Cerebral Pharmacokinetics of Tremor-Producing Harmala and Iboga Alkaloids

Zetler, G.; Singbartl, G.; Schlosser, Lucie

doi:10.1159/000136294

Cited by 95 publications

(60 citation statements)

References 4 publications

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“…While the affinity of ibogaine for rc-opioid receptors is slightly lower than for NMDA receptors, brain concentrations of ibogaine after pharmacologically relevant doses would be sufficient to occupy these receptors (Zetler et al, 1972). The recent report (Pearl et al.…”

Section: Discussionmentioning

confidence: 97%

Structurally modified ibogaine analogs exhibit differing affinities for NMDA receptors

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Skolnick

Bertha

et al. 1996

European Journal of Pharmacology

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Based on both preclinical findings and anecdotal evidence in man. the psychoactive indole alkaloid ihogaine 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 (+ )- 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.kWords:

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Section: Discussionmentioning

confidence: 97%

Structurally modified ibogaine analogs exhibit differing affinities for NMDA receptors

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Skolnick

Bertha

et al. 1996

European Journal of Pharmacology

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“…Laboratory animals injected with high doses acutely exhibit action tremor that resembles ET (Fuentes and Longo, 1971;Zetler et al, 1972). Human volunteers exposed to high doses display a coarse, reversible action tremor (Lewin, 1928).…”

Section: Introductionmentioning

confidence: 99%

“…Harmane is very lipid soluble (Zetler et al, 1972), and broadly distributed within the rat brain (Anderson et al, 2006;Matsubara et al, 1993;Moncrieff, 1989). Brain concentrations are several fold higher than those in the blood in both exposed (i.e., harmane-injected) laboratory animals and in control animals (Anderson et al, 2006;Zetler et al, 1972).…”

Section: Introductionmentioning

confidence: 99%

Elevated blood harmane (1-methyl-9H-pyrido[3,4-b]indole) concentrations in essential tremor

Louis

2008

NeuroToxicology

127

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Essential tremor (ET) is a widespread late-life neurological disease. Genetic and environmental factors likely play an etiological role. Harmane (1-methyl-9H-pyrido[3,4-b]indole) is a potent tremor-producing neurotoxin. In 2002, we demonstrated elevated blood harmane concentrations in an initial sample of 100 ET cases compared to 100 controls. Between 2002 and 2007, we assembled a new and larger sample of ET cases and controls. We now attempt to replicate our previous findings. Cases and controls were frequency-matched on age, gender, and race. Blood harmane concentrations were quantified by high performance liquid chromatography. Subjects comprised 150 ET cases and 135 controls (mean age 65.3 ± 15.5 vs. 65.5 ± 14.2 years, p = 0.94). Mean log blood harmane concentration was ∼50% higher in cases than controls (0.50 ± 0.54 g -10 /ml vs. 0.35 ± 0.62 g -10 /ml, p = 0.038). In a logistic regression analysis, log blood harmane concentration was associated with ET (OR adjusted 1.56, 95% CI 1.01 -2.42, p = 0.04), and odds of ET was 1.90 (95% CI 1.07 -3.39, p = 0.029) in the highest vs. lowest log blood harmane tertile. Log blood harmane was highest in ET cases with familial ET (0.53 ± 0.57 g -10 /ml), intermediate in cases with sporadic ET (0.43 ± 0.45 g -10 /ml) and lowest in controls (0.35 ± 0.62 g -10 /ml) (test for trend, p = 0.026). Blood harmane appears to be elevated in ET. The higher concentrations in familial ET suggests that the mechanism may involve genetic factors.

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“…More extensive pharmacokinetic data as well as additional studies to localize the site of action of ibogaine (for example, studies involving microinfusions into brain regions) are needed to test these hypotheses further. The relatively lower concentration of noribogaine in the cerebellum may be related to its five-fold lower potency as a tremorigenic agent (Zetler et al 1972). The ibogaine congener 18-methoxycoronaridone has also been reported to have less tremorigenic effect than ibogaine while retaining other biological activity (Glick et al 1996b).…”

Section: Discussionmentioning

confidence: 99%

Noribogaine Generalization to the Ibogaine Stimulus Correlation with Noribogaine Concentration in Rat Brain

Zúbaran¹,

Shoaib

Stolerman

et al. 1999

Neuropsychopharmacology

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The discriminative stimulus effects of ibogaine and noribogaine in rats have been examined in relation to their concentrations in blood plasma and brain regions and to receptor systems through which they have been proposed to act. Rats were trained to discriminate ibogaine (10 mg/kg IP), the NMDA antagonist dizocilpine (0.08 mg/kg IP) or the -opioid agonist U50,488 (5 mg/kg IP) from vehicle inIbogaine is a naturally occurring psychoactive alkaloid derived from the roots of the African shrub Tabernanthe iboga. Extracts of T. iboga are used for religious purposes in African cults. In the period from 1985 onward, several United States patents have claimed efficacy for ibogaine in the treatment of a wide variety of drugdependence syndromes (e.g., Lotsof 1985Lotsof , 1992. These claims have attracted the attention of scientists, and there have been more than 60 scientific publications addressing several issues related to ibogaine and drug dependence.Animal studies and uncontrolled observations in humans indicate that ibogaine can reduce withdrawal symptoms and self-administration of some drugs (Cappendijk and Dzoljic 1993;Sheppard 1994). Interestingly, in certain behavioral and neurochemical investigations, ibogaine has been characterized to have long-term effects persisting for at least 19 hours after its administration (Maisonneuve et al. 1991). In individuals given 5 mg of ibogaine, this drug could not be detected after 4 hours using thin-layer chromatography (Ley et al. 1996). Because the presence of ibogaine in plasma cannot explain its protracted actions, the possibility that an ibogaine metabolite persists for a longer period than the parent compound has been considered. Using quantitative gas chromatography/mass spectrometry, it was possible to detect the ibogaine metabolite 12-hydroxyi- (Mash et al. 1995a); while more than 90% of the ibogaine absorbed was eliminated 24 hours after its administration, the concentration of the metabolite was still appreciable at this time. Ligand-binding studies suggest that noribogaine, like ibogaine itself, may interact with diverse types of receptor (Mash et al. 1995a;Staley et al. 1996). The primary metabolite noribogaine is produced through demethylation of ibogaine (Mash et al. 1995a). Ibogaine is lipophilic and concentrated in fat, and might be converted to noribogaine after slow release from fat tissue (Hough et al. 1996). Sequestration of ibogaine into lipophilic compartments in the brain may result in low drug concentrations in the extracellular fluid and the more polar nature of noribogaine suggests that it may achieve relatively higher concentrations than the parent compound (Staley et al. 1996). Schechter and Gordon (1993) showed that rats can be trained to discriminate the interoceptive stimuli produced by ibogaine using drug discrimination procedures similar to those employed for many other drugs. In such studies, ibogaine has been found to partially cross-generalize with several drugs acting directly or indirectly as serotonergic agonists. Thus ibogaine genera...

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Cerebral Pharmacokinetics of Tremor-Producing Harmala and Iboga Alkaloids

Cited by 95 publications

References 4 publications

Structurally modified ibogaine analogs exhibit differing affinities for NMDA receptors

Structurally modified ibogaine analogs exhibit differing affinities for NMDA receptors

Elevated blood harmane (1-methyl-9H-pyrido[3,4-b]indole) concentrations in essential tremor

Noribogaine Generalization to the Ibogaine Stimulus Correlation with Noribogaine Concentration in Rat Brain

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