Effect of oral tryptamines on the gut microbiome of rats-a preliminary study

Abstract

Background: Psilocybin and related tryptamines have come into the spotlight in recent years as potential therapeutics for depression. Research on the mechanisms of these effects has historically focused on the direct effects of these drugs on neural processes. However, in addition to such neural effects, alterations in peripheral physiology may also contribute to their therapeutic effects. In particular, substantial support exists for a gut microbiome-mediated pathway for the antidepressant efficacy of other drug classes, but no prior studies have determined the effects of tryptamines on microbiota.

Methods: To address this gap, in this preliminary study, male Long Evans rats were treated with varying dosages of oral psilocybin (0.2 or 2 mg/kg), norbaeocystin (0.25 or 2.52 mg/kg), or vehicle and their fecal samples were collected 1 week and 3 weeks after exposure for microbiome analysis using integrated 16S ribosomal DNA sequencing to determine gut microbiome composition.

Results: We found that although treatment with neither psilocybin nor norbaeocystin significantly affected overall microbiome diversity, it did cause significant dose- and time-dependent changes in bacterial abundance at the phylum level, including increases in Verrucomicrobia and Actinobacteria, and decreases in Proteobacteria.

Conclusion and implications: These preliminary findings support the idea that psilocybin and other tryptamines may act on the gut microbiome in a dose- and time-dependent manner, potentially identifying a novel peripheral mechanism for their antidepressant activity. The results from this preliminary study also suggest that norbaeocystin may warrant further investigation as a potential antidepressant, given the similarity of its effects to psilocybin.

Keywords: Actinobacteria; Gut microbiome; Norbaeocystin; Proteobacteria; Psilocybin; Rat; Verrucomicrobia.

Figure 1. Effects of psilocybin and norbaeocystin treatment on microbial diversity.

Effects of low dosage 0.2 mg/kg of psilocybin (P-low), high dosage 2 mg/kg of psilocybin (P-high), low dosage 0.25 mg/kg of norbaeocystin (N-low), and high dosage 2.52 mg/kg of norbaeocystin (N-high) on taxonomic composition of bacterial communities at the phylum level 1 week after treatment (A) or 3 weeks after treatment (B). Effects of P-low and P-high (C) and N-low and N-high (D) on microbial diversity, measured by Shannon diversity index. Significant differences in diversity at the phylum level between groups were determined by a two-way ANOVA followed by FDR-corrected post hoc comparisons analysis. p < 0.05 was considered statistically significant.

Figure 2. Effects of psilocybin and norbaeocystin treatment on abundance of major microbial phyla at the phylum level and their ratio.

Effects of low dosage 0.2 mg/kg of psilocybin (P-low) and high dosage 2 mg/kg of psilocybin (P-high) (A), low dosage 0.25 mg/kg of norbaeocystin (N-low) and high dosage 2.52 mg/kg of norbaeocystin (N-high) (B) on Firmicutes abundance. Effects of P-low and P-high (C) and N-low and N-high (D) on Bacteroidetes abundance. Effects of P-low and P-high (E) and N-low and N-high (F) on the Firmicutes/Bacteroidetes ratio. Significant differences in relative abundance of Firmicutes or Bacteroidetes bacterial population and the Firmicutes/Bacteroidetes ratio between groups were determined by a two-way ANOVA followed by FDR-corrected post hoc comparisons analysis. p < 0.05 was considered statistically significant. *Indicated statistical significance.

Figure 3. Effects of psilocybin and norbaeocystin treatment on abundance of minor microbial phyla at the phylum level.

Effects of low dosage 0.2 mg/kg of psilocybin (P-low) and high dosage 2 mg/kg of psilocybin (P-high) (A), low dosage 0.25 mg/kg of norbaeocystin (N-low) and high dosage 2.52 mg/kg of norbaeocystin (N-high) (B) on Proteobacteria abundance. Effects of P-low and P-high (C) and N-low and N-high (B) on Actinobacteria abundance. Effects of P-low and P-high (E) and N-low and N-high (F) on Verrucomicrobia abundance. Effects of P-low and P-high (G) and N-low and N-high (H) on Tenericutes abundance. Significant differences in relative abundance of bacterial population were determined by a two-way ANOVA followed by FDR-corrected post hoc comparisons analysis. p < 0.05 was considered statistically significant. *Indicated statistical significance.