Psilocybin as a fast-acting and long-lasting antidepressant for adolescence: Proposing NeuroD1 as a biomarker of its long-term plasticity
Rubén García‐cabrerizo, Itziar Beruete-Fresnillo, Pedro Bergas-Cladera, M. Julia García‐fuster
Biomedicine & Pharmacotherapy October 30, 2025 DOI: 10.1016/j.biopha.2025.118720 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study Peer reviewed |
|---|---|
| Population | Adolescent Sprague-Dawley rats of both sexes |
| Intervention | Psilocybin |
| Dose | 0.3 and 1 mg/kg |
| Duration | 7-day repeated dosing, with assessments at 30 minutes, 1 day, and 15 days post-treatment |
| Topics | Neuroplasticity Psilocybin |
| Keywords | Antidepressant Hippocampal formation Hallucinogen Pharmacology Biomarker Hippocampus Fluoxetine |
| Citations | 3 |
| Key findings | Oral psilocybin (0.3 and 1 mg/kg) produced rapid and long-lasting antidepressant-like effects in adolescent rats of both sexes, with increased hippocampal NeuroD1 expression paralleling the sustained behavioral response. |
Abstract
Adolescent depression is a significant public health concern, yet treatment options remain limited, particularly due to age- and sex-related differences in antidepressant efficacy. This study explored for the first time the potential antidepressant-like response of psilocybin in adolescence by examining acute, repeated and persistent effects in Sprague-Dawley rats of both sexes, as measured under the stress of the forced-swim test. As compared to other studies, we relied on a more translational approach by administering psilocybin orally (oral gavage, o.g.), while elucidating its hallucinogenic-like potential through head-twitch responses. Finally, hippocampal neurogenesis markers were evaluated as potential biomarkers of psilocybin's antidepressant-like responses in adolescence (1- and 16-days post-treatment). The main results showed that: (1) acute psilocybin (1 mg/kg, 30 min) induced subjective hallucinogenic effects, as measured by head-twitch responses, independently of the route of administration (i.p. vs. o.g.), and without changing locomotor activity; (2) acute psilocybin (0.3 and 1 mg/kg, o.g., 30 min) exerted a rapid antidepressant-like response that coincided with the course of hallucinogenic-like responses; (3) repeated psilocybin (0.3 and 1 mg/kg, 7 days, 1 dose/day, o.g.) induced an antidepressant-like response while increased several hippocampal neurogenesis markers (Ki-67: cell proliferation, NeuroD1: neural progenitors and BrdU: cell survival) as measured 1-day post-treatment; and (4) the long-lasting antidepressant-like effects of psilocybin (observed up to 15-days post-treatment) paralleled hippocampal NeuroD1 regulation. Interestingly these effects were observed for rats independently of sex (mixed-sex cohort). To the best of our knowledge, these results are the first ones to underscore oral psilocybin's potential as a fast-acting and long-lasting antidepressant during adolescence, a developmental stage marked by high vulnerability to depression and reduced response to conventional treatments, while also proposing NeuroD1 as a putative biomarker of its long-term plasticity.
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
Cited by 4
- Multilevel Mechanisms and Clinical Efficacy of Psilocybin in Depression Treatment: A Systematic Review International Journal of Molecular Sciences September 10, 2026
- Blocking 5-HT2B receptors abolishes psilocybin’s efficacy in the rat forced swim test Journal of Psychopharmacology June 23, 2026
- Psilocybin and Mental Health Outcomes: Scoping Review with ☸SAIMSARA SAIMSARA Journal June 15, 2026
- Beyond head-twitch response: Acute psilocybin affects spontaneous behaviors in rats in a dose-dependent manner. Journal of Psychopharmacology August 25, 2026
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and 47 more in the library