Overview

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

Eligibility

• INCLUSION CRITERIA:

        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 (all genders).
             Justification: Many neural processes change with age, and these changes could
             introduce unwanted variability in both behavioral and MRI signals.
          -  Participants who are able to become pregnant must have a negative pregnancy test on
             all study days.
          -  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 be a regular 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).
        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.
          -  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
          -  Participants with Major Depressive Disorder who are using medication must be stable on
             medication for 3 months
          -  Subjects with suicidal ideation where outpatient treatment is determined unsafe
          -  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
          -  Contraindication to MRI as determined by MRI Safety Screening form.
        Nicotine Dependent Arm
          -  Participants cannot self-report compromised respiratory function such as severe
             obstructive sleep apnea or severe chronic obstructive pulmonary disease.
          -  Participants cannot have uncontrolled ADHD.
        Control Arm
          -  May not have regularly used any nicotine product in the past year. Must have an
             expired carbon monoxide level of less than or equal to 5 ppm.
          -  Must not have a history of excessive substance use that may impact reward function, as
             evaluated by the PI, MAI, and/or designee.
          -  Current pharmacological treatment for opioid use disorder (i.e., use of methadone)
          -  May not have (or currently be treated/medicated for) any diagnoses/conditions
             contraindicated for use of methylphenidate.
          -  Participants may not have a diagnosis of ADHD (irrespective of medication use) or
             present with undiagnosed ADHD during screening.