Mind over matter: the microbial mindscapes of psychedelics and the gut-brain axis
This review (2024) examines the potential role of the gut microbiome in mediating the effects of psychedelic drugs on behaviour. It argues that the current understanding of psychedelic mechanisms, focused primarily on serotonin 2A receptor agonism, is incomplete and needs to incorporate the gut microbiome and its (two-way) interactions with the brain.
Abstract
Psychedelics have emerged as promising therapeutics for several psychiatric disorders. Hypotheses around their mechanisms have revolved around their partial agonism at the serotonin 2 A receptor, leading to enhanced neuroplasticity and brain connectivity changes that underlie positive mindset shifts. However, these accounts fail to recognise that the gut microbiota, acting via the gut-brain axis, may also have a role in mediating the positive effects of psychedelics on behaviour. In this review, we present existing evidence that the composition of the gut microbiota may be responsive to psychedelic drugs, and in turn, that the effect of psychedelics could be modulated by microbial metabolism. We discuss various alternative mechanistic models and emphasize the importance of incorporating hypotheses that address the contributions of the microbiome in future research. Awareness of the microbial contribution to psychedelic action has the potential to significantly shape clinical practice, for example, by allowing personalised psychedelic therapies based on the heterogeneity of the gut microbiota.
Research Summary of 'Mind over matter: the microbial mindscapes of psychedelics and the gut-brain axis'
Introduction
The paper opens by situating the gut microbiota as a central component of the gut-brain axis, emphasising that the microbial metagenome considerably expands the host's biochemical repertoire and influences digestion, immune priming, enterohepatic circulation and neural signalling. Earlier research has documented consistent differences in faecal microbiota composition between healthy people and those with psychiatric or neurologic conditions, and causal links have been shown in animal models where behavioural traits can be transferred via faecal microbiota transplantation. At the same time, a resurgence in clinical and mechanistic psychedelic research has demonstrated substantial therapeutic potential of serotonergic psychedelics for disorders such as treatment-resistant depression, PTSD, OCD and addiction, with actions largely attributed to 5-HT2A receptor activation, altered large-scale brain connectivity and enhanced neuroplasticity. Caspani and colleagues note a gap in the literature: despite long-standing knowledge that many psychedelic compounds are plant-derived and that plant compounds can have antimicrobial properties, there is little direct research on how psychedelics interact with the gut microbiome and whether the microbiome contributes to psychedelics' psychological effects. The review therefore aims to synthesise existing evidence—both direct and indirect—on interactions between serotonergic psychedelics and the microbiota-gut-brain axis, to generate mechanistic hypotheses, identify knowledge gaps, and outline implications for personalised medicine and future research frameworks.
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Caspani, G., Ruffell, S. G., Tsang, W., Netzband, N., Rohani-Shukla, C., Swann, J. R., & Jefferies, W. A. (2024). Mind over matter: the microbial mindscapes of psychedelics and the gut-brain axis. Pharmacological Research, 207, 107338. https://doi.org/10.1016/j.phrs.2024.107338
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