Mood Effects of Serotonin Agonists: Depression (MESA-D)

July 1, 2025 updated by: University of Chicago
This study will examine the effect of a low dose of the 5HT2A agonist LSD (26 µg), compared to placebo, on acute and protracted mood states in individuals with depression. The investigators will assess the relationship between mood-related symptoms and EEG as a neurophysiological marker.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Depression is one of the leading mental health disorders in the U.S, with an estimated 21 million adults having at least one major depressive episode in the past year. Existing antidepressant medications have limited efficacy, undesirable side effects and can take weeks to months to provide relief of symptoms. Compounds that modulate serotonin 2A receptor signaling have potential to elicit rapid antidepressant effects, and one promising example of these compounds is lysergic acid diethylamide (LSD). There are widespread reports that very low doses of LSD improve mood and energy without producing hallucinogenic effects. Yet, these effects have not been rigorously tested under blinded, placebo-controlled conditions. There is an urgent need for controlled studies to assess the potential efficacy and the mechanisms that mediate any therapeutic effects.

In a preliminary double-blind, placebo-controlled study, the investigators found that depressed individuals reported acute mood enhancing effects after a single low dose of LSD, as well as improvements in anhedonia and sleep disturbance related symptoms, for as long as two days after the dose (preliminary data). The mechanisms underlying these effects are not known. While the acute mood enhancing effects may be due to direct actions of the drug at serotonin 2A receptors, animal models suggest that the sustained antidepressant-like effects of LSD are mediated by enhanced neural plasticity. In healthy humans, low doses of LSD produce sustained neurophysiological changes detected via EEG and on sleep measures, some of which may be related to antidepressant effects. In animal models, LSD produces long-lasting antidepressant-like responses as well as increased synaptic and dendritic growth in cortical regions days after drug exposure. Notably, these changes in structural plasticity are dependent on brain derived neurotrophic factor (BDNF), a protein that peaks after 24 hours in animal models.

In the current study the investigators will examine acute and delayed improvements in mood following a single low dose of LSD, in individuals with major depressive disorder (MDD). The investigators will examine the mechanisms underlying these antidepressant effects by assessing drug-induced neurophysiological changes using depression-sensitive behavioral tasks, EEG, and changes in sleep quality and architecture.

Study Type

Interventional

Enrollment (Estimated)

48

Phase

  • Early 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 Contact

Study Locations

  • United States
    • Illinois
      • Chicago, Illinois, United States, 60637
        • Recruiting
        • University of Chicago
        • Contact:
        • Principal Investigator:
          • Harriet de Wit

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

  • Adult

Accepts Healthy Volunteers

Yes

Description

Inclusion Criteria:

  • English Fluency
  • high school education or higher
  • BMI between 19-30 kg/m2

Exclusion Criteria:

  • individuals with a medical condition contraindicating study participation as determined by the study physician (e.g., liver disease, abnormal EKG, liver or cardiovascular disease)
  • high blood pressure (>140/90)
  • current suicidal ideation or suicide attempt in past 12 months
  • past year severe substance use disorder
  • personal or first-degree relative with history of psychosis
  • currently taking any psychiatric medication (for conventional antidepressants must be off for ≥ 2 weeks)
  • active panic disorder
  • severe obsessive-compulsive disorder
  • severe post-traumatic stress disorder
  • women who are pregnant or planning to become pregnant

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: Other
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Placebo Comparator: placebo
distilled water (0.26 mL)
Drug: Placebo
Distilled water
Experimental: LSD (26 micrograms)
LSD tartrate in tasteless solution (0.26 mL)
Drug: LSD
The serotonin 2A receptor agonist LSD

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Acute Mood Measures
Time Frame: Peak change (~2 hours post-drug) from pre-drug baseline
Acute (Profile of Mood States scale ratings from 0-60).
Peak change (~2 hours post-drug) from pre-drug baseline
Acute Mood Measures
Time Frame: Peak change (~2 hours post-drug) from pre-drug baseline
Acute (Visual Analog Scale questionnaires, scale ratings from 0-100).
Peak change (~2 hours post-drug) from pre-drug baseline
Delayed Mood Measures
Time Frame: Change from baseline (orientation) to 48-hour followup
Delayed depressed mood measures (Beck Depression Inventory [score range: 0-63, higher scores greater symptoms severity] and Inventory of depression and anxiety symptoms [score range: 0-48, higher scores increased severity])
Change from baseline (orientation) to 48-hour followup
Effort expenditure for reward (EEFRT) Behavioral Task Performance
Time Frame: 2 hours post-drug administration
Effort Expenditure for Reward Task
2 hours post-drug administration
Sleep Quality
Time Frame: Change from baseline (pre-drug) to Night 0, 1, and 2 post-drug
Electroencephalogram (EEG) power to assess time spent in Rapid Eye Movemeent [REM] and slow wave sleep
Change from baseline (pre-drug) to Night 0, 1, and 2 post-drug
Sleep Quality
Time Frame: Change from baseline (pre-drug) to Night 0, 1, and 2 post-drug
subjective measures of sleep function (Karolinska sleep log)
Change from baseline (pre-drug) to Night 0, 1, and 2 post-drug

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Self-reported feelings of connection using Likert scale conversation questionnaires
Time Frame: Collected at the end of the session, 270 minutes post-drug administration
ratings of connectedness
Collected at the end of the session, 270 minutes post-drug administration
Natural Language Processing using large language model
Time Frame: during 45 minute conversation, occurring 150 min after drug administration
Differences in speech content across drug conditions will be assessed using a sentiment analysis score
during 45 minute conversation, occurring 150 min after drug administration
Facial expression analysis using HUMEAI software for positive and negative affect
Time Frame: during 45 minute conversation, occurring 150 min after drug administration
Changes in emotional facial expressions during conversations across drug conditions (positive, negative affect)
during 45 minute conversation, occurring 150 min after drug administration
Self-Esteem implicit association test
Time Frame: 2 hours post drug
Changes in Self-esteem IAT scores across drug conditions
2 hours post drug

Collaborators and Investigators

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

Sponsor

University of Chicago

Collaborators

National Institute on Drug Abuse (NIDA)

Investigators

  • Principal Investigator: Hanna Molla, University of Chicago

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

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)

June 9, 2025

Primary Completion (Estimated)

June 1, 2026

Study Completion (Estimated)

June 1, 2026

Study Registration Dates

First Submitted

April 22, 2025

First Submitted That Met QC Criteria

June 3, 2025

First Posted (Actual)

June 12, 2025

Study Record Updates

Last Update Posted (Actual)

July 3, 2025

Last Update Submitted That Met QC Criteria

July 1, 2025

Last Verified

July 1, 2025

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • IRB24-1947
  • 5R01DA002812-35 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

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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