Cannabis use disorder contributes to the morbidity of schizophrenia, leading to, poorer overall functioning. The typical antipsychotic drugs are of limited value in controlling cannabis use in these """"""""dual diagnosis"""""""" patients. This study will assess whether new antipsychotic medications, introduced into clinical practice in the past decade, are of value for this purpose. Preliminary data suggest that the atypical antipsychotic drug clozapine (CLOZ), currently used primarily for treatment resistant patients, may limit cannabis use in """"""""dual diagnosis"""""""" patients with schizophrenia much more effectively than do either typical antipsychotics or the """"""""novel"""""""" (post-CLOZ) antipsychotic risperidone (RISP). In a recently published paper, we have hypothesized (a) that CLOZ will lessen substance use in such """"""""dual diagnosis"""""""" patients in part because of its mechanism of action that includes release of dopamine (DA) in the prefrontal cortex (PFC), and (b) that the CLOZ-induced release of DA in the PFC will decrease negative symptoms (an effect shared especially by the novel antipsychotic RISP). Moreover, we have further hypothesized, (c) that through its diverse effects on both dopaminergic and noradrenergic systems, CLOZ (but not RISP or typical antipsychotics) will help to normalize dysfunctional brain reward circuits that may underlie the comorbid substance use in patients with schizophrenia. In the proposed study, patients comorbid for both schizophrenia and a cannabis use disorder will be randomly assigned to double-blind treatment (for 12 weeks) with either CLOZ or RISP. The primary aim of this study is to launch a carefully controlled pharmacological trial of the short-term effects of CLOZ and RISP on cannabis use in this population to test the hypothesis that patients treated with CLOZ will have decreases in cannabis use as compared to patients treated with RISP. A secondary aim is to begin to investigate the process by which CLOZ produces its effects on cannabis use through study of negative symptoms. A subsidiary aim is to begin to address key auxiliary measures of the effects of CLOZ in this """"""""dual diagnosis"""""""" population: psychiatric symptoms, quality of life, and measures of neuropsychological functions. If the results of this study confirm the preliminary data, they could suggest a new use for CLOZ, one that could have important public health implications.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
Project #
Application #
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Montoya, Ivan
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Harvard University
Schools of Medicine
United States
Zip Code
Brunette, Mary F; Dawson, Ree; O'Keefe, Christopher D et al. (2011) A randomized trial of clozapine vs. other antipsychotics for cannabis use disorder in patients with schizophrenia. J Dual Diagn 7:50-63
Green, Alan I; Noordsy, Douglas L; Brunette, Mary F et al. (2008) Substance abuse and schizophrenia: pharmacotherapeutic intervention. J Subst Abuse Treat 34:61-71
Riggs, Paula; Levin, Frances; Green, Alan I et al. (2008) Comorbid psychiatric and substance abuse disorders: recent treatment research. Subst Abus 29:51-63
Green, Alan I; Drake, Robert E; Brunette, Mary F et al. (2007) Schizophrenia and co-occurring substance use disorder. Am J Psychiatry 164:402-8
Green, Alan I (2007) Pharmacotherapy for schizophrenia and co-occurring substance use disorders. Neurotox Res 11:33-40
Roth, Robert M; Brunette, Mary F; Green, Alan I (2005) Treatment of substance use disorders in schizophrenia: a unifying neurobiological mechanism? Curr Psychiatry Rep 7:283-91
Green, Alan I; Tohen, Mauricio F; Hamer, Robert M et al. (2004) First episode schizophrenia-related psychosis and substance use disorders: acute response to olanzapine and haloperidol. Schizophr Res 66:125-35
Noordsy, Douglas L; Green, Alan I (2003) Pharmacotherapy for schizophrenia and co-occurring substance use disorders. Curr Psychiatry Rep 5:340-6
Green, Alan I; Burgess, Ellen S; Dawson, Ree et al. (2003) Alcohol and cannabis use in schizophrenia: effects of clozapine vs. risperidone. Schizophr Res 60:81-5
Green, Alan I; Canuso, Carla M; Brenner, Mark J et al. (2003) Detection and management of comorbidity in patients with schizophrenia. Psychiatr Clin North Am 26:115-39

Showing the most recent 10 out of 11 publications