Investigation to Understand and Optimize Psilocybin
NCT Number: NCT06512194
Acronym: OPTIMIZE
Status: NOT_YET_RECRUITING
Study Type: INTERVENTIONAL
Phases: PHASE2
Conditions: Depression
Interventions: DRUG: Psilocybin|DEVICE: Transcutaneous Auricular Vagus Nerve Stimulation (taVNS)|DEVICE: Sham taVNS|OTHER: Treatment as Usual
Sponsor: Elaine Sandler
Collaborators: Usona Institute|Tiny Blue Dot Foundation|Steadman Philippon Research Institute|Emory University
Sex: ALL
Age: ADULT, OLDER_ADULT
Enrollment: 141
Study Design: Allocation: RANDOMIZED|Intervention Model: PARALLEL|Masking: QUADRUPLE (PARTICIPANT, CARE_PROVIDER, INVESTIGATOR, OUTCOMES_ASSESSOR)|Primary Purpose: TREATMENT
Start Date: 2025-02
Completion Date: 2029-02
Locations: Vail Health Behavioral Health, Edwards, Colorado, 81632, United States

Summary:
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.

Primary Outcome Measures: Montgomery-Åsberg Depression Rating Scale (MADRS) score, The MADRS is a 10-item depression rating scale that includes questions on the following symptoms: 1. Reported sadness, 2. Apparent sadness, 3. Inner tension, 4. Reduced sleep, 5. Reduced appetite, 6. Concentration difficulties, 7. Lassitude, 8. Inability to feel, 9. Pessimistic thoughts, and 10. Suicidal thoughts. Items are scored via a blinded clinical interview and rated to capture the patient's clinical state over the prior week. Each item yields a score of 0 to 6, and higher scores indicate more severe depression. The overall score ranges from 0 to 60. For this study, the structured MADRS interview will be used., Baseline 2, Week 8 Post-Psilocybin Dosing|Sheehan Disability Scale (SDS) score, The SDS is a 3-item visual analogue scale that uses visual-spatial, numeric, and verbal descriptive anchors simultaneously to assess disability across 3 domains: work, social life, and family life. Typically, 4 scores are derived from the scale in research studies - 1 for each of the work, social life and family life disability measures and an aggregate total score of these 3 scores combined. Total score can range from 0-30 with higher scores indicating higher impairment., Baseline 2, Week 8 Post-Dose|Quality of Life Enjoyment and Satisfaction Questionnaire Short-Form (Q-LES-Q) score, The Short Form version (Q-LES-Q-SF) will be used in this trial. The measure contains 16 items that assess quality of life. A total score is derived from summing the first 14 items on the scale, with the last 2 items serving as stand-alone queries. Total score can range from 14 to 70 with higher scores indicating better quality of life., Baseline 2, Week 8 Post-Dose
Secondary Outcome Measures: Electronically Activated Recorder (EAR), The EAR is a naturalistic observation method that uses an audio recording app worn by subjects to silently and unobtrusively record short samples of ambient sounds while subjects go about their daily lives. These recordings can then be transcribed for subjects' natural daily speech, as well as coded for a wide range of aspects of subjects' objectively assessed locations, activities, conversations, social environments, and other behaviors. In the present study, the EAR allows us to measure how subjects' daily behaviors, activities and social interactions change over the course of the study., Up to 55 days|Voicediary, Voicediaries will be collected via the Fabla Voicediary App. The app will collect brief speech samples from subjects' talking about (a) the events of their days and (b) retrospective reflections on their experience of psilocybin (after dosing)., Up to 35 days|Ecological Momentary Assessment (EMA), EMA will be conducted via the Fabla Voicediary app. The app will send notifications to subjects' smartphones for assessments three times per day. Each item on the assessments will include 2 slider-type items assessing valence and arousal, 3 free response items assessing current context, 2 items assessing connectedness, 1 item assessing sense of meaning, and 2 collaboratively developed items that are personalized to the subject. In addition, one end-of-day assessment will also include 1 item about hours of sleep the previous night, 1 item about substance use in the past 24 hours, and 1 item asking whether subjects have had conversations about their upcoming (during pre-dosing) or past (during post-dosing) psilocybin experiences, and with whom., Up to 35 days|Challenging Experiences Questionnaire (CEQ) score, The CEQ is a 26-item questionnaire that consists of seven factors of challenging experience with psilocybin mushrooms: fear, grief, feeling of losing your sanity (insanity), feel as though you are dying (death), feelings of isolation, physiological distress, and paranoia. The CEQ uses a 6-point response scale \[0: None/not at all, 1: So slight cannot decide, 2: Slight, 3: Moderate, 4: Strong; 5: Extreme (more than ever before in my life)\] to indicate the degree to which a participant experiences each of a series of subjective effects during their psilocybin session. Total CEQ score is expressed as the percentage of the total possible ratings on the scale. Total score can range from 0-100% with higher scores indicating a greater challenging experience., Day 1 Post-Dose, Week 8 Post-Dose|Warwick-Edinburgh Mental Wellbeing Scale (WEMWBS) score, The WEMWBS has 14 questions scored using 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". The scale is scored by summing the response to each item. The minimum scale score is 14 and the maximum is 70. Scores reflect feelings and thoughts in the two weeks prior to answering the questionnaire with higher scores indicating better well-being., Baseline 1, Baseline 2, Week 2 Post-Dose, Week 4 Post-Dose, Week 8 Post-Dose|Psychedelic Assisted Therapy Adverse Events (PATAE), The PATAE was developed to assess pre-dosing and post-acute dosing adverse events that may occur during psychedelic-assisted therapy due to the pharmacologic and psychotherapeutic components, as well as their interaction. The PATAE consists of 54 items that assess across 7 domains: sociocultural, psychospiritual, interpersonal, behavioral, psychotherapy-related, and perceptual., 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, The MEQ30 is a 30-item self-report measure developed to assess the effects of classic psychedelics in laboratory studies. It covers the major dimensions of the classic mystical experience: unity, transcendence, noetic quality, sacredness, positive mood, and ineffability/paradoxicality. The MEQ has 4 sub scales: 1) transcendence, 2) positive mood, 3) ineffability, and 4) mystical. The total possible range for each sub scale and total score is 0-100% with higher percentages indicating a larger mystical experience. Typically, a complete mystical experience is defined as scoring 60% or more on all four MEQ30 sub scales., Day 1 Post-Dose, Week 8 Post-Dose|Emotional Breakthrough Inventory (EBI) score, The EBI is a 6-item self-report scale that assesses the presence and severity of emotionally challenging/distressing experiences that occur during a psychedelic experience. The scale utilizes visual analog responses captured on a line anchored by "not at all" on one end and "very much so" on the other. Experiences queried include 1) facing emotionally difficult feelings that are usually pushed aside; 2) experiencing a resolution of a personal conflict/trauma; 3) being able to explore challenging emotions and memories; 4) having an emotional breakthrough; 5) getting a sense of closure on an emotional problem, and 6) achieving an emotional release followed by a sense of relief. The total possible score ranges from 0-100 with higher scores indicating a greater emotional breakthrough., Day 1 Post-Dose, Week 8 Post-Dose|Psychological Insight Questionnaire (PIQ) score, The PIQ is a 23-item instrument designed to query self-perceived attainment of insight during a psychedelic experience. It comprises two subscales: (a) Avoidance and Maladaptive Patterns Insights and Goals; and (b) Adaptive Patterns Insights. Sub scale and total scores range from 0 to 5 with a higher score indicating great psychological insight., Day 1 Post-Dose, Week 8 Post-Dose|Ego Dissolution Inventory (EDI) score, The EDI is an 8-item self-report scale designed to measure ego-dissolution. Each item is scored on a visual analogue scale from 0 to 100 with the following statements at the lower and upper end, respectively: "No, not more than usually" and "Yes, I experienced this completely/entirely." The total possible range of scores for the EDI is 0-100 with higher scores indicating a greater ego dissolution., Day 1 Post-Dose, Week 8 Post-Dose|Awe Experiences Questionnaire (AWE) score, The AWE is a 30-item self-report scale that measures the state of awe. Each items is rated on a scale of 1 to 7, with 1 representing "Strongly Disagree" and 7 representing "Strongly Agree". The total possible range of scores for the AWE is 1-7 with higher scores indicating a greater awe., Day 1 Post-Dose, Week 8 Post-Dose