Human Cortical Serotonin 2A Receptor Occupancy by Psilocybin Measured Using [11C]MDL 100,907 Dynamic PET and a Resting-State fMRI-Based Brain Parcellation

This neuroimaging study (n=4) used positron emission tomography (PET) with a 5-HT2A receptor agonist radioligand (that would light up on scans) and cortical regions of interest (ROIs) to determine the regional occupancy of 5-HT2A receptors after oral administration of a psychoactive dose of psilocybin (10mg/70kg). Three areas with the greatest occupancy were within the default mode network (DMN). There was high variability across individuals.

Abstract

“Psilocybin (a serotonin 2A, or 5-HT_2A, receptor agonist) has shown preliminary efficacy as a treatment for mood and substance use disorders. The current report utilized positron emission tomography (PET) with the selective 5-HT_2A receptor inverse agonist radioligand [¹¹C]MDL 100,907 (a.k.a. M100,907) and cortical regions of interest (ROIs) derived from resting-state functional connectivity-based brain parcellations in 4 healthy volunteers (2 females) to determine regional occupancy/target engagement of 5-HT_2A receptors after oral administration of a psychoactive dose of psilocybin (10 mg/70 kg). Average 5-HT_2A receptor occupancy across all ROIs was 39.5% (± 10.9% SD). Three of the ROIs with the greatest occupancy (between 63.12 and 74.72% occupancy) were within the default mode network (subgenual anterior cingulate and bilateral angular gyri). However, marked individual variability in regional occupancy was observed across individuals. These data support further investigation of the relationship between individual differences in the acute and enduring effects of psilocybin and the degree of regional 5-HT_2A receptor occupancy.”

Authors: Frederick S. Barrett, Yun Zhou, Theresa M. Carbonaro, Joshua M. Roberts, Gwenn S. Smit, Roland R. Griffiths & Dean F. Wong

Summary

Psilocybin, a serotonin 2A receptor agonist, was shown to occupy 39.5% of 5-HT2A receptors in 4 healthy volunteers after oral administration of a psychoactive dose of psilocybin (10 mg/70 kg). However, there was marked individual variability in regional 5-HT2A receptor occupancy.

INTRODUCTION

Psilocybin is a psychedelic drug that has shown preliminary efficacy as a treatment for depression, anxiety and substance use disorders. However, there is a high degree of between-subject variability in the subjective effects occasioned by psilocybin and other psychedelic drugs.

Recent studies have shown that differences in regional brain activity and connectivity are associated with individual differences in acute subjective effects of psychedelics, but these studies are limited in their ability to explain why different individuals experience these effects differently.

Psilocybin and other psychedelics such as LSD act by agonizing the 5-HT2A receptor, and this agonism is accompanied by subjective, cognitive, and neural effects. The regional distribution and degree of 5-HT2A receptor occupancy by psychedelics has yet to be demonstrated in humans.

A pilot study used positron emission tomography to determine the regional occupancy of 5-HT2A receptors in the human brain after oral administration of psilocybin. The study found that [11 C]MDL 100,907 had favorable test-retest reliability and was highly selective for the 5-HT2A receptor.

This pilot study used PET to examine the effect of psilocybin on 5-HT2A receptor occupancy in various cortical regions. The results showed that 5-HT2A receptor occupancy decreased in the regions studied after psilocybin administration.

Participants

Six healthy individuals were enrolled, two dropped out before any PET or drug administration procedures, and four completed all procedures. Volunteers were recruited from those who completed a comparative pharmacology study of psilocybin and dextromethorphan under blinded conditions. At least one month elapsed between final psychoactive drug administration in the parent study and the beginning of the current study. All volunteers underwent medical and psychiatric screening before the current study, and were excluded if they had a history of substance dependence, were pregnant, nursing, had a current significant medical condition, were taking any centrally-acting serotonergic drug, or antidepressant or antipsychotic medication, or were positive for drugs of abuse.

Procedures

Participants in the parent study had established good rapport with two study team members who served as monitors for all five experimental drug administration sessions. They were informed that they would receive the same dose of psilocybin in the current study.

Volunteers underwent MRI and resting-state functional MRI scans, and a baseline PET scan with [11 C] MDL 100,907 was completed at least two days before the blocking scan. They were instructed to refrain from using any drugs while enrolled in the study. During the PET scan, participants were instructed to turn their attention inward while listening to a standard playlist of music. They were administered psilocybin 80 min before the radiotracer injection for the blocking scan.

MRI Acquisition and Preprocessing

High-resolution structural images and resting-state blood-oxygenation level-dependent data were collected for each participant using a 3T Siemens Skyra whole-body scanner. The images were segmented into gray matter, white matter, and cerebrospinal fluid masks. Data were preprocessed with slice timing correction, motion correction, co-registration to the MPRAGE image, normalization to the MNI template using the normalized mutual information algorithm, smoothing, motion scrubbing, linear detrending, regression of nuisance variables including motion, and band-pass filtering.

PET Acquisition, Preprocessing, and Quantification

A radiotracer, [11 C]MDL 100,907, was synthesized using C-11 methylation and used to measure availability of the 5-HT2A receptor. PET images were obtained using a 30-frame acquisition protocol and were registered to baseline PET images and MRI images using SPM and MATLAB.

The ROI time activity curves were calculated by applying the ROIs generated from resting-state data to dynamic PET images, and the ROI percent occupancy was calculated by multiplying the ROI TACs by the binding potential.

− BPND (blocking ) BPND (baseline)

The remaining 137 ROIs were re-fitted with the SRTM model and the BP and occupancy by psilocybin were calculated for each retained ROI.

RESULTS

A representative volunteer’s 5-HT2A receptor binding potential and 5-HT2A receptor occupancy by psilocybin are presented in Table 1. The right angular gyrus and the reference region (cerebellum) demonstrate greatest 5-HT2A receptor occupancy by psilocybin.

DISCUSSION

Studies have shown that 5-HT2A receptors are expressed in primary sensory regions and the default mode network, and that this may be a mechanism of therapeutic effects of psychedelics.

This report provides additional evidence for substantial psilocybin occupancy of 5-HT2A receptors throughout the cortex in humans, using a different 5-HT2A ligand than had previously been used.

This pilot study had a small sample size and did not test for genetic polymorphisms or differences in the bioavailability of psilocybin and its active metabolite psilocin.

The current report demonstrates that psilocybin occupies cortical 5-HT2A receptors and that further investigations into the relationship between 5-HT2A receptor occupancy and subjective effects may yield important insights.

AUTHOR CONTRIBUTIONS

The authors thank the people who helped them with the study and the people who read the final version of the manuscript.

FUNDING

This publication was made possible by the Johns Hopkins Institute for Clinical and Translational Research (ICTR) and the National Center for Advancing Translational Sciences (NCATS). The views expressed in this article do not necessarily reflect those of the Drug Enforcement Agency.

ACKNOWLEDGMENTS

The authors thank Mary Cosimano, Ethan Hurwitz, Lorena Gapasin, Gwyndell Duncan, Karen Edmonds, Jose Leon, Michael Hans, Bineyam Gebrewold, and Dr. Chakradhar Mishra for their assistance.