Acute psilocybin or ethocybin leads to a sustained increase in Pavlovian aversion memory in male mice
David Ernst Hogg, Jennifer Romanos, Jamie Albiez, Céline Hofer, Sarah Wicki, Ali Özgür Argunşah, Hannes Sigrist, Jan Thomann, Dino Luethi, Franz X. Vollenweider, Christopher R. Pryce
Frontiers in Pharmacology September 22, 2026 DOI: 10.3389/fphar.2026.1918182 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal study Peer reviewed |
|---|---|
| Population | Male mice |
| Interventions | Psilocybin Ethocybin |
| Dose | 3 mg/kg per os |
| Duration | 15-day chronic social stress or control handling, then Pavlovian aversion learning 2 days later, drug 1 day later, and memory testing 3 days after drug |
| Measures | freezing behavior, head twitch responses |
| Topics | Psilocybin |
| Key points | Psilocybin and ethocybin, given after Pavlovian aversion learning, increased subsequent aversive memory expression in male mice, with more freezing behavior during tone and context presentation than vehicle. The authors propose that a comparable effect in humans with stress- and trauma-related affective disorders might increase the psychotherapeutic accessibility of such memories. |
Abstract
There is considerable interest in the concept that psychedelic compounds might facilitate reorganization of emotional processing with therapeutic benefit; in particular, amelioration of excessive focus on past, current and potential-future aversive events, a dominant emotional-cognitive state in stress-related affective disorders. Translational animal models can advance understanding of specific aspects of this concept, namely, those relating to subconscious emotional memories and their neurobiology. In male mice, chronic social stress (CSS) leads to excessive tone/context-foot shock Pavlovian aversion learning (PAL) and memory (PAM), measured as time spent in freezing behavior, and provides a model for generalized excessive focus on aversion. Sub-chronic administration of SSRI antidepressant between PAL and PAM reverses the excessive PAM of CSS mice. Here we applied the model to investigate acute and sustained behavioral and neurobiological effects of psilocybin (PSY) and ethocybin (ETH). In control male mice, both psychedelics at 3 mg/kg per os resulted in 1–2 h of blood-brain exposure to the respective major metabolites psilocin and ethocin, and to head twitch responses. In the main experiment, mice underwent either 15-day CSS or control handling (CON), followed 2 days later by PAL, 1 day later by PSY, ETH or vehicle (VEH), and 3 days later by PAM testing and then brain collection. Relative to VEH, PSY and ETH led to increased PAM expression as more time spent in freezing behavior during tone/context presentation. In a subset of these same mice, there was no psychedelic effect on densities of the two glutamatergic synaptic proteins investigated, vGluT1 or Homer1 in prelimbic cortex or amygdala. This study demonstrates that PSY and ETH lead to a sustained increase in aversive emotional memory expression in male mice. A similar effect in humans with stress- and trauma-related affective disorders might increase the psychotherapeutic accessibility of such memories.
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 42
- Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. The Lancet Psychiatry May 17, 2016
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
- Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action Neuroreport December 1, 1998
- Psychedelics and the essential importance of context. Journal of Psychopharmacology February 15, 2018
- Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Neuron July 5, 2021
and 37 more in the library