The Promising Connection Between Psilocybin, the Gut Microbiome, and the Brain

Did you know that gut feelings, scientifically speaking, are an actual thing?

Indeed, feelings arise from the limbic system, tucked deep inside the brain and perched on top of the brain stem and spinal cord. The vagus nerve, spanning from the brain to the large intestine, acts as the information highway carrying messages between these two organs. The vagus nerve is the main nerve of the parasympathetic nervous system and plays a crucial role in mood regulation, heart rate, digestion, and immunity.

Hormones and neurotransmitters produced in our gut and brain are a different type of messenger – called a chemical messenger. Neurotransmitters can either be inhibitory (calming) or excitatory (energetic). For example, GABA is a calming neurotransmitter that, among other things, helps us sleep well. Conversely, epinephrine is an energetic neurotransmitter that provides us with the stamina and motivation we need to take action in fight-flight situations. 

The relation between the gut and the mind

Over the last couple of decades, the significant influence of the gut microbiome on this complex and interconnected system has come to light, putting scientific conversations around the microbiota-gut-brain axis (MGB-axis) at center stage (1). It is now understood that having a diverse gut microbiome allows us to make a healthy combination of the hormones and neurotransmitters we need for both a balanced body and mind.

On the other hand, studies show that a lack of microbial diversity can throw our mix of neurotransmitters off balance. There is growing data from both animal and human clinical trials linking gut dysbiosis (imbalance) with a broad spectrum of psychiatric and nervous system disorders – all stemming from inflammation (2).

The concept that “all disease begins in the gut” has been attributed to a variety of sources – from Ayurvedic medicine to Hippocrates. Regardless of its true origins, scientists have only just begun to give gut microbes the attention they so rightfully deserve. It is now believed that 70-90% of our human cells are bacterial, and though we have microbes all over our bodies, the majority of them live in our gastrointestinal (GI) tract.

The relatively new term “psychobiotics” refers to the use of probiotics to improve mental health. And by now, there have been enough preclinical studies to show the beneficial role of probiotics in psychiatry (3), plus some small sample-size studies showing them as an effective antidepressant (4).

The introduction of psilocybin in Western medicine

Psilocybin mushrooms were first introduced to Western cultures in 1955, when R. Gordon Wasson, a VP from J.P. Morgan, traveled to Mexico to visit the indigenous curandera (medicine woman) María Sabina. Wasson was on a mission to try the magic mushroom known as “God’s flesh” as part of a Velada ceremony. It is believed that the Mazatec tribe had been using psilocybin mushrooms for thousands of years to commune with God and heal the sick. Initially, María Sabina was reluctant to introduce Wasson to the ceremony because he didn’t appear to need healing.

However, she was eventually persuaded when he expressed a desire to find God. Soon after his visit, Wasson wrote an essay for Life Magazine sharing his life-changing experience. This led flocks of beatniks, hippies, celebrities like Bob Dylan and John Lennon, and other seekers to the remote village. One of those visitors was American author and psychologist Timothy Leary, who, together with Richard Alpert (aka Ram Dass), were professors at Harvard University in 1960.

Leary returned to Harvard, saying that he learned more about himself during his 5-hour psychedelic trip than he had during his fifteen years in school. Together, the pair began to explore the effects of psychotropic substances on the human mind with the introduction of the Harvard Psilocybin Project.

Following the study, an overwhelming majority of the 167 participants claimed their experience with psilocybin had changed their lives for the better. But the experiment was not to be long-lived. All the publicity surrounding shrooms eventually got Leary and Alpert fired from Harvard. Soon after, psilocybin was banned in both the US and Mexico, though its recreational use continued despite being labeled as a controlled substance.

After a 25-year hiatus, clinical trials on psychedelics like psilocybin mushrooms started to come back in the 1990s, this time with more sophisticated brain imaging tools and clinical studies to measure their impact. While psychedelics research is still considered to be in its relatively early stages of discovery, there is mounting evidence that one of psilocybin’s major benefits lies in its ability to ease our transition between different activity states. For example, going from extreme excitement to falling asleep or going from feelings of intense fear to immense joy. 

Psychedelic researcher Robin Carhart-Harris uses the analogy of a ski slope to explain the effects of psilocybin on the brain. He says that every ski slope develops tracks as people move down the hill, making it increasingly harder to ski around the previously carved paths. Similarly, our minds create patterns as we navigate through life – which why we sometimes get stuck in a rut.

Psychedelic mushrooms have the ability to disrupt these patterns, making it easier for us to “change our minds.” Psilocybin does this by activating receptors on our brain cells for serotonin, the “feel-good hormone.” It has also shown great potential in treating a broad range of deep-seated psychological disorders involving rigid patterns of thought, emotion, and behavior that prevent people from living their best lives.

Serotonin is made in both our brain and gut and helps us regulate important things like attention, behavior, and body temperature. It also plays a role in regulating digestion, circulation, and respiration — all of the processes essential for life. Given psilocybin’s influence on this vital hormone, it could prove to be a serious game-changer in the fields of psychiatry and neuroscience.

How psilocybin can have a positive influence on the MGB-axis

1. Stress Response

The idea that chronic stress can lead to mental health dysfunction is not new. In fact, stress (especially in early life) has been shown to change the makeup of our gut microbiome when bacteria leak out of the intestines, and the body responds by releasing inflammatory cytokines. As a result, the microbiota-gut-brain axis overreacts to stress – ultimately setting us on a trajectory that weakens our ability to bounce back from hard times.

In one animal study, scientists found that psilocybin can make us more resilient to future stresses over the long term when the HPA axis is exposed to the intense temporary “shock” brought on by psilocybin treatment (5). Researchers use scales like The Five Dimensional Altered States of Consciousness to measure and describe the psychedelic experience, which can include visual and auditory hallucinations, feelings of spiritual bliss, and loss of ego/physical self. Interestingly, a survey of 3,000 people found that those who had experienced a psychedelic trip emerged with newfound positive beliefs surrounding death and dying that were very similar to those who had had a near-death experience. 

In microdoses, psilocybin also holds great promise for those suffering from long-term depression (LTD). In a human study of 27 participants with LTD, researchers found a significant reduction in depression after receiving only two doses (20mg and 30mg per 154lbs, respectively) of psilocybin over a 1-month period. Follow-ups one to twelve months after treatment showed that the severity of participants’ depression remained low. More studies are needed to establish whether psilocybin’s antidepressant effects might last longer than just a year.

 Recently, in the largest double-blind study of its kind, researchers found that there is a dose-response relationship in patients with treatment-resistant depression who received a single 25mg microdose of psilocybin. Ultimately, patients who received even smaller doses improved, but not as much as the ones who received 25mg.

Most standard antidepressants have to be taken consistently and over long periods, making compliance tricky. Even then, only an average of 50% of psychiatry patients see a marked improvement in their symptoms, and over half of those taking medications for mental health report moderately severe side effects. For these reasons, psilocybin may be a promising alternative treatment option that offers safe and lasting relief after just one to two treatments.

2. Sociability

You may have heard about the importance of social connection for physical, mental and emotional well-being. Studies show that people with expansive social networks tend to feel more connected, less stressed out, and have a more diverse gut microbiome than those who are socially isolated. This aligns with the Hygiene Hypothesis and the belief that exposure to germs and certain infections helps the immune system develop. In contrast, socially isolated people are more likely to have reduced microbial diversity and increased feelings of anxiety and stress.

In the right therapeutic set and setting, psilocybin therapy can increase our sense of belonging, aid in our production of oxytocin (the “love hormone”), and make us more sociable – essentially strengthening our resilience to stress and improving our mental health.

3. Reward center of the brain

There is some scientific evidence linking gut dysbiosis with substance use disorders. People with microbial imbalances are more prone to addiction in the first place, and substance use can make matters worse.

The good news is that addiction researchers have seen some promising early results in treating substance abuse disorders and psychedelics.

This new evidence demonstrates how psychedelic therapy has the potential to reshape our reactions and habits around stress via the microbiota-gut-brain axis (6). Therefore, the next time we have a challenging day, we are far less likely to self-soothe with addictive substances we may have turned to in the past. 

In one small-scale study of ten alcohol-dependent patients, psilocybin significantly reduced their frequency of drinking days for up to three years post-treatment. In another study of fifteen tobacco-dependent participants, 80% had quit smoking for up to six months after treatment. The most common reasons that participants quit were: 

• A more hopeful outlook on the future that eclipsed their immediate desires
• A strengthened belief in their ability to quit
• Changed life priorities/values that made quitting more important than smoking

The results seen with psilocybin treatment are a significant improvement compared to what is usually observed with behavioral therapies and medications in which 50–60% of patients with substance abuse disorders relapse within six to twelve months after treatment. 

4. Inspires healthier habits

Some early studies also point to the possibility that psilocybin influences the microbiota-gut-brain axis in a way that may help nudge people closer to their dietary and fitness goals. In turn, they have the motivation to adopt healthier habits that may have been eluded in the past.

Essential variables for ongoing investigation

As researchers begin to understand how the microbial makeup of our gastrointestinal tract can be modified to support mental and physical health, we may see customized dietary interventions integrated into psychedelic therapy that address individual variability.

For example, the addition of probiotics and prebiotics can help target the pathways involved in microbial messaging inside the MGB-axis by modifying the composition of the gut microbiome if there is dysbiosis. This could lead to major advances in the fields of psychology, psychiatry, and neuroscience, with the potential to bring homeostasis (balance) to a multitude of stubborn mental health disorders that share common mechanisms. 

There are limitations to these studies on psilocybin. Some of them have a small sample size, for instance. Also, because the US government still classifies psilocybin as a CSA Schedule I drug along with substances like heroin, it must be administered under very controlled conditions. Additionally, most clinical studies exploring the role of the gut microbiome in disease have to consider the natural variations in microbial composition from one person to the next (7).

One “size” does not fit all. Factors like age, sex, body mass index, medications, and lifestyle are just a few of the variables that can complicate the analysis of the gut microbiome. To expand on existing microbiota-gut-brain axis research, it is important that future studies identify and include those essential variables in their ongoing investigations.

The future of psilocybin treatment for the microbiota-gut-axis

To sum up, the current clinical trials on psilocybin suggest that its effects on our brain’s serotonin receptors may have far-reaching mental health benefits. Psilocybin has been shown to have a remarkable safety record and seems to produce long-lasting results that far surpass our current antidepressant and anti-anxiety therapies.

Clinical trials on psilocybin’s positive influence on the gut microbiome and mental health may still be in the somewhat early stages of research. However, the correlation appears very promising. With larger and longer-term trials underway, we are beginning to see the emergence of a very important, holistic therapy that has the potential to help liberate many people from the behaviors that no longer serve them.

As we begin to understand more about the intimate relationship between our microbiota-gut-brain axis and mental health, coupled with psilocybin’s ability to interact with both, further research in this area could lead to more targeted and personalized treatment plans. By prioritizing the gut microbiome and integrating dietary strategies like probiotics, health professionals can improve outcomes in patients with a wide range of nervous system disorders.

As clinical studies get behind the idea that our bodies and minds function as one interconnected system, we may see practitioners of neuroscience, psychiatry, gastrointestinal disorders, and nutrition unite around the overarching goal of healthcare – regardless of their specialty.

References

1. Kelly, John R., Gerard Clarke, Andrew Harkin, Sinead C. Corr, Stephen Galvin, Vishnu Pradeep, John F. Cryan, Veronica O’Keane, and Timothy G. Dinan. 2023. “Seeking the Psilocybiome: Psychedelics Meet the Microbiota-Gut-Brain Axis.” International Journal of Clinical and Health Psychology 23 (2): 100349. https://doi.org/10.1016/j.ijchp.2022.100349.
2. Cryan, John F., Kenneth J. O’Riordan, Caitlin S. M. Cowan, Kiran V. Sandhu, Thomaz F. S. Bastiaanssen, Marcus Boehme, Martin G. Codagnone, et al. 2019. “The Microbiota-Gut-Brain Axis.” Physiological Reviews 99 (4): 1877–2013. https://doi.org/10.1152/physrev.00018.2018.
3. Johnson, Dinyadarshini, Sivakumar Thurairajasingam, Vengadesh Letchumanan, Kok-Gan Chan, and Learn-Han Lee. 2021. “Exploring the Role and Potential of Probiotics in the Field of Mental Health: Major Depressive Disorder.” Nutrients 13 (5). https://doi.org/10.3390/nu13051728.
4. Poluektova, Elena, Roman Yunes, and Valery Danilenko. 2021. “The Putative Antidepressant Mechanisms of Probiotic Bacteria: Relevant Genes and Proteins.” Nutrients 13 (5): 1591. https://doi.org/10.3390/nu13051591.
5. Jones, Nathan T, Zarmeen Zahid, Sean M Grady, Ziyad W Sultan, Zhen Zheng, Matthew I Banks, and Cody J Wenthur. 2020. “Delayed Anxiolytic-like Effects of Psilocybin in Male Mice Are Supported by Acute Glucocorticoid Release.” BioRxiv, August. https://doi.org/10.1101/2020.08.12.248229.
6. Veen, Bas T.H. de, Arnt F.A. Schellekens, Michel M.M. Verheij, and Judith R. Homberg. 2016. “Psilocybin for Treating Substance Use Disorders?” Expert Review of Neurotherapeutics 17 (2): 203–12. https://doi.org/10.1080/14737175.2016.1220834.
7. Daniel, Jeremy, and Margaret Haberman. 2017. “Clinical Potential of Psilocybin as a Treatment for Mental Health Conditions.” Mental Health Clinician 7 (1): 24–28. https://doi.org/10.9740/mhc.2017.01.024.