Emotions and brain function are altered up to one month after a single high dose of psilocybin

Abstract

Psilocybin is a classic psychedelic compound that may have efficacy for the treatment of mood and substance use disorders. Acute psilocybin effects include reduced negative mood, increased positive mood, and reduced amygdala response to negative affective stimuli. However, no study has investigated the long-term, enduring impact of psilocybin on negative affect and associated brain function. Twelve healthy volunteers (7F/5M) completed an open-label pilot study including assessments 1-day before, 1-week after, and 1-month after receiving a 25 mg/70 kg dose of psilocybin to test the hypothesis that psilocybin administration leads to enduring changes in affect and neural correlates of affect. One-week post-psilocybin, negative affect and amygdala response to facial affect stimuli were reduced, whereas positive affect and dorsal lateral prefrontal and medial orbitofrontal cortex responses to emotionally-conflicting stimuli were increased. One-month post-psilocybin, negative affective and amygdala response to facial affect stimuli returned to baseline levels while positive affect remained elevated, and trait anxiety was reduced. Finally, the number of significant resting-state functional connections across the brain increased from baseline to 1-week and 1-month post-psilocybin. These preliminary findings suggest that psilocybin may increase emotional and brain plasticity, and the reported findings support the hypothesis that negative affect may be a therapeutic target for psilocybin.

Figure 1

Longitudinal effects of a single high dose of psilocybin on amygdala and anterior cingulate response to facial emotional stimuli. Percentage of BOLD signal change (on the ordinate) for the [emotion > all stimuli] contrast are plotted for each emotional condition (angry, fearful, happy, neutral, and sad). Each panel of the figure presents contrast values for a different region of interest. Error bars are standard error. Dark blue bars plot values for baseline, turquoise bars plot values for 1 week post-psilocybin, and yellow bars for 1 month post-psilocybin. ACC: anterior cingulate cortex.

Figure 2

Longitudinal effects of a single high dose of psilocybin on brain response to high conflict trials in the emotional conflict Stroop task. T-values from whole-brain voxel-wise contrasts for high-demand incongruent (CI) greater than low-demand congruent (CC) trials [CI > CC] are presented for (A) 1 week post-psilocybin compared to baseline, (B) 1 month post-psilocybin compared to baseline, and (C) 1 week post-psilocybin compared to 1 month post-psilocybin. Each panel contains sagittal, coronal, and axial slices that display the significant clusters that were observed in the whole-brain general linear model analysis, with the in-plane coordinate for a given slice found in the top left-hand corner of each slice. Significant clusters in each slice are circled in yellow. CI: an incongruent Stroop trial that followed a congruent Stroop trial – this is a high-demand trial, as the trial involves both incongruent emotional information as well as a response-switch from responding to a congruent trial to responding to an incongruent trial; CC: a congruent Stroop trial that followed another congruent Stroop trial – this is a low-demand trial, as the trial involves congruent emotional stimuli and does not require response-switching from the previous trial.

Figure 3

Longitudinal effects of a single high dose of psilocybin on the strength of static functional brain connectivity. Static functional connections (edges) that significantly increase (red lines) or decrease (blue lines) in strength (A) at 1 week compared to baseline, (B) at 1 month compared to baseline, and (C) at 1 week compared to 1 month are plotted in circle brains (https://bioimagesuiteweb.github.io/webapp/connviewer.html). The left and right side of each panel represents left and right hemispheres of the brain, respectively. Each dot in the inner ring of dots in each hemisphere corresponds to a node or region of interest within the brain, and the outer band of color provides a color code indicating the lobe of the brain within which each node resides. Color to lobe mapping is provided in the inset legend. Each edge is significantly different between time points (p < 0.05 after correction for multiple comparisons using the Bonferroni method).

Figure 4

Effects of psilocybin on edge-wise and network-based static functional connectivity. (A) Static functional connectivity is shown for all pairwise functional connections (268 nodes × 268 nodes = 35,778 edges) at each time point. Each row and each column represents a single node (ROI) as defined by the Shen 268-node functional brain atlas. The color of each off-diagonal cell in the connectome matrix represents the Pearson correlation value (r) for each edge (between the given nodes) in the brain. Nodes are grouped together in rows and columns by network as defined in the Shen atlas, with black lines marking the border between networks in the matrix. (B) Differences in static functional connectivity are shown within and between canonical networks for 1 Week > Baseline, 1 Month > Baseline, and 1 Week > 1 Month. Each row and column represents a single brain network as defined by the Shen 268-node functional brain atlas. The diagonal cells represent differences in within-network connectivity between time points, and off-diagonal cells represent differences in between-network connectivity between time points. MF = medial frontal network, FP = frontoparietal network, DM = default mode network, SubC = subcortical-cerebellum network (including the salience network), SM = somatosensory-motor network, MedV = medial visual network, OccP = occipital pole network, and LatV = lateral visual network.