Oxa-Iboga alkaloids lack cardiac risk and disrupt opioid use in animal models.
Václav Havel, Andrew C Kruegel, Benjamin Bechand, Scot Mcintosh, Leia S. Stallings, Alana Hodges, Madalee G. Wulf, Mel Nelson, Amanda Hunkele, Michael Ansonoff, John E Pintar, Christopher Hwu, Rohini S Ople, Najah Abi-Gerges, Saheem A. Zaidi, Vsevolod Katritch, Mu Yang, Jonathan A Javitch, Susruta Majumdar, Scott E Hemby, Dalibor Sames
Nature Communications September 20, 2024 DOI: 10.1038/s41467-024-51856-y (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Male rats and primary human cardiomyocytes |
| Interventions | oxa-iboga compounds oxa-noribogaine |
| Dose | a single dose or a short treatment regimen |
| Topics | Ibogaine |
| Keywords | Drug discovery Pain management Drug safety |
| Citations | 18 |
| Key points | Oxa-iboga compounds lack proarrhythmic cardiac effects and show superior efficacy in reducing opioid intake and relapse in animal models, acting as atypical kappa opioid receptor agonists. |
Abstract
Ibogaine and its main metabolite noribogaine provide important molecular prototypes for markedly different treatment of substance use disorders and co-morbid mental health illnesses. However, these compounds present a cardiac safety risk and a highly complex molecular mechanism. We introduce a class of iboga alkaloids - termed oxa-iboga - defined as benzofuran-containing iboga analogs and created via structural editing of the iboga skeleton. The oxa-iboga compounds lack the proarrhythmic adverse effects of ibogaine and noribogaine in primary human cardiomyocytes and show superior efficacy in animal models of opioid use disorder in male rats. They act as potent kappa opioid receptor agonists in vitro and in vivo, but exhibit atypical behavioral features compared to standard kappa opioid agonists. Oxa-noribogaine induces long-lasting suppression of morphine, heroin, and fentanyl intake after a single dose or a short treatment regimen, reversal of persistent opioid-induced hyperalgesia, and suppression of opioid drug seeking in rodent relapse models. As such, oxa-iboga compounds represent mechanistically distinct iboga analogs with therapeutic potential.
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 16
- Classic Psychedelics in Pain Modulation: Mechanisms, Clinical Evidence, and Future Perspectives ACS Chemical Neuroscience June 6, 2025
- Rare but relevant: Ibogaine and cardiovascular complications-prolonged QT interval and ventricular arrhythmias. Addiction January 20, 2026
- Deciphering Ibogaine’s Matrix Pharmacology: Multiple Transporter Modulation at Serotonin Synapses Journal of the American Chemical Society December 26, 2025
- Ibogaine: Therapeutic Potential, Cardiac Safety, and Translational Perspectives in the Treatment of Substance Use Disorders—A Scoping Review Molecules February 4, 2026
- Noribogaine altered intrinsic properties of thalamocortical neurons in a sex-dependent manner Progress in Neuro-Psychopharmacology and Biological Psychiatry August 1, 2025
and 11 more in the library
Cites 27
- A non-hallucinogenic psychedelic analogue with therapeutic potential. Nature 2021
- Treatment of acute opioid withdrawal with ibogaine. American Journal on Addictions 1999
- Glial Cell Line-Derived Neurotrophic Factor Mediates the Desirable Actions of the Anti-Addiction Drug Ibogaine against Alcohol Consumption Journal of Neuroscience January 19, 2005
- Ibogaine treatment outcomes for opioid dependence from a twelve-month follow-up observational study. The American Journal of Drug and Alcohol Abuse 2018
- A non-hallucinogenic LSD analog with therapeutic potential for mood disorders. Cell Reports March 28, 2023
and 22 more in the library