Investigation to Understand and Optimize Psilocybin

This study will examine whether the antidepressant effect of a single dose of psilocybin administered with psychological support can be increased and extended via the use of post-dosing transcutaneous auricular Vagus Nerve Stimulation (taVNS), a known inducer of neuroplastic brain processes believed to be involved in the therapeutic effects of psilocybin. In addition, the study will examine objectively measured aspects of real-world social behavior known to promote wellbeing. Finally, the study will explore strategies for improving our ability to identify pre-treatment or early post-treatment behavioral responses to psilocybin predictive of good and bad longer-term therapeutic outcomes.

One hundred forty-one adults ages 18 to 70 experiencing a major depressive episode of at least 60 days duration of moderate or greater severity at screening will be enrolled to obtain evaluable data on approximately 120 subjects.

All subjects will receive a single 25 mg dose of psilocybin using a "set and setting" therapeutic approach that will include 1) several hours of preparatory sessions prior to dosing and 2) the presence of two facilitators throughout the dosing session; and 3) several post dosing integration sessions with a facilitator. Following the psilocybin dosing session, subjects will be randomized with a 1-to-1-to-1 allocation to 1) 7 days of twice daily transcutaneous auricular Vagus Nerve Stimulation (taVNS) vs. 2) 7 days of twice daily sham taVNS vs. 3) treatment as usual (TAU), comprised of 3 post-psilocybin dosing integration sessions. Of note, because the provision of post-dosing integration sessions is current standard of care for psychedelic assisted therapy, subjects randomized to taVNS or sham will also receive 3 post dosing integration sessions, in keeping with the study's goal of evaluating whether TAU can be enhanced by the addition of taVNS. Both taVNS and sham sessions will be paired with prompts for subjects to focus on key elements of their' psychedelic experiences and with selections of music used during the psilocybin dosing session. This pairing approach is consistent with data demonstrating that the effect of taVNS is maximized when the procedure is used in conjunction with contextual cues relevant to the sought behavioral change.

Assessments throughout study participation will assess depression, anxiety, well-being, functional disability, quality of life, social behavior, suicidal ideation, and adverse events prior to, and post-psilocybin dosing.

Eligibility Criteria:
Inclusion Criteria:

* Has major depressive disorder (MDD) with a depressive episode of ≥ 60 days duration
* Moderate or greater depressive severity, as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS)
* English or Spanish speaking (able to provide informed consent and complete questionnaires in one of these languages)
* Medically healthy

Exclusion Criteria:

* History of any exclusionary medical or psychiatric conditions
* Known family history of a psychotic disorder in a first degree relative
* Endorses current active suicidal ideation with a specific plan in the prior 2 weeks
* Has made a suicide attempt in the prior 6 months
* Current presence of a substance use disorder (including tobacco dependence) that would induce withdrawal symptoms that would disallow a subject being able to remain substance free for the 7-10-hour psilocybin dosing period
* Abnormal electrocardiogram (ECG) at screening
* Unwilling or unable (e.g., due to withdrawal symptoms) to discontinue any current prescription psychotropic medications (e.g., all classes of antidepressants including monoamine oxidase inhibitors, antipsychotics, anxiolytics, mood stabilizers such as lithium, anticonvulsants, mood stabilizers, etc.) for the duration of the trial
* Not suitable for study participation due to other reasons at the discretion of the investigators