Randomized Controlled Trial Targeting Noradrenergic Stress Mechanisms in Alcoholism With Doxazosin
Phase: PHASE2
Conditions: Alcoholism
Sponsor: University of Wisconsin, Madison

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Title Page 
 
TITLE: RCT TARGETING NORADRENERGIC STRESS MECHANISMS IN ALCOHOLISM WITH 
DOXAZOSIN 
PI NAME AND INSTITUTIONAL AFFILIATION: JOHN J. CURTIN; UNIVERSITY OF WISCONSIN, 
DEPARTMENT OF PSYCHOLOGY 
PROTOCOL VERSION DATE:  11/07/19 
COORDINATING CENTER IDENTIFICATION (IF APPLICABLE): N/A 
CO-INVESTIGATORS (IF APPLICABLE): 
DR. CRAIG W BERRIDGE  
DR. ALEKSANDRA ZGIERSKA 
STUDY COORDINATORS: SUSAN SCHNECK 
FUNDING SPONSOR:  NIAAA  
CLINICALTRIALS.GOV IDENTIFIER: NCT02989493 
 
 

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Table of Contents 
Title Page ............................................................................................................................................................................... 1 
Project Summary and Abstract .......................................................................................................................................... 4 
Specific Aims ......................................................................................................................................................................... 5 
Background and Significance ............................................................................................................................................. 6 
A1. Drug Addiction, Norepinephrine, And Unpredictable Stressors .................................................................................. 6 
A2. Startle Potentiation During Stressor Exposure ............................................................................................................. 6 
A3. The No Shock, Predictable Shock, Unpreditable Shock (NPU) Task ............................................................................. 7 
A4. Preliminary Evidence .................................................................................................................................................... 7 
A5. Novel Treatments For Stress And Alcoholism Via Ne System ...................................................................................... 9 
A6. Why Repurpose Doxazosin? ....................................................................................................................................... 10 
Innovation ............................................................................................................................................................................ 11 
Research Design & Methods ............................................................................................................................................ 13 
C1. Brief Overview............................................................................................................................................................. 13 
C2. Participants and Recruitment Sites ............................................................................................................................. 13 
C3. General Procedures .................................................................................................................................................... 13 
C4. Doxazosin Dosing Schedule ......................................................................................................................................... 17 
C5. Medical Monitoring And Medication Compliance ...................................................................................................... 17 
C6. NPU Stress‐Reactivity Task.......................................................................................................................................... 18 
C7. Brief Motivational Interventions ................................................................................................................................. 18 
Statistical Analysis: ............................................................................................................................................................ 20 
Planned Data Analysis for Specific Aims ........................................................................................................................... 20 
Timeline ............................................................................................................................................................................. 20 
Protection of Human Subjects .......................................................................................................................................... 21 
D1. Risks to the Subjects ................................................................................................................................................... 21 
D2. Adequacy of Protection against Risks: ........................................................................................................................ 24 
D3. Potential Benefits of the Proposed Research to Human Subjects and Others .......................................................... 27 
D4. Importance of the Knowledge to be Gained .............................................................................................................. 27 
D5. Data and Safety Monitoring Plan................................................................................................................................ 27 
Data and Record Keeping:................................................................................................................................................ 30 
Data Management ............................................................................................................................................................ 30 
Confidentiality ................................................................................................................................................................... 30 

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Data Collection Methods .................................................................................................................................................. 30 
Study Records Retention Policy ........................................................................................................................................ 30 
Appendix A: Surveys, Questionnaires and Interviews .................................................................................................. 43 
Surveys and Questionnaires.............................................................................................................................................. 43 
Interviews .......................................................................................................................................................................... 43 
Appendix B: Participant Handouts ................................................................................................................................... 44 
Appendix C: Eligibility Criteria Checklist ......................................................................................................................... 45 
Appendix D: Glossary & Abbreviations ........................................................................................................................... 49 
Abbreviations .................................................................................................................................................................... 49 
Glossary ............................................................................................................................................................................. 49 
 
 
 

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Project Summary and Abstract  
 
Current pharmacotherapy for alcohol and drug addiction yields relatively low probability for attaining long-term 
recovery. The recent dramatic reduction in R&D by the pharmaceutical industry for novel medications to treat 
psychiatric conditions, particularly substance use disorders, provides a strong impetus to “repurpose” currently 
available compounds that may be effective treatment alternatives. Orally available, brain-penetrant 1-
noradrenergic (NE) receptor antagonists are widely used to treat hypertension. Additionally, 1-NE antagonists 
are increasingly used to treat post-traumatic stress disorder (PTSD), consistent with the well-documented role 
of NE in mediating multiple behavioral and physiological processes in stress. Stress is a significant contributor 
to alcohol/drug relapse. Stress-related reinstatement is a well-validated animal model of addiction and 1-NE 
antagonists reduce relapse in this animal model. NIAAA Director George Koob has made strong calls for 
translational research on stress-mechanisms in humans. This preclinical evidence in animals suggests the use 
of 1-NE antagonists may be useful in relapse prevention including stress-related relapse. To test this 
hypothesis, we propose two complementary preclinical and clinical objectives in humans: 
1. To translate the preclinical evidence from animal models to stress-induced relapse in humans via direct 
pharmacological antagonism of the NE system in abstinent alcoholics with doxazosin, an 1-NE blocker. 
 
2. To screen the efficacy of doxazosin to target stress-related relapse mechanisms in abstinent alcoholics as 
a cost-effective first step to repurpose this 1-NE antagonist for relapse prevention in addiction. 
 
These two objectives will be accomplished in a randomized controlled trial (RCT) of recently abstinent 
alcoholics, to examine the efficacy of 8 mg doxazosin (vs. placebo, between-subjects) on stress reactivity and 
clinical outcome measures (e.g., heavy drinking) during an 8 week treatment period. We assess doxazosin’s 
impact on stress-related relapse mechanisms using a well-validated human model of stressor reactivity (NPU 
task) at baseline (pre-treatment), and after 4 weeks and 8 weeks of treatment. The NPU task has strong 
translational ties to both methods and measures from the preclinical literature in animals. This task has 
demonstrated reliable, robust effects of drug administration and drug deprivation in drug dependent users. As 
such, it serves as an attractive early surrogate endpoint post-treatment to assess treatment efficacy and 
examine stress mechanisms. Repurposing existing pharmaceutical agents has recently been promoted by NIH 
director, Francis Collins, as a research priority. Tom Insel and others have strongly advocated for the 
development and use of early surrogate endpoints in clinical research. This project aligns well with the NIMH 
RDoC focus on dimensions of observable behavior and neurobiological measures in psychopathology 
research. This project also anticipates changes at NIMH to capitalize on simultaneous examination of 
mechanism and outcome in RCTs. 
 
 

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Specific Aims 
Current pharmacotherapy for alcohol and drug addiction yields relatively low probability for attaining long-term 
recovery. The recent dramatic reduction in R&D by the pharmaceutical industry for novel medications to treat 
neuropsychiatric conditions, particularly substance use disorders, provides a strong impetus to repurpose 
currently available compounds that may be effective treatment alternatives1,2. Orally available, brain-penetrant 
1-noradrenergic (NE) receptor antagonists are widely used to treat hypertension and related conditions. 
Additionally, 1-NE antagonists are used in the treatment of post-traumatic stress disorder (PTSD)3, consistent 
with the well-documented role of NE in mediating multiple behavioral and physiological processes in stress4. 
Stress is a significant contributor to relapse5,6. Stress-related reinstatement is a well-validated animal model of 
addiction7–9 and 1-NE antagonists reduce relapse in this animal model10. Additional evidence suggests that 
NE contributes to drug- and cue-related reinstatement/relapse9,11. This preclinical evidence in animals 
suggests the use of 1-NE antagonists may be useful in relapse prevention including stress-related relapse12–
15. To test this hypothesis, we propose two complementary preclinical and clinical objectives in humans. 
1. To translate the strong preclinical evidence from animal models to stress-induced relapse in humans via 
direct pharmacological antagonism of the NE system in abstinent alcoholics using doxazosin, an FDA-
approved 1-NE antagonist.  
 
2. To screen the efficacy of doxazosin to target stress-related relapse mechanisms in abstinent alcoholics as 
a cost-effective first step to repurpose this 1-NE antagonist for relapse prevention in addiction16–18. 
 
These objectives will be accomplished by between-subject, double-blind placebo-controlled administration of a 
therapeutic dose of doxazosin (8 mg/day) to recently abstinent alcoholics for 8 weeks. We assess doxazosin’s 
impact on stress-related relapse mechanisms using a well-validated human model of stressor reactivity 
(unpredictable shock threat in the NPU task19) at baseline, 4 weeks and 8 weeks post-treatment. The NPU task 
has strong translational ties to both methods and measures from the preclinical literature in rodents and non-
human primates20,21. This task has demonstrated reliable, robust effects of drug administration and drug 
deprivation in drug dependent users22–26. As such, the NPU task serves as an attractive early surrogate 
endpoint to examine stress mechanisms. Clinical outcome measures (heavy drinking days) will be measured 
throughout the 8-week medication period. To accomplish our two objectives, we pursue two specific aims: 
AIM 1: Examine effects of a therapeutic dose of doxazosin on responses to unpredictable stressors in 
NPU task. The aim is to obtain preliminary evidence via a laboratory surrogate endpoint to repurpose 
doxazosin for the treatment of stress-induced relapse mechanisms in alcoholism. PREDICTIONS: Following 
four and eight weeks of therapeutic dosing, doxazosin (8 mg vs. placebo, between-subjects) will selectively 
reduce response to unpredictable (vs. predictable) stressors indexed by physiological defensive reactivity 
(startle potentiation) in abstinent alcoholics. 
AIM 2: Examine effects of a therapeutic dose of doxazosin on early clinical outcome measures. The aim 
is to obtain additional evidence via clinical outcome measures to repurpose doxazosin for the treatment of 
stress-induced relapse mechanisms in alcoholism. PREDICTIONS: Following eight weeks of therapeutic 
dosing, doxazosin (8 mg vs. placebo, between-subjects) will decrease heavy drinking days during the 
medication treatment period.  
 
 
 

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Background and Significance 
A1. Drug Addiction, Norepinephrine, And Unpredictable Stressors 
Stressors are potent instigators of relapse to drug use in clinical research with abstinent drug dependent 
humans and preclinical relapse models (i.e., stressor-induced reinstatement) in rodents5,7. In rodents, brain 
norepinephrine (NE) levels are elevated in response to both discrete stressors27–32 and drug deprivation9,33. In 
humans, plasma and CSF NE-metabolite levels are elevated during alcohol deprivation34–36 and in response to 
acute stressors37–39, suggesting similar NE involvement in drug withdrawal and stressor response in humans. 
In rodents and non-human primates, manipulations that increase central nervous system (CNS) NE levels 
(e.g., yohimbine, NET inhibitor, NE injections) increase drug-seeking behavior across a wide class of drugs 
including alcohol40, nicotine41, cocaine42–44, heroin45, and methamphetamine46. Although all three central 
noradrenergic receptor classes (post-synaptic 1 & ß; autoreceptor 2) are implicated in the etiology of 
addiction, 1-NE receptors may be particularly impactful on stress-induced relapse and drinking/drug use 
outcomes more generally. Doxazosin and prazosin, which are selective noradrenergic 1-NE receptor 
antagonists, reduce baseline alcohol consumption47, particularly in alcohol-preferring genetic strains of rats48–
51. Noradrenergic 1-NE antagonists block escalation of drug-seeking behavior in rodent models of 
dependence for alcohol47, cocaine52, opioids53, and nicotine54. Chronic prazosin treatment concurrently reduces 
anxiety-like behavior and alcohol intake in rodents55. Most critically, systemic administration of 1-NE 
antagonists blocks reinstatement of alcohol self-administration that is induced by unpredictable footshock 
stressors or directly increased NE via yohimbine10. Based on this and other preclinical evidence, primarily from 
animal models, 1-NE antagonists have obvious treatment potential for reducing stressor-induced relapse in 
alcohol and other drug addiction. However, clear translation of this preclinical evidence from animals on the 
role of 1-NE in stress-induced relapse among human abstinent alcoholics requires explicit manipulation of the 
NE system during stressor exposure. Thus, one important translational aim of the proposed research is to 
manipulate the NE system via eight week treatment with 8mg/day doxazosin (an 1-NE receptor antagonist) 
and confirm its impact on response to stressors in human alcoholics with a sensitive and precise laboratory 
stressor task that putatively engages this NE system. 
Unfortunately, “stress” remains ill-defined and inconsistently operationalized in both preclinical and clinical 
research on drug addiction in humans. Research on stress responding implicates central nervous system, 
endocrine, and peripheral biological systems that produce changes in affect, arousal, and attention56–59. 
However, research is rapidly accruing to suggest that the CNS negative affect component of the stress 
response, and more specifically, acute response to a subset of stressors that are unpredictable (vs. 
predictable), may provide a critical mechanism to account for stressor-induced relapse among drug dependent 
rodents and humans7. These unpredictable stressors (i.e., ambiguous or otherwise ill-defined, low probability, 
temporally imprecise stressors) appear to produce phenomenologically distinct responding via partially 
separable neural mechanisms relative to predictable stressors (i.e., well-defined, high probability, imminent 
stressors)20. Critically, the NE system has been selectively implicated in response to unpredictable rather than 
predictable stressors20. Moreover, unpredictability is a cardinal feature of the typical stressors that humans 
experience in their daily lives (e.g., uncertain job/financial security, unpredictable interpersonal conflicts, legal 
problems, inconsistent social support, illness/death of self or family) and these types of stressors often 
instigate relapse. As such, examination of NE mechanisms in stress-related relapse requires measures in 
tasks that can parse unpredictable vs. predictable stressors. 
A2. Startle Potentiation During Stressor Exposure 
Programmatic affective neuroscience research has relied heavily on startle potentiation as a primary measure 
of defensive system activation to parse the neural mechanisms involved in response to unpredictable vs. 
predictable stressors. In addition, the use of startle potentiation to index affective response to stressors among 

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rodents, non-human primates, and humans has provided an important animal-human translational bridge in 
this research21,60,61. As such, we have detailed knowledge of the neurobiology of the startle response and its 
potentiation21,61–63. Startle potentiation also can be measured with minimal disruption of task-related processes 
and reduced influence by demand characteristics than measures under volitional control (e.g., self-report). 
In preclinical rodent models, startle potentiation during unpredictable stressors has strongly implicated NE and 
corticotropin-releasing factor (CRF) sensitive pathways through the lateral divisions of the central amygdala 
(CeA) and bed nucleus of the stria terminalis (BNST)20,64,65. In contrast, distinct pathways through the medial 
division of the CeA appear responsible for startle potentiation during predictable stressors20,66,67. A large corpus 
of research implicates CRF as a critical mediator of the stress response, particularly to unpredictable 
stressors20,68, and NE is a powerful modulator of extrahypothalamic CRF69–71. In rodents, 1-NE agonists elicit 
stress-related behaviors (e.g., decreased exploratory behavior) and 1-NE blockade reduces stress-induced 
changes in behavior70. Specifically, 1-NE antagonists reduce startle potentiation in rodents due to stressor 
exposure72, direct manipulations of CRF69, and other stress-relevant neurotransmitter systems (e.g., 
dopamine73). Baseline startle response in prospectively predicts subsequent voluntary alcohol intake and 
preference74, representing a translational marker of risk prediction. In humans, the startle response is 
potentiated by pharmacological challenge that elevates NE levels via yohimbine in healthy controls and 
particularly in drug dependent populations75,76. However, the effect of an 1-NE antagonist on startle 
potentiation has not been examined in humans to date. Thus, startle potentiation during unpredictable 
stressors represents 1) a psychophysiological index of heightened response to stressors, 2) is sensitive to 
CNS NE system activation in rodents, 3) has well known neurobiological substrates in rodents, and 4) and can 
be assessed in rodents, non-human primates, and humans, positioning it as an attractive translational 
measure. 
A3. The No Shock, Predictable Shock, Unpreditable Shock (NPU) Task 
Research in affective neuroscience has relied extensively on cued stressor (e.g., threat of electric shock) tasks 
to explicate psychological and neurobiological mechanisms involved in the negative affective response to 
stressors in animals and humans. Christian Grillon at NIH has developed a cued-stressor task called the “No 
Shock, Predictable Shock, Unpredictable Shock” (NPU) task to carefully contrast response to unpredictable vs. 
predictable stressors19,77. Predictable shock conditions involve administration of 100% cue-contingent, 
imminent electric shock. Unpredictable shock conditions involve temporally and probabilistically uncertain 
administration of shock. Startle potentiation during unpredictable shock (relative to no-shock blocks) provides 
the primary measure of negative affective response to stressors that in rodents engages both NE system 
activity and elicits etiologically relevant behaviors for addiction (i.e., stressor-induced reinstatement). This task 
represents a direct translation of methods and measures used in rodents to parse the neural mechanisms 
involved in response to unpredictable vs. predictable stressors20,66. Dr. Curtin’s (PI) laboratory has successfully 
used this task with humans in a number of studies to date22,24,78,79. We will use startle potentiation in this task in 
the proposed research as an assay of an early surrogate endpoint to assess treatment efficacy (AIM 1). 
A4. Preliminary Evidence 
Recent research from Curtin’s lab (R03 AA13422; R01 AA15384; R01 DA033809; R36 DA022373; P50 
DA19706) provides compelling evidence that 1) unpredictable stressors in the NPU and related tasks 
potentiate the startle response, 2) anxiolytic drugs robustly and selectively reduce startle potentiation during 
unpredictable (vs. predictable) stressors, and 3) drug deprivation or abstinence robustly and selective increase 
startle potentiation during unpredictable (vs. predictable stressors). 
Moberg & Curtin (2009) demonstrated that a moderate dose of alcohol (target BAC= 0.08%) selectively 
reduced startle potentiation during unpredictable but not predictable threat of electric shock in the NPU task 
(see red box in left panel of Figure 1)22. In other research, Curtin and colleagues demonstrate similar selective 

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effects of varying doses of alcohol on unpredictable stressors when unpredictability was established via 
manipulation of the timing78, probability24, intensity79, and location80 of the threat. In the more recent of these 
studies79,80, self-reported negative affect was also measured and it displayed comparable selective effects of 
alcohol during unpredictable stressors. Similarly, benzodiazepines also selectively reduce startle potentiation 
to unpredictable stressors81. These studies provide evidence that startle potentiation in the NPU and related 
tasks that manipulate stressor unpredictability provide a sensitive index of the effects of pharmacological 
agents on negative affective response to stressors. 
In a parallel line of research, Curtin and colleagues have demonstrated that drug deprivation or abstinence 
selectively increases startle potentiation to unpredictable (vs. predictable) stressors. For example, Moberg & 
Curtin (2012)26, demonstrated that alcoholics in early (1-8 weeks) abstinence displayed selectively increased 
startle potentiation during unpredictable (vs. predictable) shock threat relative to matched controls (see red box 
in right panel of Figure 1). Similarly, cigarette smokers displayed elevated startle response selectively during 
unpredictable stressors (vs. predictable stressors) after 24-hours of nicotine deprivation compared to non-
deprived smokers23. Heavy daily marijuana smokers showed significantly increased startle potentiation during 
unpredictable stressors after three days of marijuana deprivation relative to non-deprived smokers and non-
smoker controls25. These studies demonstrate that selectively elevated startle potentiation during unpredictable 
stressors provides an objective, non-invasive physiological assay of the effects of drug deprivation and 
abstinence across alcohol and other addictive drugs. 
This human data, in combination with ample evidence from rodent models on NE and startle potentiation 
during unpredictable threats20,69,82,83, support our use of a manipulation of the NE system via an 1-NE 
antagonist (doxazosin) in the NPU task to advance translational research to target mechanisms for novel 
pharmacological treatments of stress-induced relapse in humans (Preclinical objective 1; AIM 1). In addition, 
the body of preclinical evidence on startle potentiation during unpredictable stressors in animals and humans 
supports the use of the NPU task as an early surrogate endpoint, which combined with clinical outcome 
measures, can be used to provide preliminary evidence of the efficacy of doxazosin as a treatment to reduce 
stress-induced relapse (Clinical objective 2; AIMS 1-2). Validation of doxazosin’s effects on NPU task via 
clinical outcomes would lay the groundwork for using the NPU task to screen (e.g., surrogate endpoint) for 
future drug development (e.g., CRF-antagonists) prior to moving to larger/longer and more expensive clinical 
trials. 

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We believe this preliminary evidence also establishes that Curtin’s laboratory has the expertise necessary to 
recruit clinical samples of alcohol and other drug dependent users, precisely manipulate and measure stress, 
and safely administer drugs in the laboratory. Curtin’s lab has the infrastructure to conduct clinical trials. His 
current R01 (DA033809) examines the impact of treatment with nicotine replacement therapy on stress 
mechanisms in smokers (via NPU task) and their predictive utility regarding smoking cessation. Curtin has 
recruited Co-Is and consultants with complementary expertise in randomized controlled trials and clinical and 
research administration and management of 1-NE antagonists in humans and rodents (see publications and 
grant support from biosketches of Berridge, Zgierska, Ahearn, and McKee). Of note, Dr. Ahearn has extensive 
experience conducting RCT with 1-NE antagonists as the site PI for a multi-center national VA cooperative 
study to evaluate the efficacy of prazosin as a treatment PTSD related nightmares in combat veterans. 
A5. Novel Treatments For Stress And Alcoholism Via Ne System 
A number of FDA-approved pharmaceutical compounds that have effects on the central NE system have been 
clinically available for decades, primarily for their peripheral effects for the treatment of hypertension and 
related cardiovascular health issues. These drugs all effectively reduce the effects of NE by either blocking the 
1 (e.g., doxazosin, prazosin) or  (e.g., propranolol, carvedilol) receptors on the post-synaptic neuron or 
activating the pre-synaptic 2 autoreceptor (e.g., clonidine, lofexidine) to inhibit further NE release. There is 
mounting preclinical evidence that all three classes of receptors are intricately involved in the stress response 
and also are critical mechanisms for stress-induced relapse in addiction. Indeed clonidine is recommended as 
a second-line medication for tobacco cessation84 and widely used to treat the physical withdrawal syndromes 
of alcohol and opioid withdrawal85. However, due to the side effect profile (e.g., sedative effects), clonidine is 
often not well tolerated as a long-term maintenance medication84,86–88. Similarly, propranolol is commonly used 
off-label to treat somatic symptoms of performance anxiety, but recent work has yielded mixed evidence for the 
treatment of other stress-related disorders such as PTSD89,90. Thus, although there is strong preclinical 
evidence to support the investigation of all three classes of drugs as treatments, 1-NE antagonists (e.g., 
doxazosin, prazosin) appear to be the most promising candidate class for therapeutic effects on stress-related 
relapse. 

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For example, prazosin, a highly selective (Ki=0.12–0.31)91,92 1-NE receptor antagonist, has become the focus 
of a promising body of research on the treatment of post-traumatic stress-disorder (PTSD) and alcoholism93,94, 
which are frequently comorbid and share a common feature of heightened stress-reactivity. Over the past 
decade, Raskind and colleagues have led a series of clinical trials that demonstrate prazosin is an effective 
treatment of hyperarousal, sleep-disturbances, and global functioning among patients with PTSD3,95–98. During 
the course of these studies they anecdotally observed that individuals with both PTSD and alcoholism also 
stopped or reduced their alcohol use. Encouraged by these findings, Simpson, and colleagues (2010)12 
conducted a small (N = 24) Phase 2 randomized clinical trial for alcohol dependence and found that prazosin 
(up to 16 mg/day for 6 weeks) reduced the drinks per day and number of days drinking in the final weeks of 
treatment. 
In another small trial (N = 17), Fox and colleagues (2012)13 demonstrated that among treatment-seeking 
alcohol dependent adults, prazosin (16 mg/day for 4 weeks) reduced self-reported alcohol craving and 
negative affect in response to guided imagery exposure to stress. This is the first evidence in humans 
implicating 1-NE in stress-induced relapse in addiction. However, this surrogate endpoint of stress-related 
imagery reactivity has less direct ties to preclinical rodent models of stress reactivity than our model of startle 
potentiation in the NPU task. Furthermore, the primary outcome measures were self-reported negative affect 
and measures of peripheral nervous system activation (e.g., cortisol, ACTH). Although there has been 
considerable interest in the field regarding abnormalities in HPA axis functioning among human drug 
dependent individuals, George Koob and others have provided compelling evidence that CRF and NE 
pathways within the central nervous system, rather than the periphery, are the key mediators of stress-induced 
relapse mechanisms7,68. Startle potentiation during unpredictable stressors provides a measure that has 
stronger direct ties to CNS stress system activity in the extended amygdala, which mediates relapse in 
preclinical rodent models7,20. 
These initial positive findings in humans12,13 have generated substantial excitement in the field that 1-NE 
antagonists, including prazosin and doxazosin, may represent novel treatments for alcohol dependence99,100. In 
particular, 1-NE antagonists may provide longer term adjunct therapy (i.e., maintenance up to several years 
or longer) to support relapse prevention in the face of stressors. 1-NE antagonists are not contraindicated 
with first line treatments for alcohol dependence and in fact prazosin has been found to increase the 
effectiveness of naltraxone in reducing alcohol consumption in rodent models101. As further evidence of this 
excitement for 1-NE antagonists for treatment, NIAAA has recently funded two larger RCTs (N = 120-150) to 
investigate the efficacy of prazosin for alcoholism treatment (Clinical Trials: NCT00762710 & NCT00585780). 
A6. Why Repurpose Doxazosin? 
As the preliminary evidence of prazosin’s efficacy has mounted over the past few years, attention is now 
poised to shift to another, perhaps even more promising 1-NE receptor antagonist, doxazosin. Doxazosin has 
a similar chemical structure to prazosin, but has a more favorable clinical profile for alcoholism treatment. 
Importantly, doxazosin has a significantly longer half-life (16-22hrs102) compared to prazosin (2-3hrs103). 
Therefore, doxazosin only requires once/daily dosing as opposed to 2-3x/day dosing of prazosin. This is not 
insignificant, as medication compliance represents a major obstacle in treatment of substance use disorders. 
Both medications have been used for decades with millions of patients demonstrating good safety profiles and 
generally well tolerated side effects. Furthermore, in normotensive adults doxazosin can be used at morning or 
night and has minimal hypotensive effects (particularly compared to prazosin)104,105, increasing its utility in 
clinical practice. Of practical importance, doxazosin is available in generic formulation and therefore affordable. 
A nascent body of research has begun to support the use of doxazosin for the treatment of PTSD, alcoholism, 
or other drug dependence. In 2013 Rasmussen and colleagues provided the first preclinical evidence that 

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doxazosin reduces alcohol drinking in alcohol-preferring rats51. De Jong and colleagues demonstrated that 8 
mg doxazosin improved PTSD symptoms in a small (N=12), open label trial106; currently being followed up in 
the VA system (NCT01959022). Doxazosin (4-8 mg/day) reduced subjective pleasure associated with acute 
cocaine administration107 and increased the number of cocaine-negative urine screens (vs. placebo) in a pilot 
treatment study108. Our consultant, Dr. Sherry McKee, is currently conducting a trial examining the effects of 4 
mg or 8 mg doxazosin (vs. placebo) on surrogate endpoints for stress-induced smoking lapse behavior (using 
a lab model not suitable for alcoholics; NCT01730846). There is also one ongoing NIAAA-funded Phase 2 RCT 
of 16mg/day doxazosin treatment for alcoholism that is investigating clinical outcomes broadly, but not 
mechanisms of change or stress-relevant processes specifically (NCT01437046). 
Our application builds on the animal and human preclinical evidence of the role of 1-NE mechanisms in 
stress-related relapse, promising evidence of prazosin’s treatment efficacy, clear practical clinical advantages 
of doxazosin relative to prazosin, and nascent but encouraging evidence with doxazosin. We believe our 
Phase 2 clinical trial of doxazosin focused on an early surrogate endpoint of unpredictable stressor reactivity 
(i.e., 4 week NPU task), with complementary clinical outcomes (i.e., heavy drinking measures), is well timed to 
be highly impactful (Clinical objective 2; AIMS 1-2). We believe that the parallel pursuit of mechanism 
(Preclinical objective 1; AIM 1) in this application further increases the potential impact of this research.  
Innovation 
This research is innovative in its tight translation of research findings from animal models to the examination of 
human addiction etiology and treatment (“bench to bedside”) using tasks (NPU task), measures (startle 
potentiation), and manipulations (1-NE antagonist) that have been used in almost identical form in both 
animals (rodents, non-human primates) and humans20. Cross-species translational research is common, but 
often done with methods that are so divergent across species that successes and failures alike are difficult to 
interpret unambiguously. This is not the case with the research proposed in this application. Although the 
animal preclinical evidence for NE stress mechanisms is well established, direct manipulation of this system in 
humans via administration of an 1-NE antagonist is innovative. 
This research is innovative in its simultaneous pursuit of both preclinical animal to human translation of 
mechanism and human preclinical to clinical translation of this mechanism to treatment. This allows us to 
simultaneously use our intervention (1-NE antagonist) as a treatment for alcoholism (AIM 2) while also 
probing for mechanisms in the etiology of alcoholism with respect to neuroadaptations in the stress system 
resulting from chronic alcohol use7 (AIM 1). This approach anticipates changes that NIMH Director Tom Insel 
will implement for future RCTs funded by NIMH109–111, but which remain uncommon in addiction research. 
This research is also innovative in its use of a laboratory surrogate endpoint to screen drug efficacy (AIM 1). 
David Kessler, former FDA Commissioner, has observed that the considerable advances in AIDS research can 
be attributed, in part, to the development of “surrogate endpoints” such as HIV viral load that index treatment 
effects in randomized clinical trials far earlier than the obvious clinical endpoint of survival duration. Kessler 
and others (e.g., Insel, Hyman) have strongly advocated the development of such surrogates for other 
diseases: measures that index effects that are linked with ultimate outcomes, but that can be obtained 
relatively quickly and inexpensively1,17,112,113 (AIM 1 & 2). 
Our use of startle potentiation during unpredictable stress in the NPU task is also consistent with the “Fast Fail 
Trials (FAST)” initiative114 at NIMH that seeks to identify new or repurposed compounds that merit more 
elaborative testing concomitant with efforts to identify targets in the brain for the development of additional 

12 
 
candidate compounds. Compounds that are found to engage a target in the brain and alter an indicator of brain 
function advance quickly for additional evaluation. 
Insel also clearly argues that given substantial cuts in R&D budgets for new psychiatric drugs at most major 
pharmaceutical companies the near term outlook of novel molecular targets is grim1,2. Therefore, it is critical to 
take advantage of existing compounds with proven safety record acting on neurotransmitter systems that have 
been implicated in the etiology of psychiatric disorders. Repurposing existing pharmaceutical agents has 
recently been promoted by NIH director, Francis Collins, as a research priority1,115,116. The current proposal is 
one clear example of this theme to screen doxazosin for repurposing for the treatment of stress-induced 
relapse in alcoholism (AIM 2). 
Our focus on startle potentiation to unpredictable and predictable stressors that can be measured along a 
continuum from normal to abnormal aligns well with the current paradigm shift advocated by the NIMH’s 
Research Domain Criteria (RDoC). Briefly, RDoC calls for a dimensional approach to studying the roots of 
human behavior at multiple levels of analysis that cuts across DSM diagnostic categories1,117–120. Our proposed 
research examines individual differences defined within the Negative Valence System (i.e., acute threat/fear to 
predictable stressors and potential threat/anxiety to unpredictable stressors) using a task recommended by the 
NIMH workgroup121. Furthermore, we index these dimensions across levels of analysis (neurotransmitter, 
physiology, self-report, drinking behavior). Although this task is used to study abnormal processes in abstinent 
alcoholics, it exemplifies an approach to evaluate stress-reactivity dysregulation that spans not only multiple 
addictive drugs (e.g., tobacco, marijuana, opiates); but likely other disorders (e.g., PTSD) that may share a 
common neuroadaptation that manifests as a heightened stress response. 
 
 

13 
 
Research Design & Methods 
C1. Brief Overview 
Recently abstinent (1-8 weeks) alcoholics will be recruited to participate in an eight-week double-blind, 
randomized placebo-controlled trial (RCT) examining the effects of an 1-NE antagonist (doxazosin) on the 
defensive (physiological) response to stressors using a well-validated animal-human translational stressor task 
(NPU task). Study Visit 1 provides a pre-treatment baseline assessment of participants’ NPU task stress-
sensitivity prior to doxazosin/placebo administration. Next, participants are randomly assigned between-
subjects to initiate an 8-week dose escalation schedule up to 8 mg maximum doxazosin dose or placebo as 
they continue their efforts to abstain from alcohol. After four weeks (Study Visit 2) of treatment, participants will 
return to complete the NPU task again, and at both four weeks (Study Visit 2) and eight weeks (Study Visit 3), 
to assess clinical outcomes. These visits allow for evaluation of the effect of a therapeutic dose of doxazosin 
on the early surrogate endpoint of stress-reactivity (unpredictable shock threat in NPU task; Visit 2; AIM 1) and 
proximal clinical outcomes (heavy drinking days; Visits 2 & 3; AIM 2).  
C2. Participants and Recruitment Sites 
Participants: We will recruit abstinent alcoholics (38% female) aged 18-65 years. Participants will meet criteria 
for Alcohol Use Disorder with at least moderate severity (>4 DSM-5 criteria) and be at least one but no more 
than eight weeks abstinent from alcohol use at Screening Visit, and still abstinent at Visit 1. Participants who 
are eligible at screening but lapsed at Visit 1 will be rescheduled when they are again at least 1 week 
abstinent. Participants will be excluded if they have a lifetime history of severe and persistent mental illness 
(SPMI; e.g., bipolar disorder, schizophrenia, suicidal ideation or psychosis) or current substance use disorder 
and is not currently pursuing abstinence (other than alcohol or nicotine). Participants with co-morbid Axis 1 
disorders will be included unless they are using medications that affect the startle response or contraindicate 
doxazosin use. 
Participants must be able to read and write in English and have normal or corrected-to-normal vision and 
hearing. Participants will be excluded for: color blindness as task stimuli include colored geometric shapes; use 
of current medications acting directly on the noradrenergic system (e.g., clonidine, propranolol); any medical 
condition or concomitant medication that contraindicates the administration of doxazosin or electric shock. 
Women must test negative for pregnancy in a urine screen at all interim study visits, agree to use a reliable 
form of birth control, and may not be breastfeeding during the study. See Appendix for full eligibility criteria. 
Recruitment sites: We plan to recruit participants from 5 local treatment sites across two large healthcare 
centers: Access Community Health Centers and Journey Mental Health Center. Curtin has pre-existing 
connections with both centers as recruitment sites in other funded research (R01 AA024391). These sites were 
selected to support recruitment of a diverse set of patients, adequate patient flow for study recruitment, and 
patient access to the study site. Journey Mental Health Center provided treatment to approximately 1500 
patients with alcohol use disorder in 2013. Access Community Health provided treatment to approximately 
3000 patients with alcohol or other substance use disorder in 2013.  We will also be doing community 
recruitment by posting information in places likely to be seen by the target population.  This would include 
locations such as Alcoholics Anonymous meetings and buses and online sites like Facebook and Craigslist. 
We will also recruit participants via advertisements on television and radio stations.  
C3. General Procedures 
All study visits, with the exception of the screening visit, will take place in the Clinical Research Unit (CRU) 
outpatient unit at the University of Wisconsin Hospital (see letter of support from CRU). All participants will 
complete a total of three outpatient study visits in addition to the screening visit (see Table 1 for outline of 
procedures).  

14 
 
At the screening visit, which will take place at the Addiction Research Center offices, general laboratory 
procedures and risks and benefits will be explained to the participants and informed consent will be obtained. 
Inclusion/exclusion criteria will be confirmed using interviews conducted by a bachelors- or master-level clinical 
psychologist (under direct supervision of a licensed clinical psychologist), a urine pregnancy test (females 
only), blood pressure and heart rate, and self-report questionnaires (Medical Screening Questionnaire) (see 
Appendix C). Participants will complete the CIWA-Ar; if the participant is currently symptomatic of alcohol 
withdrawal, Study Visit 1 will be scheduled at least one week in the future. The psychologist will confirm alcohol 
use disorder diagnosis, establish that the potential participant is free from severe and persistent mental illness 
and current suicidal ideation, and document any other current Axis I disorders by administering the Structured 
Clinical Interview for DSM Disorders-Research Version (SCID-RV; see letter of support from Dr. Burk). The 
SCID-RV interviews will be audio recorded to permit clinical supervision and inter-rater reliability. These 
recordings will be deleted immediately after review.  
At Study Visit 1 (CRU), participants will provide a breath sample to verify an initial blood alcohol concentration 
(BAC) of 0.00 (Alcosensor IV; Intoximeters, Inc.). Participants will complete the CIWA-Ar; if they are currently 
symptomatic of alcohol withdrawal, Study Visit 1 will be rescheduled at least one week in the future. The 
provider will conduct a medical history/exam and review current medication. Medical staff will collect orthostatic 
vital signs, a blood sample for lab tests, and a urine sample to verify no pregnancy (females only). The provider 
will also conduct an ECG (see further details about safety procedures in Protection of Human Subjects 
section). Participants will then complete a variety of self-report batteries, for post hoc individual differences 
analyses (see Appendix A). 
Study staff will then prepare the participant for the NPU task with the application of physiological sensors. Next 
participants receive a series of shocks of increasing intensity (7 mA maximum) to assess their subjective 
tolerance threshold as per standard procedures from our laboratory22,128. Their subjective maximum tolerated 
shock from the screening visit is used during the NPU tasks at both Visit 1 and Visit 2 to minimize individual 
differences in subjective pain tolerance. Next participants complete the NPU task (see below). After the NPU 
task, participants will be randomly assigned to drug group (doxazosin vs. placebo; between-subjects) in a 
stratified blocked schedule by sex using urn randomization procedures129,130. The randomization and double-
blind will be implemented and maintained by the UW Pharmaceutical Research Center (see letter of support), 
which is located in the same building as the CRU. All participants are told that they will receive either 
doxazosin or placebo during the study, but neither the participants nor the research staff will be aware of the 
group they are randomized to receive. Participants who are off study and were consented under a previous 
protocol which promised unblinding will still be unblinded, via phone contact after their last visit. 
Participants will take the first study medication dose at home that evening after Study Visit 1 (Treatment Day 
1). Staff will call participants on Day 2 to confirm initial compliance and monitor any adverse events. 
Participants continue 8 weeks of treatment including an 18-day escalating dose schedule up to a therapeutic 
dose (8 mg) of doxazosin (or placebo; see Doxazosin Dosing Schedule below). Additionally, participants will 
attend four medical monitoring visits during the first month of treatment (see below). 
Participants will return after 4 and 8 weeks of treatment (Study Visit 2 & 3) to complete a timeline-follow-back 
(TLFB) procedure to assess drinking since the previous visit to index drinks per days to asses heavy drinking 
days for this 8 week treatment period. At 4 weeks (Study Visit 2) we will again assess stress-reactivity in the 
NPU task. If participant reports a binge-drinking episode one week or less prior to Study Visit 2, staff will 
administer the CIWA-Ar. If participant is currently symptomatic of alcohol withdrawal, Study Visit 2 will be 
rescheduled. In addition, at both visits participants complete breath and self-report tests as outlined above and 
detailed in table below. Upon completing their final study visit all participants will be debriefed and receive their 
final study payment.  

15 
 
Participants receive partial compensation at each Study Visit; they receive $320 for study procedures 
(approximately 16.5 hrs across screening visit, three study visits and four medical monitoring visits), and up to 
$200 in bonuses: $25 for attending their first hospital visit, $25 for keeping all their original appointments, $25 
for being on time to all their hospital visits, $25 for medication compliance (at least 90%), and $100 for 
attending all visits and completing all study procedures. Total compensation is therefore up to $520  If 
participants are deemed not eligible at the screening session they will be paid $25 at that time.  

16 
 
p
Table 1: Overview of 
Study Procedures and 
Timeline CATEGORY
PROCEDURE
Screening Visit
STUDY VISIT 1
MONITORING VISITS
STUDY VISIT 2
STUDY VISIT 3
DAY 0
DAY 1
DAY 6, 10, 14, 18
DAY 29
DAY 57
SCREENING
Consent
X
Inclusion/exclusion criteria - self-report
X
Inclusion/exclusion criteria - medical
X
Lab chemistry
Blood chemistry (Chem-12: CBC, TSH)
X
In-stream pregnancy test
X
Urine analysis pregnancy test
X
X
X
Medical history
X
Concomitant medications
X
Physical exam
X
Vital signs
X
X
ECG
X
Psychiatric evaluation
SCID
X
Self report assessment battery Self report (Qualtrics) battery
X
X
SAFETY & COMPLIANCE
Study visit monitoring
Vital signs; Adverse events
X
X
X
Monitoring visits: Adverse events; vitals
X
Staff phone calls: Adverse events
Phone call reminder
X
X
X
Pill counts; self-report
X
X
X
Review  of smart caps logs (opening times/dates)
X
X
X
Behavioral intervention
Brief motivational intervention (follow ing NPU task)
X
X
On lapse
Acute craving (for study 
release)
Desire for Alcohol Scale (follow ing NPU task; 
repeat as needed)
X
X
OUTCOMES
Startle potentiation and self-report negative affect 
in NPU task
X
X
Perceived Stress Scale
Past w eek
Past w eek
Past w eek
Past w eek
Blood alcohol concentration (via breath test)
X
X
X
X
X
TLFB (continuous abstinence, days drinking/w eek, 
drinks/day)
Since last visit
Since last visit
Since last visit
Since last visit
Craving
Penn Alcohol Craving Scale
Past w eek
Past w eek
Past w eek
Past w eek
Day 2, 36, 43, 50
Medication compliance
Stress reactivity
Alcohol use
TREATMENT DAY:
Eligibility
Pregnancy test (females only)
Medical history/exam
Treatment monitoring

17 
 
C4. Doxazosin Dosing Schedule 
All doxazosin and matched-placebo 
capsules will be prepared and blinded by 
the University of Iowa Pharmaceuticals, 
randomized by the UW Pharmaceutical 
Research Center and distributed through 
the UW CRU. Half the participants 
(N=80) will receive doxazosin and half 
(N=80) will receive a matched number of 
placebo pills daily for 8 weeks of 
treatment. The target therapeutic dose (8 mg doxazosin) will be achieved after an 18-day dose escalation 
schedule. Medication will be distributed across 6 visits. Participants will be provided 3-5 days of extra pills of 
their current dose at each distribution to provide flexibility in missed appointments; however, participants will 
not receive their next escalated dose until they attend an in-person visit. On study completion all participants 
will taper off doxazosin (or placebo) over 5 days using a protocol successfully employed by our consultant Dr. 
McKee in a recently completed smoking cessation trial. Participants who withdraw from the study will be 
tapered using the same protocol. There are no adverse effects with rapid cessation that may occur in other 
noradrenergic drugs (e.g., propranolol rebound hypertension)131. 
C5. Medical Monitoring And Medication Compliance 
Participants’ safety will be evaluated by the study staff and medical staff via measurement of vital signs and 
self-report of medication side effects, adverse events, medication compliance and alcohol use at each of the 
three Study Visits (Day 1, 29, 57). Study staff will call participants on Day 2 to monitor (via self-report) adverse 
events and initial compliance with taking the first pill on Day 1. In addition, participants will attend four 
additional Medical Monitoring Visits at the UW Hospital the day of each dose escalation (Day 6, 10, 14, 18) for 
similar evaluation. As such, participants are evaluated in person prior to each dose escalation and at 4 weeks 
and 8 weeks into treatment. 
Participants will complete safety check-ins weekly between Study Visit 2 and 3 (Day 36, 43, 50) to evaluate 
safety via self-report of medication side effects, adverse events, medication compliance, and alcohol use. 
These check-ins can occur via phone call or electronic survey according to participant preference. For 
participants who opt for electronic surveys, study staff will follow-up via phone if the participant reports side 
effects or problems or if the participant does not complete the survey. While we anticipate that subjects will 
tolerate study medication well, should participants experience adverse medication side effects, titration will be 
stopped at the highest tolerable dose. Maximum achieved dose will be included as a covariate in preliminary 
statistical models. 
Medication compliance will be facilitated and increased by several complementary methods. First, participants 
will receive automated reminders sent daily to their cell phone. These messages will remind them to take their 
study medication and can be sent via SMS text-message. These prompts also remind participants to contact 
study staff if they have any side effects or barriers to compliance. This strategy has been successfully 
implemented in previous addiction trials12,132,133. Medication bottles will also be equipped with a medication 
event monitoring system (smart caps). Smart caps are reusable and provide a time stamped medication 
use/bottle access. They also provide a programmable visual and auditory reminder of administration time to 
increase compliance.  At all medical monitoring and study visits medication compliance will be assessed by 
study staff via pill count and download of smart caps logs.  
TABLE 2
TREATMENT DAY DISPENSATION DAY (mg/capsule)
DAILY DOSE
1 - 5
Day 1: Study Visit 1 (1 mg)
1 mg qd
6 - 9
Day 6: Monitoring Visit 1 (2 mg)
2 mg qd
10 - 13
4 mg qd
14 - 17
6 mg qd
18 - 28
Day 18: Monitoring Visit 4 (4 mg)
8 mg qd
29 - 56
Day 29: Study Visit 2 (4 mg)
8 mg qd
57
Day 57: Study Visit 3 (6 x 1 mg)
6 mg qd
58
Day 58 (4 x 1 mg)
4 mg qd
59
Day 59 (2 x 1 mg)
2 mg qd
60
Day 60 (1 x 1 mg)
1 mg qd
TREATMENT
TAPER

18 
 
C6. NPU Stress-Reactivity Task 
Participants view a series of colored square “cues” on a 
computer in a blocked design19,22. There are three block 
types: No Shock (N), Predictable Shock (P), and 
Unpredictable Shock (U). Each type of shock block is 
presented twice and the no shock blocks are presented 
three times, with blocks counterbalanced both within- and 
between-subjects (e.g., 2 block orders: PNUNUNP, 
UNPNPNU). All blocks include 6 cues presented for 5s in 
the center of the computer monitor separated by a 
variable inter-trial-interval (ITI; mean 15s, range 10-20s). Electric shock is administered .25s prior to cue offset 
during every cue in the Predictable shock blocks so that the appearance of the cue ‘predicts’ that the shock will 
occur in a few seconds. Electric shock is administered at pseudo-random times during both cues and ITIs in the 
Unpredictable shock blocks so that the occurrence of the shock is completely unpredictable by the participant. 
Six electric shocks are administered in each Predictable and Unpredictable shock block. No electric shock occurs 
during the no-shock blocks. Participants are verbally informed of the cue-shock contingencies to ensure robust 
block differences. The task lasts approximately 20min. 
The primary dependent measure in the NPU task is startle potentiation. The eye-blink startle response is 
elicited with a binaurally presented acoustic startle probe (50ms, 102dB white noise with near instantaneous 
rise time). Startle probes occur at 4.5s post cue-onset on a random subset of 4 cues in every block. Serial 
position of startle probes across the three block types (No Shock, Predictable Shock, Unpredictable Shock) is 
counterbalanced within-subjects. Electromyogram (EMG) activity to the startle probes is recorded from two Ag-
AgCl sensors placed according to published guidelines beneath the eye over the orbicularis oculi muscle134. 
Electromyogram activity is sampled at 2000Hz with an online bandpass filter (1-500Hz) using NeuroScan Grael 
bioamplifiers (Compumedics USA, El Paso, TX). Offline processing includes a high-pass filter (4th order 28Hz 
Butterworth filter), creating epochs from 50ms pre-probe to 250ms post-probe, signal rectification and 
smoothing (30Hz lowpass filter). The startle response is quantified as the peak amplitude 20-100ms post-
acoustic probe onset relative to a 50ms pre-probe baseline. Startle potentiation during cues is calculated 
separately for unpredictable and predictable blocks as the difference between response to probes during shock 
and no-shock blocks. After the NPU task, participants retrospectively report their negative affective state during 
each block type (Post-Experimental Questionnaire, PEQ). We recently found this self-report measurement is 
sensitive to the anxiolytic effects of alcohol79,80. 
C7. Brief Motivational Interventions 
At Study Visits 1 and 2 all participants will receive standardized 30 min psychosocial support sessions focused 
primarily on motivational enhancement therapy (MET) for relapse prevention135–137 and treatment compliance 
provided by BS, MS or PhD level clinicians (see letter of support from Dr. Burk). For clinical supervision 
purposes, the MET sessions will be audio recorded; these recordings will be deleted immediately after review. 
Brief motivational enhancement therapy and related interventions have been demonstrated to affect drinking 
behavior across a variety of treatment provision settings from primary care to specialty addiction treatment 
clinics137–139. The primary purpose of including MET is to improve clinical outcomes related to alcohol 
abstinence in all research participants. There are likely to be secondary benefits; MET may also increase 
medication compliance and decrease study attrition. 
The provision of MET to all research participants also provides additional risk reduction regarding our use of 
the NPU task. It is unlikely that the NPU task would substantially affect craving and/or relapse risk after release 
from the monitored medical setting. The NPU task represents a robust laboratory stressor but it is no more 

19 
 
stressful than other common everyday stressors. Moreover, it is punctate and terminates with the conclusion of 
the task, unlike many other life stressors. Nonetheless, brief MET during each study visit initiated after the NPU 
task provides an additional safeguard against increased craving and/or relapse risk following the NPU task. In 
addition we will provide an additional 30 minutes of MET at any study visit if relapse is reported and the 
participant requests counseling.  We also measure participants’ self-reported craving on arrival at the CRU and 
immediately prior to release. Participants are required to return to their baseline levels of craving before 
release (see Protection of Human Subject).  
C8. Plan for Intoxicated Participants 
Participants who arrive intoxicated to any study visit, including potential participants who arrive intoxicated to 
the screening, will be questioned about their method of transportation. If the participant affirms that they are not 
driving themselves (walking, public transportation, driven by a friend) they will be permitted to leave with no 
further intervention.  
If the participant affirms that they drove themselves, we will offer to call a cab or a friend to drive them. If this 
offer is declined, we will suggest that they should stay in the CRU or ARC until their BAC registers below 0.03.  
This release criterion has been used for many years in our other UW research that involves alcohol 
administration to research participants.  As such, it seems equally appropriate for release for an ineligible 
participant who has self-administered their own alcohol.   By way of comparison, a BAC of 0.08 is considered 
per se evidence of impairment from alcohol and with a BAC of > 0.05 alcohol impairment can be considered a 
contributing factor when accident or injury occurs.   
If the participant declines to stay and indicates they plan to drive themselves, we will tell the participant that we 
will call the campus police so that the participant can make a more informed decision about what course of 
action to take. If the participant continues to indicate they plan to drive, we will call the campus police if the 
participant is driving away and provide information about the possibility of an impaired driver in the vicinity. We 
will not reveal the participant’s name to the police in order to protect their confidentiality. 
 
 

20 
 
Statistical Analysis: 
Planned Data Analysis for Specific Aims 
Analyses for quantitative and dichotomous dependent measures will be accomplished within either General or 
Generalized (binomial family with logit link function) Linear Models, respectively, using R140. In the sections 
below, we briefly describe the primary factors in statistical models to evaluate each Specific Aim. All models 
will include number of days abstinent at Visit 1 as an interactive between-subjects regressor to evaluate if drug 
effects and outcomes are comparable across alcoholics who vary in their previous duration of abstinence (1-8 
weeks) on study initiation, although this has not moderated the effects on NPU task in our preliminary studies. 
Numerous individual difference measures (e.g., sex, mood/anxiety disorder comorbidity, tobacco use, trait 
affect, alcohol dependence severity, other treatment) are available to add to these models as interactive 
between-subject regressors in secondary analyses to evaluate possible individual difference moderators of 
drug effects. 
AIM 1: Unpredictable startle potentiation from the NPU task at 4 weeks will be analyzed in separate general 
linear models controlling for baseline NPU responses (Visit 1) with repeated measures on Condition 
(unpredictable vs. predictable shock). A between-subjects regressor for Treatment (8 mg doxazosin vs. 
placebo) will be included. Aim 1 predictions will be supported by significant Treatment X Condition interactions 
with doxazosin producing selectively larger reduction in startle potentiation during unpredictable relative to 
predictable shock.  
AIM 2: Any heavy drinking (coded yes vs. no dependent if the participant reported any days where they 
consumed >4 drinks per day in men/ >3 drinks per day in women during the medication period) will be 
analyzed in a generalized linear models with a between-subjects regressor for Treatment (8 mg doxazosin vs. 
placebo). To be conservative, this analysis will be pursued as an intent to treat (ITT) analysis. Aim 2 
predictions will be supported by significant Treatment effects with doxazosin producing selectively lower 
proportion of participants reporting any heavy drinking.  This outcome is measured at Visits 2 & 3 and can be 
obtained even if the participant arrives with positive BAC.  
Timeline 
This project will be completed within five years of its funding. This goal is reasonable given our team’s 
expertise in conducting both randomized controlled trials and psychophysiological laboratory research working 
with drug administration, community participants, and stress reactivity. Based on prior recent experience with a 
similar population of alcoholics who completed multiple laboratory visits, we anticipate that 85% of participants 
who complete the first visit will return to complete the study. We can complete up to five study visits per week 
and expect to average approximately 3 study visits per week to account conservatively for no-shows, failed 
eligibility criteria, equipment failure, and other data loss. We anticipate completing data collection in 4 years, 
allowing time at the beginning of the grant period for set-up and final pilot testing and the end of the grant 
period for manuscript preparation. 
 
 

21 
 
Protection of Human Subjects 
 
D1. Risks to the Subjects 
 
Human Subjects Involvement and Characteristics. Alcohol dependent participants (age 18-65 years old) in 
early abstinence (at least 1 week but no more than 8 weeks since last alcohol use) will be recruited for the 
study. The ethnic background of the study participants will reflect the demographics of our recruitment sites. 
No one will be excluded from participation in the study because of minority group membership. Participants 
must be able to read and write in English. 
 
On arrival at the Addiction Research Center space in Brogden Hall for the screening visit, participants will be 
provided with and asked to sign a consent form that details all procedures involved. An in-stream urine 
pregnancy test will be performed if potential subject is female. This test will not be recorded in any identifiable 
record but merely used to determine eligibility.  
 
Psychological/behavioral screenings and diagnostic assessments are performed by bachelors or graduate 
level clinicians (doctoral students in clinical psychology) from the Psychology Research and Training Clinic 
(PRTC) and supervised by a licensed PhD level clinical psychologist. The PRTC provides fee-for-service 
structured interviewing and diagnostic assessment for research protocols (see letter of support from Dr. Linnea 
Burk, director of PRTC). The diagnosis of alcohol use disorder will be established by administration of the 
research version of the Structured Clinical Interview for DSM-5 (SCID146,147).  
 
On arrival at the Clinical Research Unit (CRU) in the University of Wisconsin Madison Hospital for the first 
study visit all participants will complete medical screening that will include review of medical history, review of 
medications, and screening clinical exam conducted by the provider. Medical staff will conduct clinical 
assessment to determine vital signs (including sitting and standing blood pressure and heart rate 
determinations). Twelve-lead ECG will be obtained in all participants. Laboratory evaluation will include 
chemistry panel comprehensive metabolic profile (Chem-12, assessing kidney and liver function, glucose level 
and electrolyte status), complete blood count (CBC), and thyroid stimulating hormone (TSH). All study visits 
will include blood alcohol concentration (BAC) breath-testing. A pregnancy test for women of childbearing 
potential will occur at all visits with the exception of Visit 3. This is not needed at Visit 3 as tapering the dose, 
which would be the response to a positive pregnancy test, will happen at this visit for all subjects.  
 
Clinical assessment, clinical exam, and all other medical and medication screenings and monitoring will be 
conducted by medical staff. ECG interpretations will be confirmed by the study physician. All measures are 
reviewed by study staff to ensure that participants can safely use doxazosin and participate in the study. 
Specifically, participants will be excluded for FDA contraindications for doxazosin. All women of childbearing 
potential will be required to agree to use a study-approved method of birth control or abstinence to prevent 
pregnancy during the course of the study. Medically-related issues, if needed, will be discussed by the 
research staff and medical staff with a designated study physician who will be timely available via pager or cell 
phone. 
 
Exclusion criteria are divided into three broad categories of Medical, Psychiatric/Behavioral, and 
Medications/Therapies. These criteria are all implemented to protect human subject safety, except where 
noted with an asterisk (*) denoting scientific/theoretical reasons. See Appendix C (Eligibility Criteria Checklist) 
for detailed description of eligibility criteria, assessment measures and assessors. 
 
Medical exclusion  
 
Past or current coronary artery disease, cerebrovascular accident, unstable angina, history of 
myocardial infarction, history of congestive heart failure. 
 
Current chronic renal or hepatic insufficiency, pancreatitis, immunosuppressive therapy, diabetes, or 
cancer with systemic effects or therapy. 
 
Meniere’s disease, benign positional vertigo, or narcolepsy. 

22 
 
 
A pre-existing hypotension (systolic blood pressure < 100 mmHg) or hypertension (systolic blood 
pressure > 160 mmHg) or orthostatic hypotension (systolic blood pressure drop > 20mmHg or diastolic 
blood pressure drop >10mm Hg after two minutes standing) and report of dizziness, lightheadedness, 
unsteadiness or other problems (nausea, blurry vision) after two minutes standing from seated position.  
 
Tachycardia >100 beats/minute. 
 
Heart rate <56 beats/minute. 
 
Heart rate 56-59 beats/minute AND clinical judgment from study physician that heart rate would 
preclude a safe participation for the potential participant 
 
Moderate hepatic impairment assessed via liver enzyme tests. 
 
Electrocardiogram abnormalities indicates concerns of cardiac function, as determined by study 
physician’s clinical over-read. 
 
Allergy or previous adverse reaction to doxazosin or other 1-NE antagonist. 
 
Scheduled or reported plans for cataract surgery prior to study completion [Excluded due to risk of 
Floppy Iris Syndrome]. 
 
Currently symptomatic of alcohol withdrawal. CIWA-Ar Score >10, or positive for any “visual, auditory or 
tactile disturbances” or for “orientation and clouding of sensorium”. 
 
Discharged from inpatient treatment for alcohol use disorder or alcohol detoxification within past 7 days. 
 
Currently medically unstable. 
 
*Current treatment for chronic pain condition. [Excluded because brief electric shocks are administered 
during NPU stress-reactivity task]. 
 
*Uncorrected auditory/vision problems. [Excluded because primary measure in NPU stress-reactivity 
task relies on eyeblink reflex to acoustic startle probe]. 
 
*Color blindness. [Excluded because colored images identify critical differences between predictable, 
unpredictable, and no-shock conditions in the NPU stress-reactivity task.] 
 
Other self-reported acute or unstable illness, in the opinion of the study team, would preclude a safe 
and reliable study participation. 
 
Medical exclusion (Females Only) 
 
Women of childbearing potential with self-reported current pregnancy, positive or undetermined 
pregnancy test results, do not agree to use a study-approved form of birth control until after study 
completion (see below), or who are breastfeeding will be excluded. 
 
Definition: Women of childbearing potential are females who have experienced menarche and do not meet the 
criteria for women not of childbearing potential. Women not of childbearing potential are females who are 
permanently sterile (e.g., hysterectomy, bilateral oophorectomy) or postmenopausal. Postmenopausal is 
defined as 12 consecutive months with no menses without an alternative medical cause. 
 
Definition: Acceptable birth control is defined as the following methods of contraception: abstinence; hormonal 
contraceptives (e.g. combined oral contraceptives, patch, vaginal ring, injectables, and implants); intrauterine 
device (IUD) or intrauterine system (IUS); vasectomy of partner and tubal ligation; “single” barrier methods of 
contraception (e.g. male condom, female condom, cervical cap, diaphragm, contraceptive sponge) with use of 
spermicide; or “double barrier” method of contraception (e.g. male condom with diaphragm, male condom with 
cervical cap). 
 
Psychological/Behavioral exclusion 
 
Self-reported lifetime diagnosis of schizophrenia, schizoaffective disorder, psychotic disorder NOS, 
Bipolar Disorder (with manic episode), borderline personality disorder, or any neurocognitive disorder 
that may impair a reliable, safe participation. 
 
Any current active substance use disorder for which the potential participant is not currently pursuing 
abstinence, other than alcohol or tobacco. 
 
Blood alcohol concentration above 0.00. 
 
Medications/Therapies exclusion 

23 
 
 
Currently prescribed or used within past week: doxazosin or other 1-NE antagonist (e.g., prazosin, 
terazosin). 
 
Currently prescribed or used within past week: sildenafil (Viagra), tadalafil (Cialis), and vardenafil 
(Levitra) will not be permitted during the study because of increased risk of hypotension in combination 
with 1-NE antagonists. [Increased risk of hypotension in combination with alpha1-NE antagonists]. 
 
Currently used daily or used within past week: alpha1 agonists (e.g., midodrine, metaraminol, 
oxymetazoline, phenylephrine). [Excluded because these medications directly alter alpha1 
noradrenergic neurotransmission.] Note: these cold medicines and nasal decongestants require 
rescheduling of Study Visit 1 or Study Visit 2 if used within 72 hours of visit; otherwise, they are non-
exclusionary. 
 
Currently used daily or used within past week: benzodiazepines (e.g., diazepam, chlordiazepoxide, 
lorazepam, clonazepam, alprazolam), zolpidem (Ambien), zaleplon (Sonata), zopiclone (Imovane), 
eszipclone (Lunesta), dozapin (Silenor). 
 
Males only: Currently prescribed and used daily or within past 2 weeks: Trazodone.  
 
*Currently prescribed or used within past week: substances with stimulant properties (e.g., d-
amphetamine, methylphenidate) or alternative medications with stimulant properties (e.g., ephedra, 
pseudophedrine). [Excluded because these medications directly alter CNS noradrenergic 
neurotransmission.] 
 
*Currently prescribed or used within past week: beta-blockers (e.g., propanolol), 2 agonists (e.g., 
clonidine, guanfacine, dexmedetomidine), and SNRI anti-depressants (e.g., venlafaxine, duloxetine, 
atomoxetine, viloxazine). [Excluded because these medications directly alter CNS noradrenergic 
neurotransmission.] 
 
*Currently prescribed or used within 2 weeks: Disulfiam (Antabuse). [Excluded because may alter 
noradrenergic neurotransmission.] 
 
Sources of Research Materials.  All research materials obtained from participants will be collected directly 
from them. They will consist exclusively of self-reports, medical evaluations and records of psychophysiological 
responding. There will be no use of archival records or other such data. 
 
Potential Risks.  The potential physical risks involved in this study can be grouped in seven categories 
outlined below 
1. Skin irritation from sensor application or gel: It is possible that either the sensor gel or the application 
process may produce some skin irritation and/or redness. 
 
2. Auditory harm or discomfort from startle probes: The risk of physical harm is very low but some 
participants may find the startle probe uncomfortable.   
 
3. Physical or psychological harm from electric shock: The risk of physical harm is very low but 
participants may vary to some degree in how distressing they find the electric shock.  
 
4.  Non-negative pregnancy test: There is a possible risk that a participant may become upset from an 
unexpectedly non-negative pregnancy test result. An additional risk is that pregnant women using alcohol 
place fetus at risk for adverse effects and themselves at risk of placement in custody to protect the fetus.  
 
5. Side effects from study medication (doxazosin): The most common side effects associated with 
doxazosin are drop in blood pressure, dizziness, headache, drowsiness, lack of energy, weakness, 
palpitations, and nausea. Orthostatic hypotension and syncope (i.e., fainting) can occur in some individuals. 
Alpha1-NE antagonists have been associated with the so-called “first-dose phenomenon” whereby the 
possibility of fainting is higher after the first dose in 1% of the population. Syncope risk is increased with 
dehydration, especially when moving from lying or seated to standing. It is also possible that orthostatic 
hypotension and syncope could occur after the first dose following increase in dosage, or if therapy with the 
drug is interrupted.   

24 
 
 
One rare but serious side effect is priapism, which is a painful penile erection sustained for hours, that can lead 
to permanent impotence/erectile dysfunction if not promptly treated. The prescribing information for doxazosin 
suggests that this risk occurs less than once every several thousand people. 
 
6.  Confidentiality failure:  The questionnaires and psychophysiological measures to be used in the proposed 
research are generally of a benign nature. However, some self-report questionnaires yield sensitive information 
regarding alcohol use. If confidentiality is broken the information collecting in this study could have 
unanticipated or untoward consequences for the participant's reputation, employability, or legal status. 
 
7.  Alcohol craving following stressor exposure:   Participants are exposed to a stressor task (the NPU 
Task) during study visits 1 and 2.  It is possible that this stressor could elicit mild, brief alcohol craving in study 
participants. 
 
D2. Adequacy of Protection against Risks:   
In this section, we outline the protections in place to reduce the risk associated with the risks identified in D1. 
 
1. Risks from sensor application: In addition to warning the participants of these risks, research assistants 
will attend multiple training sessions, including direct practice with sensor application, prior to being cleared to 
attach sensors to research participants. They will also be trained to ask participants to inform them of any 
discomfort so they can adjust or stop the procedure. Additionally, the alcohol pads are the same as those used 
in hospitals or other health facilities so it is likely the participants have experienced them, and the exfoliant is 
no different than ones from a drug or beauty store. The sensor gel used is similar in salt concentration to 
human perspiration, reducing the possibility of this risk. 
 
2.  Risks from Startle probes:  At a maximum of 105dB, the intensity of these stimuli is safely below levels at 
which there might be any risk of pain or physical damage as established by OSHA and NIOSH guidelines. 
Specifically, risk associated with noise exposure is reduced in the current experiment by limiting noise intensity 
to 105dB, limiting total noise exposure time to no more than 5s, and using broad spectrum noise (i.e., white 
noise). The portion of the experiment in which white noise bursts will be delivered to participants will last 
approximately 30 minutes. During this period, participants will be exposed to no more than 75 50-millisecond 
bursts of white noise for a total of 3.75s seconds of exposure. The noises will be delivered via Sennheiser HD-
280 headphones. The signal will be calibrated with a slow response meter with A-weighting (B&K sound level 
meter model 2203). The signal presented for calibration will be 5 sounds in length. 
 
The OSHA recommended limit for noise exposure at 105 dB is no more than 1 hour/day (OSHA section 1910-
95). According to the more conservative National Institute for Occupational Safety and Health (NIOSH) 
guidelines (http://www.cdc.gov/niosh/98-126.html), workers should not be exposed to 105 dB for more than 4 
min and 43 sec per 8 hour day. As such, the exposure in the current experiment is far under the more 
conservative limit recommended by NIOSH. By comparison, noise levels in small music venues (e.g., bars) 
often exceed 105 dB, and noise levels at rock and roll shows often exceed 115 dB. Participants are 
occasionally in these environments for more than 1 hour. An additional safety factor is that "white noise" is 
being employed. White noise is full spectrum, so there is no single frequency with concentrated energy. This 
acts as further protection to the subject by preventing the focus of energy to a limited area of the basilar 
membrane in the subject's cochlea. 
 
3.  Risks from Shocks:  There is no reason to believe that the magnitude of this distress exceeds that 
normally encountered in everyday life. Moreover, participants are forewarned that they will receive these 
electric shocks during the experiment and that they can terminate their participation without prejudice at any 
time during the procedure. 
 
The risk of physical harm associated with the administration of electric shock is minimal. The shock parameters 
and procedures have been used in previous work that has been conducted in Dr. Curtin's lab over the past 20 
year and other laboratories at other institutions (e.g., see Grillon et al., 1997, 2012 from the NIH).  

25 
 
The shocks will have an intensity ranging from 0.5 to 7.0 milliamperes and duration of 200 milliseconds. The 
shocks will be delivered via finger electrodes placed on the index and pointer fingers of their hand. These 
electrodes are specially-designed to prohibit the possibility of connecting to fingers on opposite hands.  
 
A complex digital input to the shock unit is required to trigger shock administration. This prevents unintended 
shock administration in the event of computer failure. Moreover, the shock unit is current-limited and designed 
to automatically shut-off if current is administered for longer than 1000ms. The shock unit has two levels of 
optical isolation from connections to the computer and the subject will be isolated from any AC current source 
at all times. 
 
4.  Risks from non-negative Pregnancy test: The experimenters who conduct these tests will be specifically 
trained to handle the possibility of such outcomes by noting the conclusiveness of negative results, but also 
stressing the ambiguity of non-negative outcomes. They would be ready with specific advice about where to 
get more precise follow-up testing and about how to get counseling if desired. Inasmuch as the pregnancy test 
is the equivalent of a health screening, it could be construed as a benefit rather than as a risk because non-
negative results--although potentially distressing--could promote early, informed and thus more favorable 
health decisions than might be possible if knowledge of the pregnancy were obtained later.  
 
To avoid collecting information on illicit drug or alcohol use from pregnant women, a pregnancy test will be 
administered at the beginning of the screening visit prior to the SCID substance abuse module. If a woman's 
pregnancy test turns out to be positive, she will be considered ineligible for participation and no further testing 
(e.g., SCID) conducted. This test will be repeated at all study visits with the exception of Visit 3. Women are 
required to maintain an effective form of birth control throughout their study participation.  As such, onset of 
pregnancy during the study period is low. 
 
5.  Risks from study medications:  Half of the participants (N = 80) will take doxazosin for 8 weeks on an 18 
day escalating dose schedule consistent with recent doxazosin studies with cocaine108 and tobacco dependent 
samples (see Research Strategy Section).  Participants will be made aware of the common side effects of 
doxazosin before they consent to participate in the study. It should be noted that doxazosin has been FDA-
approved and widely used clinically for forty years by millions of people worldwide.  
 
Study staff will have direct contact with participants on 10 occasions during the 8-week study period to assess 
for any adverse events, medication side effects, and answer questions about treatment. This includes three 
Study Visits (Day 1, 29, 57), four Medical Monitoring Visits (Day 6, 10, 14, 18) and four Safety Check-ins via 
phone or electronic survey (Day 2, 36, 43, 50). All study visits will be conducted in the University of Wisconsin-
Madison Hospital CRU under medical supervision. A registered nurse will be present in the CRU during all 
study visits to monitor for drug side effects and provide appropriate medical attention. Orthostatic vital signs will 
be checked by CRU-RN at all study visits. Any participants experiencing significant side effects will be 
withdrawn from the study and provided medical attention from the study nursing staff and/or physician as 
needed. Adverse events will be monitored, and “stopping rules” will be applied if needed (see Stopping rules). 
 
Participants will be educated about potential side effects of doxazosin and ways to mitigate risk. For instance, 
to reduce the risk of syncope upon standing from bed in the morning, participants will be instructed to slowly sit 
up and stay on the edge of their bed for 5 minutes before standing following the initial doses of doxazosin. 
Additional instructions will encourage participants to keep well-hydrated and urinate while sitting down rather 
than standing. They will be strongly discouraged from driving or operating heavy machinery within 24 hours of 
the first dose, or at any dose escalation. 
 
It will be recommended that participants continue to take doxazosin before bed, however clinical research has 
shown that doxazosin is safe to take in morning or evening and with or without food. Doxazosin is not sedating 
nor are there concerns of rebound hypertension following rapid cessation of use that occur with other 
noradrenergic agents, such as clonidine131. 
 

26 
 
If symptoms of hypotension (such as dizziness) are reported, the participant will be encouraged to increase 
fluid intake if a negative fluid balance may be playing a role. If hypotension is noted in the CRU settings, the 
medical staff, upon the study physician orders, is able to place a peripheral venous access and administer IV 
fluids, such as normal saline, that can provide an effective treatment for orthostatic hypotension. 
 
Participants will be encouraged to continue whatever treatment for alcohol use they were receiving prior to 
study enrollment throughout the duration of the study. They will be instructed that the study medication is not 
approved as pharmacotherapy for their alcohol use disorder and therefore will not substitute for their existing 
treatments and other supports. Participants will be instructed to contact the study staff immediately if they 
experience any adverse events during these 8 weeks. The study physician will make medical 
recommendations as appropriate to handle the adverse events. The UW Pharmaceutical Research Center will 
break the drug blind to inform the participant and study physician if a situation arises where this information is 
critical to providing appropriate medical care.  
 
Doxazosin in usual medical practice is used to treat high blood pressure and urinary retention associated with 
benign prostatic hyperplasia; these indications have been associated with certain practices for medication 
initiation and titration that are optimized for these conditions. In this study, doxazosin is used as an alcohol 
relapse prevention pharmacotherapy. In this context, the considerations for optimal dosing take into account 
the risk-benefit ration of a given dose and its titration protocol versus, potential benefits of doxazosin therapy. 
Research documents the overall safety and superior results of the titration protocols similar to the proposed 
one, when compared with a slower-titration protocol or placebo for relapse prevention (or improving outcomes) 
among individuals with substance use disorders (108,148, https://clinicaltrials.gov/ct2/show/NCT01730846). In 
addition, the risk of alcohol relapse is highest in the first 3 months after stopping drinking in alcohol dependent 
adults, suggesting that effective interventions, when implemented early in the recovery, have the best potential 
to prevent relapse. Therefore, both evidence and conceptual framework derived from a natural history of 
alcohol dependence suggest an increased benefit of the proposed, previously-tested titration schedule in 
alcohol dependent adults, compared to a slower titration, typical in hypertension or BPH. Although the potential 
benefit of the proposed titration schedule and dosing appears to outweigh the potential risks (side effects) in 
this clinical population, we propose additional safeguards (i.e., the dose titration protocol will be modified – 
slower titration, lower final dose) if the participant experiences side effects requiring such a modification. 
 
Serious but rare side effects: We will counsel the participants about the symptoms of priapism, a rare but 
serious side effect of doxazosin. We will inform them that this condition, if occurs, requires emergent evaluation 
and treatment. Should these symptoms occur, the study physician and/or the participant's personal clinician 
will be immediately contacted, and the participant will be directed to go to the emergency department right 
away. Our clinical experience corroborates the package insert information that this is indeed a rare condition. 
However, to further mitigate the risk, we have added an exclusionary criterion that those receiving medications 
commonly prescribed for erectile dysfunction, such as sidenafil or tadalafil, will not be eligible. Recent or 
current use of trazodone, another medication which can increase the risk of priapism in combination with 
doxazonsin, is also an exclusionary criteria. 
 
6.  Risk of Confidentiality failure:  All data will be coded by participant number only and any personal 
identifiers linking participants to their reports on surveys and questionnaires will be detached and destroyed as 
soon as participation is completed or disqualification occurs. All data are stored electronically on a secure 
server in the Department of Psychology, or in two UW sponsored electronic databases Qualtrics (self-report 
questionnaires, study forms) and OnCore (participant-tracking), which have accepted measures to protect 
participant confidentiality and are compliant with all national clinical research policies. PHI will link to 
individuals’ participation in OnCore and HealthLink only and only the minimal necessary information will be 
entered into the participant's medical record in order to protect their confidentiality regarding alcohol and drug 
use status. In addition, a Certificate of Confidentiality (CoC) has been secured from the National Institute of 
Alcohol Abuse and Alcoholism in order to protect identifiable research information from forced disclosure. A 
CoC allows an investigator and others who have access to research records to refuse to disclose identifying 
information on research participants in any civil, criminal, administrative, legislative, or other proceeding, 
whether at the federal, state, or local level. 

27 
 
 
7.  Risk of alcohol craving:  There is a possibility that following the NPU stressor task in study visits 1 and 2, 
alcohol-dependent participants will experience alcohol craving, due to the mild stressor exposure.  Generally, 
cravings subside with the simple passage of time. However, all participants will also receive brief (30 minute), 
standardized Motivational Enhancement Therapy (MET) to support continued abstinence at study visits 1 and 
2 following completion of the NPU task. Participants will complete a brief alcohol craving questionnaire, a 6-
item subset of the 14-item version of the Desires for Alcohol Questionnaire (DAQ6) upon arrival at the 
laboratory and after completing all study procedures at each study visit. The items include: “I want a drink so 
much I can almost taste it”, “My desire to drink now seems overwhelming”, “I would do almost anything to have 
a drink now”, “I am going to drink as soon as I possibly can”, “I would consider having a drink now”, “I would 
accept a drink now if it was offered to me.” Participants will be required to remain at the CRU until their craving 
ratings return to baseline on each item of the scale. In our recent study with 58 abstinent alcoholics, only 5 
participants were required to stay in the lab for a brief period of time until their cravings returned to baseline 
simply by the passage of time.  
 
Thirty minutes of motivational therapy will be administered to participants two times during the regular course 
of the study. Additionally, if participants report strong cravings or alcohol use, an additional 30 minute session 
of motivational counseling will be provided to help them to recover their abstinence goals. Referrals to local 
treatment providers will always be available to participants, and referral to these providers or back to the 
participant's own treatment provider will be made in case further intervention is warranted. 
 
D3. Potential Benefits of the Proposed Research to Human Subjects and Others 
Considering the safeguards outlined above, any potential risks associated with participation in this project 
appear to have been minimized. There is strong reason to believe that participants assigned to receive 
doxazosin treatment may have a reduced risk of relapse to alcohol use during the 8 week treatment period. 
However this is unknown to date and is indeed a goal of the study to determine the efficacy of doxazosin. It is 
possible that simple accountability related to study participation and contact with research/medical study staff 
will reduce participants’ relapse risk. Including brief MET at study visits 1-2 is likely to further support those 
goals of relapse prevention.  
 
All participants will be paid for their time invested during study procedures. Participants will be paid $320 for 
time spent in visits, plus a $100 bonus for completing all eight visits, as well as up to $75 in bonuses for 
attending/not rescheduling/being on time to all visits, and a $25 bonus for meeting a 90% threshold for 
medication compliance. These modest inducements represent reasonable compensation for time spent in the 
study and are not considered coercive.  
 
Aside from these factors, there is not likely to be any immediate, direct benefit to the participant other than a 
better understanding of the processes and purposes of psychological and biomedical research acquired 
through experience and debriefing. However, the knowledge that can reasonably be expected to result from 
the proposed study has potentially important implications for the field of addiction treatment. 
 
D4. Importance of the Knowledge to be Gained 
As indicated above, the risks associated with this research appear to have been minimized. In contrast, the 
potential importance of the knowledge to be gained and its clinical application is high. Specifically, the costs to 
both individuals and the society as a whole resulting from alcoholism are high. The research proposed in this 
application is designed to address potentially important affective and pharmacological mechanisms in the 
etiology and maintenance/relapse of alcohol dependence. Most importantly, this study aims to investigate the 
utility of doxazosin as a potential treatment of stress-induced relapse in alcoholism, which is not well treated by 
any currently available pharmacotherapy for drug addiction. 
 
D5. Data and Safety Monitoring Plan 
 
Monitoring the progress of study and the safety of participants. The Principal Investigator will be 
responsible for routine monitoring of the study’s progress. This includes scheduled monthly meetings with 

28 
 
study staff and the study MD, and review of written documentation. Data that are reviewed at these meetings 
include the number and type of participants enrolled, the number and reasons for exclusions from enrollment, 
the number treated and the stage of treatment, summary of adverse events, individual review of serious 
adverse events and study participation and outcome data. In addition, any unanticipated health events that 
raise concerns (e.g., serious mood or behavioral changes, suicidal ideation, abnormal test results) will be 
immediately reported to the PI and the study physicians.  
 
To facilitate participant safety, study participants must meet study eligibility criteria. Once enrolled, study 
protocol will assess for the presence of adverse events at each study visit by querying participants as to 
whether they have experienced any adverse side effects associated with study medications. Participants who 
report development of severe side effects associated with doxazosin (which is unlikely) will be discontinued 
from further study participation as a precaution. Such events will be immediately reported to the PI and study 
physicians. If significant psychiatric or medical symptoms are reported, the participant will be referred, as 
needed, to the appropriate emergency medical or psychiatric services.  
 
Stopping rules.  Study will be stopped if two patients experience SAEs diagnosed to be related to the study 
drug and affect same organ system (e.g., cardiac, hepatic, renal or central nervous system). More specific 
examples are a three-fold elevation above baseline of serum liver enzyme (hepatic function) and creatinine 
(kidney function) levels, and QTc interval prolongation over 500 ms (or 50 ms increase over baseline) or other 
documented serious ECG abnormalities. 
 
The study would resume after thorough evaluation and if it is deemed that the continuation of study activities is 
determined safe to participants by the study physicians, the study investigators, the IRB, and the funding 
agency representative. 
 
Plans for assuring compliance with requirements regarding the reporting of adverse events. This Data 
Safety and Monitoring Plan requires that investigators notify NIH and the University of Wisconsin IRB of the 
occurrence of any serious adverse event (SAE), or any adverse event (AE), which is severe, unexpected, and 
possibly related to study medication or protocol. Such notification must occur within five days of investigators 
becoming aware of the event. If the serious adverse event might be related to drug use, both the Food and 
Drug Administration and the manufacturer will also be notified within five days of investigators becoming aware 
of the event. Examples of serious adverse events would be untoward medical or treatment occurrences that 
result in death, are life-threatening, require hospitalization or prolonging of existing hospitalization, create 
persistent or significant disability/incapacity, or involve congenital abnormality/birth defects. Unanticipated 
adverse events would include less serious problems that merit reporting because they are severe, unexpected, 
and possibly related to study participation. Any serious adverse event (SAE) will be queried and reported even 
if it appears that the serious adverse event is unrelated to treatment participation. The PI will be responsible for 
the accurate documentation, investigation and follow-up of all study-related adverse events. 
 
Adverse event assessment, recording, reporting and investigation will be accomplished through staff training, 
structured or standardized assessments of untoward occurrences/events, and regular monitoring by study 
investigators. The Principal Investigator has ultimate responsibility for ensuring that serious adverse events are 
detected and reported in a timely manner. All serious or unanticipated adverse events will be reviewed by the 
study physicians. Additionally, the IRB will receive an annual report of all serious adverse events and adverse 
events meeting the criteria listed above. 
 
Plans for assuring that any action resulting in a temporary or permanent suspension of an NIH-funded 
clinical trial is reported to the NIH grant program director responsible for the grant. The NIH grant 
program director will be notified within five days if the Principal Investigator deems it necessary to suspend the 
study. In the case of a temporary suspension, the Principal Investigator will develop a plan for continuation of 
the study and discuss this plan with the NIH grant program director in a reasonable time frame.  
 
Plans for assuring data accuracy and confidentiality and protocol compliance. The Principal Investigator 
will refine existing protocols for assuring data accuracy and protocol compliance. Such protocols will include 

29 
 
data verification and protocol compliance checks as well as other quality assurance procedures. The Principal 
Investigator will also be responsible for ensuring that the data for the project are securely stored, that storage 
is in compliance with University and federal regulations and that no unauthorized persons have access 
(electronic or physical) to any participant-identifiable data.  
 
 

30 
 
Data and Record Keeping: 
Data Management 
Study staff will collect and maintain all information on secure servers managed by the university, including the 
university Qualtrics and OnCore servers, or on a private secure server managed by the research team. Any 
hard copy study data will be kept in a locked cabinet which only the Project Director and Project Coordinator 
can access, in a locked room in the Psychology department in Dr. Curtin’s laboratory. 
The Principal Investigator will oversee data verification and protocol compliance checks as well as other quality 
assurance procedures. The Principal Investigator will also be responsible for ensuring that the data for the 
project are securely stored, that storage is in compliance with University and federal regulations and that no 
unauthorized persons have access (electronic or physical) to any participant-identifiable data. 
Confidentiality 
The UW Institute of Clinical and Translational Research (ICTR) provides UW researchers with comprehensive 
data management software tools (Online Collaborative Research Environment; OnCore) and support, which 
helps ensure confidentiality of data. The self-report and psychophysiological measures that will be used in the 
proposed research are generally of a benign nature. However, some self-report questionnaires could yield 
sensitive information. Consequently, all data will be coded by participant number only and any personal 
identifiers linking participants to their reports on surveys and questionnaires will be detached and destroyed as 
soon as participation is completed or disqualification occurs.  
Data Collection Methods 
All research materials obtained from participants will be collected directly from them. They will consist 
exclusively of self-reports, medical evaluations, biological samples, and records of psychophysiological 
responding. There will be no use of archival records or other such data. 
Surveys and interviews will be administered to the participant by study staff via iPad. The iPads access the 
University’s secure Qualtrics account and data is entered there directly. At no time is data ever saved on the 
iPads. 
Physiological data is collected by study staff using our lab’s psychophysiology equipment, and saved directly to 
our secure server in the Department of Psychology 
Biologic samples (blood, urine) will be collected by medical staff at the Clinical Research Unit (CRU) according 
to standard medical practice, and handled and disposed of using standard CRU procedures. 
Smart cap data will be stored in an online password protected platform. All data stored on this platform is 
coded only.  
The SCID-RV interviews and the MET sessions will be audio recorded. The SCID or MET clinician will review 
these recordings alongside the licensed clinical psychologist for supervision purposes. These recordings will 
be deleted immediately after review. 
Study Records Retention Policy 
All de-identified data and associated study documents will be archived according to IRB and University policies 
and retained for seven years.  
In accordance with Federal Open Access policies, de-identified datasets and analysis materials will be made 
available using approved Data Sharing practices identified by the University’s Research Data Services. 
 

31 
 
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Appendix A: Surveys, Questionnaires and Interviews 
 
All self-report surveys, questionnaires, and interviews are completed by the participant in the privacy of the 
Addiction Research Center or an outpatient room in the Clinical Research Unit in the University of Wisconsin 
Hospitals and Clinics. Questionnaires are administered on paper, lab computers, or iPads via the UW-Madison 
Qualtrics Survey Hosting Service. 
 
Surveys and Questionnaires 
 
Alcohol Dependence Scale (ADS): Standard questionnaire providing a quantitative measures of the 
severity of alcohol dependence. 
 
Alcohol Use Disorders Identification Test (AUDIT): Standard questionnaire about quantitative alcohol 
use. 
 
Alcohol Use History Questionnaire –  questions about alcohol use history 
 
Anxiety Sensitivity Index (ASI-3): Standard questionnaire about anxiety. 
 
Demographics: Standard questionnaire about age, gender, race, and ethnicity. 
 
Depression Anxiety Stress Scales (DASS): Standard questionnaire about depression and anxiety 
symptoms. 
 
Desires for Alcohol Scale (DAQ): Subset of items from standard questionnaire about the participants’ 
desire/craving of alcohol. 
 
Distress Tolerance Questionnaire (DTQ): Standard questionnaire about reactions to stressful situations.   
 
Feedback: Standard questionnaire about the participant’s experience in the study. 
 
Intolerance of Uncertainty Scale (IUS): Standard questionnaire about anxiety and reactions to 
uncertainty. 
 
Mindful Attention Awareness Scale (MAAS): Questions about positive/negative affect and mindfulness 
 
Multidimensional Personality Questionnaire- Short form (MPS): Standard questionnaire about 
personality and temperament. 
 
Obsessive Compulsive Drinking Scale (OCDS): Standard questionnaire about obsessionality and 
compulsivity related to craving and drinking behavior. 
 
Penn Alcohol Craving Scale (PACS): Standard questionnaire for assessing alcohol craving.  
 
Perceived Stress Scale (PSS): Standard questionnaire about the perception of stress. 
 
Post-Experiment Questionnaire (PEQ): Standard questionnaire about the participants’ emotions during 
the experiment. 
 
Interviews 
 
Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised (CIWA-Ar): Standard assessment of 
Alcohol Withdrawal Symptoms. 
 
Screening Survey (previously referred to as MSQ): Standard questionnaire from our laboratory about 
health-related behaviors for screening purposes. 
 
Structured Clinical Interview for DSM Disorders (SCID): Standard structured clinical interview for 
diagnoses of DSM Disorders. Module E: Substance Use Disorders. 
 
Timeline Follow Back (TLFB): Standard questionnaire about estimates of daily drinking in past month. 
 
 
 

44 
 
Appendix B: Participant Handouts 
 
1. Research Participation Information and Consent Form 
2. Information Sheet for Research Subjects 
3. Authorization to Use and/or Disclose Identifiable Health Information for Research 
4. Doxazosin Package Insert 
5. Directions to CRU & Map 
6. Health Facts For You 
 
 
 
 

45 
 
Appendix C: Eligibility Criteria Checklist 
 
Inclusion Criteria: General 
Criteria 
Eligible 
Response 
Assessment 
Measure 
Assessor 
Can the participant read and write in 
English? 
Yes 
Self-report 
Screening 
Survey 
ARC Staff 
Age (Date of birth) 
Age 18-65 
Self-report 
Screening 
Survey 
ARC Staff 
Last alcohol consumption 
<8 weeks 
ago 
Self-report 
SCID 
ARC Staff 
Last alcohol consumption 
>1 week 
ago 
Self-report 
SCID 
ARC Staff 
Meets criteria for DSM5 past Alcohol 
Use Disorder, Mild (≥2 criteria) 
Yes 
Clinical 
Interview 
SCID 
ARC Staff 
Meets criteria for DSM5 Alcohol Use 
Disorder, Moderate (>4 criteria) 
Yes 
Clinical 
Interview  
SCID 
ARC Staff 
Currently pursuing abstinence from 
alcohol 
Yes 
Self-Report 
Screening 
Survey 
ARC Staff 
 
Exclusion Criteria: Medical 
Criteria 
Eligible 
Response 
Assessment 
Measure 
Assessor 
Is blood alcohol concentration above 
0.00? 
No 
BAC breath test n/a 
ARC Staff 
Heart rate >100 beats/ minute after 
five minutes seated?  
[Tachycardia] 
No 
Clinical 
Assessment 
n/a 
Medical 
Staff 
Heart rate <56 beats/ minute after 
five minutes seated? 
No 
Clinical 
Assessment 
n/a 
Medical 
Staff 
Heart rate 56-59 beats/minute after 
five minutes seated AND clinical 
judgment from study physician that 
heart rate precludes safe 
participation 
No 
Clinical 
Assessment 
n/a 
Medical 
Staff 
Systolic BP <100 after five minutes 
seated? 
[Pre-existing hypotension] 
No 
Clinical 
Assessment 
n/a 
Medical 
Staff 
Systolic blood pressure > 160 mmHg 
after five minutes seated? 
[Pre-existing hypertension] 
No 
Clinical 
Assessment 
n/a 
Medical 
Staff 
After five minutes seated, stand up: 
Systolic BP drop >20mm Hg or 
diastolic BP drop >10mm Hg and 
report of dizziness, lightheadedness, 
unsteadiness or other problems 
(nausea, blurry vision) after two 
minutes standing?  
[Orthostatic hypotension] 
No 
Clinical 
Assessment 
n/a 
Medical 
Staff 
Frequent dizziness, unsteadiness, 
lightheadedness or other symptoms 
upon standing (> once/week)? 
No 
Self-Report 
Screening 
Survey 
ARC Staff 

46 
 
Colorblind 
[For NPU stress task] 
No 
Medical History 
and Clinical 
Exam 
n/a 
Medical 
Staff 
Hearing/Seeing problems  
[For NPU stress task] 
No 
Medical History 
and Clinical 
Exam 
n/a 
Medical 
Staff 
Current treatment for chronic pain 
condition  
[For NPU stress task] 
No 
Medical History 
and Clinical 
Exam 
n/a 
Medical 
Staff 
Past or current coronary artery 
disease, cerebrovascular accident, 
congestive heart failure? 
No 
Medical History 
and Clinical 
Exam 
n/a 
Medical 
Staff 
Current renal insufficiency, liver 
insufficiency or moderate hepatic 
impairment, diabetes, 
immunosuppressive therapy, or 
cancer with systemic effects or 
therapy? 
No 
Medical History 
and Clinical 
Exam 
n/a; Labs 
Medical 
Staff 
Polyneuropathy? 
No 
Medical History 
and Clinical 
Exam 
n/a 
Medical 
Staff 
Past or current pancreatitis? 
No 
Medical History 
and Clinical 
Exam 
n/a 
Medical 
Staff 
Benign positional vertigo, Meniere’s 
disease or narcolepsy? 
No 
Medical History 
and Clinical 
Exam 
n/a 
Medical 
Staff 
Previous allergic or adverse reaction 
to doxazosin or other alpha1 
norepinephrine antagonist? 
No 
Medical History 
n/a 
Medical 
Staff 
Scheduled or reported plans for 
cataract surgery prior to study 
completion? 
[Floppy Iris Syndrome] 
No 
Medical History 
and Clinical 
Exam 
n/a 
Medical 
Staff 
Currently symptomatic of alcohol 
withdrawal? 
[CIWA-Ar Score > 10, or positive for 
any ‘visual, auditory or tactile 
disturbances,’ or for ‘orientation and 
clouding of sensorium’] 
No 
Medical History 
and Clinical 
Exam  
CIWA-Ar 
Medical 
Staff 
Discharged from inpatient treatment 
for alcohol use disorder or alcohol 
detoxification within past 7 days? 
No 
Medical History 
and Clinical 
Exam 
n/a 
Medical 
Staff 
Currently stable? 
Yes 
Medical History 
and Clinical 
Exam 
n/a 
Medical 
Staff 
ECG clinical over-read indicates 
concerns of cardiac function? 
No 
ECG 
n/a 
Medical 
Staff 
Other self-reported acute or unstable 
illness that, in the opinion of the study 
team, would preclude a safe and 
reliable study participation? 
No 
Medical 
History, Clinical 
Exam, Clinical 
Interview 
Screening 
Survey 
Medical 
Staff and 
ARC Staff 
 
Exclusion Criteria: Medical (Female Participants) 

47 
 
Criteria 
Eligible 
Response 
Assessment 
Measure 
Assessor 
Are pregnancy test results positive or 
undetermined? 
No 
Urine 
pregnancy test 
n/a 
UW Lab 
Women of childbearing potential 
(see definition below) must agree to 
use one of the following forms of 
birth control until after study 
completion (see definition below).  
Yes 
Consent 
Process 
Screening 
Survey 
ARC Staff 
Breastfeeding?  
No 
Consent 
Process 
Screening 
Survey 
ARC Staff 
Definition: Women of childbearing potential are females who have experienced menarche and do not meet the 
criteria for women not of childbearing potential. Women not of childbearing potential are females who are 
permanently sterile (e.g., hysterectomy, bilateral oophorectomy) or postmenopausal. Postmenopausal is 
defined as 12 consecutive months with no menses without an alternative medical cause. 
Definition: Acceptable birth control is defined as the following methods of contraception: abstinence; hormonal 
contraceptives (e.g. combined oral contraceptives, patch, vaginal ring, injectables, and implants); intrauterine 
device (IUD) or intrauterine system (IUS); vasectomy of partner and tubal ligation; “single” barrier methods of 
contraception (e.g. male condom, female condom, cervical cap, diaphragm, contraceptive sponge) with use of 
spermicide; or “double barrier” method of contraception (e.g. male condom with diaphragm, male condom with 
cervical cap). 
 
Exclusion Criteria: Psychological/Behavioral 
Criteria 
Eligible 
Response 
Assessment 
Measure 
Assessor 
Self-reported lifetime diagnosis of 
schizophrenia schizoaffective 
disorder, psychotic disorder NOS, 
bipolar disorder (with manic 
episode), borderline personality 
disorder, or any neurocognitive 
disorder that may impair a reliable, 
safe participation? 
No 
Clinical 
Interview, Self-
report 
Screening 
Survey; 
SCID 
Medical 
Staff; ARC 
Staff 
Current suicidal ideation? 
No 
Clinical 
Interview 
SCID 
ARC Staff 
Meets criteria for DSM5 Substance 
Use Disorder AND not currently 
pursuing abstinence, other than 
alcohol or tobacco? 
No 
Clinical 
Interview 
SCID 
ARC Staff 
 
Exclusion Criteria: Medications/Therapies 
Criteria 
Eligible 
Response 
Instrument 
Measure 
Assessor 
Currently prescribed or used within 
past week: doxazosin or other 
alpha1-NE antagonist (e.g., prazosin, 
terazosin)? 
No 
Medication 
Inventory 
n/a 
Medical 
Staff 
Currently prescribed or used within 
past week: substances with stimulant 
properties (e.g., d-amphetamine, 
methylphenidate, ephedra, 
pseudoephedrine)? 
No 
Medication 
Inventory 
n/a 
Medical 
Staff 

48 
 
[Medications directly alter CNS 
noradrenergic neurotransmission.] 
Currently prescribed or used within 
past week: Sildenafil (Viagra), 
tadalafil (Cialis), and vardenafil 
(Levitra)?  
[Increased risk of hypotension in 
combination with alpha1-NE 
antagonists.] 
No 
Medication 
Inventory 
n/a 
Medical 
Staff 
Currently prescribed or used within 
past week: beta-blockers (e.g., 
propanolol), alpha2 agonists (e.g., 
clonidine, guanfacine, 
dexmedetomidine), and SNRI (e.g., 
venlafaxine, duloxetine, atomoxetine, 
viloxazine), antivirals (boceprevir), 
chemotherapy (pazopanib)? 
[Medications directly alter CNS 
noradrenergic neurotransmission.]  
No 
Medication 
Inventory 
n/a 
Medical 
Staff 
Currently used daily or used within 
past week: alpha1 agonists (e.g., 
midodrine, metaraminol, 
oxymetazoline, phenylephrine)? 
[Medications that alter alpha1 
noradrenergic neurotransmission.]  
No (within 
72 hours 
of Study 
Visit 1 or 
2) 
Medication 
Inventory 
n/a 
Medical 
Staff 
Currently used daily or used within 
past week: Benzodiazepines (e.g., 
diazepam, chlordiazepoxide, 
lorazepam, clonazepam, alprazolam), 
zolpidem (Ambien), zaleplon 
(Sonata), zopiclone (Imovane), 
eszipclone (Lunesta), dozapin 
(Silenor)? 
No 
Medication 
Inventory 
n/a 
Medical 
Staff 
Currently prescribed and used daily 
or used within past 2 weeks: 
Trazodone? 
No 
Medication 
Inventory 
n/a 
Medical 
Staff 
Currently prescribed or used within 2 
weeks: Disulfiram (Antabuse)?  
[Medication alters noradrenergic 
metabolism.] 
No 
Medication 
Inventory 
n/a 
Medical 
Staff 
 
Discharge criteria 
Criteria 
Discharge 
Response 
Assessment 
Measure 
Assessor 
Alcohol craving self-report returned 
to baseline? 
Yes 
Self-report 
6 item 
Desires for 
Alcohol 
Questionnaire 
ARC Staff 
 
 
 
 
 

49 
 
Appendix D: Glossary & Abbreviations 
 
Abbreviations 
AE: Adverse Event 
ARL: Addiction Research Lab 
ARL Staff: Addiction Research Lab Staff. Supervised by John Curtin (PI) 
BAC: Blood alcohol concentration 
BP: Blood pressure 
CNS: Central nervous system 
CRU: Clinical Research Unit 
DSM-5: Diagnostic and Statistics Manual of Mental Disorders – Fifth Edition 
ICTR: Institute for Clinical and Translational Research 
IRB: Institutional Review Board 
MET: Motivational Enhancement Therapy 
NE: Norepinephrine 
NIAAA: National Institute of Alcohol Abuse and Alcoholism 
NIH: National Institutes of Health 
NPU Task: No Shock, Predictable Shock, Unpredictable Shock Task 
OnCore: Online Collaborative Research Environment 
PI: Principal Investigator 
QD: One dose per day 
PRC: Pharmaceutical Research Center 
RCT: Randomized Clinical Trial 
SAE: Serious Adverse Event 
UW: University of Wisconsin 
 
Glossary 
 
Women of childbearing potential: Females who have experienced menarche and do not meet the criteria for 
women not of childbearing potential.  
Women not of childbearing potential: Females who are permanently sterile (e.g., hysterectomy, bilateral 
oophorectomy) or postmenopausal. Postmenopausal is defined as 12 consecutive months with no menses 
without an alternative medical cause. 
Acceptable birth control: The following methods of contraception: abstinence; hormonal contraceptives (e.g. 
combined oral contraceptives, patch, vaginal ring, injectables, and implants); intrauterine device (IUD) or 
intrauterine system (IUS); vasectomy of partner and tubal ligation; “single” barrier methods of contraception 
(e.g. male condom, female condom, cervical cap, diaphragm, contraceptive sponge) with use of spermicide; or 
“double barrier” method of contraception (e.g. male condom with diaphragm, male condom with cervical cap).