Psychopharmacology (2012) 219:981–990 Table 2 Physiological and behavioral effects of placebo and THC (mean± SD) Heart rate (beats per minute) VAS feeling high VAS internal perception VAS external perception VAS alertness VAS contentedness VAS calmness Placebo 68.9±8.5 0.2±0.8 −0.4±1.5 1.5±2.5 −1.5±7.8 −1.5±4.7 1.5±7.9 THC 83.8±20.8 19.5±19.9 1.3 ±2.7 6.7 ±9.6 −10.6±9.7 −4.2 ±4.8 1.8 ±10.7 p 0.018a 0.009a 0.086 0.13 0.028a 0.11 0.94 a Significant difference between THC and placebo decreased “alertness” (F(1,10) = 6.6, p < 0.03) and induced a trend towards increased “internal perception” (reflecting inner feelings that do not correspond with reality) (F(1,10) = 3.6, p < 0.09) (see Table 2). Performance MID task Repeated-measures ANOVA with drug (two levels) and condition (two levels) as within-subject factors showed a significant effect of condition (F(1,10) = 22.0, p = 0.001), indicating that subjects were faster on reward trials than on neutral trials, and a near significant effect of drug (F(1,10) = 4.5, p = 0.06), indicating that subjects were slower after THC administration compared to placebo (see Fig. 2). A post hoc paired t test per condition indicated that this effect was most pronounced during reward trials (t = 2.2, p = 0.051). fMRI results Anticipation ANT ROIs included left and right caudate nucleus, left and right parietal cortex, middle cingulate, left and right cerebellum, left pre/postcentral gyrus, left insula, anterior cingulate/supplementary motor area, right inferior orbito- frontal gyrus, right middle and inferior frontal gyrus, and the thalamus/brain stem (see Fig. 3a and Figure S1 and Table S1a). Repeated-measures MANOVA revealed no significant effect of drug (F = 0.01, p = 0.9) or drug by condition (F = 0.03, p = 0.9) (see Fig. 4a). A significant drug by condition by ROI interaction effect (F = 2.5, p < 0.05) indicated that drug by condition effects differed between ROIs. Follow-up analysis per ROI (not corrected for multiple comparisons) revealed no significant drug effect in individual ROIs. One ROI, the right inferior orbitofrontal gyrus, showed a significant drug by condition interaction effect (F = 7.9, p < 0.05; see Fig. 4b and Table S1b). This interaction was a 985 result of a larger signal increase in anticipation of a reward after THC administration than after placebo administration. However, the individual ROI effect did not survive correction for multiple comparisons. Feedback FB ROIs included the inferior parietal and temporal gyrus bilaterally, posterior and anterior cingulate, middle orbito- frontal gyrus, and right superior frontal gyrus (see Fig. 3b and Figure S2 and Table S2a). No differences were found in FB ROIs between THC and placebo during neutral feedback (see Fig. 5a). A repeated-measures MANOVA showed that during reward trials, THC administration caused a significant reduction in reward-related brain activity (drug effect, F = 13.1; p < 0.01; see Fig. 5a), indi- cating that THC reduced the signal for hits as well as misses. Further analysis per ROI (not corrected for multiple comparisons; see Fig. 5b and Table S2b) showed that this main drug effect was present in the left inferior parietal cortex (F = 5.5, p < 0.05), inferior temporal gyrus bilaterally (left, F = 8.2, p < 0.05 and right, F = 7.4, p < 0.05), and at trend level in the posterior cingulate (F = 4.8, p < 0.1) and right inferior parietal cortex (F = 4.2, p < 0.1). In addition, an overall interaction effect of drug by condition by ROI (F = 4.6; p = 0.001) was found, indicating that the drug by condition effect differed between ROIs. This interaction was a result of the fact that two different drug by condition interaction effects were found in individual ROIs: THC decreased the signal Fig. 2 Performance of the MID task. Error bars denote Standard Error of the Mean (SEM)