The paradigm of mental health treatment is undergoing a significant shift characterized by a resurgent interest in the therapeutic potential of psychedelic substances ^[1][2][3][1,2,3]. Concurrently, the role of the gut microbiome in mental health has emerged as a prominent field of study ^[4][5][4,5]. The intersection of these two fields has given rise to an exciting frontier of research in the psychedelic renaissance, investigating the interaction between the gut microbiome and psychedelics.

The role of the microbiome in mental health is based on the intricate relationship between the gut and the brain, often referred to as the gut–brain axis ^[6][7][10,11]. The gut–brain axis is a complex bidirectional communication system that integrates neural, hormonal, and immunological signaling between the gut and the brain ^[8][9][10][12,13,14]. It has been implicated in a variety of psychological and neurological conditions, including anxiety, depression, stress, cognitive impairment, and sleep disorders, and plays a vital role in mental health.

A central player in this communication system is the gut microbiome, a richly diverse ecosystem of microorganisms in the human gastrointestinal tract ^[11][12][9,15]. The microbiome contributes significantly to our overall health, influencing digestion, immunity, mood, and cognition. Over the past decade, research has unveiled the profound influence that the gut microbiome can have on the brain and behavior, leading to the emergence of the field of psychobiotics, which explores how modifications of the microbiome can affect mental health.

The gut microbiome’s role in modulating the effects of drugs has been well-established in the context of various medications, including antipsychotics and antidepressants ^[13][14][16,17]. More recently, research has turned its attention to the potential role of the gut microbiome in modulating the effects of psychedelic substances. The therapeutic efficacy of psychedelics has gained renewed interest, driven by promising results from clinical trials investigating their potential to treat mental health disorders such as depression, anxiety, and post-traumatic stress disorder (PTSD) ^[15][16][18,19].

Evidence suggests that the gut microbiome could be implicated in the metabolism and bioavailability of psychedelic substances and their therapeutic effects. For example, recent studies have indicated that specific gut bacteria can modulate the metabolism of N,N-dimethyltryptamine (DMT), a psychoactive compound found in ayahuasca, which may influence the bioavailability and pharmacological effects of DMT in the host ^[16][17][19,20]. Furthermore, the individual variability in gut microbiome composition may influence the bioavailability and effects of psychedelic substances, emphasizing the potential for a personalized approach in psychedelic therapy. In Misera et al. illustrate how the gut microbiota influences psychiatric treatment efficacy [4]. Antipsychotic drugs alter the microbiota composition, which can mitigate psychiatric symptoms and potentially induce metabolic disorders—a common reason for treatment discontinuation. Probiotic supplementation may alleviate metabolic issues and augment drug effectiveness, highlighting a complex interplay between microbiota, psychopharmacology, and mental health outcomes.

The human gut microbiome profoundly influences our health and well-being, not only in terms of physical health but also as a modulator of brain function and behavior, including mood, cognition, and stress responses ^[18][19][23,47]. With the ongoing psychedelic renaissance exploring the therapeutic potentials of psychedelic substances like psilocybin, lysergic acid diethylamide (LSD), and ayahuasca, it is essential to consider the role of the gut microbiome in this narrative.

Psychedelic substances can induce potent changes in consciousness, leading to significant alterations in perception, mood, and cognitive processes ^[20][21][48,49]. The profound effects of these substances have sparked renewed interest in their therapeutic potential, particularly for mental health disorders such as depression, anxiety, and PTSD ^[22][23][50,51].

Kelly et al. illustrate how the microbiota–gut–brain (MGB) axis may modulate responses to psychedelic therapy, acting as a biofeedback system ^[24][52]. Initial MGB activity could help identify individuals more likely to benefit from such therapy. Before treatment, adjustments to the MGB axis could enhance responsiveness. During treatment, the MGB axis might affect psychedelic drug metabolism variability, whereas post-treatment, reinforcing MGB signaling could promote and sustain beneficial behavioral changes toward homeostasis.

Furthermore, recent evidence suggests the gut microbiome might play a role in the metabolism and bioavailability of these psychedelic substances, which could impact their pharmacological effects. For instance, Nichols et al. found that the gut bacterium Bifidobacterium modulates the metabolism of N,N-dimethyltryptamine (DMT), a psychoactive compound found in ayahuasca ^[25][53]. This finding hints at the possibility that the therapeutic effects of psychedelics may, in part, be contingent upon the composition of an individual’s gut microbiota.

The metabolic capacity of the gut microbiota extends to a variety of psychedelic substances, including psilocybin, LSD, and mescaline. Research by Mezquita et al. indicated that certain bacterial strains possess the necessary enzymes to convert psilocybin, found in “magic mushrooms”, into its active metabolite psilocin ^[26][54]. Furthermore, Nichols et al. found that the gut bacterium Enterococcus faecalis possesses the enzyme lysergic acid diethylamide N-demethylase, which can degrade LSD ^[27][55].

Another line of investigation focuses on mescaline, a psychoactive compound found in the peyote cactus. Preliminary research by Saito et al. suggested that specific bacterial strains could metabolize mescaline into different metabolites in vitro ^[28][56]. While these studies provide preliminary evidence of microbiome involvement in the metabolism of various psychedelic compounds, further research is necessary to understand the extent and implications of these interactions for the bioavailability, effects, and individual variability in response to these substances.

The gut microbiota modulates the gut–brain axis, a bidirectional communication system between the enteric and central nervous systems, and can influence various brain functions ^[29][30]. For example, alterations in the gut microbiota have been linked to mood disorders like depression and anxiety, suggesting a role for the microbiome in modulating emotional responses ^[30][31][57,58]. However, more research is needed to test these hypotheses and understand the precise mechanisms involved.

The potential interaction between the gut microbiome and psychedelic substances represents a promising area of research within the psychedelic renaissance. By investigating these interactions, people might gain novel insights into how psychedelics work, the factors influencing their effects, and new methods to optimize their therapeutic potential.