Impact of Progesterone on Stress Reactivity and Cannabis Use
Phase: PHASE2
Conditions: Cannabis Use
Sponsor: Medical University of South Carolina

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Impact of progesterone on stress reactivity and cannabis use 
 
A. SIGNIFICANCE 
A.1. Prevalence of cannabis use disorder (CUD) and need for effective treatments. Current data suggest 
that 2.5% of adults (Hasin et al., 2016) and 3.0% of adolescents (Han et al., 2017) in the United States meet 
Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria for CUD (DSM-IV or DSM 5). Though 
estimates vary, several studies have suggested that approximately 8-10% of individuals who have experimented 
with cannabis at least once in their lifetime develop DSM-IV cannabis dependence (Lopez-Quintero et al. 2011; 
Wagner and Anthony 2002). In 2014, over one million Americans received treatment for cannabis related 
problems (SAMHSA, 2015).  Although a high demand for effective interventions exists, few specific treatments 
have been developed for CUD. Further, the treatments that have been examined have had limited efficacy, with 
few individuals achieving abstinence (Sherman & McRae-Clark, 2016). As such, it is critical to explore new 
strategies to improve treatment outcomes.   
A.2. Sex differences in CUD. Preclinical studies have demonstrated important sex differences in regards to 
cannabis. Females are more sensitive to the behavioral, psychological, and reinforcing effects of cannabinoids, 
and demonstrate faster acquisition of self-administration, higher rates of responding, and increased rates of 
drug-induced reinstatement than males (Craft et al., 2013; Fattore et al., 2009; Fattore et al., 2007). Clinical 
investigations have also revealed cannabis-related sex differences. Across substances of abuse, including 
cannabis, men are at greater risk for lifetime use disorder diagnosis (Becker & Hu, 2008). However, cannabis 
using women show greater abuse liability (Cooper & Haney, 2014), more rapid progression from use to disorder 
(Khan et al., 2013; Kerridge et al., 2018), more severe withdrawal symptoms (Copersino et al., 2010; Herrmann 
et al., 2015; Sherman et al., 2017), and greater barriers to care (Becker et al., 2017). Further, there is emerging 
evidence that women may not respond as well to CUD treatment as men (McRae-Clark et al., 2015a; McRae-
Clark et al., 2015b; Sherman et al., 2016).  
A.3. Stress reduction as a target intervention for cannabis using women. Among chronic users of cannabis, 
stress has been shown to be a significant factor in initiation and maintenance of use (see Hyman & Sinha 2009 
for review). For example, in a treatment seeking sample, Copeland and colleagues (2001) found stress relief to 
be the most commonly reported benefit from, and reason for continuing, cannabis use. Our group demonstrated 
that completion of a social stress task increased craving in individuals with CUD (McRae-Clark et al., 2011). 
Studies have also shown that cannabis users expect tension reduction from use (Galen & Henderson, 1999) and 
that coping motives are associated with levels of cannabis use (Bonn-Miller et al., 2007) and cannabis-related 
problems (Simons et al., 2005; Lee et al., 2007). Further, stress-related factors such as negative life events (Wills 
et al., 2001; Windle & Wiesner, 2004) and traumatic stress (Lipschitz et al., 2003; Bremner et al., 1996; Vlahov 
et al., 2004; Schiff et al., 2007) have demonstrated associations with cannabis use. It has therefore been 
suggested that interventions specifically focused on reducing, tolerating, and coping appropriately with stressors 
could improve treatment outcomes in cannabis users (Hyman & Sinha, 2009), and such an approach may have 
particular relevance for women.  
Women report more severe negative affect symptoms and greater related functional impairment during cannabis 
withdrawal than men (Copersino et al., 2010; Hermann et al., 2015, Sherman et al., 2017). Studies in adolescents 
and young adults have indicated that females are more likely to use cannabis as a coping strategy for tension 
and stress (Simons et al., 1998; Terry-McElrath et al., 2009; Cuttler et al., 2016), whereas males often identify 
enhancing positive affect as a motive for cannabis use (Chabrol et al., 2005; Newcomb et al., 1998). Congruent 
findings have been demonstrated in human laboratory paradigms, with cannabis-using women reporting 
increased craving following stress tasks as compared to men (Buckner et al., 2011). Of note, exposure to trauma 
has been shown to impact stress responding in cannabis using women, but not men, suggesting that 
consideration of past traumatic experiences may be important in sex-specific treatment development (Chao et 
al., 2018). 
A.4. Progesterone and substance abuse. A growing literature suggests that the ovarian hormone 
progesterone, which fluctuate naturally during the menstrual cycle, may play a key role in sex differences in 
substance abuse (Moran-Santa Maria et al., 2014). Preclinical research from our SCOR demonstrated that when 
progesterone levels are low (during the estrous phase in rats) females evidence greater cocaine seeking-
behavior (Feltenstein & See, 2007). Vallee and colleagues (Vallee et al., 2014) examined the effects of 
pregnenolone, a precursor to progesterone, on THC administration in rats and reported that it suppressed THC-
induced effects including hypothermia, locomotor suppression, and analgesia, as well as dampened 
neurobiological effects in reward-related brain regions (VTA, NAc). Numerous preclinical studies have also 

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shown progesterone administration attenuates the reinforcing effects of cocaine (Frye, 2007; Evans & Foltin, 
2010) and reduces drug-reinstatement and self-administration of cocaine (Anker et al., 2007; Larson et al., 2007) 
and nicotine (Mello, 2010).  
Clinical studies in tobacco, amphetamine, and cocaine users examining endogenous ovarian hormones 
support these findings. Women in the luteal phase of the menstrual cycle, when progesterone is high, showed 
decreased subjective cocaine (Evans, Haney, & Foltin, 2002; Sofuoglu et al., 1999) and amphetamine (Justice 
et al., 1999) effects compared to women in the follicular phase, while female smokers randomly assigned to quit 
during the luteal phase had lower relapse rates than those assigned to quit during the follicular phase (Allen et 
al., 2008). Research from one of our previous SCOR projects found that increasing levels of endogenous 
progesterone were associated with a 37% increase in the odds of smoking abstinence in women undergoing a 
relatively brief 4-week course of nicotine replacement therapy (Saladin et al., 2015). Of special note, our most 
recent SCOR project (Gray & Saladin, PIs) examined the association between daily salivary progesterone levels 
and cigarettes smoked per day over a 2-week period; preliminary findings indicated that increased levels of daily 
progesterone were associated with decreased cigarettes smoked per day in non-abstaining women (β=-0.32; 
SE=0.14; p<0.05). Further, we recently demonstrated that high levels of endogenous progesterone attenuate 
subjective responses of anxiety and craving to drug-cues that are preceded by a stressor, suggesting a role of 
progesterone in reducing stress-induced relapse (Moran-Santa Maria, 2018). 
Recent clinical studies have investigated exogenous progesterone as a potential pharmacologic intervention 
for substance use disorders. Compared to placebo, progesterone has been shown to attenuate subjective and 
physiological effects of cocaine in female cocaine users (Evans & Foltin, 2006; Sofuoglu et al., 2002; 2004), as 
well as decrease cue-induced craving and cortisol response in early abstinent cocaine-dependent women (Fox 
et al., 2013). In a 12-week trial, progesterone reduced weekly cocaine use in post-partum cocaine-dependent 
women compared to placebo (Yonkers et al., 2014). Exogenous progesterone, compared to placebo, has also 
been shown to attenuate craving and subjective effects of smoking (Sofuoglu et al. 2001; 2011), and improve 
cognitive performance in women but not men (Sofuoglu et al., 2011). 
A.5. Progesterone may address sex differences in negative affect and stress reactivity and improve 
outcomes for female cannabis users. Preclinical work has demonstrated that allopregnanolone (Allo), a key 
metabolite of progesterone, decreases indices of anxiety and reduces stress-induced elevations of 
adrenocorticotropic hormone (ACTH) and corticosterone (Patchev et al., 1996; Bitran et al., 1995; Biggio et al., 
2014). Animal studies have also reported that decreased levels of Allo in select neurons in the medial prefrontal 
cortex, hippocampus and basolateral amygdala are associated with augmented fear responses (Pibiri, Nelson, 
Guidotti, Costa, & Pinna, 2008) and that changes in Allo levels are inversely associated with anxiety-related 
behaviors (Frye & Walf, 2002, 2004; Frye, Walf, Rhodes, & Harney, 2004; Gulinello, Orman, & Smith, 2003; 
Rhodes & Frye, 2001; Walf, Sumida, & Frye, 2006). Other preclinical data indicate that progesterone dampens 
corticotropin-releasing factor (CRF)-enhanced startle responding (Toufexis, Davis, Hammond, & Davis, 2004). 
Studies in humans suggest that progesterone has sedative properties (deWit et al., 2001; Solderpam et al., 
2004) and can dampen cortisol activity and decrease stress-induced alertness, arousal and negative mood 
(Childs et al., 2010). There is also a small but growing body of animal and human findings that suggests 
progesterone is implicated in the pathophysiology of several anxiety disorders, notably PTSD and panic disorder 
(Nillni, Toufexis, & Rohan, 2011; Rasmusson et al., 2006). These studies show progesterone (and/or Allo) may 
have the ability to reduce anxiety related symptomatology. Lastly, two studies have reported on the effects of 
progesterone on stress responding and drug craving in cocaine dependent individuals. In the first study, Sinha 
et al., (2007) reported that women with high serum levels of progesterone showed significantly lower stress-
induced and drug cue-induced cocaine craving, and trends towards reduced drug cue-induced anxiety level and 
lower drug cue-induced systolic and diastolic blood pressure levels compared to women with low serum 
progesterone. Fox and colleagues (2013) reported that cocaine-dependent women but not men receiving 
progesterone reported lower ratings of negative emotion and higher ratings of relaxed mood following a stress 
exposure. Collectively, these findings, coupled with the preclinical and clinical (exogenous/endogenous) 
progesterone data discussed above, suggest that progesterone has anxiolytic-like properties that may diminish 
the effects of stress, particularly in drug using women, and be protective against relapse. 
A.6. Ambulatory assessment of stress cue reactivity. To date, the majority of cue reactivity assessment in 
cannabis users has occurred in the laboratory. While such a setting provides significant experimental control, it 
lacks the ecological validity that defines the rich context of cannabis users’ day-to-day natural environment. 
Ambulatory assessment refers to the collection of self-report, physiological, or other data from individuals in their 
natural environment, and allows for examination of real-world outcomes that may not be measurable by other 

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traditional research methodologies. In our previous SCOR, we utilized ambulatory assessment to conduct the 
first evaluation of sex influences on smoking- and stress cue-elicited craving in response to standardized cues 
presented in the natural environment of cigarette smokers (Wray et al., 2015; Tomko et al., 2017). Participants 
received pictorial smoking, stress, and neutral cues on a mobile device four times per day for two weeks using 
Cue Reactivity Ecological Momentary Assessment (CREMA; Warthen & Tiffany, 2009; Wray et al., 2015). We 
found that female smokers endorsed greater craving, stress, and negative affect than male smokers when 
exposed to stress cues, relative to neutral imagery (Wray et al., 2015). This real-world methodology also provides 
the unique opportunity to examine sex differences in the influence of stress/negative affect on real-world 
substance use behavior in daily life.  
A.7.Endocannabinoids. Surprisingly little is known about how heavy cannabis use or cannabis dependence 
can affect the endocannabinoid (eCB) system, particularly in women. Preclinical research has shown that 
anandamide (AEA) and 2-Arachidonoylglycerol (2-AG) levels in different regions of the brain fluctuate 
throughout the menstrual cycle, and there is evidence of a bidirectional interaction between hormones, 
predominantly estrogens, and eCBs [1]. Additionally, repeated THC administration has been shown to lead to 
decreased levels of AEA and 2-AG in the rat striatum, and increased AEA in the limbic forebrain [2]. 
In humans, levels of AEA in plasma have been shown to shift over the menstrual cycle, peaking during 
ovulation, followed by the follicular phase, and with levels lowest during the luteal phase [3,4]. As with animal 
models, AEA was highly correlated with levels of estradiol and luteinizing hormone [4]. In one study, heavy 
cannabis users were observed to have higher serum 2-AG after 24 hours abstinence relative to controls, 
without any difference seen in AEA, OEA, or PEA [5], but this is contradicted by another study, which found 
significantly reduced AEA and OEA in individuals with cannabis abuse or dependence [6]. Finally, women have 
been shown to have a different eCB response to exogenous THC administration than men, and change-from-
baseline OEA concentrations were found to be related to THC concentration [7]. 
Notably, no studies of heavy or dependent cannabis users have controlled for menstrual cycle phase when 
measuring eCB levels. Further, it is unclear how eCBs are affected by heavy cannabis use due to limited, 
contradicting results. No research has been conducted on how a brief period of abstinence might affect eCBs 
in this population, nor have other molecules implicated in the eCB system been assayed (e.g. SEA, NADA). To 
address these research gaps, we look to assess blood eCB levels in cannabis-dependent women in the 
follicular phase of the menstrual cycle that are both currently using or one week abstinent, and in the luteal 
phase after presumed resumption of use. We will also examine the effects of exogenous progesterone versus 
placebo taken during the abstinence period on blood eCB levels. To determine if there are gender differences 
in eCB levels, we will also collect samples in male participants, and compare across groups. 
 
A.8. Summary. Numerous sex differences in behavioral, biological, and clinical correlates of substance use 
disorders have been identified (Becker et al., 2017), yet there exists a dearth of sex-informed treatment options. 
Women are more likely to use cannabis for stress reduction (Simons et al., 1998; Terry-McElrath et al., 2009; 
Cuttler et al., 2016) and demonstrate increased cannabis craving after stress compared to men (Buckner et al., 
2011); as such, interventions targeting stress response may have particular salience for cannabis using women.  
Ovarian hormones have been identified as potential mechanisms of these stress-related disparities (Moran-
Santa Maria et al., 2014), and recent clinical trials have begun to examine progesterone’s utility as a possible 
pharmacotherapeutic agent (Evans & Foltin, 2006; Fox et al., 2013; Sofuoglu et al., 2001; 2004; 2011). While 
progesterone has shown promise as a treatment for women with cocaine and tobacco use disorders, it has not 
yet been tested in cannabis users. Progesterone may effectively target stress-related craving and cannabis 
withdrawal symptoms in women, thus reducing relapse rates and improving daily functioning.  
B. INNOVATION 
The proposed study will test truly novel hypotheses. Specifically, it will build on our previous SCOR work 
identifying progesterone as an important target in stress-related craving and relapse, while expanding the focus 
to a previously unstudied addictive disorder. To our knowledge, there are no previous or ongoing studies 
investigating this promising approach to treating CUD. Additionally, we plan to examine the potentially important 
effect that progesterone may have on stress, one of the most important contributors to continued cannabis use 

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in women. We adopt a novel dual-level approach by examining progesterone’s effects on stress provoked in a 
laboratory stress paradigm and on stress occurring during a 3-week period of naturalistic observation. In the 
latter case, we will use innovative mobile technology to measure stress repeatedly during and after progesterone 
treatment. This will allow assessment of craving and stress reactivity in the “day to day” natural environment of 
cannabis users. These approaches differ significantly from other research teams investigating progesterone in 
other drugs of abuse (i.e., Sofuoglu et al. focused on acute non-stress-provoked laboratory effects in cigarette 
smokers and cocaine users, and Allen et al. focused on cessation via potential effects of progesterone on 
impulsivity in cigarette smokers) and represent a highly innovative “next step” in sex-specific treatment 
development for CUD. 
APPROACH 
C.1. Preliminary Studies.  
C.1.a. Capacity of Research Team. Completion of the proposed research will require experience with 1.) 
recruitment, retention, and assessment of cannabis use disordered individuals, 2.) administration of exogenous 
progesterone, 3.) ambulatory assessments, 4.) stress induction procedures, and 5.) collection and interpretation 
of progesterone levels. As detailed below, the research team has the expertise to successfully conduct the 
proposed work and a proven track-record in similar research areas. The proposed project will be co-directed by 
Drs. Aimee McRae-Clark and Michael Saladin. Dr. McRae-Clark is a Professor in the Department of Psychiatry 
and a productive clinical researcher with NIH-funding focused on clinical trials and human laboratory work with 
cannabis using individuals. Dr. Michael Saladin is a Professor in the Department of Health Sciences and 
Research and clinical psychologist with expertise in craving, ovarian hormone measurement, and the interface 
between stress and substance use disorders. Drs. McRae-Clark and Saladin have both been investigators with 
the MUSC SCOR since its inception. Co-investigators will also contribute meaningfully to the conceptualization, 
conduct, and reporting of this research. Dr. Kevin Gray is a board-certified psychiatrist with significant experience 
in conducting CUD clinical trials; he will provide the necessary medical expertise to monitor for participant safety 
throughout the study. Drs. Brian Sherman and Rachel Tomko, clinical psychologists, have experience with 
human laboratory studies involving cannabis using participants and ambulatory assessment, respectively.  Of 
note, all members of the investigative team have a history of successful collaborations.  
C.1.b. Experience with Recruitment, Retention, and Assessment of Cannabis Use Disordered Individuals. 
Dr. McRae-Clark has successfully conducted multiple NIH-funded studies involving cannabis using individuals 
(K23DA15540, PI: McRae-Clark; R21DA018221, PI: McRae-Clark; R21DA022424; PI: McRae-Clark; 
R01DA026782, PI: McRae-Clark; R21DA034089, PI: McRae-Clark; UG3DA04323, MPIs McRae-Clark/Gray). 
We have an active recruitment network in place. As such, we do not anticipate any issues with successful 
recruitment of the proposed study sample.  
C.1.c. Experience with Administration of Exogenous Progesterone. We recently completed a small pilot trial 
(n=8) 
comparing 
progesterone 
to 
placebo 
administration in cannabis using women during 
cannabis withdrawal. Conduct of this trial allowed us 
to validate the research procedures that will be 
utilized in the proposed study, including (1) 
pharmacy compounding procedures for micronized 
progesterone and matching placebo capsules, (2) 
ability to recruit and retain cannabis using individuals 
willing to abstain from cannabis use for the required 
study period, (3) feasibility of using ambulatory 
assessment to verify cannabis abstinence and 
medication adherence, and (4) ability to increase 
endogenous progesterone levels with twice daily 
exogenous progesterone administration (see Figure 
1; p=0.027). Supporting our study rationale, 
preliminary data also provided suggestive evidence 
of a potential treatment by time interaction (p=0.071) 
in regards to cannabis craving, with women receiving progesterone reporting reduced cannabis craving 
compared to women receiving placebo over the five-day treatment period.  
C.1.d. Experience with Ambulatory Assessments. Our research group has developed ambulatory 
assessment tools to assess stress reactivity and drug craving, collect data on drug use and withdrawal 

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symptoms, validate abstinence, and measure and encourage medication adherence. As discussed above, in our 
previous SCOR, we modified the Cue Reactivity Ecological Momentary Assessment (CREMA) paradigm to 
assess cue- and stress-related nicotine craving (Wray et al., 2015). Over 80% of CREMA sessions were 
successfully completed (Tomko et al., 2017), supporting the feasibility of remote collection of stress reactivity 
and craving data. Our previous work involved four CREMA sessions per day; in the current proposal, three 
sessions per day will be utilized, which will likely improve compliance with session completion. We have also 
capitalized on the capabilities of the REDCap data system to remotely collect self-report and video confirmation 
of drug use biomarkers and medication adherence (Tomko et al., 2018). In a subsequent smoking cessation 
clinical trial, we found high compliance with video completion (73.8%) and self-reports (74.8%). Further, all 
participants agreed that the surveys and videos were easy to use, and 78.9% of participants preferred the 
REDCap assessments to traditional, paper measures.  In an ongoing clinical pharmacotherapy trial for CUD 
(UG3DA04323), we have also found high compliance with video uploads for medication adherence, with a 
median of 80% of medication doses verified.  
C.1.e. Experience with Stress Induction Procedures. Our research team has extensive experience with the 
use of stress induction paradigms in cannabis using 
individuals. We administered the Trier Social Stress 
Task (TSST), which will be used in the proposed study, 
to 87 cannabis-dependent individuals. Cannabis 
craving (as measured by the Marijuana Craving 
Questionnaire, MCQ) was significantly elevated 
following the TSST (p=0.029) (McRae-Clark et al., 
2011). Of interest, female participants reported 
increased craving following the TSST as compared to 
male participants (Figure 2; p=0.027), congruent with 
the notion that acute social stressors may be more 
closely related to relapse in cannabis using women vs. 
men. This work also underscores a need for further 
evaluation of (a) sex differences in response to 
stressors, and (b) therapeutic interventions focused on 
stress reduction.  
As discussed above in Significance, our previous 
SCOR utilized the CREMA platform to expose 
cigarette smokers to stress and neutral images from 
the International Affective Picture System. Consistent 
with our hypotheses in cannabis users, we found 
(Figure 3) significant sex by cue type interactions 
indicating that females vs. males endorsed greater 
craving (b=0.10, SE=0.03, p<0.01), stress (b=0.27, 
SE=0.04, p<0.01), and negative affect (b=0.24, 
SE=0.03, p<0.01) following the presentation of 
stressful vs. neutral cues. These analyses take into 
account time since last cigarette, pre-cue stress and 
craving, and day in study have replicated these 
findings (In figure, bars denote significant differences 
between post-cue model-based means). 

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C.1.f. Experience with the Collection and Interpretation of Ovarian Hormone Levels. The previous three 
iterations of our SCOR project have focused primarily on advancing knowledge about the role of both menstrual 
cycle phase and ovarian hormones in sex differences in cigarette smoking behavior and cessation (Carpenter et 
al., 2006; Carpenter et al., 2008; Gray et al., 2010; Saladin et al., 2015a; Saladin et al., 2015b; Schiller et al., 
2012; Weinberger et al., 2015; Allen et al., 2016). Our publication record on this topic attests to our experience 
collecting and interpreting ovarian hormone data. One major goal of our most recent SCOR component (Saladin 
& Gray PIs) was to evaluate relationships between daily ovarian hormone levels and subjective responses to 
smoking and stress cues presented in the natural environment of smokers (via an iPhone app). This goal was 
achieved by having male and female smokers collect daily saliva samples (half hour after awakening) over a 
14-day period. These samples were then assayed, using commercially available immunoassay kits 
(Salimetricstm), by qualified laboratory technicians at MUSC’s Clinical and Translational Research Center 
(CTRC). This study has permitted our research group to become highly proficient/experienced at the effective 
collection of daily biological samples and has yielded a rich data set. Preliminary analyses of the data indicate 
high levels of compliance with daily sample collection. Specifically, more than 90% of the participants who 
completed the study protocol provided ≥ 80% of the daily saliva samples. This high level of compliance resulted 
in stable and meaningful estimates of daily progesterone levels during the collection period, as indicated in 
Figure 4. Briefly, the figure shows the mean daily salivary progesterone levels (and SEs) of female smokers as 
a function of days (self-report) since last menses; it shows that progesterone levels are low and stable during 
most of the first half (follicular phase) of the menstrual cycle, followed by a steep rise during the early- and mid-
portions of the second half of the cycle (luteal phase), followed by a decline as the next menses approach. The 
depicted pattern of time-dependent progesterone variation closely resembles that which has been reported in 
greater scientific literature (Schiller et al., 2012; 
Wira et al., 2015; Balen, 2007; Laycock & 
Meeran, 2012; Starr & McMillan, 2007). We 
believe these findings attest to our group’s 
ability to reliably collect and assay large 
volumes of daily saliva samples for the 
purposes of estimating daily fluctuations in 
progesterone hormone levels.     
C.2. Research Design and Methods. In this 
project, the impact of progesterone on stress-
related cannabis craving will be investigated in 
cannabis use disordered men and women. Cue 
Reactivity Ecological Momentary Assessment (CREMA), involving the assessment of reactivity to stressful cues, 
will be conducted three times daily during a one-week period of cannabis cessation; participants will be 
randomized to receive either progesterone or placebo during the abstinence period. Participants will be followed 
for two weeks after the cessation period to track return to cannabis use. Naturalistically collected stress reactivity 
data will be complemented by administration of a validated laboratory stress procedure (TSST) immediately after 
the cessation period, and daily salivary sampling will be used to track changes in progesterone levels. A 
schematic of study procedures is shown. 
C.2.a. Participants. A total of 160 non-treatment seeking men (n=90) and women (n=70) with CUD, aged 18 to 
45 years of age, will be randomized over a 54-month period. Additional inclusion criteria include consent to 
random assignment and ability to read and provide informed consent. Exclusion criteria include women who are 
pregnant, nursing, or planning to become pregnant during the course of the study; having a history of or current 
major psychiatric or medical disorder; and meeting criteria for moderate or severe use disorder for another 
substance with the exception of nicotine. A detailed list of inclusion/exclusion criteria can be found below.  

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C.2.b. Recruitment. Participants will be recruited primarily through media advertisements. Participants may also 
be recruited through ResearchMatch.org.  As noted above in C.1.b., we have had good results using this method 
in previous studies.   
C.2.c. Procedures.  
C.2.c.1. Strategies to Ensure a Robust and Unbiased Approach and Rigor and Transparency. As detailed 
throughout this section, the proposed study will achieve robust and unbiased results via several design features 
including: explicit inclusion/exclusion criteria; randomization of treatment condition; placebo control; blinding; use 
of validated laboratory and interview/self-report measures and methods; explicit hypotheses with a priori/targeted 
data analytic plan; precision sample size estimation; a priori/strategic management of retention/attrition and 
missing data; and careful consideration of potential confounds. All experimental details are reported in a detailed 
and fully transparent manner to support replication. 
 
C.2.c.2. Screening and Eligibility Assessment. Individuals interested in participating will be screened either 
by telephone or in person by the research study intake coordinator. A quick screen will be used to initially 
determine study eligibility. This questionnaire is focused on inclusion/exclusion psychiatric diagnoses, medical 
status, current medication regimen, and ability and willingness to fill out the necessary assessments and commit 
to completion of study procedures.  Potential participants will be given a full description of the study procedures 
and asked to read and sign an IRB-approved Informed Consent Form if they choose to participate. 
Inclusion/exclusion criteria are detailed below. 
Inclusion Criteria: 1.) Able to provide informed consent and function at an intellectual level sufficient to allow 
accurate completion of all assessment instruments. 2.) Meet DSM-5 criteria for mild, moderate or severe 
cannabis use disorder (within the past three months) and report using cannabis at least five times weekly over 
the past month. While individuals may also meet criteria for mild use disorders of other substances, they must 
identify cannabis as their primary substance of abuse. 3.) Age 18-45. 4.) For women, regular menses (every 25-
35 days). 5.) Consent to remain abstinent from alcohol for 12 hours prior to study visits, and all other drugs other 
than cannabis or nicotine for the duration of the study. 6.) Women of childbearing potential must agree to utilize 
an effective means of birth control. 7.) Must consent to random assignment. 
 
Exclusion Criteria: 1.) Women who are pregnant, nursing or of childbearing potential and not practicing an 
effective means of birth control. 2.) Women who are amennorheic or using progesterone-based contraceptives. 
3.) Evidence or history of major medical illnesses, including liver diseases, abnormal vaginal bleeding, suspected 
or known malignancy, thrombophlebitis, deep vein thrombosis, pulmonary embolus, clotting or bleeding 
disorders, heart disease, diabetes, history of stroke or other medical conditions that the investigator deems as 
contraindicated for the individual to be in the study. 4. ) Subjects taking antipsychotics (unless for indication other 
than psychosis), or regularly taking opiates or benzodiazepines 5.) History of or current psychotic disorder or 
bipolar affective disorder. 6.) Current suicidal or homicidal ideation/risk. 7.) Known allergy to progesterone or 
peanuts (vehicle for micronized progesterone). 8.) Meet DSM-5 criteria for moderate or severe substance use 
disorder (other than nicotine or cannabis) within the past 60 days. 9.) Unable to comply with study procedures 
or pose threat to study staff. 
a. Screening and Diagnostic Instruments. Quick Screen: This assessment will quickly determine whether an 
individual meets study inclusion or exclusion criteria. The instrument is designed to assess for substance 
dependence and obvious psychiatric, medical, and logistic exclusions. Mini-International Neuropsychiatric 
Interview (M.I.N.I.): The M.I.N.I. is a brief structured interview that was designed to assess DSM-5 diagnoses 
using a series of questions in dichotomous format (yes/no). Earlier studies have found that the M.I.N.I. is similar 
in sensitivity, specificity, and inter-rater reliability to other lengthier diagnostic interviews, such as the SCID-I/P 
(Sheehan et al., 1998). The alcohol and drug use disorder modules will be used to thoroughly assess both current 
and lifetime diagnostic status for abuse and dependence. It has excellent inter-rater and test-retest reliability 
(First et al., 2002). Participants will also have a physical exam. Menstrual History Diary: Participants will be 
asked to estimate the timing of their cycle for the 90-days prior to study entry and to track their cycle during study 
participation. Perceived Stress Scale (PSS): The Perceived Stress Scale is a 10-item assessment of daily 
stress (Cohen et al., 1983) that has previously been used in substance use research (Fox et al., 2009; Hyman 
et al., 2007). Adverse Childhood Experiences (ACE) Questionnaire: The ACE questionnaire assesses 
childhood maltreatment and exposure to household dysfunction. It has been utilized to examine the relationship 
between adverse childhood experiences and health risk behavior in adulthood (Felitti et al., 1998). In addition to 
providing data to assess the impact of daily stress and early childhood trauma on cannabis use and stress 
reactivity, utilization of the PSS and ACE will likely allow for potential cross-SCORE collaborations as these 
scales have been previously recommended as components of the core assessment battery utilized across 

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centers. Coronavirus Impact Scale: 12 item questionnaire assesses life changes that have occurred as a result 
of the coronavirus (Stoddard & Kaufman, 2020). We will also ask how substance use has been impacted 
b. Substance-Related Instruments. Time Line Follow-back: The Time Line Follow-back (TLFB; Sobell & 
Sobell, 1992) is a calendar-based instrument designed to assess daily substance consumption. Cannabis use 
will be recorded in times used per day as well as quantity (e.g., grams, number of blunts/joints) in order to 
standardize for different types of cannabis use. Urine Drug Screening: Qualitative drug screens will be 
performed using the One Step Multi-Drug Test Dip Card (DrugconfirmTM), a lateral flow chromatographic 
immunoassay for the qualitative detection of drug or drug metabolite in the urine at the following cutoffs (ng/ml): 
cocaine (300), amphetamines (1000), THC (50), opiates (2000), and benzodiazepines (300). In addition, 
quantitative urine cannabinoid drug screens will be performed using the AXSSYM® system from Abbott 
Laboratories. This assay is semi-quantitative with a detection cut-off value of 30.00 ng/ml (Abbott AXSSYM® 
System package insert). Urine creatinine will also be obtained, as creatinine normalization has been proposed 
as a method to differentiate new cannabis use from residual drug excretion (Huestis & Cone, 1998; Schwilke et 
al, 2011). Results will be used to ascertain abstinence prior to study procedures, cannabinoid levels, and to 
substantiate self-reports of all substance use.  Breathalyzer (AlcoSensor III, Intoximeters, Inc., St. Louis):  To 
ascertain abstinence from alcohol prior to study visits, participants will have their breath sampled for the presence 
of alcohol (Alco-Sensor III, Intoximeters Inc., St. Louis, MO). Inventory of Drug-Taking Situations (IDTS) 
(Annis et al., 1997): This instrument measures typical drug using situations based on Marlatt and Gordon’s (1985) 
eight category taxonomy. This instrument contains eight subscales mapping frequency of use in eight distinct 
types of situations including use during negative situations (unpleasant emotions) and positive situations (social 
situations).  Although initially developed to assess alcohol use, this scale has been modified for use with drug 
abusers and has demonstrated sensitivity to sex differences (Ross et al., 1994). 
c. Remote screening visit alternative. Patients may also complete the initial visit remotely if warranted. In this 
case, subjects will be electronically consented through a secure platform such as Doxy.me or Redcap. The 
informed consent will be emailed to the participant prior to the video call. The patient will have the opportunity to 
ask questions on the call and will electronically sign the document. A signed copy will be emailed to the 
participant. The M.I.N.I interview and medical history then be conducted, also via Doxy.me. If clinically indicated, 
patients may have a physical exam the UDS visit. To date, no patients have been excluded due to physical exam 
findings.  Patients will be advised to find a private location during these procedures to protect privacy and 
confidentiality. Patients will be sent survey links to complete self-report questionnaires.  
d. Blood draws: In order to investigate the impact of moderate to heavy cannabis use and menstrual cycle on 
the endocannabinoid system, blood will be taken at Days 1, 8 and 22. 
C.2.c.3. Progesterone Administration Procedures (Study Days 1-7). Following completion of screening 
procedures, participants will be scheduled to come to the clinic for training on CREMA and saliva (progesterone) 
collection procedures. The TLFB calendar will be completed. For female participants, menstrual history data will 
be used to schedule this session in the early follicular phase to standardize progesterone (or placebo) 
administration. During the early follicular phase, defined as the first 7 days after the onset of menses, ovarian 
hormones are low and largely invariant (approximately <1.1 ng/ml for progesterone and <85 pg/ml for estradiol; 
Chabbert-Buffet et al., 1998). This is critical for two reasons; first, to minimize the interaction between 
endogenous and exogenous sex hormones, and second, to achieve consistency between males and females 
as progesterone levels in men are steady and similar to levels observed in women during most of the follicular 
phase (Zumoff et al., 1990). At this visit, a urine sample will be collected to assess baseline cannabinoid level 
for purposes of cannabis abstinence verification (described below). Participants will be instructed to refrain from 
cannabis use during this study period.  
a. Medication Randomization. Randomization will be done by the MUSC Investigational Drug Service, who will 
keep a record of the blind and be available should unblinding be required. Randomization will be stratified on the 
presence/absence of nicotine use as well as the presence/absence of comorbid anxiety disorders (as these 
disorders can influence stress reactivity). 
b. Micronized progesterone (Prometrium; 200mg): Progesterone is a hormone released mainly during the 
luteal phase of the menstrual cycle and pregnancy, and has been used for over 50 years in the treatment of 
various disorders including ovarian failure, premenstrual symptoms, amenorrhea, dysfunctional uterine bleeding, 
menopausal symptoms and for contraception (de Lignieres, 1999; Simon, 1995). Because it is poorly absorbed 
and has extensive first pass metabolism, several synthetic progesterone derivatives have been synthesized and 
marketed. However, these synthetic progesterone derivatives have additional androgenic, corticosteroid and 

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anabolic effects and have been associated with unfavorable side effects including fluid retention, androgenic 
effects (e.g., unwanted hair growth and acne) and alterations in lipid profile (Goodman, Gilman, Hardman, 
Gilman, & Limbird, 1996). Consequently, micronized progesterone formulations that can be taken orally have 
been developed to overcome the poor absorption of progesterone and the unfavorable side effects of synthetic 
progesterones (McAuley, Kroboth, & Kroboth, 1996; Simon, 1995). The safety, tolerability and efficacy of 
micronized progesterone have been demonstrated in multiple studies. Acute effects of micronized progesterone 
on physiological, performance and subjective measures have been investigated over a wide dose range, from 
200 to 2,000 mg/day (Freeman, Rickels, Sondheimer, & Polansky, 1995; Gron, Friess, Herpers, & Rupprecht, 
1997; Schweizer, Case, Garcia-Espana, Greenblatt, & Rickels, 1995). Micronized progesterone provides a 
specific pharmacological tool to investigate the effects of this hormone, devoid of the additional pharmacological 
effects of synthetic progesterone derivatives. 
Participants will be provided with a seven-day supply of progesterone or placebo.  Randomization to treatment 
will be done by the MUSC Investigational Drug Service (IDS). Dosing will begin in the evening on study day 1. 
On study days 2-7 participants will take medication at home in the morning and evening, and on day 8 the final 
dose will be taken at in the morning prior to completion of the laboratory stress task (described below). 
Progesterone and matching placebo capsules will be prepared and dispensed by the MUSC IDS. Previous 
studies (Fox et al., 2013; Sofuoglu et al., 2001; 2011) have used twice daily administration of 200mg 
progesterone during the early follicular phase to achieve stable levels of progesterone comparable to normal 
luteal phase levels (2-20 ng/ml). Safety and tolerability of micronized progesterone have been established in 
numerous studies with nicotine (Sofuoglu et al., 2001; 2011) and cocaine (Evans & Foltin, 2006; Fox et al., 2013; 
Reed et al., 2011 Sofuoglu et al., 2002; 2004) dependent individuals.  
c. Cannabis Abstinence Verification. Cannabis abstinence will be assessed using self-report, saliva drug 
testing, and cannabinoid levels. Self-report will be collected at study visits using the TLFB as well as collected 
daily through mobile surveys or “morning reports” completed via mobile electronic device. Participants will be 
trained to self-administer saliva drug screening (Oratect FDA approved saliva test.). This test is able to detect 
THC in saliva for up to 14 hours. Participants will be instructed to complete two saliva drug tests daily using the 
RedCap video upload procedure described below under Medication Adherence/Drug Test Monitoring.  A test will 
be completed in the office on Day 1 so patients can practice the procedure. Cannabinoid levels will also be 
assessed using urine toxicology collected on Study Days 8 and 22. Creatinine-corrected cannabinoid levels will 
be compared from Day 1 to Day 8 to confirm abstinence during the study period. Our group has recently 
published on the need for utilization of multiple methods to determine cannabis abstinence (Baker et al., in 
press). Contingency management (monetary compensation) procedures will be incorporated to promote 
abstinence (described below). 
d. Medication Adherence/Drug Test Monitoring. Participants will record themselves taking their morning and 
evening medication doses as well as completing the twice daily saliva drug test swab procedure. Photos of the 
completed saliva test will be uploaded.A survey link will be sent to the participant’s (or study provided) cell phone 
via CREMA app alert twice daily.  Video capture will occur as part of a RedCap survey. As discussed in the 
Preliminary Data section, we have previously utilized this technology successfully for both medication adherence 
monitoring and to remotely assess substance use. To encourage compliance with study procedures, participants 
will receive $10 for completion of each medication adherence video. Participants will receive an additional $30 
for each saliva drug screen that is negative for all drugs of abuse. A similar compensation schedule was effective 
in our pilot progesterone study. Study staff will call participants twice during this week to see if they are having 
any difficulties with the procedures or side effects from the medication. Study staff will also text abstinence 
reminders to patients whose saliva tests positive for drugs of abuse. 
e. CREMA Assessment. Cue Reactivity Ecological Momentary Assessment (CREMA; Warthen & Tiffany, 2009; 
Wray, Godleski, & Tiffany, 2011; Wray et al., 2015) is a cue reactivity assessment in which photographic stimuli 
are presented multiple times per day on a mobile electronic device (i.e iPhone). In cases where participants do 
not have a smart phone or do not wish to use their own device for the purposes of the study, a phone will be 
provided. Participants will be instructed to keep their phone with them at all times. Phones will be password 
protected to prevent access to the study assessments and surveys by anyone other than the participant. Auditory 
alarms will alert participants to complete three, randomly scheduled CREMA sessions per day (session duration 
= 3-4 minutes). Alarms will be distributed over a 12-hour period, divided into three, 4-hour blocks with a minimum 
time of 30 minutes between alarms/CREMA sessions. In order to accommodate varying participant wake-sleep 
schedules, participants will be able to choose the 12-hour period during which they will be prompted and this 
may vary from weekdays to weekends. There will be two types of picture cues that differ based on content: 

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stress-related (i.e., a child in distress) or neutral (i.e., sunglasses). Both stress and neutral picture cues will be 
derived from the International Affective Picture System or IAPS (Lang, Bradley, & Cuthbert, 1998). The IAPS is 
a set of over 1000 pictures which have been normed across 18 separate studies on three key features of emotion: 
(1) valence (feeling happy vs. unhappy), (2) arousal (feeling excited vs. calm) and (3) dominance (feeling in 
control vs. controlled). The photos that will be employed in the proposed study will be matched for valence and 
arousal using normative values provided with the IAPS. Specifically, stress and neutral pictures will be drawn 
from the mid-range of quantitative valence and arousal ratings; this should serve to minimize widely disparate 
responding from one trial to the next. Of the three CREMA sessions presented each day, one will contain a single 
neutral picture, one will contain a stress-related picture and one will not show picture cues, but will collect data 
on ambient (non-cue elicited) stress and craving, as well as cannabis use since last assessment (detailed below). 
We chose this frequency of stress cue presentation (once daily for 21 days) based on our previous CREMA 
work, which showed that stress responsiveness was maintained across 21 CREMA-based stressful picture 
presentations. 
At the start of each CREMA session, participants will be asked to stop using cannabis (if they are at the time), 
and provide ratings on craving, mood, and stress using a modified version of the Within Session Rating Scale 
(Childress et al., 1986). This visual analog scale is anchored with adjectival modifiers (“not at all, mildly, 
moderately, and extremely”). The scale includes items assessing anxiety, stress, irritability, and craving, and we 
have utilized it successfully in numerous previous studies. If the session is one of the two daily picture 
assessments, next a photograph (either stress-related or neutral) will be presented and the participant will be 
instructed to look at it carefully for 10 seconds. Each picture cue will appear only once during the study. An alarm 
will sound at the end of each trial, after which participants will complete a post-cue Within Session Rating Scale 
assessment, ratings of how carefully they looked at the photographs and their distraction level during each trial, 
and data on their cannabis use since last assessment. If the session is only collecting ambient stress and craving, 
immediately after the Within Session Rating Scale the participants will be asked to record data on cannabis use 
since the last assessment session. To encourage CREMA session completion, participants will be compensated 
$5.00 for each completed session. Previous studies employing lower incentive strategies have reported 80-90% 
CREMA completion rates (Gass et al., 2012; Warthen et al., 2009), including in our previous SCOR (Wray et al., 
2015); we have slightly increased compensation to maximize potential data collection over the 3-week period.  
CREMA sessions will begin on Day 2.  
f. Progesterone Salivary Sample Collection. Participants will be instructed to collect a saliva sample each 
morning (1/2 hour after awakening). Samples will be dispensed into containers supplied by study staff and stored 
in participants’ home freezers until bringing the samples to a subsequent study visit for analysis of progesterone 
levels. These daily home collection and storage procedures have been used in numerous previous studies with 
excellent participant adherence and sample quality (Edler et al., 2007; Klump et al., 2008). As discussed above 
in Preliminary Data, we successfully utilized a similar procedure in our last SCOR project. Participants will receive 
$10 daily for collection of ovarian hormone salivary samples. 
g. Cannabis Withdrawal Assessment. The Cannabis Withdrawal Scale (CWS; Allsop et al., 2011) will be used 
to assess cannabis withdrawal symptoms, including negative affect and craving. CWS is a 19-item self-report 
measure that assesses withdrawal symptoms in the past 24 hours. The CWS will be administered twice daily 
during the progesterone administration phase as part of the RedCap medication adherence survey that will be 
sent via text message. Participants will be asked to respond with reference to the past 12 hours.  
In order to assist participants with completing instruments and assessments at home, we will provide them with 
a link to an instructional video on YouTube and an FAQ sheet. These items will be emailed to participants after 
their Day 1 visit. 
h. Cognitive Testing. Cognitive functioning will be assessed at BL and Study Day 8 to examine whether 
cognitive functioning is improved following progesterone administration and cannabis abstinence or whether 
changes in cognitive functioning mediate stress reactivity. Implicit cognitive function will be assessed using the 
Cannabis Approach-Avoidance Task (Jacobus et al., 2018; Sherman et al., 2018) which assesses the automatic 
tendency to approach rather than avoid drug cues, a cannabis adaptation of the dot-probe task that has shown 
sensitivity across substances of abuse (Field et al., 2006; Garland et al., 2013) which assesses cannabis 
attentional bias, and a cannabis adaptation of the Implicit Association Task (Wiers et al., 2011) which assesses 
cannabis memory bias. Explicit cognitive function shown to be impacted by SUDs will be assessed, including 
working memory – verbal (WAIS-IV Digit Span Subscale) and nonverbal (N-Back) (McClernon et al., 2016) tasks, 
and the Symbol Digit Modalities Test (SDMT) (Smith, 1982) which measures sustained attention, response 
speed, and visuomotor coordination.  

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As cognitive testing is not a primary outcome, it will not be completed at visit 1 or 8 when exposure needs to be 
limited for health and safety. 
C.2.c.4. Laboratory Stress Induction Session (Day 8). Following the one-week period of progesterone or 
placebo administration, participants will return to the study clinic to complete a laboratory stress task (Trier Social 
Stress Test, TSST). Data from this task will be used to complement the “real world” stress reactivity data collected 
via CREMA. If participants become unable to attend the session on Day 8, they may be re-scheduled for the 
following day. However, participants will not be re-scheduled after Day 9. 
a. Session Preparation. Participants will be instructed to arrive at 11:00am on the day of the TSST, and to avoid 
caffeinated beverages on the test day since caffeine can inflate reactivity to the stressor. If the individual is 
nicotine-dependent, (s)he will be provided with a nicotine patch throughout their study visit. Upon arrival, the 
participant will be breathalyzed and will provide urine and saliva samples, which will be tested for the presence 
of marijuana, cocaine, opiates, barbiturates, benzodiazepines, and stimulants. The urine sample will also be 
quantitatively analyzed for cannabinoids and creatinine to confirm past week cannabis abstinence. At 10:30am, 
saliva (progesterone) will be collected, and a blood pressure cuff will be placed on the participant’s arm. Two 
baseline assessments of subjective, hormonal (cortisol; see Assessments below for details), and physiologic 
measures (blood pressure and heart rate) will be collected, one at 11:40am and the second at 11:55am.  
b. TSST. The TSST is a standardized psychological stress challenge which has been used extensively in 
research studies. A meta-analysis supports its utility for provoking a HPA axis stress response in a laboratory 
setting (Dickerson & Kemeny, 2004). We have used it in our previous work to induce a robust and reliable 
physiological stress response in cocaine, alcohol, and cannabis-dependent individuals (McRae et al., 2006; 
McRae-Clark et al., 2011; Waldrop et al., 2010). At 12:00pm, the participant will be told that (s)he will give a 
speech and perform an arithmetic task. The topic of the speech will be why (s)he should be hired for a particular 
job (the individual’s “dream job”). The participant will deliver the speech as though speaking to a group of 
potential employers. The experimenter then tells the participant that (s)he has 5 minutes to prepare the speech 
and starts the countdown clock (placed in view of the individual). The experimenter leaves the room to allow the 
participant to prepare. Five minutes later, three individuals unfamiliar to the participant (the audience) enter the 
room and are seated; the individual will be instructed by one audience member to stand and begin his/her 
prepared speech (without notes). The speech will be delivered for 5 minutes. If the individual pauses, (s)he will 
be instructed to continue. At the end of the speech task, the individual will be instructed to serially subtract 13 
from 1,022 as quickly and accurately as possible. The mental math recitation will continue for 5 minutes, at the 
end of which time, the spokesperson will instruct the individual to stop and be seated, and the audience leaves 
the room. At this point, a saliva sample will be collected (for cortisol) and physiological (blood pressure and heart 
rate) and subjective measures (Within Session Rating Scale, Marijuana Craving Questionnaire, STAI) obtained. 
Measurements will also be obtained at 5-, 30-, and 60-minutes post-task. 
Modifications may be made to TSST procedures if necessary for patient and staff safety, ie fewer confederates, 
remote procedures. 
c. Assessments.  Self-Report Measures. Within Session Rating Scale:  As described above and used with the 
CREMA sessions, to allow for cross-task comparisons. State-Trait Inventory (STAI): The STAI is a 20-item self-
report scale (Spielberger, 1983) employing a Likert-scale format with four responses per item (1-4). Ten of the 
STAI items measure feelings of stress and anxiety, while the remaining ten items measure feelings of relaxation. 
The STAI has good psychometric properties. Marijuana Craving Questionnaire (MCQ): The MCQ (Heishman et 
al., 2001) is a Likert-based self-assessment of cannabis craving shown to be a valid and reliable instrument for 
measuring cannabis craving. The 12-item MCQ will be used, which has been constructed by selecting the three 
items from each factor of the full 47-item MCQ that exhibited the most within-factor reliability. Physiological 
Measures. Heart rate and blood pressure will be measured using an intermittently inflatable cuff as indices of 
physiological arousal during the test session. Hormonal Measure. Cortisol: Cortisol will also be measured in 
unstimulated passive saliva using the Salimetrics expanded range, high sensitivity salivary cortisol enzyme 
immunoassay kit. This kit has a lower sensitivity level of <0.003 µg/dL. The correlation between salivary and 
serum cortisol has been shown to be high (r=0.91, p<0.0001). Cortisol is commonly measured as an indication 
of stress response in human laboratory studies.  
d. Discharge. Following the 60-minute assessment, participants will be given instructions regarding monitoring 
of stress and cannabis use over the next seven days. A member of the research staff will be available to discuss 
management of any cravings if they remain elevated at the end of study procedures. 
C.2.c.5. Follow-up Assessment (Days 8-21). During the follow-up period, participants will continue to be 

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queried three times daily regarding stress and craving levels (as assessed by the Within Session Rating Scale), 
as well as cannabis use in order to determine precipitants of, and sex differences in, return to use. As detailed 
above, two of these sessions will also include picture presentations (one neutral picture session and one stress-
related picture session) to continue to assess stress reactivity during this period. Daily saliva samples will also 
be collected by participants as above. This monitoring will continue for two weeks following the laboratory stress 
session. At the end of the two weeks, on Day 22, participants will return to the clinic. At this visit, participants will 
return collected salivary hormone samples, provide a urine drug screen to validate self-reports of drug use, turn 
in any clinic-provided phones, complete a questionnaire regarding their experience with the CREMA and 
REDCap surveys, and be provided referrals to treatment if interested.  
Participant Compensation: Participants will be compensated $40 for completing the screening visit ($20 for 
physical, $20 for interview) and $20 for Day 1. Participants will receive $5 for each completed CREMA session, 
for a total possible compensation of $300. Participants will receive a $5 bonus for each day they complete all 3 
sessions for a possible total of $100.  During the cannabis abstinence and progesterone administration period, 
participants can earn a total of $120 for completing saliva tests $360 for negative salivary drug tests and $140 
for completing medication adherence video uploads. Participants will receive $190 for daily collection of salivary 
samples for ovarian hormone measurements. Participants will also be compensated $100 for Study Visit 8 ($50 
if they re-schedule for Day 9) and $100 for Study Visit 22 , for a total potential compensation of $1470. If they 
borrowed an iPhone and do not return it they will be paid $50 for Visit 22. ClinCards may be mailed to participants 
or obtained at their first clinic visit.  Participants will complete a w-9 which may be done in person or via Doxy.me. 
Confidentiality: Confidentiality of all research data will be maintained by keeping all data in a locked file, limiting 
access to the computer database to only study personnel, and by using patient code numbers as opposed to 
names on all paperwork.   
Data Management and Reduction: All paper-based assessments (other than laboratory reports) will be entered 
into REDCap, a secure, web-based application designed exclusively to support data capture for research 
studies. REDCap provides an intuitive interface for data entry (with data validation), audit trails for tracking data 
manipulation, and automated export procedures for data downloading to statistical packages such as SPSS and 
SAS. Quarterly database management and data integrity audits will be conducted.     
C.2.d. Statistical Considerations 
C.2.d.1. Statistics and Data Analysis (complete data analytic plan is provided in Biostatistics Resource Core) 
Aim 1: Examine the impact of exogenous progesterone on stress cue reactivity and cannabis craving 
and withdrawal symptoms during a period of cannabis abstinence in the natural environment. 
The primary measures of interest are stress and craving ratings in response to stress-related cues using Cue 
Reactivity Ecological Momentary Assessment (CREMA) in heavy cannabis using women and men. Hypothesis 
1: Compared to placebo, progesterone will attenuate reactivity to stress cues presented in the natural 
environment among women vs. men with CUD. Hypothesis 2: Compared to placebo, progesterone will attenuate 
cannabis craving and withdrawal symptoms among women vs. men with CUD. To assess these hypotheses 
multilevel generalized linear mixed effects models with repeated measures (GLMMs) will be developed using 
CREMA session response data from the 1-week period during active medication administration.  Pre-cue stress 
and craving rating will be centered and used as a time varying covariate in all analysis. Least squares means 
and associated standard errors will be used for post-hoc comparisons of cue response and CWS scores between 
treatment group assignments globally as well as time-specific (AM, PM) treatment group differences.  Least 
squares means and associated standard errors will also be used for post-hoc comparisons of craving and stress 
response between women and men over time. Relevant interactions will be assessed in the models. 
Aim 2: Examine the impact of exogenous progesterone on stress cue reactivity during a laboratory 
stressor task.  
Following the initial 7-day active exogenous progesterone treatment period, participants will return for a 
laboratory-based stressor a session.  The primary study outcomes of interest in Aim 2 are the differential craving, 
stress and anxiety responses of progesterone- vs. placebo-treated participants in response to the psychosocial 
stressor (TSST).  Hypothesis 1: Compared to placebo, progesterone will attenuate stress cue reactivity during a 
human laboratory stress paradigm among women but not men with CUD.  Immediately prior to and following the 
TSST (baseline, +0, +5, +30, and +60 minutes), self-reported measures of stress and craving will be collected.  
To assess the effect of exogenous progesterone administration on stress and craving response to the TSST, 
linear mixed effects models will be developed to assess differential treatment responses over time.  The primary 
independent variable of interest will be randomized treatment assignment (progesterone vs. placebo). In addition 
to overall treatment differences, least squares means and associated standard errors will be used for post-hoc 

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comparisons between treatment groups at each post-cue time point. Additionally, sex will be added to the model 
and differential effect of progesterone will be assessed using an interaction term.  When significant, stratified 
treatment effects will be compared and presented across females and males. 
Aim 3: Evaluate stress, sex, and endogenous progesterone influences on cannabis craving and use. 
Endogenous progesterone levels (via saliva samples) will be obtained daily for two weeks following the 
completion of the active medication portion of the study. Daily progesterone levels will be assessed for 
associations with stress and craving responses to stress vs. neutral CREMA cues.  Hypothesis 1: Among women, 
higher daily levels or increasing endogenous progesterone will be associated with decreased cannabis use. To 
evaluate this hypothesis, a multilevel generalized linear mixed effects models with repeated measures (GLMMs) 
will be developed using CREMA session response data from the 2-week follow up period. Statistical models will 
include day and subject level data, measured longitudinally. Daily salivary progesterone levels will be included 
as the primary independent predictor cannabis use. Relevant interactions will be assessed in all models.  
Additionally, increases in progesterone during the early luteal phase of each female participant’s cycle will be 
evaluated; models will include dynamic changes in progesterone (between day rates of change) as a predictor 
of attenuated cannabis use. Exploratory Hypothesis 2: High stress will be associated with cannabis craving and 
return to cannabis use in women more than men. Time from the laboratory session to return to cannabis use 
(latency, in days) will be computed for all study participants. Kaplan-Meier estimates and log-rank tests will be 
used to assess initial relationships between measures of stress reactivity during the TSST (e.g., subjective 
stress, anxiety, BP, HR, cortisol) and relapse/latency while Cox proportional hazards models will be developed 
to assess the differential latency to use across sex for each stress reactivity measure during the TSST (using an 
appropriate interaction term; e.g. Peak TSST stress response x sex). Additionally, daily stress and craving 
responses to CREMA picture cues will serve as time-dependent covariates in latency models to assess the 
influence of recent stress and craving responses on relapse/latency. 
 
C.2.d.2. Missing Data and Attrition. Missing data in longitudinal studies can be a problematic feature but can 
be mitigated through study design considerations. In order to minimize missing data and study attrition, study 
simplification and enhanced communication between study coordinators and participants will be emphasized. 
We will make every effort to prevent attrition, e.g., telephone reminders prior to visits, participation compensation, 
flexible scheduling, and reinforcing adherence at each visit. However, these methods do not ensure that all data 
will be collected and appropriate analytic methods will be employed to accommodate missing data (Refer to 
Biostatistics Resource Core for a more detailed discussion).   
C.2.d.3. Power and Sample Size (complete sample size estimation is provided in Biostatistics Resource Core). 
In the proposed study, cue response and withdrawal data will be tested using GLMMs (assuming a Gaussian 
distribution) and the study will be powered to sufficiently address the smallest effect sizes determined to be 
clinically meaningful for the study hypothesis. Fox and colleagues (2013) examined exogenous progesterone 
and placebo administration on cue response in 42 cocaine dependent participants. Results indicated that female 
participants receiving placebo experienced larger negative emotion scores in response to stress-related cues 
than male participants on placebo (Δ=4.7; SDP=3.4; between sex Cohen’s d >1.0, p<0.01). Fox and colleagues 
also found that administration of exogenous progesterone reduced stress-cue related negative emotions 
significantly in women (Δ=2.4; SDP=3.4, d=0.71) but not in men (Δ=-0.7; SDP=3.3 d=-0.2; treatment x sex 
interaction Δ=3.1; SDP=4.7, d=0.67). Assuming a similar response profile between treatment assignments and 
sex as above, a sample size of 64 participants (32 women, 32 men to each treatment assignment) randomized 
to the progesterone vs. placebo groups would guarantee 80% power with a type 1 error rate of 5% to detect the 
least effect size of d=0.67 in the stress reduction treatment x sex interaction (total n=128) during the 7-day, active 
treatment CREMA assessment period. Although the proposed study is of relatively short duration, we do 
anticipate 10% attrition between randomization and the end of the 1-week active treatment period and laboratory 
session. Thus, inflating the necessary sample size to 70 participants (35 men and 35 women), a total of n=140 
randomized participants will be needed. Due to app issues at the beginning of the study, some initial data is 
unusable, so we will randomize 90 men. Additionally, data from our recently completed SCOR project, which 
examined daily salivary progesterone levels and cigarette smoking behavior for 14 consecutive days in untreated 
female participants, indicated that increased levels of daily progesterone within participant was associated with 
decreased cigarettes smoked per day (β=-0.32; SE=0.14; p<0.05). To detect a similar correlation (β=±0.32; 
SD=1.0) between daily progesterone levels and associated daily use metrics in the proposed study, the 
randomized sample of 70 women (62 with available follow up data), with 14 days of follow up use data, and with 
an autocorrelation of 0.9, would provide 80% power. The proposed sample size of n=160 randomized 

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participants would provide 80% power or better to detect the proposed between sex and treatment comparisons 
noted in the primary study aims. 
C.2.e. Design Considerations. i) Choice of between vs. within participant design. We considered 
implementation of a within-subject crossover design but opted instead for a between-subjects parallel-group 
comparison study for multiple reasons.  Most notably, a within-subjects approach risks potential carryover effects 
between conditions, as well as potential dampening of cue reactivity and participant response fatigue over 
extended periods of testing across conditions. Additionally, withdrawal symptoms may not present consistently 
or reliably across multiple conditions in series without a lengthy/sustained return to ad libitum cannabis use 
between conditions. ii) Choice of administration of progesterone during cannabis withdrawal. Cannabis 
withdrawal is characterized by increased anxiety, irritability, craving, and physiological symptoms, which peak 
within the first 2-3 days of abstinence (Budney et al., 2008). Acute cannabis withdrawal is therefore an ideal 
period to investigate potential therapeutic effects of progesterone on stress cue reactivity and craving. iii) Focus 
on progesterone. The proposed study focuses on progesterone because evidence suggests that estradiol may 
enhance drug reinforcement and cue-reactivity. In preclinical studies, estradiol has been shown to increase 
dopamine release in the ventral striatum in response to nicotine administration (Thompson et al., 1994), and 
facilitate methamphetamine-induced conditioned place preference (Chen et al., 2003) and cocaine self-
administration (Lynch, 2008; Lynch et al., 2001). Clinical research on menstrual cycle phase has demonstrated 
greater smoking cue-elicited neural activity and craving response during the follicular phase (where estradiol 
dominates) compared to the luteal phase (Franklin et al., 2015; Mendrek et al., 2014). Likewise, women with a 
higher estradiol to progesterone ratio took more cigarette puffs and smoked more of a cigarette in a smoking 
topography study (Schiller et al., 2012). Furthermore, compared to men, women smokers in the follicular phase 
showed increased stress response and arousal while women in the luteal phase showed increased craving 
(Saladin et al., 2015b). Together, evidence suggests that estradiol enhances drug reinforcement and cue-
reactivity, and hence may contribute to the more deleterious outcomes observed in substance using women. 
Accordingly, we have focused this project on expanding knowledge about the treatment potential of progesterone 
(as characterized in the Significance above) by examining its effects on stress reactivity and substance use in 
persons with CUD. iv) Male comparison group. Apart from the obvious relevance of a male comparison group 
in studies of sex differences, there are empirical grounds for including men in proposed study. Sofuoglu et al., 
(2004) found that 2 oral doses of 200 mg progesterone significantly dampened cardiovascular responsiveness 
(diastolic BP) to iv cocaine in male, not female, cocaine users. Likewise, Fox et al., (2014) reported that 
exogenous progesterone vs. placebo attenuated cue-induced cocaine craving and cortisol responses in both 
men and women, suggesting that progesterone may also have some treatment potential for male cocaine users. 
Based on these and similar findings (Childs et al., 2010), we believe the proposed study’s inclusion of both 
women and men with CUD will optimize our ability to identify therapeutic effects of progesterone that are either 
unique to one sex, or present in both.  
C.2.f. Operational Plan and Research Timetable. Funding for five years is requested. The first three months 
will be used for hiring and training personnel and preparing for study initiation. As we have previously established 
standard operating procedures, we anticipate a rapid study start-up. 54 months will be needed for participant 
recruitment and data collection. The final three months will be used for data analysis and manuscript preparation. 
 
PROTECTION OF HUMAN SUBJECTS 
1. RISKS TO THE SUBJECTS 
a. Human Subjects Involvement and Characteristics 
Admission into the study is open to men and women and to all racial and ethnic groups, age 18-45. 160 
cannabis use disordered individuals (90 men and 70 women) will be recruited primarily through internet and 
newspaper advertisements. Inclusion/exclusion criteria that apply to all participants are listed below: 
 
General Inclusion / Exclusion Criteria 
Inclusion Criteria 
1. Able to provide informed consent and function at an intellectual level sufficient to allow accurate completion 
of all assessment instruments.  

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2. Meet DSM-5 criteria for mild, moderate or severe cannabis use disorder (within the past three months) and 
report using cannabis at least five times weekly over the past month. While individuals may also meet criteria 
for mild use disorders of other substances, they must identify cannabis as their primary substance of abuse 
and must not meet criteria for any other moderate or severe substance use disorder (except tobacco) within 
the last 60 days.  
3. Age 18-45.  
4. For women, regular menses (every 25-35 days).  
5. Consent to remain abstinent from alcohol for 12 hours prior to study visits, and all other drugs other than 
cannabis or nicotine for the duration of the study.  
6. Women of childbearing potential must agree to utilize an effective means of birth control.  
7. Must consent to random assignment. 
 
 
 
Exclusion Criteria 
1. Women who are pregnant, nursing or of childbearing potential and not practicing an effective means of birth 
control.  
2. Women who are amennorheic or using progesterone-based contraceptives.  
3. Evidence or history of major medical illnesses, including liver diseases, abnormal vaginal bleeding, 
suspected or known malignancy, thrombophlebitis, deep vein thrombosis, pulmonary embolus, clotting or 
bleeding disorders, heart disease, diabetes, history of stroke or other medical conditions that the investigator 
deems as contraindicated for the individual to be in the study.  
4. Subjects taking antipsychotics (unless for indication other than psychosis), or regularly taking opiates or 
benzodiazepines. 
5. History of or current psychotic disorder or bipolar affective disorder.  
6. Current suicidal or homicidal ideation/risk. 
7. Known allergy to progesterone or peanuts (vehicle for micronized progesterone).  
8. Unwilling or unable to maintain abstinence from alcohol 12 hours prior to study visits and all other drugs 
other than cannabis or nicotine for the duration of the study.  
9. Meet DSM-5 criteria for moderate or severe substance use disorder (other than nicotine or cannabis) within 
the past 60 days. 
10. Unable to comply with study procedures or pose threat to study staff. 
 
b. Sources of Materials 
Research material obtained from individual participants includes questionnaires and interviews with study 
personnel, ambulatory assessment data, and saliva and urine samples. To ensure confidentiality, all participant 
data will be letter/number coded, and only the investigators will have access to the master lists of codes. The 
research material will be obtained specifically for research purposes.  Written research material obtained will 
be stored in the Addiction Sciences Division, in an office that is locked when not in use. Urine samples will be 
stored and processed in the Clinical Neurobiology Laboratory; saliva samples will be stored and processed in 
the Medical University of South Carolina Research Nexus Laboratory.  
 
c. Potential Risks 

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1. Risks due to progesterone: Micronized progesterone is generally well tolerated. The most common adverse 
effect is headache. Other adverse effects that occurred at rates of 10% or more and at greater rates than 
placebo include headache, dizziness, abdominal cramps, breast pain, breast tenderness, joint pain, 
depression, dizziness, abdominal bloating, hot flashes, urinary problems, and vaginal discharge. 
 
2. Risks due to study procedures: Participants will be asked not to smoke cannabis for 7 days. During this 
cannabis abstinence period, participants may experience symptoms of cannabis withdrawal such as craving 
cannabis, mild anxiety, insomnia, irritability, restlessness, stomachache, headache, nausea, loss of energy or 
appetite, chills, and diaphoresis. These symptoms are generally transient.  
 
3. Potential risks of rating scales and questionnaires: These are all non-invasive, should add no risk, and have 
been used without difficulty or any adverse events in our previous studies. The only minor inconvenience could 
be the time taken to complete them. Some participants may feel uncomfortable disclosing personal thoughts 
and feelings.  
 
4. Risks of stress induction procedures: There is a small risk of increased stress or cannabis craving as a 
result of the TSST and CREMA procedures; however, it will likely not differ substantially from the reactivity 
elicited by stimuli commonly encountered in the day-to-day environment of study participants. Participants that 
report sustained significant stress or craving after the laboratory session will be provided a debriefing to 
address symptoms. 
5. Risks of blood draw: The risks of drawing blood include temporary discomfort from the needle stick, bruising, 
and infection. Fainting could occur. 
6. Risks of loss of confidentiality: Careful efforts aimed at maintaining confidentiality have been effective in 
previous research, and only participants’ code numbers will be recorded on the forms themselves to protect 
confidentiality. Phones provided by study staff to participants will be password protected to limit access to 
study assessments and pictures; participants utilizing their own phones will be asked to password protect their 
device for the duration of the study.  
 
2. ADEQUACY OF PROTECTION AGAINSTS RISKS  
a. Recruitment and Informed Consent 
Potential study participants will primarily be recruited through the use of advertisements (internet, newspaper). 
Medical records will not be reviewed to identify potential study participants.  The study PI, a Co-I, or other 
qualified study staff will obtain informed consent. The informed consent form includes a detailed description of 
the study procedures, along with statements regarding participants’ rights to withdraw from the procedure at 
any time without consequences. The informed consent form will be explained to participants in easy-to-
understand language, and subjects will be instructed to read the form carefully prior to signing it.  Consent will 
be documented by the signature of the participant on the informed consent agreement, accompanied by the 
signature of the individual obtaining the consent. 
 
b. Protections Against Risks 
All study participants will be closely monitored for psychiatric and medical stability. All sessions will be 
conducted under the supervision of experienced personnel. If crisis intervention is necessary, senior staff will 
be available to evaluate the subject and provide an intervention or referral. If hospitalization is indicated, the 
patient will be hospitalized through the Center for Drug and Alcohol Programs at MUSC or an appropriate 
referral will be made. All participants will be fully informed that they may withdraw from the study at any time 
without penalty.  
 

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To ensure confidentiality, all participant data will be coded by letters and/or numbers, and only the investigators 
will have access to the master lists of codes.  All participant records will be kept in a locked cabinet in an office 
that will be locked at times when not in use. The research staff understands the importance of maintaining 
confidentiality, and this method of maintaining confidentiality has been used for several years by our research 
group and has been effective. All electronic databases are stored on HIPAA-compliant servers with restricted 
access. All co-investigators and study personnel have completed (or will complete upon hiring) training in Good 
Clinical Practices as mandated by NIH and the MUSC IRB. 
 
 
Participants will be taught about potential side effects of progesterone, and will be closely followed by 
psychiatrists, a PharmD, and other members of the research team. Pregnancy tests will be performed prior to 
progesterone administration. Adverse events will be monitored throughout the study. A member of the 
research staff will be available to discuss management of any craving urges if craving remains elevated at the 
end of any study procedures. 
 
 
3. POTENTIAL BENEFITS OF THE PROPOSED RESEARCH TO THE SUBJECT AND OTHERS 
Possible risks to study participants include adverse reactions to progesterone administration or stress induction 
procedures. Potential benefits include detailed assessment of substance use and referral for treatment. 
Participants in the progesterone condition may experience a reduction in withdrawal symptoms. The minimal 
risks are reasonable in relation to the potential benefits to be gained from the study. 
 
 4. DATA AND SAFETY MONITORING PLAN  
Trial Management.  
The study will be managed from the Addiction Sciences Division within the Department of Psychiatry and 
Behavioral Sciences at the Medical University of South Carolina. The target population is described above in 
the inclusion/exclusion criteria.  
Data Management and Analysis.  
Data will be entered by research assistants directly into a computer using standard database software using 
REDCap. The data analysis plan is outlined in the Data Analysis Plan section.  
Quality Assurance.  
Quarterly data audits will be conducted. Confidentiality protections are outlined above.  
Regulatory Issues.  
Potential conflicts of interest will be reported using the upcoming NIH rules for disclosure. Adverse Events 
(AEs)/Serious Adverse Events (SAEs) occurring during the course of the project will be collected, documented, 
and reported in accordance with protocol and IRB reporting requirements. All research staff involved with 
adverse event reporting will receive general and protocol specific AE/SAE training including identification, 
assessment and evaluation, and documentation and reporting. A research assistant will identify any potential 
adverse events during the course of the study from participant self-report and administration of the visit 
assessments and procedures. The research assistant will provide information to a study physician, who will be 
responsible for AE/SAE assessment and evaluation including a determination of seriousness and study 
relatedness. Any significant actions taken by the local IRB and protocol changes will be relayed to 
ORWH/NIDA.  
Definition of AE and SAE.  
An Adverse Event (AE) is defined as any untoward medical occurrence in a study subject administered a 
pharmaceutical product that does not necessarily have a causal relationship with this treatment (ICH GCP). 
Any unwanted change, physically, psychologically or behaviorally, that occurs in a study participant during the 

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course of the trial is an adverse event. A Serious Adverse Event (SAE) is defined as an adverse event that has 
one of the following outcomes:  
• Results in death,  
• Is life-threatening,  
• Requires inpatient hospitalization or prolongation of existing hospitalization,  
• Results in persistent or significant disability/incapacity,  
• Is a congenital anomaly/birth defect OR  
• Requires intervention to prevent one of the above outcomes.  
 
Documentation and Reporting.  
AEs/SAEs are documented and reported as per protocol and IRB requirements. Research staff will identify 
adverse events and obtain all available information to assess severity, seriousness, study relatedness, 
expectedness, outcome and the need for change or discontinuation in the study intervention. Adverse events 
are generally documented on AE Logs and AE Case Report Forms (CRFs). Additional relevant AE information 
if available should be documented in a progress note in the research record as appropriate to allow monitoring 
and evaluating of the AE. If the AE meets the definition for serious, appropriate SAE protocol specific reporting 
forms are completed and disseminated to the appropriate persons and within the designated timeframes as 
indicated above. For each AE/SAE recorded, the research staff will follow the AE/SAE until resolution, 
stabilization or until the participant is no longer in the study as stated in the protocol. When a reportable SAE is 
identified, the research staff will notify the MUSC Institutional Review Board (IRB) within 24 hours and 
complete the AE report form in conjunction with the PI. The MUSC IRB meets monthly and is located at 165 
Cannon Street, Rm. 501, Charleston, SC 29425. Communication with the IRB is through email, memos, official 
IRB forms, and online reporting. A report will also be sent to the NIH program officer assigned to the project.  
If complete information is not available when the initial 24-hour SAE report is disseminated, follow-up 
information will be gathered to enable a complete assessment and outcome of the event. This information may 
include hospital discharge records, autopsy reports, clinic records, etc. The research staff will attach copies of 
source documents to the SAE report for review by the PI and for forwarding to the NIH program officer as 
appropriate within 2 weeks of the initial SAE report. In addition, the PI will provide a signed, dated SAE 
summary report, which will be sent to the ORWH/NIDA Medical Safety Officer within two weeks of the initial 
SAE report.  
We will report adverse events to the Medical University of South Carolina (MUSC) Institutional Review Board 
(IRB) online as soon as possible, but no later than 10 working days after the investigator first learns of the 
event. The MUSC IRB AE reporting requirements are as follows: All deaths that occur during the study or 30 
days post termination from the study are required to be reported as adverse events even if they are expected 
or unrelated. Other adverse events are reportable to the MUSC IRB if the AE is unexpected AND related or 
possibly related AND serious or more prevalent than expected. All three criteria must be met for an AE to be 
reported to the MUSC IRB. The IRB definition of unexpected is that the AE is not identified in nature, severity 
or frequency in the current protocol, informed consent, investigator brochure or with other current risk 
information. The definition of related is that there is a reasonable possibility that the adverse event may have 
been caused by the drug, device or intervention. Reportable AEs are reviewed by the IRB Chair and reported 
to the IRB Board at the next meeting.  
Trial Safety.  
The potential risks and benefits and methods to minimize these risks are outlined above. The research staff will 
report any unexpected AEs or any scores of “severe” on the side-effect symptom rating form or any FDA-
defined serious AEs to the PI within 24 hrs so that the PI can decide on the appropriate action. All unexpected 
AEs will be monitored while they are active to determine if treatment is needed. Study procedures will follow 
the FDA’s Good Clinical Practice Guidelines (www.fda.gov/oc/gcp). Any outside requests for information or any 
breaches in confidentiality will be reported to Dr. McRae-Clark.  

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Trial Efficacy.  
An interim analysis is not planned at this time; however, an analysis will be performed if requested by ORWH/ 
NIDA or the DSMB.  DSM Plan Administration.  
Drs. McRae-Clark and Saladin will be responsible for monitoring the study, and will participate in weekly study 
meetings. A DSM report will be filed with the IRB and ORWH/NIDA on a yearly basis, unless greater than 
expected problems occur. The report will include participant characteristics, retention and disposition of study 
participants, quality assurance issues and reports of AEs, significant/unexpected AEs and serious AEs. We will 
report outcomes at the end of the trial.  
DSM Board.  
A Data Safety and Monitoring Board will be formed to monitor both the rate and severity of adverse events. 
This panel will include 3 clinicians with expertise in substance use disorders and a statistician.  
 Risk Benefit Ratio.  
The assessments and questionnaires are non-invasive and have inherently minimal risks. Potential risks of 
concern are loss of confidentiality and adverse events to progesterone and stress induction procedures. As 
discussed above, our research team will attempt to minimize these risks. Knowledge gained by the proposed 
study would help fill an important void in development of a potential gender-specific treatment for cannabis use 
disorders. 
5. IMPORTANCE OF THE KNOWLEDGE TO BE GAINED 
This study may provide important information that can improve treatment for future patients with cannabis and 
other drug use disorders. The moderate risks of the investigation are considered reasonable in relation to the 
expected knowledge to be gained.   
 
6. CLINICALTRIALS.GOV REQUIREMENTS 
In accordance with Public Law 110-85, this project will be registered at the ClinicalTrials.gov Protocol 
Registration System Information Website prior to study initiation.