In this episode of The Mind-Gut Conversation, Dr. Emeran Mayer speaks with Dr. Erin Mauney, a pediatric gastroenterologist and researcher at Harvard and Massachusetts General Hospital, about one of the first clinical trials of psilocybin-assisted therapy for patients with treatment-resistant irritable bowel syndrome.

The conversation begins with a question that took nearly forty years to settle within gastroenterology, and that remains contested today. Is IBS a disorder of the gut, or a disorder of the interaction between the gut and the brain? Dr. Mauney argues that pain itself implies central processing, and that once the brain is understood as an active participant rather than a bystander, an entirely different set of therapeutic possibilities opens up.

Dr. Mauney explains the model underlying her work. The brain functions as a prediction machine, constantly anticipating what signals from the body will mean. In chronic pain conditions, that machinery can become locked into a pattern where ordinary gut sensations are interpreted as danger. Psychedelics appear to open a temporary window of neuroplasticity in which those predictions become more flexible, which is why the preparation and integration therapy surrounding each dosing session may matter as much as the compound itself.

They also discuss the methodological problems facing the field. Blinding is nearly impossible when participants can identify what they received. The intervention combines a drug and a psychotherapy that regulators would prefer to evaluate separately. And there is an open commercial question about whether the subjective psychedelic experience can be removed from these compounds altogether, along with a real debate about what would be lost if it were.

Dr. Mauney is clear that this is early-stage science built on a small open-label pilot. The conversation is less a claim about efficacy than a look at how the next chapter of brain-gut medicine is being built, and at what a reductionist Western model still has to learn from practices used ritually for millennia.

Key Topics Covered:

• Why IBS is best understood as a disorder of gut-brain interaction
• How the brain’s prediction machinery becomes locked into chronic pain
• What a psilocybin-assisted therapy protocol actually involves
• Whether the psychedelic experience itself is essential to the benefit
• Why blinding and placebo control are so difficult in this research
• The durability of benefit and what happens in the year after treatment
• Possible applications in IBD, celiac disease, and other chronic pain conditions
• Where psychedelic research in gastroenterology may be headed next

Chapters:

0:00 – Introduction
3:23 – IBS as a Brain-Gut Disorder
7:40 – Entering Psychedelic Research
13:22 – How Psilocybin Could Affect the Gut
15:43 – Inside the Trial
17:50 – The Brain and Pain Prediction
21:18 – Side Effects and Patient Experience
25:40 – Does the Psychedelic Experience Matter?
29:57 – Ritual and Western Medicine
32:15 – The Placebo Question
36:33 – Combining Therapies
39:10 – Brain Imaging
40:56 – Practical Challenges
44:07 – Durability of Benefits
47:23 – Overlap With Other Conditions
49:28 – Where the Research Goes Next
54:11 – Looking Ahead

FAQ:

Why is IBS considered a disorder of gut-brain interaction rather than a gut disorder?

Dr. Mauney points out that IBS is defined in part by pain, and pain necessarily involves central processing. If the condition were purely intestinal, it would be characterized only by altered bowel habits. What clinicians actually see includes GI-specific anxiety, avoidance of food and travel, and a progressively narrowing life, all of which reflect the brain and the behaviors built around the symptoms rather than the gut alone.

How could a drug that acts mainly on the brain reduce abdominal pain?

The working model draws on the idea that the brain is a prediction machine. Rather than processing every incoming signal, it anticipates what those signals will mean. In IBS, that prediction can become biased toward danger, amplifying ordinary gut sensations into pain. Psychedelics appear to loosen those predictions for a period of time, which may allow the brain to receive signals from the gut without immediately interpreting them as threatening. Dr. Mauney is careful to describe this as a model rather than an established mechanism.

What does psilocybin-assisted therapy actually involve?

In this trial, each participant was paired with two psychotherapists who stayed with them throughout. There were several hours of preparatory therapy before the first dose, a full dosing day lasting six to eight hours with both therapists present, integration sessions afterward, and then a second dosing day followed by further integration. A substantial portion of the protocol involves no drug at all.

What dose was used, and was it a microdose?

The trial used 25 milligrams of psilocybin, a dose commonly used in other clinical studies. This reliably produces a perceptible psychedelic experience and is not a microdose. Dr. Mauney also notes that the data she has seen on microdosing is not compelling, and that chronic serotonergic exposure raises separate safety questions.

How long do the benefits last?

Participants have been followed out to one year. Dr. Mauney reports good effect at that point, and notes that in many cases patients continued to improve after therapy ended, which she attributes to ongoing reflection and integration rather than any lingering pharmacological action.

Is the psychedelic experience itself necessary?

Dr. Mauney considers this an empirical question that has not been answered. She acknowledges the commercial appeal of a compound that produces neuroplastic effects without a subjective experience, but argues that the experience is what prompts patients to reconsider how much control they have over their lives, and that removing it would likely remove much of the therapeutic value.

Why is it so hard to run a placebo-controlled trial of psychedelics?

Participants can almost always identify which group they were assigned to. Researchers have tried using other psychoactive but non-psychedelic agents as comparators, and none has worked well. Dr. Mauney adds a further complication. The intervention combines a drug with a psychotherapy, and regulators generally want those components separated, which she views as a poor fit for conditions where mind and body cannot be cleanly divided.

Is this treatment available to patients now?

No. This was an open-label pilot study of thirteen participants. Dr. Mauney describes the data as preliminary, though promising. Larger controlled trials, along with questions about therapist training, credentialing, cost, and scalability, would need to be addressed before this could become part of routine gastroenterology care.