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The Ibogaine Dossier
The Ibogaine Dossier

NYU Conference on Ibogaine Nov 5-6, 1999

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The Ibogaine Dossier

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The Ibogaine Bibliography

Last update: 03/05/97; Due to a database problem a number of abstracts appeared incorrectly after our previous update (02/18/97).

1. Ibogaine and Cocaine Abuse: Pharmacological Interactions at Dopamine and Serotonin Receptors. Sershen, H., Hashim, A. and Lajtha, A. Brain Res Bull 42(3):161-168, 1997.

Abstract: Ibogaine is an indole alkaloid that has been of interest in recent years due to its putative efficacy in the treatment of drug dependence. For the most part, animal data have shown attenuation of some of the effects of stimulant drugs, for example, motor stimulation and self-administration. The mechanism of this inhibition of drug-induced behavior seems to suggest the action of the dopamine, serotonin, NMDA, kappa, and/or sigma receptor sites, as indicated by the affinity of ibogaine to receptor selective ligands in binding competition studies. However, affinity for receptors does not in itself indicate their involvement. In vitro perfusion studies have proven a useful model to study the effect of ibogaine on neurotransmitter systems and the functional effects of such interactions. This review summarizes these data and the support of multiple effects of ibogaine, and the potential importance of its action on serotonergic modulation of dopamine release.

2. The psychopharmacology of hallucinogens. Abraham, H.D., Aldridge, A.M. and Gogia, P. Neuropsychopharmacology 14:285-298, 1996.

Abstract: The strychnine-insensitive glycine site on the N-methyl-D- aspartate (NMDA) receptor complex is a target for development of a host of therapeutic agents including anxiolytics, antidepressants, antiepileptics, anti-ischemics and cognitive enhancers. In the present experiments, the discriminative stimulus effects of (+)-HA-966 [R-(+)-3-amino-1-hydroxypyrrolid-2- one), a low-efficacy partial agonist of the glycine site, was explored. Male, Swiss-Webster mice were trained to discriminate (+)-HA-966 (170 mg/kg i.p.) from saline in a T- maze under which behavior was controlled by food. Other glycine partial agonists, 1-amino-1-cyclopropanecarboxilic acid and D-cycloserine, fully substituted for the discriminative stimulus effects of (+)-HA-966 despite known differences in other pharmacological effects of these compounds. The glycine site antagonist, 7-chlorkynurenic acid, did not substitute for (+)- HA-966. Likewise other functional NMDA antagonists acting at nonglycine sites of the NMDA receptor also did not substitute: neither the high (dizocilpine) or low affinity (ibogaine) ion-channel blocker, the competitive antagonist, NPC 17742 [2R,4R,5S-2-amino-4,5-(1,2- cyclohexyl)-7-phosphonoheptanoic acid], nor the polyamine antagonist, ifenprodil, substituted for (+)-HA-966. Although the full agonist, glycine, did not substitute, this compound fully blocked the discriminative stimulus effects of (+)-HA-966. In a separate group of mice trained to discriminate 0.17 mg/kg of dizocilpine from saline, (+)-HA-966 produced a maximum of only 50% dizocilpine-appropriate responses. These data suggest that the discriminative stimulus effects of (+)-HA-966 are based upon its partial agonist actions at the strychnine-insensitive glycine site. Furthermore, the lack of substitution of compounds with phencyclidine- like effects (dizocilpine, ibogaine and NPC 17742) or sedative properties (NPC 17742 and (-)-HA-966) suggests that these side-effects may not be part of the subjective effect profile of glycine partial agonists

3. Neuroendocrine and Neurochemical Effects of Acute Ibogaine Administration - A Time-Course Evaluation. Ali, S.F., Newport, G.D., Slikker, W., Rothman, R.B. and Baumann, M.H. Brain Res 737:215-220, 1996.

Abstract: Ibogaine (IBO) is an indole alkaloid that is reported to facilitate drug abstinence in substance abusers. Despite considerable investigation, the mechanism of IBO action in vivo and its suitability as a treatment for drug addiction remains unclear. The present study was designed to evaluate the time- course effects of acute IBO on neuroendocrine and neurochemical indices. Adult male rats were treated with i.p. saline or 50 mg/kg IBO and sacrificed 15: 30, 60, 120 min and 24 h later. Trunk blood was collected for hormone measures and brains were dissected for neurochemical analyses. IBO produced a rapid elevation in plasma prolactin that declined to control levels by 60 min. Corticosterone levels increased 15 min after drug administration, continued to increase for 120 min, but returned to control levels 24 h after dosing. IBO decreased dopamine (DA) concentrations in the striatum and frontal cortex at 30, 60 and 120 min after injection while DA metabolites, 3,4- dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), were elevated over the same time period. 24 h after IBO, DOPAC concentrations in striatum and HVA levels in the frontal cortex were below control values. Serotonin (5-HT) and its metabolite 5- hydroxyindole acetic acid (5-HIAA) were decreased at 60 min after IBO administration only in the striatum. These data indicate that a single injection of IBO produces a spectrum of effects that includes: (I) elevation of plasma prolactin and corticosterone, (2) short- and long-term effects on DA neurotransmission, and (3) modest, transient effects of 5- HT neurotransmission. The effects of IBO reported herein may have relevance to the anti-addictive properties of this drug, and this proposal warrants further investigation

4. Modulation of morphine-induced antinociception by ibogaine and noribogaine. Bagal, A.A., Hough, L.B., Nalwalk, J.W. and Glick, S.D. Brain Res 741:258-262, 1996.

Abstract: The potential modulation of morphine antinociception by the putative anti-addictive agent ibogaine and its active metabolite (noribogaine) was investigated in rats with the radiant heat tail-flick test. Ibogaine pretreatment (40 mg/kg, i.p., 19 h) significantly decreased morphine (4 mg/kg, s.c.) antinociception, with no effects in the absence of morphine. However, co-administration of ibogaine (1-40 mg/kg, i.p.) and morphine (4 mg/kg, s.c.) exhibited a dose-dependent enhancement of morphine antinociception. Co-administration of noribogaine (40 mg/kg, i.p.) and morphine also resulted in an increase in morphine antinociception, while noribogaine pretreatment (19 h) had no effect on morphine antinociception. The results show that ibogaine acutely potentiates morphine antinociception ant that noribogaine could be the active metabolite responsible for this effect. However, the inhibitory effects of a 19 h ibogaine pretreatment, which resemble ibogaine-induced inhibition of morphine's stimulant properties, cannot be accounted for by noribogaine.

5. Neurochemical and Behavioral Interactions Between Ibogaine and Nicotine in the Rat. Benwell, M.E.M., Holtom, P.E., Moran, R.J. and Balfour, D.J.K. Brit J Pharmacol 117:743-749, 1996.

Abstract: 1 In vivo brain microdialysis has been employed to investigate the effects of ibogaine on nicotine-induced changes in dopamine overflow in the nucleus accumbens (NAc) of freely moving rats. The effects of the compound on locomotor responses to nicotine and behaviour in the elevated plus-maze were also examined. 2 No changes were observed in the dopamine overflow or the locomotor activity of the animals following the administration of ibogaine (40 mg kg(-1), i.p.). However, ibogaine, administered 22 h earlier, significantly (P<0.01) attenuated the increase in dopamine overflow but not the hyperlocomotion, evoked by nicotine. 3 In the elevated plus-maze test, significant reductions in the open:total runway entries in both saline- treated controls (P<0.05) and nicotine-treated (P<0.01) rats were obtained when the animals were tested 22 h after pretreatment with ibogaine (40 mg kg(-1), i.p.). The total activity was significantly (P<0.01) greater in the nicotine-treated rats but this response was not affected by ibogaine pretreatment. 4 Administration of ibogaine was associated with reductions in the tissue levels of 5-hydroxyindoleacetic acid (5-HIAA) in the NAc (P<0.01) and striatum (P<0.05) and an increase in the level of this metabolite in the medial prefrontal cortex (mPFC) (P<0.01) while the levels of dopamine and 5-hydroxytryptamine (5- HT) in the mPFC were reduced (P<0.05). The DOPAC/dopamine (P<0.05) and 5- HIAA/5-HT (P<0.01) ratios were significantly increased in the mPFC for at least 7 days after a single treatment with ibogaine. 5 Ibogaine attenuates the nicotine-induced increases in dopamine overflow in the NAc and may, therefore, inhibit the rewarding effects of this drug. However, the long lasting anxiogenesis induced by ibogaine warrant further investigation before its use could be recommended for smokers

6. Ibogaine block of the NMDA receptor - in vitro and in vivo studies. Chen, K., Kokate, T.G., Donevan, S.D., Carroll, F.I. and Rogawski, M.A. Neuropharmacology 35:423-431, 1996.

Abstract: 1. Ibogaine, a proposed anti-addictive agent, has been found to interfere with the acquisition of a weak morphine-induced place preference. The present series of experiments determined if ibogaine would interfere with the expression of a previously established morphine (5 mg/kg) place preference. 2. A single injection of 40 mg/kg of ibogaine 24 h, 12 h or 4 h prior to the preference test (Experiment 1) or 80 mg/kg of ibogaine 24 hr prior to the preference test (Experiment 3) did not interfere with the expression of a morphine conditioned place preference. 3. Furthermore two injections of 40 mg/kg of ibogaine 48 h and 24 h or 24 h and 4 h prior to testing (Experiment 2) did not interfere with the expression of a morphine place preference. 4. Ibogaine appears to be incapable of attenuating the expression of a previously established one-trial morphine place preference. [References: 27]

7. Effects of Ibogaine, and Cocaine and Morphine After Ibogaine, on Ventral Tegmental Dopamine Neurons. French, E.D., Dillon, K. and Ali, S.F. Life Sci 59:PL199-PL205, 1996.

Abstract: Ibogaine, an indole containing alkaloid, has been shown to reduce the rate of injection of morphine and cocaine in self- administration protocols. Since morphine- and cocaine-induced modulation of dopamine release is impulse dependent and essential for their reinforcing effects, disruption of dopamine neuronal activity by ibogaine could explain its purported 'antiaddictive' properties. Therefore, the present study was designed to determine. (1) the acute effects of ibogaine on the activity of VTA dopamine neurons, and (2) whether ibogaine pretreatment causes a persistent modification of the dopamine neuronal response to morphine and cocaine. Extracellular recordings in anesthetized animals found that intravenous ibogaine markedly excited VTA dopamine neuronal firing. However, ibogaine pretreatment (6-8 hr and 19 hr before) failed to alter either the spontaneous activity of VTA neurons, or the response of these dopamine neurons to morphine or cocaine. Thus, ibogaine's excitatory effect on VTA neurons is not longlasting nor does it persistently alter cocaine- or morphine-induced changes in dopamine neuron impulse activity. Therefore, other mechanisms must be explored to account for the proposed antiaddictive properties of ibogaine.

8. Ibogaine Like Effects of Noribogaine in Rats. Glick, S.D., Pearl, S.M., Cai, J. and Maisonneuve, I.M. Brain Res 713:294-297, 1996.

Abstract: Ibogaine is a naturally occurring alkaloid that has been claimed to be effective in treating addiction to opioids and stimulants; a single dose is claimed to be effective for 6 months. Analogously, studies in rats have demonstrated prolonged (one or more days) effects of ibogaine on morphine and cocaine self- administration even though ibogaine is mostly eliminated from the body in several hours. These observations have suggested that a metabolite may mediate some of the effects of ibogaine. Recently, noribogaine was identified as a metabolite of ibogaine. Accordingly, the present study sought to determine, in rats, whether noribogaine had pharmacological effects mimicking those of ibogaine. Noribogaine (40 mg/kg) was found to decrease morphine and cocaine self-administration, reduce the locomotor stimulant effect of morphine, and decrease extracellular levels of dopamine in the nucleus accumbens and striatum. All of these effects were similar to effects previously observed with ibogaine (40 mg/kg); however, noribogaine did not induce any ibogaine-like tremors. The results suggest that noribogaine may be a mediator of ibogaine's putative anti-addictive effects

9. 18 Methoxycoronaridine, a Nontoxic Iboga Alkaloid Congener: Effects on Morphine and Cocaine Self Administration and on Mesolimbic Dopamine Release in Rats. Glick, S.D., Kuehne, M.E., Maisonneuve, I.M., Bandarage, U.K. and Molinari, H.H. Brain Res 719:29-35, 1996.

Abstract: Ibogaine, a naturally occurring iboga alkaloid, has been claimed to be effective in treating addiction to opioids and stimulants, and has been reported to inhibit morphine and cocaine self- administration in rats. However, ibogaine also has acute nonspecific side effects (e.g. tremors, decreased motivated behavior in general) as well as neurotoxic effects (Purkinje cell loss) manifested in the vermis of the cerebellum. 18- Methoxycoronaridine (MC) is a novel, synthetic iboga alkaloid congener that mimics ibogaine's effects on drug self- administration without appearing to have ibogaine's other adverse effects. Acutely, in rats, MC decreased morphine and cocaine self- administration but did not affect bar-press responding for water. In some rats, treatment with MC (40 mg/kg) induced prolonged decreases in morphine or cocaine intake lasting several days or weeks. MC had no apparent tremorigenic effect, and there was no evidence of cerebellar toxicity after a high dose (100 mg/kg) of MC. Similar to the effects of ibogaine and other iboga alkaloids that inhibit drug self-administration, MC (40 mg/kg) decreased extracellular levels of dopamine in the nucleus accumbens. MC therefore appears to be a safer, ibogaine- like agent that might be useful in the treatment of addictive disorders

10. Tissue distribution of ibogaine after intraperitoneal and subcutaneous administration. Hough, L.B., Pearl, S.M. and Glick, S.D. Life Sci 58:PL119-PL122, 1996.

Abstract: The distribution of the putative anti-addictive substance ibogaine was measured in plasma, brain, kidney, liver and fat after ip and sc administration in rats. One hr after ip dosing (40 mg/kg), drug levels ranged from 106 ng/ml (plasma) to 11,308 ng/g (fat), with significantly higher values after sc administration of the same dose. Drug levels were 10-20 fold lower 12 hr after the same dose. These results suggest that: 1) ibogaine is subject to a substantial "first pass" effect after ip dosing, domonstrated by higher drug levels following the sc route, 2) ibogaine shows a large accumulation in adipose tissue, consistent with its lipophilic nature, and 3) persistence of the drug in fat may contribute to a long duration of action.

11. Structurally Modified Ibogaine Analogs Exhibit Differing Affinities for NMDA Receptors. Layer, R.T., Skolnick, P., Bertha, C.M., Bandarage, U.K., Kuehne, M.E. and Popik, P. Eur J Pharmacol 309:159-165, 1996.

Abstract: Based on both preclinical findings and anecdotal evidence in man, the psychoactive indole alkaloid ibogaine has been suggested to have anti-addictive properties. Previous studies indicate that blockade of NMDA receptors may mediate at least some of the putative anti-addictive actions of ibogaine. The potencies of a series of ibogaine analogs to inhibit (+)-[3-H-3]5-methyl-10,11- dihydro-5H- dibenzo-[a,d]cyclohepten-5,10-imine ([H-3]MK-801) binding to NMDA receptors were examined. This series of analogs included the putative ibogaine metabolite O- desmethylibogaine, its metabolism resistant analog O-t- butyl-O-desmethylibogaine, the iboga alkaloids (+/-)- ibogamine, (+/-)-coronaridine, tabernanthine, harmaline, and the indolotropanes endo-3-(1- methylindol-2-yl)-8-methyl- 8-azabicyclo[3.2.1]octane (RS 075194- 190), exo-3-(1- methylindol-2-yl)-8-methyl-8- azabicyclo[3.2.1]octane (RS 075237-190) and endo-3-(indol-2-yl)-8- methyl-8- azabicyclo[3.2.1]octane (RS 025989-190). Among these compounds, ibogaine was the most potent inhibitor of [H- 3]MK-801 binding (K-i = similar to 1.2 mu M), whilst the compounds with the greatest structural similarity to ibogaine, O- desmethylibogaine and O-t-butyl-O- desmethylibogaine were less potent (K-i = similar to 5.5 and 179.0 mu M, respectively). In morphine-dependent mice, ibogaine, but not O-desmethylibogaine or O-t-butyl-O- desmethylibogaine, attenuated naloxone precipitated withdrawal jumping. These findings are consistent with the hypothesis that inhibition of the expression of morphine dependence by ibogaine is related to its NMDA receptor antagonist properties NIDDK, NIH, NEUROSCI LAB, BLDG 8, ROOM 111, BETHESDA, MD 20892, USA NIDDK, NIH, MED CHEM LAB, BETHESDA, MD, USA UNIV VERMONT, DEPT CHEM, BURLINGTON, VT, USA POLISH ACAD SCI, INST PHARMACOL, KRAKOW, POLAND

12. Determination of Ibogaine in Plasma by Gas Chromatography Chemical Ionization Mass Spectrometry. Ley, F.R., Jeffcoat, A.R. and Thomas, B.F. J Chromatogr 723:101-109, 1996.

Abstract: Ibogaine is a naturally occurring indole alkaloid that is currently being considered as a treatment medication for drug dependence. Although there have been a variety of investigations regarding the mechanisms of action and pharmacology of ibogaine, relatively little has been reported regarding quantitative methods. Because of the paucity of analytical methodologies, studies involving the pharmacokinetics and metabolism of ibogaine have also been limited. A method is described for the determination of ibogaine levels in plasma by gas chromatography- methane chemical ionization mass spectrometry. [(CH3)-C-13-H- 2]Ibogaine was synthesized and used as an internal standard to control for recovery during sample preparation. The assay requires one mi of plasma and is shown to be a selective and sensitive means of ibogaine quantitation

13. Ibogaine fails to interrupt the expression of a previously established one-trial morphine place preference [Review]. Luxton, T., Parker, L.A. and Siegel, S. Progress Neuropsychopharmacology & Biol Psych 20:857-872, 1996.

Abstract: The selective kappa agonists U50488 (10 mg/kg, i.p.) and spiradoline (1 mg/kg, i.p.) attenuated the locomotor activating effects of a morphine challenge (5 mg/kg, i.p.) administered 19 h later in rats. This antagonism of morphine by a re agonist was reversed by the selective kappa antagonist, norbinaltorphimine (10 mg/kg, s.c.). Furthermore, the kappa opioid antagonism of morphine was enhanced by prior morphine exposure (2 doses of 30 mg/kg, i.p. administered once a day for 2 days). The present data suggest that kappa-mu opioid interactions may occur over time periods that exceed the acute durations of drug actions. [References: 36]

14. Obovamine, a New Indole Alkaloid from Stemmadenia Obovata. Madinaveitia, A., Reina, M., Delafuente, G., Gonzalez, A.G. and Valencia, E. J NAT.PROD. 59:185-189, 1996.

Abstract: The stem bark of the Panamanian plant Stemmademia obovata has afforded a new ibogaine-type alkaloid, obovamine (1), whose structure was determined by a combination of spectral interpretation and chemical correlations. Ten known alkaloids, coronaridine, coronaridine hydroxyindolenine, voacangine, voacangine hydroxyindolenine, (19S)-heyneanine, (19S)-heyneanine hydroxyindolenine, (19S)-voacristine, (19S)-voacristine hydroxyindolenine, ajmalicine, and ajmalicinine, were also isolated. Voacangine was the main alkaloid constituent

15. Effect of Ibogaine on Morphine and U 50,488H Induced Analgesia and Hypothermia in the Mouse. Matwyshyn, G.A. and Bhargava, H.N. FASEB J 10:2618, 1996.

16. Ibogaine neurotoxicity: a re-evaluation. Molinari, H.H., Maisonneuve, I.M. and Glick, S.D. Brain Res 737:255-262, 1996.

Abstract: Ibogaine is claimed to be an effective treatment for opiate and stimulant addiction. O'Hearn and Molliver, however, showed that ibogaine causes degeneration of cerebellar Purkinje cells in rats. The present study re-examined cerebellar responses to the high doses of ibogaine used by O'Hearn and Molliver (100 mg/kg or 3 x 100 mg/kg) and sought to determine when a lower dose (40 mg/kg), one effective in reducing morphine and cocaine self-administration produced similar responses. Purkinje cell degeneration was evaluated with a Fink-Heimer II stain, and enhanced glial cell activity with an antibody to glial fibrillary acidic protein. Every rat treated with a high dose of ibogaine displayed clear evidence of Purkinje cell degeneration. The degeneration consistently occurred in the intermediate and lateral cerebellum, as well as the vermis. Purkinje cells in lobes 5 and 6 were particularly susceptible. Given the response properties of cells in these lobules, this finding suggests long-term motor deficits produced by ibogaine-induced degeneration should preferentially affect the head and upper extremity. In marked contract, rats given the smaller dose of ibogaine displayed no degeneration above the level seen in saline-treated animals. When combined with information on other compounds, these data suggest that the degenerative and anti-addictive properties of ibogaine reflect different actions of the drug.

17. Effect of Ibogaine on Cocaine Withdrawal Anxiogenesis in Mice. Onwere, I., Chakrabarti, A., Ali, S.F. and Onaivi, E.S. FASEB J 10:2595, 1996.

18. Ibogaine interferes with the establishment of conditioned taste avoidance produced by morphine and lithium. Parker, L.A. and Siegel, S. Learning & Motivation 27(2):170-178, 1996.

19. Prolonged antagonism of morphine-induced locomotor stimulation by kappa opioid agonists - enhancement by prior morphine exposure. Pearl, S.M. and Glick, S.D. Neurosci Lett 213:5-8, 1996.

20. Ibogaine, a putatively anti-addictive alkaloid. Popik, P. and Glick, S.D. Drugs of the Future 21(11):1109-1115, 1996.

Abstract: Ibogaine (NIH 10567, EndabuseTM) is among psychoactive indole alkaloids isolated from the shrub, Tabernanthe iboga. Preclinical studies demonstrate that ibogaine reduces self-administration of both cocaine and morphine, as well as attenuates the symptoms of morphine withdrawal. Several anecdotal observations in man seem to support the notion that ibogaine may have anti-addictive properties. Despite several years of intensive research, the mechanism of anti-addictive action of ibogaine has not been unequivocally defined. This is perhaps due to the fact that the neurochemical and molecular basis of drug addiction is by itself poorly understood. The recently identified antagonistic activity of ibogaine on N-methyl-D-aspartate (NMDA) receptors as well as its agonist activity at k opioid receptors are highly regarded as a possible mechanisms of these anti-addictive actions. However, it should be mentioned that ibogaine interacts with several neurotransmitter systems, including serotonin uptake sites and sigma sites, and that at least some of ibogaine's actions have been attributed to a long-lasting metabolite, possibly O-desmethylibogaine.

21. Facilitation of memory retrieval by the anti-addictive alkaloid, ibogaine. Popik, P. Life Sci 59:PL379-PL385, 1996.

Abstract: Anecdotal observations in humans indicate that indole alkaloid ibogaine may have anti-addictive properties. It has been suggested that the therapeutic action of ibogaine may depend upon facilitated access to the past experiences, purportedly influencing the initiation of drug addiction. To determine if ibogaine may facilitate memory retrieval, rats were trained in the Morris maze spatial navigation task. It has been found that ibogaine (0.25 or 2.5 mg/kg) or O-desmethyl-ibogaine (2.5 mg/kg) but not t-Butyl ibogaine, administered just before the test trial, facilitated spatial memory retrieval compared to rats receiving placebo treatment. It is concluded that although previously described NMDA receptor antagonist properties of ibogaine may represent a locus for at least some of its actions, other mechanisms, involving facilitation of memory retrieval may be of importance for its anti-addictive effects.

22. Effects of ibogaine and noribogaine on phosphoinositide hydrolysis. Rabin, R.A. and Winter, J.C. Brain Res 731:226-229, 1996.

Abstract: The purported efficacy of ibogaine for the treatment of drug dependence may be due in part to an active metabolite. Ibogaine undergoes first pass metabolism and is O-demethylated to 12- hydroxy-ibogamine (12-OH ibogamine). Radioligand binding assays were conducted to identify the potency and selectivity profiles for ibogaine and 12-OH ibogamine. A comparison of 12-OH ibogamine to the primary molecular targets identified previously for ibogaine demonstrates that the metabolite has a binding profile that is similar, but not identical to the parent drug. Both ibogaine and 12-OH ibogamine demonstrated the highest potency values at the cocaine recognition site on the 5-HT transporter. The same rank order (12-OH ibogamine > ibogaine), but lower potencies were observed for the [H-3]paroxetine binding sites on the 5-HT transporter. Ibogaine and 12-OH ibogamine were equipotent at vesicular monoamine and dopamine transporters. The metabolite demonstrated higher affinity at the kappa-1 receptor and lower affinity at the NMDA receptor complex compared to the parent drug. Quantitation of the regional brain levels of ibogaine and 12-OH ibogamine demonstrated micromolar concentrations of both the parent drug and metabolite in rat brain. Drug dependence results from distinct, but inter-related neurochemical adaptations, which underlie tolerance, sensitization and withdrawal. Ibogaine's ability to alter drug- seeking behavior may be due to combined actions of the parent drug and metabolite at key pharmacological targets that modulate the activity of drug reward circuits. [References: 66]

23. Ibogaine and noribogaine potentiate the inhibition of adenylyl cyclase activity by opioid and 5-HT receptors. Rabin, R.A. and Winter, J.C. Eur J Pharmacol 316:343-348, 1996.

Abstract: The effects of the putative anti-addictive compound ibogaine and its principal metabolite, noribogaine, on adenylyl cyclase activity were determined in various areas of the rat brain. Neither compound altered either basal or forskolin-stimulated adenylyl cyclase activities in the frontal cortex, midbrain or striatum. However, in all three brain areas the addition of ibogaine and noribogaine significantly enhanced inhibition of adenylyl cyclase activity by a maximally effective concentration of morphine. Similarly, both compounds also potentiated the inhibition of hippocampal adenylyl cyclase activity by a maximally effective concentration of 5-hydroxytryptamine (5-HT). Although ibogaine appears to be more potent than noribogaine in augmenting opioid- and 5-HT-mediated inhibition of adenylyl cyclase activity, both compounds appear to be of comparable efficacy. Neither compound, however, modified the inhibitory action of the muscarinic acetylcholine agonist, carbachol, on adenylyl cyclase activity. The present data indicate that ibogaine and noribogaine cause a selective increase in receptor-mediated inhibition of adenylyl cyclase activity. This potentiation may be involved in the pharmacological actions of these compounds.

24. Neuropharmacological characterization of local ibogaine effects on dopamine release. Reid, M.S., Hsu, K., Souza, K.H., Broderick, P.A. and Berger, S.P. J Neural Transm 103:967-985, 1996.

Abstract: Ibogaine is claimed to be an effective treatment for opiate and stimulant addiction. O'Hearn and Molliver, however, showed that ibogaine causes degeneration of cerebellar Purkinje cells in rats. The present study re-examined cerebellar responses to the high doses of ibogaine used by O'Hearn and Molliver (100 mg/kg or 3 x 100 mg/kg) and sought to determine whether a lower dose (40 mg/kg), one effective in reducing morphine and cocaine self- administration, produced similar responses. Purkinje cell degeneration was evaluated with a Fink-Heimer II stain, and enhanced glial cell activity with an antibody to glial fibrillary acidic protein. Every rat treated with the high dose of ibogaine displayed clear evidence of Purkinje cell degeneration. The degeneration consistently occurred in the intermediate and lateral cerebellum, as well as the vermis. Purkinje cells in lobules 5 and 6 were particularly susceptible. Given the response properties of cells in these lobules, this finding suggests any long-term motor deficits produced by ibogaine-induced degeneration should preferentially affect the head and upper extremity. In marked contrast, rats given the smaller dose of ibogaine displayed no degeneration above the level seen in saline- treated animals. When combined with information on other compounds, these data suggest that the degenerative and 'anti- addictive' properties of ibogaine reflect different actions of the drug. [References: 25]

25. Ibogaine, a Putative Treatment for Drug-Addiction -Neuropathology in Rats and Mice. Scallet, A.C., Ye, X., Rountree, R.L., Schmued, L.C. and Ati, S.F. Brain Pathol 6:356, 1996.

26. Ibogaine selectively inhibits nicotinic receptor-mediated catecholamine release. Schneider, A.S., Nagel, J.E. and Mah, S.J. Eur J Pharmacol 317:R1-R2, 1996.

Abstract: The effects of ibogaine, a putative anti-addictive drug, on stimulated catecholamine release were examined in cultured chromaffin cells to clarify its mechanism(s) of action. Low concentrations of ibogaine (1-10 mcM) had a selective inhibitory action on nicotinic receptor-mediated catecholamine release, while higher concentrations (100 mcM) inhibited additional modes of stimulated catecholamine release. These results suggest a selective inhibitory action of ibogaine at the nicotinic acetylcholine receptor, possibly at the receptor ion channel site.

27. The Effect of Ibogaine on Sigma Receptor Mediated and NMDA Receptor Mediated Release of (H 3) Dopamine. Sershen, H., Hashim, A. and Lajtha, A. Brain Res Bull 40:63-67, 1996.

Abstract: The indole alkaloid ibogaine has been suggested to have potential for inhibiting dependency on stimulant drugs. Radioligand binding studies have suggested possible multisite actions of ibogaine: affinity at the kappa-opioid, NMDA, and sigma receptors, with effects on dopamine (DA) release. To further investigate the multiplicity of sites of action of ibogaine and the presynaptic regulation of the DA release, the effect of ibogaine on NMDA- and sigma-receptor-mediated efflux of [H-3]DA was measured in striatal tissue from C57BL/6By mice. Striatal tissue was incubated in vitro with [H-3]DA and the effect on DA release was measured. Both NMDA (25 mu M) and the sigma receptor agonist (+/-)-pentazocine (20 mu M) alone increased the efflux of DA. (+/-)-Pentazocine (100 nM) did not inhibit the NMDA-evoked release. MK-801 (5 mu M) completely inhibited the NMDA-evoked release and inhibited the (+/-)- pentazocine-evoked release by 49%. Ibogaine (10 mu M) itself increased the efflux of DA; at 1 mu M it was without effect. Ibogaine (1 mu M) inhibited the NMDA-evoked release of DA by 31% and inhibited the (+/-)-pentazocine-evoked release by 48%. In addition, the level of basal release of DA obtained after the NMDA- or (+/-)-pentazocine-evoked-release remained higher in the tissue exposed to ibogaine throughout. The results suggest that sigma receptors can regulate the release of DA, along with an action at the NMDA receptor. We previously reported action of ibogaine at the kappa-opioid site. The elevated basal release of DA in the presence of ibogaine after NMDA-or (+/-)-pentazocine- evoked release may reflect the ibogaine-induced removal of the tonically active kappa-opioid system that acts presynaptically to reduce dopamine release. The kappa-opioid system also appears to be inhibitory on both the NMDA and sigma receptors

28. Effect of Ibogaine on Cocaine Induced Efflux of (H 3) Dopamine and (H 3) Serotonin from Mouse Striatum. Sershen, H., Hashim, A. and Lajtha, A. Pharmacol Biochem Behav 53:863-869, 1996.

Abstract: Ibogaine, an indole alkaloid with proposed antiaddictive properties, has structural similarity to serotonin and has been shown to have affinity to the kappa-opioid binding site. In addition to the dopamine system, the serotonin system is a major target for cocaine action and the opioid system can affect the serotonin system. Therefore, the present study examined the effect of ibogaine on cocaine-induced, electrically evoked efflux of [H-3]dopamine and [H-3]serotonin from striatal tissue incubated in vitro, and their modulation by the kappa-opioid system. Cocaine (10(-6) M) added in vitro increased the fractional efflux of both [H-3]dopamine (FRS(2)/FRS(1) = 2.42 +/- 0.36) and [H-3]serotonin (FRS(2)/FRS(1) = 1.31 +/- 0.06). Mice treated in vivo with ibogaine (40 mg/kg or 2 times 40 mg/kg, IP) and killed 2 or 18 h later still showed the cocaine-induced increase in [H-3]dopamine, but [H-3]serotonin efflux was not increased. The 5-HT1B agonist CGS-12066A (10(-6) M, added in vitro) increased [H-3]dopamine release, but did not alter cocaine- induced efflux of [H-3]dopamine. CGS-12066A did not affect [H- 3]serotonin release, but the cocaine-induced increase in [H- 3]serotonin was inhibited. CGS-12066A (1 mg/kg, SC) potentiated cocaine (25 mg/kg, SC)-induced locomotor activity. Ibogaine pretreatment reduced both the cocaine and the CGS- 12066A cocaine- induced increase in locomotor activity. The kappa- opioid agonist U-62066 (10(-6) M, added in vitro) reduced both [H-3]dopamine and [H-3]serotonin release. This inhibitory effect was blocked by in vivo administration of ibogaine. U-62066 did not alter cocaine- induced [H-3]dopamine efflux, but reduced cocaine-induced [H- 3]serotonin efflux. In striatal tissue from ibogaine-pretreated mice, U-62066 restored the cocaine-induced increase in [H- 3]serotonin release. U-62066 (1 mg/kg, SC) potentiated cocaine- induced behavior and maintained an increased locomotor activity after ibogaine treatment. The results suggest that ibogaine may block the cocaine-mediated effects on serotonergic transmission, that subsequently modulate dopamine release. The kappa-opioid modulation of serotonergic transmission is also involved

29. The Effect of Ibogaine on Sigma Receptor Mediated and NMDA Receptor Mediated Release of (H 3) Dopamine. Sershen, H., Hashim, A. and Lajtha, A. J Neurochem 66:S59, 1996.

30. Pharmacological screen for activities of 12-hydroxyibogamine - a primary metabolite of the indole alkaloid ibogaine. Staley, J.K., Ouyang, Q., Pablo, J., et al. Psychopharmacology 127:10-18, 1996.

Abstract: Local perfusion with ibogaine (10(-6)M-10(-3)M) via microdialysis probes in the nucleus accumbens or striatum of rats produced a biphasic dose-response effect on extracellular dopamine levels. Lower doses (10(-6)-M-10(-4)M) produced a decrease while higher doses (5 x 10(-4)M-10(-3)M) produced an increase in dopamine levels. Dihydroxyphenylacetic acid (DOPAC) levels were not effected. Naloxone (10(-6)M) and norbinaltorphimine (10(-6)M-10(-5)M) did not affect dopamine levels, but when co-administered with ibogaine (10(-4)M) blocked the decrease in dopamine levels produced by ibogaine. Ibogaine (10(-3)M) stimulation of dopamine levels in the striatum was calcium independent and not blocked by tetrodotoxin (10(-5)M). Pretreatment with cocaine (15 mg/kg), reserpine (5 mg/kg) or alpha-methyl-para-tyrosine (250 mg/kg) given intraperitoneally significantly reduced ibogaine (10(-3)M) stimulation of striatal dopamine levels. In striatal synaptosomes, both ibogaine and harmaline (10(-7)-10(-4)M) produced dose-dependent inhibition of [H-3]-dopamine uptake. These findings suggest that ibogaine has both inhibitory and stimulatory effects on dopamine release at the level of the nerve terminal. It is suggested that the inhibitory effect is mediated by kappa opiate receptors while the stimulatory effect is mediated by interaction with the dopamine uptake transporter. [References: 43]

31. Determination of ibogaine and 12-hydroxy-ibogamine in plasma by gas chromatography positive ion chemical ionization mass spectrometry. Alburges, M.E., Foltz, R.L. and Moody, D.E. J Anal Toxicol 19:381-386, 1995.

32. A Single Injection of Ibogaine Produces Selective Neurochemical Changes in Mouse Brain. Ali, S.F., Chetty, S.C., Meng, X.M., Newport, G.D. and Slikker, W. J Neurochem 65:S172, 1995.

33. Ibogaine and its congeners are sigma 2 receptor-selective ligands with moderate affinity. Bowen, W.D., Vilner, B.J., Williams, W., Bertha, C.M., Kuehne, M.E. and Jacobson, A.E. Eur J Pharmacol 279:R1-R3, 1995.

Abstract: Ibogaine (12-methoxyibogamine) exhibited moderate affinity for sigma 2 sites (Ki = 201 nM) and low affinity for sigma 1 sites (Ki = 8554 nM), thus showing 43-fold selectivity for sigma 2 receptors. Tabernanthine (13-methoxyibogamine) and (+/-)- ibogamine had sigma 2 Ki = 194 nM and 137 nM, respectively. However, they showed 3- to 5-fold higher sigma 1 affinity compared to ibogaine, resulting in about 14-fold selectivity for sigma 2 sites over sigma 1. A potential ibogaine metabolite, O- des-methyl-ibogaine, had markedly reduced sigma 2 affinity relative to ibogaine (Ki = 5,226 nM) and also lacked significant affinity for sigma 1 sites. (+/-)-Coronaridine ((+/-)-18- carbomethoxyibogamine) and harmaline (1-methyl-7-methoxy-3,4- dihydro-beta-carboline) lacked significant affinity for either sigma subtype. Thus, sigma 2 receptors could play a role in the actions of ibogaine

34. High Affinity Ibogaine Binding to a Mu Opioid Agonist Site. Codd, E.E. Life Sci 57:PL315-PL320, 1995.

Abstract: The naturally occurring indole alkaloid ibogaine is of interest because of its reported ability to block drug seeking behavior for extended periods. The compound also potentiates morphine- induced analgesia in mice and reduces certain naltrexone- precipitated withdrawal signs in morphine-dependent rats. Although these results might suggest ibogaine interaction with opioid receptors, previous receptor binding studies (Brain Res. 571:242-247, 1980) found that ibogaine had a K-i value of only 2 mu M for the kappa opioid receptor and was virtually inactive in blocking mu and delta receptor binding (K-i > 100 mu M). The present investigation of ibogaine interaction with the mu opioid receptor from mouse forebrain labeled with [H-3]- naloxone, however, yielded significantly more potent mu opioid K- i values. LIGAND analysis indicated that the data were best fit by a two site binding model, with K-i values of about 130 nM and 4 mu M, reflecting ibogaine recognition of different agonist affinity states of the receptor. Inclusion of 100 mM NaCl in the assay to induce the agonist low affinity state of the receptor, reduced ibogaine's inhibition of [H-3]-naloxone binding. These results suggest that ibogaine is an agonist at the mu opioid receptor with a K-i value of about 130 nM, potentially explaining ibogaine's antinociceptive effects as well as its reported reduction of opioid withdrawal symptoms and attenuation of drug seeking behavior

35. Effects of Ibogaine on Responding Maintained by Food, Cocaine and Heroin Reinforcement in Rats. Dworkin, S.I., Gleeson, S., Meloni, D., Koves, T.R. and Martin, T.J. Psychopharmacology 117:257-261, 1995.

Abstract: The effects of ibogaine (40 and 80 mg/kg, IF), an indole alkaloid proposed for the treatment of drug abuse, were determined in three different groups of rats responding under an FR10 schedule of food, cocaine or heroin reinforcement. Ibogaine (80 mg/kg, IF) given 60 min before the start of the session resulted in a 97% decrease in the number of ratios completed under the food reinforcement schedule and resulted in a decrease in responding the following day. Neither 40 mg/kg ibogaine given 60 min prior to the session nor 80 mg/kg given 24 h before the session suppressed responding maintained by cocaine infusions (0.33 mg/infusion). Pretreatment with 80 mg/kg ibogaine either 60 or 90 min prior to the session suppressed cocaine self- administration on the day it was administered and the longer pretreatment continued to suppress responding for 48 h. Responding maintained by heroin (18 mu g/infusion) was the most sensitive to the effects of ibogaine. Both 40 and 80 mg/kg ibogaine resulted in an almost complete suppression of responding following a 60-min pretreatment period. Responding maintained by heroin returned to control levels the day following the administration of ibogaine

36. Identification and quantification of the indole alkaloid ibogaine in biological samples by gas chromatography-mass spectrometry. Gallagher, C.A., Hough, L.B., Keefner, S.M., Seyed-Mozaffari, A., Archer, S. and Glick, S.D. Biochem Pharmacol 49:73-79, 1995.

Abstract: A sensitive and highly selective analytical chemical method for measuring the indole alkaloid ibogaine in biological samples has been developed. The method utilizes organic extraction, derivatization with trifluoroacetic anhydride, and detection by combined gas chromatography-mass spectrometry. The deuterated analog of ibogaine, O-[Cd3]-ibogaine, was synthesized and used as an internal standard for the method. Standard curves, constructed from variable amounts of ibogaine (50-400 ng) and a fixed amount of internal standard (250 ng) were linear. The method has an approximate detection limit of at least 20 ng/mL of tissue extract (180 ng/g tissue), with a coefficient of variation of 8 to 12.5%. Chemical stability studies with the method found that aqueous ibogaine solutions (1-10 mg/mL) could be stored at 10 degrees for up to 7 months with no more than 10% loss. The method was also used to measure brain ibogaine levels in rats 1 and 19 hr after a single dose of drug (40 mg/kg, i.p.); the results suggest a rapid disappearance of the drug after i.p. dosing. The method will help reveal the pharmacokinetic properties of this putative anti-addictive agent in animals and humans

37. Identification and Quantitation of Ibogaine and an O Demethylated Metabolite in Brain and Biological Fluids Using Gas Chromatography Mass Spectrometry. Hearn, W.L., Pablo, J., Hime, G.W. and Mash, D.C. J Anal Toxicol 19:427-434, 1995.

38. Comparison of the hallucinogenic indole alkaloids ibogaine and harmaline for potential immunomodulatory activity. House, R.V., Thomas, P.T. and Bhargava, H.N. Pharmacology 51:56-65, 1995.

Abstract: The immunomodulatory potential of the indole alkaloids ibogaine and harmaline was examined in a panel of in vitro immune function assays. These assays were chosen to assess T-cell regulatory and effector function, B-cell function, macrophage function, and natural killer-cell function. The in vitro exposure to either ibogaine or harmaline resulted in a dose-related suppression of all immune functions examined except macrophage function. This suppression was noted at various concentrations in different assays, but was generally only associated with high concentrations (10-100 mumol/l)

39. Effects of Ibogaine on Sensory Motor Function, Activity, and Spatial Learning in Rats. Kesner, R.P., Jacksonsmith, P., Henry, C. and Amann, K. Pharmacol Biochem Behav 51:103-109, 1995.

Abstract: Ibogaine, a naturally occurring alkaloid, has been show to reduce naloxone-precipitated withdrawal symptoms from morphine. Given the clinical possibilities, it is important to determine ibogaine's effects on sensory-motor function, activity, learning, and memory. Long-Evans rats injected with doses of 20- 60 mg/kg of ibogaine displayed slower response times on sensory and sensory-motor tests and were impaired in performing specific motor reflexes at doses of 40-60 mg/kg. Furthermore, these rats showed a marked reduction in locomotor and nonlocomotor activity, as well as emotionality at doses ranging from 10-40 mg/kg. At the higher doses the rats appeared to be virtually inactive. There were also deficits in learning a spatial location task (a dry- land version of the Morris water-maze). The deficits, however, were probably due to a reduction in locomotor activity and reduction in detection of sensory information. In a final experiment, a single injection of 40 mg/kg of ibogaine had marked deleterious effects on the acquisition of the spatial location task 1 but not 7 days after the injection, even though in this case there were no effects on sensory motor function 1 or 7 days after the injection. Thus, there are severe sensory- motor activity and learning problems while the animal is under the influence of ibogaine (acute effect) as well as long-term consequences on learning without concomitant changes in sensory- motor function

40. Ibogaine in the treatment of chemical dependency disorders: clinical perspectives. Lotsof, H.S. Multidisciplinary Association for Psychedelic Studies 5:1995.

41. Ibogaine Possesses a Selective Affinity for Sigma(2) Receptors. Mach, R.H., Smith, C.R. and Childers, S.R. Life Sci 57:PL57-PL62, 1995.

Abstract: The alkaloid ibogaine is potentially useful to reduce craving for several drugs of abuse, but its mechanism of action is not known. In the current study, in vitro studies were conducted in order to determine the affinity of ibogaine for sigma receptors. Our results indicate that ibogaine has a relatively high affinity for sigma(2) receptors (K-i = 90.4 and 250 nM) and a significantly lower affinity for sigma(1) receptors (K-i = 9310 nM). These data suggest that ibogaine may have a higher affinity at sigma(2) receptors than any other known CNS receptor. Its low affinity for sigma(1) receptors also suggests that ibogaine may be a suitable lead compound for structure-activity relationship studies aimed at developing sigma(2)-selective ligands

42. Properties of Ibogaine and Its Principal Metabolite (12 Hydroxyibogamine) at the MK 801 Binding Site of the NMDA Receptor Complex. Mash, D.C., Staley, J.K., Pablo, J.P., Holohean, A.M., Hackman, J.C. and Davidoff, R.A. Neurosci Lett 192:53-56, 1995.

Abstract: The putative anti-addiction alkaloid ibogaine and its principal metabolite 12-hydroxyibogamine appear to act at the (+)-5 methyl- 10,11-dihydro-5H-dibenzo[a,d]cycloheten-5-10 maleate (MK-801) binding site in the N-methyl-D-aspartate (NMDA)- receptor cation channel. This conclusion is based on findings that both compounds competitively displaced specific [H-3]MK-801 binding to membranes from postmortem human caudate and cerebellum and from frog spinal cord. Ibogaine was 4-6-fold more potent than its metabolite and both compounds were less potent (50-1000-fold) than MK-801 binding to the NMDA receptor. In addition, ibogaine (100 mu M) and 12-hydroxyibogamine (1 mM) blocked (85-90% of control) the ability of NMDA (100 mu M, 5 s) to depolarize frog motoneurons in the isolated frog spinal cord. The prevention of NMDA- depolarizations in frog motoneurons showed use-dependency and was very similar to the block produced by MK-801. In view of the abilities of MK-801 to affect the responses to addictive substances in pre-clinical investigations, our results are compatible with the idea that the ability of ibogaine and 12- hydroxyibogamine to interrupt drug-seeking behavior may, in part, result from their actions at the MK-801 binding site

43. A Preliminary Report on the Safety and Pharmacokinetics of Ibogaine. Mash, D.C., Douyon, R., Hearn, W.L., Sambol, N.C. and Sanchez-Ramos, J. Biol Psychiat 37:652, 1995.

44. Identification of a Primary Metabolite of Ibogaine That Targets Serotonin Transporters and Elevates Serotonin. Mash, D.C., Staley, J.K., Baumann, M.H., Rothman, R.B. and Hearn, W.L. Life Sci 57:PL45-PL50, 1995.

Abstract: Ibogaine is a hallucinogenic indole with putative efficacy for the treatment of cocaine, stimulant and opiate abuse. The purported efficacy of ibogaine following single dose administrations has led to the suggestion that a long-acting metabolite of ibogaine may explain in part how the drug reduces craving for psychostimulants and opiates. We report here that 12- hydroxyibogamine, a primary metabolite of ibogaine, displays high affinity for the 5-HT transporter and elevates extracellular 5- HT. In radioligand binding assays, 12- hydroxyibogamine was 50- fold more potent at displacing radioligand binding at the 5-HT transporter than at the DA transporter. Ibogaine and 12- hydroxyibogamine were equipotent at the dopamine transporter. In vivo microdialysis was used to evaluate the acute actions of ibogaine and 12-hydroxyibogamine on the levels of DA and 5-HT. Administration of 12- hydroxyibogamine produced a marked dose- related elevation of extracellular 5-HT. Ibogaine and 12- hydroxyibogamine failed to elevate DA levels in the nucleus accumbens over the dose range tested. The elevation in synaptic levels of 5-HT by 12- hydroxyibogamine may heighten mood and attenuate drug craving. The effects of the active metabolite on 5- HT transmission may account in part for the potential of ibogaine to interrupt drug- seeking behavior in humans

45. Excitotoxic Insult Due to Ibogaine Leads to Delayed Induction of Neuronal Nos in Purkinje Cells. O'Hearn, E., Zhang, P. and Molliver, M.E. Neuroreport 6:1611-1616, 1995.

Abstract: IBOGAINE causes degeneration of Purkinje cells (PKCs), presumably via activation of neurons in the inferior olive leading to release of glutamate at climbing fiber terminals. Following ibogaine administration, some Purkinje cells express NADPH-diaphorase and neuronal NOS (nNOS), neither of which is present normally in these cells. The induction of NOS is delayed in onset, dose-related, and detected in neurons adjacent to degenerated PKCs. The results demonstrate that nNOS induction can follow excitotoxic neuronal injury or perturbation. However, NO is unlikely to participate in the initial phase of PKC damage. Both the late induction of nNOS and the spatial relationship between damaged and nNOS-expressing PKCs are consistent with a role for NO in either neuronal recovery or delayed cell death following excitotoxic injury

46. Prior Morphine Exposure Enhances Ibogaine Antagonism of Morphine Induced Locomotor Stimulation. Pearl, S.M., Johnson, D.W. and Glick, S.D. Psychopharmacology 121:470-475, 1995.

Abstract: Ibogaine is currently being investigated for its potential use as an anti-addictive agent. In the present study we sought to determine whether prior morphine exposure influences the ability of ibogaine to inhibit morphine-induced locomotor stimulation. Female Sprague-Dawley rats were pretreated once a day for 1-4 days with morphine (5, 10, 20 or 30 mg/kg, IF) or saline and then received ibogaine (40 mg/kg, IF) 5 h after the last morphine pretreatment dose. Compared to rats pretreated with saline, rats pretreated with morphine (10, 20 or 30 mg/kg, IF) before ibogaine (40 mg/kg, IF) showed a significant reduction in morphine-induced (5 mg/kg, IF) locomotor stimulation when tested 19 h after ibogaine administration. Furthermore, this effect was apparent over a range of ibogaine (5-60 mg/kg, IF) and morphine test (2.5- 5 mg/kg, IF) dosages. Doses of ibogaine (5 and 10 mg/kg, IF) which alone were inactive inhibited morphine-induced locomotor activity when rats had been pretreated with morphine. These results, showing that morphine pre-exposure affects ibogaine activity, suggest that variable histories of opioid exposure might account for individual differences in the efficacy of ibogaine to inhibit opioid addiction

47. Radioligand Binding Study of Noribogaine, a Likely Metabolite of Ibogaine. Pearl, S.M., Herrickdavis, K., Teitler, M. and Glick, S.D. Brain Res 675:342-344, 1995.

Abstract: Radioligand-binding studies were performed to ascertain the actions of noribogaine, a suspected metabolite of ibogaine, on opioid receptors. Consistent with previous results, ibogaine showed highest affinity for kappa opioid receptors (K-i = 3.77 +/- 0.81 mu M), less affinity for mu receptors (K-i = 11.04 +/- 0.66 mu M) and no affinity for delta receptors (K-i > 100 mu M). Noribogaine showed a higher affinity than ibogaine for all of the opioid receptors: kappa K-i = 0.96 +/- 0.08 mu M, mu K-i- = 2.66 +/- 0.62 mu M and delta K-i = 24.72 +/- 2.26 mu M. These data suggest that noribogaine is active in vivo and that it may contribute to ibogaine's pharmacological effects

48. 100 years of ibogaine: neurochemical and pharmacological actions of a putative anti-addictive drug. [Review]. Popik, P., Layer, R.T. and Skolnick, P. Pharmacol Rev 47:235-253, 1995.

Abstract: Ibogaine (NIH 10567, Endabuse) is one of the psychoactive indole alkaloids found in the West African shrub, Tabernanthe iboga. Since its introduction to Western medicine more than a century ago, ibogaine has had a variety of uses ranging from a trypanocide to an adjunct for psychotherapy. However, during the past decade, anecdotal observations have led to the hypothesis that ibogaine possesses "anti-addictive" properties. Preclinical studies demonstrating that ibogaine reduces self-administration of both cocaine and morphine and attenuates the symptoms of morphine withdrawal support this hypothesis. Unresolved, however, is the mechanism(s) responsible for these putative "anti-addictive" and other psychopharmacological effects of ibogaine. This manuscript reviews the ibogaine literature, from the initial botanical description of Tabernanthe iboga over 100 years ago to potential molecular mechanisms for its "anti-addictive" properties.

49. NMDA Antagonist Properties of the Putative Antiaddictive Drug, Ibogaine. Popik, P., Layer, R.T., Fossom, L.H., et al. J Pharmacol Exp Ther 275:753-760, 1995.

Abstract: Both anecdotal reports in humans and preclinical studies indicate that ibogaine interrupts addiction to a variety of abused substances including alcohol, opiates, nicotine and stimulants. Based on the similarity of these therapeutic claims to recent preclinical studies demonstrating that N-methyl-D- aspartate (NMDA) antagonists attenuate addiction-related phenomena, we examined the NMDA antagonist properties of ibogaine. Pharmacologically relevant concentrations of ibogaine produce a voltage-dependent block of NMDA receptors in hippocampal cultures (K-i, 2.3 mu M at -60 mV). Consistent with this observation, ibogaine competitively inhibits [H-3]1-[1-(2- thienyl)-cyclohexyl]piperidine binding to rat forebrain homogenates (K-i, 1.5 mu M) and blocks glutamate-induced cell death in neuronal cultures (IC50, 4.5 mu M). Moreover, at doses previously reported to interfere with drug-seeking behaviors, ibogaine substitutes as a discriminative stimulus (ED(50), 64.9 mg/kg) in mice trained to discriminate the prototypic voltage- dependent NMDA antagonist, dizocilpine (0.17 mg/kg), from saline. Consistent with previous reports, ibogaine reduced naloxone- precipitated jumping in morphine-dependent mice (ED(50), 72 mg/kg). Although pretreatment with glycine did not affect naloxone-precipitated jumping in morphine-dependent mice, it abolished the ability of ibogaine to block naloxone- precipitated jumping. Taken together, these findings link the NMDA antagonist actions of ibogaine to a putative ''antiaddictive'' property of this alkaloid, its ability to reduce the expression of morphine dependence

50. Attenuation of Alcohol Intake by Ibogaine in 3 Strains of Alcohol Preferring Rats. Rezvani, A.H., Overstreet, D.H. and Leef, Y.W. Pharmacol Biochem Behav 52:615-620, 1995.

Abstract: Alcohol-preferring (P), Fawn-Hooded (FH) and alcohol- accepting (AA) rats were injected intraperitoneally (IP) or subcutaneously (SC) with different doses (10, 30, and 60 mg/kg) of Ibogaine or vehicle. In a separate experiment, FH rats were administered intragastrically (IG) with either 60 mg/kg of Ibogaine or vehicle for 5 days. In addition, the effects of Ibogaine on blood alcohol concentrations were measured. Our data show that, contrary to the SC administration of Ibogaine, IP administration of the agent significantly and dose-dependently reduced alcohol intake in these rats. Subchronic IG administration of 60 mg/kg of Ibogaine into FH rats significantly reduced alcohol intake without the development of tolerance or a significant effect on food or water intake. A single IP injection of 60 mg/kg Ibogaine into FH rats did not affect the blood alcohol levels. These results show that Ibogaine when injected IP or IG, but not SC, can significantly reduce alcohol intake without an effect on blood alcohol concentrations or food intake. These findings may suggest the involvement of Ibogaine's metabolite(s) in reducing alcohol intake. Although the neuronal mechanism(s) of action of Ibogaine on the regulation of alcohol intake is not fully understood, it is speculated that Ibogaine or its metabolite(s) exerts its attenuating effect on alcohol intake by modulating neurotransmitters/neuromodulators proposed to be involved in regulation of alcohol consumption

51. The Effect of Ibogaine on Kappa Opioid Induced and 5 HT3 Induced Changes in Stimulation Evoked Dopamine Release in Vitro from Striatum of C57BL/6By Mice. Sershen, H., Hashim, A. and Lajtha, A. Brain Res Bull 36:587-591, 1995.

Abstract: Ibogaine is an indole alkaloid that has been suggested to have potential efficacy for interrupting dependency on stimulant drugs. The kappa-opioid and serotonin 5-HT3 systems may be involved in the action of ibogaine, related to their modulation of dopaminergic transmission. The kappa-opioid agonist U 62066 attenuated the in vitro stimulation-evoked efflux of tritium label from striatal tissue prelabeled with [H-3]dopamine. In mice pretreated with ibogaine . HCI (40 mg/kg IP given 2 h prior or 2 x 40 mg/kg and animals killed 18 h later), the inhibitory effect of U 62066 on stimulation-evoked release of tritium was eliminated, The 5-HT3 agonist phenylbiguanide had a biphasic effect on stimulation-evoked release of tritium; at 10(-6) M phenylbiguanide, stimulation-evoked release was attenuated. At 10(-5) M the basal outflow of tritium was increased. Ibogaine pretreatment had no effect on basal or stimulation-evoked release in the presence of 10(-6) M phenylbiguanide, but increased the stimulation-evoked outflow of tritium in the presence of 10(-5) M phenylbiguanide. Cocaine (10(-6) M), a dopamine uptake blocker, increased the electrically-evoked release of dopamine; ibogaine pretreatment did not affect the enhanced electrically-induced release of [H-3]dopamine by in vitro cocaine. The effects of ibogaine on the kappa-opioid and 5- HT3 receptors, located presynaptically on striatal dopamine terminals, modulating dopamine release may partly underlie its putative antiaddictive properties

52. Medicinal Chemical Studies of Antiinflammatory and Analgesic Natural Products. Shen, T.Y. J Chin Chem Soc 42:617-621, 1995.

Abstract: Following the discovery of salicylates and its conversion to aspirin, natural products research has provided many promising leads for further modification as anti-inflammatory and analgesic agents. Recent studies have focused on biosynthesis inhibitors of eicosanoids and receptor antagonists of the platelet activating factor, including a new class of dual functional inhibitors derived from neolignans. The highly potent analgesic alkaloid epibatidine from the frog skin has been synthesized and recharacterized as a very strong acetylcholine nicotinic receptor agonist. Some novel epibatidine analogs have shown promise as potential CNS drugs and research probes for clarifying the anti- addictive property of the African alkaloid ibogaine

53. Receptor Binding Profile Suggests Multiple Mechanisms of Action Are Responsible for Ibogaines Putative Anti Addictive Activity. Sweetnam, P.M., Lancaster, J., Snowman, A., et al. Psychopharmacology 118:369-376, 1995.

Abstract: The indole alkaloid ibogaine (NIH 10567, Endabuse) is currently being examined for its potential utility in the treatment of cocaine and opioid addiction. However, a clearly defined molecular mechanism of action for ibogaine's putative anti- addictive properties has not been delineated. Radioligand binding assays targeting over 50 distinct neurotransmitter receptors, ion channels, and select second messenger systems were employed to establish a broad in vitro pharmacological profile for ibogaine. These studies revealed that ibogaine interacted with a wide variety of receptors at concentrations of 1-100 mu M. These included the mu, delta, kappa, opiate, 5HT(2), 5HT(3), and muscarinic(1 and 2) receptors, and the dopamine, norepinephrine, and serotonin uptake sites. In addition, ibogaine interacted with N-methyl-D-aspartic acid (NMDA) associated ion and sodium ion channels as determined by the inhibition of [H-3]MK-801 and [H- 3]bactrachotoxin A 20-alpha- benzoate binding (BTX-B), respectively. This broad spectrum of activity may in part be responsible for ibogaine's putative anti- addictive activity

54. Anti Addiction Drug Ibogaine on Trial. Touchette, N. Nature Med 1:288-289, 1995.

55. Discriminative Stimulus Effects of R (+) 3 Amino 1 Hydroxypyrrolid 2 One, ((+) Ha 966), a Partial Agonist of the Strychnine Insensitive Modulatory Site of the N Methyl D Aspartate Receptor. Witkin, J.M., Brave, S., French, D. and Geterdouglass, B. J Pharmacol Exp Ther 275:1267-1273, 1995.

Abstract: The strychnine-insensitive glycine site on the N-methyl-D- aspartate (NMDA) receptor complex is a target for development of a host of therapeutic agents including anxiolytics, antidepressants, antiepileptics, anti-ischemics and cognitive enhancers. In the present experiments, the discriminative stimulus effects of (+)-HA-966 [R-(+)-5-amino-1-hydroxypyrrolid- 2-one], a low-efficacy partial agonist of the glycine site, was explored. Male, Swiss-Webster mice were trained to discriminate (+)-HA-966 (170 mg/kg i.p.) from saline in a T-maze under which behavior was controlled by food. Other glycine partial agonists, 1-amino-1-cyclopropanecarboxilic acid and D-cycloserine, fully substituted for the discriminative stimulus effects of (+)-HA- 966 despite known differences in other pharmacological effects of these compounds. The glycine site antagonist, 7- chlorkynurenic acid, did not substitute for (+)-HA-966. Likewise other functional NMDA antagonists acting at nonglycine sites of the NMDA receptor also did not substitute: neither the high (dizocilpine) or low affinity (ibogaine) ion-channel blocker, the competitive antagonist, NPC 17742 [2R,4R,5S-2-amino-4,5-(1,2- cyclohexyl)-7-phosphonoheptanoic acid], nor the polyamine antagonist, ifenprodil, substituted for (+)-HA-966. Although the full agonist, glycine, did riot substitute, this compound fully blocked the discriminative stimulus effects of (+)-HA-966. In a separate group of mice trained to discriminate 0.17 mg/kg of dizocilpine from saline, (+)-HA-966 produced a maximum of only 50% dizocilpine-appropriate responses. These data suggest that the discriminative stimulus effects of (+)-HA-966 are based upon its partial agonist actions at the strychnine-insensitive glycine site. Furthermore, the lack of substitution of compounds with phencyclidine-like effects (dizocilpine, ibogaine and NPC 17742) or sedative properties (NPC 17742 and (-)-HA-966) suggests that these side-effects may not be part of the subjective effect profile of glycine partial agonists

56. Ibogaine modulates cocaine responses which are altered due to environmental habituation: in vivo microvoltammetric and behavioral studies. Broderick, P.A., Phelan, F.T., Eng, F. and Wechsler, R.T. Pharmacol Biochem Behav 49:711-728, 1994.

Abstract: Ibogaine, a serotonergic (5-HTergic) indole alkaloid, was studied for cocaine modulatory effects on four parameters of behavior by computerized infrared photocell beam detection. The behavioral parameters were: a) locomotor activity (ambulations), b) rearing, c) stereotypy (fine movements, primarily grooming), and d) agoraphobia [(thigmotaxis) a natural tendency to avoid the center of the behavioral chamber]. With each behavioral data point, dopamine (DA) release, and serotonin (5-HT) release were detected within seconds in nucleus accumbens (NAcc) of the same behaving male Sprague-Dawley rats, using in vivo electrochemistry (voltammetry). Ibogaine was administered (40 mg/kg IP) for 4 consecutive days. Importantly, the DAergic and the 5-HTergic responses to (SC) cocaine and two behavioral responses, ambulations and central ambulations, were reduced in intensity due to extended time spent in the novel behavioral chamber (habituated). Rearing and fine movement patterns were not habituated. The results show that ibogaine downmodulated the (SC) cocaine-induced increase in NAcc DA release (p < 0.0001) and potentiated the (SC) cocaine-induced decrease in NAcc 5-HT release (p < 0.0001). Concurrently, ibogaine downmodulated cocaine-induced ambulation (p < 0.0001) and central ambulation behavior (p < 0.0001). On the other hand, the behavioral parameters that did not exhibit habituation, i.e., rearing behavior and fine movement behavior, were not downmodulated by ibogaine (p < 0.1558) (p < 0.3763), respectively. Furthermore, ibogaine itself did not significantly alter NAcc DA release over the 2-h period studied (p < 0.9113) although individual time points were significantly affected bidirectionally. Concurrently ibogaine significantly increased 5-HT release (p < 0.0155). Behaviorally, ibogaine appears to be a weak psychostimulant. The data show a critical modulatory role for 5-HT in ibogaine-cocaine interactions. Also elucidated as critical is the efficacy of ibogaine when the response to (SC) cocaine is decreased due to the habituation of the animals to their environment

57. The inhibitory effect of norharman on morphine withdrawal syndrome in rats: comparison with ibogaine. Cappendijk, S.L., Fekkes, D. and Dzoljic, M.R. Behav Brain Res 65:117-119, 1994.

Abstract: Norharman (20 mg/kg, i.p.) and ibogaine (40 mg/kg, i.p.) significantly attenuated naloxone (4 mg/kg, i.p.)-precipitated withdrawal syndrome in morphine-dependent rats. Several withdrawal signs, such as teeth-chattering, chewing, penile licking and diarrhoea, were decreased by both norharman and ibogaine. In addition, norharman reduced also the withdrawal grooming and rearing. It is concluded that both norharman and ibogaine are inhibitors of withdrawal syndrome in morphine- dependent rats

58. Effects of Iboga Alkaloids on Morphine and Cocaine Self Administration in Rats Relationship to Tremorigenic Effects and to Effects on Dopamine Release in Nucleus Accumbens and Striatum. Glick, S.D., Kuehne, M.E., Raucci, J., et al. Brain Res 657:14-22, 1994.

Abstract: Ibogaine, a naturally occurring alkaloid, has been claimed to be effective in treating addiction to opioid and stimulant drugs and has been reported to decrease morphine and cocaine self- administration in rats. The present study sought to determine if other iboga alkaloids, as well as the chemically related harmala alkaloid harmaline, would also reduce the intravenous self- administration of morphine and cocaine in rats. Because both ibogaine and harmaline induce tremors, an effect that may be causally related to neurotoxicity in the cerebellar vermis, the temorigenic activities of the other iboga alkaloids were assessed. Lastly, in view of the involvement of the dopaminergic mesolimbic system in the actions of drugs of abuse, the effects of some of the iboga alkaloids on extracellular levels of dopamine and its metabolites in the nucleus accumbens and striatum were determined. All of the tested alkaloids (i.e., ibogaine, tabernanthine, R- and S-coronaridine, R- and S- ibogamine, desethylcoronaridine, and harmaline) dose-dependently (2.5-80 mg/kg) decreased morphine and cocaine intake in the hour after treatment; decreases in morphine and cocaine intake intake were also apparent the day after administration of some but not all of these alkaloids (i.e., ibogaine, tabernanthine, desethylcoronaridine, and the R-isomers of coronaridine and ibogamine). In some rats, there were persistent decreases in morphine or cocaine intake for several days after a single injection or after two or three weekly injections of one or another of these alkaloids; R-ibogamine produced such effects more consistently than any of the other alkaloids. At the doses used to assess effects on drug self-administration, ibogaine, tabernanthine, desethylcoronaridine and harmaline all induced tremors for at least 2-3 h; both enantioners of both coronaridine and ibogamine induced very weak no tremors. Using in vivo microdialysis, the effects of the R- and S-enantiomers of coronaridine and ibogamine on extracellular dopamine levels in the nucleus accumbaens and striatum were compared. The R- entantiomers decreased dopamine levels in both brain regions whereas the S-enantiomers produced no significant changes in dopamine levels in either region. The results of this study indicate that the 'anti-addictive' and tremorigenic effects of the iboga alkaloids can be dissociated and that long-term effects of these alkaloids on drug self-administration appear to be related to initial decreases in dopaminergic activity in specific brain areas

59. Evidence that ibogaine releases dopamine from the cytoplasmic pool in isolated mouse striatum. Harsing, L.G.,Jr., Sershen, H. and Lajtha, A. J Neural Transm Gen Sect 96:215-225, 1994.

Abstract: We measured the effect of ibogaine on the tritium efflux from isolated mouse striatum preloaded with [3H]dopamine ([3H]DA). Ibogaine increased the basal tritium outflow in a concentration- dependent manner, but it was without effect on electrical stimulation-induced tritium overflow. Separation of the released radioactivity after ibogaine administration showed that this drug increased the release of [3H]DA and [3H]-dihydroxyphenylacetic acid ([3H]DOPAC), but the efflux of O-methylated-deaminated metabolites was not changed. The dopamine (DA)-releasing effect of ibogaine was reduced by the DA uptake inhibitors cocaine and nomifensine. The tritium efflux evoked by ibogaine was not altered by omission of Ca2+ from the perfusion buffer or by inhibition of the voltage-sensitive Na+ channels with tetrodotoxin. Ibogaine maintained its effect on release from superfused striatum prepared from reserpine-pretreated mice. The ibogaine-induced tritium release measured from mouse striatum that was preloaded with [3H]DA was not affected by the D-2 DA receptor ligands (-)-quinpirole and (+/-)-sulpiride, indicating that the ibogaine-induced release is not subject to presynaptic autoreceptor regulation. Ibogaine failed to affect [3H]DA uptake and retention in mouse striatum. These data indicate that at the nerve terminal level ibogaine releases DA, and the primary source for the release is probably the cytoplasmic pool. The DA- releasing effect of ibogaine may have importance in mediation of its hallucinogenic action, as seen in a frequent practice in African cults

60. Dose dependence of ibogaine neurotoxicity. Molinari, H.H., Maisonneuve, I.M. and Glick, S.D. Soc Neurosci Abstracts 20:504, 1994.(Abstract)

61. The putative anti-addictive drug ibogaine is a competitive inhibitor of [3H]MK-801 binding to the NMDA receptor complex. Popik, P., Layer, R.T. and Skolnick, P. Psychopharmacology 114:672-674, 1994.

Abstract: Ibogaine is a putative anti-addictive drug with potential efficacy for the treatment of opiate, stimulant, and alcohol abuse. We now report ibogaine is a competitive inhibitor (Ki, 1.01 +/- 0.1 microM) of [3H]MK-801 binding to N-methyl-D- aspartate (NMDA) receptor coupled cation channels. Since MK-801 can attenuate the development of tolerance to morphine and alcohol as well as sensitization to stimulants in preclinical studies, the reported ability of ibogaine to modify drug-seeking behavior in man may be attributable to a blockade of NMDA receptor coupled cation channels

62. Ibogaine research update: phase I human study. Sanchez-Ramos, J. and Mash, D.C. Multidisciplinary Association for Psychedelic Studies 4:11, 1994.

Abstract: We have recently received approval to begin Phase I studies to assess the safety, metabolism and pharmacokinetics of ibogaine in volunteers who have already experienced ibogaine. As of the moment, the effects of 1 mg/kg p.o. have been studied in three volunteers who had previously experienced ibogaine at much higher doses while in Holland. No tremor or ataxia was noted, and no hallucinogenic effects were noted. The subjects felt nothing at all other than perhaps being somewhat calmer than usual. Pharmacokinetic profiling is currently being done with samples of blood taken from these subjects. These results are to be reported to the FDA before commencing with the next dosage level, 2 mg/kg.

63. Effect of ibogaine on serotonergic and dopaminergic interactions in striatum from mice and rats. Sershen, H., Hashim, A. and Lajtha, A. Neurochem Res 19:1463-1466, 1994.

Abstract: The effect of ibogaine (Endabuse, NIH 10567) on serotonin uptake and release, and on serotonergic modulation of dopamine release, was measured in striatal tissue from rats and mice. Two hours after treatment in vivo with ibogaine (40 mg/kg i.p.) the uptake of labeled [3H]serotonin and [3H]dopamine uptake in striatal tissue was similar in the ibogaine-treated animal to that in the control. The 5HT1B agonist CGS-12066A (10(-5) M) had no effect on stimulation-evoked tritium release from mouse or rat striatal tissue preloaded with [3H]serotonin; however, it elevated tritium efflux from striatal tissue preloaded with [3H]dopamine. This increase was not seen in mice treated with ibogaine 2 or 18 hours previously, or in rats treated 2 hours before. Dopamine autoreceptor responses were not affected by ibogaine pretreatment in either mouse or rat striatal tissue; sulpiride increased stimulation-evoked release of tritium from tissue preloaded with [3H]dopamine. The long-lasting effect of ibogaine on serotonergic functioning, in particular, its blocking of the 5HT1B agonist- mediated increase in dopamine efflux, may have significance in the mediation of its anti-addictive properties

64. Ibogaine reduces preference for cocaine consumption in C57BL/6By mice. Sershen, H., Hashim, A. and Lajtha, A. Pharmacol Biochem Behav 47:13-19, 1994.

Abstract: After a period of forced exposure to 300 mg/l cocaine HCl in drinking water for a period of one week, followed by forced exposure to 200 mg/l cocaine for an additional week, male C57BL/6By mice developed a preference for cocaine when given a choice of drinking either water or a solution containing cocaine (200 mg/l). The mean daily intake of cocaine during the choice period was 26 +/- 1 mg/kg or, when expressed as the ratio of cocaine over total fluid intake, represented a cocaine preference of 71 +/- 2%. Administration of ibogaine HCl (40 mg/kg, two injections 6 h apart) two weeks after the beginning of the choice period reduced the cocaine preference for at least five days; the mean daily intake of cocaine was reduced by 38% (to 16 +/- 1 mg/kg per day; p < 0.05) and cocaine preference was reduced to 41 +/- 2% (cocaine fluid consumption/total fluid intake). An acute challenge injection of cocaine (25 mg/kg SC) produced a significant increase in cocaine-induced locomotor activity and stereotypy in mice previously exposed to cocaine in their drinking water (cocaine choice group). Five days after ibogaine administration, locomotor and stereotypy activity were significantly lower after a challenge injection of cocaine (25 mg/kg SC). Brain levels of cocaine 35 min after the challenge injection of cocaine were approximately 25% higher in ibogaine- treated mice (7.2 +/- 0.5 and 9.3 +/- 0.8 micrograms/g wet wt for water vs. mice treated with water plus ibogaine and 9.3 +/- 0.2 and 11.8 +/- 0.7 micrograms/g wet wt for cocaine drinking vs. cocaine drinking plus ibogaine treatment).(ABSTRACT TRUNCATED AT 250 WORDS)

65. A preliminary investigation of ibogaine: case reports and recommendations for further study. Sheppard, S.G. J Subst Abuse Treat 11:379-385, 1994.

Abstract: A naturally occurring substance, ibogaine, was taken by seven individuals who were addicted to opiates. Ibogaine, an alkaloid with psychotropic effects at doses of 200-300 mg and above, was taken in single doses of 700-1800 mg by the subjects in the study. At the end of the 24-38-hr psychoactive period induced by the drug at these doses, none of the subjects displayed significant opiate withdrawal symptoms. At the lowest dose of 700 mg, one subject recontinued his drug abuse after 2 days; of the remaining six individuals who took 1,000 mg or above, two relapsed after a number of weeks, one reverted to intermittent heroin use, and three appear to have remained drug-free 14 weeks or more after undergoing this experimental treatment. Ibogaine may be of value in the present and could serve as a model for the development of improved agents for the treatment of substance abuse in the future

66. Dependence studies of new compounds in the rhesus monkey, rat and mouse (1992). [Review]. Aceto, M.D., Bowman, E.R., Harris, L.S. and May, E.L. NIDA Res Monogr 132:459-516, 1993.

67. Inhibitory effects of ibogaine on cocaine self-administration in rats. Cappendijk, S.L. and Dzoljic, M.R. Eur J Pharmacol 241:261-265, 1993.

Abstract: In order to determine the potential anti-addictive properties of ibogaine, we used the cocaine self-administration model in rats. The results indicate that a single injection of ibogaine (40 mg/kg i.p.) produced a significant decrease of cocaine intake, which remained unaltered for more than 48 h. Since the half-life time of ibogaine is short, this might suggest the involvement of one or several active metabolites of ibogaine in cocaine intake. Repetitive administration of ibogaine on three consecutive days also induced a pronounced decrease of cocaine intake. However, a more prominent inhibitory effect on cocaine intake was observed in animals treated repeatedly with ibogaine (40 mg/kg i.p.), once each week for 3 consecutive weeks. These results indicate that ibogaine or its metabolite(s) is a long-lasting interruptor of cocaine dependence, which supports similar observations from uncontrolled clinical studies

68. Local effects of ibogaine on extracellular levels of dopamine and its metabolites in nucleus accumbens and striatum: interactions with D-amphetamine. Glick, S.D., Rossman, K., Wang, S., Dong, N. and Keller, R.W.,Jr. Brain Res 628:201-208, 1993.

Abstract: Systemic administration of ibogaine (40 mg/kg, i.p.) has been reported to induce both acute (1-3 h) and persistent (19-20 h) changes in extracellular levels of dopamine and its metabolites in the nucleus accumbens and striatum. In the present study, local administration of ibogaine to the striatum and nucleus accumbens produced effects that mimicked both the acute and persistent effects of systemic administration: perfusion with high concentrations (200 and 400 microM) of ibogaine mimicked the acute effects (decreased extracellular dopamine levels and increased extracellular metabolite levels) whereas perfusion with a low concentration (10 microM) of ibogaine mimicked the persistent effects (decreased extracellular levels of DOPAC). These results indicate that ibogaine acts directly in brain regions containing dopaminergic nerve terminals and that long- lasting effects of systemically administered ibogaine might be mediated by persisting low levels of ibogaine. Locally administered ibogaine (10 microM) was also found to enhance the effects of systemically administered D-amphetamine (1.25 mg/kg, i.p.) on extracellular dopamine levels, and conversely, systemically administered ibogaine (40 mg/kg, i.p.; 19 h pretreatment) enhanced the effects of locally administered D- amphetamine (1-10 microM). These results indicate that, in addition to a metabolic mechanism implicated previously, a pharmacodynamic mechanism contributes to the interaction between ibogaine and D-amphetamine. The relevance of such mechanisms to claims regarding ibogaine's anti-addictive properties is unclear

69. Reaching a state of wellness: multistage explorations in social neuroscience. Kaplan, C.D., Ketzer, E., De Jong, J. and De Vries, M. Social Neurosci Bull 6:6-7, 1993.

70. Degeneration of Purkinje cells in parasagittal zones of the cerebellar vermis after treatment with ibogaine or harmaline. O'Hearn, E. and Molliver, M.E. Neuroscience 55:303-310, 1993.

Abstract: The indole alkaloids ibogaine and harmaline are beta-carboline derivatives that cause both hallucinations and tremor. Reports that ibogaine may have potent anti-addictive properties have led to initiatives that it be tested for the treatment of opiate and cocaine addiction. In this study, ibogaine-treated rats were analysed for evidence of neurotoxic effects because human clinical trials of ibogaine have been proposed. We recently found that ibogaine induces a marked glial reaction in the cerebellum with activated astrocytes and microglia aligned in parasagittal stripes within the vermis. Based on those findings, the present study was conducted to investigate whether ibogaine may cause neuronal injury or degeneration. The results demonstrate that, after treatment with ibogaine or harmaline, a subset of Purkinje cells in the vermis degenerates. We observed a loss of the neuronal proteins microtubule-associated protein 2 and calbindin co-extensive with loss of Nissl-stained Purkinje cell bodies. Argyrophilic staining of Purkinje cell bodies, dendrites and axons was obtained with the Gallyas reduced silver method for degenerating neurons. Degenerating neurons were confined to narrow parasagittal stripes within the vermis. We conclude that both ibogaine and harmaline have selective neurotoxic effects which lead to degeneration of Purkinje cells in the cerebellar vermis. The longitudinal stripes of neuronal damage may be related to the parasagittal organization of the olivocerebellar climbing fiber projection. Since these drugs produce sustained activation of inferior olivary neurons, we hypothesize that release of an excitatory amino acid from climbing fiber synaptic terminals may lead to excitotoxic degeneration of Purkinje cells

71. Ibogaine induces glial activation in parasagittal zones of the cerebellum. O'Hearn, E., Long, D.B. and Molliver, M.E. Neuroreport 4:299-302, 1993.

Abstract: Ibogaine, an indole alkaloid, has been proposed for treatment of drug addiction, yet its mechanism, site of action, and possible neurotoxicity have not been determined. Since neuronal injury is known to activate neurologlial cells, we investigated potential neurotoxic effects of this drug in rats by examining expression of specific glial markers. After treatment with ibogaine (100 mg kg-1 i.p.; 1-3 doses), we observed increased cytochemical markers in both microglia (OX-6, OX-42, W3/25) and astrocytes (GFAP), associated with striking morphologic changes in these cells. Activated glial cells were restricted to longitudinally oriented, parasagittal stripes within the vermis of cerebellar cortex. The ibogaine-induced activation of cerebellar glial cells is highly suggestive of neuronal degeneration, most likely of Purkinje cells

72. Cocaine discrimination is attenuated by isradipine and CGS 10746B. Schechter, M.D. Pharmacol Biochem Behav 44:661-664, 1993.

Abstract: The discriminative stimulus properties of cocaine are thought to be mediated by dopaminergic mechanisms that may be modulated by calcium ion influx and/or interact with 5-hydroxytryptamine3 (5- HT3) receptors. To test these possibilities, rats were trained to discriminate between the stimulus properties of 10.0 mg/kg cocaine and its vehicle in a two-lever, food-motivated operant task. Once trained, rats showed a dose-related decrease in discriminative performance when tested with lower cocaine doses. An analysis of the dose-response curve indicated an ED50 value of 3.04 mg/kg. Pretreatment with the presynaptic dopamine release- inhibiting agent CGS 10746B (20-40 mg/kg) resulted in a dose- related decrease in cocaine discrimination with the highest dose significantly attenuating cocaine discrimination. Pretreatment with 10-30 mg/kg isradipine, a calcium channel blocker, also resulted in a dose-related decrease in cocaine discriminative performance. In contrast to these positive results, pretreatment with the 5-HT3 receptor antagonist MDL 72222 (3.5-7.0 mg/kg), or the same doses of ibogaine, did not significantly affect cocaine discrimination. The results suggest that cocaine controls differential responding in a discriminative stimulus task by mechanisms that involve presynaptic release of dopamine, which may be regulated by neuronal calcium influx through L-type calcium channels

73. Comparison of the behavioral effects of ibogaine from three sources: mediation of discriminative activity. Schechter, M.D. and Gordon, T.L. Eur J Pharmacol 249:79-84, 1993.

Abstract: Ibogaine is an alkaloid employed for its hallucinatory properties in West Central Africa which has been the subject of alleged efficacy as an aid in the interruption and treatment of chemical dependency. The major sources of the Schedule I agent are: Sigma Chemical Co., the National Institute on Drug Abuse and as NDA International Inc.'s Endabuse. The intent of the present study was to, for the first time, train rats to discriminate the interoceptive stimuli produced by (10 mg/kg, intraperitoneally administered) ibogaine. Once trained, these rats were used to investigate the dose-response effects to ibogaine from each of the three suppliers. In addition, stimulus generalization to the dopamine antagonist CGS 10476B, as well as to the serotonergically active compounds fenfluramine, TFMPP (1-(m- trifluoromethylphenyl)piperazine, DOI (1-(2,5-dimethoxy-4- iodophenyl)-2-aminopropane), MDMA (3,4- methylenedioxymethamphetamine), quipazine and LSD, was tested. The results indicate that ibogaine is readily discriminable from its vehicle and that ibogaine from each of the three supplies produced statistically similar discrimination with ED50 values ranging from 2.5 to 3.4 mg/kg. In addition, various doses of the novel drugs tested produced, at best, intermediate ibogaine- appropriate responding and, thus, no drug tested can be considered to generalize to ibogaine-like stimuli. Discussion concerns the multiple actions of ibogaine that have been cited in the scientific literature. The similarity in potency of ibogaine from three potential suppliers should allow for pre-clinical work using any of these research samples to be comparable

74. Interrupting drug dependency with ibogaine: a summary of four case histories. Sisko, B. Multidisciplinary Association for Psychedelic Studies 4:15-24, 1993.

75. Evaluation of new compounds for opioid activity, 1992. [Review]. Woods, J.H., France, C.P., Medzihradsky, F., Smith, C.B. and Winger, G.D. NIDA Res Monogr 132:517-578, 1993.

Abstract: Ibogaine, a serotonergic (5-HTergic) indole alkaloid, was studied for cocaine modulatory effects on four parameters of behavior by computerized infrared photocell beam detection. The behavioral parameters were: a) locomotor activity (ambulations), b) rearing, c) stereotypy (fine movements, primarily grooming), and d) agoraphobia [(thigmotaxis) a natural tendency to avoid the center of the behavioral chamber]. With each behavioral data point, dopamine (DA) release, and serotonin (5-HT) release were detected within seconds in nucleus accumbens (NAcc) of the same behaving male Sprague-Dawley rats, using in vivo electrochemistry (voltammetry). Ibogaine was administered (40 mg/kg IP) for 4 consecutive days. Importantly, the DAergic and the 5-HTergic responses to (SC) cocaine and two behavioral responses, ambulations and central ambulations, were reduced in intensity due to extended time spent in the novel behavioral chamber (habituated). Rearing and fine movement patterns were not habituated. The results show that ibogaine downmodulated the (SC) cocaine-induced increase in NAcc DA release (p < 0.0001) and potentiated the (SC) cocaine-induced decrease in NAcc 5-HT release (p < 0.0001). Concurrently, ibogaine downmodulated cocaine-induced ambulation (p < 0.0001) and central ambulation behavior (p < 0.0001). On the other hand, the behavioral parameters that did not exhibit habituation, i.e., rearing behavior and fine movement behavior, were not downmodulated by ibogaine (p < 0.1558) (p < 0.3763), respectively. Furthermore, ibogaine itself did not significantly alter NAcc DA release over the 2-h period studied (p < 0.9113) although individual time points were significantly affected bidirectionally. Concurrently ibogaine significantly increased 5-HT release (p < 0.0155). Behaviorally, ibogaine appears to be a weak psychostimulant. The data show a critical modulatory role for 5-HT in ibogaine-cocaine interactions. Also elucidated as critical is the efficacy of ibogaine when the response to (SC) cocaine is decreased due to the habituation of the animals to their environment

76. Dependence studies of new compounds in the rhesus monkey and mouse (1991). [Review]. Aceto, M.D., Bowman, E.R., Harris, L.S. and May, E.L. NIDA Res Monogr 119:513-558, 1992.

77. Mechanisms of action of ibogaine and harmaline congeners based on radioligand binding studies. Deecher, D.C., Teitler, M., Soderlund, D.M., Bornmann, W.G., Kuehne, M.E. and Glick, S.D. Brain Res 571:242-247, 1992.

Abstract: Assays using radioligands were used to assess the actions of ibogaine and harmaline on various receptor types. Ibogaine congeners showed affinity for opiate receptors whereas harmaline and harmine did not. The Ki for coronaridine was 2.0 microM at mu- opiate receptors. The Kis for coronaridine and tabernanthine at the delta-opiate receptors were 8.1 and 3.1 microM, respectively. Ibogaine, ibogamine, coronaridine and tabernanthine had Ki values of 2.08, 2.6, 4.3 and 0.15 microM, respectively, for kappa-opiate receptors. Long-lasting, dose-dependent behavioral effects of ibogaine have been reported. The possibility that these effects were due to irreversible binding properties of ibogaine at kappa- receptors was considered; however, radioligand wash experiments showed a rapid recovery of radioligand binding after one wash. A voltage-dependent sodium channel radioligand demonstrated Ki values in the microM range for all drugs tested. Using radioligand binding assays and/or 36Cl- uptake studies, no interaction of ibogaine or harmaline with the GABA receptor- ionophore was found. The kappa-activity of ibogaine (or an active metabolite) may be responsible for its putative anti-addictive properties whereas the tremorigenic properties of ibogaine and harmaline may be due to their effects on sodium channels

78. Effects of ibogaine on naloxone-precipitated withdrawal in morphine-dependent mice. Frances, B., Gout, R., Cros, J. and Zajac, J.M. Fundam Clin Pharmacol 6:327-332, 1992.

Abstract: In naive mice, ibogaine at a tremorigenic dose (30 mg/kg, ip), did not produce antinociception but did potentiate the antinociceptive potency of morphine in the tail-flick test. In morphine-dependent mice, ibogaine did not eliminate withdrawal symptoms but significantly increased the number of repetitive vertical jumps induced by naloxone, whatever the duration of the chronic morphine treatment. By comparison, repetitive jumping induced by alpha-napthoxyacetic acid (alpha-NOAA), a non- convulsant drug which induced jumping without affecting other morphine-withdrawal signs, was not significantly modified by ibogaine. These results indicate that while acute antinociceptive effects of morphine are modulated by ibogaine, this drug, shown to alleviate opiate dependence in man, does not attenuate in mice opioid withdrawal manifestations

79. Differential effects of ibogaine pretreatment on brain levels of morphine and (+)-amphetamine. Glick, S.D., Gallagher, C.A., Hough, L.B., Rossman, K.L. and Maisonneuve, I.M. Brain Res 588:173-176, 1992.

Abstract: Previous studies in rats have shown that ibogaine inhibits neurochemical and behavioral effects of morphine yet potentiates similar effects of (+)-amphetamine. To assess whether these different functional interactions have a metabolic basis, brain levels of morphine and (+)-amphetamine were measured by gas chromatography-mass spectrometry after ibogaine pretreatment (19 h before injection of morphine or (+)-amphetamine). Ibogaine pretreatment had no effect on brain morphine levels, either at 30 min or 2 h after morphine injection; however, ibogaine significantly increased brain amphetamine levels at 30 min and, to a greater extent, at 2 h after (+)-amphetamine injection. These and other data suggest that ibogaine irreversibly inhibits an amphetamine-metabolizing enzyme. The functional interactions between ibogaine and (+)-amphetamine, but not those between ibogaine and morphine, may result from a hepatic drug-drug interaction

80. Effects of ibogaine on acute signs of morphine withdrawal in rats: independence from tremor. Glick, S.D., Rossman, K., Rao, N.C., Maisonneuve, I.M. and Carlson, J.N. Neuropharmacology 31:497-500, 1992.

Abstract: Because of the claim that ibogaine suppresses the symptoms of "narcotic withdrawal" in humans, the effect of ibogaine on naltrexone-precipitated withdrawal signs in morphine-dependent rats was assessed. Morphine was administered subcutaneously through implanted silicone reservoirs for 5 days. Ibogaine (20, 40 or 80 mg/kg, i.p.) or saline was administered 30 min prior to challenge with naltrexone (1 mg/kg, i.p.) and withdrawal signs were counted for the following 2 hr. Ibogaine (40 and 80 mg/kg) significantly reduced the occurrence of four signs (wet-dog shakes, grooming, teeth chattering and diarrhea) during naltrexone-precipitated withdrawal; three other signs (weight loss, burying and flinching) were unaffected. Ibogaine induces head and body tremors lasting for 2-3 hr and the tremors might have interfered with the expression of opioid withdrawal. To examine this issue, another experiment was conducted in which ibogaine (40 mg/kg) or saline was administered 4 hr prior to challenge with naltrexone. Although there was a complete absence of tremors, ibogaine still significantly reduced the occurrence of the same four signs of withdrawal

81. Rapid method for interrupting or attenuating poly-drug dependency syndromes. Lotsof, H.S. U.S. Patent no. 5,152,994:1992.

82. Acute and prolonged effects of ibogaine on brain dopamine metabolism and morphine-induced locomotor activity in rats. Maisonneuve, I.M., Rossman, K.L., Keller, R.W.,Jr. and Glick, S.D. Brain Res 575:69-73, 1992.

Abstract: Ibogaine, an indolalkylamine, proposed for use in treating opiate and stimulant addiction, has been shown to modulate the dopaminergic system acutely and one day later. In the present study we sought to systematically determine the effects of ibogaine on the levels of dopamine (DA) and the dopamine metabolites 3,4 dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in tissue at several time points, between 1 h and 1 month post-injection. One hour after ibogaine- administration (40 mg/kg i.p.) a 50% decrease in DA along with a 37-100% increase in HVA were observed in all 3 brain regions studied: striatum, nucleus accumbens and prefrontal cortex. Nineteen hours after ibogaine-administration a decrease in DOPAC was seen in the nucleus accumbens and in the striatum. A week after administration of ibogaine striatal DOPAC levels were still reduced. A month after ibogaine injection there were no significant neurochemical changes in any region. We also investigated the effects of ibogaine pretreatment on morphine- induced locomotor activity, which is thought to depend on DA release. Using photocell activity cages we found that ibogaine pretreatment decreased the stimulatory motor effects induced by a wide range of morphine doses (0.5-20 mg/kg, i.p.) administered 19 h later; a similar effect was observed when morphine (5 mg/kg) was administered a week after ibogaine pretreatment. No significant changes in morphine-induced locomotion were seen a month after ibogaine pretreatment. The present findings indicate that ibogaine produces both acute and delayed effects on the tissue content of DA and its metabolites, and these changes coincide with a sustained depression of morphine-induced locomotor activity

83. Interactions of ibogaine and D-amphetamine: in vivo microdialysis and motor behavior in rats. Maisonneuve, I.M., Keller, R.W.,Jr. and Glick, S.D. Brain Res 579:87-92, 1992.

Abstract: Ibogaine, an indolalkylamine, has been proposed for use in treating stimulant addiction. In the present study we sought to determine if ibogaine had any effects on the neurochemical and motor changes induced by D-amphetamine that would substantiate the anti-addictive claim. Ibogaine (40 mg/kg, i.p.) injected 19 h prior to a D-amphetamine challenge (1.25 mg/kg, i.p.) potentiated the expected rise in extracellular dopamine levels in the striatum and in the nucleus accumbens, as measured by microdialysis in freely moving rats. Using photocell activity cages, the same ibogaine pretreatment enhanced the stimulatory motor effects induced by a wide range of D-amphetamine doses (0.625, 1.25, 2.5 or 5 mg/kg, i.p.). These findings suggest that ibogaine might increase the reinforcing efficacy of D- amphetamine. However, since high doses of D-amphetamine can be aversive, the potentiation of D-amphetamine's effects by ibogaine might also lead to a decrease in the reinforcing efficacy of D- amphetamine

84. Interactions between ibogaine and cocaine in rats: in vivo microdialysis and motor behavior. Maisonneuve, I.M. and Glick, S.D. Eur J Pharmacol 212:263-266, 1992.

Abstract: To investigate a possible basis for the proposed anti-addictive property of ibogaine, the effects of an ibogaine (40 mg/kg i.p.) pretreatment on in vivo neurochemical and motor effects induced by cocaine (20 mg/kg i.p.) were studied. Ibogaine, administered 19 h earlier, potentiated the increase in extracellular dopamine levels in striatum and nucleus accumbens as well as the stimulated motor activity induced by cocaine. Although high doses of cocaine can become aversive by producing an anxiogenic reaction, it is unknown whether the potentiation of cocaine's effects by ibogaine would also cause aversion and lead to a decrease in cocaine addiction

85. Stimulus effects of ibogaine in rats trained with yohimbine, DOM, or LSD. Palumbo, P.A. and Winter, J.C. Pharmacol Biochem Behav 43:1221-1226, 1992.

Abstract: The stimulus effects of ibogaine were compared with those of yohimbine, an alpha 2-adrenoceptor antagonist, 2,5-dimethoxy-4- methylamphetamine (DOM), a 5-hydroxytryptamine2 (5-HT2) agonist, and lysergic acid diethylamide (LSD), a nonspecific 5-HT agonist. Rats were trained with either yohimbine (6 mg/kg), DOM (0.6 mg/kg), or LSD (0.1 mg/kg) vs. no treatment in a two-lever discrimination task. Tests of generalization were then conducted with ibogaine. In yohimbine-trained animals, 39.7% of responses following ibogaine (15 mg/kg) were on the drug-appropriate lever, but this response level was not significantly different from no treatment-appropriate responding. A response distribution that was significantly different from responding under both drug and no treatment training conditions was observed in DOM-trained rats after administration of 15 mg/kg ibogaine. Pizotyline (BC-105) blocked all DOM-appropriate responding produced by ibogaine. In LSD-trained animals, 20 mg/kg ibogaine mimicked LSD. Pizotyline blocked LSD-appropriate responding produced by ibogaine in five of six animals. The present data suggest the involvement of 5-HT2 receptor activity, and the possibility of a 5-HT1A contribution, in the stimulus properties of ibogaine

86. Ibogaine antagonizes cocaine-induced locomotor stimulation in mice. Sershen, H., Hashim, A., Harsing, L. and Lajtha, A. Life Sci 50:1079-1086, 1992.

Abstract: Ibogaine (40 mg/kg i.p.), when given 2 hours before an acute injection of cocaine (25 mg/kg s.c.) to C57BL/6 mice, reduced the cocaine-induced locomotor stimulation. Such stimulation was also reduced in the ibogaine-treated mice when a second injection of cocaine was given 24 hr later. Thus, the reduction in locomotor activity was not just the short-term depression of locomotor activity seen after ibogaine administration. When mice were given a daily injection of cocaine for 3 days and ibogaine was given after the cocaine injection on day 3, and again on day 4, cocaine- induced locomotor activity was reduced three hours later on day 4. On days 5 and 9 of the cocaine administration, with no further ibogaine treatment ambulatory counts were still lower in the ibogaine-pretreated mice. Locomotor stimulation induced by amphetamine (10 mg/kg) was not affected by ibogaine. An acute injection of ibogaine resulted in a transient increase in turnover of dopamine, as indicated by the increase in the ratio of metabolites of the dopamine to dopamine, followed by a decrease in the metabolites in striatum and frontal cortex 24 hr later. In vivo treatment with ibogaine did not affect the binding of [3H]WIN 35,248 to the cocaine binding site in striatal tissue measured in vitro. In addition, ibogaine added in vitro had a weak affinity to the WIN 35,248 binding site (IC50 for cocaine = 120 nM and for ibogaine = 1,500 nM). The results suggest that ibogaine may have induced a selective change in the dopaminergic system that results in a decrease in responsiveness to cocaine that persisted for at least 1 week

87. Ibogaine reduces amphetamine-induced locomotor stimulation in C57BL/6By mice, but stimulates locomotor activity in rats. Sershen, H., Harsing, L.G.,Jr., Hashim, A. and Lajtha, A. Life Sci 51:1003-1011, 1992.

Abstract: The effect of ibogaine hydrochloride on locomotor stimulation induced by d-amphetamine sulfate was tested in male C57BL/6By mice and in female Sprague-Dawley rats. In mice, locomotor stimulation induced by d-amphetamine at 1 or 5 mg/kg s.c. was reduced by prior administration of one or two injections of ibogaine (40 mg/kg), given 2 or 18 hours earlier. This reduction in locomotor activity persisted for two days. Locomotor stimulation induced by a higher dose (10 mg/kg) of d-amphetamine was not reduced by such prior administration of ibogaine. A lower dose of ibogaine (20 mg/kg) did not reduce the subsequent locomotor activity induced by d-amphetamine. Ibogaine decreased striatal dopamine levels, while d-amphetamine increased them. Ibogaine treatment (2 x 40 mg/kg, 18 hours apart) induced a decrease by 30% in the level of striatal dopamine and its metabolites measured in tissue extracts 3 hours after the second ibogaine injection. One hour after d-amphetamine (5 mg/kg) administration, the level of striatal dopamine increased by 26%. Although the level of striatal dopamine was initially lower in the ibogaine-pretreated mice, d-amphetamine (5 mg/kg) administration induced an increase in striatal dopamine and its metabolites. The effect of ibogaine seems to be species specific, since in rats pretreated with ibogaine 18 hours before d- amphetamine, locomotor stimulation induced by d-amphetamine was further increased. In addition, the in vitro electrical-evoked release of [3H]dopamine from striatal tissue was either unchanged or inhibited in the presence of d-amphetamine, and after ibogaine pretreatment in vivo, the release of tritium in the presence of d- amphetamine was inhibited or stimulated in mice and rats, respectively

88. Evaluation of new compounds for opioid activity (1991). [Review]. Woods, J.H., Medzihradsky, F., Smith, C.B., Winger, G.D. and France, C.P. NIDA Res Monogr 119:559-603, 1992.

89. Dependence studies of new compounds in the rhesus monkey and mouse (1990). [Review]. Aceto, M.D., Bowman, E.R., Harris, L.S. and May, E.L. NIDA Res Monogr 105:640-681, 1991.

90. Effects and aftereffects of ibogaine on morphine self-administration in rats. Glick, S.D., Rossman, K., Steindorf, S., Maisonneuve, I.M. and Carlson, J.N. Eur J Pharmacol 195:341-345, 1991.

Abstract: Ibogaine, a naturally occurring alkaloid, has been claimed to be effective in treating addition to opiate and stimulant drugs. As a preclinical test of this claim, the present study sought to determine if ibogaine would reduce the intravenous self- administration of morphine in rats. Ibogaine dose dependently (2.5-80 mg/kg) decreased morphine intake in the hour after ibogaine treatment (acute effect) and, to a lesser extent, a day later (aftereffect); while the acute effect could be attributed to abnormal motor behavior (whole body tremors), the aftereffect occurred at a time when ibogaine should have been entirely eliminated from the body and when there was no obvious indication of ibogaine exposure. In some rats, there was a persistent decrease in morphine intake for several days or weeks after a single injection of ibogaine; other rats began to show such persistent changes only after two or three weekly injections whereas a few rats were apparently resistant to prolonged aftereffects. Aftereffects could not be attributed to a conditioned aversion. Although ibogaine also depressed responding acutely in rats trained to bar-press for water, there was no evidence of any aftereffect a day or more later; the interaction between ibogaine and morphine reinforcement was therefore somewhat specific. Further studies are needed to characterize the nature of the ibogaine-morphine interaction as well as to determine if ibogaine also affects the self-administration of other drugs

91. Rapid method for interrupting or attenuating the nicotine/ tobacco dependency syndrome. Lotsof, H.S. U.S. Patent no. 5,026,697:1991.

92. Interactions between ibogaine, a potential anti-addictive agent, and morphine: an in vivo microdialysis study. Maisonneuve, I.M., Keller, R.W.,Jr. and Glick, S.D. Eur J Pharmacol 199:35-42, 1991.

Abstract: Ibogaine, an indolalkylamine, has been claimed to be effective in abolishing drug craving in heroin and cocaine addicts. The present study used in vivo microdialysis to determine the effects of ibogaine on extracellular levels of dopamine (DA) and its metabolites and the effects of ibogaine pretreatment on morphine stimulation of brain DA systems. Acutely, ibogaine (40 mg/kg i.p.) decreased extracellular DA levels in the striatum, increased them in the prefrontal cortex and had no significant effects in the nucleus accumbens. Nineteen hours after ibogaine injection. DA levels were still decreased in the striatum and the metabolite levels were lower in all three regions. When injected 19 h prior to a morphine challenge (5 mg/kg i.p.), ibogaine (40 mg/kg, i.p.) prevented the rise in DA levels in all three regions normally observed after a morphine injection. A high dose of morphine (30 mg/kg i.p.), administered alone, produced no increase in extracellular DA levels; it is therefore unclear whether ibogaine antagonized or potentiated the effects of the lower dose of morphine. Regardless of the nature of this interaction, it appears that ibogaine affects brain DA systems for a period of time that exceeds its elimination from the body and, during this time, alters the responses of these systems to morphine

93. Ibogaine fails to reduce naloxone-precipitated withdrawal in the morphine dependent rat. Sharpe, L. and Jaffe, J. NIDA Res Monogr 105:477, 1991.

94. Ibogaine fails to reduce naloxone-precipitated withdrawal in the morphine-dependent rat. Sharpe, L.G. and Jaffe, J.H. Neuroreport 1:17-19, 1990.

Abstract: Because of anecdotal reports in which ibogaine eliminates opioid withdrawal symptoms in humans, we studied this phenomenon in the rat model. Ibogaine (5, 10, 20 and 40 mg kg-1, s.c.) was administered 15 min before naloxone (0.5 mg kg-1, s.c.) in morphine dependent rats (3 days after the s.c. implantation of a 75 mg morphine pellet). Of the 12 withdrawal signs scored, the only significant changes observed after ibogaine (compared with vehicle control) was a decrease in grooming (10 mg kg-1) and an increase in teeth chatter (5 mg kg-1). In spite of ibogaine's apparent interaction with several neurotransmitter receptor systems, it does not alleviate opioid withdrawal in this animal model at non-tremorigenic (5 and 10 mg kg-1) or tremorigenic (20 and 40 mg kg-1) doses

95. Dependence studies on new compounds in the rhesus monkey, rat and mouse (1989). Aceto, M.D., Bowman, E.R., Harris, L.S. and May, E.L. NIDA Res Monogr 95:578-631, 1989.

Abstract: Norcocaine dose-dependently attenuates abrupt morphine withdrawal in rhesus monkeys. These results suggest a possible role for this metabolite in the interaction of cocaine with the opioid system. [References: 10]

96. Rapid method for attenuating the alcohol dependency syndrome. Lotsof, H.S. U.S. Patent no. 4,857,523:1989.

97. Effect of ibogaine on naloxone-precipitated withdrawal syndrome in chronic morphine-dependent rats. Dzoljic, E.D., Kaplan, C.D. and Dzoljic, M.R. Arch Int Pharmacodyn Ther 294:64-70, 1988.

Abstract: Ibogaine, an indole alkaloid, administered intracerebroventricularly 4-16 micrograms, attenuated a naloxone- precipitated withdrawal syndrome in chronic morphine-dependent rats. It appears that ibogaine has a more consistent effect on certain selective withdrawal signs related to the locomotion. This might explain an attenuating effect of ibogaine on some withdrawal signs. However, due to complex interaction of ibogaine with serotonin and other neurotransmitter systems, the mechanism of ibogaine antiwithdrawal effect remains unknown and requires further elucidation

98. Dependence studies of new compounds in the rhesus monkey, rat and mouse (1986). Aceto, M.D., Bowman, E.R., Harris, L.S. and May, E.L. NIDA Res Monogr 76:392-447, 1987.

99. Neocortical rhythmic slow activity during wakefulness and paradoxical sleep in rats. Depoortere, H. Neuropsychobiology 18:160-168, 1987.

Abstract: In the present study, we investigated the different types of neocortical rhythmic slow activity (RSA) during wakefulness and paradoxical sleep as well as their pharmacological modification. During wakefulness, the high-frequency (7-9 Hz) RSA1 type, which is atropine-resistant, is accentuated by forebrain stimulation and is abolished by urethane, clonidine and alcuronium. These drugs induce the low-frequency (4-6 Hz) RSA2 type that is atropine-sensitive and is activated by cholinergic agents and by some drugs such as tabernanthine, ibogaine, vincamine, SL 76.188- MS (10-chloro-hexahydrocanthinone methanesulphonate). The effects of pilocarpine and SL 76.188-MS on RSA2 are antagonized by atropine and hemicholinium-3, which suggests the involvement of a cholinergic pathway in the neocortical RSA activation (as has been demonstrated for the hippocampal RSA). During paradoxical sleep, two types of RSA are also observed: RSAT, of low frequency (5-7 Hz) present during its tonic components, and RSAp, of high frequency (7-9 Hz) which is well correlated with phasic phenomena such as bursts of rapid eye movements generated, or controlled, by cholinergic mechanisms. Imipramine reduces phasic phenomena and the periods of neocortical RSAp. Alcuronium does not modify RSAp in paradoxical sleep-deprived rats and suppress RSA1 during arousal, observations which would suggest that RSAp and RSA1 are regulated by two distinct central mechanisms. The EEG studies of neocortical RSA during wakefulness and paradoxical sleep allow the selection and the differentiation of pharmacological agents. Furthermore, this approach not only may represent a basis for the treatment of deficits in the regulation of vigilance and memory, but also a novel strategy for the analysis of RSA type of paradoxical sleep with respect to antidepressant and anxiolytic treatment

100. Dependence studies of new compounds in the rhesus monkey, rat, and mouse (1985). Aceto, M.D., Harris, L.S. and May, E.L. NIDA Res Monogr 67:399-452, 1986.

101. Rapid method for interrupting the cocaine and amphetamine abuse syndrome. Lotsof, H.S. U.S. Patent no.4,587,243:1986.

102. Rapid method for interrupting the narcotic addiction syndrome. Lotsof, H.S. U.S. Patent no. 4,499,096:1985.

103. Phytochemical investigation of Tabernaemontana crassa. van Beek, T.A., de Smidt, C. and Verpoorte, R. J Ethnopharmacol 14:315-318, 1985.

Abstract: From the stembark of Tabernaemontana crassa the alkaloid ibogaine was isolated as the major component. Ibogaine showed activity against the gram-positive Bacillus subtilis. Conopharyngine was identified as one of the minor compounds

104. Cholecystokinin octapeptide (CCK-8), ceruletide and analogues of ceruletide: effects on tremors induced by oxotremorine, harmine and ibogaine. A comparison with prolyl-leucylglycine amide (MIF), anti-Parkinsonian drugs and clonazepam. Zetler, G. Neuropharmacology 22:757-766, 1983.

Abstract: Cholecystokinin octapeptide (CCK-8), ceruletide (caerulein, CER) and 10 analogues of ceruletide, were studied in mice for antagonism of the tremors induced by harmine (5 mg/kg, s.c.), ibogaine (20 mg/kg, s.c.) and oxotremorine (0.2 mg/kg, s.c.). The following reference drugs were tested for comparison: prolyl- leucylglycine amide (MIF), atropine, haloperidol, biperiden, ethopropazine, trihexyphenidyl, methixene and clonazepam. All treatments were subcutaneous, the antagonists being given 10 min (in some trials 30 min) before the tremorogen. Tremorolytic potency (ED50) was calculated from dose-response curves. Against the tremors induced by either harmine or ibogaine, CCK-8 and ceruletide, as well as many of the analogues of ceruletide had greater tremorolytic potency than the reference drugs. Against oxotremorine, however, ceruletide and its most potent analogue, Nle8-CER (other analogues were not tested) were inactive and MIF showed very little effectiveness. Additional experiments on hypothermia and sedation as well as evaluation of previous studies on other central actions suggested that the tremorolytic effect of CCK-like peptides is independent of other central effects. The CCK-like peptides may play a physiological role in the regulation of extrapyramidal motor activity

105. [Modification of awake-sleep equilibrium by tabernanthine and some of its derivatives in the cat (author's transl)]. [French]. Da Costa, L., Sulklaper, I. and Naquet, R. Rev Electroencephalogr Neurophysiol Clin 10:105-112, 1980.

Abstract: Intraperitoneal injections (ip.) of 4 alkaloid derivatives of ibogamine: tabernanthine tartrate (2 mg/kg), methoxy-16 ibogaine tartrate (SAD 121 - 3 mg/kg), methoxy-16 tabernanthine tartrate (SAD 122 - 2 mg/kg), and tabernanthine parachlorophenoxyacetate (SAD 103 - 7 mg/kg), were administered to chronically implanted cats. Tabernanthine tartrate and SAD 103 provoke an increase in wakefulness level, a reduction in the level of slow wave sleep (SOL) and transient blocking of paradoxical sleep (SP). The duration of this action is much longer with SAD 103 than with tabernanthine tartrate. The inverse is provoked by SAD 121 and SAD 122, with slight increases in SOL and SP levels. Problems raised by the waking effect of tabernanthine tartrate and SAD 103 are discussed in the context of the neurobiology of sleep

106. [The effect of alkaloids from Tabernanthe iboga H. Bn. on the response of isolated organs to catecholamines and the possible role of calcium exchange. Case of Ibogaine]. [French]. Valette, G. and Leclair, M.F. C R Acad Sci Hebd Seances Acad Sci D 285:1147-1150, 1977.

Abstract: On isolated Rat duodenum, ibogaine (70 mumoles/l) increases the hypertonic effect following the addition of Calcium ions to the organ previously decalcified. Moreover, this alkaloid increases the hypotomic effect resulting from decalcification of the normal organs. These actions are taken into account with the potentiating effects of ibogaine on noradrenaline and dopamine responses observed on rat vas deferens

107. [Detection of ibogaine in organic liquids]. [French]. Bertol, E., Mari, F. and Froldi, R. J Chromatogr 117:239-241, 1976.

108. [Indole alkaloids induction of tremors: effect on photosensible epilepsy in Papiopapio]. [French]. Brailowsky, S., Walter, S., Vuillon-Cacciuttolo, G. and Serbanescu, T. C R Seances Soc Biol Fil 169:1190-1193, 1975.

Abstract: Harmaline and ibogaine i.v. administration induced in the photosensitive baboon restlesness and tremor (8-12 Hz). The former increased the EEG frequency particularly in central regions with appearance of bursts at 20-24 c/s and blocked by somatic movement. The latter produced a slight enhancement of frontal fast rhythms. Both drugs blocked the spontaneous paroxysmal activity with little effect on photosensitivity. These effects lasted for 2-4 hrs. Vincamine produced agitation during 15 min. post-i.v.-administration and showed an "hypervigilant" EEG. Nor vincamine or Hydergine altered the degree of photosensitivity. Cerebellar involvement in the action of harmaline and ibogaine is discussed

109. Gas chromatographic determination of ibogaine in biological fluids. Cartoni, G.P. and Giarusso, A. J Chromatogr 71:154-158, 1972.

110. The identification of ibogaine in biological material. Dhahir, H.I., Jain, N.C. and Thornton, J.I. J Forensic Sci Soc 12:309-313, 1972.

111. Methods for the detection and determination of ibogaine in biological materials. Dhahir, H.I., Jain, N.C. and Forney, R.B. J Forensic Sci 16:103-108, 1971.

112. Psychotherapeutic possibilities of new fantasy-enhancing drugs. Naranjo, C. Clin Toxicol 2:209-224, 1969.

Abstract: ibogaine

113. Tabernanthe iboga: an african narcotic plant of social importance. Pope, H.G.,Jr. Econ Bot 23:174-184, 1969.


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