OBJECTIVE: This systematic review aims to evaluate the impact of psilocybin on patients experiencing psychiatric symptoms, with a focus on health-related quality of life (HRQoL) and safety. METHOD OF RESEARCH: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we searched the PubMed database and identified studies published from January 2011 to December 2021 pertaining to the impact of psilocybin on psychiatric symptoms. Two authors independently conducted a focused analysis and reached a final consensus on five studies meeting the specific selection criteria. Study bias was addressed using the Cochrane risk of bias tool. RESULTS: The impact of psilocybin on psychiatric symptoms was examined in five randomized controlled trials (RCTs). Four studies administered 1 to 2 doses of psilocybin, with doses ranging from 14mg/70kg to 30mg/70kg, and one study administered a fixed dose of 25mg to all participants. Administration of psilocybin resulted in significant and sustained reduction in symptoms of anxiety and depression, enhanced sense of wellbeing, life satisfaction, and positive mood immediately after psilocybin administration and up to six months after conclusion of treatment. All studies included some form of psychotherapy, and none reported serious adverse effects. CONCLUSION: RCTs show the efficacy of psilocybin in the treatment of anxiety and depression symptoms, as well as improvement in HRQoL, and no serious side effects. However, additional research is necessary to characterize predictors of treatment response, patient screening requirements, effectiveness in broader clinical populations, and guidelines for psilocybin-assisted psychotherapy.