Clinical trial NCT02579421
Conditions: Marijuana Dependence
Sponsor: University of Minnesota
Start date: 2015-11-01; Completion date: 2017-07-27
Enrollment: 58 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to examine the role of progesterone (a naturally occurring hormone found in both men and women) on reducing marijuana use. The investigators will see if progesterone effects impulsivity, withdrawal, mood and stress during marijuana cessation.

Detailed description:
This double-blind, randomized pilot clinical trial will prescreen an estimated 250 potential subjects, consent and further evaluate approximately 100 potential subjects, and ultimately enroll 70 subjects to ensure 40 subjects will provide a primary marijuana reduction outcome measure at four weeks post quit date. Subjects will be stratified by sex then randomized to one of two treatment groups (n=20 per drug group, 50% female): progesterone (PRO; 200mg 2x/day) or Placebo (PBO). Telephone screening and visit invitation (20 minutes) leads to the consent process and in-person screening including medical-psychiatric evaluation for inclusion/exclusion (two visits, two hours each), then randomization and medication start (7 days), then stable medication (28 days) with medication reduction and final evaluation (7 days).

Arms: arm 1: 200 mg progesterone BID arm 2: placebo BID arm 3: 200 mg progesterone BID arm 4: placebo BID
Interventions: intervention 1: Progesterone intervention 2: placebo
Intervention descriptions: intervention 1: generic progesterone intervention 2: placebo

Protocol documents:
Prot_SAP_000.pdf: 
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SCOR Grant: 
Project 4 
 
Sex Differences and Progesterone: 
Association with Impulsivity and Marijuana Reduction in Co-Users of Marijuana and Nicotine 
Cigarettes 
 
Short Title: Hormones & Reduction in Co-Users 
 
Principal Investigator: 
Sharon S. Allen, M.D., Ph.D. 
 
 
 
 
 
 
 
Study Protocol 
 
 
 
Version: 
6.0 
 
 
 
 
 
Date: January 24, 2017 


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Significance 
Marijuana is one of the most commonly used, behaviorally addictive, substances in the world, surpassed only 
by caffeine, alcohol and nicotine.  Marijuana use has gradually risen over the last several decades and with 
increasing legalization, relaxing of restrictions, and no firm regulation this trend is likely to continue.  
Approximately 1 in 10 users develop an addiction to marijuana, and this fraction is even higher for adolescents 
(Hall, 2009).  Adolescents are particularly at risk since marijuana use contributes to more adverse long-term 
outcomes with earlier use and has potential effects on brain adolescent development (Volkow, 2014).  In 2012, 
overall use among 12th graders was > 30%, lower than alcohol use (about 40%), but greater than tobacco use 
(approximately 18%) (Johnston, 2012).  Further in all age groups (12-65) from 2007 to 2012 marijuana use has 
increased with >300 days/year of use occurring at a rate of approximately 5% and >20 days/month of use 
occurring at approximately 7%.  
Sex hormone research to date indicates that estrogen is associated with the facilitation of drug-abuse 
behaviors, whereas progesterone is associated with reduction of these behaviors (Carroll & Anker, 2010; 
Lynch & Sofuoglu, 2010).  While the clinical literature is mixed, our work offers additional support for this theory 
as the luteal phase (high progesterone) of the female menstrual cycle appears to be associated with 
decreased smoking-related symptomatology (Allen et al 2009b) and improved smoking cessation outcomes 
(Allen et al 2008; Allen et al 2009c) relative to the follicular phase (low progesterone).   
Illicit drug users appear to be more impulsive than non-users (Bickel et al 2001) and sex differences have been 
observed in this association such that females are more susceptible to the effects of impulsivity than men 
(Nieva et al 2011).  Preliminary evidence suggests sex hormones may play a role as females who have 
recently quit smoking have less impulsive behavior while in the luteal phase than in the follicular phase (Allen 
et al 2009a). Further, within the animal literature, delivery of exogenous progesterone has been shown to 
decrease impulsive behavior (Llaneza & Frye, 2009). 
Taken together, these data suggest that progesterone may improve marijuana use outcomes perhaps by 
reducing impulsive behavior.  However, the clinical literature on this topic is lacking. Therefore, in this pilot 
study, we are proposing a double-blind randomized controlled trial to assess the role of exogenous 
progesterone on impulsivity and change in marijuana use in a sample of males and females who are co-users 
of marijuana and nicotine cigarettes.In the first 3 years of our P50 SCOR entitled “Sex Differences and 
Progesterone: Effects on Impulsivity, Smoking and Cocaine Abuse” (P50 DA033942, Carroll PI) we have noted 
an immediate opportunity to follow an interesting and potentially important finding.  In Project 1 entitled “Sex 
Differences and Progesterone: Effects on Impulsivity and Smoking Cessation” we have found that a large 
percentage of subjects screened have marijuana use concurrent with their nicotine dependence (23% of 1704 
screening phone calls), and were therefore ineligible for the nicotine study. With IRB approval, we have already 
been collecting additional screening data on these concurrent nicotine and marijuana users to prepare for a 
future application on the efficacy of progesterone as treatment for marijuana addiction.   
As the number of marijuana users has continued to grow in Minnesota, with approximately 8% of the 
population reporting to have used marijuana within the last year, we have an excellent opportunity in our 
demographic area, and it would be informative to carry out a pilot study on the effects of progesterone (vs 
placebo) on this population that are co-users of marijuana and nicotine and to compare them to the nicotine 
group currently being studied. 
Marijuana abuse is growing in the age group we are studying (20-60 years) and may continue to increase as 
other states in addition to Washington and Colorado legalize marijuana. There is a high rate of co-use with 
nicotine and given we are successfully recruiting nicotine dependent subjects we feel that we have an 
exceptional opportunity to capture this comorbid population and examine effects of progesterone treatment for 
cessation of marijuana.  
Specific Aims 
This study will be similar to the ongoing double-blind clinical trial of Progesterone (PRO) vs. placebo (PBO) for 
cigarette smoking cessation which is successfully being conducted (currently in year 4 of 5).  We will enroll a 
parallel participant group of marijuana smokers who are co-using nicotine cigarettes, randomized 1:1 to PRO 
vs. PBO in a pilot double-blind trial, adjusting the protocol to address our time constraints. Our aims are: 
Primary Aim: To estimate the association between PRO vs. PBO and percent reduction of marijuana use in 


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males and females who are co-users of cigarettes.  
Hypothesis 1a.  Males and females randomized to exogenous PRO will have greater percent reduction 
in marijuana use compared to those randomized to placebo.  
Hypothesis 1b. Males compared to females, regardless of randomization, will have greater percent 
reduction of marijuana use. 
Hypothesis 1c. Males and females, regardless of randomization, with higher levels of serum 
progesterone, will have a greater percent reduction in marijuana use. 
Exploratory Aim: To estimate the association between impulsivity and percent reduction in marijuana use in 
males and females who are co-users of cigarettes. 
 
Hypothesis 2a. Males and females with lower impulsivity at baseline will have greater reductions in 
 
marijuana use.  
Hypothesis 2b. Higher serum levels of progesterone in males and females are predicted to reduce 
impulsivity and marijuana use.    
Methods 
Study Design, Recruitment and Subject Sample 
Study Design. This double-blind, randomized pilot clinical trial will prescreen an estimated 250 potential 
subjects, consent and further evaluate approximately 100 potential subjects, and ultimately enroll 70 subjects 
to ensure 40 subjects will provide a primary marijuana reduction outcome measure at four weeks post quit 
date. Subjects will be stratified by sex then randomized to one of two treatment groups (n=20 per drug group, 
50% female): progesterone (PRO; 200mg 2x/day) or Placebo (PBO).  They will take the medication for 5 
weeks and will attend weekly clinic visits (see Visit Sequence & Procedure below for more information).   
Setting: This project will be conducted at the Delaware Clinical Research Unit (DCRU). The DCRU has 
both inpatient and outpatient resources for the spectrum of biomedical research including special capabilities 
that were developed for study of substance use disorders. The Clinical and Translational Sciences Institute 
(CTSI), runs the DCRU and functions parallel to and supports the activities of the NIH funded CTSI, which it 
predated. The DCRU includes: reception area, examination rooms, meeting rooms, clinical interview rooms, 
testing rooms for computer based performance tasks, a wet lab for handling bloods and other specimens, 
freezers (to -80°C), all essential staff offices, each with multiple telephone and computer lines through the 
University of Minnesota servers, locked limited access protocol, equipment and medication rooms, as well as 
secure cabinets for study files and essential supply and support areas and services. 
 
Recruitment: To meet recruitment goals, we aim to enroll a total of 70 subjects (~6 subjects/month) to 
ensure a final sample size of 20 females and 20 males completing the study. Our primary recruitment method 
will be advertising in the mainstream media. While this type of recruitment can be challenging, our team has 
been successful with this form of recruitment.  For example, our current study (PRO for smoking cessation) 
has had success with Facebook, Craigslist, TV, and radio advertising. Specifically, over the past seven 
months, we have received an estimated 300 phone calls from interested participants which resulted in the 
enrollment of 30 subjects (~8 subjects/month).  
 
Study Sample. This study will enroll males (n=35) and females (n=35) who self-report use marijuana 
>4days per week and are interested in changing their marijuana use. Specific eligibility criteria are as follows: 
 
Inclusion: Males 18-60 years old, females 18-50 years old, stable physical and mental health, self-
report Timeline Follow-Back (TLFB) indicating current marijuana use ≥4 days/week for ≥1 year, positive urine 
THC dipstick test (> 50ng/mL; indicating  marijuana use in the past 48-72 hours), motivated to change their 
marijuana use (>1 on a 10-point Likert-type scale), regular or sporadic use of nicotine cigarettes (> 1 cigarettes 
in the past 30 days) , self-report of regular menstrual cycles >6 months (female only), willing to use double-
barrier contraception if sexually active and not surgically sterilized (female only), ability to comply with study 
procedures, ability to provide informed consent. 
 
Exclusion: Current breastfeeding (females only), current or planned pregnancy within the next three 
months (females only), DSM-IV diagnoses for psychotic disorders, bipolar disorder, ADHD, major depressive 


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disorder within the last 3 months, substance dependence within the last 3 months with the exception of nicotine 
and marijuana dependence, unstable psychotropic medications (<3 months), current use of exogenous 
hormones, finasteroid (propecia), efavirenz, red clover, ketoconazole and other drugs that are CYP3A4 
inhibitors, conditions contraindicated to progesterone treatment (including, but not limited to, thrombophlebitis, 
deep vein thrombosis, pulmonary embolus, clotting or bleeding disorders, heart disease, diabetes, history of 
stroke, allergy to peanuts, hypersensitive to progesterone and liver dysfunction).   
Visit Sequence & Procedures  
 
Screening Visits (Visits 1 and 2): Candidates completing the consent process will be screened in a two-
visit process (with the option of completing visits 1 and 2 simultaneously). For males, this two-visit process will 
be scheduled within two weeks of completion of the phone interview. For females, this two-visit process will be 
scheduled during the follicular phase of their menstrual cycle (in order to avoid any potential menstrual phase 
effects on marijuana use or mood measures, as well as to limit wait time for initial study procedures) (details 
below). Therefore, after the phone screen females will be told to contact the study coordinator with the first day 
of their next period, and then the two-part screening visits will be scheduled during days 1-7 (where Day 1 is 
the onset of menses) of the menstrual cycle.  
 
At the first of two screening visits (Screening Visit 1), the study will be described in detail to candidates 
by the study coordinator, and informed consent will be obtained. Subjects agreeing to participate will undergo 
medical, psychiatric and other evaluation to determine eligibility. The medical evaluation will include: brief 
physical exam (height, weight, blood pressure, heart rate, and medical history interview), psychiatric interview, 
carbon monoxide level and a blood draw (for measurement of serum hormone levels and liver function via ALT 
and AST measurement), a urine pregnancy test (females only) and a drug screening for marijuana (see THC 
Urine Dipstick Test for more information). Trained staff will conduct all interviews including the Structured 
Clinical Interview for DSM-IV (SCID; First, 1995) and instrument administration. Self-report instruments 
measuring impulsivity, personality characteristics, stress, caffeine use, tobacco use, marijuana use, craving 
and behavior will be completed. At the second screening visit (Screening Visit 2; scheduled within two days of 
Screening Visit 1), impulsivity tasks will be completed. The investigators will review the data to determine 
eligibility. Subjects meeting eligibility criteria will be given instructions on when to come back for their Baseline 
Visit (details below). 
 
Baseline Visit (Visit 3): Female subjects will be instructed to come into the clinic within three days of the 
start of their Luteal Phase for their baseline visit and to start medication (PRO or PBO). Female subjects will 
self-report menstrual cycle length at their screening visit and staff will determine when their Luteal Phase will 
most likely begin.  Male subjects will be instructed to come into the clinic according to their assigned delay (per 
randomization list generated by the Statistical Analysis Core). This visit will occur seven days prior to quit date. 
At this visit, subjects will be randomized to PRO or PBO within strata defined by sex. The Statistical Analysis 
Core (SAC) will generate the randomization tables (one for each sex, 1:1 allocation using randomly permuted 
blocks of size 2 and 4), and the Clinical Trials Research Pharmacy will use it to determine randomization 
assignment. Randomization assignment will be stored in a secure file in a secure location at the Clinical Trials 
Research Pharmacy, to be shared only with the SAC. All other project staff including PI and study coordinator, 
as well as the participant, will remain blinded to the randomization assignment. At the baseline visit subjects 
will provide a blood sample (for hormone assessment), urine sample for THC, breath sample (to confirm 
smoking status via carbon monoxide breathalyzer), have their vital signs (blood pressure, heart rate, weight) 
measured, be informed of their quit date, and receive brief behavioral counseling to prepare for their quit date. 
At the end of this visit subjects will be compensated for their time, given study medication along with 
instructions for taking the medication (beginning at 8PM that day), as well as a clinic visit schedule for the 
remaining clinic visits. This visit will take approximately one hour to complete. 
 
Marijuana Change Date Assignment: Change date (Week 0) will be set for 7 days following the 
Baseline Visit.  Since this entails a delay of variable duration from Screening Visit 2 to Baseline Visit (thus 
impacting timing of medication initiation) across female subjects, each male subject will be matched to a 
female subject for a similar delay so that, across the male and female groups, study procedures will be follow a 
similar chronology. 
• 
 
Weeks 0-5 (Visits 4-9): The Week 0 clinic visit will occur on the assigned “Marijuana Change Date”. 
Subjects will attend clinic visits on a weekly basis thereafter for 5 weeks. At weeks 0, 2, 4, and 5, blood 
samples will be collected and stored for the analysis of hormones.  Urine samples will be collected at each 


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clinic visit for the visual inspection of riboflavin (assessing medication compliance), biochemical 
confirmation of THC, and for a pregnancy test (females only).  Urine will be saved and stored on Weeks 0, 
2, 4, and 5 for cotinine analysis. 
Subjects will also complete several forms and questionnaires (described below). Subjects will return the 
medication bottle and unused medication, be given a new one-week supply and adverse events will be 
assessed. At Week 4, subjects will complete impulsivity tasks and study medication will be discontinued.  
Finally, subjects will receive brief, behavioral counseling at each clinic visit. At the end of each visit subjects will 
be paid for their time. These visits will take approximately 30-45 minutes to complete.  
 
 
Study Adherence: To encourage compliance the following will occur: (1) at the Baseline Visit, subjects 
will be given a schedule of all remaining appointments; (2) at each visit the subjects will be given an 
appointment reminder card for the next visit; (3) reminder calls, texts and/or emails (per subject’s preference) 
will be placed or sent the day before each visit; (4) subjects will be routinely reminded that regardless of their 
marijuana use that their data are valuable and important; and (5) regardless of marijuana use, subjects will be 
compensated at each visit (described below). If a subject misses a visit, study staff will try to reach him/her by 
phone that day to reschedule for one to three days later. If that does not work, staff will contact the subject’s 
designated ‘contact person’ (i.e., someone who does not live with the subject but knows how to get in touch). If 
a subject does not attend any visits after the screening visits, he/she will be labeled as a “drop” and replaced. If 
the subject discontinues from the study after randomization but before the final follow-up visit, he/she will be 
labeled an “incomplete” but not replaced. If a subject does not quit on their assigned quit date or relapses later, 
she/he will be encouraged to stay in the study and make another quit attempt; such that we will follow them for 
the length of the study regardless of marijuana use. Subjects who complete the weekly follow-up period after 
quit date, regardless of marijuana use, will be labeled a “completer” for the primary outcome and not replaced. 
 
THC Urine Dipstick Test: The THC Urine Dipstick Test      Figure 2. Dipstick Test Results 
is a one-step immunoassay that qualitatively detects delta-9-
tetrahydrocannabinol in urine. The results obtained are of a 
preliminary nature and is for screening purposes only.  THC, 
psychoactive component of marijuana, is a central system 
stimulant relaxant. THC in marijuana is strongly absorbed by 
fatty tissues in various organs and a metabolite form of THC, 
delta-9-tetrahydrocannabinol, is present in urine 48-72 hours 
after a smoking-section. This is what denotes a marijuana 
user.   
 
The THC Urine Dipstick Test is an 
immunochromatography device based on the principle of 
competitive immunoassay. The nitrocellulose membrane of the 
dipstick is immobilized with THC-protein conjugate on the test 
zone (see Figure 2). Antibodies against THC, which have been 
conjugated with colloidal gold, are impregnated on a porous pad overlapping the bottom end of the membrane. 
When the sample pad of the dipstick is dipped into the urine sample to perform the test, by capillary attraction, 
the urine will flow through the porous pad towards the other end of the assay strip. The antibody-gold 
conjugate dissolved by the urine sample will flow with the liquid front-end. In the absence of THC, the antibody-
gold conjugate will bind to the immobilized drug conjugate causing a visible red band to appear at the test 
zone. However, when a sufficient concentration of THC (>50 ng/mL) is present in the urine sample, the THC in 
urine will bind with the antibody and saturate the binding capacity of the antibody-gold conjugate, thus, no 
visible band will appear at the test zone. 
 
Possible Results: NEGATIVE: If there is no THC present in urine, there will be a rose-color bands 
appearing on both the control and the test section.  POSITIVE: A positive result is observed when there is a 
control line and no test line and indicates a minimum THC concentration of 50 ng/mL. At concentrations less 
than 50 ng/mL, there may be weak signal appearing at the test line area.  INVALID: If there is no rose-color 
band visible in the control window, then the test result is invalid. (Source: Acro Biotech Inc., Rancho 
Cucamonga, CA, www.acrobiotec.com)   
Subject Compensation 


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Subjects will receive compensation at each clinic visit for their time and effort. Subjects will be paid $25 for 
Screening Visit 1 and $25 for Screening Visit 2. For each follow-up visit they attend, they will be compensated 
$20 for their time, for completing study procedures and to cover transportation costs. Subjects will also 
complete the Balloon Analogue Risk Task (BART) twice during the study. The average compensation a subject 
can earn from this task is $35. The subject will also be eligible for a study bonus upon study completion: $30 
for attending W5 and $50 for missing no more than 1 follow-up clinic visit (must not be Week 4).   
Therefore, subjects will receive approximately $340 ($25 Screening Visits x 2 visits + $20 follow-up visits x 7 
visits + $80 in bonus payments + an average of $70 in BART payments). 
 
Study Medication  
Subjects will be stratified by sex and then randomly assigned to PRO or PBO, as described above.  All 
medication (active and placebo) will be prepared by the University of Minnesota Clinical Trials Research 
Pharmacy, which is a specialized facility that prepares medication for clinical trials including our ongoing 
research. The research pharmacist (D Luke Pharm D) will provide medications. There will be oversight and 
monitoring with regular audits by local regulatory boards including the IRB and DSMB. This study requires 
double-blind procedures, therefore progesterone will be over encapsulated and be identical to the placebo 
capsules. Medications will be discontinued at the Week 4 clinic visit.  Adverse events will be assessed at each 
clinic visit. 
Progesterone: The progesterone will be given in the form of an active or placebo micronized natural 
progesterone (generic Prometrium). All subjects will take 200 mg twice daily (approximately 8am and 8pm) for 
five weeks starting seven days prior to the assigned change date. The dosage was selected to ensure that 
serum progesterone levels will be consistent with those observed in the natural Luteal phase of the menstrual 
cycle (6-14 ng/mL) since that phase has been shown to be favorable for smoking cessation (Allen et al 2008). 
We expect the following serum progesterone levels by group (Figure 5):0 (1) females + PRO 9-13 ng/mL; (2) 
males + PRO 6-7 ng/mL; (3) females + PBO, varies by menstrual phase from 1-14 ng/mL; and (4) males + 
PBO 0-1 ng/mL (Goletiani et al 2007; Reed et al 2010; Yen et al 1999). Delivery of exogenous progesterone 
has been successfully used in other studies and is generally well tolerated (Sofouglu et al 2001; Sofouglu, et al 
2004; Goletaini et al 2007; Reed et al 2010). The most common adverse effect in males and females is 
sedation. Less common effects include breakthrough bleeding (females), nausea (females and males) and 
breast tenderness (females) (de Lignieres, 1999; Goletaini et al 2007). While it is possible that progestins may 
contribute to risk for thromboembolism, we will be using natural micronized progesterone instead of synthetic 
progestins. Natural micronized progesterone is not known to be associated with thromboembolic risk (PDR, 
2002; Goletaini et al 2007), and consequently is a safer choice. Micronized progesterone is not a form of birth 
control. Therefore, all female subjects will be educated on the importance of using a double-barrier method to 
protect against pregnancy.  
Study Measures 
We will assess marijuana use using two methods (self-report, biochemical confirmation). First, at each clinic 
visit the TimeLine Follow-Back (TLFB) method will be completed. The TLFB is a validated retrospective data 
capture technique (Sobell et al 1996).  Second, at each clinic visit we will measure urinary THC levels (see 
table 1for all study measures and when they are collected). 
Impulsivity Measures: Subjects will complete three self-report measures that have been computerized at each 
clinic visit beginning at Screening Visit 2. These measures will assess the characteristics of impulsivity, 
inhibition, planfulness, and cognitive impairments, key areas of focus in this grant.  
• Behavioral Inhibition/Activation scales (BIS/BAS): 20-item form is commonly used to study externalizing 
tendencies (Carver and White, 1994). Investigators in Project II have used this instrument with success.  
• Barratt Impulsiveness Scale (BIS): 30-item self-report measure of self-control (Patton et al 1995). Doran 
and colleagues (2004) demonstrated that impulsivity, as measured with this item, was a predictor of 
smoking relapse.  
• Brief Self Control Scale (BSCS): This item consists of 13 questions rated on a 4-point scale from “very 
true” to “very false” on items reflecting the ability to control problematic behaviors (Tangney et al 2004).  
The Impulsivity Tasks represent two forms of impulsivity, 1) impaired cognitive inhibitory mechanisms, and 2) 


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deficits in motor inhibitory mechanisms. “Delay discounting” entails higher-level cognitive inhibitory processes 
that may characterize the behavior of individuals who are drug dependent (Bickel and Marsch, 2001) tobacco 
users (Baker et al. 2003), cocaine users (Monterosso et al, 2001), other drug users (e.g. Vuchinich and 
Simpson, 1998; Kollins, 2003) and pathological gamblers (Dixon et al, 2003).  The following items will be 
completed at Screening Visit 2 and Week 4.  
• Delay Discounting Task: Developed by de Wit and colleagues (Richards et al, 1999), delay discounting 
refers to the reduction in value of a reward over time relative to its immediate worth. One’s discount rate, 
also known as a time preference, is a measurable individual difference and involves a series of choices 
(e.g. Petry and Casarella, 1999): one option is an immediate payment (e.g. $1); the second option is a 
larger payment (e.g. $50) after a delay (e.g. 6 hours to 25 years). Titrating the payment amounts at each 
delay interval allows the identification of points of indifference (the point at which the subject switches 
from choosing the immediate to the larger reward at a given delay interval). We additionally included a 
probability discounting condition to measure risk aversion in addition to time preference (Richards et al, 
1999). 
• GoStop Task: This task measures response inhibition.  A series of five-digit numbers are presented on a 
computer monitor at a rate of 500ms for ever two seconds. Subjects are instructed to click the mouse 
button when the number they see is identical to the previous number. Half of the numbers change color 
from black to red at 50, 150, 250 and 350. Subjects are instructed to respond to the matching number 
only when the displayed number is black. The primary outcome of this task is the percent of inhibition 
failures for the 150ms delay (Dougherty et al 2008). This item has been successfully used to assess 
tobacco dependence and smoking behavior (Billieux et al 2010). 
• Balloon Analogue Risk Task (BART): This task, with 30 replications/session, is a measure of risk-taking. 
It involves displaying a small balloon on a computer screen. Each “pump” to inflate the balloon 
accumulates five cents, with each pump potentially breaking the balloon. The average pumps to the 
breaking point is 64. To ensure attentive responding, subjects will receive the actual amount of money 
accrued on this task. The primary outcome on this task was the number of exploded balloons divided by 
the number of trials (Lejuez et al, 2002). 
• Immediate Memory Task / Delayed Memory Task (IMT/DMT): This task is a continuous performance task 
that has two phases. First, the IMT displays a series of five-digit numbers in on a computer monitor for 
500 ms followed by a blank screen 500 ms. Subjects click the mouse button whenever an identical 
number is displayed. Next, the DMT requires the subject to remember a five-digit number and compare it 
to another that is presented 3.5 seconds later. During the 3.5 interval subjects are presented with a 
distracter (12345) and told to ignore it. The primary outcome of this task is the IMT/DMT ratio which is 
defined as the proportion of commission errors to correct detections (Mathias et al 2002). This item is 
included as it we have used it in prior studies to identify menstrual phase differences in impulsivity and 
attention (see Preliminary Studies B.2.1.), and therefore is expected to be sensitive to the group 
differences in sex and progesterone. 
Independent Measures (sex, randomization, and serum progesterone):  
Sex will be collected via self-report on the Demographics form completed at Screening Visit 1.  
Randomization, assignment (PRO vs. placebo) will be known as of the Baseline Visit to the SAC and Clinical 
Trials Research Pharmacy, but not will be known to other staff or participants until after completion of all 
measurements. Participants will be informed on their randomization assignment in a letter mailed within six 
months of the study’s completion; this letter will also briefly summarize the study’s findings.  
Measurement of serum progesterone will be measured by collecting a blood sample at Screening, Bassline 
and Weeks 0, 2, 4, and 5.. Blood (20cc) will be drawn then centrifuged. The serum stored at -20°C in sealed 
storage tubes to prevent evaporation. Approximately two mL of serum will be analyzed by the University of 
Minnesota Laboratories for progesterone sample. The remaining serum (approximately two to four mL) will be 
used for estradiol measurement (described below) and/or stored as back-up to be used in the event that 
problems occur during analyses. 
Other Covariates: Information on potential covariates is collected at the clinic visits, including:  
• Cannabis Use Disorder ID test (CUDIT-R, Adamson et al 2010): This item is 8 questions that screens for 


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problematic cannabis use.  The domains captured in this questionnaire are consumption, abuse, 
dependence and psychological features. This screening test has been shown to have 91% sensitivity and 
90% specificity.  This item will be completed at Screening Visit 1.  
• Marijuana Craving Questionnaire (MCQ-SF; Heishman et al 2008): This item includes 12 questions that 
assess 4 characteristics of craving, compulsivity, emotionality, expectancy and purposefulness.  This item 
will be completed at Screening Visit 1. This item will be completed at each clinic visit thereafter.   
• Cannabis Withdrawal Scale (CWS; Allsop et al 2011): This item measures the intensity of cannabis 
withdrawal symptoms and the distress or functional impairment caused by each symptom using a 10-
point Likert scale.  This item will be completed at Screening Visit 1. This item will be completed at each 
clinic visit thereafter.   
• Severity of Dependence Scale Cannabis (SDS-C; Swift et al 2000): This 5 item questionnaire is sensitive 
to the severity of cannabis dependence. This item will be completed at Screening Visit 1.  
• Reasons for Quitting Marijuana Questionnaire (Stephens et al 1995): This item is 29 questions that 
assess participant’s reasons the quit marijuana. This item will be completed at the Baseline visit.   
• Self-Efficacy Questionnaire (Stephens et al 1995): This item is 20 questions that assess a participant’s 
self-efficacy for quitting marijuana. This item will be completed at the Baseline visit.   
• Cigarette Smoking Behavior: Specifically, number of cigarettes smoked per day during ad libitum 
smoking, self-reported number of past quit attempts, past longest quit attempt, motivation to quit 
smoking, and social influences such as partner smoking. This item will be completed at Screening Visit 1 
only.  
• Fagerström Test for Nicotine Dependence (FTND; Heatherton et al 1991): This item will be administered 
during the first screening session to assess level of nicotine dependence. The FTND is a 6-item self-
report measure derived from the Fagerström Tolerance Questionnaire. This item will be completed at 
Screening Visit 1 only.  
• Minnesota Nicotine Withdrawal Scale (MNWS; Hughes & Hatsukami, 1998): This item includes 
measurement of: irritability, anger, anxiety, difficulty concentrating, restlessness, depressed or sad mood, 
and hunger. MNWS scores are calculated without the item of craving. We have changed the wording of 
the craving item to ’desire to smoke,’ and its mean scores are analyzed separately in light of evidence 
suggesting distinct patterns of craving from other withdrawal symptoms (Hughes & Hatsukami 1998). 
This item will only be completed once during the screening process.  This item will be completed at 
Screening Visit 1.  This item will be completed at each clinic visit thereafter.   
• Questionnaire for Smoking Urges (QSU-brief; Cox et al. 2001): This item is the shortened version of the 
QSU (Tiffany & Drobes, 1991) and will assess smoking urges. It includes 10 items clustered into two 
factors similar to those assessed by the longer version of QSU. Factor 1 includes items that indicate a 
strong desire and intention to smoke. Factor 2 includes items indicating expectation of a relief from 
negative affect with an urgent desire to smoke (Cox et al, 2001). This item will only be completed once 
during the screening process. This item will be completed at Screening Visit 1. This item will be 
completed at each clinic visit thereafter.   
• Cigarette Smoking Stage of Change Questionnaire (SOC; Prochaska et al, 1993) This 3-item 
questionnaire will be used to assess readiness to quit smoking cigarettes.  It will classify the sample into 
two groups - those who are 1) in the “active/preparation” stage of quitting and those who are in the 2) 
“contemplation/pre-contemplation” stage. 
• Profile of Mood States (POMS; McNair et al, 1971): On this 72-item form subjects use a 5-point Likert-
type scale, to indicate 10 subscales (Evans et al 1998) including positive mood, arousal, vigor, elation, 
friendly, fatigue, tension-anxiety, depression-dejection, confusion, and anger-hostility.  This item will only 
be completed once during the screening process. This item will be completed at Screening Visit 1. This 
item will be completed at each clinic visit thereafter.   
• Beck Depression Inventory-II (BDI-II, Beck et al, 1996): This is the most commonly used screening 
measure for adults and will be used to assess depressive symptoms. This item will only be completed 
once during the screening process.  This item will be completed at Screening Visit 1. This item will be 


Page 9 of 19 
completed at each clinic visit thereafter.   
• Perceived Stress Scale (PSS; Roberti et al, 2006): This ten item questionnaire will measure perceived 
stress. The items are rated on a 5-point scale, ranging from 0 (never) to 4 (very often), and they focus on 
events during the last week. The scale has adequate reliability and validity.  This item will only be 
completed once during the screening process. This item will be completed at Screening Visit 1. This item 
will be completed at each clinic visit thereafter.   
• Columbia-Suicide Severity Rating Scale:  This questionnaire (C-SSRS; Posner et al, 2009) will be 
completed at each clinic visit to assess suicidal ideation, given this is listed as an SAE on the Prometrium 
label.  If any item of suicidality is endorsed referrals to the appropriate mental health care will be made.     
• Sociodemographic Variables: At the first screening visit we will collect information on age, race/ethnicity, 
education, income and other related variables. This item will be completed at Screening Visit 1 only. 
• Serum Estradiol: Blood samples will be collected at Screening, Baseline and Weeks 0, 2, 4, and 5 to 
allow for the measurement of serum estradiol. Following identical procedures described above for serum 
progesterone, approximately two mL of serum will be analyzed by University of Minnesota Laboratories. 
• Leisure Time Exercise Questionnaire (LTEQ): This questionnaire has four-items to assess strenuous, 
moderate and mild exercise completed during leisure time and has high reliability (r=0.83, 0.85; Gordin & 
Shepard, 1985).  This item will be completed at Screening Visit 2. This item will be completed at each 
clinic visit thereafter.  
• Life Event Occurrence Survey (LEOS; McKee et al, 2005): This item will assess and account for the 
presence of current or recent significant life events. This measure includes 38 yes/no questions 
assessing various events that may have happened in the last six months including aspects of work, social 
life, family and finances. The measure includes instructions on how to rate the level of disruption the 
event caused in the subjects life from none too severe disruption. This measure will be administered at 
screening visit 1 and the final visit W5.    
• Caffeine Use:  Caffeine use will be collected via self-report at each clinic visit using the TimeLine 
FollowBack methods in which participants will report the total number of ounces of caffeinated beverages 
drank per day for each of the last 7 days. 
• Tobacco Use:  Tobacco use will be collected via self-report at each clinic visit using the TimeLine 
FollowBack methods in which participants will report the total number of cigarette smoked per day for 
each of the last 7 days.  
• Adverse Childhood Experience (ACE):  Participants will complete this form at the SC2 visit. 
Debriefing Questionnaire:  At end of study participation or Week 4, whichever is later, participants will complete 
a questionnaire to indicate which study medication (active or placebo) they thought they were on.  
 
 
 
 
 
 
Table 1. Study Measures at Each Time Point 
 
SC1 
SC2 
BL 
Week   
0 
Week  
1 
Week  
2 
Week  
3 
Week   
4 
Week  
5 
Intake Form: Demographics, baseline characteristics 
INTAKE 
Medical History: Assess inclusion/exclusion criteria 
MH 
Structured Clinical Interview for DSM Disorders 
SCID 
MN Impulsive Disorders Interview: Buying, stealing, hair 
pulling, anger, gambling, sex, binge eating 
MIDI 
 
 
 
 
 
 
 
 


Page 10 of 19 
Randomization: Progesterone or Placebo 
RAND 
Cannabis Use Disorder Identification Test: Disorder 
CUDIT-
R 
 
 
 
 
 
 
 
 
Severity of Dependence Scale-Cannabis: Dependence 
SDS-C 
SDS-C 
Cannabis Withdrawal Scale: Withdrawal 
CWS 
CWS 
CWS 
CWS 
CWS 
CWS 
CWS 
CWS 
Marijuana Craving Questionnaire: Craving 
MCQ-SF 
MCQ-SF 
MCQ-SF 
MCQ-SF 
MCQ-SF 
MCQ-SF 
MCQ-SF 
MCQ-SF 
Reasons for Quitting Questionnaire: Marijuana 
RFQ 
RFQ 
RFQ 
RFQ 
Self-Efficacy Questionnaire: Confidence to resist marijuana 
SE 
SE 
SE 
SE 
Fagerström Test for Nicotine Dependence:  Nicotine 
dependence 
FTND 
 
 
 
 
 
 
 
 
Minnesota Nicotine Withdrawal Scale: Withdrawal, craving 
MNWS 
MNWS 
MNWS 
MNWS 
MNWS 
MNWS 
MNWS 
MNWS 
Questionnaire for Smoking Urges: Intention to smoke, 
anticipation of relief from negative affect 
QSU 
 
QSU 
QSU 
QSU 
QSU 
QSU 
QSU 
QSU 
Cigarette Smoking Stage of Change Questionnaire: Readiness 
to quit smoking cigarettes 
SOC 
 
SOC 
 
 
SOC 
 
SOC 
SOC 
Columbia-Suicide Severity Rating Scale: Suicidal ideation   
C-SSRS 
C-SSRS 
C-SSRS 
C-SSRS 
C-SSRS 
C-SSRS 
C-SSRS 
C-SSRS 
Adverse Events: Since you last visit… 
AE 
AE 
AE 
AE 
AE 
AE 
AE 
Perceived Stress Scale: Perceived stress 
PSS 
PSS 
PSS 
PSS 
PSS 
PSS 
PSS 
PSS 
Profile of Mood States: Positive mood, arousal, vigor, elation, 
friendly, fatigue, tension-anxiety, depression-dejection, etc. 
 
POMS 
POMS 
POMS 
 
 
 
POMS 
 
Beck Depression Inventory-II: Depressive symptoms 
BDI-II 
BDI-II 
BDI-II 
BDI-II 
BDI-II 
BDI-II 
BDI-II 
BDI-II 
Adverse Childhood Experiences: childhood maltreatment 
ACE 
Life Event Occurrence Survey: Significant life events  
LEOS-R 
LEOS-R 
Leisure Time Exercise Questionnaire: Strenuous, moderate 
and mild exercise  
 
LTEQ 
LTEQ 
LTEQ 
LTEQ 
LTEQ 
LTEQ 
LTEQ 
LTEQ 
Behavioral Inhibition/Activation scales: Motivational systems 
(appetitive & avoidance) 
 
BIS/BAS 
BIS/BAS 
BIS/BAS 
BIS/BAS 
BIS/BAS 
BIS/BAS 
BIS/BAS 
BIS/BAS 
Barratt Impulsiveness Scale: Impulsivity and self-control  
BIS 
BIS 
BIS 
BIS 
BIS 
BIS 
BIS 
BIS 
Brief Self Control Scale: Ability to control problematic 
behaviors 
 
BSCS 
BSCS 
BSCS 
BSCS 
BSCS 
BSCS 
BSCS 
BSCS 
Delay Discounting Task: Evaluates discount rates for rewards, 
impulsivity 
 
DD 
 
 
 
 
 
DD 
 
Debriefing Questionnaire: Perception of rand. assignment 
(PRO/PBO) 
 
 
 
 
 
 
 
DQ 
 
Study Satisfaction Survey: Taking meds, working with staff, 
etc. 
 
 
 
 
 
 
 
 
SS 
Time-Line Follow-Backs: 
Marijuana: Since you last visit... (TPD - Times per day) 
MJ 
MJ 
MJ 
MJ 
MJ 
MJ 
MJ 
MJ 
Cigarettes: Since you last visit… (CPD) 
CPD 
CPD 
CPD 
CPD 
CPD 
CPD 
CPD 
CPD 
Caffeine: Since you last visit... (ozs.) 
CAFF 
CAFF 
CAFF 
CAFF 
CAFF 
CAFF 
CAFF 
CAFF 
Computer Tasks: 
Immediate/Delayed Memory Task: Impulsivity & attention 
 
IMT 
DMT 
 
 
 
 
 
IMT 
DMT 
 
GoStop Computer Task: Response inhibition 
GoStop 
GoStop 
Balloon Analogue Risk Task: Risk-taking 
BART 
BART 
Biological Specimen Collection: 
Blood (plasma/serum): Hormones  
BLOOD 
BLOOD 
BLOOD 
BLOOD 
BLOOD 
BLOOD 
Urine: THC and Cotinine 
URINE 
URINE 
URINE 
URINE 
URINE 
URINE 
URINE 
URINE 
Analysis Plan  
Our primary outcome is change in marijuana use as defined by the TLFB at the week 4 visit relative to the 
baseline visit. This is a pilot study to generate data to potentially motivate and justify a future fully-powered 
study of PRO and marijuana cessation, so the intent of these analyses is to estimate magnitude and direction 
of treatment effects and associations with impulsivity (sex-specific and overall). While we expect baseline 
covariates to be balanced across treatment groups due to the randomization, this pilot study is small so both 
unadjusted and adjusted assessments of effects will be carried out by including the randomized treatment 
assignment and pre-specified adjusting covariates such as age, baseline progesterone, estradiol, baseline 


Page 11 of 19 
impulsivity measures, etc. This pre-specified list will be determined by the study team during the finalization of 
the protocol, prior to the first study enrollment. We expect these analyses to be somewhat conservative, since 
they do not explicitly account for the randomized permuted blocking (Matts and Lachin, 1988). An analysis that 
accounts for the blocking (such as a stratified Mantel-Haenzel test) cannot be generalized to include the 
adjustment for impulsivity measures, for example, which are a focus of this proposal. All persons randomized 
and with a measured primary outcome at the week 4 visit will be included in this analysis, regardless of 
whether or not they ever took any of their assigned treatment (intent-to-treat analysis); persons with missed 
visits are discussed below.  
Addressing Hypothesis 1a: An unadjusted assessment of the treatment effect will come from a linear model 
of percent reduction in marijuana use on randomized treatment assignment, separately by sex. Hypothesis 
1b: A linear model including both males and females will be used to estimate the overall gender effect on 
percent reduction in marijuana use. Hypothesis 1c: A linear model including both males and females will be 
used to estimate the association of serum progesterone with percent reduction in marijuana use; we will 
separately consider baseline progesterone, cumulative progesterone (summed over weeks 0-4), and week 4 
progesterone. 
Addressing Hypothesis 2a: A linear model including both males and females will be used to estimate the 
association of impulsivity with percent reduction in marijuana use. Hypothesis 2b: A linear model including 
both males and females will be used to estimate the interaction between baseline impulsivity and baseline 
serum progesterone on percent reduction in marijuana use. 
Missing data plan: Quality assurance plans are described below. The primary outcome analysis will be 
carried out using two parallel models: one model will exclude subjects for whom we were unable to obtain a 
week 4 TLFB or urine THC. Since ‘missing at random’ is a strong statistical assumption to make, we will also 
carry out a parallel model that uses multiple imputation of the week 4  TLFB and urine THC based on an 
individual’s previous visits’ TLFB and urine THC levels. We will also examine whether persons missing their 
week 4 visit differed in their baseline characteristics or treatment assignment from persons not missing their 
week 4 visit. 
Power: This is a pilot study to generate data to potentially motivate and justify a future fully-powered study of 
PRO and marijuana use. This study will estimate magnitude and direction of treatment effects and associations 
with impulsivity (sex-specific and overall). Hence, no power calculations are provided.  
 
Data Safety and Monitoring Plan, Board, and Administration.  
The Admin Core Director (Carroll) and the Statistical Analysis Core Director (Eberly) of the P50 will jointly 
organize review by the Data Safety and Monitoring Board (DSMB). The Project PI (S. Allen) will 
administratively oversee complying with reporting requirements. The DSMB will meet annually and will, post 
meeting, provide a summary of discussion, which will be conveyed to NIDA. This report will include subject 
demographics, expected versus actual recruitment rates, summary of any quality assurance or regulatory 
issues, summary of adverse events (AEs) or serious adverse events (SAEs) which may have occurred, and 
any changes in the protocol as a result of these issues. The DSMB will receive current data and blinded data 
unless a specific request or cause to view un-blinded data is evident. The final report will be complete and 
inclusive with the unblended data set. 
The Project Coordinator (N. Tosun) and PI (S. Allen) will meet on a weekly basis to review the study’s 
progress.  The team will meet regularly and as needed regarding data and project safety. Additionally, all key 
personnel will meet regularly regarding overall progress, specific problems and problem resolution. The daily 
monitoring of subjects will be the coordinator’s responsibility.   
Participants will be closely monitored throughout the trial. A summary of all data, with the exception of 
information that entails breaking the blind, will be provided to the DSMB at annual meetings. SAE’s will be 
reported to the head of the DSMB when they have been identified and characterized. The chair of the DSMB 
may request a special meeting of the panel as needed. The Board will consist of Drs. Frances Levin (Chair), 
Dr. Joy Schmitz, Dr. Paul Pentel, and an expert in marijuana abuse (TBN). These individuals will serve to 
monitor all the SCOR projects involving human subjects, including this project.  


Page 12 of 19 
The group will meet on an annual basis and review data including recruitment, progress, safety, adverse 
events, and serious adverse events associated with the study. The DSMB meeting will include open, closed 
and executive sessions. The Principal Investigator, co-investigators, statisticians, and study coordinators will 
attend the open session and present during the meeting. The purpose of the open session is to provide 
relevant information to the Board about general aspects of the trial. The open session will focus on the 
background of the study, the protocol, status of the study, problems with accrual and follow-up, baseline 
demographic data, compliance issues, frequency of adverse events, documentation of endpoints, data quality 
issues, flow of forms, data based protocol modification issues, and any other issue regarding the studies under 
review that can be discussed without reference to interim comparative results. 
Following the open session, a closed session will be held if deemed appropriate and necessary by the DSMB 
Chair. During the closed session, the chairperson (Frances R Levin MD) will conduct the review of all issues 
and puts each issue to a vote. This session will be attended by the DSMB members and if necessary the 
statistician and principal investigator. During the closed session, the discussions will focus on the treatment 
safety, requesting and reviewing additional information if needed and updating the Board on actions taken 
related to their actions and recommendations of the previous meeting. 
Following the closed session, an executive meeting may be held, at the discretion of the DSMB Chair. The 
executive meeting will be restricted to DSMB members. During these sessions, the Board may discuss any 
sensitive issues surrounding the clinical trials under review. 
The Board Chairperson will prepare a draft report of the meeting along with minutes for inclusion in the final 
DSMB report. The report will outline and summarize discussion during the open and closed sessions of the 
meeting. Recommendations and action items will be clearly marked within the body of the report. If the DSMB 
conducts an executive session, a statement will be included in the Minutes of the Meeting stating that an 
executive session was conducted, but content of the discussion will be retained by the chair and not included 
in the report. The draft report shall be reviewed and edited by all Board members prior to issuance of the final 
report. 
If deemed necessary, the DSMB can request to know whether or not the participant received active medication 
or placebo. If they believe that termination of the trial is warranted, the blind of all study participants will be 
broken. DSMB recommendations will be communicated to the NIDA Project Officer soon after the DSMB 
meetings.  
 
Affiliation and contact information for the DSMB members are listed below (additional marijuana expert 
member TBN): 
 
Frances R Levin MD, Professor 
Department of Psychiatry 
Columbia University 
New York Psychiatric Institute, Unit 66 
1051 Riverside Drive 
New York, NY 
Tel: 212 543 5896 
Email: frl2@columbia.edu 
 
Joy Schmitz PhD 
Department of Psychiatry and Behavioral Science 
University of Texas Medical School-Houston 
Email: joy.m.schmitz@uth.tmc.edu 
 
Paul Pentel MD 
Hennepin County Medical Center 
Department of Medicine 
University of Minnesota Medical School 
Email: pentel@umn.edu 
 


Page 13 of 19 
Data Management  
Data Acquisition and Transmission.  Data collection at study visits will take the form of subjective measures 
(forms), blood and urine samples, and will be identified with a four-digit identification number.  Samples will be 
collected and stored with the subject ID code only.  The coordinator will keep the code that links the subject ID 
with the identity of the subject in a database protected by two-levels of security, stored separately from the 
data.   
Data Entry Methods.  All self-report data collection items throughout the study will be self-administered per 
direction of study staff via a computer program (REDCap; http://project-redcap.org/) to improve the quality of 
data (by avoiding missing data, illegible data, etc) and limit the time spent on data entry and cleaning.  Any 
data not entered directly into a computer system (i.e. height, weight, blood pressure) will be double entered on 
our password protected server by trained data entry personnel at the Tobacco Research Programs using the 
REDCap data entry programs.  The study coordinator will be available to monitor the data and correct any 
discrepancies based on source documents.   
Quality Assurance 
Data collected via computer programs (REDCap) will be monitored by the study coordinator by random 
inspection of completed forms, and any problems detected will be discussed with the PI.  The SAC (Eberly, 
Director) will analyze the data using the SAS program.  In addition, the SAC will provide support in developing 
data entry programs.  Data analyses will be completed at the end of the study.  For missing data: Persons who 
do not attend a week 4 visit, assessment of the primary outcome is not directly possible. During their week 5, 
study staff will attempt to contact them in order to collect by phone and/or email a self-reported recall of 
marijuana use as of week 4; outcomes collected in this way will be denoted separately in the study database.  
Trial Safety 
Potential Risks and Benefits for Participants.  The potential risks for study subjects are minimal to moderate.  
To help protect subject privacy, we will obtain a Certificate of Confidentiality from the National Institutes of 
Health. The researchers can use this Certificate to legally refuse to disclose information that may identify a 
subject in any federal, state, or local civil, criminal, administrative, legislative, or other proceedings, for 
example, if there is a court subpoena. The researchers will use the Certificate to resist any demands for 
information that would identify a subject, except as explained below. 
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).  
Subjects will be told that a Certificate of Confidentiality does not prevent them or a member of their family from 
voluntarily releasing information about themselves or their involvement in this research. If an insurer, employer, 
or other person obtains their written consent to receive research information, then the researchers may not use 
the Certificate to withhold that information.   
Medical histories for all subjects will be reviewed prior to entry into the study and all subjects will be under 
medical supervision while in the study.  Urine and breath samples will be obtained and should not present risk 
to the subjects.  Blood samples will be obtained by trained phlebotomists.  A minimal amount of blood will be 
collected (20cc) per collection. Blood drawing may result in slight discomfort, bruising, or there may be some 
soreness at the puncture site. In some cases there may be dizziness or fainting.   
Progesterone is generally well tolerated.  The most common adverse effect is sedation. Other less common 
adverse effects include menstrual irregularity (spotting or breakthrough bleeding; females only) dizziness, 
cramps, nausea, fatigue, headache and breast tenderness (de Lignieres, 1999; Simon, 1995, Sofuglu, 2009). 
Other side effects attributed to synthetic progesterone including depression, fluid retention, pruritus, jaundice, 
rash and thrombotic disorders, are unlikely to occur.  Recently there have been reports of increased risk of 
stroke, coronary artery disease, venous thromboembolism and breast cancer in postmenopausal females who 
have been on long-term hormone replacement treatment with estradiol and progestin (medroxyprogesterone) 
combination (Anonymous, 2002; Grady et al., 2002; Hulley et al., 2002; Nelson et al., 2002). While some of 
these adverse events develop after years of treatment, venous thromboembolism is seen within the first year of 
treatment (Anonymous, 2002). It is possible that progestins may contribute to thromboembolism seen during 
estradiol and progestin treatment and thromboembolism is listed in the PDR as one of the adverse events for 


Page 14 of 19 
medroxyprogesterone treatment (PDR, 2002). In contrast to synthetic progestins, natural progesterone is not 
known to cause thromboembolism (PDR, 2002). However, as a safety measure for these serious adverse 
events, we will exclude subjects with history of thrombophlebitis, deep vein thrombosis, pulmonary embolus, 
clotting or bleeding disorders, heart disease, diabetes or history of stroke. Possible adverse events from 
Progesterone will be assessed weekly by the research nurse (Schulz, NP) in consultation with the study 
physician (Allen, MD).  If the side effects cannot be tolerated the medication dosage will be decreased to 200 
mg once/day for those on the active medication. 
Although uncomfortable, marijuana withdrawal symptoms do not pose significant health risks.  Subjects who 
participate in this study will be asked to quit or reduce their marijuana use on an assigned quit date.  This may 
result in increased irritability, anxiety, tension, decreased appetite or sleeplessness.  
Adverse Events: An adverse event is any unwanted experience or event occurring during the course of a 
clinical trial.  At each visit, research assistants will collect pertinent information on any AE’s and meet with the 
Nurse Practitioner (NP) at least once per week.  The NP will decide if the AE was related to the study 
medication and give recommendations for follow-up.  In cases where the NP is unavailable or if the AE needs 
immediate attention, it will be escaladed to the PI immediately for acknowledgment and recommendations.  
The study investigators will follow all AEs to the point of a satisfactory resolution.  A study subject may be 
withdrawn from the study if the PI determines it is the best decision for protection of the safety of the subject.  
All AEs will be assessed to determine if they meet criteria for an SAE.  AEs will be quantified separately by sex 
and treatment groups and compared across treatment groups with Fisher’s exact test (for binary events) or 
with chi-square test (for counts of events or event rates).  The event will be documented as to whether there is 
1) no relationship between the study drug and the adverse event, 2) the adverse event is unlikely related to 
administration of the study drug, 3) the adverse event is possibly related to study drug administration, or 4) the 
adverse event is probably related to the administration of the study drug.  
Serious Adverse Events (SAE): A serious adverse event is defined as an outcome that is 1) fatal or life-
threatening, 2) significantly or permanently disabling or incapacitating, 3) requires or prolongs inpatient 
hospitalization, or 4) results in a congenital anomaly. SAE’s, whether or not related to study medication, will be 
reported to the IRB and NIDA.  All drug related adverse events of a non-serious nature are reported to the 
University of Minnesota’s IRB on an annual basis.  Serious adverse events will be reported by telephone to the 
IRB, and to NIDA and the FDA within the three days of our receipt of information regarding the event and 
written reports will be submitted within ten days.  If a subject either withdraws from the study or the investigator 
decides to discontinue a subject due to SAE, the subject will have appropriate follow-up medical monitoring.  
Monitoring will continue until the problem requiring hospitalization was resolved or stabilized with no further 
change expected, is clearly unrelated to study medication, or results in death.  Outcome of SAEs will be 
periodically reported to NIDA.  A summary of the SAEs that occurred during the previous year will be included 
in the annual progress report to NIDA.  Finally, the PI will ensure that serious adverse events are reported to 
NIDA via the serious adverse event tracking and reporting system at https://saetrs.nida.nih.gov/. 
The Principal Investigator will then take appropriate action (including study modification) as agreed upon by 
these monitoring groups including the DSMB when needed.  The Principal Investigator will determine whether 
the seriousness of the event warrants removal of the participant from the study.  Appropriate diagnostic and 
therapeutic interventions will be initiated and the participant will be medically followed and kept under 
observation as long as medically indicated. After the review of the data, the DSMB report will make 
recommendations about whether the trial should continue with or without modifications, or be terminated. Any 
potential conflict of interest in the Data and Safety Monitoring Board will be disclosed.  
Protection against Risk.  Subjects will be told the potential risks involved in this study.  Although risks to 
subjects in the proposed study are minimal, the following actions will be taken to minimize these risks.  We will 
exclude subjects with health conditions that may be exacerbated by their participation.  Subjects will be 
monitored regularly by medical personnel employed by the study.  Dr. Sharon Allen (PI) will be available for 
emergency phone calls 24 hours/day and for office visits in case of problems.  Blood will be collected by 
trained phlebotomists to reduce the risks involved with blood draws.   
During Progesterone administration, the first dose of the study medication will be taken at 8 PM to minimize 
possible sedation from initiation of progesterone treatment. Subjects will be warned about using caution when 
driving a motor vehicle or operating machinery. Subjects will also be warned about the side effects associated 
with Progesterone.  Further, although unlikely, the study physician (Dr. Allen, PI) will be alert to the earliest 


Page 15 of 19 
manifestations of thrombotic disorders including thrombophlebitis, cerebrovascular disorders, pulmonary 
embolism, and retinal thrombosis (PDR, 2002). If any of these occur or are suspected, the study medication 
will be discontinued immediately and medical treatment will be sought.  
Potential Benefits of the Proposed Research to the Subjects and Others 
Whereas no assurance can be made to an individual subject that he/she will personally benefit from such 
research, the experience should be beneficial.  Subjects will have the opportunity to learn about their marijuana 
use behavior and receive behavioral counseling.  Society may benefit from a better understanding of the role of 
sex hormones on marijuana use and impulsivity.  A better understanding of this relationship will help improve 
treatment strategies for marijuana use. The risks in relation to the potential benefits are minimal to the 
individual research subject and virtually nonexistent to society in general.   
Trial Efficacy 
No interim analyses of efficacy are planned for the proposed study.  
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Protocol Changes: 
 
Version 2.0 (IRB approved 01/29/2016) 
• 
Expanded on the significance of sex hormones on drug abuse and impulsivity. 
• 
Inclusion criteria: decreased the cut-off for motivation to quit using marijuana (from a ≥7 on a Likert-type  
scale to ≥1)  
Inclusion criteria: decreased the cut-off for minimum cigarette use (from ≥4 days per week to ≥1 days per 
month) 
• 
Provided more information on the THC urine dipstick used to verify marijuana status. 
• 
Provided more information on the study drug: progesterone 200mg. 
 
Version 3.0 (IRB approved 03/25/2016) 


Page 19 of 19 
• 
Removed Figure 1 as it was causing confusion with IDS pharmacy.  Further description and clarification 
regarding the medication schedule was added. 
• 
Relaxed the criteria for receiving participation bonus from not missing any visits to allowing subjects to miss 
one visit and still collect the bonus payment. 
 
Version 4.0 (IRB approved 07/18/2016) 
• 
A discrepancy was found between the ICF and protocol.  The ICF stated that blood draws would only be 
collected at SC, BL, W0, W2, W4 and W5.  The protocol stated that blood draws would be collected at each 
clinic visit.  The protocol was amended to match the ICF. 
 
Version 5.0 (IRB approved 11/15/2016) 
• 
RA’s collection information on AE’s 
 
Version 6.0 (IRB Approved 02/13/2017) 
• 
Increased subject compensation