2026 ECNP Congress

PS01-1200

Microbiome depletion prevents psilocybin’s antidepressantlike effects in adolescent rats of both sexes

Itziar Beruete-Fresnillo — M.J. Garcia-Fuster, R. Garcia-Cabrerizo · University of the Balearic Islands, Research Institute of Health Sciences- IUNICS, Palma, Spain

2026 ECNP Congress

Adolescent depression is a significant public health concern, yet treatment options remain limited, partly due to age- and sex-related differences in antidepressant efficacy. We recently showed that oral psilocybin induces rapid and long-lasting antidepressant-like effects in adolescent rats of both sexes, supporting its potential as a fast-acting and long-lasting therapeutic candidate for this vulnerable developmental stage [1]. Given the role of the gut microbiome in brain function, emotional behavior and antidepressant efficacy [2, 3], this study explored whether antibiotic-induced gut microbiome depletion modulates the antidepressant-like response of psilocybin in adolescent Sprague-Dawley rats. Rats of both sexes (33 males and 30 females) received either regular drinking water or a broad-spectrum antibiotic (ABX) cocktail in the drinking water throughout adolescence, from postnatal day (PND) 23 to PND 56. To label newly generated hippocampal cells before treatment exposure, all rats received BrdU injections (2 x 50 mg/kg, i.p., 12 h apart, for 3 consecutive days; PND 27-29). Later, rats were treated with psilocybin (1 mg/kg/day) or vehicle (saline, 2 ml/kg/day) by oral gavage for 7 days during mid-adolescence (PND 34-40). Antidepressant-like responses were assessed in the forced-swim test as time spent immobile, 30 min after the first administration and 1, 8 and 15 days after repeated treatment. Since no significant main effects of sex or interactions involving sex were observed, rats of both sexes were combined and analyzed through two-way ANOVAs, with ABX exposure and psilocybin treatment as independent variables. The main results showed that acute psilocybin produced a rapid antidepressant-like response in water-treated rats, as shown by reduced immobility 30 min post-treatment. Two-way ANOVA revealed a significant main effect of psilocybin (F1,59=5.018, p=0.0289) and a significant ABX x psilocybin interaction (F1,59=4.324, p=0.0419), indicating that this rapid response was absent in microbiome-depleted rats. Similarly, 1 day after repeated treatment, two-way ANOVA showed significant main effects of psilocybin (F1,59=51.03, p<0.0001) and ABX (F1,59=8.024, p=0.0063), together with a significant ABX x psilocybin interaction (F1,59=13.91, p=0.0004), demonstrating that the antidepressant-like effect of repeated psilocybin was prevented by ABX exposure. When evaluating the long-lasting antidepressant-like responses, psilocybin still reduced immobility in water-treated rats 8 and 15 days post-treatment, while this sustained response was absent in ABX-treated rats. Two-way ANOVAs confirmed significant main effects of psilocybin (8 days: F1,59=22.82, p<0.0001; 15 days: F1,59=27.17, p<0.0001) and significant ABX x psilocybin interactions (8 days: F1,59=5.301, p=0.0249; 15 days: F1,59=8.571, p=0.0048), with no main effects of ABX at either time point. Overall, antibiotic-induced microbiome depletion blocked the rapid, repeated and long-lasting antidepressant-like effects of oral psilocybin in adolescent rats. Ongoing experiments will determine whether these behavioral responses are paralleled by long-term changes in hippocampal neurogenesis and plasticity-related markers, including BrdU-labelled cell survival and NeuroD1-positive neural progenitors. These findings highlight the critical role of the gut microbiome in psilocybin’s rapid and sustained antidepressant-like effects during adolescence, while supporting the need to further explore microbiome-gut-brain mechanisms as modulators of psychedelic-based therapeutic strategies.

References

  1. .García-Cabrerizo R, Beruete-Fresnillo I, Bergas-Cladera P, García-Fuster MJ. Psilocybin as a fast-acting and long-lasting antidepressant for adolescence: Proposing NeuroD1 as a biomarker of its long-term plasticity. Biomed Pharmacother. 2025 Dec;193:118720. doi: 10.1016/j.biopha.2025.118720.
  2. .Cryan JF, Dinan TG. Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci. 2012 Oct;13(10):701-12. doi: 10.1038/nrn3346.
  3. .Guzzetta KE, Cryan JF, O’Leary OF. Microbiota-Gut-Brain Axis Regulation of Adult Hippocampal Neurogenesis. Brain Plast. 2022 Oct 21;8(1):97-119. doi: 10.3233/BPL-220141.