Brain serotonin 2A receptor binding predicts subjective temporal and mystical effects of psilocybin in healthy humans
Pre-drug neocortical 5‑HT2A receptor binding (measured with [11C]Cimbi‑36 PET) predicted the temporal profile of psilocybin’s subjective effects in healthy volunteers—higher binding was associated with a shorter peak plateau but a longer return to normal consciousness—and correlated negatively with retrospective mystical-type experience (MEQ total). This first demonstration that individual 5‑HT2A levels shape both temporal and mystical features of the psilocybin experience suggests such binding may influence therapeutic outcomes and merits study in clinical populations.
Authors
- Gitte Knudsen
- Patrick Fisher
- David Erritzoe
Published
Abstract
Background
Psilocybin is a serotonergic psychedelic with psychoactive effects mediated by serotonin 2A receptor (5-HT2AR) activation. It produces an acute psychedelic altered state of consciousness with a unique phenomenology that can be temporally characterized by three intensity phases: onset of psychoactive effect, a peak plateau and return to normal consciousness.
Aims
We evaluated whether pre-drug brain 5-HT2AR binding predicted the three phases of psilocybin subjective drug intensity (SDI) and retrospective self-report of mystical type experiences in healthy individuals.
Method
Sixteen participants completed a pre-drug [11C]Cimbi-36 positron emission tomography scan to assess 5-HT2AR binding. On a separate day, participants completed a single psilocybin session (oral dose range 0.2–0.3 mg/kg), during which SDI was assessed every 20 min. The Mystical Experience Questionnaire (MEQ) was completed at the end of the session. The three SDI phases were modelled using segmented linear regressions. We evaluated the associations between neocortex 5-HT2AR binding and SDI/MEQ outcomes using linear regression models.
Results
Neocortex 5-HT2AR was statistically significantly negatively associated with peak plateau duration and positively with time to return to normal waking consciousness. It was also statistically significantly negatively associated with MEQ total score.
Conclusion
This is the first study to investigate how individual brain 5-HT2AR binding predicts subjective effects of a single dose of psilocybin. Our findings reinforce the role of cerebral 5-HT2AR in shaping the temporal and mystical features of the psychedelic experience. Future studies should examine whether individual brain levels of 5-HT2AR have an impact on therapeutic outcomes in clinical studies.
Research Summary of 'Brain serotonin 2A receptor binding predicts subjective temporal and mystical effects of psilocybin in healthy humans'
Introduction
Psilocybin is a serotonergic psychedelic that produces an acute altered state of consciousness typically described in three temporal phases: an onset of psychoactive effects, a peak plateau, and a return to normal waking consciousness. These acute effects frequently include perceptual alterations and changes in selfhood, affect and meaning, and can include so-called mystical-type experiences characterised by unity, profound positive mood, transcendence of time and space, and ineffability. Previous research indicates that dose, personality, and set and setting influence psilocybin responses, and that psilocybin’s effects are primarily mediated by agonism at the serotonin 2A receptor (5-HT2AR). However, it is unknown whether pre-drug individual differences in brain 5-HT2AR binding predict temporal features of the acute subjective drug intensity (SDI) time course or the magnitude of retrospective mystical-type experiences. Stenbaek and colleagues set out to test whether baseline neocortical 5-HT2AR binding, measured with the agonist PET tracer [11C]Cimbi-36, predicts three modelled temporal parameters of SDI (onset slope, duration of peak plateau, and return slope) and retrospective scores on the Mystical Experience Questionnaire (MEQ) following a single oral psilocybin session in healthy volunteers. The study therefore investigates a candidate neurobiological marker that could help explain individual differences in the phenomenology of the psychedelic experience and potentially inform future clinical research on predictors of therapeutic response.
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Study Details
- Study Typeindividual
- Journal
- Compound
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- APA Citation
Stenbæk, D. S., Madsen, M. K., Ozenne, B., Kristiansen, S., Burmester, D., Erritzoe, D., Knudsen, G. M., & Fisher, P. M. (2021). Brain serotonin 2A receptor binding predicts subjective temporal and mystical effects of psilocybin in healthy humans. Journal of Psychopharmacology, 35(4), 459-468. https://doi.org/10.1177/0269881120959609
References (24)
Papers cited by this study that are also in Blossom
Barrett, F. S., Griffiths, R. R. · Current Topics in Behavioral Neurosciences (2017)
Barrett, F. S., Johnson, M. W., Griffiths, R. R. · Journal of Psychopharmacology (2015)
Bonson, K. R. · Neuropsychopharmacology (1996)
Brown, R. T., Nicholas, C. R., Cozzi, N. V. et al. · Clinical Pharmacokinetics (2017)
Carhart-Harris, R. L., Bolstridge, &. M., Day, C. M. J. et al. · Psychopharmacology (2017)
Dolder, P. C., Schmid, Y., Steuer, A. E. et al. · Clinical Pharmacokinetics (2017)
Dos Santos, R. G., Hallak, J. E. · Neuroscience and Biobehavioral Reviews (2020)
Gonza ´lez-Maeso, J., Weisstaub, N. V., Zhou, M. et al. · Neuron (2007)
Griffiths, R. R., Richards, W. A., Mccann, U. et al. · Journal of Psychopharmacology (2006)
Holze, F., Duthaler, U., Vizeli, P. et al. · British Journal of Clinical Pharmacology (2019)
Show all 24 referencesShow fewer
Johnson, M. W., Garcia-Romeu, A., Cosimano, M. P. et al. · Journal of Psychopharmacology (2014)
Johnson, M. W., Griffiths, R. R. · Neurotherapeutics (2017)
Johnson, M. W., Hendricks, P. S., Barrett, F. S. et al. · Pharmacology and Therapeutics (2019)
Johnson, M. W., Richards, W. A., Griffiths, R. R. · Journal of Psychopharmacology (2008)
Kometer, M., Schmidt, A., Bachmann, R. et al. · Biological Psychiatry (2012)
Maclean, K. A., Johnson, M. W., Griffiths, R. R. · Journal of Psychopharmacology (2011)
Madsen, M. K., Fisher, P. M., Burmester, D. et al. · Neuropsychopharmacology (2019)
Madsen, M. K., Fisher, P. M., Stenbæk, D. S. et al. · European Neuropsychopharmacology (2020)
Moreno, F. A., Wiegand, C. B., Taitano, E. K. et al. · Journal of Clinical Psychiatry (2006)
Kraehenmann, R., Nielson, E. M., May, D. G. et al. · Frontiers in Pharmacology (2018)
Preller, K. H., Vollenweider, F. X. · Behavioral Neurobiology of Psychedelic Drugs (2016)
Ross, S., Bossis, A. P., Guss, J. et al. · Journal of Psychopharmacology (2016)
Studerus, E., Gamma, A., Kometer, M. et al. · PLOS ONE (2012)
Vollenweider, F. X., Vollenweider-Scherpenhuyzen, M. F. I., Bäbler, A. et al. · NeuroReport (1998)
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