The Neural Underpinnings of Depression and Cannabis Use in Young People Living With HIV

To elucidate mechanisms of substance use disorders (SUD) and comorbid mental illnesses in people living with HIV (PLWH), the study team seeks to investigate reward and pain circuitry in cannabis use and depression comorbidity, two highly prevalent conditions in PLWH. The study team proposes a tightly integrative study to test the overall hypothesis that cannabis use and depression in young PLWH have an additive effect, inducing both reward deficits and pain hypersensitivity, and that this pattern will predict worse outcomes at 1 year follow-up.

Study Overview

• Status: Recruiting
• Conditions: Depression; HIV; Cannabis Use Disorder
• Intervention / Treatment: Behavioral: MRI Study

Detailed Description

We propose to investigate reward and pain circuitry in cannabis use and depression comorbidity, two highly prevalent conditions in PLWH. We will focus on young adults (ages 18-34) to minimize HIV neuronal chronicity effects and in light of the high rates of substance use and reduced adherence to HIV treatment in this age group. Our proposed model is: 1) Both reward dysfunction (deficits in reward learning, expectancy, attainment, positive prediction errors) and pain hypersensitivity (pain sensitivity, aversion, negative prediction errors) contribute to cannabis use and depression comorbidity in young PLWH. 2) The habenula (Hb), a small limbic hub, plays a pivotal regulatory role in these processes by inhibiting ventral tegmental area (VTA) reward signals to the nucleus accumbens (NAc) following pain and loss. 3) THC, a major component of cannabis, exerts its psychoactive analgesic effects by binding to cannabinoid 1 receptors in the reward and pain systems, including the anterior cingulate (ACC), periaqueductal gray (PAG), thalamus, amygdala, VTA, NAc, and Hb, creating temporary relief of mood and pain symptoms but resulting in long-term alterations in reward circuitry that exacerbate depression and substance use. 4) Capitalizing on improvements in fMRI resolution, our novel imaging methods overcome prior technical constraints to study the Hb and other small structures critical to reward and pain processing.We will test the overall hypothesis that cannabis use and depression in young PLWH have an additive effect, inducing both reward deficits and pain hypersensitivity, and that this pattern will predict worse outcomes at 1 year follow-up. Investigators will utilize a 2×2 factorial design: 1) 70 depressed cannabis users; 2) 70 depressed cannabis non-users; 3) 70 non-depressed cannabis users; and 4) 70 non-depressed cannabis non-users. To capture a wide range of illness severity, investigators will include subthreshold depression and cannabis use on ≥20 days of the past 30 days. Comprehensive clinical evaluations, a computerized reward task, and blood tests for CD4+ count, VL, and serum THC will be performed at baseline, 6- and 12 months. fMRI (resting-state, RFT, RPET, pain task) and cognitive tests will be done at baseline.

• Study Type: Interventional
• Enrollment (Estimated): 280
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Vilma Gabbay, MD; Phone Number: 305-243-2382; Email: vxg595@med.miami.edu

Study Locations

• United States
  • Florida
    • Miami, Florida, United States, 33136
      • Recruiting
      • University of Miami
      • Principal Investigator: Vilma Gabbay, MD
      • Contact: Jasmine Agreda, BS; Phone Number: 305-243-5510; Email: jja145@med.miami.edu
      • Sub-Investigator: Joanna Starrels, MD
      • Sub-Investigator: Anjali Sharma, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 34 years (Adult)
• Accepts Healthy Volunteers: No

Study Population

Participants will be recruited in South Florida through the UM health-care system and other local community organizations.

Description

Inclusion Criteria:

• HIV seropositivity confirmed with lab report, medical records, or HIV testing.
• Between the ages of 18-39 years
• Fluency in English or Spanish
• Ability to provide informed consent and perform study procedures, including estimated full-scale intelligence quotient (IQ) >75 to ensure that participants are able to understand the study.
• Cannabis users: To capture a wide range of cannabis use frequency, meeting Diagnostic and Statistical Manual 5 (DSM-5) criteria for Cannabis use Disorder (CUD) will not be required. However, in order to ensure sufficient exposure, cannabis use will be significant (self-reported use on ≥20 of the prior 30 days and positive THC urine toxicology).
• Depressed: In order to capture a wide range of depression illness severity, we will allow participants with subthreshold depression, defined as a raw severity score of ≥12 on the Montgomery Asberg Depression Rating Scale (MADRS).

Exclusion Criteria:

• Perinatally acquired HIV infection, as early neurodevelopmental alterations and HIV legacy effects may exist in this group
• Pregnancy or lactation
• Current Substance Use Disorder other than cannabis or nicotine
• Certified for or self-reported medical cannabis use, or intent to become certified
• Current cocaine use by self-report or urine toxicology
• central nervous system (CNS) disease or injury, or neuro-degenerative disease
• Unique pain syndromes (e.g. multiple sclerosis, rheumatoid arthritis);
• Severe medical illness such as end-stage renal disease, heart failure, cirrhosis, or cancer
• MRI contraindication such as claustrophobia, metallic ink tattoos, or pacemaker.

Depressed cannabis non-users:

• At baseline, all participants will be psychotropic-medication-free for ≥1 month prior to study enrollment (or ≥3 months for medications with longer half-lives). Benzodiazepines and sleeping aids taken on an as-needed basis will be allowed, however we will require a 4-day abstinence period before the scan.
• Exclusionary are participants with a DSM-5 diagnoses of bipolar disorder, psychotic disorders, autism spectrum disorders, and all non-cannabis substance-related disorders will be exclusionary. disorder (PTSD) are not uncommon among depressed individuals and will be
• Anxiety disorders, obsessive-compulsive disorder (OCD), and post-traumatic stress are allowed as long as depressive symptoms are primary.

atypical of depression. • Suicidal ideations (SI) without a specific plan (defined as passive SI) are common in depression and will be allowed. However, if SI constitutes an imminent risk to self or others (defined as active SI), the participant will be withdrawn from the study and emergency procedures will be initiated immediately, including ER admission.

Depressed cannabis users:

• Exclusion criteria will be the same as depressed cannabis non-users except for cannabis use.

Non-depressed cannabis users:

• Will have no major psychiatric conditions other than cannabis use/disorder.

Non-depressed cannabis non-users:

• Exclusion criteria will be the same as for non-depressed cannabis users; in addition participants will not report cannabis use in the prior 90 days and have a urine toxicology test negative for cannabis.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• 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: Neural Underpinnings of Depression Group; All participants will undergo neuroimaging and behavioral tests. during the course of the study (12 months).	Behavioral: MRI Study; fMRI Tasks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Addiction Severity Index (ASI)	The number of days using illicit opioids in the past 30 days per self-report as collected through the Addiction Severity Index.	Up to 1 year
Montgomery Asberg Depression Rating Scale (MADRS) Scale	Measures the severity of depressive episodes in patients with mood disorders Scale 0-60 higher more severe	Up to 12 months
Temporal Experience of Pleasure Scale (TEPS)	Self-report measure allowing the assessment of anticipatory and consummatory pleasure 25 to 120 higher more pleasure	Up to 12 months
Neural Circuitry measured by MRI	Measured using Magnetic Resonance Imaging. Summary beta values representing the level of brain activity will be calculated.	Baseline

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Daily Sessions Frequency Age Quantity of Cannabis Use Inventory (DFAQ- CU)	Measures cannabis consumption Score range 0 to 185. The higher the score, the greater the usage of cannabis.	Up to 12 months
Timeline Followback (TLFB)	Tool to obtain a variety of estimates of marijuana, cigarette, and other drug use. scores range from days of use (0-30)	Up to 12 months
tetrahydrocannabinol (THC) Metabolite, Serum	Suggests use of, or exposure to, a product containing THC. pmol/mL	Up to 12 months
Fagerström Test for Nicotine Dependence full-term normal delivery (FTND)	The FTND is a validated, 6-item self-report instrument that evaluates the intensity of physical addiction to nicotine. Three items are rated yes/no (0/1), and the other three items are rated on a scale from 0-3. Items are summed to yield a total score of 0-10, with higher scores reflecting greater nicotine dependence.	Up to 12 months
Beck Depression Inventory-II (BDI-II)	Designed to assess the presence and severity of depressive symptoms Score 0-63 higher the score greater the depression	Up to 12 months
Snaith-Hamilton Pleasure Scale (SHAPS)	Measures anhedonia, the inability to experience pleasure Score 0-42 greater the score greater the pleasure.	Up to 12 months
Alcohol Use Disorders Identification Test-Consumption (AUDIT-C)	Alcohol consumption will be measured using total score on the 3-item Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) which includes typical quantity and frequency, and frequency of binge drinking (# of drinks modified by age based on the NIAAA Youth Guide). Higher score indicates worse outcomes.	Up to 12 months
Cannabis Use Problem Identification Test (CUPIT)	6-item self-reported questionnaire assessing cannabis use and dependence; Range 3-82, higher values indicating a more severe cannabis use disorder.	Up to 12 months
Pittsburgh sleep quality index	Assesses sleep quality and disturbances over a month period Scores 0-24 higher the score greater sleep dysfunction	up to 12 months
Brief Pain Inventory (BPI)	Assesses the severity of pain and its impact on functioning. Pain questionnaire (0-10; higher score=worse)	up to 12 months
Pain Anxiety Symptom Scale (PASS-20)	Measures fear and anxiety responses specific to pain Range 0-100 higher the more anxiety symptoms	up to 12 months
HIV RNA test	HIV RNA test detects HIV and not antibodies 20 to 10,000,000 copies/mL higher the amount the more infectious	Baseline
cluster of differentiation 4 (CD4+) / cluster of differentiation 8 (CD8+)	Monitors the immune system Flow cytometry will be used to detect serum CD4, CD8	Up to 12 months
HIV Visual Analogue Scale (HIV-VAS)	The VAS asks individuals to mark a line at the point along a continuum showing how much of each drug they have taken in the last 4 weeks 0-30 higher score worse pain	12 month

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Internalized Stigma HIV Score range 40-160 higher then greater the stigma and negative internal thoughts	Looks at a person living with HIV experiences and negative feelings or thoughts about their HIV status.	Baseline
Internalized Stigma HIV Score range 40-160 higher then greater the stigma and negative internal thoughts	Looks at a person living with HIV experiences and negative feelings or thoughts about their HIV status.	6 month
Internalized Stigma HIV Score range 40-160 higher then greater the stigma and negative internal thoughts	Looks at a person living with HIV experiences and negative feelings or thoughts about their HIV status.	12 month
Anxiety Sensitivity Index (ASI) Range 0-74 Higher the score the greater and diverse amount of concerns a participant has about their anxiety.	Different concerns someone could have regarding their anxiety.	Baseline
Anxiety Sensitivity Index (ASI) Range 0-74 Higher the score the greater and diverse amount of concerns a participant has about their anxiety.	Different concerns someone could have regarding their anxiety.	6 month
Anxiety Sensitivity Index (ASI) Range 0-74 Higher the score the greater and diverse amount of concerns a participant has about their anxiety.	Different concerns someone could have regarding their anxiety.	12 month
The Beck Anxiety Inventory (BAI) Range 0-63. Higher the score the greater the intensity of anxiety.	Assess the intensity of physical and cognitive anxiety symptoms during the past week.	Baseline
The Beck Anxiety Inventory (BAI) Range 0-63. Higher the score the greater the intensity of anxiety.	Assess the intensity of physical and cognitive anxiety symptoms during the past week.	6 month
The Beck Anxiety Inventory (BAI) Range 0-63. Higher the score the greater the intensity of anxiety.	Assess the intensity of physical and cognitive anxiety symptoms during the past week.	12 month
Multidimensional Scale of Perceived Social Support (MSPSS) Range 0-60 Higher the score the greater the perceived social support.	Measure of perceived adequacy of social support from three sources.	Baseline
Multidimensional Scale of Perceived Social Support (MSPSS) Range 0-60 Higher the score the greater the perceived social support.	Measure of perceived adequacy of social support from three sources.	6 month
Multidimensional Scale of Perceived Social Support (MSPSS) Range 0-60 Higher the score the greater the perceived social support.	Measure of perceived adequacy of social support from three sources.	12 month
Life Events Checklist (LEC) - higher number greater trauma	A measure of exposure to potentially traumatic events., higher number greater trauma	Baseline
Life Events Checklist (LEC)- higher number greater trauma	A measure of exposure to potentially traumatic events	12 month
3-item R-UCLA Loneliness Scale Range 3-9. Higher the lonelier a participant feels	Measures three dimensions of loneliness.	Baseline
3-item R-UCLA Loneliness Scale Range 3-9. Higher the lonelier a participant feels	Measures three dimensions of loneliness.	12 month
Patient-Reported Outcome Measurement Information System (PROMIS-10) Range 10-50 Higher the score the better a participant scores their overall wellbeing.	A set of person-centered measures that evaluates and monitors physical, mental, and social health.	Baseline
Urban Life Stress Scale Range 21-105. Greater the number the worse the potential sources of stress.	Measures community-level stressors as potential sources of psychological and emotional stress.	Baseline
Beck Scale for Suicide Ideation (BSSI) Range 0-38 Higher the score the greater the suicide ideation.	Instrument for detecting and measuring the current intensity of the patients' specific attitudes, behaviors, and plans to commit suicide during a specific time period.	Baseline
Beck Scale for Suicide Ideation (BSSI) Range 0-38 Higher the score the greater the suicide ideation	Instrument for detecting and measuring the current intensity of the patients' specific attitudes, behaviors, and plans to commit suicide during a specific time period.	6 month
Beck Scale for Suicide Ideation (BSSI) Range 0-38 Higher the score the greater the suicide ideation	Instrument for detecting and measuring the current intensity of the patients' specific attitudes, behaviors, and plans to commit suicide during a specific time period.	12 month

Collaborators and Investigators

• Sponsor: University of Miami
• Collaborators: National Institute on Drug Abuse (NIDA)
• Investigators: Principal Investigator: Vilma Gabbay, MD, University of Miami

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2022
• Primary Completion (Estimated): July 30, 2027
• Study Completion (Estimated): July 30, 2027

Study Registration Dates

• First Submitted: July 1, 2022
• First Submitted That Met QC Criteria: July 7, 2022
• First Posted (Actual): July 12, 2022

Study Record Updates

• Last Update Posted (Actual): July 28, 2025
• Last Update Submitted That Met QC Criteria: July 22, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Behavioral Symptoms; Substance-Related Disorders; Chemically-Induced Disorders; Mood Disorders; Depression; Depressive Disorder; Marijuana Abuse
• Other Study ID Numbers: 20230798; R01DA054885 (U.S. NIH Grant/Contract)

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: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No