Mood Effects of Serotonin Agonists: Depression

NCT ID: NCT07017478

Last Updated: 2025-07-03

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: EARLY_PHASE1
• Total Enrollment: 48 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-06-09
• Study Completion Date: 2026-06-01

Brief Summary

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.

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.

Conditions

LSD; Major Depressive Disorder; Depression

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: OTHER
• Blinding Strategy: TRIPLE

Study Groups

placebo

distilled water (0.26 mL)

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Distilled water

LSD (26 micrograms)

LSD tartrate in tasteless solution (0.26 mL)

Group Type: EXPERIMENTAL

LSD

Intervention Type: DRUG

The serotonin 2A receptor agonist LSD

Interventions

LSD

The serotonin 2A receptor agonist LSD

Intervention Type: DRUG

Placebo

Distilled water

Intervention Type: DRUG

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 40 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

National Institute on Drug Abuse (NIDA)

NIH

Sponsor Role: collaborator

University of Chicago

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Hanna Molla

Role: PRINCIPAL_INVESTIGATOR

University of Chicago

Locations

University of Chicago

Chicago, Illinois, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Hanna Molla

Role: CONTACT

hmolla@uchicago.edu

7737023560

Facility Contacts

Hanna Molla

Role: primary

hmolla@uchicago.edu

References

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Reference Type: BACKGROUND

PMID: 38033123 (View on PubMed)

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Reference Type: BACKGROUND

PMID: 36844032 (View on PubMed)

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Reference Type: BACKGROUND

PMID: 34791625 (View on PubMed)

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PMID: 38280630 (View on PubMed)

Walsh CA, Gorfinkel L, Shmulewitz D, Stohl M, Hasin DS. Use of Lysergic Acid Diethylamide by Major Depression Status. JAMA Psychiatry. 2024 Jan 1;81(1):89-96. doi: 10.1001/jamapsychiatry.2023.3867.

Reference Type: BACKGROUND

PMID: 37819655 (View on PubMed)

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Moliner R, Girych M, Brunello CA, Kovaleva V, Biojone C, Enkavi G, Antenucci L, Kot EF, Goncharuk SA, Kaurinkoski K, Kuutti M, Fred SM, Elsila LV, Sakson S, Cannarozzo C, Diniz CRAF, Seiffert N, Rubiolo A, Haapaniemi H, Meshi E, Nagaeva E, Ohman T, Rog T, Kankuri E, Vilar M, Varjosalo M, Korpi ER, Permi P, Mineev KS, Saarma M, Vattulainen I, Casarotto PC, Castren E. Psychedelics promote plasticity by directly binding to BDNF receptor TrkB. Nat Neurosci. 2023 Jun;26(6):1032-1041. doi: 10.1038/s41593-023-01316-5. Epub 2023 Jun 5.

Reference Type: BACKGROUND

PMID: 37280397 (View on PubMed)

Allen N, Jeremiah A, Murphy R, Sumner R, Forsyth A, Hoeh N, Menkes DB, Evans W, Muthukumaraswamy S, Sundram F, Roop P. LSD increases sleep duration the night after microdosing. Transl Psychiatry. 2024 Apr 15;14(1):191. doi: 10.1038/s41398-024-02900-4.

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Hutten NRPW, Quaedflieg CWEM, Mason NL, Theunissen EL, Liechti ME, Duthaler U, Kuypers KPC, Bonnelle V, Feilding A, Ramaekers JG. Inter-individual variability in neural response to low doses of LSD. Transl Psychiatry. 2024 Jul 15;14(1):288. doi: 10.1038/s41398-024-03013-8.

Reference Type: BACKGROUND

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Reference Type: BACKGROUND

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Related Links

https://doi.org/10.3389/fpsyt.2022.1076459

Husain et al., 2022

https://doi.org/10.1007/s40263-021-00877-y

Ling et al., 2022

https://doi.org/10.1016/j.bpsc.2024.01.002

Murphy et al., 2024

https://doi.org/10.1016/j.celrep.2018.05.022

Ly et al., 2018

https://doi.org/10.1038/s41593-023-01316-5

Moliner et al., 2023

https://doi.org/10.1038/s41398-024-02900-4

Allen et al., 2024

https://doi.org/10.1038/s41398-024-03013-8

Hutten et al., 2024

https://doi.org/10.1016/j.biopsych.2019.05.019

Bershad et al., 2019

Other Identifiers

5R01DA002812-35

Identifier Type: NIH

Identifier Source: secondary_id

View Link

IRB24-1947

Identifier Type: -

Identifier Source: org_study_id