Orexin s Role in the Neurobiology of Substance Use Disorder

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 or medical conditions-that impact reward function. 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. 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 and no detected cotinine. 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.