Clinical trial NCT01598896
Conditions: Cannabis Dependence Marijuana Dependence
Keywords: Cannabis Dependence Marijuana Dependence Cannabis Use Disorders Cannabis Withdrawal Dronabinol Clonidine Schizophrenia
Sponsor: Mclean Hospital
Start date: 2012-05-01; Completion date: 2017-08-01
Enrollment: 12 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Cannabis use disorders are an important public health problem in the United States, but no effective pharmacotherapies are available to treat these disorders. People with schizophrenia are more likely than healthy people to abuse cannabis. Cannabis use may worsen clinical outcomes in this group, making the identification of pharmacotherapy to treat cannabis dependence in those with schizophrenia important. The investigators intend to test the combination of dronabinol, a cannabinoid agonist, and the α2-adrenergic agonist clonidine, for cannabis dependence in subjects with schizophrenia. The combination of dronabinol and clonidine may alleviate 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 dronabinol and clonidine, when added to MM, on cannabis use patterns in cannabis-dependent patients with schizophrenia.

Hypothesis: The investigators predict that combination pharmacotherapy of dronabinol and clonidine will significantly reduce cannabis use compared to those receiving placebo.

Detailed description:
Subjects will receive either the combination of dronabinol and clonidine or placebo in addition to medical management (MM) over a 10-week treatment period. Following treatment completion, subjects will have follow-up visits until 14 weeks after treatment initiation. This pilot study will evaluate the feasibility of the combination of dronabinol and clonidine for cannabis dependence and will establish effect sizes for a larger trial.

Cannabis use disorders are highly prevalent in the United States and rising among high school seniors, making the identification of efficacious treatments for cannabis dependence of critical clinical and public health significance. Schizophrenia is overrepresented among those with cannabis dependence. At the completion of this study, the investigators hope to have improved our understanding of the relationship of the pharmacotherapy combination of dronabinol and clondine on cannabis use.

Arms: arm 1: Dronabinol titrated to 5 mg three times daily, Clonidine 0.1 mg twice daily arm 2: Placebo
Interventions: intervention 1: Dronabinol intervention 2: Clonidine intervention 3: Placebo
Intervention descriptions: intervention 1: Dronabinol titrated to 5 mg three times daily intervention 2: Clonidine 0.1 mg twice daily intervention 3: One placebo capsule by mouth twice daily

Protocol documents:
Prot_SAP_001.pdf: 
 
 
1 
MCLEAN HOSPITAL IRB 
PROTOCOL SUMMARY 
 
 
Answer all questions accurately and completely in order to provide the McLean Hospital IRB with 
the relevant information to assess the risk-benefit ratio for the study.  Do not leave sections blank. 
 
1. PRINCIPAL/OVERALL INVESTIGATOR 
Kevin P. Hill, M.D., M.H.S. 
 
 
2. PROTOCOL TITLE 
Combination of Dronabinol and Clonidine for Cannabis Dependence in Patients with 
Schizophrenia  
 
3. FUNDING 
NARSAD Young Investigator Award 
 
4. VERSION DATE 7/26/16 
 
5. SPECIFIC AIMS 
Aim 1: Assess the relationship of treatment with the combination of dronabinol and 
clonidine or placebo on cannabis use patterns in cannabis-dependent subjects with 
an Axis 1 psychiatric disorder. 
 
Aim 2: Assess  the  relationship  of  treatment  with  the  combination  of  dronabinol  and 
clonidine or placebo on cannabis withdrawal symptoms in cannabis-dependent subjects 
with an Axis 1 psychiatric disorder. 
 
6. BACKGROUND AND SIGNIFICANCE 
People with schizophrenia are more likely than healthy people to abuse cannabis 
(Kovasznay  et  al.  1997).  Although  it  is  unclear  why  this  is  true,  pati ents  with 
schizophrenia may use cannabis to alleviate unpleasant affective symptoms (Gregg et 
al. 2007). Cannabis dependence may trigger psychotic symptoms and worsen the 
outcome of the disease in this group (Linszen et al. 1994).    Unfortunately, effective 
medications for cannabis-dependent schizophrenic individuals have not been identified. 
Combinations of medications may offer advantages not available with monotherapy. Haney  
et al. (2008) showed that the combination of THC and the α2-adrenergic receptor  
agonist lofexidine decreased symptoms of cannabis withdrawal, craving, and relapse  
in a human lab study of daily cannabis smokers. Although lofexidine is not approved  
for use by the United States Food and Drug Administration (FDA), clonidine, another  
α2- adrenergic receptor agonist, is FDA-approved and commonly used in clinical  
practice. Therefore,  we  build  upon  this  exciting  finding  by  proposing  a  pilot  study   
of  the combination of THC, specifically Dronabinol (Marinol®, Solvay Pharmaceuticals,  
Marietta, GA, or generic, specific manufacturer to be determined)  which is an  
orally-active cannabinoid agonist that is approved by the FDA for the treatment of  
anorexia associated with weight loss in patients with AIDS and nausea and vomiting  
associated with cancer chemotherapy (Marinol® product information); and clonidine as 
 a treatment for cannabis dependence in schizophrenic individuals. 
Our study may provide initial evidence for a readily available, effective treatment for 
cannabis dependence in subjects with schizophreni a. This combination treatment may 
reduce cannabis withdrawal symptoms that function as an obstacle for subjects with 
schizophrenia trying to stop using cannabis. 
 
 
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Version Date:  July 26, 2016 
7. RESEARCH DESIGN AND METHODS 
Briefly describe study design and ant icipated enrollment, i.e., number of subjects to be enro lled 
by researchers study-wide and by McLean researchers.  Provide a brief summary o f the 
eligibilit y criteria (for example, age range, gender, medical condit io n) .  Include any local site 
restrict ions, for example, “Enro llment at McLean will be limited to adults although the sponsor’s 
protocol is open to both children and adults.” 
 
8.1.    Overview 
W e will conduct a Stage 1 pilot feasibility study at McLean Hospital to develop a 
combination of medication protocol to   treat  cannabis  dependence   in  subjects   with  
schizophrenia, schizoaffective, or any Axis I disorder.  In  a randomized,  double-blind,  
placebo-controlled  trial,  18  cannabis-dependent  male  an female subjects ages 18-45 
with an Axis 1 psychiatric disorder will receive medical management (MM) over a 10-
week period, with half receiving treatment with the combination of dronabinol and 
clonidine and half receiving placebo. Subjects will receive either the combination of 
dronabinol 5 mg by mouth three times daily and clonidine 0.1 mg my mouth twice daily 
or placebo in addition to MM over a 10-week treatment period. A follow-up visit after 
treatment at week 14 will evaluate the durability of treatment effects on drug use and 
psychosocial outcomes. Primary outcomes will include self-report of cannabis smoking 
and  results  of  quantitative  urine  drug  screens  for  cannabis.  W e  also  will  assess 
cannabis withdrawal symptoms, including mood and craving. Mixed models ANOVA will 
be used to analyze the data. 
 
 
8.2.    Participants 
Subjects are cannabis-dependent male and female volunteers with mental illness 
ages 18-45 years old and will be recruited via newspaper advertisements, word of 
mouth, web-based advertisements, and the Psychotic Division Clinical Research Core 
(Protocol # 2009-P-002016).. 
A total of 18 cannabis-dependent volunteers with (9 men, 9 women) an Axis 1 psychiatric  
Disorder will serve as subjects. Factoring in a potential 20% dropout of those who actually 
begin the protocol, we estimate that 7-8 people will probably be exposed to dronabinol in this 
pilot study. In order to meet the target sample of 18 completers (8 subjects per group), we 
expect to recruit about 50 subjects and have 35 sign the informed consent form. Of those  who  
sign  the  informed  consent  form,  14-18  will  probably  end  up  being randomized. 
W omen must use a medically-approved method of contraception to participate in the 
study (e.g. birth control  pills, IUD, condoms). During the physical, the physician will 
ensure that the potential volunteer is using adequate methods to prevent pregnancy. 
 
 
Briefly describe study procedures.  Include any local site restrict ions, for example, “Subjects 
enro lled at McLean will not participate in the pharmacokinet ic portion of the study.”  Describe 
study endpo ints. 
 
 
 
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 
 
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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.  We  may  also  send  letters  to  individuals  from  the  "Gene 
regulation and linkage analysis in bipolar disorder and schizophrenia" study (protocol 
number: 2004p002535) who have previously consented to being contacted by letter. 
 
Psychiatric  Evaluation.     A  Structured  Clinical  Interview-  DSM-IV  (SCID)  will  be 
performed by a qualified research assistant, clinical psychologist, or psychiatrist. 
 
Physical Exam.  The medical exam will be performed by a physician.  A blood draw and 
12-lead ECG will be performed by a research assistant; results will be interpreted by a 
study physician. 
 
Safety Monitoring. The subjects will undergo the following screening procedures: a) 
Detailed   history   of   cannabis   use;   b)   Review  of   DSM-IV   criteria   for   cannabis 
dependence;  c)  Review  of  DSM-IV  criteria  for  schizophrenia  and  schizoaffective 
disorder; d) Medical  history and  concomitant  medication  record; e) Physical 
examination; f) Laboratory screen that includes CBC, electrolytes, and BUN/creatinine; 
g) Urine measurement of THC; h) Urinalysis and urine pregnancy test for women; i) 12- 
lead electrocardiograph (ECG); j) urine toxicology screen; k) blood alcohol testing; l ) 
Positive and Negative Syndrome Scale (PANSS); m) Columbia Suicide Severity Rating 
Scale (C-SSRS). 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, 5, 
10, and 14 weeks as well. Given that according to its labeling, dronabinol should not be 
taken  with  alcohol,  sedatives,  hypnotics,  or other  psychoactive  substances  because 
they could potentiate the central nervous system effects of dronabinol, urine toxicology 
and blood alcohol testing will be done weekly along wi th the twice weekly quantitative 
THC urine screens during treatment. W omen of childbearing potential will have urine 
pregnancy tests weekly each time a urine sample is given in addition to pregnancy tests 
at 4 and 8 weeks during treatment; women who become pregnant will have their 
medication discontinued and will be referred to an obstetrician; like all subjects, they will 
still be followed for research visits. Suicide risk will be assessed by the physician at 
each MM visit. 
 
Study Restrictions 
Subjects will be instructed to keep us informed of any medications initiated after their 
enrollment in the study. Subjects will be reminded of the potential for additive CNS 
depression resulting from concomitant use of dronabinol and alcohol, opioid analgesics, 
benzodiazepines,  and  barbiturates.  They  will  be  warned  initially  of  these  potential 
additive effects during the informed consent process. Participants will be warned not to 
drive,  operate  machinery,  or  engage  in  any  hazardous  activity  while  receiving 
dronabinol.  Subjects  will  also  be  informed  that  clonidine  may  cause  drowsiness, 
dizziness, or lightheadedness associated with orthostatic hypotension. These effects 
may be worse if taken with alcohol or other medications that can cause drowsiness. 
Subjects will be warned not to abruptly stop taking clonidine. 
 
 
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Subjects will also be informed that data on the use of antipsychotic medications and 
dronabinol and/or clonidine is lacking. Due to the potential for sedation and possible 
hypotension in subjects taking these medications together, we will monitor carefully for 
these symptoms while educating subjects about these possible side effects. 
 
8.2.1.b. 
 
Informed consent. Eligible subjects 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.      Research staff will stratify subjects 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., dronabinol-clonidine 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.    W e  plan  to  screen  50 
subjects in the course of 20 months to achieve our desired sample size. 
 
8.2.1.e.  Study Visits. Following eligibility for the study (as determined by the baseline-1 
visit), subjects will come to the laboratory for a baseline-2 visit to complete research 
assessments,  provide  a  urine  sample,  and  begin  daily  diaries  and  Actiwatch  (see 
Section 8.5.2.a.)Subjects will then come to the clinic twice a week during the study 
medication treatment phase.   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 a follow-up assessment visit at 14 weeks. . Subjects will  also 
come in once weekly during weeks 11, 12, and 13 following the 10-week treatment 
period to provide a urine sample, and hand in daily diaries/actiwatch. 
 
 
Subjects will be randomized to receive either dronabinol and clonidine or placebo. 
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: 2 capsules three times 
daily for 10 weeks. Each capsule will contain either dronabinol, clonidine, or placebo. 
Subjects in the dronabinol-clonidine group will take 5 mg of dronabinol three times daily 
for 10 weeks (between 7:00-9:00 AM, 3:00-5:00 PM and 9:00-11:00 PM). Subjects in 
this group will also take clonidine 0.1 mg po bid (between 7:00-9:00 AM and 9:00-11:00 
PM) for 8 weeks, followed by a taper to cl onidine 0.1 mg po qhs for the last 2 weeks of 
 
 
 
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the protocol. 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. 
See Table 1 for a schedule of study visits. 
 
Table 1  Schedule of Measures 
Measur e                                                          Baseline 1 and 2 Weekl y   Monitoring   Follow-up    Week 14 
Week 1 
Weeks 5,10 
 
Diagnostic Assessment 
1.  Structured Clinical Interview 
 X B1 
for DSM-IVa 
Drug and Alcohol Assessment 
2.  Quantitative Urine Toxicological 
XB1,B2 
Xb 
X 
X 
X 
Analysisb 
3.  Addiction Severity Index                          XB2                                       X               X                      X 
4.  Drug and Alcohol Use Questionnaire       XB1 
5.  Weekly Drug and Alcohol Use Inventory XB1,B2               X               X              X                      X 
6.  Marijuana Goals Questionnaire                XB1 
7.  Marijuana Craving Questionnaire            XB1,B2               X               X               X                      X 
8.  Marijuana Withdrawal Checklist              XB1,B2               X               X               X                      X 
Mood and Impulsivity Assessment 
9. Quick Inventory of Depressive 
Symptomatology 
XB1,B2 
X 
X 
10. Barratt Impulsiveness Scale 
XB1,B2 
X 
X 
11. Beck Anxiety Inventory 
XB1,B2 
X 
X 
Medical & Safety Assessment 
12.  Physical examination 
XB1 
X 
13. ECG 
XB1 
X 
14.  Urine pregnancy test 
XB1,B2 
X 
X 
X 
X 
 
15. Vital Signsc 
XB1,B2 
X 
X 
X 
X 
16. Positive and Negative Syndrome Scale XB1,B2 
17. Behavioral Activity Rating Scale 
XB1 
X 
18. Laboratory testsd 
XB1 
X 
X 
19. Adverse Events & Side Effects 
XB1,B2 
X 
X 
X 
X 
20. Columbia Suicide Severity 
XB1 
X 
X 
X 
X 
21. Marijuana Perceptions of Risk and           XB1                                                        X                       X 
Experiences Questionnaire (MPRE) 
Rating Scale 
 
aFull SCID at baseline 
bTwice a week during treatment 
cVital Signs include pulse and blood pressure (sitting and standing) 
dTests include urinalysis, liver function tests, electrolytes, complete blood count, & blood chemistries 
B1= Baseline 1 (screening visit) 
B2=Baseline 2 (baseline 2 visit post screen for subjects who qualify for participation before treatment begins) 
 
8.2.1.f.  Clinical Emergencies.  If a subject is intoxicated, the subject will be evaluated 
medically, sent home in a taxi  when safe, and the appointment re-scheduled.   If a 
subject 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 subject 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. 
 
 
 
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8.2.1.g.  Subject Payments.  Volunteers will receive a $50 honorarium for attending the 
initial assessment interview, $25 for baseline-2 visit, and $50 for follow-up visits at 5, 10, 
and 14 weeks.  They may earn $25 for each urine sample given on a non-MM day in the 
first 5 weeks of the treatment and $30 for each urine sample given on a non -MM day 
during the last 5 weeks of treatment.   They will be compensated $50 for the W eek 1 
monitoring visit and $30 for each of three actiwatch diary UA visits at wks 11,12, and 13. 
They may also receive a bonus of up to $100 for successful completion of all diaries. 
They may earn a total of $740 for their participation in the study.   Medication will be 
free. 
A payment request will be submitted for each part of the study they finish. The 
research assistants will arrange for payment to be sent via mail to the subjects. 
 
8.3. Treatment. (Dr. Hill has been granted IND 108676 by the FDA to use this 
medication combination in this protocol.) 
Dronabinol  (Marinol®,  Solvay  Pharmaceuticals,  Marietta,  GA)  is  an  orally-active 
cannabinoid  agonist  that  is  approved  by  the  FDA  for  the  treatment  of  anorexia 
associated with weight loss in patients with AIDS and nausea and vomiting associated 
with cancer chemotherapy (Marinol® product information).  Dronabinol will be titrated to 
5  mg three times daily in the dronabinol-clonidine group. Doses of up to 90 mg of 
dronabinol  daily  have  been  well-tolerated  in  studies  of  its  effects  upon  cannabis- 
dependent individuals (Levin and Kleber 2008, Haney et al. 2008, Haney et al. 2004, 
Budney et al. 2007). 
Clonidine (Catapres®, Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT) is α2- 
adrenergic  agonist  that is approved  by  the FDA  for  the treatment  of  hypertension 
(Catapres® product information).  Clonidine will be administered at 0.1 mg twice daily in 
the dronabinol-clonidine group prior to a 2-week taper to clonidine 0.1 mg po qhs. 
Placebo will be vegetable capsules (Gallipot, Inc., St. Paul, MN) double 
encapsulated into 00 capsules. 
Physicians  are  ACLS-trained  and  have  access  to  a  “crash  cart” located in  the 
laboratory.  All  study  personnel  are  basic  life  support-trained  and  have  practiced 
assisting a physician in the event of an emergency. 
 
8.3.1.c.  Dose Adjustment. 
Subjects  who experience uncomfortable side effects (e.g., drowsiness or vertigo) 
may have their dose lowered from 2 capsules three times a day to 2 capsules twice 
daily by eliminating the middle dose of the day; a subject receiving active medication, 
for example, could then have a dronabinol dose reduction to 10 mg of dronabinol daily. 
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 it, the subject will be maintained on the lower dose. If a subject cannot tolerate 
2  capsules  twice  per  day,  the  medication will  be  discontinued, and the subject will 
be tapered off of the Clonidine, but  the  subject  will continue to be followed for research 
visits. Similarly, we will monitor for potential cardiovascular side effects resulting from 
clonidine pharmacotherapy. At each medical management visit, we will assess vital 
signs and ask the subject about symptoms of orthostatic hypotension, such as dizziness 
when rising to stand from a seated position, blurry vision, or weakness. If subjects 
describe these symptoms without meeting exclusionary blood pressure criteria, we will 
hold the third set of capsules to see 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 
 
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it, the  subject  will  be  maintained on  the lower  dose.  If  a  subject  cannot  tolerate 2 
capsules twice 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. Subjects 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 subject is not adherent to the medication 
regimen,  the  clinician  evaluates  the  reasons  and  helps the  subject  devise  plans  to 
enhance medication adherence. Subjects 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” (W isniewski 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. 
 
8.5. Research Measures. 
See Table 8.2 for the schedule of assessments. 
 
8.5.1. Diagnostic Assessment.  To make the diagnoses 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.  .  Quantative 
urine screens will also be measured during weeks 11, 12, 13, and 14 following the 10- 
week  treatment  period.  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.  W e  will  send  the  urine  samples  to  Quest 
Diagnostics Laboratory  (Cambridge, MA, a NIDA-certified laboratory), where the urines 
 
 
 
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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. W e 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. W e 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 subject also reports using no 
cannabis since the previous urine test. 
 
8.5.2.b.  Self-Report.  W e will use 3 methods of self-report in an effort to determine the 
most appropriate and effective method for use in this population. An ActiW atch-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). W e will provide subjects with a packet of 1 page, self- 
addressed, prepaid postage Daily Diary pages which subjects will be asked to fill out 
between 7:00 and 9:00 a.m. each day and.hand them in during their weekly visits. The 
diary consists of a series of questions about marijuana and other drug use as well as 
eating  habits. During weeks 11, 12, and 13 subjects will have 1 weekly Diary/Actiwatch 
visit to hand in their daily diaries, , provide a urine sample, and have their Actiwatch 
data downloaded. 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 
5,10, 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  marijuana  use  (urine 
screens plus days of use), we will examine other substance use (using urine screens 
plus days of other substance use). W e will use this method to determine the number of 
days of marijuana use and of any substance use (and conversely, days of abstinence). 
W e  will  examine  ASI  composite  scores  as  secondary  measures  of  substance  use 
outcome. W e 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 W eekly 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 subject is 
seeking abstinence or reduction in marijuana use. A 12-item self-administered 
questionnaire, the Marijuana Craving Questionnaire, will be used to assess craving at 
 
 
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baseline and weekly during treatment and at the 14-week follow-up visit (Heishman et 
al. 2009).   A short form of the Marijuana W ithdrawal Checklist 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 subject 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 subject. 
A 6-page questionnaire that we created titled Marijuana Perceptions of Risk and 
Experiences (MPRE), will be distributed at baseline, and once during weeks 5, 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.       W e will monitor subjects’ mood and 
impulsivity throughout the study using 3 assessments. The Beck Anxiety Inventory (BAI) 
is a 21-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 
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. 
 
 
 
8.6.       Medication Adherence Assessment.       The proposed studies involve chronic 
administration of medication given under double-blind conditions. Three methods of 
medication adherence will be used as multiple methods are preferred (W eiss 2004): 1) 
pill counts will be made; 2) subjects will record when they take their capsules on the 
ActiW atch-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 subject 
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 subject. 
 
 
8.8. 
Data Management 
 
All data collected will be de-identified with subject 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 subject 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  subjects.  Of  note,  every  attempt  will  be  made  to  continue  assessing 
subjects even if they drop out of treatment. In addition, we will replicate all anal yses with 
the completers only. The primary and secondary outcome variables are intended to 
 
 
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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 dronabinol and clonidine 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) duri ng 
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 i n 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. 
In secondary analyses of mood outcomes, mood episodes will be assessed during 
treatment  and  post-treatment  follow-up,using  the  QIDS-SR,  ,  BAI,  and  BIS-11;  ; 
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 dronabinol and clonidine 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 measure of the 
outcome. 
 
 
 
For studies invo lving treatment or diagnosis, provide informat ion about standard of care at 
McLean (e.g., BWH, MGH) and indicate how the study procedures differ from standard care. 
Provide informat ion on available alternat ive treatments, procedures, or methods of diagnosis. 
 
 
The standard of care for cannabis dependence is psychotherapy; our treatment 
centers upon a medication. 
 
 
Describe how risks to subjects are minimized, for example, by using procedures which are 
consistent with sound research design and which do not unnecessarily expose subjects to risk or 
by using procedures already being performed on the subject for diagnostic or treatment purposes. 
\ 
 
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Care will be taken to minimize risk. In addition to carefully screening prior to 
enrollment, we have scheduled regular laboratory visits during which we will carefully 
monitor response to medication or placebo with respect to side effects and changes in 
mood. 
 
 
 
Describe explicit ly the methods for ensuring the safet y of subjects.  Provide object ive criteria for 
removing a subject from the study, for example, object ive criteria for worsening disease/lack of 
improvement and/or unacceptable adverse events.  The inclusio n of object ive drop criteria is 
especially important in studies designed with placebo control groups. 
 
8.3.1.b.  Safety Monitoring. 
In order to monitor potential side effects from the initial dose of dronabinol, subjects 
will be observed at the laboratory facility for 4 hours following the following the first dose 
of the day in week 1. Subjects will come into the Behavioral Psychopharmacology 
Research Laboratory 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). Subjects will remain in the natural 
settings laboratory for a minimum of 2 hours and a maxi mu m of 6 hours while having 
vital signs taken every 30 minutes. Subjects will be allowed to leave the facility by cab 
after being cleared by a study physician. Subjects will be allowed to leave the facility if 
they have 1) pulse rate greater than or equal to 50 beats per minute or less than or 
equal to 135 beats per minute; 2) blood pressure less than or equal to 140/90 and 
greater than or equal to 90/50; and 3) Behavioral Activity Rating Scale (BARS) score of 
less than 6. If pulse is decreasing, blood pressure is increasing, or BARS is increasing 
at the 2-hour assessment, the subject will remain an addition 30 minutes until the trend 
for these parameters is in the correct direction and the subject meets criteria for medical 
clearance. 
During the 10-week treatment period, subjects will be seen for a MM visit and for 
urine screen visit. Medication compliance and side effects will be monitored at all visits. 
The initial visit in week 1 will include a monitored administration of medication described 
above. Subjects will have follow-up visits at 5, 10 and 14 weeks that will include a urine 
screen, blood sampling for laboratory testing, as well as evaluation for medication side 
effects. 
 
Stopping Criteria. New psychotic symptoms thought to be related to dronabinol 
administration that are present at any pre-dose assessment or that remain present at 
the end of a 2-hour monitoring period will result in stopping of dronabinol. Clonidine 
stopping  criteria  include  bradycardia  less  than  or  equal  to  50  bpm,  supine  blood 
pressure of less than or equal to 100/65, a seated blood pressure of less than or equal 
to 90/60, or orthostatic change of >20 systolic or >10 diastolic on standing, at screening 
or any pre-dose assessment, or symptoms attributable to low BP (i.e. lightheadedness 
or dizziness on standing). Adverse events or side effects resulting from administration of 
either  dronabinol  or  clonidine  that  persist beyond  7  days  will  warrant  a  call  to  the 
subjects PCP if they have one, and a decision will be made by the study physician 
about possible continued participation. If the subject is stopped, they will be followed for 
follow-up visits only. 
Clinically significant lab abnormalities (liver function tests ≥3X normal, for example) 
will be rechecked immediately and, if determined to be clinically significant by the study 
 
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physician, the subject will be removed from the protocol and followed for follow-up visits 
only. W orsening psychotic symptoms that predated study medication will warrant a call 
to the subject’s psychiatrist and possible removal  from the protocol if the patient is 
thought to be unstable by either the outpatient psychiatrist or the study physician. 
Similarly,  suicidal  ideation  will  warrant  contact  with  the  outpatient  psychiatrist  and 
possible removal from the protocol. Suicidal ideation with a plan will result in immediate 
removal from the protocol and the subject will be escorted by staff to the Psychiatric 
Emergency Room. 
Events that may lead to stopping of the study include physiological side effects 
attributed to study medication such as seizure, psychomi metic reactions (hallucinations, 
paranoia, etc.), suicide, or other deaths. If any one of these occurs in 2 subjects, we will 
consider stopping the study if those effects can reasonably be associated with study 
participation. Due to the potential of dronabinol to lower seizure threshold, we will halt 
the  study if  2  subjects  have seizures during  their  participation.  If  any  one  besides 
seizure occurs in 3 subjects, we will halt the study. 
 
 
 
FORESEEABLE RISKS AND DISCOMFORTS 
Provide a brief descript ion of any foreseeable risks and discomforts to subjects.  Include those 
related to drugs/devices/procedures being studied and/or administered/performed solely for 
research purposes.  In addit ion, include psychosocial risks, and risks related to privacy and 
confident ialit y.  When applicable, describe risks to a developing fetus or nursing infant. 
 
 
The screening process and questions related to a subject’s psychiatric history may 
cause discomfort. W hile dronabinol is FDA-approved for treatment of nausea related to 
cancer chemotherapy, subjects may experience side effects when taking nabilone, 
including hallucinations, paranoia, extreme fear; fast heart rate; feeling light-headed, 
fainting; or unusual thoughts or behavior.  Less serious side effects are also possible 
including drowsiness, euphoria, weakness, lack of coordination; depression, anxiety, 
confusion, dry mouth; headache, trouble concentrating; insomnia. Subjects will also be 
informed that clonidine may cause drowsiness, dizziness, or lightheadedness 
associated with orthostatic hypotension. These effects may be worse if taken with 
alcohol or other medications that can cause drowsiness. Subjects will be warned not to 
abruptly stop taking clonidine. 
 
EXPECTED BENEFITS 
Describe both the expected benefits to individual subjects participat ing in the research and the 
importance of the knowledge that may reasonably be expected to result fro m the study.  Provide 
a brief, realist ic summary of potential benefits to subjects, for example, “It is hoped that the 
treatment will result in a partial reduction in tumor size in at least 25% of the enrolled subjects.” 
Indicate how the results of the study will benefit future patients with the disease/condit ion being 
studied and/or societ y, e.g., through increased knowledge of human physio logy or behavior, 
improved safety, or techno logical advances. 
 
 
At the completion of this study, we hope to have improved our understanding of 
the relationship of the combination of dronabinol and clonidine on cannabis use. 
 
 
 
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EQUITABLE SELECTION OF SUBJECTS 
The risks and benefits of the research must be fairly distributed among the populat ions that stand 
to benefit from it.  No group of persons, for example, men, women, pregnant women, childr en, 
and minorit ies, should be categorically excluded from the research wit hout a good scient ific or 
ethical reason to do so. Please provide the basis fo r concluding that the study population is 
representative of the population that stands to potent ially benefit fro m this research. 
Men, women, and minorities will all be recruited.  Pregnant women and children 
will be excluded in part due to the lack of data on the safety of dronabinol in these 
groups. 
 
When people who do not speak English are excluded from participat ion in the research, provide 
the scient ific rationale for doing so.  Individuals who do not speak English should not be denied 
participat ion in research simply because it is inconvenient to translate the consent form in 
different languages and to have an interpreter present. 
Proficiency in English is necessary for a long-term treatment study that includes 
10 MM sessions and ensures that the participants can properly convey any subtle side 
effects that relate to their safe participation in this study. 
RECRUITMENT PROCEDURES 
Explain in detail the specific methodology that will be used to recruit subjects.  Specifically 
address how, when, where and by who m subjects will be ident ified and approached about 
participat ion.  Include any specific recruit ment methods used to enhance recruit ment of women 
and minorit ies. 
 
9.  Human Subjects  and Recruitment  Strategies: 
 
9.1. 
Sample Size:  In order to meet the target sample of 18, W e plan to screen 50 
subjects ages 18-45 in the course of 20 months to achieve our desired sample size. 
 
9.2.     Advertising:  Subjects will be recruited via websites, newspaper advertisements, 
flyers on campus, word-of-mouth, and the Psychotic Division Clinical Research Core. 
W e will not specifically recruit subjects from particular patient units at McLean. Subjects 
may not be inpatients at McLean at the time of their participation in the study. 
 
9.3.    Inclusion criteria 
Inclusion: 
1) Age range 18-45 years; 2) DSM-IV diagnosis of cannabis dependence, based on 
the Structured Clinical   Interview for DSM-IV (SCID); 3) DSM-IV diagnosis of 
an Axis 1 psychiatric disorder, based on the Structured Clinical Interview for DSM-IV 
(SCID); 4) express a desire to quit cannabis use within the next 30 days; 4) have 
used cannabis on 20 days within the past 30 days (i.e., an average of
5 day per 
week); 5) identify cannabis as their primary drug of abuse; 6) stable on antipsychotic 
medication for   1 month; 7) for women of childbearing age, a negative pregnancy test at 
screening with agreement to use adequate contraception to prevent pregnancy and 
monthly  pregnancy  tests;  8)  consent  for  us  to  communicate  with  their  prescribing 
clinician if one exists; 9) furnish the names of 2 locators, who would assist study staff in 
locating them during the study period; 10) live close enough to McLean Hospital  
to attend study visits; 11) plan to stay in the Boston area for the next 3 months;  
12) are willing and able to sign informed consent; and 13) must be psychiatrically stable,  
with no psychiatric medication changes in the 4 weeks prior to their screening visit.  
 
 
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9.4. 
Exclusion criteria 
1) Current diagnosis of other drug or alcohol dependence (excluding nicotine); 2) 
significant cardiac disease as indicated by history or suspected by abnormal ECG or 
history of cardiac symptoms; 3) Positive and Negative Syndrome Scale (PANSS) 
subscale for positive symptoms of psychosis item > 3 (moderate) at baseline evaluation; 
4) current medical condition that could prevent regular study attendance; 5) liver 
function tests >3 times the upper limit of normal range; 6) history of seizure disorder or 
history of head trauma or CNS insult that could predispose the subject to seizures; 7) 
taking Clozapine, Wellbutrin, Mirtazapine, and/or Guanfacine; 8) current suicidal risk; 9) 
bradycardia less than or equal to 50 bpm, supine blood pressure of less than or equal 
to 100/65, a seated blood pressure of less 
than or equal to 90/60, or orthostatic change of >20 systolic or >10 diastolic on 
standing, at screening or any pre-dose assessment, or symptoms attributable to low BP 
(i.e. lightheadedness or dizziness on standing); 10) mental retardation or organic mental 
disorder; 11) 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; 12) pregnant, nursing, or, if a woman of childbearing 
potential, not using a form of birth control judged by the investigator to be effective; 13) 
concomitant treatment with opioid analgesics, sedative hypnotics, or other known CNS 
depressants; 14) known hypersensitivity to cannabinoids or sesame oil or clonidine; 15) 
disease of the gastrointestinal system, liver, or kidneys that may impede metabolism or 
excretion of dronabinol; 16) inability to read or write in English that would hinder their 
ability to follow study procedures; 17) history of seizures or a family history of seizures. 
 
Provide details o f remunerat ion, when applicable.  Even when subjects may derive medical 
benefit from participat ion, it is often the case that extra hospital visits, meals at the hospital, 
parking fees or other inconveniences will result in addit ional out -of-pocket expenses related to 
study participation.  Invest igators may wish to consider providing reimbursement for such 
expenses when funding is available 
Subject Payments. Volunteers will receive a $50 honorarium for attending the initial 
assessment interview, $25 for baseline-2 visit, and $50 for follow-up visits at 5, 10, and 
14 weeks.  They may earn $25 for each urine sample given on a non-MM day in the first 
5 weeks of the treatment and $30 for each urine sample given on a non -MM day during 
the last 5 weeks of treatment. They will be compensated $50 for the W eek 1 monitoring 
visit and $30 for each of three actiwatch diary  UA visits at weeks 11, 12, and 13. They 
may also receive a bonus of up to $100 for successful completion of all diaries.  They 
may earn a total of $740 for their participation in the study. Medication will be free. 
A payment request will be submitted for each part of the study they finish.  The 
research assistants will arrange for payment to be sent via mail to the subjects. 
CONSENT PROCEDURES 
Explain in detail how, when, where, and by who m consent is obtained, and the timing of consent 
(i.e., how long subjects will be given to consider participat ion).  For most studies invo lving more 
than minimal risk and all studies invo lving invest igational drugs/devices, a licensed physician 
invest igator must obtain informed consent.  When subjects are to be enrolled fro m among the 
invest igators’ own patients, describe how the potent ial for coercion will be avo ided. 
 
Informed consent. Eligible subjects 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 
 
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it in detail with the volunteer.  After a physician answers any questions the volunteer 
may have concerning the study, he/she will be asked to provide their informed 
consent.  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. 
DATA AND SAFETY MONITORING 
Describe the plan for monitoring the data to ensure the safety of subjects.  The plan should 
include a brief description of (1) the safet y and/or efficacy data that will be reviewed; (2) the 
planned frequency of review; and (3) who will be responsible for this review and for determining 
whether the research should be altered or stopped.  Include a brief descript ion of any stopping 
rules for the study, when appropriate.  Depending upon the risk, size and co mplexit y o f the 
study, the invest igator, an expert group, an independent Data and Safety Monitoring Board 
(DSMB) or others might be assigned primary responsibilit y for this mo nitoring act ivit y. 
 
NOTE: Regardless of data and safety mo nitoring plans by the sponsor or others, the principal 
invest igator is ult imately responsible for protecting the rights, safet y, and welfar e of subjects 
under his/her care. 
 
 
Safety Monitoring.  Dronabinol and clonidine both have been shown to have favorable 
safety profiles; they have been well-tolerated in several clinical trials and few adverse 
events   have   been   reported.   Nonetheless,   we   will   monitor   safety   through   the 
standardized methods described above in the MM visits. W e will have a low threshold 
for obtaining additional medical workup during the study if the subject reports medical 
symptoms.   If   a  subject   has  a  clinically  significant  laboratory   or   other  medical 
abnormality that cannot be attributed to another cause, the subject’s medication will be 
discontinued and the subject will be followed for research visits. 
 
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  24  weeks.  Laboratory  data 
(urinalysis,  blood  chemistries,  complete  blood  count,  electrolytes,  and  liver  function 
tests) will be done at baseline and 5, 10, and 14 weeks as well. W omen of childbearing 
potential will have urine pregnancy tests at 4, 8, and 14 weeks during the study; women 
who become pregnant will have their medication discontinued and will be referred to an 
obstetrician; like all subjects, they will still be followed for research visits. 
 
 
 
Describe the plan to be fo llowed by the Principal Investigator/study staff for review of adverse 
events experienced by subjects under his/her care, and when applicable, for review of sponsor 
safet y reports and DSMB reports.  Describe the plan for reporting adverse events to the sponsor 
and the McLean IRB and, when applicable, for submitting sponsor safet y reports and DSMB 
reports to the McLean IRB.  When the invest igator is also the sponsor of the IND/IDE, include 
the plan for reporting of adverse events to the FDA and, when applicable, to invest igators at 
other sites. 
 
NOTE: In addit ion to the adverse event reporting requirements of the sponsor, the principal 
invest igator must fo llow the McLean Hospital IRB guidelines for Adverse Event Reporting 
 
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The Principal Investigator assumes responsibility for ensuring informed consent, 
data management, and the detection and reporting of adverse events.  In general, the 
data to be reviewed will include screening data, baseline data, efficacy data, safety 
data, quality assurance data, accrual status including projections, and any other data 
that will help in the assessment of the effectiveness of the clinical trial. 
The risk associated with participating in this study is moderate. Dronabinol has 
been established as a safe treatment for nausea associated with cancer chemotherapy. 
Clonidine is a safe treatment for hypertension.  Consequently, serious side effects 
associated with this treatment are not expected. There will be on-call medical coverage 
to respond to any adverse events throughout the clinical trial. 
The Principal Investigator will conduct a review of all adverse events and 
determine the attribution and grade of severity of the adverse event by using the 
following scales: 
Attribution of Risk Categories: 
Definite:  Adverse event(s) will clearly be related to investigational agent(s) or 
other intervention 
Probable: Adverse event(s) will likely be related to investigational agent(s) 
Possible: Adverse event(s) may be related to investigational agent(s) 
Unlikely:  Adverse event(s) will doubtfully be related to investigational agent(s) 
Unrelated: 
Adverse event(s) will clearly not be related to the investigational 
agents(s) 
Grades of Risk: 
0:  No adverse event or within normal limits 
1:  Mild adverse event 
2:  Moderate adverse event 
3:  Severe adverse event resulting in hospitalization or prolongation of existing 
hospitalization, a persistent or significant disability/incapacity, or a congenital 
anomaly/birth defect 
4:  Life-threatening or disabling adverse event 
5:  Fatal adverse event 
Serious adverse events (SAEs) include any untoward medical occurrence that at 
any dose results in death or the immediate risk of death, hospitalization or the 
prolonging of an existing hospitalization, persistent or significant disability/incapacity or 
a congenital anomaly/birth defect. Subjects will be terminated from participation if the 
investigator feels that subjects' health or well-being may be threatened by continuation 
in the study. Serious unanticipated adverse events will be reported within 48 hours to 
the McLean Hospital IRB and NIDA. W e will directly report to the FDA whenever their 
magnitude or frequency exceeds expectations. The principal investigator will evaluate 
the adverse event and determine whether the adverse event affects the Risk/Benefit 
ratio of the study and whether modifications to the protocol are required. In addition, he 
will conduct a review of all adverse events at least semi -annually, and he will evaluate 
the frequency and severity of the adverse events and determine if modifications to the 
protocol or consent form are required. 
MONITORING AND QUALITY ASSURANCE 
Describe the plan to be fo llowed by the principal investigator/study staff to monitor and assure 
the validit y and integrit y of the data and adherence to the IRB-approved protocol.  Specify who 
will be responsible for monitoring, and the planned frequency of monitoring.  For example, 
 
 
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specify who will review the accuracy and co mpleteness of case report form entries, source 
documents, and infor med consent. 
 
NOTE: Regardless of mo nitoring plans by the sponsor or others, the principal invest igator is ult 
imately responsible for ensuring that the study is conducted at his/her investigative site in 
accordance with the IRB-approved protocol, and applicable regulations and requirements of the 
IRB. 
 
The research assistants will be responsible for day-to-day monitoring of the 
validity and integrity of the data. Dr. Hill will meet with the research assistants to discuss 
data monitoring on a monthly basis and will sample subject data folders monthly as well. 
 
For guidance, refer to the fo llowing McLean policies: 
Data and Safet y Monitoring Plans and Quality Assurance 
Adverse Event Reporting Guidelines 
PRIVACY AND CONFIDENTIALITY 
Describe methods used to protect the privacy of subjects and maintain confident ialit y of data 
collected.  This typically includes such pract ices as subst ituting codes for names and/or medical 
record numbers; removing face sheets or other ident ifiers from completed 
surveys/quest ionnaires; proper disposal of printed computer data; limit ed access to study data; 
use of password-protected computer databases; training for research staff on the importance of 
confident ialit y o f data, and storing research records in a secure location. 
 
NOTE: Additional measures, such as obtaining a Certificate of Confidentialit y, should be 
considered and are strongly encouraged when the research invo lves the collection of sensit ive 
data, such as sexual, criminal or illegal behaviors. 
 
Data Management 
 
All data collected will be de-identified with subject ID numbers and used for 
research purposes only.  W ritten 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 subject ID numbers and kept in a password protected file on a password 
protected computer. 
 
To help us protect patient privacy, we have obtained a Certificate of Confidentiality 
From the National Institutes of Health.  We can use this Certificate to legally refuse to disclose 
information that may identify a patient in any federal, state, or local civil, criminal, 
administrative, legislative, or other proceedings. The Certificate cannot be used to resist a 
demand for information from personnel of the United States Government that is used for auditing 
or evaluation of Federally funded projects or for information that must be disclosed in order to 
meet the requirements of the federal Food and Drug Administration (FDA).  
 
 
SENDING SPECIMENS/DATA TO RESEARCH COLLABORATORS OUTSIDE MCLEAN 
Specimens or data collected by McLean invest igators will be sent to research collaborators 
outside McLean, indicate to whom specimens/data will be sent, what informat ion will be sent, 
and whether the specimens/data will contain identifiers that could be used by the outside 
collaborators to link the specimens/data to individual subjects. 
Not applicable. 
 
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RECEIVING SPECIMENS/DATA FROM RESEARCH COLLABORATORS OUTSIDE 
MCLEAN 
When specimens or data collected by research co llaborators outside McLean will be sent 
to McLean investigators, indicate from where the specime ns/data will be obtained and 
whether the specimens/data will contain ident ifiers that could be used by McLean invest 
igators to link thespecimens/data to individual subjects.  When appropriate, submit 
documentation of IRB approval and a copy of the IRB-approved consent form from the 
inst itution where the specimens/data were collected. 
 
Not applicable.  
 
REFERENCES 
Budney AJ, Novy, PL, Hughes JR. (1999) Marijuana withdrawal among adults seeking 
treatment for marijuana dependence. Addiction 94, 1311-1322. 
Budney AJ, Vandrey RG, Hughes JR. (2007) Oral delta-9-tetrahydrocannabinol 
suppresses cannabis withdrawal symptoms. Drug Alcohol Depend 86, 22-29. 
Catapres® product information. (2008). Boehringer Ingelheim Pharmaceuticals, 
Ridgefield, CT. 
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