Clinical trial NCT02892110
Conditions: Substance Use Disorder
Keywords: Marijuana use Varenicline/Chantix Motivational enhancement therapy
Sponsor: Medical University of South Carolina
Start date: 2017-02-13; Completion date: 2018-11-27
Enrollment: 72 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Marijuana is the most commonly used illicit drug. There is high demand for effective interventions for cannabis use disorder, yet few specific treatments for have been developed. This study will evaluate the efficacy of varenicline for reducing marijuana use in people who use marijuana frequently.

Detailed description:

Arms: arm 1: 2 mg daily arm 2: 2 mg daily
Interventions: intervention 1: Varenicline intervention 2: Placebo
Intervention descriptions: intervention 1: 2 mg daily intervention 2: 2 mg daily

Protocol documents:
Prot_SAP_000.pdf: 
Program Director/Principal Investigator (Last, First, Middle):  McRae-Clark, Aimee                                                                                  1 
 
Version date 3.12.2018 
 
Advancing Varenicline as a Treatment for Cannabis Use Disorder 
 
A. SIGNIFICANCE 
Overview of the Problem. The prevalence of cannabis use in the United States more than doubled between 
2001 and 2013, from 4.1% to 9.5% of the adult population (Hasin et al., 2015). In 2014, over one million 
Americans received treatment for cannabis related problems (SAMHSA, 2015).  Although a high demand for 
effective interventions exists, few specific treatments have been developed for cannabis use disorder (CUD). 
Further, current evidence-based treatments have limited efficacy, with few individuals achieving abstinence 
(Compton & Pringle, 2004; Kadden et al., 2007; Nordstrom & Levin, 2007; Vandrey & Haney, 2009; Sherman & 
McRae-Clark, in press). As such, it is critical to explore new strategies to improve treatment outcomes.   
Nicotinic Acetylcholine Receptors as Potential Targets for CUD Medication Development. Nicotinic 
acetylcholine receptors (nACHr) are highly expressed in the mesocorticolimbic dopamine system (Dani & 
Bertrand, 2007) and also contribute to drug-related reward processes by impacting glutamate, and consequently 
dopamine, release (Fu et al., 2000; Kaiser & Wonnacott, 2000). As such, these receptors have been identified 
as potential targets for addiction treatment. Varenicline is a selective nACHr partial agonist of the α4β2 subtype 
and a full agonist of the α7 subtype (Mihalak et al., 2006), and is arguably the most effective first line 
pharmacotherapy for promoting tobacco cessation (Aubin et al., 2008; Eisenberg et al., 2008; Gonzales et al., 
2006; Jorenby et al., 2006; Nides et al., 2006). Given its partial agonist profile, varenicline likely exerts its effects 
via dual mechanisms. First, it partially activates α4β2 receptors in the ventral tegmental area (VTA), resulting in 
increased dopamine levels and a reduction in withdrawal symptoms and craving (Rollema et al., 2007; Reperant 
et al., 2010). Further, through its antagonist properties, varenicline also blocks the ability of nicotine to further 
stimulate dopamine release, thereby attenuating nicotine’s reinforcing effects during smoking (Coe et al., 2005).  
Varenicline reliably reduces reactivity to smoking-related cues among tobacco users via its effects on reward 
and cognitive circuitry (Brandon et al., 2011; Franklin et al., 2011; Hartwell et al., 2013). 
Given that the mesolimbic dopamine system is a key element in the brain reward pathways and that increased 
dopaminergic transmission in these pathways is important for the reinforcing effects of multiple drugs of abuse 
(Roberts et al, 1980; Taylor & Robbins, 1984; Koob & LeMoal, 1997; Tanda et al, 1997; Volkow et al., 2016), 
varenicline has been identified as a prime candidate medication for evaluation in other substance use disorders 
(Crunelle et al., 2010). Positive findings have been reported in regards to varenicline reducing alcohol cue 
reactivity (Schacht et al., 2014), reducing alcohol self-administration among heavy drinking smokers (McKee et 
al., 2009), improving drinking outcomes in preliminary clinical trials (Fucito et al., 2011; Mitchell et al., 2012), and 
reducing alcohol use in a large, placebo-controlled trial (Litten et al., 2013). A recent case series also reported 
reductions in amount of enjoyment of cannabis and self-report of cannabis use among cannabis- and nicotine-
dependent individuals receiving varenicline (Newcombe et al., 2015). To date, however, varenicline has not been 
evaluated in a controlled clinical trial for treatment of CUD. 
Importantly, and particularly relevant to the present proposal, α4β2 nACHRs in corticothalamic circuitry, which 
are saturated with varenicline dosing (Lotfipour et al., 2012), have also been heavily implicated in prefrontally 
mediated attentional and inhibitory control (IC) (Sarter & Paolone, 2011). In addition, α7 nACHRs are involved 
in hippocampal-dependent memory function (Levin et al., 2006). nACHr agonists improve frontally mediated 
executive function among nicotine-naïve animals (Levin et al., 2006) and humans (Froeliger et al., 2009). 
Varenicline has been shown to improve multiple forms of attention (Rhodes et al., 2012) including inhibitory 
control (Austin et al., 2014) among treatment-seeking tobacco users and in nicotine-naïve animal models 
(Rollema et al., 2009; Terry et al., 2016). Given that cannabinoid agonists inhibit cholinergic transmission (Varvel 
et al, 2001; Lichtman et al., 2002; Vukadinovic et al., 2013), the cholinergic system in particular may play an 
important role in cannabis-induced cognitive dysfunction. As such, varenicline, as a cholinergic modulator in 
prefrontal circuitry, is a promising candidate treatment to ameliorate frontal-executive dysfunction (Sofuoglu et 
al., 2010). 
Cognitive Function and Cannabis Use Outcomes. Cognitive impairments may predict poor response to 
behavioral treatments in drug users (Aharonovich et al., 2008; Caroll et al., 2011; Verdejo-Garcia et al., 2012), 
and pharmacotherapy targeting cognitive function has been proposed as a promising strategy for treatment of 
CUD (Sofuoglu et al., 2010). Acute and chronic effects of cannabis use on neuropsychological functioning have 


Program Director/Principal Investigator (Last, First, Middle):  McRae-Clark, Aimee                                                                                  2 
 
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been well characterized (for review, see Crean et al., 2011; Broyd et al., 2016; Curran et al., 2016). Laboratory 
experiments where controlled doses of cannabis have been administered reveal acute effects on attention 
processes (Morrison et al., 2009; Solowij et al., 1995). Similar memory impairments have also been 
demonstrated following chronic cannabis use (Solowij & Battisti, 2008). Of note, greater cognitive deficits are 
associated with number of lifetime cannabis use episodes (Medina et al., 2007) and with severity of CUD (Filbey 
& Yezhuvath, 2013). 
Inhibitory Controland Varenicline. Inhibitory control (IC) tasks have proven to be an effective probe of 
executive function in individuals with a substance use disorder (Moeller et al., 2016). Cannabis users (Tapert et 
al., 2007) and nicotine dependent smokers (Froeliger et al., 2012; Froeliger et al., 2013; Kozink et al., 2010) 
demonstrate a pattern of dysregulated hyperactivity in lateral prefrontal (i.e. right inferior frontal gyrus: R. IFG) 
BOLD response during attention and inhibitory control tasks, without benefits in task performance, suggestive of 
a compensatory mechanism to perform task demands. This is significant, as the R.IFG is a key node in a 
corticothalamic circuitry that mediates inhibiting a prepotent motor response in order to execute a goal directed 
behavior (Rae et al., 2015; Swann et al., 2012). Moreover, hyperactivity in IFG-BOLD response during inhibitory 
control tasks is associated with worse cessation outcomes across multiple substance use disorders (see Moeller 
et al., 2016). When taken together, those findings are consistent with our pilot data from smokers (N=26) 
performing an IC task which reveals that less task-related IFG BOLD response and stronger IC task-based 
functional connectivity between R.IFG and thalamus (henceforth corticothalamic circuit) is associated with: 
forgoing smoking for a longer period of time, and upon initiation, lighter smoking during ad lib smoking in the lab 
(see Preliminary Data). Work in an α7 knockout mouse model implicates an important role of the α7 receptor in 
mediating IC (Hoyle et al., 2006), and in tobacco users varenicline improves aspects of inhibitory control (Austin 
et al., 2014), posited as a key mechanistic aspect of varenicline’s established efficacy for tobacco cessation. 
Varenicline improves attentional control among healthy non-smokers (Mocking et al., 2013) and smokers in a 
state of nicotine withdrawal (Patterson et al., 2009). In summary, the extant literature in animal and human 
models of substance use disorders, including CUD, reliably demonstrates that deficits in executive functionthat 
are associated with the ongoing maintenance of drug use may be amenable to treatment with varenicline. 
Comorbidity of Cannabis and Tobacco Use Disorders. Cannabis and tobacco use often co-occur (SAMHSA, 
2015), and approximately half of adults seeking treatment for cannabis use also use tobacco (Peters et al., 
2012). Individuals using both cannabis and tobacco have been shown to have more psychosocial problems 
(Moore & Budney, 2001) and worse cannabis use treatment outcomes (de Dios et al., 2009; Gray et al., 2011; 
Moore & Budney, 2001) than individuals using cannabis alone. However, to date, limited research has focused 
on interventions targeting both cannabis and tobacco use. Given its proven efficacy in tobacco cessation, it is 
possible that varenicline may improve both cannabis and tobacco use outcomes in co-using individuals. Of note, 
though, in the work of Litten and colleagues (2013), the impact of varenicline on drinking was similar for smokers 
and nonsmokers, suggesting that varenicline’s efficacy in this population was independent of its tobacco 
cessation effects.  
Adherence and Varenicline Treatment Outcomes. An evaluation of varenicline adherence found that of 1,477 
patients prescribed varenicline for smoking cessation, only 24% were adherent to the three-month course of 
therapy (Liberman et al., 2013). Importantly, adherent individuals were 93% more likely to quit smoking than 
non-adherent or partially adherent individuals. Similarly, Catz and colleagues (2011) found in the COMPASS 
trial that good adherence to varenicline was associated with a two-fold increase in 6-month smoking quit rates 
compared with poor adherence (52% vs. 25%). An analysis of factors that influenced adherence in the 
COMPASS trial found the most frequently endorsed reasons for premature medication discontinuation were side 
effects and perceived lack of need (Catz et al., 2011). These findings suggest that adherence interventions 
providing timely side effect management and encouraging longer term use of medications are needed to 
maximize treatment effectiveness.  
Summary and Scientific Premise. There is a critical need to develop safe and effective medications for CUD. 
Impairment in executive function is observed across substance use disorders and is particularly relevant to CUD 
(Cabrera et al., 2016; Curran et al., 2016). Inhibitory control, a clinically important and measurable component 
of executive function, is (a) impaired in CUD (Filbey & Yezhuvath, 2013; Nicholls et al., 2015; Tapert et al., 2007), 
(b) reliably measured by our team (Froeliger et al., 2012, 2013; Preliminary Data), (c) predictive of substance 


Program Director/Principal Investigator (Last, First, Middle):  McRae-Clark, Aimee                                                                                  3 
 
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use disorder cessation outcomes (Moeller et al., 2016), and (d) a known key component of varenicline’s 
mechanism (Austin et al., 2014; Lotfipour et al., 2012). Varenicline’s application to individuals with CUD 
represents a mechanistically intriguing avenue of research, with potential promise of improving clinical outcomes. 
We thus propose an initial UG3 proof-of-concept trial focused on functional imaging to evaluate mechanism as 
well as to collect preliminary clinical outcome data on varenicline’s impact of cannabis-related withdrawal and 
cannabis use.  If warranted by positive UG3 findings, a subsequent fully-powered UH3 trial will comprehensively 
evaluate safety and efficacy.  The UG3/UH3 mechanism is ideally suited to efficiently yet thoroughly evaluate a 
medication with strong rationale but no prior trials within the target population.  
Even if the UG3 “proceed-or-not-proceed” hypothesis is refuted, the UG3 would cost- and time-effectively provide 
a wealth of functional imaging and behavioral data important to broadening our understanding of CUD and 
potential pathways for pharmacological treatment.  If, instead, the UG3 hypothesis is supported, we would be 
able to efficiently proceed with a fully powered trial to comprehensively evaluate varenicline’s safety and efficacy 
in CUD.   
B. INNOVATION 
The proposed research is innovatively designed to efficiently and strategically evaluate varenicline as a 
promising candidate pharmacotherapy for CUD. The UG3 proof-of-concept trial incorporates advanced 
functional neuroimaging to evaluate varenicline’s effects on inhibitory control and cannabis cue reactivity, with 
clear criteria to determine whether or not to proceed with the fully-powered UH3 clinical trial to comprehensively 
evaluate varenicline’s safety and efficacy for CUD.  This innovative approach is consistent with the field’s 
emerging use of neuroimaging to assess the effectiveness of substance use disorder treatments (Cabrera et al., 
2016). In both trials, an advanced medication adherence system will be utilized to both accurately measure 
adherence as well as enhance medication taking behavior throughout the trial. 
C. RESEARCH DESIGN 
Capacity of Research Team. Completion of the proposed research will require experience with recruitment and 
retention of individuals with CUD, varenicline clinical trial management, administration of neurocognitive tasks 
and cannabis cue reactivity within functional magnetic resonance imaging (fMRI) paradigms, and adherence 
monitoring. As detailed below, the research team has a proven track record in these research areas. The 
proposed project will be co-directed by Drs. Aimee McRae-Clark and Kevin Gray, productive clinical researchers 
with NIH-funding primarily focused on clinical trials and human laboratory work with cannabis and tobacco using 
individuals. Co-investigators will also contribute meaningfully to the conceptualization, conduct, and reporting of 
this research. Dr. Brett Froeliger leads multiple NIH-funded projects utilizing fMRI techniques to characterize the 
impact of drug use on neurocognition and to predict clinical outcomes. Dr. Lindsay Squeglia has expertise in 
cannabis cue reactivity paradigm development and fMRI modeling of cue induced craving.  
Experience with Recruitment and Retention of Individuals with CUD. Dr. McRae-Clark has completed 
multiple NIH-funded studies involving cannabis using individuals (McRae-Clark et al, 2009; McRae-Clark et al, 
2010; McRae-Clark et al. 2015; McRae-Clark et al., 2016). Dr. Gray also has led multiple trials assessing 
medications in individuals with CUD, including the recently completed NIDA Clinical Trials Network Achieving 
Cannabis Cessation—Evaluating N-Acetylcysteine as a Treatment (ACCENT) protocol (Gray et al., 2012; 
McClure et al., 2014). We have an active recruitment network in place, and have been able to consistently 
surpass recruitment goals.  
Varenicline Clinical Trial Management. Drs. McRae-Clark and Gray have significant experience in the 
management of individuals receiving varenicline, both clinically and in the context of research protocols (Gray et 
al., 2012; Gray et al., 2015; Hartwell et al., 2013; McClure et al., 2015). Dr. Gray is currently conducting a clinical 
trial assessing the safety and efficacy of varenicline in an adolescent population (U01DA031779; PI: Gray) as 
well as a trial examining the combination of varenicline and N-acetylcysteine for smoking cessation 
(R01DA038700; PIs: Froeliger, Gray, and Kalivas). 
Neurocognitive Tasks. In an ongoing laboratory study (R01DA033459), Drs. Froeliger and Gray are examining 
relations between corticothalamic neural circuitry mediating IC (Rae et al., 2015) and the ability to refrain from 
smoking behavior during a laboratory-based smoking resistance task (SRT). Sated smokers (n=26) were first 
fMRI scanned while performing the GoGo/NoGo task that is proposed herein (Chikazoe et al., 2009), a well-


Program Director/Principal Investigator (Last, First, Middle):  McRae-Clark, Aimee                                                                                  4 
 
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validated probe of IC and a 
process posited to be a 
transdiagnostic factor of 
relapse 
vulnerability 
(Moeller et al., 2016).  
Immediately following the 
fMRI 
phase, 
smokers 
performed the SRT in 
which 
a 
monetary 
contingency is in place to 
refrain from smoking while 
being 
presented 
with 
smoking 
cues 
in 
the 
laboratory for up to one 
hour. 
When 
smokers 
elected to smoke in favor 
of 
earning 
money 
to 
remain abstinent, smoking topography (e.g., # of puffs) was recorded and relations with fMRI BOLD signal 
examined. We found that worse task performance (Fig 1, Box A: R=.41, p=.04) and exaggerated BOLD response 
in R. IFG (Fig 1, Box B: t= 3.54, p<.05) predicted smoking sooner during the SRT; weaker task-based functional 
connectivity in corticothalamic circuitry (Fig 2, Box C) predicted smoking more heavily upon initiation. These 
findings are consistent with the literature demonstrating that dysregulated prefrontal function during IC is 
predictive of worse treatment outcomes (Moeller et al., 2016), yet also extends the literature by linking the 
corticothalamic pathway (Jahanshahi et al., 2015) to the ability to resist drug use.  
Cannabis Cue Reactivity (CR). Drs. McRae-Clark and Gray 
have developed CR paradigms and demonstrated an ability to 
elicit cannabis craving in both adult (McRae-Clark et al., 2011) 
and adolescent (Gray et al., 2008) populations, and have 
experience with fMRI evaluation of varenicline’s effects on 
tobacco cue reactivity (Hartwell et al., 2013). Recently, Drs. 
Squeglia and Gray have developed a cannabis fMRI CR task, 
with cues relevant to US populations, to investigate cue-elicited 
activation. Cannabis and neutral images were matched on 
factors such as color, complexity, and context. A mix of active 
(e.g., smoking a joint) and passive (e.g., cannabis plant) pictures 
were used. Data were collected in a pilot study of 25 regular, 
heavy cannabis users (48% women, mean age = 18.7  0.51; 
using cannabis twice daily on average). Analysis of the fMRI data 
showed significant activation (voxel-level z=3.7, p=.0001; cluster-corrected p<.05) in bilateral medial prefrontal, 
striatum, anterior cingulate, subcallosal, precuneus, and posterior cingulate cortex during the cannabis vs. non-
cannabis neutral cues (see Figure 2). These results are consistent with those found in a Dutch-specific cannabis 
CR task (Cousijn et al., 2013) and a tactile cannabis task (Filbey et al., 2009), suggesting the cannabis cues 
developed for this task were effective at eliciting increased activation in brain regions involved in reward 
processing. Advantageously, this task displays cues relevant to American cannabis users, covers a range of 
cannabis use methods, and does not require a tactile component. 
Adherence Monitoring.  All varenicline and placebo tablets will be dispensed in bottles equipped with a MEMS 
6 TrackCap.  In addition, subjects will record themselves taking their morning and evening medication doses and 
then submit these videos to research staff via RedCap survey. Subjects may use their personal smartphones for 
video submission.  If they do not have a smartphone, one will be loaned to them during the course of the study, 
as video submissions may only be completed on a smartphone (cannot be completed on a computer).  A survey 
link will be sent to the subject via text message twice daily.  Video capture will occur as part of the RedCap 
Figure 2. Robust activation was elicited from 
cannabis, compared to neutral, stimuli in heavy 
cannabis users in reward regions including the 
medial prefrontal cortex and anterior cingulate 
highlighted below (n=25). 
 
Box A. IC-Behavior - Smoking        Box B. IC-BOLD - Smoking       Box C. tbFC – Smoking 
Behavioral Correlate                                 Functional Correlate                           Corticothalamic correlate 
 
Figure 1. Dysregulated inhibitory control mechanisms subserve drug-use behavior.  Worse task 
performance (Fig x, Box A: β = 0.08, R2 = .20) and exaggerated BOLD response in right IFG (Fig x, BoxB: 
β= -1.7, R2 = .35) predict smoking sooner during the SRT. Using the functional defined rIFG (Box B) as a 
seed (Box C-red cluster) in a task-based functional connectivity (tbFC) analysis, weaker connectivity with the 
thalamus (Box C-green cluster: -corticothalamic circuit) predicted smoking more heavily upon initiation; 
including # puffs (r=-.44, p=.02), total puff volume (r=-.51, p=.008) and total puff duration (r=-.46, p=.018).  
Significance for fMRI statistics was defined at α = .05 (Monte Carlo: p<.005;). 
0
10
20
30
40
50
60
70
80
90
100
0
20
40
60
NoGo Accuracy (% correct)
Time to Smoke (min)


Program Director/Principal Investigator (Last, First, Middle):  McRae-Clark, Aimee                                                                                  5 
 
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survey.  Videos are automatically stored on some Android smartphones, and participants will be informed of that 
so they can delete the files, if necessary.  Participants using iPhones (and using loaner iPhones from our group) 
will not have stored videos on their phone and nothing will need to be deleted. 
Research Design and Methods. The first phase (UG3) is a proof-of-concept pilot study to test mechanistic 
hypotheses and preliminarily evaluate safety and initial efficacy of varenicline in cannabis using individuals. 
Clearly defined milestones, focused on varenicline versus placebo reduction in cannabis related outcomes, will 
be met before proceeding to Phase 2 (UH3), a fully powered clinical trial to assess clinical outcomes to potentially 
advance the FDA approval of varenicline for the treatment of CUD.  
UG3 Overview. As shown in Figure 
3, if there is scanner availability 
within approximately 2 weeks, fMRI-
eligible individuals with CUD will 
complete an initial fMRI paradigm 
including GoGo/No-Go inhibitory 
control and cannabis cue reactivity 
tasks. Subjects who are not fMRI 
eligible 
or 
are 
unable 
to 
be 
scheduled for scanning within 2 weeks of screening will complete these same behavioral scanner tasks via 
computer in the clinic (pre- and post-varenicline versus placebo treatment).  All participants will  be randomized 
to a proof-of-concept six-week course of varenicline or placebo treatment, an abbreviated course chosen to 
efficiently detect mechanistic and preliminary clinical signals of varenicline’s effects (Gray et al., 2015; Saladin 
et al., 2015). Cannabis use outcomes (urine cannabinoid tests and self-report) will be measured at twice weekly 
clinic visits, and at a post-treatment follow-up safety visit. A repeat fMRI session will be completed with eligible 
individuals who completed an initial scan at the end of the 6-week treatment period to evaluate varenicline versus 
placebo differences in inhibitory controland cannabis cue reactivity.  
Participants. A total of 72 participants with CUD, aged 18 and over and using cannabis at least 3 days per week, 
will be recruited over an 18-month period. Additional inclusion criteria include consent to random assignment, 
ability to read and provide informed consent, and interest in CUD treatment. Exclusion criteria include women 
who are pregnant, nursing, or planning to become pregnant during the course of the study; having a history of 
bipolar, psychotic or medical disorder that would limit ability to participate; and meeting criteria for any moderate 
or severe non-cannabis substance use disorder. Detailed inclusion/exclusion criteria are in Human Subjects. 
Recruitment. Recruitment is planned to occur through both clinical referral and advertising. This approach has 
been used effectively for years in large-scale CUD clinical trials at MUSC.  
Procedures. 
Strategies to Ensure a Robust and Unbiased Approach. As detailed throughout this section, the proposed study 
will achieve robust and unbiased results via several design features including: explicit inclusion/exclusion criteria; 
randomization of treatment condition; placebo control; blinding; use of validated measures and methods; explicit 
hypotheses and corresponding planned statistical analyses; power estimates; planned handling of 
retention/attrition and missing data; objective adherence monitoring; and careful consideration of potential 
confounds.  
Screening and Eligibility Assessment. Individuals will be screened by the research study intake coordinator. An 
initial pre-screen, focused on inclusion/exclusion psychiatric diagnoses, medical status, current medication 
regimen, and ability and willingness to commit to completion of study procedures, will be used to initially 
determine potential study eligibility. Interested individuals will be given a full description of the study procedures 
and asked to read and sign an IRB-approved informed consent form before participating in a detailed, 
comprehensive screening and assessment phase.  
Diagnostic/Descriptive Assessment. The MINI International Neuropsychiatric Interview (MINI) will be used to 
assess psychiatric and substance use diagnoses. A medical history, physical exam, laboratory assessment 
(comprehensive metabolic panel and complete blood count) will be completed. An fMRI safety screening 
DAY 
3
0
7
42
0.5 mg qAM 
0.5 mg BID 
1 mg BID 
Varenicline (VAR)/Placebo 
49
Screening/ 
Assessment 
Post-
Treatment 
Follow-Up 
fMRI 1 
Twice-weekly clinic visits  
(UDS, self-report, medication management) 
fMRI 2 
Figure 3. 


Program Director/Principal Investigator (Last, First, Middle):  McRae-Clark, Aimee                                                                                  6 
 
Version date 3.12.2018 
 
questionnaire will be conducted to determine if the individual is eligible to undergo the fMRI scanning portion of 
the study. In the event that an individual is found to be ineligible to participate in this research protocol completely, 
he or she will be given an appropriate referral for further medical care or to an appropriate treatment program.  
If found eligible, a randomization visit, including fMRI scanning session if eligible, will be scheduled, and ongoing 
cannabis use will be tracked between initial assessment and randomization. 
Treatment Assignment. Eligible individuals will be randomized to receive double-blind varenicline or matching 
placebo. Randomization (stratified on gender and smoking status) and dispensing will be performed by the 
MUSC Investigational Drug Service, a centralized research pharmacy that compounds and manages clinical trial 
medications. Matching varenicline and placebo tablets will be provided by Pfizer, at the standard recommended 
dose of 0.5mg daily for three days, then 0.5mg twice daily for four days, and then 1mg twice daily for the 
remainder of the six-week treatment period. If necessary, medication dose may be reduced to 0.5mg twice daily 
for tolerability. Medication treatment will be initiated following completion of the fMRI paradigm and/or baseline 
visit.  
Scan sessions. If there is scanner availability within approximately 2 weeks, participants who qualify for fMRI 
procedures will undergo two fMRI scans (pre- and post-varenicline versus placebo treatment). In order to 
facilitate ease of scanner scheduling, subjects’ scanning and initial therapy session visit may be conducted on 
separate days if needed.  Subjects will be instructed to abstain from cannabis and alcohol for a minimum of 12 
hours prior to scanning to avoid acute intoxication during procedures. Breath (to determine carbon monoxide 
and alcohol levels) and urine toxicology samples will be collected before each scan. In addition, participants will 
also be asked to provide a saliva sample to verify abstinence from recent cannabis use through use of 
SalivaConfirm® testing (Confirm Biosciences, Inc.). Pre- and post-fMRI state craving measures will be collected. 
Each imaging session will include a resting-state, inhibitory control, and cannabis cue reactivity task scan and 
last approximately 60 minutes total. 
T1-weighted structural: A high-resolution anatomical scan (magnetization prepared rapid gradient echo) will 
be acquired to allow subsequent registration to functional images and region-of-interest (ROI) definition 
(parameters: repetition/echo time (TR/TE)= 1900/2.26 ms; flip angle (FA)= 9°; field of view (FOV)= 256 mm2; 
voxel size= 1 mm2; 192 contiguous 1-mm-thick slices). 
Resting–state functional connectivity (rsFC): The resting-state scan consists of a 6-minute, eyes-closed 
period. Similar to our previous work (Froeliger et al., 2015), rsFC will be assessed using the conn13 SPM8 
toolbox. First, experimental design variables, pre-processed functional images will be filtered with a 0.01 to 0.08 
Hz band-pass filter and normalized (modulated to preserve volume). 5-mm spheres will be created around MNI 
coordinates for a priori regions of interest (ROIs) that include: insula, nucleus accumbens, dACC, rACC and 
inferior, middle and superior frontal gyri. The conn13 toolbox uses PCA to isolate potentially confounding noise 
from nuisance covariates using default settings. Individuals’ white matter and CSF templates, in-scanner heart-
rate (HR), respiration rate and movement parameters will be included as covariates. Connectivity matrix for each 
seed will be entered into separate 2 (Varenicline: Yes, No) x 2 (Time: Scan1, Scan2) ANOVA models. We will 
follow-up with exploratory whole brain analyses. 
GoGo/NoGo Inhibitory Control (IC) Task. During the inhibitory control task, which will be the main task of 
interest in determining whether or not to proceed from the UG3 mechanistic proof-of-concept project to the fully-
powered UH3 clinical trial, fMRI BOLD response will be collected from participants as they perform a 
“GoGo/NoGo” task (Chikazoe et al., 2009). Participants are instructed to press a button in response to common 
(75% of trials) and rare (12.5%) Go stimuli while inhibiting responding to rare NoGo stimuli (12.5%). The task 
provides errors of omission and reaction times during Go trials, and errors of commission on NoGo trials. 
Behavioral performance data will be analyzed in SAS. fMRI task data will be entered into a first-level, whole-
brain analysis using the General Linear Model to examine BOLD response to each of the 5 trials of interest: 
NoGocorrect, NoGoincorrect, RareGocorrect, RareGoincorrect, and Goincorrect. Each event will be modeled as a delta 
regressor (onset dur. = 0) and convolved with a canonical hemodynamic response function. Motion will be 
removed through rigid body rotation and translation and parameters included as covariates. A high-pass filter 
(128 seconds; .008 Hz) will be applied to remove slow signal drift.  


Program Director/Principal Investigator (Last, First, Middle):  McRae-Clark, Aimee                                                                                  7 
 
Version date 3.12.2018 
 
 
The Cannabis Cue Reactivity (CR) Task. During the cannabis cue reactivity task, participants are shown 
pseudorandomly interspersed images of cannabis (i.e., cannabis plant, cannabis-related paraphernalia) and 
neutral (e.g., pine cone, trumpet) images, visual control images 
(i.e., blurred images), and a fixation cross (see Figure 4). The 
cannabis stimuli were matched by color, hue, and complexity. 
Blurred images and the fixation crossed trials are used as contrasts 
to evaluate attention and non-cannabis specific effects. Based on 
pilot data (see above), this task reliably activates reward regions, 
including bilateral medial prefrontal, striatum, anterior cingulate, 
subcallosal, precuneus, and posterior cingulate cortex in heavy 
cannabis-users. Stimuli are presented in six 120-s epochs, each 
consisting of four 24-s blocks of an image type (one block each of 
cannabis, non-cannabis control, and fixation). Each block is 
followed by a 6-s washout period, allowing the hemodynamic 
response from the previous block to decline before the next is 
presented. A 12-m gradient-echo EPI sequence will be acquired 
(parameters: repetition/echo time (TR/TE)= 2200/35 ms; flip 
angle  (FA)= 90°; field of view (FOV)= 220 x 220 mm; voxel size= 
3.00 x 3.00 mm; 37 contiguous 3-mm-thick slices). A magnetic fieldmap will also be acquired to allow geometric 
unwarping and cost-function masking of EPI images induced by magnetic field inhomogeneities.  
Psychosocial Treatment. All participants will receive brief motivational enhancement therapy consisting of three 
individual sessions. The first session will occur  during the first week of medication administration, and the second 
session will occur approximately one week later. Sessions will incorporate use of a personalized feedback report 
summarizing the participant’s problems related to use, reasons for quitting, and high-risk situations for use. The 
major goals of the first session will be to build rapport, identify issues related to health behavior change, and 
goal setting. The second session will focus on assessment/review of goals and barriers to goal achievement. 
The third session will occur at approximately Week 4 and will be used to follow-up on action plans. We have 
successfully used a similar intervention in previous cannabis treatment studies (McRae-Clark et al, 2009; 
McRae-Clark et al, 2010; McRae-Clark et al. 2015) to provide an evidence-based treatment platform for all 
participants.  
Assessments. Table 1 provides an overview of assessments with a brief description of the instruments below. 
 
SCR 
fMRI1/ 
RAN 
Wk1 
Wk2 
Wk3 
Wk4 
Wk5 
Wk6/ 
fMRI2 
FU 
Pre-screen, MINI, H&P, CBC/CMP 
× 
 
 
 
 
 
 
 
 
Self-Efficacy, Reasons for Quitting 
× 
 
 
 
 
 
 
 
 
Marijuana Problem Scale, CGI-S 
× 
 
 
 
 
 
 
× 
× 
Urine Pregnancy Test 
× 
× 
 
 
 
× 
 
× 
 
TLFB, HAM-A, HAM-D, C-SSRS, MCQ, CWS, PSQI 
× 
× 
× 
× 
× 
× 
× 
× 
× 
Barratt Impulsiveness Scale 
× 
 
 
 
 
 
 
× 
 
Urine Drug Test, Carbon Monoxide & Alcohol Breathalyzers 
× 
× 
×× 
×× 
×× 
×× 
×× 
×× 
× 
Saliva Drug Test 
 
× 
 
 
 
 
 
× 
 
Urine Cotinine  
× 
 
× 
× 
× 
× 
× 
× 
× 
Adverse Events, ConMeds, Medication Management 
× 
× 
× 
× 
× 
× 
× 
× 
× 
RedCap, Pill Count 
 
 
× 
× 
× 
× 
× 
× 
 
SCR=Screen, RAN=Randomization, FU=Follow-Up 
 
1.  Screening and Diagnostic Instruments. Pre-Screen: This assessment will be used to determine whether an 
individual is likely to meet inclusion or exclusion criteria for the study when they first present. The instrument is 
designed to assess for substance use disorders and obvious psychiatric, medical, and logistic exclusions. Mini-
International Neuropsychiatric Interview (MINI): The MINI is a brief structured interview that was designed to 
assess DSM-5 diagnoses using a series of questions in dichotomous format (yes/no) (Sheehan & Lecrubier, 
Figure 4. Cannabis cue reactivity paradigm with active and 
passive cues. BOLD response during cannabis (e.g., 
cannabis plant, joint) vs. neutral (e.g., pine cone, trumpet)
cues will be the main contrast of interest. 


Program Director/Principal Investigator (Last, First, Middle):  McRae-Clark, Aimee                                                                                  8 
 
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2003; Sheehan et al, 1998).  
2.  Psychiatric and Functioning Assessments. Clinical Global Impression of Severity Scale (CGI-S): The CGI-
S (Guy, 1976) is used to record the severity of illness at time of assessment on a scale of 1 (normal, no illness) 
to 7 (among the most extremely ill patients). Hamilton Anxiety and Depression Rating Scales (HAM-A & 
HAM-D): These validated scales assess severity of anxiety and depressive symptoms (Hamilton, 1959, 1960). 
Barratt Impulsiveness Scale (BIS-11): This questionnaire is designed to assess the personality/behavioral 
construct of impulsiveness (BIS-11; Patton et al., 1995).  Pittsburgh Sleep Quality Index (PSQI): The PSQI is 
a standardized measure of sleep quality that assesses a variety of sleep disturbances over the past week or 
month (Buysse et al., 1989). Columbia-Suicide Severity Rating Scale (C-SSRS): The C-SSRS (Posner et al., 
2011) is a brief, low-burden suicide assessment scale administered by a clinician. We have successfully used 
this instrument in multiple previous trials, and it is regarded as the gold standard of suicidality assessment in 
clinical trials.   
3. Substance-Related Instruments. Time-Line Follow-Back (TLFB): The TLFB (Sobell & Sobell, 1992) is a 
calendar-based instrument designed to assess daily substance consumption. Although initially designed to 
assess alcohol use, we have successfully modified this instrument to assess for other drug use. Cannabis use 
will be recorded as times used per day, with each time being defined as cannabis use separated by an hour of 
no cannabis.  We will use established methods to standardize for different types of cannabis use (joints, bowls, 
blunts, etc.), as well as determining overall amount used per day. Tobacco, alcohol, and other substance use 
will also be assessed. Urine Drug Testing: The urine drug tests will qualitatively screen for the presence of 
opioids, cocaine, amphetamines, and benzodiazepines. Urine cannabinoid tests will be performed using the 
AXSSYM® system from Abbott Laboratories. This assay is semi-quantitative with a detection cut-off value of 
30.00 ng/ml (Abbott AXSSYM® System package insert). Urine creatinine will also be obtained, as creatinine 
normalization has been proposed as a method to differentiate new cannabis use from residual drug excretion 
(Huestis and Cone, 1998; Schwilke et al, 2011). Saliva Drug Testing: In addition to urine testing, participants 
will also be asked to provide a saliva sample prior to scanning sessions to verify recent abstinence from cannabis 
use through use of SalivaConfirm® testing (Confirm Bioscience, Inc.). This test is able to detect THC in saliva 
for up to 14 hours. Carbon Monoxide Breathalzyer: This method will be used during all study visits to detect 
residual levels of carbon monoxide from recent smoked tobacco or cannabis use. A “cut-off” of 8 parts per million 
will be used as a biological abstinence confirmation measure (SRNT Subcommittee on Biochemical Verification, 
2002). Urine Cotinine: Nicotine is metabolized to cotinine by the liver. Cotinine has a longer half-life than 
nicotine, and thus serves as a more reliable biomarker of cigarette smoking (Zevin et al., 2000). Consensus 
guidelines support urine cotinine testing to biologically confirm 7-day abstinence, with a recommended “cut-off” 
of 50ng/ml (SRNT Subcommittee on Biochemical Verification, 2002). In the UG3 trial urine cotinine will be 
measured at screening as biological confirmation of smoking status.  Urine cotinine measurement will be 
repeated weekly for those who are determined to be smokers. Marijuana Craving Questionnaire (MCQ): The 
MCQ (Heishman et al, 2001) is a Likert-based self-assessment of cannabis craving shown to be a valid and 
reliable instrument for measuring cannabis craving. The 12-item MCQ will be used, which has been constructed 
by selecting the three items from each factor of the full 47-item MCQ that exhibited the most within-factor 
reliability (Heishman et al, 2009). Cannabis Withdrawal Scale (CWS): The Cannabis Withdrawal Scale (Allsop 
et al, 2011) is comprised of 19 items for which participants rate severity of symptoms in the previous 24 hours. 
Marijuana Use Summary Sheet/Self-Efficacy Questionnaire/Marijuana Problem Scale/Reasons for 
Quitting Questionnaire: These worksheets, created by Stephens and colleagues (2000), will be used to gather 
information from participants to prepare personalized feedback reports  for use in the motivational enhancement 
sessions.  
4. Safety Assessment. Medication Management, Concomitant Medications, and Adverse Event 
Evaluation: Using our team’s established procedures, medication management, including tracking of 
concomitant medications, review and encouragement of cannabis abstinence and study medication adherence, 
and adverse event evaluation, will be led by the medical clinician. Adverse events (AEs) will be assessed serially. 
The type of AE, severity of AE, and the relationship to study medication will be recorded. AEs will be coded on 
a weekly basis using Medical Dictionary for Regulatory Activities (MedDRA) rules.  
5. Adherence. Pill counts will be completed at each clinic visit. Adherence will also be monitored using MEMS 6 


Program Director/Principal Investigator (Last, First, Middle):  McRae-Clark, Aimee                                                                                  9 
 
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Trackcaps.  In addition, as outlined previously, subjects will be asked to record and upload videos of themselves 
taking each medication dose via smartphone and RedCap. 
Follow-up plan. Following the 6-week trial, a post-treatment follow-up visit will occur, and participants will be 
referred for appropriate substance use management.. In the event that an AE occurs during the study, a 
participant will be followed until resolution. 
 
Primary and Secondary Outcome Measures 
Outcomes will be compared between participants randomized to receive double-blind varenicline versus 
placebo.  
The primary efficacy outcome will be cannabis withdrawal during active treatment, as measured by the negative 
affect items of the Cannabis Withdrawal Scale (items 5 [“I felt nervous], 6 [“I had some angry outbursts”], 7 [“I 
had mood swings”], 8 [“I felt depressed”], 9 [“I was easily irritated”], 15 [“Life seemed an uphill struggle”], 18 [“I 
felt physically tense”], restlessness (item 11, “I felt restless), and/or urge to smoke (items 1 and 10, “The only 
thing I could think about was smoking some cannabis” and “I had been imagining being stoned”). These items 
were chosen based on previous trials of varenicline in tobacco smoking cessation trials (Jorenby et al., 2006; 
Gonzales et al., 2006).   
Secondary efficacy outcomes will include a) cannabis use quantity (reduction between baseline and end of 
treatment); b) cannabis abstinence (weeks 3-6 of active treatment, after the initial 2-week grace period, inclusive 
of medication titration and initial targeted quit date); and c) cannabis craving as measured by the Marijuana 
Craving Questionnaire during active treatment. Cannabis abstinence will be defined based on values published 
by Schwilke et al. (2010) in which residual urinary excretion was modeled in chronic cannabis users, with gender 
and racial corrections for urinary creatinine excretion (Barr et al., 2005). As such, the criterion for abstinence will 
be set at 300 ng/mg CN-THCCOOH for African American male participants, 350 ng/mg CN-THCCOOH for non-
African American male participants and African American female participants, and 500 ng/mg for non-African 
American female participants. In exploratory fashion, we will additionally examine mood (Hamilton Depression 
Rating Scale [HAM-D]), anxiety (Hamilton Anxiety Rating Scale [HAM-A]), concentration (HAM-A item 5 [difficulty 
in concentration]) and sleep (Cannabis Withdrawal Scale items 12 [“I woke up early”], 14 [“I had nightmares 
and/or strange dreams”], and 17 [“I had trouble getting to sleep at night”]; HAM-D items 4-6 [initial, middle, and 
delayed insomnia]; HAM-A item 4 [insomnia]; and Pittsburgh Sleep Quality Index). 
Secondary safety outcomes will be a) the frequency of treatment-emergent adverse events (AEs), an approach 
similar to those of varenicline phase III smoking cessation studies (Gonzales et al., 2006; Jorenby et al., 2006); 
b) treatment-emergent adverse events leading to medication discontinuation and c) the occurrence of treatment-
related serious adverse events (SAEs). Adverse events will be assessed by trained clinicians with significant 
experience in varenicline clinical trial conduct. All AEs will be evaluated for potential causality to study drug 
treatment. Depression and anxiety will be reflected by HAM-D and HAM-A scales ratings, suicidality will be 
reflected via C-SSRS ratings.   
The exploratory mechanistic outcomes will include a) corticothalamic pathway BOLD response signal change 
from baseline during the fMRI inhibitory control Go-No Go task, b) corticolimbic negative affect pathway BOLD 
response signal change from baseline during the fMRI negative emotional cue reactivity task, c) 
mesocorticolimbic reward pathway BOLD response signal change from baseline during the fMRI cannabis cue 
reactivity task, and d) strength of resting state functional connectivity in relation to phenotypic differences (e.g., 
impulsivity as measured by the Barratt Impulsivity Scale, cannabis use disorder severity as measured by DSM-
5 criteria met for CUD by the MINI diagnostic interview, and trait-negative affect as measured by the HAM-A and 
HAM-D). 
 
Statistical Analysis  
Data Management Plan. All data will be entered into a standard software package. Macro programs will be 
written to check the data for logical consistency and values out of possible range. Quarterly database 
management and data integrity audits will be conducted. 


Program Director/Principal Investigator (Last, First, Middle):  McRae-Clark, Aimee                                                                                  10 
 
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Efficacy: Primary Analysis  
Categorical clinical and demographic variables will be assessed by chi-square tests of independence, while 
continuous variables will be assessed using Student’s t-test.  In addition to baseline group differences, 
preliminary analysis of baseline characteristics with negative affect/withdrawal and cannabis use outcomes of 
interest will examine significant correlates of abstinence functional deficits.  Characteristics significantly 
associated with these outcomes will be included as covariates in the initial stages of model development.  
Cannabis specific withdrawal and negative affect (Hamilton Anxiety Rating Scale [HAM-A], Hamilton Depression 
Rating Scale [HAM-D], negative affect component of Cannabis Withdrawal Scale [CWS]) will be measured at 
weekly visits during the treatment portion of the study. General linear mixed effects models will be developed to 
test the efficacy of treatment with varenicline as compared to placebo in reduction of measured withdrawal and 
negative affect during weeks 3-6.  Model assumptions will be verified using analysis of residual and appropriate 
transformations will be employed when necessary. 
Safety: Primary Analysis  
Similar to varenicline phase III tobacco cessation studies (Gonzales et al., 2006; Jorenby et al., 2006), we define 
a treatment-emergent adverse event as any adverse event occurring between treatment initiation and one week 
following treatment conclusion.  Non-inferiority analysis will be utilized to compare adverse event rates between 
varenicline and placebo groups (Piaggio et al., 2006). 
Secondary Outcomes Analyses  
Secondarily, we plan to preliminarily investigate the efficacy of varenicline, compared to placebo, in reducing 
cannabis use quantity (Timeline Follow-Back) and increasing the proportion of cannabis-abstinent participants 
(urine cannabinoid test, Weeks 3-6; abstinent definition provided above). A combination of self-reported cannabis 
use as well as negative urine cannabinoid tests (UCTs) during Weeks 3 through 6 will be sufficient to estimate 
cannabis use quantity changes and assign abstinence (yes/no) and assess the treatment effect on clinical 
outcomes.  General linear mixed effects models will be used to estimate changes in cannabis use and differential 
effects of treatment on the use patterns.  Logistic regression models will be used to assess continuous 
abstinence proportions across treatment assignments. Analysis models will be reported both unadjusted and 
adjusted for significant clinical covariates (determined as associated with abstinence from the baseline analysis 
as well as known clinical confounders). Additionally, we plan to analyze the effect of varenicline on weekly 
abstinence from cannabis across the full treatment course.  Generalized linear mixed effects models will be 
constructed to estimate treatment group differences in abstinence across the entire time course using the 
methods of generalized estimating equations (GEE).  Additionally, data on cannabis craving (MCQ) will be 
collected from all participants at weekly visits.  Generalized linear mixed effects models will be constructed to 
estimate treatment group differences in craving scores during the treatment phase of the study. 
 
To evaluate the impact of varenicline on inhibitory control, hypothesis testing will be conducted by (a) entering 
NoGocorrect -RareGocorrect contrast images into a 2 (Group: varenicline, placebo) x 2 (Time: Pre, Post) 
rmANOVA and examining within an IC mask that includes right inferior frontal gyrus, preSMA, thalamus and 
primary motor cortex, and (b) entering memory-load contrast images (1-0; 2-0) into a 2 (Group: varenicline, 
placebo) x 2 (Time: Pre, Post) rmANOVA. To evaluate the impact of varenicline on negative emotional cue 
reactivity, BOLD response during the negative emotional vs. neutral trials will be the primary contrast of interest 
to test hypotheses that varenicline reduces negative affect and BOLD response in the corticolimbic negative 
affect pathway [e.g. rostral anterior cingulate, amygdala]. To evaluate the impact of varenicline on cannabis cue 
reactivity, BOLD response during the cannabis vs. non-cannabis trials will be the primary contrast of interest to 
test hypotheses that varencline reduces marijuana craving and BOLD response in mesocorticolimbic reward 
pathway [e.g. dorsal anterior cingulate (dACC), ventral striatum]. Similar to Froeliger et al. (2015), fMRI 
functional-connectivity data analyses will be performed with conn14 toolbox for SPM12, and hypothesis testing 
will be conducted using ROI-ROI explorer to characterize mean rZ values between ROIs of interest (e.g., R. IFG 
and thalamus). Where significant differences are observed, parameter estimates (from task-based models) and 
mean rZ values (from connectivity models) from each ROI will be extracted and relations with clinical endpoints 
examined.  Additionally, parameter estimates and rZ values from each model will be evaluated as a potential 


Program Director/Principal Investigator (Last, First, Middle):  McRae-Clark, Aimee                                                                                  11 
 
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simple mediator in the efficacy pathway between varenicline and abstinence. Since the outcome variable 
(abstinence) in the mediation analysis is binary, we will rescale each coefficient according to the standard 
deviations of the predictor and outcome variables (MacKinnon et al., 1993). Small sample mediation has been 
shown to be unstable and thus we will resample with replacement 5000 times to create a bootstrapped 
confidence interval around the indirect effect (Bollen & Stine, 1990; Shrout & Bolger, 2002). When the indirect 
effect confidence interval does not contain zero, we will be able to state, with some certainty, that BOLD signal 
changes partially mediate the causal pathway between varenicline and cannabis abstinence.   
Gender and smoking status will be explored as a potential moderators of study outcomes (i.e., clinical and fMRI) 
through model interactions. Medication adherence (MEMS cap, RedCap video, and self-report) will be assessed 
across treatment assignment as well as included as an additional variable in the primary efficacy and secondary 
craving/withdrawal models to examine any potential impact adherence may have on study outcomes. RedCap 
and MEMS cap data will be utilized as the primary (most stringent) markers of medication adherence, and we 
will secondarily conduct analyses of concordance between these data and self-report adherence.  
Secondary Safety Analysis  
Of particular interest will be adverse events leading to medication discontinuation and the occurrence of 
treatment-related serious adverse events (SAEs).  We will specifically compare neuropsychiatric adverse events 
(assessed through psychiatric interview) using non-inferiority testing, as well as depression/anxiety (Hamilton 
Anxiety Scale [HAM-A] and Hamilton Depression Scale [HAM-D]) and suicidality (Columbia—Suicide Severity 
Rating Scale [C-SSRS]) ratings using one-sided 2-sample t-tests.   
Participant Retention Analysis 
Total number of treatment visits attended will be compared across treatment groups using a Poisson regression 
test, while the number of days retained will be assessed using Cox Proportional Hazards regression models. 
Missing Data and Attrition. Missing data in longitudinal studies can be a problematic feature but can be mitigated 
through study design considerations. In order to minimize missing data and study attrition, design simplification 
and enhanced communication between study staff and participants will be emphasized.  We will make every 
effort to prevent attrition (e.g., phone/text visit reminders, participation compensation, reinforcing adherence to 
the study protocol at each visit).  In addition, in keeping with the Intent-to-Treat Principle, we will make every 
effort to continue assessments for the entire course of randomized treatment, even among those who fail to 
adhere to randomized assignment or stop participating in the study assigned intervention. 
Continuation Milestone Criteria. The decision on whether or not to proceed with the subsequent UH3 fully-
powered clinical trial will rest upon findings specific to the effect of varenicline, relative to placebo, on a number 
of key markers of efficacy. Specifically, we hypothesize that participants receiving varenicline, compared to those 
receiving placebo, will demonstrate attenuated levels of reported withdrawal-related negative affect at the end 
of the treatment portion of the study.  This will provide evidence to support or refute our hypothesis regarding 
varenicline’s mechanistic role in CUD. In randomized clinical trials assessing the efficacy of varenicline as 
compared to placebo for the reduction in smoking behavior, withdrawal and craving, Gonzales et al (2006) and 
Jorenby et al (2006) found that varenicline was superior to placebo in the reduction of withdrawal (as well as use 
and craving).  Specific to withdrawal symptoms, those treated with varenicline as compared to placebo reported 
significantly less negative affect [Gonzales: Δ=-0.19; SEM=0.04; effect size (ES)=-0.30 and Jorenby: Δ=-0.13; 
SEM=0.04; ES=-0.21], less restlessness [Gonzales: Δ=-0.14; SEM=0.05; ES=-0.16 and Jorenby: Δ=-0.10; 
SEM=0.05; ES=-0.12], and reduced urges to smoke [Gonzales: Δ=-0.54; SEM=0.06; ES=-0.67 and Jorenby: 
Δ=-0.48; SEM=0.06; ES=-0.63] during study treatment. A) In keeping with these clinically relevant differences, 
we anticipate seeing effects equal to or greater than the more conservative of the two results (Gonzalez) in a 
CUD population.  Thus, meeting or exceeding these criteria will be used as the threshold for clinically relevant 
evidence that would trigger justification to proceed with the UH3 trial.  In addition to the primary outcomes, 
secondary clinical outcomes include both a reduction in cannabis use quantity and cannabis use abstinence at 
the end of the treatment portion of the study.  We hypothesize a greater reduction in cannabis use quantity and 
greater cannabis abstinence will be recorded in the group randomized to varenicline as compared to placebo.   B) 
A Cohen’s d effect size of ≥0.4 in the secondary outcome of cannabis use reduction and/or an Odds Ratio of 
abstinence ≥1.5 in the varenicline group as compared to the placebo group will be used as an additional threshold 


Program Director/Principal Investigator (Last, First, Middle):  McRae-Clark, Aimee                                                                                  12 
 
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for clinically relevant evidence that would trigger justification to proceed with the UH3 trial.  Meeting or exceeding 
the thresholds stated in A) and/or B) would provide the necessary clinical evidence justifying a fully powered 
efficacy clinical trial of varenicline as compared to placebo in the treatment of cannabis use disorder. 
Power Calculation and Sample Size 
The primary focus of the UG3 study is to assess whether varenicline, compared to placebo, will evidence equal 
or greater reductions in cannabis withdrawal-related negative affect during the final 4 weeks of treatment (after 
initial 2-week grace period, inclusive of medication titration and initial targeted quit date).  Assuming a strong 
correlation between withdrawal and negative affect measures taken weekly within each subject (rho=0.8), a 
sample of n=68 participants (34 in each treatment group) will have adequate power (80%) to detect a clinically 
relevant effect size of d=0.60 between the two groups.  With the stated sample size, similar between group 
differences (d=0.60) in weekly cannabis use quantity will be detectible between groups.  
 For the secondary abstinence analysis, the necessary sample size sufficient to estimate 50% of a fully-powered 
Phase 3 clinical trial for the abstinence endpoint will be determined. To show that treatment with varenicline will 
yield an abstinence rate at least 20% greater than placebo at the end of study treatment under the most 
conservative conditions, at a 15% placebo abstinence rate, a sample size of n=72 participants (n=36 per 
group) in each treatment assignment will provide 80% power with a type 1 error of 5% to detect this difference 
at the end of a fully-powered study.  Thus, 50% of the study sample would require 36 participants per treatment 
arm in the UG3 portion of the study.  Since we aim only to measure futility and do not plan on stopping for early 
efficacy, no alpha spending penalty has been incorporated into the study sample size.   
 
Design Considerations 
Comorbid tobacco use. As discussed above, individuals using both cannabis and tobacco have worse cannabis 
use treatment outcomes. Although data from a large RCT in alcohol using individuals found an effect of 
varenicline on drinking outcomes regardless of tobacco use status (Litten et al., 2013), it is possible that a 
differential effect of varenicline will be found among tobacco and non-tobacco using individuals with CUD. 
Therefore, in the initial UG3 trial, smoking status will be explored as a potential moderator of treatment response 
Consideration of gender as a biological variable. In contrast to findings for stimulant drugs, there does not appear 
to be a strong effect of menstrual cycle phase on response to cannabis (for review, see Terner and de Wit, 2006).  
However, our recent work revealed a significant gender by treatment interaction in individuals with CUD, with 
women randomized to buspirone having fewer negative urine cannabinoid tests than women randomized to 
placebo (p=0.007), and men randomized to buspirone having significantly lower creatinine adjusted cannabinoid 
levels as compared to those randomized to placebo (p=0.023) (McRae-Clark et al., 2015). These findings support 
the need to consider gender as a critical variable in treatment investigations; as such, gender will be explored 
as a potential moderator of treatment response.  
Inclusion of neuroimaging. Normalization of inhibitory control as well as reduction in cannabis cue reactivity may 
reflect key underlying mechanisms of varenicline’s effect on CUD. Further, findings may help establish which 
individuals may respond optimally to varenicline treatment.  
Timeline. The first three months will be used for staff training and preparing for study initiation. Eighteen months 
will be needed for participant recruitment and data collection. The final three months will be used for data 
analysis, determination of milestone accomplishment, and discussion with NIDA staff regarding progression to 
the UH3 phase. At a recruitment rate of approximately four participants per month (a rate consistently achieved 
in our prior studies), we anticipate no difficulty completing the study in this timeframe. 
 
PROTECTION OF HUMAN SUBJECTS 
RISKS TO THE SUBJECTS 
a. Human Subjects Involvement and Characteristics 


Program Director/Principal Investigator (Last, First, Middle):  McRae-Clark, Aimee                                                                                  13 
 
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Admission into the study is open to men and women and to all racial and ethnic groups, age 18-65. Seventy-two 
individuals with cannabis use disorder will be recruited primarily through clinical referrals and internet and 
newspaper advertisements. Inclusion/exclusion criteria that apply to all participants are listed below: 
 
General Inclusion Criteria  
       •   Must meet DSM-5 criteria for cannabis use disorder and use cannabis at least 3 days per week in the   
          last 30 days. 
• Must be between the ages of 18 and 65 years.  
• If female and of childbearing potential, must agree to use acceptable methods of birth control for the 
duration of the trial. 
• Must consent to random assignment, and be willing to commit to medication ingestion. 
• Must be able to read and provide informed consent. 
• Must have body weight >110lbs (50kg) and have BMI between 18 and 35kg/m2 
• Must function at an intellectual level and have knowledge of the English language to sufficiently  allow for 
accurate completion of assessments. 
Additional Inclusion Criteria for fMRI Eligibility 
       •   Must be right-handed. 
General Exclusion Criteria 
• Women who are pregnant, nursing, or plan to become pregnant during the course of the study. 
• Individuals with severe renal impairment (creatinine clearance less than 30 mL per minute). 
• Lifetime history of DSM-5 Bipolar I or II Disorder, Schizophrenia or otherpsychotic disorder.  Stably treated 
MDD, Dysthymia, GAD, Social Phobia, and Specific Phobia diagnoses are acceptable (i.e. same dose of 
medication  has been prescribed for at least 2 months prior to screening and no changes in current 
medication expected during course of the trial). 
• Suicidal ideation or behavior within the past 6 months. Subjects who are believed to be at suicidal or 
homicidal risk (answers ‘yes’ on questions 4 or 5 of C-SSRS) will be referred for assessment by a qualified 
mental health professional. 
• Concomitant use of psychotropic medications, with the exception of stable doses (defined as no dosing 
adjustments in the past two months) of non-MAO-I antidepressants, non-benzodiazepine anxiolytics, and 
ADHD medications. 
• Current use of medications prescribed for mania or psychosis. 
• Current use of buproprion or nortryptiline. 
• Moderate or severe non-cannabis substance use disorders within the past 60 days with the exception of 
tobacco use disorder. 
• Individuals taking an investigational agent within the last 30 days before baseline visit. 
• Individuals with clinically significant medical disorders or lab abnormalities. 
• Any individual at screening with SGOT (AST) or SGPT (ALT) greater than 3 times the upper limit of normal 
and/or total bilirubin greater than two times the upper limit of normal. 
• Individuals with clinically significant cardiovascular disease in the past 6 months (e.g., myocardial 
infarction, CABG, PTCA, severe or unstable angina, serious arrhythmia, or any clinically significant ECG 
conduction abnormality. 
• Individuals with clinically significant cerebrovascular disease in the past 6 months such as TIA, CVA, or 
stroke. 
• Hypersensitivity to varenicline.  
• Individuals who have participated in the clinical trial of any investigative compound within the last 60 days. 
 
 
 
 


Program Director/Principal Investigator (Last, First, Middle):  McRae-Clark, Aimee                                                                                  14 
 
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Additional Exclusion Criteria for fMRI Eligibility 
• Any psychiatric or medical issues, including claustrophobia, ferrous metal implants, pacemakers, or other 
electronic devices that would interfere with ability to participate in and successfully complete scanning 
procedures. 
• Any person unable to lie still within the fMRI scanner for the required period of time to obtaine useful 
images (use of anxiolytics will not be permitted for anxiety/claustrophobia related to scanning procedures). 
b. Sources of Materials 
Research material obtained from individual participants includes questionnaires and interviews with study 
personnel, and breath, blood, and urine samples. To ensure confidentiality, all participant data will be 
letter/number coded, and only the investigators will have access to the master lists of codes. The research 
material will be obtained specifically for research purposes.  Written research material obtained will be stored in 
the Addiction Sciences Division, in an office that is locked when not in use. Blood and urine samples will be 
stored in the Clinical Neurobiology Laboratory.  
c. Potential Risks 
The varenicline package insert details adverse events associated with the medication. Specifically, it reports that 
“the most common adverse reactions (>5% and twice the rate seen in placebo-treated patients) were nausea, 
abnormal (e.g., vivid, unusual, or strange) dreams, constipation, flatulence, and vomiting.” Meta-analyses of the 
four main adverse events in varenicline versus placebo groups in adult trials yielded relative risks (RRs) of 3.21 
(95% CI 2.71, 3.80) for nausea, 1.50 (95% CI 1.26, 1.79) for insomnia, 2.79 (95% CI 2.09, 3.72) for abnormal 
dreams, and 1.20 (95% CI 1.00, 1.45) for headache (Cahill et al., 2009). While post-marketing anecdotal reports 
of psychiatric adverse events led to an FDA “black box” warning for varenicline, a reanalysis of controlled trials 
revealed no evidence that varenicline is associated with neuropsychiatric adverse events (Thomas et al., 2015). 
There is a potential risk of loss of confidentiality. Exposure to cannabis cues and completion of the neurocognitive 
tasks may produce some craving for cannabis or other discomfort. However, this discomfort is usually brief and 
participants will be in the cannabis-free safety of a clinic environment. There is a chance that some of the pictures 
used in the negative affect task may cause some emotional distress. Since the scanner requires participants to 
be motionless in an enclosed environment, there is the possibility of a claustrophobic reaction or anxiety or 
discomfort secondary to being stationary for approximately 60 minutes per scan. Ferrous objects that are 
undetected could move during scans. This could lead to tissue damage and hemorrhage.  
ADEQUACY OF PROTECTION AGAINSTS RISKS  
a. Recruitment and Informed Consent 
Participants will primarily be recruited through clinical referrals and the use of advertisements (internet, 
newspaper). Participants may also be recruited from the Ralph H. Johnson VAMC and the College of Charleston. 
Medical records will not be reviewed to identify potential study participants unless patients have requested to be 
contacted through a research permissions registry.  A study PI, Co-I, or other qualified study staff will obtain 
informed consent. The informed consent form includes a detailed description of the study procedures, along with 
statements regarding participants’ rights to withdraw from the procedure at any time without consequences. The 
informed consent form will be explained to participants in easy-to-understand language, and participants will be 
instructed to read the form carefully prior to signing it.  Consent will be documented by the signature of the 
participant on the informed consent agreement, accompanied by the signature of the individual obtaining the 
consent. 
b. Protections Against Risks 
All study participants will be closely monitored for psychiatric and medical stability. All study procedures will be 
conducted under the supervision of experienced personnel. If crisis intervention is necessary during screening 
or study enrollment, senior staff will be available to evaluate the subject and provide an intervention or referral. 
In regards to suicidality, any participant endorsing suicidality on the C-SSRS (either during screening or at a 
subsequent study visit) will be assessed for safety by a psychiatrist.  If hospitalization is indicated, the patient 


Program Director/Principal Investigator (Last, First, Middle):  McRae-Clark, Aimee                                                                                  15 
 
Version date 3.12.2018 
 
will be hospitalized through MUSC or an appropriate referral will be made. All participants will be fully informed 
that they may withdraw from the study at any time without penalty.  
To ensure confidentiality, all participant data will be coded by letters and/or numbers, and only the investigators 
will have access to the master lists of codes.  All participant records will be kept in a locked cabinet in an office 
that will be locked at times when not in use. The research staff understands the importance of maintaining 
confidentiality, and this method of maintaining confidentiality has been used for several years by our research 
group and has been effective. All electronic databases are stored on HIPAA-compliant servers with restricted 
access. RedCap video clips will only be viewed by approved research staff and will be deleted when the study 
has ended and data analysis is complete. All co-investigators and study personnel have completed (or will 
complete upon hiring) training in Good Research Practices as mandated by the MUSC IRB. 
 
Participants will be taught about potential side effects of varenicline and will be closely followed by psychiatrists, 
a PharmD, and other members of the research team. Pregnancy tests will be performed prior to medication 
initiation and monthly during the study. Participants will be excluded if they have a known hypersensitivity to 
varenicline. Adverse events will be assessed at each clinic visit, and all participants will be provided with an after-
hours emergency contact number in the event that an adverse event occurs when the clinic is closed.  
If abnormalities in the brain images are found, a participant will be immediately referred to an appropriate clinical 
care provider. A careful metal screening history will be taken from each participant to assess the possibility of 
metal devices. Individuals will be screened with a metal detector for the possibility of implanted metal objects 
since magnetic movement of a metal device or metal injury could result in injury or risk to life. Prior exposure to 
pictures of the scanner, getting into the scanner, and seeing others in the scanner often reduces psychological 
discomfort or identifies people for whom scanning is not appropriate. Subjects are able to ask study staff to stop 
the negative affect scanning task at any time if they feel too upset by the pictures.  
POTENTIAL BENEFITS OF THE PROPOSED RESEARCH TO THE SUBJECT AND OTHERS 
Possible risks to study participants include adverse reactions to varenicline and risks associated with fMRI 
scanning. Benefits include detailed assessment of cannabis use and receipt of an evidence-based psychosocial 
treatment for cannabis use disorder. The minimal risks are reasonable in relation to the potential benefits to be 
gained from the investigation.    
IMPORTANCE OF THE KNOWLEDGE TO BE GAINED 
This study may help accelerate approval of varenicline for treatment of cannabis use disorder. Presently, there 
are no FDA-approved medications for cannabis use disorder. The moderate risks of the investigation are 
considered reasonable in relation to the expected knowledge to be gained.   
CLINICALTRIALS.GOV REQUIREMENTS 
In accordance with Public Law 110-85, this project will be registered at the ClinicalTrials.gov Protocol 
Registration System Information Website prior to study initiation.