Differential effects of psilocybin derivatives on fentanyl-induced conditioned place preference in male and female mice.
Tiffini N Lovell, Peter B James, Skylar L Hodgins, Samuel Johnson Noya, Patrick Arner, Ana-Clara Bobadilla
Journal of Psychopharmacology August 30, 2026 DOI: 10.1177/02698811261478613 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Male and female C57BL/6J mice |
| Interventions | Psilocin 4-MeO-MiPT 4-HO-MiPT |
| Measures | conditioned place preference (CPP), elevated plus maze (EPM) |
| Topics | Psilocybin |
| Keywords | 4-ho-mipt 4-meo-mipt 5-ht2ar agonist Cpp Epm Sud Fentanyl Psychedelics Sex differences |
| Key findings | Psilocin reduced fentanyl CPP exclusively in females, 4-MeO-MiPT reduced CPP in both sexes, and 4-HO-MiPT had no effect. None of the compounds significantly altered anxiety-like behaviors in the EPM. |
Abstract
Fentanyl is the leading cause of fatal overdoses worldwide, and repeated use may lead to substance use disorder (SUD). In SUD, drug-associated contexts can trigger reward-related behavior even in the absence of the drug. Psychedelic compounds may weaken context-drug associations, reducing reward-related behavior to fentanyl. We evaluated the effects of the psychedelic psilocin and its derivatives, 4-MeO-MiPT and 4-HO-MiPT, on fentanyl-induced conditioned place preference (CPP) in male and female C57BL/6J mice. Mice were conditioned to distinct fentanyl and saline control contexts, then assessed for fentanyl place preference before and after treatment with one of the test compounds. Anxiety-related side effects of each compound were evaluated using an elevated plus maze (EPM) model. Psilocin reduced fentanyl CPP exclusively in females, 4-MeO-MiPT in both sexes, and 4-HO-MiPT had no effect. None of the compounds significantly altered anxiety-like behaviors in EPM. These findings support further preclinical investigations of the sex-dependent effects of psilocin and 4-MeO-MiPT on fentanyl reward behavior.
Comparable studies
Other preclinical and animal studies on psilocybin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice Mice | 2021 | Experimental study | |
| Psychedelics reopen the social reward learning critical period Mice | 2023 | Experimental study in mice | |
| Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species. C57BL/6J mice | 2020 | Experimental study with dose-response experiments | |
| Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning Mice | 2013 | Experimental study |
Citations in the library
Cites 25
- Human hallucinogen research: guidelines for safety. Journal of Psychopharmacology July 1, 2008
- The Therapeutic Potential of Psychedelic Drugs: Past, Present, and Future. Neuropsychopharmacology April 26, 2017
- A non-hallucinogenic psychedelic analogue with therapeutic potential. Nature 2021
- Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors Science February 16, 2023
- Efficacy and safety of psilocybin-assisted treatment for major depressive disorder: Prospective 12-month follow-up Journal of Psychopharmacology February 1, 2022
and 20 more in the library