Background: Consumption of natural cannabis (NC) and synthetic cannabinoids (SCs) has been associated with psychotic disorders. We compared the prevalence of use, consumer profiles, and psychosis-inducing potential of NC and SCs in a specific high-risk population. Methods: This prospective pilot study included 332 patients (18-64 years, mean 36.83, SD 13.33). Patients' sociodemographics and medical histories as well as illicit substance use and psychiatric symptom histories were collected using a drug consumption survey that assessed the use of new psychoactive substances and the Psychotic Symptoms Interview. Results: In total, 7.2% of all patients, 10.6% of psychotic patients, and 4.5% of nonpsychotic patients reported SC consumption. Compared with SCs, NC was consumed much more frequently by its users (mean 222.73, SD 498.27). NC and SC use induced persistent psychosis. Psychotic symptoms were first experienced by patients with a history of NC or SC use during intoxication and persisted after cessation (>1 year) of drug use. Positive and negative symptoms tended to be more severe in SC and NC users, respectively. Conclusions: NC and SCs may cause different symptom clusters. These relationships should be further evaluated.