Lasting effects of a single psilocybin dose on resting-state functional connectivity in healthy individuals

This fMRI study (n=10) found that a single dose of psilocybin (14-21mg/70kg) decreased the executive control network (ECN) one week later, but didn’t elicit other lasting (neuronal) effects at that time and at 3-months follow-up. The changes correlated with an increase in mindfulness at the 3-month mark. But other changes (in resting-state functional connectivity, RSFC) have yet to be found.

Abstract

“Background Psilocybin is a psychedelic drug that has shown lasting positive effects on clinical symptoms and self-reported well-being following a single dose. There has been little research into the long-term effects of psilocybin on brain connectivity in humans.

Aims Evaluate changes in resting-state functional connectivity (RSFC) at one week and three months after one psilocybin dose in 10 healthy psychedelic-naïve volunteers and explore associations between change in RSFC and related measures.

Methods Participants received 0.2-0.3 mg/kg of psilocybin in a controlled setting. Participants completed resting-state fMRI scans at baseline, one week and three months post-administration and [¹¹C]Cimbi-36 PET scans at baseline and one week. We examined changes in within-network, between-network and region-to-region RSFC. We explored associations between changes in RSFC and psilocybin-induced phenomenology as well as changes in psychological measures and neocortex serotonin 2A receptor binding.

Results Psilocybin was well tolerated and produced positive changes in well-being. At one week only, the executive control network (ECN) RSFC was significantly decreased (Cohen’s d=-1.73, p_FWE=0.010). We observed no other significant changes in RSFC at one-week or three-months, nor changes in region-to-region RSFC. Exploratory analyses indicated that decreased ECN RSFC at one week predicted increased mindfulness at three months (r =-0.65).

Conclusions These findings in a small cohort indicate that psilocybin affects ECN function within the psychedelic “afterglow” period. Our findings implicate ECN modulation as mediating psilocybin-induced, long-lasting increases in mindfulness. Although our findings implicate a neural pathway mediating lasting psilocybin effects, it is notable that changes in neuroimaging measures at three months, when personality changes are observed, remain to be identified.“

Authors: Drummond E-W. McCulloch, Martin K. Madsen, Dea S. Stenbæk, Sara Kristiansen, Brice Ozenne, Peter S. Jensen, Gitte M. Knudsen & Patrick M. Fisher

Summary

Methods

Participants received 0.2-0.3 mg/kg psilocybin and completed resting-state fMRI and PET scans. We examined changes in RSFC, psychological measures and serotonin 2A receptor binding.

Results

Psilocybin was well tolerated and produced positive changes in well-being. There were no other significant changes in RSFC at one-week or three-months.

Conclusions

Psilocybin affects the executive control network (ECN) within the psychedelic “afterglow” period, and this effect is likely to mediate long-lasting increases in mindfulness.

Introduction

Psilocybin is a prodrug of the psychedelic psilocin (4-hydroxy-N,N-dimethyltryptamine). It has been used to treat a variety of disorders including major depressive disorder, treatment-resistant depression, obsessive-compulsive disorder, terminal cancer-associated anxiety, demoralisation, and smoking and alcohol addiction.

Healthy volunteers have reported persistent changes in personality and mood following a single medium-to-high dose of psilocybin. These effects have been reported to last more than a year.

Psychedelic drugs are being medicalised rapidly despite a limited understanding of the neurobiology underpinning therapeutic effects. Resting-state functional connectivity (RSFC) is a measure of the brain’s organisation into networks, which correlates with personality traits and aligns with known functional and structural topology.

During the psychedelic experience, psilocybin decreases synchronised BOLD activity of the major hubs of the default mode network, increases between-network RSFC and increases global RSFC across the sensory cortex, while decreasing global connectivity in associative regions.

Drug availability confounds relating effects to lasting changes, and previous studies have not evaluated correlations between change in RSFC and change in personality or other psychological traits.

In the current study, psilocybin altered network connectivity in 10 healthy, psychedelic naive individuals at one-week and three months after administration. We also examined whether the self-reported experience was correlated with long-term changes in brain connectivity.

Participants

The study was approved by the Danish Medicines Agency and the ethics committee for the capital region of Copenhagen.

Participants underwent screening for somatic illness, psychiatric disorders, and neurological conditions. Exclusion criteria were: present or previous primary psychiatric disease, significant somatic condition/disease, intake of drugs suspected to influence test results, non-fluent Danish language skills, and pregnancy.

Experimental Procedures

Participants were informed about the study, completed a urine test, and completed an MRI scan session. They were also given a NEO Personality Inventory-Revised and a Mindfulness Attention and Awareness Scale.

Two supportive psychologists conducted open-label psilocybin sessions including participants who listened to a standardised music playlist. Subjective drug intensity was measured every 20 mins using a 0-10 Likert scale, and questionnaires were completed at the end of the session.

Participants filled out questionnaires after their psilocybin experience, including the revised Mystical Experiences Questionnaire (MEQ30) and the Ego-Dissolution Inventory (EDI), and one week and three months after their psilocybin experience.

Positron Emission Tomography (PET)

Positron Emission Tomography (PET) data were collected from participants at baseline and one week following psilocybin administration. The non-displaceable binding potential (BPND) of [11C]Cimbi-36 was estimated using a simplified reference tissue model.

Magnetic resonance imaging scan parameters

Magnetic resonance imaging data was acquired on a 3T Prisma scanner (Siemens, Erlangen, Germany) using a 64-channel head/neck coil. Ten minutes of resting-state BOLD fMRI data was acquired after structural image acquisition (15-20 minutes after scanning onset) and prior to task-related fMRI measures not described here.

Resting-state fMRI pre-processing

Resting-state fMRI data were pre-processed using SPM12, and then the time series were filtered with a bandpass filter from 0.008 to 0.09 Hz, and then the six motion parameters were estimated and regressed. Then the mean denoised time series were extracted from regions-of-interest for further analysis.

Statistical Analysis

Statistical analyses were performed on 28 within- and between-network comparisons at each time point. The effects of time were compared separately using paired t-tests, and the Bonferroni-Holm method was used to adjust p-values.

Correlations

Correlations were performed between change in ECN connectivity and MAAS, 5-HT2AR, and personality measures, as well as between change in ECN connectivity and the psychedelic experience.

Barrett replication analysis

Barrett et al. (2020) applied a previously described analysis framework to the Shen268 atlas and found that edges with statistically significant non-zero mean connectivity after Bonferroni correction were retained for paired t-tests evaluating change from baseline at one-week or three-months.

Results

Population

Six male and four female participants participated in this study. All participants experienced well-tolerated acute psychedelic effects, and self-reported changes in personality, including increased trait openness and mindfulness.

Lasting psilocybin effects on network connectivity

Psilocybin had a short-term effect on network connectivity, with a decrease in ECN within-network connectivity at one week and an increase at three months. No other within- or between-network connectivity effects were statistically significantly altered at one week or three months.

Replication of previous study

We attempted to replicate previously reported findings from a similar study by examining the connectivity of edges based on the Shen268 atlas. We observed a similar proportion of edges showing a time effect, although fewer total edges showed evidence for significant connectivity.

Exploratory associations with ECN functional connectivity

We explored the association between ECN RSFC and self-report measures of the psychedelic experience, 5-HT2AR, personality, and persisting effects.

Associations were observed between changes in ECN functional connectivity at one-week and three-months and self-reported change in MAAS score at three-months.

Neocortex 5-HT2AR

Changes in neocortex 5-HT2AR binding were not correlated with changes in ECN connectivity at one week, but were correlated with changes in ECN RSFC at three months.

Persisting Effects Questionnaire

The positive subscales of the Persisting Effects Questionnaire loaded strongly onto a single latent construct, and were negatively associated with change in ECN RSFC.

Discussion

Psilocybin decreased ECN RSFC in healthy volunteers after one week, but not at three months. This suggests that alterations in ECN connectivity may underlie psilocybin’s clinical and behavioural effects.

Executive Control Network Connectivity

Psilocybin administration decreased executive control network connectivity, which is consistent with qualitative reports in addiction patients and long-term tai-chi practitioners. This decrease was also associated with increased trait mindfulness.

Psilocybin has been shown to be extremely efficacious in the treatment of depression, which is partly characterised by deficits in executive functions. It is unclear whether psilocybin-induced changes in connectivity would produce the well-being states described by such connectivity signatures in healthy, untreated individuals.

Psilocybin has been shown to reduce connectivity in the executive control network (ECN) in individuals with OCD and addiction, suggesting that reducing ECN connectivity may be therapeutically beneficial.

Additional Effects on Connectivity

Psilocybin induces small to medium changes in RSFC within and between networks, but not large scale changes in network connectivity structure. Thus, future studies evaluating similar effects of psilocybin on RSFC would require sample sizes >60 to be adequately statistically powered.

Psilocybin has a small effect on DMN RSFC, but this effect is not persistent. Acute disruption of the DMN may still be therapeutically relevant, and this effect is consistent with a study that scanned individuals one day after the psychedelic experience.

Associations with Executive Control Network Change

Through exploratory analyses we observed three notable associations with change in ECN RSFC. These associations included increased mindfulness score at three-months, decreased 5-HT2AR at one-week, and a latent construct of positive persisting effects, reflecting positive items from the PEQ, at three-months.

Barrett Replication

We sought to replicate recent findings from a study similar to ours, but none of the effects remained statistically significant when controlling for multiple comparisons.

Limitations

Although the sample size of 10 individuals limits statistical power, the data reported here provide a firmer foundation for future studies in clinical and healthy cohorts with larger samples. Additional studies in patient groups are needed to delineate the neurobiological basis of therapeutic effects of serotonergic psychedelics including psilocybin.

Psilocybin administration reduced executive control network connectivity at one-week but not at three-months, and may be associated with change in neocortex 5-HT2AR as well as change in mindfulness and persistent positive psychological effects.

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Figure Legends

Psilocybin effects on within- and between-network resting-state connectivity were studied using MRI. The results show that the effects are statistically significant after adjustment across 28 tests. Executive control network connectivity was significantly decreased at one-week but not at three-months, and a linear latent variable model was developed to explain the relationship between change in ECN connectivity at one-week and PEQ responses at three-months.