Human Cortical Serotonin 2A Receptor Occupancy by Psilocybin Measured Using [11C]MDL 100,907 Dynamic PET and a Resting-State fMRI-Based Brain Parcellation
Using [11C]MDL 100,907 PET and resting‑state fMRI‑derived cortical parcellation in four healthy volunteers, a single oral psychoactive dose of psilocybin produced mean cortical 5‑HT2A receptor occupancy of 39.5% (±10.9%), with the highest occupancy (63–75%) in default mode network regions (subgenual anterior cingulate and bilateral angular gyri). Significant inter‑individual variability was observed, supporting further study of how regional 5‑HT2A occupancy relates to acute and lasting effects of psilocybin.
Authors
- Roland Griffiths
- Frederick Barrett
- Theresa Carbonaro
Published
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.
Research Summary of 'Human Cortical Serotonin 2A Receptor Occupancy by Psilocybin Measured Using [11C]MDL 100,907 Dynamic PET and a Resting-State fMRI-Based Brain Parcellation'
Introduction
Barrett and colleagues frame psilocybin as a 5-HT 2A receptor agonist with emerging therapeutic promise for mood and substance use disorders, while noting large between-subject variability in both acute subjective effects (for example, mystical or peak experiences, visual imagery, fear or anxiety) and longer-term clinical outcomes. Previous human neuroimaging and pharmacological antagonist studies implicate 5-HT 2A receptor signalling in those acute and downstream neural effects, and recent PET work has linked plasma psilocin, neocortical 5-HT 2A occupancy, and subjective measures. However, prior molecular imaging reports have tended to characterise whole-neocortex binding rather than regional distributions of occupancy, leaving unresolved whether and where regional 5-HT 2A receptors are engaged by psychedelics in humans. This open-label pilot study set out to measure regional cortical 5-HT 2A receptor occupancy by psilocybin in healthy volunteers. Using [11C]MDL 100,907 PET scanning, the investigators tested the hypothesis that binding of this selective 5-HT 2A inverse agonist would decrease across a broad set of cortical regions after oral psilocybin, with region definitions derived from subject-specific resting-state functional connectivity parcellations so that occupancy could be interrogated in functionally homogeneous, study-relevant ROIs.
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Study Details
- Study Typeindividual
- Journal
- Compound
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- APA Citation
Barrett, F. S., Zhou, Y., Carbonaro, T. M., Roberts, J. M., Smith, G. S., Griffiths, R. R., & Wong, D. F. (2022). Human Cortical Serotonin 2A Receptor Occupancy by Psilocybin Measured Using [11C]MDL 100,907 Dynamic PET and a Resting-State fMRI-Based Brain Parcellation. Frontiers in Neuroergonomics, 2. https://doi.org/10.3389/fnrgo.2021.784576
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