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 .…”

Rethinking Therapeutic Strategies for Anorexia Nervosa: Insights From Psychedelic Medicine and Animal Models

“…Although it is well known that psilocybin, or more specifically its active metabolite, psilocin, acts as an agonist at multiple serotonergic sites, including the 5-HT 2A , 5-HT 1A , and 5-HT 2C receptors Tyls et al, 2016;Daniel and Haberman, 2017), focus has centered on the 5-HT 2A receptor binding profile of psilocin due to the finding that specific 5-HT 2A antagonists (e.g., ketanserin) block the majority of subjective effects of the drug in human subjects (Carter et al, 2007) and psilocybin-induced discrimination learning in mice (Winter et al, 2007). Psilocybin intake results in dose-dependent occupancy of the 5-HT 2A receptor in the human brain, and both plasma psilocin levels and 5-HT 2A binding are closely associated with subjective ratings of the intensity of psychedelic experiences (Madsen et al, 2019).…”