Clinical trial NCT01347762
Conditions: Cannabis Dependence Marijuana Dependence
Keywords: cannabis dependence marijuana dependence cannabis use disorders cannabis withdrawal nabilone
Sponsor: Mclean Hospital
Start date: 2010-06-01; Completion date: 2017-06-09
Enrollment: 84 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Cannabis use disorders are an important public health problem in the United States, but there are no effective medications available to treat these disorders. The investigators intend to test a medication with interesting properties, nabilone, as a treatment for cannabis dependence and to study the relationship of this treatment with the brain using functional MRI brain scans. Nabilone and marijuana have similar effects upon behaviors and the human body, suggesting that nabilone may decrease cannabis withdrawal symptoms while allowing treatment-seeking patients to benefit from behavioral treatments when they are trying to stop using cannabis. The investigators propose to assess the relationship of nabilone, when added to behavioral treatment, on cannabis use patterns in cannabis-dependent patients. The investigators also aim to determine the effects of nabilone on performance on neuropsychological tests and to assess the correlation of neuropsychological performance to brain changes using functional MRI brain scans. The investigators hypothesize that patients receiving nabilone will reduce their use of cannabis more than patients receiving placebo during this 10-week treatment trial.

Detailed description:
Cannabis use disorders are an important public health problem in the United States, but no effective pharmacotherapies are available to treat these disorders. The investigators intend to test a novel agonist pharmacotherapy, nabilone, for cannabis dependence and to study the relationship of this treatment with the brain using BOLD fMRI measures. The behavioral and physiological effects of nabilone and Δ9-THC overlap, suggesting that nabilone may ameliorate cannabis withdrawal symptoms while allowing treatment-seeking outpatients to benefit from medical management (MM) sessions when they are trying to stop using cannabis. The investigators propose to assess the relationship of nabilone, when added to MM, on cannabis use patterns in cannabis-dependent patients. The investigators also aim to determine the effects of nabilone on performance on neuropsychological tests and to assess the correlation of neuropsychological performance to brain changes using BOLD fMRI measures.

In this pilot study, subjects will receive either nabilone or placebo in addition to medical management (MM) over a 10-week treatment period. Subjects' responses to neuropsychological testing carried out while the subject is receiving fMRI scans at 3 time points: at baseline, 4 weeks, and 10 weeks. Following treatment completion, subjects will have a follow-up visit at 14 weeks. This pilot study will evaluate the feasibility of nabilone treatment for cannabis dependence and will establish effect sizes for a larger trial in which subjects will receive high-dose nabilone, low-dose nabilone, or placebo in addition to MM.

Arms: arm 1: nabilone titrated to 2 mg daily arm 2: Placebo
Interventions: intervention 1: Nabilone intervention 2: Placebo
Intervention descriptions: intervention 1: nabilone titrated to 1 mg by mouth twice daily intervention 2: one placebo capsule by mouth twice daily

Protocol documents:
Prot_SAP_000.pdf: 
McLean Hospital Application to the Institutional Review Board (IRB) 
                                   Nabilone for Cannabis Dependence Detailed Protocol 
     
 
 
 
1 
Version Date: 4/14/17 
1. Title: Nabilone for Cannabis Dependence: A Pilot Study 
 
2.Principal Investigator: Kevin P. Hill, M.D., M.H.S., Psychiatrist-In-Charge, Alcohol 
and Drug Abuse Treatment Program, 617 855 4501. 
 
2.b.Medical Monitor Emergency Coverage: Dr. Kevin Hill (BPRL) 
 
3.Facilities: Alcohol and Drug Abuse Treatment Program (ADATP), Proctor House, and 
the BPRL—NeuroImaging Center, McLean Hospital. 
 
4.Estimated Duration of the Study: February 2010- June 2017. The estimated 
duration changed after Dr. Hill was awarded NIDA grant 1K99DA029115-01, “Nabilone 
for Cannabis Dependence: Imaging and Neuropsychological Performance.”  This pilot 
study will be conducted out during the K99 period of the award in preparation for a 
larger clinical trial to be conducted during the R00 period.  
 
5.Specific Aims: 
Aim 1: Assess the impact of treatment with either nabilone or placebo on cannabis use 
patterns. 
 
 
.  
Aim 2: Assess the impact of treatment with either nabilone or placebo on performance 
on neuropsychological testing. 
 
 
 
6.Progress Report and Preliminary Studies: Not applicable. 
 
7.Background and Significance: 
 
Despite the alarming prevalence of cannabis dependence and the corresponding 
impact upon public health, no consistent pharmacological treatments exist for this 
disorder.  Nabilone (Cesamet®) is a synthetic cannabinoid FDA-approved for cancer 
chemotherapy with behavioral and physiological effects that overlap with Δ9-THC (Stark 
and Dews 1980, Mendelson and Mello 1984).   Nabilone is safe and well-tolerated, with 
side effects that diminish with repeated administration (Lemberger et al. 1982).  
Nabilone’s properties make it an attractive option for study as an agonist treatment, and 
it may be a better choice than dronabinol for agonist treatment because nabilone is not 
cross-reactive with urine assays used to detect recent cannabis use (Fraser and 
Meatherall 1989).  
 
8.Research and Design Methods: 
 
8.1. 
Overview 
We will conduct a Stage 1 pilot feasibility study at McLean Hospital to develop a 
medication to treat cannabis dependence. (FIGURE 1) In a randomized, double-blind, 
placebo-controlled trial, 60 cannabis-dependent subjects ages 18-45 will receive 
medical management (MM) over a 10-week period, with half receiving nabilone 
treatment and half receiving placebo.  Participants will receive either 6 mg nabilone or 
placebo in addition to medical management (MM) over a 10-week treatment period. 


McLean Hospital Application to the Institutional Review Board (IRB) 
                                   Nabilone for Cannabis Dependence Detailed Protocol 
     
 
 
 
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Following treatment completion, participants will have a follow-up visits at 11, 12, 13, 
and 14 weeks.    Primary outcomes will include self-report of cannabis smoking and 
results of quantitative urine drug screens for cannabis.  We also will assess craving and 
other marijuana withdrawal symptoms as secondary measures.  Mixed models ANOVA 
will be used to analyze the data. 
 
The protocol described in this document has been approved by the FDA under IND 
107862 to Dr. Hill. 
 
8.2. 
Participants 
      Male and female participants  (ages 18-45) will be recruited from the Boston 
metropolitan area via websites, newspaper advertisements, flyers, and word-of-mouth.  
In order to meet our target sample of 60 study completers- (participants who complete 
all study procedures), we expect to recruit about 120 participants and have 90 sign the 
informed consent form . (Our target sample size is 60 completers with 30  per group: 30 
Placebo and 30 Nabilone).  From ongoing studies of cannabis smokers at McLean, we 
expect to recruit at least 3 participants a month for our study.   
 
8.2.1. Study Procedure 
8.2.1.a. Recruitment and Intake. 
Interested individuals will respond to advertisements by leaving a message (first 
name and call back number only) in the BPRL recruiting voice mailbox.  Research 
assistants will call them back with 24 to 48 hours and conduct an initial phone screen 
that takes about 15 minutes.  It will cover basic inclusion and exclusion criteria, as well 
as a brief description of the study to determine if the person is interested in participating. 
If the volunteer is appropriate and agrees to participate, they will be invited to come to 
the BPRL for a physical and psychiatric evaluation (SCID).  Treatment alternatives will 
also be offered to the prospective participant if they decide not to participate or are not 
eligible for participation.  
The initial assessment interview will be done by a research assistant and the study 
physician and take about 3 hours.  Volunteers will first be asked to sign the informed 
consent (see 8.2.1.b). Once they have agreed to participate, they will undergo a 
comprehensive evaluation that will include medical, psychiatric, and drug use histories 
as well as physical, psychiatric, and laboratory examinations. The study will be 
explained and an intake package, including all Drug and Alcohol and Mood and 
Impulsivity Assessments (see Table 8.1), will be administered.  More specifically, the 
participants will undergo the following screening procedures:a) Detailed history of 
cannabis use; b) Review of DSM-IV criteria for cannabis dependence; c) Medical history 
and concomitant medication record; d) Physical examination; e) Laboratory screen that 
includes CBC, electrolytes, and BUN/creatinine; f) Urine measurement of THC; g) 
Urinalysis and urine pregnancy test for women; h) 12-lead electrocardiograph (EKG) i) 
urine toxicology screen; j) blood alcohol testing; k) Columbia Suicide Severity Rating 
Scale (C-SSRS). Suicide risk will be assessed by the physician at each MM visit. 
 


McLean Hospital Application to the Institutional Review Board (IRB) 
                                   Nabilone for Cannabis Dependence Detailed Protocol 
     
 
 
 
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8.2.1.b.Informed consent.Eligible participants will complete standard consent 
documentation.  Prior to the volunteer being asked any question about his/her health, 
the volunteer will be given a consent form to read.  The research assistant will go over it 
in detail with the volunteer.  After a physician investigator answers any questions the 
volunteer may have concerning the study, he/she will be asked to provide their informed 
consent to the licensed physician investigator. If enrolled in the study, consent to 
communicate with their other clinicians will be obtained.  Clinicians will be notified of 
their patients’ enrollment in the study, thus allowing them to carefully monitor for 
changes in mood while they are undergoing treatment to stop use of cannabis. 
 
8.2.1.c.Randomization.  Participants will be stratified according to their self-reported 
frequency of cannabis use in the past 30 days:  1) daily use; and 2) non-daily use.  The 
stratification procedure will guard against the possibility that one of the experimental 
conditions (i.e., nabilone or placebo) will be overrepresented by daily users, while non-
daily users will predominantly be randomized into the other condition. 
 
8.2.1.d.Availability and Flow of Subjects into Treatment.  We plan to screen 120 
participants in the course of 20 months to achieve our desired sample size.   
 
8.2.1.e.Study Visits.  Participants will come to the clinic twice a week.  One visit will 
include a medical visit (dispensing of pills and Medical Management; see Sections 
8.3.1.b, 8.3.2) and research assessments, including a urine screen (see Section 8.5.2.a 
and Table 8.2).  The other visit will consist only of a urine screen (see Section 8.5.2.a).  
After the 10-week treatment period, participants will have 1 follow-up assessment visit 
at 14 weeks. During weeks 11, 12, and 13 participants will have 1 weekly 
Diary/Actiwatch visit to hand in their daily diaries, have their Actiwatch data 
downloaded, and provide a urine sample.  
 
8.2.1.f.Clinical Emergencies.  If a participant is intoxicated, the participant will be 
evaluated medically, sent home in a taxi when safe, and the appointment re-scheduled.  
If a participant experiences a problem that requires clinical intervention during the 
course of the study (e.g., mania, suicidal ideation, or dangerous intoxication), we will 
evaluate the situation medically, make an appropriate recommendation, and help the 
participant to implement this plan.  This could involve hospitalization at McLean, referral 
to the hospital's outpatient program, or other medical or psychiatric treatment, as 
clinically appropriate. 
 
8.2.1.g.Participant Payments 
 
Volunteers will receive a $50 remuneration for attending the initial assessment interview 
and an additional $50 for the baseline visit.  They may earn $25 for each urine sample 
given on a non-MM day in the first 5 weeks of treatment and then $30 for each urine 
sample given on a non-MM day in the last 5 weeks of treatment, and they may earn $50 
for attending the follow-up assessment at 14 weeks. They may earn $30.00 for each of 
three Actiwatch /Diary visits at weeks 11, 12, and 13 as well as $50 for the final follow-
up visit. Additionally they may receive a $40 bonus for attending all follow-up visits and 
returning the Actiwatch.  They may also receive a bonus of up to $100 for successful 


McLean Hospital Application to the Institutional Review Board (IRB) 
                                   Nabilone for Cannabis Dependence Detailed Protocol 
     
 
 
 
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completion of their diaries. They may earn a total of $705 for their participation in the 
study.  Medication will be free.  In special circumstances, a subject may receive up to 
$50 in public transportation cards. 
FIGURE 1. Study Schema 
 
 
 
 
 
Volunteer Response to Announcement 
 
 
 
Phone Screen 
 
 
 
 
 
 
 
 
 
Inclusion, exclusion criteria 
 
Eligible and agrees to attend  
initial assessment 
 
 
 
 
 
Ineligible 
 
 
 
 
 
 
 
 
 
 
 
Assessment Interview  
 
 
Baseline  
 
 
 
Informed Consent 
 
 
 
 
 
 
 
 
 
 
 
Diagnosis of Cannabis Dependence (DSM-IV) 
 
 
 
 
 
Clinical Laboratory Testing 
 
 
 
 
 
 
Urine THC measurement 
 
 
 
 
 
 
 
Randomization 
 
 
 
 
 
Ineligible 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BIS-11, BAI, QIDS, PANAS, TLFB, MWC, MCQ 
 
 
 
 
 
Daily diaries, ActiWatch distributed 
 
10-week  
 
1)NAB + MM 
 
 
 
 
 
 
2)PLA + MM 
 
MM begins* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4 weeks 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10 weeks 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
14 weeks  
 
 
 
 
 
 
 
 
 
 
 
End of Study, Data Analysis 
 
 
8.3. Treatment. 
8.3.1Nabilone. 
8.3.1.a.Rationale for Dose.Nabilone (Cesamet®, Meda Pharmaceuticals, Somerset, 
NJ) is a potent synthetic cannabinoid receptor type 1 (CB1) agonist that received FDA 
approval in 2006 for the treatment of nausea and vomiting associated with cancer 
chemotherapy (Cesamet® product information).  Nabilone will be titrated to 6 mg daily in 
the nabilone group.  Nabilone 2 mg was well-tolerated in the pilot study we recently 
completed and doses up to 8 mg have been well-tolerated in other patient populations.  
Recent studies have demonstrated safety of nabilone at doses greater than the 2 mg 
maximum dose previously covered in IND 107862.  Dr. Haney’s group used up to 8 mg 
 TLFB  
BIS-11, BAI, QIDS, PANAS, ASI, MWC, MCQ 
TLFB 
BIS-11, BAI, QIDS, PANAS, ASI, MWC, MCQ 
TLFB, BIS-11, BAI, QIDS, PANAS, ASI, MWC, MCQ 


McLean Hospital Application to the Institutional Review Board (IRB) 
                                   Nabilone for Cannabis Dependence Detailed Protocol 
     
 
 
 
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daily without incident (Haney et al. 2013, Bedi et al. 2013) in cannabis-dependent 
participants and another group have used up to 3 mg daily in a participants with 
peripheral neuropathy (Toth et al. 2012, Bestad and Toth 2011).  As a result, the FDA 
has permitted a maximum dose of nabilone 6 mg daily under Dr. Hill’s IND 107862.   
 
 
 
8.3.1.b.Procedures for Dispensing Medication.   
Subjects will be randomized to receive either placebo or nabilone.  Dr. Hill or the 
research assistants will present 7 day prescriptions to the McLean pharmacy and the 
subject will receive blister packs containing 1 week of medication or placebo, separated 
into daily doses.  Subjects will be asked to return unused pills at each weekly medical 
visit; study staff will then perform a pill count for the study record.  All groups will receive 
capsules following the same schedule: 4 capsules twice daily for 10 weeks.  Each 
capsule will contain either nabilone or placebo, and riboflavin 25 mg (to help assess 
compliance).  Subjects in the nabilone group will take 1 mg of nabilone at bedtime for 1 
week, then increase to 1 mg of nabilone twice daily (between 7:00-9:00 a.m. and 9:00-
11:00 p.m.) for 1 week, then 2 mg nabilone twice daily for 1 week, then 3 mg nabilone 
twice daily for 6 weeks  before tapering the medication over the final 1 week by taking 2 
mg nabilone twice daily for 2 days, then 1 mg twice daily for 2 days, then 1 mg at 
bedtime for 3 days before stopping.  This schedule is designed to maximize the time 
spent at the maximum dose.  Subjects will be assessed for side effects prior to each 
dosing increase and the study physician will decide if increasing the dose as scheduled 
is appropriate. 
 
 
 
In order to monitor potential side effects from the initial dose of nabilone or dose 
increases, participants will be observed at the laboratory facility for 3 hours following the 
following the second dose of the day in weeks 1, 2, 3, and 4.  Participants will come into 
the Behavioral Psychopharmacology Research Laboratory in the evenings for 
monitoring by a research assistant and a study physician.  This observation period is 
follows the SAMHSA guidelines for induction of buprenorphine, another agonist 
pharmacotherapy (CSAT 2004).  Participants will remain in the natural settings 
laboratory for 3 hours while having vital signs taken every 30 minutes.  Participants will 
be allowed to leave the facility after being cleared by a study physician.  Participants will 
be allowed to leave the facility if they have 1) pulse rate less than 120 beats per minute; 
2) blood pressure less than 140/90. 
 
8.3.1.c.Dose Adjustment.    
Subjects who cannot tolerate dose increases either subjectively or by monitoring of 
vital signs (hypotension, for example), will remain at the dose they were taking prior to 
the increase (4 mg daily, 2 mg daily, or 1 mg daily).  Subjects who experience 
uncomfortable side effects (e.g., drowsiness or vertigo) may have their dose lowered 
from 6 capsules a day to 4 or from 4 capsules a day to 2; a subject receiving active 
nabilone, for example, could then have a dose reduction from 6 mg of nabilone daily to 
4 mg daily (or lower).  None of the subjects in Study 1 required a dose reduction.  If this 
leads to fewer side effects, the study physician will ask if the subject is willing to try the 
full dose again.  If not, or if the subject tries the full dose again and is unable to tolerate 


McLean Hospital Application to the Institutional Review Board (IRB) 
                                   Nabilone for Cannabis Dependence Detailed Protocol 
     
 
 
 
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it, the subject will be maintained on the lower dose.  If a subject cannot tolerate 2 
capsules per day, the medication will be discontinued, but the subject will continue to be 
followed for research visits. 
 
 
 
 
8.3.2. Medical Management Visits. 
 
8.3.2.a.Weekly Visits with the Study Physician.  Participants will be seen weekly during 
treatment by the study physician for medical visits.  In addition to dispensing the study 
medication, the physician will utilize Medical Management (MM) (Pettinati et al 2004), a 
manualized treatment that was used in the NIAAA COMBINE Study.  MM was derived 
from empirically-tested manualized therapies (Carroll and O'Malley 1996, Mason and 
Goodman 1997) that were originally designed to approximate a primary care approach 
to the treatment of alcohol dependence.  The treatment is delivered by a medical 
professional who monitors medication side effects, provides strategies to increase 
medication adherence (Volpicelli et al. 1997), and supports abstinence.  The initial 40-
60 minute session includes reviewing the cannabis dependence diagnosis and negative 
consequences from smoking marijuana, recommending abstinence, providing 
medication information, and offering strategies to enhance medication adherence. In 
subsequent 15-25 minute visits, recent substance use, overall functioning, medication 
adherence, and side effects are discussed.  Session structure varies according to drug 
use status and medication adherence.  If a participant is not adherent to the medication 
regimen, the clinician evaluates the reasons and helps the subject devise plans to 
enhance medication adherence.  Participants who use cannabis are given common-
sense behavioral recommendations, such as avoiding parties where marijuana will be 
present.  Presence and severity of side effects will be obtained through a standard 
Adverse Events Checklist as well as the “Frequency and Intensity of Side Effects 
Rating/Global Report of Side Effects Burden” (Wisniewski et al. 1997), a 2-minute 
questionnaire that assesses the frequency, intensity, and level of burden of side effects. 
Medication adherence will be assessed in several ways, as outlined below in Section 
8.6.These sessions will be audiotaped and a sample will be rated by a senior clinician in 
order to ensure fidelity to the MM process. 
 
8.4.  Safety Monitoring.Nabilone has been shown to have a favorable safety profile; it 
has been well-tolerated in several clinical trials and no adverse events have been 
reported (Ware et al. 2008, Frank et al. 2008, Skrabek et al. 2008).  Drug-drug 
interactions are not a major concern with nabilone because it does not induce 
cytochrome P450 3A4 isoenzymes and lacks significant 3A4 inhibitory effect (Nahas et 
al. 2002). Nonetheless, we will monitor safety through the standardized methods 
described above in the MM visits.  We will have a low threshold for obtaining additional 
medical workup during the study if the subject reports medical symptoms.  If a 
participant has a clinically significant laboratory or other medical abnormality that cannot 
be attributed to another cause, the participant’s medication will be discontinued and the 
participant will be followed for research visits.  
 


McLean Hospital Application to the Institutional Review Board (IRB) 
                                   Nabilone for Cannabis Dependence Detailed Protocol 
     
 
 
 
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As discussed above in Section 8.2.i.a, the study physician will perform a physical 
examination and obtain an ECG at baseline and at 14 weeks.  Laboratory data 
(urinalysis, blood chemistries, complete blood count, electrolytes, and liver function 
tests) will be done at baseline and at 14 weeks as well.  Given that according to its 
labeling, nabilone should not be taken with alcohol, sedatives, hypnotics, or other 
psychoactive substances because they could potentiate the central nervous system 
effects of nabilone, urine toxicology and blood alcohol testing will be done weekly along 
with the twice weekly quantitative THC urine screens during treatment.  Women of 
childbearing potential will have urine pregnancy tests weekly each time a urine sample 
is given in addition to pregnancy tests at weeks at 4, 10, and 14 weeks during 
treatment; women who become pregnant will have their medication discontinued and 
will be referred to an obstetrician; like all participants, they will still be followed for 
research visits. 
 
8.5. Research Measures. 
See Table 8.2 for the schedule of assessments.   
 
8.5.1. Diagnostic Assessment.  To make the diagnosis of cannabis dependence, the 
Structured Clinical Interview for DSM-IV (SCID) (First 1996) will be used.   
 
8.5.2. Drug and Alcohol Use Assessment. 
 
8.5.2.a.Urine Screens.  The primary outcome measure will be cannabis use, as 
measured by twice-weekly quantitative urine screens during treatment.  Cannabis is a 
particularly challenging drug of abuse for measuring outcome because of the false-
positive urine screens that can occur as the result of long-term accumulation of 
cannabis metabolites. In an attempt to avoid false-positive results, we will obtain 2 
supervised urine samples weekly:  1 at the medical visit and 1 on another day, ordinarily 
with 3-4 days separation from the clinical visits (e.g., Monday-Thursday, Tuesday-
Friday, or Monday-Friday); this should maximize the time frame covered by our urine 
screens.  We will send the urine samples to Quest Diagnostics Laboratory  (Cambridge, 
MA, a NIDA-certified laboratory), where the urines will be screened by immunoassay for 
the THC metabolite 11-nor-carboxy-∆ 9-tetrahydrocannabinol (THC-COOH) as well as 
other drugs of abuse.  Urine creatinine concentrations will also be measured to assess 
urine concentration.  The threshold for detection of THC-COOH will be 20 ng/ml. 
Samples positive for this metabolite will undergo further analysis by gas 
chromatography-mass spectroscopy to obtain quantitative THC-COOH concentration; 
we will then calculate the ratio of this metabolite to urine creatinine concentration.  We 
will adopt the method of Heustis and Cone (1998) to differentiate new marijuana use 
from residual drug excretion as a result of previous use; these recommendations are 
based on their controlled clinical studies of urinary excretion profiles of creatinine and 
marijuana metabolites following marijuana administration in humans.  We will label a 
urine negative (i.e., abstinent from cannabis) if 1) the ratio of THC-COOH to creatinine 
in the urine does not increase by >50% from the ratio obtained in the previous urine 
screen, and 2) the participant also reports using no cannabis since the previous urine 
test.    
 


McLean Hospital Application to the Institutional Review Board (IRB) 
                                   Nabilone for Cannabis Dependence Detailed Protocol 
     
 
 
 
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8.5.2.b.Self-Report.  We will use 3 methods of self-report in an effort to determine the 
most appropriate and effective method for use in this population.  An ActiWatch Score 
will be determined via compact, wrist-worn, battery-operated activity monitors that are 
excellent devices for monitoring multiple drug use, drug craving, and sleep/wake activity 
(Licata et al., under review).  We will provide participants with a packet of 1 page, self-
addressed, prepaid postage Daily Diary pages which participants will be asked to fill out 
between 7:00 and 9:00 a.m. each day and hand them in during their weekly visits to the 
lab.  The diary consists of a series of questions about cannabis and other drug use as 
well as eating and sleeping habits.  During the weekly visits, we plan to collect cannabis 
use data using the Timeline Follow Back(TLFB) (Sobel and Sobel 1992) protocol that 
was developed for alcohol.   
 
8.5.2.c.Other Drug and Alcohol Use Assessment.Severity of cannabis and other 
substance use and its associated problems will be assessed at baseline and weeks 
4,10, and 14 with the Addiction Severity Index (ASI, 5th edition) (McLellan et al. 1992), a 
widely-used and independently-validated interview that measures the severity of 
problems in 7 areas of functioning that are frequently affected in patients with SUDs:  
drug use, alcohol use, employment, legal status, medical condition, social functioning, 
and psychological status.  In addition to our primary focus on cannabis use (urine 
screens plus days of use), we will examine other substance use (using urine screens 
plus days of other substance use).  We will use this method to determine the number of 
days of cannabis use and of any substance use (and conversely, days of abstinence).  
We will examine ASI composite scores as secondary measures of substance use 
outcome.  We will also use the self-administered Drug and Alcohol Use Questionnaire.  
This measure, administered at baseline, addresses the context of lifetime and recent 
drug and alcohol use, as well as sociodemographic data.  At each treatment visit, 
patients will complete a brief Weekly Drug and Alcohol Use Inventory, indicating their 
number of days using marijuana, other drugs, and alcohol during the previous week.  
The Marijuana Goals Questionnaire (Griffin et al. 1989) is a brief questionnaire 
administered at baseline to assess treatment goals, specifically, whether a participant is 
seeking abstinence or reduction in cannabis use.  A 12-item self-administered 
questionnaire, the Marijuana Craving Questionnaire (MCQ), will be used to assess 
craving at baseline and weekly during treatment and at the 14-week follow-up visit 
(Heishman et al. 2009).  A short form of the Marijuana Withdrawal Checklist (MWC) will 
be used to assess withdrawal symptoms at baseline and weekly during treatment and at 
the 14-week follow-up visit (Budney et al. 1999). If there is a discrepancy among results 
obtained by these methods of substance use assessment, we will meet with the 
participant and have a conversation about their substance use.  After the conversation, 
we will use our clinical judgment to determine the level of use that we believe is most 
accurate for that participant.  A new 6-page questionnaire that we created, the 
Marijuana Perceptions of Risk and Experiences Questionnaire (MPRE), will be 
distributed at baseline, and once during weeks 4, 10 and 14 to assess each participant’s 
perceptions of cannabis risk/harm and his or her motivations to quit/continue using 
cannabis throughout the course of treatment. 
 
8.5.3.Mood and Impulsivity Assessments.  We will monitor participants’ mood 
throughout the study using 3 assessments. The Beck Anxiety Inventory (BAI) is a 21-


McLean Hospital Application to the Institutional Review Board (IRB) 
                                   Nabilone for Cannabis Dependence Detailed Protocol 
     
 
 
 
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item self-report measure that can be used to assess the severity of anxiety. The Quick 
Inventory of Depressive Symptomatology (QIDS-SR) is a short self-report questionnaire 
for depressive symptoms used successfully in the STAR*D project.  The Positive and 
Negative Affect Scale(PANAS) is a 20-item self-report scale in which mood variables 
are rated by participants on a 1-5 scale.  The Barratt Impulsiveness Scale (BIS-11) is a 
commonly used tool to measure impulsivity in various neuropsychological disorders as 
well as in substance abuse.  Three dimensions can be assessed using this scale, which 
include Cognitive Impulsivity, Motor Impulsivity, and Non-planning Impulsivity. 
 
 
Table 8.1  Schedule of Measures 
Measure  
 
 
     
 
     Baseline    Weekly   Weeks 4 &10  Week 14     
Diagnostic Assessment 
1. 
Structured Clinical Interview for DSM-IVa  X 
 
 
 
 
 
 
 
Drug and Alcohol Assessment 
2.    Quantitative Urine Toxicological Analysisb X 
Xb 
X 
 
X 
 
 
3.    Addiction Severity Index 
X 
 
X 
 
X 
4. 
Drug and Alcohol Use Questionnaire 
X 
5. 
Weekly Drug and Alcohol Use Inventory 
X 
X  
X 
 
X 
6. 
Marijuana Goals Questionnaire 
X 
 
 
 
 
7. 
Marijuana Craving Questionnaire 
X 
X 
X 
 
X 
8. 
Marijuana Withdrawal Checklist 
X 
X 
X 
 
X 
9.  
Marijuana Perceptions of Risk and  
 
Experiences  
X                   
X                        X  
 
Mood and Impulsivity Assessment 
10.    Quick Inventory of 
 
Depressive Symptomatology 
X 
 
X  
 
X 
11.    Beck Anxiety Inventory 
X 
 
X 
 
X 
12. Positive and Negative Affect Scale 
X 
 
X 
 
X 
13.  Barratt Impulsiveness Scale 
X 
 
X  
 
X 
Medical & Safety Assessment (medical visits) 
14. Physical examination 
X 
 
 
 
X 
15. ECG 
X 
 
 
 
X 
16. Urine pregnancy test 
X 
 
X 
 
X 
17. Laboratory testsc 
X 
 
 
 
X 
18. Adverse Events & Side Effects 
X 
X 
 
 
X 
19. Columbia Suicide Severity Rating Scale 
X 
X 
X 
 
X 
 
aFull SCID at baseline 
bTwice a week during treatment;  
cTests include urinalysis, liver function tests, electrolytes, complete blood count, & blood 
chemistries 
 
8.6.Medication Adherence Assessment.  The proposed studies involve chronic 
administration of medication given under double-blind conditions. Three methods of 


McLean Hospital Application to the Institutional Review Board (IRB) 
                                   Nabilone for Cannabis Dependence Detailed Protocol 
     
 
 
 
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medication adherence will be used as multiple methods are preferred (Weiss 2004): 1) 
pill counts will be made; 2) participants will record when they take their capsules on the 
ActiWatch-Score device; 3) urinary riboflavin levels (a 25 mg dose will be given with 
each dose of medication) will be measured using a UV spectrophotometer.  If there is a 
discrepancy among results obtained by these methods, we will meet with the participant 
and have a conversation about their medication adherence.  After the conversation, we 
will use our clinical judgment to determine the level of adherence that we believe is 
most accurate for that participant. 
 
8.8. 
Data Management 
All data collected will be de-identified with participant ID numbers and used for 
research purposes only.  Written records will be kept in a locked file cabinet in a locked 
office.  They will be destroyed after 5 years.  Computerized data files will also be de-
identified with participant ID numbers and kept in a password protected file on a 
password protected computer. 
 
8.9.  Statistical Analysis 
 
The primary data analysis will be an intent-to-treat analysis, which includes all 
randomized participants.  Of note, every attempt will be made to continue assessing 
participants even if they drop out of treatment. In addition, we will replicate all analyses 
with the completers only.  The primary and secondary outcome variables are intended 
to explore various aspects of response to therapy and to help define a clinically 
meaningful response. The primary outcome measures, Actiwatch-scores, daily diaries, 
TLFB self-report data, in addition to quantitative urinary THC metabolites, have been 
chosen for their ability to indicate daily use of cannabis by relying on self-report of use.  
 Specifically, for assessing the effect of nabilone on cannabis use patterns, we 
propose to use the generalized estimating equations (GEE) approach to longitudinal 
analysis, appropriately accounting for the positive correlation among repeated urine 
screen assessments within the same individual.   
Analyses of secondary substance use outcomes will focus on the number of days of 
cannabis use and of any substance use (and conversely, days of abstinence) during 
treatment and post-treatment follow-up.  In addition, we will also examine the ASI Drug 
and Alcohol composite scores.  Frequency of days of cannabis use (and any substance 
use and days of abstinence) will be analyzed via a log-linear (or Poisson) regression 
model, controlling for pre-treatment frequency of days of cannabis use.  Although log-
linear regression methods are considered appropriate for the analysis of count or 
frequency data, in many biomedical applications, count data have variability that far 
exceeds that predicted by the Poisson distribution; we expect that days of cannabis use 
(and any substance use and days of abstinence) will not be an exception.  Linear mixed 
effects models will be used to examine the effect of treatment group on changes in the 
ASI Drug and Alcohol composite scores during treatment and post-treatment follow-up 
assessments (as determined by the group-by-time interaction in the linear mixed effects 
regression models).  The linear mixed effects model will include random intercepts and 
slopes to appropriately account for correlation among repeated measures and 
heterogeneity of variance over time; the model will be fit using PROC MIXED in SAS.  


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                                   Nabilone for Cannabis Dependence Detailed Protocol 
     
 
 
 
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In secondary analyses of mood outcomes, mood episodes will be assessed during 
treatment and post-treatment follow-up, using the QIDS, BAI, and PANAS; changes in 
risk of mood episodes during treatment and post-treatment follow-up assessments will 
be analyzed via a logistic regression model (similar to the logistic model above) that will 
be fit using the GEE approach (as implemented in PROC GENMOD in SAS) to account 
for correlation among repeated binary outcomes on the same individual.  To examine 
the effect of nabilone on changes in risk for mood episodes during treatment and post-
treatment follow-up, the logistic regression model will include the effects of treatment 
condition and the baseline measureof the outcome.  
 
9. Human Subjects and Recruitment Strategies: 
 
9.1. 
Sample Size: In order to meet the target sample of 60 completers, we expect to 
recruit 120 participants, ages 18-45, and have 90 of them sign the informed consent 
form. 
 
9.2. 
Advertising: Participants will be recruited via websites, newspaper 
advertisements, flyers on campus, and word-of-mouth.  We will not specifically recruit 
participants from particular patient units at McLean.  Participants may not be inpatients 
at McLean at the time of their participation in the study.  
 
 
9.3. 
Inclusion criteria 
1) Age range 18-45 years; 2) DSM-IV diagnosis of cannabis dependence, based 
on the Structured Clinical Interview for DSM-IV (SCID); 3) express a desire to quit 
cannabis use within the next 30 days; 4) have used cannabis on 4 days within the past 
30 days (i.e., an average of 1 day per week); 5) for women of childbearing age, a 
negative pregnancy test at screening with agreement to use adequate contraception to 
prevent pregnancy and monthly pregnancy tests; 6) consent for us to communicate with 
their prescribing clinician; 7) furnish the names of 2 locators, who would assist study 
staff in locating them during the study period; 8) live close enough to McLean Hospital 
to attend study visits; 9) plan to stay in the Boston area for the next 3 months; and 10) 
are willing and able to sign informed consent. 
9.4. 
Exclusion criteria 
1) Current diagnosis of other drug or alcohol dependence (excluding nicotine); 2) 
recent (within 3 months) significant cardiac disease; 3) current serious psychiatric 
illness or history of psychosis, schizophrenia, bipolar type I disorder; 4) current medical 
condition (including significant laboratory abnormalities, such as liver function tests >5 
times the upper limit of normal range) that could prevent regular study attendance; 5) 
mental retardation or organic mental disorder; 6) acutely dangerous or suicidal 
behavior; 7) currently in a residential treatment setting in which substance use is 
monitored and restricted, since the restricted access to drugs could represent an 
important confounding variable; 8) pregnant, nursing, or, if a woman of childbearing 
potential, not using a form of birth control judged by the investigator to be effective; 9) 
concomitant daily treatment with opioid analgesics, sedative hypnotics, or other known 
CNS depressants; 10) known hypersensitivity to cannabinoids or sesame oil ; 11) 
disease of the gastrointestinal system, liver, or kidneys that may impede metabolism or 


McLean Hospital Application to the Institutional Review Board (IRB) 
                                   Nabilone for Cannabis Dependence Detailed Protocol 
     
 
 
 
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excretion of nabilone; 12) inability to read or write in English.  The potential hazards of a 
Schedule II medication like nabilone underscore the importance of English proficiency in 
this medication trial; 13) a history of seizures, head trauma or other history of CNS insult 
that could predispose the subject to seizures . 
 
10.  
Miscellaneous Information: 
 
 If the participant wants to terminate the study, he/she may do so at any time. 
 
 Any questions or concerns related to this study should be directed to Dr. Hill. 
 
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