Ibogaine and the inhibition of acetylcholinesterase

Alper, Kenneth; Reith, Maarten E. A.; Sershen, Henry

doi:10.1016/j.jep.2011.12.006

Cited by 12 publications

(5 citation statements)

References 36 publications

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“…Ibogaine binds with reported affinities in the 10–30 μM range to M1 and M2 muscarinic cholinergic receptors and is generally assumed to act as an agonist (1,2); however, functional studies have not been performed. Although ibogaine is concentrated in brain tissue relative to serum in the animal model (119) and in the two cases reported here that reported on brain levels (cases #3 and #13), an older literature (120,121), as well as more recent data (122), indicates that the inhibition of acetylcholinesterase by ibogaine in vitro is negligible over the range of ibogaine concentrations observed in both blood and brain in this series. It is unclear whether the apparent association of ibogaine with bradycardia could possibly be related to orthosteric agonist actions at muscarinic cholinergic receptors, or to effects involving sodium channels (123) or other signal transduction pathways.…”

Section: Discussionmentioning

confidence: 49%

Fatalities Temporally Associated with the Ingestion of Ibogaine

Alper

Stajíc

Gill

2012

Journal of Forensic Sciences

117

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Ibogaine is a naturally occurring psychoactive plant alkaloid that is used globally in medical and nonmedical settings for opioid detoxification and other substance use indications. All available autopsy, toxicological, and investigative reports were systematically reviewed for the consecutive series of all known fatalities outside of West Central Africa temporally related to the use of ibogaine from 1990 through 2008. Nineteen individuals (15 men, four women between 24 and 54 years old) are known to have died within 1.5-76 h of taking ibogaine. The clinical and postmortem evidence did not suggest a characteristic syndrome of neurotoxicity. Advanced preexisting medical comorbidities, which were mainly cardiovascular, and/or one or more commonly abused substances explained or contributed to the death in 12 of the 14 cases for which adequate postmortem data were available. Other apparent risk factors include seizures associated with withdrawal from alcohol and benzodiazepines and the uninformed use of ethnopharmacological forms of ibogaine.

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Section: Discussionmentioning

confidence: 49%

Fatalities Temporally Associated with the Ingestion of Ibogaine

Alper

Stajíc

Gill

2012

Journal of Forensic Sciences

117

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“…Here, two possible mechanisms were proposed: (1) inhibition of acetylcholinesterase by the drug; and (2) an agonistic action on muscarinic acetylcholine receptors. Whereas the former potential mechanism could plausibly be ruled out by showing that ibogaine’s inhibition of acetylcholinesterase is physiologically negligible [50], muscarine receptor agonism still remains an option. Thus, ibogaine’s reported affinities for M 1 and M 2 muscarinic receptors are in the low micromolar range [2,4,51].…”

Section: Effects On the Cardiovascular Systemmentioning

confidence: 99%

“…A further postulated mechanism by which ibogaine could induce bradycardia is a blockade of voltage-gated sodium channels [1,4,49,50]. Indeed, ibogaine has low micromolar affinity for sodium channels in the brain [49,51,52], and cardiac sodium channel blockers can exert a bradycardic effect [53,54].…”

Section: Effects On the Cardiovascular Systemmentioning

confidence: 99%

The Anti-Addiction Drug Ibogaine and the Heart: A Delicate Relation

2015

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The plant indole alkaloid ibogaine has shown promising anti-addictive properties in animal studies. Ibogaine is also anti-addictive in humans as the drug alleviates drug craving and impedes relapse of drug use. Although not licensed as therapeutic drug and despite safety concerns, ibogaine is currently used as an anti-addiction medication in alternative medicine in dozens of clinics worldwide. In recent years, alarming reports of life-threatening complications and sudden death cases, temporally associated with the administration of ibogaine, have been accumulating. These adverse reactions were hypothesised to be associated with ibogaine’s propensity to induce cardiac arrhythmias. The aim of this review is to recapitulate the current knowledge about ibogaine’s effects on the heart and the cardiovascular system, and to assess the cardiac risks associated with the use of this drug in anti- addiction therapy. The actions of 18-methoxycoronaridine (18-MC), a less toxic ibogaine congener with anti-addictive properties, are also considered.

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“…The mechanism by which ibogaine causes bradycardia remains unknown, and is an interesting and clinically significant toxicological question for future study. Although an older literature suggested inhibition of acetylcholinesterase as a basis for bradycardia, this is not supported by contemporary assay techniques [41]. Ibogaine binds to sodium channels in animal brain tissue with low micromolar affinity [4], and there is an association of sodium channel blockade with bradycardia [42].…”

Section: Discussionmentioning

confidence: 99%

hERG Blockade by Iboga Alkaloids

et al. 2015

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The iboga alkaloids are a class of naturally occurring and synthetic compounds, some of which modify drug self-administration and withdrawal in humans and preclinical models. Ibogaine, the prototypic iboga alkaloid that is utilized clinically to treat addictions, has been associated with QT prolongation, torsades de pointes and fatalities. hERG blockade as IKr was measured using the whole-cell patch clamp technique in HEK 293 cells. This yielded the following IC50 values: ibogaine manufactured by semisynthesis via voacangine (4.09 ± 0.69 µM) or by extraction from T. iboga (3.53 ± 0.16 µM); ibogaine's principal metabolite noribogaine (2.86 ± 0.68 µM); and voacangine (2.25 ± 0.34 µM). In contrast, the IC50 of 18-methoxycoronaridine, a product of rational synthesis and current focus of drug development was >50 µM. hERG blockade was voltage dependent for all of the compounds, consistent with low-affinity blockade. hERG channel binding affinities (K i) for the entire set of compounds, including 18-MC, ranged from 0.71 to 3.89 µM, suggesting that 18-MC binds to the hERG channel with affinity similar to the other compounds, but the interaction produces substantially less hERG blockade. In view of the extended half-life of noribogaine, these results may relate to observations of persistent QT prolongation and cardiac arrhythmia at delayed intervals of days following ibogaine ingestion. The apparent structure-activity relationships regarding positions of substitutions on the ibogamine skeleton suggest that the iboga alkaloids might provide an informative paradigm for investigation of the structural biology of the hERG channel.

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Ibogaine and the inhibition of acetylcholinesterase

Cited by 12 publications

References 36 publications

Fatalities Temporally Associated with the Ingestion of Ibogaine

Fatalities Temporally Associated with the Ingestion of Ibogaine

The Anti-Addiction Drug Ibogaine and the Heart: A Delicate Relation

hERG Blockade by Iboga Alkaloids

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