The Psychedelic Psilocin Suppresses Activity of Central Amygdala Corticotropin-Releasing Factor Receptor 1 Neurons and Decreases Ethanol Drinking in Female Mice
Sarah N. Magee, Allison C. Sereno, Maria Echeveste Sanchez, Emer Shannon, Asad Mohsin, Sarah L. Mott, Sara Faccidomo, Clyde W. Hodge, Melissa A. Herman
Journal of Neuroscience November 10, 2025 DOI: 10.1523/jneurosci.0652-25.2025 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Female CRF1:GFP mice (ethanol-naive and chronic ethanol-exposed) |
| Intervention | Psilocin |
| Topics | Addiction Psilocybin |
| Keywords | Ethanol Metabolite Hallucinogen Receptor Extended amygdala Anhedonia Pharmacology Endocrinology Kindling Therapeutic effect Corticosterone Self-administration Mediator |
| Key findings | Psilocin acutely decreases ethanol consumption and reduces relative CRF1 activation in the central amygdala of mice. |
Abstract
Alcohol use disorder (AUD) is a highly prevalent disorder with limited therapeutic options. The central amygdala (CeA) is a critical brain region as dysregulation within the CeA and the corticotropin-releasing factor (CRF) system are associated with AUD pathology. CeA CRF1 receptors regulate alcohol drinking and have served as a therapeutic target in alcohol treatment. One emerging potential therapeutic for AUD is psilocybin. Psilocybin has been shown to decrease drinking in some clinical studies; however, the effects are variable and the underlying mechanisms are poorly understood. Psilocybin engages many brain regions, including the CeA, and may produce therapeutic effects on drinking through interactions with CeA CRF1 neurons. The current study explores the effects of psilocin, the active metabolite of psilocybin, on voluntary ethanol drinking and CeA CRF1 activity to understand potential mechanisms underlying the therapeutic effects of psilocin. Psilocin acutely decreased ethanol consumption in mice exposed to two different models of chronic ethanol exposure without producing changes in locomotor behavior. Psilocin increased CeA activation and decreased relative CRF1 activation in CeA subregions from ethanol-naive female CRF1:GFP mice. These results were also observed in chronic ethanol-exposed mice at 24 and 72 h withdrawal timepoints. Psilocin increased corticosterone at 24 h withdrawal but not at 72 h withdrawal. Collectively, these results demonstrate that psilocin engages CeA circuitry and decreases relative CRF1 activation, in parallel with acute reductions in drinking. These results contribute to our understanding of the mechanisms underlying the actions of psilocin and inform the interpretation of therapeutic effects in clinical studies.
Comparable studies
Other preclinical and animal studies on psilocybin for addiction, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psychedelics reopen the social reward learning critical period Mice | 2023 | Experimental study in mice | |
| Psilocybin targets a common molecular mechanism for cognitive impairment and increased craving in alcoholism | 2021 | Preclinical study | |
| Psilocybin and LSD have no long-lasting effects in an animal model of alcohol relapse Male and female rats | 2020 | Preclinical animal study | |
| Psilocybin-induced default mode network hypoconnectivity is blunted in alcohol-dependent rats Healthy rats and a rat model of alcohol relapse | 2023 | Randomized, placebo-controlled crossover pharmaco-fMRI study | |
| Psilocybin prevents reinstatement of alcohol seeking by disrupting the reconsolidation of alcohol-related memories. Male and female Marchigian Sardinian alcohol-preferring (msP) rats | 2023 | Preclinical experimental study |