Cannabis sativa contains over sixty cannabinoids, including ∆-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). CBD lacks psychoactivity and may attenuate the subjective effects produced by THC. Sativex, a whole-plant cannabinoid extract oromucosal spray, contains THC and CBD in a ratio of nearly 1:1. It was approved by Health Canada in 2005 as a prescription medication for neuropathic pain in multiple sclerosis (MS) and will be evaluated in Phase III trials in the U.S. in patients with advanced cancer for the treatment of pain refractory to opiates. No studies have examined changes in regional brain activity with functional magnetic resonance imaging (fMRI) during completion of cognitive tasks or affective measures after administration of Sativex. We seek to characterize physiological and affective condition, subjective state, cognitive performance, and concomitant changes in activation of specific brain regions (blood oxygen level-dependent BOLD signal) with fMRI after oromucosal administration of Sativex and oral administration of THC. Our secondary objective is to characterize the pharmacokinetics of THC and CBD and metabolites in plasma, urine, and oral fluid. Participants receive synthetic THC 5 mg, synthetic THC 15 mg, two actuations of Sativex (5.4 mg THC and 5.0 mg cannabidiol), six actuations of Sativex (16.2 mg THC and 15.0 mg cannabidiol), and placebo in random order. 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.