Clinical TrialCrossoverHealthy VolunteersPsilocybinPlaceboPlaceboRecruiting

The Neurobiological Effect of 5-HT2AR Modulation

Non-randomised sequential experimental-medicine study (estimated n=200) using single oral doses of psilocybin and ketanserin to probe 5-HT2A receptor effects in healthy volunteers with PET and MRI outcomes.

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Target Enrollment
200 participants
Study Type
Phase I interventional
Design
Non-randomized, single Blind

Detailed Description

This experimental medicine project compares psilocybin (5-HT2A agonist) and ketanserin (5-HT2A antagonist) effects on brain function using MRI and multiple PET tracers (CIMBI-36, UCB-J) in healthy volunteers.

Design includes sequential allocation across subprojects examining receptor occupancy, long-term effects (1 and 12 week follow-ups), and functional connectivity with single oral dosing (25 mg specified in one subproject) and repeated neuroimaging assessments.

Study Protocol

Preparation

sessions

Dosing

1 sessions

Integration

sessions

Study Arms & Interventions

Psilocybin

experimental

Single oral psilocybin dose used across subprojects (25 mg specified in Subproject 2c).

Interventions

  • Psilocybin25 mg
    via Oral• single dose

    25 mg specified in Subproject 2c; other subprojects use a single oral dose (unspecified).

Ketanserin

active comparator

Oral 5-HT2A antagonist used for occupancy and fMRI comparisons.

Interventions

  • Placebo
    via Oral• single dose

    Ketanserin oral dose (unspecified) — encoded as non-listed active comparator.

Placebo

inactive

Oral placebo comparator used in Subproject 2c.

Interventions

  • Placebo
    via Oral• single dose

    Placebo oral capsule.

Participants

Ages
18 – 99
Sexes
Male & Female

Inclusion Criteria

  • Inclusion Criteria:
  • 1) Healthy individuals above 18 years of age.

Exclusion Criteria

  • 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 Protocol, Arms & Participants

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Study Details

Locations

Neurobiology Research Unit, Rigshospitalet — Copenhagen, Denmark

Related Publications

Open AccessindividualSecondary analysis

Psilocybin-induced changes in brain network integrity and segregation correlate with plasma psilocin level and psychedelic experience

This fMRI study (n=15) investigated the effects of psilocybin (14-21mg/70kg) on the brain and found that the higher the psilocin (active metabolite of psilocybin) and subjective drug experience (SDI) correlated with lower network integrity and segregation (less top-down, more bottom-up).

Published
Journal
European Neuropsychopharmacology
Authors
Madsen, M. K., Stenbaek, D. S., Arvidsson, A., Armand, S., Marstrand- Joergensen, M. R., Johansen, S. S., Linnet, K., Ozenne, B., Knudsen, G. M., Fisher, P. M.
Open AccessindividualLong-term follow-up

Psilocybin-Induced Mystical-Type Experiences are Related to Persisting Positive Effects: A Quantitative and Qualitative Report

In healthy volunteers given medium–high doses of psilocybin, greater acute mystical-type experiences (MEQ total score)—notably the Positive Mood and Mysticality subscales—were associated with persisting positive psychological effects at three months, whereas Transcendence of Time and Space and Ineffability were not. The paper also provides the first qualitative descriptions of complete mystical experiences after oral psilocybin, emphasising themes of cosmic connection, familial love and profound beauty.

Published
Journal
Frontiers in Pharmacology
Authors
McCulloch, D. E-W., Madsen, M. K., Jensen, P. S., Ozenne, B., Armand, S., Knudsen, G. M., Fisher, P. M., Stenbæk, D. S., Grywacz, M. Z.
Open AccessindividualPrimary

Navigating the chaos of psychedelic neuroimaging: A multi-metric evaluation of acute psilocybin effects on brain entropy

In a 28-participant, 121-scan fMRI study, acute psilocybin produced consistent increases on a subset of entropy measures (e.g. Shannon entropy of the spatial eigendistribution, path-length, instantaneous correlations, brain‑state switching and short-timescale sample entropy) while eight of 14 metrics showed no effect and Lempel‑Ziv complexity was inconsistently positive. Limited correlations across metrics indicate these entropy measures index distinct aspects of brain dynamics rather than a single unified construct.

Published
Journal
MedRvix
Authors
McCulloch, D. E-W., Olsen, A. S., Ozenne, B., Armand, S., Madsen, M. K., Knudsen, G. M., Fisher, P. M., Stenbæk, D. S.
Open AccessindividualSecondary analysis

Psilocybin’s effect on human brain synaptic plasticity

A single psilocybin dose increased frontal and hippocampal synaptic density in healthy participants one week after dosing, measured with [11C]UCB-J PET targeting synaptic vesicle glycoprotein 2A (SV2A). Participants dosed in a therapeutic-like room showed stronger mystical-type experiences, longer-lasting psychological benefits and greater synaptic increases than those dosed inside an MRI scanner, indicating that psilocybin’s neuroplastic effects are modulated by environmental context.

Published
Journal
Research Square
Authors
Johansen, A., Plavén-Sigray, P., Madsen, M. K., Søndergaard, A., Messel, C., Geisler, M., Nasser, A., McCulloch, D. E-W., Beliveau, V., Vassilieva, A., Lund, A., Lehel, S., Ozenne, B., Stenbæk, D. S., Fisher, P. M., Svarer, C.
Paywallmeta

Effects of psilocybin on sleep quality and brain microstructure in chronic cluster headache

This observational study (n=11) of people with chronic cluster headache examined three doses of psilocybin (10 mg/70 kg) and found that self-reported sleep quality improved after treatment. Brain scans showed differences in microstructure and water diffusivity between patients and healthy controls, but psilocybin did not produce clear average changes in these measures.

Published
Journal
Journal of Psychopharmacology
Authors
Brendstrup-Brix, K., Ozenne, B., Fisher, P. M., Stenbæk, D. S., Petersen, A. S., Armand, S., McCulloch, D. E. W., Marstrand-Joergensen, M. R., Ulv Larsen, S. M., Johansen, A., Jensen, R. H., Knudsen, G. M., Madsen, M. K.
Open Accessindividual

Multi-metric evaluations of acute psychedelic effects on fMRI brain entropy

This brain imaging study (n=28) examined how psilocybin affected several fMRI-based measures of brain entropy in healthy volunteers. Some entropy metrics rose with subjective and objective drug effects, but many did not change and the measures were only weakly related to each other, suggesting they do not capture a single brain process.

Published
Journal
Nature Communications
Authors
McCulloch, D. E. W., Olsen, A. S., Ozenne, B., Larsen, K., Stenbæk, D. S., Armand, S., Madsen, M. K., Knudsen, G. M., Fisher, P. M.

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