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

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 [ 11 C]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 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. 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 timeconcentration curves varied but psilocin levels were closely associated with psychedelic experience.

Designer drugs: mechanism of action and adverse effects

“…Traditional psychedelics, such as the phenethylamine 3,4,5trimethoxyphenethylamine (mescaline), the tryptamines N,N-dimethyltryptamine (DMT) and psilocybin, and the ergot alkaloid lysergic acid diethylamide (LSD), have a history of being used for religious purposes, as therapeutic agents, and as illicit black market drugs. Although psychedelics interact with various pharmacological targets, their psychedelic effects are mainly mediated by 5-HT 2A receptor agonism (Geyer and Vollenweider 2008;Kraehenmann et al 2017;Madsen et al 2019;Nichols 2004Nichols , 2016Preller et al 2018;Vollenweider et al 1998). Affinity for 5-HT 2A and 5-HT 2C receptors is correlated with the amount of drug that induces psychedelic effects in humans (Fig.…”

“…Similar to other psychedelics, 5-HT 2A receptor agonism plays a key role in mediating the psychedelic effects of naturally occurring and synthetic tryptamine psychedelics (Fantegrossi et al 2008;Halberstadt 2016;Madsen et al 2019;Vollenweider et al 1998). Although mediating opposing functional effects on 5-HT 2A receptors, the concurrent activation of 5-HT 1A receptors has been suggested to contribute to the qualitative effects of tryptamine psychedelics, distinguishing them from phenethylamine psychedelics (Fantegrossi et al 2008;Halberstadt and Geyer 2011;Nichols 2004Nichols , 2016Winter et al 2000).…”

A mechanistic model of the neural entropy increase elicited by psychedelic drugs

“…Another exciting possibility is to explore model parameters to examine potential non-linearities in their implications for different relevant aspects of brain function. For example, there are some reasons to believe that the dose-response relationship is non-linear for psychedelics and that over a certain threshold dosage (level of 5HT2A-R stimulation) -new subjective and global brain function properties can feature 39 .…”

How does it feel to be on psilocybin? Dose-response relationships of subjective experiences in humans

“…Meaning of Percepts compared to experienced psilocybin users [55,62]. In addition, inter-individual variability in pharmacokinetics was reported in terms of plasma psilocin levels and 5-HT2AR occupancy, which were found to correlate with the overall subjective experience [71][72][73][74]. Brain structure metrics could also exert influence, since the rostral anterior cingulate thickness correlated with subscales of the Altered States of Consciousness Rating Scale Oceanic Boundlessness [75].…”