The Neurobiological Effect of 5-HT2AR Modulation (NeuroPharm2)

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.

Study Overview

• Status: Recruiting
• Conditions: Basic Science
• Intervention / Treatment: Drug: Psilocybine; Drug: Ketanserin

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.

• Study Type: Interventional
• Enrollment (Estimated): 200
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Gitte M Knudsen, Professor; Phone Number: +45 35456720; Email: gmk@nru.dk
• Study Contact Backup: Name: Patrick M Fisher, PhD; Phone Number: +45 35456714; Email: patrick.fisher@nru.dk

Study Locations

• Denmark
  • Copenhagen, Denmark, 2100
    • Recruiting
    • Neurobiology Research Unit, Rigshospitalet
    • Contact: Gitte M Knudsen, Professor
    • Contact: Patrick M Fisher, PhD; Phone Number: +4535456714; Email: patrick.fisher@nru.dk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1) Healthy individuals above 18 years of age.

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

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

Exclusion Criteria (For Subproject 2c):

1. Presence of or previous primary psychiatric disease (DSM IV axis 1 or WHO ICD-10 diagnostic classifications).
2. 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).
3. Previous or present neurological condition/disease, significant somatic condition/disease or intake of drugs suspected to influence test results.
4. Non-fluent Danish language skills or pronounced vision or hearing impairment.
5. Previous or present learning disability.
6. Pregnancy.
7. Breastfeeding.
8. Contraindications in regard to MRI scanning.
9. Alcohol or drug abuse.
10. Allergy to test drugs.
11. Abnormal ECG or intake of QT prolonging medication.
12. Previous significant side-effects in regard to hallucinogenic drugs.
13. Previous use of hallucinogenic drugs.
14. Body weight under 45 kg.
15. Ethical concerns regarding the administration of a psychedelic drug.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Project 1: Occupancy of psilocybin/ketanserin; After baseline MRI & 5-HT2AR PET-imaging, participants will be allocated to undergo either one oral dose of psilocybine or one oral dose of ketanserin. After drug administration, participants will undergo two CIMBI-36 PET scans.	Drug: Psilocybine; Oral dose of psilocybine.; Other Names: Psilocybin; Drug: Ketanserin; Oral dose of ketanserin.; Other Names: Ketensin
Other: Project 3: Functional connectivity; After baseline MRI scanning and CIMBI-36 PET, participants will undergo one psilocybine-intervention fMRI scan and one ketanserin-intervention fMRI scan. If P2 shows there are long term effects of psilocybine on 5-HT2AR levels, psilocybine will be fixed as the second intervention. If not, interventions will be randomized.	Drug: Psilocybine; Oral dose of psilocybine.; Other Names: Psilocybin; Drug: Ketanserin; Oral dose of ketanserin.; Other Names: Ketensin
Other: Project 2: Long term effects of psilocybin; After baseline MRI & CIMBI-36 PET-imaging, participants will receive one dose of oral psilocybine intervention. One and 12 weeks after dosing, participants will undergo post-intervention PET-scan. Subproject B: After baseline MRI & UCB-J PET-imaging, participants will receive one dose of oral psilocybine intervention. One week after dosing, participants will undergo post-intervention UCB-J PET-scan. Subproject C: After baseline MR imaging, participants will receive one dose of oral psilocybine (25 mg) or placebo. One month after dosing, participants will undergo a post-intervention MRI scan.	Drug: Psilocybine; Oral dose of psilocybine.; Other Names: Psilocybin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Psilocin/ketanserin blood concentrations and 5-HT2A receptor occupancy (i.e., binding potential).	The investigators aim to model relations psilocin/ketanserin blood drug concentrations and receptor occupancy, using C11-Cimbi-36 PET imaging.	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	Cimbi-36 PET scan binding potential at baseline and at one-week post psilocybin, and potentially also at 12 weeks post psilocybin.	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	Correlations between blood levels of ketanserin and psilocin and the estimated associated receptor occupancy with functional MRI neuroimaging data, including resting state networks. Changes in synaptic density will be assessed with 11C-UCB-J PET scans before and 1 week after psilocybin intervention.	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	Project 2, Subproject B. UCB-J PET scan binding potential at baseline and at one-week post psilocybin.	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	Project 2, Subproject C. Resting-state and task-based fMRI measures at baseline and one month post psilocybin.	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).	Differences in CEQ scores between groups (psilocybin with music compared to psilocybin without music). Effects are measured on a Likert-scale ranging from 0 (Not all all) to 5 (Extremely; More than ever). Higher scores thus reflect a more challenging experience. Project 2, Subproject C. PsiloZonic.	Immediately post-intervention.
Anxiety Outcome Measure 2: Acute psychological effects as assessed using 5D-Altered States of Consciousness (5D-ASC) scale.	Differences in 5D-ASC anxiety scores between groups (psilocybin with music compared to psilocybin without music). Effects are measured on a Visual analogue scale (VAS) scale ranging from 0 (No, not more than usually) to 100 (Yes, much more than usually). Higher scores on dimension anxiety thus reflect more anxiety. Project 2, Subproject C. PsiloZonic.	Immediately post-intervention.
Anxiety Outcome Measure 3: Acute psychological effects as assessed using Extended Subjective Drug Intensity (eSDI) scale.	Differences in eSDI anxiety scores between groups (psilocybin with music compared to psilocybin without music). Effects are measured on a Likert-scale ranging from 0 (Not all all) to 10 (Very much). Higher scores on item anxiety thus reflect more anxiety. Project 2, Subproject C. PsiloZonic.	During intervention.
Transformative Experiences Outcome Measure 1: Acute psychological effects as assessed using Mystical Type Experiences Questionnaire (MEQ) scale.	Differences in MEQ scores between groups (psilocybin with music compared to psilocybin without music). Effects are measured on a Likert-scale ranging from 0 (Not all all) to 5 (Extremely). Higher scores thus reflect a more profound mystical type experience. Project 2, Subproject C. PsiloZonic.	Immediately post-intervention.
Transformative Experiences Outcome Measure 2: Acute psychological effects as assessed using Psychological Insights Questionnaire (PIQ) scale.	Differences in PIQ scores between groups (psilocybin with music compared to psilocybin without music). Effects are measured on a Likert-scale ranging from 0 (Not all all) to 5 (Extremely). Higher scores thus reflect more psychological insight. Project 2, Subproject C. PsiloZonic.	Immediately post-intervention.
Transformative Experiences Outcome Measure 3: Acute psychological effects as assessed using Emotional Breakthrough Questionnaire (EBI) scale.	Differences in EBI scores between groups (psilocybin with music compared to psilocybin without music). Effects are measured on a Visual analogue scale (VAS) scale ranging from 0 (No, not more than usually) to 100 (Yes, much more than usually). Higher scores thus reflect more emotional breakthrough. Project 2, Subproject C. PsiloZonic.	Immediately post-intervention.
Persisting Effects Outcome Measure 1: Persisting psychological effects as assessed using Persisting Effects Questionnaire (PEQ) scale.	Differences in PEQ scores will be assessed between groups (psilocybin with music compared to psilocybin without music). Effects are measured on a Likert-scale ranging from 0 (Not all all) to 5 (Extremely). Higher scores thus reflect more persisting effects. Project 2, Subproject C. PsiloZonic.	One and three months post-intervention.

Collaborators and Investigators

• Sponsor: Gitte Moos Knudsen
• Investigators: Study Chair: Gitte M Knudsen, Professor, Neurobiology Research Unit, Rigshospitalet

Study record dates

Study Major Dates

• Study Start (Actual): March 3, 2017
• Primary Completion (Estimated): June 1, 2027
• Study Completion (Estimated): June 1, 2027

Study Registration Dates

• First Submitted: September 14, 2017
• First Submitted That Met QC Criteria: September 20, 2017
• First Posted (Actual): September 21, 2017

Study Record Updates

• Last Update Posted (Actual): October 16, 2023
• Last Update Submitted That Met QC Criteria: October 12, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Platelet Aggregation Inhibitors; Psychotropic Drugs; Serotonin Agents; Serotonin Antagonists; Hallucinogens; Psilocybin; Ketanserin
• Other Study ID Numbers: H-16026898

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Via database of Center for Integrated Molecular Brain Imaging (Knudsen et al 2016, NeuroImage) data will be available for neuroscience research community contingent on approval by scientific board.
• IPD Sharing Time Frame: Upon project completion
• IPD Sharing Access Criteria: All researchers can request access to data from the database by completing a standardized application form to provide detailed information about the specific database request. The application form and guidelines are available here. Please note that there are some formal requirements that must be fulfilled if the data request is from an international researcher. For example we do not have permission for sharing data outside of the EU, so researchers from a non-EU country will have to come here to work on the data instead.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No