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

Frederick S Barrett,Joshua M Roberts,Yun Zhou,Roland R Griffiths,Dean F Wong,Gwenn S Smith,Theresa M Carbonaro

doi:10.3389/fnrgo.2021.784576

Abstract

Psilocybin (a serotonin 2A, or 5-HT2A, 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-HT2A 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-HT2A receptors after oral administration of a psychoactive dose of psilocybin (10 mg/70 kg). Average 5-HT2A receptor occupancy across all ROIs was 39.5% (± 10.9% SD). Three of the ROIs with 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-HT2A receptor occupancy.

Highlights

There is a high degree of between-subject variability in the subjective effects occasioned by psilocybin and other psychedelic drugs
A number of recent functional magnetic resonance imaging studies have shown that individual differences in acute subjective effects of psychedelics, such as visual imagery (Carhart-Harris et al, 2016b; Kaelen et al, 2016) and degree of peak experiences described as “ego-dissolution” (Carhart-Harris et al, 2014) tend to covary with individual differences in regional brain activity and connectivity
Preliminary evidence suggests that behavioral outcomes of psychedelic experience (Sampedro et al, 2017) and clinical outcomes from psychedelic therapy (Carhart-Harris et al, 2017; Roseman et al, 2017; Mertens et al, 2020) may be associated with changes in regional brain activity and connectivity that persist after acute drug effects have subsided

Summary

Introduction

Psilocybin is a psychedelic drug that has shown preliminary efficacy as a treatment for depression and anxiety (Carhart-Harris et al, 2016a, 2021; Griffiths et al, 2016; Ross et al, 2016; Davis et al, 2021) as well as substance use disorders (Johnson et al, 2014, 2017; Bogenschutz et al, 2015). Preliminary evidence suggests that behavioral outcomes of psychedelic experience (Sampedro et al, 2017) and clinical outcomes from psychedelic therapy (Carhart-Harris et al, 2017; Roseman et al, 2017; Mertens et al, 2020) may be associated with changes in regional brain activity and connectivity that persist after acute drug effects have subsided. While these studies are critical to understanding the underlying neurobiology of psychedelic experiences, they are limited in terms of identifying the mechanisms that determine individual differences in these experiences. Acute alteration of visual system activity may cause hallucinations (Kometer and Vollenweider, 2018), this activity does not explain why this might happen to a different degree in different individuals

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