Depression and especially treatment resistant depression (TRD) have profound health and economic impacts. Our project supports the development and validation of new innovative therapies for people living with this disorder. The primary objective of this study is to evaluate the efficacy and safety of psilocybin assisted psychotherapy in people with TRD to an active control. We hypothesise that three sessions of Psychedelic Assisted Psychotherapy (PAP) with psilocybin will result in a greater improvement in symptoms of depression than three sessions of identical PAP provided with a comparator agent. If successful, this will lead to the conduct of a subsequent multi-site phase 3 trial to report findings of the therapeutic value, benefits and risks of psilocybin for the treatment of TRD, including the size of effect, the quality of evidence and the applicability of the evidence to real-world use in Australia.