Clinical TrialMajor Depressive Disorder (MDD)PsilocybinPsilocybinPsilocybinRecruiting

Investigation to Understand and Optimize Psilocybin (OPTIMIZE)

This interventional trial (n=141) will investigate whether transcutaneous auricular VNS (taVNS) after a single 25 mg psilocybin dose enhances antidepressant effects in adults with major depressive episodes.

Target Enrollment
141 participants
Study Type
Phase II interventional
Design
Randomized, quadruple Blind

Detailed Description

Participants receive a single 25 mg oral dose of psilocybin within a "set and setting" framework including preparatory sessions, two facilitators during dosing and post-dose integration sessions.

After dosing, subjects are randomised to taVNS, sham taVNS, or no taVNS to evaluate effects on depressive symptoms, anxiety, well-being, functional outcomes, social behaviour and safety.

Outcomes include clinical rating scales, measures of real-world social behaviour and early behavioural responses associated with longer-term treatment outcomes.

Study Protocol

Preparation

sessions

Dosing

1 sessions

Integration

sessions

Therapeutic Protocol

support

Study Arms & Interventions

Psilocybin + taVNS

experimental

Single 25 mg oral psilocybin dose followed by twice-daily transcutaneous auricular VNS (taVNS) for 7 days with guided prompts and music.

Interventions

  • Psilocybin25 mg
    via Oral• single dose• 1 doses total
  • Compound
    via Other• twice daily for 7 days

    taVNS device to left ear; sessions paired with music and reflective prompts.

Psilocybin + Sham taVNS

active

Single 25 mg oral psilocybin dose followed by twice-daily sham taVNS for 7 days with guided prompts and music.

Interventions

  • Psilocybin25 mg
    via Oral• single dose• 1 doses total
  • Compound
    via Other• twice daily for 7 days

    Sham device simulating sensations without therapeutic stimulation; paired with music and prompts.

Psilocybin only

active comparator

Single 25 mg oral psilocybin dose with standard psychological support; no taVNS or sham device.

Interventions

  • Psilocybin25 mg
    via Oral• single dose• 1 doses total

Participants

Ages
18 – 70
Sexes
Male & Female

Inclusion Criteria

  • Inclusion Criteria:
  • Current diagnosis of Major Depressive Disorder (MDD) with a depressive episode lasting ≥ 60 consecutive days at screening, confirmed by structured clinical interview.
  • Medically healthy as determined by the screening physician, with no significant medical conditions that would interfere with participation or safety.
  • Ages 18–70 years; able to provide informed consent.

Exclusion Criteria

  • Exclusion Criteria:
  • History or presence of any psychiatric or medical condition that 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.
  • Current active suicidal ideation with a specific plan within the prior 2 weeks as assessed by clinical interview and validated instrument (e.g., C-SSRS).
  • Suicide attempt within the prior 6 months.
  • Current diagnosis of a substance use disorder.
  • Abnormal ECG at screening that may increase risk (e.g., prolonged QTc, arrhythmias) as determined by the study physician.
  • Unwilling or unable to discontinue prescription psychotropic medications for the duration of study participation, including required washout periods.
  • Any condition, finding, or behaviour (including suspected deception or noncompliance) that renders the participant unsuitable or likely to interfere with data integrity or safety.

Study Details

Locations

Vail Health Behavioral Health — Edwards, Colorado, United States

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