The ENHANCE Study: taVNS and Psilocybin

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.

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 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