Determining peripheral modulation of the endocannabinoid system (ECS) may be important for differentiating individuals with schizophrenia. Such differentiation can also be extended to subgroups of individuals, those who use cannabis and antipsychotic medications, particularly those who are treatment resistant. Patients and controls were recruited from the outpatient clinic of the Psychosis Group of the University of São Paulo, Brazil. A final sample of 93 individuals was divided into 3 groups: patients with schizophrenia using clozapine (treatment-resistant) (n = 29), patients with schizophrenia using another antipsychotic (n = 31), and controls (n = 33). By measuring the proteins and metabolites involved in the ECS pathways in the peripheral blood, AEA (anandamide), 2-AG (2-arachidonoyl ethanolamine), and CB2 receptor (peripheral) were quantified. Individuals reporting lifetime cannabis use had lower 2-AG plasma levels (p = 0.011). Regarding the CB2 receptor, the values of patients with schizophrenia and controls were similar, but those of patients using antipsychotics other than clozapine differed (p = 0.022). In generalized linear models to control for confounders, the use of cannabis remained the only factor that significantly influenced 2-AG levels. The relationship for non-clozapine antipsychotics as the only factor related to CB2 changes was marginally significant. We found for the first time that cannabis use and non-clozapine antipsychotic medication are potentially involved in the modulation of the ECS, specifically influencing 2-AG endocannabinoid and CB2 receptor levels. More studies regarding the ECS are needed since it has been increasingly related to the physiopathology of schizophrenia.