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 preprint DOI: 10.21203/rs.3.rs-9103509/v1 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Translational rat model |
|---|---|
| Population | Rats |
| Intervention | oxa-noribogaine |
| Topics | Addiction Neuroplasticity Ibogaine |
| Keywords | Glutamatergic Prefrontal cortex Alcohol consumption Signalling Alcohol dependence Pharmacology Neurotrophic factors Drug |
| Key points | 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.
In the evidence
This study is part of the evidence base for a synthesis in the library. Here is how each one recorded it.
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Oxa-noribogaine reduced alcohol consumption and relapse-like drinking in rats by strengthening learning from negative drinking outcomes, matching or exceeding ibogaine's efficacy without detectable motor or cardiac liabilities.
Synthesized
Comparable studies
Other preclinical and animal studies on ibogaine for addiction, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Glial Cell Line-Derived Neurotrophic Factor Mediates the Desirable Actions of the Anti-Addiction Drug Ibogaine against Alcohol Consumption Rats | 2005 | Experimental study | |
| Effects of ibogaine on acute signs of morphine withdrawal in rats: independence from tremor. Morphine-dependent rats | 1992 | Randomized controlled trial | |
| Autoregulation of glial cell line-derived neurotrophic factor expression: implications for the long-lasting actions of the anti-addiction drug, Ibogaine. Dopaminergic-like SHSY5Y cell line | 2006 | In vitro cell culture study | |
| A dose-response study of ibogaine-induced neuropathology in the rat cerebellum. Rats | 2000 | Dose-response study | n = 30 |
| Oral noribogaine shows high brain uptake and anti-withdrawal effects not associated with place preference in rodents. Mice and rats | 2016 | Experimental study with three experiments |