Conditions: Methamphetamine Use Disorder
Keywords: sleeplessness stress Cue reactivity
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 7
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine the effects of SUVO on sleep, stress, and cue reactivity/craving and to evaluate the preliminary safety and side effects profile of suvorexant (SUVO)

Detailed description:

Arms:
arm 1: After 1 week of placebo treatment there will be 1 week of wash out period before start of study medication arm 2: After 1 week of SUVO treatment there will be 1 week of wash out period before start of placebo

Interventions: intervention 1: suvorexant (SUVO) intervention 2: Placebo
Intervention descriptions: intervention 1: Participants will receive 20mg of SUVO for 7 days. Participants will be directed to take the medication between 9:30 PM and 10:00PM. intervention 2: Participants will receive 0mg of placebo for 7 days. Participants will be directed to take the medication between 9:30 PM and 10:00PM.

Protocol document:
Prot_SAP_000.pdf: 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The effects of suvorexant on sleep, stress, and cue-reactivity in methamphetamine use disorder 
 
NCT05711862 
 
Version Date: 10/09/2023 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


2 
 
Protocol Title: 
The effects of suvorexant on sleep, stress, and cue-reactivity in methamphetamine use disorder 
Principle Investigator: Dr. Heather Webber 
Co-Investigators: 
Drs. Joy M. Schmitz, Scott D. Lane, Robert Suchting, and Michael Weaver 
Study Coordinator: 
Jessica Vincent 
Population: 
Participants with methamphetamine use disorder 
Number of Sites: 
single site (BBSB) 
Study Duration: 
4 weeks 
 
 
Project Summary: 
 
Methamphetamine (MA) has re-emerged as the next substance use crisis in the United States. Unlike the opioid 
crisis, treatment of MA use disorder is significantly more challenging without an FDA-approved medication. Most of the 
candidate drugs tested to date focus on modulating monoaminergic pathways, yielding limited evidence of benefit. New 
interventions aimed at novel biological mechanisms are needed. 
Converging evidence highlights the orexin system as a promising target for addressing key mechanisms in the 
recovery from substance use disorders, including regulating sleep architecture, buffering hyper-arousal and stress 
responses, and modulating reward processing and drug-motivated behaviors1–5. Activation of orexin (OX) receptors by 
psychostimulant drugs mediates arousal (OX2R) and reward (OX1R) functions and, by contrast, blockade of both 
receptors produces attenuation of these physiological and behavioral functions6. In preclinical animal models, selective 
OX1 R /OX2 R receptor antagonism has been shown to reduce MA self-administration and MA-induced reinstatement 
responding7,8. In humans with cocaine use disorder, we demonstrated that treatment with the FDA-approved dual 
orexin receptor antagonist suvorexant (SUVO) improved outcomes in relapse-related domains of sleep, stress, and cue 
reactivity9. Here, we propose to expand these promising findings by examining the effects of SUVO in humans with MA 
use disorder, an understudied clinical population for whom there is no currently approved treatment indication. 
The primary goal of the study is to assess the effects of SUVO on physiological sleep (actigraphy, EEG) and self- 
reported sleep quality. We will also assess two other domains linked to the orexin system and commonly related to MA 
relapse including stress and cue reactivity/craving. Our overarching hypothesis is that treatment with SUVO will 
attenuate disruptions in sleep, stress, and cue reactivity/craving. By engaging these relapse-related target mechanisms, 
this work will provide critical proof-of-concept evidence for a subsequent R01. To that end, we will employ a within- 
subjects, two group cross-over design (N=12) and take a multimodal approach to assessing sleep, stress, and cue 
reactivity/craving. Participants will complete stress reactivity and electroencephalogram (EEG) laboratory tasks, self- 
report, and drug use measures after one week of SUVO, washout, and placebo (PL), order counterbalanced between 
groups. Participants will also wear an activity watch at night in order to have their sleep monitored via actigraphy. 
 
Primary Hypotheses and Specific Aims: 
 
Primary Aim 1: Determine the effects of SUVO on sleep, stress, and cue reactivity/craving 
Hypothesis 1a: SUVO compared to placebo will improve sleep outcomes assessed by actigraphy (total sleep 
time, wake after sleep onset), self-report (Pittsburg Sleep Quality Index), and EEG (resting state alpha power); 
Hypothesis 1b: SUVO compared to placebo will improve acute stress reactivity as measured by physiological 
responses (cold-pressor task induced cortisol and HR/BP) and subjective ratings (Visual Analog Scale; Depression 
Anxiety Stress Scale). 
Hypothesis 1c: SUVO compared to placebo will reduce cue reactivity/craving as measured by LPP to 
methamphetamine images and self-report (Brief Substance Craving Scale). 
Exploratory Aim 2: Evaluate the preliminary safety and side effects profile of SUVO. 
 
Primary outcome measures: self-reported sleep, resting state alpha power, LPP, self-reported stress, and cortisol 
measured at each study visit after 1-week of SUVO, washout, and PL; total sleep time and wake after sleep onset 
measured nightly via actigraphy watch 
 
Secondary outcome measures: methamphetamine use (TLFB and UDS) measured at each study visit after 1-week of 
SUVO, washout, and PL; side effects questionnaire, BDI, and CSSRS measured at each study visit after 1-week of SUVO, 
washout, and PL 
IRB NUMBER: HSC-MS-22-0796 
    IRB APPROVAL DATE: 10/09/2023 


3 
 
65 years old 
Background and Rationale: 
 
Public health significance of MA use disorder. MA use disorder 1) is surging in recent years, contributing to a 
massive (~180%) increase in overdose related MA deaths from 2015-201910, 2) presents a tremendous economic burden 
to society (likely >$48 billion/year)11, and 3) leads to severe impacts on physical/mental health and social functioning11. 
The role of sleep, stress, and cue reactivity in addiction. MA use has marked effects on several interconnecting 
neurobiological processes such as sleep, stress, and cue reactivity. Chronic MA use and MA withdrawal is associated with 
poorer sleep quality12. Severe sleep disturbances can aggravate MA use disorder symptoms, such as drug craving and 
stress, and are commonly a large barrier to treatment success2,12. Similarly, stress is a critical part of the initiation and 
maintenance of addiction, e.g., use of substances to alleviate negative mood states13,14. Stress and anxiety are known to 
trigger cravings and use of drugs of abuse in turn activates stress pathways, which together can increase vulnerability to 
cue-induced relapse15–17. Cue reactivity is a hallmark feature of addiction, where previously innocuous stimuli become 
associated with drug reward and acquire incentive properties18. Cue-induced craving is central to addiction and can 
continue to occur during abstinence, triggering relapse18. Taken together, a medication targeting sleep, stress, and/or 
cue reactivity would be of interest in treating MA and other substance use disorders. 
Objective measurement of critical processes. Research suggests that subjective measures may not capture the 
substantial heterogeneity in risk for relapse19, especially in persons with substance use disorders, who may lack insight20. 
Further, despite longstanding debate in the literature, there is no accepted self-report measure of craving. Recognizing 
these limitations, the current study will take a multi-modal approach to measuring relevant constructs related to use 
and relapse21. First, sleep measurement will be enhanced by leveraging actigraphy methods in addition to self-reported 
sleep22. While including a neuroimaging measure during sleep is out of the scope of the current study, waking effects on 
sleep disruptions will also be assessed with resting state electroencephalogram (EEG). For stress, salivary cortisol and 
heart rate/blood pressure assessments will be taken before and after induction of stress with the cold pressor task. 
Finally, cue reactivity and craving will be assessed both with self-report and the late positive potential (LPP), an EEG 
component that reflects the motivational relevance of a stimulus23–25. 
Orexin system as a novel target for MA treatment. One system that has been neurobiologically linked to 
regulating these processes is the orexin system. Orexins are a class of amino acid peptides that are sourced in the 
hypothalamus for which two receptors have been discovered (OX1R, OX2R). Orexins are neuromodulators: they exert 
their effects through regulation of GABA and glutamate. While the orexin system is widely known for regulating 
appetite26 and arousal/sleep27,28, it has widespread connections throughout the brain and is now known to modulate a 
wide variety of other behaviors including stress, reward-seeking behaviors, and reactivity to reward cues29. Critically, 
recent evidence indicates that selective OX1R/OX2R receptor antagonism reduced MA self-administration/MA-induced 
reinstatement responding7,8 as well as blocked MA-induced hyperarousal and sleep impairment in preclinical studies30. 
While pharmacological interventions in animal models studies show promise, medication development for MA use 
disorder has largely failed31,32. However, there is one FDA-approved orexin compound indicated for the treatment of 
insomnia: Suvorexant (SUVO), a dual orexin receptor antagonist. FDA-approval of suvorexant for the treatment of 
insomnia helps pave the way for rapidly advancing the development of orexin-based therapies for the treatment of MA 
use disorder and other addictions. In the current study participants will receive SUVO and placebo in a cross-over design, 
have their sleep measured via actigraphy, undergo an EEG assessment, and complete laboratory tasks to assess stress 
and MA cue reactivity. 
 
Methods: 
 
Overall study design. We will use a two-group cross-over design. Each group will complete three conditions, each lasting 
one week. 12 participants will be randomized to one of the two groups. Group one (n=6) will receive one-week placebo, 
one-week washout, and one-week SUVO. Group two (n=6) will receive one-week SUVO, one-week washout, and one- 
week placebo. During the washout period, the participants will not receive any pills. Eligibility criteria and baseline 
measures will be collected on Day 0 before the start of week one. Participants will come to the clinic once a week on 
Monday for 4 weeks. On Day 1 (Monday) of the first week, the participants will receive their medication and actigraphy 
watches. Each following Monday, they will complete self-report and drug use measures, as well as the laboratory tasks 
(cold pressor and EEG). Table 1 outlines the schedule of assessments. We will aim to enroll a total of 16 participants to 
complete 12, with dropouts being replaced, if possible. 
 
Participants, Recruitment, and Setting. The participants will consist of non-treatment-seekIiRnBg iNnUdiMviBduEaRl:sHmSeCe-tMinSg-2D2S-M
07-96 
5 criteria for MA use disorder. All participants will be between the ages of 18- 
aIRndB fAluPePnRtOinVEAnLglDisAhT. E: 10/09/2023 


4 
 
c nature of th 
Individuals will be excluded if they meet the following criteria: presence of an alcohol use disorder (AUD), reporting 
binge drinking (>7 drinks for women and >14 drinks for men), greater than mild substance use disorder on any other 
illicit drug; any medical conditions contraindicating SUVO (e.g., severe pulmonary disease, severe cardiovascular disease 
or clinically abnormal ECG, severe liver or kidney disease, seizure disorder, or sleep disorder – particularly narcolepsy); 
currently taking medications with known drug interactions with SUVO (e.g., MAO inhibitors, anticonvulsants, 
haloperidol, phenothiazines, anesthetics, and any sedative); pregnant or breast feeding; current DSM-5 psychiatric 
disorder or neurological disease requiring on-going treatment that would make participation unsafe; history of seizure 
disorder; head injury with loss of consciousness in the last 5 years. Eligibility criteria will be assessed at baseline and will 
be conducted by licensed counselors and the medical director (Dr. Weaver). The study will be conducted at the Center 
for Neurobehavioral Research on Addiction (CNRA), where the PI (Dr. Webber) and Co-Is (Drs. Schmitz, Lane, Suchting) 
have experience conducting treatment and laboratory-based studies in substance use populations. Recruitment will 
follow typical CNRA protocols, including local advertising in print/radio, recruitment companies (Build Clinical/TrialFacts) 
and referrals from prior CNRA studies and the Houston area. Data analyses will be performed by Dr. Robert Suchting, a 
biostatistician also affiliated with the CNRA, with expertise in the application of quantitative methods to investigate 
experimental and clinical outcomes related to EEG, sleep, and psychostimulant use9,23. 
 
Table 1. Schedule of Assessments 
0 
(Intake) 
1 
(PL or SUVO) 
2 
(washout) 
3 
(PL or SUVO) 
4 
(Final) 
Study Day 
M-F 
M 
T 
W 
R 
F 
S 
S 
M 
T 
W 
R 
F 
S 
S 
M 
T 
W 
R 
F 
S 
S 
M 
Consent and Baseline Screening (UDS, SCID, ASI, 
KMSK, TLFB, physical/ psychiatric eval) 
X 
Receive Study Medication (SUVO or PL) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medication Compliance 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Actigraphy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Self-report Sleep, Stress, Craving, MA use (PSQI, 
ISS, PROMIS-SF, DASS, VAS, BSCS, BDI, TLFB), and 
UDS 
X 
X 
X 
Laboratory Tasks (Cold Pressor, EEG) 
X 
X 
X 
SCID - Structured Clinical Interview for DSM-5, ASI - Addiction Severity Index33; KMSK - Kreek-McHugh-Schluger-Kellogg scale34; TLFB - 
Timeline Followback35; PSQI – Pittsburg Sleep Quality Index; ISS – Insomnia Severity Index; PROMIS-SF – Patient Reported Outcomes 
Measurement Information System Short Form Sleep Disturbance; BDI – Beck’s Depression Inventory; DASS – Depression Anxiety Stress 
Scale36; VAS – Visual Analogue Scale of Stress37; BSCS – Brief Substance Craving Scale38. 
 
Payment and Compensation. Participants will receive $40 for the baseline evaluation. As methamphetamine users tend 
to live further outside the city, we are budgeting extra for bus/parking validation/rideshare options, up to $30 per visit. 
Participants will receive $50 for each laboratory visit (3 visits total) and a completion bonus on their final visit for $50. If 
medication compliance is reached, participants will receive an extra $10 at each clinic visit (for more information see 
Medication Compliance). 
 
Baseline Screening. As a part of the CNRA general evaluation protocol (HSC-MS-0322), participants will receive a full 
physical and psychiatric evaluation on the first day including: a medical-history questionnaire, physical examination, 
urine drug screen (UDS), pregnancy test, blood draw, and ECG. Clinicians will administer the SCID, the ASI, the KMSK, 
and TLFB to assess current diagnoses, severity, chronicity, and daily use of MA (Table 1). UDS will be used to assess 
eligibility and substance use at baseline as well as on EEG testing days. It will also be used to assess medication 
compliance. 
 
Medication. Suvorexant (Belsomra®) is a dual orexin receptor antagonist and an FDA-approved medication for the 
treatment of insomnia. Prior research in humans indicates it is safe in human populations39–42. While this would be the 
first study assessing SUVO in MA users, a prior study from our group indicated that SUVO was safely administered to 
individuals with cocaine use disorder9. Our prior study used a conservative 2-week dose titration schedule (Week 1: 
10mg; Week 2: 20mg), with no serious adverse effects reported or observed. In the current study, participants will 
receive 20mg of SUVO for 7 days, the highest allowed FDA dose. Study medication will be compounded by CNRA 
pharmacists using size 00 capsules. Each dose will contain 20mg (active medication) or 0mg (placebo) of suvorexant, 
25mg of riboflavin, and cornstarch filler. The half-life is about 12 hours on average and steaIdRyB-sNtaUtMe pBlEaRsm: HaSC-MS-22-0796 
concentrations occur in 3 days with daily administration43. Due to the hypnoti 
IeRBdrAugP,PpRaOrVticAipLaDnAtsTwEi:ll1b0e/09/2023 


5 
 
howed that 
directed to take the medication at 10:00PM. 
 
Medication Compliance. Because SUVO will be administered in the evening at 10:00 PM, compliance is a high priority. 
Compliance will be assessed with CAROMA (cell-phone assisted remote observation of medication adherence)44. 
Participants record short videos of themselves taking the medication and send it to the CNRA study cell phone or save 
the videos to show study staff in person. Riboflavin will be added to medication capsules and urine ultraviolet 
fluorescent tests will be conducted at the weekly clinic visit to assess compliance. Text-based medication reminders with 
required text replies (Y/N) will also be used. If CAROMA, pills count, riboflavin readings, and text replies agree, then 
participants will be paid $10 per visit for compliance. Payments are adjusted downward if the measures do not agree9. 
Specifically, if compliance is reached for 7 days, then the participant will receive the full $10, up to 6 days: $7, up to 4 
days: $5, up to 2 days: $3, less than 2 days: $0. 
Measures. 
Sleep (Actigraphy). Sleep will be monitored using an activity tracker watch (FitBit Charge 5, FitBit Inc., San 
Francisco, CA). Fitbits demonstrate superior accuracy and sensitivity with minimal bias compared to other models45. The 
Charge 5 is the most recent model. Data will be downloaded via the FitBit app onto an IRB-approved and HIPA compliant 
research iPad. The following outcome measures will be calculated: total sleep duration and wake after sleep onset, two 
outcomes that are considered good indicators of sleep quality46. 
Sleep (Resting State EEG). Resting state EEG will be collected on test days to assess the waking effects of sleep 
quality. The primary outcome variable will be alpha power (8-12 Hz), which reflects a state of eyes closed wakeful 
rest47,48. Decreasing alpha during eyes closed is an indicator of entry into early sleep stages when drowsy49. As such, eyes 
closed alpha power is decreased after sleep deprivation and negatively correlated with sleepiness50–53. Importantly, 
differing results can be observed for eyes open and eyes closed conditions51, with more alpha during eyes open 
indicating sleepiness (which is the opposite to eyes closed). Therefore, both eyes open and eyes closed conditions will be 
measured and analyzed separately. Resting alpha power will be collected at each test day. See EEG Protocol for details. 
Sleep (Self-Report). The PSQI is a well-validated and reliable measure of sleep quality54–56. We will use the total 
summary score of the 18-items as the main outcome variable. We will also use the ISS57 and PROMIS58-SF as secondary 
self-reported measures of sleep. 
Stress (Physiological). The cold pressor task will be used to induce and measure the stress response. The cold 
pressor task reliably activates the sympathetic nervous system and the HPA axis which is observed by increases in heart 
rate, blood pressure, and cortisol59–62. HPA-axis activation during the CPT can be increased by incorporating a social 
evaluative component. These will include 1) a study member dressed in a white labcoat and taking notes on a clipboard; 
and 2) a webcam and monitor showing the participant’s face (no recording will actually be taken). Participants will be 
informed that their facial expressions will be assessed during the CPT. The addition of these social components during 
the CPT has been demonstrated to selectively activate the HPA-axis and significantly increase salivary cortisol levels63. 
During the CPT, participants will submerge their dominant arm in an ice-water bath for up to 2 minutes. Physiological 
measures of stress reactivity will include HR, BP, and salivary cortisol consistent with previous studies from our 
group37,64. Saliva samples will be collected before and after in swabs using the Cortisol-Salivette® system (Sarstedt) and 
measured using the Cortisol ELISA Kit (Enzo Life Sciences), per manufacture instructions. Subjective stress will be 
assessed before and after using a single-item VAS question (see below) and HR/BP will also be collected before during 
and after the CPT. 
Stress (Self-Report). Subjective stress levels will be assessed with the DASS-2136, a validated and reliable 
measure of core symptoms associated with depression, anxiety and stress. We will also use a Visual Analogue Scale 
(VAS) (“Please rate your current stress level”: 0=no stress, 10=extreme stress) to assess current subjective stress levels37. 
These measures will be collected on each test day prior to the laboratory tasks. 
Cue Reactivity/Craving (LPP). The late positive potential (LPP) is an event-related potential component thought 
to reflect the motivational relevance of visual stimuli25,65. The LPP to drug images is enhanced in drug users compared to 
controls, is correlated with craving, and tracks with abstinence 66–68, thus serving as an objective measure of cue 
reactivity/cue-induced craving. EEG will be collected on test days prior to the cold pressor task. The Picture Viewing Task 
will be used to elicit the LPP. Suvorexant might lead to decrease drug use through reducing reactivity toward drug cues. 
Therefore, the picture viewing task will provide this neural assessment of cue reactivity. In the task, the participants 
view images in four categories, pleasant, unpleasant, methamphetamine, and neutral. The other image categories are 
necessary, so that we can ensure the brain reactivity is specifically in response to drug imagIResBaNnUdMnoBtEjRu:stHsSaCli-eMntS-22-0796 
images. This is a standard task used in the EEG literature and a meta-analysis s 
dIRruBgAuPsPeRrsOhVaAveLaDnAinTcEr:e1a0s/e0d9/2023 


6 
 
.
response to drug images with a large effect size69. 
Cue Reactivity/Craving (Self-Report). The Brief Substance Craving Scale (BSCS) will be used to assess current MA 
craving38. The BSCS will be assessed on each test day prior to laboratory tasks. 
Safety/Side Effects. A 31-item questionnaire will be administered on each test day to assess side effects and 
adverse events. The Colombia Suicide Severity Rating Scale (CSSRS)70 and Beck’s Depression Inventory (BDI)71 will be 
administered at each visit per NIH guidelines. Breath alcohol concentration will also be assessed at each visit to assess 
for current intoxication. 
 
EEG Protocol. On EEG days, participants will be seated comfortably in front of a monitor, fitted for the EEG cap, and the 
electrodes will be prepared with conductive gel. EEG will be collected using a 64-channel actiCAP electrode cap, 
amplified with BrainAmp MR and digitized using Brain Vision Recorder (Brain Products, Munich). The EEG machine is 
situated within the CNRA on the first floor of the Behavioral and Biomedical Sciences Building. Before collection, 
impedances will be maintained below 50 k(OHM), as suggested by the manufacturers. The sampling rate will be 250 Hz 
and data will be filtered with .1 Hz high-pass and 100 Hz low-pass filters. Resting State EEG. Resting state EEG will be 
collected prior to the Picture Viewing Task (below). We will collect resting EEG for 3 minutes with eyes opened and 3 
minutes with eyes closed. Picture Viewing Task. The Picture Viewing task will be used to elicit the LPP, reflecting the 
motivational salience of a stimulus. During this task, participants are asked to view a slideshow of images including 
pleasant, unpleasant, neutral, and MA-related images. EEG Data Reduction. Data reduction will be performed with Brain 
Vision Analyzer 2, MATLAB, and BESA. Resting state data will be analyzed using the fast-Fourier transform. The primary 
outcome of interest will be alpha power (8-12Hz) although other frequencies will also be explored. Picture Viewing Task 
data will be segmented (200 ms pre-stimulus to 1000 ms post-stimulus) by the following conditions: unpleasant, 
pleasant, methamphetamine, and neutral images. The LPP will be defined as the mean amplitude between 400-800ms 
post stimulus over an ROI of central-parietal electrodes used in prior reports23. 
 
Data Analytic Strategy: 
 
Overview. Analyses will primarily rely on generalized linear modeling (GLM) for cross-sectional analyses and generalized 
linear mixed modeling (GLMM) for longitudinal analyses. This approach allows for various outcome distributions and 
multilevel data. All models will account for repeated observations with via the best-fitting structure of level-2 
intercepts/slopes. We will aim to collect full data on 12 participants. Other participants who drop out or are withdrawn 
will be excluded from analyses, depending on how much data we are able to collect. If only a few data points are 
missing, generalized linear mixed modeling will natively handle missing outcome data. GLMM natively handles missing 
data by allowing unequally spaced observations between participants; any other issues related to missing data will be 
handled via explicit modeling of missingness or imputation. Analyses will be performed in R72 via packages lme473, 
rstan74, and brms75. Confounders: Preliminary data analyses will inspect relationships between sample characteristics, 
predictors, and outcomes via GLMM. Variables that demonstrate a relationship with both the predictor and outcome in 
a model meet criteria for being potential confounders76,77 and yield models with and without covariate adjustment. We 
report the simpler model if inferences are not affected by these covariates and report both models otherwise. 
Inference: Analyses will be run in parallel frequentist and Bayesian models. Frequentist results yield the probability of 
the data (or data more extreme), given the null hypothesis, while Bayesian results directly yield the probability of an 
alternative hypothesis78,79. Weakly informative priors will be used for all Bayesian analyses in order to emphasize the 
influence of the present data. Multiplicity: All a priori frequentist models will be evaluated at the α=0.05 (two-tailed) 
significance level, and will employ false discovery rate (FDR) to control for Type I error across any post hoc analyses. 
Bayesian models will be evaluated via PP threshold guidelines in the literature80,81 suggesting that PP = 75% to 90% 
indicates moderate evidence, PP = 91% to 96% indicates strong evidence, and PP = 97% or above indicates very strong to 
extreme evidence. Assumptions: Posterior predictive checking, scale reduction factors (“rhat”), and effective sample 
size will be used to evaluate Bayesian assumptions. Evaluation for frequentist models will use graphical evidence and 
statistical tests. 
 
Specific Hypothesis Testing. 
Aim 1: GLMM for repeated measures will separately model each outcome measure as a function of treatment 
condition, with Level-2 effects included for best fit. Outcomes will include measures of sleep (H1a: actigraphy; self- 
report sleep quality; EEG), acute stress reactivity (H1b: physiological responses; subjective IrRatBinNgUs)ManBdERcu: eHSC-MS-22-0796 
reactivity/craving (H1c: LPP to methamphetamine images; self-report craving) 
IRB APPROVAL DATE: 10/09/2023 


7 
 
Aim 2: Descriptive statistics will evaluate the frequency of adverse events (AEs) and severe adverse events 
(SAEs) between and within conditions. Logistic regression will evaluate presence (vs. absence) of specific AEs as a 
function of condition. 
 
Sample Size and Power. 
The current study is primarily concerned with deriving a preliminary range of plausible effect sizes for the effect 
of treatment; as such, power estimates are provided here purely as due diligence. Frequentist estimates rely on 
G*Power 3.1.9.7 and focus on a simplified model predicting the effect of treatment on one given normally-distributed 
outcome. Assuming two-sided alpha = 0.05, N = 12, 3 total measurements, a correlation among repeated measures of r 
= 0.15, the current proposal has 80% power to detect an effect size Cohen’s f = 0.59. Notably, Bayesian inference will 
provide probabilistic estimates of the effect of treatment irrespective of sample size. 
 
Protection of Human Subjects: 
 
Recruitment and Informed Consent 
The study will be conducted at the Center for Neurobehavioral Research on Addiction (CNRA), where the PI (Dr. 
Webber) and Co-Is (Drs. Schmitz, Lane, Suchting, Weaver) have experience conducting treatment and laboratory-based 
studies in substance use populations. Recruitment will follow typical CNRA protocols, including local advertising in 
print/radio, recruitment companies (Build Clinical/TrialFacts) and referrals from prior CNRA studies and the Houston 
area. We will also recruit from the Department of Psychiatry Recruitment Registry: HSC-MS-23-0768. Our study and 
contact information will be shared with potential subjects that are on the psychiatry waitlist via the Department of 
Psychiatry website or e-mail blasts. 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 methamphetamine cravings/use. 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. 
 
Selection Criteria 
Eligible participants will: 
1. Be between the ages of 18 and 65 years old 
2. Meet DSM-5 criteria for methamphetamine use disorder 
3. Be fluent in English and able to understand the consent form 
Participants will be excluded if they: 
1. Have an alcohol use disorder or report binge drinking (>7 drinks for women and >14 drinks for men) 
2. Have a greater than mild substance use disorder on any other illicit substance 
3. Have any medical conditions contraindicating SUVO (e.g., severe pulmonary disease, severe cardiovascular 
disease or clinically abnormal ECG, severe liver or kidney disease, seizure disorder, or sleep disorder – 
particularly narcolepsy) 
4. Are currently taking medications with known drug interactions with SUVO (e.g., MAO inhibitors, anticonvulsants, 
haloperidol, phenothiazines, anesthetics, and any sedative) 
5. Are pregnant or breast feeding 
6. BMI > 30 (women only) 
7. Have a current DSM-5 psychiatric disorder or neurological disease requiring on-going treatment that would 
make participation unsafe 
8. Have history of seizure disorder 
IRB NUMBER: HSC-MS-22-0796 
IRB APPROVAL DATE: 10/09/2023 


8 
 
egnancy an 
9. Have a head injury with loss of consciousness in the last 5 years 
 
Assessment of Criteria 
Eligibility will be carefully assessed in person at the CNRA. Participants will receive a full physical and psychiatric 
evaluation on the first day including: a medical-history questionnaire, physical examination, urine drug screen, 
pregnancy test, and ECG. SCID-5 will be conducted by licensed counselors and the physical examination will be 
performed by medical director (Dr. Weaver, M.D.). 
 
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 eligibility/baseline assessment, experimental testing, and end-of-study. The biological specimens 
obtained from all subjects will include urine, saliva for cortisol assessment, and breath samples for alcohol detection. 
Individuals who volunteer to participate will be assigned a subject number (e.g., 15000), under which all information 
collected will be filed. All materials will be obtained for the specific purposes of this research. 
 
Potential Risks 
Study Medication (suvorexant). 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. 
Psychometric Testing. Items on certain psychological/psychiatric questionnaires and interviews might be 
perceived as personally discomforting to some subjects. 
Actigraphy. Participants may experience mild discomfort while acclimating to wearing the device during sleep. 
EEG Task. The EEG may lead to redness or skin irritation where the sensors are placed. This will almost always 
disappear after a few hours. The images that the participants will view will contain sexual and violent images (including 
erotic scenes and mutilated bodies) and may upset some participants. Viewing drug images can induce craving. 
Cold Pressor Task. 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 90 seconds. There are no lasting effects 
(physical or physiological) from placing the hand and wrist in ice water (0° Celsius) for 90 seconds. 
Psychiatric/Physical Examination. There is a slight risk of bruising and infection in the blood draw procedures. 
Disclosing mental health information during the clinical interview can be uncomfortable for some participants. 
Confidentiality. There is always a risk of loss of confidentiality when participating in research. 
 
Adequacy of Protection Against Risks 
Study Medication (suvorexant). We will screen very carefully for alcohol use and suicide symptoms. It will be 
made explicit that participants should not drink alcohol for the duration of the study. We will use the mental health 
counselors SCID-screeners to enroll only those with low risk for alcohol abuse. The Columbia Suicide Severity Rating 
Scale (CSSRS) will be administered at each visit (see additional details below), as per NIH/FDA guidelines. Indication of 
regular alcohol use by SCID, intake self-report, or breath alcohol, or indication of increase in suicidality as measured by 
the CSSRS will result in study stopping (see details below). Will exclude for any patients takIinRgBCNYUPM
3ABiEnRh:ibHitSoCrs-M; pSa-t2i2e-n0t7s96 
with severe hepatic impairment; and women who are or become pregnant. Pr 
dIRdrBugAPtePsRtsOaVrAe LadDmAiTnEis:te10re/0d9/2023 


9 
 
take necess
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, 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. 
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 via CAROMA, 
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. 
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 the 
report to DSMB. 
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. 
Behavioral and Psychometric Testing. The participants do not have to answer any questions they do not feel 
comfortable answering and can not take part in the study. 
EEG Task. Participants will be shown example images during the consent process and will be told they can stop 
viewing the images at any time. Those who think they will be affected by the pictures (erotic, mutilations, and drug- 
related images) can choose to not participate. 
Cold Pressor Task. Participants will be told that if the level of pain is too uncomfortable, they should remove the 
hand immediately. 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. 
IRB NUMBER: HSC-MS-22-0796 
Psychiatric/Physical Examination. Our experienced phlebotomist will 
aIrRyBpArePcPaRuOtioVnAsLtoDATE: 10/09/2023 


10 
 
prevent unnecessary bruising during venipuncture. All risks and protections are discussed further in the general 
evaluation of eligibility protocol (HSC-MS-0322). 
Confidentiality: 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., 15000), 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. 
 
Potential Benefits of the Proposed Research to the Subject and Others 
This study should help compliment and advise clinical research focused on stopping methamphetamine use, preventing 
relapse through improvement in relapse-related constructs (e.g., sleep problems, stress, and cue-reactivity). Subjects 
will be told if unusual information is discovered during the study that will make a difference in treatment for this or 
other problems. 
 
Subject Payment 
Participants will receive $40 for the baseline evaluation. As methamphetamine users tend to live further outside the city, 
we are budgeting extra for bus/parking validation/rideshare options, up to $30 per visit. Participants will receive $50 for 
each laboratory visit (3 visits total) and a completion bonus on their final visit for $50. If medication compliance is 
reached, participants will receive an extra $10 at each clinic visit. 
 
Importance of Knowledge to be Gained 
Research participation may assist non-treatment seeking subjects in abstaining from MA during study, and via study 
completion protocol, bring them into contact with treatment resources at our research center and in the community. 
MA use disorder 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 reducing MA use. Suvorexant (and 
orexin agonists more broadly), may help reduce sleep disruptions and attenuate stress and 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 MA 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. 
 
Inclusion of Women and Minorities 
We aim to enroll nearly 50/50% male/female representation. In our prior study recruiting methamphetamine users, we 
enrolled a sample consisting of ~40% female. We will employ targeted advertising strategies to achieve gender 
representation in the proposed study as needed, including distribution of educational material and referral information 
at women’s clinics in Houston and the surrounding communities (e.g., Passages for Women, Saving Grace Women’s 
Home, Sober Living for Women). Also informed by our prior study, we expect the minority distribution to be 
approximately 12% Hispanic/Latino, with the racial breakdown being 12% Black/African American, 71% White, and 17% 
Other or more than one race. 
 
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 children with MA use disorder 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. 
IRB NUMBER: HSC-MS-22-0796 
Data Safety and Monitoring Plan 
IRB APPROVAL DATE: 10/09/2023 


11 
 
ychiatry. 20
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/or physician, use of standardized assessments, continued medical 
monitoring during the study, procedures to monitor medication compliance (CAROMA). As PI, Dr. Webber will assure 
that the above systems are in place and functioning properly during the study. 
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 2023. 
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 and the Monitoring Committee. 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. 
 
REFERENCES 
1. 
James MH, Fragale JE, O’Connor SL, Zimmer BA, Aston-Jones G. The orexin (hypocretin) neuropeptide system is a 
target for novel therapeutics to treat cocaine use disorder with alcohol coabuse. Neuropharmacology. 
2021;183:108359. doi:10.1016/j.neuropharm.2020.108359 
2. 
Fragale JE, James MH, Avila JA, et al. The Insomnia-Addiction Positive Feedback Loop: Role of the Orexin System. 
Front Neurol Neurosci. 2021;45:117-127. doi:10.1159/000514965 
3. 
Moorman DE. The hypocretin/orexin system as a target for excessive motivation in alcohol use disorders. 
Psychopharmacology (Berl). 2018;235(6):1663-1680. doi:10.1007/s00213-018-4871-2 
4. 
Matzeu A, Martin-Fardon R. Targeting the orexin system for prescription opioid use disorder. Brain Sci. 
2020;10(4):226. doi:10.3390/brainsci10040226 
5. 
Mehr JB, Bilotti MM, James MH. Orexin (hypocretin) and addiction. Trends Neurosci. 2021;44(11):852-855. 
doi:10.1016/j.tins.2021.09.002 
6. 
Harris GC, Aston-Jones G. Arousal and reward: a dichotomy in orexin function. Trends Neurosci. 2006;29(10):571- 
577. doi:10.1016/j.tins.2006.08.002 
7. 
Khosrowabadi E, Karimi-Haghighi S, Jamali S, Haghparast A. Differential Roles of Intra-accumbal Orexin Receptors 
in Acquisition and Expression of Methamphetamine-Induced Conditioned Place Preference in the Rats. 
Neurochem Res. 2020;45(9):2230-2241. doi:10.1007/S11064-020-03084-1/FIGURES/6 
8. 
Zlebnik NE, Holtz NA, Lepak VC, Saykao AT, Zhang Y, Carroll ME. Age-specific treatment effects of 
orexin/hypocretin-receptor antagonism on methamphetamine-seeking behavior. Drug Alcohol Depend. 
2021;224:108719. doi:10.1016/J.DRUGALCDEP.2021.108719 
9. 
Suchting R, Yoon JH, Miguel GGS, et al. Preliminary examination of the orexin system on relapse-related factors in 
cocaine use disorder. Brain Res. 2020;1731:146359. doi:10.1016/j.brainres.2019.146359 
10. 
Han B, Compton WM, Jones CM, Einstein EB, Volkow ND. Methamphetamine Use, MIReBthNam
UMphBeEtRam
: HinSeCU-MseS-22-0796 
Disorder, and Associated Overdose Deaths Among US Adults. JAMA Ps 
21IR;7B8(A1P2P):R1O32V9A-1L3D4A2.TE: 10/09/2023 


12 
 
doi:10.1001/JAMAPSYCHIATRY.2021.2588 
11. 
Sommers I, Baskin D, Baskin-Sommers A. Methamphetamine use among young adults: Health and social 
consequences. Addict Behav. 2006;31(8):1469-1476. doi:10.1016/J.ADDBEH.2005.10.004 
12. 
Valentino RJ, Volkow ND. Drugs, sleep, and the addicted brain. Neuropsychopharmacol 2019 451. 2019;45(1):3-5. 
doi:10.1038/s41386-019-0465-x 
13. 
Khantzian EJ. The Self-Medication Hypothesis of Addictive Disorders: Focus on Heroin and Cocaine Dependence. 
In: The Cocaine Crisis. Springer US; 1987:65-74. doi:10.1007/978-1-4613-1837-8_7 
14. 
Khantzian EJ. The self-medication hypothesis of substance use disorders: A reconsideration and recent 
applications. Harv Rev Psychiatry. 1997;4(5):231-244. doi:10.3109/10673229709030550 
15. 
Goeders NE. The impact of stress on addiction. Eur Neuropsychopharmacol. 2003;13(6):435-441. 
doi:10.1016/J.EURONEURO.2003.08.004 
16. 
Sinha R. Chronic Stress, Drug Use, and Vulnerability to Addiction. Ann N Y Acad Sci. 2008;1141(1):105-130. 
doi:10.1196/ANNALS.1441.030 
17. 
Sinha R. How does stress increase risk of drug abuse and relapse? Psychopharmacol 2001 1584. 2001;158(4):343- 
359. doi:10.1007/S002130100917 
18. 
Seow LSE, Ong WJ, Hombali A, Asharani P V., Subramaniam M. A Scoping Review on Cue Reactivity in 
Methamphetamine Use Disorder. Int J Environ Res Public Heal 2020, Vol 17, Page 6504. 2020;17(18):6504. 
doi:10.3390/IJERPH17186504 
19. 
Moretti J, Poh EZ, Rodger J. rTMS-Induced Changes in Glutamatergic and Dopaminergic Systems: Relevance to 
Cocaine and Methamphetamine Use Disorders. Front Neurosci. 2020;14. doi:10.3389/fnins.2020.00137 
20. 
Moeller SJ, Hajcak G, Parvaz MA, Dunning JP, Volkow ND, Goldstein RZ. Psychophysiological prediction of choice: 
Relevance to insight and drug addiction. Brain. 2012;135(11):3481-3494. doi:10.1093/brain/aws252 
21. 
Parvaz MA, Rabin RA, Adams F, Goldstein RZ. Structural and Functional Brain Recovery in Individuals with 
Substance Use Disorders During Abstinence: A Review of Longitudinal Neuroimaging Studies. Drug Alcohol 
Depend. Published online January 19, 2022:109319. doi:10.1016/J.DRUGALCDEP.2022.109319 
22. 
Sadeh A, Acebo C. The role of actigraphy in sleep medicine. Sleep Med Rev. 2002;6(2):113-124. 
doi:10.1053/SMRV.2001.0182 
23. 
Webber HE, de Dios C, Wardle MC, et al. Electrophysiological responses to emotional and cocaine cues reveal 
individual neuroaffective profiles in cocaine users. Exp Clin Psychopharmacol. Published online February 25, 2021. 
doi:10.1037/pha0000450 
24. 
Schupp H, Cuthbert BN, Bradley MM, Hillman CH, Hamm AO, Lang PJ. Brain processes in emotional perception: 
Motivated attention. Cogn Emot. 2004;18(5):593-611. doi:10.1080/02699930341000239 
25. 
Hajcak G, Foti D. Significance? Significance! Empirical, methodological, and theoretical connections between the 
late positive potential and P300 as neural responses to stimulus significance: An integrative review. 
Psychophysiology. 2020;57(7):1-15. doi:10.1111/psyp.13570 
26. 
Sakurai T, Amemiya A, Ishii M, et al. Orexins and Orexin Receptors: A Family of Hypothalamic Neuropeptides and 
G Protein-Coupled Receptors that Regulate Feeding Behavior. Cell. 1998;92(4):573-585. doi:10.1016/S0092- 
8674(00)80949-6 
27. 
Chemelli RM, Willie JT, Sinton CM, et al. Narcolepsy in orexin Knockout Mice: Molecular Genetics of Sleep 
Regulation. Cell. 1999;98(4):437-451. doi:10.1016/S0092-8674(00)81973-X 
28. 
Lin L, Faraco J, Li R, et al. The Sleep Disorder Canine Narcolepsy Is Caused by a Mutation in the Hypocretin 
(Orexin) Receptor 2 Gene. Cell. 1999;98(3):365-376. doi:10.1016/S0092-8674(00)81965-0 
29. 
James MH, Mahler S V., Moorman DE, Aston-Jones G. A Decade of Orexin/Hypocretin and addiction: Where are 
we now? Curr Top Behav Neurosci. 2017;33:247-281. doi:10.1007/7854_2016_57/COVER/ 
30. 
Berro LF, Moreira-Junior E da C, Rowlett JK. The dual orexin receptor antagonist almorexant blocks the sleep- 
disrupting and daytime stimulant effects of methamphetamine in rhesus monkeys. Drug Alcohol Depend. 
2021;227:108930. doi:10.1016/J.DRUGALCDEP.2021.108930 
31. 
Ballester J, Valentine G, Sofuoglu M. Pharmacological treatments for methamphetamine addiction: current status 
and future directions. http://dx.doi.org/101080/1751243320171268916. 2016;10(3):305-314. 
doi:10.1080/17512433.2017.1268916 
32. 
Schmitz JM, Wardle MC, Weaver MF, Heads AM, Yoon JH, Lane SD. Pharmacological treatment of 
psychostimulant use disorders. APA Handb Psychopharmacol. Published online ApriIlR1B8,N2U01M9B:5E3R3:-H56S0C.-MS-22-0796 
doi:10.1037/0000133-024 
IRB APPROVAL DATE: 10/09/2023 


13 
 
lcoholism Tre
33. 
McLellan AT, Kushner H, Metzger D, et al. The fifth edition of the addiction severity index. J Subst Abuse Treat. 
1992;9(3):199-213. doi:10.1016/0740-5472(92)90062-S 
34. 
Kellogg SH, McHugh PF, Bell K, et al. The Kreek-McHugh-Schluger-Kellogg scale: A new, rapid method for 
quantifying substance abuse and its possible applications. Drug Alcohol Depend. 2003;69(2):137-150. 
doi:10.1016/S0376-8716(02)00308-3 
35. 
Sobbell LC, Sobell MB. Alcohol Timeline Followback Users’ Manual. Addiction Research Foundation; 1995. 
36. 
Antony MM, Cox BJ, Enns MW, Bieling PJ, Swinson RP. Psychometric properties of the 42-item and 21-item 
versions of the Depression Anxiety Stress Scales in clinical groups and a community sample. Psychol Assess. 
1998;10(2):176-181. doi:10.1037/1040-3590.10.2.176 
37. 
Vujanovic AA, Wardle MC, Liu S, Dias NR, Lane SD. Attentional bias in adults with cannabis use disorders. J Addict 
Dis. 2016;35(2):144-153. doi:10.1080/10550887.2015.1116354 
38. 
Mezinskis JP, Honos-Webb L, Kropp F, Somoza E. The Measurement of Craving. 
http://dx.doi.org/101300/J069v20n03_07. 2008;20(3):67-85. doi:10.1300/J069V20N03_07 
39. 
Rhyne DN, Anderson SL. Suvorexant in insomnia: efficacy, safety and place in therapy. Ther Adv drug Saf. 
2015;6(5):189-195. doi:10.1177/2042098615595359 
40. 
Herring WJ, Connor KM, Ivgy-May N, et al. Suvorexant in Patients With Insomnia: Results From Two 3-Month 
Randomized Controlled Clinical Trials. Biol Psychiatry. 2016;79(2):136-148. doi:10.1016/J.BIOPSYCH.2014.10.003 
41. 
Kuriyama A, Tabata H. Suvorexant for the treatment of primary insomnia: A systematic review and meta-analysis. 
Sleep Med Rev. 2017;35:1-7. doi:10.1016/J.SMRV.2016.09.004 
42. 
Herring WJ, Snyder E, Budd K, et al. Orexin receptor antagonism for treatment of insomnia. Neurology. 
2012;79(23):2265-2274. doi:10.1212/WNL.0B013E31827688EE 
43. 
Bennett T, Bray D, Neville MW. Suvorexant, a Dual Orexin Receptor Antagonist for the Management of Insomnia. 
Pharm Ther. 2014;39(4):264. Accessed August 31, 2022. /pmc/articles/PMC3989084/ 
44. 
DeWorsop D, Creatura G, Bluez G, et al. Feasibility and success of cell-phone assisted remote observation of 
medication adherence (CAROMA) in clinical trials. Drug Alcohol Depend. 2016;163:24-30. 
doi:10.1016/J.DRUGALCDEP.2016.02.045 
45. 
Chinoy ED, Cuellar JA, Huwa KE, et al. Performance of seven consumer sleep-tracking devices compared with 
polysomnography. Sleep. 2021;44(5). doi:10.1093/sleep/zsaa291 
46. 
Ohayon M, Wickwire EM, Hirshkowitz M, et al. National Sleep Foundation’s sleep quality recommendations: first 
report. Sleep Heal. 2017;3(1):6-19. doi:10.1016/J.SLEH.2016.11.006 
47. 
Knyazev GG, Slobodskoj-Plusnin JY, Bocharov A V., Pylkova L V. The default mode network and EEG alpha 
oscillations: An independent component analysis. Brain Res. 2011;1402:67-79. 
doi:10.1016/J.BRAINRES.2011.05.052 
48. 
Jann K, Dierks T, Boesch C, Kottlow M, Strik W, Koenig T. BOLD correlates of EEG alpha phase-locking and the 
fMRI default mode network. Neuroimage. 2009;45(3):903-916. doi:10.1016/J.NEUROIMAGE.2009.01.001 
49. 
Ferreira C, Deslandes A, Moraes H, et al. Electroencephalographic changes after one night of sleep deprivation. 
Arq Neuropsiquiatr. 2006;64(2 B):388-393. doi:10.1590/S0004-282X2006000300007 
50. 
Wu J, Zhou Q, Li J, Chen Y, Shao S, Xiao Y. Decreased resting-state alpha-band activation and functional 
connectivity after sleep deprivation. Sci Rep. 2021;11(1):1-10. doi:10.1038/s41598-020-79816-8 
51. 
Wang Y, Liu Z, Zhou Q, Chen X. Wavelet Packet Entropy Analysis of Resting State Electroencephalogram in Sleep 
Deprived Mental Fatigue State. Vol 11580 LNAI. Springer International Publishing; 2019. doi:10.1007/978-3-030- 
22419-6_35 
52. 
Verweij IM, Romeijn N, Smit DJA, Piantoni G, Van Someren EJW, van der Werf YD. Sleep deprivation leads to a 
loss of functional connectivity in frontal brain regions. BMC Neurosci. 2014;15:1-10. doi:10.1186/1471-2202-15- 
88 
53. 
Ochab JK, Szwed J, Oleś K, et al. Observing changes in human functioning during induced sleep deficiency and 
recovery periods. PLoS One. 2021;16(9 September):1-26. doi:10.1371/journal.pone.0255771 
54. 
Tang J, Liao Y, He H, et al. Sleeping problems in Chinese illicit drug dependent subjects. BMC Psychiatry. 
2015;15(1):1-7. doi:10.1186/S12888-015-0409-X/TABLES/5 
55. 
Mahfoud Y, Talih F, Streem D, Budur K. Sleep Disorders in Substance Abusers: How Common Are They? Psychiatry 
(Edgmont). 2009;6(9):38. Accessed July 12, 2022. /pmc/articles/PMC2766287/ 
56. 
Brooks AT, Krumlauf MC, Whiting BP, Clark RJ, Wallen GR. Are you Sleeping? Pilot CoIRmBpNarUisMonBEoRf S: eHlSf-CR-eMpoS-r2te2d-0796 
and Objective Measures of Sleep Quality and Duration in an Inpatient A 
IRaBtmAePnPtRPOroVgArLamD.ASTuEb:st10/09/2023 


14 
 
Bayesian Data Anal
Abuse. 2012;6(1):135-139. doi:10.4137/SART.S10385 
57. 
Bastien CH, Vallières A, Morin CM. Validation of the Insomnia Severity Index as an outcome measure for insomnia 
research. Sleep Med. 2001;2(4):297-307. doi:10.1016/S1389-9457(00)00065-4 
58. 
Yu L, Buysse DJ, Germain A, et al. Development of Short Forms From the PROMISTM Sleep Disturbance and Sleep- 
Related Impairment Item Banks. https://doi.org/101080/154020022012636266. 2012;10(1):6-24. 
doi:10.1080/15402002.2012.636266 
59. 
Velasco M, Gómez J, Blanco M, Rodriguez I. The cold pressor test: pharmacological and therapeutic aspects. Am J 
Ther. 1997;4(1):34-38. doi:10.1097/00045391-199701000-00008 
60. 
McRae AL, Saladin ME, Brady KT, Upadhyaya H, Back SE, Timmerman MA. Stress reactivity: biological and 
subjective responses to the cold pressor and Trier Social stressors. Hum Psychopharmacol Clin Exp. 
2006;21(6):377-385. doi:10.1002/HUP.778 
61. 
Lovallo W. The Cold Pressor Test and Autonomic Function: A Review and Integration. Psychophysiology. 
1975;12(3):268-282. doi:10.1111/J.1469-8986.1975.TB01289.X 
62. 
Geliebter A, Gibson CD, Hernandez DB, et al. Plasma cortisol levels in response to a cold pressor test did not 
predict appetite or ad libitum test meal intake in obese women. Appetite. 2012;59(3):956-959. 
doi:10.1016/J.APPET.2012.08.025 
63. 
Schwabe L, Haddad L, Schachinger H. HPA axis activation by a socially evaluated cold-pressor test. 
Psychoneuroendocrinology. 2008;33(6):890-895. doi:10.1016/J.PSYNEUEN.2008.03.001 
64. 
Dias NR, Schmitz JM, Rathnayaka N, et al. Anti-saccade error rates as a measure of attentional bias in cocaine 
dependent subjects. Behav Brain Res. 2015;292:493-499. doi:10.1016/j.bbr.2015.07.006 
65. 
Schupp H, Cuthbert BN, Bradley MM, Cacioppo JT, Ito T, Lang PJ. Affective picture processing: The late positive 
potential is modulated by motivational relevance. Psychophysiology. 2000;37(2):257-261. doi:10.1111/1469- 
8986.3720257 
66. 
Franken IHA, Dietvorst RC, Hesselmans M, Franzek EJ, van de Wetering BJM, Van Strien JW. Cocaine craving is 
associated with electrophysiological brain responses to cocaine-related stimuli. Addict Biol. 2008;13(3-4):386- 
392. doi:10.1111/j.1369-1600.2008.00100.x 
67. 
Dunning JP, Parvaz MA, Hajcak G, et al. Motivated attention to cocaine and emotional cues in abstinent and 
current cocaine users - an ERP study. Eur J Neurosci. 2011;33(9):1716-1723. doi:10.1111/j.1460- 
9568.2011.07663.x 
68. 
Parvaz MA, Moeller SJ, Goldstein RZ. Incubation of cue-induced craving in adults addicted to cocaine measured 
by electroencephalography. JAMA Psychiatry. 2016;73(11):1127-1134. doi:10.1001/jamapsychiatry.2016.2181 
69. 
Webber HE, de Dios C, Kessler DA, Schmitz JM, Lane SD, Suchting R. Late positive potential as a candidate 
biomarker of motivational relevance in substance use: Evidence from a meta-analysis. Neurosci Biobehav Rev. 
2022;141:104835. doi:10.1016/j.neubiorev.2022.104835 
70. 
Posner K, Brown GK, Stanley B, et al. The Columbia-suicide severity rating scale: Initial validity and internal 
consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry. 
2011;168(12):1266-1277. doi:10.1176/appi.ajp.2011.10111704 
71. 
Beck, Ward, Mendelson, Mock, Erbaugh. Beck’s Depression Inventory. Published online 1961. 
72. 
R Core Team. R: A language and environment for statistical computing. Published online 2021. https://www.r- 
project.org/ 
73. 
Bates D, Machler M, Bolker B, Walker S. Fitting linear mixed-effects models using lme4. Published online 2014. 
http://dx.doi.org/10.18637/jss.v067.i01 
74. 
Stan Development Team. RStan: The R interface to Stan. R package version 2.18.2. Published online 2018. 
75. 
Bürkner PC. brms: An R package for Bayesian multilevel models using Stan. J Stat Softw. 2017;80:1-28. 
doi:10.18637/jss.v080.i01 
76. 
Assmann SF, Pocock SJ, Enos LE, Kasten LE. Subgroup analysis and other (mis)uses of baseline data in clinical 
trials. Lancet. 2000;355(9209):1064-1069. doi:10.1016/S0140-6736(00)02039-0 
77. 
Pocock SJ, Assmann SE, Enos LE, Kasten LE. Subgroup analysis, covariate adjustment and baseline comparisons in 
clinical trial reporting: current practice and problems. Stat Med Stat Med. 2002;21:2917-2930. 
doi:10.1002/sim.1296 
78. 
McElreath R. Statistical Rethinking: A Bayesian Course with Examples in R and Stan. CRC Press, LLC; 2018. 
doi:10.1201/9781315372495 
IRB NUMBER: HSC-MS-22-0796 
79. 
Gelman A, Carlin JB, Stern HS, Dunson D., Vehtari A, Rubin DB. 
ysIRisB(3ArdPPERdO.).V3ArLd eDdA.TCER:C10/09/2023 


15 
 
Press, LLC; 2013. 
80. 
Harold Jeffreys. The Theory of Probability. Oxford Univ Press. 1998;3:432. Accessed April 11, 2022. 
https://books.google.com/books?hl=en&lr=&id=vh9Act9rtzQC&oi=fnd&pg=PA1&dq=The+Theory+of+Probability 
&ots=ffTCKZZ2nS&sig=IKKIjX2u5DPlHwpj0YX8cpYaMJc#v=onepage&q=The Theory of Probability&f=false 
81. 
Lee MD, Wagenmakers EJ. Bayesian Cognitive Modeling: A Practical Course. Cambridge University Press; 2013. 
doi:10.1017/CBO9781139087759 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IRB NUMBER: HSC-MS-22-0796 
IRB APPROVAL DATE: 10/09/2023