The Neurobiological Effect of 5-HT2AR Modulation

Study arms

• 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 · Drug: Ketanserin

• 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

• 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 · Drug: Ketanserin

Interventions

• DrugPsilocybine

  Oral dose of psilocybine.

  Also known as: Psilocybin

• DrugKetanserin

  Oral dose of ketanserin.

  Also known as: Ketensin

Primary outcomes

1. 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.

   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).

2. 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.

   Time frame: Change in Cimbi-36 binding potential from baseline to one week post psilocybin (and potentially also at 12 weeks after psilocybin).

3. 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.

   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)

4. 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.

   Time frame: Change in UCB-J binding potential from baseline to one week post psilocybin.

5. 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.

   Time frame: Change in fMRI measures from baseline to one month post psilocybin

6. 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.

   Time frame: Immediately post-intervention.

7. 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.

   Time frame: Immediately post-intervention.

8. 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.

   Time frame: During intervention.

9. 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.

   Time frame: Immediately post-intervention.

10. 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.

    Time frame: Immediately post-intervention.

11. 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.

    Time frame: Immediately post-intervention.

12. 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.

    Time frame: One and three months post-intervention.

Individual participant data

Plan to share: Yes — 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.

Supporting information: Study protocol