The psychoactive property of the alkaloid ibogaine is known for centuries. The drug has achieved notoriety in the treatment of addiction due to its potential effects. Beside receptors, the interaction profile of ibogaine includes neurotransmitters like sertonin and dopamine transporters, whereby ibogaine was able to inhibit substrate induced transport. The inhibition occurs with IC50 values in the micromolar range. Signaling via monoamines including dopamine and serotonin is considered to occur by volume transmission, that depends on diffusion from exocytotic release sites to receptor activation and reuptake sites. Serotonin and dopamine transporters are responsible for reuptake of their substrates through which they shorten the lifetime of extracellular serotonin and dopamine after release. Therefore, serotonin and dopamine transporters are important targets for therapeutic compounds, such as the clinically relevant serotonin reuptake inhibitors used as antidepressants. Psychostimulant abusive drugs, e.g. cocaine and amphetamines including mephedrone and methylone, affect the homeostasis of serotonin and dopamine in the synaptic cleft. The results show that ibogaine inhibits both, substrate induced transport and substrate induced ionic currents. Ibogain is able to increase the accessibility in the permeation pathway. Thereby, ibogaine connects the substrate binding site with the cytoplasm. The reaction rate of these pathway residues was used as a measure of accessibility. The reactivity was decreased via cocaine and antidepressant drugs and increased by serotonin and ibogaine. In this study, the mechanistic basis of ibogaine action on serotonin transporter was addressed and extended to the analysis to dopamine transporters. Hereby, an adapted model compatible with all constraints was presented and imposed by published findings and data. Ibogaine is structurally similar to serotonin, implying that both bind at the same site. However, the analysis predicts that ibogaine does not bind to the substrate binding site. Ibogaine directly binds from the extracellular milieu to a distinct binding site that is accessible in a cytoplasm-facing conformation of the transporter.