The ENHANCE Study: taVNS and Psilocybin

NCT05866471 | Recruiting Phase 1 FDA Drug

• 3 other identifiers: 2024-0463A538900Protocol Version 12/30/25
• Study Type: interventional
• Target: 108
• Locations: 1 country
• Sites: 1

Brief Summary

This study will examine whether combining a single dose of psilocybin with non-invasive transcutaneous auricular vagus nerve stimulation (taVNS), a potential inducer of neuroplasticity and enhanced memory formation, will enhance the long-term beneficial behavioral effects of psilocybin when compared to sham taVNS or no VNS by allowing memory for insights gained during the psychedelic experience to remain vivid after they will have faded in subjects who receive psilocybin followed by sham taVNS or no VNS.

Conditions

Vagus Nerve Stimulation; Healthy; Psychedelic Experiences

Keywords

Psilocybin; Psychedelics; Vagus Nerve Stimulation; Healthy Volunteer

Outcome Measures

Primary Outcomes (4)

• Memory Experiences Questionnaire (MEM-Q-PSIL): Comparison of taVNS Administration vs. Treatment as Usual

  The MEM-Q is 31-item self-report scales designed to measure 10 phenomenological qualities of autobiographical memories: Vividness, Coherence, Accessibility, Time Perspective, Sensory Details, Visual Perspective, Emotional Intensity, Sharing, Distancing and Valence. Ratings are made on a 5-point Likert scale, ranging from 1 (strongly disagree) to 5 (strongly agree).

  8 weeks

• Functional Magnetic Resonance Imaging (fMRI): Comparison of taVNS Administration vs. Treatment as Usual

  Activation in brain regions associated with cued autobiographical memory retrieval will be assessed with fMRI. Group comparisons will examine differences in whole brain blood oxygenated level dependent (BOLD) signal and connectivity based on previously established seed-based methods using a priori brain regions implicated in autobiographical memory retrieval corresponding dosing session stimuli. The study team will update with more specific information when the details are confirmed.

  Day 1 and Day 56 Post- Psilocybin Dose

• Warwick-Edinburgh Mental Wellbeing Scale (WEMWBS): Comparison of taVNS Administration vs. Treatment as Usual

  The WEMWBS is a 14-item self-report scale that was designed to measure the psychological well-being of a population. The questions use a five-point Likert scale. The items are all worded positively and cover both feeling and functioning aspects of mental wellbeing. Items on the questionnaire are rated on a 5-point scale, where 1= "None of the time", 2= "rarely", 3= "some of the time", 4= "often", 5= "all the time". A total scale score is calculated by summing the 14 individual item scores. The total possible range of scores for the WEMWBS is 14-70 with higher scores indicating a greater well-being.

  8 weeks

• Summary of Adverse Events

  Adverse events (AEs) categorized by CTCAE v5.0 criteria at all assessments (6 study visits).

  up to 8 weeks

Study Arms (4)

Group 1: Sham taVNS + Psilocybin + taVNS

EXPERIMENTAL

Group 1 will receive twice daily sham taVNS for 7 days immediately prior to psilocybin dosing. Post-psilocybin dosing, they will receive twice-daily taVNS paired with psychedelic session contextual cues for 7 days.

Drug: Psilocybin; Device: Transcutaneous auricular Vagus Nerve Stimulation (taVNS); Other: Sham taVNS

Group 2: Sham taVNS + Psilocybin + Sham taVNS

SHAM COMPARATOR

Group 2 will receive twice daily sham taVNS for 7 days immediately prior to psilocybin dosing. Post-psilocybin dosing, they will receive twice-daily sham taVNS paired with psychedelic session contextual cues for 7 days.

Drug: Psilocybin; Other: Sham taVNS

Group 3: Sham taVNS + Psilocybin + Psychosocial Support Alone

ACTIVE COMPARATOR

Group 3 will receive twice daily sham taVNS for 7 days immediately prior to psilocybin dosing. Post-psilocybin dosing, they will receive psychosocial support alone, comprised of an integration session 1 day and 1-week post-psilocybin dosing. They will not receive active or sham taVNS post-psilocybin.

Drug: Psilocybin; Behavioral: Psychosocial Support Alone; Other: Sham taVNS

Group 4: taVNS + Psilocybin + Sham taVNS

ACTIVE COMPARATOR

Group 4 will receive twice daily taVNS for 7 days immediately prior to psilocybin dosing. Post-psilocybin dosing, they will receive twice-daily sham taVNS paired with psychedelic session contextual cues for 7 days.

Drug: Psilocybin; Device: Transcutaneous auricular Vagus Nerve Stimulation (taVNS); Other: Sham taVNS

Interventions

Psilocybin DRUG

The psilocybin is produced under Good Manufacturing Practice and is in a capsule that contains 25 mg of botanically-derived psilocybin.

Also known as: Psilocybine, Psilocibin, Filament Health Psilocybin, PEX010

Group 1: Sham taVNS + Psilocybin + taVNS; Group 2: Sham taVNS + Psilocybin + Sham taVNS; Group 3: Sham taVNS + Psilocybin + Psychosocial Support Alone; Group 4: taVNS + Psilocybin + Sham taVNS

Psychosocial Support Alone BEHAVIORAL

Participants assigned to Psychosocial Support Alone will not receive taVNS following psilocybin dosing.

Group 3: Sham taVNS + Psilocybin + Psychosocial Support Alone

Transcutaneous auricular Vagus Nerve Stimulation (taVNS) DEVICE

For both the active and sham taVNS procedure, participants will be provided with, and trained on, taVNS devices that apply gentle stimulation to the left ear via either electrodes or an earpiece that fits over the left ear.

Group 1: Sham taVNS + Psilocybin + taVNS; Group 4: taVNS + Psilocybin + Sham taVNS

Sham taVNS OTHER

For both the active and sham taVNS procedure, participants will be provided with, and trained on, taVNS devices that apply gentle stimulation to the left ear via either electrodes or an earpiece that fits over the left ear.

Group 1: Sham taVNS + Psilocybin + taVNS; Group 2: Sham taVNS + Psilocybin + Sham taVNS; Group 3: Sham taVNS + Psilocybin + Psychosocial Support Alone; Group 4: taVNS + Psilocybin + Sham taVNS

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• English speaking
• Ability/willingness to complete all study activities
• Modest reduction in emotional well-being
• Blood pressure and heart rate within established ranges at screening
• Use of acceptable contraceptive methods (sexually active males and women of childbearing potential)

You may not qualify if:

• Clinically significant safety lab abnormalities (i.e., Complete Blood Count with Differential, Comprehensive Metabolic Panel, and urinalysis)
• Current or clinically significant psychiatric disorder that, in the investigator's judgment, would interfere with participation or increase risk
• Current use of drugs or medications, prescribed or otherwise, that may interact with psilocybin
• Use of investigational drugs, biologics, or devices within 30 days of enrollment
• Use of psychedelic or related agents within three months of Dosing Day
• Clinically significant electrocardiogram (ECG)
• Vitals outside acceptable range
• Pregnancy and currently breastfeeding
• Unwillingness to go without tobacco products for 12 hours or more
• Inability to undergo fMRI scanning
• Recent ear trauma, hearing loss (if clinically significant), or deafness
• Family history of a psychotic disorder in a first degree relative

Sponsors & Collaborators

• University of Wisconsin, Madison: lead
• Tiny Blue Dot Foundation: collaborator

Study Sites (1)

University of Wisconsin - Madison

Madison, Wisconsin, 53715, United States

RECRUITING

MeSH Terms

Interventions

Psilocybin; Psychiatric Rehabilitation

Intervention Hierarchy (Ancestors)

Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Tryptamines; Indolizidines; Indolizines; Rehabilitation; Therapeutics; Health Services; Health Care Facilities Workforce and Services

Study Officials

• Charles Raison, MD

  University of Wisconsin, Madison

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Program Manager

CONTACT

608-265-4987; enhance@psychiatry.wisc.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: randomization will be stratified by sex

Study Record Dates

• First Submitted: May 10, 2023
• First Posted: May 19, 2023
• Study Start: January 27, 2025
• Primary Completion (Estimated): November 1, 2027
• Study Completion (Estimated): January 1, 2028
• Last Updated: January 23, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will share
• Time Frame: Following publication of primary study findings.
• Access Criteria: All de-identified data will be made available to qualified researchers in a way that protects subject confidentiality and adheres to HIPAA policies. Both internal and external requests for data will be handled by the Principal Investigator (PI) to ensure equitable access, fairness, and safeguards. After reviewing a short proposal prepared by an external investigator, the PI will approve requests with appropriate experimental design, scientific merit, and Institutional Review Board (IRB) approval and recommend revisions for proposals requiring further justification or modifications. Informed consent documents will provide sufficient detail about the intent to archive, share, and re-analyze data. MRI data will also be shared upon request using the same data sharing process described above. To facilitate interpretation of the data, imaging parameters, gender, age, and racial information will be shared and associated with the dataset.

Locations

US (1)