Oxa-noribogaine reduces alcohol drinking through aversion learning and by altering glutamatergic activity in the mPFC
Marcus W. Meinhardt, Ivan Skorodumov, Florian Walter, Merve Akan, Tobias Buchborn, Yéléna Le Prieult, Marvin M. Urban, Rainer Spanagel, Livia von Ammon, Carsten Hopf, Liubov S. Kalinichenko, Christian Mueller, Christine Winter, Ravit Hadar, Asude Zülal Gül, Ben Massuda, Maj Hildebrandt, Esi Domi, Adana Keshishian, Roberto Ciccocioppo, Dalibor Sames, Václav Havel, Leah C Solberg Woods, Angela Beeson
Research Square March 31, 2026 DOI: 10.21203/rs.3.rs-9103509/v1 via OpenAlex
Summary
AI-generated from the abstractA compound derived from ibogaine, oxa-noribogaine, reduces alcohol consumption in rats by strengthening learning from negative drinking outcomes. It produces sustained decreases in alcohol intake and relapse-like drinking, matching or exceeding ibogaine's efficacy without detectable motor or cardiac side effects. These effects involve transient changes in prefrontal brain activity, lasting alterations in glutamatergic signaling after aversion-related learning, and normalization of neurotrophic signaling in cortico-striatal circuits. The results generalize across multiple models, genetically diverse animals, and independent study sites, identifying oxa-noribogaine as a promising treatment candidate for alcohol use disorder.
Study at a glance
| Characteristics | Translational rat model Peer reviewed |
|---|---|
| Population | Rats |
| Intervention | oxa-noribogaine |
| Topics | Addiction Neuroplasticity |
| Keywords | Glutamatergic Prefrontal cortex |
| Key finding | Oxa-noribogaine reduces alcohol consumption by strengthening learning from negative drinking outcomes in translational rat models of alcohol dependence. |
Abstract
Abstract Alcohol use disorder is a major global health problem, and current treatments often fail to produce lasting reductions in harmful drinking1,2. Psychedelic-assisted therapies may promote durable behavioural change by enhancing brain plasticity during emotionally meaningful experiences, but progress has been limited by a lack of experimental models that capture these context-dependent effects3,4. Here we show that the ibogaine-derived compound oxa-noribogaine reduces alcohol consumption by strengthening learning from negative drinking outcomes in translational rat models of alcohol dependence. The compound produces sustained decreases in alcohol intake and relapse-like drinking, matches or exceeds the efficacy of its parent compound ibogaine, and does so without detectable motor or cardiac liabilities. These behavioural effects are associated with transient changes in prefrontal brain activity, lasting alterations in glutamatergic signalling after aversion-related learning, and normalization of neurotrophic signalling in cortico-striatal circuits. The therapeutic effects generalize across several translational models, genetically diverse animals and independent study sites. Together, these findings identify oxa-noribogaine as a promising and potentially safer treatment candidate for alcohol use disorder. More broadly, the results establish a preclinical framework for studying psychedelic-inspired therapies that harness context-dependent neuroplasticity to reduce compulsive substance use and support adaptive behavioural change.