Suvorexant to Reduce Symptoms of Nicotine Use: A Double-blind, Placebo-controlled Study
Phase: PHASE2
Conditions: Smoking Cessation
Sponsor: The University of Texas Health Science Center, Houston

 
 
 
 
 
 
 
 
 
 
 
 
 
Suvorexant to reduce symptoms of nicotine use: A double-blind, placebo-controlled study 
 
NCT04234997 
 
Version Date: 10/12/2023 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

f the quit
4
Title: Suvorexant to reduce symptoms of nicotine use: A double-blind, placebo-controlled study 
 
Principal Investigator: Robert Suchting 
Co-Investigators: Scott D. Lane, Joy M. Schmitz, Michael F. Weaver, Luba Yammine, Jin H. Yoon 
 
ABSTRACT 
Background Cigarette smoking is the number one preventable cause of death and morbidity in the US1,2. A 
number of FDA-approved pharmacotherapies for smoking are available, however the vast majority of smokers 
do not respond to these medications and relapse is highly common3. Risk of relapse is particularly high 
immediately after the initial quit attempt when nicotine withdrawal symptoms are the strongest4. These findings 
highlight the need to continue developing novel therapies that can address smoking relapse, particularly during 
the initial quit attempt when relapse risk is greatest. Within the hypothalamus, the orexin (aka hypocretin) 
system is involved in maintaining homeostatic processes (i.e., sleep/wakefulness, food intake, etc.) through 
negative-feedback mechanisms. However, the orexin system also has extra-hypothalamic projections into 
multiple brain areas pertinent to substance use disorders (SUDs). These areas map on well to factors known to 
precipitate smoking relapse such as 1) disrupted sleep, 2) dysregulated stress and anxiety, 3) reaction to drug- 
related stimuli, and 4) drug reward. Results from both pre-clinical and recent human studies support the orexin 
system as a promising target to address smoking relapse. However, important human translational studies are 
needed carefully assessing how orexin engages each target of relapse risk. 
Proposed Study A randomized, double-blind, parallel group, placebo-controlled design will assess an orexin 
receptor antagonist (suvorexant 0 vs. 20 mg) on relapse risk following overnight smoking abstinence among 
cigarette smokers. The ultimate goal will be to assess the impact of the orexin system on smoking relapse in a 
human laboratory model. Primary measures of interest will include (1) a two-component smoking relapse 
model (latency to smoking; reward magnitude) in which participants will have the opportunity to smoke their 
own cigarettes, (2) self-reported nicotine craving and withdrawal, (3) sleep metrics using self-report and 
actigraphy, and (4) self-reported changes in stress, anxiety, and stress reactivity using a modified cold-pressor 
task with a social component demonstrated to increase stress response. The current proposal seeks to obtain 
critical pilot data to support a future NIH grant application. To that end, the present study will demonstrate our 
ability to evaluate laboratory-based measures of smoking relapse risk and objective measures of sleep 
obtained using sleep-watch actigraphy. 
 
PRIMARY HYPOTHESES AND SPECIFIC AIMS 
Specific Aim 1: Assess the impact of suvorexant on established measures of smoking relapse risk (craving, 
withdrawal, stress reactivity, latency to self-administration). 
Hypothesis 1: Participants receiving suvorexant (vs. placebo) will demonstrate lower craving, stress reactivity, 
and longer latency to self-administration of cigarettes in a human laboratory experiment. 
Specific Aim 2: Validate the somnolent effect of suvorexant on sleep metrics in a sample of individuals with 
tobacco use disorder. 
Hypothesis 2: Participants receiving suvorexant (vs. placebo) will demonstrate superior sleep metrics, including 
higher perceived sleep quality, longer duration of sleep, lower restless sleep). 
Exploratory Aim: Examine the potential moderating effect of suvorexant on the relationship between sleep 
metrics and established measures of smoking relapse (noted in Aim 1). 
Exploratory Hypothesis The relationship between superior sleep metrics (quality, duration, restlessness) and 
measures of smoking relapse risk (lower craving, withdrawal, stress reactivity, and latency) will be magnified in 
participants receiving suvorexant (vs. placebo). 
 
1. BACKGROUND AND RATIONALE 
Public Health Impact of Smoking and Treatment Challenges Smoking is the leading cause of death and 
morbidity in the U.S., responsible for nearly half a million deaths annually1,5. FDA-approved pharmacotherapies 
for smoking cessation (i.e., nicotine replacement therapy, bupropion, varenicline) significantly increase the 
likelihood of smoking abstinence, but relapse continues to be a significant challenge3. Among the millions of 
smokers that attempt to quit each year, most relapse within a few days o 
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unfortunate as remaining abstinent during the initial two weeks of the quit attempt is a robust and reliable 
predictor of longer-term abstinence, even when abstinence is promoted with pharmacotherapy or intensive 
behavioral intervention6–9. These results highlight the importance of identifying interventions that can address 
relapse risk early in the quit attempt. 
Potential Targets to Address Early Smoking Relapse Withdrawal from cigarette smoking is associated with 
a number of dysphoric symptoms that can precipitate smoking relapse. Below, we describe a number of key 
risk factors that have the potential to be addressed by targeting the orexin system. 
Dysregulated Sleep Smokers have poorer sleep compared to non-smokers across virtually every measure of 
sleep quality (i.e., latency to sleep, quality of sleep, duration of sleep, time spent in deep sleep, rates of 
insomnia, daytime sleepiness, etc.) in studies using polysomnography as well as self-report10. Smoking 
cessation can exacerbate poor sleep11 and insomnia is a clinically verified symptom of nicotine withdrawal 
reported by up to 42% of abstinent smokers12–14. Studies using polysomnography and sleep diaries report 
reduced sleep quality shortly after smoking cessation, which normalizes 3 to 12 months later12,15–19. A recent 
review assessed 10 studies that explicitly examined sleep metrics in relation to smoking cessation outcomes10. 
Of 10 studies, 8 noted that sleep metrics measured before and/or during cessation predicted smoking relapse. 
Only one study assessed a sleep intervention (cognitive-behavioral therapy for insomnia) and observed better 
reported sleep quality and greater latency to smoking relapse20. Interestingly, although current of FDA- 
approved pharmacotherapies for smoking (i.e., NRT, bupropion, varenicline) can alleviate nicotine withdrawal 
and craving, they all have side effects that negatively affect sleep quality (e.g., vivid dreams, insomnia, etc.). 
Taken together, these findings mark sleep as an important clinical target that can be impacted through clinical 
interventions that subsequently improve smoking outcomes. 
Stress and Anxiety Stress and anxiety contribute to all phases of in the development of SUDs and are 
intimately connected with cigarette smoking21. Exposure to stressors in a human laboratory setting increases 
craving to smoke22–24. Smoking rates are significantly higher among populations with stress and anxiety 
disorders compared to the general population25–29, and stress relief and relaxation are commonly cited as 
reasons for smoking30–33. Smoking dose-dependently activates the HPA-axis34–39, and smoking cessation 
results in HPA-axis hypoactivity, which is associated with more severe withdrawal and craving as well as 
predictive increased risk of smoking relapse11,40,41. 
The Orexin System The orexins are a class of recently discovered amino acid peptides concentrated in the 
hypothalamus with projections widely distributed throughout the brain including the mesolimbic reward 
pathway42,43. The orexin system is neuromodulatory, increasing neural action potentials via the regulation of 
glutamate and GABA. A primary role appears to be in energy homeostasis, which affects systems associated 
with sleep, stress/anxiety, arousal, vigilance, and reward modulation44–48. In regards to nicotine, blocking orexin 
transmission reduces nicotine self-administration and seeking in rats43. In humans, a recent study observed 
that decreased orexin levels during the initial 24 hours of abstinence independently predicted time to smoking 
relapse49. Suvorexant is an FDA-approved, schedule IV compound indicated for the treatment of insomnia. 
Suvorexant is an antagonist for the two currently identified orexin receptors, OX1R/OX2R, and the only 
compound available in the US with specificity for the orexin receptor system. We recently completed a clinical 
trial assessing the effects of two weeks of suvorexant on inhibitory control, drug-cue reactivity, anxiety/stress, 
and sleep among non-treatment seeking individuals with cocaine use disorder50. This study was the first 
human laboratory-based experiment to examine the orexin system in human psychostimulant users, and the 
current proposal represents a natural extension of that study to cigarette smoking. 
 
METHODS 
Study Design To accomplish the project aims, we will utilize a randomized, double-blind, parallel group, 
placebo-controlled design, whereby consenting participants will be block-randomized to receive suvorexant 0 
mg or 20 mg. Randomization will be stratified on tobacco use disorder severity (lower vs. higher defined by 
Fagerström Test for Nicotine Dependence (FTND) scores < 5 vs. ≥ 5, respectively). Table 1 (below) provides 
an outline of study-related procedures and assessments. 
 
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Table 1. Outline of procedures and assessments 
BL 
Day 1 Day 8 
Baseline Screening 
Physical Exam, Medical History, Labs, ECG, Urine Pregnancy Test, 
SCID, ASI, KMSK, TLFB 
X 
Smoking Related Measures 
FTND 
QSU, MNWQ, Self-Report, Breath CO 
X 
X 
X 
X 
Stress/Anxiety Related Measures 
HAM-A, PSS, DASS-21, VAS 
X 
X 
X 
Sleep Related Measures 
PROMIS Sleep Disturbance Short Form, Epworth, PSQI 
Actigraphy Sleep Monitoring (Garmin Vívosmart® 3) 
X 
X 
X 
Receive 7 days of suvorexant (0 or 20 mg) 
X 
Relapse Risk Assessment 
Stress Reactivity Assessment (HR, BP, salivary cortisol, VAS) 
Dual-Component Smoking Relapse Assessment 
X 
X 
X 
X 
SCID - Structured Clinical Interview for DSM-5, ASI - Addiction Severity Index; KMSK - Kreek-McHugh- 
Schluger-Kellogg scale; TLFB - Timeline Followback; FTND – Fagerstrom Test for Nicotine Dependence; 
QSU – Questionnaire on Smoking Urges-brief; MNWQ – Minnesota Nicotine Withdrawal Questionnaire; 
CO – Carbon Monoxide; HAM-A – Hamilton Anxiety Rating Scale; PSS – Perceived Stress Scale; DASS- 
21 – Depression Anxiety Stress Scales; VAS – Visual Analog Scale; PSQI – Pittsburgh Sleep Quality 
Index; HR – Heart Rate; BP – Blood Pressure 
 
Participant Recruitment and Setting (N = 20, n = 10/group) will consist of otherwise healthy, cigarette 
smokers that report smoking at least 10 cigarettes/day, are between 18 and 65 years old and fluent in English, 
without greater than mild substance use disorder on drugs other than nicotine. Because suvorexant is a 
sedative-hypnotic contraindicated with alcohol use, participants will be excluded if they: meet DSM-5 criteria for 
an alcohol use disorder; report recent problem drinking (5/4 drinks for males/females in < 2.5 hours or > 10 
alcoholic drinks per week); report being unwilling to stop using alcohol in the evening for the two weeks of the 
study; are pregnant, nursing, or planning on becoming pregnant during the course of the study; or if they have 
any other illness, condition, or use of medications which in the opinion of the PI and/or admitting physician 
would preclude safe and/or successful completion of the study. Recruitment strategies will include local 
advertising in print media, public service announcements on radio, and referrals to Center for Neurobehavioral 
Research on Addiction (CNRA) in the Houston metropolitan area. We will also recruit from the Department of 
Psychiatry Recruitment Registry: HSC-MS-23-0768. 
Research Team PI: Robert Suchting, Ph.D. Dr. Suchting is an Assistant Professor in the Department of 
Psychiatry & Behavioral Sciences, with a primary research program involving novel applications of biostatistics 
and data science to health outcomes. However, his recent endeavors have expanded to first-hand research in 
substance use disorders and psychopharmacology, resulting in two pertinent first-author publications 
investigating (1) the effects of suvorexant on relapse-related factors in cocaine use disorder50 and (2) the 
strongest predictors of the first smoking lapse during a quit attempt51. The present study will be supported by 
the infrastructure and research team at the CNRA, including Jin Yoon, Ph.D., a frequent collaborator of the PI 
that will assist in the implementation of the current experimental design, and mentorship from Scott Lane, 
Ph.D., with expertise in psychopharmacology and the neurological bases for addiction. 
Study Medication & Medication Compliance Participants will be randomized to receive either suvorexant 0 
or 20 mg for 7 days. 20 mg is currently the highest FDA-approved dose. The bioavailability of suvorexant is > 
80% and it is highly protein-bound, with a half-life of approximately 12 hours and plasma steady-state is 
reached within three days 52. Because suvorexant is a hypnotic with a moderate half-life, participants will be 
informed to take the medication at 10:00 PM. Compliance will be assessed using both Medication Event 
Monitoring Systems (MEMS) pill bottles that record the time/frequency of bottle openings as well as riboflavin. 
Measures 
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ts directly y 
Baseline Screening As part of the CNRA general evaluation protocol (HSC-MS-05-0322), to determine 
eligibility, participants will receive a comprehensive medical and psychiatric evaluation including: a medical- 
history questionnaire, physical examination, laboratory chemistries (e.g., blood chemistry screen, complete 
blood count, urinalysis and urine pregnancy test), and ECG. Clinicians will conduct the SCID, the ASI53, the 
KMSK54 assessment of lifetime substance use interview, and TLFB55. 
Smoking-Related Measures Nicotine dependence will be assessed using the FTND56.Self-report will be used 
to collect self-reported number of cigarettes used in the past 7 days. Nicotine craving will be assessed using a 
brief, 10-item version of the Questionnaire of Smoking Urges (QSU-brief)57. Nicotine withdrawal will be 
assessed using the 8-item MNWQ58. Breath CO will be used to measure severity of smoking and overnight 
smoking abstinence. 
Sleep-Related Measures Quality of sleep in the past week will be primarily assessed using the PROMIS Sleep 
Disturbance Short Form59, a well validated and reliable subjective measure of sleep quality. Secondary 
measures will include the Epworth Sleepiness Scale60, and PSQI61. Sleep actigraphy (total hours, levels, and 
movement) will be measured via the Garmin Vívosmart® 3 device as validated by recent research62. 
Stress and Anxiety Measures Stress and anxiety will be assessed using standard, validated questionnaires 
using the HAM-A63, PSS64, and DASS-2165. Additionally, a single-item VAS measure will be used to assess 
self-reported stress. 
Human Laboratory Measures Experimental measures will be conducted on study days 1 and 8. Participants 
will be instructed to stop smoking by 10 pm the day before, in order to ensure they meet the breath CO 
criterion (CO ≤ 4 ppm) indicating overnight abstinence. In addition to measuring nicotine craving and 
withdrawal using the QSU and MNWQ, respectively, we will conduct two additional assessments. 
Stress Reactivity Stress reactivity will be assessed using a modified version of the CPT on study days 1 and 8. 
The CPT involves participants submerging their dominant arm in an ice-water bath for up to 2 min. The CPT is 
widely used to induce stress in human laboratory studies and activates major stress systems in the body66–69. 
Stress activation can be significantly increased by incorporating a social evaluative component68, which will be 
done by having a study member present wearing a white lab coat and holding a clipboard. Participants will also 
be videotaped and informed that their facial expressions will be assessed. Stress levels will be assessed using 
both subjective and physiological measures, including HR, BP, and salivary cortisol, consistent with previous 
studies from our group70,71. 
Smoking Relapse Assessment A dual-component smoking relapse assessment will be conducted in which 
participants will have the opportunity to self-administer their preferred brand of cigarettes72. Participants will 
earn $1 for every 5 min they do not smoke for the first 50 minutes (for a total of $10). At 50 minutes or once 
participants indicate they want to smoke, they will be given $7 to either purchase their preferred brand of 
cigarettes ($1 per cigarette) or keep. The two dependent variables will be latency to smoke the first cigarette 
and total number of cigarettes smoked. 
Study Compensation Participants will be provided $40 for completing the baseline screening. They will 
receive $50 for attending each study visit and a $50 bonus for completing the study/returning study equipment. 
Additionally, participants will receive $5 compensation per visit for parking and/or bus fare. As noted above, 
participants may earn up to $34 across visits during the smoking relapse assessment (if achieving maximum 
latency and zero cigarette purchase), bringing total possible compensation to $234/participant. Upon study 
completion, participants may be given the opportunity to earn an additional $20 for referring new participants to 
the study that successfully enroll and also complete all study procedures. 
 
DATA ANALYSIS PLAN 
Confounding Variables Preliminary data analyses will inspect relationships between baseline/demographic 
variables, experimental group, and specified outcome variables via traditional statistical tests (e.g., chi-square, 
Mann-Whitney-Wilcoxon, Kruskal-Wallis, and t-tests). Baseline covariates that demonstrate a relationship with 
both assigned group and outcome variables meet criteria for being potential confounders73,74 and will be 
included as a covariate in any statistical models for hypothesis testing. All analyses will statistically control for 
the stratification variables (detailed above in the Study Design section). 
Inferential Paradigm Following recommendations for clinical trials in the literature75–77 analyses will proceed 
using parallel frequentist and Bayesian statistical inference. Frequentist 
dIRthBeNpUrMobBaEbRil:itHySoCf-MthSe-1d9a-0ta966 
(or data more extreme), given the null hypothesis, while Bayesian resul  
 ieIRldBtAhePPpRrOobVaAbLiliDtyAoTfEa: 1n0/12/2023 

oach of the
for all hyp 
alternative hypothesis78. If possible, Bayesian analyses will incorporate informative priors as they develop in 
the literature; otherwise, weakly informative priors will be incorporated as a default (e.g., for regression 
coefficients: ~N[µ=0,σ2=100]; for non-linear outcomes this prior applies to the coefficient within the link- 
function). Sensitivity analyses using optimistic and pessimistic, skeptical priors will evaluate prior 
assumptions79. Assessing the convergence of Bayesian analyses on the posterior distributions via Monte-Carlo 
Markov chain (MCMC) will use graphical (Trace Plot, Autocorrelation Plot) and quantitative (Geweke 
Diagnostics, Gelman-Rubin Diagnostics, and Heidelberger-Welsh Diagnostics) evidence. Evaluation of 
posterior distributions will permit statements regarding the probability that effects of varying magnitudes exist, 
given the data. Statistical analyses will use SAS v. 9.4 and the most up-to-date stable release version of the R 
statistical computing environment80 using packages rstan80 and brms81. 
Statistical Modeling Analyses will primarily use generalized linear modeling (GLM) with multilevel 
components (GLMM) for correlated observations. Specifically, for each hypothesis, GLMM will model each 
outcome measure of interest as a function of group, potential confounding variables (as described above), and 
random effects to account for correlated observations where necessary. Continuous, count, and dichotomous 
outcomes will utilize normal, Poisson/negative binomial, and binomial distribution families respectively, with 
identity, log, and logit link functions as appropriate. Evaluation of distributional assumptions will use residual 
plots, formal statistical tests, and posterior predictive checking. Violations of assumptions will be addressed via 
transformation, robust estimation, stratification, and/or coefficient scaling where appropriate. 
Missingness & Multiple Comparisons While the short nature of the proposed trial should reduce the 
prospect of missing data, for the frequentist analyses, missing data will be addressed via maximum likelihood, 
explicit modeling of missingness, and/or imputation. Bayesian analyses will use joint modeling of outcomes 
and missingness to handle missing data82. Each approach is robust to ignorable missingness (i.e. MCAR and 
MAR). Analyses will address non-ignorable missingness using pattern-mixture modeling83. Sensitivity analyses 
will permit evaluation of the robustness of findings to missing data assumptions. While Bayesian analyses are 
not influenced by traditional concerns of multiplicity, frequentist analyses will utilize false discovery rate (FDR) 
to control for Type I error across multiple tests for secondary outcomes where delineated. 
Exploratory Data Analyses Where not otherwise specified, to maximize the utility of the present data, 
exploratory analyses will evaluate relationships between variables captured as part of the study. For example, 
while not represented in specific hypotheses, changes in self-reported smoking behavior as functions of other 
variables in the present study will be explored. 
Specific Analyses 
Hypothesis 1: GLMM will model each primary relapse risk outcome (craving (QSU), stress reactivity (heart rate 
and salivary cortisol), and latency to self-administration) as a function of the main effects and interaction 
between time (pre vs. post) and treatment group, including any necessary control variables (as defined above 
in the confounding variables section) and a random intercept for participant. Secondary measures of craving 
and stress reactivity will be assessed in similar fashion with Type I error correction for the frequentist analyses. 
Hypothesis 2: GLMM will model each sleep metric (quality, duration, and restlessness) as a function of the 
main effects and interaction between time (pre vs. post) and treatment group, including control variables and a 
random intercept for participant. Secondary measures for sleep will be assessed in similar fashion with Type I 
error correction for the frequentist analyses. 
Exploratory Hypothesis GLMM will model each relapse risk outcome (craving, stress reactivity, and latency to 
self-administration) as a function of the main effects and all higher-order interactions between time (pre vs. 
post), given sleep metrics (in unique models: quality, duration, and restlessness), and treatment group, 
including control variables and a random intercept for participant. 
Sample Size and Power Considerations 
Frequentist Analyses With regard to sample size, the current proposal is limited to a maximum credible sample 
of N = 20 (n = 10/group) that may be accrued in the given time window and the budget of the funding 
mechanism. While the specific analyses proposed above will be thoroughly evaluated, ultimately the research 
proposed here will be exploratory and hypothesis-generating for the purpose of a larger-scale trial. Given these 
limitations, frequentist power calculations are presented as due diligence for the current proposal (conducted 
via G*Power 3.1.9.4) and focus on the broadest analytic goal presented by Hypothesis 1 (change over time for 
each treatment group for a given relapse risk outcome). Assuming alpha = 0.05, a maximum credible sample 
size N = 20 (10/group) provides 80% power to detect a large effect size Cohen’s f = 0.66. 
Bayesian Analyses An advantage of the dual frequentist/Bayesian appr 
cIRuBrreNnUtMpBroEpRo:sHaSl Cis-MthSe-19-0966 
ability of Bayesian inference to provide probabilistic estimates of effects 
oIthReBsAePsPeRvOeVnAinL tDhAeTcEo:n1t0e/1x2t /2023 

information to other
of lower power to detect small effect sizes. Given the exploratory nature of the present research, Bayesian 
analyses will focus on posterior probabilities ≥ 0.75 (equivalent to a Bayes factor = 0.33 or 3.0) to emphasize 
the value in discerning a signal for model effects across analyses. 
 
DATA SAFETY MONITORING PLAN 
 
E1. Human Subjects Involvement and Participant Characteristics 
The study will test 20 current cigarette smokers, 18 to 65 years old that report smoking at least 10 
cigarettes/day (half pack). Notably, because the study medication (suvorexant) is contraindicated with alcohol 
use, we will exclude subjects with alcohol use disorders (via screening at intake). We will also exclude those 
individuals meet DSM-5 criteria for an alcohol use disorder or report recent problem drinking (5/4 drinks for 
males/females in < 2.5 hours or > 10 alcoholic drinks per week) or those who report being unwilling to stop 
using alcohol in the evening for the two weeks of the study. Additional exclusion criteria include individuals that 
are pregnant, nursing, or planning on becoming pregnant during the course of the study; or if they have any 
other illness, condition, or use of medications which in the opinion of the PI and/or admitting physician would 
preclude safe and/or successful completion of the study. This will be accomplished via full medical evaluation 
at intake by Dr. Michael Weaver, M.D., CNRA Medical Director. The study will be conducted at the 
Neurobehavioral Research Laboratory at the CNRA. Recruitment strategies will include local advertising in 
print media, public service announcements on radio, and referrals to CNRA in the Houston metropolitan area. 
We expect to enroll a minimum of 2 participants per month to meet recruitment goals; however, we will be able 
to accommodate four simultaneous participants. Participants will be required to participate for 3 days 
(intake/screening, baseline observations, and one follow-up observation one week later). Research data will be 
collected at each scheduled time point. 
 
Men and women of all ethnic backgrounds will be recruited to participate. It is anticipated that the subject 
demographic profile will closely mirror the larger population from which they are recruited, however, because 
we are recruiting cigarette smokers, we expect to a broader range of subjects from which to select. URN 
randomization will stratify participants by sex (male/female), tobacco use disorder severity (lower vs. higher 
defined by Fagerström Test for Nicotine Dependence (FTND) scores < 5 vs. ≥ 5, respectively), and craving 
(lower vs. higher, defined by Questionnaire of Smoking Urges-brief (QSU-brief) scores < 50 vs. ≥ 50, 
respectively). Concomitant use of e-cigarette or vaping products is permitted if participants otherwise satisfy 
inclusion/exclusion criteria. 
 
Children (defined here per NIH guidelines as 19-21 years old) will be included in this research. From a safety 
perspective, risks of exposure to the proposed study medication in cigarette smoking children have not been 
established. The safety and efficacy of the proposed study medication should be established in adults first, 
before conducting this type of treatment research in children. 
 
Exclusion criteria will include: (1) meeting criteria for diagnosis with a substance use disorder on drugs other 
than nicotine or cannabis; (2) greater than moderate cannabis use; (3) have a DSM-IV axis I psychiatric 
disorder or neurological disease or disorder requiring ongoing treatment and/or making study participation 
unsafe; (4) significant current suicidal or homicidal ideation; (5) medical conditions contraindicating 
administration of suvorexant (e.g., severe pulmonary disease, severe cardiovascular disease or clinically 
abnormal EEG, severe liver or kidney disease, seizure disorder, or sleep disorder – particularly narcolepsy); 
(6) taking medications known to have significant drug interactions with the study medication(s) (e.g., MAO 
inhibitors, anticonvulsants, haloperidol, phenothiazines, anesthetics, and all sedatives); (7) currently or recently 
(last 3 months) treated for substance use [other than nicotine] or another psychiatric condition; (8) conditions of 
probation or parole requiring reports of drug use to officers of the court; (9) impending incarceration; (10) 
pregnant or nursing for female patients; (11) inability to read, write, or speak English [required for lab tasks and 
psychometric scales]; (12) unwillingness to sign a written informed consent form; (13) subjects with alcohol use 
disorders or report recent problem drinking (5/4 drinks for males/females in < 2.5 hours or > 10 alcoholic drinks 
per week). All subjects who are excluded will be given referral 
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A guideline
E2. Sources of Materials 
 
We will obtain information about subjects from structured interview evaluations, physical examinations, self- 
report measures, and computerized behavioral tasks. This information will be collected at specified time points 
during the study phases of intake, baseline assessment, experimental testing, and end-of-study. The biological 
specimens obtained from all subjects will include urine and breath samples for alcohol detection. Individuals 
who volunteer to participate will be assigned a subject number (e.g., 10500), under which all information 
collected will be filed. All materials will be obtained for the specific purposes of this research. 
 
E3. Potential Risks 
 
Suvorexant (BELSOMRA) is an orexin receptor antagonist indicated for the treatment of insomnia, 
characterized by difficulties with sleep onset and sleep maintenance. Recommended dose is 10 mg, 1x per 
night taken within 30 minutes of going to bed, with at least 7 hours of planned time before awakening. If the 10 
mg dose is well tolerated but not optimally effective, it can be increased but not to exceed 20 mg once daily. 
Medication is taken PO, with dosage in tablets of 5, 10, 15, and 20 mg. Contraindicated in patients with 
narcolepsy. Precautions include daytime somnolence; dose-related risk of impaired alertness and motor 
coordination, including impaired driving; patients taking 20 mg should be cautioned against next-day driving; 
nighttime “sleep-driving” and other complex behaviors while out of bed and/or not fully awake; worsening of 
depression or suicidal thinking; compromised respiratory function; sleep paralysis, hypnagogic/hypnopompic 
hallucinations. Risk of the above symptoms increases with use of CNS depressants and alcohol. In obese 
women (BMI > 30), there is increased risk of exposure-related adverse effects. Belsomra is a schedule-IV 
compound with mild/modest abuse-potential in the same class as existing sleep medications and anxiolytics. 
The most common adverse reactions include somnolence and slowed motor coordination. Not recommended 
for use in patients taking strong CYP3A inhibitors, efficacy may be reduced, or for patients with severe hepatic 
impairment. Based on animal data, Belsomra may cause fetal harm. 
 
Risks for Behavioral and Psychometric Testing. Items on certain psychological/psychiatric questionnaires 
and interviews might be perceived as personally discomforting to some subjects. Similarly, subjects may 
experience discomfort due to withdrawal symptoms as part of the smoking relapse assessment. With regard to 
the actigraphy sleep monitoring, participants may experience mild discomfort while acclimating to wearing the 
device during sleep. While subjects may be uncomfortable reporting these issues, the risks of serious sequelae 
are extremely low. 
 
Risks for Cold Pressor Test. Individuals with cardiovascular disorders and neurological disorders should not 
participate. This information will be obtained during medical screening. Due to individual variation in pain and 
cold sensitivity, for some subjects the cold water may become too painful to sustain immersion for 120 
seconds. There are no lasting effects from placing the hand and wrist in ice water (0° Celsius) for 120 seconds. 
 
Risks for Physical Examination. The intake screening and physical exam are part of the CNRA General 
Evaluation protocol, and are approved under protocol HSC-MS-05-0322 and detailed therein. 
 
E4. Adequacy of Protection Against Risks 
 
Procedures to Minimize Drug-Related Risks 
We will screen very carefully for alcohol use and depressive symptoms. It will be made explicit that participants 
are not to drink alcohol in evening. We will use the Alcohol Use Disorders Identification Test (AUDIT) score 
and our mental health counselors SCID-screeners to enroll only those with low risk for alcohol abuse. Subjects 
will report no current depressive symptomatology (Beck Depression Inventory, or BDI < 15), with no past 
depressive episodes or suicidal ideation. The Columbia Suicide Severity Rating Scale (CSSRS) will be 
administered at each visit (see additional details below), as per NIH/FD 
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the report t
alcohol use by AUDIT score, intake self-report, or breath alcohol, or indication of increase in depressive 
symptomatology / suicidality as measured by the CSSRS will result in study stopping (see details below). Will 
exclude for any patients taking CYP3A inhibitors; patients with severe hepatic impairment; and women who are 
or become pregnant. Pregnancy and drug tests are administered on via urinalysis on lab testing days. Women 
of childbearing capacity must be taking one form of birth control. We will exclude for women with BMI > 30 to 
decrease risk of side effects. 
 
In addition to the rigorous screening criteria for inclusion. At the end of each experimental day, cardiovascular 
measures will be taken and the subject will be evaluated for signs of impairment or side effects, first by a 
research assistant and then by the research nurse, medical director, or PI. The assessment battery includes 
subjective effects questionnaire, nystagmus, touching nose, balance, and walking a straight line). If 
cardiovascular measures are normal, within the range of pre-dose levels, and the subject is determined to be 
unimpaired, the subject will be released. If any signs of intoxication are detected, participants will be required 
to remain at the experimental site until such symptoms are no longer observed. 
 
In the event of either an unexpected adverse event or a prolonged period of intoxication, we have several 
measures in place. First, Dr. Weaver (CNRA medical director) has clinical experience and training in 
emergency medicine. Thus, a physician will be in the immediate vicinity of laboratory at all times. Offices and 
clinical space are within 100 feet of the lab. Collaborating MDs can be paged at any time during the day. 
Second, Ben Taub Hospital, a level 5 emergency medical center is located just minutes away from BBSB. 
Finally, in the event of extended sedation, intoxication, or impairment, in which any subject does not appear 
clear-headed, feeling well, and in full control of his or her behavior, two steps will be taken. First, the subject 
will remain in the lab until such time that the primary or a co-investigator deems that it is safe for him or her to 
leave (e.g., passing the sobriety test described above). In the event of extended impairment, we will arrange 
(and pay for) a taxi service to drive the subject back to his/her home rather than having to use METRO. We will 
administer the Columbia Suicide Severity Rating Scale (CSSRS screening version) at each visit to assess 
suicidality and depressive symptoms, consistent with current FDA best practices. If the screening indicates 
change in suicidal ideation, we will administer the full version. If suicidality is judged to clinically significant as 
per CSSRS scoring criteria, we will (1) report the event to CPHS within 48 hours; (2) remove the patient from 
the study; (3) make a referral to either the BBSB outpatient mood disorders clinic or UT HCPC, depending on 
consultation from Dept of Psychiatry outpatient faculty at BBSB. 
 
For the cold pressor task, participants will be told that if the level of pain is too uncomfortable, they should 
remove the hand immediately and not wait to the end of the 120 sec test period. Each participant will be able to 
test the water temperature for 10 sec prior to beginning the procedure. These details are presented in the 
informed consent document. Because there are no sustained effects of cold water, if a participant cannot 
sustain the immersion for 120 sec at baseline, it will not preclude repeated testing on the follow-up lab test day. 
 
Other Protections Against Risk. The following procedures will be taken to safeguard against adverse 
medication events: (1) careful initial intake evaluation to determine eligibility based on inclusion/exclusion 
criteria; (2) thorough physical evaluation prior to treatment, consisting of physical examination, standard 
laboratory tests, electrocardiogram, toxicology screen, pregnancy test, and vital signs; (3) repeated tests 
during treatment; (4) daily monitoring of pill taking using MEMS caps, returned pill counts, and self-report; (5) 
weekly review of adverse events and medication compliance; (6) regular evaluation by the study physician (Dr. 
Weaver). Specific criteria will be used to exclude potential subjects for whom any of the study medications is 
contraindicated. Any abnormal physiological, psychological, or behavioral event will be evaluated and, if 
indicated, will result in the subject’s removal from the study. 
 
For all three experiments included in this project, we will use an Adverse Event Log (AEL) based on NIDA 
SAFTEE procedures. The AEL will record the duration, severity, and frequency or any adverse events, signs, 
and symptoms. An evaluation will be made as to the event’s relationship to the study drug(s), scaled as 
unrelated, unlikely, possible, and probable. The AEL will be included in 
IRB NUMBER: HSC-MS-19-0966 
oIRDBSAMPBP.ROVAL DATE: 10/12/2023 

IRB APPROVAL DATE: 10/12/2023 
 
Subjects will be monitored regularly for compliance with the study requirements, including the dosing regimen 
and breath alcohol testing upon arrival at the laboratory each day of testing. Written and verbal information 
about the medication will be given to all participants. This information will remind the subject to: (1) take food 
shortly after medication if needed to relieve gastric irritation; (2) inform the treatment research clinic nurse or 
physician of any over-the-counter and prescription medication taken, especially: cough medication, diarrhea 
medication, narcotic medication; (2) notify treatment research clinic nurse or physician of any side effects that 
persist or worsen. The study physician, nurse, and PI will review cases involving clinical deterioration of 
increased symptomatology or substance abuse. Appropriate actions will be taken, including study termination 
with proper referral. 
 
Confidentiality will be protected in several ways. All information collected solely for research purposes will be 
kept in locked, restricted access files. Individual subject information will be transferred to outside sources only 
with the express written request of the subject. Subjects will receive a copy of their signed consent form. All 
personnel associated with this grant have successfully completed ethics training in the Protection and Welfare 
of Human Participants, and certification is on file at the Health Science Center CPHS and office of sponsored 
projects. All intake and experimental data that are collected will be uploaded onto a laboratory database, 
computers dedicated to data storage and management. These computers are protected by password. All data 
will be treated as confidential information. All data including urine samples, medical and psychiatric intake 
exams, and behavioral and drug administration data – will be obtained solely for research purposes. All 
individuals who elect to participate and sign the informed consent agreement will be assigned a subject 
number (e.g., 3200), which will serve as that subject’s identifier (rather than name or SS#). A log book and 
electronic database that connect participants’ identifying information with subject number are kept in a locked 
file cabinet and room and password protected, respectively. 
 
Recruitment and Informed Consent. Participants will be self-referred in response to various study 
advertisements. All CNRA recruitment materials have been approved by CPHS for ongoing studies over the 
past 5 years. Individuals who call for information will be given a brief description of the study. Those interested 
will then be asked to answer questions about their current substance use. A trained research assistant will 
conduct this telephone-screening interview. Eligible subjects will be scheduled for an in-person intake visit at 
the CNRA, first floor BBSB. The first intake appointment will begin with the presentation of the informed 
consent form. The consent form will detail the requirements of study participation (e.g., # of visits, type of data 
collected, time commitment, etc.). 
 
Subjects will be told that the purpose of the study is to evaluate the effects of medications on human behavior 
related to mood, sleep, and cigarette smoking. Information about the components of the experimental 
procedure will be explained. Details of the random assignment procedure (placebo or active dose) will be 
explained. Subjects will be informed of their attendance expectations. Other information on the consent form 
will include a full description of study requirements, reimbursement, risks, benefits, alternatives, and the role of 
the local IRB. All questions will be answered before written consent is requested. All research conducted in our 
laboratory and the CNRA has prior approval from the Committee for the Protection of Human Subjects (CPHS) 
of the University of Texas Health Science Center - Houston. 
 
E5. Potential Benefits of the Proposed Research to the Subject and Others 
All services provided in these studies will be free. The studies should help compliment and advise clinical 
research focused on stopping cigarette smoking and preventing relapse. Subjects will be told if unusual 
information is discovered during the study that will make a difference in treatment for this or other problems. By 
taking part in this research, subjects may help themselves toward recovery and others with similar problems. 
 
Subject Payment. Participants will be provided $40 for completing the baseline screening. They will receive 
$50 for attending each study visit and a $50 bonus for completing the study/returning study equipment. 
IRB NUMBER: HSC-MS-19-0966 

IRB APPROVAL DATE: 10/12/2023 
 
Additionally, participants will receive $5 compensation per visit for parking and/or bus fare. As noted above, 
participants may earn up to $34 across visits during the smoking relapse assessment (if achieving maximum 
latency and zero cigarette purchase), bringing total possible compensation to $234/participant. Upon study 
completion, participants may be given the opportunity to earn an additional $20 for referring new participants to 
the study that successfully enroll and also complete all study procedures. 
 
E6. Importance of the Knowledge to be Gained. 
Research participation may assist subjects in abstaining from cigarette smoking during study, and via study 
completion protocol, bring them into contact with treatment resources at our research center and in the 
community. Nicotine dependence is marked by repeated relapse, leading to devastating consequences on a 
personal and societal level. Currently there is no medication that has been shown to be broadly effective in 
improving withdrawal symptoms via improved sleep metrics. Suvorexant (and orexin agonists more broadly) 
may help reduce sleep disruptions and attenuate craving, helping to reduce risk of relapse. This experiment 
will compliment and provide valuable information to our ongoing and future addiction work, and contribute to 
the knowledge base in the treatment of tobacco use disorder. Our procedures have been designed to minimize 
the probability of risks. Our research center has an excellent track record in conducting human 
psychopharmacology experiments and clinical trials with the utmost attention to safety. 
 
E7. Inclusion of Women and Minorities 
Women, minorities, and children will be included at minimum to the extent that they are reflected in this 
population. In previous clinical studies at the Treatment Research Clinic (TRC), the percentage of females and 
males is approximately 20% and 80% respectively; however, this imbalance reflects a historical trend of 
studies focusing on male-dominated drugs of abuse (e.g., cocaine). Recruitment efforts will seek to achieve a 
50-50 balance and further stratify group membership on the basis of sex. 
 
The ethnic representation has been 67% Black, 25% White, and 8% Hispanic. The medical center environment 
is not known to be uniquely avoided by any particular ethnic group and patients view it as favorable and 
neutral. Nevertheless, we are prepared to implement recruitment procedures to ensure a more diverse patient 
population. These procedures include: 1) Targeted advertising in newspapers which serve minority 
communities (e.g., Hispanic or Latino communities). 2) Distribution of flyers and notices in neighborhoods 
known to have a high minority population. 3) Engaging in outreach activities on an ongoing basis, e.g., 
contacting church and community leaders in the Hispanic communities to provide educational material about 
cigarette smoking and its consequences; providing contact information to aid in referrals to our clinic (see Core 
for additional details). 
 
E8. Inclusion of Children 
Children (age 18-21years) will be included in this research. From a safety perspective, risks of exposure to the 
proposed study medication in tobacco-dependent children have not been established. The safety and efficacy 
of the proposed study medication should be established in adults first, before conducting this type of treatment 
research in children. 
 
E9. Data and Safety Monitoring Plan (NIH/NIDA specific issues) 
1. The Principal Investigator will be responsible for knowing the policies of the local IRB (the UT – Houston 
Committee for the Protection of Human Subjects, CPHS). The PI will adhere to CPHS policies and maintain 
accurate documentation of CPHS correspondence and reports (e.g., annual report). The PI is responsible for 
documentation and handling of all possible study-related adverse events. The Treatment Research Clinic 
(TRC) within our Center for Neurobehavioral Research on Addictions (CNRA) has longstanding data collection 
and safety monitoring systems in place that will be available for the proposed study. These include staff 
training, weekly audit of data collection/entry, medical screening with results reviewed by on-site nurse and 
physician, use of standardized assessments, continued medical monitoring during the study, procedures to 
monitor medication compliance (MEMS caps, texts). As PI, Dr. Suchting will assure that the above systems are 
in place and functioning properly during the study. 
IRB NUMBER: HSC-MS-19-0966 

IRB APPROVAL DATE: 10/12/2023 
 
2. A Monitoring Committee will provide additional, independent oversight of data related to subject safety. This 
committee will perform the following activities: (a) review the research protocol and plans for data and safety 
monitoring; (b) evaluate study progress, including data quality, participant recruitment rates, retention rates, 
outcome and adverse experience data, and risk versus benefit profile; (c) make recommendations to the PI for 
a discontinuation of study medication for an individual patient based on adverse experiences; (d) make 
recommendations to terminate the study because of safety concerns; and (e) protect the confidentiality of the 
data and the results of monitoring. The Committee will be blind to study medication, unless they believe that 
termination of the trial is warranted. This committee meets annually to review all CNRA studies, and this 
present study will be added to the DSMB review in 2020. The DSMB report is submitted annually to CPHS. 
3. Adverse events (AE) will be reported to the UT-CPHS on an annual basis. Serious adverse events will be 
reported immediately (verbally within 24 hours) to the UT-CPHS, the Monitoring Committee, and to the NIDA. 
A written report will follow as soon as possible but in no more than three days. The written report will be in the 
format required by the local IRB and will contain information regarding the date of the AE, description of the 
AE, severity rating (Grade 1 to 4), assessment of cause, whether the AE indicates an increased risk for current 
or future subjects, and whether changes to the informed consent form are necessary. 
4. We will also use an ongoing Adverse Event Log (AEL) based on NIDA SAFTEE procedures. The AEL will 
record the duration, severity, and frequency or any adverse events, signs, and symptoms. An evaluation will be 
made as to the event’s relationship to the study drug(s), scaled as unrelated, unlikely, possible, and probable. 
The AEL will be included in the report to DSMB. 
 
E10. Specific Issues: NIDA / NACDA Guidelines on Administration of Drugs to Human Subjects. 
Risk/Benefit. These issues are described in sections E1 through E6. As noted above, the potential for 
advances in scientific and treatment domains related to addiction are considerable. Based on the qualifications 
and long history of work in this area by the investigative team and the careful screening and monitoring for 
subject safety, we feel there is a favorable balance of potential benefit against risk. 
Data Safety Monitoring Board is described in E9. 
Informed Consent is described in section E4. 
Subject Selection is described in section E1. 
Confidentiality is described in section E4. 
Medical and Psychological Screening and Services are described in sections E1, E4, and E9, as well as 
sections D1 and D2 of the application. 
Administration of Drugs to Individuals Who Have Never Used Drugs. Study drugs will not be administered 
to subjects who have never used drugs. By definition all subjects will be cigarette smokers. 
 
Involvement of Individuals Currently Addicted to Drugs and/or Are Frequent Drug Abusers. We have 
taken into consideration the need to assess the participant's ability to provide informed consent (via use of 
screening and the Shipley-2 aptitude assessment). At study end, subjects will receive a follow up medical 
examination and a session with a licensed counselor in our treatment research clinic, who will provide 
information about treatment options and referrals. As described thoroughly in D1, D2, E1 and E4 we have 
rigorous medical examination and screening procedures to assure the absence of any medical or mental 
condition for which further drug exposure would be contraindicated. Our procedures do not entail exposure to 
higher doses, rates of administration, or new route of administration than they would normally encounter by 
under usual circumstances. If subjects have participated in prior clinical drug intervention trials at our treatment 
research clinic, a complete list of drugs and dosing protocols will be reviewed and kept in his/her evaluation 
record. Subjects using any current CNS active medications will be excluding from testing and rescheduled (if 
medication use was idiosyncratic, e.g., OTC for recent cold or headache) or excluded (if medication use is 
regular or for a chronic condition). In particular, we will exclude subjects with alcohol use disorders or report 
recent problem drinking (5/4 drinks for males/females in < 2.5 hours or > 10 alcoholic drinks per week), as 
suvorexant is contraindicated with alcohol due to potentially dangerous interactions with regard to sedative 
effects. 
 
Administration of Drugs to Incarcerated Individuals. Individuals who are currently on parole or probation 
with random drug testing by court officers, or who are currently incarcerated, will be excluded 
 
Administration of Drugs to Individuals with Mental Disorders. Individuals with DSM-IV Axis - I mental 
disorders other than SUD will be excluded. 
IRB NUMBER: HSC-MS-19-0966 

IRB APPROVAL DATE: 10/12/2023 
 
full control 
Drug Doses and Routes of Administration. The proposed dose in these experiments (20 mg) have been 
safely given to human subjects in previous laboratory experiments and clinical trials. Standard routes of 
administration (PO capsules) will be used. No doses will be given outside the range of those already 
administered to humans in previous studies and indicated in the prescribing information in the investigator’s 
brochure. 
 
Prior and Current Drug Treatment Status. All subjects in the proposed experiments will receive a follow up 
medical examination and a session with a licensed counselor in our treatment research clinic, who will provide 
information about treatment options and referrals. 
 
Prior and Current Treatment Experience. If subjects have participated in prior clinical drug intervention trials 
at our treatment research clinic, a complete list of drugs and dosing protocols will be reviewed and kept in 
his/her evaluation record. Subjects using any current CNS active medications will be excluding from testing 
and rescheduled (if medication use was idiosyncratic, e.g., OTC for recent cold or headache) or excluded (if 
medication use is regular or for a chronic condition). 
 
Women of childbearing potential will not be excluded from these experiments. 
 
Pregnant Women will be excluded from these experiments, and urine pregnancy testing will be performed at 
each visit to the research center. 
 
Special Considerations Across the Lifespan. Individuals under the age of 19 will be excluded from this 
research due to risks and unknown effects of these drugs in adolescents, and ethical concerns of administering 
drugs of abuse to individuals this age. Additionally, individuals this age may be in school, which would preclude 
the normal daytime participation time. We will also exclude individuals over age 55, as elderly subjects also 
constitute a vulnerable population with regard to drug effects. Additionally, changes in anatomy and physiology 
in the elderly that may alter the metabolism and short and long-term effects of drugs, compromising both safety 
and scientific validity. 
 
Study Personnel Training and Experience. All medical and psychiatric screening and interviews will be 
conducted by trained clinicians, who are first trained by experienced SCID interviewers using standardized 
training videotapes from Biometrics Research, NY. All personnel associated with this grant have successfully 
completed ethics training in the Protection and Welfare of Human Participants, and certification is on file at the 
Health Science Center CPHS and office of sponsored projects. CNRA pharmacists will carry out preparation of 
medication; distribution of medication by research assistants will follow after training has been conducted by 
the PI (Suchting). 
 
Infection Risk Reduction Counseling and Testing. As described in sections D1, D2, E1 and E4, we 
recognize these risks and have included the necessary tests and precautions for disease transmission and 
infection risk (HIV, tuberculosis (TB), hepatitis, syphilis). HIV counseling will be made available as deemed 
appropriate by medical personnel in the treatment research center. 
 
Safety of Research Participants Outside of the Research Site. These issues are addressed in section E4. 
They are repeated here for clarity. In addition to the screening criteria for inclusion, each visit to the laboratory 
will include a full side effects profile. Additionally, subjects will be evaluated for signs of impairment or side 
effects, first by a research assistant and then by a PI and CNRA research nurse. The assessment battery 
includes subjective questionnaire, nystagmus, touching nose, balance, and walking a straight line. If the 
subject is determined to be unimpaired, s/he will be released promptly. If any signs of sedation or other 
impairment are detected, participants will be required to remain at the experimental site until such symptoms 
are no longer observed. In the event of either an unexpected adverse event or heavy sedation, we have 
several measures in place. First, Dr. Weaver (CNRA medical director) is a licensed MD with clinical experience 
and training in emergency medicine. Thus, a physician will be in the immediate vicinity of laboratory. Offices 
and clinical space are contiguous to the lab. Second, Ben Taub Hospital, a level 5 emergency medical center 
is located less then 5 minutes away from our building. Finally, in the event of extended sedation or impairment, 
in which any subject does not appear clear-headed, feeling well, and in 
IRB NUMBER: HSC-MS-19-0966 
of his or her behavior, two 

IRB APPROVAL DATE: 10/12/2023 
 
steps will be taken. First, the subject will remain in the lab until such time that the PI, medical director, or 
research nurse deems that it is safe for him or her to leave (e.g., passing the test described above). Second, if 
necessary, we will arrange for a taxi service to drive the subject back to his/her home. 
 
The following procedures will be taken to safeguard against adverse medication events: (1) careful initial intake 
evaluation to determine eligibility based on inclusion/exclusion criteria (including exclusion for alcohol use 
disorder or frequent regular use); (2) thorough physical evaluation prior to treatment, consisting of physical 
examination, standard laboratory tests, electrocardiogram, toxicology screen, pregnancy test and vital signs; 
(3) repeated tests during treatment; (4) daily monitoring of pill taking using MEMS caps, returned pill counts, 
and self-report; (5) weekly review of adverse events and medication compliance; (6) evaluation by the study 
physician (Dr. Weaver). Specific criteria will be used to exclude potential subjects for whom any of the study 
medications is contraindicated. Any abnormal physiological, psychological, or behavioral event will be 
evaluated and, if indicated, will result in the subject’s removal from the study. 
 
For this project, we will use an Adverse Event Log (AEL) based on NIDA SAFTEE procedures. The AEL will 
record the duration, severity, and frequency or any adverse events, signs, and symptoms. An evaluation will be 
made as to the event’s relationship to the study drug, scaled as unrelated, unlikely, possible, and probable. 
The AEL will be included in the report to DSMB. Relevant information is also included in section E9. 
 
Referral to Treatment. As noted above, at study end subjects will receive a follow up medical examination 
and a session with a masters-level licensed counselor or RN in our treatment research clinic, who will provide 
information about treatment options and referrals. If depression or suicidal ideation is measured at risk during 
the study, participation will be terminated and appropriate referrals made (see above). 
 
Incomplete Disclosure. We have no elements of deception in this project, other than withholding of dose 
information to subjects about dose contents on days of testing (e.g., suvorexant or placebo). However, 
informed consent documents will contain full disclosure of the drug that may be received during the course of 
the experiments, along with potential side effects. No information about study risks will be withheld from 
subjects. 
 
Payment for Participation in Research. Subjects will be paid daily for attendance and for performance on the 
behavioral tasks, and a bonus at the end of the study for completion. Participants will be provided $40 for 
completing the baseline screening. They will receive $50 for attending each study visit and a $50 bonus for 
completing the study/returning study equipment. Additionally, participants will receive $5 compensation per 
visit for parking and/or bus fare. As noted above, participants may earn up to $34 across visits during the 
smoking relapse assessment (if achieving maximum latency and zero cigarette purchase), bringing total 
possible compensation to $234/participant. 
 
F. Vertebrate Animals 
Not applicable. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IRB NUMBER: HSC-MS-19-0966 

y-provoking 
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