Shortened LSD Intervention for Major Depressive Disorder (SLIM)

The purpose of this study is to determine the safety and clinical effectiveness of a shortened lysergic acid diethylamide (LSD) experience. This will be achieved by administering the drug risperidone 45-minutes after the administration of LSD.

Study Overview

• Status: Not yet recruiting
• Conditions: Major Depression; Major Depression Moderate; Major Depression Severe
• Intervention / Treatment: Drug: LSD; Drug: Risperidone

Detailed Description

This study will administer open-label oral LSD hemi-L-tartrate 250 µg followed 45 minutes later by oral risperidone 1 mg to 10 participants with Major Depressive Disorder (MDD) for a pilot investigation into the effects of abbreviated LSD on depression. Participants will be monitored for 10.5 hours and assessed for subjective effects and discharge readiness at several time points following the dose. The main aim of this study is to test whether risperidone can be used to abbreviate the subjective effects of LSD, and whether this abbreviated LSD experience will have any potential therapeutic benefit in patients with MDD.

• Study Type: Interventional
• Enrollment (Estimated): 10
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Matthew Nielsen, BA; Phone Number: 917-991-0642; Email: mnielse7@jh.edu

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21224
      • Johns Hopkins Center for Psychedelic and Consciousness Research
      • Contact: Matthew Nielsen, BA; Phone Number: 917-991-0642; Email: mnielse7@jh.edu
      • Principal Investigator: Sandeep Nayak, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Have given written informed consent
• Meet DSM-5 criteria for MDD
• MADRS >= 28 at screening Can read, write, and speak English fluently
• Be judged by study team clinicians to be at low risk for suicidality

Exclusion Criteria:

• Women who are pregnant, nursing, or not practicing an effective means of birth control
• Cardiovascular conditions: hypertension with resting blood pressure systolic >139 or diastolic >89, angina, heart rate > 99, a clinically significant ECG abnormality (e.g., atrial fibrillation, QTc > 450), TIA in the last 6 months stroke, peripheral or pulmonary vascular disease, cardiac valvulopathy
• Epilepsy
• Insulin-dependent diabetes; if taking oral hypoglycemic agent, then no history of hypoglycemia
• Currently taking antipsychotics, or MAO inhibitors
• Patients taking antidepressant medications and unable to taper
• Moderate or strong CYP2D6 inhibitor antidepressants must undergo a washout period of 4 weeks or five half-lives prior to treatment
• Currently taking CYP2D6 inhibitor other than an antidepressant that will be tapered
• Currently taking efavirenz, Acetaldehyde dehydrogenase inhibitors such as disulfiram (Antabuse), Alcohol dehydrogenase inhibitors, or UGT1A9 inhibitors or UGT1A10 inhibitors such as phenytoin, regorafenib, eltrombopag
• Have a seizure disorder, multiple sclerosis, history of significant head trauma, CNS tumor, movement disorders or any neurodegenerative condition
• Morbidly obese (>100 lbs. above ideal body weight, or BMI >=40, or BMI >=35 with high blood pressure or diabetes)
• Be judged by a study team clinician to be at risk for moderate or severe alcohol or benzodiazepine withdrawal
• Body weight < 45 kg
• Significant acute adverse reaction (e.g., dystonia) to an antipsychotic
• Current or past history of meeting DSM-5 criteria for Schizophrenia, Psychotic Disorder (including substance-induced), Bipolar I or II Disorder or Major
• Depression with psychotic features
• Have a first degree relative with schizophrenia, psychotic disorder (unless substance induced or due to a medical condition), or Bipolar I Disorder.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: LSD + Risperidone	Drug: LSD; Participants will be administered LSD followed 45-minutes later by risperidone.; Drug: Risperidone; Participants will be administered LSD followed 45-minutes later by risperidone.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Montgomery Asberg Depression Rating Scale (MADRS)	Score range from 0 to 60. Higher scores indicate worse depression symptoms	1 month

Collaborators and Investigators

• Sponsor: Johns Hopkins University
• Investigators: Principal Investigator: Sandeep Nayak, MD, Johns Hopkins University

Publications and helpful links

Helpful Links

• Center for Psychedelic and Consciousness Research

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2026
• Primary Completion (Estimated): July 1, 2027
• Study Completion (Estimated): December 1, 2027

Study Registration Dates

• First Submitted: March 25, 2026
• First Submitted That Met QC Criteria: March 25, 2026
• First Posted (Actual): March 31, 2026

Study Record Updates

• Last Update Posted (Actual): April 3, 2026
• Last Update Submitted That Met QC Criteria: March 30, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: depression; MDD; major depression; LSD; lysergic acid diethylamide; major depressive
• Additional Relevant MeSH Terms: Mental Disorders; Behavioral Symptoms; Mood Disorders; Depressive Disorder; Behavior; Depression; Depressive Disorder, Major; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, Fused-Ring; Alkaloids; Pyrimidines; Pyrimidinones; Heterocyclic Compounds, 4 or More Rings; Ergot Alkaloids; Ergolines; Lysergic Acid; Risperidone; Lysergic Acid Diethylamide
• Other Study ID Numbers: IRB00460674

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No