Neurobehavioral Substrates of Propranolol's Effects on Drug Cue Reactivity (ProCue)

The central objective of this project is to obtain proof-of-concept data demonstrating the effects of propranolol (a beta-adrenergic antagonist) on neurobiological responses to personal smoking environments and behavioral responses in a laboratory smoking behavior task. Human cigarette smokers (N = 50) will take photographs of locations where they do and do not smoke cigarettes. They will then be randomly assigned to receive either propranolol (40 mg) or placebo prior to completing: A) An MRI session assessing neural responses to personal smoking/non-smoking environments, standard smoking/non-smoking environments and proximal smoking/non-smoking cues; and B) A laboratory session examining smoking behavior in response to environmental cues.

Study Overview

• Status: Completed
• Conditions: Cigarette Smoking
• Intervention / Treatment: Drug: Propranolol; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 44
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • Duke University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 51 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Between the ages of 18 and 55
• Generally healthy
• Right-handed
• Smoke >= 5 cigarettes/day of a brand delivering 0.5 mg nicotine (FTC method)
• Have been smoking regularly for >= 1 year, with a stable smoking pattern over the past 6 months
• Have an expired CO concentration of >= 10 ppm or urinary cotinine > 100 ng/ml
• Are able to identify at least 4 smoking and 4 non-smoking enviornments

Exclusion Criteria:

• Inability to attend all required sessions
• Significant health problems that would interfere with completion of study procedures
• Presence of conditions that would make MRI unsafe (e.g. pacemaker)
• Presence of exclusionary psychopathology based on MINI interview (current alcohol/substance use disorder moderate or severe pmild is allowable], any history of bipolar disorder or psychosis). Individuals in early remission from substance use disorder (not in a controlled environment) may also be allowed at the PIs discretion
• Current use of psychoactive medications per self-report or urine screen. Certain prescribed medications are allowable at the PI's discretion if appropriate documentation (e.g. copy of prescription or physician letter) is provided
• Positive breath alcohol concentraiton Pregnant, breastfeeding, or planning to become pregnant during the course of study
• Problems with vision that cannot be corrected with contacts or glasses
• Current regular use of smokeless tobacco, smoking cessation medications or non-combustible nicotine products (e.g. e-cigarettes)
• Plans to alter smoking pattern (e.g. reduction, uptake, cessation) during course of study
• Current use of beta-adrenergic medication
• Systolic blood pressure < 90 mmHg or diastolic blood pressure < 60 mmHg (sitting or standing)
• Low resting heart rate (< 60 beats per minute)
• Abnormal EKG
• Presence of severe anemia (per complete blood count)
• Presence of electrolyte imbalance that could impact blood pressure (per metabolic panel)
• Presence of any other contraindications for propranolol (e.g. cardiovascular disease, bronchial asthma, prior allergic reaction)

Note that the above criteria reflect general guidelines for decision-making, but ultimate determinations are left to the discretion of the study physician. Presence of minor (e.g. asymptomatic bradycardia in the range of 50-60 in an otherwise healthy adult) or transient (e.g. electrolyte imbalance readily addressed via changes in fluid intake) may still be deemed eligible to participate.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Propranolol; Propranolol Capsule: 40 mg IR, administered 2x at separate laboratory sessions	Drug: Propranolol; Participants will take one dose of Propranolol (40mg IR) on two separate occasions.
Placebo Comparator: Placebo; Placebo Capsule: No active ingredients, administered 2x at separate laboratory sessions	Drug: Placebo; Participants will take one dose of Placebo on two separate occasions.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
BOLD Activation to Smoking Cues - Amygdala	BOLD activation in amygdala (% Signal Change). These are analyzed as separate units for each Trial Type (6 total: Proximal Non-Smoking, Proximal Smoking, Standard Environment Non-Smoking, Standard Environment Smoking, Personal Environment Non-Smoking, personal Environment Smoking), MRI Run (4 total: The task was divided into 4 runs to allow for participant breaks) and Brain Hemisphere (2 total: Left and Right). These are only presented by trial type as MRI Run and Brain Hemisphere are not variables of interest.	MRI Scan: 2-3 hours post-administration
BOLD Activation to Smoking Cues - Anterior Insula	BOLD activation in Anterior Insula (% Signal Change). These are analyzed as separate units for each Trial Type (6 total: Proximal Non-Smoking, Proximal Smoking, Standard Environment Non-Smoking, Standard Environment Smoking, Personal Environment Non-Smoking, personal Environment Smoking), MRI Run (4 total: The task was divided into 4 runs to allow for participant breaks) and Brain Hemisphere (2 total: Left and Right). These are only presented by trial type as MRI Run and Brain Hemisphere are not variables of interest.	MRI Scan: 2-3 hours post-administration
BOLD Activation to Smoking Cues - Anterior Hippocampus	BOLD activation in Anterior Hippocampus (% Signal Change). These are analyzed as separate units for each Trial Type (6 total: Proximal Non-Smoking, Proximal Smoking, Standard Environment Non-Smoking, Standard Environment Smoking, Personal Environment Non-Smoking, personal Environment Smoking), MRI Run (4 total: The task was divided into 4 runs to allow for participant breaks) and Brain Hemisphere (2 total: Left and Right). These are only presented by trial type as MRI Run and Brain Hemisphere are not variables of interest.	MRI Scan: 2-3 hours post-administration
BOLD Activation to Smoking Cues - Posterior Hippocampus	BOLD activation in Posterior Hippocampus (% Signal Change). These are analyzed as separate units for each Trial Type (6 total: Proximal Non-Smoking, Proximal Smoking, Standard Environment Non-Smoking, Standard Environment Smoking, Personal Environment Non-Smoking, personal Environment Smoking), MRI Run (4 total: The task was divided into 4 runs to allow for participant breaks) and Brain Hemisphere (2 total: Left and Right). These are only presented by trial type as MRI Run and Brain Hemisphere are not variables of interest.	MRI Scan: 2-3 hours post-administration
BOLD Activation to Smoking Cues - Medial Prefrontal Cortex	BOLD activation in Medial Prefrontal Cortex (% Signal Change). These are analyzed as separate units for each Trial Type (6 total: Proximal Non-Smoking, Proximal Smoking, Standard Environment Non-Smoking, Standard Environment Smoking, Personal Environment Non-Smoking, personal Environment Smoking), MRI Run (4 total: The task was divided into 4 runs to allow for participant breaks) and Brain Hemisphere (2 total: Left and Right). These are only presented by trial type as MRI Run and Brain Hemisphere are not variables of interest.	MRI Scan: 2-3 hours post-administration
fMRI BOLD Connectivity	Connectivity with right amygdala when viewing proximal smoking images, using a right anterior hippocampus seed region (psychophysiological interaction analysis; PPI). Larger values represent greater connectivity between these regions while viewing proximal smoking images.	MRI Scan: 2-3 hours post-administration
Cue-Provoked Craving - Proximal Cues	During MRI Scans, participants rated their craving in response to the question "While focusing on the place/object, I craved a cigarette." using a 1 (Do not agree) to 8 (Strongly agree) scale immediately following each image. Ratings were then averaged within each image category (total scale range of 1-8). Higher values represent greater craving.	MRI Scan: 2-3 hours post-administration
Cue-Provoked Craving - Standard Environment Images	During MRI Scans, participants rated their craving in response to the question "While focusing on the place/object, I craved a cigarette." using a 1 (Do not agree) to 8 (Strongly agree) scale immediately following each image. Ratings were then averaged within each image category (total scale range of 1-8). Higher values represent greater craving.	MRI Scan: 2-3 hours post-administration
Cue-Provoked Craving - Personal Environment Cues	During MRI Scans, participants rated their craving in response to the question "While focusing on the place/object, I craved a cigarette." using a 1 (Do not agree) to 8 (Strongly agree) scale immediately following each image. Ratings were then averaged within each image category (total scale range of 1-8). Higher values represent greater craving.	MRI Scan: 2-3 hours post-administration

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Laboratory Visit - Self-Reported Craving	Self-reported craving to smoke following presentation of personal smoking environments (prior to ad-lib smoking period). Assessed using the average rating across four questions drawn from the Questionnaire on Smoking Urges: (1) While focusing on those places...nothing would have been better than smoking a cigarette; (2) While focusing on those places...I had the urge for a cigarette; (3) While focusing on those places...all I wanted right then was a cigarette; (4) While focusing on those places...I craved a cigarette. Participants rated each item on an 11-point scale ranging from 0 (Do not agree) to 100 (Strongly agree) in 10-point intervals. These ratings were averaged across items for analysis. higher values represent greater craving. Tiffany, S. T., & Drobes, D. J. (1991). The development and initial validation of a questionnaire on smoking urges. British Journal of addiction, 86(11), 1467-1476.	Lab Task: 2-3 hours post-administration
Laboratory Visit - # Cigarette Puffs	Number of cigarette puffs taken during ad lib smoking period while participants view images of their personal smoking environment. Smoking was video recorded and puffs were coded by two raters.	Lab Task: 2-3 hours post-administration

Collaborators and Investigators

• Sponsor: Duke University
• Collaborators: National Institute on Drug Abuse (NIDA); National Institutes of Health (NIH)

Study record dates

Study Major Dates

• Study Start (Actual): January 16, 2018
• Primary Completion (Actual): July 15, 2019
• Study Completion (Actual): July 15, 2019

Study Registration Dates

• First Submitted: October 10, 2017
• First Submitted That Met QC Criteria: October 12, 2017
• First Posted (Actual): October 16, 2017

Study Record Updates

• Last Update Posted (Actual): August 13, 2020
• Last Update Submitted That Met QC Criteria: July 30, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Vasodilator Agents; Propranolol
• Other Study ID Numbers: Pro00083809

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Detailed protocols, datasets and additional information will be available from the Principal Investigator and research team upon request. In order to maintain compliance with HIPAA requirements (as well as university data security policies), all data will be de-identified according to HIPAA guidelines prior to being shared. Personal images themselves will not be made publicly available due to privacy concerns. However, a brief description of each image (e.g. "Front porch of home") will be made available. Data would be provided in widely accessible formats (e.g. csv/xls), along with a detailed data dictionary describing all elements and coding and study protocols.
• IPD Sharing Time Frame: We anticipate making data available within six months of study completion. It will be available for an indefinite period of time.
• IPD Sharing Access Criteria: Contact PI for details
• IPD Sharing Supporting Information Type: Study Protocol

Drug and device information, study documents

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