Orexin s Role in the Neurobiology of Substance Use Disorder

NCT05630781 | Recruiting

• 2 other identifiers: 10001066001066-DA
• Study Type: interventional
• Target: 140
• Locations: 1 country
• Sites: 1

Brief Summary

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 in those with nicotine dependence. In an independent arm, the interaction between suvorexant and a dopamine agonist (methylphenidate) on cognitive function will be assessed in non-smoking individuals. 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 in the nicotine dependent arm. Endpoints: In nicotine-dependent individuals, 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. In those without nicotine-dependence, the impact of suvorexant and the interaction of acute methylphenidate and suvorexant on brain function will be assessed. This arm will provide insight into how suvorexant impacts reward/cognition as well as impacts the pharmacological influence of methylphenidate on those same measures. Study Population:\<TAB\> Nicotine dependence arm:140 subjects; Volunteers who are between the ages of 18-60 and are daily smokers/vapers. Control arm: 80 subjects; Volunteers who are between the ages of 18-60 and are non-smokers/vapers This study will be conducted at the NIDA-IRP, Biomedical Research Center, in Baltimore, MD. Description of Study Intervention: Nicotine dependence arm: Suvorexant at 10 mg single dose, and Suvorexant at 10 mg daily for approximately 7 days. Control arm: 1. Tolerability visit with one MRI scan post-20mg methylphenidate, 4 acute drug administration (6-14 days in randomized order: 1. Placebo + placebo; 2. 20mg suvorexant + Placebo; 3. Placebo + 40mg methylphenidate; 4. 20 mg suvorexant + 40mg methylphenidate max) Study Duration: 5 years Participant Duration: 1-2 months

Conditions

Nicotine Dependence

Keywords

Orexin Antagonish; fMRI; Substance Use Disorder; Nicotine Dependence

Outcome Measures

Primary Outcomes (4)

• fMRI - cue reactivity

  Test whether acute and/or chronic suvorexant reduces smoking/vaping cue reactivity

  each scan visit

• cue reactivity and suvorexant effectiveness

  Determine whether baseline variance in cue reactivity contributes to suvorexant s effectiveness

  each scan visit

• task based fMRI

  Determine whether suvorexant blunts reward sensitivity

  each scan visit

• fMRI

  to assess not only whether there is an interaction between acute methylphenidate and suvorexant on brain function and reward/cognition, but also whether any sex differences within this interaction exist

  each scan visit

Secondary Outcomes (2)

• wearable watch sensor

  2 weeks of daily watch wearing

• Resting state fMRI

  each scan visit

Study Arms (2)

Control Arm

ACTIVE COMPARATOR

80 Volunteers who are between the ages of 18-60 and are non-smokers/vapers. 1. Baseline visit with 1 fMRI scans pre- and post-20mg methylphenidate, 4 acute drug administration (6-14 days in randomized order: 1. Placebo + placebo; 2. 20mg suvorexant + Placebo; 3. Placebo + 40mg methylphenidate; 4. 20 mg suvorexant + 40mg methylphenidate max)

Drug: Belsomra; Drug: Placebo; Drug: Methylphenidate

Nicotine Dependence Arm

EXPERIMENTAL

140 Volunteers who are between the ages of 18-60 and are daily smokers/vapers. Suvorexant at 10 mg single dose, and Suvorexant at 10 mg daily for approximately 7 days.

Drug: Belsomra; Drug: Placebo

Interventions

Placebo DRUG

comparator taken for approximately 10 days

Control Arm; Nicotine Dependence Arm

Methylphenidate DRUG

Control Arm: Baseline visit with 2 fMRI scans pre- and post-20mg methylphenidate, 4 acute drug administration (6-14 days in randomized order: 1. Placebo + placebo; 2. 20mg suvorexant + Placebo; 3. Placebo + 40mg methylphenidate; 4. 20 mg suvorexant + 40mg methylphenidate max)

Control Arm

Belsomra DRUG

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 7 days. After the first chronic scan, participants will switch to the other drug for an additional approximately 7 days and then scanned a final time.

Control Arm; Nicotine Dependence Arm

Eligibility Criteria

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

You may qualify if:

• In order to be eligible to participate in this study, an individual must meet all of the following criteria:
• All Participants
• Participants will be volunteers between the ages of 18-60 at the time of enrollment in the study (both sexes). Justification: Many neural processes change with age, and these changes could introduce unwanted variability in both behavioral and MRI signals.
• Able and willing to provide written informed consent, which includes agreement to all Lifestyle Considerations at the time of study consent.
• Nicotine Dependence Arm
• Participants must smoke/vape a minimum of 4 times per week 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).

You may not qualify if:

• An individual who meets any of the following criteria will be excluded from participation in this study:
• All Participants
• 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.
• 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.
• Participant cannot have any history of neurological disorders, including seizures, epilepsy, or cognitive impairment which may impact MRI metrics.
• 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 35.
• Participants cannot be using a CYP3A inhibitor/inducer (metabolism by CYP3A is the major elimination pathway for suvorexant)
• Participants cannot have any past or present significant cardiac disorders or cerebrovascular conditions such as palpitations, tachycardia, use of the cardiac medication Digoxin, arrhythmias, acute coronary syndrome, ischemic heart disease, or uncontrolled hypertension.
• Participants cannot have narcolepsy.
• Participants cannot self-report complex sleep behaviors such as sleep driving, preparing and eating food or making phone calls.

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

Tobacco Use Disorder; Substance-Related Disorders

Interventions

suvorexant; Methylphenidate

Condition Hierarchy (Ancestors)

Chemically-Induced Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Phenylacetates; Acids, Carbocyclic; Carboxylic Acids; Organic Chemicals; Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

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: CROSSOVER
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 24, 2022
• First Posted: November 30, 2022
• Study Start: February 15, 2023
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2027
• Last Updated: April 13, 2026

Record last verified: 2026-04-06

Locations

US (1)