Novel Class of Psychedelic Iboga Alkaloids Disrupts Opioid Use
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, Najah Abi-Gerges, Saheem A. Zaidi, Vsevolod Katritch, Mu Yang, Jonathan A Javitch, Susruta Majumdar, Scott E Hemby, Dalibor Sames
bioRxiv (Cold Spring Harbor Laboratory) July 23, 2021 preprint DOI: 10.1101/2021.07.22.453441 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study |
|---|---|
| Population | Rats |
| Intervention | oxa-noribogaine |
| Topics | Ibogaine |
| Keywords | Pharmacology Opioid Receptor |
| Citations | 3 |
| Key points | Oxa-noribogaine suppresses opioid intake and seeking in rat models without cardiac risk, unlike noribogaine. |
Abstract
Abstract 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.
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
Cites 20
- 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
- The Anti-Addiction Drug Ibogaine and the Heart: A Delicate Relation Molecules January 29, 2015
and 15 more in the library