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

Neuropsychopharmacology. 2019 Jun;44(7):1328-1334. doi: 10.1038/s41386-019-0324-9. Epub 2019 Jan 26.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Benzylamines
  • Brain / drug effects*
  • Brain / metabolism*
  • Carbon Radioisotopes
  • Female
  • Hallucinogens / pharmacology*
  • Humans
  • Male
  • Phenethylamines
  • Positron-Emission Tomography
  • Protein Binding
  • Psilocybin / blood*
  • Psilocybin / pharmacology*
  • Receptor, Serotonin, 5-HT2A / metabolism*
  • Serotonin 5-HT2 Receptor Agonists / pharmacology

Substances

  • Benzylamines
  • Carbon Radioisotopes
  • Cimbi-36
  • Hallucinogens
  • Phenethylamines
  • Receptor, Serotonin, 5-HT2A
  • Serotonin 5-HT2 Receptor Agonists
  • Psilocybin