Long-QT Syndrome Induced by the Antiaddiction Drug Ibogaine

Hoelen, Dianne W M; Spiering, Wilko; Valk, Gerlof D.

doi:10.1056/nejmc0804248

Cited by 41 publications

(38 citation statements)

References 3 publications

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“…Ibogaine has demonstrated good preclinical evidence as an anti-addictive agent (Glick et al, 1991; 1994), as well as anecdotal reports and preliminary clinical findings showing promise as an aid in opioid detoxification and substance use disorder treatment (Alper et al, 1999; Lotsof, 1995; Schenberg et al, 2014). However, concerns remain about safety and toxicity of ibogaine, tempering the widespread implementation of ibogaine research and treatment for the time being (Alper et al, 2012; Hoelen et al, 2009). Preclinical data and basic human research on Salvinorin A (SA) suggest an important role for the Kappa opioid receptor system in modulating addiction, mood, and consciousness (Addy et al, 2012; 2015; Freeman et al, 2014; Johnson et al, 2011; 2016); though clinical research has yet to provide evidence for therapeutic use of SA, which remains an important direction for future research (Butelman & Kreek, 2015; Chavkin, 2011).…”

Section: Discussionmentioning

confidence: 99%

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Clinical applications of hallucinogens: A review.

Garcia-Romeu

Kersgaard

Addy³

2016

Experimental and Clinical Psychopharmacology

158

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Hallucinogens fall into several different classes, as broadly defined by pharmacological mechanism of action, and chemical structure. These include psychedelics, entactogens, dissociatives, and other atypical hallucinogens. Although these classes do not share a common primary mechanism of action, they do exhibit important similarities in their ability to occasion temporary but profound alterations of consciousness, involving acute changes in somatic, perceptual, cognitive, and affective processes. Such effects likely contribute to their recreational use. However, a growing body of evidence indicates that these drugs may have therapeutic applications beyond their potential for abuse. This review will present data on several classes of hallucinogens with a particular focus on psychedelics, entactogens, and dissociatives, for which clinical utility has been most extensively documented. Information on each class is presented in turn, tracing relevant historical insights, highlighting similarities and differences between the classes from the molecular to the behavioral level, and presenting the most up-to-date information on clinically oriented research with these substances, with important ramifications for their potential therapeutic value.

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Section: Discussionmentioning

confidence: 99%

“…Concerns over possible cardiac toxicity have come from reports of human fatalities associated with the ingestion of ibogaine (Hoelen et al, 2009). Ibogaine is typically administered at a dosage of 10–25 mg / kg of body weight (Alper et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Clinical applications of hallucinogens: A review.

Garcia-Romeu

Kersgaard

Addy³

2016

Experimental and Clinical Psychopharmacology

158

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“…Therefore, ibogaine has never been subjected to thorough preclinical testing. Several cases of sudden death after ibogaine intake have been reported and were most likely caused by cardiac arrhythmias (Maas and Strubelt, 2006;Hoelen et al, 2009;Alper et al, 2012). Additional evidence for ibogaine's cardiotoxicity is provided by case reports on acquired long-QT intervals and resulting cardiac tachyarrhythmias subsequent to ingestion of this alkaloid (Hoelen et al, 2009;Paling et al, 2012;Pleskovic et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

“…Several cases of sudden death after ibogaine intake have been reported and were most likely caused by cardiac arrhythmias (Maas and Strubelt, 2006;Hoelen et al, 2009;Alper et al, 2012). Additional evidence for ibogaine's cardiotoxicity is provided by case reports on acquired long-QT intervals and resulting cardiac tachyarrhythmias subsequent to ingestion of this alkaloid (Hoelen et al, 2009;Paling et al, 2012;Pleskovic et al, 2012). Most recently, we could provide direct experimental evidence for a reduction of currents through hERG channels by ibogaine: the alkaloid concentration that reduced the currents by 50% (IC 50 ) was shown to be 4 mM (Koenig et al, 2012(Koenig et al, , 2013.…”

Section: Introductionmentioning

confidence: 99%

Mechanism of hERG Channel Block by the Psychoactive Indole Alkaloid Ibogaine

Thurner

Stary-Weinzinger

Gafar

et al. 2014

The Journal of Pharmacology and Experimental Therapeutics

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Ibogaine is a psychoactive indole alkaloid. Its use as an antiaddictive agent has been accompanied by QT prolongation and cardiac arrhythmias, which are most likely caused by human ether a go-go-related gene (hERG) potassium channel inhibition. Therefore, we studied in detail the interaction of ibogaine with hERG channels heterologously expressed in mammalian kidney tsA-201 cells. Currents through hERG channels were blocked regardless of whether ibogaine was applied via the extracellular or intracellular solution. The extent of inhibition was determined by the relative pH values. Block occurred during activation of the channels and was not observed for resting channels. With increasing depolarizations, ibogaine block grew and developed faster. Steady-state activation and inactivation of the channel were shifted to more negative potentials. Deactivation was slowed, whereas inactivation was accelerated. Mutations in the binding site reported for other hERG channel blockers (Y652A and F656A) reduced the potency of ibogaine, whereas an inactivation-deficient double mutant (G628C/S631C) was as sensitive as wild-type channels. Molecular drug docking indicated binding within the inner cavity of the channel independently of the protonation of ibogaine. Experimental current traces were fit to a kinetic model of hERG channel gating, revealing preferential binding of ibogaine to the open and inactivated state. Taken together, these findings show that ibogaine blocks hERG channels from the cytosolic side either in its charged form alone or in company with its uncharged form and alters the currents by changing the relative contribution of channel states over time.

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“…Recently, alarming reports of life-threatening cardiac arrhythmias and sudden death cases [4–12], temporally associated with the ingestion of ibogaine, have accumulated. We [13–16] and others [17] hypothesized that these were related to the drug’s propensity to block human ether-a-go-go-related gene (hERG) potassium channels in the heart, which can result in retardation of ventricular action potential (AP) repolarization and prolongation of the QT interval in the electrocardiogram (ECG) [18].…”

Section: Introductionmentioning

confidence: 99%

Anti-addiction Drug Ibogaine Prolongs the Action Potential in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes

et al. 2016

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Ibogaine is a plant alkaloid used as anti-addiction drug in dozens of alternative medicine clinics worldwide. Recently, alarming reports of life-threatening cardiac arrhythmias and cases of sudden death associated with the ingestion of ibogaine have accumulated. Using whole-cell patch clamp recordings, we assessed the effects of ibogaine and its main metabolite noribogaine on action potentials in human ventricular-like cardiomyocytes derived from induced pluripotent stem cells. Therapeutic concentrations of ibogaine and its long-lived active metabolite noribogaine significantly retarded action potential repolarization in human cardiomyocytes. These findings represent the first experimental proof that ibogaine application entails a cardiac arrhythmia risk for humans. In addition, they explain the clinically observed delayed incidence of cardiac adverse events several days after ibogaine intake. We conclude that therapeutic concentrations of ibogaine retard action potential repolarization in the human heart. This may give rise to a prolongation of the QT interval in the electrocardiogram and cardiac arrhythmias.

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Long-QT Syndrome Induced by the Antiaddiction Drug Ibogaine

Cited by 41 publications

References 3 publications

Clinical applications of hallucinogens: A review.

Clinical applications of hallucinogens: A review.

Mechanism of hERG Channel Block by the Psychoactive Indole Alkaloid Ibogaine

Anti-addiction Drug Ibogaine Prolongs the Action Potential in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes

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