Elucidating the Relevance of the Psychedelic Experience to Psilocybin's Anti-Anhedonic Effects

NCT07490353 | Recruiting Phase 1 DMC

• 2 other identifiers: PSY-NIL-00162024-519265-22-00
• Study Type: interventional
• Target: 85
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this clinical trial is to systematically categorize potential prohedonic effects of psilocybin in patients with anhedonia in depression. The main questions it aims to answer are: Primary Objectives

• Take 25 mg of psilocybin p.o. in two sessions, in one of the two sessions they will take 1 mg risperidone p.o. before ingestion of psilocybin, to block psilocybin's acute psychedelic effects.
• Undergo 3 MRI sessions, one before the first psilocybin session ('baseline') and one session each on the day after each respective psilocybin session.
• Perform a variety of tasks during each fMRI session to asses the treatment's effects on anhedonia.

Conditions

Depression - Major Depressive Disorder; Anhedonia

Keywords

Psilocybin; Psilocin; Psychedelic; Anhedonia; Depression; MRI; fMRI; functional MRI; Pharmaco-Imaging; MDD; Serotonin; Risperidone

Outcome Measures

Primary Outcomes (16)

• Aesthetic task

  This task is designed to evoke and probe the nature and extent of the aesthetic experience. Two sets of stimuli will be presented. Each set consists of 20 pieces of self-selected music with 10 pieces inducing highly hedonic experiences and 10 neutral pieces. After stimulus presentation, subjects will rate how aesthetically moving the experience was, whether they experienced chills, and what the valence of the experience was on a Likert scale.

  From enrolment until the second assessment session (up to 9 weeks after enrolment)

• Monetary Incentive Delay (MID) Task

  The MID task is established to evoke and assess reward and punishment, which are centrally involved in anhedonia. The task observes several stages of reward processing, i.e., reward prediction, anticipation and reward consumption. The aim of the paradigm is to maximize gain and avoid loss by fast reaction upon presentation of a target stimulus. A trial starts with the presentation of a cue, indicating the potential gain or loss (e.g., -1€, +3€). After a variable delay of for instance 3-5 seconds the target stimulus is shown, and subjects press a button as fast as possible. If the reaction is within a given time limit the amount is gained or loss avoided. Otherwise, the amount is not gained or lost. Each button press is followed by immediate feedback, showing the outcome and the accumulated amount of money.

  From enrolment until the last imaging session (up to 8 weeks after enrolment)

• Sexual arousal task

  This task has been implemented by our group to assess changes to sexual arousal, a central and burdensome, yet often understudied, component of anhedonia. During this task, subjects are presented images intended to be sexually arousing and are instructed to denote the extent to which they find the image arousing.

  From enrolment until the last imaging session (up to 8 weeks after enrolment)

• Cognitive Flexibility Inventory (CFI)

  The CFI is a 20-item self-report measure to assess two aspects of cognitive flexibility: the adaptive ability to perceive multiple alternative explanations for life occurrences and the ability to generate multiple alternative solutions to difficult situations, as well as having an internal locus of control, or the tendency to perceive difficult situations as somewhat controllable.

  From enrolment until the last follow-up session (expected at about 12 weeks after enrolment)

• Intensity rating

  A self-reported rating of the subjective intensity of the acute psychedelic experience will be collected after each medication session on a scale from 0 (not at all) to 4 (extreme).

  From enrolment until the second medication session (up to 8 weeks after enrolment)

• Warwick-Edinburgh Mental Well-being Scale (WEMWBS)

  The WEMWBS is a self-report scale which will be used to assess mental well-being over the course of study participation.

  From enrolment until the last follow-up session (expected at about 12 weeks after enrolment)

• Beck-Depression-Inventory (BDI)

  The BDI is a self-rated scale which is used to assess symptoms of depression.

  From enrolment until the last follow-up session (expected at about 12 weeks after enrolment)

• Montgomery-Åsberg Depression Rating Scale (MADRS)

  The MADRS is a observer-rated scale which is used to assess symptoms of depression.

  From enrolment until the last follow-up session (expected at about 12 weeks after enrolment)

• Dimensional Anhedonia Rating Scale (DARS)

  The DARS is a self-report scale that measures anhedonia across four domains on a five-point-likert scale.

  From enrolment until the last follow-up session (expected at about 12 weeks after enrolment)

• Aesthetic Experiences Scale (AES)

  The AES is a self-report scale which is used to assess aesthetic experiences in the form of 'aesthetic chills', the response of goose bumps and shivers in response to the arts.

  From enrolment until the last follow-up session (expected at about 12 weeks after enrolment)

• Temporal Experience of Pleasure Scale (TEPS)

  The TEPS is a self-rating scale which is used to assess the experience of anticipatory and consummatory experiences of pleasure.

  From enrolment until the last follow-up session (expected at about 12 weeks after enrolment)

• Barcelona Music Reward Questionnaire (BMRQ)

  The BMRQ is a psychometric scale designed to assess different factors underlying the experience of music reward, as measured through 20 items on a 5-point Likert scale.

  From enrolment until the last follow-up session (expected at about 12 weeks after enrolment)

• 5-Dimensional Altered States of Consciousness Rating (5D-ASC)

  Properties of the psychedelic experience as assessed via the 5D-ASC, a a 94-item self-report scale that assesses the participants' alterations from normal waking Consciousness.

  From enrolment until the second medication session (up to 8 weeks after enrolment)

• Mystical Experience Questionnaire (MEQ30)

  Properties of the psychedelic experience as assessed via the MEQ30, a 30 point self-rated scale, which is used to measure the intensity of common aspects of a psychedelic experience (divided into mystical, positive mood, transendence of time and space, and ineffability).

  From enrolment until the second medication session (up to 8 weeks after enrolment)

• Challenging Experience Questionnaire (CEQ)

  Properties of the psychedelic experience as assessed via the Challenging Experience Questionnaire (CEQ), an instrument designed to measure challenging psychological experiences associated with the acute effects of psychedelics.

  From enrolment until the second medication session (up to 8 weeks after enrolment)

• Connor-Davidson Resilience Scale (CD-RISC)

  The CD-RISC is a self-rating scale which is used to assess changes in study participants' resilience over the course of their participation.

  From enrolment until the last follow-up session (expected at about 12 weeks after enrolment)

Secondary Outcomes (4)

• Cytokine panel

  From enrolment until the last follow-up session (expected at about 12 weeks after enrolment)

• Brain-derived neurotrophic factor (BDNF) concentration

  From enrolment until the last follow-up session (expected at about 12 weeks after enrolment)

• Neural activity

  Over the course of the three MRI sessions (3-14 days after enrolment, 1 day after the first medication session, 6 weeks after the second measurement)

• Brain network dynamic complexity

  Over the course of the three MRI sessions (3-14 days after enrolment, 1 day after the first medication session, 6 weeks after the second measurement)

Other Outcomes (1)

• Side effect monitoring

  From enrolment until the last follow-up session (expected at about 12 weeks after enrolment)

Study Arms (2)

Psilocybin first, psilocybin + risperidone second

EXPERIMENTAL

Participants recieve psilocybin alone in the first session, psilocybin and risperidone in the second session

Drug: Psilocybin (Usona Institute); Drug: Risperidone 1 MG; Diagnostic Test: MRI

Psilocybin + risperidone first, psilocybin second

EXPERIMENTAL

Participants recieve psilocybin and risperidone in the first session, psilocybin alone in the second session

Drug: Psilocybin (Usona Institute); Drug: Risperidone 1 MG; Diagnostic Test: MRI

Interventions

Psilocybin (Usona Institute) DRUG

Participants will recieve two doses of Psilocybin 25 mg to be taken orally over the course of the study.

Also known as: Psilocybin

Psilocybin + risperidone first, psilocybin second; Psilocybin first, psilocybin + risperidone second

Risperidone 1 MG DRUG

30 minutes before administration of psilocybin in one of the sessions to inhibit acute psychedelic effects

Also known as: Risperidone, Risperdal

Psilocybin + risperidone first, psilocybin second; Psilocybin first, psilocybin + risperidone second

MRI DIAGNOSTIC_TEST

Over the course of the study, participants will undergo three MRI measurement sessions. * M1 (baseline, before treatment) * M2 \& M3 (one day after each psilocybin session)

Psilocybin + risperidone first, psilocybin second; Psilocybin first, psilocybin + risperidone second

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• All participants:
• General health based on medical history, physical examination, blood draw, and electrocardiogram
• Age 18 to 55 years
• Right-handedness (due to potential lateralization effects of left-handed subjects)
• Willingness and competence to sign the informed consent form
• Normal BMI weight range (18.5-24.9)
• Specific to healthy subjects:
• Psychiatric health based on structured clinical interview for DSM-5 (SCID)
• No concomitant medication
• Specific to anhedonia patients:
• Major depressive episode (first or recurrent) based on structured clinical interview for DSM-5 (SCID) and ICD-10
• Fulfilling the ICD-10 diagnostic criterion of anhedonia
• No concomitant medication, specifically also free of antidepressants or other psychopharmaceuticals (for at least 2 weeks, 5 weeks for fluoxetin)

You may not qualify if:

• All participants:
• Current or history of neurological disease
• Current medical illness requiring treatment
• Pregnancy or current breastfeeding
• Current or former substance dependency
• Any contraindication for MRI
• Failure to comply with the study protocol or to follow the instruction of the investigating team
• Failure to confirm effective use of contraception in females at least 8 weeks before and after study participation each
• First-degree relative with bipolar disorder or schizophrenia
• Specific to healthy subjects:
• \- Psychiatric diagnosis
• Specific to anhedonia patients:
• \- Psychiatric comorbidities excluding anxiety disorders and/or obsessive-compulsive disorders

Sponsors & Collaborators

• Medical University of Vienna: lead
• University of Vienna: collaborator

Study Sites (1)

Medical University of Vienna, Department of Psychiatry and Psychotherapy, Division of General Psychiatry

Vienna, Vienna, 1160, Austria

RECRUITING

MeSH Terms

Conditions

Anhedonia; Depression

Interventions

Psilocybin; Risperidone

Condition Hierarchy (Ancestors)

Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Behavioral Symptoms; Behavior

Intervention Hierarchy (Ancestors)

Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Tryptamines; Indolizidines; Indolizines; Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring

Study Officials

• Marie Spies, Priv.-Doz. DDr.

  Medical University of Vienna, Department of Psychiatry and Psychotherapy, Division of General Psychiatry

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Marie Spies, Priv.-Doz. DDr.

CONTACT

+43 1 40400; marie.spies@meduniwien.ac.at

Clemens Schmidt, MD

CONTACT

+43 1 40400; clemens.schmidt@meduniwien.ac.at

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Full Professor in Clinical Neurosciences

Study Record Dates

• First Submitted: November 17, 2025
• First Posted: March 24, 2026
• Study Start: November 1, 2025
• Primary Completion (Estimated): May 31, 2028
• Study Completion (Estimated): May 31, 2028
• Last Updated: March 24, 2026

Record last verified: 2026-03

Locations

AU (1)