This unregistered trial (n=30) was an open-label, uncontrolled pilot study of psilocybin for treatment-resistant depression in patients and healthy controls, which found that psilocybin reduced pessimism bias and improved depressive symptoms.
This synthetic trial has been added to our database because a psychedelic paper (about a clinical trial) references this trial, but no (live) registration can be found. The study investigated the effects of psilocybin on pessimism biases in patients with treatment-resistant depression (TRD) compared to matched healthy controls.
Participants received two oral doses of psilocybin, 10 mg and 25 mg, administered one week apart alongside psychological support. The primary outcomes measured changes in future-event forecasting accuracy and depressive symptom severity using the QIDS-SR scale.
Results indicated that psilocybin treatment significantly decreased pessimism bias and improved depressive symptoms in the TRD group. Furthermore, patients demonstrated more accurate predictions of future life events following treatment, a change not observed in the healthy control group.
Patients with treatment-resistant depression receiving two oral dosing sessions of psilocybin (10 mg and 25 mg) one week apart, with psychological support.
Initial safety dose
Subsequent treatment dose administered 1 week after the first dose
Matched, untreated non-depressed healthy control subjects.
Psilocybin with psychological support produced rapid symptom reductions in treatment‑resistant depression and, on fMRI, elicited post‑treatment decreases in temporal cortex cerebral blood flow including the amygdala (the latter correlating with symptom improvement) alongside increased resting‑state functional connectivity within the default‑mode network. Increased vmPFC–bilateral inferior lateral parietal connectivity and decreased parahippocampal–prefrontal connectivity predicted 5‑week response, prompting the authors to propose a post‑acute “reset” therapeutic mechanism distinct from acute psychedelic effects.