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 [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.

Fig. 1

Psilocin and intensity rating time course. a Plasma psilocin levels. Individual data points are measured plasma psilocin concentrations, fitted with spline fits. b Time course of subjective intensity ratings. Time = 0 indicates time of psilocybin ingestion

Fig. 2

Psilocybin occupancy of 5-HT2AR. [¹¹C]Cimbi-36 BP_ND map of the cortical surface of the left hemisphere of Subject 5 at baseline and at the first post-psilocybin intervention scan. Color bar in units BP_ND

Fig. 3

Relationship between mean within-scan plasma psilocin levels and neocortical 5-HT2AR occupancy. Estimated EC₅₀ [95% CI]: 1.95 [1.16; 3.15] μg/L and Occ_max [95% CI]: 76.6 [67.3; 88.0]%

Fig. 4

Subjective intensity of the psychedelic experience at the time of the PET scan, neocortical 5-HT2AR occupancy and plasma psilocin concentration. a Relationship between intensity ratings and neocortical 5-HT2AR occupancy. The fitted line was obtained using a quadratic function. b Relationship between intensity and psilocin concentration, fitted to a single site receptor binding model