Investigation to Understand and Optimize Psilocybin
- Conditions
- Depression
- Interventions
- Device: Transcutaneous Auricular Vagus Nerve Stimulation (taVNS)Device: Sham taVNSOther: Treatment as Usual
- Registration Number
- NCT06512194
- Lead Sponsor
- Charles Raison
- Brief 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.
- 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 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.
Recruitment & Eligibility
- Status
- NOT_YET_RECRUITING
- Sex
- All
- Target Recruitment
- 141
- 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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Group 2: Psilocybin + Treatment as Usual + Sham taVNS Psilocybin Post-psilocybin dosing, Group 2 will receive twice-daily sham taVNS paired with psychedelic session contextual cues for 7 days. They will also receive treatment as usual (TAU) comprised of an integration session 1-day, 1-week, and 2-weeks post-psilocybin dosing. Group 1: Psilocybin + Treatment as Usual + taVNS Psilocybin Post-psilocybin dosing, Group 1 will receive twice-daily taVNS paired with psychedelic session contextual cues for 7 consecutive days. They will also receive treatment as usual (TAU) comprised of an integration session 1-day, 1-week, and 2-weeks post-psilocybin dosing. Group 1: Psilocybin + Treatment as Usual + taVNS Transcutaneous Auricular Vagus Nerve Stimulation (taVNS) Post-psilocybin dosing, Group 1 will receive twice-daily taVNS paired with psychedelic session contextual cues for 7 consecutive days. They will also receive treatment as usual (TAU) comprised of an integration session 1-day, 1-week, and 2-weeks post-psilocybin dosing. Group 1: Psilocybin + Treatment as Usual + taVNS Treatment as Usual Post-psilocybin dosing, Group 1 will receive twice-daily taVNS paired with psychedelic session contextual cues for 7 consecutive days. They will also receive treatment as usual (TAU) comprised of an integration session 1-day, 1-week, and 2-weeks post-psilocybin dosing. Group 2: Psilocybin + Treatment as Usual + Sham taVNS Sham taVNS Post-psilocybin dosing, Group 2 will receive twice-daily sham taVNS paired with psychedelic session contextual cues for 7 days. They will also receive treatment as usual (TAU) comprised of an integration session 1-day, 1-week, and 2-weeks post-psilocybin dosing. Group 2: Psilocybin + Treatment as Usual + Sham taVNS Treatment as Usual Post-psilocybin dosing, Group 2 will receive twice-daily sham taVNS paired with psychedelic session contextual cues for 7 days. They will also receive treatment as usual (TAU) comprised of an integration session 1-day, 1-week, and 2-weeks post-psilocybin dosing. Group 3: Psilocybin + Treatment as Usual Psilocybin Post-psilocybin dosing, Group 3 will receive treatment as usual (TAU), comprised of an integration session 1 day, 1-week and 2-weeks post-psilocybin dosing. Group 3: Psilocybin + Treatment as Usual Treatment as Usual Post-psilocybin dosing, Group 3 will receive treatment as usual (TAU), comprised of an integration session 1 day, 1-week and 2-weeks post-psilocybin dosing.
- Primary Outcome Measures
Name Time Method Montgomery-Åsberg Depression Rating Scale (MADRS) score Baseline 2, Week 8 Post-Psilocybin Dosing 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.
Sheehan Disability Scale (SDS) score Baseline 2, Week 8 Post-Dose 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.
Quality of Life Enjoyment and Satisfaction Questionnaire Short-Form (Q-LES-Q) score Baseline 2, Week 8 Post-Dose 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.
- Secondary Outcome Measures
Name Time Method Electronically Activated Recorder (EAR) Up to 55 days 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.
Voicediary Up to 35 days 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).
Ecological Momentary Assessment (EMA) Up to 35 days 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.
Challenging Experiences Questionnaire (CEQ) score Day 1 Post-Dose, Week 8 Post-Dose 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.
Warwick-Edinburgh Mental Wellbeing Scale (WEMWBS) score Baseline 1, Baseline 2, Week 2 Post-Dose, Week 4 Post-Dose, Week 8 Post-Dose 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.
Psychedelic Assisted Therapy Adverse Events (PATAE) Baseline 1, Baseline 2, Day 1 Post-Dose, Week 1 Post-Dose, Week 2 Post-Dose, Week 4 Post-Dose, Week 8 Post-Dose 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.
30-item Mystical Experiences Questionnaire (MEQ30) score Day 1 Post-Dose, Week 8 Post-Dose 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.
Emotional Breakthrough Inventory (EBI) score Day 1 Post-Dose, Week 8 Post-Dose 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.
Psychological Insight Questionnaire (PIQ) score Day 1 Post-Dose, Week 8 Post-Dose 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.
Ego Dissolution Inventory (EDI) score Day 1 Post-Dose, Week 8 Post-Dose 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.
Awe Experiences Questionnaire (AWE) score Day 1 Post-Dose, Week 8 Post-Dose 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.
Trial Locations
- Locations (1)
Vail Health Behavioral Health
🇺🇸Edwards, Colorado, United States