Written by: Rhonda Thygesen, CBR Alumni

Edited by: Alexandra Witt, PhD Candidate, Pryzdial Lab

Paper: Mind over matter: the microbial mindscapes of psychedelics and the gut-brain axis, Jefferies Lab.         https://pubmed.ncbi.nlm.nih.gov/39111558/

Psychedelics, such as psilocybin and LSD, have gained attention as promising therapies for psychiatric disorders like depression and PTSD. While much of the focus has been on how these substances enhance neuroplasticity and brain connectivity, recent research from the CBR highlights an overlooked aspect: the role of the gut microbiota in modulating psychedelic effects via the gut-brain axis.

A recent review by the Jefferies lab titled “Mind over matter: the microbial mindscapes of psychedelics and the gut-brain axis,” explores how the gut microbiome—often referred to as the body’s “second brain”—may play a crucial role in how psychedelics alter mood and behaviour.

Three proposed pathways of interaction between psychedelics and the gut microbiome.

The gut-brain axis is a communication network linking the gastrointestinal tract and the central nervous system. This connection is mediated through the gut microbiota, the trillions of microorganisms that live in the digestive system. These microbes not only help with digestion but also influence cognitive functions, mood, and behavior.

This review presents evidence that psychedelics may alter the composition of the gut microbiota. In turn, gut bacteria may produce metabolites that interact with the brain. These metabolites can impact neurotransmitter activity, impacting mood and behavior. For instance, certain bacteria are known to produce short-chain fatty acids and other bioactive molecules that influence brain function. Thus, the gut may influence how psychedelics affect mental health, suggesting that the therapeutic effects of psychedelics might be co-mediated by both brain activity and gut microbiota.

The review presents three possible ways that the gut microbiome could influence the effects of psychedelics:

1. Direct Target: The gut microbiome itself could be a direct target of psychedelics, altering its composition and, in turn, affecting the psychological outcome.
2. Indirect Modulator: The gut microbiome could modulate the bioavailability and effectiveness of psychedelic drugs, indirectly influencing their impact on the brain and behavior.
3. Secondary Effect: Changes in the gut microbiome might occur as a secondary effect of psychedelics, with the primary influence being on the brain, and the microbiome adapting in response to changes in brain activity.

These three pathways highlight the complex bidirectional relationship between the brain and gut, and open the door to personalized approaches in psychedelic therapy. Since the gut microbiome differs significantly between individuals, variations in microbial composition may explain why people respond differently to psychedelic treatments. Future research could help clinicians tailor psychedelic therapies based on each patient’s microbial landscape, leading to more effective and personalized treatment plans.

Additionally, this understanding could enhance the development of new treatments for psychiatric disorders, particularly those resistant to traditional therapies4. The review emphasizes the need for future clinical studies to investigate how manipulating the gut microbiota could optimize the therapeutic effects of psychedelics.

While much remains to be explored, the potential for psychedelics to influence the gut-brain axis presents an exciting new frontier for mental health treatment. The review encourages further investigation into how gut microbiota shape the effects of psychedelics, and whether this relationship could be harnessed to improve clinical outcomes in psychiatric care.

References:

• 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, 107338.
• Cryan, J. F., & Dinan, T. G. (2012). Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nature reviews neuroscience, 13(10), 701-712.
• Carhart-Harris, R. L., Bolstridge, M., Rucker, J., Day, C. M., Erritzoe, D., Kaelen, M., … & Nutt, D. J. (2016). Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. The Lancet Psychiatry, 3(7), 619-627.
• Nohesara, S., Abdolmaleky, H. M., Zhou, J. R., & Thiagalingam, S. (2023). Microbiota-Induced Epigenetic Alterations in Depressive Disorders Are Targets for Nutritional and Probiotic Therapies. Genes, 14(12), 2217.