CLIN & NEUROBIOL EFFECTS OF CANNABIS DEPENDENCE IN YOUNG ADULTS

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Cannabis dependence remains a major public health problem in young adults under 30 years of age. One reason may be that cannabis use decreases executive functioning, creating a vulnerability to fail to inhibit maladaptive behaviors, such as using drugs. It is our hypothesis that greater severity of cannabis dependence is associated clinically with greater severity of impairment on neuropsychological tasks involving executive 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 following administration of the CBI cannabinoid receptor antagonist, rimonabant, or placebo in adult volunteers with cannabis dependence in a double-blind randomized design. THC concentrations and neurochemical measures that parallel emotional measures of withdrawal may inform pre-clinical studies in Components 3 and 4. Specific Aim # 2: To determine the presence and persistence of impairment on CANTAB tasks of executive function relative to severity of cannabis dependence (see Specific Aim # 1) in young adult volunteers with cannabis dependence relative to normal controls. Specific Aim # 3: To identify the presence and 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. To accomplish these aims, a 28-day longitudinal study will be conducted with two primary components: 1.) a single-dose, double-blind, placebo-controlled study of precipitated cannabis withdrawal in the laboratory using the CBI receptor antagonist, rimonabant 90 mg po, followed by four weekly assessments of key symptoms of cannabis withdrawal in a naturalistic setting, and 2.) neuropsychological assessment and fMRI with task stimuli selected for sensitivity to cannabis-related impairment, administered on the first and following 28 days of monitored abstinence in a naturalistic environment. Subjects will be 40 young adults with cannabis dependence and 20 demographically similar non-using controls. Consistent with the translational objectives of the Center, tasks are derived from the Cambridge Neuropsychological Test Automated Battery (CANTAB) to permit cross-species comparison with non-human primates studied in Component 3 (Taffe) and teens in Component 2 (Tapert). The unique collaboration between parallel teen and non-human primate projects will facilitate the overall Center objective of identifying neurobiological mechanisms through which developmental stage and pattern of cannabis exposure intersect to impair executive cognitive functioning, thereby increasing vulnerability to cannabis dependence.