Psychedelics and the Gut Microbiome: Unraveling the Interplay and Therapeutic Implications

[Craigo]

ABSTRACT: Classic psychedelics and the gut microbiome interact bidirectionally through mechanisms involving 5-HT2A receptor signaling, neuroplasticity, and microbial metabolism. This viewpoint highlights how psychedelics may reshape microbiota and how microbes influence psychedelic efficacy, proposing microbiome-informed strategies such as probiotics or dietary interventions to personalize and enhance psychedelic-based mental health therapies.

Psychedelics and the Gut Microbiome: Unraveling the Interplay and Therapeutic Implications

https://pubs.acs.org/doi/abs/10.1021/acschemneuro.5c00418

 A fascinating new view-piece synthesizing the current literature exploring psychedelic / gut / microbiome interaction in the context of depression. Wang and colleagues emphasise that "the baseline composition and functional state of the microbiome can shape psychedelic pharmacology and therapeutic efficacy, while the psychedelic experience itself can remodel the gut microbiome in ways that influence ongoing physiological and psychological adaptation."

At the cellular level they note psychedelics suppress the production of pro-inflammatory cytokines IL-6 and TNF-α through 5-HT2A receptor-mediated inhibition of NF-κB signalling: "this immunomodulatory action establishes an anti-inflammatory milieu that favors the growth of beneficial commensal bacteria."

Compounds such as psilocybin and DMT "reduce pro-inflammatory cytokine expression and enhance epithelial barrier integrity, promoting the expansion of anti-inflammatory taxa."

They note, the microbiome is not a passive bystander: "gut bacteria express a variety of enzymes capable of biotransforming these substances, thereby shaping their pharmacokinetic profiles. For instance, Bifidobacterium species have been shown to affect the metabolism of DMT, potentially altering the intensity and duration of ayahuasca experiences. Similarly, in vitro studies have identified bacterial strains that dephosphorylate psilocybin into its active form, psilocin, suggesting that individual differences in microbiota composition may underlie variability in therapeutic response."

Wang et al. refer early human data noting that "although human studies remain limited, early observations suggest that psychedelic treatment may be associated with alterations in fecal microbial diversity in patients with depression."

These observations support what the authors call a "systems-level perspective of psychedelic therapy - one that encompasses not only neural targets but also immunological, endocrine, and microbial domains."

The article is behind a paywall, send me a message if you'd like a copy of the article. 

For more reading the article cites this paper "Seeking the Psilocybiome: Psychedelics meet the microbiota-gut-brain axis" 

https://pmc.ncbi.nlm.nih.gov/articles/PMC9791138/ 

In the context of CH, with new evidence of persistent immune-inflammatory activity suggests psychedelic therapy not as acting solely on the brain but by potentially intersecting with the upstream gut-barrier-immune processes that maintain systemic inflammation that are now attributed as a causative agent in migraine. The paper also goes some way to positing a possible reason for the variations we see in busting efficacy. This area of research is fascinating and I think the piece provides a further and new angle as to the role gut health may play in CH alongside recent findings in migraine although there is much road to travel before we have any concrete evidence of this.  Still mulling my thoughts, all I offer here is a view - always interested in yours. With respect, Craig.