Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin

Abstract

Psychedelic drugs have a long history of use in healing ceremonies, but despite renewed interest in their therapeutic potential, we continue to know very little about how they work in the brain. Here we used psilocybin, a classic psychedelic found in magic mushrooms, and a task-free functional MRI (fMRI) protocol designed to capture the transition from normal waking consciousness to the psychedelic state. Arterial spin labeling perfusion and blood-oxygen level-dependent (BOLD) fMRI were used to map cerebral blood flow and changes in venous oxygenation before and after intravenous infusions of placebo and psilocybin. Fifteen healthy volunteers were scanned with arterial spin labeling and a separate 15 with BOLD. As predicted, profound changes in consciousness were observed after psilocybin, but surprisingly, only decreases in cerebral blood flow and BOLD signal were seen, and these were maximal in hub regions, such as the thalamus and anterior and posterior cingulate cortex (ACC and PCC). Decreased activity in the ACC/medial prefrontal cortex (mPFC) was a consistent finding and the magnitude of this decrease predicted the intensity of the subjective effects. Based on these results, a seed-based pharmaco-physiological interaction/functional connectivity analysis was performed using a medial prefrontal seed. Psilocybin caused a significant decrease in the positive coupling between the mPFC and PCC. These results strongly imply that the subjective effects of psychedelic drugs are caused by decreased activity and connectivity in the brain's key connector hubs, enabling a state of unconstrained cognition.

Fig. 1.

Subjective ratings (n = 30). Displayed are mean values + SEs. Ratings were given shortly after the scans. Subjects were instructed that “no more than usually” refers to normal waking consciousness. All 10 items were scored significantly higher after psilocybin than placebo (P < 0.01).

Fig. 2.

Decreased CBF after psilocybin (ASL perfusion fMRI). Regions where there was significantly decreased CBF after psilocybin versus after placebo are shown in blue (z: 2.3–3.7). Mixed effects analysis, z > 2.3, P < 0.05 whole-brain cluster-corrected, n = 15. LH, left hemisphere; RH, right hemisphere. Note, we observed no increases in CBF in any region.

Fig. 3.

Group CBF changes over time (Left) and CBF vs. subjective effects (Right). Plots on the left show blood flow changes over time for the thalamus, ACC, and PCC. These plots were made by calculating the postinfusion change in CBF as a percentage of the preinfusion CBF. This process was done for each ROI for each individual subject and then the group mean was plotted. Note, these plots are shown for display purposes; error bars are not included because the inclusion of error is implicit in the statistical parametric maps shown in Fig. 2. Plots on the right show the relationship between ROI CBF changes after psilocybin-infusion for each subject and their ratings of the intensity of the subjective effects given 5- and 12-min postinfusion (plotted are the average of these two ratings). There was a significant negative correlation between ACC CBF change postpsilocybin and intense subjective effects (Pearson's correlation, r = −0.55, P = 0.017, one-tailed) and CBF vs. intensity met a trend level significance for the thalamus and PCC (P < 0.01).

Fig. 4.

Brain deactivations after psilocybin. (Upper) Regions where there was a significant decrease in the BOLD signal after psilocybin versus after placebo (z: 1.8–3). Mixed-effects analysis, z > 1.8, P < 0.05 whole brain cluster corrected, n = 15. (Lower) Regions where there was a consistent decrease in CBF and BOLD after psilocybin. For display purposes, significant BOLD decreases were calculated within a mask based on the ASL result (Fig. 2) at an uncorrected voxel level threshold of P = 0.05. Note, we observed no increases in CBF or BOLD signal in any region.

Fig. 5.

Psilocybin-induced changes in vmPFC (red) functional connectivity. (Top) Regions where activity was positively coupled to that of the vmPFC are shown in orange and regions where activity was “negatively” coupled to activity in the vmPFC are shown in blue (it should be noted however, that the appearance of negative connectivity is forced by regression of the global signal). (Middle) Significant increases (orange) and decreases (blue) in functional connectivity after psilocybin infusion. (Bottom) Increases and decreases in functional connectivity after psilocybin that were significantly greater than any connectivity changes after placebo. All analyses were mixed effects, z > 2.3, P < 0.05 whole-brain cluster corrected, n = 15. Note: The significant psycho-physiological interactions in the posterior PCC and left lateral parietal region suggest that the positive coupling (under placebo) has decreased significantly. This finding should not necessarily be interpreted as a negative coupling, simply a significant decrease in a positive coupling.