Major Depressive Disorder (MDD)Depressive DisordersAnxiety DisordersSubstance Use Disorders (SUD)Palliative & End-of-Life DistressNeuroimaging & Brain MeasuresHealthy VolunteersPsilocybin

Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels

This single-blind study (n=8) provides the first report of the positive correlation between the intensity of psychedelic effects, cerebral occupancy of the 5-HT2A receptor, and plasma psilocybin levels in humans after a single dose of psilocybin (3-30mg).

Authors

  • David Erritzoe
  • Gitte Knudsen
  • Patrick Fisher

Published

Neuropsychopharmacology
individual Study

Abstract

The main psychedelic component of magic mushrooms is psilocybin, which shows promise as a treatment for depression and other mental disorders. Psychedelic effects are believed to emerge through the stimulation of serotonin 2A receptors (5-HT2ARs) by psilocybin’s active metabolite, psilocin. We here report for the first time the relationship between the intensity of psychedelic effects, cerebral 5-HT2AR occupancy and plasma levels of psilocin in humans. Eight healthy volunteers underwent positron emission tomography (PET) scans with the 5-HT2AR agonist radioligand [11C]Cimbi-36: one at baseline and one or two additional scans on the same day after a single oral intake of psilocybin (3-30 mg). 5-HT2AR occupancy was calculated as the per cent change in cerebral 5-HT2AR binding relative to baseline. Subjective psychedelic intensity and plasma psilocin levels were measured during the scans. Relations between subjective intensity, 5-HT2AR occupancy, and plasma psilocin levels were modelled using non-linear regression. Psilocybin intake resulted in dose-related 5-HT2AR occupancies up to 72%; plasma psilocin levels and 5-HT2AR occupancy conformed to a single-site binding model. The subjective intensity was correlated with both 5-HT2AR occupancy and psilocin levels as well as questionnaire scores. We report for the first time that intake of psilocybin leads to significant 5-HT2AR occupancy in the human brain and that both psilocin plasma levels and 5-HT2AR occupancy are closely associated with subjective intensity ratings, strongly supporting that stimulation of 5-HT2AR is a key determinant for the psychedelic experience. Important for clinical studies, psilocin time-concentration curves varied, but psilocin levels were closely associated with the psychedelic experience.

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Research Summary of 'Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels'

Introduction

Psilocybin is the principal psychoactive compound in magic mushrooms and a classic serotonergic psychedelic whose subjective effects resemble those of LSD and mescaline. Recent clinical trials have reported therapeutic potential for psilocybin across several neuropsychiatric conditions, including treatment-resistant major depressive disorder, cancer-related anxiety and depression, and substance use disorders. Pharmacological and preliminary imaging studies have implicated the serotonin 2A receptor (5-HT2AR) as the principal molecular mediator of psychedelic effects, but direct human evidence linking psilocybin's active metabolite (psilocin) plasma concentrations, cerebral 5-HT2AR target engagement and the subjective psychedelic experience was lacking. D. and colleagues set out to characterise, in humans, the relationships among plasma psilocin levels, cerebral 5-HT2AR occupancy and subjective intensity of psychedelic effects. Using the 5-HT2AR agonist PET radioligand [11C]Cimbi-36, the study aimed to quantify receptor occupancy after oral psilocybin and to model how occupancy and psilocin concentrations relate to concurrent self-reported intensity and to standard psychedelic experience questionnaires administered after the imaging sessions.

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Study Details

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Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo

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LSD induces increased signalling entropy in rats' prefrontal cortex

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31 cited
The Potential Role of Psychedelic Drugs in Mental Health Care of the Future

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Clinical and biological predictors of psychedelic response in the treatment of psychiatric and addictive disorders: a systematic review

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60 cited
Trial of Psilocybin versus Escitalopram for Depression

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927 cited
Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice

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Psilocin acutely disrupts sleep and affects local but not global sleep homeostasis in laboratory mice

Thomas, C. W., Blanco-Duque, C., Breant, B. et al. · Translational Psychiatry (2021)

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

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Positive expectations predict improved mental-health outcomes linked to psychedelic microdosing

Kaertner, L. S., Steinborn, M. B., Kettner, H. et al. · Scientific Reports (2021)

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Discriminative Stimulus Effects of Substituted Tryptamines in Rats

Gatch, M. B., Hoch, A., Carbonaro, T. M. · ACS Pharmacology and Translational Science (2020)

8 cited
Investigation of the Structure-Activity Relationships of Psilocybin Analogues

Klein, A. K., Chatha, M., Laskowski, L. J. et al. · ACS Pharmacology and Translational Science (2020)

The History of Psychedelics in Psychiatry

Nichols, D. E., Walter, H. · Pharmacopsychiatry (2020)

Pivotal Mental States

Brouwer, A., Carhart-Harris, R. L. · Journal of Psychopharmacology (2020)

Improved colour blindness symptoms associated with recreational psychedelic use: Results from the Global Drug Survey 2017

Ferris, J. A., Nutt, D. J. · Drug Science Policy and Law (2020)

7 cited
Therapeutic effects of classic serotonergic psychedelics: A systematic review of modern-era clinical studies

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Brain serotonin 2A receptor binding predicts subjective temporal and mystical effects of psilocybin in healthy humans

Stenbæk, D. S., Madsen, M. K., Ozenne, B. et al. · Journal of Psychopharmacology (2020)

Psychedelic drugs: neurobiology and potential for treatment of psychiatric disorders

Vollenweider, F. X., Preller, K. H. · Nature Reviews Neuroscience (2020)

The therapeutic potential of microdosing psychedelics in depression

Kuypers, K. P. C. · Therapeutic Advances in Psychopharmacology (2020)

Historic psychedelic drug trials and the treatment of anxiety disorders

Weston, N. M., Gibbs, D., Bird, C. I. V. et al. · Depression and Anxiety (2020)

A potential role for psilocybin in the treatment of obsessive-compulsive disorder

Jacobs, E. · Journal of Psychedelic Studies (2020)

Psychedelic Psychiatry’s Brave New World

Nutt, D. J., Erritzoe, D., Carhart-Harris, R. L. · Cell (2020)

A single psilocybin dose is associated with long-term increased mindfulness, preceded by a proportional change in neocortical 5-HT2A receptor binding

Madsen, M. K., Fisher, P. M., Stenbæk, D. S. et al. · European Neuropsychopharmacology (2020)

Acute effects of psilocybin on glutamate concentration levels, functional connectivity and subjective state

Mason, N. L., Feilding, A., Ramaekers, J. G. · European Neuropsychopharmacology (2020)

Therapeutic mechanisms of psilocybin: Changes in amygdala and prefrontal functional connectivity during emotional processing after psilocybin for treatment-resistant depression

Mertens, L. J., Wall, M. B., Roseman, L. et al. · Journal of Psychopharmacology (2020)

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REBUS and the Anarchic Brain: Toward a Unified Model of the Brain Action of Psychedelics

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