This study investigates the feasibility, safety, and efficacy of psilocybin in treating unipolar treatment-resistant depression. Twelve patients with moderate to severe depression received two oral doses of psilocybin (10 mg and 25 mg, 7 days apart) in a supportive setting. Psychological support was provided throughout the sessions. The primary outcome measure was patient-reported intensity of psilocybin's effects, and depressive symptoms were assessed using the Quick Inventory of Depressive Symptoms (QIDS). Psilocybin was well tolerated, with no serious adverse events. The acute psychedelic effects became detectable 30-60 minutes after dosing and subsided within 6 hours. Depressive symptoms were significantly reduced 1 week and 3 months after high-dose treatment, with marked improvements in anxiety and anhedonia. The study provides preliminary evidence for the safety and efficacy of psilocybin in treating treatment-resistant depression, suggesting the need for further rigorous trials to explore its therapeutic potential.This study investigates the feasibility, safety, and efficacy of psilocybin in treating unipolar treatment-resistant depression. Twelve patients with moderate to severe depression received two oral doses of psilocybin (10 mg and 25 mg, 7 days apart) in a supportive setting. Psychological support was provided throughout the sessions. The primary outcome measure was patient-reported intensity of psilocybin's effects, and depressive symptoms were assessed using the Quick Inventory of Depressive Symptoms (QIDS). Psilocybin was well tolerated, with no serious adverse events. The acute psychedelic effects became detectable 30-60 minutes after dosing and subsided within 6 hours. Depressive symptoms were significantly reduced 1 week and 3 months after high-dose treatment, with marked improvements in anxiety and anhedonia. The study provides preliminary evidence for the safety and efficacy of psilocybin in treating treatment-resistant depression, suggesting the need for further rigorous trials to explore its therapeutic potential.