Clinical trial NCT04139668
Conditions: Cannabis Use Disorder
Sponsor: Centre for Addiction and Mental Health
Start date: 2021-06-09; Completion date: 2022-06-13
Enrollment: 1 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to investigate the safety and effectiveness of 12 weeks treatment with an extended-release injectable form of naltrexone (Vivitrol) combined with a psychological intervention in 10 treatment-seeking adults with Cannabis Use Disorder. The hypotheses are that Vivitrol combined with a psychological intervention will be well tolerated, and will reduce cannabis use, improve abstinence rates, and reduce cannabis withdrawal and craving.

Detailed description:
This study will be an open-label trial, with no placebo control. Ten male or female treatment-seeking adults with Cannabis Use Disorder (CUD) will be recruited. All participants will receive 3 x 4ml intramuscular injections of Vivitrol (380mg naltrexone). Injections will be administered once every 4 weeks for 12 weeks. In addition, all participants will receive a weekly psychological intervention (Motivational Enhancement Therapy and Cognitive Behavioral Therapy; MET/CBT) for 12 weeks.

The aim of this study is to investigate if the proposed Vivitrol dosing schedule, combined with MET/CBT, is appropriate for subsequent randomized controlled trials in people with CUD. This will be achieved by assessing the safety and effectiveness of 12 weeks open-label treatment with Vivitrol (3 x 4 ml intramuscular injections, 380mg naltrexone) combined with weekly MET/CBT.

Safety will be assessed by monitoring adverse events during the 12 week treatment period, and up to 3 months follow-up. Effectiveness will be assessed after 12 weeks of treatment and at 3 month follow-up using: (1) seven-day point prevalence cannabis abstinence, (2) percentage of days of cannabis use, (3) amount of cannabis use, and (4) effects on withdrawal symptom scores, craving scores and number of urine samples screened positive for cannabis use.

Arms: arm 1: All participants will receive three 4ml doses of extended-release naltrexone 380mg (Vivitrol), administered by intramuscular injection. Three injections will be administered to each participant; one injection every 4 weeks for 12 weeks of treatment. In addition, all participants will receive weekly Motivational Enhancement Therapy and Cognitive Behavioral Therapy for 12 weeks.
Interventions: intervention 1: Naltrexone 380 MG [Vivitrol] intervention 2: Motivational Enhancement Therapy and Cognitive Behavioral Therapy
Intervention descriptions: intervention 1: Three 4ml intramuscular injections of naltrexone 380mg (Vivitrol) administered over 12 weeks (one injection every 4 weeks) intervention 2: Weekly Motivational Enhancement Therapy and Cognitive Behavioral Therapy (MET/CBT), based upon the Brief Counselling for Marijuana Dependence Manual published by the Substance Abuse and Mental Health Services Administration (SAMHSA), for 12 weeks

Protocol documents:
Prot_SAP_000.pdf: 
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VIVITROL ASSOCIATED WITH BEHAVIORAL-RELAPSE PREVENTION STRATEGY AS 
TREATMENT FOR CANNABIS USE DISORDER 
 
Principal Investigator:  
Bernard Le Foll, MD PhD  
Head Translational Addiction Research Laboratory, CAMH 
Co-Investigators: 
 
Tony George, MD 
 
 
 
 
Clinician Scientist, CAMH 
                                                    
                                                Benedikt Fischer, Ph.D 
                                                Chair in Addiction Research, University of Auckland 
 
Lena Quilty, PhD 
Psychologist and Independent Scientist, Clinical Research, CAMH 
 
Jose Trigo, PhD 
Senior Research Scientist, Battelle, Baltimore 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Principal Investigator Signature: _______________________  Date: _____________ 
 
 
 
 
 
 
 
 
 
 
(dd/mm/yy) 
 
 
Qualified Investigator Signature: _______________________  Date: _____________ 
 
 
 
 
 
 
 
 
 
 
                                                                      (dd/mm/yy) 
 
 
 


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INTRODUCTION 
 
Cannabis exposure, use disorders and treatment in North America 
Cannabis is the most widely used illicit substance worldwide [1]. Those who have used 
cannabis at least once (aged 15 to 64) are estimated to be 128-232 million, or 2.7 to 4.9% of the world’s 
population [2]. There is a high prevalence of use in North America and a gradual increase since 2007 
[2]. Cannabis use prevalence has important implications for public health [3-5] and its use has been 
associated with a variety of health problems including cognitive [6] and respiratory impairment [7], 
psychotic episodes [8], injury risk [9] and dependence [10, 11]. Research indicates that about 8% of 
those who ever use cannabis may develop cannabis dependence [12, 13]. However, there is currently 
no approved pharmacotherapy for cannabis dependence [14, 15]. Due to the significant impact of 
problematic cannabis use on individuals and society, and thereby, the increasing demand for treatment, 
several research teams have focused on developing medications for cannabis dependence treatment 
[14, 16]. These studies have mainly tested the potential utility of pharmacotherapies available for other 
indications (e.g. cannabinoid drugs, antidepressants, anxiolytics, and antipsychotics).  
 
 Cannabis use prevalence is important for public health [5, 17, 18], as it could be shown, that 
the number of problem users and cannabis-attributable problems depend on overall prevalence. 
Research indicates that about 10% of those who ever use cannabis become regular daily users [19], 
which in turn is a strong risk factor for any kind of cannabis-attributable health problems including 
cannabis use disorders.  In 2008, 4.2 million Americans had past year dependence or abuse, 
representing 1.7 percent of the total population aged 12+; this made up 60.1% of all illicit drug 
dependence or abuse.  In 2007, 15.8% of people entering drug abuse treatment programs in the UWS 
reported cannabis as their primary drug of abuse (61% of those under 15), representing nearly 288,000 
treatment admissions [20].  In Canada, where the study will take place, treatment for problematic 
cannabis use consists mainly of cognitive behavioral interventions. This is similar to the common 
practice in the US and worldwide. Despite the fact that this approach is similar for other psychoactive 
and no novel treatments have been added, a consistently increasing number of individuals with 
cannabis problems have been admitted to treatment.  Specifically, in the past decade, some 25 - 30% 
of admissions to publicly funded addiction treatment programs across Canada involved individuals with 
cannabis related problems [21, 22].  According to the Drug and Alcohol Treatment Information System 
(DATIS), admissions to publicly funded addiction treatment services in 2009/2010 in the province of 
Ontario, a 38.2% of total cases admissions involved cannabis as a problem substance [23], which 
represents an increase from previous reports [24].   
 
Interactions between Opioids and Cannabinoids  
Opioids and cannabinoids share some common characteristics on their ability to modulate pain, 
produce sedation, hypotension and motor depression [25-28]. In fact, opioids and cannabinoids have 
been shown able to modulate their function at many different levels including cross-tolerance, mutual 
potentiation, and receptor cross talk in pre-clinical models [25, 27-31]. Moreover, specific receptors for 
both the endogenous opioid system and the endogenous cannabinoid system (i.e., CB1 and μ-opioid 
receptors) have an overlapped distribution in the limbic system of rodents [32-34]. The intracellular 
signal response (i.e., G-protein activation) of μ-opioid receptors can be modulated by the stimulation of 
CB1 receptors [35, 36]. The administration of CB1 agonists is able to regulate the endogenous release 
of opioids [35, 37-41] and μ-opioid receptor density [42] and intra-accumbens infusions of the 
cannabinoid antagonist rimonabant decreased intravenous self-administration of heroin in rats [43]. On 
the other hand, it has been shown that the opioid antagonist naloxone was able to block THC-induced 
dopamine efflux in the NAc of rats [44]. In fact, studies have shown that opioid antagonists reduce both 
the discriminative stimulus and reinforcing effects of CB1 agonists [45-47], suggesting that opioid 
receptor antagonists could reduce cannabis abuse liability.  
 


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Based in the pre-clinical research mentioned above it is plausible to think that intervening in the 
endogenous opioid system might have consequences as well in the endogenous cannabinoid system 
and its function in humans (and vice versa; indeed, it has been shown that cannabinoids were able 
modulate opiate dependence [48, 49]). Therefore, several studies have tested the effects of different 
doses of naltrexone (0, 12, 25, 50, or 100 mg capsules) in cannabinoid effects both in marijuana 
smokers and nonmarijuana smokers [50, 51]. These early studies found that this oral form of naltrexone 
enhanced the subjective and cardiovascular effects of marijuana [51]. These effects seem to vary with 
marijuana use history [50, 51]. Those findings were surprising as the blockade of mu opioid receptor 
decreased reinforcing effects of THC in animals. More recently, it has been shown that chronic 
administration of naltrexone (e.g. 16 days) decreases cannabis self-administration and the subjective 
effects of cannabis in daily cannabis users [52]. Moreover, ongoing open label clinical trials are 
currently testing the effects of both long-acting injectable naltrexone (Vivitrol®) and oral naltrexone 
(Revia®, 50 mg per day) in cannabis-dependent patients (ClinicalTrials.gov Identifiers NCT02088177 
and NCT01560013, respectively). The duration of treatments in these trials is 2 months (2 injections) for 
Vivitrol® and 35 days for Revia®. The safety and effectiveness of long term (i.e. 12 weeks) injectable 
extended-release naltrexone has been recently tested in patients with opioid dependence showing 
promising results [53]. However, in spite of the evidence showing clear interactions between the opioid 
and the endocannabinoid systems, no randomized clinical trial has yet evaluated the long-term efficacy 
of long-acting naltrexone Vivitrol® (380 mg, 4 mL intramuscular injection) in cannabis dependent 
subjects that are treatment seekers in comparison with placebo.  
This project will test the safety and effectiveness of long term (i.e. 12 weeks) administration of 
the injectable extended-release of naltrexone; Vivitrol®. Vivitrol® is primarily used in the management of 
alcohol and opioid dependence. Naltrexone maintenance (e.g. oral) seems a promising treatment for 
cannabis use disorder (CUD). Therefore, administering Vivitrol® may have therapeutic properties for 
treatment of cannabis use disorder. The data collected will be used to ensure that the administration 
schedule we have planned for the subsequent future randomized clinical trials is appropriate. 
 
In this study we will focus on the tolerability and effectiveness of the antagonist at the μ-opioid 
receptor, Vivitrol®, to reduce cannabis use, increase abstinence rates and reduce cannabis withdrawal 
and craving. 
 
 
OVERVIEW 
The study will be open label, with no placebo control. Ten male and female subjects seeking 
treatment for cannabis dependence subjects will undergo study procedures as outlined below. 
Treatment with Vivitrol® will start at day 1 (week 1) and a target quit date will be set up at Day 7 (but 
subjects will be allowed to stop using cannabis before if they are willing and able to). There will be a 
total of 12 weeks (3 injections, 1 every 4 weeks) of exposure to Vivitrol®. Study visits will occur weekly 
during the medication phase of the study. Motivational Enhancement Therapy and Cognitive Behavioral 
Therapy (MET/CBT) will also start at Week 1 and therefore, all participants will receive a combination of 
pharmacotherapy (Vivitrol® 4 mL intramuscular injection) associated with MET/CBT for 12-weeks in 
accordance with the intervention practices shown to be effective in treatment of cannabis dependence 
[54]. The intervention will be adapted from the Brief Counseling for Marijuana Dependence manual 
published by the Substance Abuse and Mental Health Services Administration (SAMHSA). In addition, 
to ensure compliance a Contingency Management plan will be implemented with $5 voucher that will be 
provided at each visit that is attended and at which biological samples have been provided, but with 5$ 
voucher loss for a missed appointment. The vouchers will be provided at end of treatment phase and at 
end of the follow-up phase.    
At study visits, vital signs and self-report ratings will be collected. The subjects will have to come 
once per week (during treatment phase) to the center to assess cannabis and other substances usage 


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and will be asked to provide urine samples (see Summary of Study Assessments). As there may be 
compliance issues, a contingency management approach will be also implemented.  
Following the medication phase, participants will have a follow-up weekly for another four weeks and 
then monthly until the 3 month follow up visit after the treatment starting date. We are planning to enroll 
10 subjects.  
 
Study Flow Schema 
 
 
 
 
 
 
 
Subjects will be pre-screened initially during a telephone interview in which basic medical, psychiatric, 
and substance abuse histories will be obtained without personal identifiers, contact information will be 
collected only for eligible participants as for pre-screening. The qualified subjects will then be assessed 
using the Structured Clinical Interview for DSM 5 (SCID) and we will assess presence of CUD using 
DSM 5 criteria. We will enroll a total of 10 subjects, that will be treated open-label (non blinded) with 
Vivitrol 380 mg.  
 
 
Experimental group 
Experimental condition  
Group #1 (n=10) 
Vivitrol® 380 mg, 4 mL intramuscular injection + MET/CBT 
 
 
 
 
 
 
 
 
 
 
 
 


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Summary of Study Assessments 
 
Assessment 
Baseline 
Weekly 
(Weeks 1-12) 
Weekly 
(Weeks 13-16) 
Monthly 
(months 5-6) 
Informed Consent  
X 
 
 
 
Psychiatric Evaluation (including 
SCID) 
 
X 
 
 
 
 
DSM5 criteria for CUD 
X 
X (week 12 only) 
X (week 13 only) 
X (end of trial) 
Demographic 
X 
 
 
 
Bloodwork (including CBC), 
Urinalysis 
 
X 
X (prior to 2nd and 3rd 
Vivitrol injections) 
 
 
X (end of trial) 
EKG 
X 
X (week 1 only) 
 
X (end of trial) 
Physical Exam 
X 
 
 
X (end of trial) 
Urine Toxicology 
X 
X (before Vivitrol 
administration) 
X 
X 
Vital Signs, Carbon Monoxide 
X 
X 
X 
X 
Serum Pregnancy Test (Females 
only) 
X 
If needed 
If needed 
If needed 
Urine Pregnancy Test (Females 
only) 
X 
X 
X 
X 
FTND, Cigarette, alcohol and 
caffeine Time-line Follow-Back 
(TLFB) 
X 
X 
X 
X 
Smoking Diary 
X 
X 
X 
X 
Cannabis TLFB, Marijuana 
withdrawal checklist (MWC), 
Marijuana Craving Questionnaire 
(MCQ) 
X 
X 
X 
X 
Beck Depression Inventory-II 
(BDI-II), Hamilton Anxiety Scale 
(HAM-A),  Hamilton Depression 
Rating Scale (HDRS), Brief 
Psychiatric Rating Scale (BPRS), 
Profile of Mood States, Drug 
Effects Questionnaire (DEQ), 
Addiction Research Center 
Inventory marijuana scale, St 
Mary’s Hospital Sleep 
Questionnaire (SMHSQ) 
X 
X 
X 
X 
SAFTEE 
X 
X 
X (week 13 only) 
X (end of trial) 
ASI, World Health Organization 
Disability Assessment Schedule 
(WHODAS) 
X 
X (week 12 only) 
X (week 13 only) 
X (end of trial) 
Urine for THC metabolite analysis 
X 
X 
X 
X 
Vivitrol® administration 
 
X  
(once every 4 weeks) 
 
 
MET/CBT 
 
X 
 
 
 


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Trial Objectives and Purpose: 
                       
Primary and Secondary Outcome Measures 
Our primary outcome measures: 1) for tolerability will be the number of subjects that drop out because 
of SAEs and 2) for piloting efficacy will be the seven-day point prevalence cannabis abstinence at the 
end of medication phase and at the 3 month follow-up;  
 
Secondary outcome measures will be 1) percentage of days of cannabis use over the study duration 
until the 3 month follow-up; 2) amount of cannabis use over the study duration until the 3 month follow 
up.  3) effects on withdrawal symptoms scores, craving scores and number of urine samples screen as 
positive.  
Abstinence status will be also based on the urine samples collected during the trial. 
 
PRELIMINARY RESULTS 
A CUD treatment clinic has been set up at the Addiction Medicine Service (AMS)/Concurrent 
Outpatient Medical & Psychosocial Addiction Support Service (COMPASS) that is using the CBT-MET 
approach as standard of care. We have recruited subjects for pharmacotherapy trial for CUD at CAMH. 
Those preliminary results demonstrate the feasibility of recruiting the subjects for this study.  
 
METHODS: 
Subjects 
Inclusion criteria 
 
Adult (18-64) male or female (gender to be analyzed as a covariate)  
 
Understand and willing to comply with study requirements and restrictions 
 
Willing to use appropriate contraceptive method throughout the study  
 
Otherwise healthy as judged by investigator based on medical history, physical exam, 
vitals, ECG and labs 
 
DSM 5 criteria for current CUD 
 
Report cannabis as primary drug of abuse 
 
Have cannabis positive urine drug screen  
 
Treatment seeking cannabis smoker 
 
Exclusion criteria 
 
Meets DSM 5 diagnostic criteria for a current severe mental disorder, including 
substance-related and addictive disorders, other than CUD, tobacco use disorder, and 
caffeine-related disorders 
 
Unstable medical conditions 
 
Pregnant or breast-feeding 
 
Positive urine drug test for opioids (including methadone, morphine, buprenorphine) or 
benzodiazepines (unless prescribed) at baseline  
 
Any IM gluteal administration 30 days prior to baseline 
 
Participation in a clinical trial of a pharmacological agent within 30 days prior to baseline  
 
Known intolerance and/or hypersensitivity to naltrexone, carboxymethylcellulose, or 
polylactide-coglycolide 
 
Any finding that, in the view of the principal investigator, would compromise the subject’s 
ability to fulfill the protocol visit schedule or visit requirement (e.g. unadjudicated 
charges and/or pending parole hearings) 
 


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Pre-study Screening and Baseline/follow up evaluations and questionnaires that will be used:  
a) 
Structured Clinical Interview for DSM 5 severe mental disorders, including substance-related 
and addictive disorders, other than CUD, tobacco use disorder, and caffeine-related disorders.  
b) 
DSM 5 Criteria for CUD for the past month at baseline, end of treatment and end of follow-up 
c) 
Demographic assessments. 
d) 
 Psychiatric/Medical Evaluation and Physical Examination by study physician Weight (kg) and 
Vital Signs (Temperature, Pulse, Blood Pressure and Respiration Rate). Carbon monoxide will 
be taken at each study visit to assess exposure to smoke (will reflect both cannabis and 
tobacco exposure). 
e) 
 12-lead Electrocardiogram (EKG).  
f) 
Blood work, including complete blood count (CBC), electrolytes, renal and liver function tests 
will be carried out at baseline and prior to the 2nd and 3rd Vivitrol injections.  
g) 
For female subjects, a serum pregnancy test (beta-HCG) at inclusion (and when deemed 
needed) and weekly urine pregnancy test will be performed. Female subjects will be asked if 
they are lactating.  
h) 
 Ten-panel urine toxicology screen at baseline, and at each study visit to ensure absence of illicit 
drug use.  
i) 
 Substance use assessment including the age of first use, age of regular use, 
number of days in the past 30 days that the substance was used, number of days in the past 
week that the substance use used, and the amount of the substance used per using day (i.e. 
joints per day for cannabis). 
j) 
 Cannabis Use will be assessed by toxicology and self-report. Participants will provide a urine 
sample every week (see assessment schedule). The timeline follow-back (TLFB) will be used to 
assessing the number of days cannabis was smoked, the amount smoked, and the amount of 
money spent on cannabis since their last appointment.  Smoking diaries will also be completed 
daily outlining how much cannabis was obtained at a time, how many days that amount lasted, 
and what amount, if any, was shared.   
j) 
Addiction Severity Index self-report version. 
k) 
Cannabis Withdrawal will be assessed using the Marijuana Withdrawal Checklist with 16 4-point 
items indicating severity during the prior 24 hours [55]. Cannabis craving will be assessed using 
the Cannabis Craving Questionnaire (MCQ) [56]. 
l) 
The sleep disturbance will be assessed using the St Mary’s Hospital Sleep Questionnaire 
(SMHSQ), a self-report instrument developed for use with psychiatric and medical in-patients 
[57]. 
m) 
The Hamilton Anxiety Scale (HAM-A), will be used to assess the affective and vegetative 
symptoms of anxiety [58].  
n) 
Depressive symptoms will be assessed using the Beck Depression Inventory-II (BDI-II - a self-
report depression rating scale has been used extensively in depression treatment research [59]) 
and the Hamilton Depression Rating Scale (HDRS), 21-item version, a clinical administered 
rating scale for depression with well-established reliability and validity [60]; The Profile of Mood 
States [61] will also be used. 
o)  
Psychotic symptoms will be assessed using the Brief Psychiatric Rating Scale (BPRS)  
p) 
Cigarette smoking history including timeline follow-back (TLFB) for the past one week [62];  
Pack-Years (average daily smoking consumption in packs per day multiplied by the years 
smoked); Fagerstrom Test for Nicotine Dependence (FTND).  
q) 
Alcohol and caffeinated beverage use TLFB for the past one week [62].  
r) 
The SAFTEE will be used to monitor for treatment-emergent medication side effects. 
s) 
Participants will complete the Drug Effects Questionnaire (DEQ). The DEQ has five items (feel, 
high, dislike, like, and more) measured on a 100 mm visual analog scale; the revised Addiction 
Research Center Inventory marijuana scale [66] will also be used 
t)          The World Health Organization Disability Assessment Schedule (WHODAS) will be used to 


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monitor disability status at baseline and at the end of treatment and follow-up. 
 
 
 
Pharmacological Treatment: Vivitrol® 380 mg, 4 mL intramuscular injection  
Pilot Study in 10 subjects: 
There is currently limited information to guide us on the Vivitrol® dosage to use in cannabis dependent 
individuals that likely have developed strong tolerance to cannabinoids. We are planning to administer 
Vivitrol® (380 mg, 4 mL intramuscular injection) every 4 weeks. Only eligible participants will be 
administered study medication (i.e. as per inclusion/exclusion criteria). On the day of the scheduled 
injection of Vivitrol® participants will be observed by qualified staff (i.e. staff performing injection) for 5-
10 minutes for possible injection site reactions. Following injection of study medication the subjects will 
remain at CAMH facility for rest of study assessments (approx. 30 min to 1 h), so study staff will be able 
to monitor possible systemic AEs post-dosing. Medications and supportive measures will be available 
at CAMH clinic as per expected side effects of study medication. Additionally, participants in the study 
will be regularly assessed during the trial (see above schedule of assessments) for changes in health 
status, these assessments include ECG, vitals and CBC. The subjects in this study will be treatment-
seekers that fit our inclusion/exclusion criteria and that will be treated open-label to ensure good 
tolerability. These 10 subjects will allow us to determine if our schedule for dosing is appropriate for the 
subsequent RCTs. 
 
Biological sample collection (excludes samples used for general health assessments) 
Urine samples will be collected weekly.  All participants will have urine samples collected on the weekly 
visit.  At any point that biological samples are taken, information about the last time the participant may 
have smoked cannabis and last used the study medication will be collected.   All urine samples will be 
taken at the beginning of the visit to standardize the time.  Each urine sample obtained will have 
creatinine measures and THC quantification determined by the CAMH laboratory. Appropriate 
temperature control until analysis will be maintained. 
 
Biological sample collection for general health assessments 
Urine and blood samples for general health assessments will be collected at Baseline and at the end of 
trial (see Summary of Study Assessments). 
 
Psychological support: MET/CBT intervention 
All subjects will receive a weekly MET/CBT session with a trained therapist. This is an adaptation of a 
nine-week MET/CBT intervention which has been previously studied for the treatment of cannabis 
dependence and has been found to be effective [54]. The intervention in the proposed study 
emphasizes th e development of motivation for change and the implementation of skills to reduce and 
abstain from cannabis use, using the Brief Counseling for Marijuana Dependence manual published by 
the Substance Abuse and Mental Health Services Administration (SAMHSA). In this intervention, use of 
empathic therapeutic style helps resolve ambivalence, increase discrepancies about personal goals 
and cannabis use, and elicit motivation to change. Once ambivalence about cannabis use is addressed, 
the sessions focus on the cognitive, behavioral and emotional changes necessary for dealing with 
cannabis dependence while supplying coping strategies for predictable obstacles. As studies of 
psychosocial interventions in cannabis dependence have shown that more intensive interventions have 
a more sustainable outcome [54], the MET/CBT sessions in the proposed trial will continue for 12 
weeks.  The current SAMHSA manual provides an outline for this intervention for 9 weeks and provides 
4 additional elective topics.  In this study, participants will receive the 9 weekly sessions as outlined and 
then provided 3 of these elective topics for a total of 12 weeks.  These elective topics will be identical 
amongst all participants.  Addition of this intervention will allow for the necessary conditions to assess 
the additive value of treatment with Vivitrol® for cannabis use disorder.  


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We will seek participant’s permission to audio record the MET/CBT sessions. A proportion of these 
audio recordings will be reviewed by a member of the research team to confirm that the assessment 
measures and the psychotherapy are provided according to standardized instructions [63-65]. 
MET/CBT may be conducted remotely by video call (i.e. Webex) if necessary. Remote therapy sessions 
will be conducted in accordance with the CAMH Research Guidelines for Virtual Participant Sessions. 
 
Remote (WebEx) session conduct: Participants who provide consent for email communication will be 
sent a WebEX link and related information using an email template. Participants will be reminded that 
email is not secure means of communication and that there are potential security risks associated with 
videoconferencing software; that they will be required to provide an emergency contact, an alternate 
contact number, and their current address to confirm their location in case there are safety concerns; 
that their audio (but not video) will be recorded; and that a member of the technical team may join the 
call if there are technical problems.  
At the beginning of the session, the participant will be reminded that audio (but not video) will be 
recorded and the fixed location, emergency contact, and alternate contact number of the participant will 
be confirmed. Participants will be reminded of relevant contingencies; i.e., if there is a technical issue, a 
member of the technical team may join the call; if the participant unexpectedly drops off the WebEx call, 
the alternate contact information will be used to regain contact; and if there are any safety concerns, the 
participant’s location and emergency contact information will be used to contact emergency services.     
 
Recruitment: 
Participants will be mainly recruited from individuals seeking treatment within the CAMH Addiction 
Program.  Information about this study may be presented to individuals through a brochure that will be 
present within the clinics or potentially by a clinician directly to their patients.  After reviewing the 
information in the brochure, interested parties can contact the study staff through the telephone number 
provided in this brochure to obtain further detailed information about the study. In addition, staff in 
clinics at CAMH may identify potential participants that are CAMH clients who indicated via the 
concurrent disorder screener collected by Access CAMH on initial intake that they would be interested 
in being contacted for research. Clinic staff would then contact the client to provide study details. Clinic 
staff will be provided with a script to use when contacting clients who have indicated interest in learning 
more about research projects they may be eligible for.  CLEARR process for recruitment - a delegated 
Research Coordinator under the supervision of a CLEARR team recruiting clinician will identify potential 
participants and notify the client’s clinician about the client’s eligibility to participate in this research 
study. The clinician will then ask their client if they would be willing to meet with a study team member 
about participating in this study. Only with a clients’ agreement will they be approached. If a client is 
enrolled in the study and consents to it, their participation in this study will be noted in their medical 
chart. Subjects will be also recruited from other addiction clinics or medical centers located in Toronto, 
by word of mouth, smoke paraphernalia shops (e.g. brochures/posters will be made available at these 
shops), local advertisement in Toronto newspapers, social online networks (e.g. facebook), and through 
posters distributed in and around the CAMH and the University of Toronto campuses and on the CAMH 
“find a study” registry. Ads will also be posted online on U of T bulletins, Craigslist and similar websites, 
local magazines such as NOW! Or Eye Weekly and other mass media as radio, TTC, tv (e.g. Tim’s tv 
advertisement) or online advertisement platforms at google ads or in youtube (e.g. as inserted 
advertisement) may also be used to recruit prospective subjects. Ads and fliers will be will approved by 
CAMH’s Research Ethics Board (REB). Subject eligibility will be initially determined through a 
telephone interview prescreening to assess potential eligibility. 
 
Participant Compensation: 
Once participants are deemed eligible to be enrolled in the study (following baseline assessments) the 
total monetary compensation provided to participants in this study will be $700.  They will be provided 


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$200 upon completion of the first 4 weeks of the trial, $200 after completion of the 12 week medication 
phase and $300 after completion of the follow-up period.   
 
Due to the frequent visits required to CAMH, participants will also be provided with TTC tickets (or its 
cash value if preferred by participants) during treatment and follow-up visits as required. 
 
Contingency Management 
Participants will be provided with a $5 voucher for each visit where a sample of urine or blood is 
collected, however for each missed appointment, a $5 value will be subtracted from the total amount.  
These vouchers will be provided at two separate times, after completion of the treatment phase of the 
study, and after completion of the follow-up period. 
 
In order to engage participants and to maximize returns to CAMH for weekly visits, a “fish-bowl prize” 
system will be instituted where during each visit participants will have a chance to reach within a large 
bowl/drum and select a ticket which provides a chance to win a prize.  These prizes will range from 
tickets containing motivational messages, a small prize such as a pen or notepad, a $5 gift card to Tim 
Hortons up to a to a maximum prize of $50 in the form of a gift card to a number of establishments 
including restaurants, grocery stores, or retail merchants. 
 
Data analysis: All analyses will be implemented in SPSS v24.0. Associations with p-values of less than 
0.05 will be considered statistically significant, and all tests will be 2-sided. The data will be screened 
prior to analysis to ensure that the underlying assumptions for all subsequent statistical procedures are 
met. Preliminary analyses will include chi-square tests, t-tests, and Mann-Whitney U tests. 
Our Primary outcome measures will be: 1) tolerability which will be assessed by determining the 
number of participants who withdraw from the study because of SAEs and 2) pilot efficacy of this 
intervention will be assessed by assessing seven-day point prevalence cannabis abstinence one week 
after the end of medication phase; and at 3 month follow up.  Secondary outcome measures will be: 1) 
percentage of days of cannabis use over the study duration until the 3 month follow up; 2) amount of 
cannabis use over the study duration until the 3 month follow up; 3) effects on withdrawal symptoms 
scores, craving scores and number of urine samples screen as positive and 4) DSM5 criteria for CUD 
at the end of treatment and follow-up as compared with baseline. Efficacy analyses of count variables 
(e.g. number of joints per week) will be performed using generalized estimating equations (GEEs), 
specifying a negative-binomial distribution for the counts. Linear mixed models will be used to analyze 
continuous, secondary outcome measures (e.g. mood and anxiety ratings, physiological measures). All 
efficacy analyses will be by intention-to-treat. Treatment week will measure changes within-subjects. 
Subjects will be considered abstinent based on self-report TLFB. Thus, standard urine sampling for 
THC metabolites will be use as a measure of abstinence in this study. Urine samples will be collected 
and analyzed for THC metabolites.  
 
Procedure for accounting for missing, unused, and spurious data: In the final report the 
procedures used to deal with missing, unused or spurious data in statistical analyses will be described.  
 
Procedures for reporting deviations from the original statistical plan: Any deviation from the 
planned statistical analyses will be described in the final report. 
 
Power calculation: The goal is to collect pilot data to demonstrate tolerability and trend for efficacy of 
Vivitrol® for treatment of cannabis dependence. We are hypothesizing that the use of cannabis will 
decrease by at least 50% after treatment with Vivitrol®. Assuming Cannabis use of around 9.5 g (SD = 
5) at baseline [as per paper], a sample of 10 subjects will give us 80% power to detect a decrease in 
cannabis use of 50% from baseline to the last time point. The power calculation was conducted through 
Monte Carlo simulation, where 5000 replications were conducted. It was also assumed that the 


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correlation between baseline and the last time point was 0.6. A Mixed Effect Model was adjusted for 
each replication, where Time was the only Fixed Effect and Subjects entered the model as Random 
Effects. The power in such simulation is defined as the proportion of the replications where the Time 
effect is significant at confidence level 0.05 and two tailed test. No dropout was assumed.  
 
Termination of the Study 
Reasons for withdrawing individual subjects from the study may include one or more of the following: 
 
1) 
Severe side effects;  
2) 
Major protocol deviation; 
3) 
Subject lost to follow-up; 
4) 
Withdrawal of consent; 
5) 
Pregnancy 
 
Any subject may be discontinued from the study at the discretion of the investigators if it is deemed to be in 
the best interest of the subject. 
 
Study Documentation 
Investigators will retain a subject identification code list if they need to contact subjects after the study. This 
list will contain the complete name, identification number, address and phone number of all subjects and 
will be held confidentially at the investigators site after completion of the study. 
A CRF will be completed for each subject enrolled in the study. A subject screening log, noting reasons for 
screen failure, where applicable, will be maintained for all subjects. All information recorded on the CRFs 
for this study will be consistent with the subject’s source documentation (e.g. medical records). The 
investigator will document the obtained informed consent and record all medication administration, medical 
history, results of laboratory tests and adverse events in the CRF. Laboratory printouts and psychometric 
assessments will be considered source documents and will be incorporated into the CRF without 
transcription in a confidential manner. 
 
The data collected during the study will be typed or written onto the CRF and other study documents using 
a ballpoint pen. If an error is made, it will be crossed out with a single horizontal line, and the new 
information clearly recorded next to the error, initialed and dated. Correction fluid is not allowed at any 
time. 
 
REDCap will be used as a case report form and as a data collection tool. Data collected directly into 
REDCap will be the following self-report questionnaires, which will be completed directly by the participant 
under the supervision of research staff: FTND, MWC, MCQ, BDI, POMS, DEQ, SMHSQ, WHODAS, ASI. 
The participant identity/identification number will be checked by research staff at the time any self-report 
questionnaires are administered. Where REDCap is used for the purpose of data collection (i.e. in the case 
of self-report questionnaires), the data entered into REDCap will be considered as source. Data may be 
collected on paper CRFs where REDCap is not available, and if so such data will later be transcribed into 
REDCap. Other study data collected on source documents (such as paper CRFs) will be transcribed into 
REDCap, with source documents retained securely. The investigators will maintain the accuracy and 
completeness of REDCap records for each participant. No PHI will be stored in REDCap. All data entered 
into REDCap will be stored in a de-identified manner (i.e. coded with participant number).  
 
REDCap may also be used instead of a paper telephone screening form to capture data collected 
during an initial telephone interview for screening purposes. No PHI will be stored in the REDCap 
screening project. Instead, all data entered into REDCap will be stored in a de-identified manner (i.e. 
coded with participant screening number). 
 


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Archiving of Study Documentation 
Study data and other essential documents will be retained in a secure setting by the investigators for a 
period of 25 years as required by Health Canada regulations. 
 
 
Confidentiality 
All personal study participant data collected and processed for the purposes of this study will be managed 
by the investigators and their research staff with adequate precautions to ensure the confidentiality of this 
data, and in accordance with applicable national and local laws and regulations on personal data 
protection. Study data will be de-identified or coded. A master linking log with identifiers will be kept and 
stored separately from the data. The ethics committees approving this research and Health Canada will be 
granted direct access to the study participant’s original medical records for verification of clinical trial 
procedures and/or data, without violating the confidentiality of the subjects, to the extent permitted by the 
law and regulations. In any presentations of the results of this study at meetings or in publications, the 
subject’s identity will remain confidential. 
 
Summary of risks and benefits to subjects: 
 
Risks Associated with the Medication 
Vivitrol® is a medication approved by the U.S. Food and Drug Administration for the treatment of alcohol 
and opioid dependence. Therefore, current evidence shows only the risks of using Vivitrol® associated 
with opioid and alcohol dependence. The risks of using Vivitrol® associated with cannabis use disorder are 
still unknown. Research staff and study physicians will be made aware of the serious adverse reactions 
that may be associated with Vivitrol® therapy in clinical use, which include: severe injection site reactions, 
eosinophilic pneumonia, serious allergic reactions, unintended precipitation of opioid withdrawal, 
accidental opioid overdose and depression and suicidality.  
 
The adverse events seen most frequently in association with Vivitrol® therapy for alcohol dependence (i.e., 
those occurring in ≥5% and at least twice as frequently with Vivitrol® than placebo) include nausea, 
vomiting, injection site reactions (including localized swelling, itching of the skin, nodules and swelling), 
muscle cramps, dizziness or syncope, somnolence or sedation, anorexia, decreased appetite or other 
appetite disorders.  
 
The adverse events seen most frequently in association with Vivitrol® therapy in opioid-dependent patients 
(ie, those occurring in ≥2% and at least twice as frequently with Vivitrol® than placebo) were hepatic 
enzyme abnormalities, injection site pain, nasopharyngitis, insomnia, and toothache. 
 
Female participants will be required to take measures to avoid becoming pregnant during the study. 
Acceptable contraceptive methods include: barrier methods of contraception (e.g. male condom, female 
condom, cervical cap, diaphragm, contraceptive sponge).  
 
Note: No barrier method by itself achieves a highly effective standard of contraception. The proper use 
of diaphragm or cervical cap includes use of spermicide and is considered one barrier method. The 
cervical cap and contraceptive sponge are less effective in parous women. The use of spermicide alone 
is not considered a suitable barrier method for contraception. 
 
When used consistently and correctly, "double barrier" methods of contraception (e.g. male condom 
with diaphragm, male condom with cervical cap) can be used as an effective alternative to the highly 
effective contraception methods described below. The consistent and correct use of a male condom in 


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association with spermicide may be considered an acceptable barrier method in some clinical trial 
settings, for this study the above decision will be at the discretion of the study physician. 
 
Female participants that underwent or currently using highly effective methods of contraception (i.e. 
hormonal contraceptives, intrauterine device (IUD) or intrauterine system (IUS)), will be also eligible for 
the trial. 
 
Potential participants will be informed of these and other additional information regarding study medication 
during the informed consent process.  
 
 
 
Other warnings and precautions to follow with Vivitrol® include: 
 
Vulnerability to Opioid Overdose: Following Vivitrol® treatment opioid tolerance is reduced from 
pretreatment baseline, and patients are vulnerable to potentially fatal overdose at the end of a dosing 
interval, after missing a dose, or after discontinuing Vivitrol® treatment. Attempts to overcome blockade 
may also lead to fatal overdose (see product information for Vivitrol® for more detail).  
 
Injection Site Reactions: In some cases, injection site reactions may be very severe. Some cases of 
injection site reactions required surgical intervention see product information for Vivitrol® for more detail). 
 
Precipitation of Opioid Withdrawal: Opioid-dependent and opioid-using patients, including those being 
treated for alcohol dependence, should be opioid-free before starting Vivitrol®  treatment, and should notify 
healthcare providers of any recent opioid use. An opioid-free duration of a minimum of 7-10 days is 
recommended for patients to avoid precipitation of opioid withdrawal that may be severe enough to require 
hospitalization (see product information for Vivitrol® for more detail). Participants will be advised to be off 
all opioids, including opioid-containing medicines, for a minimum of 7 – 10 days before starting Vivitrol® in 
order to avoid precipitation of opioid withdrawal, opioid use will be based in self-report and urine drug 
screen during baseline and before treatment initiation, only those participants showing absence of opioid in 
urine will initiate treatment with Vivitrol®. For those patients transitioning from buprenorphine or methadone 
they may be vulnerable to precipitation of withdrawal symptoms for as long as two weeks. Healthcare 
providers will therefore inquiry about any recent use of opioids or any history of opioid dependence before 
starting Vivitrol® to avoid precipitation of opioid withdrawal.  
 
Hepatotoxicity: Cases of hepatitis and clinically significant liver dysfunction were observed in association 
with Vivitrol® treatment during the clinical development program and in the postmarketing period. 
Discontinue use of Vivitrol® in the event of symptoms or signs of acute hepatitis (see product information 
for Vivitrol® for more detail). The results of liver function tests and CBC prior to the 2nd and 3rd Vivitrol 
injections will serve as safety monitoring for treatment-emergent AEs and to better inform the clinical 
judgment regarding the safety of continued dosing of Vivitrol in the present study. 
 
Depression and Suicidality: Monitor patients for the development of depression or suicidal thinking (see 
product information for Vivitrol® for more detail).  
 
When Reversal of Vivitrol® Blockade Is Required for Pain Management: In an emergency situation in 
patients receiving Vivitrol®, suggestions for pain management include regional analgesia or use of non-
opioid analgesics (see product information for Vivitrol® for more detail). 
 
 


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Study staff will recommend participants to inform their primary care physician/clinic of their 
participation on this study. Alternatively, if participants are agreeable (i.e. during the informed 
consent), study staff will notify their primary care physician(s) or specialist(s) of their participation 
in this study. Additionally, a wallet card will be provided to participants in this study to alert 
medical personnel to the fact that they are taking Vivitrol®.  
 
Physicians should include the following issues in discussions with participants/patients for whom 
they prescribe Vivitrol®:  
 
Advise patients that if they previously used opioids, they may be more sensitive to lower doses of opioids 
and at risk of accidental overdose should they use opioids when their next dose is due, if they miss a dose, 
or after Vivitrol® treatment is discontinued. It is important that patients inform family members and the 
people closest to the patient of this increased sensitivity to opioids and the risk of overdose.  
 
Advise patients that because Vivitrol® can block the effects of opioids, patients will not perceive any effect 
if they attempt to self-administer heroin or any other opioid drug in small doses while on Vivitrol®. Further, 
emphasize that administration of large doses of heroin or any other opioid to try to bypass the blockade 
and get high while on Vivitrol® may lead to serious injury, coma, or death.  
 
Patients on Vivitrol® may not experience the expected effects from opioid-containing analgesic, 
antidiarrheal, or antitussive medications.  
 
Advise patients that a reaction at the site of Vivitrol® injection may occur. Reactions include pain, 
tenderness, induration, swelling, erythema, bruising, or pruritus. Serious injection site reactions including 
necrosis may occur. Some of these injection site reactions have required surgery. Patients will receive their 
injection from a healthcare provider qualified to administer the injection. Patients should be advised to seek 
medical attention for worsening skin reactions.  
 
Advise patients that they should be off all opioids, including opioid-containing medicines, for a minimum of 
7 – 10 days before starting Vivitrol® in order to avoid precipitation of opioid withdrawal. Patients 
transitioning from buprenorphine or methadone may be vulnerable to precipitation of withdrawal symptoms 
for as long as two weeks. Ensure that patients understand that withdrawal precipitated by administration of 
an opioid antagonist may be severe enough to require hospitalization if they have not been opioid-free for 
an adequate period of time, and is different from the experience of spontaneous withdrawal that occurs 
with discontinuation of opioid in a dependent individual. Advise patients that they should not take Vivitrol® 
if they have any symptoms of opioid withdrawal. Advise all patients, including those with alcohol 
dependence, that it is imperative to notify healthcare providers of any recent use of opioids or any history 
of opioid dependence before starting Vivitrol® to avoid precipitation of opioid withdrawal.  
Advise patients that Vivitrol® may cause liver injury. Patients should immediately notify their physician if 
they develop symptoms and/or signs of liver disease.  
 
Advise patients that they may experience depression while taking Vivitrol®. It is important that patients 
inform family members and the people closest to the patient that they are taking Vivitrol® and that they 
should call a doctor right away should they become depressed or experience symptoms of depression. 
 
Advise patients to carry documentation to alert medical personnel to the fact that they are taking Vivitrol® 
(naltrexone for extended-release injectable suspension). This will help to ensure that patients obtain 
adequate medical treatment in an emergency.  
 
Advise patients that Vivitrol® may cause an allergic pneumonia. Patients should immediately notify their 
physician if they develop signs and symptoms of pneumonia, including dyspnea, coughing, or wheezing.  


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Advise patients that they should not take Vivitrol® if they are allergic to Vivitrol® or any of the microsphere 
or diluent components.  
 
Advise patients that they may experience nausea following the initial injection of Vivitrol®. These episodes 
of nausea tend to be mild and subside within a few days post-injection. Patients are less likely to 
experience nausea in subsequent injections. Patients should be advised that they may also experience 
tiredness, headache, vomiting, decreased appetite, painful joints and muscle cramps.  
 
Advise patients that because Vivitrol® is an intramuscular injection and not an implanted device, once 
Vivitrol® is injected, it is not possible to remove it from the body.  
 
Advise patients that Vivitrol® has been shown to treat alcohol and opioid dependence only when used as 
part of a treatment program that includes counseling and support.  
 
Advise patients that dizziness may occur with Vivitrol® treatment, and they should avoid driving or 
operating heavy machinery until they have determined how Vivitrol® affects them. 
 
 
Other events were observed during the Vivitrol® Clinical Studies (in alcohol- and/or opioid-dependent 
subjects treated with Vivitrol®), including events for which a drug cause was remote, events that were so 
general as to be uninformative, and those events reported only once that did not have a substantial 
probability of being acutely life-threatening (see product information for Vivitrol® for more detail). 
 
Adverse Events Reporting 
In the event of a serious adverse event (SAE), whether related to study drug or not, the Principal / 
Qualified investigator will notify REB of its occurrence and will submit the necessary documentation to their 
attention within timelines provided in CAMH SOP HSR207 Serious Adverse Event (SAE) Reporting.  Only 
SAEs that are Serious unexpected adverse drug reaction (SUADR) will be reported to Health Canada as 
outlined in ICH E2A Clinical Safety Data Management Definitions and Standards for Expediting Reporting. 
While only SAEs and SUADRs will be reported as documented above, every adverse event will be 
assessed and recorded in the subject’s research record by research staff working on the study and 
reviewed regularly by the Principal/Qualified Investigator. AEs will be documented and reported as 
mandated by current regulations.   
 
The trial will be conducted in compliance with protocol, GCP, and applicable regulatory requirements. 
 
 
Direct Access to Source data/documents: The PI and QI will permit trial-related monitoring, audits, REB 
review, and regulatory inspections, by providing direct access to source data/documents. This is outlined in 
the informed consent form. Monitoring will be conducted according to the study monitoring plan. 
 
 
Financing and insurance: The study is funded by the Alkermes Inc. This study is performed under usual 
arrangements for studies that are conducted at CAMH. No specific insurance has been taken.  
 
 
Publication policy: Scientific publications of study data will be sought in peer reviewed journals and 
authorship will be in accordance with journal policies.  
 


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