Psilocybin Microdosing on Cognition, Mood and Quality of Life

NCT07449351 | Not Yet Recruiting Early Phase 1 DMC FDA Drug

• 1 other identifier: HHC-2025-0200
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

This study is being conducted to evaluate how of 30 days of intermittently microdosed psilocybin affects mood, cognition, subjective well-being and structural/functional MRI results compared to a placebo. Investigators hypothesize that compared to placebo, 30 days of intermittently microdosed psilocybin will produce observable changes in mood, cognition, subjective well-being and MRI, in the absence of psychedelic experiences.

Conditions

Psychedelic Microdosing Effects on Mood, Cognition, Subjective Well-being and MRI

Keywords

Psychedelics; Psilocybin; MRI; fMRI; Microdosing

Outcome Measures

Primary Outcomes (14)

• The Complex Working Memory Span (CWMS) Task- fMRI measure

  CWMS Task assesses immediate plus delayed recall and working memory by assessing working memory capacity by presenting a list of stimuli to be recalled while simultaneously performing a secondary task. This task uses a fully crossed design which includes both same-domain CWMS conditions (e.g. verbal storage combined with verbal processing) as well as cross-domain CWMS conditions (e.g., verbal storage combined with spatial processing). BOLD signal Infrontal lobe.

  From enrollment to end of treatment at 8 weeks.

• NEO-Five-Factor-Inventory (NEO-FFI)

  The NEO-FFI is a self-description questionnaire with 60 items for the measurement of the "big five": neuroticism, extraversion, openness, agreeableness, and consciousness. It uses a 5-point Likert scale ranging from "completely disagree" to "fully agree.

  From enrollment to end of treatment at 8 weeks.

• Beck Depression Inventory

  This scale has a total of 21 items. Each item is scored from 0-3 points, and the total score ranges from 0-63 points. The higher the score, the higher the degree of depression.

  From enrollment to end of treatment at 8 weeks.

• Beck Anxiety Inventory

  Beck Anxiety Inventory is a 21-item self-reported questionnaire which measures the existenceand severity of symptoms of anxiety. Each of the 21 items on BAI tool represents an anxiety symptom. A total score of 0 - 7 is interpreted as a "Minimal" level of anxiety; 8 - 15 as "Mild"; 16 - 25 as "Moderate", and 26 - 63 as "Severe".

  From enrollment to end of treatment at 8 weeks.

• Harvard Flourishing Measure

  12 questions, rating from 0 to 10 per question, sum score to calculate the 'flourish measure' will be used.

  From enrollment to end of treatment at 8 weeks.

• NIH Toolbox Cognitive Battery

  Cognitive function will be assessed using the NIH Toolbox Cognition Battery, administered on an iPad.

  From enrollment to end of treatment at 8 weeks.

• Ecological Momentary Assessments (EMAs) w/ MindLamp

  Once-daily questions (EMAs) about mood and sleep will be sent via the MindLamp smartphone app.

  From enrollment to end of treatment at 8 weeks.

• Switching Stroop Test

  Stroop task measures response inhibition or response interference control. Participants will be shown a series of word colors that are either congruent or incongruent with the color of the word itself. The participant will be asked to respond to the color of the word and not the word itself. Responses are made with the keyboard. The incongruent condition is the more difficult condition of the two. Reaction time is recorded and a cost score is calculated, with shorter cost scores indicating better performance.

  From enrollment to end of treatment at 8 weeks.

• Penn Conditional Exclusion Test

  Neurocognition measure of reasoning \& problem solving in PennCNB. Scores will be transformed into z-scores. The key score will assess perseverative errors. Lowest score = 0, no max score. A higher score is correlated with worse performance, i.e. more perseverative errors.

  From enrollment to end of treatment at 8 weeks.

• Flanker Inhibitory Control and Attention Test

  This test is designed to evaluate an individual's ability to concentrate their attention while inhibiting automatic response tendencies that could potentially hinder goal achievement. This is the percent correct outcome from this assessment.

  From enrollment to end of treatment at 8 weeks.

• Face Name Associated Memory Exam

  The score ranges from 0 to 130, with a higher score indicating better speed of processing.

  From enrollment to end of treatment at 8 weeks.

• 9-hole pegboard dexterity test

  The Nine-Hole Peg Test (9HPT) is used to measure finger dexterity in patients with various neurological diagnoses. Time to complete the test as quickly as possible

  From enrollment to end of treatment at 8 weeks.

• NIH Toolbox Cognitive Battery

  The Nine-Hole Peg Test (9HPT) is used to measure finger dexterity in patients with various neurological diagnoses. Time to complete the test as quickly as possible

  From enrollment to end of treatment at 8 weeks.

• Neurite Orientation Dispersion and Density Imaging (NODDI)

  Assessing synaptic plasticity in MRI

  From enrollment to end of treatment at 8 weeks.

Secondary Outcomes (2)

• Complex Working Memory Span task

  From enrollment to end of treatment at 8 weeks.

• fMRI

  From enrollment to end of treatment at 8 weeks.

Study Arms (2)

Psychedelic group

ACTIVE COMPARATOR

An imperceptible dose of psilocybin in capsules will be administered to subjects three times weekly for four weeks. Assessments will be conducted once weekly. After 30 days of a steady dose of psilocybin, subjects will be re-assessed with baseline measures.

Drug: Psliocybin

Placebo group

PLACEBO COMPARATOR

An dose of placebo in capsules, identical to the active, will be administered to subjects three times weekly for four weeks. Assessments will be conducted once weekly. After 30 days of a steady dose of psilocybin, subjects will be re-assessed with baseline measures.

Drug: Placebo

Interventions

Psliocybin DRUG

2.0mg powdered psilocybin derived from Psilocybe cubensis mushrooms, in capsules, provided three times weekly for four weeks

Psychedelic group

Placebo DRUG

0mg matching capsules, provided three times weekly for four weeks

Placebo group

Eligibility Criteria

• Age: 21 Years - 40 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• No history of psychedelic use
• Able to read, speak, and understand English
• Able and willing to provide written informed consent, and willing to commit to study protocol
• Women of childbearing potential must be on a highly effective birth control method

You may not qualify if:

• Positive screen for recreational drugs or alcohol on test day will result in rescheduling the appointment
• Current mood, developmental, or psychotic disorders (e.g., schizophrenia, affective disorders) per DSM-V
• Current or past alcohol or substance use disorder per DSM-V
• IQ \<70 on the Weschler Abbreviated Scale of Intelligence
• Serious medical, neuro-ophthalmological, or neurological illness (e.g., cancer, seizure disorders, encephalopathy)
• Current pregnancy, breastfeeding, or ineffective birth control methods
• History of head trauma with loss of consciousness lasting \>30 minutes or concussion in last 30 days
• Any medical/neurological condition that could compromise neurocognitive performance (e.g., epilepsy, multiple sclerosis, fetal alcohol syndrome)
• Anyone deemed unsafe to study personnel for any reason; e.g., suicidal ideation
• Focal brain lesion seen on structural MRI
• MRI contraindications (e.g., implanted metallic object, severe claustrophobia)

Sponsors & Collaborators

• Yale University: lead
• Hartford HealthCare: collaborator

Study Sites (1)

Olin Neuropsychiatry Research Center

Hartford, Connecticut, 06106, United States

Location

Study Officials

• Godfrey Pearlson, MD

  Yale University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Godfrey Pearlson, MD

CONTACT

860-545-7757; godfrey.pearlson@hhchealth.org

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, CARE PROVIDER
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Psychiatry and Neuroscience, Founding Director Olin Neuropsychiatry Research Center

Study Record Dates

• First Submitted: February 26, 2026
• First Posted: March 4, 2026
• Study Start: April 1, 2026
• Primary Completion (Estimated): April 1, 2028
• Study Completion (Estimated): April 1, 2028
• Last Updated: March 31, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)