Brain serotonin 2A receptor binding predicts subjective temporal and mystical effects of psilocybin in healthy humans

This fMRI study (n=16) found that pre-drug brain serotonin (5-HT) 2a receptor binding predicted the duration of subjective effects (peak and time to baseline) of psilocybin (14-21mg).

Abstract

“Background: Psilocybin is a serotonergic psychedelic with psychoactive effects mediated by serotonin 2A receptor (5-HT2AR) activation. It produces an acute psychedelic altered state of consciousness with a unique phenomenology that can be temporally characterized by three intensity phases: onset of psychoactive effect, a peak plateau and return to normal consciousness.

Aims: We evaluated whether pre-drug brain 5-HT2AR binding predicted the three phases of psilocybin subjective drug intensity (SDI) and retrospective self-report of mystical type experiences in healthy individuals.

Method: Sixteen participants completed a pre-drug [11C]Cimbi-36 positron emission tomography scan to assess 5-HT2AR binding. On a separate day, participants completed a single psilocybin session (oral dose range 0.2–0.3 mg/kg), during which SDI was assessed every 20 min. The Mystical Experience Questionnaire (MEQ) was completed at the end of the session. The three SDI phases were modelled using segmented linear regressions. We evaluated the associations between neocortex 5-HT2AR binding and SDI/MEQ outcomes using linear regression models.

Results: Neocortex 5-HT2AR was statistically significantly negatively associated with peak plateau duration and positively with time to return to normal waking consciousness. It was also statistically significantly negatively associated with MEQ total score.

Conclusion: This is the first study to investigate how individual brain 5-HT2AR binding predicts subjective effects of a single dose of psilocybin. Our findings reinforce the role of cerebral 5-HT2AR in shaping the temporal and mystical features of the psychedelic experience. Future studies should examine whether individual brain levels of 5-HT2AR have an impact on therapeutic outcomes in clinical studies.”

Authors: Dea Siggaard Stenbæk, Martin Korsbak Madsen, Brice Ozenne, Sara Kristiansen, Daniel Burmester, David Erritzoe, Gitte Moos Knudsen & Patrick MacDonald Fisher

Notes

This paper is included in our ‘Top 12 Articles on Psychedelics and Serotonin (5HT) Receptors‘

“Lower pre-drug 5-HT2AR binding was associated with longer peak effects, a more rapid decrease in SDI effects and higher MEQ scores.”

Summary

Mystical type experiences are reported for centuries, and have a common core of phenomenological features. They have been shown to have beneficial effects.

Participants must be over 18 years of age, have no contraindications to radiation, be healthy, and have no history of heart disease or blood donation.

Data were pooled across two studies from our research group investigating psilocybin 5-HT2AR occupancy and changes in 5-HT2AR one week after psilocybin intervention. Written informed consent was obtained from all individuals after a complete description of the study.

Measures

On the intervention day, subjective intensity was measured using a 0 – 10 Likert scale. Participants responded orally and the supporting psychologists noted their responses.

Participants completed the revised Mystical Type Experience Questionnaire (MEQ) at the end of the intervention day and approximately 6 h after ingestion of psilocybin. The MEQ contains 30 items and is calculated by averaging all items.

PET and MR imaging were performed on participants, who were scanned with an HRRT PET scanner with an approximate in-plane resolution of 2 mm. Participants attended a preparatory consultation with the two psychologists who would assist them on the intervention day.

Participants received psilocybin orally in 3 mg capsules with a glass of water on the intervention day, and were provided with interpersonal support and a standardized selection of supportive music. Six participants completed at least one PET scan on the intervention day.

Data analyses

The three phases of the psychedelic experience were modelled using a segmented linear regression model, and three outcomes were derived for each participant: onset slope coefficient, duration of peak plateau, and return slope coefficient.

Descriptive statistics

Table 1 shows descriptive data for the study sample, which included 16 healthy research participants. No adverse reactions to the drug were observed, and no participants required interpersonal crisis support.

Estimation of SDI parameters

Our segmented two-breakpoint model showed excellent fit, capturing nearly all variance in SDI, and taking 143 min to return from peak to normal waking consciousness.

5-HT2AR binding and subjective drug effects

Pre-drug 5-HT2AR binding was negatively associated with peak plateau duration and positively associated with return slope coefficient. Lower brain 5-HT2AR binding was not statistically significantly associated with onset slope coefficient.

Pre-drug 5-HT2AR binding was negatively associated with the MEQ total score, and positive mood changes, mystical experiences and transcendence of time and space were negatively associated with the MEQ total score.

Discussion

This study investigated the relationship between brain 5-HT2AR PET binding and psilocybin-induced psychedelic effects in healthy individuals. Lower pre-drug 5-HT2AR binding was associated with longer peak effects and higher MEQ scores.

Although the mystical-type experience is well established for long-term transformative benefits of psilocybin in healthy research participants, further studies are warranted to elucidate whether the temporal structure of SDI is similarly predictive of beneficial long-term changes.

The temporal dynamics of the 5-HT2AR-psilocin interaction may be different in individuals with lower 5-HT2AR density, or the psilocin-5-HT2AR interaction dynamic may be associated with plasma psilocin pharmacokinetics.

A study found that 5-HT2AR was a central neuro-molecular mechanism in mediating the psychedelic experience, and suggested that pre-drug 5-HT2AR binding predicts therapeutic effects of psilocybin in clinical populations.

Methodological considerations

Results should be interpreted in light of some limitations, and a larger study should be performed to confirm the results.