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.
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.
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.
Papers cited by this study that are also in Blossom
Atasoy, S., Leor, R., Kaelen, M. et al. · Scientific Reports (2017)
Barrett, F. S., Krimmel, S. R., Griffiths, R. R. et al. · NeuroImage (2020)
Bogenschutz, M. P., Forcehimes, A. A., Pommy, J. A. et al. · Journal of Psychopharmacology (2015)
Rodríguez-Fornells, A., Ribeiro, S., Sanches, R. F. et al. · European Neuropsychopharmacology (2015)
This manuscript is a narrative, hypothesis-generating review rather than a systematic review. The study does not report a formal, reproducible search strategy or pre-specified inclusion/exclusion criteria; instead, the investigators assembled direct and indirect evidence from human, animal and in vitro studies that bear on potential psychedelic–microbiome interactions. The authors explicitly acknowledge the speculative nature of parts of their synthesis and rely on related literature about serotonergic drugs (for example, SSRIs), microbial modulation of host serotonin, microbial effects on drug metabolism, and mechanistic studies of immune, neuroendocrine and neural effects. Evidence sources reported in the extracted text include preclinical animal experiments, in vitro immunological assays, human observational and experimental studies of psychedelics, studies of antidepressant–microbiome interactions, and microbiome intervention studies (for example probiotics) that relate to brain connectivity or neuroplasticity. The review integrates these strands into conceptual figures and a summary table of shared biological targets. Where direct data linking psychedelics to microbiome changes are scarce, the authors draw on mechanistic pathways (serotonergic signalling, host–microbial co-metabolism, immune and HPA axis interactions, vagal signalling) to build testable hypotheses about mediation and moderation roles for the microbiome.
The review collates a set of empirical and mechanistic findings that together suggest bidirectional interactions between serotonergic psychedelics and the gut microbiome. Direct studies are currently sparse: the authors identify a single, non-peer-reviewed rodent study reporting that oral psilocybin and an analogue increased Verrucomicrobia and Actinobacteria and decreased Proteobacteria in rat faecal samples, without changing overall alpha diversity. Complementary evidence derives from related domains: selective serotonin reuptake inhibitors (SSRIs) alter gut microbial composition and possess antimicrobial activity, and phytochemicals in psychedelic plants (for example compounds in Banisteriopsis caapi and Peyote) show antibacterial and antifungal properties in vitro. Several mechanisms by which the microbiome could shape psychedelic responses are described. Gut bacteria can directly metabolise xenobiotics and participate in host–microbial co-metabolism (for example enterohepatic recycling), thereby changing drug bioavailability, activity or toxicity. The bacterial enzyme tryptophanase can divert host tryptophan to indole, reducing substrate for serotonin synthesis, and microbial-derived inflammatory signals (for example LPS) can upregulate host indoleamine-2,3-dioxygenase (IDO), shifting tryptophan metabolism toward kynurenine. An animal model of maternal immune activation showed an enhanced hallucinogenic-like response to DOI, and taxa-level correlations were reported between certain bacterial families and cortical 5-HT2A receptor density (Ruminococcaceae and Candidatus saccharibacteria positively correlated; Lactobacillaceae negatively correlated), suggesting a potential microbial influence on receptor expression. The authors review shared biological targets through which psychedelic–microbe interplay might influence brain and behaviour. Immune modulation: psilocybin reduced TNF-α and IL-1β in an in vitro macrophage model; psilocin and DMT altered microglial markers in mice; DOI suppressed TNF-α in a 5-HT2A-dependent manner; ayahuasca reduced certain T lymphocyte subsets and systemic CRP in humans. HPA axis effects: several psychedelics (LSD, psilocybin, ayahuasca, DMT) increased ACTH and cortisol in humans, and DOI/DOB raised corticosterone in rats, linking psychedelic exposure to stress-axis activation which is itself responsive to microbiome state. Brain connectivity: psychedelics consistently decrease within-network connectivity of the default mode network (DMN) and increase cross-network connectivity; alterations in DMN connectivity have been associated with inflammatory markers and with specific bacterial taxa in clinical samples. Neuroplasticity: psychedelics modulate genes linked to plasticity, long-term potentiation (LTP) and synaptogenesis; psilocybin showed dose-dependent effects on hippocampal neurogenesis (increasing at 0.1 mg/kg, decreasing at 1.0 mg/kg in rodents), DMT and 5-MeO-DMT stimulated neurogenesis in vitro and in vivo, while LSD and DOI had no significant effects in some rat studies. Parallel microbiome literature shows germ-free or antibiotic-treated animals have impaired neurogenesis and that probiotics or faecal transfers can restore plasticity measures. The authors formalise three causal scenarios: (1) psychedelics act on the microbiome and microbial shifts mediate therapeutic effects; (2) the microbiome modulates psychedelic responses (for example via drug metabolism), acting as a moderator; (3) psychedelics alter psychological state and these neural/behavioural changes secondarily reshape the microbiome. They emphasise that all three scenarios could operate concurrently. In applied terms, the review highlights translational opportunities: known pharmacogenetic predictors (CYP2D6 polymorphisms affecting psilocybin and DMT metabolism; HTR2A variants influencing receptor function) illustrate how biological heterogeneity affects psychedelic response, and the authors propose that baseline microbial signatures might similarly predict efficacy or adverse effects and be targeted via probiotics, dietary interventions or other microbiome-directed strategies to optimise outcomes.
Caspani and colleagues interpret the assembled evidence as suggestive but preliminary: there is a plausible, multi-level rationale for interactions between serotonergic psychedelics and the gut microbiome, yet direct empirical data remain limited. They argue that both psychedelic compounds and the microbiome converge on shared physiological systems—serotonergic signalling, immune function, the HPA axis, large-scale brain networks and neuroplasticity—which could mediate or modulate therapeutic effects. Rather than asserting a single causal pathway, the authors endorse a systems-biology perspective that recognises the microbiome as a ‘‘convergence hub’’ integrating multiple biofeedback loops. Key limitations are acknowledged. The paper is not a systematic review and therefore does not claim exhaustiveness; evidence specific to psychedelics' effects on gut microbiota composition is scarce and includes non-peer-reviewed data. Many inferences are drawn from related pharmacology (for example SSRIs) or from preclinical models, and human observational findings can be confounded by lifestyle factors such as diet and exercise. The authors call for carefully designed future studies to address four priority areas: (1) identify gut microbes and microbial enzymes involved in psychedelic metabolism, (2) measure the effects of psychedelics on microbiome composition and function in humans and animals, (3) map baseline microbial profiles to heterogeneity in clinical and subjective outcomes, and (4) evaluate the safety and efficacy of microbiome-targeted interventions to optimise psychedelic therapies. Implications for clinical practice are framed cautiously. The investigators suggest that integrating microbiome assessment into psychedelic therapy research could enable stratification of patients, more precise dosing or route selection, and adjunctive microbiome-targeted strategies to enhance response and reduce adverse effects. They underscore the need for multi-modal, longitudinal and mechanistic studies to translate these ideas into evidence-based personalised approaches, while controlling for confounders and thoroughly assessing safety.
The review concludes that serotonergic psychedelics and the gut microbiota are likely to be linked through bidirectional, multi-level interactions, and that the microbiome may act both as a mediator and a moderator of psychedelic effects on brain function and mental health. Caspani and colleagues advocate for future investigations to adopt systems-biology, multimodal approaches that incorporate microbiome data when modelling psychedelic action. Such integrative research could inform new, personalised psychedelic treatment strategies tailored to an individual's multi-system biological signature.
For over hundreds of thousands of years, microbes and humans have engaged in a co-evolutionary dance, forging a symbiotic relationship that has profoundly influenced their respective physiologies. Comprising approximately 30 trillion eukaryotic cells, the human body exists in harmonious synergy with an estimated 40 trillion microbial cells. Most of these microbes, consisting of bacteria, archaea, fungi, and viruses, reside in the human gastrointestinal (GI) tract and are collectively known as the gut microbiota. The information included in the metagenome (i.e., the sum genetic information of these diverse micro-organisms) exceeds that of the human genome by approximately 100-150 times. Many of these genes encode microbial enzymes that perform metabolic functions absent from the human genome, significantly expanding the biochemical flexibility of the host. For example, the gut microbiota is essential for the digestion of certain dietary compounds (e.g. fibre), is required for the production of vitamins and other biologically-active compounds, and plays a key role in the enterohepatic circulation. Additionally, these microbial genes are integral for the priming of the immune system. This priming enables the immune system to recognize self-antigens, including those from commensal microbes, and mount a response against pathogenic antigens. The intricate interplay between the microbial metagenome and host functions highlights the indispensable contributions of the gut microbiota to the overall health and functionality of the human body. The gut microbiota is an integral component of the gut-brain axis, the bidirectional communication network between the GI tract and the central nervous system (CNS). This two-way interaction is mediated by immune, endocrine (i.e. hypothalamic-pituitary-adrenal [HPA] axis), and neural pathways, including the vagus nerve, (seefor a review of these mechanisms). This intricate crosstalk forms the basis for the 'top-down' influence, where psychological states impact gut function and microbial composition-illustrated, for instance, by the effects of stress on gastrointestinal motility, permeability, and the release of luminal neurotransmitters. Simultaneously, it underscores the 'bottom-up' influence, where gut microbes exert effects on brain function and behaviour, exemplified by the impact of gut microbial composition on feeding patterns and obesity. This reciprocal communication underscores the holistic integration of physiological and psychological factors within the gut-brain axis, emphasizing its pivotal role in shaping both mental and gastrointestinal well-being. The last two decades have seen an increasing number of studies exploring the role of the microbiota-gut-brain axis on brain function and behaviour. Human studies have demonstrated significant differences in the faecal microbiota composition of healthy participants and those with depression, post-traumatic stress disorder (PTSD)], Parkinson's disease, and more, pointing to a clear relationship between abnormal brain function and variation in the gut microbiota. In addition to these association studies, causality has also been demonstrated with the ability to transfer behaviours via the microbiota. Kelly et al. demonstrated that inoculating antibiotic-treated rats with the faecal microbiota of depressed patients resulted in the development of behavioural symptoms of depression, including anhedonia and anxiety, alongside pathological changes observed in this disease, such as elevated plasma kynurenine and kynurenine/tryptophan ratio. Similarly, a recent study by Fan et al.demonstrated that faecal microbiota transplantation from individuals with anorexia nervosa (AN) to germ-free mice leads to the emergence of AN-like behaviour, alongside weight loss and AN-like gene expression patterns in both hypothalamic and adipose tissues in recipient mice. These studies highlight the causal relationship between microbiome composition and behaviour and makes the microbiota a powerful tool to transfer healthy behavioural and physiological traits.
In the mid-2000s, concurrently with the emergence of studies demonstrating the transferability of host phenotype through the gut microbiota, a resurgence in psychedelic research unfolded, marking the onset of the psychedelic renaissance. A wealth of studies has since shown the remarkable therapeutic potential of these drugs for the treatment of several disorders, including treatment-resistant depression, anxiety, obsessive-compulsive disorder (OCD)and addiction. Psychedelics constitute a category of psychoactive compounds well studied for their hallucinogenic properties. True to their etymology, with "psyche" and "delos" derived from the Greek words for "mind" or "soul" and "to show," respectively, psychedelic drugs exert a profound influence on consciousness. These substances induce potent subjective effects, encompassing hallucinations, distortions in self and reality perception, shifts in cognition and emotion, and, notably, the elicitation of mystical and self-transcendent experiences, often characterized by phenomena like ego dissolution. The mechanisms of action of psychedelics have been described at the pharmacological and neural level, as well as at brain-circuit and psychological levels, (seefor a review). At the pharmacological level, activation of 5HT 2A receptors on cortical layer V pyramidal neurons, and the subsequent increase in neuronal firing, leads to synaptogenesisand anti-inflammatory processes via the modulation of gene transcription. 5HT 2A receptors are widely expressed throughout the brain, in both cortical and subcortical areas (;), and are responsible for learning and memory, perception of pain and sleep. Research has shown that the subjective effects of psychedelic drugs correlate with 5HT 2A receptor occupancy. At a higher level, psychedelics are thought to affect the cortico-striato-thalamo-cortical circuits, a feedback loop where inhibitory control of the thalamus by the pre-frontal cortex allows for the filtering of sensory and interoceptive inputs before this information is relayed back to higher-level cortical areas. Upon activation of 5HT 2A receptors by psychedelics, negative feedback of the thalamus from the prefrontal cortex is reduced, leading to an overload of sensory information sent to the sensory cortex via the thalamus. These changes in cortical-thalamic connectivityare thought to underlie alterations in perception experienced by participants during the psychedelic experience. Another hypothesis suggests the involvement of claustrum-cortical decoupling in the effects of psychedelics, especially effects on cognition. The Relaxed Beliefs Under Psychedelics (REBUS) model suggests that psychedelics affect the normal ability of the brain to predict incoming sensory information, and generating a prediction error to update our internal model that shapes our perception of reality. This model also proposes that psychedelics increase the brain's entropy state, by enhancing the connectivity between brain areas that are not normally connected. This loosening of prior predictions is thought to underlie the ability of psychedelics to free the mind of rigid, maladaptive thinking patterns that are characteristic of internalising disorders, like depression, PTSD, OCD, and AN. While 5HT 2A receptors are the main target of psychedelic action, it is important to note that these drugs bind to other receptors with varying affinities: for instance, LSD binds to 5-HT subtypes 1 A, 1B, 1D, 1E, 2 A, 2B, 2 C, 5 A, 6, and 7 as well as dopaminergic receptors subtypes D1 and D2, while DMT and 5-MeO-DMT, in addition to various serotonergic and dopaminergic receptor subtypes, also bind a number of ionotropic and metabotropic glutamate receptors, acetylcholine, Trace-Amine-Associated Receptors (TAAR), and the opioid-like receptor sigma-1 (Sig1R). In addition, while classic psychedelics (also known as "serotonergic psychedelics" due to their chemical and structural similarity to the serotonin molecule) are characterised by partial agonism at the 5HT 2A receptor, non-classic psychedelics such as ketamine and MDMA, while eliciting similar subjective effects, exhibit different mechanisms of action (outside of serotonin receptors). This review will mainly focus on classic psychedelics due to the known relationship between serotonin and the gut microbiota.
Many psychedelic compounds are naturally-occurring (e.g. psilocybin from Psilocybe mushrooms, ayahuasca from the Banisteriopsis caapi vine, mescaline from the Peyote and San Pedro cacti) and have been used in ritual and religious practices in many cultures for centuries. The notion that many medicinal plants have antimicrobial properties, and that changes in the gut microbiota can impact brain function and behaviour via the gut-brain axis suggests that the psychological effect of psychedelic drugs is likely to be partly mediated by the gut microbiota. However, the exact impact of psychedelics on the composition of the gut microbiota remains unexplored. In this review, we aim to present the existing evidence supportive of a role for the microbiome in mediating the psychological effects of psychedelics. Due to the lack of research directly linking the gut microbiome and psychedelics, we will draw on existing knowledge of the serotonergic system and the drugs that target it, like serotonergic antidepressants, to build hypotheses around the interaction between serotonergic psychedelics and the microbiota-gut-brain axis, and highlight the knowledge gaps that need to be addressed to facilitate and accelerate progress in this field. Then, we reflect on how knowledge on psychedelic-gut microbe interactions can shape clinical practice; specifically, how the heterogeneity of a patient's microbiota can be used to explain and predict the variability in responses to psychedelic-based therapies, towards the implementation of personalised medicine approaches. Finally, in an effort to establish new guidelines for psychedelic research, we present an example of an integrated framework that takes into account the biology of the individual patient at different systems levels, including, but not limited to, the gut microbiota.
Rigorous scientific investigations of the impact of serotonergic psychedelics on the composition and structure of the gut microbiota are lacking. At the moment of writing this review, only one (not peerreviewed) paper has been published around the changes induced by oral psilocybin and related tryptamines on the rat gut microbiota. In this paper, 16 S ribosomal DNA sequencing of faecal samples collected from rats treated with either psilocybin or its analogue norbaeocystin demonstrated a significant increase in Verrucomicrobia and Actinobacteria, and a decrease in Proteobacteria relative to control rats, although overall bacterial (alpha) diversity was unaffected. While still a preliminary finding, this paper supports a potential mechanism of action for psilocybin(s) that is mediated by the gut microbiome and justifies further research in this field. Additionally, it is well established that selective serotonin reuptake inhibitors (SSRIs) can change the composition of the gut microbiota, and exhibit significant antimicrobial activity. Similarly, anecdotal reports of the purgative and laxative effects of some psychedelics, primarily ayahuasca, place the gut microbiota as a potential target of psychedelic action. This is consistent with the notion that serotonin receptors, including the 2 A subtype, the primary target of all classic psychedelics, are expressed throughout the GI tract and that serotonin exerts local effects on gut function, for example by enhancing peristalsis. Modulations in the gut environment driven by altered serotonin, including transit time and secretions, can in turn modify the community structure and function of the microbiota. Conversely, the gut microbiota modulates serotonin synthesis via several direct and indirect mechanisms. Certain gut microbes are able to synthesise serotonin directly, while others are able to stimulate local serotonin synthesis and release by enterochromaffin cells, and alter the circulating and central concentrations of serotonin. In fact, the bacterial enzyme tryptophanase can convert the serotonin precursor tryptophan into indole, reducing the host's availability of tryptophan for serotonin production. Additionally, pro-inflammatory cytokines and other inflammatory mediators, including those derived from gut bacteria (e.g. lipopolysaccharides [LPS], cell wall components from Gram negative bacteria), promote the expression of the host enzyme indoleamine-2,3-dioxygenase (IDO), which converts tryptophan to kynurenine. As such, the composition of the gut microbiota, and its translocation from the gut, has important consequences on the availability of serotonin, and therefore, on mood and behaviour. While the direct effect of serotonin on gut microbes remains unclear, Fung et al. reported an increase in some species of spore-forming gut bacteria from Turicibacteraceae, Clostridiales, Lachnospiraceae and Ruminococcaceae after oral administration of serotonin to wildtype rats, along with the ability of some of these species (e.g. Turicibacter sanguinis) to take up serotonin thanks to a sodium symporter-related protein with sequence and structural homology to mammalian serotonin reuptake transporter SERT. This reciprocal interaction between serotonin and the gut microbiota suggests that serotonergic psychedelics may directly and indirectly affect the composition of the gut microbiota. In addition, there is preliminary evidence that some of the chemical compounds found in psychedelics have anti-microbial, anti-viral and even mild antibiotic effects. For example, a phytochemical analysis of the main constituents of the ayahuasca vine resulted in the identification of compounds, like B. caapi and P. harmala, that inhibited the growth of four pathogenic and antibiotic-resistant Gram-positive and four Gramnegative bacteria. Similarly, components of the Peyote cactus (Lophophora Williamii) were shown to be effective against 18 different penicillin-resistant strains of Staphylococcus aureus. Additionally, alkaloids often found in psychedelic plants, like mescaline and ayahuasca, are able to intercalate into the bacterial cell wall and/or DNAand exhibit antibacterial, anti-fungaland anti-viral properties. These results indicate that, like serotonergic antidepressant drugs, psychedelic compounds are likely to affect the composition of the gut microbiota. Given the crosstalk between the gut microbiome and the brain, it is possible that these microbial alterations contribute to the impact of serotonergic psychedelics on brain function.
Several human and animal studies have demonstrated the modulatory effects of the gut microbiome on drug responses. Thus, in addition to being a potential target, the gut microbiome is also likely to play a significant role in shaping the individual response to psychedelic drugs. Firstly, this may be due to the known impact of gut microbial composition on drug metabolism and bioavailability. The mechanisms through which the gut microbiota can alter drug metabolism were reviewed in. In brief, different species of gut bacteria can metabolise a broad range of xenobiotics, converting them it into their active, inactive and even toxic forms. Gut microbes can also intercalate into host metabolism, in a process known as host-microbial co-metabolism. An example is enterohepatic recycling: in the liver, host enzymes inactivate a drug (e.g. by conjugation), but after biliary excretion from the gall bladder into the gut, microbes can reactivate the drug (e.g. by deconjugation) before reabsorption into the systemic circulation through the hepatic portal vein. Metabolism of a compound by the microbiota can also lead to toxic by-products, contributing to adverse drug responses. Some drugs can bind the bacterial cell directly, while others can compete with bacteria (or their metabolites) for the same host substrates. Other indirect interactions include the ability of gut microbial metabolites to modulate host gene expression via epigenetics mechanisms, and to modulate immune pathways in the host, with downstream effects on drug efficacy and responses. In patients with major depressive disorder, for example, the efficacy of SSRIs was associated with high relative abundance of Blautia, Bifidobacterium and Coprococcus species. An increase in the hallucinogenic effect of the psychedelic 2,5-dimethoxy-4-iodoamphetamine (DOI) was observed in a mouse model of maternal immune activation (MIA) that presented with cognitive impairments, altered gut microbial composition and upregulated 5-HT 2A receptors in the frontal cortex. The hallucinogenic effect was assessed via the head-twitch response, rapid side-to-side rotational head movement considered as a proxy of hallucinogenic effects mediated by the activation of 5-HT 2A receptors. Specifically, a significant association was found between certain bacterial taxa and the density of 5-HT 2A receptors (Ruminococcaceae and Candidatus (saccharibacteria) were positively correlated; Lactobacillaceae were negatively correlated). The notion that gut microbes can interact with and modulate serotonergic receptors is notable as it suggests that the effect of psychedelics on these receptors can be modulated by the individual's unique gut microbial composition.
The evidence reviewed thus far suggests that psychedelics may alter gut microbial composition, and that the gut microbiome may shape responses to psychedelics (Fig.). However, how does this interplay affect transmission via the gut-brain axis? How does it affect behaviour? One possible mechanism lies in the modulation of serotonergic neurotransmission: both serotonergic psychedelics and certain gut microbes are able to modulate central serotonin levels. Other mechanisms may include their effect on immune and neuroendocrine (i.e. the HPA axis) systems, on brain connectivity networks and neuroplasticity processes. These biological systems/processes (summarised in Table) are shared targets of both psychedelic drugs and the gut microbiome and point to potential interconnected mechanisms of action. The details of these processes will be explained below.
A common target of psychedelics and gut microbiota is the immune system. The anti-inflammatory and immune-modulating properties of psychedelics are well-established, and are in line with the known anti-inflammatory effect of serotonin. Psilocybin inhibits the production of TNF-α and IL-1β in human U937 macrophage cells treated with the pro-inflammatory stimulus LPS. Psilocin (the active component of psilocybin) and DMT were shown to decrease the expression of the bacterial toll-like receptor 4 (TLR4), p65 and CD80, and increase the mRNA abundance of the TREM2 receptor in mouse primary microglia. Animal studies reported that LSD (100 μM) inhibited B lymphocyte and NK cell proliferation and pro-inflammatory cytokine release (IL-2, IL-4, and IL-6) in an in vitro mouse study, while DOI suppressed TNF-α levels in a 5-HT 2A receptor-dependent manner, as well as TNF-α-induced pro-inflammatory markers in the small intestine. In humans, ayahuasca decreases CD4+ and CD3+ T lymphocytes and increase in NK cells; it also decreases the circulatory levels of the inflammatory marker C-reactive protein (CRP). The effect of ketamine on the immune system is less clear, as an increaseand decreasein the pro-inflammatory cytokine IL-6 has been reported. Overall, these results suggest that immunomodulatory properties are common to all class of psychedelic compounds. Conversely, the immune system is in constant dialogue with the microbiome. Microbe-immune interactions in early life prime the immune system to recognise and respond to threats while "ignoring" selfantigens, and the crosstalk between the gut microbiota and the immune system is an essential component of the gut-brain axis. Chronic inflammation is also an important underlying factor in both gut dysbiosisand psychopathology, including depression and trauma. Thus, psychedelics may impact on brain function and psychological state by modulating microbe-immune interactions.
The HPA axis, the main component of the neuroendocrine system, controls an individual's physiological response to stress, and its function is known to be abnormally heightened in psychiatric disorders, including depression and anxiety. It has become clear, since early microbiome studies, that the HPA axis is one of the main communication pathways between the gut and the brain. In fact, cortisol receptors are expressed along the GI tract, and gut epithelial cells, enteroendocrine cells as well as local cells of the immune system are responsive to cortisol, with downstream effects on gut microbial composition. Specifically, an overactive HPA axis (and chronically elevated cortisol levels) have been reported to alter the composition of the gut microbiota and lead to inflammation via a leaky gut barrier. Additionally, the absence of a gut microbiome has been shown to lead to an overreactive HPA axis and stress response in germ-free mice, suggesting the importance of the gut microbiome for a normal physiological response to stress. Similarly, several studies have reported a significant effect of psychedelics on the HPA axis. Human studies have indicated that intake of psychedelic drugs like LSD, psilocybin, ayahuascaand DMTincrease adrenocorticotropic hormone (ACTH) and cortisol secretion. A dose-dependent increase in ACTH and corticosterone was also reported in rats treated with DOI and the related 1-(2, 5-dimethoxy-4-bromophenyl)-2-aminopropane (DOB). While evidence is still scarce, these results suggest that the HPA axis may be another pathway through which psychedelic-induced changes to the microbiota may affect emotional state and behaviour.
Interestingly, the same cortical networks that are affected by psychedelics (mainly via serotonergic receptors in cortical layer V) are also responsive to both inflammatory/stress-related and microbial signals. One of these networks is the default mode network (DMN), comprising of precuneus, posterior cingulate cortex (PCC), medial prefrontal cortex (mPFC) and inferior parietal cortex. It is involved in mind-wandering and self-referential processes, including autobiographical memories, but is inactive during active cognitive tasks. Research has implicated abnormalities in DMN functional connectivity in psychiatric disorders, like depression, anxiety, OCD, PTSD, attention deficit hyperactive disorder (ADHD,), schizophrenia, and AN. In fact, hyperconnectivity in the DMN is associated to tendencies of excessive rumination and negative self-referential thoughts. Importantly, resting-state brain imaging studies consistently report the DMN as a target of psychedelic drugs. For example, acute treatment with both psilocybin and LSD leads to a decrease in functional connectivity within different nodes of the DMN, like the mPFC, the PCC the medial posterior DMN, while increasing connectivity between the DMN and other resting-state networks. DMT (ayahuasca) was shown to decrease the thickness of the PCC. The overall "decoupling" effect of these drugs on the DMN is thought to be responsible for the decrease in rumination following treatment with psychedelics. There is evidence that the DMN is responsive to signals from the immune system and the gut microbiota. In patients with Crohn's disease, an inflammatory bowel disease characterised by chronic inflammation and gut dysbiosis, the functional connectivity of the DMN is abnormally high. Several papers report an association between plasma pro-inflammatory markers, e.g. IL-6, suggestive of systemic inflammation, and a reduction in DMN connectivity. A study by Xi et al. showed that correlations normally exist between specific bacterial taxa and DMN functional connectivity, which become disrupted in bipolar depression. Similarly, a negative relationship exists between faecal Bacteroides and the functional connectivity between the left dorsolateral prefrontal cortex (dlPFC) and the DMN in major depression. Interventions targeted to the gut microbiota can be effective in modulating brain connectivity, as demonstrated by a study where a 4-week multi-strain probiotic administration resulted in beneficial changes in DMN functional connectivity. Therefore, there is evidence that psychedelic-induced shifts in gut microbial composition may lead to beneficial changes in brain connectivity.
Neuroplasticity is a physiological process that describes the ability of the brain to respond and adapt to external stimuli by changing its structure and connections. This usually occurs via the formation of new neurons (neurogenesis), synapses (synaptogenesis) and dendrites (dendritogenesis). The vagus nerve, through its innervation of the GI tract, is a potential route by which changes in the local gut environment (e.g. gut microbial composition, or the presence of active compounds, like psychedelics) can stimulate neuroplasticity in crucial brain circuits involved in arousal, reward and cognition. In fact, central BDNF levels are responsive to electrical stimulation of the vagus nerve, and in turn, can be dampened by severing afferent vagal fibres. Psychiatric and neurodevelopmental disorders like depressionand autism spectrum disorderare characterised by abnormalities in neurogenesis. The absence of a normal gut microbiota was shown to lead to deficits in neurogenesis and in its underlying processes, like long-term potentiation (LTP), in the hippocampus of germ-free miceand antibiotic-treated mice. Interestingly, gut microbiome-induced deficits in neurogenesis have been reconducted to microglia activation, indicating a role for the brain's immune system in the formation of new neurons. Importantly, treatment with probiotics was effective in restoring neurogenesis, promoting hippocampal LTP and dendritogenesis and in increasing brain-derived neurotrophic factor (BDNF) levels. Similarly, cortical plasticity changes that are normally observed as a result of environmental enrichment were abolished in antibiotic-treated mice, but could be normalised via a microbiota transfer from healthy donor mice. The relationship between psychedelics and neurogenesis is more complex: psilocybin increases hippocampal neurogenesis at low doses (0.1 mg/kg), but decreases it at higher doses (1.0 mg/kg); however, repeated administration of a high dose (1.5 mg/kg weekly for 4 weeks) was reported to increase the formation of new neurons in the dorsal ganglia. DMT and 5-MeO-DMT stimulated neurogenesis both in vitro and in vivo, while LSD and DOI had no significant effect in rats. Nevertheless, a large number of studies indicate that psychedelics, including psilocybin, LSD, DMT and DOI, increase the expression of intermediate early genes (IEGs) and other genes involved in neuroplasticity, promote LTP and stimulate the formation and growth of new synapses and dendrites. In conclusion, there is potential that psychedelic-induced alterations to the microbiota may perturb their influence on neuroplasticity, possibly via the vagus nerve. In summary, several biological processes are responsive to both psychedelic drugs and to shifts in gut microbial composition. This suggests that these processes may act as shared mechanisms of action, explaining how the interplay between microbial and psychedelic 'forces' modulate transmission via the gut-brain axis to affect brain function and behaviour. For example, it is possible that psychedelics impact on psychological state by modulating the cross-talk between gut microbes and (1) the serotonergic system, (2) inflammation, (3) the HPA axis, (4) brain connectivity networks and/or (5) neuroplasticity. Alternatively, it is possible that the composition of a person's gut microbiome modulates responses to psychedelics by altering (1) serotonergic neurotransmission, (2) immune state, (3) HPA axis reactivity, (4) brain connectivity networks and/or (5) neuroplasticity processes.
While the effects of psychedelics on brain function have been described with significant resolution at the molecular, cellular and network level, whether and how much of these effects are also due to peripheral action (outside of the brain, e.g. on the microbiota) remains unclear. This review reports existing evidence that part of the effects of psychedelics on psychological state may be due to their impact on the gut microbiome and its related systems (e.g. the immune system). However, questions remain on the directionality of these relationships, and on the role that the microbiota plays in them. A first possibility is that psychedelics improve psychological symptoms by modulating the composition and metabolic function of the gut microbiota (Fig.). A favourable shift in microbial composition can improve brain and mental health via the gut-brain axis. In this case, the microbiome is a direct target of psychedelics and a mediator of psychedelic action on psychopathology. A second possibility is that psychedelics act directly on psychopathology, but the magnitude of their effect is dependent on gut microbial composition (Fig.). An example of this situation would be gut bacteria affecting drug metabolism (or any of the processes described in Table), contributing to the heterogeneity in responses to psychedelics. In this case, the microbiome is a modulator of psychedelic action. A third possibility is that psychedelics act directly on psychological state, and that changes in mental state cause downstream changes in microbial composition (Fig.). This implies that the microbiome is an indirect player in this relationship and that changes in the microbiota is a response to the psychedelic intervention. Our take is that all of these options may be true: beautifully worded in, at the interface between the human host and the environment, the gut microbiome can be thought of as the "convergence hub" between multiple biofeedback systems regulating multiple aspects of human physiology. Accordingly, it becomes imperative for future research to adopt a systems biology approach, interpreting data within the framework of complex interactions that intertwine these interconnected systems. This necessitates an exploration across all levels, from micro to macro, and consideration of different time scales to unveil the nuanced dynamics at play. Fig.. Potential local and distal mechanisms underlying the effects of psychedelic-microbe crosstalk on the brain. Serotonergic psychedelics exhibit a remarkable structural similarity to serotonin. This figure depicts the known interaction between serotonin and members of the gut microbiome. Specifically, certain microbial species can stimulate serotonin secretion by enterochromaffin cells (ECC) and, in turn, can take up serotonin via serotonin transporters (SERT). In addition, the gut expresses serotonin receptors, including the 2 A subtype, which are also responsive to psychedelic compounds. When oral psychedelics are ingested, they are broken down into (active) metabolites by human (in the liver) and microbial enzymes (in the gut), suggesting that the composition of the gut microbiome may modulate responses to psychedelics by affecting drug metabolism. In addition, serotonergic psychedelics are likely to elicit changes in the composition of the gut microbiome. Such changes in gut microbiome composition can lead to brain effects via neuroendocrine, blood-borne, and immune routes. For example, microbes (or microbial metabolites) can (1) activate afferent vagal fibres connecting the GI tract to the brain, (2) stimulate immune cells (locally in the gut and in distal organs) to affect inflammatory responses, and (3) be absorbed into the vasculature and transported to various organs (including the brain, if able to cross the blood-brain barrier). In the brain, microbial metabolites can further bind to neuronal and glial receptors, modulate neuronal activity and excitability and cause transcriptional changes via epigenetic mechanisms. Created with BioRender.com.
Shared targets between psychedelics and microbiome. The table below summarises some biological processes that are responsive to both psychedelic drugs and to shifts in gut microbial composition, which could explain the effect of psychedelic-microbe crosstalk on the brain. • 5HT2A receptors are expressed on cells of the immune system• some bacterial species (e.g. • Increased ACTH and cortisol in response to LSD, psilocybin, ayahuascaand DMTin humans • cortisol receptors are expressed in the gutTable(continued ) • Germ-free mice exhibit deficits in neurogenesis and LTP• DMT and 5-MeO-DMT stimulated neurogenesis both in vitro and in vivo• Mice treated with antibiotics show impaired neurogenesis• LSD and DOI had no significant effect on neurogenesis in rats• Different probiotic mixes were effective in restoring neurogenesis, promoting hippocampal LTP and dendritogenesis and in increasing BDNF levels• Enrichment-related cortical plasticity was abolished in antibiotictreated mice, but could be normalised via a microbiota transfer from healthy donor mice• Many psychedelic drugs promote LTP and stimulate the formation and growth of new synapses and dendrites3. Conclusion
One of the aims of this review is to consolidate existing knowledge concerning serotonergic psychedelics and their impact on the gut microbiota-gut-brain axis to derive practical insights that could guide clinical practice. The main application of this knowledge revolves around precision medicine. Several factors are known to predict the response to psychedelic therapy. Polymorphism in the CYP2D6 gene, a cytochrome P450 enzymes responsible for the metabolism of psilocybin and DMT, is predictive of the duration and intensity of the psychedelic experience. Poor metabolisers should be given lower doses than ultra-rapid metabolisers to experience the same therapeutic efficacy. Similarly, genetic polymorphism in the HTR2A gene can lead to heterogeneity in the density, efficacy and signalling pathways of the 5-HT 2A receptor, and as a result, to variability in the responses to psychedelics. Therefore, it is possible that interpersonal heterogeneity in microbial profiles could explain and even predict the variability in responses to psychedelic-based therapies. As a further step, knowledge of these patterns may even allow for microbiota-targeted strategies aimed at maximising an individual's response to psychedelic therapy. Specifically, future research should focus on working towards the following aims: (1) Can we target the microbiome to modulate the effectiveness of psychedelic therapy? Given the prominent role played in drug metabolism by the gut microbiota, it is likely that interventions that affect the composition of the microbiota will have downstream effects on its metabolic potential and output and, therefore, on the bioavailability and efficacy of psychedelics. For example, members of the microbiota that express the enzyme tyrosine decarboxylase (e.g., Enterococcus and Lactobacillus) can break down the Parkinson's drug L-DOPA into dopamine, reducing the central availability of L-DOPA. As more information emerges around the microbial species responsible for psychedelic drug metabolism, a more targeted approach can be implemented. For example, it is possible that targeting tryptophanase-expressing members of the gut microbiota, to reduce the conversion of tryptophan into indole and increase the availability of tryptophan for serotonin synthesis by the host, will prove beneficial for maximising the effects of psychedelics. This hypothesis needs to be confirmed experimentally. (2) Can we predict response to psychedelic treatment from baseline microbial signatures? The heterogeneous and individual nature of the gut microbiota lends itself to provide an individual microbial "fingerprint" that can be related to response to therapeutic interventions. In practice, this means that knowing an individual's baseline microbiome profile could allow for the prediction of symptomatic improvements or, conversely, of unwanted side effects. This is particularly helpful in the context of psychedelic-assisted psychotherapy, where an acute dose of psychedelic (usually psilocybin or MDMA) is given as part of a psychotherapeutic process. These are usually individual sessions where the patient is professionally supervised by at least one psychiatrist. The psychedelic session is followed by "integration" psychotherapy sessions, aimed at integrating the experiences of the acute effects into longterm changes with the help of a trained professional. The individual, costly, and time-consuming nature of psychedelic-assisted psychotherapy limits the number of patients that have access to it. Therefore, being able to predict which patients are more likely to benefit from this approach would have a significant socioeconomic impact in clinical practice. Similar personalised approaches have already been used to predict adverse reactions to immunotherapy from baseline microbial signatures. However, studies are needed to explore how specific microbial signatures in an individual patient match to patterns in response to psychedelic drugs. In a similar way, the individual variability in the microbiome allows to stratify and group patients based on microbial profiles, with the goal of identifying personalised treatment options. The wide diversity in the existing psychedelic therapies and of existing pharmacological treatments, points to the possibility of selecting the optimal therapeutic option based on the microbial signature of the individual patient. In the field of psychedelics, this would facilitate the selection of the optimal dose and intervals (e.g. microdosing vs single acute administration), route of administration (e.g. oral vs intravenous), the psychedelic drug itself, as well as potential augmentation strategies targeting the microbiota (e.g. probiotics, dietary guidelines, etc.).
Due to limited research on the interaction of psychedelics with the gut microbiome, the present paper is not a systematic review. As such, this is not intended as exhaustive and definitive evidence of a relation between psychedelics and the gut microbiome. Instead, we have collected and presented indirect evidence of the bidirectional interaction between serotonin and other serotonergic drugs (structurally related to serotonergic psychedelics) and gut microbes. We acknowledge the speculative nature of the present review, yet we believe that the information presented in the current manuscript will be of use for scientists looking to incorporate the gut microbiome in their investigations of the effects of psychedelic drugs. For example, we argue that future studies should focus on advancing our knowledge of psychedelicmicrobe relationships in a direction that facilitates the implementation of personalised medicine, for example, by shining light on: (1) the role of gut microbes in the metabolism of psychedelics; (2) the effect of psychedelics on gut microbial composition; (3) how common microbial profiles in the human population map to the heterogeneity in psychedelics outcomes; and (4) the potential and safety of microbial-targeted interventions for optimising and maximising response to psychedelics. In doing so, it is important to consider potential confounding factors mainly linked to lifestyle, such as diet and exercise.
This review paper offers an overview of the known relation between serotonergic psychedelics and the gut-microbiota-gut-brain axis. The hypothesis of a role of the microbiota as a mediator and a modulator of psychedelic effects on the brain was presented, highlighting the bidirectional, and multi-level nature of these complex relationships. The paper advocates for scientists to consider the contribution of the gut microbiota when formulating hypothetical models of psychedelics' action on brain function, behaviour and mental health. This can only be achieved if a systems-biology, multimodal approach is applied to future investigations. This cross-modalities view of psychedelic action is essential to construct new models of disease (e.g. depression) that recapitulate abnormalities in different biological systems. In turn, this wealth of information can be used to identify personalised psychedelic strategies that are targeted to the patient's individual multi-modal signatures.
WAJ is a founder and shareholder of the University of British Columbia Start-up Mynd Life Sciences. All other authors declare no known competing interests.
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