Psilocybin and Ketamine for Major Depressive Disorder and Treatment-Resistant Depression: A Review of Recent Clinical Trials

Abstract This narrative review presents the current state of knowledge on the use of psilocybin and ketamine in the treatment of depression, including treatment-resistant depression (TRD). Drawing on data from clinical trials conducted between 2000 and 2025 -including studies such as COMP001 and NCT03866174 - we analyzed the efficacy, safety, and therapeutic potential of these substances as interventions in the treatment of depression. Particular attention was given to randomized, placebo-controlled trials, especially phase II and III studies, as well as to data obtained from long-term follow-up observations. In the reviewed studies, treatment efficacy was assessed using standardized tools such as the MADRS, QIDS, or HAMD scales. The findings of our analysis indicate that both psilocybin (including its synthetic form COMP360) and ketamine (administered via various routes) demonstrate a rapid and clinically Significant antidepressant effect, often observable after a single dose. These substances appear to have a relatively favorable safety profile, particularly when used in controlled environments and accompanied by appropriate psychotherapeutic support. We also examined the impact of dosing strategies, psychological integration, and the potential of these interventions to reduce suicidal ideation and tendencies. Our analysis highlights the necessity and relevance of conducting further research aimed at the standardization of therapeutic protocols and the integration of psychedelic-assisted interventions with conventional methods of treating depression.