Defining Neurobiological Links Between Substance Use and Mental Illness

NCT05538910 | Recruiting

• 2 other identifiers: 10000922000922-DA
• Study Type: interventional
• Target: 620
• Locations: 1 country
• Sites: 1

Brief Summary

Background: Nicotine dependence leads to about 480,000 deaths every year in the United States. People with major depressive disorder (MDD) are twice as likely to use nicotine compared to the general population. They have greater withdrawal symptoms and are more likely to relapse after quitting compared with smokers without MDD. More research is needed on how nicotine affects brain function in those with MDD. Objective: To understand how nicotine affects symptoms of depression and related brain function. Eligibility: People aged 18 to 60 years, at the time of consent, with and without MDD who do not smoke cigarettes or use other nicotine products. Design: Participants will have 2 or 3 study visits over 1 year. Participants will have 2 MRI scans no less than 4 days apart. Each scan visit will last 5 to 7 hours. At each scan, they will have urine and breath tests to screen for recent use of alcohol, nicotine, and illegal drugs. Before each scan, they will take 1 of 2 medications: nicotine or placebo. Participants will receive each medication once. They will not know which medication they are receiving at each scan. For each MRI scan, they will lie on a table that slides into a cylinder. Sometimes they will be asked to lie still. Sometimes they will complete tasks on a computer. Tasks may include identifying colors or playing games to win money. Each scan will take about 2 hours. Participants will answer questions about their thoughts, feelings, and behaviors before and after each scan. They will have a blood test after each scan.

Conditions

Major Depressive Disorder; Substance Use Disorder; Normal Physiology

Keywords

fMRI; Reward Function; Affective Processing; Interoceptive Awareness

Outcome Measures

Primary Outcomes (4)

• 4.Nicotine effects and symptoms of MDD

  Greater expression of MDD symptoms will related to a larger nicotine-induced impact within that domain.

  At each scan visit

• 3. Task and Resting State Brain

  Relate static and temporal dynamic resting state brain function to nicotinic effects.

  At each scan visit

• 2.Task-fMRI

  2\. Evaluate nicotine agonism on: 1) different phases of reward processing, 2) brain/behavioral measures of attentional bias using the classic and emotional Stroop task, and 1.3. 3) interoceptive awareness. 4) confidence on value-based decisions, determine the influence of sex in the context of points 1-3.

  At each scan visit

• 1.Resting-fMRI

  1.Determine the impact of nicotine agonism on the brain s inherent function and organization at rest.

  At each scan visit

Secondary Outcomes (1)

• Determine the relationship between blood-based biomarkers, such as inflammatory makers/metabolomics and nicotinic effects

  Ongoing

Study Arms (2)

Arm 1: Placebo

PLACEBO COMPARATOR

Placebo patch + Placebo Pill

Other: Placebo Nicotine Patch

Arm 2: Nicotine Patch

EXPERIMENTAL

Nicotine Patch + Placebo Pill

Drug: Nicotine Patch

Interventions

Nicotine Patch DRUG

Study drug: 7.5 mg Nicotine Patch which will be administered in a double blind, randomized manner

Arm 2: Nicotine Patch

Placebo Nicotine Patch OTHER

Comparator

Arm 1: Placebo

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• To be eligible for this study, an individual must meet all the following criteria assessed under the currently approved NIDA IRP screening protocol for the evaluation of potential research subjects (here referred to as the NIDA screening protocol). This is a protocol led by the Office of the Clinical Director (OCD) at the National Institute on Drug Abuse Intramural Research Program (NIDA IRP) to assess potential research participants eligibility for entering clinical protocols at the NIDA/IRP. Additional details can be found in the NIDA screening protocol documents. As routinely done at the NIDA IRP, the screening procedures and data collected under the NIDA
• screening protocol will capture information above and beyond what is necessary to determine eligibility for this protocol but allows the Investigators to assess the eligibility criteria for this protocol.
• In order to be eligible to participate in this study, an individual must meet all of the following criteria:
• All Participants:
• Able and willing to provide written informed consent.
• Both sexes and all ethnic origins, age between 18 and 60 at the time of consent. Justification: Many neural processes change with age, and these changes could introduce unwanted variability in both behavioral and MRI signals.
• Be generally healthy
• Absence of pregnancy and breastfeeding. Justification: study procedures and drugs used in the current protocol may complicate pregnancy or be transferred to nursing children. Assessment tool(s): Urine and/or serum pregnancy tests, and clinical interview. Urine pregnancy tests will also be conducted at the beginning of each imaging visit.
• Have a Breath Alcohol Value of 0 on all study visit days involving scanning. Participant may be rescheduled if this value is greater than 0.
• MDD Subjects:
• Meet DSM-5 diagnostic criteria for current MDD at screening Clinical judgement will be used to interpret criteria.
• Have a baseline (Hamilton Depression) HAM-D score indicative of current depression as evaluated by clinical staff.
• Current stable serotonin modulating drug (e.g. SSRI/SNRI/serotonin modulator) treatment is allowed (no changes in the last 2 months). Specific medications will be evaluated by the MAI.
• Remitted MDD Subjects:
• Meet DSM-5 diagnostic criteria for remitted MDD (full remission or partial remission or past depression) Clinical judgement will be used to interpret criteria.

You may not qualify if:

• An individual who meets any of the following criteria will be excluded from participation in this study:
• Subjects with suicidal ideation where outpatient treatment is determined unsafe.
• Lifetime history or current diagnosis of any of the following psychiatric illnesses: organic mental disorder, schizophrenia, schizoaffective disorder, delusional disorder, psychotic disorders not otherwise specified, bipolar disorder, patients with mood congruent or mood incongruent psychotic features. The MAI and/or PI/LI will reserve the right to exclude based psychiatric history not explicitly described in this criterion
• Are cognitively impaired or have a learning disability severe enough to have required intervention throughout most or all of K-12 education. The MAI will reserve the right to evaluate if a participant s history of educational placement is likely to represent a learning disability that could significantly impact the data gathered in this study based on the severity and type of learning disability. Justification: Cognitive impairment and learning disabilities may be associated with altered brain functioning in regions recruited during laboratory task performance.
• Heavy caffeine users (consume greater than 500 mg on a regular or daily basis. This is approximately five 8 fl oz cups of coffee). Participants will be asked to not deviate from their typical caffeine use on all scanning days.
• May not have regularly used any nicotine product in the past year; must never have been daily nicotine users for more than 1 month.
• Must have an expired carbon monoxide level of less than or equal to 5 ppm and cotinine levels consistent with a non-smoker. Depending on the commercially available test used, a level equivalent to a non-smoker status will be used, ideally indicative of a urine cotinine level of around 10 ng/ml. However, given the known limitations of rapid tests to return specific quantifications of cotinine levels, if the present test is unable to quantify cotinine at this level, the lowest level of detection will be used as a cut off and MAI / PI discretion may be used to determine whether this cut off coupled with participant history and environmental factors indicates personal nicotine use versus secondhand smoke environment.
• History of moderate or severe substance use disorder in the past 6 months (other than caffeine)
• Current pharmacological treatment for opioid use disorder (i.e., use of methadone)
• Current use of illegal drugs other than marijuana as measured by urine drug screen Marijuana will not be allowed in the 24 hours prior to scanning based on self-report. Study day can be rescheduled to accommodate.
• Participants may not use anticholinergic drugs (i.e., scopolamine), dopamine enhancing drugs (i.e. methylphenidate), or other medications that may impact MRI measures (i.e. benzodiazepines) prior to any scanning visit within a timeframe that is likely to directly
• impact the study questions. MAI discretion regarding timeframe of allowed use will be based on half-life, pharmacology of the drug in question, and pattern of use by the participant. Scanning visit timing can be adjusted to accommodate.
• May not use drugs that directly enhance dopamine (i.e., methylphenidate) in the week prior to any scanning visit. Scanning visit timing can be adjusted to accommodate.
• Any past or present significant cardiovascular, cerebrovascular, or respiratory conditions, including arrhythmias, acute coronary syndrome, ischemic heart disease, or, uncontrolled hypertension
• Body mass index (BMI) lower than 18.5 kg/m\^2

Sponsors & Collaborators

• National Institute on Drug Abuse (NIDA): lead

Study Sites (1)

National Institute on Drug Abuse

Baltimore, Maryland, 21224, United States

RECRUITING

MeSH Terms

Conditions

Depressive Disorder, Major; Substance-Related Disorders

Interventions

Tobacco Use Cessation Devices

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders; Chemically-Induced Disorders

Intervention Hierarchy (Ancestors)

Therapeutics

Study Officials

• Amy C Janes, Ph.D.

  National Institute on Drug Abuse (NIDA)

  PRINCIPAL INVESTIGATOR

Central Study Contacts

NIDA IRP Screening Team

CONTACT

(800) 535-8254; researchstudies@nida.nih.gov

Amy C Janes, Ph.D.

CONTACT

(667) 312-5164; amy.janes@nih.gov

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 8, 2022
• First Posted: September 14, 2022
• Study Start: February 2, 2023
• Primary Completion (Estimated): December 30, 2027
• Study Completion (Estimated): December 31, 2027
• Last Updated: May 5, 2026

Record last verified: 2026-05-01

Locations

US (1)