/ Abstract An estimated 30-40% of cancer patients experience clinically significant anxiety and depression. The burden of suffering caused by psychiatric distress has profound negative impacts on quality of life (QOL), medication adherence, increased rates of completed suicide, and even decreased cancer survival rates. Approximately 25% of cancer patients with advanced or terminal cancer experience clinically significant existential distress characterized by demoralization, hopelessness, absence of purpose or meaning, loss of dignity, and hastened desire for death. Pharmacologic and psychosocial treatments are commonly used to treat depression, anxiety and existential distress in cancer patients, but their effectiveness is limited and mixed. Psilocybin is a psychedelic tryptamine with a good physiologic-psychological safety profile in human lab and clinical research, producing highly salient meaningful experiences, often described as spiritual/mystical states of mind, associated with enduring (months to years) positive changes in cognition, affect, behavior, and spirituality. Based on extensive preliminary data, psilocybin-assisted therapy has demonstrated both safety and preliminary efficacy to improve cancer-related depression and anxiety (effect size = 0.82-1.69), and existential distress while improving quality of life, Participants in preliminary trials found the experience to be both acceptable and highly meaningful and spiritual. Building on this strong foundation of preliminary work, we propose to conduct a two-site, active placebo-controlled, double-blind, parallel design, randomized controlled trial of single high dose psilocybin-assisted therapy versus active placebo (very low dose psilocybin) for 200 participants with advanced cancer and baseline psychiatric distress. All participants will receive preparatory, active dosing, and integrative therapy sessions as part of the psilocybin and active placebo groups. We propose to conduct the following aims: 1) To assess the short- and long-term effects of psilocybin on mental health (e.g. anxiety, depression, existential distress) outcomes; 2) To assess the effects of psilocybin on QOL; and 3) To evaluate the contribution of psilocybin-induced psychological change mechanisms (mystical experience, personality trait openness, cognitive flexibility) on acute and long-term mental health outcomes (depression, anxiety, existential distress). We will collect baseline measures and follow up of outcomes at 1 day, 1 week, 8 weeks, 12 weeks, and 24 weeks (6 months). The proposed study will impact clinical care for persons with advanced cancer by testing an innovative, evidence-based intervention to improve depression, anxiety, existential distress, and quality of life. The study is significant because it addresses important mental health domains of suffering in patients with life-limiting cancer. The study is innovative as the potentially first effective therapy to impact existential distress. Furthermore, this study will further the science by evaluating the psychological change mechanisms for this promising new therapeutic intervention.