Cannabis is the most used illicit substance in the United States. Previous studies suggest that atypical antipsychotics decrease the frequency and the amount of substance use in subjects with and without psychotic illness. So far, there are no controlled studies assessing the effectiveness of atypical antipsychotics for decreasing cannabis and other substance use in individuals with cannabis use disorders. The investigators postulate that the atypical antipsychotic quetiapine ER is an effective agent for improving substance use outcomes in subjects with cannabis use disorders. In this pilot study, the investigators will test this hypothesis in heavy cannabis users (i.e., individuals who are cannabis dependent and smoke three times or more per week). Because 50% of these heavy cannabis users report histories of psychotic experiences (i.e., attenuated positive symptoms) while smoking and are at risk for recurring psychotic symptoms, the investigators will focus this pilot clinical trial on this subgroup of cannabis users in order to increase the risk/benefit ratio of this study and target a population that may also benefit from the antipsychotic effect of quetiapine ER. Considering the lack of controlled studies assessing the efficacy of atypical antipsychotics in heavy cannabis users, assessing the effectiveness of an atypical antipsychotic medication on substance use and clinical outcomes in this population is critical for improving the prognosis of these individuals.

Thus, the aims of this randomized, double-blind, placebo-controlled study are to assess the efficacy of an atypical antipsychotic (quetiapine ER) in 120 subjects with cannabis dependence, a recent history (within a year) of attenuated psychotic symptoms, and using cannabis 3 times or more per week for: (1) decreasing the use of cannabis and other substances; and (2) preventing the recurrence of psychotic experiences. The investigators will also assess the effects of quetiapine ER on craving and mood, and its tolerability. This project will be a 12-week, randomized, double-blind, placebo-controlled study with quetiapine ER and it will include a comprehensive assessment of symptoms, substance use, and side effects.

This study will benefit the field by providing unique data on the relative efficacy and tolerability of treatment with atypical antipsychotics in heavy cannabis users with a vulnerability to psychosis. This study will be the basis for future studies assessing the long-term efficacy and tolerability of atypical antipsychotics in individuals with cannabis use disorders.

Inclusion Criteria:

• DSM-IV-defined diagnosis of cannabis dependence (304.30) assessed with the Structured Clinical Interview for Axis I DSM-IV Disorders (SCID-I/P) (First 1998))
• one or more attenuated positive symptoms with a score 3 ('moderate'), 4 ('moderate severe'), or 5 ('severe but not psychotic') during the past year assessed with the Structured Interview for Prodromal Syndromes (SIPS) and the Scale of Prodromal Symptoms (SOPS) (McGlashan et al, 2001)
• lifetime treatment with antipsychotic medication less than 2 weeks
• cannabis use for more than one year
• cannabis use three or more days per week on average for the past 3 months
• aged 18 to 65
• competent and willing to sign informed consent
• for women, a negative urine pregnancy test and agreement to use a medically accepted method of birth control during the study.

Exclusion Criteria:

• DSM-IV criteria for schizophrenia, schizophreniform disorder, schizoaffective disorder, a psychotic disorder due to a general medical condition, psychosis NOS, delusional disorder, brief psychotic disorder, shared psychotic disorder, or a mood disorder (major depression or bipolar) with psychotic features assessed with the Structured Clinical Interview for Axis I DSM-IV Disorders (SCID-I/P) (First 1998)
• DSM-IV diagnosis of any psychoactive substance dependence other than cannabis or nicotine
• being in an environment with no access to cannabis (e.g., hospitalization, residential treatment, jail, ..) for more than one week during the past three months preceding study entry
• serious neurological or endocrine disorder or any medical condition or treatment known to affect the brain
• use of medications that have an effect on monoamines (e.g., antidepressants
• severe medical or physical illnesses
• criteria of the National Cholesterol Education Program (NCEP) for a metabolic syndrome (Expert panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, 2001)
• medical condition that requires treatment with a medication that has psychotropic effects
• significant risk of suicidal or homicidal behavior
• cognitive or language limitations, or any other factor that would preclude subjects providing informed consent or participating in study procedures
• treatment with medications for addiction
• treatment with medication having a risk of addiction (e.g., benzodiazepines, barbiturates)
• history of treatment resistance to quetiapine ER
• medical contraindications to quetiapine ER
• hypersensitivity to quetiapine ER or any of its component
• for women, pregnant, breastfeeding, or intention to become pregnant during the study timeframe