Animal and human studies indicate that cannabidiol (CBD), a major constituent of cannabis, has anxiolytic properties. However, no study to date has investigated the effects of this compound on human pathological anxiety and its underlying brain mechanisms. The aim of the present study was to investigate this in patients with generalized social anxiety disorder (SAD) using functional neuroimaging. Regional cerebral blood flow (rCBF) at rest was measured twice using (99m)Tc-ECD SPECT in 10 treatment-naïve patients with SAD. In the first session, subjects were given an oral dose of CBD (400 mg) or placebo, in a double-blind procedure. In the second session, the same procedure was performed using the drug that had not been administered in the previous session. Within-subject between-condition rCBF comparisons were performed using statistical parametric mapping. Relative to placebo, CBD was associated with significantly decreased subjective anxiety ( p < 0.001), reduced ECD uptake in the left parahippocampal gyrus, hippocampus, and inferior temporal gyrus ( p < 0.001, uncorrected), and increased ECD uptake in the right posterior cingulate gyrus ( p < 0.001, uncorrected). These results suggest that CBD reduces anxiety in SAD and that this is related to its effects on activity in limbic and paralimbic brain areas.