Clinical trial NCT02187224
Conditions: Alcohol Dependence Post-Traumatic Stress Disorder (PTSD)
Keywords: Alcohol Dependence Post-Traumatic stress disorder (PTSD) Progesterone
Sponsor: Yale University
Start date: 2016-09-01; Completion date: 2021-09-08
Enrollment: 13 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This is a randomized control trial with an anticipated 36 participants diagnosed with post-traumatic stress disorder (PTSD) and comorbid alcohol dependence. Participants will be randomized to receive either progesterone (200 mg. bid) or placebo in identical looking capsules for three days.

One goal of this research study is to test if progesterone is more effective than placebo in reducing craving after exposure to trauma cues and alcohol cues in a laboratory paradigm among men and women with AD and PTSD. We hypothesize that progesterone in comparison to placebo will significantly reduce craving for alcohol in response to trauma cues alone and in combination with alcohol cues in individuals with AD and PTSD.

A second goal is to examine if there are gender differences in progesterone effects on stress and alcohol cue-induced craving. We hypothesize that the effects of progesterone on stress and craving will be stronger in women than in men. Participants will be recruited primarily through advertisement, but also through the clinical facilities at the VA and from other collaborators.

Detailed description:

Arms: arm 1: For the three days prior to each test day every participant in this arm will receive one progesterone capsule (200 mg. bid) on the first day and 2 progesterone capsules per day for days 2 and 3. On the test day the participant will receive the last progesterone capsule (200 mg.bid). On the test day two scripts will be read one trauma related script (most traumatic experience) and one neutral script (relaxed scene given by participant) arm 2: For the three days prior to each test day every participant in this arm will receive one placebo capsule on the first day and 2 placebo capsules per day for days 2 and 3. On the test day the participant will receive the last placebo capsule. On the test day two scripts will be read one trauma related script (most traumatic experience) and one neutral script (relaxed scene given by participant)
Interventions: intervention 1: Progesterone intervention 2: Placebo (for Progesterone)
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
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PROJECT DESCRIPTION 
Title: Attenuation of Stress Response Using Progesterone in Individuals with Alcohol 
Dependence and Post-Traumatic Stress Disorder 
1. Principal Investigator:
Elizabeth Ralevski, PhD 
Authorized Prescribers: Ismene Petrakis MD, Albert Arias MD, Gihyun Yoon MD, Louis Trevisan 
MD 
2. Purpose:
Primary Aims: 
1.To test if progesterone (PROG) is more effective than placebo in reducing craving after
exposure to trauma or stress cues in a laboratory paradigm among men and women with a)
comorbid AUD and PTSD and b) AUD only.
We hypothesize that progesterone in comparison to placebo will significantly reduce craving for
alcohol in response to trauma cues in individuals with a) comorbid AUD and PTSD and b) AUD
only. Craving for alcohol will be measured using a self-report Visual Analog Scale - Craving
(VASC) and the Alcohol Urge Questionnaire (AUQ).
Secondary Aims: 
1. To test if progesterone attenuates stress-induced anxiety, measured by the State Trait
Anxiety Inventory (STAI-6).
2: To describe PROG’s subjective mood effects, we will use the Differnetial Emotion Scale
(DES-R)
3: To describe PROG’s effects on cognitive performance, we will assess the ability to inhibit
incongruent competing conflicts using the Stroop Color/Word test (Stroop).
Exploratory Aims: 
1. To test if progesterone is more effective than placebo in reducing drinking and relapse during
one month following exposure to trauma cues using the Timeline Follow Back Method (TLFB).
2. To examine if there are gender differences in progesterone effects on stress and alcohol cue-
induced craving.
We hypothesize that the effects of progesterone on stress and craving will be stronger in
women than in men.
3. Background:
Alcohol use disorder (AUD) is one of the most prevalent of all psychiatric disorders(Grant et al.,
2004; Kessler et al., 1994) with a considerable morbidity and mortality that is
preventable(Johnson, 2008). It is also among the most costly health care problems with an
estimated economic burden of $185 billion dollars per year(Harwood, 1998). Evidence shows
that alcohol use and abuse is strongly correlated with psychiatric disorders associated with
stressful events, notably Post Traumatic Stress Disorder (PTSD)(Cottler, Compton, Mager,
Spitznagel, & Janca, 1992; Helzer, Robins, & McEvoy, 1987; Jacobson et al., 2008; Keane &
Kaloupek, 1997; Kulka et al., 1990; Resnick, Kilpatrick, Dansky, Saunders, & Best, 1993;
Reynolds et al., 2005). The rates of PTSD among individuals with AUD are higher than those in
the general population(Kessler et al., 1997). This comorbidity is associated with more severe
clinical impairment, poorer treatment prognosis, more severe symptoms of PTSD, higher
relapse rates, higher reports of family problems, and heavier drinking when compared to
individuals with either AUD or PTSD alone (Brady, Killeen, Saladin, Dansky, & Becker, 1994;
NCT02187224


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Brown, Stout, & Mueller, 1999; Foa & Williams, 2010; Ouimette, Finney, & Moos, 1999; Read, 
Brown, & Kahler, 2004). Currently, there are no FDA approved or effective treatments for 
individuals with PTSD and AUD indicating an urgent need for the development of novel 
pharmacologic treatments for these patients.  
 
Although the co-occurrence of substance use disorders and PTSD is well documented in the 
literature, mechanisms that perpetuate and maintain the relationship between them are not 
completely understood. It has been shown that stress can be a trigger for relapse and a main 
contributing factor to the reinforcing effects of alcohol (R. Sinha, Kimmerling, Doebrick, & 
Kosten, 2007; R. Sinha, Robinson, & O'Malley, 1998). Therefore, the study of neural systems 
that mediate the stress response and identification of factors that can predict successful 
treatments are clinically relevant and of paramount importance. 
 
Stress reactivity and link to craving (evidence from laboratory studies): Several studies 
have documented the positive association between chronic stress early in life and increased 
likelihood of substance abuse later in life(Dembo, Dertke, Borders, Washburn, & Schmeidler, 
1988; Enoch, 2011; Harrison, Fulkerson, & Beebe, 1997; Kaplan, Martin, Johnson, & Robbins, 
1986; Widom, Weiler, & Cottler, 1999; Wills, McNamara, Vaccaro, & Hirky, 1996). Laboratory 
studies that have used cue reactivity paradigms using both stress inducing cues (fear, 
anxiety)(Breese et al., 2005; Childress et al., 1994; Cooney, Litt, Morse, Bauer, & Gaupp, 1997; 
R. Sinha, 2009; R. Sinha et al., 2009; Stasiewicz et al., 1997), and alcohol cues (smell of 
alcohol)(Coffey et al., 2002; Smith-Hoerter, Stasiewicz, & Bradizza, 2004) provide evidence that 
both types of cues increase craving for alcohol in individuals with AUD, and stressful stimuli 
have been shown to be as powerful in eliciting self-reported craving for alcohol as is exposure to 
alcohol cues(Meisler, 1996; R. Sinha et al., 2009; R. Sinha, Garcia, Kemp, Krystal, & O'Malley, 
2005). Abundant evidence shows that PTSD is associated with abnormalities in stress reactivity.  
For example, most but not all studies show that individuals with PTSD have increased levels of 
the hormones commonly associated with stress response including norepinephrine, 
epinephrine, and cortisol when compared to healthy controls(Bremner, Krystal, Southwick, & 
Charney, 1996; Lemieux & Coe, 1995; Lupien, McEwen, Gunnar, & Heim, 2009; R. Yehuda, 
1998; R Yehuda, 2009). Laboratory studies using techniques to simulate stress, such as 
anticipating public speaking, show increased levels of cortisol(Bremner et al., 1996; Heim et al., 
2000; Van der Kolk, 2004) and increases in negative affect (such as fear, sadness or anger) as 
well as PTSD symptoms(Calhoun, Dennis, & Beckham, 2007) in individuals with PTSD and in 
those who have experienced severe trauma. 
 
A relatively new area of study is the relationship between stress and drug taking behavior in 
individuals with comorbid PTSD and AUD. As do individuals without comorbid disorders, 
individuals with dual diagnosis of AUD and PTSD report increased levels of stress and craving 
for alcohol after exposure to stress inducing cues(T.M Chaplin et al., 2010; Coffey et al., 2002; 
Coffey, Stasiewicz, Hughes, & Brimo, 2006). As expected, individuals exposed to stress (trauma 
imagery) and alcohol cues (alcoholic drink), report stronger desire for alcohol than when 
exposed to neutral imagery or non-alcoholic cues (T.M Chaplin et al., 2010; Coffey et al., 2002; 
Coffey et al., 2006). Also, craving is stronger when trauma and alcohol cues are combined as 
compared to craving when trauma or alcohol cues are presented alone suggesting an additive 
effect. Further, the data collected by our group shows that veterans diagnosed with PTSD and 
AUD reported significantly more craving for alcohol when exposed to trauma imagery than when 
exposed to stressful or neutral imagery (see pilot data).  In AUD with PTSD, stress inducing 
cues (trauma imagery) lead to significant increases in craving for alcohol. 
Can stress reactivity paradigms predict outcome and alcohol relapse? There is increasing 
evidence that laboratory paradigms evaluating stress reactivity (R. Sinha, Kimmerling, et al., 
2007) are clinically relevant and may be useful in predicting outcomes and relapse in patients 
with alcohol dependence. For example, stress-induced craving has been shown to be 
associated with drinking outcomes in alcoholics followed for 90 days after discharge from an 


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inpatient treatment program(Breese et al., 2005). Stress induced craving has also been used as 
a marker for relapse; individuals with greater stress reactivity have a shorter time to relapse to 
their preferred substance than individuals with lesser stress reactivity (R. Sinha, Garcia, Paliwal, 
Kreek, & Rounsaville, 2006). These findings suggest that attenuation of trauma-related distress 
may be effective in reducing both craving and negative affect (such as fear, sadness or anger) 
in individuals with AUD and PTSD. Coffey and his colleagues (Coffey et al., 2006) exposed 
individuals with AUD and PTSD, in the laboratory, to personalized trauma and neutral scripts 
followed by exposure to their favorite beverage or water in a counterbalanced fashion. After the 
laboratory sessions participants were assigned to either exposure therapy or relaxation therapy 
followed by a second laboratory session. Exposure therapy attenuated the stress response. 
Rates of alcohol relapse were not recorded, therefore, no conclusions can be drawn about the 
relationship among stress reactivity, decrease in PTSD symptoms, craving and relapse to 
drinking. Our own data (see pilot data) with veterans diagnosed with AUD and PTSD shows that 
treatment attenuated the stress response, and stress reactivity predicted relapse; stronger 
stress reactivity was related to higher number of drinking days 3 months after treatment 
(r=0.603). 
 
Progesterone and its effects on stress and craving: Progesterone is a hormone produced by 
both males and females in gonads and adrenal glands. Progesterone is also synthesized in the 
brain by oligodendrocytes and neurons, and as such is considered a “neurosteroid”(Brinton et 
al., 2008). In premenopausal women, progesterone levels fluctuate during the menstrual cycle. 
In the follicular phase of the menstrual cycle, women have low progesterone levels that are 
comparable to those in men, < 1 ng/ml(Murphy & Allison, 2000). Women have higher 
progesterone levels than men during the luteal phase of the menstrual cycle (2-28 ng/ml), 
especially during pregnancy (9 to 200 ng/ml) (Buffet, Djakoure, Maitre, & Bouchard, 1998). 
Progesterone and its metabolites interact with multiple neurotransmitter receptors including 
GABAA, glycine, sigma1, kainate, serotonin3, and nicotinic receptors(Chesnoy-Marchais, 2009; 
Dar & Zinder, 1997). Several studies have successfully administered progesterone during the 
first 7 days of the follicular phase (Justice & De Wit, 2000; Sofuoglu, Babb, & Hatsukami, 2001, 
2002; Tan, McFarlane, & Lipworth, 1997b). Also, a number of studies have examined the effects 
of progesterone on stress and craving in the laboratory among smokers(Sofuoglu, Mouratidis, & 
Mooney, 2011) and cocaine dependent men and women(Fox, Sofuoglu, Morgan, Tuit, & Sinha, 
2013; R. Sinha, Fox, et al., 2007). Progesterone significantly improved cognitive performance 
and reduced smoking urges in smokers (Sofuoglu et al., 2011). Using the same laboratory 
paradigm men and women with cocaine dependence and matched for age, years of education, 
and drug use were given either progesterone (200mg bid) or placebo for 7 days before 
exposure to 5-minute personalized stress, neutral and drug cue scripts(Fox et al., 2013) 
Progesterone was well tolerated by both men and women. Progesterone, compared to placebo, 
significantly decreased cue-induced craving for cocaine and improved cognitive performance in 
both men and women. Also, women in comparison to men reported improved negative mood, 
lower blood pressure, and greater relaxation suggesting that progesterone’s efficacy may be 
moderated by gender. This is consistent with other findings showing that women with high 
progesterone levels report significantly lower stress-induced and cue-induced craving for 
cocaine than women with low progesterone levels(R. Sinha, Fox, et al., 2007). Gender 
differences in stress-related disorders(Kajantie & Phillips, 2006), physiological response to 
stress(Allen, Boquet, & Shelley, 1991), and emotional response to stress and craving(T. M. 
Chaplin, Hong, Bergquist, & Sinha, 2008; R. Sinha & Rounsaville, 2002; Taylor et al., 2006; 
Zahn-Waxler, 2000) have been well documented, indicating that gender may play an important 
role in the response to stress and craving.  Currently, progesterone is being evaluated as a 
treatment for cocaine and tobacco addiction(Institute, 2013). 
 
Preliminary Data: (I) Our group has extensive experience conducting laboratory studies 
and working with patients with dual diagnoses. We have conducted clinical trials with over 250 
participants diagnosed with AUD and PTSD. Recent publications on this topic include: 1) 


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Petrakis et al.  Noradrenergic vs. serotonergic antidepressant with/without naltrexone for 
veterans with PTSD and comorbid alcohol dependence. Neuropsychopharmacology, 2012; 2) 
Ralevski et al. Quality of life in veterans with alcohol dependence and co-occurring mental 
illness. Addictive Behaviors, 2013; 3) Fuehrlein et al. Characteristics and drinking patterns of 
veterans with alcohol dependence with and without post traumatic stress disorder. Addictive 
Behaviors, 2013.  
(II) Ongoing studies: Pilot data from a study conducted by our group “Relationship between 
stress and craving in veterans diagnosed with PTSD and AD”. Main objectives of this study are: 
1) to test how an attenuation of stress response will affect alcohol craving, 2) to examine 
relationship between stress and craving, and 3) to determine if laboratory induced stress 
predicts relapse during treatment. The study has III phases. In phase I all subjects participate in 
a laboratory session and are exposed to neutral, stressful and trauma imagery (randomly 
assigned).  In phase II they undergo treatment with either prazosin or placebo for 12 weeks.  
After at least 6 weeks of treatment they participate in a second laboratory session that is 
identical to the session in phase I.  During the laboratory session craving, anxiety, and 
cardiovascular responses are measured.  Eighteen veterans completed the study.  
 
 
Results: Dually diagnosed veterans reported significantly more 
craving for alcohol when exposed to trauma imagery than when 
exposed to stressful or neutral imagery (p<0.001) (Figure 1). The 
stress response decreased with treatment, and those with high 
stress response on prazosin reported greater, but not statistically 
significant, change in their drinking at the end of treatment 
(Figure 2). Also, there was a significant relationship (r=0.603) 
(Figure 3) between craving and the number of drinking days at 
follow up.  
Conclusions: The preliminary findings show that veterans with 
dual diagnosis report strong craving after exposure to trauma 
related imagery. Based on this result we eliminated the stress condition for the present 
study. The trauma-induced response predicted drinking at the end of treatment and at follow 
up.  
 
These finding support the notion that reactivity to stress may increase the susceptibility 
for relapse.   
 
This study demonstrates that we have experience with this paradigm.   
 
It validates the ability of our research team to recruit individuals with AUD and PTSD. 
 
4.  Significance:   
To our knowledge, this study is the first to examine the ability of progesterone to reduce trauma 
or stress-induced craving in individuals diagnosed with a) comorbid AUD and PTSD and b) AUD 
only.  Positive findings from this study will: 1) provide evidence that progesterone is important in 
mediating stress and alcohol craving, 2) provide insight into the underlying mechanisms of 
stress and alcohol craving, 3) help identify a potential marker that will distinguish who may be at 
Figure 1. Means and Standard Errors for Alcohol Craving Following Exposure to Neutral, Stress, and 
Trauma Imagery Before and After Treatment 
 
Figure 2. Change in Drinking Days in High and Low Stress 
Responders and those on Prazosin or Placebo 
 
-20
-10
0
10
20
30
40
Change in Drinking Days
Placebo
Prazosin
Craving Before Treatment
0
2
4
6
8
Neutral
Stress 
Trauma
Stress Condition
Mean Response on 
Craving Scale
Pre-imagery
Post-imagery
Recovery
Craving After Treatment
0
2
4
6
8
Neutral
Stress 
Trauma
Stress Condition
Mean Response on 
Craving Scale
Pre-imagery
Post-imagery
Recovery
Low Stress 
High Stress 
Figure 3. Relationship between Stress Reactivity 
and Drinking at Follow up 
 


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higher risk for alcohol relapse, and 4) provide a platform for other exploratory studies that can 
include the use of progesterone as treatment options for AUD and PTSD.   
 
 
5. Research Plan:   
 
Participants: Participants (N=72 completers) will be eligible for the study if they fullfill the 
following criteria: 
 
Inclusion criteria: 
a) men (n=36) and women (n=36) age 21 to 60; 
b) have current diagnosis of either: 
1. AUD and comorbid PTSD  
OR 
2. AUD 
AUD will be determined by Structured Clinical Interview for DSM-5 (SCID-5) 
(First, Spitzer, Gibbon, & Williams, 2015).  PTSD will be determined by Clinician   
 
Administered PTSD scale (CAPS-5)(Weathers et al., 2013) and by SCID-5);  
c) drink regularly (determined by TLFB and recorded 90 days prior to the interview);  
d) are not in an active phase of alcohol withdrawal;  
e) are not at risk for suicide; if on medication, they must be on a stable dose for at least 2 
weeks;  
f) for women, have regular menses every 25-35 days.  
 
Exclusion Criteria:  
a) current SCID diagnosis of any psychotic disorder; substance use disorder (other than 
alcohol, nicotine, and marijuana) in the past 30 days;  
b) current unstable medical condition; positive test results at more than one baseline 
appointment on urine drug screens conducted for opiates, cocaine, benzodiazepines, 
and barbiturates (marijuana is allowed);  
c) for women, amenorrhea, use of oral contraceptives;  
d) known allergy to progesterone or peanuts (vehicle for micronized progesterone);  
e) history of thrombophlebitis, deep vein thrombosis, pulmonary embolus, clotting or 
bleeding disorders, heart disease, or history of stroke. 
 
Methods: All participants will complete 1 test day. In order to control for gender differences in 
progesterone levels we will test women in the follicular phase of the menstrual cycle. This 
experiment is a between-subject design. Before the test day every participant will receive either 
progesterone (200 mg. bid) or placebo in identical looking capsules for three days. In previous 
studies with addicted individuals, this dosing schedule of progesterone attenuated stress-
induced craving and improved cognitive function(Fox et al., 2013; Sofuoglu et al., 2011). On the 
fourth day they will attend the laboratory session. The study will consist of four phases. 1) We 
will first recruit participants, obtain informed consent, and evaluate eligibility for the study. 2) 
Following completion of intake assessments, participants will receive a full physical examination 
to further determine eligibility. 3) If eligible they will be randomized to start pre-treatment with 
either progesterone or placebo and scheduled for the laboratory session. 4) Follow-up: 
Participants will be contacted approximately 1 day after completing the stress lab to see how 
they are doing and to answer questions about their drinking.They will also be asked to come for 
one follow up session 1 month later to determine their drinking habits following the lab session. 
Initial Assessments:  Participants will be interviewed with the SCID and CAPS for diagnostic 
evaluation. The TLFB(Sobell & Sobell, 1992) will be used to document the degree of daily 
alcohol consumption in the three months prior to study entry. Participants will have a psychiatric 
and medical examination by one of the investigators. Study data will be collected and managed 
using REDCap electronic data capture tools hosted at VA CT Healthcare System. REDCap 


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(Research Electronic Data Capture) is a secure, web-based application designed to support 
data capture for research studies, providing 1) an intuitive interface for validated data entry; 2) 
audit trails for tracking data manipulation and export procedures; 3) automated export 
procedures for seamless data downloads to common statistical packages; and 4) procedures for 
importing data from external sources (Harris et al 2009). 
    
Screening and Baseline:  Each participant will sign an informed consent. The study will be 
conducted with the approval of  the VA Connecticut Human Subject Subcommittee. As part of 
the screening procedure detailed clinical assessment (to determine diagnosis), and medical 
assessments (physical exam, medical history, blood work and electrocardiogram) will be 
conducted. Those participants who fulfill all the inclusion and exclusion criteria will be enrolled in 
the study. On the first visit participants will be asked to come for a script development session. 
Also, women will be instructed to call the clinic when their menses starts and begin taking the 
study medication within the first 4 days of their menstrual cycle. The procedure is implemented 
in order to give some flexibility to female subjects and to ensure that they can finish the study 
during the early follicular phase (within the first seven days of the menstrual cycle). 
 
Script Development Session: Scripts will be developed during a visit prior to the first laboratory 
session. Two scripts will be developed for each participant based on a procedure developed by 
our group. Participants with AUD and comorbid PTSD will develop one trauma related script and 
one neutral script.  Participants with AUD only will develop one stress related script (since they 
have not experienced trauma) and one neutral script. 
The trauma related scripts will be based on the “most traumatic” experience the 
participant could recall. The stress imagery script will be based on subjects’ description of a 
recent personal stressful event (e.g. breakup with significant other, a verbal argument with a 
significant other or family member or unemployment-related stress, such as being fired or laid off 
from work).  Subjects will be acclimated to the procedures, warned of the risks, and trained on 
relaxation techniques. The neutral script will be based on previously developed neutral scripts 
that will consist of a relaxed beach scene commonly experienced by most individuals but 
personalized for each participant. Any trauma, stressful, or neutral experience related to 
substance use will not be considered in order to avoid eliciting internal cues related to 
substance use. Individual scripts will be developed using scene construction questionnaires 
(Rajita Sinha & Tuit, 2012). In order to maximize the differences in stress reaction between 
conditions among those with AUD and PTSD we eliminated the stress imagery since trauma 
imagery elicited stronger stress reaction when compared to neutral (see preliminary data). The 
questionnaires elicit details regarding the event and individuals involved, including physical 
sensations, thoughts, emotions, and cues related to the event described. Each scene will be 
audiotaped for presentation during each laboratory session. Each tape will be 5 min. long. 
 
Relaxation Technique: Subjects will be introduced to all self-report measures and instructed 
how to complete them.  In order to minimize baseline imagery variability participant will be given 
relaxation and imagery training, as described in the imagery training procedures manual (Rajita 
Sinha & Tuit, 2012).  Relaxation training will be approximately 10 minutes and will consist of 
progressive muscle relaxation technique.  The imagery training will consist of two types of 
visualizations.  First, participants will be asked to visualize an unemotional scene, such as 
reading a magazine.  Second, they will be presented with an unemotional but physically 
arousing scene, such as exercising in a gym.  Here, the emphasis will be placed on assuring 
that participants are aware of physiological changes, increased heart rate, or breathing.  
Subjects will be given instructions throughout the imagery exercises regarding the process of 
imagining the scenes and maintaining the visualization for an extended period of time.   
 
 
Medication: All participants will be asked to take progesterone or placebo for three days leading 
up to the laboratory test day. They will be asked to take the first dose of medication 


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(progesterone or placebo) at night to minimize possible sedation from progesterone treatment. 
The following morning they will come to the clinic to take the second dose in the morning and 
will be given three additional doses (one to take at night the same day and two doses – morning 
and night for the following day). On the fourth day they will come in the morning for the 
laboratory session and will take one last dose in the lab. For women, the treatment will be 
initiated within the first 4 days of the menstrual cycle, day one being the first day of menses, and 
will be completed within the early follicular phase. 
   
Laboratory sessions:  Laboratory sessions will be conducted on the Biological Studies Unit at 
the West Haven VA with trained personnel, and a psychologist or MD will be on call during the 
laboratory session.  Additionally, all participants will be cleared by a study doctor prior to leaving 
the lab at the end of the imagery session (see Table 1 for details).  Participants will be asked to 
arrive around 10:00 am. On arrival there will be a urine and breath alcohol concentration (BrAC) 
check. If clear to start an IV line will be placed. Those who test positive for any substance (other 
than marijuana) will be discharged. Blood pressure and pulse will be monitored continuously. 
Subjective measures of craving for alcohol, anxiety, affect, and cognitive functioning will be 
administered shortly after the set up.  Prior to the presentation of the 1st and 2nd tapes, the 
relaxation technique will be used.  Two conditions will be administered in a counterbalanced 
order: Trauma/Stress script and  Neutral script. Subjective measures of craving, anxiety, affect, 
and cognitive functioning will be presented:1) prior to presentation of the scripts, b) immediately 
after presentation of each script, and c) following a 5 minute recovery period. After the last 
recovery period and assessments subjects will be encouraged to use the relaxation techniques. 
Craving and emotional distress will be evaluated throughout the session and subjects must 
return to baseline levels prior to being discharged from the unit. Subjects will wear an 
ambulatory physiological monitor (APM) (Eqivital EQ02, Vivonoetics, San Diego, CA) that 
collects continuous ECG, respiration, and activity for 20 minutes while at quiet rest at baseline, 
and throuout the stress challenge procuedure. After completion of the scheduled portion of a 
session, any subject that reports residual craving or distress will participate in guided relaxation 
procedures with a clinically-trained psychologist for up to one additional hour. Relaxation has 
also been shown to reduce PTSD symptoms(Hamid & Neissi, 2009). If craving or emotional 
distress persists after an hour of relaxation training, the subject will receive an individual 
counseling session with a psychologist who is experienced in psychotherapy for PTSD. If 
craving or emotional distress persists after the psychotherapy session, the subject will be 
escorted to the Emergency Department and treated by the on-call psychiatrist.  
 
Table 1. Summary of procedures and measures during the test day 
(Note: all times are approximate) 
 
Condition  
                 Event 
                                                   Measures 
 
Time  
 
Biochemical 
Physiologic 
                    Subjective 
Baseline 
10:00 am  
Baseline measures 
 
 
 
Study medication administration 
Urine, BrAC,  
Blood collection  
for: progesterone,  
ALLO, and  
estradiol (women) 
HR/BP APM 
SEQ, VASC, AUQ, VASA, STAI, DES-R, 
Stroop, TLFB 
 
11:30 am 
Meal 
 
 
 
 
Tape 1 
11:50 am 
Relaxation period 
 
 
 
12:00 pm 
Measures before presentation of  
1st tape 
 
 
HR/BP APM 
VASC, AUQ, VASA, STAI, DES-R, Stroo


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12:20 pm 
Presentation of 1st tape 
 
HR/BP APM 
 
12:25 pm 
Measures after 1st tape 
 
HR/BP APM 
VASC, AUQ, VASA, STAI, DES-R, Stroo
12:45 pm 
Recovery  
 
HR/BP APM 
 
12:50 pm 
Measures after recovery 
 
HR/BP APM 
VASC, AUQ, VASA, STAI, DES-R, Stroo
 
1:10 pm 
5 minute break 
 
 
 
Tape 2 
1:15 pm 
Relaxation period 
 
 
 
1:25 pm 
Measures before presentation  
of 2nd tape 
 
HR/BP APM 
VASC, AUQ, VASA, STAI, DES-R, Stroo
1:45 pm 
Presentation of 2nd tape 
 
HR/BP APM 
 
1:50 pm 
Measures after 2nd tape  
 
HR/BP APM 
VASC, AUQ, VASA, STAI, DES-R, Stroo
2:10 pm 
Recovery 
 
HR/BP APM 
 
2:15 pm  
Measures after recovery 
Blood ALLO 
HR/BP APM 
VASC, AUQ, VASA, STAI, DES-R, Stroo
 
Progesterone:  
Progesterone, a natural hormone, is safe and well-tolerated by women. The safety, 
tolerability and efficacy of micronized progesterone is well established and it is FDA approved 
for hormone replacement therapy (HRT), absence of menstrual periods (amenorrhea), and 
infertility treatment. The recommended dose of progesterone for hormone replacement 
treatment is 200 to 400 mg/day, given as a single evening dose.  After oral administration, 
micronized progesterone reaches its peak plasma levels in two to three hours and has an 
elimination half-life of three to four hours (McAuley et al, 1996). Because of its short half-life 
progesterone will be given twice daily to maintain stable plasma levels. Progesterone doses 
higher than 400 mg/day will not be used since they are more likely to cause sedation. The 
safety and tolerability of micronized progesterone are well established. Others have used 
micronized progesterone in several previous studies with male and female smokers and 
cocaine users (Sofuoglu et al, 2001; Sofuoglu et al, 2009; Sofuoglu et al, 2011). Progesterone 
was well-tolerated and there were no serious adverse events. The most common adverse 
effect is mild sedation. Other less common adverse effects include menstrual irregularity, 
spotting or breakthrough bleeding, dizziness, cramps, nausea, fatigue, headache, an allergic 
reaction, and breast tenderness. Other side effects attributed to synthetic progestin, including 
depression, fluid retention, pruritus, jaundice, rash and thrombotic disorders have not been 
observed with natural progesterone. Women will be warned to use caution when driving a 
motor vehicle or operating machinery while undergoing study treatment. 
There is black-box warning for progesterone regarding the risk for cardiovascular disorders 
and breast cancer. The black box warning mentions the Women’s Health Initiative (WHI) study 
in which treatment of postmenopausal women (50 to 79 years of age) with daily oral 
conjugated estrogens combined with medroxyprogesterone acetate (MPA), relative to 
placebo, reported increased risks of deep vein thrombosis, pulmonary embolism, stroke, and 
myocardial infarction (Hammond, 2005). The pharmacological effects of MPA, a progestin, 
differ significantly from those of progesterone. MPA, but not progesterone, has well-
characterized androgenic, glucocorticoid and anabolic effects and have been associated with 
unfavorable side effects including fluid retention, androgenic effects, alterations in lipid profile, 
increase risk for breast cancer (Fournier et al, 2008; Fournier et al, 2005), and cardiovascular 
events (Hermsmeyer et al, 2008). In contrast to MPA, progesterone is not known to cause 
these adverse events (Fournier et al, 2008; Fournier et al, 2005; Hermsmeyer et al, 2008).  
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, or history of stroke, breast cancer or other cancers. Subjects will be 


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9 
 
warned about these side effects and the physician will be alerted to the earliest manifestations 
of thrombotic disorders including thrombophlebitis, cerebrovascular disorders, pulmonary 
embolism, and retinal thrombosis. If any of these occur or be suspected, the study medication 
will be discontinued immediately. In previous studies conducted in the VA CT Healthcare 
System, micronized progesterone was well tolerated by both male and female cigarette smokers 
and cocaine users.  Subjects will complete a questionnaire to note any important side-effects 
using the Side Effects Questionnaire (SEQ) prior to randomization (baseline), at the medication 
visit, and prior to the start of the laboratory session. 
 
Progesterone effects in men: In contrast to the cyclic changes in progesterone levels in normally 
menstruating women, men have steady levels of plasma progesterone. The physiological levels 
of plasma progesterone in men are similar to the follicular phase progesterone levels found in 
women (Zumoff et al., 1990). 
In a number of previous studies, progesterone treatment has been given to men mainly for the 
treatment of hypertension, COPD, or benzodiazepine withdrawal  (Dolly & Block, 1983; Friess, 
Tagaya, Trachsel, Holsboer, & Rupprecht, 1997; Gron, Friess, Herpers, & Rupprecht, 1997; 
Pinet, Tessonnier, Ravel, & Orehek, 2001; Rylance et al., 1985; Schweizer, Case, Garcia-
Espana, Greenblatt, & Rickels, 1995; Tan, McFarlane, & Lipworth, 1997a; Zwillich, Natalino, 
Sutton, & Weil, 1978). The duration of progesterone treatment in these trials ranged from weeks 
to months with a daily dose ranging from 200 mg to over 1, 500 mg. In men, progesterone 
treatment has been well tolerated with sedation as the main side effect in higher doses 
(Schweizer et al., 1995).  
 
Subjective Outcome Measures:  Craving for alcohol will be assessed using a Visual Analogue 
Scale - Craving (VASC) and the Alcohol Urge Questionnaire (AUQ) (Bohn, Krahn, & Staehler, 
1995).  Participants will be asked to rate their degree of craving for alcohol, “how much do you 
crave alcohol at that particular moment”. On the VASC their responses can range from 0= “not 
at all”, to 10= “extremely high”. On the AUQ the responses will be measured on an 
unodimentional Likert-type scale. Anxiety will be assessed using a Visual Analogue Scale - 
Anxiety (VASA) and the State Trait Anxiety Inventory (STAI) (Julian, 2011).  Participants will be 
asked to rate their level of anxiety, for example, how “anxious, tense and/or jittery” they feel at 
that particular moment.  On the VASA their responses can range from 0= “not at all” to 10= 
“extremely high”. On the STAI their responses can range from 1 “not al all” to 4 “very much so”. 
Affect will be measured using the Differential Emotions Scale-Revised (DES-R)(Izard, 1972). 
Participants rate on a 5-point scale the extent to which each word describes how they feel at the 
present moment from 1= “not at all” to 5= “extremely”. Cognitive Measures: Stroop color/Ward 
Test (Golden, 1976). The Stroop test has been used to measure the ability to inhibit incongruent 
competing conflicts. The number of raw items read for each trial is recorded and converted to 
standardized T scores. The Timeline Follow-Back (TLFB) method(Sobell & Sobell, 1992) will be 
used to document the degree of daily alcohol consumption for 90 days at screening, at the 
laboratory session, and at the 1 month following the lab session. 
 
Cardiovascular and Hormone Outcome Measures:  Blood pressure and pulse will be 
assessed using an SD-700 monitor.  To assure greater accuracy for the initial time points 
(baseline and time 0) four measures of blood pressure and pulse will be taken, and their 
average will constitute the single blood pressure and pulse measure.  A single reading will be 
used for the other time points during testing. During the laboratory sessions we will also collect 
blood samples to examine the levels of allopregnanolone (ALLO) - the active metabolite of 
progesterone –  and markers of inflammation to explore the relationship between these 
biomarkers and behavioral effects (urges for alcohol, anxiety, mood, cognitive functioning) of 
progesterone and alcohol. ECG RR intervals will be edited to remove artifact and ectopy using 
CarioEdit software. High and low frequency HRV will be calculated using CardioBatch software 
(Mind/Body Institute, U Ill Chicago).  


ER0008 v.2/22/2021 
10 
 
 
Subject Payments: Participants will be paid $70 for screening and diagnostic evaluation, $80 
for scripting, $25 for each medication visit (2), $250 for the laboratory session, and $50 for the 
follow up session. Therefore, participants could earn up to $500. 
 
Power Analysis: Sample size estimates were determined using craving from our preliminary 
data.  Assuming a large effect size for the within-subject comparison between progesterone and 
placebo (d’=0.50)(Cohen, 1988), α=.05 and two-sided test, we have 80% power to detect such 
an effect size as statistically significant with n=30 subjects. Assuming 20% dropout rate we 
need to recruit 36 subjects in order to have complete data on 30 subjects per group.  
 
Method for data collection and analyses: Prior to performing statistical analyses, we will 
calculate descriptive statistics and will assess whether the distributions of all measures conform 
to normality. We will apply transformation or use nonparametric methods as necessary. We will 
estimate effect sizes in order to inform the design of potential future definitive studies.  For the 
primary hypotheses we will use mixed effects models to assess change in stress reactivity after 
administration of progesterone vs. placebo.  Study medication (progesterone and placebo), and 
gender will be a between subject factors, condition (trauma vs nutral) and time (pre, post and 
recovery following script presentation) will be used as within-subject factors. The primary stress 
reactivity variables will be craving.  We will first compute descriptive statistics for each variable 
and will assess data distributions. All tests will be two-sided at 0.05 level of significance.  We will 
use the Schwartz-Bayesian criterion (BIC) to select the best-fitting correlation structure within 
subject. 
 
Study Duration: Two years. 


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11 
 
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