 Experimental Design and Methods: This randomized, double blind, double-dummy, placebo-controlled, within- and between-subject study evaluates the effects of oral THC and oromucosal administration of SativexRegistered Trademark on brain activation and subjective, affective, cognitive, and physiologic measures. Cannabis users undergo a thorough medical, psychiatric including structured diagnostic interview, and psychosocial including Addiction Severity Index evaluation. They enter the research unit the morning of the dosingscanning session. Each cannabis-using participant receives, in random order, synthetic THC 5 mg, synthetic THC 15 mg, two actuations of SativexRegistered Trademark 5.4 mg THC and 5.0 mg cannabidiol, six actuations of SativexRegistered Trademark 16.2 mg THC and 15.0 mg cannabidiol, and placebo. There is an interval of at least five days between dosing sessions. Physiological, psychological, and behavioral measures are monitored throughout the study to determine onset, magnitude, and duration of effects and to correlate with THC and cannabidiol pharmacokinetics. Changes in BOLD signal in multiple brain areas are determined with five fMRI scans during the completion of cognitive tasks and affective measures after cannabinoid and placebo administration. Eighteen controls undergo neuroimaging, psychological, and behavioral monitoring as do cannabis users to control for practice effects. Primary outcome measures include changes in physiologic effects, subjective effects, BOLD signal, affect, and cognitive task performance in relation to THC, CBD, and metabolites plasma concentrations. Secondary objectives are to monitor the disposition of THC, CBD, and metabolites in plasma, urine, and oral fluid. Primary statistical analysis for changes in affect, cognitive performance, and physiologic and subjective effects is a within-subject analysis of variance ANOVA or equivalent analysis. Changes in BOLD signal determined by fMRI are compared between groups and dosing conditions using repeated-measures ANOVA. Based upon power analyses, we estimate needing 18 cannabis users and 18 controls to complete the experiment. 