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

This open-label (n=12) study investigated brain function (increased plasticity) and positive and negative affect. After a high dose of psilocybin (25mg/70kg), the positive effect increased and stayed elevated. Negative effects returned to normal at 1-month.

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.”

Authors: Frederick S. Barrett, Manoj K. Doss, Nathan D. Sepeda, James J. Pekar & Roland R. Griffiths

Notes

This paper (and a few others) were reflected on in this blog post on Medium.

Summary

Studies suggest that psilocybin, a classic psychedelic drug, may have efficacy for the treatment of depression and anxiety. The neural and psychological mechanisms underlying the enduring therapeutic effects of psychedelic drugs are not well-understood.

Increased negative affect, reduced positive affect, and hypersensitivity to negatively biased information are hallmarks of mood disorders and are also a core component of the cycle of addiction. The amygdala and anterior cingulate cortex are implicated in supporting aberrant negative affect in substance use disorders.

Psychedelic drugs have been shown to reduce processing of negative affective stimuli and increase positive mood in humans. These effects may be sustained after other acute effects of psychedelic drugs have resolved.

Neuroimaging evidence suggests that psychedelic drugs affect emotion perception through modulation of amygdala response to negative affective stimuli, but recent qualitative and self-report evidence suggests that psychedelic drugs may also affect emotion perception through changes in top-down control of emotion.

Psychedelics have been shown to decrease resting-state connectivity within the default mode network (DMN) and between and within a number of sensory and cognitive brain networks, and may also increase connectivity within higher-order cortical brain networks.

A high dose of psilocybin, administered one day before, one week after, and one month after, increased positive affect, reduced negative affect, changed neural response to emotional stimuli, and changed resting state functional connectivity. Participants completed the Big Five Inventory, the Tellegen Absorption Scale, and three separate emotion processing tasks one day before, one week after, and one month after psilocybin. The enduring effects of psilocybin were determined to be in the amygdala and ACC.

psilocybin reduced negative affect and increased positive affect, and reduced stress, negative affect, anxiety, tension, depression, and total mood disturbance 1 week after psilocybin, and returned towards baseline ratings 1 month after psilocybin.

Main effects of time point were observed on DPES joy, content, pride, compassion, and amusement scales. Post-hoc tests demonstrated that DPES scores were significantly greater both 1 week and 1 month after psilocybin compared to baseline.

Psilocybin led to changes in the neural response to affective stimuli, but no effect of condition, timepoint, or interaction between timepoint and condition was observed.

ROI analysis revealed that timepoint had a main effect on BOLD response to stimuli in the emotion recognition task in left amygdala, right amygdala, and left ACC, but not right ACC. Post-hoc comparisons demonstrated that left and right amygdala responses to facial stimuli were reduced at 1 week, but returned to baseline levels at 1 month. There was no significant difference in left or right amygdala response to emotional stimuli across time.

Performance accuracy was near ceiling at baseline and increased from baseline to 1 week and 1 month after psilocybin. No significant effects were observed in amygdala or ACC response to the emotion discrimination task.

Psilocybin increased neural response to conflicting emotional information in decision-making circuits, and participants performed at ceiling across all timepoints in the emotional conflict Stroop task.

A contrast of high-demand incongruent trials that follow congruent trials can alter cognitive control processes. Greater BOLD response was observed in dorsal lateral prefrontal (DLPFC) and medial orbitofrontal (MOFC) cortex, and in somatosensory cortex and fusiform gyrus at 1 week compared to 1 month after psilocybin.

Psilocybin had significant effects on several self-report measures of affect, including depression, anxiety, and stress.

Psilocybin increases resting state functional connectivity across brain networks. This increase was evenly distributed across different brain lobes and networks, and there were more numerical increases than numerical decreases in functional connectivity within and between networks one week and one month after psilocybin.

Discussion

A single high dose of psilocybin decreased negative affect, decreased amygdala responses to emotional stimuli, increased reward-learning, attention, and decision-making circuits, and increased functional connectivity at both 1 week and 1 month post-psilocybin.

The effects of psilocybin on the amygdala and anterior cingulate cortex were observed well after psilocybin would have been eliminated from the body and beyond expected transient effects of receptor trafficking that may be occurring after psilocybin administration.

The neuroplastic period during which psilocybin administration alters the neural processing of affective stimuli may explain the sustained effects of psilocybin on affect and brain function.

A single high dose of psilocybin improved the response of the human brain to high conflict trials in the emotional conflict Stroop task, as shown by the increased number of significant clusters in the 1 week post-psilocybin compared to baseline, 1 month post-psilocybin compared to 1 month post-psilocybin analysis.

Psilocybin increases the top-down control of emotional processes by increasing the activity of the DLPFC and OFC. The MOFC and DLPFC have dense bidirectional structural connections that facilitate top-down modulation of salience detection and reward learning.

A single high dose of psilocybin improved brain response to high conflict trials in the emotional conflict Stroop task, with significant differences between 1 week and baseline and 1 week and 1 month.

The longitudinal effects of a single high dose of psilocybin on the strength of static functional brain connectivity are shown in Figure 3. The strength of these connections significantly increased or decreased at 1 week, 1 month, and 1 week after 1 month.

The suppression of amygdala response to negative affective stimuli may lead to an overall shift in affect, but no behavioral change was observed during the emotional conflict Stroop.

The fusiform gyrus is involved in interoceptive mapping and the appraisal of social emotional stimuli. It contains specialized regions that respond to facial stimuli.

Only three other studies have reported effects of a psychedelic drug that lasted beyond the acute drug effect. One such study showed increased amygdala response to negative facial affect stimuli in patients with treatment-resistant depression. A potential explanation for the short-term rebound effect in amygdala response after psilocybin administration is that serotonergic signaling is altered, with re-expression occurring up to 48 hours later. However, the current study found that increased amygdala reactivity one day after psilocybin administration was associated with therapeutic outcomes.

The current study found that connectivity across a number of brain networks was increased 1 week and 1 month post-psilocybin, and that this increase was consistent with previous reports of increased connectivity in the default mode network (DMN) one or two days after psychedelic drug administration.

Figure 4 shows that psilocybin affects edge-wise and network-based static functional connectivity in the brain. The differences in static functional connectivity between time points are shown within and between canonical brain networks for 1 Week > Baseline, 1 Month > Baseline, and 1 Week > 1 Month.

Psilocybin administration leads to increases in openness and extroversion and decreases in neuroticism. The strongest effect of psilocybin on Big-Five personality traits was an increase in conscientiousness.

Limitations include small sample size, open-label nature of study, and lack of multiple time points prior to psilocybin administration. However, moderate to strong effect sizes were observed across both self-report and neurobiological outcomes.

conclusions

Psilocybin administration may lead to shifts in affect and the neural correlates of affective processing that endure beyond acute drug effects. These changes may underlie both mood and substance use disorders.

While negative affect and brain response to affective stimuli were reduced 1 week after psilocybin, they rebounded at the 1 month timepoint, suggesting that psilocybin may have initiated a dynamic and neuroplastic process.

Twelve volunteers, 7 females, mean age 32.1 7.5 years, were included in this open-label, within-subjects, longitudinal pilot study. They were medically healthy and psychiatrically healthy, and had negative urine pregnancy tests and common drugs of abuse tests.

The sample was racially homogenous, had a Bachelor’s degree or higher, and reported limited lifetime use of hallucinogens. All participants provided informed consent and were compensated $240 upon completion of the study.

Methods

Participants underwent preparation, acute care, and aftercare for psilocybin administration sessions following published safety guidelines. They completed a single psilocybin administration session lasting roughly 7 hours and using established procedures91 based on several previous and ongoing studies with healthy participants89,92 – 95 and clinical populations1,4.

Psilocybin was administered to participants in a study at the Johns Hopkins Bayview Medical Center. Blood pressure, heart rate, and staff ratings were assessed after capsule administration.

A battery of questionnaires was completed by participants one day before, one week after, and one month after psilocybin administration to assess emotional function. The Profile of Mood States (POMS)46 is a 65-item rating scale with a 5-point response format that measures tension, depression, anger, fatigue, confusion, vigor, and total mood disturbance. The Dispositional Positive Emotions Scale (DPES) is a 38-item Likert scale with a 7-point response format, the Depression Anxiety Stress Scale (DASS) is a 21-item rating scale with a 4-point response format, and the State-Trait Anxiety Inventory (STAI) is a 40-item rating scale with a 4-point response format.

Participants completed measures of personality at screening and again one month after psilocybin. The Tellegen Absorption Scale is a 34-item rating scale with a 4-point response format.

Participants completed the emotion discrimination, emotion recognition, and emotional conflict Stroop tasks on a 3T Philips MRI scanner, and their blood-oxygenation level-dependent (BOLD) signal was measured using echo-planar imaging.

Brain Imaging at the Kennedy Krieger Institute in Baltimore, MD was used to measure facial emotional processing during MRI. Stimuli were presented on a Plexiglas shield and participants made responses using a fiber-optic, MR-safe response device.

Participants viewed an array of three images containing either three emotional (fearful or angry) facial expressions or three geometric shapes. They completed four 30 s blocks of face-matching trials interleaved between five 30 s blocks of shape-matching trials.

Participants were presented with 60 facial expressions, 12 for each emotion, and were instructed to press a button to identify the emotion expressed on each face.

Emotional conflict Stroop requires participants to identify the valence of emotional facial expressions with overlaid emotional words. Stimuli are pseudorandomized to control for the order of congruent and incongruent stimuli, balancing for order effects across gender and emotional valence of the target stimulus.

Self-report questionnaires were used to determine the persisting effects of psilocybin on self-report affect measures. Paired t-tests were used to test for changes in personality measures between screening and 1-month post-psilocybin.

Preprocessing and analysis of task-based BOLD data was performed on all fMRI scans to determine the response of the left and right amygdala and left and right ACC to task conditions in each fMRI task.

Subject-level GLM design matrices consisted of six motion parameters, a motion sensoring regressor, a linear term to model signal drift, and regressors of interest for each task. For the emotion discrimination task, face blocks and shape blocks were regressed, and an emotion greater than all stimulus contrast was fit for each emotional condition. For the emotional conflict Stroop task, incongruent trials were regressed, and two contrasts were fit for high-demand incongruent trials.

SPM12, MaRSBaR, and MATLAB were used to conduct GLM analyses, and a one-way ANOVA was fit to subject-level ROI contrasts to determine a main effect of time-point on BOLD response in each ROI for each task.

Resting state fMRI data were preprocessed and nuisance parameters were regressed, then parcellated using the Shen 268-node functional brain atlas. One subject was excluded from resting state analysis for missing resting-state data from the 1 week time-point.

Static functional connectivity between each edge was calculated using Pearson correlations. Significant edges were identified using separate one-sample t tests across participants for each edge and timepoint, and contrasted between time points using paired t tests.

Two resting-state scans were collected at each MRI visit, and the edges of eight canonical functional networks were averaged and compared across time points to explore within and between network differences.

Acknowledgements

This work was supported by the National Institute on Drug Abuse (NIDA), the Heffter Research Institute, the Steven and Alexandra Cohen Foundation, and the NIH.

Author contributions

F.S.B. secured funding, conceptualized, designed, and performed the experiment, M.D. analyzed the data and wrote the manuscript, and N.S. performed the experiment.

Additional information

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