Psilocybin-induced changes in brain network integrity and segregation correlate with plasma psilocin level and psychedelic experience

This fMRI study (n=15) investigated the effects of psilocybin (14-21mg/70kg) on the brain and found that the higher the psilocin (active metabolite of psilocybin) and subjective drug experience (SDI) correlated with lower network integrity and segregation (less top-down, more bottom-up).

Abstract of Psilocybin-induced changes in brain network integrity and segregation correlate with plasma psilocin level and psychedelic experience

“The emerging novel therapeutic psilocybin produces psychedelic effects via engagement of cerebral serotonergic targets by psilocin (active metabolite). The serotonin 2A receptor critically mediates these effects by altering distributed neural processes that manifest as increased entropy, reduced functional connectivity (FC) within discrete brain networks (i.e., reduced integrity) and increased FC between networks (i.e., reduced segregation). Reduced integrity of the default mode network (DMN) is proposed to play a particularly prominent role in psychedelic phenomenology, including perceived ego-dissolution. Here, we investigate the effects of a psychoactive oral dose of psilocybin (0.2-0.3 mg/kg) on plasma psilocin level (PPL), subjective drug intensity (SDI) and their association in fifteen healthy individuals. We further evaluate associations between these measures and resting-state FC, measured with functional magnetic resonance imaging, acquired over the course of five hours after psilocybin administration. We show that PPL and SDI correlate negatively with measures of network integrity (including DMN) and segregation, both spatially constrained and unconstrained. We also find that the executive control network and dorsal attention network desegregate, increasing connectivity with other networks and throughout the brain as a function of PPL and SDI. These findings provide direct evidence that psilocin critically shapes the time course and magnitude of changes in the cerebral functional architecture and subjective experience following psilocybin administration. Our findings provide novel insight into the neurobiological mechanisms underlying profound perceptual experiences evoked by this emerging transnosological therapeutic and implicate the expression of network integrity and segregation in the psychedelic experience and consciousness.“

Authors: Martin K. Madsen, Dea S. Stenbaek, Albin Arvidsson, Sophia Armand, Maja R. Marstrand-Jorgensen, Sys S. Johansen, Kristian Linnet, Brice Ozenne, Gitte M. Knudsen & Patrick M. Fisher

Summary

The authors thank the staff and students of the Copenhagen University Hospital Rigshospitalet for their assistance.

Abstract

Psilocybin, an emerging transnosological therapeutic, produces psychedelic effects via engagement of cerebral serotonergic targets by psilocin (active metabolite). This study shows that psilocin critically shapes the time course and magnitude of changes in the cerebral functional architecture and subjective experience following psilocybin administration.

Main Text

Introduction

Current neuroscientific models hold that multiple macroscale cerebral functional networks shape behavior and phenomenal experience. Reduced network integrity and segregation may underlie the psychedelic experience after intake of psilocybin, but neuroimaging experiments are sparse. Psilocybin induces an altered state of consciousness and has long-lasting beneficial effects in healthy individuals and patients with depression, anxiety and addiction. The psychedelic compound’s active metabolite psilocin is tightly coupled to both cerebral 5-HT2AR occupancy and the psychedelic experience.

Acute psilocybin effects have been studied in four BOLD fMRI resting-state functional connectivity experiments: reduced RSFC within the default mode network (DMN), increased RSFC between networks, and increased global RSFC. These studies did not assess plasma psilocin level (PPL) while measuring brain function. We collected data on brain function, phenomenal experience and PPL at multiple time points throughout the psilocybin psychedelic experience to elucidate the extent to which network integrity and segregation map on to PPL and phenomenal experience alterations.

We hypothesized that PPL and SDI would correlate negatively with DMN and average within-network RSFC, reflecting reduced network integrity, and positively with average between-network RSFC, reflecting reduced network segregation.

Participants underwent MRI data acquisition prior to and after psilocybin administration, and after a 10-minute rs-fMRI scan. They rated the perceived subjective drug intensity of the experience, and a blood sample was obtained to quantify plasma level of free (unconjugated) psilocin.

Participants completed self-report questionnaires to assess the overall psychedelic experience, and psilocin plasma concentrations were measured using ultra performance liquid chromatography and tandem mass spectrometry. Magnetic resonance imaging data was acquired on a 3T Siemens Prisma scanner.

FC was computed within networks and between networks, and linear mixed-effects regression analysis was used to model the association between FC and PPL and SDI, respectively. GCOR and LCOR maps were included in separate linear mixed-effects models with PPL or SDI as independent variables, respectively. Standard clinical dose response profile for psilocybin was constructed by spline fits of 0.3 mg/kg psilocin time course data and estimated using the predicted PPL curve and model parameters.

We found that the plasma psilocin level and subjective effects exhibited highly similar temporal trajectories and correlated positively. The administered dose of psilocybin induced a profoundly altered state of consciousness, measured with the 11-Dimension Altered States of Consciousness questionnaire, the revised Mystical Experiences Questionnaire and the Ego-Dissolution Inventory.

Seven resting-state networks were analyzed, comprising 36 regions-of-interest (ROIs), with within-network RSFC and between-network RSFC correlated positively. PPL and SDI were statistically significantly positively correlated with average between-network RSFC.

We evaluated the associations between PPL and SDI with RSFC of individual networks and between network pairs. We found that PPL and SDI were statistically significantly negatively correlated with the dorsal attention network (DMN), the salience network (SAN), and the executive control network (ECN).

Local correlation associations with PPL and SDI LCOR measures FC between each voxel and its local neighborhood voxels. PPL and SDI were negatively correlated with LCOR in several regions belonging to DMN, ECN, visual cortex, and bilateral temporal regions.

PPL and SDI showed statistically significant positive associations with GCOR in areas belonging to DAN and ECN (bilateral superior frontal gyri and bilateral intraparietal sulci), as well as the thalamus. Here we evaluated how plasma psilocin and the psychedelic experience map onto RSFC measures of functional network integrity and segregation. We found that psilocin negatively correlates with DMN network integrity and SAN network integrity, and negatively correlates with overall network integrity.

Psilocybin and lysergic acid diethylamide (LSD) reduced network segregation in the psychedelic state, but only for some networks. Further, these effects were more pronounced for higher-level networks such as DMN and SAN compared to lower-level unimodal networks. The GCOR analysis and the spatially constrained networks analyses converge, showing desegregation among the DMN, ECN, DAN and sensory networks as PPL rises and psychedelic phenomenology intensifies.

The DMN, ECN, and SAN have been implicated in attention regulation, and psilocybin-induced disruption of these networks may contribute to the unitive experience of psychedelics. Two other fMRI studies used WBC analyses, which yield measures similar to the GCOR analysis, but their findings are not in line with our findings. These discrepancies may be due to differences in psilocybin pharmacokinetics, BOLD signal denoising procedures, head motion or analytical method.

The REBUS and anarchic brain theories propose that 5-HT2AR agonist psychedelic compounds impair the function of high order networks, including the default mode network (DMN). Psilocin dose-dependently reduces network integrity and segregation, and thus is compatible with the neurobiological mechanisms proposed in the REBUS hypothesis. The thalamic GCOR increased with SDI, compatible with the thalamic gating theory of psychedelic drug action, which posits that impaired thalamic filtering contributes to psychedelic experiences.

We replicated our previous finding that PPL and SDI display similar temporal trajectories and correlate positively. In addition, we observed considerable interindividual variability in maximum PPL and time to reach C max, which suggests that interindividual differences in subjective effects and clinical response are at least partly explained by PPL. Our study is not without limitations, but multiple measurements were done for each subject over time and a placebo condition could have helped identify potential expectancy effects on RSFC and SDI.

The present study evaluated real-time measures of phenomenal experience, network integrity and segregation, and head motion effects after psilocybin in individuals with no or limited experience with psychedelic drugs. The results demonstrate that psilocin critically shapes the time course and magnitude of changes in the cerebral functional architecture.

The study was supported by Innovation Fund Denmark, Independent Research Fund Denmark, Ester M. og Konrad Kristian Sigurdssons Dyrevrnsfond, Rigshospitalet’s Research Council, the Lundbeck Foundation, and Fund Denmark, Medical Sciences. All authors declare no conflicts of interest.

Contributors

PMF and GMK designed the study, MKM wrote the protocol, MKM contributed to data collection, analysis, interpretation and writing the first draft of the manuscript, DSS conceptualized the main psychological outcome of the study, SA contributed with guiding at psilocybin interventions, participant preparation and integration, and BO contributed to data analysis and interpretation.

Plasma psilocin level and subjective drug intensity are correlated in Fig 1. One subject displayed a disjunction between PPL and SDI.

Psilocin level was negatively associated with default mode network resting-state functional connectivity and average within-network RSFC, and positively associated with average between-network RSFC and subjective drug intensity.

Fig. 3 shows the results of the individual networks analysis, which showed an association between plasma psilocin level (PPL) and functional connectivity (FC) as well as an association between subjective drug intensity (SDI) and FC.

Results of the local correlation (LCOR) and global correlation (GCOR) analyses show that visual cortex, default mode network hubs, posterior cingulate cortex, temporal cortex, and bilateral anterior prefrontal cortex are associated with plasma psilocin level and subjective drug intensity.