This study aims to test the **effectiveness, safety, and comfort** of a new treatment called **COMP360** for people with **treatment-resistant depression (TRD)**, which means their depression hasn't improved with other treatments. The study is *international* and involves many centers. It uses a method where some participants receive the real treatment and others receive a fake one, called a *placebo*, without knowing which they get. Participants will be randomly given either COMP360 or a placebo, with a 2:1 chance of getting the treatment. It involves three main parts: a 6-week initial phase, a 20-week re-treatment phase, and a 26-week open-label phase, totaling about 62 weeks. The study will help see if a single dose of COMP360 can reduce depression symptoms when combined with *psychological support*. **Key Points:** - The study lasts about **62 weeks** with several parts. - Participants must be **18 or older** with TRD. - **No cost or compensation** details are specified. **Eligibility**: Participants should have tried at least two depression treatments without success and agree to stop certain medications. Some mental health conditions and treatments may exclude participation.