The objective of this systematic review was to determine if higher concentrations of urinary bufotenine occur in patients with a mental illness compared to healthy controls. Bufotenine is an alkaloid with psychedelic and psychoactive properties that closely resembles the structure of serotonin. Bufotenine naturally occurs in Anadenanthera seeds and is secreted along with 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT) in the venom of the Bufo alvarius toad. There is evidence that bufotenine is produced endogenously in human subjects and is associated with mental illness, in particular schizophrenia and autism spectrum disorder. A total of eight full-text papers were included in the review, with a total of 609 participants, of whom 275 had a psychiatric diagnosis and 318 were healthy controls. In 226 out of 275 (82%) patients with a mental illness, urinary bufotenine was detected, compared with only 92 of 318 (29%) non-psychiatric subjects. The findings in the studies were somewhat heterogeneous; five out of eight studies found higher concentrations of urinary bufotenine in those with a mental illness than those without, of which three studies showed a statistically significant difference. One study failed to detect any urinary bufotenine in any of their subjects, and two out of the eight found a significant overlap of urinary bufotenine concentrations between those with a mental illness and healthy controls. Consequently, at present, it is likely too early to propose bufotenine as a possible biomarker for mental illnesses. Yet, further research is certainly merited, especially given that endogenously produced bufotenine could be implicated in the pathophysiology of mental illnesses.