Investigation to Understand and Optimize Psilocybin

Official title

An Investigation of Strategies to Understand and Optimize the Antidepressant Effects of Psilocybin (The OPTIMIZE Study)

Overview

This study will examine the effects of a single dose of psilocybin, administered with psychological support, on symptoms of depression. It will also assess whether different post-dosing interventions, including a non-invasive technique called transcutaneous auricular Vagus Nerve Stimulation (taVNS), influence various psychological and behavioral outcomes. In addition, the study will explore objective measures of real-world social behavior and identify early behavioral responses that may be associated with long-term treatment outcomes.

Detailed description

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 to 1) taVNS (7 days of twice daily taVNS), 2) sham taVNS (7 days of twice daily sham taVNS), or 3) no taVNS.

Both taVNS and sham sessions will include guided prompts encouraging participants to reflect on key aspects of their psychedelic experience, accompanied by music previously used during the psilocybin dosing session.

Participants will complete assessments at multiple time points to evaluate depression, anxiety, well-being, functional disability, quality of life, social behavior, suicidal ideation, and adverse events before and after psilocybin dosing.

Interventions

• Drug Psilocybin
  The psilocybin used in this study is synthesized under Good Manufacturing Practice (GMP) guidelines and is provided in a capsule containing 25 mg of synthetic psilocybin.
• Device Transcutaneous Auricular Vagus Nerve Stimulation (taVNS)
  Participants will be provided with a taVNS device and trained on its use. The device delivers gentle stimulation to the left ear.
• Device Sham taVNS
  Participants will be provided with a taVNS device and trained on its use. The device delivers gentle stimulation to the left ear. In the sham condition, the device will simulate the sensations of active taVNS without delivering therapeutic stimulation.

Primary outcome measures

• Montgomery-Åsberg Depression Rating Scale (MADRS) score [Time frame: Baseline 2, Week 8 Post-Psilocybin Dosing]
• PROMIS Ability to Participate in Social Roles and Activities - Short Form 8a [Time frame: Baseline 2, Week 8 Post-Dose]
• Quality of Life Enjoyment and Satisfaction Questionnaire Short-Form (Q-LES-Q) score [Time frame: Baseline 2, Week 8 Post-Dose]

Secondary outcome measures (11)

• Electronically Activated Recorder (EAR) [Time frame: Up to 55 days]
• Voicediary [Time frame: Up to 35 days]
• Ecological Momentary Assessment (EMA) [Time frame: Up to 35 days]
• Challenging Experiences Questionnaire (CEQ) score [Time frame: Day 1 Post-Dose, Week 8 Post-Dose]
• Warwick-Edinburgh Mental Wellbeing Scale (WEMWBS) score [Time frame: Baseline 1, Baseline 2, Week 2 Post-Dose, Week 4 Post-Dose, Week 8 Post-Dose]
• Psychedelic Assisted Therapy Adverse Events (PATAE) [Time frame: Baseline 1, Baseline 2, Day 1 Post-Dose, Week 1 Post-Dose, Week 2 Post-Dose, Week 4 Post-Dose, Week 8 Post-Dose]
• 30-item Mystical Experiences Questionnaire (MEQ30) score [Time frame: Day 1 Post-Dose, Week 8 Post-Dose]
• Emotional Breakthrough Inventory (EBI) score [Time frame: Day 1 Post-Dose, Week 8 Post-Dose]
• Psychological Insight Questionnaire (PIQ) score [Time frame: Day 1 Post-Dose, Week 8 Post-Dose]
• Ego Dissolution Inventory (EDI) score [Time frame: Day 1 Post-Dose, Week 8 Post-Dose]
• Awe Experiences Questionnaire - Short Form (AWE-SF) score [Time frame: Day 1 Post-Dose, Week 8 Post-Dose]

Eligibility criteria

Inclusion criteria

Current diagnosis of Major Depressive Disorder (MDD), with a depressive episode lasting ≥ 60 consecutive days at the time of screening, as confirmed by structured clinical interview

Medically healthy, as determined by the screening physician, with no significant medical conditions that would interfere with participation or affect the safety of the subject.

Exclusion criteria

History or presence of any psychiatric or medical condition that, in the opinion of the investigator, could pose a safety risk, interfere with participation, or confound study results (e.g., bipolar disorder, psychosis, seizure disorder, or cardiovascular disease).

Known family history of a psychotic disorder (e.g., schizophrenia or schizoaffective disorder) in a first-degree relative (biological parent, full sibling, or child).

Current active suicidal ideation with a specific plan within the prior 2 weeks, as assessed via clinical interview and validated instrument (e.g., C-SSRS).

Suicide attempt within the prior 6 months, regardless of intent or lethality.

Current diagnosis of a substance use disorder

Abnormal ECG at screening that may increase risk during participation (e.g., prolonged QTc, arrhythmias, or other clinically significant findings as determined by the study physician).

Unwilling or unable to discontinue prescription psychotropic medications (e.g., antidepressants, antipsychotics, anxiolytics, lithium, anticonvulsants, or mood stabilizers) for the duration of study participation, including any necessary washout period as determined by the investigator.

Any condition, finding, or behavior (including suspected deception or noncompliance) that, in the opinion of the investigator, renders the participant unsuitable for the study or likely to interfere with the integrity of the data or safety of the subject.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

United States · 1 center

• Vail Health Behavioral Health — Edwards

Identifiers

NCT: NCT06512194 · 20243954

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗