Cannabis dependence remains a major public health problem in young adults under 30 years of age. Onereason may be that cannabis use decreases executive functioning, creating a vulnerability to fail to inhibitmaladaptive behaviors, such as using drugs. It is our hypothesis that greater severity of cannabisdependence is associated clinically with greater severity of impairment on neuropsychological tasks involvingexecutive functioning, operationally defined center-wide as mental control, initiative and fluency, selfmonitoring,working memory and attention, and inhibition.
Specific Aim # 1: To characterize the severity of cannabis dependence on subjective (e.g., anxiety, craving)and objective (e.g. plasma ACTH, cortisol, MHPG) measures using precipitated withdrawal followingadministration of the CBI cannabinoid receptor antagonist, rimonabant, or placebo in adult volunteers withcannabis dependence in a double-blind randomized design. THC concentrations and neurochemicalmeasures that parallel emotional measures of withdrawal may inform pre-clinical studies in Components 3and 4.
Specific Aim # 2: To determine the presence and persistence of impairment on CANTAB tasks ofexecutive function relative to severity of cannabis dependence (see Specific Aim # 1) in young adultvolunteers with cannabis dependence relative to normal controls.
Specific Aim # 3: To identify the presenceand persistence of abnormality in brain activity relative to severity of cannabis dependence (see Specific Aim# 1) using fMRI with probes of frontal cortex function developed with Dr. Tapert in Component 2. Toaccomplish these aims, a 28-day longitudinal study will be conducted with two primary components: 1.) asingle-dose, double-blind, placebo-controlled study of precipitated cannabis withdrawal in the laboratoryusing the CBI receptor antagonist, rimonabant 90 mg po, followed by four weekly assessments of keysymptoms of cannabis withdrawal in a naturalistic setting, and 2.) neuropsychological assessment and fMRIwith task stimuli selected for sensitivity to cannabis-related impairment, administered on the first andfollowing 28 days of monitored abstinence in a naturalistic environment. Subjects will be 40 young adultswith cannabis dependence and 20 demographically similar non-using controls. Consistent with thetranslational objectives of the Center, tasks are derived from the Cambridge Neuropsychological TestAutomated Battery (CANTAB) to permit cross-species comparison with non-human primates studied inComponent 3 (Taffe) and teens in Component 2 (Tapert). The unique collaboration between parallel teenand non-human primate projects will facilitate the overall Center objective of identifying neurobiologicalmechanisms through which developmental stage and pattern of cannabis exposure intersect to impairexecutive cognitive functioning, thereby increasing vulnerability to cannabis dependence.
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