Clinical trial NCT01685073
Conditions: Drug Addiction
Keywords: marijuana cannabis treatment insomnia relapse
Sponsor: Johns Hopkins University
Start date: 2012-09-01; Completion date: 2018-07-01
Enrollment: 127 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The number of people seeking treatment for marijuana-related problems is on the rise, yet there is no currently accepted medication proven to help them quit. Frequent marijuana users have reported that they have trouble sleeping when they try to quit, and that the loss of sleep can lead to relapse. This research is designed to measure the severity of sleep problems in people as they are trying to quit heavy use of marijuana, and to investigate whether extended-release zolpidem (Ambien CR®) can improve quit rates among people trying to stop using marijuana.

Detailed description:

Arms: arm 1: Participants receive active zolpidem nightly in addition to psychosocial therapy during 12-week treatment of a cannabis use disorder arm 2: Participants receive placebo medication during a 12-week psychosocial treatment for a cannabis use disorder
Interventions: intervention 1: Zolpidem extended-release intervention 2: MET/CBT
Intervention descriptions: intervention 1: nightly administration of zolpidem extended-release intervention 2: a standardized 12-week therapy consisting of motivational enhancement therapy (MET) and cognitive behavior therapy (CBT) for treating cannabis use disorders will be administered to all study participants

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Date: December 15, 2015 
Principal Investigator: Ryan Vandrey, Ph.D. 
Application Number: NA_00068969 
NCT01685073 
Title: The Role of Sleep in the Treatment of Cannabis Use Disorders 


Date: December 15, 2015    
Principal Investigator: Ryan Vandrey, Ph.D. 
Application Number: NA_00068969 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
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Johns Hopkins Medicine - eForm A 
 
 
 
• Use the section headings to write the eForm A, inserting the appropriate material in 
each. If a section is not applicable, leave heading in and insert N/A. 
• When submitting eForm A (new or revised), enter the date submitted to the field at 
the top of eForm A. 
 
*************************************************************************************************** 
 
 
1. 
Abstract 
 
Admissions to U.S. treatment programs for cannabis-related problems have more than doubled since the 
mid 1990's and now number approximately 1.2 million per year. Clinical trials indicate that a majority of 
those who enter treatment for cannabis problems relapse. Disturbed sleep is one of the most prominent 
symptoms of the cannabis withdrawal syndrome, and recent laboratory research has demonstrated that 
heavy cannabis users experience clinically significant sleep problems following abrupt cessation of use. 
Similar abstinence induced effects on sleep and sleep-related risk of relapse are known to occur during 
withdrawal from other drugs of abuse, and, importantly, research has shown that adding sleep 
improvement interventions to alcohol treatment programs results in significantly improved clinical 
outcomes. This suggests that interventions targeting sleep disturbance among cannabis users trying to 
quit could help initiate initial periods of abstinence and reduce relapse. Treatment-seeking cannabis users 
who report an effect of cannabis on sleep quality will be randomized to one of two treatment interventions: 
1) a computerized psychosocial therapy for cannabis use (cMET/CBT), Contingency Management (CM), 
plus nightly administration of extended-release zolpidem, or 2) cMET/CBT, CM, plus nightly placebo 
administration. The treatment intervention will last for 12 weeks and follow-up assessments will be 
conducted at 3 and 6 months after the completion of treatment. Participants will complete cMET/CBT 
therapy modules once weekly, complete assessments and provide observed urine specimens for 
toxicological testing twice weekly (e.g. Mon/Thurs, Tues/Fri), and self-administer study medication nightly 
during treatment. The mechanism by which we believe extended-release zolpidem will benefit study 
participants is an improvement in sleep. To ascertain the relationship between sleep continuity and 
cannabis use outcomes, objective sleep assessments (PSG) will be conducted 4 times during the study 
(weeks 1, 10, and 12 during treatment, and at 3 month follow-up). Sleep diaries and objective, automated 
sleep monitoring with EEG headband and actigraphy assessments will also be collected to provide 
secondary, and more frequent, measures of sleep. The proposed clinical trial will be the first controlled 
examination of sleep quality and the effects of a clinical intervention designed to improve sleep among 
heavy cannabis users during a quit attempt.  
 
2. 
Objectives  
 
Objective 1: Prospectively examine objective and subjective measures of sleep quality in a sample of 
heavy cannabis users receiving psychosocial treatment to quit use of cannabis. 
 
Objective 2: Determine whether administration of extended-release zolpidem, compared with placebo, will 
increase abstinence rates (number of negative urines submitted) among cannabis users. 
 
Objective 3: Determine whether sleep continuity mediates the relationship between zolpidem treatment 
and cannabis abstinence rates as indicated by urine toxicology results. 
 
 


Date: December 15, 2015    
Principal Investigator: Ryan Vandrey, Ph.D. 
Application Number: NA_00068969 
 
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3. 
Background  
 
More individuals in the U.S. meet criteria for current and lifetime cannabis use disorders than meet 
criteria for any other illicit drug use disorder. In 2009 an estimated 4.3 million Americans were dependent 
on or abused cannabis, which represents 1.7% of the total population aged 12 or older, and 61% of all 
cases of illicit drug dependence or abuse. Uncontrolled use of cannabis is associated with all the 
fundamental features of drug addiction including tolerance to the drug, withdrawal upon cessation, 
negative psychosocial and health consequences, and the inability to cut down or stop use despite the 
desire to do so and/or the recognition that use of the drug is causing problems. Treatment admissions for 
cannabis-use disorders have more than doubled since 1992 and the number of drug abuse treatment 
admissions where cannabis is the primary problem drug is now 1.2 million, which exceeds the number of 
treatment admissions for any other drug except alcohol. As is common with other abused substances, the 
majority of adults and adolescents seeking treatment for cannabis-related disorders have great difficulty 
achieving periods of sustained cannabis abstinence.  
 
The current research base for effective interventions in the treatment of cannabis use disorders is limited 
to psychosocial/behavioral treatments. Even with the most highly effective psychosocial treatment, only 
about half of those who enroll in treatment achieve a period of sustained abstinence, and among those, 
approximately half return to use within a year. Based on clinical research of other abused drugs, the most 
promising strategy for improving drug use outcomes in the treatment of cannabis use disorders would be 
to identify pharmacological interventions that could be combined with existing psychosocial treatments. 
One pharmacological approach shown to be effective for treating drug use disorders is to reduce drug 
withdrawal effects. Clinical trials conducted for the treatment of opioid and nicotine dependence clearly 
demonstrate that administration of medications known to reduce withdrawal, in combination with 
psychosocial therapies, can significantly improve treatment outcomes relative to psychosocial treatments 
alone. Evidence from structured survey studies with cannabis users suggests that cannabis withdrawal 
contributes to failed quit attempts and relapse, but prospective research demonstrating this association is 
lacking, as is controlled clinical evaluation of pharmacological interventions known to attenuate cannabis 
withdrawal. 
 
A valid, reliable, and pharmacologically specific cannabis withdrawal syndrome has been demonstrated in 
nonhuman and human studies. Withdrawal symptoms may include: anger and aggression, anxiety, 
depressed mood, irritability, restlessness, sleep difficulty and strange dreams, decreased appetite and 
weight loss, headaches, physical tension, sweating, stomach pain, nausea/vomiting, and general physical 
discomfort. Most symptoms onset within the first 24 hours of cessation, peak within the first week, and 
last approximately 1-2 weeks. However, sleep-related symptoms of cannabis withdrawal have been 
shown to persist up to 45-days, and may last even longer.  
 
Among the cannabis withdrawal symptoms that are reliable and frequently observed, disturbed sleep is a 
particularly attractive target for clinical intervention. In recent survey studies, sleep difficulty during prior 
cannabis quit attempts was endorsed by 67-73% of adults. In one survey, 65% of people who had tried to 
quit use of cannabis indicated that sleep difficulty during abstinence had contributed to relapse on at least 
one previous quit attempt. A survey of non-treatment seekers indicated that 32% had experienced sleep 
problems during past periods of abstinence (not necessarily quit attempts), of which 48% reported having 
taken a tranquilizer/sedative, used alcohol, or returned to use of cannabis specifically to improve sleep. 
These studies highlight the fact that sleep difficulty is common, is perceived as a barrier to cessation, and 
also that there may be a disparity in the frequency or severity of abstinence-induced sleep problems 
among cannabis users trying to quit versus those not trying to quit. 
 
Because recall bias could skew accounts in retrospective reporting, sleep disturbance during cannabis 
abstinence and its relationship to relapse has been evaluated in prospective laboratory studies in order to 


Date: December 15, 2015    
Principal Investigator: Ryan Vandrey, Ph.D. 
Application Number: NA_00068969 
 
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corroborate the clinical survey studies just described. Inpatient studies using polysomnography (PSG) 
assessments of sleep indicate that, indeed, abrupt abstinence from daily cannabis use negatively impacts 
the quantity and quality of sleep. In a recent study conducted in our lab (NA_00017909), observed 
alterations of sleep continuity (sleep latency, sleep efficiency) and sleep architecture (REM) induced by 
abrupt cannabis abstinence met criteria commonly used in the diagnosis of sleep disorders.  During a 
second phase of this study, administration of extended-release zolpidem attenuated these abstinence-
induced sleep disturbances suggesting the potential clinical utility of administering hypnotic medication to 
help induce abstinence and prevent relapse among those in treatment for cannabis use disorders.  
 
Because studies in which sleep continuity and architecture were objectively measured so far have been 
conducted with non-treatment seekers in residential settings, confirmatory data obtained prospectively 
from cannabis users trying to quit is warranted. In the proposed study we will obtain comprehensive 
measures of cannabis use and sleep from participants receiving outpatient treatment for cannabis use 
disorders. This will allow us to assess whether or not cannabis abstinence induced changes in sleep 
quality and/or architecture obtained from treatment-seekers maintained in their home environment are 
comparable to those observed in prior laboratory studies, and to determine whether changes in sleep 
mediate drug use outcomes during a quit attempt. This type of study is needed to confirm whether sleep 
is indeed a clinically important withdrawal symptom, and also to determine the external validity of the 
inpatient laboratory research methods being used to characterize and assess the clinical importance of 
cannabis withdrawal.  
 
The primary aim of this project is to test the efficacy of extended-release zolpidem (Ambien CR®) to 
reduce sleep problems and relapse in treatment-seeking cannabis users. As described above, there is a 
clear need for improving cannabis use treatment interventions. Pharmacotherapies that reduce 
withdrawal and interventions that improve sleep quality have enhanced clinical outcomes in the treatment 
of other drug use disorders. We hypothesize that use of extended-release zolpidem as an adjunct therapy 
to psychosocial therapy will attenuate abstinence-induced sleep dysfunction, and that this improvement in 
sleep will mediate improvements in cannabis abstinence rates compared with study participants who 
receive placebo medication. Extended-release zolpidem was selected over other potential 
pharmacotherapy candidates because it is approved by the FDA and widely used as an effective 
treatment for insomnia, has a good safety, side effect, and abuse liability profile relative to other FDA-
approved hypnotic medications. Demonstrating a positive effect of extended-release zolpidem on 
cannabis use outcomes in the proposed study would provide an additional clinical tool for treating 
cannabis use disorders that could be immediately and widely disseminated. The medication is widely 
available, relatively inexpensive (generic formulations are now commercially available), and would be of 
little added burden to patients or treatment providers. These characteristics should help adoption into 
regular clinical practice. Because sleep disturbance appears to be so prevalent among heavy cannabis 
users, particularly those seeking treatment, there is potential for this simple adjunct intervention to have a 
relatively broad clinical impact.  
 
 
4. 
Study Procedures 
a. Study design, including the sequence and timing of study procedures   
(distinguish research procedures from those that are part of routine care). 
 
The proposed study will be a double blind outpatient clinical trial in which eligible participants will be 
randomized to one of two treatment interventions: 1) a computerized psychosocial therapy that 
incorporates Motivational Enhancement Therapy and Cognitive-Behavioral Therapy (cMET/CBT), 
Contingency Management (CM, incentives for achieving abstinence), plus nightly administration of 
extended-release zolpidem, or 2) cMET/CBT, CM, plus nightly administration of matching placebo. The 
treatment intervention will last for 12 weeks and follow-up assessments will be conducted at 3, 6, and 12 
months after the completion of treatment. Participants will complete cMET/CBT therapy modules once 


Date: December 15, 2015    
Principal Investigator: Ryan Vandrey, Ph.D. 
Application Number: NA_00068969 
 
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Version 3 Dated:   06/2007 
 
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weekly, complete assessments and provide observed urine specimens for toxicological testing twice 
weekly (e.g. Mon/Thurs, Tues/Fri), and self-administer study medication nightly during treatment. 
Participants will receive monetary rewards for achieving abstinence using an escalating schedule of 
reinforcement based on the results of the twice weekly urine drug tests.  Objective sleep assessments 
(PSG) will be conducted at baseline to screen for sleep disorders, and 6 times during the study (weeks 1, 
6, 10, and 12 during treatment, and at 3 and 12 month follow-ups). Sleep diaries and objective, automated 
sleep monitoring with EEG headband and actigraphy assessments will also be collected to provide 
secondary, and more frequent, measures of sleep. 
 
Study Setting. Study procedures will be conducted at the Behavioral Pharmacology Research Unit (BPRU) 
and at the Behavioral Sleep Medicine Program (BSMP). The BPRU outpatient research unit contains 
dedicated areas for conducting confidential interviews and assessments, computer workstations with 
internet capability that are maintained on a secure network, a laboratory for collecting observed urine 
specimens, on site pregnancy testing capability, resources for shipping specimens for additional testing, a 
research pharmacy, and office space for research staff. The BSMP has 2 private interview rooms and two 
fully equipped psychophysical testing rooms for use in this study. The exception to the BPRU and BSMP 
serving as the research setting is that some measures of sleep will be collected in the participants’ home 
environment.  
 
Participants. We propose to enroll up to 200 cannabis smokers who are seeking treatment for cannabis-
related problems and report associations between cannabis use and sleep quality. Enrollment will be 
limited to those who report effects of cannabis use on sleep because they are most likely to benefit from 
this intervention. This will also maximize the likelihood that a clinical effect of the study medication will be 
observed. Based on clinical surveys, we expect this to represent approximately 70% of those seeking 
treatment. We will exclude study volunteers with intrinsic sleep disorders other than insomnia and 
circadian rhythm disorders (e.g, sleep apnea, periodic limb movement disorders) prior to randomization. 
Based on our prior research studies, we estimate that 10-15% of participants will meet exclusion criteria 
for sleep apnea or periodic limb movement disorder during the screening PSG assessment. Those 
participants will be referred to treatment in the community for their sleep and cannabis use problems.  
 
Participant Recruitment. Participants will be recruited into the study via media advertising, word-of-mouth 
communication, and referrals from medical and clinical care units within the Johns Hopkins Medical 
Institution. Advertisements will seek cannabis users who are interested in treatment for problems related 
to cannabis use.  
 
Screening and Intake. Volunteers will receive a brief screening over the telephone and will be scheduled 
for an intake appointment if they meet initial eligibility criteria. Upon arrival for the intake assessment, 
written informed consent to participate will be obtained. The intake interview will include face-to-face 
diagnostic interviews and computerized assessment components that will take approximately 4 hours to 
complete. These will include a comprehensive assessment of health status including physical and mental 
health history, sleep history, and recreational drug use history. A urine sample will undergo toxicology 
screening for evidence of recent use of commonly abused drugs and urine pregnancy testing will be 
conducted for female volunteers. Ineligible study volunteers will be referred to treatment services provided 
by other community clinics near the volunteer’s residence. 
 
At intake, a locally constructed Medical History Interview and Physical examination will be conducted that 
collects information on health, drug use, and sleep including relationship between cannabis use and sleep 
quality. The DSM-IV Checklist will be used to determine participant eligibility and will characterize the 
sample in terms of lifetime and current Axis I psychiatric disorders. In cases where a diagnosis of 
psychiatric disorder is apparent, participants will be referred for treatment at community mental health 
facilities. The Time-line Follow-Back (TLFB) procedure will be used to obtain a detailed account of the 
amount and frequency of recent substance use during the prior 3 months. A 20-item Self-efficacy 
Inventory will be used to assess ability to avoid use of cannabis in situations involving negative affect, 
social discomfort, and presence of others using cannabis. The Marijuana Problems Scale will be used to 


Date: December 15, 2015    
Principal Investigator: Ryan Vandrey, Ph.D. 
Application Number: NA_00068969 
 
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assess negative social, occupational, physical, and personal consequences associated with cannabis use 
in reference to the prior 90 days. The Readiness to Change Questionnaire will assess current stages of 
change (e.g. pre-contemplation, contemplation, and action) with regards to cannabis use. The Marijuana 
Goals Questionnaire will assess treatment goals of abstinence versus reduced use. Information from 
intake assessments will be entered into the cMET/CBT system, which will automatically generate 
personalized feedback reports for use during treatment. Smith’s Measure of Morningness and 
Eveningness will be conducted as a circadian rhythm assessment.  The Dysfunctional Beliefs and 
Attitudes about Sleep (DBAS) questionnaire will be administered as a predictive tool regarding sleep 
difficulty later in treatment, and the Insomnia Severity Index (ISI) will be used to assess insomnia 
characteristics. We will use an adapted questionnaire that combines section of the Posttraumatic 
Diagnostic Scale (PDS) and Posttraumatic Checklist – Stressor (PCL-S) questionnaire to assess for 
symptoms of PTSD. Lastly, we will conduct 2 measures of Delay Discounting, which measure the degree 
with which participants devalue larger greater rewards for smaller immediate rewards.  One is a 
hypothetical task in which participants make a series of choices between receiving a $1,000 delayed 
hypothetical reward and a smaller immediate reward (e.g., $500). The magnitude of the smaller immediate 
option is adjusted across trials until an indifference point is determined, i.e., until the smaller immediate 
and larger later rewards are considered equivalent in subjective value.  The second task, called the Quick 
Discounting Operant Task (QDOT), assesses the degree to which delaying a real monetary reward 
decreases its present value for the participant. Participants make a series of choices between receive a 
real 80-cent reward and an adjusting smaller immediate reward (e.g., 40 cents). Upon selection of one of 
the options, a coin machine attached to the computer automatically dispenses the selected reward amount 
in coins either immediately or after the specified delay has elapsed. The magnitude of the smaller 
immediate option is adjusted across trials until an indifference point is determined, i.e., until the smaller 
immediate and larger later rewards are considered equivalent in subjective value.  Participants can earn a 
maximum of $16 based on their responses on this task that they are allowed to keep.  Delay Discounting 
measures have been shown to predict treatment outcomes in prior research, but there has not been a 
comparison of these two different approaches (hypothetical vs. actual reinforcer delivery) in the same 
clinical trial. 
 
Those eligible for the study based on the initial intake assessment will then be scheduled for an outpatient 
overnight sleep assessment to be conducted as soon as possible, targeting completion within 5 business 
days. The purpose of this sleep assessment is to screen participants for evidence of pre-morbid intrinsic 
sleep disorders (sleep apnea, periodic limb movement disorder) and to acclimate participants to sleeping 
while connected to PSG equipment. Participants will come to the Johns Hopkins BSMP where they will be 
wired for the outpatient sleep assessment and will then be transported via taxi home (a more detailed 
description of PSG assessment procedures is provided below under the heading “Polysomnography 
(PSG)”.  Participants eligible for study participation following the PSG assessment will then be scheduled 
to begin treatment.  Study volunteers will be instructed that they will be expected to initiate an attempt to 
completely abstain from cannabis at the start of treatment.  Thus, treatment will begin on a “quit day” 
designated by the study volunteer in coordination with the research staff.   
 
Randomization. Participants will be assigned to one of two treatment conditions: 1) cMET/CBT/CM + 
extended-release zolpidem or 2) cMET/CBT/CM + placebo (detailed descriptions provided below). 
Treatment assignment will be conducted using a balanced minimization procedure in which we will stratify 
study participants based on abstinence (> 24 hours) at the time of intake, tobacco smoking status (daily 
vs. non-daily, and gender. Data from prior cannabis treatment trials suggest that non-smokers and those 
reporting > 24 hours of abstinence prior to intake have better outcomes compared with smokers and those 
reporting no abstinence at intake. Gender will be balanced as a practical safeguard against unknown 
influences on outcome. Participants will be scheduled for their first session within 7 days of the intake 
assessment.  
 
Psychosocial Therapy (cMET/CBT). A computer program will be used to deliver an intervention that 
combines aspects of Motivational Enhancement Therapy (MET) and Cognitive Behavioral Therapy (CBT). 


Date: December 15, 2015    
Principal Investigator: Ryan Vandrey, Ph.D. 
Application Number: NA_00068969 
 
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Version 3 Dated:   06/2007 
 
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The intervention is based on content from empirically tested treatment manuals, and was recently 
developed and validated by Budney and colleagues for outpatient treatment of cannabis use disorders in 
adults. cMET/CBT consists of 13 distinct modules. The first two modules use principles of MET to facilitate 
initial behavior change and enhance motivation to quit use of cannabis. Modules 3-12 incorporate 
established CBT methodology and include modules on coping with other life problems, understanding 
cannabis use patterns, coping with craving, managing thoughts about using drugs, problem solving, drug 
refusal skills, coping with lapses, managing negative moods, and assertiveness skills. Module 13 is a post-
treatment module designed to enhance maintenance of abstinence and review skills used to cope with 
lapse or relapse episodes. During the first 8 weeks, participants complete the two MET modules and six 
core CBT modules (1 module/week). During weeks 9-12, they complete one elective CBT module each 
week and during week 12 will also complete the post-treatment module. Within each module, cMET/CBT 
employs interactive exercises and worksheets to enhance learning and personalize content. cMET/CBT 
replicates many of the key features of therapist-delivered treatment, but does so in a systematic and 
replicable fashion.  
 
Participants will access cMET/CBT primarily via the Internet using private computer workstations located 
in the BPRU clinic. They will use a unique password to log into their customized cMET/CBT program. 
Audio accompaniment is provided throughout the program for those who have reading difficulties or prefer 
audio, and each computer workstation will be equipped with headphones for listening to audio portions of 
the program. The first module incorporates training for participants in use of the program. cMET/CBT has 
an electronic reporting system that allows staff to view password-protected, browser-based reports that 
summarize patient activity on the cMET/CBT and provide summary information about interactive exercises 
completed on the computer (e.g., reports of recent drug use, circumstances of use). In this study, a 
therapist will receive electronic reports for each participant to be reviewed during two scheduled face-to-
face check-in sessions. Participants will be able to access their cMET/CBT program via the Internet, which 
will enable practice or review of elements of their program between weekly sessions during treatment, and 
for up to 6 months after treatment. The cMET/CBT system enables secure access from any computer with 
high-speed Internet access.  
 
Case Management. In order to monitor progress on cMET/CBT and address any crises or service needs 
that arise during the study, participants will be assigned a case management therapist. They will have an 
initial 30-minute meeting with the therapist immediately prior to the first computerized session. This 
meeting will orient participants to the treatment intervention, with particular emphasis on explaining how 
cMET/CBT works and discussing the purpose and plan for therapist contact throughout treatment. In 
weeks 4 and 12, additional 30-minute meetings will be held where the therapist will ask questions about 
progress, discuss any issues with the computer intervention, and encourage use of cMET/CBT 
programming between sessions and during follow-up to assist with cannabis-related clinical issues. During 
the Week 12 session, the therapist will assess and discuss the participant’s need for more treatment 
services and will make appropriate referrals. The meetings will explicitly not involve MET, CBT, or other 
therapy-oriented forms of counseling. 
 
Participants will meet with a research assistant twice per week during treatment to gain access to the 
computer workstation, address cMET/CBT problems or other study questions, and to provide urine 
specimens. At each visit, the research assistant will ask participant about medical events/care they have 
received, changes in concomitant medications, and will conduct a brief interview to check for clinical crises 
including suicidal ideation and will make referrals to the case management therapist or staff psychiatrist as 
needed. The research assistant will also review any adverse events (AEs) reported at each visit, asking 
follow up questions with participants as appropriate to help the study staff to determine whether each AE 
is study related. 
 
Contingency Management (CM).  An abstinence incentive program will be administered, which provides 
monetary incentives to study participants for cannabis abstinence verified by urine toxicology testing.  
Prior research has clearly demonstrated that use of abstinence-contingent incentives is an effective 


Date: December 15, 2015    
Principal Investigator: Ryan Vandrey, Ph.D. 
Application Number: NA_00068969 
 
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means of increasing abstinence from cannabis and other drugs compared with MET/CBT alone.  
Maximizing overall study abstinence rates in the present study is desirable because it will increase the 
number of participants in which we will be able to evaluate the effect of abstinence on sleep, thus 
increasing statistical power for aims related to the effect of the medication on sleep during abstinence and 
the effect of sleep on relapse.  Use of CM is also a motivational tool for study participants to conform to 
the instruction to initiate abstinence right at the start of treatment, rather than to delay their quit attempt. 
Conformity in the onset of abstinence in the present study is important for optimizing sleep-related data 
collection and analysis in relation to cannabis use and abstinence. This will greatly enhance our ability to 
interpret findings with confidence. 
 
The CM intervention will be implemented according to the following schedule and procedures. 
 
Weeks 1-2 
A $5 voucher will be earned for each urine specimen provided regardless of the test results.  The 
reason for this is that it typically takes at least 2 weeks for urine drug screens to test negative for 
cannabis among frequent users. 
 
Weeks 3-12 
Cannabis-free samples/reports. During weeks 3-12, participants will earn monetary bonuses 
when urine specimens test negative for cannabis, and self-report having abstained from using 
cannabis. During weeks 3-12, the first cannabis-free sample/report will earn $1.50; with each 
consecutive cannabis-free sample/report collected thereafter earning an increment of $1.50 above 
the previously earned amount.  An additional $10 bonus will be added for each week during which 
both samples/reports are cannabis-negative. Monetary bonuses will be delivered to participants 
during scheduled clinic visits once urine test results are available.  It is possible that test results will 
not be available the same day as the specimens are obtained. 
 
Cannabis-positive samples/reports. No monetary bonuses are earned for a cannabis-positive 
urine sample or “self-report” of use.  Following a positive sample, the bonus for the next cannabis-
free sample/report will be reset to the $1.50 value, with subsequent cannabis-free samples/reports 
handled based on the DELIVERY SCHEDULE below.  In order to encourage participants to get 
back on track with abstinence after a positive sample/report, if they provide 3 consecutive negative 
samples then bonus earnings will return to what they had been prior to the positive sample/report.  
Clients who provide cannabis-positive samples/reports during weeks 3-12 will not earn the 
maximum amount of abstinence bonuses listed below. 
 
 
DELIVERY SCHEDULE ($/DAY) 
 
WEEK       SAMPLE 1   SAMPLE 2 
BONUSES 
$/WEEK 
 
TOTAL 
1 
 
$5.00  
$5.00 
 ---------- 
$10.00  
$10.00 
 
  (noncontingent) 
(noncontingent) 
 
 
 
2 
 
$5.00  
$5.00 
 ---------- 
$10.00  
$20.00 
 
  (noncontingent) 
(noncontingent) 
 
 
 
 
 
 
3 
 
$1.50  
$3.00 
 $10.00  
$14.50  
$34.50 
4 
 
$4.50  
$6.00 
 $10.00  
$20.50  
$55.00 
5 
 
$7.50  
$9.00 
 $10.00  
$26.50  
$81.50 
6 
 
$10.50  
$12.00 
 $10.00  
$32.50  
$114.00 
7 
 
$13.50  
$15.00 
 $10.00  
$38.50  
$152.50 
8 
 
$16.50  
$18.00 
 $10.00  
$44.50  
$197.00 
9 
 
$19.50  
$21.00 
 $10.00  
$50.50  
$247.50 
10  
$22.50  
$24.00 
 $10.00  
$56.50  
$304.00 


Date: December 15, 2015    
Principal Investigator: Ryan Vandrey, Ph.D. 
Application Number: NA_00068969 
 
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Version 3 Dated:   06/2007 
 
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11  
$25.50  
$27.00 
 $10.00  
$62.50  
$366.50 
12  
$28.50  
$30.00 
 $10.00  
$68.50  
$435.00 
 
TOTAL POSSIBLE DOLLARS EARNED = $435.00 
 
 
Medication. Study participants will receive medication for daily administration throughout the 12-week 
treatment intervention period. Medication will be dispensed for outpatient use with instructions to take a 
single dose each night 30 minutes prior to when they plan to go to sleep. Participants will initially receive a 
4-day supply of medication (time to next appointment plus 1 day). After this they will receive additional 
doses at scheduled visits such that they maintain at least a one-week medication supply. This will ensure 
that medication administration can continue in the event of a missed clinic visit, adverse weather, holidays, 
or planned vacations. Doses will be packaged and labeled with a quality assurance code, and the phone 
number for contacting BPRU medical staff 24 hours/day. In the event of an emergency, BPRU medical 
staff will be able to break the blind using the QA code. 
 
Study medications (active and placebo) will be prepared by our research pharmacy using an 
encapsulation method. The outer capsule will be packed with an inert substance and contain a pill, either 
commercial zolpidem or a placebo pill of similar size and color, but unfortunately lacking the appropriate 
branding stamp. Participants randomized to receive active medication will receive a single target dose 
containing 12.5 mg extended-release zolpidem each day for the first 10 weeks of the treatment 
intervention. The 12.5mg dose was selected because it is the recommended dose for healthy adults under 
age 65 based on clinical trials for treating insomnia. It has been shown to be safe and effective for daily 
use in the treatment of insomnia in healthy individuals for up to 1 year with no evidence of tolerance or 
rebound insomnia. Because heavy cannabis users may react differently to extended use of the 
medication, a drug taper will be conducted during Weeks 11 and 12 so that we can detect disordered 
sleep patterns or other effects that may occur following discontinuation of the medication, whether due to 
rebound effects of the medication or the emergence of pre-morbid sleep disorders that may have been 
masked by chronic cannabis use and medication during the first 10 weeks. During the 14-day taper, 12.5 
mg extended-release zolpidem will be administered on days 1, 3, 6, 10, and 14, and placebo will be 
administered on remaining days. Participants will not be informed about the taper, but all participants will 
be told that they could receive placebo medication during the study.  
 
While the 12.5 mg dose is commonplace for use in the treatment of insomnia, dose adjustments may be 
required to maximize therapeutic benefit in this study.  Participants will complete assessments about 
medication side effects and sleep during each clinic visit. Based on weekly reviews of these reports, if 
there is an indication that the current dose is not being tolerated, daily dose will be reduced by 6.25 mg.  
Contrarily, if evidence of clinically important sleep disturbance is present, the investigators will issue a 
recommendation for study dose to increase by 6.25 mg.  All recommended dose changes will be 
submitted to the BPRU pharmacy, who will manage blind medication conditions.  Those participants 
assigned to the active medication condition, will receive appropriate dose adjustments.  However, to 
ensure the safety of participants and minimize the likelihood of medication abuse/dependence, the daily 
dose of zolpidem administered will never exceed double the daily recommended dose (25 mg/night).  
 
During the study, we will assess medication adherence in 2 ways.  First, the BPRU pharmacy will add 
15mg acetazolamide (a sub-clinical “micro” dose) to each medication capsule (active and placebo doses) 
to allow for urine toxicology testing of medication usage.  For comparison, clinical use of acetazolamide for 
altitude sickness, epilepsy, glaucoma, or edema is typically in the range of 250-750mg/day.  
Acetazolamide is excreted unchanged in urine and a recent trial supported by NIDA suggests that it is a 
good biomarker of medication adherence for up to 96 hours (Hampson et al, under review; documentation 
provided in IRB application supplementary materials). The first urine specimen obtained each week during 
treatment will be split and a portion of the specimen submitted to an external toxicology laboratory for 
analysis to detect the presence of acetazolamide.  Participants will be compensated $6 per week that 


Date: December 15, 2015    
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acetazolamide testing confirms self-report of medication adherence (whether positive for those who report 
taking the medication, or negative for those who report not taking the medication).  Thus, we want to 
incentivize accurate self-reports and not overly incentivize taking the medication among individuals who 
may take it and not report side effects in order to earn more money.  At the end of the study, a bonus of 
$50 will be paid to participants who have positive urine acetazolamide tests on 7-8 weeks, a bonus of $75 
will be paid to participants who have positive urine acetazolamide tests on 9-10 weeks, and a bonus of 
$150 will be paid to participants who have positive urine acetazolamide tests on 11-12 weeks. In addition, 
we will use electronic medication packaging (e.g. MEMS cap) to monitor when study participants access 
medication.  This will be used to validate self-report and provide immediate reinforcement for medication 
adherence since there will likely be a delay of 2-4 weeks for getting urine toxicology results.  Participants 
will earn compensation on an escalating schedule based on the electronic medication monitors during the 
study to encourage continuous adherence.  Participants will be paid $0.50 the first day they self-report 
taking the medication at bedtime as instructed AND the electronic monitor indicates the medication 
container was opened at an appropriate time.  The amount of compensation will then increase by $0.25 
each day to a maximum of $2 per day.  If a day of medication use is missed, or the time stamp on the 
opening of the container does not match sleep time, compensation for taking the medication is reset back 
to $0.50 and participants must again work their way up to $2/day.  The total possible compensation for full 
medication adherence is $384.75 (maximum of $222 for urine toxicology; $162.75 for self-report confirmed 
by electronic monitoring). 
 
Sleep Assessment. Sleep will be assessed via polysomnography (PSG), EEG headband, actigraphy, 
DBAS, ISI, and sleep diaries. 
 
Polysomnography (PSG). PSG will conducted while participants sleep at home during weeks 1, 10, and 12 
during treatment, and at the 3 and 12 month follow-ups. On PSG nights, participants will come to the 
laboratory 2-3 hours before their habitual bedtime. Certified PSG technicians will wire participants for 
sleep recording using standardized procedures for ambulatory PSG recording with demonstrated 
reliability. Recommended placement for EEG, EOG, and EMG according to the American Academy of 
Sleep Medicine (AASM) will be used. We will acquire 6 EEGs (F4-A1, F3-A2, C4-A1, C3-A2, O1-A2, O2-
A1), right and left electro-oculograms (EOGs) linked to a single mastoid, submental EMGs, bilateral 
anterior tibialis muscles, and ECG (single modified ECG lead II). Respiratory function and effort will be 
measured via oronasal thermistor, nasal air pressure transducer, pulse oximetry, and abdominal and 
thoracic inductance plethysmographic belts. All EEG and EMG signals will be acquired at a base sampling 
rate of 500Hz using a Compumedics, Safiro polygraph. This device is strapped to the body, permitting full 
range of motion and mobility within the home. Once sensor placement is finished and tested, the technician 
will provide instruction regarding the placement of respiratory sensors at bedtime and how to initiate and 
terminate recording using an event marker on the device. Prior to lights out, participants will call the 
technician to ensure the device and sensors are functioning properly. The sampling rates and montage 
used in this protocol meet or exceed AASM scoring and data acquisition procedures. PSG data will be 
stored on DVDs and a secure server that is backed up daily. Certified PSG technicians will score each 
record according to AASM criteria. All clinical indices will be calculated and a report generated by 
Somnologica software. Dr. Smith will review all scored records using a rigorous quality assurance program 
to ensure the reliability and validity of the reports.  
 
EEG Headband. Portable, wireless EEG monitors will be used to obtain additional objective sleep data 
during the 12-week intervention.  EEG headbands use EEG leads placed on the forehead via elastic 
headband to provide objective measures of sleep continuity and basic sleep architecture (light sleep, deep 
sleep, REM sleep, and awake).  We will use commercially available EEG headband units (e.g. Zeo, Sleep 
Profiler) that meet or exceeds US safety standards.  Validation studies have been conducted showing that 
data from EEG headbands correlate highly with PSG.  EEG headbands will be used in order to capture 
valid data at least once per week during the study.  On the occasion that there is a malfunction in data 
capture (battery not fully charged, corrupt file), participants will be asked to repeat use of the EEG 
headband until data from one sleep night is captured for the week.  


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Actigraphy. On the first day of treatment, participants will be provided with a small, inexpensive actigraphy 
monitor to wear continuously during the 12-week intervention. Actigraphy monitors use an accelerometer 
to measure movement and is equipped with an event marker so that participants can indicate lights out 
each night. Algorithms from actigraphy data provide objective estimates of circadian rhythm and sleep 
continuity and have been shown to be sensitive to treatment changes. These specific devices and their 
algorithms will be validated against the PSG assessments obtained in this study. For the purpose of this 
study, actigraphy measures of sleep latency, wake after sleep onset time, sleep efficiency and total sleep 
time will be derived as secondary measures of sleep continuity. 
 
Self-report assessments. Participants will call in to the lab to record their time to sleep and time awake 
each day.  They will also complete a sleep diary assessment in which they will record time to bed and final 
awakening, sleep latency, number of awakenings, subjective sleep quality, level of arousal upon 
awakening, and sleep continuity parameters each day they come to the laboratory. Sleep diaries are 
widely used in sleep/insomnia research and have demonstrated sound psychometric properties, significant 
correlations with PSG, and sensitivity to treatment.  In addition, the ISI will be administered weekly and the 
DBAS will be administered monthly during treatment to assess for changes in clinically important sleep 
patterns and beliefs. 
 
Circadian Rhythm Assessment.  We will assess circadian rhythm using a self-report questionnaire 
(Smith’s Measure of Morningness/Eveningness) and via analysis of urinary melatonin over 24 hours.  Both 
measures will be conducted during Week 1 and Week 12 to investigate any changes over time related to 
changes in cannabis use.  For urine collection, participants will be provided with collection bottles to take 
home with them during the clinic visit prior to a scheduled PSG.  They will be instructed to obtain samples 
from each urine void beginning after the first void on the prior day up to and including the first void of that 
day in accordance with standard procedures.  Each specimen will be labeled with the time of collection.  
Urine toxicology testing will be conducted by a certified external toxicology laboratory for quantitative 
creatinine and the primary metabolite of melatonin, 6-sulpha- toxymelatonin (aMT6s).  
 
Cannabis Use Assessment. The primary study outcome measure will be rates of cannabis abstinence. 
Cannabis use will be assessed via urine toxicology testing and self-report using the TLFB. Consent to 
participate in the study will include agreement to provide urine specimens under direct staff observation 
twice weekly (Mon–Thurs or Tues–Fri) during treatment and at each follow-up assessment. All specimens 
will be tested for 11-nor-delta-9-THC-9-carboxylic acid (THCCOOH), the primary marijuana metabolite 
using a THCCOOH cutoff level of 50 ng/mL. We will also address adulteration and inadvertent dilution of 
urine specimens. In prior studies, diluted urine specimens caused by use of diuretics and/or consumption 
of large quantities of liquid represent the vast majority of threats to validity. We will test for creatinine 
(using the standard cutoff of 20 ng/mL per SAMSHA testing guidelines), and 4 other indicators of 
adulteration (pH level, glutaraldehyde, nitrites, and oxidants). When urine specimens are deemed invalid, 
participants will be asked to provide another specimen within 4–24 hours. Urine specimens obtained at 
intake and the first specimen collected on Weeks 2, 4, 6, 8, 10 and 12 will be sent to a certified external 
toxicology laboratory for quantitative GC-MS analysis. This will allow for an assessment of outcomes by 
intake urine cannbinoid concentration, and for assessment of sleep measures by cannabinoid 
concentration, as well as change in quantitative concentration over time by group.  Urine specimens 
collected during Week 1 and Week 12 will also be tested for evidence of synthetic cannabinoid use to 
assess whether participants shift from using cannabis to more readily available and more difficult to detect 
cannabinoid products such as Spice and K2. 
 
Additional Assessments. At each clinic visit, participants will complete the TLFB in which they will report 
daily use of cannabis, alcohol and other drugs. They will also complete a Medication Side-Effects 
Questionnaire and Marijuana Withdrawal Checklist. For each of these measures, participants will rate 
adjectives on a 4-point scale (none, mild, moderate, severe) based on their experience of potential 
medication side effects (obtained from clinical trials and described on the package insert) and cannabis 


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withdrawal symptoms since their last clinic visit. Vital signs will also be obtained via automated monitor.  
During Weeks 6 and 12 we will re-administer the PCL-S to assess for changes in PTSD symptoms, and at 
Week 12 the two Delay Discounting tasks will be repeated. 
 
In-person, 90-minute assessment interviews will be conducted 3, 6 and 12 months after completion of 
treatment. At each follow-up, the measures administered at intake will be repeated. Data on cannabis use 
and other treatment participation/change efforts will be collected for the full 3-6 month window to create a 
seamless database regarding drug use and treatment participation both within and external to the study. 
Urine drug testing will be conducted using the protocol employed during treatment. Treatment satisfaction 
questionnaires will be collected to provide additional information on participant perceptions of the 
treatment they received and whether perceptions change over time. A home-based PSG assessment will 
be conducted at the 3 and 12-month follow-up assessments to screen for evidence of emergent sleep 
disorders. Provisions will be made to collect some follow-up data by phone or by mail for those unable or 
unwilling to come to the clinic. 
 
b. Study duration and number of study visits required of research participants. 
 
The treatment period of the study will last for 12 weeks. Participants will have 30-60-minute appointments 
twice per week at the BPRU during the 12 weeks of treatment.  Additional visits, approximately 90-minutes 
in duration, are required to wire participants for the home-based sleep assessments during Weeks 1, 6, 
10, and 12. Participants will have follow-up appointments 3 months (interview and sleep assessment; 180 
minutes), 6 months (interview only; 90-minutes), and 12 months (interview and sleep assessment; 180 
minutes) after treatment ends.  
 
c. Blinding, including justification for blinding or not blinding the trial, if applicable. 
 
Administration of capsules containing zolpidem or placebo during the study will be double blind.  Blinding 
of the medication during the study is required to reduce expectancy bias and is standard scientific practice 
for this type of research.  
 
d. Justification of why participants will not receive routine care or will have current therapy 
stopped. 
 
Routine medical care for any illness will not be affected during this study. 
 
e. Justification for inclusion of a placebo or non-treatment group. 
 
All study participants will receive an active treatment (cMET/CBT + CM) for treating problems related to 
cannabis use.  Placebo medication is included for some participants in this trial for scientific integrity in the 
evaluation of the effectiveness of zolpidem as an adjunct therapy for improving abstinence and reducing 
withdrawal in heavy cannabis users.  The consequences of cannabis withdrawal are not life threatening 
and we do not anticipate any serious adverse events related to the study procedures to occur. 
 
f. Definition of treatment failure or participant removal criteria. 
 
We intend to use an intent-to-treat approach for participant inclusion in the proposed study.  
Thus, our intent is to retain and include all participants in the study once randomized.  Exceptions 
to this may include immediate study discharge of participants who exhibit unacceptable behavior 
in the clinic, attempt to steal of purposefully damage study equipment, or who have a serious 


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adverse event related to the study medication/procedures.  The study investigators may 
discharge participants for other reasons not known at this time. 
 
g. Description of what happens to participants receiving therapy when study ends or if a 
participant’s participation in the study ends prematurely. 
 
Participants will be offered referrals to community treatment clinics when the study ends or if their 
participation ends prematurely.  
 
5. 
Inclusion/Exclusion Criteria 
 
Inclusion criteria: 
1) Age 18-55 years. Those older than 55 will be excluded due to significant changes in sleep and 
poor tolerability of 12.5 mg dose of extended-release zolpidem that can occur with increased 
age.  
2) Use of cannabis on > 50 of prior 90 days and seeking treatment for cannabis-related problems 
3) Report difficulty sleeping without use of cannabis, or using cannabis to get better sleep  
4) Able and willing to give informed consent to participate 
 
Exclusion criteria: 
1) Currently meets DSM criteria for dependence on a drug other than cannabis or nicotine, history 
of dependence on sedative/hypnotic drugs, or current Axis I psychiatric disorder associated 
with significant effects on sleep (e.g. major depression) 
2) Moderate sleep apnea (apnea/hypopnea index > 15) or periodic limb movement disorder 
(arousal index > 15) during intake PSG assessment 
3) Pregnant, breast feeding, or planning to become pregnant within the next 3 months 
4) Current psychosis, dementia, suicidal ideation, or other conditions associated with severe 
cognitive/social impairment 
5) Allergy to any ingredient in extended-release zolpidem or prior adverse reaction to zolpidem 
6) Current use of drugs that are strong inhibitors or inducers (e.g. ritonavir, nefazodone, 
carbamazapine) of metabolism via cytochrome P450 3A4 enzymes (primary system for 
metabolism of zolpidem), or current illness resulting in severe hepatic impairment  
7) Use of hypnotic medications to resolve sleep difficulties more than 4 times in the prior month 
8) Currently meets DSM criteria for alcohol abuse, dependence, or self-reports use of 20 or more 
standard drinks of alcohol per week in the prior month  
9) History of or current evidence of significant medical or psychiatric illness judged by the principal 
investigator or medical monitor to put the participant at greater risk of experiencing an adverse 
event or that could otherwise negatively impact the integrity of the trial, including, but not limited 
to: CNS disorders, COPD; cardiac disease (e.g. CHF, arrhythmias, CAD and valvular heart 
diseases); or pulmonary disease  
10) Sa02 by Pulse Oximetry of < 95% for 5min or greater while awake and seated 
 
 
6. 
Drugs/ Substances/ Devices 
a. The rationale for choosing the drug and dose or for choosing the device to be used. 
 
Zolpidem extended-release (Ambien CR®) was selected for use in this study because it is a short-acting 
nonbenzodiazepine hypnotic approved by the FDA for the treatment of insomnia.  Zolpidem acts as a 
selective agonist at the alpha-1 subunit of the GABAA receptor.  The recommended dose of the extended-
release formulation of zolpidem for a healthy adult under 65 is 12.5 mg.  At that dose, mean peak plasma 
levels are reached after 1.5 hours, and the elimination half-life is approximately 2.8 hours.  Clinical trials 


Date: December 15, 2015    
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have demonstrated that zolpidem, in both its rapid and extended-release formulations, significantly 
reduces latency to persistent sleep, reduces nocturnal awakenings, and increases total sleep time.  Other 
studies have shown zolpidem to reliably increase slow-wave sleep.  Under acute drug effect conditions, 
zolpidem likely impairs memory and psychomotor functioning, but controlled studies suggest that these 
effects do not perisit past waking the day after taking the medication.  The most frequently reported side 
effects reported during clinical trials were headache (19% versus 15% receiving placebo), somnolence 
(15% versus 2% receiving placebo), dizziness (12% versus 5% receiving placebo), and nausea (7% 
versus 4% receiving placebo). 
 
A sub-clinical “micro” dose (15mg; versus clinical doses of 250-750mg) of acetazolamide powder will be 
added to all medication capsules to be used as a biomarker of medication adherence.  Acetazolamide will 
be obtained from a clinical manufacturing company (Letco Medical) and added to study capsules 
unchanged.  Acetazolamide was selected because it is rapidly absorbed and excreted without metabolism 
in urine, where it can be non-invasively sampled.  In a recent study conducted by NIDA and investigators 
at the University of Kentucky, acetazolamide was added to 30mg oxycodone in a blind clinical laboratory 
study and the pharmacokinetic profile was evaluated.  The rate of urinary elimination decreased steadily 
following cessation of dosing (half-life =16.1±3.8h, n=10) with low inter-subject variability. For each of four 
consecutive mornings after dosing cessation, the rates of urinary acetazolamide elimination remained 
quantifiable and significantly declined in a predictable manner.  There was no effect of acetazolamide on 
oxycodone pharmacodynamics, Cmax, Tmax or elimination half-life, and no adverse events associated 
with acetazolamide dosing. 
 
 
b. Justification and safety information if FDA approved drugs will be administered for non-
FDA approved indications or if doses or routes of administration or participant 
populations are changed. 
 
Our prior research has shown that abrupt cessation of heavy cannabis use results in sleep disturbances 
that resemble insomnia.  Although the medication has not been approved by the FDA for use in the 
treatment in cannabis use disorders per se, it has been approved by the FDA for use in the treatment of 
insomnia. We have obtained an IND (103,211) from the FDA to conduct research to investigate the effects 
of extended-release zolpidem in the treatment of cannabis use disorders.  
 
c. Justification and safety information if non-FDA approved drugs without an IND will be 
administered.  
 
Not applicable to this protocol.  
 
7. Study Statistics 
a. Primary outcome variable. 
 
Primary outcome variable is the number of urine samples negative for cannabis use.  
 
b. Secondary outcome variables. 
 
Cannabis use indices including duration of continuous cannabis abstinence, self-reported 
frequency and amount of cannabis use obtained from the TLFB, and quantitative urine toxicology 
results. Sleep PSG indices including latency to persistent sleep, sleep efficiency, total sleep time, 
% REM, % SWS. Headband EEG, actigraphy and sleep diary indices including sleep continuity, 
sleep efficiency, sleep architecture and sleep quality.  


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c. Statistical plan including sample size justification and interim data analysis. 
 
Sample Size: A sample size of 100 is needed to have 80% power to detect differences in the 
number of urine samples negative for cannabis use, assuming 23% negative urines in the placebo 
group (average abstinence rate in prior clinical trials of MET/CBT), and 40% or greater negative 
urines (40% increase from placebo estimate) in the extended-release zolpidem group. A sample 
size of 77 is needed to have 80% power to detect differences in sleep efficiency based on the 
effect size of 0.90 obtained for the effect of zolpidem vs. placebo on sleep efficiency in our prior 
inpatient study. For the relationship between zolpidem and sleep efficiency, with a sample size of 
100 we would have 80% power to detect effects of size 0.82 or greater. Power to detect an effect 
of sleep efficiency after controlling for treatment assignment was calculated via simulation. With 
100 participants and a 40% increase in negative urines we would have 80% power to detect odds 
ratios of 1.54 or greater. Note that we have requested to increase the total sample size to exceed 
100 because the CM condition was added after we had run an initial cohort of 18 study 
participants.  Because this is expected to significantly alter abstinence rates, which could impact 
study outcomes, the participants enrolled to date will be considered pilot subjects and will not be 
included in the primary study analyses.  Further, due to lower than expected medication adherence 
rates and higher than expected rates of study drop out, we plan to randomize up to 200 
participants in order to achieve a target of 100 participants who are retained in treatment and are 
compliant with the medication.  Our primary analyses will still be conducted as an intent-to-treat as 
detailed below, but we wish to have adequate power to detect differences in sub-group analyses 
as well. 
 
Preliminary Analyses:  We will examine whether study completers differed from those who failed 
to complete the study with regard to demographic or cannabis use variables or response to 
abstinence (withdrawal, craving).  This will inform the generality of study results.  
 
We will examine the data for missing values. When applicable, we will impute scores by averaging 
the closest pre and post values; otherwise our statistical approach will accommodate missing data.   
 
Initial descriptive statistics on main outcome variables will be calculated including frequency tables, 
histograms, and measures of central tendency and variation.  Unusual data values will be identified 
and the associated records will be double checked for accuracy.  Continuous variables not meeting 
assumptions required for parametric analyses will be either transformed or analyzed by the 
nonparametric counterpart of the parametric approach typically employed to ensure proper 
inferences. 
 
Outcome Analyses: Longitudinal logistic regression will examine the effect of treatment group and 
time on the number of negative urine samples, controlling for variables used in the stratified 
randomization, where log odds(-urineij) = βo+ β1Zolpidem+ β2Timej+ β3-px3-p+εij. This statistical 
approach will also be used for outcomes from PSG and subjective sleep ratings.  
 
To test the relationship between improvement in sleep and reduction in cannabis use, mediation 
will be established in 3 steps using the following longitudinal regression models and PSG data from 
weeks 1, 6, and 10 (prior to dose taper): 
1) Medication accounts for variations in sleep efficiency, Efficiencyij = βo+ β1Zolpidem+ 
β2Timej+ β3-px3-p+εij. 
2) Variations in sleep efficiency account for variations in probability of a negative urine, log 
odds(-urineij) = βo+ β1Efficiency+ β2Timej+ β3-px3-p+εij. 
3) The relationship between extended-release zolpidem and probability of negative urine is 
attenuated after controlling for sleep efficiency, log odds(-urineij) = βo+ β1
*Zolpidem+ 


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β2Timej+ β3-px3-p+εij and log odds(-urineij) = βo+ β1Zolpidem+ β2Timej+ β3Efficiency +β4-px4-
p+εij , from which we can calculate proportion of treatment effect explained (PTE). Testing 
the null hypothesis that β1
*= β1 is equivalent to testing β3=0 in the full model, provided that 
step 1 is successful (e.g., the correlation is nonzero). 
 
d. Early stopping rules. 
 
A DSMB has been formed to assess the progress and safety of this study every 6 months 
following study initiation.  The study may be stopped based on the recommendation of the board 
for any concerns related to feasibility, safety, or efficacy at any time. 
 
8. 
Risks 
a. Medical risks, listing all procedures, their major and minor risks and expected 
frequency. 
 
Participants may experience cannabis withdrawal symptoms while trying to quit cannabis use during the 
study. Cannabis withdrawal symptoms may include anger and aggression, anxiety, depressed mood, 
irritability, restlessness, sleep difficulty and strange dreams, decreased appetite, weight loss, headaches, 
physical tension, sweating, stomach pain, nausea, vomiting, increased blood pressure, and general 
physical discomfort. These symptoms have been observed in prior studies when participants abruptly stop 
using cannabis. There are no reports in the current literature of severe physiological or psychiatric 
consequences resulting from cannabis withdrawal. Some cannabis withdrawal symptoms may be 
attenuated in participants who are assigned to the extended-release zolpidem drug condition.   
 
Other potential risks relate to administration of extended-release zolpidem. Under acute drug effect 
conditions, zolpidem likely impairs memory and psychomotor functioning, but controlled studies suggest 
that these effects do not persist past waking the day after taking the medication. The most frequently 
reported side effects reported during clinical trials were headache, somnolence, dizziness, and nausea. 
Though rare in incidence, there have been reports of suicidal ideation and “sleep-driving” among patients 
taking zolpidem. Zolpidem is classified as a Schedule IV narcotic along with most other hypnotics. 
Zolpidem has a moderate abuse liability relative to other hypnotics. A history of illicit substance use is 
reported as a risk factor for zolpidem abuse, but we are not aware of any reports that specifically indicate 
that past or present cannabis use was associated with an increased risk for zolpidem abuse or 
dependence.    
 
Breech of confidentiality about self-reported drug use and biological tests indicating recent drug use is also 
a risk. 
 
b. Steps taken to minimize the risks. 
 
Recruiting and Informed Consent. Participants are not a "vulnerable population" as defined by human 
subjects protection guidelines; that is, they are not minors, pregnant women, under legal coercion or 
restriction, or mentally impaired. They are competent adults who provide their voluntary written informed 
consent. Participants will be recruited via media advertisements that clearly state the nature and intent of 
the study or referrals from other health service providers aware of the nature of the research. The consent 
process will inform the participant in detail of the procedures, time involvement, compensation, risk, and 
treatment options other than participation in our study. The staff member obtaining written informed 
consent will have completed training specific to obtaining informed consent in the conduct of human 
research. Particular emphasis will be given to providing information regarding the potential risks involved 
with taking the study medication. Volunteers will also be instructed that they may withdrawal from 


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participation at any time without losing any of the compensation that they have earned to that point.  
Participants will be provided with a research card to be kept on their person while participating in the 
study.  The card will indicate that the person is actively participating in a study in which they could receive 
zolpidem or placebo, and will list contact information for the study team.  Participants will be encouraged 
to share this information with medical providers they come in contact with during the study.  
  
Cannabis Withdrawal and Medication Side Effects.  It is unlikely that any adverse event should 
arise that requires medical or psychiatric treatment. Volunteers for this study with current depression, the 
major risk factor for development of suicidal ideation, will be excluded from the study and referred to 
community treatment programs. Study volunteers who have blood pressure that exceeds 140 mmHg 
systolic or 90 mmHg diastolic during the intake assessment will receive a brief consultation from a medical 
staff member and provided a written letter encouraging them to see their primary care doctor to discuss 
methods of getting blood pressure under control.  Because cannabis abstinence has been shown to 
increase blood pressure in some cases, study volunteers with a high initial blood pressure must return to 
the laboratory with blood pressure below 140/90 mmHg before being allowed to begin study participation.  
Vitals will be tracked and observed at each visit during the study when blood pressure assessments 
>140/90 mmHg will continue to be monitored with medical review and referrals as needed.  At any time, 
SBP >180 mmHg or DBP >110 mmHg will prompt immediate evaluation by the study physician and 
referral to the emergency room if deemed necessary.  These participants are also reviewed to determine if 
it is safe for them to remain in the clinical trial. Participants with a history of abusing sedative/hypnotic 
drugs will also be excluded to minimize the likelihood that the study medication gets used outside of the 
intended dosing regimen. We will also limit access to study medication to a maximum of 7 doses at a time, 
except under special circumstances when additional doses may be dispensed to account for holidays, 
expected inclement weather, or planned vacations. Participants will be informed of the risk of “sleep 
driving” or occurrences in which they might engage in behaviors during the night, but have no memory the 
following day. We will recommend to participants that they inform others they live with to help monitor their 
behavior during the night and take any other necessary precautions against driving or operating 
dangerous machinery during nighttime hours. All participants will be instructed prior to initiating the study 
that they should call the study PI, medical monitor, and/or 911 in the event of suicidal ideation onset or the 
occurrence of any other significant adverse event during participation in the study. Should an adverse 
event or injury occur at the research facility, the medical, nursing, and several research staff at BPRU are 
trained in CPR, and mobile emergency crash carts are available at multiple locations in the building. If 
appropriate, participants would be taken to the Johns Hopkins Bayview Medical Center Emergency 
Department, located across the street from the research facility. Blood pressure and heart rates will be 
monitored at each clinic visit, and any PSG assessments that exhibit evidence of an abnormal ECG will be 
referred to study medical staff for review and consultation. The Principal Investigator will be immediately 
notified of any serious adverse events that arise. These include reports of severe side effects from study 
medication, accidents, or hospitalization episodes that occur while individuals are participating in the 
study. In any instance of a serious adverse event, the Principal Investigator will immediately provide a 
detailed report to the IRB, FDA, NIH, and DSMB.  
 
Ongoing review of eligibility.  A review of all current study participants is conducted during weekly lab 
meetings, where staff review patient progress as well as any medical events or changes in patient 
concomitant medication.  In any case where an ongoing study participant has a change in health status or 
medication that meets a study exclusion criterion, the medical and scientific team will meet and discuss 
the safety and scientific risk/benefit of retaining versus withdrawing the study participant.  
 
Confidentiality. Participants’ names will be recorded only on the informed consent and necessary medical 
and payment forms. Anonymous participant identification numbers will be used on all other forms and 
labeling of biological fluids and test results. All information gathered will be kept in locked research staff 
offices or file cabinets located within a secure building protected with security guards and video 
surveillance 24-hours per day. All medical information obtained will be handled in accordance with HIPAA 


Date: December 15, 2015    
Principal Investigator: Ryan Vandrey, Ph.D. 
Application Number: NA_00068969 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 17 of 18 
regulations. Only research staff will have access to participant records. The limits of confidentiality (e.g. 
suspected child abuse or neglect, or harm to self or others) will be discussed in detail with the participants 
during the informed consent process. To reduce the likelihood of patient records disclosure we intend to 
apply for a Certificate of Confidentiality. These methods have been successful in prior research studies. 
 
c. Plan for reporting unanticipated problems or study deviations. 
 
In any case in which a participant ceases study participation due to medication/cannabis side effects or 
cannabis withdrawal, the Principal Investigator will make a detailed report to the IRB and will disclose the 
medication condition to the volunteer in attempt to help the volunteer avoid the medication and a similar 
reaction in the future. No serious adverse events are anticipated.  
 
A Data and Safety Monitoring Board (DSMB) has been established to provide oversight on this project 
during its execution. David Neubauer, MD will serve as the chair of the DSMB. The DSMB will convene 
every 6 months to review cumulative summaries of adverse events, results of quantitative urine toxicology 
testing for biomarkers of zolpidem use among those in the active treatment condition, and participant 
accrual and retention rates over the course of the 5-year trial. Safety reviews and interim analyses will all 
be conducted with drug conditions remaining blind (e.g., conditions A and B). The medication blind will be 
broken at the request of the DSMB if there is a safety concern or question about efficacy that they think 
may warrant stopping the study early.  
 
Adverse Events (AEs) will be defined on the basis of the NIH Guidelines on Data and Safety Monitoring for 
Intervention Trials. These guidelines define an AE as any reaction, side effect or untoward event that 
occurs during the course of the clinical trial, whether or not the event is considered related to the study 
interventions. A new illness, symptom, unfavorable or unintended sign, or worsening of a pre-existing 
condition or abnormality will be considered an AE. Stable chronic conditions such as diabetes that are 
present prior to study entry and do not worsen will not be considered AEs. 
 
Dr. Vandrey will make immediate reports for serious adverse events (SAEs), defined as any event that is 
fatal, near fatal, produces substantial disability, or requires hospitalization, to study co-investigators, the 
DSMB, the IRB, the Johns Hopkins Risk Management Office, the Department of Psychiatry Chair, 
Program Officer at NIDA, and the FDA.  
 
d. Legal risks such as the risks that would be associated with breach of confidentiality. 
 
With confidentiality procedures in place, the legal risks of this study are minimal. 
 
e. Financial risks to the participants. 
 
The financial risk to study participants is minimal. Costs related to this research will be supported 
by NIDA grant U01-DA031784.  Participants will be compensated for their participation to offset 
the costs associated with travel to and from the clinic and for their time involvement. 
 
9. 
Benefits 
a. 
Description of the probable benefits for the participant and for society. 
 
Study volunteers may directly benefit by receiving treatment for cannabis use problems at no cost. All 
study participants will receive evidence-based psychosocial treatment tailored for adult cannabis users. 
Half of the study participants will also receive extended-release zolpidem, a medication hypothesized to 
provide additional clinical benefit resulting in improved abstinence outcomes. If effective, use of extended-


Date: December 15, 2015    
Principal Investigator: Ryan Vandrey, Ph.D. 
Application Number: NA_00068969 
 
JHMIRB eFormA  01 
Version 3 Dated:   06/2007 
 
Page 18 of 18 
release zolpidem could quickly and easily be adopted in clinical interventions for cannabis use disorders 
on a broad scale. Approximately 1.2 million Americans enroll in treatment for cannabis use disorders each 
year, so it could be argued that many others would benefit from the conduct of this study if it indeed results 
in the identification and adoption of a medication that significantly improves abstinence rates when 
combined with traditional psychosocial treatments for cannabis use disorders. Because we anticipate only 
relatively minor risks (cannabis withdrawal; zolpidem side effects) to study participants, we feel that the 
proposed research has a positive risk benefit ratio. 
 
10. 
Payment and Remuneration 
a. 
Detail compensation for participants including possible total compensation, 
proposed bonus, and any proposed reductions or penalties for not completing the 
protocol. 
 
Participants will receive compensation according to the schedule below. 
 
 Completing the intake assessment:  $20 
PSG assessment:  
 
 
$50/each (6 assessments for $300 total) 
Headband EEG assessment 
$10/week (12 weeks for $120 total)  
24-hour urine collection 
 
$10/collection (2 collections for $20 total)  
Follow-up Visits (3, 6, & 12 month): $50/each (3 assessments for $150 total) 
Complete 2 clinic visits/week  
$10/week (12 weeks for $120 total) 
Compliant with sleep diary calls 
$10/week (12 weeks for $120 total) 
Abstinence contingent incentives 
$435 (maximum amount)  
Medication adherence incentives 
$384.75 (maximum amount) 
Quick Discounting Operant Task 
$32 (maximum amount) 
Equipment Return 
 
 
$30 
 
The total possible amount of remuneration is $1731.75.  
 
 
11. 
Costs 
a. 
Detail costs of study procedure(s) or drug (s) or substance(s) to participants and 
identify who will pay for them. 
 
The only direct costs to the participants will be their transportation to and from Bayview for all study 
appointments. That cost has been factored into the compensation for participating.  All other study-related 
costs will be paid for by NIDA grant U01-DA031784.