For most of my career, when psychotherapy is paired with another treatment, I have appreciated that the the combination will produce a better outcome.
Medication plus psychotherapy. Exposure therapy plus medication. Ketamine plus psychotherapy or integration.
So as psilocybin moved closer to psychiatry, I made the same assumption: of course this will eventually become psilocybin-assisted psychotherapy.
☕️ I hope that is where the field lands.
But the latest research has made me question where this is going.
The Assumption Hiding in the Name…… (Treatment).
Psilocybin research has moved remarkably quickly.
COMP360, Compass Pathways' proprietary synthetic formulation of psilocybin, has now produced positive results in its Phase 3 program in treatment-resistant depression (TRD).
And this was not an easy population. Participants across these trials had long-standing, recurrent illness that had already failed multiple treatments — and a longer current depressive episode is itself associated with poorer treatment outcomes.
In the single-dose pivotal trial, a single 25-mg dose produced a significantly greater improvement in depression scores than the control condition at Week 6, with the difference on the MADRS on the order of about three to four points (Goodwin et al., New England Journal of Medicine, 2022). The larger Phase 3 trial (roughly 580 participants, comparing 25 mg with a low-dose control) likewise showed a statistically significant advantage of a similar magnitude at Week 6 (Guidetti et al., Molecular Psychiatry, 2026).
📌 Among participants who improved, an effect was detectable rapidly — as early as the day after treatment — and longer-term follow-up suggests benefit can persist for months in responders (Goodwin et al., Journal of Clinical Psychiatry, 2025).
That combination of a rapid onset after very infrequent dosing with potential durability measured in months is what makes these findings so compelling.
COMP360 is now moving through the FDA regulatory process.
But here is where it takes a strange turn.
The treatment being developed isn't exactly psilocybin-assisted psychotherapy.
It is psilocybin administered with psychological support.
Those aren't necessarily the same thing.
☕️ What Is Psilocybin Doing to the Brain?
Psilocybin is converted in the body to psilocin, which strongly activates serotonin 5-HT2A receptors, particularly in cortical regions involved in perception, cognition and our sense of self (Reiff et al., American Journal of Psychiatry, 2020).
For several hours, the brain begins communicating differently.
One of the networks affected is the default mode network, a group of interconnected brain regions involved in self-referential thinking, autobiographical memory and the internal narrative we carry around with us.
One way to think about it is that psilocybin temporarily makes the brain less rigid.
Brain networks that normally communicate in predictable patterns become less synchronized. Connections between networks change. The usual boundaries between them become less distinct (Siegel et al., Nature, 2024).
There is also growing evidence that psychedelics may temporarily increase neuroplasticity — the brain's ability to modify and reorganize connections.
Animal and laboratory research suggests psilocybin can promote dendritic spine formation and synaptic remodeling in frontal cortical circuits, an effect that depends on 5-HT2A signaling (Shao et al., Nature, 2025).
So, a simplified model might look something like this:
Psilocybin loosens entrenched patterns while temporarily making the brain more receptive to forming new ones.
And that leads directly to my question at the center of this article.
If the brain becomes unusually receptive to change during and after psilocybin treatment, how much does what happens during that window matter?
Six Hours — But Not Six Hours of Therapy
A psilocybin treatment session seems to be much more involved compared to writing a prescription for an SSRI.
Patients are prepared beforehand. The drug is administered in a controlled environment. The experience lasts for hours. Similar to some ketamine-based clinics, patients may wear eyeshades and listen to music. Trained personnel remain nearby to monitor safety and provide reassurance when needed.
But that doesn't mean six hours of psychotherapy are occurring.
In fact, the psychological support delivered during the dosing session is intentionally non-directive and minimal. The trained person present is instructed to remain open and supportive without actively guiding or interpreting the experience (Goodwin et al., New England Journal of Medicine, 2022; Fonzo et al., American Journal of Psychiatry, 2025).
A patient may be having one of the most psychologically unusual experiences of his or her life while the trained person sitting nearby is deliberately not directing that experience.
Drug, Experience or Psychotherapy?
This leaves us with at least three possible therapeutic ingredients.
The pharmacology. Psilocybin changes serotonin signaling, brain-network organization and neuroplasticity.
The psychedelic experience. The altered state itself; changes in perception, emotion, autobiographical memory and sense of self may contribute to improvement.
What happens around the experience. Preparation, environment, human support and potentially psychotherapy or subsequent integration may influence how the experience is interpreted and incorporated into someone's life.
The problem is that these variables are difficult to separate.
And there may be another variable we underestimate:
the setting itself.
We Have Talked About This Before
We have discussed environment repeatedly here at Eva's Tea.
We have talked about Eva's house and about medical environments that seem almost perfectly designed to produce the opposite feeling.
Harsh overhead lighting. A cold examination room. An uncomfortable chair. Noise in the hallway. A television playing somewhere.
We tend to treat these things as background details.
During a psychedelic experience, I am not sure they remain background details.
If psilocybin temporarily changes how the brain processes sensory information, emotion and self-perception while increasing its capacity for change, then the experience surrounding the medication may become part of the treatment whether we intend it to or not.
“Support” Is Not Psychotherapy
A trained professional who remains with a patient, monitors safety, provides reassurance during distress and intervenes when necessary is providing an important clinical service.
But that person is not providing psychotherapy.
☕️ ☕️ Wouldn't psychotherapy amplify the outcome? I'm guessing that is the future direction.
Does every patient need psychotherapy before and after treatment?
Does psychotherapy improve the response but isn't necessary for it?
Does the psychedelic experience itself do most of the therapeutic work?
We don't know. And the trial designs so far can't fully tell us — the comparisons generally pair the drug (or a control) with the same psychological support, which means the specific contribution of the psychotherapeutic element remains entangled with the drug effect (Hosein et al., EClinical Medicine, 2025).
An Unusually Difficult Scientific Question
The psychedelic effect makes research blinding difficult. The environment is unusually controlled. Human support is present. Expectations may be powerful. And the subjective experience itself may be part of the mechanism rather than simply a side effect.
Other data sharpen the puzzle. A head-to-head trial against escitalopram did not separate psilocybin from the SSRI on its primary endpoint, and a more recent randomized trial in TRD missed its primary responder endpoint while favoring psilocybin on a secondary measure (Fonzo et al., American Journal of Psychiatry, 2025; Mertens et al., JAMA Psychiatry, 2026).
What part of psilocybin treatment works?
The molecule?
The altered state?
The environment?
The person sitting quietly beside you?
The conversation you have several days later?
Or some combination of all of them?
Where I Think This Is Going
I still suspect the best version of psychedelic treatment will ultimately offer patients both biological treatment and meaningful psychological care.
A traditional antidepressant might require a 30-minute medication appointment and a trip to the pharmacy.
Psilocybin may require a patient to spend much of the day in a specially designed room with trained personnel nearby.
So what happens when your next antidepressant isn't a pill you take every morning — but a six-hour appointment?
That's where we'll go in Part II: Your Next Antidepressant May Be a Six-Hour Appointment — What Psilocybin Could Look Like When Psychedelic Medicine Leaves the Research Center.
Selected References
Goodwin, G. M., Aaronson, S. T., Alvarez, O., Arden, P. C., Baker, A., Bennett, J. C., … Malievskaia, E. (2022). Single-dose psilocybin for a treatment-resistant episode of major depression. The New England Journal of Medicine, 387(18), 1637–1648. https://doi.org/10.1056/NEJMoa2206443
Guidetti, C., Fava, M., & Papakostas, G. I. (2026). Novel approaches in depression treatment: From rapid-acting antidepressants to personalized interventions. Molecular Psychiatry. Advance online publication. https://doi.org/10.1038/s41380-025-03145-3
Hosein, M. M., Reid, M. J., Walser, S., et al. (2025). Considerations and cautions for the integration of psilocybin into routine clinical care: A consensus statement from the US National Network of Depression Centers' Task Group on Psychedelics and Related Compounds. EClinicalMedicine, 89, 103480. https://doi.org/10.1016/j.eclinm.2025.103480
Park, D., Lee, G., Lee, W. G., Kim, S., et al. (2025). The therapeutic potential of psilocybin beyond psychedelia through shared mechanisms with ketamine. Molecular Psychiatry, 30(10). https://doi.org/10.1038/s41380-025-03019-8
Siegel, J. S., Subramanian, S., Perry, D., Kay, B. P., Gordon, E. M., Laumann, T. O., … Dosenbach, N. U. F. (2024). Psilocybin desynchronizes the human brain. Nature, 632(8023), 131–138. https://doi.org/10.1038/s41586-024-07624-5