Psilocybin - Induced Neuroplasticity in the Treatment of Major Depressive Disorder

November 3, 2026 updated by: Deepak C. D'Souza, Yale University

The primary goal of this pilot study is to investigate whether psilocybin alters neuroplasticity in people with major depressive disorder. The primary hypothesis is that psilocybin will result in neuroplastic changes that parallel improvement in symptoms of depression.

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

Detailed Description

In this placebo-controlled, blinded study, individuals with depression will participate in 2 experimental sessions approximately 4 weeks apart during which they will receive two of the following three interventions: 1) placebo, 2) low dose psilocybin (0.1 mg/kg), and 3) medium dose psilocybin (0.3 mg/kg).

Study Type

Interventional

Enrollment (Estimated)

18

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Connecticut
      • West Haven, Connecticut, United States, 06516
        • VA Connecticut Healthcare System, West Haven Campus

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Diagnosed with Major Depressive Disorder (MDD), single or recurrent episode, and currently experiencing a Major Depressive Episode (MDE)
  • Failed to achieve a satisfactory clinical response to at least one adequate antidepressant trial during the current depressive episode
  • Currently engaged in treatment with a mental health clinician

Exclusion Criteria:

  • Axis I psychotic disorder (e.g. schizophrenia, bipolar I, depression with psychosis)
  • Axis I psychotic disorder in first degree relative
  • Currently taking a conventional antidepressant medication
  • Unstable medical or neurological conditions
  • Significant cognitive disorders
  • History of intolerance to drugs known to significantly alter perception e.g., psilocybin, LSD, salvinorin A, mescaline, etc.
  • Pregnant, breastfeeding, lack of adequate birth control
  • Urine toxicology positive to drugs of abuse on experimental test days

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Placebo/Low Dose Psilocybin

Subjects in this arm receive placebo in the first session and low dose psilocybin in the second session.
Drug: Low Dose Psilocybin

0.1 mg/kg psilocybin capsule

Drug: Placebo

microcrystalline cellulose capsule
Experimental: Placebo/Medium Dose Psilocybin

Subjects in this arm receive placebo in the first session and medium dose psilocybin in the second session.
Drug: Placebo

microcrystalline cellulose capsule

Drug: Medium Dose Psilocybin

0.3 mg/kg psilocybin capsule
Experimental: Low Dose Psilocybin/Placebo

Subjects in this arm receive low dose psilocybin in the first session and placebo in the second session.
Drug: Low Dose Psilocybin

0.1 mg/kg psilocybin capsule

Drug: Placebo

microcrystalline cellulose capsule
Experimental: Medium Dose Psilocybin/Placebo

Subjects in this arm receive medium dose psilocybin in the first session and placebo in the second session.
Drug: Placebo

microcrystalline cellulose capsule

Drug: Medium Dose Psilocybin

0.3 mg/kg psilocybin capsule

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Changes in electrical brain activity associated with neuroplasticity measured by Electroencephalography (EEG)
Time Frame: One day and two weeks after each experimental session

An auditory Long Term Potentiation (LTP) task will assess changes in neuroplasticity. For the EEG task, the outcome measures will include stimulus-evoked time x frequency analysis (e.g., spectral power)
One day and two weeks after each experimental session

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Changes in verbal memory [ Time Frame: One day and two weeks after each experimental session ]
Time Frame: One day and two weeks after each experimental session

This will be measured by a modified computer version of the Rey Auditory Verbal Learning Test (RAVLT), administered while EEG data is collected. The EEG outcomes will include time x frequency analysis (e.g., spectral power) during the learning and recognition phases of the task.
One day and two weeks after each experimental session
Change in mood symptoms using the GRID-Hamilton Depression Rating Scale (GRID-HAM-D)
Time Frame: Four weeks before the initiation of testing, the day before and after each experimental session, and one and two weeks after each experimental session.

The GRID-Hamilton Depression Rating Scale is a clinician-administered rating scale designed to assess severity of depressive symptoms. It includes 17 items, nine of which are scored on 5-point scale, and eight of which are scored on a three-point scale. The score range for the GRID-HAMD is 0 to 52, with higher score indicating more severe depression.
Four weeks before the initiation of testing, the day before and after each experimental session, and one and two weeks after each experimental session.
Change in mood symptoms using the Quick Inventory of Depressive Symptoms (QIDS-SR16)
Time Frame: Four weeks before the initiation of testing, the day before and after each experimental session, one and two weeks after each experimental session, then monthly for three months after the last experimental session.

The QIDS-SR16 is a 16-item self-reported rating scale designed to assess severity of depressive symptoms.
Four weeks before the initiation of testing, the day before and after each experimental session, one and two weeks after each experimental session, then monthly for three months after the last experimental session.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Yale University

Collaborators

Heffter Research Institute

Investigators

  • Principal Investigator: Deepak D'Souza, MD, Yale University

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 27, 2018

Primary Completion (Actual)

July 8, 2021

Study Completion (Estimated)

December 1, 2026

Study Registration Dates

First Submitted

April 13, 2018

First Submitted That Met QC Criteria

June 5, 2018

First Posted (Actual)

June 13, 2018

Study Record Updates

Last Update Posted (Actual)

November 5, 2026

Last Update Submitted That Met QC Criteria

November 3, 2026

Last Verified

November 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2000022394

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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