Ibogaine, a plant alkaloid used in alternative medicine for addiction despite not being a licensed therapeutic, can disturb heart rhythm. At therapeutic concentrations it inhibits hERG potassium channels, which can cause life-threatening arrhythmias. This study examined ibogaine and its analog 18-methoxycoronaridine (18-MC) on cardiac ion channels using patch clamp techniques and computer simulations. Ibogaine reduced hERG currents at low micromolar concentrations (IC50, 4 µM) and, at higher concentrations, also inhibited sodium channels. 18-MC was less potent. In guinea-pig cardiomyocytes, ibogaine did not prolong the action potential at low concentrations; higher concentrations shortened it. Computer modeling suggested calcium channel blockade counteracts hERG inhibition's prolonging effect. Ibogaine is potentially proarrhythmic but may also have antiarrhythmic properties.
MDMA can cause serotonin syndrome shortly after administration and serotonergic injury days or weeks later, but these two adverse effects do not always occur together, suggesting different underlying mechanisms. In rats, both a high dose (10 mg/kg three times at 2-hour intervals) and a low dose (2 mg/kg three times) increased extracellular serotonin enough to trigger serotonin syndrome of equal intensity. Modifying the environment intensified the syndrome without further raising serotonin levels. Only the high dose, which produced high MDMA concentrations in the brain, caused serotonergic injury. The findings indicate that extracellular serotonin initiates the syndrome, while postsynaptic receptor activity drives its intensification. Brain MDMA concentration determines injury initiation, and reactive oxygen species generation influences injury intensification.