The RECAP2 Study: Midazolam and Psilocybin

Role of Experience, Conscious Awareness, and Plasticity in Psilocybin's Behavioral Effects - Follow-Up Study (The RECAP 2 Study)

The goal of this clinical trial is to learn about the role that inducing neuroplasticity (the brain's ability to adapt and change) plays in the behavioral effects of psilocybin in people who have experienced a mild decline in emotional wellbeing.

Researchers will compare different doses of psilocybin combined with midazolam or placebo to see what dose induces increased wellbeing.

Participants will:

• Receive one of four possible combinations of medications
• Undergo an MRI
• Complete questionnaires
• Undergo transcranial magnetic stimulation (TMS) and EEG

Study Overview

• Status: Recruiting
• Conditions: Psilocybin
• Intervention / Treatment: Drug: Psilocybin; Drug: Psilocybin; Drug: Midazolam; Drug: Saline

Detailed Description

The purpose of this study is to investigate the role that inducing neuroplasticity plays in the behavioral effects of psilocybin in people with modest decrements in emotional wellbeing.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: RECAP Study Contact; Phone Number: 608-263-4852; Email: recap2@psychiatry.wisc.edu

Study Locations

• United States
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • Recruiting
      • UW School of Medicine and Public Health

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Age 18 to 65 years at screening, of any identified gender and racial/ethnic group
• Physically healthy; does not meet criteria for an exclusionary medical condition
• English-speaking (able to provide consent and complete questionnaires)
• Modest decrement in self-reported wellbeing without the presence of a DSM-5 Axis I mood or anxiety disorder
• Able to undergo magnetic resonance imaging (MRI) and transcranial magnetic stimulation (TMS)

Exclusion Criteria:

• Exclusionary DSM-5 psychiatric diagnosis and/or active suicidal ideation
• Exclusionary medical conditions
• Clinically significant safety lab abnormalities (i.e., Complete Blood Count with Differential, Comprehensive Metabolic Panel, and urinalysis)
• Clinically significant electrocardiogram (ECG)
• Use of psychotropic or CNS-altering medications within 3 months of screening
• Hypertension or tachycardia

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group 1: Psilocybin and intravenous (IV) midazolam; Psilocybin (25 mg) + IV midazolam	Drug: Psilocybin; 25mg of psilocybin; Other Names: Psilocybine; Psilocibin; Drug: Psilocybin; 1mg of psilocybin; Other Names: Psilocybine; Psilocibin; Drug: Midazolam; The goal of the midazolam dosing regimen is to induce amnesia of the psychedelic experience without inducing over-sedation during the dosing session.
Experimental: Group 2: Psilocybin and IV saline; Psilocybin (25 mg) + IV saline (placebo for midazolam)	Drug: Psilocybin; 25mg of psilocybin; Other Names: Psilocybine; Psilocibin; Drug: Psilocybin; 1mg of psilocybin; Other Names: Psilocybine; Psilocibin; Drug: Saline; Saline will be administered as a placebo for midazolam
Experimental: Group 3: Psilocybin and IV midazolam; Psilocybin (1 mg/control) + IV midazolam	Drug: Psilocybin; 25mg of psilocybin; Other Names: Psilocybine; Psilocibin; Drug: Psilocybin; 1mg of psilocybin; Other Names: Psilocybine; Psilocibin; Drug: Midazolam; The goal of the midazolam dosing regimen is to induce amnesia of the psychedelic experience without inducing over-sedation during the dosing session.
Experimental: Group 4: Psilocybin and IV saline; Psilocybin (1 mg/control) + IV saline	Drug: Psilocybin; 25mg of psilocybin; Other Names: Psilocybine; Psilocibin; Drug: Psilocybin; 1mg of psilocybin; Other Names: Psilocybine; Psilocibin; Drug: Saline; Saline will be administered as a placebo for midazolam

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Warwick-Edinburgh Mental wellbeing Scale (WEMWBS)	WEMWBS is a 14-item questionnaire in which participants describe their experience of each item. It is scored on a 5-point Likert scale, possible range of 14-70 where higher scores indicate higher levels of wellbeing.	Baseline to 7 days post-dose
Change in Brief Experiential Avoidance Questionnaire (BEAQ)	The BEAQ is a 15-item questionnaire assessing participants agreement with wellbeing statements. It is scored on a 6-point Likert scale, ranging from 15-90 with higher scores indicating a greater tendency towards experiential avoidance	Baseline to 7 days post-dose
Change in transcranial magnetic stimulation evoked potential (TEP) amplitude	TEP measures neural excitability in the stimulated region of the brain.	Baseline to 7 days post-dose
Change in Probabilistic Reversal Learning (PRL)	Participants are presented with two stimuli or options and learn which one is more likely to be associated with a reward based on feedback after each trial. After a certain number of trials, the reward contingencies are reversed, meaning the previously advantageous option becomes less likely to be rewarded, and vice versa. The task assesses how quickly and effectively individuals can adapt to these changes in reward contingencies. Researchers analyze various performance metrics, such as the speed of reversal, the number of errors, and the patterns of choices (e.g., win-stay, lose-shift).	Baseline to 7 days post-dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Altered States of Consciousness (ASC) questionnaire	Participants will complete a selection of several questions from the ASC questionnaire that strongly associate positively or negatively with later antidepressant effect of psilocybin in patients with treatment resistant depression or capture classic features of the psychedelic experience. During the dosing session, investigator will repeatedly ask selected items from the ASC scale to get a "real time" measure of what the participants are experiencing. Each of these items will be scored separately. Higher score are indicative of a more intense psychedelic experience.	Dosing 1 day
Change in TEP amplitude	TEP measures neural excitability in the stimulated region of the brain.	Baseline to 28 days post-dose
Emotional Breakthrough Inventory (EBI)	The EBI is a 6-item scale that assesses the presence and severity of emotionally challenging/distressing experiences that occur during a psychedelic experience. Participants rate to what extent the statements apply to their experience by marking a single line across each scale. Scale ranges from not at all to very much so. Higher scores (more slashes toward the 'very much so' end) on the scale have been associated with enhanced well-being following psychedelic use	Dosing 1 day
Psychological Insight Questionnaire (PIQ)	The PIQ is a 23-item instrument designed to query self-perceived attainment of insight during a psychedelic medicine session. Items are rated on a 6-point Likert scale, 0 = no not at all and 5 = extremely. Possible scares range from 0-115, with higher scores indicating greater insight.	Dosing 1 day
Change in WEMWBS	WEMWBS is a 14-item questionnaire in which participants describe their experience of each item. It is scored on a 5-point Likert scale, possible range of 14-70 where higher scores indicate higher levels of wellbeing.	Baseline to 28 days post-dose
Change in BEAQ	The BEAQ is a 15-item questionnaire assessing participants agreement with wellbeing statements. It is scored on a 6-point Likert scale, ranging from 15-90 with higher scores indicating a greater tendency towards experiential avoidance	Baseline to 28 days post-dose
Change in PRL	Participants are presented with two stimuli or options and learn which one is more likely to be associated with a reward based on feedback after each trial. After a certain number of trials, the reward contingencies are reversed, meaning the previously advantageous option becomes less likely to be rewarded, and vice versa. The task assesses how quickly and effectively individuals can adapt to these changes in reward contingencies. Researchers analyze various performance metrics, such as the speed of reversal, the number of errors, and the patterns of choices (e.g., win-stay, lose-shift).	Baseline to 28 days post-dose

Collaborators and Investigators

• Sponsor: University of Wisconsin, Madison
• Collaborators: Vail Health Foundation
• Investigators: Principal Investigator: Charles Raison, MD, University of Wisconsin, Madison

Publications and helpful links

Helpful Links

• Take the pre-screening survey

Study record dates

Study Major Dates

• Study Start (Actual): August 7, 2025
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): December 1, 2027

Study Registration Dates

• First Submitted: November 14, 2024
• First Submitted That Met QC Criteria: November 15, 2024
• First Posted (Actual): November 18, 2024

Study Record Updates

• Last Update Posted (Actual): April 3, 2026
• Last Update Submitted That Met QC Criteria: March 31, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: sub-optimal wellbeing
• Additional Relevant MeSH Terms: Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Alkaloids; Indoles; Inorganic Chemicals; Chlorine Compounds; Indole Alkaloids; Indolizidines; Indolizines; Benzazepines; Benzodiazepines; Tryptamines; Sodium Compounds; Chlorides; Hydrochloric Acid; Midazolam; Psilocybin; Sodium Chloride
• Other Study ID Numbers: 2024-0852; A538900 (Other Identifier: UW Madison); SMPH/PSYCHIATRY/PSYCHIATRY (Other Identifier: UW Madison); Protocol Version 12/12/2025 (Other Identifier: UW Madison)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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