Orexin s Role in the Neurobiology of Substance Use Disorder

Sponsor

National Institute on Drug Abuse (NIDA) (NIH)

Overall Status

Not yet recruiting

CT.gov ID

NCT05630781

Collaborator

(none)

140

Enrollment

Location

Arms

58.8

Anticipated Duration (Months)

2.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Background:

Tobacco use leads to about 480,000 deaths each year in the US. Several treatment aids can help people stop smoking, but as many as 75% of those who quit will start again within a year. Researchers are looking for new ways to help people stop smoking.

Objective:

To find out if a drug called suvorexant can reduce the desire to smoke or vape among people who are dependent on nicotine.

Eligibility:

Healthy adults aged 18-60 who have smoked or vaped daily for at least the past year.

Design:

Participants will have 5 or 6 visits about a week apart. They will have a brief physical exam at each visit. They will provide urine and have their breath tested. They will fill out questionnaires about their thoughts, feelings, and behaviors.

Participants will have a total of 5 magnetic resonance imaging (MRI) scans. They will lie still on a table that slides into a tube. They will perform thinking tasks during the scans; they will play games on a computer or look at pictures.

At 2 visits, participants will take a pill by mouth prior to the MRI scan. They may receive either the study drug or a placebo. The placebo looks just like the study drug but contains no active ingredients. They will not know which type of pill they are taking.

For 2 weeks during the study, participants will take their pills once a day at home.

Throughout the study, participants will wear a watch-like device to record their sleep habits. They will complete a daily diary to record their smoking, vaping, mood, sleep, cravings, and side effects.

Condition or Disease	Intervention/Treatment	Phase
Nicotine Dependence	Drug: Placebo Drug: Belsomra	N/A

Detailed Description

Study Description:

Despite the availability of pharmacotherapy for some substance use disorders, relapse vulnerability is still a significant issue. This suggests medications with alternative mechanisms of action should be explored to address this unmet need. Substantial preclinical research indicates that orexin antagonism blunts the internally and externally triggered motivation to attain abused substances. This research project will translate these preclinical findings into the clinical domain by administering the FDA approved orexin antagonist, suvorexant, to those with a substance use disorder. Suvorexant's ability to blunt neurobiological correlates of substance misuse will be assessed. This will be assessed following acute and repeated drug administration. Baseline individual differences will be considered to determine whether neurobiological variance influences suvorexant's impact.

Objectives:

The objective is to determine the acute and chronic impact of the orexin antagonist, suvorexant, on neurobiological and behavioral factors linked with substance use disorders. Whether such effects are mediated by baseline characteristics will be tested. Given suvorexant is an FDA approved treatment for insomnia, sleep will be evaluated as well.

Endpoints:

Suvorexant's impact on brain function will be assessed several ways by evaluating: 1) resting function, 2) reactivity to drug cues, 3) reactivity to non-drug related cognitive tasks. Sleep and nicotine use will be measured throughout the study period.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

140 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Basic Science

Official Title:

Orexin's Role in The Neurobiology of Substance Use Disorder

Anticipated Study Start Date :

Feb 6, 2023

Anticipated Primary Completion Date :

Dec 31, 2027

Anticipated Study Completion Date :

Dec 31, 2027

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo taken for approximately 10 after acute administration and scan	Drug: Placebo comparator taken for ~10 days
Active Comparator: Suvorexant taken for approximately 10 after acute administration and scan	Drug: Belsomra randomized, double-blind, placebo-controlled crossover design study: Participants will undergo a baseline scan followed by 2 acute drug administration scans where suvorexant or placebo is administered in a randomized manner where both the participant and study staff administering drug are blind. Following the second acute scan, participants will continue with the drug they received at Scan 2 for approximately 10 days. After the first chronic scan, participants will switch to the other drug for an additional 10 days and then scanned a final time.

Arm

Intervention/Treatment

Placebo Comparator: Placebo

taken for approximately 10 after acute administration and scan

Drug: Placebo

comparator taken for ~10 days

Active Comparator: Suvorexant

taken for approximately 10 after acute administration and scan

Drug: Belsomra

randomized, double-blind, placebo-controlled crossover design study: Participants will undergo a baseline scan followed by 2 acute drug administration scans where suvorexant or placebo is administered in a randomized manner where both the participant and study staff administering drug are blind. Following the second acute scan, participants will continue with the drug they received at Scan 2 for approximately 10 days. After the first chronic scan, participants will switch to the other drug for an additional 10 days and then scanned a final time.

Outcome Measures

Primary Outcome Measures

task based fMRI [each scan visit]
Determine whether suvorexant blunts reward sensitivity
cue reactivity and suvorexant effectiveness [each scan visit]
Determine whether baseline variance in cue reactivity contributes to suvorexant s effectiveness
fMRI - cue reactivity [each scan visit]
Test whether acute and/or chronic suvorexant reduces smoking/vaping cue reactivity

Secondary Outcome Measures

wearable watch sensor [2 weeks of daily watch wearing]
Determine the impact of suvorexant on sleep
Resting state fMRI [each scan visit]
Determine the impact of acute and chronic suvorexant on the brain s inherent resting function

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 60 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

INCLUSION CRITERIA:

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

Participants will be male and female volunteers between the ages of 18-60. Justification: Many neural processes change with age, and these changes could introduce unwanted variability in both behavioral and MRI signals.
Participants must be a daily smoker/vaper with a urine cotinine level corresponding to nicotine user status for the specific test being used (typically corresponding to a urine cotinine above about 200 ng/ml) and have been smoking or vaping consistently for at least the past year (excluding quit attempts).
Female participants must have a negative pregnancy test on all study days.

EXCLUSION CRITERIA:

An individual who meets any of the following criteria will be excluded from participation in this study:

Participants cannot meet DSM-5 criteria for lifetime and/or current psychotic disorders such as bipolar disorder, schizophrenia, schizoaffective disorder
Participants cannot meet DSM-5 criteria for current substance use disorders other than nicotine and marijuana and cannot meet criteria for current moderate or severe alcohol use disorder
Participants cannot have positive illicit drug and alcohol screen on each study visit other than for nicotine or marijuana.
Participants must report no marijuana use within 24 hours of the study visit as confirmed by self-report.
Medications with the potential to depress CNS function will be assessed by the MAI, PI, or a physician's assistant and participants excluded as necessary.
Participants cannot have a history of major head trauma resulting in cognitive impairment, seizure, or other neurological disorders.
Participants cannot be pregnant or breastfeeding. Justification: The impact of suvorexant on the developing fetus and infant.
Individuals with severe hepatic impairment will be excluded
Participants cannot be obese as determined by a Body Mass Index (BMI) of greater than

Participants cannot be using a CYP3A inhibitor/inducer (metabolism by CYP3A is the major elimination pathway for suvorexant)
Participants cannot have a current cardiac disorder such as palpitations, tachycardia and/or use of the cardiac medication Digoxin
Participants cannot have narcolepsy
Participants cannot self-report complex sleep behaviors such as sleep driving, preparing and eating food or making phone calls
Participants cannot self-report compromised respiratory function such as severe obstructive sleep apnea or severe chronic obstructive pulmonary disease
Participants cannot have current major depressive disorder (within the past 6 months) and/or indorse suicidal ideation on the Beck Depression Inventory.
Subjects that cannot speak English. Justification: To include non-English speakers, we would have to translate the consent and other study documents and hire and train bilingual staff, which would require resources that we do not have and could not justify, given the small sample size for each experiment. Additionally, the data integrity of some of the cognitive tasks and standardized questionnaires used in this study would be compromised as they have only been validated in English. Most importantly, ongoing communication regarding safety procedures is necessary when participants are undergoing MRI procedures. The inability to effectively communicate MRI safety procedures in a language other than English could compromise the safety of non-English speaking participants.