The Neurobiological Effect of 5-HT2AR Modulation

Overview

The investigators wish to investigate neurobiological effects of serotonin 2A receptor modulation in healthy volunteers, contrasting effects of an agonist (psilocybin) and an antagonist (ketanserin). Magnetic resonance imaging (MRI) and positron emission tomography (PET) will be used as neuroimaging tools.

Detailed description

This project applies an experimental medicine strategy coupled with human functional and molecular neuroimaging to elucidate the effects of 5-HT2A receptor (5-HT2AR) modulation on brain function and mood in healthy individuals. We compare psilocybin (5-HT2AR agonist) and ketanserin (5-HT2AR antagonist) effects on brain function to identify neural mechanisms mediating the clinical effects of psilocybin and, more broadly, to establish this comparative strategy as a pathway for delineating pharmacological effects on the brain in humans.

Interventions

• Drug Psilocybine
  Oral dose of psilocybine.
• Drug Ketanserin
  Oral dose of ketanserin.

Primary outcome measures

• Psilocin/ketanserin blood concentrations and 5-HT2A receptor occupancy (i.e., binding potential). [Time frame: Change in Cimbi-36 binding potential from baseline PET to intervention PET 1 and PET 2 scans (same day for psilocybin, and two consecutive days for ketanserin).]
• Effects of psilocybin on Cimbi-36 binding potential at baseline and at one and twelve weeks [Time frame: Change in Cimbi-36 binding potential from baseline to one week post psilocybin (and potentially also at 12 weeks after psilocybin).]
• Effects of psilocybin and ketanserin on brain function assessed with fMRI and PET [Time frame: Changes in functional connectivity (fMRI) from Baseline MR to intervention MR scans for ketanserin (one or three weeks after baseline MR) and psilocybin (one or three weeks after baseline)]
• Effects of psilocybin on UCB-J binding potential at baseline and at one week [Time frame: Change in UCB-J binding potential from baseline to one week post psilocybin.]
• Effects of psilocybin on brain function assessed with fMRI at baseline and one month [Time frame: Change in fMRI measures from baseline to one month post psilocybin]
• Anxiety Outcome Measure 1: Acute psychological effects as assessed using Challenging Experiences Questionnaire (CEQ). [Time frame: Immediately post-intervention.]
• Anxiety Outcome Measure 2: Acute psychological effects as assessed using 5D-Altered States of Consciousness (5D-ASC) scale. [Time frame: Immediately post-intervention.]
• Anxiety Outcome Measure 3: Acute psychological effects as assessed using Extended Subjective Drug Intensity (eSDI) scale. [Time frame: During intervention.]
• Transformative Experiences Outcome Measure 1: Acute psychological effects as assessed using Mystical Type Experiences Questionnaire (MEQ) scale. [Time frame: Immediately post-intervention.]
• Transformative Experiences Outcome Measure 2: Acute psychological effects as assessed using Psychological Insights Questionnaire (PIQ) scale. [Time frame: Immediately post-intervention.]

Eligibility criteria

Inclusion criteria

1\) Healthy individuals above 18 years of age.

Exclusion Criteria (For Subprojects 1, 2a, 2b, and 3):

• Presence of or previous primary psychiatric disease (DSM axis 1 or WHO ICD-10 diagnostic classifications) or in first-degree relatives.
• Previous or present neurological condition/disease, significant somatic condition/disease or intake of drugs suspected to influence test results.
• Non-fluent Danish language skills.
• Vision or hearing impairment.
• Previous or present learning disability.
• Pregnancy.
• Breastfeeding.
• Contraindications in regard to MRI scanning.
• Alcohol or drug abuse.
• Allergy to test drugs.
• Participation in studies in which participant has received more than 10 mSv of radiation or other significant exposure to radiation.
• Abnormal ECG or intake of QT prolonging medication.
• Previous significant side-effects in regard to hallucinogenic drugs.
• Use of hallucinogenic drugs 6 months previous to inclusion.
• Blood donation 3 months before and after project participation
• Body weight under 50 kg.
• Plasma ferritin levels outside normal range

Exclusion Criteria (For Subproject 2c):

• Presence of or previous primary psychiatric disease (DSM IV axis 1 or WHO ICD-10 diagnostic classifications).
• Presence of or previous primary psychiatric disease with psychosis symptoms or hypomania (DSM IV axis 1 \[drug/alcohol abuse/dependence, schizophrenia and other psychoses\] or WHO ICD-10 diagnostic classifications \[F10-29, as well as F30-39 with psychotic symptoms, F60\]) in first-degree relatives (parents or siblings).
• Previous or present neurological condition/disease, significant somatic condition/disease or intake of drugs suspected to influence test results.
• Non-fluent Danish language skills or pronounced vision or hearing impairment.
• Previous or present learning disability.
• Pregnancy.
• Breastfeeding.
• Contraindications in regard to MRI scanning.
• Alcohol or drug abuse.
• Allergy to test drugs.
• Abnormal ECG or intake of QT prolonging medication.
• Previous significant side-effects in regard to hallucinogenic drugs.
• Previous use of hallucinogenic drugs.
• Body weight under 45 kg.
• Ethical concerns regarding the administration of a psychedelic drug.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Single blind

Primary purpose

Basic science

Study locations

Denmark · 1 center

• Neurobiology Research Unit, Rigshospitalet — Copenhagen

Publications

• Johansen A, Plaven-Sigray P, Madsen MK, Sondergaard A, Messel C, Geisler M, Nasser A, McCulloch DE, Beliveau V, Vassilieva A, Lund A, Lehel S, Ozenne B, Stenbaek DS, Fisher PM, Svarer C, Knudsen GM. Psilocybin's effect on human brain synaptic plasticity. Transl Psychiatry. 2026 Jul 15. doi: 10.1038/s41398-026-04285-y. Online ahead of print. PMID 42457666
• Brendstrup-Brix K, Ozenne B, Fisher PM, Stenbaek DS, Petersen AS, Armand S, McCulloch DE, Marstrand-Joergensen MR, Ulv Larsen SM, Johansen A, Jensen RH, Knudsen GM, Madsen MK. Effects of psilocybin on sleep quality and brain microstructure in chronic cluster headache. J Psychopharmacol. 2026 May 29:2698811261449380. doi: 10.1177/02698811261449380. Online ahead of print. PMID 42212900

Identifiers

NCT: NCT03289949 · H-16026898

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗