Pairing Psilocybin With Transcutaneous Auricular Vagus Nerve Stimulation (ENHANCE)

• ClinicalTrials.gov Identifier: NCT05866471
• Recruitment Status: Not yet recruiting
• First Posted: May 19, 2023
• Last Update Posted: May 16, 2024
• Sponsor: University of Wisconsin, Madison
• Collaborator: Tiny Blue Dot Foundation
• Information provided by (Responsible Party): University of Wisconsin, Madison

Study Description

Brief Summary:

This study will examine whether combining a single dose of psilocybin with non-invasive transcutaneous auricular vagus nerve stimulation (taVNS), a known inducer of neuroplasticity and enhanced memory formation, will enhance the long-term beneficial behavioral effects of psilocybin when compared to sham taVNS 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.

Condition or disease	Intervention/treatment	Phase
Healthy; Psychedelic Experiences; Vagus Nerve Stimulation	Drug: Psilocybin; Device: Transcutaneous auricular Vagus Nerve Stimulation (taVNS); Device: Sham taVNS; Behavioral: Treatment as Usual (TAU)	Phase 1

Detailed Description:

One hundred and eight adults 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 University of Wisconsin-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 treatment as usual post- psilocybin 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). 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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 108 participants
• Allocation: Randomized
• Intervention Model: Factorial Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Basic Science
• Official Title: Activating Neuroplasticity to ENHANCE the Perception Box Expanding Effects of Psilocybin
• Estimated Study Start Date: August 2024
• Estimated Primary Completion Date: July 2027
• Estimated Study Completion Date: October 2027

Arms and Interventions

Arm	Intervention/treatment
Experimental: Group 1: Sham taVNS + Psilocybin + 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.	Drug: Psilocybin; The psilocybin is produced under Good Manufacturing Practice and is in a capsule that contains 25 mg of botanically-derived psilocybin.; Other Names: Psilocybine, Psilocibin; Filament Health Psilocybin; PEX010; Device: Transcutaneous auricular Vagus Nerve Stimulation (taVNS); 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.; Device: Sham taVNS; 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.
Sham Comparator: Group 2: Sham taVNS + Psilocybin + 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.	Drug: Psilocybin; The psilocybin is produced under Good Manufacturing Practice and is in a capsule that contains 25 mg of botanically-derived psilocybin.; Other Names: Psilocybine, Psilocibin; Filament Health Psilocybin; PEX010; Device: Sham taVNS; 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.
Active Comparator: Group 3: Sham taVNS + Psilocybin + Treatment as Usual; Group 3 will receive twice daily sham taVNS for 7 days immediately prior to psilocybin dosing. Post-psilocybin dosing, they will receive treatment as usual (TAU), comprised of an integration session 1 day and 1-week post-psilocybin dosing.	Drug: Psilocybin; The psilocybin is produced under Good Manufacturing Practice and is in a capsule that contains 25 mg of botanically-derived psilocybin.; Other Names: Psilocybine, Psilocibin; Filament Health Psilocybin; PEX010; Device: Sham taVNS; 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.; Behavioral: Treatment as Usual (TAU); Participants assigned to TAU will not receive taVNS following psilocybin dosing.
Active Comparator: Group 4: taVNS + Psilocybin + 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.	Drug: Psilocybin; The psilocybin is produced under Good Manufacturing Practice and is in a capsule that contains 25 mg of botanically-derived psilocybin.; Other Names: Psilocybine, Psilocibin; Filament Health Psilocybin; PEX010; Device: Transcutaneous auricular Vagus Nerve Stimulation (taVNS); 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.; Device: Sham taVNS; 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.

Outcome Measures

Primary Outcome Measures :

1. Memory Experiences Questionnaire (MEM-Q): Comparison of taVNS Administration vs. Treatment as Usual [ Time Frame: 8 weeks ]
   The MEM-Q is a 63-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).
2. Functional Magnetic Resonance Imaging (fMRI): Comparison of taVNS Administration vs. Treatment as Usual [ Time Frame: 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.
3. Warwick-Edinburgh Mental Wellbeing Scale (WEMWBS): Comparison of taVNS Administration vs. Treatment as Usual [ Time Frame: 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.
4. Summary of Adverse Events [ Time Frame: up to 8 weeks ]
   Adverse events (AEs) categorized by CTCAE v5.0 criteria at all assessments (6 study visits).

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 70 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

• English speaking
• Ability/willingness to complete all study activities
• Modest decrement 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 screening
• 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

Contacts and Locations

Contacts

Contact: Program Manager; 608-265-4987; raisonlab@psychiatry.wisc.edu

Locations

United States, Wisconsin

University of Wisconsin - Madison

Madison, Wisconsin, United States, 53715

Contact: Program Manager raisonlab@psychiatry.wisc.edu

Sub-Investigator: Christopher Nicholas, PhD

Sponsors and Collaborators

University of Wisconsin, Madison

Tiny Blue Dot Foundation

Investigators

• Principal Investigator: Charles Raison, MD; University of Wisconsin, Madison

More Information

• Responsible Party: University of Wisconsin, Madison
• ClinicalTrials.gov Identifier: NCT05866471
• Other Study ID Numbers: 2024-0463; A538900 ( Other Identifier: UW Madison ); Protocol Version 4/16/24 ( Other Identifier: UW Madison )
• First Posted: May 19, 2023
• Last Update Posted: May 16, 2024
• Last Verified: May 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: De-identified data including, but not limited to, demographics, questionnaires, adverse events, and fMRI data may be made available to qualified researchers upon request.
• 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.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University of Wisconsin, Madison:

Psilocybin; Psychedelics; Vagus Nerve Stimulation; Healthy Volunteer

Additional relevant MeSH terms:

Psilocybin; Hallucinogens; Physiological Effects of Drugs; Psychotropic Drugs