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 licenced 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.

Mechanism of hERG Channel Block by the Psychoactive Indole Alkaloid Ibogaine

“…Indeed, we showed that ibogaine also targets cardiac Na v 1.5 sodium and Ca v 1.2 calcium channels (IC 50 values of 142 and 163 mM, respectively) (Koenig et al, 2013) without affecting K v 7.1 channels mediating I Ks (IC 50 .. 100 mM, unpublished data). When tested on isolated guinea pig cardiomyocytes, the action potential prolonging effect of hERG channel inhibition by clinically relevant ibogaine concentrations was counteracted by the simultaneous block of calcium channels.…”

“…Previously, ibogaine had been shown to reduce currents through recombinant hERG channels with half-maximal inhibition at about 3 mM (Koenig et al, 2012(Koenig et al, , 2013. In all subsequent experiments that do not include complete concentration dependences, 3 mM ibogaine was used as representative concentration.…”

“…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. Low micromolar concentrations of ibogaine were also detected in human blood plasma after ingestion of typical doses (0.5-1 g) (Mash et al, 1998), and plasma protein binding was found to be approximately 65% (Koenig et al, 2013).…”

“…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. Low micromolar concentrations of ibogaine were also detected in human blood plasma after ingestion of typical doses (0.5-1 g) (Mash et al, 1998), and plasma protein binding was found to be approximately 65% (Koenig et al, 2013). Drugs with IC 50 values for hERG current inhibition within or close to their range of therapeutic plasma concentrations have a high propensity to cause QT prolongation and to trigger torsade de pointes arrhythmias (Redfern et al, 2003).…”

A pharmacological basis of herbal medicines for epilepsy

“…The anticonvulsant and psychoactive alkaloid ibogaine was found to be an open-channel blocker of NMDA [179] and nicotinic acetylcholine receptors [180]. It also reduced human Na v 1.5 Na + and Ca v 1.2 Ca 2+ currents [181], and was found to block the human ethera-go-go-related gene (hERG) K + channels in the heart, explaining its arrhythmogenic activity [180]. N-methyl-D-aspartate receptors were also blocked by the alkaloid huperzine A [182].…”