2026 ECNP Congress

PS04-4217

Gut microbiome depletion alters psilocybin-induced prosocial effects in adult mice

Pedro Bergas-Cladera — R. Garcia-Cabrerizo · University of the Balearic Islands, Research Institute of Health Sciences- IUNICS, Palma, Spain

2026 ECNP Congress

Social deficits are a core dimension of several stress-related and psychiatric disorders, and current treatments show limited efficacy in restoring social functioning. Psychedelics such as psilocybin have recently gained interest for their rapid antidepressant potential and their capacity to modulate social cognition, emotional processing and behavioral flexibility [1, 2]. In a previous study, we observed that oral psilocybin enhances social behavior in adult C57BL/6 mice in a dose-, time- and sex-dependent manner. Since the gut microbiome is increasingly recognized as a regulator of social behavior, emotional processing and psychedelic-related mechanisms [3], the present study investigated whether antibiotic-induced microbiome depletion modulates the prosocial effects of psilocybin. Adult male and female C57BL/6 mice (n=80) received regular water or a broad-spectrum antibiotic cocktail throughout the experiment. After one week of antibiotic exposure, mice were treated once daily with psilocybin (1 mg/kg/day) or vehicle by oral gavage for 7 consecutive days. Social behavior was evaluated using the reciprocal social interaction test 30 min after the first administration and 1 day after repeated treatment, analyzing direct social interactions such as anogenital sniffing, nose-to-body and nose-to-nose interactions. Three days after repeated treatment, sociability and social novelty were also assessed using the three-chamber test. Data from the reciprocal social interaction test were analyzed using three-way ANOVAs with sex, antibiotic exposure and psilocybin treatment as independent variables. For the three-chamber test, since no sex differences were observed, males and females were pooled and data were analyzed using ANOVAs including antibiotic exposure, psilocybin treatment and either sociability or social novelty as factors, depending on the phase of the test. Consistent with our previous findings, but revealing an additional modulatory role of the microbiome, acute psilocybin effects depended on sex and antibiotic exposure. For direct social interaction, ANOVA revealed a significant main effect of sex F1,72=10.93, p=0.0015 and a significant sex x antibiotics x psilocybin interaction F1,72=6.385, p=0.0137, indicating that the acute prosocial response was not uniformly expressed across groups. Similar three-way interactions were detected for anogenital sniffing and nose-to-body interaction, whereas nose-to-nose interaction showed a main effect of sex. After repeated treatment, psilocybin produced a clearer prosocial profile that was strongly influenced by antibiotic exposure. Direct social interaction showed significant main effects of antibiotics F1,72=17.96, p<0.0001 and psilocybin F1,72=9.369, p=0.0031, together with significant antibiotics x psilocybin F1,72=6.481, p=0.0130 and sex x antibiotics x psilocybin interactions F1,72=7.094, p=0.0095, suggesting that microbiome depletion interfered with the response to repeated psilocybin. Consistently, anogenital sniffing showed significant antibiotics, psilocybin and antibiotics x psilocybin effects. In the three-chamber test, mice displayed robust sociability F1,152=551.1, p<0.0001 and social novelty preference F1,152=170.7, p<0.0001, but no significant effects of antibiotics, psilocybin or their interactions were observed. Overall, these results suggest that gut microbiome depletion modulates psilocybin-induced prosocial responses in the reciprocal social interaction test, particularly after repeated exposure, while leaving basal sociability and social novelty largely intact. Current experiments are evaluating long-lasting social responses after repeated psilocybin, together with microbiome-related and neurobiological markers that may define gut-brain mechanisms underlying psychedelic-induced prosocial effects.

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.
  2. Liebnau J, Betzler F, Kerber A. Catalyst for change: Psilocybin’s antidepressant mechanisms-A systematic review. J Psychopharmacol. 2025 May;39(5):397-415.
  3. Sherwin E, Bordenstein SR, Quinn JL, Dinan TG, Cryan JF. Microbiota and the social brain. Science. 2019 Nov 1;366(6465):eaar2016. doi: 10.1126/science.aar2016.