Clinical trial NCT03137082
Conditions: Alcohol Abstinence
Keywords: Alcohol Use Disorder Guanfacine Stress Craving Gender Relapse
Sponsor: Stony Brook University
Start date: 2017-07-12; Completion date: 2021-03-31
Enrollment: 32 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Guanfacine may preferentially reduce craving and improve cognitive control in women with Alcohol Use Disorder (AUD), compared to men. As these behaviors are related to relapse, the objectives of this study are to conduct a 10-week out-patient clinical trial to examine the effects of Guanfacine Extended Release (XR; 3mgs) versus placebo on drinking measures in women with AUD.

Detailed description:
Gender-specific variation in sympathetic sensitivity (Fox et al., 2014; Fox and Sinha, 2009; Cahill, 2003; Heinsbroek et al., 1991) may mean that guanfacine is particularly efficacious in attenuating drinking in women, rather than men with Alcohol Use Disorder (AUD). Thus, the investigators propose a double blind, placebo-controlled, 10-week randomized clinical trial to examine the effects of Guanfacine XR (3mgs/daily) versus placebo in 60 women with AUD. This will include twice weekly appointments comprising medical management and contingency management protocols, collection of urine, breathalyzer screens, and vitals. Measures of craving and mood will also be assessed. Parallel laboratory challenge studies will also be conducted both on admission to out-patient treatment and again following 4 weeks of treatment, in order to better elucidate the potentially therapeutic mechanisms of guanfacine. Participants will be exposed to a personal stress versus relaxing imagery condition, 1 condition per day, in a randomized order. Craving, anxiety, mood, cognitive control, heart rate and blood pressure (HRBP), and biological stress system markers will be assessed at baseline, following imagery and at various recovery timepoints.

Arms: arm 1: * Guanfacine XR tablet by mouth every 24 hours for 12 weeks
* 21 day titration: 1 mg/d (day 1-7); 2mgs/d (day 7-21)
* Full dose: 3mgs/d (day 21- day 70)
* 2 week taper: 2mgs/d (day 71-77); 1mg/d (day 77-83) arm 2: * Guanfacine XR tablet by mouth every 24 hours for 12 weeks
* 21 day titration: 1 mg/d (day 1-7); 2mgs/d (day 7-21)
* Full dose: 3mgs/d (day 21- day 70)
* 2 week taper: 2mgs/d (day 71-77); 1mg/d (day 77-83)
Interventions: intervention 1: Guanfacine XR 3mgs/daily intervention 2: Placebo (for guanfacine)
Intervention descriptions: intervention 1: Guanfacine 3mg tablet intervention 2: Sugar pill manufactured to mimic guanfacine tablets

Protocol documents:
Prot_SAP_000.pdf: 
STUDY PROTOCOL - 960249 
 
TITLE:  Guanfacine to reduce relapse risk in women with alcohol use 
disorder (AUD) 
 
 
 
INVESTIGATORS:  Helen C Fox (PI), PhD; James Swain, MD; Ricardo Caceda, MD, 
PhD (back up MD); Asif Karim, MD (back up MD) 
Research Coordinators: Erin Vacey; Suraj Bera 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


l markers of change underpinning Guanfacine’s efficacy. Sixty women with AUD will be recruited 


Protocol – IRB960249 
      
A. SPECIFIC AIMS 
Approximately 5.7 million women in the US meet criteria alcohol use disorder (AUD). While this 
figure remains significantly lower than men, the traditional gender gap is rapidly converging as a 
result of sharp elevations in women’s drinking patterns due, in part, to socioeconomic gains within 
the labor force. As gender specific risk factors for AUD place women at a considerable 
disadvantage in terms of clinical health outcomes, this sharp increase in alcohol consumption 
urgently necessitates the development of interventions that have been specifically tailored to 
women. In view of this, preliminary data from our laboratory has shown that the alpha2 adrenergic 
agonist, Guanfacine, attenuates the negative reinforcing effects of alcohol and enhances 
cognitive regulation in the face of stress, preferentially in early abstinent women compared with 
men. We suggest that this may be due to gender-specific variation in sympathetic sensitivity. 
Thus, we propose a double blind, placebo-controlled, 10-week randomized clinical trial to 
examine the preliminary effects of Guanfacine extended release (GXR, 3mgs/daily) in 60 women 
with AUD. A parallel experimental study using a stress versus neutral imagery exposure paradigm 
will also be conducted following 7 weeks of treatment (when at full dose), to examine the stress-
to take part in the 10-week outpatient trial for GXR (3mgs/daily) versus placebo (PLA). This will 
include twice weekly appointments comprising medical management and contingency 
management protocols, collection of urine, breathalyzer screens, and vitals. Measures of craving 
and mood will also be assessed. In week 10 participants, will take part in a laboratory challenge 
sessions, where they will be exposed to a personal stress versus relaxing imagery condition in a 
randomized order. Craving, anxiety, mood, cognitive control, HRBP, and biological stress system 
markers will be assessed at baseline, following imagery and at various recovery timepoints. A 
follow-up interview will be conducted 30 days following outpatient completion. As our prior 
research has also shown to Guanfacine to be highly efficacious in reducing nicotine craving 
following exposure to stress in both cocaine dependent and alcohol dependent populations, we 
additionally include a sub-sample of treatment-seeking nicotine dependent women who do not 
meet criteria for AUD.  In view of prior research, we anticipate that GXR will be safe and well 
tolerated in women with AUD (H1); lead to greater abstinence and treatment adherence 
compared with the PLA group (primary outcome measures) (H2a) as well as greater attenuation 
of withdrawal symptoms and improved regulatory function (secondary outcome measures) both 
during outpatient treatment (H2b) and following stress exposure in the laboratory (H3a). We also 
anticipate that GXR-related changes to stress response in the laboratory will predict improved 
primary alcohol use outcomes (H3b). Exploratory aims will examine the effects of GXR versus 
placebo on a sub-sample of nicotine dependent women who do not meet criteria for AUD. 
Findings will help to elucidate unique stress-system mechanisms which support attenuation of 
drinking and smoking in women with AUD prior to further assessment in larger randomized clinical 
trials. This is of paramount importance to developing medications that are integral to the health 
and well-being of an increasingly vulnerable sub-population of drinkers 
B. BACKGROUND AND SIGNIFICANCE 
1.1 Overview: Over the last decade, the traditional gender gap in alcohol use and abuse rates 
has been converging across ethnicities 41 due to socioeconomic factors 42, 43. For example, 
between 1999 and 2008, the number of young women admitted to emergency rooms for being 
dangerously intoxicated rose by 52%, while the rate for young men, rose just 9% 44. Moreover, 
although the number of women who fit research criteria for alcohol abuse is increasing 45, they 
continue to be under-represented in clinical trials 46 and as such sex-specific treatment 
information for alcohol is sporadic 6. Factors such as “telescoping”, or propensity for the 
comparatively quick progression from use to dependence typically observed in women 47, as 
well as a dearth in FDA-approved medications tested and validated in populations of alcoholic 
women 6, together highlight the urgent need for gender-sensitive medications. In view of this, we 


propose a preliminary double blind, placebo controlled, 10-week randomized clinical trial (RCT) 
to examine the initial safety and efficacy of the alpha2 adrenergic agonist, Guanfacine extended 
release (GXR; 3mgs/day) in 60 women with AUD, and a sub-sample of nicotine dependent 
women without AUD. The design also incorporates an experimental challenge study using a 
stress versus neutral imagery exposure paradigm to further elucidate some of the stress 
mechanisms potentially underlying GXR’s efficacy in improving primary drinking outcomes in 
women with AUD. We anticipate that findings will help to form the basis of a larger Phase II clinical 
trial. 
1.2 Stress system changes underlying alcohol withdrawal, craving & relapse: Extensive evidence 
shows that overactive hypothalamic CRH 21, 48, 49, as well as hyperactivity in sympathetic 
neurotransmission, 10, 13, 38, 50, and signaling 7, 9 all play a critical role in withdrawal symptom 
development 51, alcohol craving 13 nicotine craving 160,161, and relapse 52, 53. As such, 
chronic core stress system up-regulation may contribute to increased risk of alcohol relapse in 
several ways: First, the pathophysiology of both AUD, anxiety disorders, negative affect and 
physiological hyperarousal all share common elevated extra-hypothalamic CRF and NE circuitry 
53-57. This suggests that these mechanisms play a key role in the negative reinforcing and 
aversive motivational states underlying alcohol craving and compulsive alcohol seeking 6, 38, 39, 
58. Second, sympathetic overdrive impinges upon medial prefrontal circuits 59 inducing α1 
receptor stimulation and desensitizing alpha2 receptors, impairing attentional processes by 
attenuating salient “signals” and increasing irrelevant “noise” 60-62. Taken together, elevated 
HPA-SAM activity during early withdrawal from alcohol underlies negative reinforcement and 
weakens prefrontal adrenergic systems allowing for less control over rewarding and aversive 
motivational states, hence, promoting compulsive alcohol seeking.  
1.3 Sympathetic dominance in women with AUD: Prior research from our own laboratory and 
those of others, has shown that enhanced anxiety and emotional sensitivity to stress as well as 
dysregulated autonomic output may represent unique risk factors for drinking in women, 
compared with men 26, 27, 34. We have used a well-validated human paradigm to model stress-
related craving within the laboratory and demonstrate that enhanced anxiety, arousal and 
negative affect following personalized stress are selective aspects of the motivational craving or 
wanting “state” in socially drinking, substance abusing and alcohol dependent women relative to 
men 26, 27, 34, 63. High basal heart rate and NE levels are also specific to alcoholic women 6, 
64, as well as female smokers 159 and linked to a dampened sympathetic and cardiovascular 
arousal response to stress 38, 64, providing a gender-sensitive pathway to elevated alcohol 
craving, and one which is qualitatively different to that observed in men 6, 27. These findings also 
corroborate clinical surveys and longitudinal studies which have shown that internalizing 
emotions such as negative mood and anxiety are predictive of drinking to a much greater extent 
in women than men 65-67. In addition, sexual dimorphism of LC-NE activation, dendritic 
morphology and feedforward regulation of the HPA axis 67-70 suggests that these core 
sympathetic systems may play a key role in the vulnerability of women to stress exposure and 
the negative reinforcing aspects of alcohol craving during early abstinence. We therefore propose 
that Guanfacine, which inhibits NE levels via stimulation of presynaptic alpha2-adrenergic 
receptors 71, 72, will be particularly effective in attenuating the gender-sensitive anxiolytic and 
autonomic arousal aspects of craving and relapse vulnerability in AUD women. 


1.4.1 Preliminary Data 1: We conducted a randomized, double blind, placebo-controlled 
laboratory study examining the gender effects of 3-weeks Guanfacine immediate release (GUA 
2 to 3mgs; b.i.d) using a 12 day titration schedule in a sample of early abstinent treatment-seeking 
alcohol dependent men and women (N=24; 8F/16M). Method: Following 3-weeks of abstinence, 
all participants were exposed to three, 10-min personalized guided imagery scenarios (i) stress, 
ii) cue, iii) combined stress/cue), one per day, across 3 consecutive days in a random, 
counterbalanced order. Alcohol craving, nicotine craving, anxiety, negative mood, cardiovascular, 
HPA and sympathetic measures were acquired at baseline, immediately following imagery, and 
at various recovery time-points until 1 hour post imagery. Results: GUA was found to be safe and 
well tolerated in both men and women, with fatigue being the most commonly reported side-
effect. All symptoms were reported as being mild to moderate and dissipated within the initial two 
weeks of inpatient stay. At baseline, GUA reduced cardiovascular output in women compared 
with both PLA groups (p<.0001, in all cases). Following imagery exposure, a series of Medication 
Group X Gender X Time-point interactions showed that immediately following all 3 imageries the 
GUA females reported significantly attenuated anxiety [F5, 644 = 2.8, p<.02], sadness [F5, 644 
= 2.4, p<.04], arousal [F5, 644 = 3.7, p=.003] behavioral arousal (sweaty palms, crying) [F1, 30 
= 3.6, p=0.06] as well as increased positive mood [relaxed state: F5, 644 = 2.7, p<.02; Joy: F5, 
644 = 2.8 p<.02] compared with the PLA females (Fig 1). Importantly these attenuations in stress 
reactivity occurred alongside decreased alcohol craving across all conditions in the GUA females 
compared with the PLA females [F5, 644 = 2.7, p=.02]. No such discrepancy was observed 
between GUA and PLA males, with the exception of nicotine craving and SBP which was 
attenuated in both the male and female GUA groups. Findings support preclinical studies showing 
attenuation of alcohol-seeking, relapse and other negative reinforcing aspects of alcohol craving 
following alpha2 agonism. 
 
Importantly, the robust effects of GUA in women may again be related to a sensitized sympathetic 
profile in the PLA women relative to PLA males, suggesting the need for a particular threshold of 
emotional and sympathetic arousal to optimize Guanfacine’s efficacy in women. This also 
corroborates studies that have shown GUA and GXR to be effective in treating conditions 
characterized by elevated catecholaminergic psychopathology, including attention-deficit 
hyperactivity disorder (ADHD) 73-77 and drinking in high, but not low alcohol consuming rats 23. 
On the basis of these findings we propose that 10-weeks of GXR will be well-tolerated and safe 
in AUD women (H1a). GXR will also promote abstinence and adherence to treatment (H2a) by 
attenuating withdrawal, craving, anxiety, and negative mood, during treatment (H2b), and during 
stress in the laboratory (H3a).  
1.4 Regulatory processes as a target for treatment: Stress-related sympathetic sensitivity may 
highlight an important gender-sensitive aspect of compulsive alcohol seeking in AUD women. In 
addition, aberrations in sympathetic stress arousal also impinge upon prefrontal networks integral 
to cognitive reappraisal 78. For example, greater activity in regulatory regions such as the VMPC 
and sub-genular ACC following stress is associated with lower autonomic arousal 79-82. These 


control circuits are therefore intrinsically enmeshed with the stress response, and reflect an 
overall ability to cognitively regulate or reappraise during provocation 83. As such, they play an 
integral role in marshalling attention and supporting goal-oriented behaviors including planning, 
decision-making and impulse control, which contribute to treatment outcome 84-86. Targeting 
regulatory mechanisms which profoundly impact everyday life 87 may therefore allow for the 
development of medications that are gender-sensitive and also demonstrate high ecological 
validity outside of the laboratory. In support, data from two prior studies show that a) inability to 
cognitively inhibit during stress in the laboratory can predict fewer number of days to relapse 
following treatment discharge (Fig. 2a), and b) that GXR strengthen these relapse-related 
cognitive processes preferentially in substance abusing women (Fig. 2b). 
Sixty-two early abstinent alcoholics were 
compared with 107 cocaine dependent 
individuals and 74, socially drinking 
controls 
on 
Stroop 
color/word 
performance, 
prior 
to 
and 
following 
exposure to 3 personalized imagery 
conditions (stress, cue, neutral). Following 
exposure to stress, both cocaine (p=.002) 
and alcohol dependent (p=.05) individuals 
were less able to inhibit or regulate pre-
potent responses compared with controls. 
The alcohol group was subsequently 
categorized into either “good” or “bad” 
performers of Stroop (using a median split) 
and survival curves were plotted for both 
groups as a function of Stroop performance following stress. Proportional hazards modeling  
indicated that good ability to regulate in the face of stress challenge, was significantly associated 
with a reduced chance of relapse following discharge (x² = 8.78; p=.01; HR = 1.46; 95% CI, 0.96-
2.2). Similar findings were also observed following an identical analysis in the cocaine dependent 
individuals (not shown). 
1.5.2 Preliminary Data 3 (Fig. 2b):  
We subsequently examined whether GUA (immediate 
release) could enhance these mechanisms during early 
abstinence. Using a sample of men and women co-
dependent on alcohol and cocaine (N=40; 13F/27M) we 
administered the Stroop test prior to and following 
exposure to 3 imagery conditions (stress, cue, combined 
stress/cue). After adjusting for baseline variation, a 
Medication X Gender effect [F1, 19 = 5.6, p<.03] showed 
Stroop performance to be significantly enhanced 
following all imagery conditions in the GUA women, but 
not the GUA men (Fig 2b). These findings corroborate 
GUA-related improvements in sustained attention, motor 
and response inhibition across a variety of species 88-92, 
via stimulation of post-synaptic alpha2 receptors93, 94. It also corroborates our own research 
demonstrating increased BOLD activation in ventral and lateral regions of the prefrontal cortex 
during stress in cocaine and alcohol co-dependent men and women 18. The current gender-
effects of GUA may also emphasize the role of stress and its effect on regulatory processes, as 
providing a key target mechanism for drinking in women. We therefore propose that during a 10-
week period, GXR will promote abstinence and adherence to treatment (H2a) by improving 


emotion regulation, cognitive regulation and impulse control during treatment (H2b), and during 
stress in the laboratory (H3a).  
 
In order to more fully elucidate the mechanisms underpinning GXR’s effects in AUD women, we 
additionally examine whether GXR-related changes to tonic and phasic stress system activity in 
the laboratory can predict drinking outcome measures during treatment. Our preliminary and 
published findings indicate that sensitized autonomic stress activity and ability to regulate during 
challenge are known to a) have a substantial impact on achieving and maintaining alcohol 
abstinence 85, and b) also characterize drinking in women. As such, we propose that attenuated 
craving, anxiety, negative mood, autonomic function and enhanced cognitive control following 
stress in the lab will predict improved outcome during a 10-week treatment trial (H3b). 
As an exploratory aim, we propose examining the efficacy of GXR versus placebo in a small 
subsample of women who are dependent on nicotine, but do not meet criterial for AUD. Prior 
preclinical research has indicated greater anxiety-like behaviors following stress-related nicotine 
exposure in female compared with male rats 157,158.  Moreover, studies from our own laboratory 
have indicated that Guanfacine significantly reduces stress- and cue-induced nicotine craving in 
both cocaine dependent and alcohol dependent individuals co-morbid for nicotine 18,29,30.  
Moreover, attenuation was significantly greater in females (See Fig 3a-c.). 
 
Fig.3c Nicotine Craving across all 3 imagery conditions & time-points in early abstinent cocaine 
dependent individuals 
D. RESEARCH DESIGN AND 
METHODS  
Rationale / overview 
Sixty women meeting criteria for moderate to severe alcohol use disorder (AUD) will be recruited 
to take part in a 10-week outpatient treatment trial for GXR (3mgs/daily) versus PLA. On the basis 


that up to 30% of women may drop-out following the initial few sessions109, 110 we anticipate 
that at least 42 women will also run through a parallel laboratory paradigm during week 10 
Outpatient treatment will include twice weekly appointments comprising medical management 
(MM) and contingency management (CM) protocols, collection of urine drug screens, 
breathalyzers, and vitals. Alcohol craving, use, and withdrawal as well as perceived stress, 
anxiety, mood, impulsivity and emotion and cognitive regulation will also be assessed. All 
participants who have been on Guanfacine for 9 weeks will take part in a laboratory challenge 
session, where they will be exposed to 2, personalized guided imagery conditions (stress and 
neutral in a counterbalanced order). Craving, anxiety, mood, cognitive control, HRBP, plasma 
cortisol, ACTH, and catecholamines will be assessed at baseline, following imagery exposure 
and at various recovery time-points. A follow-up interview will be conducted 30 days following 
outpatient treatment completion. 
 
Research Site 
The proposed R21 will be conducted at the Health Sciences Center (HSC) located at University 
Hospital Stony Brook, which additionally offers a wide range of treatment modalities for 
dementia, depression, anxiety, psychotic and bipolar spectrum disorders, as well as all 
psychiatric disorders associated with acute and chronic medical illness. The facility is excellently 
equip for running phase I clinical trials in alcohol and substance abusers, offering treatments in 
psychopharmacology, individual and group counseling as well as comprehensive evaluation 
and medical management. The department is also fully staffed with highly experienced, multi-
disciplinary board-certified psychiatrists and clinicians, including Dr. Ricardo Caceda who 
specializes in addiction psychiatry. Physical examinations and other medical evaluations 
necessary to determine eligibility for the current research will be conducted at the Clinical 
Research Center (CRC), located at 33 Research Way in Setauket, by a study nurse 
coordinator. The laboratory challenge studies will also be conducted at the CRC. The 
department of Psychiatry is fully staffed with substance abuse clinicians and a range of mental 
health professionals well versed in outpatient procedures and NIH protocols.  Excellent 
laboratory and office space is available to conduct stress induction procedures, cognitive testing 
and day to day research.   
 
Study sample 
Human Subjects: This study aims to recruit 60 women seeking out-patient treatment and who 
meet current DSM-V criteria for moderate-to-severe alcohol use disorder (AUD). In addition we 
will recruit a separate small sub-sample of 10 women who are nicotine dependent and 
treatment-seeking, but do not meet criteria for AUD. On the basis that up to 30% of participants 
may drop-out of treatment after the initial few sessions109, 110, we anticipate that at least 49 
AUD women will run through the laboratory stress challenge. AUD women enrolled in this study 
will predominantly come from low socio-economic backgrounds in Suffolk County, Long Island. 
In addition the Health Science Center at Stony Brook Hospital comprises a dedicated 
Comprehensive Psychiatric Emergency Program (CPEP) which sees 6200 patient visits per 


year, with referrals commonly being made for persons with alcohol abuse and mental illness. 
Each patient is evaluated by a psychiatrist with regard to present episode, past psychiatric 
history, substance abuse, family and psychosocial context, medical history, and current status. 
Mental status and physical examinations are also made and potential referrals filtered into the 
appropriate research programs. CPEP additionally has close links to 67 alcohol and substance 
use disorder facilities across Long Island, including 8 detoxification centers, 6 inpatient clinics, 
and 7 residential programs all in close proximity.  In relation to the racial and ethnic background 
of the women typically referred to CPEP: 70% are Caucasian (and of those 10% are Hispanic) 
and 30% are African American. As a result, we expect that the projected demographics of our 
sample will follow the above race breakdown. Subjects will be recruited by the research team 
based in the Department of Psychiatry at Stony Brook, through general practitioners at Stony 
Brook hospital and advertisements in local area newspapers, radio and other print media as 
well as study flyers posted in community buildings in the Suffolk County area. We propose the 
following strategies to encourage women into the study: 
Recruitment & retention strategies tailored to women: a) Research indicates that 
community involvement plays an integral role in recruiting both women and ethnic minorities into 
clinical trials 142. In view of the proposed study, both Dr Fox and the recruitment teams based 
at Stony Brook Psychiatry, will maintain regular contact with Suffolk County Communities of 
Solution and the Long Island Counsel of Alcohol and Drug Dependence. Regular meetings will 
be organized with objectives to work closely with prominent community leaders within the local 
area in order to devise culturally appropriate community-based participatory recruitment 
strategies encouraging women from ethnic minorities into our research projects. b) As women 
are more likely to seek care for alcohol use disorders within primary care settings143, we intend 
to focus recruitment efforts within medical health centers and approach a local network of 
general practitioners within Stony brook hospital willing to inform women of our treatment 
program; c) Treatment will predominantly be focused on psychoeducational techniques directed 
at the needs of women, incorporating issues associated with stress, self-esteem, domestic 
violence, parenting, caregiving status, trauma, anxiety, negative mood and eating; d) As 
research has shown that programs which allow women to bring their children have higher rates 
of retention and are a predictor of better treatment outcomes, we will encourage women to bring 
their children with them to all visits. The outpatient department at Stony Brook, employs several 
research assistants and associates with additional expertise in running developmental research 
protocols, and the Child and Adolescent Psychiatry Department is well-equipped to offer onsite 
child-care assistance while mothers complete the treatment visits with clinical staff; e) we have 
budgeted for local transportation if required146; The following inclusion / exclusion criteria will 
be required for eligibility: 
 
 
Addendum as per COVID -19 CDC guidelines:  
All potential / ongoing participants will be screened for exposure to the COVID-19 virus 
using the CDC guidelines below:  
1. Have you traveled to the following places in the last 14 days?  
-China, Iran, Japan, any country in Europe or South Korea? (Note that all level 3 
and level 2 countries/regions listed on the CDC website are included; CDC is 
checked regularly for updates.  
 
2.  Have you had any of the following symptoms in the last 14 days without confirmation it was 
NOT COVID -19 


A flu positive test result or chronic medical condition? Fever greater than 100.4 deg F? Cough, 
difficulty breathing, sore throat? 
3. In the past 14 days have you lived with, visited, cared for, or been in a room for a prolonged 
period of time with someone who is under investigation or has been confirmed for COVID-
19/ Corona virus infection?  
 
Any YES response the subject will be asked to make an appointment for a later date and 
will be directed to the Coronavirus Hotline/phone triage center set up at Stony Brook 
Hospital 631-638-1320. 
 
Any and all subjects need to be asymptomatic for all scheduled visits ongoing through the study.  
Safe distancing practices will be implemented at all in office meetings, should they occur. Virtual 
visits will be utilized for any visits as the need sees fit. 
 
Inclusion/Exclusion Criteria: Inclusion Criteria: i) Females, aged 18-60 years, ii) must meet 
DSM-V criteria for AUD, iii) must produce positive urine toxicology screens on admission to 
study, or have recently been through a detox protocol, iv) must demonstrate good health as 
verified by screening examination. Liver Function Tests (LFT) should not exceed 3 units above; 
Bilirubin Total 0-1 MG/DL Conjugated, (D. Bilirubin) 0-0.35 MG/DL, Unconjugated (I.D. Bilirubin) 
0.2-0.65 MG/DL, SGOT 10-40 IU/L, SGPT 10-40 IU/L, Alkaline Phosphatase 40-112 U/L, Total 
Protein 6-8.5 GM/DL Albumin 3.5-5 GM/DL, and Globulin 2-3.5 GM/DL.v) must be able to read 
English and complete study evaluations vi) must be able to provide informed written and verbal 
consent. Women currently stable on SSRI medication will be included in the study. Exclusion 
Criteria: i) Meeting current use disorder for any other psychoactive substance, excluding 
nicotine. ii) Having any other current Axis I psychiatric disorders requiring treatment/medication, 
with the exception of SSRIs, iii) EKG evidence at baseline screening of any clinically significant 
conduction abnormalities, including a Bazlett’s QTc  of >470 msec. iv) must not be on 
monophasic contraceptives, nursing or pregnant, v) active significant medical illness within the 
past six months (i.e. cancer), vi) documented autoimmune disease (i.e. Lupus, Crohn’s/UC, 
Hashimoto’s) vii) documented neurological illness (i.e. seizure disorder, h/o stroke, excluding a 
single childhood febrile seizure) or a history of migraine headaches as determined by a 
physician, viii) documented diagnosis of diabetes mellitus or use of diabetic agents, ix) 
documented history of head trauma with prolonged loss of consciousness.  
 
A small sub-sample of women will be recruited that meet all Inclusion and Exclusion criteria with 
the exception of not meeting criteria for AUD, and instead meeting criteria for tobacco use 
disorder. The inclusion & exclusion criteria for this group will be as follows: 
Inclusion Criteria: i) Females, aged 18-60 years, ii) they must meet criteria for tobacco use 
disorder (TUD) as determined by the DSM 5, iii) they must demonstrate good health as verified 
by screening examination, iv) they must be able to read English and complete study evaluations 
v) They must be able to provide written and verbal consent . Exclusion Criteria: i) meeting 
current use disorder for any psychoactive substance, excluding nicotine. ii) having any other 
current Axis I psychiatric disorders or medical conditions requiring treatment/medication, with 
the exception of SSRIs. iii) EKG evidence at baseline screening of any clinically significant 
conduction abnormalities, including a Bazett’s QTc of >470 msec. iv) must not be on 
monophasic contraceptives, nursing or pregnant. 
 
 
 
 


SAFETY GUIDELINES FOR THE COVID-19 VIRUS DURING ALL SCREENING VISITS: 
 
Addendum as per COVID -19 CDC guidelines:  
All potential / ongoing participants will be screened for exposure to the COVID-19 virus 
using the CDC guidelines below:  
4. Have you traveled to the following places in the last 14 days?  
-China, Iran, Japan, any country in Europe or South Korea? (Note that all level 3 
and level 2 countries/regions listed on the CDC website are included; CDC is 
checked regularly for updates.  
 
5.  Have you had any of the following symptoms in the last 14 days without confirmation it was 
NOT COVID -19 
A flu positive test result or chronic medical condition? Fever greater than 100.4 deg F? Cough, 
difficulty breathing, sore throat? 
6. In the past 14 days have you lived with, visited, cared for, or been in a room for a prolonged 
period of time with someone who is under investigation or has been confirmed for COVID-
19/ Corona virus infection?  
 
Any YES response the subject will be asked to make an appointment for a later date and 
will be directed to the Coronavirus Hotline/phone triage center set up at Stony Brook 
Hospital 631-638-1320. 
 
Any and all subjects need to be asymptomatic for all scheduled visits ongoing through the study.  
Safe distancing practices will be implemented at all in office meetings, should they occur. Virtual 
visits will be utilized for any visits as the need sees fit. 
 
Screening 
Screening & intake: After consented telephone screening, eligible participants will meet with a 
research assistant for an initial intake session where informed consent, physical examinations, 
blood work (liver function tests, glucose and complete blood count) and alcohol screening will be 
conducted. We will also take a blood sample in order to collect exosomal microRNA in order to 
assess whether any differences in transcription factors that are known to affect stress and 
drinking, exist between several candidate microRNA genes [miR-21; miR-26; miR-146a; miR-
10a]. Demographic data will be assessed using standard self-report forms. The SCID-I 119 will 
be used to determine AUD and/or Tobacco Use Disorder, and the possible presence of any Axis 
1 psychiatric and/or substance use disorder. The State/Trait Anxiety Inventory (STAI); 120 will be 
used to ascertain the presence of state and trait anxiety symptoms. The Alcohol Urges 
Questionnaire (AUQ) 121: is a reliable and valid 8item scale that can be used for repeated 
assessments of alcohol craving 122. The Alcohol Use Disorders Identification Test (AUDIT) is a 
10-item screening instrument designed to distinguish between low risk drinkers and individuals 
with hazardous and harmful patterns of alcohol consumption (WHO, 1992). We will also include 
The Drinking Motives Questionnaire (DMQ; Cooper, 1994) which is a 20-item well-established 
scale that assesses social, coping, enhancement and social conformity motives for drinking. The 
Perceived Stress Scale (PSS; 123): is a 14 item self-report assessing the degree to which 
situations are appraised as threatening or demanding. The Early Trauma Inventory (ETI; 162) is 
a 56-item interview to measure childhood trauma. The Beck Depression Inventory (BDI 124) is 
regarded as a well-established, sensitive self-report measure of depressive symptoms. The 


Menstrual Cycle Questionnaire (MCQ) is a 30-item standardized instrument documenting 
symptoms, typical cycle and period length. Female subjects will complete the questionnaire at 
baseline. The Barratt Impulsiveness Scale (BIS-11125) is a globally well-established 
questionnaire designed to assess the personality/behavioral construct of impulsiveness126. The 
Difficulties in Emotion Regulation Scale (DERS; 127): is a well-validated measure of emotion 
dysregulation. Items reflect impulse control; emotional awareness, regulation and clarity. We will 
also administer the UPPS Impulsive Behavior Scale (UPPS or UPPS-P; Whiteside and Lynam, 
2001) to more thoroughly examine a personality model of impulsivity. The scale comprises 45-
items which measure impulsivity across dimensions of the Five Factor Model of personality, 
including urgency, sensation seeking, lack of premeditation and lack of perseverance. The 
Fagerström Test for Nicotine Dependence (FTND;128) will be used to determine smoking 
dependence. The Shipley Institute of Living Scale 129 provides a global measure of cognitive 
functioning and IQ. The Time-Line Follow Back (TLFB) Interview 130 will be used to assess all 
alcohol and drug use in the last 3 months. The assessment uses a calendar prompt to facilitate 
recall of alcohol use during a targeted period. Urine samples & Breathalyzers: will ensure current 
alcohol use. Urine samples will also ensure the potential participants are not pregnant. The 
Multidimensional Scale of Perceived Social Support (MSPSS; Zimet et al., 1988) has good 
internal and test–retest reliability, and is a measure of subjectively assessed social support within 
the three domains of “family” “friends” and “Significant Other”. The Hurt Feelings Scale (Leary, 
2013) and Adult Rejection Sensitivity Scale (Downey & Feldman, 1996) are both well-validated 
measures of interpersonal social pain and rejection.  
The following updates and safety guidelines to the current are proposed due to the 
Covid-19 pandemic:  
INITIAL INTAKES: 
INTAKE 1: Subject will be read the entire consent via virtual media (ZOOM) using the share 
screen option. The subject will have the opportunity to ask questions during the virtual 
consenting.  A copy will be mailed (via email or regular mail if no email available) to the subject 
for signature prior to the first intake Subject Signature will be obtained by web application 
Docu-sign 
 https://www.docusign.com 
 Subjects will initially be screened over the phone. They will then be emailed the consent 
form to read and scheduled for a consent appointment over zoom, where they will be taken 
through the consent procedure with a research coordinator and given time to ask questions. 
Consent will be proved using Docu-sign.  Participants will then be scheduled for an 
appointment at the CRC where they will provide a baseline blood draw, HCG urine test and 
urine toxicology. An EKG test will also be performed. If a stay at home order is in place, 
subjects will be required to provide a current EKG (within the last three months) as well as 
the last blood pressure reading from their most recent primary care physician visit. If they 
are unable to provide this, they will be waitlisted until they are able attend the CRC. All 
questionnaires and clinical interviews (including the SCID) will be performed over ZOOM by 
virtual visit. All clinical testing will be reviewed by the study physician (Dr Ricardo Caceda). 
 
If the subject proves to be in good health (as confirmed with the study physician) and meets 
study inclusion / exclusion criteria, a package will be sent out in the mail by UPS. The 
package will contain a blood pressure monitor kit, urine toxicology cups, disposable 
breathalyzers for alcohol and 1 week of medication (dose determined by week in study) 


timeline calendar, blood pressure heart rate daily log,  and written instructions on how to 
perform these tests.  
 
INTAKE 2: Intake 2 will be conducted early in the morning in order to ensure that the 
initial medication dose is as close to 8am as possible.   
Once the package is received by the participant, the second intake will be performed over 
virtual media (ZOOM). The subject will first meet briefly with the study physician in order to 
establish good health. The subject will then meet with the study RA to complete 
questionnaires, the timeline follow back and take a tutorial on how to use the blood pressure 
monitor. All subjects will also provide a urine sample to assess drug use by taking a photo of 
the test strip on the urine cup using their cell phone, and sending it to the study site cell 
phone to be printed and stored in the participant binder.   
Disposable breathalyzer tests will additionally be completed and logged in the participant 
binder and results displayed via zoom.  
 
Participant will then administer the first dose of study medication or virtual media visit. 
Questionnaires and surveys will be conducted and timeline follow back will be obtained. Sit 
stand blood pressure recordings will be taken at the end of this intake.  Appointment for the 
weekly virtual visits will be scheduled.  
 
Medication 
 
At a second intake appointment participants will meet with the study MD, and once cleared begin 
the first dose of Guanfacine or placebo. They will be randomly assigned to either GXR (3mgs) or 
PLA, and will receive the exact amount of medication until their next visit, provided in unit/dose 
containers and labeled with the time and date to facilitate appropriate dosing. Riboflavin will be 
added to the medications and blood plasma assessed for medication levels every four weeks to 
ensure compliance131. The use of extended release GXR will also necessitate the use of only 1 
tablet per day, increasing likelihood of adherence 
ALL SESSIONS:  
 
SAFETY GUIDELINES FOR THE COVID-19 VIRUS DURING: 
 
WEEKLY STUDY VISITS 2 x per week – all virtual:  
All assessments will be performed by virtual visit over a secured media site.  Using ZOOM 
with end to end encryption. Subjects will be mailed via UPS with signature required: 1 BP 
monitoring kit, Urine toxicology cups, 1-week medication until titrations to the optimal dose of 
3 mg of Guanfacine or Placebo; based on the blind randomization assigned by the 
pharmacist. Subjects will receive virtual tutorials form the research staff on the use of the BP 
monitor and utilization of the urine toxicology cups through zoom. Subjects will be monitored 
via virtual media during the use of these tools each visit. All adverse events to be reported 
and documented during these visits. Reported to study MD as needed and virtual visit with 
MD as needed. All SAFTEE documents will be administered and documented. One virtual 
visit each week will include medication management, with continued assessment of the 
subject during the COVID_19 crisis to insure that additional counseling is not needed.  
 
Weekly Assessments include the following:   
 
1. SAFTEE sheet – documenting any adverse effects 


2. A series of short rating scales measuring: craving (AUQ), stress (PSS), emotion 
regulation (DERS), mood (POMS), anxiety (STAXI), depressive symptoms (BDI) and 
withdrawal symptoms (CIWA) 
3. Timeline follow back (TLFB) – subject report of daily alcohol/drug use 
3. Vitals – sitting to standing 
4. Urine toxicology screens and breathalyzer. At week 4 and week 8 participants will also 
take a pregnancy test  
5. All participants will additionally be required to obtain a blood draw at the CRC on week 4 
and week 8 in order to assess LFTs, glucose and CBC and to quantify medication levels. 
 
Procedures 
Outpatient procedures: All AUD women will be required to attend two outpatient visits per week 
for 10-weeks. All women will take part in Medical Management (MM) and Contingency 
Management (CM) protocols. All clinicians will be fully trained in these procedures, and educated 
specifically in the treatment needs of women, including relationship issues, caregiving status, 
anxiety, mood and eating132. In week 10 of treatment a 12-day taper schedule will be 
implemented 133, prior to discharge  
Dosing: Dosing will begin at Intake 2 appointment. Women receiving GXR will begin dosing at 1 
mg/d (days 1-7). Dosages will escalate to 2mg/d (days 7-21) and 3mg/g (day 21- onwards). 
Please see Appendix 5 for titration and updated taper schedule. Identical placebo tablets will be 
used. All guanfacine and placebo tablets will contain riboflavin in order to ensure compliance 
Medical management (MM) & contingency management (CM) for treatment adherence: The 
primary focus of the MM protocol134 is to assist clinicians in providing educational support 
strategies for maintaining medication adherence. It was designed for delivery in a primary care 
setting and as such is a suitable platform for use in outpatient clinical trials assessing new 
medications for alcohol 135137. Primary goals include promoting compliance via psycho-
educational methods as well as encouraging participation into self-help programs aimed at 
women134. The initial session will be 3045 minutes followed by 10 minute follow-up sessions 
once per week. In addition, all subjects will receive CM providing participants with the opportunity 
to increase chances of winning variable dollar prizes at study completion for kept appointments 
See Human Studies Section for full details of gender-specific recruitment goals (1.2) & CM 
protocol (4.1.3). 3.5.3 Outpatient Assessments: Primary Outcomes: All participants will be 
required to provide a urine and breathalyzer screen at each appointment. In addition, the Time-
Line Follow-Back Interview 130 will be used to assess all alcohol and nicotine use in the previous 
90 days at baseline and weekly during the 10 week treatment trial. Primary alcohol use outcomes 
will be: (1) time to initial drink and heavy drinking (men: ≥5 drinks; women: ≥4); (2) frequency: the 
total number of days of alcohol use; and (3) quantity: the average amount of alcohol use (no. of 
drinks) per occasion. Subjects will be considered drop-outs if they receive two phone calls and 
two letters inviting them to return. We will attempt to assess these early terminators at the time 
of discontinuation, at the 10 week termination point, and at the follow-up period. These women 
will be withdrawn from the study but considered in the intent-to-treat efficacy analyses. Secondary 
Outcomes: The following measures will be administered upon admission and twice weekly to 
assess the effects of GXR on craving, anxiety, mood, stress and regulation: AUQ; STAI; BDI; 
POMS-Bi; PSS; DERS; BIS-11 and Stroop. Data Safety: The following measures will be  
assessed: (i) Sitting and standing vital signs: every 15 minutes for one hour (ii) Liver function 
tests, glucose and Complete Blood Count (CBC): weeks 4 and 8 for abnormal values (iii) 
Systematic Assessment of Treatment Emergent Events (SAFTEE): every week to assesses the 
severity and duration of potential physical or health problems. Adverse events will be documented 
according to the criteria outlined in the Human Subjects section 6.0. (iv)  Blood draw to assess 


medication levels: weeks 4 and 8 (v) urine test to ensure the participant is not pregnant: weeks 4 
and 8. 
SAFETY GUIDELINES FOR THE COVID-19 VIRUS DURING: 
 
LAB SESSIONS:  
 
Safe distancing practices to be implemented during the pandemic crisis. NO stress 
challenge labs will be initiated until the STATE OF NEW YORK is cleared by the CDC, or 
NIH from this current DISASTER CRISIS.  
 
Laboratory Session: The laboratory challenge session will be conducted in the 10th week of 
outpatient treatment, when all participants have reached full dose. During the lab, subjects will 
be brought into the testing room at 1 PM following a smoke break to control for nicotine withdrawal 
if needed. A cotton ball will be placed inside the mouth to collect saliva, a blood pressure cuff and 
pulse oximeter used to periodically monitor vitals. After 10 minutes relaxation, baseline measures 
of alcohol craving, nicotine craving, anxiety, mood, HRBP and saliva will be collected -5 minutes 
prior to imagery exposure. Subjects will then be given headphones and asked to imagine the 
situation being described, 'as if' they were actively participating in it at that moment. The script 
(either stress or neutral) will be presented for exactly 5 minutes. All measures will be collected 
immediately following imagery (0) and again at +15 minutes and +30 minutes following imagery 
exposure. The Stroop task138 will be administered at baseline and following imagery only. All 
saliva will be placed on ice immediately, prior to storing at -20. Participants will then be given a 
1-hour break to relax, before repeating the procedure. All procedures will be identical, with the 
exception of the imagery presented (stress or neutral). The imagery order will be counterbalanced 
and neither the subject not the investigator will know the order of imagery presentation prior to 
the study. Relaxation instructions will be provided to ameliorate any residual effects of imagery. 
Imagery script development, imagery training and relaxation techniques will be conducted in the 
week prior to the laboratory sessions (see Human Subjects Section 2.4). 3.7 Follow-up 
interviews: Face-to-face interviews will be conducted 30 days after outpatient treatment 
completion. Urine and breathalyzer screens and a daily assessment of alcohol use will be 
collected using the TLFB method130 
All 30 day follow-up interviews will be conducted over zoom. 
STATISTICS 
Data Analyses Plan: Aim1: To evaluate the safety and tolerability of GXR (3mgs/day) in women 
with AUD. All potential adverse effects from both treatment groups will be recorded twice weekly 
and classified, per body system and reaction, in a frequency table. Comparisons between 
treatment groups will be conducted using t-tests, chi-square tests and ANOVAs as appropriate 
(H1a). Aim2: To determine the preliminary efficacy of 10-week GXR (3mgs/day) versus PLA 
treatment on outcome measures in women with AUD: All analyses will be conducted using the 
intent-to-treat sample, and survival analyses will be used to examine medication effects on time 
to relapse measures. In order to model time intervals between events, reoccurring event-time 
analysis will be performed 139. Hierarchical Linear Models (HLM) will be used to determine the 
effects of medication on continuous dependent variables, including % days abstinent and number 
of days in treatment (H2a), as well as secondary outcome variables, including craving, stress, 
anxiety, mood (H2b). Failures in treatment attendance will be accounted for by treating time as a 
random effect. Aim 3: To better determine the mechanisms underlying efficacy, by conducting a 
parallel laboratory study: Linear Mixed Effects (LME) models will examine the effects of 
medication on all Dependent Variables following stress versus neutral imagery within the 
laboratory (H3a). In order to elucidate the contribution of GXRrelated stress system changes in 


the laboratory on primary drinking outcomes, correlational, regression and survival analyses will 
be performed as appropriate (H3b). 
FUNDING STATUS, DETAILS 
NIAAA have stated that they are in the process of issuing a restricted NOA, pending IRB approval. 
  *HUMAN SUBJECTS RESEARCH PROTECTION FROM RISK SAFETY GUIDELINES 
FOR THE COVID-19 VIRUS DURING: 
 
LAB SESSIONS:  
 
Safe distancing practices to be implemented during the pandemic crisis. NO visits will be 
initiated until the STATE OF NEW YORK is cleared by the CDC from this current DISASTER 
CRISIS.  
 
Risk to Subjects 
Guanfacine extended release (GXR) treatment: GRX (Intuniv; manufactured by Shire) is an 
alpha2-adrenergic agonist that is known to preferentially bind to alpha-2A-adrenergic receptors 
which are highly concentrated in the prefrontal cortical regions 148. While initial reactions to 
Guanfacine are common, most symptoms are mild and include fatigue, sedation, light-
headedness, dizziness and vertigo, and tend to disappear either on continued dosing or following 
dose adjustment 18, 149. In fact, one major advantage of Guanfacine over other alpha2 
adrenergic agonists such as clonidine, is that it is less sedating with less hypotensive potential in 
both children and adults 73, 75, 111-113. No serious side effects have been noted in adult 
populations, between the ages 18-65 and there are no reported differences in responses between 
elderly and younger populations. The most serious side effect in pediatric patients are reports of 
mania and aggressive behavior in pediatric subjects with ADHD 150. This side effect has not 
been documented within adult populations and there is no evidence that Guanfacine will pose a 
greater risk to the proposed study sample than those seen in children and adults with ADHD. One 
potential risk of study participation, however, is that GXR may result in series adverse effects. As 
such, we have ensured that important precautions are in place to minimize this risk: (a) the dosing 
levels of GXR (3mgs) is within the range safely used in outpatient studies comprising children 
and adults with ADHD and tic disorders, commonly ranging from 1.5 to 4 mg/day 73, 75, 
149.Moreover, our prior published and pilot data using immediate release Guanfacine indicates 
that doses of 3mgs are well tolerated in substance and alcohol abusing men and women18, 92. 
(b) Participants` heart rate, blood pressure and self-reports of any potential adverse effects are 
monitored twice weekly while taking part in outpatient treatment (c) As this study represents a 
preliminary outpatient trial in women with AUD, we propose a longer than standard “lead in” phase 
of 21 days. Other outpatient studies recruiting young adults and administering higher doses, have 
employed 16-day titration phases 118. 
*Drawing of Blood: 
During each laboratory session, about four and a half ounces of blood will be drawn to measure 
stress system adaptations during the laboratory sessions. The amount of blood drawn for the 
tests is equal to about one fourth the blood obtained during a regular blood donation. People 
who are in good health are not usually affected by this kind of blood loss. However, to be safe, 
subjects will be warned against donating blood for at least six weeks after completing this study. 
The Imagery Procedures: 
Prior to admission, during intake procedures, a script development session will be conducted 
where information for script development is obtained. Our standard imagery script development 
procedures will be used to develop the 5-minute long personalized stress and neutral imagery 
scenarios. The stress imagery script will be based on participants’ description of a recent event 


that has happened to them in the past year, and which has been experienced as "most 
stressful". This will be determined using a 10-point visual analog scale, where a score of 10 = 
“most stressful”. Only scenarios scored as 8 or above will be used to develop into audio scripts. 
These may include breakup with a significant other, marital conflict or job-related stress. The 
neutral script will be developed from a personal nonalcohol-related relaxing situation. A 5-
minute ‘script’ of each scenario will be written using the Scene Construction Questionnaires 
technique 151, 152 where verbal and non-verbal responses and physiological and bodily 
sensations regarding the events will be incorporated into the personalized story. The script is 
then written following standard format and content procedures and subsequently recorded onto 
audiotape for presentation in the laboratory sessions 36. In addition to script development, all 
women taking part in the study will also receive imagery training in the same week in order to 
improve and standardize ability to visualize and imagine across participants. This will involve 
participants visualizing some commonplace non-emotional neutral and physically arousing 
scenes (e.g. reading a magazine; doing sit-ups). They will then be questioned about their ability 
to visualize and notice changes in physiological response. The method is adapted from Lang`s 
imagery training procedures 36, 152, and will serve to provide clear instructions on imagery 
procedure to reduce imagery variability. Both the script development procedures as well as 
exposure to imagery in the laboratory sessions involve reliving a personal stressful event. 
Moreover, the objectives of our paradigm are to induce enhanced and persistent (1 hour post 
imagery) anxiety, negative mood and alcohol craving within a controlled experimental setting. 
Although this can be particularly emotionally arousing during the sessions themselves, our 
previous experience has shown that by approximately 1 1/2 hours post imagery, there is very 
little anxiety that carries over thus posing minimal risk. It is, however, possible that some craving 
for alcohol and low affect may linger for a prolonged period following the laboratory sessions 
and in order to reduce these symptoms the following safeguards will be taken: (a) Subjects will 
participate in lab sessions in the Department of Psychiatry, in quiet, relaxation rooms. Subjects 
who have difficulty reducing their craving levels will participate in relaxation procedures to return 
craving levels to baseline both after the imagery sessions and prior to being discharged from 
the unit. We have found that relaxation procedures are particularly effective in reducing craving 
levels after stress exposure 153, 154. (b) To enhance response to relaxation procedures, 
subjects will also be trained on relaxation procedures prior to the laboratory sessions. (c) Any 
subject reporting residual craving or emotional discomfort after completion of laboratory 
sessions will receive an individual counseling session by a licensed psychologist experienced in 
therapy. The focus of this session will be coping with emotions and cravings. 
All subjects will be screened for the COVID -19 virus: subjects that have been exposed 
will be excluded until they are cleared by pcp 
 
*Physical examination and other laboratory data collection: 
All subjects recruited will receive a comprehensive physical examination and laboratory blood 
work to ensure good physical health status. The physical examinations will be conducted by the 
research nurse or the study physician located either at the Department of Psychiatry or the 
Outpatient Department at Stony Brook. Both will be well aware of study entry criteria and will 
manage physical and medical assessment accordingly. Routine laboratory blood work will 
include CBC, ESR, glucose, BUN/creatinine, electrolytes, lipid profile, liver function tests. 
Abnormal findings will be further evaluated by the study physician (Dr. Caceda) and appropriate 
medical advice will be provided. These are routine medical procedures and should add no risks 
other than those normally associated with these procedures. However, the research nurse 
coordinator, with advice from the study physician, will ensure that potential women who may be 
excluded from research due to medical reasons or pregnancy, or those who are in immediate 
need for medical or psychiatric attention, will be referred to the primary care/psychiatric care 
facilities in the network so they can receive the appropriate clinical care needed to address their 
condition. Breath screening and urine collections are performed primarily as safeguards to 


contamination of data and should add no risks other than those normally associated with these 
procedures.  
Nonspecific risks: 
Other risks from the outpatient counseling and rating scales are not beyond usual clinical 
procedures in a substance abuse treatment program. All research, medical and clinical staff are 
thoroughly and systematically trained in the confidentiality and ethical procedures associated 
with patient health information. Confidentiality of such data are specifically protected by Federal 
laws, and all records will be identified by code number only, with the master file kept under lock 
by the Principal Investigator and Project Manager. Medical Treatment for Injury: The consent 
form will specify that medical therapy will be provided for injuries sustained as a consequence of 
participation in this research. Should referral to specialists be needed, however, there are no 
outside funds available to cover the costs. 
 
Adequacy of Protection against Risks 
All subjects will be screened for the COVID -19 virus: subjects that have been exposed 
will be excluded until they are cleared by pcp 
 
 
Recruitment and consent procedures: 
Most assessments will be performed by virtual visits over the secured media site ZOOM with 
end to end encryption. However, the clinical portion of the recruitment intake process will be 
performed with the safety precautions using appropriate PPE set forth by the CDC . 
AUD treatment-seeking women will all be screened and interviewed by fully trained research 
staff who will ascertain interest in participating in the current project. If an individual expresses 
interest, she will receive an explanation of the study, risks, benefits and description of 
procedures. Subjects will be informed that participation in all components of the research is 
entirely voluntary and that all information collected will be kept confidential. All women will be 
asked to sign the research consent form if they wish to participate following resolution of any 
questions and clear indication that they understand the nature of the study and the consent. 
After obtaining written informed consent for participation in the study, the study physician will 
interview all women and review medical and psychiatric data prior to admission. 
Confidentiality: 
All women who take part in this study will be free to drop out of the study at any time without 
penalty. All data will be kept confidential except in cases of imminent danger to the participants. 
Such limits to confidentiality will be clearly explained to participants verbally and in the written 
consent forms. Confidentiality in regard to collected materials will be maintained via a numbered 
reference system maintained by the investigators. Subjects' names will appear only on a 
consent form and a "key" form kept by the PI in locked filing cabinets. Only the project manager 
and PI will have access to any forms specifying both participant name and subject number. All 
number coded subjective and biological data will be kept in locked offices with access only to 
investigators and research staff. Furthermore, good clinical and research practice procedures 
and HIPAA regulations will be followed. Subjects will be withdrawn from the study if they show 
severe psychological or symptomatic deterioration. They will subsequently be offered treatment 
as usual at the CNRU. Alternate treatment recommendations will be made and offered 
according to the subject's needs and wishes. 
 


Federal Certificate of Confidentiality: 
As the study involves the collection of sensitive data associated with alcohol use and the 
potential use of other illicit substances, a federal Certificate of Confidentiality will be obtained 
from NIH to further protect the information provided by subjects for research purposes. A 
component of this project will also involve assessing each potential participant’s alcohol and 
illicit substance use (including cannabis, cocaine, nicotine and heroin), at several intake 
appointments and during a follow-up interview, both by self-report as well as using urine 
toxicology and breath alcohol screens. If participants are intoxicated on arrival to any of these 
face-to-face appointments, appropriate preventative action may be taken. For example, in the 
case of alcohol intoxication, this may include removal of car keys and providing participants with 
adequate time in which to remain at the HSC in the attendance of a research assistant until their 
BAC is consistently below .02, as deemed appropriate by the National Advisory Council on 
Alcohol Abuse and Alcoholism (1989). Other forms of transport may also be offered including 
taxi or bus. 
Clinical deterioration, severe anxiety, depressive symptoms and suicidality: 
During the intake, outpatient and follow-up sessions, all women will be required to provide 
psychiatric information regarding anxiety and depression symptoms as well as suicidality by use 
of semistructured clinical interviews, such as The Structured Clinical Interview for DSM-IV; 
SCID-I; 119. If participants do report severe anxiety and /or depressive symptoms or suicidal 
ideation during any part of the study, either verbally to the clinical and /or research staff or via 
self-reported questionnaires, staff will conduct a further assessment of suicidality and will 
discuss the risk of imminent harm with the PI and the study physician. Referral for further 
evaluation and/or emergency treatment will be made. 
Relapse, and drop out: Every effort will be made to re-engage patients who miss 
appointments. If subjects have missed three consecutive appointments, all attempts will be 
made to bring the subject back to the outpatient clinic and after a comprehensive assessment of 
the subject’s treatment need, a formal referral will be made to appropriate inpatient, 
detoxification or intensive outpatient care. 
Potential Benefits of Proposed Research to the Subjects and Others 
Financial: Although the current study provides MM counseling and CM protocols known to 
decrease alcohol consumption155, the procedures do not have direct short-term benefits to the 
subjects. Thus, all participants will be paid $50 for the screening and baseline interviews at 
intake, $100 for each laboratory session, $50 for the follow-up interview, in addition to $25 for 
each week of outpatient treatment ($25 X 10 = $250) and the potential for money obtained via 
10-weeks of CM. 
Medical Management (MM): Each participant will be seen by a coordinator in our research staff 
individual with alcohol research and health experience, psychologist, or counselor. The general 
purpose of the counseling sessions are to: (1) acquire information about important concepts and 
aspects of recovery from addiction; (2) increase self-awareness of specific problems and issues 
in relation to addiction and recovery. This will be particularly geared towards issues pertaining to 
women, such as stress, self-esteem, domestic violence, parenting, caregiving status, trauma, 
anxiety, negative mood and eating (3) learn new coping skills to deal with problems contributing 
to or resulting from the addiction and to improve functioning. The focus of this psycho-
educational approach is on providing patients with frequent supportive contact, introduce them 
to key concepts about the recovery approach, and develop a sense of personal responsibility for 
recovery. 


Contingency Management (CM): CM has been shown to have the largest effect size of all 
psychosocial therapies for alcohol and substance abuse disorders 155, 156. As such, all 
women will also receive CM providing them with the opportunity to earn chances of winning 
dollar prizes of varying magnitudes. The chance of winning prizes will be contingent upon kept 
appointments, not clean urine toxicology screens. This will decrease the chances of CM 
masking the effects of the medication. For every two biweekly appointments attended, the 
chance to draw for a dollar prize will increase by one, making a total of 10 chances if all 
appointments are met. If appointments are missed the number of prize draw “chances” are reset 
to one. The participants draw from a prize bowl containing slips of paper stating either a dollar 
amount or “good job” (50% of the slips). The prizes will be in increments of $1 (44% of slips), 
$20 (6% of slips), and $100 (1 slip). All slips will be returned to the bowl at the beginning of 
each draw to maintain probabilities. The total prize amount will be added to the participants 
check on study completion. If subjects are unable to achieve abstinence within four weeks, they 
will be offered inpatient treatment or referred to a higher level of care at another facility. If a 
subject achieves abstinence but has occasional relapses, outpatient treatment will continue until 
either abstinence is sustained or a higher level of care is clinically indicated. 
Importance of the Knowledge to be Gained 
First, this study will contribute in providing important information regarding the role of the 
adrenergic system in stress-induced alcohol craving and relapse. Using a validated human 
laboratory model of stress-induced alcohol craving and relapse risk is a unique way of 
assessing bio-behavioral mechanisms underlying these processes which may hold wider 
implications for the assessment and treatment of a range of addictive disorders. Second, there 
is a critical need to develop new pharmacotherapies in alcoholism, especially for women. This is 
particularly significant as, to date there exists no FDA approved treatment that has been 
developed in women, or which targets stress pathophysiology in alcoholism (see Section 2.0). 
Moreover, understanding the mechanisms underlying such dysregulation and compulsive 
alcohol seeking, will provide information for the development of new tailored therapeutic agents 
for clinical testing. This study will also specifically provide important preliminary information on 
treatment efficacy of GXR in alcohol women with AUD with regard to safety, tolerability and 
ability to attenuate alcohol craving and drinking. 
  
H.   DATA SAFETY MONITORING PLAN (for more than minimal risk studies). THESE 
INDIVIDUALS ARE INDEPENDENT OF THE STUDY.  
Data Safety Monitoring Board: The Data Safety Monitoring Board for this study will include 
Kenneth Gadow, PhD, Director of Clinical Research, Cody Center for Developmental 
Disabilities at Stony brook (phone: 631-638-1549; email: kenneth.gadow@sbumed.org); and 
Evelyn Bromet, PhD, Distinguished Professor of Psychiatry and Preventative Medicine at Stony 
Brook (phone: 631-638-1920; email: evelyn.bromet@stonybrook.edu) ; and Jodi Weinstein, MD, 
Assistant Professor of Psychiatry at Stony Brook Medicine (phone: 631- 444 – 4000; email: 
Jodi.Weinstein@stonybrookmedicine.edu.)    
 
Dr Kenneth Gadow, PhD is a Professor appointed in the Department of Psychiatry at Stony 
Brook University. He is internationally known for his research in children with autism spectrum 
disorder, models of pathogenesis, ADHD, aggression, Tourette’s syndrome and 
psychopharmacology.  He is a Principal investigator on several NIH-funded 
psychopharmacology studies and is highly experienced in the requirements of data safety 
monitoring.  He is also independent of the current study. 


Dr. Evelyn Bromet, PhD is an internationally acclaimed Professor of Psychiatric Epidemiology in 
the Department of Psychiatry at Stony Brook. Her research has focused predominantly on 
environmental risk factors associated with the onset and progress of PTSD, depression and 
psychosis. She is also a past and current member of several NIH advisory committees and 
highly experienced in the conduct of NIH protocols. She is not an investigator on this study and 
will function as an independent monitor. 
Dr. Jodi Weinstein, MD is an assistant professor in the Department of Psychiatry at Stony Brook 
University. She was a medical student at Vanderbilt University and did her fellowship at 
Columbia University. She is not an investigator on this study and will function as an independent 
monitor.  
The DSMB members will evaluate all Adverse and Serious Adverse Events, and will assist the 
PI in preparing and sending the pertinent expedited reports to the Stony Brook IRB and the 
NIAAA program officer as outlined below. Dr. Jodi Weinstein will be the Physician on record and 
will be invited to all DSMB meetings. If the physician is unable to attend, he will be sent a copy 
of all Adverse Events and will be required to respond “I have reviewed all of the Adverse 
Events, and the Clinical Trial poses NO RISK AND MAY CONTINUE OR POSES RISK AND 
SHOULD NOT CONTINUE.” These notes will then be sent to IRB along with the Minutes. They 
will monitor the studies quarterly and review all adverse event sheets completed during that 
period. Although the proposed clinical trial and laboratory study includes generally safe 
procedures and we do not foresee termination of the study as a direct consequence of study 
procedures, if there is a need, the DSMB will assist the PI in making critical decisions regarding 
a particular patient continuing in a study for safety reasons. The DSMB will also review the 
summary of all Adverse and Serious Adverse Events, which will be reported annually to the 
Stony Brook IRB committee and the appropriate NIH Project Officer. 
Monitoring and reporting Adverse Events (AEs) and Serious Adverse Events (SAEs): 
Data on Adverse Events occurring during the course of conducting this study will be collected, 
documented and reported to the Stony Brook IRB board and to NIAAA. A summary of all AE’s 
will be prepared annually, by the project PI and the Data Safety Monitoring Board and submitted 
to the Stony Brook IRB committee and to NIAAA. The Stony Brook IRB requires the re-approval 
of study protocols at least annually and will not re-approve the protocol without such reports. 
Adverse Events (AE) will be defined on the basis of the NIH Guidelines on Data and Safety 
Monitoring for Intervention Trials. These guidelines define an AE as any reaction, side effect or 
untoward event that occurs during the course of the clinical trial, whether or not the event is 
considered related to the study manipulations. A new illness, symptom, unfavorable or 
unintended sign, or worsening of a pre-existing condition or abnormality will be considered an 
AE. Stable chronic conditions such as diabetes that are present prior to study entry and do not 
worsen will not be considered AEs. AEs will include events and symptoms reported by the 
subjects that are of clinical  importance as noted by the study staff. The AE Form will be used 
for recording the event and any follow-up information. The following Stony Brook IRB/FDA 
classification of AE “severity” and “attribution” will be used. 
Coding of Severity: 
0 = No adverse event or within normal limits 
1 = Mild adverse event 
2 = Moderate adverse event 
3 = Severe, resulting in psychiatric or medical hospitalization 


4 = Life-threatening adverse event5 = Fatal adverse event 
Coding of Attribution: 
1 = Unrelated to study interventions 
2 = Unlikely relationship to study interventions 
3 = Possible relationship to study interventions 
4 = Probable relationship to study interventions 
5 = Definite relationship to study interventions 
Reporting of Serious Adverse Events (SAEs): Each AE will be classified by the project PI on 
severity and attribution using the above coding and appropriate reporting procedures will be 
followed. Serious Adverse Events (SAEs) will be defined on the basis of the NIH Guidelines on 
Data and Safety Monitoring for Intervention Trials. An SAE will be any fatal event, any 
immediately life-threatening event, any permanent or substantially disabling event or any event 
that requires or prolongs inpatient hospitalization (a severity rating of 3 or above). Any 
Unexpected Event that suggests a significant hazard, contra-indication, side effect or precaution 
will also be reported.  
The project PI and the Data Safety Monitoring Board will promptly report all Unexpected 
SAEs to Stony brook IRB and to the NIH program officer within 48 hours, using the Stony 
Brook IRB adverse events reporting form.  The completed SAE Form will include 
demographic information, a narrative explanation of the event, and photocopies of any relevant 
source documents from the patient’s case report forms. The project PI will also address whether 
there is a need to re-design or amend the protocol, or a need to change the description of risk, 
either in the consent form or in the protocol. 
Reporting of other study-safety events: The project PI will inform the Data Safety Monitoring 
Board, the Stony Brook IRB committee and the NIAAA program officer promptly of any change 
in recruitment or other changes in this project that are relevant to safety, as well as any action 
taken by the Stony Brook IRB committee as a result of continuing review of this project. The 
NIH Project Officer will also be informed of any change in the status of the study protocol, 
including amendments to protocols, changes in informed consent process, or other problems 
that could affect the human subjects in the study. 
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STATISTICAL ANALYSIS PLAN 
 
Aim1: To evaluate the safety and tolerability of GXR (3mgs/day) in women with 
Alcohol Use Disorder (AUD). All potential adverse effects from both treatment groups 
were recorded twice weekly and classified. Descriptive statistics are displayed in a 
frequency table. 
Aim2: To determine the preliminary efficacy of 10-week GXR (3mgs/day) versus 
PBO treatment on outcome measures in women with AUD: Linear Mixed Effects 
(LMEs) models were used to analyze data from the intent-to-treat sample where, for all 
Dependent Variables (% no. of heavy drinking days, % no. of days abstinent, % drinks 
consumed on any one occasion, alcohol craving, depressive symptomatology, anxiety 
and emotion regulation), the Between Group Factors of Group (GXR, PBO) and Within 
Group Factors of Time-points (12-weeks), represented the Fixed Effects and Subjects 
represented the Random Effects. Demographic and drug use variables differing 
between Treatment Groups and associated with the Dependent Variables were entered 
as covariates into the models and a Compound Symmetry covariance structure was 
applied to the model. Descriptive statistics were additionally conducted on % no. of 
negative urines collected across the trial.