alter DYN levels in the striatum, substantia nigra or nucleus accumbens. Interestingly, ibogaine pretreatment dramatically enhanced cocaine-induced increases in DYN content in these structures.

PMID: 10564747 [PubMed - indexed for MEDLINE]

30: Eur J Pharmacol. 1999 Oct 21;383(1):15-21.
,


Attenuation of the reinforcing efficacy of morphine by 18-methoxycoronaridine.

Maisonneuve IM, Glick SD.

Department of Pharmacology and Neuroscience, MC-136, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208, USA. maison@ccgateway.amc.edu

In previous studies, 18-methoxycoronaridine, a novel iboga alkaloid congener, has been reported to decrease the self-administration of morphine, cocaine, ethanol and nicotine, and to attenuate naltrexone-precipitated signs of morphine withdrawal. In the present study, the nature of the interaction between 18-methoxycoronaridine and morphine was further investigated. Using in vivo microdialysis, 18-methoxycoronaridine pretreatment (40 mg/kg i.p., 19 h beforehand) was found to markedly inhibit morphine-induced (5 mg/kg, i.p.) dopamine release in the nucleus accumbens and striatum; 18-methoxycoronaridine also enhanced morphine-induced increases in extracellular levels of dopamine's metabolites. These effects, which were more prominent in the nucleus accumbens than in the striatum, suggest that 18-methoxycoronaridine selectively interferes with morphine-induced dopamine release, without altering morphine-induced stimulation of dopamine synthesis. In intravenous morphine self-administration experiments, the effects of acute 18-methoxycoronaridine treatment (40 mg/kg, p.o.) were assessed in rats responding for one of several different unit infusion dosages of morphine (0.01-0.16 mg/kg/infusion). 18-Methoxycoronaridine produced a downward shift in the entire morphine dose-response curve without any displacement to the left or right. These results suggest that 18-methoxycoronaridine reduced the reinforcing efficacy of morphine without altering its apparent potency. Together, the microdialysis and self-administration data suggest that 18-methoxycoronaridine profoundly alters mechanisms crucial to the development and maintenance of opioid addiction.

PMID: 10556676 [PubMed - indexed for MEDLINE]

31: Brain Res Bull. 1999 Apr;48(6):641-7.
,


The effects of ibogaine on dopamine and serotonin transport in rat brain synaptosomes.

Wells GB, Lopez MC, Tanaka JC.

Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia 19104-6002, USA.

Ibogaine has been shown to affect biogenic amine levels in selected brain regions. Because of the involvement of these neurotransmitters in drug addiction, the effects of ibogaine on biogenic amine transport may contribute to the potential anti-addictive properties of ibogaine in vivo. With rat brain synaptosomes as our experimental system, we measured the effects of ibogaine on the uptake and release of dopamine (DA) and serotonin (5-HT). Ibogaine competitively blocked both DA and 5-HT uptake with IC50 values of 20 microM at 75 nM 3H-DA and 2.6 microM at 10 nM 3H-5-HT. Ibogaine had no effect on K+-induced release of 3H-DA from preloaded synaptosomes, but 20 microM and 50 microM ibogaine inhibited roughly 40% and 60%, respectively, of the K(+)-induced release of 3H-5-HT from preloaded synaptosomes. In the absence of a depolarizing stimulus, ibogaine evoked a small release of 3H-DA but not 3H-5-HT. These relatively low-potency effects of ibogaine on DA and 5-HT uptake in synaptosomes are consistent with the low binding affinity of ibogaine that has been previously reported for DA and 5-HT transporters. Our results show that if ibogaine modulates DA and 5-HT levels in the brain by directly blocking their uptake, then a concentration of ibogaine in the micromolar range is required. Furthermore, if the anti-addictive effects of ibogaine require this concentration, then ibogaine likely exerts these effects through a combination of neurotransmitter pathways, because binding affinities and functional potencies of ibogaine in the micromolar range have been reported for a variety of neuronal receptors and transporters.

PMID: 10386845 [PubMed - indexed for MEDLINE]

32: Brain Res. 1999 Feb 6;818(1):96-104.
,


Differential responses by neurotensin systems in extrapyramidal and limbic structures to ibogaine and cocaine.

Alburges ME, Hanson GR.

Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, 112 Skaggs Hall, Salt Lake City, UT 84112, USA. m.e.alburges@m.cc.utah.edu

Ibogaine (Endabuse) is a psychoactive indole alkaloid found in the West African shrub, Tabernanthe iboga. This drug interrupts cocaine and amphetamine abuse and has been proposed for treatment of addiction to these stimulants. However, the mechanism of action that explains its pharmacological properties is unclear. Since previous studies demonstrated differential effects of psychotomimetic drugs (cocaine and methamphetamine) on neuropeptides such as neurotensin (NT), the present study was designed to determine: (1) the effects of ibogaine on striatal, nigral, cortical, and accumbens neurotensin-like immunoreactivity (NTLI); (2) the effects of selective dopamine antagonists on ibogaine-induced changes in NT concentrations in these brain areas; and (3) the effects of ibogaine pretreatment on cocaine-induced changes in striatal, nigral, cortical and accumbens NTLI content. Ibogaine treatments profoundly affected NT systems by increasing striatal, nigral, and accumbens NTLI content 12 h after the last drug administration. In contrast, NTLI concentrations were not significantly increased in the frontal cortex after ibogaine treatment. The ibogaine-induced increases in NTLI in striatum, nucleus accumbens and substantia nigra were blocked by coadministration of the selective D1 receptor antagonist, SCH 23390. The D2 receptor antagonist, eticlopride, blocked the ibogaine-induced increase in nigral NTLI, but not in striatum and nucleus accumbens. Ibogaine pretreatment significantly blocked the striatal and nigral increases of NTLI resulting from a single cocaine administration. Whereas many of the responses by NT systems to ibogaine resembled those which occur after cocaine, there were also some important differences. These data suggest that NT may contribute to an interaction between ibogaine and the DA system and may participate in the pharmacological actions of this drug. Copyright 1999 Elsevier Science B.V.

PMID: 9914442 [PubMed - indexed for MEDLINE]

33: Lancet. 1998 Oct 17;352(9136):1290.
,


Seeking ways to crack cocaine addiction.

Morris K.

Publication Types:
• News

PMID: 9788471 [PubMed - indexed for MEDLINE]

34: Brain Res. 1998 Aug 10;801(1-2):67-71.
,


Gender differences in kappa-opioid modulation of cocaine-induced behavior and NMDA-evoked dopamine release.

Sershen H, Hashim A, Lajtha A.

Nathan S. Kline Institute for Psychiatric Research, 140 Old Orangeburg Rd., Orangeburg, NY 10962, USA. sershen@nki.rfmh.org

It has been reported that kappa-opioids produce greater analgesia in women than in men. Sex differences are also apparent in drug-induced behaviors. Repeated administration of cocaine (25 mg/kg) produced a greater locomotor and sensitization response in C57BL/6By female mice. It was examined whether the increased sensitization in females to repeated cocaine administration was related to differences in kappa-opioid responses. The effects of the kappa agonist U62066 (spiradoline mesylate) on cocaine-induced locomotor stimulation in vivo and NMDA-mediated dopamine release in vitro were measured. In male, but not female mice, U62066 (1 mg/kg) given 30 min before cocaine potentiated the locomotor stimulation of an acute cocaine administration. U-62066 did not affect the development of locomotor sensitization with repeated cocaine administration (25 mg/kg s.c., once daily for 3 days), and a further enhanced response was not seen on days 2 and 3. It was then examined whether dopamine release, measured in vitro, plays a role in sex dependent differences in kappa-opioid- or NMDA-modulated dopaminergic function. In tissue perfusion studies, the in vitro NMDA (25 microM)-evoked release of labelled dopamine from striatum was lower in females (fractional release = 5.4 +/- 0.4 and 4.0 +/- 0.4 in male and female mouse striatum). U62066 (1 microM) and ibogaine (1 microM), an indole alkaloid claimed to be useful in the treatment of drug addiction that acts in part at the kappa-opioid receptor, both reduced the NMDA (25 microM)-evoked release of dopamine. Inhibition of the release was significantly greater in tissue from male mice. Prior in vivo cocaine administration did not alter the NMDA-evoked dopamine release. Our studies indicate that kappa-opioid and NMDA receptor activity show differences between female and male mice that may account for differences in cocaine-induced behaviors, but do not exclude the role of other hetereoceptors modulating dopamine release. Copyright 1998 Elsevier Science B.V.

PMID: 9729284 [PubMed - indexed for MEDLINE]

35: Drug Metab Dispos. 1998 Aug;26(Cool:764-8.
,


Cytochrome P4502D6 catalyzes the O-demethylation of the psychoactive alkaloid ibogaine to 12-hydroxyibogamine.

Obach RS, Pablo J, Mash DC.

Department of Drug Metabolism, Central Research Division, Pfizer, Inc., Groton, CT 06340, USA.

Ibogaine is a psychoactive alkaloid that possesses potential as an agent to treat opiate and cocaine addiction. The primary metabolite arises via O-demethylation at the 12-position to yield 12-hydroxyibogamine. In this report, evidence is presented that the O-demethylation of ibogaine observed in human hepatic microsomes is catalyzed primarily by the polymorphically expressed cytochrome P-4502D6 (CYP2D6). An enzyme kinetic examination of ibogaine O-demethylase activity in pooled human liver microsomes suggested that two (or more) enzymes are involved in this reaction: one with a low KMapp (1.1 microM) and the other with a high KMapp (>200 microM). The low KMapp activity comprised >95% of total intrinsic clearance. Human liver microsomes from three individual donors demonstrated similar enzyme kinetic parameters (mean KMapp = 0.55 +/- 0.09 microM and 310 +/- 10 microM for low and high KM activities, respectively). However, a fourth human microsome sample that appeared to be a phenotypic CYP2D6 poor metabolizer possessed only the high KMapp activity. In hepatic microsomes from a panel of human donors, the low KMapp ibogaine O-demethylase activity correlated with CYP2D6-catalyzed bufuralol 1'-hydroxylase activity but not with other P450 isoform-specific activities. Quinidine, a CYP2D6-specific inhibitor, inhibited ibogaine O-demethylase (IC50 = 0.2 microM), whereas other P450 isoform-specific inhibitors did not inhibit this activity. Also, of a battery of recombinant heterologously expressed human P450 isoforms, only rCYP2D6 possessed significant ibogaine O-demethylase activity. Thus, it is concluded that ibogaine O-demethylase is catalyzed by CYP2D6 and that this isoform is the predominant enzyme of ibogaine O-demethylation in humans. The potential pharmacological implications of these findings are discussed.

PMID: 9698290 [PubMed - indexed for MEDLINE]

36: Ann N Y Acad Sci. 1998 May 30;844:245-51.
,


Effect of ibogaine on the various sites of the NMDA receptor complex and sigma binding sites in rat brain.

Itzhak Y, Ali SF.

Department of Biochemistry and Molecular Biology (R-629), University of Miami School of Medicine, Florida 33101, USA. yitzhak@mednet.med.maimi.ed

Although the alkaloid ibogaine is a potent hallucinogenic agent some indications suggest that it may be useful for the treatment of opioid and cocaine addiction. The neurochemical mechanism(s) underlying ibogaine effects remain unclear. In the present study we investigated the interaction of ibogaine with the phencyclidine (PCP) site located in the ionophore of the N-methyl-D-aspartate (NMDA) receptor complex, with the NMDA receptor binding site, and with sigma binding sites. In well-washed membrane preparations of rat cortex and cerebellum, the PCP sites were labeled with [3H]MK-801 or [3H]1-[1(2-theinyl)-cyclohexyl]-piperidine ([3H]TCP), and the NMDA receptor with [3H]-CGP 39653. The sigma-1 and sigma-2 binding site in rat cortex and cerebellum were labeled with [3H]pentazocine and [3H]1,3-di-o-tolyl-guanidine ([3H]DTG), respectively. Results indicated that ibogaine interacts with high- and low-affinity PCP binding sites in the cortex: Ki(H) = 0.01-0.05 microM; Ki(L) = 2-4 microM, and only with low-affinity sites in the cerebellum: Ki = 2-4, microM. In contrast, ibogaine (> 100 microM) had no affinity for [3H]-CGP 39653 binding sites (cortex and cerebellum). The affinity of ibogaine for sigma-1 and -2 binding sites in cortex and cerebellum ranged from 1.5-3 microM. Since NMDA receptor antagonists (e.g., MK-801) are thought to attenuate opioid withdrawal symptoms and cocaine sensitization, it is possible that binding of ibogaine to the PCP sites contributes to its potential 'endabuse' properties. In turn, ibogaine interaction with sigma binding sites may be associated with its adverse effects.

PMID: 9668682 [PubMed - indexed for MEDLINE]

37: Brain Res. 1998 Jun 22;797(1):173-80.
,


Ibogaine acts at the nicotinic acetylcholine receptor to inhibit catecholamine release.

Mah SJ, Tang Y, Liauw PE, Nagel JE, Schneider AS.

Department of Pharmacology and Neuroscience, Albany Medical College, Albany, NY 12208, USA.

In an effort to determine mechanisms of action of the putative anti-addictive agent ibogaine, we have measured its effects on catecholamine release in a model neuronal system, cultured bovine chromaffin cells. Various modes of stimulating catecholamine release were used including nicotinic ACh receptor activation, membrane depolarization with elevated K+ and Na+ channel activation with veratridine. In addition, because ibogaine has been reported to interact with kappa opioid receptors, we tested whether kappa receptor antagonists could reverse ibogaine's effects on catecholamine release. Ibogaine, at low concentration (<10 microM) was found to selectively inhibit nicotinic receptor-mediated catecholamine release, while having no significant effect on release evoked by either veratridine or membrane depolarization with elevated K+. The inhibitory actions of ibogaine and the kappa agonists were not reversed by preincubation with the opioid antagonists nor-binaltorphimine or naltrexone, suggesting that these inhibitory effects are not mediated by the kappa opioid receptor. The effects of low dose (10 microM) ibogaine were rapidly reversible, while the inhibitory effects of higher ibogaine doses persisted for at least 19 h following ibogaine washout. The results provide evidence for a mechanism of action ibogaine at the nicotinic ACh receptor. The results are consistent with a model in which the initial high transient brain concentrations (100 microM) of ibogaine act at multiple cellular sites and then have a selective action at the nicotinic ACh receptor cation channel following its metabolism to lower brain concentrations. The present findings are relevant to potential anti-addictive actions of ibogaine and to the development of drugs to combat nicotine addiction. Copyright 1998 Elsevier Science B.V. All rights reserved.

PMID: 9630615 [PubMed - indexed for MEDLINE]

38: Nat Med. 1998 Apr;4(4):377.
,


Fight to develop drug addiction therapy.

Birmingham K.

Publication Types:
• News

PMID: 9546770 [PubMed - indexed for MEDLINE]

39: Pharmacol Biochem Behav. 1998 Feb;59(2):495-503.
,


The effects of sigma, PCP, and opiate receptor ligands in rats trained with ibogaine as a discriminative stimulus.

Helsley S, Filipink RA, Bowen WD, Rabin RA, Winter JC.

Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, 14214-3000, USA.

Although the mechanism of action of ibogaine, a hallucinogen that may be useful in the treatment of addiction, remains unknown, receptor binding studies suggest that ibogaine produces its effects via interactions with multiple receptor types. In addition to serotonergic receptors, which have been studied previously with respect to ibogaine, likely candidates include opiate, sigma (sigma), and phencyclidine (PCP) binding sites. In an attempt to determine which of these receptor interactions are involved in the in vivo effects of ibogaine, ligands for sigma, PCP, and opiate receptors were assessed for their ability to substitute for or to antagonize the ibogaine-induced discriminative stimulus (10 mg/kg I.P., 60 min presession) in Fischer-344 rats. Intermediate levels of generalization were observed with the subtype nonselective sigma ligands 3-(3-hydroxyphenyl)-N-(1-propyl)-piperidine [(+)-3-PPP] (69.0%) and 1,3-di(2-tolyl)guanidine (DTG) (73.5%) but not with the sigma1-selective agents (+)-N-allylnormetazocine [(+)-SKF 10,047] and (+)-pentazocine. These findings, along with observations that ibogaine has appreciable affinity for sigma2 receptors, suggest that these receptors may be involved in the ibogaine discriminative stimulus. With regard to opiate receptors, neither morphine, the prototypic mu agonist, nor kappa selective agonists (bremazocine,and U-50488) substituted for ibogaine. However, intermediate levels of generalization were obse

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Fru-Lindgren
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PostPosted: Mon 03 Jul, 2006 19:50    Post subject: Reply with quote

Michael ovan ser du två mejlförslag!

Jag tänker inte stillasittnade acceptera den pågående osakliga och icke vetenskapligt stödda progagandan mot ibogain. Tycker det är dags att ta LMV och den andra organisationen inför det logiska skranket.

Jag vill att du mot bkgrund av alla fakta i dessa trådarna skapar två mejl, ett var till dessa organisationer, i enlighet med mina förslag.

posta dem nedan så skickar vi dem när jag gått igenom dem ok?! Ändrar de sig inte eller gör avbön så postar vi dem som öppna brev på på flashback, etc.

skulle svida ganska illa i skinnet på dem om vi kan beslå dem med irreguljär logik, vilket jag anser att vi kan!!
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ibogain
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PostPosted: Mon 03 Jul, 2006 21:01    Post subject: Reply with quote

JAg ska skriva två bra förslag, ett till LVM och ett till ENS under morgondagen. Ska du skica dom sen? / Micke
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E.Ramoz
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PostPosted: Tue 04 Jul, 2006 07:25    Post subject: Reply with quote

ibogain wrote:
JAg ska skriva två bra förslag, ett till LVM och ett till ENS under morgondagen. Ska du skica dom sen? / Micke


DEN som har tid över av oss kommer att skicka dem efter genomgång. skriv mejlen IDAG!
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ibogain
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PostPosted: Tue 04 Jul, 2006 10:00    Post subject: Reply with quote

Till LVM

Hej!

Jag heter Michael Korn och är en före detta heroinist.
Jag har ett långt missbruk bakom mig.

Efter många års jakt på drogfrihet kom jag förra året i kontakt med Ibogain. Eftersom behandlingen inte görs i Sverige då Ibogain är förbjudet här åkte jag till Prag.

Efter endast två bahandlingar är jag helt och totalt drogfri, utan sug eller abstinens. Mitt liv vände helt över en natt!

Jag har börjat intressera mig för att hjälpa andra till drogfrihet genom att dels starta en stiftelse, Stiftelsen Iboga, samt genom att driva en hemsida och ett forum om Ibogain. www.ibogain.se

Jag har läst hundratals fallbeskrivningar från hela världen och har personlig kontakt med många som nu är drogfria med Ibogain och med flera som arbetar med att behandla behövande.

Ibogain tycks vara ett av de allra effektivaste sätten för att bryta missbruk och jag undrar nu varför det är olagligt och narkotikaklassat i Sverige och jag undrar hur man ska göra för att kunna få det godkänt som kontrollerat behandlingspreparat?

Mvh/Micke Korn

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PostPosted: Tue 04 Jul, 2006 10:09    Post subject: Reply with quote

Till ENS

Hej Ens!

Jag läste följande länk med fråga och svar:

http://www.ens2000.nu/fragelada/fraga.php?id=58

Detta får mig att fundera en hel del..

Ni skriver att "medlets effekt inte har någon vetenskaplig förankring" och jag vill därför skicka er vissa fakta som är lätta att hitta på nätet och som motsäger Ert påstående.

(Här klipper du in alla fakta som är relevant.. eller det kanske ska ligga sist i mailet?)

Jag vore tacksam om ni snarast kunde läsa det jag skickar er och återkomma till mig med de funderingar och tankar som det väcker hos er.

Varför är inte Ibogainet kändare när det uppenbarligen är ett av världens effektivaste avgiftningsmedel?

Varför svarar och agerar ni på ett sätt som gör det svårt och skrämmande för de som söker drogfrihet att kunna nå dit?

Jag har själv funnit drogfrihet efter över 20 års heroinmissbruk genom en behandling med just Ibogain och jag arbetar nu helt ideellt för att sprida kunskap om medlet och för att hjälpa fler till behandling.

Mvh/Micke KOrn
Michael@ibogain.se

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PostPosted: Wed 05 Jul, 2006 19:44    Post subject: Ibogainets antiaddiktiva egenskaper! Reply with quote

info@ens2000.se .
===========================================


Hej Ens!

Jag läste följande länk med fråga och svar:

http://www.ens2000.nu/fragelada/fraga.php?id=58

Detta får mig att fundera en hel del!

Ni skriver att "medlets effekt inte har någon vetenskaplig förankring" och jag vill därför skicka er vetenskapliga fakta som är lätta att hitta på nätet eller i vetenskapliga databankar och som skarpt motsäger Ert påstående. Se bifogade vetenskapliga förtecknig I

Jag vore tacksam om ni snarast kunde läsa det jag skickar er och återkomma till mig med de funderingar och tankar som det väcker hos er. Varför svarar och agerar ni på ett sätt som gör det svårt och skrämmande för de som söker drogfrihet att kunna nå dit genom vägar som beviserligen har fungerat för andra?

Vill ni inte verka för att sprida sanning och fakta?

Jag har själv funnit drogfrihet efter över 20 års heroinmissbruk genom en behandling med just Ibogain och jag arbetar nu helt ideellt för att sprida kunskap om medlet och för att hjälpa fler till behandling och drogfritt liv!


Med vänliga hälsningar

Micke Korn

Bilagt: Vetenskaplig förteckning, Ibogain dess antiaddiktiva egenskaper.

============================================================================================


2: Rev Neurosci. 2005;16(4):277-85.


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GDNF and addiction.

Ron D, Janak PH.

Ernest Gallo Research Center, Department of Neurology, University of California, San Francisco, Emeryville, USA. dorit@itsa.ucsf.edu

Biochemical adaptations to drugs of abuse and alcohol are especially profound in midbrain dopaminergic neurons. Long-lasting molecular and structural changes in mesolimbic dopaminergic neurons that result from chronic exposure to drugs of abuse and alcohol are thought to underlie adverse behaviors such as compulsive drug seeking and relapse. Recent studies suggest that a subset of these changes is prevented/reversed by activation of the glial cell line-derived neurotrophic factor (GDNF) signaling pathway. Behavioral effects of drugs of abuse such as cocaine and alcohol are also negatively regulated by GDNF: inhibition of the endogenous GDNF pathway enhances the activity of drugs of abuse, while administration of GDNF reduces the severity of the effects. In this review, we summarize the data implicating GDNF as a negative regulator of drug and alcohol addiction. We also provide evidence to suggest that therapies that activate GDNF signaling may be useful for the treatment of drug and alcohol addiction.

Publication Types:

· Review


PMID: 16519005 [PubMed - indexed for MEDLINE]

3: Br J Psychiatry. 2006 Feb;188:109-21.


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Complementary medicines in psychiatry: review of effectiveness and safety.

Werneke U, Turner T, Priebe S.

Division of Psychiatry, Homerton University Hospital, East Wing, Homerton Row, London E9 6SR, UK. Ursula.Werneke@elcmht.nhs.uk

BACKGROUND: The use of complementary medicines in those with mental health problems is well documented. However, their effectiveness is often not established and they may be less harmless than commonly assumed. AIMS: To review the complementary medicines routinely encountered in psychiatric practice, their effectiveness, potential adverse effects and interactions. METHOD: Electronic and manual literature search on the effectiveness and safety of psychotropic complementary medicines. RESULTS: Potentially useful substances include ginkgo and hydergine as cognitive enhancers, passion flower and valerian as sedatives, St John's wort and s-adenosylmethionine as antidepressants, and selenium and folate to complement antidepressants. The evidence is less conclusive for the use of omega-3 fatty acids as augmentation treatment in schizophrenia, melatonin for tardive dyskinesia and 18-methoxycoronaridine, an ibogaine derivative, for the treatment of cocaine and heroin addiction. CONCLUSIONS: Systematic clinical trials are needed to test promising substances. Meanwhile, those wishing to take psychotropic complementary medicines require appropriate advice.

Publication Types:

· Review


PMID: 16449696 [PubMed - indexed for MEDLINE]

4: Science. 2005 Apr 15;308(5720):345-6.


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Erratum in:

· Science. 2005 May 27;308(5726):1260.


Addiction research. Ibogaine therapy: a 'vast, uncontrolled experiment'.

Vastag B.

Publication Types:

· News


PMID: 15831735 [PubMed - indexed for MEDLINE]

5: J Neurosci. 2005 Jan 19;25(3):619-28.


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Glial cell line-derived neurotrophic factor mediates the desirable actions of the anti-addiction drug ibogaine against alcohol consumption.

He DY, McGough NN, Ravindranathan A, Jeanblanc J, Logrip ML, Phamluong K, Janak PH, Ron D.

Ernest Gallo Research Center, University of California, San Francisco, Emeryville, California 94608, USA.

Alcohol addiction manifests as uncontrolled drinking despite negative consequences. Few medications are available to treat the disorder. Anecdotal reports suggest that ibogaine, a natural alkaloid, reverses behaviors associated with addiction including alcoholism; however, because of side effects, ibogaine is not used clinically. In this study, we first characterized the actions of ibogaine on ethanol self-administration in rodents. Ibogaine decreased ethanol intake by rats in two-bottle choice and operant self-administration paradigms. Ibogaine also reduced operant self-administration of ethanol in a relapse model. Next, we identified a molecular mechanism that mediates the desirable activities of ibogaine on ethanol intake. Microinjection of ibogaine into the ventral tegmental area (VTA), but not the substantia nigra, reduced self-administration of ethanol, and systemic administration of ibogaine increased the expression of glial cell line-derived neurotrophic factor (GDNF) in a midbrain region that includes the VTA. In dopaminergic neuron-like SHSY5Y cells, ibogaine treatment upregulated the GDNF pathway as indicated by increases in phosphorylation of the GDNF receptor, Ret, and the downstream kinase, ERK1 (extracellular signal-regulated kinase 1). Finally, the ibogaine-mediated decrease in ethanol self-administration was mimicked by intra-VTA microinjection of GDNF and was reduced by intra-VTA delivery of anti-GDNF neutralizing antibodies. Together, these results suggest that GDNF in the VTA mediates the action of ibogaine on ethanol consumption. These findings highlight the importance of GDNF as a new target for drug development for alcoholism that may mimic the effect of ibogaine against alcohol consumption but avoid the negative side effects.

PMID: 15659598 [PubMed - indexed for MEDLINE]

6: Planta Med. 2004 Sep;70(9):808-12.


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Anti-HIV-1 activity of the Iboga alkaloid congener 18-methoxycoronaridine.

Silva EM, Cirne-Santos CC, Frugulhetti IC, Galvao-Castro B, Saraiva EM, Kuehne ME, Bou-Habib DC.

Laboratorio Avancado de Saude Publica, Centro de Pesquisas Goncalo Moniz, Salvador, BA, Brazil.

The Iboga alkaloid congener 18-methoxycoronaridine (18-MC) exhibits in vitro leishmanicidal and in vivo anti-addiction properties. In this paper, we describe that 18-MC inhibits HIV-1 infection in human peripheral blood mononuclear cells (PBMCs) and monocyte-derived macrophages. We found that 18-MC inhibits the replication of primary isolates of HIV-1 in a dose-dependent manner, regardless of the preferential chemokine receptor usage of the isolates, at non-cell-toxic concentrations. The antiretroviral activity of 18-MC resulted in EC (50) values of 22.5 +/- 4.7 microM and 23 +/- 4.5 microM for R5 and X4 isolates, respectively, in PBMCs, and a therapeutic index (TI) of 14.5. Similar findings were observed for inhibition of HIV-1 replication in macrophages: EC (50) equal to 12.8 +/- 5 microM and 9.5 +/- 3 microM for an R5 virus after 14 and 21 days of infection, respectively, with TI equal to 25.6 and 34.5. 18-MC moderately inhibits the HIV-1 enzyme reverse transcriptase (IC (50) = 69.4 microM), which at least partially explains its antiretroviral activity.

PMID: 15386189 [PubMed - indexed for MEDLINE]

7: Neuroscience. 2004;127(2):373-83.


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Administration of a non-NMDA antagonist, GYKI 52466, increases excitotoxic Purkinje cell degeneration caused by ibogaine.

O'Hearn E, Molliver ME.

Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. eohearn@jhmi.edu

Ibogaine is a tremorigenic hallucinogen that has been proposed for clinical use in treating addiction. We previously reported that ibogaine, administered systemically, produces degeneration of a subset of Purkinje cells in the cerebellum, primarily within the vermis. Ablation of the inferior olive affords protection against ibogaine-induced neurotoxicity leading to the interpretation that ibogaine itself is not directly toxic to Purkinje cells. We postulated that ibogaine produces sustained excitation of inferior olivary neurons that leads to excessive glutamate release at climbing fiber terminals, causing subsequent excitotoxic injury to Purkinje cells. The neuronal degeneration induced by ibogaine provides an animal model for studying excitotoxic injury in order to analyze the contribution of glutamate receptors to this injury and to evaluate neuroprotective strategies. Since non-N-methyl-D-aspartate (NMDA) receptors mediate Purkinje cell excitation by climbing fibers, we hypothesized that 1-4-aminophenyl-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI-52466), which antagonizes non-NMDA receptors, may have a neuroprotective effect by blocking glutamatergic excitation at climbing fiber synapses. To test this hypothesis, rats were administered systemic ibogaine plus GYKI-52466 and the degree of neuronal injury was analyzed in cerebellar sections. The results indicate that the AMPA antagonist GYKI-52466 (10 mg/kg i.p. x 3) does not protect against Purkinje cell injury at the doses used. Rather, co-administration of GYKI-52466 with ibogaine produces increased toxicity evidenced by more extensive Purkinje cell degeneration. Several hypotheses that may underlie this result are discussed. Although the reason for the increased toxicity found in this study is not fully explained, the present results show that a non-NMDA antagonist can produce increased excitotoxic injury under some conditions. Therefore, caution should be exercised before employing glutamate antagonists to reduce the risk of neuronal damage in human clinical disorders. Moreover, the contribution of different glutamate receptors to excitotoxic injury is complex and merits further analysis.

PMID: 15262328 [PubMed - indexed for MEDLINE]

8: Eur J Pharmacol. 2004 May 25;492(2-3):159-67.


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Novel iboga alkaloid congeners block nicotinic receptors and reduce drug self-administration.

Pace CJ, Glick SD, Maisonneuve IM, He LW, Jokiel PA, Kuehne ME, Fleck MW.

Center for Neuropharmacology and Neuroscience, The Albany Medical College, MC-136, 47 New Scotland Avenue, Albany, NY 12208, USA.

18-Methoxycoronaridine, a novel iboga alkaloid congener, reduces drug self-administration in animal models of addiction. Previously, we proposed that these effects are mediated by the ability of 18-methoxycoronaridine to inhibit nicotinic alpha3beta4 acetylcholine receptors. In an attempt to identify more potent 18-methoxycoronaridine analogs, we have tested a series of 18-methoxycoronaridine congeners by whole-cell patch clamp recording of HEK 293 cells expressing recombinant nicotinic alpha3beta4 receptors or glutamate NR1/NR2B N-methyl-d-aspartate (NMDA) receptors. The congeners exhibited a range of inhibitory potencies at alpha3beta4 receptors. Five congeners had IC(50) values similar to 18-methoxycoronaridine, and all of these were ineffective at NMDA receptors. The congeners also retained their ability to reduce morphine and methamphetamine self-administration. These data are consistent with the importance of nicotinic alpha3beta4 receptors as a therapeutic target to modulate drug seeking. These compounds may constitute a new class of synthetic agents that act via the nicotinic alpha3beta4 mechanism to combat addiction.

PMID: 15178360 [PubMed - indexed for MEDLINE]

9: Brain Res. 2004 Apr 2;1003(1-2):159-67.


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Differential effects of ibogaine on local cerebral glucose utilization in drug-naive and morphine-dependent rats.

Levant B, Pazdernik TL.

Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160-7417, USA. blevant@kumc.edu

Ibogaine, a hallucinogenic indole alkaloid, has been proposed as a treatment for addiction to opioids and other drugs of abuse. The mechanism for its putative anti-addictive effects is unknown. In this study, the effects of ibogaine on local cerebral glucose utilization (LCGU) were determined in freely moving, drug-naive, or morphine-dependent adult, male, Sprague-Dawley rats using the [(14)C]2-deoxyglucose (2-DG) method. Morphine-dependent rats were treated with increasing doses of morphine (5-25 mg/kg, s.c., b.i.d.) and then maintained at 25 mg/kg (b.i.d.) for 4-7 days. For the 2-DG procedure, rats were injected with saline or ibogaine (40 mg/kg, i.p.). 2-DG was administered 1 h after administration of ibogaine. The rate of LCGU was determined by quantitative autoradiography in 46 brain regions. In drug-naive animals, ibogaine produced significant increases in LCGU in the parietal, cingulate, and occipital cortices and cerebellum compared to controls consistent with its activity as a hallucinogen and a tremorogen. Morphine-dependent rats had only minor alterations in LCGU at the time assessed in this experiment. However, in morphine-dependent animals, ibogaine produced a global decrease in LCGU that was greatest in brain regions such as the lateral and medial preoptic areas, nucleus of the diagonal band, nucleus accumbens shell, inferior colliculus, locus coeruleus, and flocculus compared to morphine-dependent animals treated with saline. These findings indicate that ibogaine produces distinctly different effects on LCGU in drug-naive and morphine-dependent rats. This suggests that different mechanisms may underlie ibogaine's hallucinogenic and anti-addictive effects.

PMID: 15019575 [PubMed - indexed for MEDLINE]

10: Prog Neuropsychopharmacol Biol Psychiatry. 2003 Aug;27(5):781-5.


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Ibogaine attenuation of morphine withdrawal in mice: role of glutamate N-methyl-D-aspartate receptors.

Leal MB, Michelin K, Souza DO, Elisabetsky E.

Faculdade de Farmacia, Pontificia Universidade Catolica do Rio Grande do Sul, Rua da Republica 580/306, Cep: 90050-320, Porto Alegre, RS, Brazil. mirnabl@pucrs.br

Ibogaine (IBO) is an alkaloid with putative antiaddictive properties, alleviating opiates dependence and withdrawal. The glutamate N-methyl-D-aspartate (NMDA) receptors have been implicated in the physiological basis of drug addiction; accordingly, IBO acts as a noncompetitive NMDA antagonist. The purpose of this study was to evaluate the effects of IBO on naloxone-induced withdrawal syndrome in morphine-dependent mice, focusing on the role of NMDA receptors. Jumping, a major behavioral expression of such withdrawal, was significantly (P<.01) inhibited by IBO (40 and 80 mg/kg, 64.2% and 96.9% inhibition, respectively) and MK-801 (0.15 and 0.30 mg/kg, 67.3% and 97.7%, respectively) given prior to naloxone. Coadministration of the lower doses of IBO (40 mg/kg) and MK-801 (0.15 mg/kg) results in 94.7% inhibition of jumping, comparable to the effects of higher doses of either IBO or MK-801. IBO and MK-801 also significantly inhibited NMDA-induced (99.0% and 71.0%, respectively) jumping when given 30 min (but not 24 h) prior to NMDA in nonaddictive mice. There were no significant differences in [3H]MK-801 binding to cortical membranes from naive animals, morphine-dependent animals, or morphine-dependent animals treated with IBO or MK-801. This study provides further evidence that IBO does have an inhibitory effect on opiate withdrawal symptoms and suggests that the complex process resulting in morphine withdrawal includes an IBO-sensitive functional and transitory alteration of NMDA receptor.

PMID: 12921910 [PubMed - indexed for MEDLINE]

11: Pharmacol Biochem Behav. 2003 Jun;75(3):607-18.


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Anti-addictive actions of an iboga alkaloid congener: a novel mechanism for a novel treatment.

Maisonneuve IM, Glick SD.

Center for Neuropharmacology and Neuroscience, Albany Medical College, MC-136, 47 New Scotland Avenue, Albany, NY 12208, USA. maisoni@mail.amc.edu

18-Methoxycoronaridine (18-MC), a novel iboga alkaloid congener that decreases drug self-administration in several animal models, may be a potential treatment for multiple forms of drug abuse. In animal models, 18-MC reduced intravenous morphine, cocaine, methamphetamine and nicotine self-administration, oral alcohol and nicotine intake, and attenuated signs of opioid withdrawal, but had no effect on responding for a nondrug reinforcer (water) and produced no apparent toxicity [Brain Res. 719 (1996) 29; NeuroReport 11 (2000) 2013; Pharmacol. Biochem. Behav. 58 (1997) 615; Psychopharmacology (Berl.) 139 (1998) 274; NeuroReport 9 (1998) 1283; Ann. N. Y. Acad. Sci. 914 (2000) 369]. Consistent with a relationship among drug sensitization, mesolimbic dopamine, and drug-seeking behavior, 18-MC also blocked the sensitized dopamine responses to morphine and cocaine in the nucleus accumbens. An extensive series of receptor studies showed that 18-MC was most potent and somewhat selective as an antagonist at alpha3beta4 nicotinic receptors. Low-dose combinations of 18-MC with other drugs known to have this same action (e.g., mecamylamine, dextromethorphan, bupropion) decreased morphine, methamphetamine, and nicotine self-administration in rats at doses that were ineffective if administered alone. Together, the data support the hypothesis that diencephalic pathways having high densities of alpha3beta4 nicotinic receptors modulate mesocorticolimbic pathways more directly involved in drug reinforcement. Antagonists of alpha3beta4 nicotinic receptors may represent a totally novel approach to treating multiple addictive disorders, and 18-MC might be the first of a new class of synthetic agents acting via this novel mechanism and having a broad spectrum of activity.

PMID: 12895678 [PubMed - indexed for MEDLINE]

12: JAMA. 2002 Dec 25;288(24):3096, 3099-101.


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Addiction treatment strives for legitimacy.

Vastag B.

Publication Types:

· News


PMID: 12495380 [PubMed - indexed for MEDLINE]

13: J Psychoactive Drugs. 2002 Jul-Sep;34(3):239-48.


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Hallucinogens and redemption.

de Rios MD, Grob CS, Baker JR.

Associate Clinical Professor of Psychiatry and Human Behavior, University of Califomia, Irvine, USA.

This article examines drug substitution with regard to hallucinogens (ayahuasca, ibogaine, peyote and LSD) set within the concept of redemption. The model examines both religious and secular approaches to the contemporary use of hallucinogens in drug substitution, both by scientists and in religious settings worldwide. The redemptive model posits that the proper use of one psychoactive substance within a spiritual or clinical context helps to free an individual from the adverse effects of their addiction to another substance and thus restores them as functioning members of their community or group. Data is drawn from the U.S., Brazil, Peru, and West Africa. Two principle mechanisms for this are proposed: the psychological mechanism of suggestibility is examined in terms of the individual reaching abstinence goals from addictive substances such as alcohol and opiates. Neurophysiological and neurochemical mechanisms to understand the efficacy of such substitution are highlighted from ongoing research on hallucinogens. Research by two of the authors with the Unaio do Vegetal (UDV) Church in Brazil is examined in terms of the model.

PMID: 12422934 [PubMed - indexed for MEDLINE]

14: Curr Med Chem. 2002 Oct;9(20):1807-18.


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A review of chemical agents in the pharmacotherapy of addiction.

Levi MS, Borne RF.

Department of Medicinal Chemistry, School of Pharmacy, The University of Mississippi, University, MS 38677, USA.

Chemical substance abuse has tormented mankind throughout history. A number of chemical approaches have been employed in an attempt to treat chemical addiction. Unfortunately, most of these have proven unsuccessful though several chemical entities have been shown to be moderately effective. The naturally occurring alkaloid ibogaine has been reported to interrupt the cravings for alcohol, cocaine and opiates. Other alkaloids from Tabernanthe iboga, such as ibogamine and tabernanthine, provide insight into the structure activity relationship at the different receptors believed to be involved in addiction. The synthetic iboga alkaloid congener, 18-MC, also shows potential as an anti-addictive agent without the hallucinogenic effects of ibogaine. Additionally, acamprosate, BP 897, GBR12909, lofexidine and memantine have shown promising results in the treatment of addiction. All of these leads provide a start for the medicinal chemist to design anti-addictive agents, since currently no drugs are approved in the U.S. for the treatment of addictions to cocaine, methamphetamine, other stimulants or PCP.

Publication Types:

· Review


PMID: 12369879 [PubMed - indexed for MEDLINE]

15: Ann N Y Acad Sci. 2002 Jun;965:28-46.


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Ibogaine signals addiction genes and methamphetamine alteration of long-term potentiation.

Onaivi ES, Ali SF, Chirwa SS, Zwiller J, Thiriet N, Akinshola BE, Ishiguro H.

Department of Biology, William Paterson University, Wayne, New Jersey 07470, USA. OnaivaE@WPUNJ.edu

The mapping of the human genetic code will enable us to identify potential gene products involved in human addictions and diseases that have hereditary components. Thus, large-scale, parallel gene-expression studies, made possible by advances in microarray technologies, have shown insights into the connection between specific genes, or sets of genes, and human diseases. The compulsive use of addictive substances despite adverse consequences continues to affect society, and the science underlying these addictions in general is intensively studied. Pharmacological treatment of drug and alcohol addiction has largely been disappointing, and new therapeutic targets and hypotheses are needed. As the usefulness of the pharmacotherapy of addiction has been limited, an emerging potential, yet controversial, therapeutic agent is the natural alkaloid ibogaine. We have continued to investigate programs of gene expression and the putative signaling molecules used by psychostimulants such as amphetamine in in vivo and in vitro models. Our work and that of others reveal that complex but defined signal transduction pathways are associated with psychostimulant administration and that there is broad-spectrum regulation of these signals by ibogaine. We report that the actions of methamphetamine were similar to those of cocaine, including the propensity to alter long-term potentiation (LTP) in the hippocampus of the rat brain. This action suggests that there may be a "threshold" beyond which the excessive brain stimulation that probably occurs with compulsive psychostimulant use results in the occlusion of LTP. The influence of ibogaine on immediate early genes (IEGs) and other candidate genes possibly regulated by psychostimulants and other abused substances requires further evaluation in compulsive use, reward, relapse, tolerance, craving and withdrawal reactions. It is therefore tempting to suggest that ibogaine signals addiction gene products.

Publication Types:

· Review


PMID: 12105083 [PubMed - indexed for MEDLINE]

16: Nat Prod Lett. 2002 Feb;16(1):71-6.


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Extraction studies of Tabernanthe iboga and Voacanga africana.

Jenks CW.

cwj@earthling.net

The root bark of Tabernanthe iboga contains ibogaine as its predominant alkaloid and has been an important source of it. Ibogaine is used experimentally to interrupt drug addiction and allow therapeutic intervention, but is currently unaffordable to doctors in less economically developed countries. To meet this need, an extraction of alkaloids from T. iboga root bark was optimized and simplified to use only diluted vinegar and ammonia, and was successfully applied to related alkaloids from Voacanga africana bark also. The alkaloids were converted to their hydrochlorides and purified, and the minor alkaloids were recovered.

PMID: 11942686 [PubMed - indexed for MEDLINE]

17: Alkaloids Chem Biol. 2001;56:63-77.


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Drug discrimination studies with ibogaine.

Helsley S, Rabin RA, Winter JC.

Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USA.

The results of the studies described here support the hypothesis that ibogaine produces its effects via selective interactions with multiple receptors. It appears that 5-HT2A, 5-HT2C, and sigma 2 receptors are involved in mediating the stimulus effects of ibogaine. In addition, opiate receptors may also be involved. In contrast, sigma 1, PCP/MK-801, 5-HT3, and 5-HT1A receptors do not appear to play a major role. Ibogaine's hallucinogenic effects may be explained by its interactions with 5-HT2A and 5-HT2C receptors, while its putative antiaddictive properties may result from its interactions with sigma 2 and opiate receptors. Alternatively, the possibility that ibogaine's hallucinogenic properties underlie its antiaddictive effects, as previously suggested (34), would support a role for 5-HT2 receptors in mediating the reported therapeutic effects of ibogaine. Certainly many questions remain regarding ibogaine's mechanism of action. Although drug discrimination will be useful for answering some of those questions, the true potential of this technique is realized whin it is combined with other techniques. The next few years promise to be fruitful with respect to our understanding of this agent. Reasons supporting this belief include advances in the study of sigma receptors, interest in ibogaine's effects on second messenger systems, and the development of ibogaine congeners such as 18-methoxycoronaridine (35). In conclusion, the aforementioned studies should serve to guide further endeavors. Pertinent questions have been generated: What is the role of sigma receptors in the effects of ibogaine, especially with regard to addiction? How does ibogaine affect opiate neurotransmission? What effects, if any, do the Harmala alkaloids have on addiction phenomena? What is the mechanism of action of harmaline? Can 10-hydroxyibogamine serve as a discriminative stimulus and, if so, what receptor interactions mediate its stimulus effects? Does the ibogaine-trained stimulus generalize to novel agents, including 18-methoxycoronaridine?

Publication Types:

· Review


PMID: 11705117 [PubMed - indexed for MEDLINE]

18: Pharmacol Biochem Behav. 2001 Jul-Aug;69(3-4):485-91.


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Iboga compounds reverse the behavioural disinhibiting and corticosterone effects of acute methamphetamine: Implications for their antiaddictive properties.

Szumlinski KK, Haskew RE, Balogun MY, Maisonneuve IM, Glick SD.

Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, NY 12208, USA. szumlink@musc.edu

This study investigated the effects of pretreatment with the putative antiaddictive compound, ibogaine (IBO), and its synthetic derivative, 18-methoxycoronaridine (18-MC), on the changes in behaviour in an elevated plus maze and the changes in corticosterone (CORT) produced by a low dose of methamphetamine (METH). In the elevated plus maze, the acute administration of METH (0.1 mg/kg ip, -20 min) produced an increase in both the number and the duration of open arm entries relative to saline (SAL)-treated controls. No effect of METH administration was observed on the total number of arm entries. These data indicated that METH alone produced either anxiolysis or behavioural disinhibition in this paradigm. More consistent with the latter possibility, the open arm behaviour of METH controls was associated with an increase in plasma levels of CORT, supporting a facilitatory role for CORT in this METH-induced effect. Pretreatment with both IBO and 18-MC (40 mg/kg ip, 19 h earlier) antagonized the behavioural disinhibiting effects of acute METH without altering locomotor activity. In addition, both iboga agents antagonized the increase in CORT produced by METH. These data provide insight into yet another potential mechanism through which iboga compounds may exert their antiaddictive effects, a reversal of the behavioural disinhibiting properties of stimulant drugs. Furthermore, these data indicate that this reversal is related to effects of iboga compounds on the stimulation of neuroendocrine systems by stimulant drugs.

PMID: 11509208 [PubMed - indexed for MEDLINE]

19: Neuroreport. 2001 Feb 12;12(2):263-7.


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Ibogaine alters synaptosomal and glial glutamate release and uptake.

Leal MB, Emanuelli T, Porciuncula LD, Souza DO, Elisabetsky E.

Curso de Pos Graduacao em Ciencias Biologicas-Bioquimica, ICBS, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.

Ibogaine has aroused expectations as a potentially innovative medication for drug addiction. It has been proposed that antagonism of the NMDA receptor by ibogaine may be one of the mechanisms underlying its antiaddictive properties; glutamate has also been implicated in ibogaine-induced neurotoxicity. We here report the effects of ibogaine on [3H]glutamate release and uptake in cortical and cerebellar synaptosomes, as well as in cortical astrocyte cultures, from mice and rats. Ibogaine (2-1000 microM) had no effects on glutamate uptake or release by rat synaptosomes. However, ibogaine (500-1000 microM) significantly inhibited the glutamate uptake and stimulated the release of glutamate by cortical (but not cerebellar) synaptosomes of mice. In addition, ibogaine (1000 microM) nearly abolished glutamate uptake by cortical astrocyte cultures from rats and mice. The data provide direct evidence of glutamate involvement in ibogaine-induced neurotoxicity.

PMID: 11209932 [PubMed - indexed for MEDLINE]

20: Neurochem Res. 2000 Aug;25(Cool:1083-7.


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Long-lasting ibogaine protection against NMDA-induced convulsions in mice.

Leal MB, de Souza DO, Elisabetsky E.

Departamento de Farmacologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.

Ibogaine, a putative antiaddictive drug, is remarkable in its apparent ability to downgrade withdrawal symptoms and drug craving for extended periods of time after a single dose. Ibogaine acts as a non-competitive NMDA receptor antagonist, while NMDA has been implicated in long lasting changes in neuronal function and in the physiological basis of drug addiction. The purpose of this study was to verify if persistent changes in NMDA receptors could be shown in vivo and in vitro after a single administration of ibogaine. The time course of ibogaine effects were examined on NMDA-induced seizures and [3H] MK-801 binding to cortical membranes in mice 30 min, 24, 48, and 72 h post treatment. Ibogaine (80 mg/kg, ip) was effective in inhibiting convulsions induced by NMDA at 24 and 72 hours post administration. Likewise, [3H] MK-801 binding was significantly decreased at 24 and 72 h post ibogaine. No significant differences from controls were found at 30 min or 48 h post ibogaine. This long lasting and complex pattern of modulation of NMDA receptors prompted by a single dose of ibogaine may be associated to its antiaddictive properties.

PMID: 11055745 [PubMed - indexed for MEDLINE]

21: Psychopharmacology (Berl). 2000 Aug;151(2-3):234-41.


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Interactions between iboga agents and methamphetamine sensitization: studies of locomotion and stereotypy in rats.

Szumlinski KK, Balogun MY, Maisonneuve IM, Glick SD.

Center for Neuropharmacology and Neuroscience, Albany Medical College, NY 12208, USA. szumlik@mail.amc.edu

RATIONALE: The phenomenon of sensitization has been theoretically implicated in mediating various aspects of drug addiction. Recent dose-response studies demonstrated that pretreatment with the putative antiaddictive agent, ibogaine (IBO), and a synthetic iboga alkaloid congener, 18-methoxycoronaridine (18-MC), increase the potency of cocaine to elicit behavioral sensitization, an effect proposed to contribute, in part, to their ability to attenuate drug self-administration. OBJECTIVES: As abuse of the methylated amphetamine derivative, methamphetamine (METH), is a growing public health concern, the present study determined the interactions between IBO and 18-MC and the expression of METH-induced behavioral sensitization. METHODS: The effects of pretreatment with 18-MC (40 mg/kg, IP, 19 h earlier) on the expression of METH-induced locomotion (0, 0.25, 0.5, 1 and 2 mg/kg, IP) and the effects of pretreatment with either IBO or 18-MC on the expression of METH-induced stereotypy (2 and 4 mg/kg, IP) were assessed in rats treated chronically with either METH (4 mg/kg daily for 7 days) or saline. RESULTS: Compared to vehicle-pretreated controls, 18-MC produced an overall enhancement in METH-induced locomotion in rats treated chronically, but not acutely, with METH. In addition, both iboga agents increased the stereotypic response to METH. CONCLUSIONS: Iboga agents augment both the locomotor and stereotypic effects of METH in a manner consistent with previous reports for cocaine. Thus, it appears that iboga agents interact in a similar manner with the neural mechanisms mediating motor hyperactivity induced by the chronic administration of stimulant drugs.

PMID: 10972470 [PubMed - indexed for MEDLINE]

22: Toxicol Sci. 2000 Sep;57(1):95-101.


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A dose-response study of ibogaine-induced neuropathology in the rat cerebellum.

Xu Z, Chang LW, Slikker W Jr, Ali SF, Rountree RL, Scallet AC.

Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.

Ibogaine (IBO) is an indole alkaloid from the West African shrub, Tabernanthe iboga. It is structurally related to harmaline, and both these compounds are rigid analogs of melatonin. IBO has both psychoactive and stimulant properties. In single-blind trials with humans, it ameliorated withdrawal symptoms and interrupted the addiction process. However, IBO also produced neurodegeneration of Purkinje cells and gliosis of Bergmann astrocytes in the cerebella of rats given even a single dose (100 mg/kg, ip). Here, we treated rats (n = 6 per group) with either a single ip injection of saline or with 25 mg/kg, 50 mg/kg, 75 mg/kg, or 100 mg/kg of IBO. As biomarkers of cerebellar neurotoxicity, we specifically labeled degenerating neurons and axons with silver, astrocytes with antisera to glial fibrillary acidic protein (GFAP), and Purkinje neurons with antisera to calbindin. All rats of the 100-mg/kg group showed the same pattern of cerebellar damage previously described: multiple bands of degenerating Purkinje neurons. All rats of the 75-mg/ kg group had neurodegeneration similar to the 100-mg/kg group, but the bands appeared to be narrower. Only 2 of 6 rats that received 50 mg/kg were affected; despite few degenerating neuronal perikarya, cerebella from these rats did contain patches of astrocytosis similar to those observed with 75 or 100 mg/kg IBO. These observations affirm the usefulness of GFAP immunohistochemistry as a sensitive biomarker of neurotoxicity. None of the sections from the 25-mg/kg rats, however stained, were distinguishable from saline controls, indicating that this dose level may be considered as a no-observable-adverse-effect level (NOAEL).

PMID: 10966515 [PubMed - indexed for MEDLINE]

23: Toxicon. 2001 Jan;39(1):75-86.


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Iboga interactions with psychomotor stimulants: panacea in the paradox?

Szumlinski KK, Maisonneuve IM, Glick SD.

Center for Neuropharmacology and Neuroscience, MC-136, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208, USA. szumlik@mail.amc.edu

Currently, no effective therapy has been approved for the treatment of addiction to stimulant drugs (e.g., cocaine, amphetamine and its methylated derivatives). However, preclinical studies indicate that the naturally-occurring indole alkaloid, ibogaine, and a synthetic iboga alkaloid congener, 18-methoxycoronaridine (18-MC), attenuate stimulant self-administration in laboratory animals. The in vivo pharmacological interactions between iboga agents and stimulant drugs are unclear. Ibogaine enhances the increase in accumbal dopamine produced by the acute administration of stimulant drugs. Consistent with these data, both ibogaine and 18-MC potentiate the expression of stimulant-induced motor behaviors in acute and chronic stimulant-treated animals. To account for the paradox between their effects on self-administration and motor behavior, we proposed that iboga agents interfere with stimulant self-administration by increasing sensitivity to their psychomotor-activating effects. However, this interpretation is contradicted by very recent observations that 18-MC is without effect on the dopamine response to acute cocaine and that both ibogaine and 18-MC block the expression of sensitized levels of dopamine in the nucleus accumbens produced by chronic cocaine administration. Thus, a positive relationship exists between the effects of iboga pretreatment on stimulant-induced dopamine sensitization and stimulant self-administration behavior. These data indicate that iboga agents might attenuate stimulant self-administration by reversing the neuroadaptations theoretically implicated in drug craving and compulsive drug-seeking behavior.

Publication Types:

· Review


PMID: 10936624 [PubMed - indexed for MEDLINE]

24: Ann N Y Acad Sci. 2000;909:275-9.


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18-Methoxycoronaridine differentially alters the sensitized behavioral and dopaminergic responses to repeated cocaine and morphine administration. Implications for sensitization in the mediation of drug addiction.

Szumlinski KK, Maisonneuve IM, Glick SD.

Department of Pharmacology and Neuroscience, Albany Medical College, New York 12208, USA. szumlik@mail.amc.edu

PMID: 10911941 [PubMed - indexed for MEDLINE]

25: Ann N Y Acad Sci. 2000;909:88-103.


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Development of novel medications for drug addiction. The legacy of an African shrub.

Glick SD, Maisonneuve IM.

Department of Pharmacology and Neuroscience, Albany Medical College, New York 12208, USA. glicks@mail.amc.edu

Ibogaine, one of several alkaloids found in the root bark of the African shrub Tabernanthe iboga, has been claimed to be effective in treating multiple forms of drug abuse. Problems associated with side effects of ibogaine have spawned a search for more effective and safer structural derivatives. 18-Methoxycoronaridine (18-MC), a novel iboga alkaloid congener, appears to have substantial potential for broad use as an anti-addictive therapy. Like ibogaine (40 mg/kg), 18-MC (40 mg/kg) decreases the intravenous self-administration of morphine and cocaine and the oral self-administration of ethanol and nicotine in rats; unlike ibogaine, 18-MC does not affect responding for a non-drug reinforcer (water). Ibogaine and 18-MC appear to reduce the reinforcing efficacies, rather than the potencies, of drugs of abuse. Both ibogaine and 18-MC decreases extracellular levels of dopamine in the nucleus accumbens while only ibogaine increases serotonin levels in this brain region. Both ibogaine and 18-MC block morphine-induced and nicotine-induced dopamine release in the accumbens; only ibogaine enhances cocaine-induced increases in dopamine levels. Ibogaine produces whole body tremors and, at high doses (at least 100 mg/kg), cerebellar damage; 18-MC does not produce these effects. Ibogaine, but not 18-MC, causes bradycardia at high doses. Ibogaine and its metabolite noribogaine have low microM affinities for kappa and mu opioid receptors, NMDA receptors, 5HT-3 receptors, sigma-2 sites, sodium channels and the serotonin transporter. 18-MC has low microM affinities at all three opioid receptors and at 5HT-3 receptors but much lower or no affinities for NMDA and sigma-2 receptors, sodium channels, and the 5HT transporter. Both 18-MC and ibogaine are sequestered in fat and, like ibogaine, 18-MC probably has an active metabolite. 18-MC also has (+) and (-) enantiomers, both of which are active. Considered together, all of the data indicate that 18-MC should be safer than ibogaine and at least as efficacious as an anti-addictive medication.

PMID: 10911925 [PubMed - indexed for MEDLINE]

26: Brain Res. 2000 Jul 21;871(2):245-58.


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Interactions between 18-methoxycoronaridine (18-MC) and cocaine: dissociation of behavioural and neurochemical sensitization.

Szumlinski KK, McCafferty CA, Maisonneuve IM, Glick SD.

Center for Neuropharmacology and Neuroscience (MC-136), Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208, USA. szumlik@mail.amc.edu

The phenomenon of sensitization has been implicated in various aspects of drug addiction. As such, the present study determined the effects of a potential anti-addictive agent, 18-methoxycoronaridine (18-MC; 40 mg/kg, IP, 19 h earlier), on the expression of sensitization following the repeated administration of cocaine (COC; five once daily injections of 15 mg/kg, IP) or saline. The effects of 18-MC on COC metabolism were also assessed. Compared to vehicle controls, 18-MC significantly enhanced the expression of COC-induced locomotion (0, 10, 20 and 40 mg/kg, IP) in chronic COC treated rats only. In both acute and chronic COC rats, 18-MC potentiated the stereotypy induced by higher COC doses (20 and 40 mg/kg, IP). In contrast, 18-MC abolished the sensitized dopamine (DA) response in the nucleus accumbens (NAC) to COC (20 mg/kg), without altering the DA response of acute COC rats. None of the interactions between 18-MC and COC appear to be related to alterations in COC metabolism as no effect of 18-MC pretreatment was observed on extracellular levels of COC or two of its metabolites, benzoylecogonine and norcocaine. From the present findings, it is concluded that the enhancement of COC-induced behaviour produced by 18-MC pretreatment is independent of effects on either COC pharmacokinetics or COC-induced alterations in DA transmission. However, given that 18-MC decreases the self-administration of COC in laboratory animals, it is proposed that the anti-addictive efficacy of 18-MC might be related to an ability to selectively block the expression of sensitized extracellular levels of DA in the NAC in rats with previous COC experience.

PMID: 10899291 [PubMed - indexed for MEDLINE]

27: Eur J Pharmacol. 2000 Feb 25;390(1-2):119-26.


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Responses of the extrapyramidal and limbic substance P systems to ibogaine and cocaine treatments.

Alburges ME, Ramos BP, Bush L, Hanson GR.

Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, 30 S 2000 E RM 201, Salt Lake City, UT 84112, USA. m.e.alburges@m.cc.utah.edu

Ibogaine is an indolamine found in the West Africa shrub, Tabernanthe iboga, and has been proposed for the treatment of addiction to central nervous system (CNS) stimulants such as cocaine and amphetamine. The mechanism of ibogaine action and its suitability as a treatment for drug addiction still remains unclear. Since previous studies demonstrated differential effects of stimulants of abuse (amphetamines) on neuropeptide systems such as substance P, we examined the impact of ibogaine and cocaine on extrapyramidal (striatum and substantia nigra) and limbic (nucleus accumbens and frontal cortex) substance P-like immunoreactivity. Ibogaine and cocaine treatments altered substance P systems by increasing striatal and nigral substance P-like immunoreactivity concentration 12 h after the last drug treatment. However, substance P-like immunoreactivity content was not significantly increased in nucleus accumbens after treatment with either drug. The ibogaine- and cocaine-induced increases in substance P-like immunoreactivity in striatum and substantia nigra were blocked by coadministration of selective dopamine D(1) receptor antagonist (SCH 23390; R(+)-7-Chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4, 5-tetrahydro-1H-3-benzazepine hydrochloride) or dopamine D(2) receptor antagonist (eticlopride; S(-)-3-Chloro-5-ethyl-N-[(1-ethyl-2-pyrrolidinyl)methyl]-6-hydroxy-2- methoxy-benzamide hydrochloride). Most of the responses by substance P systems to ibogaine administration resembled those caused by cocaine, except in cortical tissue where multiple administration of cocaine, but not ibogaine increased substance P-like immunoreactivity. These data suggest that substance P systems may contribute to the effects of ibogaine and cocaine treatment.

PMID: 10708715 [PubMed - indexed for MEDLINE]

28: Lancet. 1999 Nov 27;354(9193):1883.


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Data accrue on "visionary" agent to interrupt addiction.

Morris K.

Publication Types:

· News


PMID: 10584734 [PubMed - indexed for MEDLINE]

29: Brain Res. 1999 Nov 13;847(1):139-42.


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Ibogaine pretreatment dramatically enhances the dynorphin response to cocaine.

Alburges ME, Hanson GR.

Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, 30 So. 2000 E. Room 201, Salt Lake City, UT, USA. m.e.albruges@m.cc.utah.edu

Ibogaine (Endabuse) is a psychoactive indole alkaloid found in the shrub, Tabernanthe iboga, which has been used to treat stimulant addiction. Because ibogaine influences the activity of neurotensin systems, a dopamine-linked neuropeptide, the present study investigated if ibogaine also influences dynorphin (DYN) pathways. Unlike neurotensin responses, ibogaine alone did not alter DYN levels in the striatum, substantia nigra or nucleus accumbens. Interestingly, ibogaine pretreatment dramatically enhanced cocaine-induced increases in DYN content in these structures.

PMID: 10564747 [PubMed - indexed for MEDLINE]

30: Eur J Pharmacol. 1999 Oct 21;383(1):15-21.


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Attenuation of the reinforcing efficacy of morphine by 18-methoxycoronaridine.

Maisonneuve IM, Glick SD.

Department of Pharmacology and Neuroscience, MC-136, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208, USA. maison@ccgateway.amc.edu

In previous studies, 18-methoxycoronaridine, a novel iboga alkaloid congener, has been reported to decrease the self-administration of morphine, cocaine, ethanol and nicotine, and to attenuate naltrexone-precipitated signs of morphine withdrawal. In the present study, the nature of the interaction between 18-methoxycoronaridine and morphine was further investigated. Using in vivo microdialysis, 18-methoxycoronaridine pretreatment (40 mg/kg i.p., 19 h beforehand) was found to markedly inhibit morphine-induced (5 mg/kg, i.p.) dopamine release in the nucleus accumbens and striatum; 18-methoxycoronaridine also enhanced morphine-induced increases in extracellular levels of dopamine's metabolites. These effects, which were more prominent in the nucleus accumbens than in the striatum, suggest that 18-methoxycoronaridine selectively interferes with morphine-induced dopamine release, without altering morphine-induced stimulation of dopamine synthesis. In intravenous morphine self-administration experiments, the effects of acute 18-methoxycoronaridine treatment (40 mg/kg, p.o.) were assessed in rats responding for one of several different unit infusion dosages of morphine (0.01-0.16 mg/kg/infusion). 18-Methoxycoronaridine produced a downward shift in the entire morphine dose-response curve without any displacement to the left or right. These results suggest that 18-methoxycoronaridine reduced the reinforcing efficacy of morphine without altering its apparent potency. Together, the microdialysis and self-administration data suggest that 18-methoxycoronaridine profoundly alters mechanisms crucial to the development and maintenance of opioid addiction.

PMID: 10556676 [PubMed - indexed for MEDLINE]

31: Brain Res Bull. 1999 Apr;48(6):641-7.


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The effects of ibogaine on dopamine and serotonin transport in rat brain synaptosomes.

Wells GB, Lopez MC, Tanaka JC.

Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia 19104-6002, USA.

Ibogaine has been shown to affect biogenic amine levels in selected brain regions. Because of the involvement of these neurotransmitters in drug addiction, the effects of ibogaine on biogenic amine transport may contribute to the potential anti-addictive properties of ibogaine in vivo. With rat brain synaptosomes as our experimental system, we measured the effects of ibogaine on the uptake and release of dopamine (DA) and serotonin (5-HT). Ibogaine competitively blocked both DA and 5-HT uptake with IC50 values of 20 microM at 75 nM 3H-DA and 2.6 microM at 10 nM 3H-5-HT. Ibogaine had no effect on K+-induced release of 3H-DA from preloaded synaptosomes, but 20 microM and 50 microM ibogaine inhibited roughly 40% and 60%, respectively, of the K(+)-induced release of 3H-5-HT from preloaded synaptosomes. In the absence of a depolarizing stimulus, ibogaine evoked a small release of 3H-DA but not 3H-5-HT. These relatively low-potency effects of ibogaine on DA and 5-HT uptake in synaptosomes are consistent with the low binding affinity of ibogaine that has been previously reported for DA and 5-HT transporters. Our results show that if ibogaine modulates DA and 5-HT levels in the brain by directly blocking their uptake, then a concentration of ibogaine in the micromolar range is required. Furthermore, if the anti-addictive effects of ibogaine require this concentration, then ibogaine likely exerts these effects through a combination of neurotransmitter pathways, because binding affinities and functional potencies of ibogaine in the micromolar range have been reported for a variety of neuronal receptors and transporters.

PMID: 10386845 [PubMed - indexed for MEDLINE]

32: Brain Res. 1999 Feb 6;818(1):96-104.


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Differential responses by neurotensin systems in extrapyramidal and limbic structures to ibogaine and cocaine.

Alburges ME, Hanson GR.

Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, 112 Skaggs Hall, Salt Lake City, UT 84112, USA. m.e.alburges@m.cc.utah.edu

Ibogaine (Endabuse) is a psychoactive indole alkaloid found in the West African shrub, Tabernanthe iboga. This drug interrupts cocaine and amphetamine abuse and has been proposed for treatment of addiction to these stimulants. However, the mechanism of action that explains its pharmacological properties is unclear. Since previous studies demonstrated differential effects of psychotomimetic drugs (cocaine and methamphetamine) on neuropeptides such as neurotensin (NT), the present study was designed to determine: (1) the effects of ibogaine on striatal, nigral, cortical, and accumbens neurotensin-like immunoreactivity (NTLI); (2) the effects of selective dopamine antagonists on ibogaine-induced changes in NT concentrations in these brain areas; and (3) the effects of ibogaine pretreatment on cocaine-induced changes in striatal, nigral, cortical and accumbens NTLI content. Ibogaine treatments profoundly affected NT systems by increasing striatal, nigral, and accumbens NTLI content 12 h after the last drug administration. In contrast, NTLI concentrations were not significantly increased in the frontal cortex after ibogaine treatment. The ibogaine-induced increases in NTLI in striatum, nucleus accumbens and substantia nigra were blocked by coadministration of the selective D1 receptor antagonist, SCH 23390. The D2 receptor antagonist, eticlopride, blocked the ibogaine-induced increase in nigral NTLI, but not in striatum and nucleus accumbens. Ibogaine pretreatment significantly blocked the striatal and nigral increases of NTLI resulting from a single cocaine administration. Whereas many of the responses by NT systems to ibogaine resembled those which occur after cocaine, there were also some important differences. These data suggest that NT may contribute to an interaction between ibogaine and the DA system and may participate in the pharmacological actions of this drug. Copyright 1999 Elsevier Science B.V.

PMID: 9914442 [PubMed - indexed for MEDLINE]

33: Lancet. 1998 Oct 17;352(9136):1290.


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Seeking ways to crack cocaine addiction.

Morris K.

Publication Types:

· News


PMID: 9788471 [PubMed - indexed for MEDLINE]

34: Brain Res. 1998 Aug 10;801(1-2):67-71.


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Gender differences in kappa-opioid modulation of cocaine-induced behavior and NMDA-evoked dopamine release.

Sershen H, Hashim A, Lajtha A.

Nathan S. Kline Institute for Psychiatric Research, 140 Old Orangeburg Rd., Orangeburg, NY 10962, USA. sershen@nki.rfmh.org

It has been reported that kappa-opioids produce greater analgesia in women than in men. Sex differences are also apparent in drug-induced behaviors. Repeated administration of cocaine (25 mg/kg) produced a greater locomotor and sensitization response in C57BL/6By female mice. It was examined whether the increased sensitization in females to repeated cocaine administration was related to differences in kappa-opioid responses. The effects of the kappa agonist U62066 (spiradoline mesylate) on cocaine-induced locomotor stimulation in vivo and NMDA-mediated dopamine release in vitro were measured. In male, but not female mice, U62066 (1 mg/kg) given 30 min before cocaine potentiated the locomotor stimulation of an acute cocaine administration. U-62066 did not affect the development of locomotor sensitization with repeated cocaine administration (25 mg/kg s.c., once daily for 3 days), and a further enhanced response was not seen on days 2 and 3. It was then examined whether dopamine release, measured in vitro, plays a role in sex dependent differences in kappa-opioid- or NMDA-modulated dopaminergic function. In tissue perfusion studies, the in vitro NMDA (25 microM)-evoked release of labelled dopamine from striatum was lower in females (fractional release = 5.4 +/- 0.4 and 4.0 +/- 0.4 in male and female mouse striatum). U62066 (1 microM) and ibogaine (1 microM), an indole alkaloid claimed to be useful in the treatment of drug addiction that acts in part at the kappa-opioid receptor, both reduced the NMDA (25 microM)-evoked release of dopamine. Inhibition of the release was significantly greater in tissue from male mice. Prior in vivo cocaine administration did not alter the NMDA-evoked dopamine release. Our studies indicate that kappa-opioid and NMDA receptor activity show differences between female and male mice that may account for differences in cocaine-induced behaviors, but do not exclude the role of other hetereoceptors modulating dopamine release. Copyright 1998 Elsevier Science B.V.

PMID: 9729284 [PubMed - indexed for MEDLINE]

35: Drug Metab Dispos. 1998 Aug;26(Cool:764-8.


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Cytochrome P4502D6 catalyzes the O-demethylation of the psychoactive alkaloid ibogaine to 12-hydroxyibogamine.

Obach RS, Pablo J, Mash DC.

Department of Drug Metabolism, Central Research Division, Pfizer, Inc., Groton, CT 06340, USA.

Ibogaine is a psychoactive alkaloid that possesses potential as an agent to treat opiate and cocaine addiction. The primary metabolite arises via O-demethylation at the 12-position to yield 12-hydroxyibogamine. In this report, evidence is presented that the O-demethylation of ibogaine observed in human hepatic microsomes is catalyzed primarily by the polymorphically expressed cytochrome P-4502D6 (CYP2D6). An enzyme kinetic examination of ibogaine O-demethylase activity in pooled human liver microsomes suggested that two (or more) enzymes are involved in this reaction: one with a low KMapp (1.1 microM) and the other with a high KMapp (>200 microM). The low KMapp activity comprised >95% of total intrinsic clearance. Human liver microsomes from three individual donors demonstrated similar enzyme kinetic parameters (mean KMapp = 0.55 +/- 0.09 microM and 310 +/- 10 microM for low and high KM activities, respectively). However, a fourth human microsome sample that appeared to be a phenotypic CYP2D6 poor metabolizer possessed only the high KMapp activity. In hepatic microsomes from a panel of human donors, the low KMapp ibogaine O-demethylase activity correlated with CYP2D6-catalyzed bufuralol 1'-hydroxylase activity but not with other P450 isoform-specific activities. Quinidine, a CYP2D6-specific inhibitor, inhibited ibogaine O-demethylase (IC50 = 0.2 microM), whereas other P450 isoform-specific inhibitors did not inhibit this activity. Also, of a battery of recombinant heterologously expressed human P450 isoforms, only rCYP2D6 possessed significant ibogaine O-demethylase activity. Thus, it is concluded that ibogaine O-demethylase is catalyzed by CYP2D6 and that this isoform is the predominant enzyme of ibogaine O-demethylation in humans. The potential pharmacological implications of these findings are discussed.

PMID: 9698290 [PubMed - indexed for MEDLINE]

36: Ann N Y Acad Sci. 1998 May 30;844:245-51.


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Effect of ibogaine on the various sites of the NMDA receptor complex and sigma binding sites in rat brain.

Itzhak Y, Ali SF.

Department of Biochemistry and Molecular Biology (R-629), University of Miami School of Medicine, Florida 33101, USA. yitzhak@mednet.med.maimi.ed

Although the alkaloid ibogaine is a potent hallucinogenic agent some indications suggest that it may be useful for the treatment of opioid and cocaine addiction. The neurochemical mechanism(s) underlying ibogaine effects remain unclear. In the present study we investigated the interaction of ibogaine with the phencyclidine (PCP) site located in the ionophore of the N-methyl-D-aspartate (NMDA) receptor complex, with the NMDA receptor binding site, and with sigma binding sites. In well-washed membrane preparations of rat cortex and cerebellum, the PCP sites were labeled with [3H]MK-801 or [3H]1-[1(2-theinyl)-cyclohexyl]-piperidine ([3H]TCP), and the NMDA receptor with [3H]-CGP 39653. The sigma-1 and sigma-2 binding site in rat cortex and cerebellum were labeled with [3H]pentazocine and [3H]1,3-di-o-tolyl-guanidine ([3H]DTG), respectively. Results indicated that ibogaine interacts with high- and low-affinity PCP binding sites in the cortex: Ki(H) = 0.01-0.05 microM; Ki(L) = 2-4 microM, and only with low-affinity sites in the cerebellum: Ki = 2-4, microM. In contrast, ibogaine (> 100 microM) had no affinity for [3H]-CGP 39653 binding sites (cortex and cerebellum). The affinity of ibogaine for sigma-1 and -2 binding sites in cortex and cerebellum ranged from 1.5-3 microM. Since NMDA receptor antagonists (e.g., MK-801) are thought to attenuate opioid withdrawal symptoms and cocaine sensitization, it is possible that binding of ibogaine to the PCP sites contributes to its potential 'endabuse' properties. In turn, ibogaine interaction with sigma binding sites may be associated with its adverse effects.

PMID: 9668682 [PubMed - indexed for MEDLINE]

37: Brain Res. 1998 Jun 22;797(1):173-80.


,

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Ibogaine acts at the nicotinic acetylcholine receptor to inhibit catecholamine release.

Mah SJ, Tang Y, Liauw PE, Nagel JE, Schneider AS.

Department of Pharmacology and Neuroscience, Albany Medical College, Albany, NY 12208, USA.

In an effort to determine mechanisms of action of the putative anti-addictive agent ibogaine, we have measured its effects on catecholamine release in a model neuronal system, cultured bovine chromaffin cells. Various modes of stimulating catecholamine release were used including nicotinic ACh receptor activation, membrane depolarization with elevated K+ and Na+ channel activation with veratridine. In addition, because ibogaine has been reported to interact with kappa opioid receptors, we tested whether kappa receptor antagonists could reverse ibogaine's effects on catecholamine release. Ibogaine, at low concentration (<10 microM) was found to selectively inhibit nicotinic receptor-mediated catecholamine release, while having no significant effect on release evoked by either veratridine or membrane depolarization with elevated K+. The inhibitory actions of ibogaine and the kappa agonists were not reversed by preincubation with the opioid antagonists nor-binaltorphimine or naltrexone, suggesting that these inhibitory effects are not mediated by the kappa opioid receptor. The effects of low dose (10 microM) ibogaine were rapidly reversible, while the inhibitory effects of higher ibogaine doses persisted for at least 19 h following ibogaine washout. The results provide evidence for a mechanism of action ibogaine at the nicotinic ACh receptor. The results are consistent with a model in which the initial high transient brain concentrations (100 microM) of ibogaine act at multiple cellular sites and then have a selective action at the nicotinic ACh receptor cation channel following its metabolism to lower brain concentrations. The present findings are relevant to potential anti-addictive actions of ibogaine and to the development of drugs to combat nicotine addiction. Copyright 1998 Elsevier Science B.V. All rights reserved.

PMID: 9630615 [PubMed - indexed for MEDLINE]

38: Nat Med. 1998 Apr;4(4):377.


,


Fight to develop drug addiction therapy.

Birmingham K.

Publication Types:

· News


PMID: 9546770 [PubMed - indexed for MEDLINE]

39: Pharmacol Biochem Behav. 1998 Feb;59(2):495-503.


,

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The effects of sigma, PCP, and opiate receptor ligands in rats trained with ibogaine as a discriminative stimulus.

Helsley S, Filipink RA, Bowen WD, Rabin RA, Winter JC.

Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, 14214-3000, USA.

Although the mechanism of action of ibogaine, a hallucinogen that may be useful in the treatment of addiction, remains unknown, receptor binding studies suggest that ibogaine produces its effects via interactions with multiple receptor types. In addition to serotonergic receptors, which have been studied previously with respect to ibogaine, likely candidates include opiate, sigma (sigma), and phencyclidine (PCP) binding sites. In an attempt to determine which of these receptor interactions are involved in the in vivo effects of ibogaine, ligands for sigma, PCP, and opiate receptors were assessed for their ability to substitute for or to antagonize the ibogaine-induced discriminative stimulus (10 mg/kg I.P., 60 min presession) in Fischer-344 rats. Intermediate levels of generalization were observed with the subtype nonselective sigma ligands 3-(3-hydroxyphenyl)-N-(1-propyl)-piperidine [(+)-3-PPP] (69.0%) and 1,3-di(2-tolyl)guanidine (DTG) (73.5%) but not with the sigma1-selective agents (+)-N-allylnormetazocine [(+)-SKF 10,047] and (+)-pentazocine. These findings, along with observations that ibogaine has appreciable affinity for sigma2 receptors, suggest that these receptors may be involved in the ibogaine discriminative stimulus. With regard to opiate receptors, neither morphine, the prototypic mu agonist, nor kappa selective agonists (bremazocine,and U-50488) substituted for ibogaine. However, intermediate levels of generalization were observed with the mixed action opiates (-)-SKF 10,047 (78.9%), (+/-)-pentazocine (73.9%), nalorphine (70.4%), and diprenorphine (75.0%) indicating a potential role for opiate receptors in the ibogaine stimulus. Partial substitution was also observed with naltrexone (55.6%) but not with naloxone or the selective kappa antagonist nor-binaltorphimine (nor-BNI). These agents were largely ineffective as antagonists of the ibogaine cue, although naloxone produced a moderate but statistically significant antagonism (69.8%). In addition, naloxone produced complete antagonism of the ibogaine-appropriate responding elicited by both (-)-SKF


Last edited by Fru-Lindgren on Wed 05 Jul, 2006 20:25; edited 1 time in total
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Fru-Lindgren
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PostPosted: Wed 05 Jul, 2006 20:09    Post subject: Ibogainets antiaddiktiva egenskaper Reply with quote

Skickat !!
=======================================0
Till LVM

Hej!

Jag heter Michael Korn och är en före detta heroinist.
Jag har ett långt missbruk bakom mig.

Efter många års jakt på drogfrihet kom jag förra året i kontakt med Ibogain. Eftersom behandlingen inte görs i Sverige då Ibogain är förbjudet här åkte jag till Prag.

Efter endast två ibogain - behandlingar är jag helt och totalt drogfri, utan sug eller abstinens. Mitt liv vände helt över en natt!

Jag har börjat intressera mig för att hjälpa andra till drogfrihet genom att dels starta en stiftelse, Stiftelsen Iboga, samt genom att driva en hemsida och ett forum om Ibogain. www.ibogain.se

Jag har läst hundratals fallbeskrivningar från hela världen och har personlig kontakt med många som nu är drogfria med Ibogain och med flera som arbetar med att behandla behövande.

Ibogain tycks vara ett av de allra effektivaste sätten för att bryta missbruk och jag undrar nu varför det är olagligt och narkotikaklassat i Sverige och jag undrar hur man ska göra för att kunna få det godkänt som kontrollerat behandlingspreparat?

Klassningen som narkotikum av typ I verkar ju dessutom kunna motsägas av vetenskapligt grundade slutsatser. Jag är tacksam för er kommentar till det.

Med vänliga hälsningar

Micke Korn
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Fru-Lindgren
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PostPosted: Mon 24 Jul, 2006 19:38    Post subject: Reply with quote

Läkemedelsverket svarar:
=========================


Tack för Din fråga. Ibogain klassas som narkotikum typ I pga sina
hallucinogena egenskaper. Det innebär dock inte att det är omöjligt att
godkänna som läkemedel så länge det finns tillräckligt gott vetenskaplig
stöd för detta. Om detta ska vara möjligt krävs dock att en
initiativtagare, alltså ett läkemedelsföretag, ansökar om godkännande
för marknadsföring och kan visa upp tillräckligt god dokumentation för
effekt och säkerhet.

Med vänliga hälsningar,

Pharmacovigilance Unit
Medical Products Agency
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Fru-Lindgren
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PostPosted: Mon 24 Jul, 2006 21:01    Post subject: Reply with quote

Skickat idag kommenterande nedan artikel från:
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http://www.ens2000.nu/fragelada/fraga.php?id=58

2006-03-07 - Mats Erikssons fråga
Ibogaine

Hej
Vad vet man om Ibogaine och dess effekter på drogberoende. Har fått fram att det är en extremt stark Hallucinogen drog, fanns många tripprapporter, har dock inte hittat några vad jag betecknar som seriösa sidor om Ibogaine och att ämnet inte finns att hitta i svenska Fass!

MvhME/Mats
Mats Eriksson

Svar

Hej!
Ibogaine är en psykoaktiv alkaloid och tillhör gruppen hallucinogener. I läkemedelsverkets förteckningar är ibogaine narkotikaklassat i förteckning I vilket innebär att medlet inte har någon medicinsk användning.
Ibogaine tas från den afrikanska växten Tabermanthe iboga och dess rotbark.
Vissa forskare har prövat medlet i avsikt att få missbrukare av alkohol och andra narkotiska preparat att upphöra med missbruket, men denna metod har ingen vetenskaplig förankring. Metoden anses kontroversiell.

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Kommentar till svar

Ingen vetenskaplig förankring? Vilken planet har ni vistats på de senaste decennierna? Det finns gott om vetenskapliga förankringar och inte bara det, det finns dessutom människor som avslutat sina tunga missbruk tack vare just Ibogain! Kan det säga något måhända?

Eller är det ni skriver bara ett led i en oändligt döv stadsapparats blinda narkotikapolitik, där det varken kan förekomma någotsomhelst positivt med någon drog överhuvudtaget?

Det är tvärtom ovetenskapligt och lögnaktigt att påstå att metoden saknar vetenskapligt stöd! Vad är det egentligen ni vill åstakomma med texter som denna? Kan ni inte hålla käften och läsa på lite innan ni blåser ur er en massa skit? Eller sover ni gott när tunga narkomaner inte får tillgång till något som beviserligen fungerat för andra?
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