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

  • A Correction to this article was published on 08 March 2019

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 stimulation of serotonin 2A receptors (5-HT2ARs) by psilocybin’s active metabolite, psilocin. We here report for the first time the relationship between 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 percent 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 modeled 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. 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 psychedelic experience.

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Change history

  • 08 March 2019

    The original version of this article contained an error in the labelling of Figures 2 and 3. While the captions and figures themselves are correct, in order to correspond with the in-text references, they have now been re-numbered in both the PDF and HTML versions of the article.

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Acknowledgements

We gratefully acknowledge the assistance of Lone Freyr, Gerda Thomsen, Svitlana Olsen, Josephine Torp, Annette Johansen, Camilla Larsen, Hanne Hansen, Vibeke Dam, Simone Pleinert, Sophia Armand, Dorthe Givard, and Peter Jensen. The John and Birthe Meyer Foundation is gratefully acknowledged for the donation of the Cyclotron and PET-scanner. We also gratefully acknowledge the University of Chemistry and Technology and the National Institute of Mental Health (Prague, Czech Republic) for production of psilocybin and Glostrup Apotek (Glostrup, Denmark) for encapsulation.

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Correspondence to Gitte M. Knudsen.

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