Guts, brains, and psychedelics: 5 Questions for psychiatrist John Kelly

Kelly discusses the psilocybiome and how it could inform psychedelic-assisted therapy.

In the last two decades, scientists have made great strides in uncovering the surprising ways that the bacteria in our stomachs — often called the gut microbiome — affect our overall health, and vice versa. The diversity of bacteria in our bodies can change with our diets, of course, but it’s also linked to our mood, stress levels, and mental health. 

Psychiatrist John R. Kelly has studied the link between mental health and the gut microbiome for nearly a decade. He’s also been an investigator on COMPASS’s psychedelic clinical trials at Trinity College Dublin. Now, he’s combining his research interests; he recently published a paper in the International Journal of Clinical and Health Psychology on what he calls the “psilocybiome,” or the intersection of psychedelic drugs and the gut microbiome. The Microdose spoke with Kelly about this potential new area of research and how it could inform psychedelic-assisted therapy.

How does the microbiome affect mental health?

When we’ve looked at the microbiome of people with depression, we’ve seen that the diversity of the microbiome is reduced. There are also some meta-analyses linking the presence of certain types of gut bacteria with pro-inflammatory signals. 

At the moment, it’s problematic to decipher cause and effect. A lot of human studies are association studies. There are other studies in the preclinical domain, where you use a rat model. In one study we did, rats were given antibiotics to suppress the microbiome, and then they were given a fecal microbiota transplant from people with depression, versus people without. Rats who received transplants from people with depression developed more symptoms of depression and anxiety than those who received transplants from the healthy microbiome. 

What do we know, so far, about how the microbiome and psychedelics might interact?

There’s one preclinical study with rats, but in terms of classical psychedelics, there’s not much else out there. The goal of the paper was to reiterate the fact that we, as individuals, are each made up of all these interrelated complex systems; that’s what makes us us. We know that microbes affect the programming of the immune system, metabolic systems, brain development, and the functioning of the pathways that manage our stress system and serotonin signaling. At this point, the idea is conceptual, but in my opinion, certainly worth exploring. 

You recently published a paper in which you use the term “psilocybiome” to describe the interactions between a host, the host’s gut microbiota, and psychedelic compounds. In your view, how would a better understanding of the “psilocybiome” be applied in the context of psychedelic-assisted therapy?

I think it could improve outcomes by playing a role in each stage of treatment and refining who would respond well to this treatment and maximizing their chances of that. If you look at COMPASS’s study results using psilocybin for treatment resistant depression, 37% of people show a response three weeks after a dose of psilocybin, and that drops to 20% at week 12. There’s room for improvement there, and even a few extra percentage points could really make a difference to people.

Thinking about the psilocybiome could play a role in each stage of treatment. Perhaps in the preparation stage, you could try to shift a person’s microbiome in some way that’s more optimal to receiving treatment. During administration, if you understand how the gut absorbs drugs, you could subtly adjust doses. And in integration, people could not only reappraise maladaptive patterns of thought and emotion, but also the relationship between behavior and microbial systems. We know, for example, that diet and exercise affect gut flora and therefore outcomes, so if integration included integrating healthier lifestyle patterns, you might see even more effective treatment. 

How might psilocybin’s effect on the microbiome look different from other mental health treatments, like antidepressant drugs?

In psilocybin clinical trials, participants are not receiving many doses. Most are receiving between 1 and 3 doses, and that’s not at all like other treatments like antidepressants, which you take every day. Previous studies with rats show that SSRIs decrease gut diversity. Even if the same is true of psilocybin, there’s more of an opportunity in using that treatment to use that initial reduction as a microbiome reset, and to build a healthier flora during the integration phase.

What are the next steps towards better understanding the psilocybiome? 

The first thing to do would be to collect various microbiome samples throughout the trials and look at how different doses affect that — including if a placebo has any impact. Researchers would have to collect dietary info as well, and look at participants’ immune systems markers to see if there is a link between all these factors. As you might know, it’s currently almost impossible to blind psychedelic studies, but in studying the microbiome, you could perhaps do that by assigning participants permutations of different doses and diets. 

It will also require interdisciplinary collaboration; all researchers have to do is start taking samples at specific time points, which we can then sequence. You could add those in as participants are already coming into the lab to do their blood tests and brain scans. But it’s a messy job to take samples, and tough to convince people to give them; it’s poop, after all.

This interview has been edited and condensed for clarity and length.