Pairing Psilocybin With Transauricular Vagus Nerve Stimulation

Study Overview
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Brief Summary
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The goal of this clinical trial is to test whether transauricular vagus nerve stimulation (taVNS) can enhance the long-term positive emotional meaningfulness of the psychedelic experience. Medically-healthy participants will receive a single 25 mg dose of psilocybin followed by 1) taVNS treatment, 2) taVNS sham treatment, or 3) treatment as usual, depending on group assignment. All participants will complete a screening visit to determine eligibility, two baseline visits, a dosing visit, and three follow-up visits. taVNS or sham taVNS will be completed at home and monitored remotely by study personnel. This study will contribute to the field of psychedelic medicine by studying ways to enhance and extend the therapeutic effects of psychedelics.

Detailed Description
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100 participants will receive an open label treatment with a single 25 mg dose of psilocybin and will be randomized with equal allocation to one of four groups. Group 1 will receive twice-daily transauricular vagus nerve stimulation (taVNS) paired with psychedelic session contextual cues for 7 days immediately post-psilocybin dosing. Group 2 will receive twice-daily sham taVNS paired with psychedelic session contextual cues for 7 days immediately post-psilocybin dosing. Group 3 will receive treatment as usual (TAU) post dosing, comprised of an integration session 1 day and 1-week post-psilocybin dosing. To address the possibility that taVNS will have direct effects on wellbeing and other relevant outcomes, Group 4 will receive twice daily taVNS for 7 days immediately prior to psilocybin dosing, and Groups 1-3 will undergo the same regimen prior to psilocybin dosing but will receive sham taVNS. Primary hypothesis-driven study endpoints will be tested in randomized groups 1-3 (taVNS vs. sham taVNS vs. TAU delivered post-psilocybin dosing).

Official Title
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Activating Neuroplasticity to ENHANCE the Perception Box Expanding Effects of Psilocybin

Conditions
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Healthy, Psychedelic Experiences, Vagus Nerve Stimulation

Intervention / Treatment
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* Drug: Psilocybin
* Device: Transauricular Vagus Nerve Stimulation (taVNS)
* Device: Sham taVNS
* Behavioral: Treatment as Usual (TAU)


Participation Criteria
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Eligibility Criteria
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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) Neurotypical Able to swallow oral medications Use of acceptable contraceptive methods (sexually active males and women of childbearing potential) Exclusion Criteria: Current use of medications that may interact with psilocybin Current exclusionary medical illness Current DSM-5 psychiatric diagnosis Clinically significant safety lab abnormalities (i.e., Complete Blood Count with Differential, Comprehensive Metabolic Panel, and urinalysis) Clinically significant electrocardiogram (ECG) Hypertension or tachycardia Pregnancy and currently breastfeeding

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1: Sham taVNS + Psilocybin + taVNS<br>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<br>* The psilocybin is produced under Good Manufacturing Practice and is in a capsule that contains 25 mg of botanically-derived psilocybin.<br>* Other names: Psilocybine, Psilocibin;Device: Transauricular Vagus Nerve Stimulation (taVNS)<br>* For both the active and sham taVNS procedure, participants will apply electrodes to two left ear targets. After electrode placement, participants will connect the electrode wire to their taVNS system and will commence self-administered vagus stimulation. The stimulation systems, which allow double-blind administration of either active or sham taVNS will require a code to initiate stimulation, which will be securely sent to participants the morning of each taVNS treatment. Once participants receive the code, they will enter it into the system to receive their randomized stimulation session (active or sham).<br>Device: Sham taVNS<br>* For both the active and sham taVNS procedure, participants will apply electrodes to two left ear targets. After electrode placement, participants will connect the electrode wire to their taVNS system and will commence self-administered vagus stimulation. The stimulation systems, which allow double-blind administration of either active or sham taVNS will require a code to initiate stimulation, which will be sent to participants via HIPAA-compliant email the morning of each taVNS treatment. Once participants receive the code, they will enter it into the system to receive their randomized stimulation session (active or sham). For sham taVNS intensity will be set at 0 mA.<br>|
| Sham Comparator: Group 2: Sham taVNS + Psilocybin + Sham taVNS<br>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<br>* The psilocybin is produced under Good Manufacturing Practice and is in a capsule that contains 25 mg of botanically-derived psilocybin.<br>* Other names: Psilocybine, Psilocibin;Device: Sham taVNS<br>* For both the active and sham taVNS procedure, participants will apply electrodes to two left ear targets. After electrode placement, participants will connect the electrode wire to their taVNS system and will commence self-administered vagus stimulation. The stimulation systems, which allow double-blind administration of either active or sham taVNS will require a code to initiate stimulation, which will be sent to participants via HIPAA-compliant email the morning of each taVNS treatment. Once participants receive the code, they will enter it into the system to receive their randomized stimulation session (active or sham). For sham taVNS intensity will be set at 0 mA.<br>|
| Active Comparator: Group 3: Sham taVNS + Psilocybin + Treatment as Usual<br>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<br>* The psilocybin is produced under Good Manufacturing Practice and is in a capsule that contains 25 mg of botanically-derived psilocybin.<br>* Other names: Psilocybine, Psilocibin;Device: Sham taVNS<br>* For both the active and sham taVNS procedure, participants will apply electrodes to two left ear targets. After electrode placement, participants will connect the electrode wire to their taVNS system and will commence self-administered vagus stimulation. The stimulation systems, which allow double-blind administration of either active or sham taVNS will require a code to initiate stimulation, which will be sent to participants via HIPAA-compliant email the morning of each taVNS treatment. Once participants receive the code, they will enter it into the system to receive their randomized stimulation session (active or sham). For sham taVNS intensity will be set at 0 mA.<br>Behavioral: Treatment as Usual (TAU)<br>* Participants assigned to TAU will not receive taVNS post-psilocybin dosing but will instead undergo integration sessions at 1 day and 1-week post-psilocybin dosing. This is the typical treatment approach following psilocybin administration.<br>|
| Active Comparator: Group 4: taVNS + Psilocybin + Sham taVNS<br>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<br>* The psilocybin is produced under Good Manufacturing Practice and is in a capsule that contains 25 mg of botanically-derived psilocybin.<br>* Other names: Psilocybine, Psilocibin;Device: Transauricular Vagus Nerve Stimulation (taVNS)<br>* For both the active and sham taVNS procedure, participants will apply electrodes to two left ear targets. After electrode placement, participants will connect the electrode wire to their taVNS system and will commence self-administered vagus stimulation. The stimulation systems, which allow double-blind administration of either active or sham taVNS will require a code to initiate stimulation, which will be securely sent to participants the morning of each taVNS treatment. Once participants receive the code, they will enter it into the system to receive their randomized stimulation session (active or sham).<br>Device: Sham taVNS<br>* For both the active and sham taVNS procedure, participants will apply electrodes to two left ear targets. After electrode placement, participants will connect the electrode wire to their taVNS system and will commence self-administered vagus stimulation. The stimulation systems, which allow double-blind administration of either active or sham taVNS will require a code to initiate stimulation, which will be sent to participants via HIPAA-compliant email the morning of each taVNS treatment. Once participants receive the code, they will enter it into the system to receive their randomized stimulation session (active or sham). For sham taVNS intensity will be set at 0 mA.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Memory Experiences Questionnaire (MEMQ) | The MEMQ 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). | 8-weeks | 
| Activation in brain regions as measured by functional magnetic resonance imaging (fMRI) | 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. | 8-weeks | 
| Warwick-Edinburgh Mental Wellbeing Scale (WEMWBS) Score | 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. | up to 10 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Psilocybin, Psychedelics, Vagus Nerve Stimulation, Healthy Volunteer