HealthyPhase 1ENHANCENCT05866471
The ENHANCE Study: taVNS and Psilocybin
A Phase 1 study testing Psilocybin, Transcutaneous auricular Vagus Nerve Stimulation (taVNS) and Psychosocial Support Alone in people with Healthy and Psychedelic Experiences, run by University of Wisconsin, Madison at 1 site in United States.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 to 70 yearsHealthy volunteers can take part
- Conditions the study is for
- Healthy, Psychedelic Experiences, Vagus Nerve Stimulation
- What is being tested?
- Psilocybin, Transcutaneous auricular Vagus Nerve Stimulation (taVNS) and Psychosocial Support Alone
- Type of treatment
- Pill or oral medicine, Medical device, Lifestyle or therapy programme
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 115 participants
- Where
- 1 siteUnited States
- Study dates
- 27 Jan 2025to Jan 2028
- Phase
- Phase 1
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 70 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- 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)
Who cannot join
- 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)
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- 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
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site, 1 recruiting
- Recruiting
University of Wisconsin - Madison
Madison, Wisconsin, 53715
Program Manager, enhance@psychiatry.wisc.edu
Christopher Nicholas, PhD
About this study
Official title: Activating Neuroplasticity to ENHANCE the Perception Box Expanding Effects of Psilocybin
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.
Read the 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.
- Conditions
- Healthy, Psychedelic Experiences, Vagus Nerve Stimulation
- Being tested
- Psilocybin, Transcutaneous auricular Vagus Nerve Stimulation (taVNS), Psychosocial Support Alone, Sham taVNS
- Keywords
- Psilocybin, Psychedelics, Vagus Nerve Stimulation, Healthy Volunteer
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PsilocybinDrug
Also called Psilocybine, Psilocibin, Filament Health Psilocybin, PEX010
The psilocybin is produced under Good Manufacturing Practice and is in a capsule that contains 25 mg of botanically-derived psilocybin.
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.
Psychosocial Support AloneBehavioural
Participants assigned to Psychosocial Support Alone will not receive taVNS following psilocybin dosing.
Sham taVNSOther
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.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: 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. Receives: 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. Receives: Drug: Psilocybin; Device: Transcutaneous auricular Vagus Nerve Stimulation (taVNS); Other: Sham taVNS |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: 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.
Measured: 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.
Measured: 8 weeks
Summary of Adverse Events
Adverse events (AEs) categorized by CTCAE v5.0 criteria at all assessments (6 study visits).
Measured: up to 8 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 May 2023
- Study start27 Jan 2025
- Primary completionNov 2027 (estimated)
- Study completionJan 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for HealthyStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Factorial
- Model description
- randomization will be stratified by sex
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 115 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of Wisconsin, Madison
- Sponsor type
- University, hospital or other
- Collaborators
- Tiny Blue Dot Foundation, Advanced Research Projects Agency for Health (ARPA-H)
- Responsible party
- Sponsor
- Investigators
- Charles Raison, MD, Principal investigator, University of Wisconsin, Madison
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05866471
- Sponsor's protocol ID
- 2024-0463
- Other IDs
- A538900, Protocol Version 9/28/26
- Acronym
- ENHANCE
- Status last verified
- Oct 2026
- First submitted
- 10 May 2023
- Last updated
- 20 Oct 2026
- Results posted
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: De-identified data including, but not limited to, demographics, questionnaires, adverse events, and fMRI data may be made available to qualified researchers upon request.