Deciphering Ibogaine’s Matrix Pharmacology: Multiple Transporter Modulation at Serotonin Synapses
Christopher Hwu, Václav Havel, Xavier Westergaard, Adriana M. Mendieta, Inis C. Serrano, Jennifer Hwu, Donna Walther, David Lankri, Tim Luca Selinger, Keer He, R. Liu, Tyler P. Shern, Steven Sun, Boxuan Ma, Bruno González, Luisina Rodríguez, Hannah J. Goodman, Hunter Wu, Mark S. Sonders, Michael H. Baumann, Ignacio Carrera, David Sulzer, Dalibor Sames
Journal of the American Chemical Society December 26, 2025 DOI: 10.1021/jacs.5c06325 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Mouse brain tissue and cell lines |
| Interventions | ibogaine noribogaine oxa-noribogaine iboga analogs |
| Topics | Serotonin Ibogaine |
| Keywords | Monoamine neurotransmitter Serotonin transporter Vesicular monoamine transporter Neurotransmission Synaptic vesicle Pharmacology Neurotransmitter transporter Dopamine transporter Reuptake inhibitor Biochemistry Opioid Alkaloids |
| Citations | 2 |
| Key findings | Ibogaine and noribogaine inhibit VMAT2 and SERT, with noribogaine inducing partial serotonin release and binding VMAT2 at a distinct site, and this dual inhibition profile (SynRI) explains the absence of catalepsy. |
Abstract
) 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 of which have been linked to the therapeutic effects of these substances. We report that ibogaine and noribogaine inhibit the transport function of the vesicular monoamine transporter 2 (VMAT2) with submicromolar potency in cell-based fluorometry assays and at individual synaptic vesicle clusters in mouse brain as demonstrated via two-photon microscopy. Examining the uptake and release of radiolabeled serotonin in isolated brain synaptic vesicles, we confirmed that ibogaine and noribogaine act as inhibitors of VMAT2 and showed that noribogaine induces partial serotonin release from synaptic vesicles. Noribogaine does not compete with the binding of dihydrotetrabenazine, an established VMAT2 inhibitor, indicating that noribogaine engages the VMAT2 transporter at a distinct binding site or conformational state. 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 somata in mouse brain slices and in rat brain synaptosomes, where ibogaine and its analogs did not act as substrate-type serotonin releasers. Noribogaine, oxa-noribogaine, and several analogs displayed dual inhibition of VMAT2 and SERT with comparable potencies, a relatively uncommon activity in the pharmacopoeia of monoamine transporter inhibitors, and were hence labeled as "Synaptic Reuptake Inhibitors" ("SynRIs"). The SynRI profile provides an explanatory model for previously reported neurochemical effects of ibogaine in rodents. Together, the updated profile of the monoamine transporter modulation offers insight into the grand complexity of the iboga pharmacology, which we termed "matrix pharmacology". The matrix pharmacology hypothesis is outlined and used to conceptualize why ibogaine and noribogaine do not induce catalepsy, as demonstrated in our study, in contrast to other VMAT2 inhibitors.
Comparable studies
Other preclinical and animal studies on ibogaine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Noncompetitive Functional Inhibition at Diverse, Human Nicotinic Acetylcholine Receptor Subtypes by Bupropion, Phencyclidine, and Ibogaine TE671/RD cells (human muscle-type nAChR) and SH-SY5Y neuroblastoma cells (human... | 1999 | In vitro study | |
| Degeneration of Purkinje cells in parasagittal zones of the cerebellar vermis after treatment with ibogaine or harmaline. Ibogaine- or harmaline-treated rats | 1993 | Experimental animal study | |
| Effects and aftereffects of ibogaine on morphine self-administration in rats. Rats | 1991 | Preclinical experimental study | |
| Effects of iboga alkaloids on morphine and cocaine self-administration in rats: relationship to tremorigenic effects and to effects on dopamine release in nucleus accumbens and striatum. Rats | 1994 | Experimental study | |
| Glial Cell Line-Derived Neurotrophic Factor Mediates the Desirable Actions of the Anti-Addiction Drug Ibogaine against Alcohol Consumption Rats | 2005 | Experimental study |
Citations in the library
Cited by 3
- Development and validation of a UPLC-MS/MS method for real-time neuropharmacokinetic monitoring of iboga alkaloids in rat brain. Journal of Pharmaceutical and Biomedical Analysis June 24, 2026
- Ibogaine for Substance Use Disorders. Advances in Therapy October 14, 2026
- The Emerging Neurobiology of Psychedelics: Critical Periods, Metaplasticity, and Extracellular Matrix Remodeling. Annual Review of Neuroscience July 1, 2026
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- Serotonin transporter-ibogaine complexes illuminate mechanisms of inhibition and transport. Nature May 1, 2019
- The ibogaine medical subculture. Journal of Ethnopharmacology January 4, 2008
and 42 more in the library