This systematic review compared psilocybin and ketamine against antidepressants and placebo for treatment-resistant depression. Psilocybin (25 mg, COMP360) cut depression scores nearly twice as much as placebo (−12 vs −5 points) and achieved remission in 57% of patients versus 28% with escitalopram. Ketamine also showed rapid relief—64% response at 24 hours versus 28% with placebo—but required ongoing dosing. Psilocybin’s unique strength was its ability to deliver lasting remissions after only one or two sessions.