A single dose of a psychedelic compound is unlikely to sound like a long-term strategy for treatment-resistant depression (TRD), yet emerging data suggest durability may depend heavily on dose, context, and patient experience. In a recent Journal of Clinical Psychiatry Podcast episode, David Feifel, MD, PhD—Professor Emeritus of Psychiatry at UC San Diego and a pioneer in interventional psychiatry—joins Ben Everett, PhD, Senior Scientific Director of The Journal of Clinical Psychiatry, to examine what a year of follow-up data reveals about single-dose psilocybin for TRD.
Key Takeaways
- Treatment-resistant depression remains a major unmet need, with conventional antidepressants often producing incomplete or short-lived benefit.
- Psilocybin is being studied as a classic psychedelic whose effects appear to depend on dose, subjective experience, and treatment context.
- Phase 2 data suggest higher doses may be associated with fewer depressive events and longer time to relapse over extended follow-up.
- Clinical implementation would require new infrastructure, training, and a shift toward interventional models of psychiatric care.
Meet the Guest
David Feifel, MD, PhD is a psychiatrist and neuroscientist with extensive experience in both clinical practice and translational research. He founded the world’s first ketamine infusion program for depression and has led clinical studies of psychedelic and neuromodulatory treatments, bringing a practical, systems-level perspective to emerging interventional approaches in psychiatry.
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Featured Article
Maintenance of Antidepressant Effect After 1 Dose of Psilocybin
This Journal of Clinical Psychiatry article reports 52-week observational follow-up data from patients who received a single dose of psilocybin, highlighting dose-dependent differences in depressive events and time to relapse.
What problem is psilocybin being studied for in psychiatry?
Psilocybin is being investigated primarily for major depressive disorder and treatment-resistant depression, populations in which standard antidepressants often fail to produce full remission. In the discussion, Dr. Feifel emphasizes that many patients labeled as “responders” to SSRIs still experience significant residual symptoms that impair quality of life.
How was psilocybin studied in treatment-resistant depression?
The phase 2 study discussed was a randomized, double-blind, dose-ranging trial in adults with TRD who received a single oral dose of synthetic psilocybin at 1 mg, 10 mg, or 25 mg. Patients discontinued antidepressants before dosing and were followed closely, with the primary endpoint assessed at three weeks and additional long-term observational follow-up extending to 52 weeks.
What did the dose-ranging results show?
All dose groups showed some improvement in depressive symptoms, but the largest and most consistent reductions occurred in the 25 mg group. According to Dr. Feifel, only the highest dose clearly separated from the lowest dose comparator, supporting a dose–response relationship rather than a purely expectancy-driven effect.
“The strongest predictor of antidepressant response wasn’t just the dose—it was whether patients experienced an emotional breakthrough during the session.”
What did the 52-week follow-up add to the findings?
The long-term observational data suggested that patients who received 25 mg experienced fewer depressive events and required antidepressant interventions later than those who received lower doses. While not powered for formal statistical testing, the pattern mirrored the short-term results and supported the idea that dose influences durability.
Why do set and setting matter for psychedelic treatments?
Unlike conventional pharmacotherapy, psychedelic effects are strongly shaped by patient expectations, preparation, and the treatment environment. Dr. Feifel explains that the same drug and dose can lead to distressing or therapeutic experiences depending on psychological readiness and clinical support, making preparation and setting integral to outcomes.
“The patient’s state of mind and the environment aren’t accessories to treatment—they’re part of the treatment.”
Does psilocybin require psychotherapy to be effective?
Based on the studies discussed, large antidepressant effects were observed without structured psychotherapy during dosing sessions. Dr. Feifel argues that while education and emotional support are essential, the therapeutic effects appear to arise primarily from the drug experience itself rather than from formal, manualized psychotherapy.
What are the implications for future clinical practice?
Dr. Feifel anticipates that psychedelics would be delivered through specialized centers with trained facilitators and appropriate infrastructure, rather than standard outpatient medication visits. He also suggests psychiatry may move toward an interventional model, where acute treatments are provided by specialized teams and coordinated with ongoing care.
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The full discussion—covering study design, safety considerations, expectancy effects, and the evolving role of interventional psychiatry—is available on the Journal of Clinical Psychiatry Podcast.
