title: Anti-addiction drug ibogaine inhibits voltage-gated ionic currents: a study to assess the drug's cardiac ion channel profile.
abstract: The plant alkaloid ibogaine has promising anti-addictive properties. Albeit not licensed as a therapeutic drug, and despite hints that ibogaine may perturb the heart rhythm, this alkaloid is used to treat drug addicts. We have recently reported that ibogaine inhibits human ERG (hERG) potassium channels at concentrations similar to the drugs affinity for several of its known brain targets. Thereby the drug may disturb the heart's electrophysiology. Here, to assess the drug's cardiac ion channel profile in more detail, we studied the effects of ibogaine and its congener 18-Methoxycoronaridine (18-MC) on various cardiac voltage-gated ion channels. We confirmed that heterologously expressed hERG currents are reduced by ibogaine in low micromolar concentrations. Moreover, at higher concentrations, the drug also reduced human Nav1.5 sodium and Cav1.2 calcium currents. Ion currents were as well reduced by 18-MC, yet with diminished potency. Unexpectedly, although blocking hERG channels, ibogaine did not prolong the action potential (AP) in guinea pig cardiomyocytes at low micromolar concentrations. Higher concentrations (≥ 10 μM) even shortened the AP. These findings can be explained by the drug's calcium channel inhibition, which counteracts the AP-prolonging effect generated by hERG blockade. Implementation of ibogaine's inhibitory effects on human ion channels in a computer model of a ventricular cardiomyocyte, on the other hand, suggested that ibogaine does prolong the AP in the human heart. We conclude that therapeutic concentrations of ibogaine have the propensity to prolong the QT interval of the electrocardiogram in humans. In some cases this may lead to cardiac arrhythmias.
authors.affiliation: Center for Physiology and Pharmacology, Department of Neurophysiology and -pharmacology, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Xaver
authors.initials: X
authors.lastname: Koenig
authors.forename: Michael
authors.initials: M
authors.lastname: Kovar
authors.forename: Lena
authors.initials: L
authors.lastname: Rubi
authors.forename: Agnes K
authors.initials: AK
authors.lastname: Mike
authors.forename: Peter
authors.initials: P
authors.lastname: Lukacs
authors.forename: Vaibhavkumar S
authors.initials: VS
authors.lastname: Gawali
authors.forename: Hannes
authors.initials: H
authors.lastname: Todt
authors.forename: Karlheinz
authors.initials: K
authors.lastname: Hilber
authors.forename: Walter
authors.initials: W
authors.lastname: Sandtner
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D016739:Behavior, Addictive / Q000188:drug therapy / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000502:physiology; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D007050:Ibogaine / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D007473:Ion Channels / Q000037:antagonists & inhibitors / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology; D026902:Potassium Channel Blockers / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; D007473:Ion Channels; D026902:Potassium Channel Blockers; D007050:Ibogaine
keywords: 18-MC; 18-Methoxycoronaridine; AP; Anti-addiction drug; Ibogaine; QT interval prolongation; Voltage-gated ion channels; action potential; hERG; hERG potassium channels; human Ether-à-go-go-Related Gene