Pregnenolone for Cannabis Use Disorder and Depression

NCT07685964 | Not Yet Recruiting Phase 1 DMC FDA Drug

• 2 other identifiers: STU202609791UG3DA066242-01
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 2

Brief Summary

This is UG3 phase of a multi-site, milestone-driven UG3/UH3 research program evaluating pregnenolone for individuals with co-occurring cannabis use disorder (CUD) and major depressive disorder (MDD). Pregnenolone is a neurosteroid that modulates cannabinoid receptor signaling and may reduce cannabis-related effects while also improving mood-related symptoms. The primary objective of the UG3 phase is to establish feasibility and generate preliminary data to support a subsequent UH3 randomized clinical trial. Key preparatory activities include obtaining regulatory approvals (including FDA Investigational New Drug \[IND\] protocol amendment and Institutional Review Board approvals), harmonizing study procedures across participating sites, and implementing data management and monitoring systems. The UG3 phase includes two main components. First, a pharmacokinetic study willcharacterize pregnenolone pharmacokinetics in adults with CUD and MDD, including measures such as half-life and clearance. Second, a pilot clinical study will evaluate the feasibility, safety, and tolerability of pregnenolone administered orally over approximately 12 weeks. Feasibility outcomes include recruitment rates, retention, and adherence to study procedures, while safety and tolerability will be assessed through adverse event monitoring and discontinuation rates. Participants will be adults aged 18 to 50 years with diagnoses of cannabis use disorder and major depressive disorder, who report frequent cannabis use and express interest in reducing their use. Clinical assessments of cannabis use, mood symptoms, and related behavioral outcomes will be collected. The UG3 phase will be used to refine study procedures, inform dosing strategies, and establish benchmarks necessary for progression to the UH3 phase. The subsequent UH3 phase will involve a multi-site, randomized, double-blind, placebo-controlled trial evaluating the efficacy of pregnenolone in reducing cannabis use and improving depressive symptoms in this population.

Conditions

Cannabis Use Disorder; Major Depressive Disorder (MDD)

Keywords

Pregnenolone; Cannabis Use; Depression; Neurosteroid; Pharmacokinetics; Feasibility Study

Outcome Measures

Primary Outcomes (1)

• Percent Days of Cannabis Use

  The Timeline Follow Back (TLFB) interview will be used to assess cannabis use. The percent days of cannabis use will be the primary outcome measure.

  12 weeks

Secondary Outcomes (2)

• Depressive Symptom Severity

  12 Weeks

• Marijuana Craving

  12 Weeks

Study Arms (2)

Pregnenolone 300mg/d

EXPERIMENTAL

Participants receive pregnenolone 300mg/d administered orally for approximately 12 weeks. The study will evaluate pharmacokinetics, safety, tolerability, and feasibility in adults with cannabis use disorder and major depressive disorder.

Drug: Pregnenolone

Pregnenolone 500mg/d

EXPERIMENTAL

Participants receive pregnenolone 500mg/d administered orally for approximately 12 weeks. The study will evaluate pharmacokinetics, safety, tolerability, and feasibility in adults with cannabis use disorder and major depressive disorder.

Drug: Pregnenolone

Interventions

Pregnenolone DRUG

Pregnenolone is a neurosteroid administered orally. It is being studied for its pharmacokinetics, safety, tolerability, and feasibility in adults with cannabis use disorder and major depressive disorder.

Pregnenolone 300mg/d; Pregnenolone 500mg/d

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Adults aged 18 to 50 years
• Diagnosis of cannabis use disorder according to DSM-5 criteria
• Diagnosis of major depressive disorder according to DSM-5 criteria
• Cannabis use on at least 4 days per week in the past 4 weeks
• Positive urine screen for tetrahydrocannabinol (THC)
• Willingness to reduce cannabis use
• Medication-free or on a stable dose of antidepressant medication
• Able to provide informed consent

You may not qualify if:

• Current diagnosis of other substance use disorders (except nicotine)
• Current or past diagnosis of psychotic disorders, bipolar disorder, or severe psychiatric conditions
• Significant or unstable medical conditions that would interfere with study participation
• Pregnant or breastfeeding
• Active suicidal or homicidal ideation requiring immediate intervention
• Use of medications that may interfere with study drug or outcomes, unless stable
• Allergy or sensitivity to pregnenolone or related compounds
• History of hormone-sensitive cancer or tumor

Sponsors & Collaborators

• National Institute on Drug Abuse (NIDA): collaborator
• The University of Texas at Dallas: collaborator
• University of Texas Southwestern Medical Center: lead

Study Sites (2)

UT Southwestern Medical Center

Dallas, Texas, 75390, United States

Location

University of Texas at Dallas

Richardson, Texas, 75080, United States

Location

Related Publications (3)

• Mason BJ, Mustafa A, Filbey FM, Brown ES. Novel pharmacotherapeutic interventions for cannabis use disorders. Current Addiction Reports. 2016.

  BACKGROUND

• Osuji IJ, Vera-Bolanos E, Carmody TJ, Brown ES. Pregnenolone for cognition and mood in dual diagnosis patients. Psychiatry Res. 2010 Jul 30;178(2):309-12. doi: 10.1016/j.psychres.2009.09.006. Epub 2010 May 21.

  PMID: 20493557 BACKGROUND

• Brown ES, Park J, Marx CE, Hynan LS, Gardner C, Davila D, Nakamura A, Sunderajan P, Lo A, Holmes T. A randomized, double-blind, placebo-controlled trial of pregnenolone for bipolar depression. Neuropsychopharmacology. 2014 Nov;39(12):2867-73. doi: 10.1038/npp.2014.138. Epub 2014 Jun 11.

  PMID: 24917198 BACKGROUND

MeSH Terms

Conditions

Depressive Disorder, Major; Depression

Interventions

Pregnenolone

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders; Behavioral Symptoms; Behavior

Intervention Hierarchy (Ancestors)

Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Hydroxycorticosteroids; Adrenal Cortex Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Progesterone Congeners; Gonadal Steroid Hormones; Gonadal Hormones

Study Officials

• E. Sherwood Brown

  University of Texas Southwestern Medical Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

E. Sherwood Brown

CONTACT

214-645-6950; SHERWOOD.BROWN@UTSouthwestern.edu

Francesca Filbey

CONTACT

972-883-2313; francesca.filbey@utdallas.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: This is a double-blind study in which participants, care providers, investigators, and outcomes assessors are masked to treatment assignment.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: Participants will be assigned to different intervention conditions in parallel groups to evaluate pharmacokinetics, feasibility, safety, and tolerability of pregnenolone in adults with cannabis use disorder and major depressive disorder.

Study Record Dates

• First Submitted: June 29, 2026
• First Posted: July 6, 2026
• Study Start (Estimated): September 1, 2026
• Primary Completion (Estimated): August 1, 2028
• Study Completion (Estimated): August 1, 2028
• Last Updated: July 6, 2026

Record last verified: 2026-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)