Schizophrenia is a relapsing disorder that produces profound effects on those afflicted once it becomes chronic, often leading to a severe and long-term disability. However, during the initial years of illness many patients are more treatment responsive and may achieve substantial periods of remission. Comorbid substance use disorder, a common concomitant of schizophrenia, is associated with increases in morbidity and mortality. Within the early phases of schizophrenia, comorbid cannabis use disorder (CUD), the most common comorbid disorder (approximately 50%), appears to be linked to a poor outcome in these patients, and may be a factor in their long-term deterioration. While data indicate that first episode patients presenting with comorbid CUD have an earlier onset of illness and a poorer outcome than those without CUD, continued cannabis use after antipsychotic treatment, which occurs in approximately 50% of these patients in the initial months after hospitalization, is associated with an even worse outcome. The apparent "toxicity" of cannabis use in first episode patients is paralleled by data from chronic patients, in whom CUD is associated with clinical exacerbations, non-compliance with treatment, poor global functioning, and increased relapse. A growing body of data suggests that a critical period exists in patients with schizophrenia during the early phases of psychosis in which symptoms and functioning continue to worsen, and that treatment with antipsychotic medications during this period may improve the natural course of the disorder. While the availability of novel antipsychotic medications has sparked further research in the early phases of schizophrenia, there have been few studies including clozapine (CLOZ). We hypothesize that CLOZ may be more effective than other novel agents in controlling cannabis use in patients with first episode schizophrenia who are comorbid for CUD. We postulate that standard antipsychotic medications do not decrease substance use in this population largely because they do not restore normal functioning of the dysfunctional dopamine (DA) pathways. CLOZ, by contrast, through its varied actions on dopaminergic, serotonergic and, particularly, noradrenergic neurons, coupled with its weak D2 and potent noradrenergic alpha2 blocking ability, may tend to have a "normalizing" effect on the signal detection capability of these dysfunctional DA systems. CLOZ is rarely used in first episode patients even though it is generally considered a highly effective medication, and more likely to prevent relapses than typical antipsychotics in both treatment refractory and non-refractory populations. While side effects of CLOZ are a clinical concern and need to be taken seriously, experience over the past 2 decades has increased the comfort level for its use. For example, agranulocytosis has actually occurred in 0.37% with implementation of the required white count monitoring system, and granulocyte stimulating therapy has provided an effective treatment for those few patients who do develop agranulocytosis. Gradual dose titration schedules appear to reduce risk for seizure and myocarditis, and experience in first episode patients suggesting that the clinically effective dose of CLOZ is lower than in chronic patients indicates that these risk should be even lower. If our hypothesis is correct, CLOZ, despite its side effect profile, may have a key therapeutic role in these patients, a role with important public health implications. Yet without a clear demonstration of the benefit/risk and benefit/burden profiles of its use, the naturalistic experiment of assessing the overall effectiveness of CLOZ in first episode patients who are comorbid for CUD is unlikely to be undertaken.