Ibogaine, a plant alkaloid used to treat drug addiction despite not being licensed, inhibits hERG potassium channels at low micromolar concentrations, which could disturb heart rhythm. At higher concentrations, it also reduces sodium and calcium currents. Its congener 18-MC blocks these ion channels with less potency. Unexpectedly, ibogaine did not prolong action potentials in guinea pig cardiomyocytes at low concentrations, and higher concentrations shortened them, likely because calcium channel inhibition counteracts hERG blockade effects. However, computer modeling of human ventricular cells suggested ibogaine does prolong the action potential in humans. The authors conclude therapeutic concentrations may prolong the QT interval, potentially leading to cardiac arrhythmias.
Ibogaine, a psychoactive alkaloid used to treat addiction, can cause dangerous heart rhythm problems by blocking hERG potassium channels. Experiments on mammalian kidney cells expressing hERG channels showed that block occurred from either side of the cell membrane and depended on pH. Block happened only when channels were activated, not when resting. Stronger depolarizations increased block speed and extent. The drug shifted channel activation and inactivation to more negative voltages, slowed deactivation, and accelerated inactivation. Mutations Y652A and F656A reduced ibogaine's potency, but an inactivation-deficient mutant remained sensitive. Molecular docking suggested binding inside the channel cavity regardless of ibogaine's protonation state. Kinetic modeling indicated preferential binding to open and inactivated states.