Understanding and Targeting Stress Reactivity in Women Veterans With Alcohol Misuse
Phase: NA
Conditions: Alcohol Use Disorder, Post Traumatic Stress Disorder
Sponsor: VA Office of Research and Development

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7.22.2022 
PI: Cathryn Holzhauer 
Protocol Title: Stress, Emotion Regulation, and Alcohol in Women Veterans 
 
1 
 
1. 
Principal Investigator: Cathryn Holzhauer, Ph.D. 
 
2. 
Purpose: 
Women are the fastest growing segment of Veterans Health Administration users1, expected 
to comprise 15% of the U.S. Veteran population by 20353. The rate of alcohol misuse among women 
Veterans is also increasing 4, with lifetime Alcohol Use Disorder (AUD) at 27%, equal to rates for male 
Veterans5. Furthermore, posttraumatic stress disorder (PTSD) is common among women Veterans with 
alcohol misuse, with co-occurrence rates up to 62%6. Daily stress and acute stressors, including their 
physiological effects, are causally related to women’s problem drinking 7-10. Stress and negative 
emotion commonly act as triggers for drinking11 and disrupt cognitive processes that are necessary for 
behavioral control12. Inhibitory control is one such cognitive process that reflects a person’s ability to 
suppress ongoing or planned behavioral processes13. Stress-induced deficits in inhibitory control may 
prevent successful coping with alcohol triggers and cravings.  
 
A previous study conducted by our lab targeted stress-induced craving and deficits in inhibitory 
control among women Veterans with alcohol misuse. Results show that use of an emotion regulation 
skill (cognitive reappraisal, CR) in the laboratory down-regulates not only stress, but also stress-
induced alcohol craving. Additionally, use of CR proximally improves women’s inhibitory control, 
particularly among women with more severe PTSD. This latter finding points to important person-level 
variability in the effects of CR on inhibitory control, suggesting that there may be key moderators, such 
as PTSD, that impact the efficacy of CR. The current study is a logical next step in this program of 
research and will build on that previous study by: (1) adding a physiological outcome measure of stress 
(Heart Rate Variability, HRV), in addition to the subjective (craving) and cognitive (inhibitory control) 
measures; (2) testing whether these laboratory findings extend to “real world” drinking behavior via 
daily longitudinal data collection; and (3) examining PTSD severity and hormonal context as 
moderators of CR’s effects on inhibitory control, craving, HRV, and drinking. Research has shown that 
serum levels of the ovarian hormone progesterone, and its metabolite allopregnanolone (ALLO), are 
associated with lower stress reactivity14, 15, less alcohol craving and use16, 17, and better ability to 
regulate emotion18. Women with PTSD, however, exhibit a deficit in the conversion of progesterone to 
ALLO15, 19. This research suggests that women with low progesterone levels, within the context of 
menstrual cycle phase or co-occurring PTSD, may be particularly prone to higher stress reactivity and 
stress-induced drinking and may benefit from using effective emotion regulation skills. 
 
 Each woman (n=80) will be randomized to one of two conditions: a control condition (n=40) or 
a condition in which participants learn to use CR to regulate stress (n=40). Of the total 80 participants, 
up to 20 non-Veteran/Civilian women will be recruited for participation. Women in the CR condition 
will be asked to practice and use this skill over a 35-day period (to encompass an entire menstrual 
cycle) and will complete daily logs of alcohol use and stress. Each participant will come in for two 
experimental sessions, scheduled at the time of her peak and lowest progesterone levels, during which 
participants in the CR condition will use that skill in response to a personalized stress induction. 
Throughout these sessions, the effect of CR on the following variables will be assessed: (1) alcohol 
craving, (2) inhibitory control, and (3) HRV. These three variables, and (4) drinking during the 35-day 
period, will be the main study outcome variables.  
 
Aim 1: Compare the effects of an emotion regulation skill (Cognitive Reappraisal, CR) to a 
control group (quiet sitting) on outcome variables. Hypothesis 1a: After a stress induction, use of CR in 
the laboratory will lead to greater improvement in alcohol craving, inhibitory control, and HRV, 

7.22.2022 
PI: Cathryn Holzhauer 
Protocol Title: Stress, Emotion Regulation, and Alcohol in Women Veterans 
 
2 
 
compared to the control group. Hypothesis 1b:  Women in the CR group will have significantly less 
stress-induced drinking over the 35-day assessment period compared to the control group. 
 
Aim 2: Examine whether PTSD severity and progesterone levels moderate the effect of CR on 
alcohol craving and use, inhibitory control, and HRV. Hypothesis 2a: PTSD will moderate the association 
between condition and outcome measures, such that women with more severe PTSD will benefit more 
from CR. Hypothesis 2b: Progesterone will moderate the association between condition and laboratory 
outcome measures, such that women will benefit more from CR when progesterone levels are lowest. 
Hypothesis 2c (Exploratory): Explore the association between the two moderators, progesterone levels 
and PTSD severity, and their relative association with stress-induced drinking. 
 
3. 
Background 
Emotion dysregulation and daily stress are causally related to women’s alcohol use: Chronic 
stress and acute trauma create a more influential pathway to substance misuse among women 
compared to men25, 26. For instance, among individuals with alcohol misuse, women are more likely than 
men to experience cravings in response to daily negative emotion and stress (e.g., arguments with loved 
ones) 7, 27-29. This association between stress and drinking may be exacerbated among individuals with 
co-occurring alcohol misuse and PTSD. For example, in a sample of Veterans and civilians with PTSD and 
AUD, drinking to cope with negative emotion was associated with alcohol use for women but not men30.  
 
Emotion regulation is a general term that refers to the way in which an individual influences 
what emotions (including stress) she experiences, when emotions are experienced, or how emotions are 
expressed 29. Drinking to cope with stress and negative emotion is common among individuals who tend 
to use maladaptive emotion regulation strategies, a tendency referred to as emotion dysregulation29. In 
other words, high emotion dysregulation may account for a person’s – and particularly women 
Veterans’ – tendency toward stress-induced drinking31. This idea has empirical support: among Veterans 
in residential substance use disorder (SUD) treatment, high emotion dysregulation (specifically: lack of 
access to emotion regulation skills, poor impulse control when distressed, and poor emotional 
awareness) was found to mediate (or explain) the relation between negative emotion and urges to 
engage in risky behaviors, including substance misuse32.   
 
Use of Cognitive Reappraisal (CR), an effective emotion regulation skill, may mitigate stress-
induced drinking and improve behavioral control among women: While findings on stress and 
women’s alcohol use have been widely research and established33, the translation of these findings to 
treatment for women has been limited. Emotion regulation skills directly target stress and negative 
emotion states and are more often inherent in treatment of emotional disorders such as anxiety, 
depression, or borderline personality disorder34. Traditional alcohol treatments have generally viewed 
stress as a contextual factor that may increase the likelihood of a drinking episode or a relapse11. Thus, 
patients are often taught how to avoid drinking in response to stress/negative emotion11, with less focus 
on teaching skills for directly mitigating the stress itself.  Directly targeting stress and negative emotion 
may be a particularly important addition to alcohol treatment for women, to help them to avoid stress-
induced drinking. Improved stress and emotion regulation as an endpoint in AUD treatment is slowly 
gaining traction35, 36 as a valuable personalized medicine approach. This study will examine if, how, and 
for whom the strategy of directly targeting stress and emotion dysregulation works; specifically, if it 
reduces craving, arousal, and drinking, and improves inhibitory control, within a sample of women with 
alcohol misuse and varying levels of PTSD.  

7.22.2022 
PI: Cathryn Holzhauer 
Protocol Title: Stress, Emotion Regulation, and Alcohol in Women Veterans 
 
3 
 
 
Cognitive Reappraisal of emotion (CR), the skill to be tested in this proposed study, is an 
antecedent-focused emotion regulation skill40, which means that CR can be used before a behavioral 
response to a stressful stimulus is fully activated. Alternatively, a response-focused emotion regulation 
skill (e.g., distracting oneself, using relaxation skills) is an attempt at regulating emotion after the 
emotion is already underway40. This distinction is important, as use of antecedent-focused emotion 
regulation has been shown to more effectively decrease negative emotion states (including at the 
physiological level), more effectively reduce behavioral expression of emotion (e.g., fighting, yelling, 
drinking), and is less often taught in alcohol treatment compared to response-focused emotion 
regulation efforts41. There is little experimental research which manipulates use of effective emotion 
regulation skills in order to understand the utility of teaching these skills in treating alcohol misuse, and 
none among women Veterans.  
 
The proposed study will assess the effect of CR on alcohol craving, cognitive (inhibitory) 
control, physiological arousal (HRV), and drinking: Stress and strong emotion are associated with 
alcohol use and other impulsive behaviors via their subjective, cognitive, and physiological effects, yet 
there is considerable discrepancy between these three measures42. For instance, an individual may not 
report feeling stressed in response to a stimulus, however physiological measures indicate a stress 
reaction. Furthermore, behavior – such as attending to alcohol-related stimuli - is often initiated before 
conscious, aware deliberation; measures of physiological arousal are an indicator of pre-conscious 
reactivity to stimuli, particularly to stressors in our environment42. Thus, physiological measures are 
important indicators of emotion and craving states, as they reflect automatic processes or reactions to a 
stimulus (e.g. a stressor) that can drive behavior and affect cognitive control42, 43.  
 
As discussed above, emotion regulation skills can be used to reduce stress, and this stress 
reduction may then improve cognitive control and decrease stress-induced alcohol use. The 
experimental portion of the proposed study would examine the acute, immediate impact of an effective 
emotion regulation skill (CR) on subjective, cognitive, and physiological outcomes of stress/negative 
emotion. Subjectively, as described above, stress increases the likelihood of drinking by increasing 
alcohol craving, particularly among women7, 28. Cognitively, stress and strong emotion deplete inhibitory 
control12, which may be another mechanism by which likelihood of alcohol misuse is increased under 
stressful conditions. Inhibitory control is one facet of impulsive behavior44 that reflects the ability to 
suppress ongoing or planned cognitive or behavioral processes13. When an individual’s inhibitory control 
is depleted (e.g., by stress), subsequent self-regulatory efforts (e.g., attempts to resist drinking) are 
more likely to fail45.  Physiologically, stress decreases heart rate variability (HRV). HRV is an especially 
potent measure of factors that are automatic and occur outside our awareness, yet can impact our 
ability to respond effectively to situational demands42, 43 – for example, a person’s ability to cope with 
the situational demand of encountering an alcohol-related trigger (e.g., driving past a liquor store, being 
offered an alcoholic drink)46. HRV increases during successful use of emotion regulation skills46, 47, and 
increased HRV and successful emotion regulation are both associated with increased blood flow in 
cerebral brain areas, which are important for behavioral control43. Thus, increased HRV may be an 
additional mechanism by which emotion regulation skills could decrease likelihood of stress-induced 
drinking. Indeed, resting HRV has been shown to associate with patients’ severity of alcohol problems48. 
In sum, stress and strong negative emotion reduce HRV, deplete inhibitory control, and increase alcohol 
craving among individuals with alcohol misuse, all of which increase likelihood of impulsive, stress-
induced alcohol use among women. The proposed study would examine whether patients’ use of 

7.22.2022 
PI: Cathryn Holzhauer 
Protocol Title: Stress, Emotion Regulation, and Alcohol in Women Veterans 
 
4 
 
cognitive reappraisal of negative emotion (CR) can acutely reverse these effects in the laboratory (Aim 1, 
Hypothesis 1a). We will also examine whether findings regarding the effect of CR on craving, inhibitory 
control, and HRV extend to actual drinking behavior over 35 days, given regular use and practice of 
those techniques (Aim 1, Hypothesis 1b).  
 
PTSD and progesterone may moderate the effect of CR among women: Aim 2 of the proposed 
study will examine potential moderators of the impact of CR on our outcome variables (craving, 
inhibitory control, HRV, and drinking). Does CR work better or worse for some women, or based on 
contextual factors? This question is consistent with a contemporary theory of addiction, which 
conceptualizes alcohol use as a manifestation of self-regulation deficits (emotion dysregulation) which 
can be improved by intervention (use of emotion regulation skills), and are influenced by moderators or 
contextual factors which are specific to the patient49. In other words, while improved emotion 
regulation may be a mechanism leading to reduced alcohol use, the extent to which emotion regulation 
skills are used and whether they are effective depends on a number of dynamic, moderating factors. 
PTSD severity and progesterone levels are two such factors that impact women’s stress reactivity50, 51, 
emotion regulation18, 52, and alcohol use17, 53. Attending to these two factors, given existing research and 
conceptual models suggesting their relevance described below, has important implications in 
personalizing treatment for women Veterans. 
 
PTSD severity as a moderating factor of the effect of CR: The high co-occurrence between PTSD 
and alcohol misuse among women is notable, especially given research that shows worse substance use 
outcomes among treatment-seeking individuals with any co-occurring SUD and PTSD when compared to 
those with SUD alone54, 55.  Women who have co-occurring alcohol misuse and PTSD may benefit from 
different interventions than women with alcohol misuse alone56. Emotion regulation skills may be one 
such therapeutic intervention that may work more or less well for women with alcohol misuse and 
PTSD56. Emotion dysregulation is a core component of PTSD, thought to give rise to a number of 
symptoms, and it can affect the symptomatology of multiple disorders57 (i.e., can have “transdiagnostic” 
implications). Among individuals with SUD, those with co-occurring PTSD use more maladaptive emotion 
regulation strategies than those without PTSD58, with ability to regulate emotion inversely associated 
with PTSD severity59. This role of emotion dysregulation in PTSD has also been found among Veterans 
specifically 52, 60. Therefore, women Veterans with co-occurring PTSD and alcohol misuse might 
experience particular benefit from learning a new emotion regulation skill. In this way, PTSD severity 
may moderate the effect of CR on alcohol craving/use, inhibitory control, and physiological arousal 
(HRV). This would by signaled in the proposed study by a significant moderating effect of PTSD symptom 
severity on the impact of CR on the study’s outcome variables (Aim 2, Hypothesis 2a).  
 
 Progesterone as a Moderating Factor: The ovarian hormone progesterone, and its metabolites, 
have been shown to be associated, in some cases causally, with women’s stress reactivity51, negative 
emotion61, and emotion regulation18. Women’s general stress reactivity (i.e., subjective feelings of 
stress, hypothalamic pituitary axis activity, and cortisol secretion in response to stressors) rises in the 
luteal (or post-ovulatory) phase of the menstrual cycle62, 63, potentiated by fluctuating levels of 
progesterone. It is believed that low levels of progesterone, especially in the follicular and late luteal 
phase, may increase women’s stress reactivity and decrease their well-being64. While the effect of 
progesterone on stress reactivity has been well researched, the extent to which this effect extends to 
behavior such as stress-induced alcohol use is less clear. However, it has been suggested that low levels 
of progesterone may increase the likelihood of use or relapse among women 28, 33, 65, and this may be the 

7.22.2022 
PI: Cathryn Holzhauer 
Protocol Title: Stress, Emotion Regulation, and Alcohol in Women Veterans 
 
5 
 
case especially among women with co-occurring PTSD as they are prone to drinking to cope with 
stress/negative emotion27, 66 and show irregularities in progesterone functioning15, 19. Alcohol craving 
and use fluctuate across the menstrual cycle17, 67, as do coping motives for drinking68 – specifically, 
craving, drinking, and coping motives appear to increase at times in the menstrual cycle when 
progesterone is low (i.e., the follicular or menstrual phase) or dropping (i.e., late luteal/premenstrual 
phase)69, 70. Additionally, research with women seeking treatment for AUD has found that negative 
affect and physical discomfort associated with fluctuating hormones across the menstrual cycle can act 
as a trigger for alcohol use17. Administration of exogenous progesterone during the early follicular phase 
(when endogenous progesterone levels are lowest) reduces substance cravings and use71, 72 and reduces 
stress reactivity14 among women with SUD. In a similar way, the effect of emotion regulation skills on 
alcohol craving and drinking – particularly stress-induced drinking – may be especially important during 
certain phases of the menstrual cycle (e.g., the follicular phase) when progesterone levels are low (Aim 
2, Hypothesis 2b). Women may be at heightened risk of stress-induced drinking and relapse when their 
endogenous levels of progesterone are low. 
 
4. 
Significance 
Personalizing care: This study is consistent with the DVA 2018-2024 Strategic Plan, with regard 
to enhancing knowledge of at-risk groups of Veterans (women Veterans with mental health conditions) 
with Veteran-salient illnesses (PTSD and alcohol misuse) and advancing the fields of personalized 
medicine to improve effectiveness of treatment. A recent study found that 30% of VA Medical Centers 
provided female-segregated (e.g., non-mixed gender) substance treatment options20, despite research 
showing that women, and especially women who have experienced trauma, often prefer female-
segregated groups38, 39. Furthermore, research with civilian women has shown that such female-
segregated treatments are most useful when female-specific programming is included39. Stress and 
emotion dysregulation are examples of antecedents to drinking that have greater relevance for women 
than men, as described above, and CR may be a specific relapse prevention strategy that therefore may 
be more relevant for women. Thus, the proposed study would provide much-needed empirical data to 
inform the development of personalized, female-specific treatment for women Veterans.  
 
Understanding the role of progesterone in stress reactivity, emotion regulation, and alcohol use: 
Ultimately, interventions for alcohol misuse may be enhanced by indirectly or directly targeting 
fluctuations in, or low levels of, progesterone. For example, psychotherapy can help women develop 
coping skills to deal effectively with hormone fluctuations (e.g., by teaching them effective emotion 
regulation skills such as CR), and pharmacotherapy can consider the use of medications to regulate 
hormonal fluctuations (to the extent that such fluctuations impact stress reactivity, emotion regulation, 
and/or craving). Veterans may be at increased risk of stress-induced relapse, or may have more difficulty 
establishing abstinence from alcohol, during certain phases of their menstrual cycle. Similar findings 
have been made in the smoking literature79.  
 
Transdiagnostic implications: The proposed research will examine whether CR has its effects on 
several mechanisms (i.e., post-stressor craving, deficits in inhibitory control, and HRV/arousal). While we 
are measuring inhibitory control and HRV given their association with alcohol misuse, these are general 
measures related to self-regulation and therefore have transdiagnostic implications within this 
population (i.e., implications related to change across diagnostic conditions). For example, if CR 
improves inhibitory control and/or HRV after the stress induction, such a finding would suggest that 
using CR can reduce impulsivity and arousal more generally within this population – and perhaps more 

7.22.2022 
PI: Cathryn Holzhauer 
Protocol Title: Stress, Emotion Regulation, and Alcohol in Women Veterans 
 
6 
 
or less effectively for women with co-occurring PTSD. Findings on the effect of CR on inhibitory control 
and HRV could have implications for improving other psychological symptoms80 among women 
Veterans, such as anxiety or depression, or other impulsive behaviors such as suicidal behavior and non-
suicidal self-injury81. Additionally, data on the moderating effect of progesterone on the impact of CR on 
physiological arousal and inhibitory control could have implications for women Veterans at certain life 
phases, e.g., for understanding and reducing impulsivity or anxiety among women post-partum82.  Past 
research has linked suicidal behavior to low estradiol and progesterone levels among women81.  
 
5. 
Research Plan 
Study methods and procedure. The proposed study will combine experimental, in-person 
sessions with daily self-report data from the women. Participation will take place across a period of at 
least 35 days, to encompass an entire menstrual cycle. All participants complete all sections of the study 
– the experimental sessions and the longitudinal (35-day) data collection. See Figure 3 for study flow and 
timing of sessions.  
 
Participants will be recruited into one of two subgroups of 40 women (for n=80 total). Subgroup 
1 will comprise 40 women who meet restrictive inclusion/exclusion criteria (“strict criteria set”) needed 
to examine Hypotheses 2b and 2c [excludes (5) Peri- or postmenopausal; (6) Endocrine disorder; (7) 
Irregular menstrual cycle]. Data from this “strict criteria set” of 40 participants will be used to examine 
hypotheses 2b and 2c, related to progesterone levels. Because there may be associations between 
progesterone and/or estradiol, stress reactivity, and alcohol use among non-normally cycling women, 
and because Study Aim 1 (Hypotheses 1a, 1b) and Hypothesis 2a do not require a sample of normally 
cycling women, Subgroup 2 will comprise 40 women Veterans who may not meet the three, more 
restrictive, hormone-related exclusion criteria.  All study procedures will be the same across subgroups, 
except that the timing of sessions may not be based on the participant’s menstrual cycle if she does not 
have a menses. Additionally, they will not be asked questions about their menses, track ovulation, or 
provide information about their menstrual cycles, which is asked of participants in subgroup 1.  
 
After establishing initial study eligibility over the phone, women will come in for session 1 
(intake session), during which they will sign consent, complete baseline measures, and complete a 
clinical assessment [comprised of the Structured Clinical Interview for DSM-5 (SCID-5)] . At this time, 
participants in Subgroup 1 will also provide information about their past three menstrual cycles, which 
will be used to estimate their current menstrual phase and estimate the start date of their next cycle (as 
used in previous research50). Each participant will then be randomized to start the remaining study 
procedures in either the early Follicular Phase (eFP, when progesterone levels are lowest) or mid-Luteal 
Phase (mLP, when progesterone levels are highest), and the remaining sessions will be tentatively 
scheduled based on estimates of menstrual cycle phases (note: women will be urn randomized92 to eFP 
or mLP based on use of hormonal contraception and severity of PTSD, AUD, and depression symptoms). 
Participants will begin the daily logs on either the 1st day of menses (if in eFP start group) or on the day 
of their luteinizing hormone (LH) surge (if in mLP start group). Participants who do not have regular 
menstrual cycles will be scheduled for session 1 and then will begin the 35-day period of completing 
daily logs any time after their initial session 1. During session 1, participants will also be educated on 
completing the electronic daily logs through REDCap and on using urine tests to estimate timing of LH 
surge (which indicates ovulation/start of luteal phase/when progesterone levels start to rise), and will 
schedule a regular day and time for weekly coaching/check in call.  
 

7.22.2022
PI: Cathryn Holzhauer
Protocol Title: Stress, Emotion Regulation, and Alcohol in Women Veterans
7
COVID-19 accommodations for sessions 1, 2, and 5: Participants will be offered the option of 
completing sessions 1, 2, and 5 via telehealth/using VA Webex, if preferred. While sessions 3 and 4 of 
the study use biological assessments that require in-person attendance, these three sessions can 
feasibly be conducted virtually. Participants will be asked if they prefer virtual sessions (for 1,2, and 5) at 
the time of the phone screen, and the requirements to have virtual sessions (e.g., reliable internet 
connection in a private space, ability to download the Webex application, reliable mail service) will be 
explained at that time. All study procedures will occur remotely, with self-report questionnaires being 
completed by participant using remote control via the Webex application. See below for details 
regarding telehealth consent process. We expect this option will substantially reduce participant 
burden, will not deviate from typical VA telehealth care, and will allow participants with compromised 
health or increased responsibilities during this time (e.g., increased childcare responsibilities) the option 
of participating in this study. Any virtual sessions will follow guidelines that are used in routine VA 
telehealth care, including the following:
1.
Communicating to the participant the importance of having private space to ensure their 
confidentiality during study sessions
2.
Establishing an emergency contact, and the location/address of participant at the time of 
the study session
3.
Using available elements of the video platform to ensure confidentiality (e.g., “locking” the 
virtual meeting room)
Figure 3. Methodology for Subgroup 1
eFP = early Follicular Phase; mLP = mid Luteal Phase; CR = Cognitive Reappraisal; CTRL= Control group; 
LH = luteinizing hormone (surge signals ovulation/start of luteal phase); HRV = heart rate variability

7.22.2022
PI: Cathryn Holzhauer
Protocol Title: Stress, Emotion Regulation, and Alcohol in Women Veterans
8
Figure 4. Methodology for Subgroup 2
Note: Laboratory Sessions follow same protocols as those outlined in Figure 3 for Subgroup 1
Details regarding consent process: Study staff will explain the project in detail, what the 
subjects should expect of the study, and what we do with their information. Study staff will also describe 
the purpose of the study to give subjects a broader scope of the researcher’s intentions. It will be 
stressed to participants that their name will not be associated with any of the data that they provide for 
the study. The importance of the participant ID number is explained as well as the fact that their 
names/contact information will not be kept with the data. 
Additionally, participants are informed that their participation is completely voluntary and that 
they can choose to withdraw from the study at any time. Also, if they choose not to answer a specific 
question, they have every right to refuse. The participants are encouraged to ask questions at multiple 
points during the consenting process. It is expected that all participants will speak English primarily. The 
consent form is written plainly to assist people with limited reading skills. Subjects also have the option 
of having the consent form read to them by a study team member or someone of their choosing.
The consent form will be reviewed with each participant and research staff providing 
information will check in at each section of the sheet to verbally ascertain whether the information was 
understood and to see if the participant has any questions. The participant will read the first paragraph 
of the informed consent form to verify their ability to read the consent form. The participant will be 
given time after review of the information sheet to read the form again and will again be asked if she 
has any questions. Any participants who are not cognitively capable of consenting will be excluded from 
the study, as outlined in the study's exclusion criteria.  
After reviewing the consent form, study staff will explicitly reiterate that the participant may 
stop the study at any time, and it will not affect their usual care, and that they will be compensated for 
all portions of the study they complete.
Consent process for participants using virtual sessions: If, at the time of the phone screen, 
participants express a preference to have virtual sessions 1, 2, and 5, study staff will use Azure-

7.22.2022 
PI: Cathryn Holzhauer 
Protocol Title: Stress, Emotion Regulation, and Alcohol in Women Veterans 
 
9 
 
encrypted email or DocuSign to send them a study consent form and a HIPAA form. Study staff will also 
send participants an ovulation kit by mail. At virtual session 1, participants will be consented and sign 
HIPAA via DocuSign or Adobe PDF electronic signature and email the form back to the study staff. 
Alternatively, if they are unable to sign consent electronically, they may print the consent and HIPAA 
forms and provide a “wet” signature. Participants will be given three options on how to return the “wet” 
signed consent form and the HIPAA form: (1) take pictures of both forms with their phone and email the 
pictures to the study staff, (2) scan both forms and email them back to study staff, or (3) they will hold 
each signed page to the camera so that the study staff can take screenshots during session 1 . All 
electronically signed HIPAA and consent forms, scanned, or screenshots of the consent and HIPAA forms 
will be saved on the secure study drive. Since participants will be required to come in person for 
sessions 3 and 4, we will ask them to bring the signed forms to us in-person or return them by mail. 
However, in the case that a participant is lost to contact before session 3, we will have the documented 
consent via the picture taken.  
 
On either first day of menses (eFP group) or day of LH surge (mLP group), in addition to starting 
daily logs, participants in Subgroup 1 will also be scheduled for session 2 (training session). Session 2 
will be scheduled to occur within either 1-5 days after onset of menses (eFP group) or 5-9 days after the 
LH surge (mLP group) (see Figure 3). Those in Subgroup 2 will be scheduled for session 2 1-5 days after 
starting their daily logs. During session 2, participants will be engaged in the development of a 
personalized stress script93, which asks them to describe the details of a recent, day-to-day stressful (but 
not traumatic) experience. This story is then developed into a six-minute script used in laboratory 
sessions 3 and 4 to induce stress. In session 2 participants also are again urn randomized (based on use 
of hormonal contraception, severity of PTSD, depression and AUD) to one of the two conditions – to 
receive the 50-minute cognitive reappraisal (CR condition) microintervention or psychoeducation on 
women’s health (control condition) with a study therapist.  
 
After session 2, during the 35-day longitudinal period, participants in the CR condition are 
instructed to use CR when experiencing stress or negative emotion until at least the end of their 35-day 
period (which started when she began her daily logs). Daily logs will be completed via REDCap, where 
two surveys per day will be sent via text message (using participants’ phone number). Five homework 
assignments will be provided for participants to use for practice over the remaining weeks, and the 
day/time of the weekly coaching sessions will be confirmed. During the weekly coaching/check-in, the 
therapist will ask about daily log completion, answer questions, and – after the training session in which 
the microintervention is delivered – will provide coaching regarding use of CR (if not in control group). 
The methods used for the longitudinal period (e.g., coaching/check-in calls, participant compensation) 
are based on similar work by Dr. Simpson, study consultant94. The timing of the remaining laboratory 
sessions – 3 and 4 – will be scheduled based on each woman’s onset of menses (in eFP group) or day of 
LH surge (in mLP).  
The personalized negative emotion script73 asks participants to tell the details of a  recent, day-
to-day stressful (but not too stressful) experience. This story told by the participants is then developed 
by study staff into a six-minute script that is used in sessions 3 and 4. This script development procedure 
has been used in several studies in the past, and Dr. Holzhauer received training on this manualized 
script development procedure from Dr. Rajita Sinha at the Yale Stress Center. (See below for details on 
reducing potential risk associated with the negative emotion induction procedure). 
All sessions 3 and 4 (experimental sessions) will follow similar protocol: (1) participants will 
provide a blood sample to assay ovarian hormone levels (progesterone and estradiol); (2) baseline 

7.22.2022 
PI: Cathryn Holzhauer 
Protocol Title: Stress, Emotion Regulation, and Alcohol in Women Veterans 
 
10 
 
salivary cortisol, progesterone, and estradiol; (3) resting baseline period; (4) 2nd baseline cortisol; (5) 
undergo the negative emotion/stress induction (listening to the personalized script that was developed 
in training session 2); (6) assess outcome variables (inhibitory control, alcohol craving, cortisol) in 
stressed state; (7) Implementation/use of CR, or sit quietly for a matched period of time (if in control 
group); (8) assess outcome variables post-CR use. HRV will be measured throughout the sessions. 
Sessions 3 and 4 will be conducted by study staff, who will have minimal, scripted interaction and study-
related conversation with the participant. To control for diurnal hormonal fluctuations and physiological 
spikes, laboratory sessions 3-4 will be scheduled between 12:00pm and 4:30pm; participants will be 
asked to abstain from nicotine and caffeine for 1 and 4 hours prior to session, respectively, and to 
abstain from eating 2-3 hours before visits.  
 
Within 5 days of the end of the 35-day period, women will be asked to return for session 5 
(follow-up session) in which they will turn in remaining daily logs, complete the Alcohol Timeline Follow-
Back (TLFB), complete end of study self-reports, and receive a full study de-briefing. Although women 
will be tracking whether or not they consumed alcohol on the daily surveys, the TLFB will be used at all 
laboratory sessions to fill in any potentially missing data and ask for details regarding number of drinks; 
this is a technique used in our team’s past research to maximize data collection.  
All sessions will be audio recorded and labeled only with the study ID number. These recordings 
will be kept on the VA network and will be accessible by study staff only. The audio recordings will be 
used by study staff for training and rating the integrity of microintervention delivery and clinical 
interviews in session 1.  
Recruitment: Research participants will be recruited from clinics at VACWM (Central Western 
Massachusetts) at the Leeds campus, and the Springfield and Worcester Outpatient Clinics as well as the 
clinics at VA Bedford Healthcare System and VACHS at the West Haven campus. We will also recruit 
women Veterans from community programs in the Central Western Massachusetts region that 
specialize in care and services to Veterans. Dr. Holzhauer or study staff will meet with health providers 
and clinic managers and provide information about this research project. Study Staff will provide them 
with a study flyer. Participants will be recruited using the following procedures:  
1) health providers from above-mentioned clinics and programs give their patients who may 
qualify a handout with study and ask the patients to contact the research team directly or if the patient 
would like the team to contact them (in which case the veteran’s information will be conveyed to the 
research team who will then call the veteran for a phone screen), and 2) Flyers posted in the above-
mentioned clinics and community programs. In addition to the clinical and community-based service 
settings, study staff will hang flyers in general community gathering spaces in CWM. 3) A study website 
which has basic study information and a place to contact study staff to request further information or an 
eligibility screen (seraresearchgroup.com). 4) Study staff will also use medical record reviews to identify 
potentially eligible participants (i.e., women Veterans with AUDIT-C scores of 3 or higher). Upon 
identifying a woman who may be eligible, we will extend an invitation to participate in our study by 
sending her a generic letter in the mail. The letter will be sufficiently generic so that if someone other 
than the intended recipient was to read the letter (e.g., a family member), there would be no 

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information that would convey information about the Veteran’s health. In cases where 3 letters have 
been sent with no reply, the same message will be sent via email using the email address listed in the 
recipient’s medical chart. Once participants contact us to indicate their interest in participating, we will 
conduct an eligibility screen either over the phone (or in person, if she preferred). Once initial eligibility 
is established, we will schedule session one. 4) Study participants will be eligible to refer up to two other 
women to us. If their referral completes our phone screen the referring woman will receive $15 in gift 
cards, regardless of whether or not the referred individual is found to be eligible for the study.   
Up to 20 non-Veteran (Civilian) women will also be recruited from the community, via flyers in 
community settings (e.g., transportation hubs, coffee shops, local Universities/Colleges, hospitals).  
All 80 women who participate in the proposed CDA-2 study will be assessed for eligibility based 
on the following:  
Inclusion Criteria: (1) Age 18 and older; (2) Current alcohol misuse, defined as scoring 3 or higher 
on the AUDIT-C; (3) If using other illicit substances, alcohol is their primary substance of use; (4) Alcohol 
use in the past 45 days; (5) Able to write and speak in English; (7) Willing to provide blood samples at 
laboratory sessions to assay hormone levels and take urine ovulation tests at home. All inclusion criteria 
will be established via participant self-report during the phone screen and confirmed at session 1. All 
inclusion criteria are the same for women in Subgroups 1 and 2.  
Exclusion Criteria: (1) Psychotic symptoms or uncontrolled Bipolar Disorder (screened for during 
session 1 using SCID-5 screening modules); (2) Brain damage or were in an accident that affects ability to 
complete the computerized task; (3) Current (past 3 months) active suicidal ideation or intent;(4) 
Current pregnancy; (5) Currently receiving treatment for alcohol use; Subjects will not be asked to 
discontinue clinically indicated medications to qualify for the study. Exclusion criteria 1-5 apply to 
participants in Subgroups 1 and 2.   
Subgroup 1 has four additional exclusion criteria:  (7) Peri- or postmenopausal; (8) Endocrine 
disorder; (9) Irregular menstrual cycle (i.e., cycle length outside of 25 to 35 days, recurrent history of 
missed periods, or vaginal bleeding between periods); (10) Use of benzodiazepines and opiates (unless 
very infrequent use or use for a discrete medical event such as dental work) and medications known to 
influence the neuroactive steroids of interest (progesterone & estradiol), including hormonal 
contraceptives; (11) Made a medication change in the past 2 months.  All women will be screened for 
these criteria during the phone screen; those who meet exclusion criteria 7-11 in addition to those 
above will be included in the study as participants in Subgroup 1.  
All exclusion criteria will be established via participant self-report during the phone screen and 
confirmed during the clinical screen via interview at session 1. Medical records will also be reviewed 
prior to session 1, with participant’s verbal consent.  
Participant Compensation. Participants will be compensated for all steps of the study, consistent 
with previous research94, to encourage completion of all sessions and daily logs. Participants will receive 

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Protocol Title: Stress, Emotion Regulation, and Alcohol in Women Veterans 
 
12 
 
gift cards for participating in sessions 1-5 ($25 for sessions 1, 2, and 5, and $30 for in-
person/experimental sessions 3 and 4).  Additionally, they will receive $4 per day/ $2 for each of the two 
surveys for each of the 35 days they complete a daily log (for a total possible of $140) and a $25 “bonus” 
for completing all laboratory sessions. Thus, total compensation for completing all elements of the study 
is $300. Additionally, if a participant must drive 20 miles or more to get to the Leeds, Springfield, or 
Worcester Campus for sessions three and four, we will compensate them in the form of gas gift cards 
based on gas mileage up to 150 miles (75 miles one way) total. We will pay in increments of $5 at a rate 
of $0.13 per mile, based on the average price of gas and gas mileage. This compensation is applicable to 
participants driving a personal automobile to sessions.  
Measures 
Clinical Intake Interviews. Master’s or doctoral-level study staff will administer the Structured 
Clinical Interview for DSM-5 (SCID-5) to assess clinical diagnoses at session 1.  
Measures of Dependent Variables.  The Alcohol Craving Questionnaire96 will be used to assess 
alcohol craving, and the Alcohol Timeline Follow Back97 (TLFB) will assess frequency/quantity of drinking 
over the 45 days prior to study enrollment, and during the study period as described above. Daily Logs 
will be sent to participant’s mobile phones, via REDCap, for every morning and mid-day (10:00am and 
2:00pm) for 35 days. Participants will complete the daily logs electronically each of the 35 days during 
the longitudinal period. The 35-day period will begin on the first day of a participant’s menstrual cycle (if 
in the eFP group) or on the day of ovulation (if in the mLP group) in Subgroup 1, and any day after 
Session 1 for Subgroup 2. The morning survey will track: any alcohol use for the previous day, frequency 
and intensity of alcohol cravings, ovulation status, and stress level over the past 24 hours. The mid-day 
survey will track momentary stress level and contain the 10 item Positive Affect/ Negative Affect Scale 
(PANAS) to track emotions. To encourage completion of the daily logs, participants will be compensated 
$4 for each day of logs completed.  
Inhibitory Control, our main outcome measure which is a measure of behavioral impulsivity44 
(see conceptual model, Figure 1), will be assessed with a computerized task (a stop-signal task, STOP-
IT98). The STOP-IT presents a horizontal block arrow and requires participants to hit a button on the 
keyboard corresponding to the arrow’s direction. On 25% of trials, the arrow suddenly turns blue, 
representing a “stop” signal that is presented at varying times. When this stop signal is presented, 
participants must withhold their learned response of pressing the key in response to arrows. 
Participants’ stop signal reaction time (SSRT) reflects varying levels of inhibitory control (lower SSRT 
reflects better inhibitory control) 98.  Heart rate variability (HRV), our main outcome measure which is a 
physiological measure of arousal and shown to be a measure of stress reactivity 43 and impacted by 
successful emotion regulation 46, 47(see conceptual model, Figure 1), will be assessed with a Biopac 
MP160 data acquisition unit with an ECG amplifier that allows for the measurement of HRV. Biopac 
software AcqKnowledge assists with analysis and calculation of HRV.  
 

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Salivary Cortisol, Progesterone, and Estradiol will be collected via passive drool and kept in a -
20º freezer. This assessment procedure is minimally invasive. Participants will be given instructions in 
passive drool collection, and be directed to use disinfectant wipes to wipe down the outside of the 
tubes, place the tubes in a small clear specimen bag. Study staff will send the specimens using shipping 
materials and directions provided by Salimetrics. Analysis of all three hormone levels will be conducted 
at Salimetrics, LLC (https://salimetrics.com), an FDA-Registered company that provides salivary 
bioscience testing. Salimetrics provides all saliva collection materials and provides analyses of hormone 
levels. All analyses will be completed without identifying information, with samples labeled only with a 
bar code that corresponds to our own tracking of participant ID number and date/time of sample 
collection.  
 
Measures for Randomization and Moderating Factors: Depression and PTSD symptom severity 
will be assessed via Beck Depression Inventory101 and the PTSD Checklist for DSM-5 with Life Events 
checklist and Criterion A (PCL-5)102, respectively. The Adverse Childhood Experiences (ACE) 
Questionnaire will provide information pertinent to PTSD diagnosis and provide important descriptive 
information about the sample123. Addition of VA’s MST (military sexual trauma) screening questions will 
serve the same purpose – to provide a comprehensive overview of participants’ trauma exposure, and 
to investigate whether MST is associated with outcomes. Severity of AUD will be measured with the 
Alcohol Use Disorder Identification Test (AUDIT103), of which the first three questions represent the 
AUDIT-C which is used for study inclusion. The SCID PTSD, AUD, and Depression modules will also 
provide clinical interview data on the diagnostics and severity of these conditions. The other moderator, 
progesterone level, will be assessed via VA laboratory blood sample. Participants will provide a blood 
sample at the VACWM laboratory, where samples will be taken by trained phlebotomists.  The samples 
are refrigerated and sent to a nearby outside lab (Quest Diagnostics, Florence MA) for analysis. To help 
estimate menstrual cycle phase, participants will also take at-home daily urine tests which indicate the 
LH (luteinizing hormone) surge indicative of ovulation (i.e., transition to luteal phase of cycle) and will 
record the results on the daily log; lastly, participants will indicate on the logs if they have their menses 
each day.  
Baseline Measures/Assessing Independent Variables: Use of CR skills at baseline and during the 
study will be measured by the Emotion Regulation Questionnaire104.  
Cognitive Reappraisal (CR) Microintervention and Control Group (Behavioral Intervention): The 
CR microintervention (session 1) is drawn from Dr. David Barlow’s empirically supported treatment for 
emotional disorders (the Unified Protocol for Transdiagnostic Treatment of Emotional Disorders70). The 
microintervention lasts 45-60 minutes and consist of four sections: (1) Introduction to cognitive 
appraisal; (2) Introducing the idea of “thinking traps” that prevent reappraisal and maintain negative 
emotion; (3) Describing CR as a strategy that can help the participant “get out” of such thinking traps; (4) 
Providing an example of this process (situationÆ negative appraisalÆ negative emotionÆ thinking 
trapÆ opportunity for CR) and have participants provide a personalized example.  

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The manualized psychoeducational control microintervention, serving as an attentional control, 
is derived from two sources: 1. The first session of the Women’s Health Education Manual71, which 
provides psychoeducation about the basic body systems and their function, with focus on components 
of the immune system and 2. Fact sheets published by the American College of Obstetricians and 
Gynecologists(ACOG)72, providing female-specific facts about cancer and heart health. None of this 
psychoeducation discusses potential relevancy of alcohol use, nor will any behavior changes be 
suggested during the control microintervention. This psychoeducational microintervention also lasts 45-
60 minutes and provides the participant with information about women’s health. 
Debriefing/minimizing risk associated with emotion induction during experimental session (3 & 
4): Dr. Holzhauer was trained by Dr. Rajita Sinha at the Yale Stress Center, who developed the Imagery 
Script Development emotion induction technique that will be used in this study (Sinha & Tuit, 2012). Dr. 
Holzhauer was trained on the emotion induction procedures, including debriefing procedures for 
participants after the inducement of negative emotion and/or craving states. Dr. Sinha has used these 
procedures in multiple studies, including individuals with substance use disorders, co-occurring mental 
health conditions, and including PTSD. This methodology has also been used by other research groups 
with Veteran populations at the VA Connecticut Healthcare System74 – using both stress (negative 
emotion) and trauma scripts. The manualized procedure uses specific methodological strategies to 
minimize the risk for extreme discomfort. One strategy is that, when developing the personalized 
negative emotion script, participants are asked to provide an example that is stressful but not overly 
stressful. Participants are asked to use a negative emotion situation that is “highly stressful, but day-to-
day events that are fairly common in today’s world”. Any potentially traumatic experiences (i.e., 
experiences that are not experienced on a regular, day-to-day basis) are not allowed. Examples of not 
allowable events include any assault, interpersonal violence, serious car accident, military trauma, etc.  
If a participant begins to describe a potentially traumatic situation (again, defined as any situation that is 
not a typical, day-to-day experience), the manual indicates that the researcher should stop the 
participant and re-state the goal of the procedure – to describe an event that is day-to-day and fairly 
common in today’s world, and re-directs the participant to think of a situation that is less intense.  This 
minimizes the likelihood that a participant would become overwhelmed with discomfort.  A second 
strategy outlined in the manualized procedure is the debriefing that is conducted at the end of the 
session, to ensure that the participant feels comfortable proceeding with their day and is not in 
emotional distress. This strategy involves giving the participant 10 minutes, with instructions to relax 
and focus on deep breathing. After this time has passed, we will re-administer the PANAS (see attached 
self-reports) and compare to their baseline state to assess whether the participant has returned to a 
baseline emotional state. In addition, the researcher will ask the participant about their emotional state, 
and provide the option of additional relaxation/debriefing. If the participant is still feeling distressed or 
would like the additional relaxation, we will use the relaxation training from Sinha & Tuit’s manual (see 
attached), which will be recorded and walk the participant through progressive muscle relaxation (PMR). 
As suggested, these debriefing strategies have been used in previous studies from Dr. Sinha’s lab 
that evoke emotion or craving states. Extensive research using the emotion induction methodology that 

7.22.2022 
PI: Cathryn Holzhauer 
Protocol Title: Stress, Emotion Regulation, and Alcohol in Women Veterans 
 
15 
 
will be used in this study73 has used these same techniques for debriefing among participants with 
substance use disorders75 after a stress/negative emotion induction. Additionally, our previous study 
with 38 women Veterans has been using this induction technique without any clinical issues arising. 
Neither Dr. Sinha nor our own study have reported significant clinical issues resulting from the 
emotion/craving induction across their various studies. We would also like to note that half of the 
participants (i.e., those in the experimental condition) will receive an emotion regulation strategy 
microintervention (i.e., CR) that is known to down-regulate distress and discomfort at both sessions. In 
the case that a participant has gone through the full debriefing procedure and is still reporting distress 
(via PANAS and/or self-report), or in the event that a participant reports any suicidal intent during her 
participation in the study, Dr. Holzhauer will take the following steps to ensure participant safety: 1. 
Contact Dr. Holzhauer to notify the study PI of the situation; 2. Walk the participant to the Walk-in 
Mental Health Clinic; 3. In the case this Clinic is unavailable, Dr. Holzhauer will contact Dr. Henry Rivera, 
the Program Manager for Outpatient Mental Health for clinical consultation. In the case of a health care 
emergency, participants will be walked to the Urgent Care Clinic for evaluation. 
Power Analysis. See Table 1 for the effect sizes and required sample sizes, for all hypotheses. Note 
that the full sample (n=80, including participants from Subgroup 1 and 2) will be evaluable for 
Hypotheses 1a, 1b, and 2a. Data from participants in Subgroup 1 (n=40) will be used to examined 
hypotheses 2b and 2c.  
 
 
Hypothesis 1a. Past studies which have examined the effects of CR on participants’ cognitive 
control (specifically, attentional bias, which is highly associated with inhibitory control)113, cigarette 
craving107, and physiological reactivity (specifically, electromyography and skin conductance)74, to a 
control group, are used to guide the study’s power analysis. While these effect sizes ranged between .09 
and .51, the high correlation between repeated measures and use of multiple measurements (2 groups 
tested across 3 measurement time points) provided estimated required samples between 4 and 12 
participants, to have sufficient power to answer Hypothesis 1a.  
 
Hypothesis 1b: This hypothesis examines the effects of CR and EA on drinking behavior over the 
course of 35 days. Table 1 shows effect sizes from a previous study94 by study consultant Dr. Simpson, 
which informed the proposed study’s methodology; the effect sizes shown in Table 1 reflect the effect 
of CR on percent days abstinent during a longitudinal period.  
 
Hypothesis 2a. While there is no research to guide our power analyses about the moderating 
effect of PTSD symptom severity on the efficacy of CR and EA, data from my VISN 1 pilot project 
provided estimated effect sizes of the interaction/moderation term (condition – CR/control – by PTSD 
symptom severity on craving and inhibitory control). Again, while these effect sizes were small, the high 
correlation between repeated measures and use of multiple measurements provided estimated 
required samples between 36 and 48 participants.  
 

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Hypothesis 2b: A previous study114 examined inhibitory control (stop signal reaction time/SSRT 
on the stop signal task, the same outcome as in the proposed study) across the follicular, luteal, and 
menstrual phases, finding longer SSRT or poorer inhibitory control in the follicular phase compared to 
the other phases. Hypothesis 2b focuses on the moderating effect of progesterone on CR, comparing 
reactivity in two phases of the menstrual cycle (eFP and mLP). The estimated effect size, shown in Table 
1, yielded a required sample of 10 women to obtain sufficient power. An additional study115 examined 
reactivity to stress and cigarette cues across the menstrual cycle among women; although estimated 
effect sizes were not provided, their total sample size was 37.  
 
Hypothesis 2c. There is a lack of research that examines the association between progesterone 
levels and PTSD symptom severity, and their relative association with any of our outcome variables. 
Therefore, this hypothesis is exploratory and will provide data for future power analyses. 
 
 

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Table 1. Power Table, by Aim & Hypothesis 
Aim & Cited Study Providing Effect Size for 
each outcome measure 
Estimated Effect 
Size 
Required n 
power=.80 
Aim 1 
1a. Main Effect of Condition on:  
 
 
        Inhibitory Control113 
η2p =.11 
12 
        Craving107  
η2p =.09 
8 
        HRV74 
η2p =.51 
4 
1b. Main effect of condition on longitudinal 
alcohol use94 
d = .78 
10 
Aim 2 
2a. Interaction Effect of Condition * PTSD on:  
 
 
        Inhibitory Control (VISN 1 CDA Pilot Data)  
η2p =.025 
48 
        Craving (VISN 1 CDA Pilot Data) 
η2p =.017 
36 
2b. Inhibitory Control in mLP v. eFP114 
η2p = .19 
10 
Note: η2p = Partial eta squared; d = Cohen’s d; Condition = Cognitive Reappraisal versus Control 
Group Effects; mLP = mid-luteal phase; eFP = early follicular phase 
 
In sum, as can be seen in Table 1, the largest required sample size would be to examine the 
moderating effect of PTSD symptom severity on the effect of the emotion regulation strategies on 
inhibitory control (Hypothesis 2a). The required sample sizes for this hypothesis were generated with 
alpha at .05, two groups and three time points, for a repeated measures ANOVA testing within (time) x 
between (condition) interaction, and the estimated effect size of the interaction term on the inhibitory 
control/SSRT outcome measure. The analysis indicated the required total sample size was 48, providing 
actual power of 0.80. Study consultant Dr. Pineles completed a study with similar methods19, with 
women across the menstrual cycle; of the 62 women who consented to the study, 51 completed study 
procedures (completion rate = 82%). We will consent 80 women, across Subgroups 1 and 2, to account 
for attrition or other difficulties related to the study procedures. 40 women will provide sufficient power 
to examine Hypotheses 2b and explore 2c.  
 
Data Collection, Storage, and Security 
Each participant will be assigned a subject number upon entry into the study, and all 
measures/records will be tracked using only this number. Most data (with the exception of inhibitory 
control task/STOP-IT performance, HRV/physiology measures, and REDCap Daily Log Surveys) will be 
collected via hard copy and will be promptly entered into a Microsoft excel electronic database. Data 
from the inhibitory control task, as well as data collected from the BIOPAC physiology monitor, will be 
temporarily stored on the PI's laptop computer, which has been approved and secured by the VA, as the 
task records results directly onto the hard drive of the computer. This data that is temporarily stored on 
the hard drive is NOT identified by any personally identifiable information, however, and only by 
participant study ID number. At the end of the day, this data from the inhibitory control task and 

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physiological data will be transferred to the Research drive with the rest of the data and compiled into a 
Microsoft Excel electronic database. The data from this task is via computer, so the original data form is 
electronic. Progesterone and Estradiol levels collected by the VACWM laboratory will be entered into 
the patients' medical records as clinical data. The hormone level values will be entered into the data 
spreadsheet on the VA network by study staff after looking them up in medical records.      
Cardiac activity is collected from a BIOPAC EKG monitor and BIOPAC’s software, Acqknowledge, 
is used to generate Heart Rate Variability (HRV) values. The cardiac data that is collected is identified 
only by a study ID number, with no identifying information (e.g. no participant age, name, initials, date 
of birth, etc.) “attached” or indicated. The cardiac data is fully deidentified by the assignation of a 
separate HRV ID number. The HRV ID and study ID number will be paired only in a database that is 
password protected.  The output data file from BIOPAC is an EKG waveform datafile, which is then used 
by software to generate output values such as HRV. These de-identified data files will be analyzed by a 
non-VA collaborator, Dr. Nnamdi Pole, at Smith College (Northampton, MA). Dr. Pole is a Professor of 
Psychology and IRB committee Chair there in 2022-2023. He is an expert in trauma and 
psychophysiological response to stress. He is collaborating with our VA team to clean, analyze, and 
publish physiological data from the current study. The files sent to him for analysis, again, are 
completely de-identified. Furthermore, the files will be saved on private USB drives and can only be 
viewed in combination with the BIOPAC-provided USB “key”. Dr. Pole’s lab will use the BIOPAC USB key 
and de-identified EKG files to clean and analyze data, generate output variables, and return to our lab. 
The data will then be uploaded to the VA network and entered into our master database.  
In order to confidentially send the daily questionnaires to participants’ phones, we will use the 
secure REDCap account of our academic affiliate, University of Massachusetts Medical School, to collect 
data. The participant’s cell phone number will be entered into REDCap in order to send them the links to 
the surveys, however the actual surveys will not collect any identifying information. Additionally, when 
the database of collected data is generated, their cell phone numbers will not be included – therefore, 
that identifying information of their phone number will not be associated with their data (which is all 
numerical anyway; i.e., meaningless to anyone who does not have the survey questions and survey 
response labels). Participants will be assigned a separate ID number for their REDCap data, that will be 
merged later, within the VA network, to their other non REDCap data. No other personally identifying 
information will be collected via REDCap. Mobile devices will be used by participants to self-report on 
urge to drink, mood, and stress level. If participants lose their smartphone, they will be at no excess risk 
of their identity or highly sensitive information being revealed to individuals outside of the study. (In 
other words, because they are not completing hard-copy surveys and only completing surveys through a 
survey link, their answers to survey questions are only accessible to the study team with access to 
REDCap).  Also, mobile surveys will use a multiple-choice format and participants will not be asked to 
enter any responses as free text. This eliminates the participant’s ability to enter any responses that 
could be used to identify them. For example, participants will be asked to respond to how much they are 
craving from 0 – not at all to 7- extremely and data will be recorded only as a numerical response.  
Personal identifiers (name & phone number) will be obtained at study screening, however this 
information will be kept in a separate electronic folder from the participants’ other information (e.g., 

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Protocol Title: Stress, Emotion Regulation, and Alcohol in Women Veterans 
 
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their self-report measures/clinical interviews) which will only be identified by their participant number. 
All electronic data will be kept on the secure VA research network 
(\\R04NHMNAS21.v01.med.va.gov\Research\Other PI Projects\Holzhauer\). The hard copy data 
(identified by participant number only) will be kept in locked drawers which will be in locked, secure 
offices within Building 12, Room 112 at the Northampton VA. Hard-copy consent and HIPAA forms with 
participant signatures (and without study ID number) will also be kept in the team's offices in locked 
drawers, separate from the de-identified study data which will be labeled only with study ID number. A 
suspected or confirmed loss of VA information will immediately be reported via email to the Study 
Investigators, Privacy Officer, Information System Security Officer, IRB and the VACWM research office. 
A copy of all research records will be retained at VACWM research department according to VA 
policies and procedures. Research data will be destroyed 6 years after the end of the FY in which the 
study is completed as required by VHA regulations and RCS-10-1. 
 
In order to reduce travel burden on participants that live further away from our main site on the 
Leeds or Worcester VACWM campus, we will provide the option for participants who choose to 
complete sessions in-person to complete their study sessions at one additional VACWM CBOCs 
(Springfield). This is offered as an alternative to at-home or virtual sessions.  The study staff who run the 
session will transport session data (i.e., hard copy self-reports and interviews) that participants 
complete back to Northampton so it can be stored with all the other study data in the research study 
office. Forms that are collected and transported will only have a participant study identification number 
on them, with the exception of the study consent form and HIPAA for session 1 (which will not have 
their study ID on them). Thus, documents with sensitive personal information will only be labeled with a 
study ID number and no participant personally identifiable information such as name or personal 
address. An inventory of the documents will be made before the transport is initiated. The consent and 
HIPAA forms will be transported in a bank bag in the trunk of a locked vehicle. The documents will be 
kept with the staff at all times during transport from Worcester to Leeds and immediately placed in 
locked cabinets after transport. 
 
Data analyses by hypothesis 
 
We will first conduct descriptive analyses and examine the distributions of all outcome 
variables, to identify any non-normal variables or other issues related to distribution. Numeric 
transformations will be performed on continuous variables to symmetrize distributions as needed. 
Missing data will also be identified and accounted for (see below).  
 
Hypothesis 1a. Effect of Cognitive Reappraisal (CR) versus control (psychoeducation) on alcohol 
craving, inhibitory control, and HRV in experimental sessions: Repeated Measures ANOVA will be 
conducted to examine the effect of CR versus control on these outcomes. Given that women will be urn 
randomized into either the CR or control condition, we do not anticipate significant differences between 
groups in terms of alcohol use, AUD severity, or PTSD severity (or other relevant variables). However, we 
will test for equivalence between groups on baseline measures prior to analyses and control for any 

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differences that may be found. The RM ANOVA will test the between-person main effects of condition 
(CR v. control) and within-person change in our outcome variables which are continuous variables 
(craving, inhibitory control, and HRV) across the three study time points (baseline, after the stressor, and 
after using CR or sitting quietly) during the lab session. For these analyses, we will use laboratory data 
from the eFP/Session 1 session, controlling for randomization to “start group” (eFP v. mLP start group). 
If a condition by time effect is found, post-hoc tests will be conducted to examine the time period(s) at 
which significant differences occur. 
Hypothesis 1b. Effect of CR versus control on daily alcohol use: This hypothesis will be tested 
using mixed effects or multilevel modeling (MLM) to examine within-person effects, between-person 
effects, and interactions of within- and between-person effects on stress-induced alcohol use across the 
35-day daily log portion of the study. These effects will be assessed according to the following MLM 
equations:  
x 
Within-person effects (Level 1): 
Drinkingij = β0 + β1*stress 
x 
Between-person effects (Level 2): 
β0= γ00 + γ01*CRj + u0 
β1 = γ10 + γ11*CRj + u1 
 
In these multi-level equations, within-person effects of stress on drinking are modeled at level 1 
across the 35 days. At level 2, between-person differences in daily drinking are modeled in the β0 
equation, where u0 represents variability in daily drinking, γ00 represents daily drinking for the control 
group, and γ01 represents the difference in daily drinking for the CR group. The β1 equation tests the 
association between stress and drinking. Here, u1 models the variability in the stress-drinking association 
across participants, γ10 represents the strength of this association for the control group, and γ11 
represents the difference in this association for the intervention (CR) group. Our hypothesis is that the 
CR microintervention group will have a significantly lower stress-drinking association than the control 
group. 
Drinking will be operationalized in two ways: (1) the above model will be tested using a binary 
outcome reflecting drinking vs. not drinking on each day, using a binomial (Bernoulli) distribution MLM; 
(2) drinking will also be modeled as a count outcome, using a negative binomial or Poisson MLM, 
depending on the distributional properties found in drinks per day variable and testing for potential 
over-dispersion.  
Hypothesis 2a. PTSD will moderate the association between condition and outcome measures: 
The moderating effect of PTSD on the effect of CR will be examined using experimental session data as 
well as longitudinal drinking data. To examine whether PTSD moderates the effect of CR on alcohol 
craving, inhibitory control, and/or HRV in the lab, we will conduct the RM ANOVA as described for 
Hypothesis 1a; however, we will enter a dichotomized PTSD variable as a third factor, and an interaction 
term of condition (CR/control) by PTSD to examine the moderating effect. Similarly, PTSD severity will be 
entered as an additional, Level 2 between-person main effect in the MLM equation described in 
Hypothesis 1b, along with the interaction of PTSD and treatment condition.  

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Hypothesis 2b. Progesterone will moderate the association between condition and outcome 
measures: Whether progesterone levels moderate the effect of CR on alcohol craving, inhibitory control, 
and HRV in the experimental sessions will be assessed, given that hormone assays will occur at the time 
of these in-person sessions. Progesterone level will be added to the RM ANOVA models described in 
Hypothesis 1a, and the interaction of progesterone level (low/high) and condition (CR/Control) will be 
tested to determine whether CR more effectively regulates stress-modulated craving, inhibitory control, 
and/or HRV when progesterone levels are low.  
 
Hypothesis 2c (Exploratory). Explore the association between the two moderators, progesterone 
levels and PTSD severity, and their relative association with stress-induced drinking: Given that this 
hypothesis is exploratory, we will first use simple statistical analyses to examine the correlation between 
PTSD severity and progesterone levels during the eFP and mLP of the menstrual cycle. We will 
additionally conduct regression analyses to compare the relative strength of statistical prediction of 
each of these two variables, entered within the same regression equations, on the change in craving, 
inhibitory control, and HRV in response to stress in the lab. These analyses will provide initial data on 
whether PTSD severity and progesterone levels are associated, and the extent to which they may have 
separate or interactive effects on alcohol-related outcomes and behavioral control. 
 
6. 
References 
 
1. Mankowski, M., Tower, L. E., Brandt, C. A., et al. (2015). Why women join the military: 
Enlistment decisions and postdeployment experiences of service members and veterans. 
Social work, 60(4), 315-323.  
2. Sinha, R., & Tuit, K. (2012). Imagery script development procedures manual. Charleston, SC: 
CreateSpace.  
3. United States Department of Veteran Affairs (2015). National center for veterans analysis and 
statistics [Press release] 
https://www.va.gov/vetdata/docs/SpecialReports/Final_Womens_Report_3_2_12_v_7.pdf 
4. Hoggatt, K. J., Jamison, A. L., Lehavot, K., et al. (2015). Alcohol and drug misuse, abuse, 
and dependence in women veterans. Epidemiologic reviews, 37(1), 23-37.  
5. Evans, E. A., Upchurch, D. M., Simpson, T., et al. (2018). Differences by Veteran/civilian 
status and gender in associations between childhood adversity and alcohol and drug use 
disorders. Social psychiatry and psychiatric epidemiology, 53(4), 421-435.  
6. Grossbard, J. R., Hawkins, E. J., Lapham, G. T., et al. (2013). Follow-up care for alcohol 
misuse among OEF/OIF veterans with and without alcohol use disorders and posttraumatic 
stress disorder. Journal of substance abuse treatment, 45(5), 409-415.  
7. Karpyak, V. M., Biernacka, J. M., Geske, J. R., et al. (2016). Gender-specific effects of 
comorbid depression and anxiety on the propensity to drink in negative emotional states. 
Addiction, 111(8), 1366-1375.  
8. Mushquash, A. R., Stewart, S. H., Sherry, S. B., et al. (2013). Depressive symptoms are a 
vulnerability factor for heavy episodic drinking: a short-term, four-wave longitudinal study of 
undergraduate women. Addict Behav, 38(5), 2180-2186. doi:10.1016/j.addbeh.2012.11.008 
9. Nolen-Hoeksema, S., & Hilt, L. (2006). Possible contributors to the gender differences in 
alcohol use and problems. The Journal of general psychology, 133(4), 357-374.  

7.22.2022 
PI: Cathryn Holzhauer 
Protocol Title: Stress, Emotion Regulation, and Alcohol in Women Veterans 
 
22 
 
10. Rubonis, A. V., Colby, S. M., Monti, P. M., et al. (1994). Alcohol cue reactivity and mood 
induction in male and female alcoholics. Journal of studies on alcohol, 55(4), 487-494.  
11. Larimer, M. E., & Palmer, R. S. (1999). Relapse prevention: An overview of Marlatt's 
cognitive-behavioral model. Alcohol research and Health, 23(2), 151-160.  
12. Scholz, U., La Marca, R., Nater, U. M., et al. (2009). Go no-go performance under 
psychosocial stress: beneficial effects of implementation intentions. Neurobiology of learning 
and memory, 91(1), 89-92.  
13. Hartmann, L., Sallard, E., & Spierer, L. (2015). Enhancing frontal top-down inhibitory control 
with Go/NoGo training. Brain Structure & Function, 12. doi:http://dx.doi.org/10.1007/s00429-
015-1131-7 
14. Fox, H. C., Sofuoglu, M., Morgan, P. T., et al. (2013). The effects of exogenous 
progesterone on drug craving and stress arousal in cocaine dependence: impact of gender 
and cue type. Psychoneuroendocrinology, 38(9), 1532-1544.  
15. Rasmusson, A. M., Pinna, G., Paliwal, P., et al. (2006). Decreased cerebrospinal fluid 
allopregnanolone levels in women with posttraumatic stress disorder. Biological psychiatry, 
60(7), 704-713.  
16. Epstein, E., Rhines, K., Cook, S., et al. (2006). Changes in alcohol craving and consumption 
by phase of menstrual cycle in alcohol dependent women. Journal of Substance Use, 11(5), 
323-332.  
17. Holzhauer, C. G., Wemm, S.E., Wulfert, E., & Cao, Z. . (under review). Fluctuations in 
progesterone moderate the relationship between daily mood and alchol use in young adult 
women.  
18. Sripada, R. K., Marx, C. E., King, A. P., et al. (2013). Allopregnanolone elevations following 
pregnenolone administration are associated with enhanced activation of emotion regulation 
neurocircuits. Biological psychiatry, 73(11), 1045-1053.  
19. Pineles, S., Nillni, Y., Pinna, G., et al. (2018). PTSD in women is associated with a block in 
conversion of progesterone to the GABAergic neurosteroids allopregnanolone and 
pregnanolone measured in plasma. Psychoneuroendocrinology, 93, 133-141.  
20. Timko, C., Hoggatt, K. J., Wu, F. M., et al. (2017). Substance Use Disorder Treatment 
Services for Women in the Veterans Health Administration. Women's Health Issues, 27(6), 
639-645.  
21. Davis, T. M., Bush, K. R., Kivlahan, D. R., et al. (2003). Screening for substance abuse and 
psychiatric disorders among women patients in a VA health care system. Psychiatric services, 
54(2), 214-218.  
22. Bradley, K. A., Bush, K. R., Davis, T. M., et al. (2001). Binge drinking among female 
Veterans Affairs patients: prevalence and associated risks. Psychology of Addictive Behaviors, 
15(4), 297.  
23. Lande, R. G., Marin, B. A., Chang, A. S., et al. (2007). Gender differences and alcohol use 
in the US Army. Journal of the American Osteopathic Association, 107(9), 401.  
24. Kay, A., Taylor, T. E., Barthwell, A. G., et al. (2010). Substance use and women's health. 
Journal of Addictive Diseases, 29(2), 139-163.  
25. Evans, E. A., Upchurch, D. M., Simpson, T., et al. (2017). Differences by Veteran/civilian 
status and gender in associations between childhood adversity and alcohol and drug use 
disorders. Social psychiatry and psychiatric epidemiology, 1-15.  
26. Hammerslag, L. R., & Gulley, J. M. (2016). Sex differences in behavior and neural 
development and their role in adolescent vulnerability to substance use. Behavioural brain 
research, 298, 15-26.  
27. Gross, J. J., & Jazaieri, H. (2014). Emotion, emotion regulation, and psychopathology: An 
affective science perspective. Clinical Psychological Science, 2(4), 387-401.  

7.22.2022 
PI: Cathryn Holzhauer 
Protocol Title: Stress, Emotion Regulation, and Alcohol in Women Veterans 
 
23 
 
28. Lehavot, K., & Simpson, T. L. (2014). Trauma, posttraumatic stress disorder, and 
depression among sexual minority and heterosexual women veterans. J Couns Psychol, 
61(3), 392-403. doi:10.1037/cou0000019 
29. Potenza, M. N., Hong, K.-i. A., Lacadie, C. M., et al. (2012). Neural correlates of stress-
induced and cue-induced drug craving: influences of sex and cocaine dependence. American 
Journal of Psychiatry, 169(4), 406-414.  
30. Levahot, K., & Simpson, T.L. (2014). Trauma, posttraumatic stress disorder, and depression 
among sexual minority and heterosexual women veterans. Journal of Counseling Psychology, 
61(3), 392-403.  
31. Westphal, M., Aldao, A., & Jackson, C. (2017). Emotion dysregulation in comorbid 
posttraumatic stress disorder and substance use disorders: A narrative review. Military 
Psychology, 29(3), 216-233.  
32. Weiss, N. H., Sullivan, T. P., & Tull, M. T. (2015). Explicating the role of emotion 
dysregulation in risky behaviors: A review and synthesis of the literature with directions for 
future research and clinical practice. Current opinion in psychology, 3, 22-29.  
33. Moeller, F. G. (2012). Sex, stress, and drug cues in addiction: Am Psychiatric Assoc. 
34. Barlow, D. H., Ellard, K.K., Fairholme, C.P., Farchione, T.J., Boisseau, C.L., Allen, L.B., & 
Ehrenreich-May, J.T. . (2011). Unified Protocol for Transdiagnostic Treatment of Emotional 
Disorders. New York, NY: Oxford University Press. 
35. DeMarce, J. M., Gnys, M., Raffa, S.D., & Karlin, B.E. (2014). Cognitive Behavioral Therapy 
for Substance Use Disorders Among Veterans: Therapist Manual. Washington, DC: U.S. 
Department of Veterans Affairs. 
36. Epstein, E. E., McCrady, B. S., Hallgren, K. A., et al. (2018). Individual versus group female-
specific cognitive behavior therapy for alcohol use disorder. Journal of substance abuse 
treatment, 88, 27-43.  
37. Kranzler, H. R., & McKay, J. R. (2012). Personalized treatment of alcohol dependence. 
Current psychiatry reports, 14(5), 486-493.  
38. Epstein, E. E., & Menges, D. (2013). Women and addiction.  
39. Greenfield, S. F., & Grella, C. E. (2009). Alcohol & Drug Abuse: What Is" Women-Focused" 
Treatment for Substance Use Disorders? Psychiatric services, 60(7), 880-882.  
40. Gross, J. J. (2001). Emotion regulation in adulthood: Timing is everything. Current directions 
in psychological science, 10(6), 214-219.  
41. Gross, J. J. (1998). The emerging field of emotion regulation: an integrative review. Review 
of general psychology, 2(3), 271.  
42. Buckman, J. F., Vaschillo, E. G., Fonoberova, M., et al. (2018). The translational value of 
psychophysiology methods and mechanisms: Multilevel, dynamic, personalized. Journal of 
studies on alcohol and drugs, 79(2), 229-238.  
43. Thayer, J. F., Åhs, F., Fredrikson, M., et al. (2012). A meta-analysis of heart rate variability 
and neuroimaging studies: implications for heart rate variability as a marker of stress and 
health. Neuroscience & Biobehavioral Reviews, 36(2), 747-756.  
44. Weafer, J., De Arcangelis, J., & de Wit, H. (2015). Sex differences in behavioral impulsivity 
in at-risk and non-risk drinkers. Front Psychiatry, 6, 72. doi:10.3389/fpsyt.2015.00072 
45. Muraven, M., & Baumeister, R. F. (2000). Self-regulation and depletion of limited resources: 
Does self-control resemble a muscle? Psychological bulletin, 126(2), 247.  
46. Ingjaldsson, J. T., Laberg, J. C., & Thayer, J. F. (2003). Reduced heart rate variability in 
chronic alcohol abuse: relationship with negative mood, chronic thought suppression, and 
compulsive drinking. Biological psychiatry, 54(12), 1427-1436.  
47. Butler, E. A., Wilhelm, F. H., & Gross, J. J. (2006). Respiratory sinus arrhythmia, emotion, 
and emotion regulation during social interaction. Psychophysiology, 43(6), 612-622.  

7.22.2022 
PI: Cathryn Holzhauer 
Protocol Title: Stress, Emotion Regulation, and Alcohol in Women Veterans 
 
24 
 
48. Eddie, D., Kim, C., Lehrer, P., et al. (2014). A pilot study of brief heart rate variability 
biofeedback to reduce craving in young adult men receiving inpatient treatment for substance 
use disorders. Applied psychophysiology and biofeedback, 39(3-4), 181-192.  
49. Roos, C. R., & Witkiewitz, K. (2017). A contextual model of self-regulation change 
mechanisms among individuals with addictive disorders. Clinical psychology review, 57, 117-
128.  
50. Pineles, S. L., Suvak, M. K., Liverant, G. I., et al. (2013). Psychophysiologic reactivity, 
subjective distress, and their associations with PTSD diagnosis. Journal of abnormal 
psychology, 122(3), 635.  
51. Stephens, M. A. C., Mahon, P. B., McCaul, M. E., et al. (2016). Hypothalamic–pituitary–
adrenal axis response to acute psychosocial stress: effects of biological sex and circulating 
sex hormones. Psychoneuroendocrinology, 66, 47-55.  
52. Klemanski, D. H., Mennin, D. S., Borelli, J. L., et al. (2012). Emotion-related regulatory 
difficulties contribute to negative psychological outcomes in active-duty Iraq war soldiers with 
and without posttraumatic stress disorder. Depression and Anxiety, 29(7), 621-628. 
doi:http://dx.doi.org/10.1002/da.21914 
53. Hien, D. A., Cohen, L. R., Miele, G. M., et al. (2004). Promising treatments for women with 
comorbid PTSD and substance use disorders. American Journal of Psychiatry, 161(8), 1426-
1432.  
54. Bradizza, C. M., Stasiewicz, P. R., & Paas, N. D. (2006). Relapse to alcohol and drug use 
among individuals diagnosed with co-occurring mental health and substance use disorders: a 
review. Clinical psychology review, 26(2), 162-178.  
55. Ouimette, P. C., Finney, J. W., & Moos, R. H. (1999). Two-year posttreatment functioning 
and coping of substance abuse patients with posttraumatic stress disorder. Psychology of 
Addictive Behaviors, 13(2), 105.  
56. Hien, D. A., Lopez-Castro, T., Papini, S., et al. (2017). Emotion dysregulation moderates the 
effect of cognitive behavior therapy with prolonged exposure for co-occurring PTSD and 
substance use disorders. Journal of anxiety disorders, 52, 53-61.  
57. Fitzgerald, J. M., Digangi, J. A., & Phan, K. L. (2018). Functional neuroanatomy of emotion 
and its regulation in PTSD. Harvard review of psychiatry, 26(3), 116-128.  
58. Weiss, N. H., Tull, M. T., Viana, A. G., et al. (2012). Impulsive behaviors as an emotion 
regulation strategy: examining associations between PTSD, emotion dysregulation, and 
impulsive behaviors among substance dependent inpatients. Journal of Anxiety Disorders, 
26(3), 453-458. doi:http://dx.doi.org/10.1016/j.janxdis.2012.01.007 
59. Fairholme, C. P., Nosen, E. L., Nillni, Y. I., et al. (2013). Sleep disturbance and emotion 
dysregulation as transdiagnostic processes in a comorbid sample. Behaviour Research & 
Therapy, 51(9), 540-546. doi:http://dx.doi.org/10.1016/j.brat.2013.05.014 
60. Kashdan, T. B., Breen, W. E., & Julian, T. (2010). Everyday strivings in war veterans with 
posttraumatic stress disorder: Suffering from a hyper-focus on avoidance and emotion 
regulation. Behavior Therapy, 41(3), 350-363. doi:http://dx.doi.org/10.1016/j.beth.2009.09.003 
61. Farage, M. A., Osborn, T. W., & MacLean, A. B. (2008). Cognitive, sensory, and emotional 
changes associated with the menstrual cycle: a review. Archives of gynecology and obstetrics, 
278(4), 299.  
62. Carroll, H. A., Lustyk, M. K. B., & Larimer, M. E. (2015). The relationship between alcohol 
consumption and menstrual cycle: a review of the literature. Archives of women's mental 
health, 18(6), 773-781.  
63. Roca, C. A., Schmidt, P. J., Altemus, M., et al. (2003). Differential menstrual cycle regulation 
of hypothalamic-pituitary-adrenal axis in women with premenstrual syndrome and controls. 
The Journal of Clinical Endocrinology & Metabolism, 88(7), 3057-3063.  

7.22.2022 
PI: Cathryn Holzhauer 
Protocol Title: Stress, Emotion Regulation, and Alcohol in Women Veterans 
 
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64. Hantsoo, L., & Epperson, C. N. (2015). Premenstrual dysphoric disorder: epidemiology and 
treatment. Current psychiatry reports, 17(11), 87.  
65. Hudson, A., & Stamp, J. A. (2011). Ovarian hormones and propensity to drug relapse: a 
review. Neuroscience & Biobehavioral Reviews, 35(3), 427-436.  
66. Weiss, N. H., Tull, M. T., Viana, A. G., et al. (2012). Impulsive behaviors as an emotion 
regulation strategy: Examining associations between PTSD, emotion dysregulation, and 
impulsive behaviors among substance dependent inpatients. Journal of anxiety disorders, 
26(3), 453-458.  
67. Mello, N. K., Mendelson, J. H., & Lex, B. W. (1990). Alcohol use and premenstrual 
symptoms in social drinkers. Psychopharmacology, 101(4), 448-455.  
68. Joyce, K. M., Hudson, A., O'connor, R., et al. (2018). Changes in coping and social motives 
for drinking and alcohol consumption across the menstrual cycle. Depression and anxiety, 
35(4), 313-320.  
69. Holzhauer, C. G., Wemm, S.E., Wulfert, E., & Cao, Z. . (under review). Fluctuations in 
progesterone moderate the relationship between daily mood and alcohol use in young adult 
women.  
70. Martel, M. M., Eisenlohr-Moul, T., & Roberts, B. (2017). Interactive effects of ovarian steroid 
hormones on alcohol use and binge drinking across the menstrual cycle. Journal of abnormal 
psychology, 126(8), 1104.  
71. Evans, S. M., & Foltin, R. W. (2006). Exogenous progesterone attenuates the subjective 
effects of smoked cocaine in women, but not in men. Neuropsychopharmacology, 31(3), 659.  
72. Sofuoglu, M., Mouratidis, M., & Mooney, M. (2011). Progesterone improves cognitive 
performance and attenuates smoking urges in abstinent smokers. Psychoneuroendocrinology, 
36(1), 123-132.  
73. Longabaugh, R., Donovan, D. M., Karno, M. P., et al. (2005). Active ingredients: how and 
why evidence-based alcohol behavioral treatment interventions work. Alcoholism: Clinical & 
Experimental Research, 29(2), 235-247.  
74. Wolgast, M., Lundh, L.-G., & Viborg, G. (2011). Cognitive reappraisal and acceptance: An 
experimental comparison of two emotion regulation strategies. Behaviour research and 
therapy, 49(12), 858-866.  
75. Carpenter, K. M., & Hasin, D. S. (1999). Drinking to cope with negative affect and DSM-IV 
alcohol use disorders: a test of three alternative explanations. Journal of studies on alcohol, 
60(5), 694-704.  
76. Sofuoglu, M., Mitchell, E., & Mooney, M. (2009). Progesterone effects on subjective and 
physiological responses to intravenous nicotine in male and female smokers. Human 
Psychopharmacology: Clinical and Experimental, 24(7), 559-564.  
77. Mattocks, K. M., Haskell, S. G., Krebs, E. E., et al. (2012). Women at war: Understanding 
how women veterans cope with combat and military sexual trauma. Social science & 
medicine, 74(4), 537-545.  
78. Brady, K. T., & Sonne, S. C. (1999). The role of stress in alcohol use, alcoholism treatment, 
and relapse. Alcohol Research, 23(4), 263.  
79. Allen, S. S., Allen, A. M., Lunos, S., et al. (2009). Patterns of self-selected smoking 
cessation attempts and relapse by menstrual phase. Addictive Behaviors, 34(11), 928-931.  
80. Mendle, J., Eisenlohr-Moul, T., & Kiesner, J. (2016). From menarche to menopause: 
women’s reproductive milestones and risk for psychopathology—an introduction to the special 
series. Clinical Psychological Science, 4(5), 859-866.  
81. Baca-Garcia, E., Diaz-Sastre, C., Ceverino, A., et al. (2010). Suicide attempts among 
women during low estradiol/low progesterone states. Journal of psychiatric research, 44(4), 
209-214.  

7.22.2022 
PI: Cathryn Holzhauer 
Protocol Title: Stress, Emotion Regulation, and Alcohol in Women Veterans 
 
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82. Allen, S. S., Allen, A. M., Lunos, S., et al. (2016). Progesterone and postpartum smoking 
relapse: a pilot double-blind placebo-controlled randomized trial. Nicotine & Tobacco 
Research, 18(11), 2145-2153.  
83. Huebner, R. B., & Tonigan, J. S. (2007). The search for mechanisms of behavior change in 
evidence-based behavioral treatments for alcohol use disorders: overview. Alcoholism: Clinical 
and Experimental Research, 31, 1s-3s.  
84. Longabaugh, R. (2007). The search for mechanisms of change in behavioral treatments for 
alcohol use disorders: A commentary. Alcoholism: Clinical and Experimental Research, 31, 
21s-32s.  
85. Strauman, T. J., Goetz, E. L., Detloff, A. M., et al. (2013). Self-regulation and mechanisms of 
action in psychotherapy: A theory-based translational perspective. Journal of personality, 
81(6), 542-553.  
86. Yonkers, K. A., Forray, A., Nich, C., et al. (2014). Progesterone for the reduction of cocaine 
use in post-partum women with a cocaine use disorder: a randomised, double-blind, placebo-
controlled, pilot study. The Lancet Psychiatry, 1(5), 360-367.  
87. Holzhauer, C. G., & Gamble, S. A. (2017). Depressive Symptoms Mediate the Relationship 
Between Changes in Emotion Regulation During Treatment and Abstinence Among Women 
With Alcohol Use Disorders.  
88. Holzhauer, C. G., Epstein, E.E., Hayaki, J., Marinchak, J.S., McCrady, B.S., & Cook, S.M. 
(2016). Moderators of sudden gains after sessions addressing comorbidity in CBT treatment 
for women with alcohol use disorders. Paper presented at the Association for Behavioral and 
Cognitive Therapies, New York, NY.  
89. Epstein, E. E., McCrady, B. S., Hallgren, K. A., et al. (2018). A randomized trial of female-
specific cognitive behavior therapy for alcohol dependent women. Psychology of Addictive 
Behaviors, 32(1), 1.  
90. Hayaki, J., Epstein, E.E., Holzhauer, C.G., Cook, S., Lorenzo, A.C., Gaba, A., & McCrady, 
B.S. . (under review). Menstrual Phase, Alcohol Consumption, and Alcohol Cravings 
Among Treatment Seeking Women.  
91. Chavez, L. J., Williams, E. C., Lapham, G., et al. (2012). Association between alcohol 
screening scores and alcohol-related risks among female Veterans Affairs patients. Journal of 
studies on alcohol and drugs, 73(3), 391-400.  
92. Stout, R. L., Wirtz, P. W., Carbonari, J. P., et al. (1994). Ensuring balanced distribution of 
prognostic factors in treatment outcome research. Journal of Studies on Alcohol, 
supplement(12), 70-75.  
93. Sinha, R. T., K.L. (2012). Imagery Script Development Procedures. New Haven, CT: Yale 
University School of Medicine. 
94. Stappenbeck, C. A., Luterek, J. A., Kaysen, D., et al. (2015). A controlled examination of two 
coping skills for daily alcohol use and PTSD symptom severity among dually diagnosed 
individuals. Behaviour research and therapy, 66, 8-17.  
95. Palacios, S., Henderson, V., Siseles, N., et al. (2010). Age of menopause and impact of 
climacteric symptoms by geographical region. Climacteric, 13(5), 419-428.  
96. Singleton, E. G., Henningfield, J.E., & Tiffany, S.E. (1994). Alcohol craving questionnaire: 
ACQ-Now: background and administration manual. Baltimore: NIDA Addiction Research 
Centre. 
97. Sobell, L. C., & Sobell, M.B. . (1996). Timeline followback user's guide: a calendar method 
for assessing alcohol and drug use. Toronto, Ontario, Canada: Addiction Research 
Foundation. 
98. Verbruggen, F., Logan, G.D., & Stevens, M.A. (2008). STOP-IT: Windows executable 
software for the stop-signal paradigm. Behavior Research Methods, 40(2), 479-483.  

7.22.2022 
PI: Cathryn Holzhauer 
Protocol Title: Stress, Emotion Regulation, and Alcohol in Women Veterans 
 
27 
 
99. Williams, D. P., Cash, C., Rankin, C., et al. (2015). Resting heart rate variability predicts 
self-reported difficulties in emotion regulation: a focus on different facets of emotion regulation. 
Frontiers in psychology, 6, 261.  
100. Zahn, D., Adams, J., Krohn, J., et al. (2016). Heart rate variability and self-control—A 
meta-analysis. Biological psychology, 115, 9-26.  
101. Beck, A., Steer, R.A., & Brown, G.K. . (1996). Beck Depression Inventory-II (BDI-II). San 
Antonio, TX: The Psychological Corporation. 
102. Weathers, F. W., Litz, B. T., Keane, T. M., Palmieri, P. A., Marx, B. P., & Schnurr, P. P. . 
(2013). The PTSD Checklist for DSM-5 (PCL-5) – LEC-5 and Extended Criterion A 
[Measurement instrument].   
103. Saunders, J. B., Aasland, O. G., Babor, T. F., et al. (1993). Development of the alcohol use 
disorders identification test (AUDIT): WHO collaborative project on early detection of persons 
with harmful alcohol consumption-II. Addiction, 88(6), 791-804.  
104. Gross, J. J., & John, O. P. (2003). Individual differences in two emotion regulation 
processes: implications for affect, relationships, and well-being. Journal of personality and 
social psychology, 85(2), 348.  
105. Lutz, W., Leach, C., Barkham, M., et al. (2005). Predicting rate and shape of change for 
individual clients receiving psychological therapy: Using growth curve modeling and nearest 
neighbor technologies. Journal of Consulting and Clinical Psychology, 73, 904-913.  
106. Sung, N. S., Crowley Jr, W. F., Genel, M., et al. (2003). Central challenges facing the 
national clinical research enterprise. Jama, 289(10), 1278-1287.  
107. Beadman, M., Das, R. K., Freeman, T. P., et al. (2015). A comparison of emotion 
regulation strategies in response to craving cognitions: Effects on smoking behaviour, craving 
and affect in dependent smokers. Behaviour Research and Therapy, 69, 29-39. 
doi:http://dx.doi.org/10.1016/j.brat.2015.03.013 
108. Buhle, J. T., Silvers, J. A., Wager, T. D., et al. (2014). Cognitive reappraisal of emotion: a 
meta-analysis of human neuroimaging studies. Cerebral cortex, 24(11), 2981-2990.  
109. Koch, K., Pauly, K., Kellermann, T., et al. (2007). Gender differences in the cognitive 
control of emotion: An fMRI study. Neuropsychologia, 45(12), 2744-2754.  
110. Ray, R. D., McRae, K., Ochsner, K. N., et al. (2010). Cognitive reappraisal of negative 
affect: Converging evidence from EMG and self-report. Emotion, 10(4), 587.  
111. Miller, S., Pagan, D., & Tross, S. . (1998). Women's Health Eduction: Peer activism for 
female partners of injection drug users. Unpublished treatment manuscript. New York. 
112. Gynecologists, T. A. C. o. O. a. (2017). Patient Fact Sheets, Women's Health.  Retrieved 
1/13/2017 
113. Szasz, P. L., Szentagotai, A., & Hofmann, S. G. (2012). Effects of emotion regulation 
strategies on smoking craving, attentional bias, and task persistence. Behaviour research and 
therapy, 50(5), 333-340.  
114. Colzato, L. S., Hertsig, G., van den Wildenberg, W. P., et al. (2010). Estrogen modulates 
inhibitory control in healthy human females: evidence from the stop-signal paradigm. 
Neuroscience, 167(3), 709-715.  
115. Gray, K. M., DeSantis, S. M., Carpenter, M. J., et al. (2009). Menstrual cycle and cue 
reactivity in women smokers. Nicotine & Tobacco Research, 12(2), 174-178.  
116. Brown, R. A., Burgess, E. S., Sales, S. D., et al. (1998). Reliability and validity of a 
smoking timeline follow-back interview. Psychology of Addictive Behaviors, 12(2), 101.  
117. Allison, P. D. (2009). Fixed effects regression models (Vol. 160): SAGE publications. 
118. Affairs, U. S. D. o. V. (2011). Massachusetts Women Veterans, Population by County.    
119. Diagnostic and statistical manual of mental disorders (DSM-5®). (2013). American 
Psychiatric Pub. 

7.22.2022 
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Protocol Title: Stress, Emotion Regulation, and Alcohol in Women Veterans 
 
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120. Brockman, R., Ciarrochi, J., Parker, P., et al. (2017). Emotion regulation strategies in daily 
life: mindfulness, cognitive reappraisal and emotion suppression. Cognitive Behaviour 
Therapy, 46(2), 91-113.  
121. Mattocks, K. M., Skanderson, M., Goulet, J. L., et al. (2010). Pregnancy and mental health 
among women veterans returning from Iraq and Afghanistan. Journal of Women's Health, 
19(12), 2159-2166.  
122. Greenfield, S. F., Brooks, A. J., Gordon, S. M., et al. (2007). Substance abuse treatment 
entry, retention, and outcome in women: A review of the literature. Drug and Alcohol 
Dependence, 86(1), 1-21. doi:http://dx.doi.org/10.1016/j.drugalcdep.2006.05.012 
123. Felitti, V. J., Anda, R. F., Nordenberg, D., Williamson, D. F., Spitz, A. M., Edwards, V., & 
Marks, J. S. (1998). Relationship of childhood abuse and household dysfunction to many of 
the leading causes of death in adults: The Adverse Childhood Experiences (ACE) Study. 
American journal of preventive medicine, 14(4), 245-258.