The ENHANCE Study: taVNS and Psilocybin

Phase 1

Recruiting

• Conditions: Psychedelic Experiences; Vagus Nerve Stimulation; Healthy
• Interventions: Drug: Psilocybin; Device: Transcutaneous auricular Vagus Nerve Stimulation (taVNS); Behavioral: Psychosocial Support Alone; Other: Sham taVNS

• Registration Number: NCT05866471
• Lead Sponsor: University of Wisconsin, Madison

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.

Detailed Description

One hundred and eight medically healthy adult volunteers with a modest decrement in wellbeing will receive a single open-label 25 mg dose of psilocybin administered within a "set and setting" (SaS) framework of psychological support provided by trained facilitators, such as has been successfully employed in prior psychedelic studies at UW-Madison. The SaS protocol will include 2-4 hours of preparation, a 6- to 8-hour psilocybin dosing session and an hour-long integration session 1 day and 9 days post dosing. All subjects will receive various combinations of active taVNS or sham taVNS prior to, or following, psilocybin dosing.

Active and sham taVNS sessions will last 20 minutes and will occur twice daily (morning and afternoon/evening) for 7 consecutive days, using an "at home" protocol that has been used safely and effectively by study collaborators. taVNS is a non-invasive low-risk procedure.

Subjects will be randomized with equal allocation to one of four conditions: 1) seven days of sham taVNS prior to psilocybin dosing and 7 days of active taVNS post- psilocybin dosing (Group 1: n=27); 2) seven days of sham taVNS prior to psilocybin dosing and 7 days of sham taVNS post- psilocybin dosing (Group 2: n=27); 3) seven days of sham taVNS prior to psilocybin dosing and psilocybin with psychosocial support post-dosing (Group 3: n=27); and 4) seven days of active taVNS prior to psilocybin dosing and 7 days of sham taVNS post- psilocybin dosing (Group 4: n=27). Importantly, participants in all groups will receive psychosocial support in addition to their randomization status (i.e., taVNS or sham taVNS prior to, or following psilocybin, or psychosocial support alone), as the provision of psychosocial support is the current standard of care for the use of psychedelics in FDA-regulated clinical trials (FDA 2023). It is anticipated that a total sample of 108 subjects will be enrolled to provide 100 subjects who complete study activities/assessments sufficient to provide evaluable data for testing study primary and exploratory outcomes.

Study Timeline

• Study First Submitted: 2023-05-10
• Study First Submitted QC: 2023-05-10
• Study First Posted: 2023-05-19
• Study Start: 2025-01-27
• Status Verified: 2025-04
• Last Update Submitted: 2025-04-09
• Last Update Posted: 2025-04-10
• Primary Completion: 2027-11
• Study Completion: 2028-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 108

Inclusion Criteria

• English speaking
• Ability/willingness to complete all study activities
• Modest reduction in emotional well-being
• Medically healthy (does not meet criteria for an exclusionary medical condition)
• Blood pressure and heart rate within established ranges at screening
• Use of acceptable contraceptive methods (sexually active males and women of childbearing potential)

Exclusion Criteria

• Clinically significant safety lab abnormalities (i.e., Complete Blood Count with Differential, Comprehensive Metabolic Panel, and urinalysis)
• Current exclusionary medical illness or Diagnostic and Statistical Manual (DSM-5) psychiatric diagnosis
• 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)
• Hypertension or tachycardia
• 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, deafness, or colorblindness
• Family history of a psychotic disorder in a first degree relative

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: FACTORIAL

Arm && Interventions

Group	Intervention	Description
Group 1: Sham taVNS + Psilocybin + taVNS	Psilocybin	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.
Group 2: Sham taVNS + Psilocybin + Sham taVNS	Psilocybin	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.
Group 3: Sham taVNS + Psilocybin + Psychosocial Support Alone	Psilocybin	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.
Group 4: taVNS + Psilocybin + Sham taVNS	Psilocybin	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.
Group 1: Sham taVNS + Psilocybin + taVNS	Transcutaneous auricular Vagus Nerve Stimulation (taVNS)	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.
Group 1: Sham taVNS + Psilocybin + taVNS	Sham taVNS	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.
Group 2: Sham taVNS + Psilocybin + Sham taVNS	Sham taVNS	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.
Group 3: Sham taVNS + Psilocybin + Psychosocial Support Alone	Psychosocial Support Alone	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.
Group 3: Sham taVNS + Psilocybin + Psychosocial Support Alone	Sham taVNS	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.
Group 4: taVNS + Psilocybin + Sham taVNS	Transcutaneous auricular Vagus Nerve Stimulation (taVNS)	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.
Group 4: taVNS + Psilocybin + Sham taVNS	Sham taVNS	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.

Primary Outcome Measures

Name	Time	Method
Memory Experiences Questionnaire (MEM-Q): Comparison of taVNS Administration vs. Treatment as Usual	8 weeks	The MEM-Q is a 31-item self-report scale 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).
Functional Magnetic Resonance Imaging (fMRI): Comparison of taVNS Administration vs. Treatment as Usual	Day 1 and Day 56 Post- Psilocybin Dose	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.
Warwick-Edinburgh Mental Wellbeing Scale (WEMWBS): Comparison of taVNS Administration vs. Treatment as Usual	8 weeks	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.
Summary of Adverse Events	up to 8 weeks	Adverse events (AEs) categorized by CTCAE v5.0 criteria at all assessments (6 study visits).

Trial Locations

Locations (1)

University of Wisconsin - Madison; 🇺🇸 Madison, Wisconsin, United States