Hwu, C. | bioRxiv Science

bioRxiv2025

Deciphering Ibogaines Matrix Pharmacology: Multiple Transporter Modulation at Serotonin Synapses

Ibogaine is the main psychoactive alkaloid produced by the iboga tree (Tabernanthe iboga) that has a unique therapeutic potential across multiple indications, including opioid dependence, substance use disorders, depression, anxiety, posttraumatic stress disorder (PTSD), and traumatic brain injury (TBI). We systematically examined the effects of ibogaine, its main metabolite noribogaine, and a series of iboga analogs at monoamine neurotransmitter transporters, some which have been linked to the oneiric and therapeutic effects of these substances. We report that ibogaine and noribogaine inhibit the transport function of the vesicular monoamine transporter 2 (VMAT2) with sub-micromolar potency in cell-based fluorimetry assays and at individual synaptic vesicle clusters in mouse brain as demonstrated via two-photon microscopy. The iboga compounds also inhibit the plasma membrane monoamine transporters (MATs), prominently including the serotonin transporter (SERT), and a novel iboga target, the organic cation transporter 2 (OCT2). SERT transport inhibition was demonstrated in serotonin axons and soma in the brain and in rat brain synaptosomes, where ibogaine and its analogs did not act as substrate-type serotonin releasers. Noribogaine showed dual inhibition of VMAT2 and SERT with comparable potency, providing an explanatory model for the known neurochemical effects of ibogaine in rodents. Together, the updated profile of the monoamine transporter modulation offers insight into the complexity of the iboga pharmacology, which we termed "matrix pharmacology". The matrix pharmacology concept is outlined and used to explain why ibogaine and noribogaine do not induce catalepsy, as demonstrated in our study, in contrast to other VMAT2 inhibitors. TOC Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/641351v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@a1cacaorg.highwire.dtl.DTLVardef@8be27org.highwire.dtl.DTLVardef@1fc320forg.highwire.dtl.DTLVardef@3a8837_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2021

Novel Class of Psychedelic Iboga Alkaloids Disrupts Opioid Addiction States

Substance use and related mental health epidemics are causing increasing suffering and death in diverse communities.1,2 Despite extensive efforts focused on developing pharmacotherapies for treating substance use disorders, there is an urgent need for radically different therapeutic approaches.3,4 Ibogaine provides an important drug prototype in this direction, as a psychoactive iboga alkaloid suggested to have the ability to interrupt opioid use in drug-dependent humans.5 However, ibogaine and its major metabolite noribogaine present considerable safety risk associated with cardiac arrhythmias.6 We introduce a new class of iboga alkaloids - "oxa-iboga" - defined as benzofuran-containing iboga analogs and created via structural editing of the iboga skeleton. The oxa-iboga compounds act as potent kappa opioid receptor agonists in vitro and in vivo, but exhibit atypical behavioral features compared to standard kappa psychedelics. We show that oxa-noribogaine has greater therapeutic efficacy in rat models of opioid use, and no cardiac pro-arrhythmic potential, in contrast to noribogaine. Oxa-noribogaine induces long-lasting suppression of morphine and fentanyl intake after a single dose, persistent reduction of morphine intake and reinforcing efficacy after a short treatment regimen, and suppression of morphine and fentanyl drug seeking in relapse models. Oxa-noribogaine also induces a lasting elevation of neurotrophin proteins in the ventral tegmental area and medial prefrontal cortex, consistent with targeted neuroplasticity induction and alteration of addiction-like states. As such, oxa-iboga compounds represent candidates for a novel type of pharmacotherapy for treatment of opioid use disorder.

pharmacology and toxicology↗