Effects of a New Behavioral Intervention on Alcohol Craving and Drinking
Phase: NA
Conditions: Alcohol Drinking, Alcohol Drinking Related Problems
Sponsor: National Institute on Drug Abuse (NIDA)

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Abbreviated Title: Lab/GMA drinking
Version Date:  2/16/2022
Abbreviated Title: Lab/GMA drinking
Protocol #: 16-DA-N140
Version Date: 2/16/2022
Title: Effects of a new behavioral intervention on alcohol craving and drinking 
NIH Principal Investigator:
David Epstein, Ph.D.
Branch: TAMB/RAPT Institute: 
NIDA IRP BRC 01B602
251 Bayview Blvd., Suite 200
Baltimore, MD 21224
Phone: 443-740-2328
E-mail: david.epstein@nih.gov

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Abbreviated Title: Lab/GMA drinking
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A. Précis
Objective: To evaluate alcohol memory retrieval-extinction, a novel behavioral procedure for 
reduction of craving and drinking, in problem drinkers.
Study population: We will collect evaluable data from up to 75 participants. Participants are 
evaluable if they complete geographical momentary assessment (GMA, described below). All 
participants will be adult alcohol drinkers (men: > 14 drinks/week or > 4 drinks/day; women: > 7 
drinks/week or > 3 drinks/day) whose drinking scores as hazardous on the Alcohol Use Disorders 
Identification Test. Participants will not be seeking treatment for an alcohol-use disorder, be 
physiologically dependent on alcohol, or have other drug use disorders.
Design: A randomized study with three groups. Participants will use smartphones to provide 
geotagged reports of alcohol craving and drinking in daily life (GMA reports) before, between, and after a 
series of laboratory sessions. During sessions, participants will drink an alcoholic beverage 
(individualized to produce a 0.06 g/dL blood alcohol content) or a soft drink. Participants will then be 
repeatedly presented with alcohol- or soft-drink-associated cues without further drinking. These are the 
memory retrieval and extinction portions, respectively, of memory retrieval-extinction. Previous studies 
suggest this procedure can robustly reduce Pavlovian associations between cues and responses such as 
craving. The mechanism seems to involve memory reconsolidation, in which freshly retrieved 
associations (e.g., “drink cues and consumption  pleasant effects”) become more vulnerable to 
disruption by extinction.
Three groups will be tested: (1) alcohol retrieval / alcohol extinction will be compared to (2) 
soft-drink retrieval / alcohol extinction and (3) alcohol retrieval / soft-drink extinction. Before and after 
retrieval-extinction, participants will be tested for alcohol craving and cue-induced physiological 
responses in laboratory sessions. Retrieval-extinction will be followed by 1 week of “follow-up” GMA 
reporting, with telephone contact 30 days thereafter.
Outcome parameters: The co-primary outcome measures are: self-reported alcohol craving in the 
laboratory sessions before and after retrieval-extinction, and GMA reports of alcohol craving and 
drinking. Daily-life responses are important because the version of retrieval-extinction we will be using, 
with retrieval induced by drinking alcohol itself, rather than alcohol cues alone, may be especially likely 
to have effects that generalize from the laboratory to daily life. Secondary outcome measures are: (1) self-
reported alcohol craving and drinking at 30-day follow-up, (2) physiological reactivity during sessions, 
and (3) urine biomarkers for alcohol consumption.

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Abbreviated Title: Lab/GMA drinking
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B. Table of Contents
A. Précis...........................................................................................................................................2
B. Table of Contents........................................................................................................................3
C. Background................................................................................................................................5
D. Study Objectives......................................................................................................................11
E. Study Design and Methods ......................................................................................................12
1. Study overview .....................................................................................................................12
2. Study procedures...................................................................................................................13
3. Follow-up/termination procedures........................................................................................26
F. Inclusion and Exclusion Criteria ..............................................................................................26
1. Inclusion criteria ...................................................................................................................27
2. Exclusion criteria ..................................................................................................................28
G. Clinical and Laboratory Methods ............................................................................................29
H. Collection and Storage of Human Specimens or Data.............................................................29
I. Statistical Analysis ....................................................................................................................30
1. Outcome measures .................................................................................................................30
2. Analysis of study outcomes ...................................................................................................30
3. Criteria for significance .........................................................................................................32
J. Required Sample Size ................................................................................................................32
K. Plans for Enrollment at Multiple Sites......................................................................................32
L. Human Subjects Protection Plan...............................................................................................33
1. The responsibilities of investigators .....................................................................................33
2. The names of investigators who will obtain informed consent..............................................33
3. Rationale for subject selection based on gender/ethnic/race categories at risk .....................33
4. Recruitment plan....................................................................................................................34
5. Justification for exclusion of vulnerable populations ...........................................................36
6. Evaluation of Risks/Discomforts and Benefits ratio.............................................................36
7. Subject monitoring................................................................................................................39
8. Conflicts of interest...............................................................................................................40
M. Protection of Participants’ Privacy and Confidentiality...........................................................40
N. Study Agents/Interventions......................................................................................................42
O. Plan for Reporting Unanticipated Problems and Adverse Events ...........................................42
P. Data and Safety Monitoring .....................................................................................................42
Q. Clinical Monitoring Plan .........................................................................................................43
R. Data/Records Management......................................................................................................43
1. Quality assurance ...................................................................................................................44
2. Relationship to other protocols ..............................................................................................44
3. Data-sharing description ........................................................................................................44
4. Technology transfer ...............................................................................................................45
S. Compensation...........................................................................................................................45
T. Scientific References................................................................................................................47

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Abbreviated Title: Lab/GMA drinking
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List of abbreviations and acronyms:
AUD: alcohol-use disorder 
CET: cue-exposure therapy 
CR: conditioned response 
CS: conditioned stimulus
EMA: ecological momentary assessment 
GMA: geographical momentary assessment 
GPS: global positioning system
US: unconditioned stimulus 
VAS: visual-analog scale

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C. Background
Cue-induced drug craving
Drug-associated environmental stimuli (i.e., cues) can significantly affect drug-abuse behaviors. 
Studies in laboratory animals show that presentation of drug cues can not only exacerbate ongoing drug 
self-administration (Goldberg & Tang, 1977; Alderson et al., 2000; Saunders & Robinson, 2010), but also 
reinstate drug seeking after periods of drug unavailability (reviewed by Bossert et al., 2013), even after a 
year (e.g., Ciccocioppo et al., 2004). Drug cues are also thought to contribute significantly to human 
substance-use disorders (SUDs) (Hyman, 2005). Significant behavioral, physiological, cognitive, and 
emotional effects of drug cues have been observed in people who use drugs (O’Brien et al., 1992; Field & 
Cox, 2008; Reynolds & Monti, 2013), and attenuating those effects has been recognized as an important 
goal in the development of better treatments (Taylor et al., 2009; Myers & Carlezon, 2010; Milton & 
Everitt, 2012).
One particularly important cue-elicited response is craving, the subjective desire for drug, which 
has long been a focus of clinical and scientific attention and has now been added to the DSM diagnostic 
criteria for substance-use disorders (Tiffany & Wray, 2012; Kavanagh et al., 2013; Haass-Koffler et al., 
2014; Grant et al., 2015). This protocol focuses on cue-induced craving for alcohol and other effects of 
alcohol cues in drinkers. We chose to assess drinking rather than other drug use because (1) there is an 
extensive literature characterizing alcohol cue effects in drinkers (reviewed by Drummond, 2000; 
Reynolds & Monti, 2013) and (2) administering alcohol to human research participants in the laboratory 
raises fewer issues than administering most other abused drugs (NIAAA document “Administering 
Alcohol in Human Studies,” Plebani et al., 2012)—and administering the drug is an essential component 
of the procedure we propose to test. The insights we gain into cue-induced craving for alcohol will likely 
be relevant to other drugs.
In people with alcohol-use disorders (AUDs), craving has been associated retrospectively and 
prospectively with greater rates of drinking (Yoon et al., 2006; Ramirez & Miranda, 2014; see also 
Fatseas et al., 2015) and greater motivation to drink (MacKillop et al., 2010; Amlung & MacKillop, 
2014). Craving can also predict relapse during or after AUD treatment (Flannery et al., 1999; Oslin et al., 
2009; Connolly et al., 2013; Papachristou et al., 2013). Finally, craving correlates with activity in brain 
areas implicated in associative learning and motivation (e.g., the ventral striatum; Schacht et al. 2013).
Accordingly, interventions that target alcohol cue effects are considered an important component of AUD 
treatment. Craving reduction is not only an important concomitant of treatment response, but is itself an 
important clinical target (Tiffany & Wray, 2012; Reynolds & Monti, 2013; Enoch, 2014).

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Abbreviated Title: Lab/GMA drinking
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Therapies based on reducing cue-induced responses: improving extinction training with memory 
retrieval beforehand
Cue-induced craving, like other effects of drug cues, follows the laws of Pavlovian learning: 
when alcohol (an unconditioned stimulus, US) is paired with initially “neutral” environmental stimuli, the 
neutral stimuli can become conditioned stimuli (CSs) capable of eliciting a variety of conditioned 
responses (CRs) such as craving. Like any CS-CR association, the association between cues and craving 
can be extinguished if the CS is presented repeatedly in the absence of the US (Blakey & Baker, 1980; 
Staiger & White, 1991; Staiger et al., 1999; Lee et al., 2007; MacKillop & Lisman, 2008). Extinction- 
based cue exposure therapies (CETs) are used in the treatment of other psychopathologies (e.g., anxiety 
disorders) but have not been widely adopted for substance-use disorders (Martin et al., 2010; Nic 
Dhonnchadha & Kantak, 2011). Some studies of alcohol CETs have produced promising results, with 
participants in CET groups showing, compared to control groups, less relapse, longer latencies to relapse, 
or less heavy drinking when they did drink (Monti et al., 1993; Drummond & Glautier, 1994; Sitharthan 
et al., 1997; Rohsenow et al., 2001). Other studies of CETs have not produced positive results or have 
not included sufficient information to evaluate their efficacy outside the laboratory, and it has been 
difficult to conclude overall that CETs are more effective than other types of treatment for AUDs 
(Conklin & Tiffany, 2002; Martin et al., 2010).
The limited success of CETs is not surprising when one considers what extinction really is.
Extinction is new learning, not an erasure of prior learning. The content of the new learning appears to be 
this association is no longer occurring in this context. Accordingly, extinguished CRs can emerge again 
in several ways: (1) renewal, the return of CRs as the context changes, (2) reinstatement, the return of 
CRs upon re-exposure to the US, and (3) spontaneous recovery, the return of CRs as time passes.
Laboratory studies of Pavlovian conditioning in human participants have demonstrated renewal (e.g. 
Collins & Brandon, 2002; Thewissen et al., 2006), reinstatement (Haaker et al., 2014), and spontaneous 
recovery (Corty & Coon, 1995). Each of these processes can produce enhancements of responding even 
when extinction training is initially successful (i.e., when it has produced significant decreases in 
responding), and together they show the limited scope of “standard” extinction training: behavior change 
depends on the particular circumstances (place, time, and drug-free state) under which extinction training 
is conducted.
Recent research suggests that the durability of extinction can be increased by a surprisingly 
simple manipulation: addition of a memory-retrieval experience shortly beforehand. In one striking 
demonstration, heroin addicts were given a brief “retrieval” presentation of heroin cues (on videotape, in

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Abbreviated Title: Lab/GMA drinking
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the absence of heroin) ten minutes before each actual extinction session (a longer period of exposure to 
paraphernalia and simulated heroin, again in the absence of heroin), and were found to have less cue 
reactivity than control participants 1, 30, and 180 days later (Xue et al., 2012). A clue as to the 
mechanism of this finding is that it depended on timing: one of the control groups underwent the same 
procedures as the experimental group, except that they saw the retrieval videotape six hours rather than 
ten minutes before each extinction session. For them, the retrieval had no measurable long-term effect. 
This suggests that the retrieval-extinction procedure works at least partly through a feature of memory 
processing called reconsolidation (Xue et al., 2012). Reconsolidation, which has now been extensively 
studied in both laboratory animals and humans, is the dynamic reprocessing of an established memory 
(i.e., a memory in long-term storage) (Alberini & Ledoux, 2013). When the content of an established 
memory is activated—brought out of long-term storage into working memory and/or conscious 
awareness—the memory can briefly become labile. It is more readily modified than if it had simply 
remained in long-term storage. A rough analogy would be opening a document that is stored on the hard 
drive of a computer. When the open document is resaved, the text of the document can be updated, or 
even erased, before the document is again stored with the same filename. (To be clear: we are using 
memory here to refer only to Pavlovian stimulus-response associations, not to narrative recollections of 
events.)
The version of the retrieval-extinction procedure that reduced heroin craving in the Xue et al. 
(2012) study uses only the CS (for example, a heroin videotape, not actual intoxication with heroin) for 
retrieval. This CS retrieval-extinction procedure has been shown in other human studies to reduce 
conditioned fear responses (Schiller et al., 2010; Oyarzun et al., 2012; Liu et al., 2014). Crucially, the 
procedure can work where “standard” extinction training without memory retrieval does not, such as: (1) 
in the establishment of an initial decrease in responding after extinction training (Xue et al., 2012), (2) in 
specific tests for the reinstatement of CRs (Oyarzun et al., 2012; Liu et al., 2014), and (3) with the 
passage of time and/or tests for spontaneous recovery of CRs (Schiller et al., 2010; Xue et al., 2012; Liu 
et al., 2014). The other major concern, renewal of the CR by a change in context, does not seem to have 
been tested in humans after CS retrieval-extinction, but has been tested in rats: CS retrieval-extinction 
reduces renewal of cocaine-trained responding in rats (Luo et al., 2015).
Initial excitement about CS retrieval-extinction has been tempered by discovery of its limitations.
In rats trained to drink beer, the effects of CS retrieval-extinction depended on the type of test used to 
assess responsiveness: rats in the experimental group were not protected from (and were actually more 
vulnerable to) reacquisition of drinking in a progressive-ratio task where beer was again available (Millan

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Abbreviated Title: Lab/GMA drinking
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et al., 2013). This problem did not occur in cocaine-trained rats when the retrieval-extinction session was 
done with the US instead of just the CS—that is, when extinction was preceded one hour earlier by an 
injection of cocaine itself (Luo et al., 2015). This US version of retrieval-extinction showed several other 
advantages over the CS version. It reduced responding to CSs that had not been specifically targeted for 
extinction—a clear advantage for treatment of human drinkers whose years of experience with alcohol 
have established far too many CSs to be presented in laboratory extinction sessions. It also sped the 
process of extinction itself, and its effects were also more resistant to renewal, reinstatement, and the 
passage of time (Luo et al., 2015).
The US version of retrieval-extinction has been used successfully in healthy humans to prevent 
the return of a recently conditioned association between a visual stimulus and an electric shock (Liu et al., 
2014). To our knowledge, it has not been tested in humans as an anticraving treatment.
The following table summarizes the expected advantages of US retrieval-extinction over older 
procedures:
Procedure
Spontaneous 
recovery over 
time
Renewal by 
context change
Reinstatement 
by priming
Effects of cues 
that were not 
specifically 
extinguished
Responding in 
a progressive- 
ratio task
Extinction 
alone
Not protected
Not protected
Not protected
Not protected
(no data)
CS retrieval- 
extinction
Protected
Protected
Protected
Not protected
Not protected
US retrieval- 
extinction
Protected
Protected
Protected
Protected
Protected
Geographical momentary assessment (GMA) of alcohol craving and drinking
Because one advantage of the US procedure is that its benefits should generalize from the 
laboratory to daily life, our study needs an outcome measure that can capture that. To that end, we will 
use real-time assessments of behavior and emotion on mobile electronic devices—a technique known as 
ecological momentary assessment (EMA) (e.g., Epstein et al., 2009), which we have expanded, with 
geolocation data, into geographical momentary assessment (GMA) (Epstein et al., 2014).
The use of EMA helps overcome the limitations of retrospective assessments, which may not 
adequately measure the dynamics of craving or accurately depict the relationships between craving and 
use (Tiffany & Wray, 2012; Kavanagh et al., 2013; Serre et al., 2015). Even once-daily reports may be 
subject to limitations such as forgetting, recall bias, and the state dependency of memory (Kirchner & 
Shiffman, 2013).

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Abbreviated Title: Lab/GMA drinking
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The use of EMA as a complement to laboratory assessments has been identified as an important 
future direction for research on cue reactivity (Reynolds & Monti, 2013). However, studies combining 
laboratory and field measures of the effects of alcohol cues have not been extensively pursued. Litt and 
colleagues (2000) first reported positive associations between the magnitude of cue-induced alcohol 
craving measured in the laboratory and the frequency of EMA reports of alcohol urges and drinking after 
discharge from treatment. Subsequently, Ramirez and Miranda (2014) reported significant associations 
between adolescent drinkers’ alcohol craving in a laboratory session and their EMA reports of craving in 
response to alcohol cues in daily life. Combinations of laboratory sessions and EMA have been used in 
pharmacotherapy studies to find medication effects on alcohol craving and/or drinking (topiramate: 
Miranda et al., 2014b; naltrexone: Miranda et al., 2014a).
In completed and ongoing protocols (NIDA-IRP Protocols 020, 385, and 407), our section has 
used EMA successfully to study drug craving and use. In the EMA component of these studies, 
participants provided three types of reports via their handheld devices: (1) responses to random prompts, 
in which participants make reports throughout the day as the device sounds a randomly programmed 
alarm, (2) event-contingent reports, which are initiated by participants when they engage in a target 
behavior (e.g., use drug) or experience a target emotion (e.g., stress or craving), and (3) responses to non- 
random interval-based prompts, in which participants make reports after a given amount of time has 
passed or at a given time each day (e.g., before going to bed). Together, these different entries provide a 
comprehensive account of events that do or do not precede or follow drug craving and use.
We have also successfully combined EMA with geolocation information obtained from the global 
positioning system (GPS) to perform geographical momentary assessment (GMA) (e.g., Epstein et al., 
2014). Using GMA, we have shown significant associations between drug craving and independently 
collected objective measures of neighborhood disorder and drug activity in the Baltimore city locations 
participants were moving through (Epstein et al., 2014). In the current study, we propose to use GMA 
because participants’ mood and behavior can be readily compared to objective information about alcohol 
availability (e.g., the addresses of businesses with liquor permits) (Freisthler et al., 2014). Laboratory 
studies have shown that information about the availability of alcohol significantly affects cue-induced 
alcohol craving, although both more (MacKillop & Lisman, 2005) and less (Papachristou et al., 2012) 
craving has been observed when alcohol is unavailable vs. available.
Previously, we have used two separate devices, one for EMA and another for GPS data 
collection. We currently propose to use a single device, a smartphone, to collect both EMA and GPS 
data. GPS receiver chipsets have become ubiquitous in smartphones and, by combining GPS information

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Abbreviated Title: Lab/GMA drinking
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with information on the strength of signals obtained from cellular data networks and wireless internet data 
connections (i.e., assisted GPS), smartphones can provide accurate location information more quickly 
than standalone GPS units and in cases where GPS signals are attenuated (e.g., indoors, in urban areas 
with many tall buildings) (Zandbergen, 2009; Zandbergen & Barbeau, 2011).
Physiological responses to alcohol cues
In addition to craving, alcohol cues can produce changes in heart rate, blood pressure, salivation, 
skin temperature, and galvanic skin response (Carter & Tiffany, 1999; Monti et al., 1999; Szegedi et al., 
2000; Reid et al., 2006; Fox et al., 2007; Hammarberg et al., 2009). These changes are another 
manifestation of the effects of associative learning with an alcohol US. Extinction training can reduce 
physiological responses to alcohol cues whether or not craving is reduced (e.g., Staiger & White, 1991; 
McCusker & Brown, 1995; Collins & Brandon, 2002), and physiological effects of alcohol cues can, in 
certain cases, predict treatment outcomes in situations where explicit craving ratings do not (Rohsenow et 
al., 1994; Garland et al., 2012). Thus, it is important for us to assess the effects of the retrieval-extinction 
procedure on cue-induced physiological responses. In heroin users, a heroin CS retrieval-extinction 
procedure reduced cue-induced changes in blood pressure as well as craving (Xue et al., 2012). We 
propose to collect physiological measures during the extinction component of the retrieval-extinction 
procedure in Sessions 2-5 and during the tests for renewal and reinstatement in Session 6 (described 
below).
Biomarkers for alcohol consumption
Although the real-time nature of EMA confers important advantages over retrospective 
assessments, EMA still has the limitations associated with self-report, such as socially desirable 
responding (Harrell, 1997). We plan to supplement EMA with the use of objective biomarkers of alcohol 
consumption, which are useful in both screening for heavy drinking and identifying relapse incidents 
(SAMHSA, 2012). Measurement of ethanol itself in breath or blood is appropriate for detecting ongoing 
intoxication or a single, recent bout of alcohol consumption. However, one breath or blood test for 
ethanol cannot establish typical consumption levels over time (e.g., chronic heavy drinking vs. an isolated 
incident), and the detection window for ethanol is only 10-12 hours after consumption (Jatlow & 
O’Malley, 2010), particularly in heavy drinkers, who can metabolize alcohol more rapidly than lighter 
drinkers (rates up to approximately 30 mg/dL/h, Winek & Murphy, 1984; Jones, 2010). Biomarkers can 
provide information about alcohol consumption outside of the intervals during which ethanol itself is 
detectable (SAMHSA, 2012). There is no single ideal biomarker for alcohol consumption, so the best 
measurements are obtained when several are combined (SAMHSA, 2012).

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Abbreviated Title: Lab/GMA drinking
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For our purpose, intermediate-term detection of recent drinking, we propose to use the 
biomarkers ethyl glucuronide (EtG) and ethyl sulfate (EtS) (SAMHSA, 2012). Although EtG alone can 
be used to detect drinking in an outpatient clinical population (McDonell et al., 2015), measuring both 
EtG and EtS reduces false positives caused by exposure to consumer products containing ethanol (e.g., 
hand sanitizers), and EtS is less subject to bacterial degradation than EtG (Ingall, 2012). Urine testing for 
EtG by immunoassay can detect heavy drinking for up to 5 days and light drinking for up to 2 days, with 
heavy drinking defined 4 or more drinks/day for men and 3 or more drinks/day for women (McDonell et 
al. 2015; see Jatlow and O’Malley 2010 for a similar estimate of duration based on mass spectrometry). 
Within this window, it may not be possible to distinguish recent moderate drinking from less recent 
heavier drinking (Ingall, 2012). Nonetheless, these detection windows are appropriate for our proposed 
study, in which participants make repeated, but not necessarily daily, visits to the laboratory over the 
course of several weeks.
We will measure EtG and EtS in urine. If new urine biomarkers for ethanol are discovered while 
we are running the protocol, we may measure those as well. We will also measure other substances in the 
urine samples (such as creatinine) that provide quality assurance for the biomarker measurements.
D. Study Objectives
The objective of this study is to test a novel behavioral intervention, US memory retrieval- 
extinction, for efficacy in attenuating cue-induced alcohol craving and drinking in problem drinkers.
Our co-primary objectives are to determine whether the retrieval-extinction procedure reduces (1) 
self-reported craving in response to alcohol cues presented in the laboratory and (2) EMA reports of 
alcohol craving and drinking in daily life. We have designated these as co-primary outcomes because 
laboratory data are more mechanistically informative and field data are more clinically relevant. We will 
assess self-reported craving during laboratory sessions conducted within and between four retrieval- 
extinction sessions, and then in tests for Pavlovian renewal and reinstatement that will follow the final 
retrieval-extinction session. We will assess changes in EMA reports before, between, and after the 
laboratory sessions. We hypothesize that, compared to the control groups, individuals receiving alcohol 
US retrieval-extinction will show reductions in craving (and possibly in drinking) over time. If we detect 
our hypothesized effects on the EMA measures alone, we will consider that sufficient evidence for the 
efficacy of the procedure. If we detect our hypothesized effects on the laboratory measures alone, we will 
consider that suggestive of possible efficacy, indicating that the procedure might need to be administered 
more intensively in future work.

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Abbreviated Title: Lab/GMA drinking
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Our secondary objectives are to test the effects of the retrieval-extinction procedure on (1) self- 
reported alcohol craving and drinking at the 30-day follow-up by telephone, (2) physiological responses 
to alcohol cues in the laboratory, and (3) biomarkers for alcohol consumption. We hypothesize that, 
compared to control groups, individuals receiving US retrieval-extinction will: report less alcohol craving 
and drinking at the 30-day follow-up telephone contact; have a reduction in physiological responses to 
cues; and have a reduction in biomarkers for alcohol consumption.
E. Study Design and Methods
1. Study overview
This is a 3-group, 6-session, randomized outpatient study in which drinkers are given access to a 
beverage that does or does not contain alcohol and are presented with cues that are or are not alcohol- 
related. For the US (unconditioned stimulus) version of the retrieval-extinction procedure, drinking 
provides the retrieval experience, which occurs before the cues are extinguished.
The three experimental groups are determined by whether the retrieval and/or extinction 
procedures involve alcohol versus control stimuli: (1) alcohol retrieval / alcohol extinction (experimental 
group) (2) soft-drink retrieval / alcohol extinction (control group A) and (3) alcohol retrieval / soft-drink 
extinction (control group B). Although soft drinks may have appetitive motivational properties of their 
own (Berns et al., 2001), we will use the soft drinks as inactive conditions as concerns craving for 
alcohol: the soft-drink retrieval condition is a no-alcohol retrieval condition, and the soft-drink extinction 
condition is a no-alcohol extinction condition. Using a soft drink rather than plain water allows for better 
matching of the sensory salience and caloric content of the alcoholic beverages, and by picking particular 
beverages (see below) we can minimize the potential for associative overlap between the soft drink and 
alcoholic beverages.   We considered several other control groups, but practical considerations forced us 
to limit our choices to what was necessary for basic interpretability of the findings.
EMA/GMA data will be collected via smartphone throughout the study. After giving written 
informed consent in the first visit, participants will be trained to use smartphones for real-time self-report.
In the first laboratory session, scheduled as soon as possible after enrollment, participants will 
provide information needed for our development of personalized imagery scripts, which we will use in 
subsequent sessions to induce craving.
Approximately 7 days later, participants will have the first of four retrieval-extinction sessions in 
which they drink beverages and undergo cue exposure/extinction. These four sessions will be spaced at 
least 2 days apart from each other.

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Approximately 7 days after the last retrieval-extinction session, we will test participants’ 
responses to alcohol cues using two Pavlovian procedures, renewal and reinstatement, that have 
previously been used in studies of laboratory animals to differentiate the effects of retrieval-extinction 
from extinction alone (Luo et al., 2015). At this visit, participants will return their smartphones.
Each participant will receive a follow-up phone call approximately 30 days after his or her last
visit.
The study will take each participant approximately 3 months to complete, depending on how
close together sessions can be scheduled. Each type of session is described in more detail in the Study 
Procedures section.
2. Study procedures
Study Timeline
1. Room tour; script interview
2, 3, 4, 5. Retrieval-extinction sessions
6. Renewal/reinstatement tests
GMA data collection
Telephone follow-up
Weeks after enrollment
Session
Beverage
EmptyPackaging
CueScript
Drinking
2-5. Retrieval
X
X
-
X
2-5. Extinction
X
X
X
-
6. Renewal, same room
X
X
X
-
6. Renewal, different room
X
X
X
-
6. Reinstatement, same room X
-
-
X
Experimental groups and randomization
As we mentioned above, we needed to limit the number of groups for practical reasons.
Participants will be randomized to one of three groups: (1) alcohol retrieval / alcohol extinction, (2) soft- 
drink retrieval / alcohol extinction, and (3) alcohol retrieval / soft-drink extinction. The use of these two 
control groups (groups 2 and 3) assesses whether the retrieval-extinction procedure requires both its 
retrieval component and its extinction component. Group 2 represents a traditional CET approach, with
1
2
3
4
8

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no relevant retrieval procedure. Group 3 controls for mere alcohol exposure in the laboratory, which has 
actually been shown to have some effect on subsequent drinking (Hodgson & Rankin, 1976; Modell et al., 
1993; Pratt & Davidson, 2005).
Randomization will be stratified by sex and by the type of alcoholic beverage (beer, wine, or 
distilled spirits) that will be served in the laboratory sessions, as determined by questionnaire and 
consultation with the participant, as described below. Blinding is not practical with our manipulations. 
To reduce expectancy effects, we will not specifically inform participants about the number or nature of 
the experimental groups; the consent form will make clear that there is at least one control condition but 
will not be more explicit than that. In the follow-up phone call, after collection of the last outcome 
measures, we will explain the three-group design of the study and debrief participants about their 
perceptions of the study. This delay of disclosure will itself be disclosed in the consent form.
Description of laboratory sessions
Overview of laboratory sessions
Sessions will be scheduled to begin at approximately 12:00 pm. Participants will be asked to 
abstain from drinking alcohol and using any illicit or over-the-counter drugs for at least 24 hours before 
the session. On arrival at each session, participants will provide a breath sample for measurement of 
blood alcohol content (BAC) and a urine sample.
Participants will be told that they may be observed when giving urine samples. There are two 
ways in which a participant’s urine collection will be observed. First, urine sample collection will be 
observed at random, with each collection from each participant having an equal chance of being observed. 
Second, urine collection will be observed if a participant attempts to tamper with the collection. Criteria 
for determinination of tampering are derived from the Direct Observation Procedures published by the US 
Department of Transportation’s Office of Drug and Alcohol Policy and Compliance 
(https://www.transportation.gov/sites/dot.gov/files/docs/ODAPC%20DOTs_Direct_Observation_Procedu 
res_Instruction_Sheet_August312009.pdf). Attempted tampering is indicated if a participant provides a 
sample with unusual characteristics (e.g., color, odor, temperature) or if a staff member sees a participant 
display paraphernalia or conduct used to tamper with urine collection. Paraphernalia include tubing, 
prosthetics, pre-prepared liquid samples, or substances to be added to urine to affect screening results.
Conduct includes attempts to dilute, substitute, or adulterate samples or behavior that facilitates the use of 
paraphernalia to dilute, substitute, or adulterate samples (e.g., bringing bags, cases, or heavy coats into the 
sample collection area when instructed not to). When there is evidence of tampering, that sample will not 
be accepted. The participant will be required to provide a urine sample under observation to continue

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with the session, and all of that participant’s subsequent urine collection will be performed under 
observation.
If BAC is >0, the session will be rescheduled; participants for whom this happens more than 
twice will be discharged from the study. Urine samples will be used for pregnancy testing for female 
participants and for measuring biomarkers for alcohol consumption for all participants. Participants will 
be rescheduled if they are intoxicated by alcohol or any other drug upon arrival, as assessed by a field 
sobriety test (described below); participants for whom this happens more than twice will be discharged 
from the study. All participants will also have a urine drug screen performed, but, because drug use per 
se is not exclusionary, we will use the urine results only to help us interpret signs of intoxication. In 
sessions that involve participants drinking an experimental beverage, participants will be weighed to 
allow us to calculate their BMIs and the volume of beverage they should be served in the session. To 
reduce variability in alcohol metabolism caused by food consumption, all participants will be asked to eat 
a light meal before arriving at the laboratory. Food will be provided on arrival if needed. To control for 
nonspecific effects of thirst, plain water will be available to participants during sessions (Litt et al., 2000). 
Tobacco/nicotine deprivation state can also affect alcohol craving and drinking (Palfai et al., 2000; 
McKee et al., 2008), so participants will be allowed periodic breaks to use tobacco if desired. At the end 
of each session that involves drinking an experimental beverage, participants will provide breath samples 
and will be released when their BAC is ≤ 0.01 g/dL, measured twice 20 minutes apart. All participants 
will be offered transportation to and from the laboratory by taxi and/or with payment for public 
transportation fares for all sessions that involve drinking an experimental beverage, as described in more 
detail in the Compensation section below.
a. Session 1:
Session 1 will occur after screening and will typically begin immediately after the participant 
gives written informed consent for the study.
Introduction to the laboratory: We will show participants the rooms where subsequent 
experimental events will take place. This limits the effects of novelty on participants’ responses in 
subsequent sessions (Collins & Brandon, 2002). The rooms will be designed to be distinguishable from 
one another, but emotionally neutral and not evocative of alcohol. To document that, we will ask 
participants to spend 5 min in each room and to write down as many different features of the room (e.g., 
wall color, furniture) as possible in 1 min and to rate the room on 100 mm visual analog scales (VAS) of
(1) pleasantness (“This room is a pleasant place to be”; 0 = “very unpleasant,” 100 = “very pleasant”) and
(2) relatedness to alcohol (“This room makes me think about drinking alcohol”; 0 = “not at all,” 100 =

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“more than anything else”). After viewing and rating the final room, participants will be asked to 
complete a VAS scale evaluating the rooms’ similarity to one another (“The rooms I was in are different 
from each other”; 0 = “very similar,” 100 = “very different”). Copies of the VAS’s are included in the 
Appendix. Order of presentation of the rooms will be counterbalanced across participants. If a 
participant gives a rating that is beyond the midpoint of the scale in the unexpected direction, we will ask 
the participant about it and try to change the relevant features of the rooms. If that does not solve the 
problem, we will still run sessions with the participant, but, in analyzing the study results, we will 
perform sensitivity analyses in which we see whether omitting that participant’s data changes our 
findings.
After seeing the rooms, participants will complete the following questionnaires:

“Most frequently consumed alcoholic beverage” questionnaire: developed in-house for this 
study, this questionnaire asks participants about the alcoholic beverage they drank most 
frequently in the previous 90 days: the kind of beverage (i.e., beer, wine, liquor), as well as the 
commercial brand and style of presentation (i.e., how the beverage was most frequently served).

Soft-drink preference questionnaire: developed in-house for this study, this questionnaire 
presents a list of beverages that do not contain alcohol or caffeine. For each beverage, 
participants are asked to rate: (1) familiarity, (2) liking, and (3) how frequently they have drunk it 
in conjunction with alcohol (i.e., as a mixer or chaser).

PhenX Toolkit Alcohol Specific Intermediate Phenotypes (ver. 13.1, www.phenxtoolkit.org): 
includes questionnaires on current alcohol craving, alcohol motives and expectancies, and acute 
subjective effects of alcohol.

Penn Alcohol Craving Scale (Flannery et al., 1999): assesses alcohol craving on a week’s 
timescale, providing a retrospective measure of craving.

Readiness to Change Questionnaire (Rollnick et al., 1992): assesses participants in terms of the 
“stages of change” (precontemplation, contemplation, action) regarding self-perceived excesses 
in drinking.

Brief Situational Confidence Questionnaire (Breslin et al., 2000): measures participants’ 
confidence in their ability to resist drinking in different types of risky situation (e.g., social 
pressure, physical discomfort).

Plymouth Sensory Imagery Questionnaire (Andrade et al., 2014): measures the vividness of 
participants’ ability to form mental images, in several sensory modalities.

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
Neighborhood Environment Walkability Scale (NEWS) (Saelens et al., 2003): an 82-item survey 
assessing types of residences, proximity to stores and facilities, access to services, aesthetic 
quality, safety from traffic and crime, and neighborhood satisfaction.

Behavioral Inhibition System / Behavioral Activation System Scales (Carver & White, 1994): 
assesses reward processing in terms of appetitive motivation, which is based on the pursuit of 
reward, versus aversive motivation, which is based on the avoidance of punishment or nonreward.
Session 1: Cue-script development: We will collect information for developing personalized sets 
of alcohol-associated stimuli to be used in Sessions 2-6. Imagery scripts will be developed adapting the 
methods of Sinha and colleagues (2003), which we have previously used to study food craving and eating 
(protocol 475). Participants will be asked to identify and describe (1) a pleasant personal situation that 
involved drinking alcohol (alcohol-related script) and (2) a pleasant personal situation that did not involve 
drinking alcohol (alcohol-unrelated script). We will avoid use of situations with strong negative 
emotional valence and/or stressful content (e.g., being cited for driving under the influence), both of 
which can affect alcohol craving (Rubonis et al., 1994; Willner et al., 1998; Fox et al., 2007; Ray, 2011).
The details required for the imagery scripts include physical and interpersonal context, verbal and 
cognitive attributions regarding people involved (including themselves), and physiological and bodily 
sensations experienced in the situation. We will write the information into a narrative and read it onto an 
audio recording for use in subsequent sessions with that participant. Each recorded script will last 
approximately 2 minutes.
To reduce variability in concentration and imagery ability, all participants will be trained in 
imagery visualization and trained to do 10 minutes of progressive muscle relaxation. The imagery 
training involves visualizing commonplace scenes presented by the script-development interviewer. The 
scenes are neutral and non-emotional in content, such as reading a magazine.
As a manipulation check, before being presented to the participants, each script will be evaluated 
by 1-2 experimenter(s) not involved in its generation. The evaluator(s) will rate the scripts on Likert 
scales (attached in Appendix) for alcohol-relatedness and emotional content. If an alcohol-related script 
scores below 3 on the 5-point Likert scale on alcohol-relatedness and/or scores above 3 on negative 
emotions, it will be revised. If an alcohol-unrelated script scores above 2 on the 5-point Likert scale on 
alcohol-relatedness and/or scores above 3 on negative emotions, it will be revised. Script revision will 
occur either (1) in Session 1 itself or (2) by telephone contact or in a separate laboratory visit scheduled to 
occur between Session 1 and Session 2. If it is needed, telephone contact or laboratory visit will be used 
only for script revision. We expect that, by working with the experimenter in the initial script

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development session, most participants will generate an acceptable script without the need for revisions. 
If revisions are required, we expect that most can be made by telephone, and so we expect the use of the 
additional lab visit to be rare. The addition lab visit for script revision is not included in the numbering of 
subsequent sessions. In our prior studies, we have never needed to revise a script.
The session will last approximately one hour. At the beginning and end of the session, 
participants will rate their alcohol craving using a one-item alcohol craving VAS adapted from that of 
MacKillop and Lisman (2008): “I want an alcoholic drink right now”; 0 = “I don’t want an alcoholic 
drink at all,” 100 = “I really want an alcoholic drink.” This urge scale will be used to measure craving 
during the extinction sessions. This same scale will be used for measuring craving during the extinction 
procedures, renewal test, and reinstatement conducted subsequently (described below). We are using a 
one-item VAS measure for craving because, in our prior studies, we have usually been better able to 
detect manipulation effects with these straightforward measures than with multi-item assessments of 
craving, and there may be good theoretical reasons for that (McGrath, 2005). We will measure craving 
for soft drinks using a similar VAS except references to alcoholic drinks are replaced by references to soft 
drinks. The alcohol and soft-drink craving scales are provided in the Appendix.
Before the end-of-session rating, participants will be given a 10-minute period with instructions 
to initiate progressive muscle relaxation and to focus on deep breathing. The relaxation procedure will be 
repeated until participants report not feeling stress and craving greater than pre-interview levels.
Participants will then be discharged.
Initiation of GMA: During Session 1, participants will each be issued a smartphone. We will 
show them how to use the phone for EMA entries and ask them to make several practice entries (which 
will not be used in data analysis). We will explain the automatic collection of location information by the 
smartphone’s GPS chipset. They will be shown how to charge the phone. They will be asked to keep the 
phone on and to carry it at all times.
GMA data will be transferred wirelessly from participants’ phones to servers located at the NIDA 
BRC under a secure communications system developed by the NIDA Biomedical Informatics Section.
Transfers will be scheduled to occur automatically at least twice a day. Participants will not have to visit 
the laboratory for these data transfers. If the remote transfers fail, we can manually initiate a wireless 
transfer when participants make their regularly scheduled laboratory visits. If that fails, we will swap out 
the participant’s phone so that the NIDA Biomedical Informatics Section can try to recover the data.
We describe the content of EMA questionnaires in a separate section below, after the description 
of the sessions.

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b. Sessions 2-5: Retrieval-extinction sessions
BAC will be checked at the start of each session and will need to be 0.00% to proceed. Session 2 
will be scheduled 2-3 days after Session 1, with 2-3 days separating each subsequent session. Under 
unusual circumstances, sessions might be separated by up to 10 days. Unusual circumstances would 
include, for example, staff shortages or unforeseeable participant emergencies that combine with Federal 
holidays or weather events. We expect such scheduling to be rare and will not present it in the consent 
form as an option. Participants will be terminated from the study as unable or unwilling to complete 
study measures if they cannot schedule a retrieval-extinction session within this 10 day window.
At the beginning of Session 2, participants will complete a timeline follow-back calendar (Sobell 
et al., 1979; Sobell et al., 1996a) covering the time between Session 1 and Session 2 to provide a 
retrospective report of drinking at “baseline” for comparison with that week’s GMA reports. At the 
beginning of Session 3-5, participants will report on their drinking in the time since their previous 
experimental session.
Retrieval: Participants will be placed in one of the two rooms they visited in Session 1. They 
will first complete a rating of their craving for alcohol and soft drinks. They will then be provided with 
either a beverage that contains alcohol (alcohol retrieval condition) or does not (soft-drink retrieval 
condition). The alcohol-containing beverage will be selected based on the types (beer, wine, spirit) and 
brands (commercial packaging) of beverages consumed in the previous 90 days, assessed by the “most 
frequently consumed alcoholic beverage” questionnaire. The participant’s most frequently consumed 
beverage will typically be chosen for use during experimental sessions, but we will also discuss the 
results of the questionnaire with each participant to determine what he/she considers “typical” liked 
drinks for him/herself. A different beverage (i.e., not the most frequently consumed beverage) may be 
chosen from among these typical drinks if the participant’s most frequently consumed beverage is not 
easily commercially available (e.g., is homemade or not in current production) or not practicable for 
attaining the study’s target BAC in the time available for drinking in the session (e.g., a beverage that has 
a very low concentration of alcohol that would require a participant with a large volume of distribution 
rapidly to consume large volumes of liquid). The goal is to arrive with the participant at a beverage that
(1) is acceptable to him/her to drink in the quantity required in the time available in the session and (2) 
provides a stimulus that is specific enough to the experience of the particular participants to be effective 
for memory retrieval and producing craving (Staiger & White, 1991). The soft drink will be based on 
participants’ reports collected in Session 1 of typical nonalcoholic beverages consumed and liked,

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screened by the experimenters to exclude caffeinated beverages and beverages commonly used by 
particular participants as mixers for alcohol.
Participants will be given a volume of alcoholic beverage necessary to produce a BAC of 0.06 ±
0.01 g/dL. We will adjust the amount of alcohol administered to attain this BAC based on equations by 
Brick (2006, Formula 14). Participants will be weighed at the beginning of each session for 
determination of total body water (Brick 2006, Formula 10), which is needed for the alcohol dose 
adjustment. Participants who do not reach the expected BAC will proceed with the rest of the session, but 
when we analyze the study data, we will perform sensitivity analyses in which we see whether omitting 
their data changes the conclusions.
The volume of soft drink we give will be adjusted for each participant to match the caloric 
content of the participant’s preferred alcoholic beverage.
To enhance retrieval, participants will be given their beverage along with an empty commercial 
package for that beverage; for example, Budweiser beer served in a pint glass along with an empty 
Budweiser can for alcohol retrieval, or Tropicana orange juice served in a tumbler alongside an empty 
Tropicana carton for soft-drink retrieval. To help standardize BAC during the subsequent extinction 
training, we will limit the time participants are given to finish the beverage, to a maximum of 40 min. 
The time each participant takes to finish the beverage will be recorded. If a participant finishes the 
beverage in less than 40 min, the extinction procedure can begin (i.e., we will not wait for the full 40 min 
to pass before initiating extinction). Before and 30 min after drinking, participants will complete the 
PhenX Measure: Acute Subjective Response to Substances questionnaire.
If a participant cannot or will not drink the whole beverage, we will measure the volume of 
beverage remaining undrunk. Participants who drink ≥ 66% of the initial volume will be allowed to 
continue with the session. Participant who drink less will be considered not to have completed the 
retrieval procedure and will not proceed to the extinction procedure. Instead, they will be asked to wait 
for discharge from the laboratory, using the procedures for release described below. Given a failure to 
complete retrieval, a retrieval-extinction session can be rescheduled once; participants who do not 
complete the beverage second time will be discharged from the protocol.
A number of previous human studies have used a fixed dose of alcohol that produces BAC of 
approximately 0.06-0.07 g/dL. Doses in that range (0.5-0.65 g/kg) are considered “moderate” (Rose et 
al., 2014). Their effects are detectable by participants (Chutuape & de Wit, 1994; Rose & Duka, 2006) 
and are rated as “liked” (Chutuape & de Wit, 1994). They have been used successfully in studies of the 
effects of alcohol priming/preloading on several behavioral and subjective endpoints: hypothetical and

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actual alcohol choice (de Wit & Chutuape, 1993; Chutuape & de Wit, 1994; Rose & Duka, 2006), food 
consumption (Rose et al., 2015), alcohol craving (see also Rankin et al., 1983; Christiansen et al., 2013; 
Rose et al., 2014), and cognitive and psychomotor test performance (Fillmore et al., 1998; Fillmore & 
Rush, 2001; Rose & Duka, 2006; Christiansen et al., 2013; Rose et al., 2014).
Extinction: The extinction procedure will begin 30 min after the end of the retrieval procedure to 
allow for alcohol absorption and distribution. Our intention is for the extinction procedure to occur when 
participants have a recent memory of alcohol intoxication, such that the temporal window of 
reconsolidation for that type of memory is open. Participants will spend the 30-min in the same room, to 
allow for the initiation of physiological monitoring (described below), and, to fill the time, participants 
will watch a series of short videos (Schiller et al. 2012).
Videos will be drawn from the popular (approx. 
(3 million subscribers) online science and technology video series SciShow and screened for emotional 
and drug-use content. Participants may be asked to answer a series of brief, open-ended questions about 
the videos. The list of videos to be used and the list of questions to be asked are provided in the 
Appendix. At the end of the 30 min, participants will provide a breath sample for determination of BAC, 
and then the extinction procedure will begin.
During extinction, participants will listen to audio recordings of the imagery scripts developed in 
Session 1. Participants receiving alcohol extinction will listen to their alcohol-related script; participants 
receiving soft-drink extinction will listen to their alcohol-unrelated script. Participants will also be given 
their preferred beverage along with empty commercial packaging; these will be the same during 
extinction as they were during retrieval, but during extinction, participants will not drink.
For all participants, cues will be presented in 5-min blocks: audio imagery scripts for 2 min, 
beverage exposure for 3 min. Once per min during the 3 min of beverage exposure, the participant will 
be instructed to take the glass in hand, raise it to his or her nose, and inhale its scent. Participants who 
drink any of the beverage during the extinction procedure will be discharged from the protocol.
There will be five blocks of cue presentation per session, with 5 min between blocks. In the time 
between blocks, the cues will be obscured from participants’ view. Participants will fill out the one-item 
alcohol craving VAS if needed and will then be instructed to relax until the next block of cues. The 
alcohol craving VAS will be given three times during the extinction session: (1) immediately before the 
first block of cues, (2) immediately after the first block of cues, and (3) immediately after the fifth, final 
block of cues. The rating taken before the first block will be used to determine whether the beverage 
itself increased craving (Christiansen et al., 2013; Rose et al., 2014). To check that participants were 
successfully attending to the cues, following the last urge scale, participants may be asked brief open-

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ended questions about the session (e.g., “Tell me about what you did in today’s session…”). Participants 
will then be allowed to remain in the room and to relax for 20 min, at which point physiological 
monitoring will be ended, yielding a total extinction time of 65 min. During this period, participants will 
be given instructions to initiate progressive muscle relaxation and to focus on deep breathing, as after the 
script generation procedure. If participants are still feeling craving or otherwise “triggered” by the cues at 
the end of this period, they will receive counseling.
Finally, participants will be asked to relax in a third, neutral room of the laboratory where their 
BAC will be checked every 20 minutes until ≤ .01%. Participants may be released from the laboratory 
when their Pre-discharge sobriety test is within normal limits and their BAC is ≤ .01%. A copy of the 
sobriety test is included in the Appendix.
Our decision to use four separate extinction sessions was based on data from previous studies, 
which showed that by the fourth session of extinction, craving for alcohol had decreased either to the 
point of not being different from that of neutral-beverage control participants, or by > 50%, or by 
reaching an asymptote such that additional sessions produced no further consistent declines craving 
(Blakey & Baker, 1980; Staiger & White, 1991; Staiger et al., 1999; MacKillop & Lisman, 2008). It is 
possible that US exposure (alcohol drinking for memory retrieval) will itself facilitate extinction (Luo et 
al., 2015). We believe that it is important to attempt to conduct a sufficient number of extinction sessions 
to allow the soft-drink retrieval / alcohol extinction group, as well as the alcohol retrieval / alcohol 
extinction group, to achieve a significant attenuation of cue effects.
c. Session 6: Post-treatment effects of cues in the laboratory
Participants will return their smartphones at the beginning of this visit. They will also complete a 
timeline follow-back calendar (Sobell et al., 1979; Sobell et al., 1996a) covering the time between Session 
5 and Session 6 to provide a retrospective report of “post-extinction” drinking for comparison with that 
week’s GMA reports.
In the session, all participants will be presented with alcohol cues and an alcohol-containing 
beverage (i.e., regardless of their previous group assignment to receive only a soft drink or soft-drink 
cues). Cue-induced craving and physiological changes will be measured in response to two procedures 
known to enhance responding after Pavlovian extinction procedures (Todd et al., 2014) and to 
differentiate the effects of extinction with or without prior memory retrieval in laboratory animals (Luo et 
al., 2015): (1) a renewal procedure, in which the extinguished response may reappear because the CS is 
presented in a new context and (2) a reinstatement procedure, in which the extinguished response may

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reappear because the US has been reintroduced to create a “priming” effect. Each participant will 
undergo both the renewal and reinstatement procedures, in that order, in one session.
Renewal-test procedures: We will use a within-participant renewal procedure based on that of 
Thewissen and colleagues (2006), who studied renewal of cue-elicited cigarette craving. Participants will 
be given alcohol cues in both the same room in which they underwent retrieval-extinction (the extinction- 
concordant room) and a different room (an extinction-discordant room). The identities of the rooms, and 
the order of their presentation in the renewal test, will be counterbalanced across participants within each 
group. Renewal is indicated by significantly greater cue reactivity in the extinction-discordant room than 
the extinction-concordant room. This is a proxy measure for the clinical problem of patients’ renewed 
craving after returning from the extinction setting to an outside environment (although, in our protocol, 
we will be attempting to assess that directly with GMA as well).
In the renewal procedure, participants will not be given an experimental beverage. Instead, in 
each room, they will rate their alcohol and soft-drink craving before and after a single block of alcohol 
cues, to be presented the same way as in the extinction sessions. In each room, physiological monitoring 
will begin 10 minutes before cue presentation and will continue for 5 minutes after the end of the craving 
ratings. This abbreviated schedule, compared to physiological monitoring used during the extinction 
procedure, is needed to allow for the tests to be completed in a timely manner with participants travelling 
between the two experimental rooms and spending time in a third, neutral room of the laboratory in 
between (described below).
BAC will be checked at the start of the session at will need to be 0.00% to proceed. Between 
their time in the first and second rooms, participants will spend 30 min in a third, neutral room and will be 
given a distractor: they will watch a series of short videos that have been screened for emotional and
drug-use content and afterwards answer brief questions about their content. Videos will be drawn from 
the popular (approx. 3 million subscribers) online science and technology video series SciShow. The list 
of videos to be used and the list of questions to be asked are provided in the Appendix. The distractor is 
intended to limit carryover effects from cue presentation in the first room to the second (Reynolds & 
Monti, 2013). After completion of the renewal test, to limit carryover from the renewal procedure to the 
subsequent reinstatement procedure, participants will be returned to the neutral room for 30 min to 
complete the distractor task for a second time with a fresh video.
Reinstatement-test procedure: We know of no prior explicit demonstrations of the reinstatement 
of extinguished drug-conditioned responses in human laboratory studies, but reinstatement has been 
documented in human studies of fear conditioning (Haaker et al., 2014).

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After the second distractor, all participants will be returned to the extinction-concordant room for 
the reinstatement procedure. Physiological monitoring will begin, and 10 min later, participants will rate 
their alcohol and soft-drink craving. They will then be given their experimental soft drink, which they 
will have 40 min to drink. 30 min later, they will again rate their alcohol and soft-drink craving. Then, 
they will be given their experimental alcoholic beverage, which they will have 40 min to drink. 30 min 
later, their BAC will be measured by breathalyzer, and they will again rate their alcohol and soft-drink 
craving. Reinstatement is indicated by greater craving after the alcoholic beverage than after the soft 
drink.
For reinstatement, the presentation of the alcoholic beverage and soft drink will be similar to the 
retrieval portion of the retrieval-extinction sessions: each beverage will be served to the participant as 
he/she typically consumes it along with its empty commercial packaging. However, we will present 
smaller volumes of beverage for reinstatement compared with retrieval. Participants will be served the 
volume of alcoholic beverage needed to give a dose of 0.3 g/kg absolute alcohol. In comparison, we 
estimate that participants will receive 0.5-0.6 g/kg absolute alcohol in retrieval, with exact doses varying 
according to each participant’s body composition to produce the target 0.06 g/dL BAC for retrieval. The 
volume of soft drink served in reinstatement will be matched to the calories in the alcoholic beverage 
served and will, thus, also be smaller than in retrieval. In previous research, 0.3 g/kg alcohol has been 
used successfully to study alcohol craving following alcohol consumption in non-dependent drinkers 
(Hutchison et al. 2001; McKee et al. 2009; Schoenmakers et al. 2008; Udo et al. 2013), and studies in 
laboratory rodents also show that smaller amounts of alcohol can prime alcohol-seeking behavior, 
compared to the amounts of alcohol consumed during animals’ self-administration training (e.g., Perry & 
McNally 2013). We believe the reduced beverage volumes used in reinstatement will allow us to observe 
a significant effect of alcohol while maintaining the comfort of participants, who are being asked to drink 
two beverages back-to-back in reinstatement, compared with the one beverage used for retrieval.
Participants will then be allowed to remain in the room and to relax for 20 min, at which point 
physiological monitoring will be ended. During this period, participants will be given instructions to 
initiate progressive muscle relaxation and to focus on deep breathing, as after the script generation 
procedure.
Finally, participants will be asked to relax in the third, neutral room of the laboratory where their 
BAC will be checked every 20 minutes until ≤ .01%. Participants may be released from the laboratory 
when their Pre-discharge sobriety test is within normal limits and their BAC is ≤ .01%.
d. Follow-up phone call

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Approximately 30 days after the final laboratory session, we will call the participant to conduct a 
timeline follow-back calendar (Sobell et al., 1979; Sobell et al., 1996a) and to administer the Penn 
Alcohol Craving Scale (Flannery et al., 1999). We will then disclose the design of the study to them, 
explain which experimental group they were in, and debrief them about their perceptions of the study 
(e.g., whether they had known that they were in a control group or the intervention group).
Following the experimental debriefing, the participant will be asked to speak to a master’s- 
degree-level counselor about his or her drinking behavior. The counselor will provide advice consistent 
with participants’ AUDIT scores (Babor et al. 2001, p. 20) and, when appropriate, referrals to treatment 
programs and support groups for alcohol-use disorders.
The same advice will be given to study candidates who score in the same range (8-15) on the 
AUDIT but who are disqualified from study participation for other reasons, such as not endorsing any 
AUDIT items beyond the first three. This would be done by screening staff toward the end of screening, 
rather than in a post-study follow-up.
Physiological monitoring during Session 2-6
We will continuously measure heart rate, blood pressure, skin conductance, and skin temperature 
during the extinction procedures in Sessions 2-5 and during the tests for renewal and reinstatement in 
Session 6. We will use these measurements to assess changes in participants’ physiological responses to 
the alcohol and soft-drink cues within and between sessions. Physiological measurements will be 
obtained using a standard laboratory physiological monitoring system: a BIOPAC or Coulbourn 
Instruments LabLinc noninvasive blood pressure amplifier with CNAP Monitor arm and finger cuffs plus 
fingertip-mounted skin temperature and conductance sensors . We have used these systems to measure 
participants’ physiological responses to drug and stress cues (NIDA IRP protocols 020, 475).
Geographical Momentary Assessment (GMA) data collection
GMA data collection will begin with the issuing of a smartphone in Session 1 and conclude at the 
beginning of Session 6, the final laboratory visit. Before being issued a smartphone, each participant will 
have an instructional session in which the assessment items and smartphone operation are explained.
EMA Entries
Participants will make the following types of entries: 
Event-contingent (EC) entries:
Drinking: We will tell participants to make an entry whenever they drink alcohol. We will use a 
questioning strategy similar to the one used successfully by Piasecki and colleagues (2014): participants 
will make an entry as soon as they finish their first drink of any drinking episode, and the smartphone will

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then automatically prompt them 30, 90, and 150 minutes later to ask about any subsequent drinks, unless 
the participant indicates that he or she is going to bed. The list of questions will be short to keep 
compliance as easy as possible. The main thing of interest, apart from the rate and volume of drinking, is 
the extent to which the participant feels that the drinking episode is ill-timed or excessive.
Craving: We will tell participants to make an entry whenever they feel a craving, urge, or 
temptation to drink.  Our use of all three terms is meant to capture the full range
of the experience; we will tell participants to report even mild or fleeting temptations or wishes. 
Random-prompt (RP) entries:
Three times per day, the smartphones will issue random prompts for participants to report their 
mood, activities, and degree of craving, with particular emphasis on recent encounters with any alcohol- 
related cues. (We will not ask participants to initiate an EC entry after every encounter with an alcohol- 
related cue because that seems likely to make them hypervigilant, changing the behaviors we are trying to 
assess.)
At each RP, we will ask whether the participant has had an unreported drink in the past hour. If 
the participant answers yes, the questions asked in a “drink” EC entry will be asked immediately 
following the RP, and the post-drink follow-up assessments (30, 90, and 150 minutes later) will be given 
as well.
Hours for RPs will be adjustable in accordance with participant’s typical sleep/wake schedule; 
participants will also be able to turn off random prompting for a limited amount of time each day, to be 
used in settings where receiving a prompt would be disruptive (such as driving or religious services). 
Measurement of blood alcohol concentration via breath (BAC):
For sessions 2-6, BAC will be measured at the start of each session and must be 0.00 to proceed. 
BAC will be measured again every 20 minutes after the last study procedure of the session until it comes 
down to ≤0.01, at which point, if the pre-discharge sobriety test is within normal limits, the participant 
can be discharged home.
3. Follow-up/termination procedures
Follow-up will be done by phone approximately 30 days after the final laboratory session, as 
described above. The follow-up phone call will terminate the participant’s enrollment in the study.
F. Inclusion and Exclusion Criteria
The enrollment target for the protocol is 100 (at least 75 of whom we anticipate will complete all 
6 study visits). We will enroll drinkers who report some problems or concerns with their own patterns of

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drinking (via their scores on the Alcohol Use Disorders Identification Test, described below), because in 
that population, reductions in cue-induced craving or drinking will constitute a benefit. Measuring those 
outcomes in lighter drinkers would have little clear meaning. However, we will not enroll drinkers who 
need or are seeking treatment for an alcohol-use disorder, because giving them alcohol in the laboratory 
would raise greater ethical issues. Our choice of population keeps us well within the guidelines laid out 
in the NIAAA document “Administering Alcohol in Human Studies”
<http://www.niaaa.nih.gov/Resources/ResearchResources/job22.htm>. We expect to have little trouble 
finding problem drinkers who are not treatment seekers: two large surveys have shown a 12-month point 
prevalence of approximately 10% for problem drinking (Sobell et al., 1996b). In the same surveys, more 
than 75% of respondents with prior drinking problems had recovered with no formal treatment or support- 
group involvement, usually returning to moderate drinking (Sobell et al., 1996b).
Thus, our target population consists of generally healthy people who feel that they ought to 
reduce their drinking somewhat, in the same way that other generally healthy people might feel that they 
ought to reduce their coffee or snack-food consumption. In all these instances, the desire to reduce 
consumption does not equate to a desire or need for formal treatment or support-group involvement.
There is no published questionnaire designed to identify members of our target population, so we are 
operationalizing the “ought to reduce” component primarily in terms of a minimum score on the Alcohol 
Use Disorders Identification Test (AUDIT), operationalizing the “not treatment-needing ” component 
primarily in terms of a maximum score on the AUDIT and the history and physical examination, and 
operationalizing the “not treatment-seeking” component in terms of study applicants’ responses to a 
specific written question (“Seeking Treatment / Seeking Abstinence” Questionnaire in the protocol 
appendix). When the MAI, or other staff involved in screening, suspects that a study applicant has a 
drinking problem more severe than the screening data overtly indicate, we will err on the side of caution 
by recommending treatment instead of enrolling the applicant. We will also discontinue sessions and 
recommend treatment for anyone whose need or desire for treatment emerges during the study.
Study candidates who score between 8 and 15 on the AUDIT but are disqualified for some other 
reason will, before they leave screening, be given the same advice and referrals that are given to people 
who have participated (see the section on follow-up phone calls for participants, page 23).
1. Inclusion criteria
(1) age between 21 and 65 years inclusive;
(2) Drinking at high levels for at least 10 different weeks during the last 90 days. High-level 
drinking for a given week can be either of the following:

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a) For women, more than 3 drinks on any single day that week, or more than 7 drinks that 
week;
b) For men, more than 4 drinks on any single day that week, or more than 14 drinks that 
week;
(3) a score ≥ 8 and ≤ 15 on the self-report version of the Alcohol Use Disorders Identification 
Test (AUDIT), with endorsement of at least one item other than 1-3, because 1-3 assess only 
consumption, not concern or consequences;
(4) self-report of liking or having neutral feelings about the sight and smell of alcoholic 
beverages;
(5) for women, practicing an effective method of birth control before entry and throughout the 
study (or postmenopausal for at least one year, or surgically sterile); negative urine pregnancy 
test at each visit.
Effective methods of birth control are those approved by the Food and 
Drug Administration (FDA) used as described in the FDA Birth Control Guide 
(http://www.fda.gov/downloads/forconsumers/byaudience/forwomen/freepublications/ucm51 
7406.pdf). These methods are: (1) intrauterine device (IUD) copper; (2) IUD with progestin;
(3) implantable rod; (4) contraceptive shot/injection; (5) oral contraceptives (combined pill, 
progestin-only pill, or extended/continuous-use combined pill); (6) contraceptive patch; (7) 
vaginal contraceptive ring; (8) diaphragm with spermicide; (9) sponge with spermicide; (10) 
cervical cap with spermicide; (11) male condom; (12) female condom; (13) male partner with 
a vasectomy. Abstinence from sexual intercourse is also an effective method of birth control.
2. Exclusion criteria
(1) risk of alcohol withdrawal, as determined by any of the following: a score ≥ 8 on the Clinical 
Institute Withdrawal Assessment for Alcohol, Revised (CIWA-Ar) following a negative 
breath test for alcohol (i.e., BAC of 0.0), lifetime history of delirium tremens or seizures 
(related to alcohol or not), endorsement of a “drinking to avoid withdrawal” symptom on the 
SCID or M.I.N.I. (M.I.N.I. Section I, “Alcohol Use Disorder,” items k1 and/or k2 answered 
affirmatively with counselor’s evaluation to verify that symptoms indicated in item k1 are 
related to the individual’s cutting down on drinking and/or the response to item k2 refers to 
withdrawal symptoms and not hangover); or physician’s judgment.
(2) currently trying to quit drinking, or planning to quit or reduce alcohol drinking via formal 
treatment or support-group attendance in the next six months;

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(3) for women: pregnancy, breastfeeding, or planning to become pregnant during the experiment;
(4) current liver disease or dysfunction, assessed by physical examination and medical history; 
and hepatitis C, chronic hepatitis B, or other current liver disease or dysfunction as assessed 
by physical examination and medical history or as reflected in blood levels more than 5 times 
the upper limit of normal in any of the following: aspartate transaminase (AST), alanine 
transaminase (ALT), or gamma-glutamyltransferase (GGT)
(5) any other medical illness or condition that in the judgment of the investigators is 
incompatible with alcohol consumption;
(6) current use of prescription or over-the-counter medications or herbal products for which 
drinking alcohol is strictly prohibited. When the metabolic half-life of the 
medication/product is known, we will require at least 7 half-lives to have elapsed before any 
session involving alcohol consumption. If the half-life is not known (as might be the case 
for some herbal preparations), we will require at least 7 days to have elapsed since the last 
use before any session involving alcohol consumption;
(7) substance-use disorder for any drug(s) other than alcohol or nicotine in the previous 12 
months;
(8) past or present diagnosis of bipolar disorder or any psychotic disorder; any history of suicide 
attempt or current suicidal ideation; present diagnosis of uncontrolled or untreated mood or 
anxiety disorder;
(9) cognitive impairment severe enough to preclude informed consent or valid self-report
G. Clinical and Laboratory Methods
These are described in section E.
H. Collection and Storage of Human Specimens or Data
Electronic data will be stored on the NIDA IRP’s secure, password-protected electronic medical- 
records system (Human Research Information System; HuRIS). Paper records will be stored in the 
Archway research space under double lock in an area not accessible to individuals who are not part of the 
study staff (BRC building; room number 01B605). After the study is completed and data have been 
analyzed, the paper records will be stored at an NIH-approved commercial facility for the storage of 
sensitive data until approval for their disposal has been given.

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Stored biological specimens will be kept in a secure freezer in the Archway’s NIDA freezer room 
until they are analyzed (BRC building; room 01B405). Specimens that are not used up in the analyses 
will be saved, but will not be used for any purpose not described in the protocol without prior IRB 
approval.
Urine samples will be kept in a secure freezer in the Archway’s NIDA freezer room until they are 
analyzed (BRC building; room 01B405) and tracked by barcode. Those that are not used up in the 
analyses will be disposed of after the study. They will not be used for any purpose not described in the 
protocol without prior IRB approval. Any unplanned loss or destruction of the samples will be reported 
by the PI to the IRB.
I. Statistical Analysis
1. Outcome measures
Primary: (1) self-reported alcohol craving during the laboratory sessions, (2) GMA reports of 
alcohol craving and drinking.
Secondary: (1) self-reported alcohol craving and drinking at the 30-day follow-up, (2) heart rate 
during laboratory sessions and GMA collection periods, and (3) biomarkers for drinking, detected in urine 
samples collected during laboratory sessions.
2. Analysis of study outcomes
There are two ways in which we are performing multiple tests of statistical significance. First, we 
have two co-primary outcomes: a lab measure and an ambulatory measure. This design is actually 
conservative, because we will not consider US retrieval-extinction fully successful if it affects only the 
first outcome (protection from renewal/reinstatement in a lab setting) without affecting the second 
outcome (changes in daily-life behavior).
Second, we need to compare our experimental group to each of the two control groups—we 
expect the control groups to be similar to each other. If the experimental group differs from only one of 
the control groups, we will have to conclude that the effect of US retrieval-extinction did not actually 
require both retrieval and extinction, and thus worked via some unexpected mechanism. Although we 
might ultimately need to perform the two comparisons separately to explore unexpected findings, our 
main planned analysis is a single test of the joint hypothesis that the experimental group differs 
simultaneously from both control groups.
Our specific tests will be as follows.

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Co-primary outcome 1: Protection from renewal/reinstatement of craving in session 6. We will 
analyze this in a linear regression model so we can control for a continuous covariate: each participant’s 
mean level of craving in prior sessions (along with any person-level covariates that improve the fit of the 
model). To test the joint hypothesis that the extinction-retrieval group differs simultaneously from both 
control groups, we will dummy-code the 3-level predictor Group using two variables: Control Group A 
(0,1) and Control Group B (0,1), thereby making our intervention group the reference level. We will then 
perform a Wald test of the joint significance of the two Control Group predictors, maintaining an alpha of
.05.
The dependent variable will be operationalized in terms of participants’ ratings of alcohol craving 
in the renewal procedure and the reinstatement procedure from session 6. For each participant, we will 
generate a summary measure of renewal susceptibility (or, for separate analyses, reinstatement 
susceptibility) using within-session scores from session 6. For renewal, the score will be calculated as:
(pre-to-post-cue craving change in discordant room) minus
(pre-to-post-cue craving change in concordant room) 
For reinstatement, the score will be calculated as:
(pre-to-post-cue craving change after alcohol) minus
(pre-to-post-cue craving change after soft drink)
Co-primary outcome 2: Reduction of craving and drinking in daily life. This will be analyzed in 
multilevel models, with the dependent variable operationalized in terms of participants’ changes in 
alcohol craving and alcohol drinking in GMA reports after the four extinction-retrieval sessions, 
controlling for any preexisting differences. Because we cannot predict the time course of differential 
changes, our main analyses here will omit GMA data from the period when the four extinction-retrieval 
sessions are occurring. The dependent variable will be daily frequency of craving reports (or, in a 
separate analysis, daily number of drinks); the independent variables will be coded the same way as in the 
models for co-primary outcome 1, with experimental group (3 levels) dummy-coded so the experimental 
group is the reference level and a Wald test of joint significance can assess whether the experimental 
group differs simultaneously from both control groups. The continuous covariate will be each 
participant’s overall frequency of craving or drinking during the baseline week of GMA.
Depending on the distribution of the dependent variable, we will use either general linear mixed 
models (e.g., SAS Proc Mixed) or generalized linear mixed models (e.g., SAS Proc Glimmix or SAS Proc 
NLMixed)—each of which provides a repeated-measures analysis that can handle missing days or early 
dropout and can accommodate person-level covariates, which will be included if they improve the fit of 
the model.  These models use maximum-likelihood estimation and allow for specification of an

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autoregressive error structure (which can be tested against alternative error structures to provide the best- 
fitting model). In supplementary analyses, we will examine the time course of any differences that 
emerge during the period when the four extinction-retrieval sessions are occurring.
Secondary outcomes: Most of the other laboratory measures, such as self-reported craving and 
drinking at the 30-day follow-up visit, urine biomarkers for drinking, and heart-rate responses to cues, 
will be analyzed by an ANCOVA approach similar to the one used for the co-primary outcome measure
1. Analysis of the GPS component of the GMA data will be more exploratory, but will include testing for 
group differences in susceptibility to alcohol craving as a function of nearness to bars and liquor stores—a 
possible reflection of cue reactivity.
3. Criteria for significance
Findings will be considered statistically significant at p ≤ .05, two-tailed, with trends noted at p ≤
.10.
J. Required Sample Size
We checked prior human studies to find likely effect sizes. For subjective drug craving, the 
difference between retrieval-extinction participants and control participants had a Cohen d of 1.12 (Xue et 
al., 2012, figure 3b, change scores for craving on day 4). In a prior human study on reinstatement of 
physiological reactivity to an extinguished (fear) cue, the difference between retrieval-extinction 
participants and control participants had a Cohen d of 1.11 (Liu et al., 2014, figure 1). These are large 
effects. We are powering our study for detection of effects that might be smaller. We used the module 
“Linear multiple regression: R-squared increase” in G*Power to determine what we could achieve with a 
realistic sample size. With evaluable data from 75 participants (25 in each of our 3 groups), we will have 
power of .80 to detect a Cohen f2 as small as 0.13 on a test of the joint hypothesis that the intervention 
group differs simultaneously from both control groups in a linear regression model that also contains a 
covariate for baseline, at a two-tailed alpha of .05. An f2 of .13 is approximately equivalent to a Cohen d 
of .61—conventionally considered a medium-sized effect. Despite the large effects seen in the prior 
studies, we think it is prudent to have power to detect a medium one.
Participants who drop out or are withdrawn from the study will be replaced. We anticipate that 
we will need to enroll 100 participants in order to have 75 complete the study.
K. Plans for Enrollment at Multiple Sites
Not applicable.

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L. Human Subjects Protection Plan
1. The responsibilities of investigators
Responsibilities and qualifications of investigators are given in the protocol appendix.
2. The names of investigators who will obtain informed consent

David H. Epstein, Ph.D.

Karran Phillips, MD, MSc

Jeremiah Bertz, Ph.D.

Kenzie L. Preston, Ph.D.

Louise Glezen, MS

Brenda Curtis, PhD

Edith Vargo, MD
Non-FTE staff members will explain the consent form to participants under the direct supervision of a 
federal employee (FTE) who will sign the consent form.
3. Rationale for subject selection based on gender/ethnic/race categories at risk
Participant selection will be equitable, without regard to nationality, race, religion, or creed. The 
anticipated racial/ethnic distribution will reflect that of the local community and drug-using population. 
According to 2010 census data, the population of Baltimore City was 63.7% black, 29.6% White, 2.3% 
Asian, and 0.4% American Indian/Alaskan Native. In the 2010 Census, 4.2% of respondents stated they 
were of Hispanic or Latino origin (US Census Bureau, accessed at www.quickfacts.census.gov, last 
revised 12/23/2011).
The inclusion and exclusion criteria were chosen to maximize generalizability while minimizing 
risk to participants. We chose an upper limit on age (65) to reduce the variability in responses to alcohol 
that might be associated with age, but we set this limit high enough so that it will most likely not 
disqualify any study applicants.
APPROVED STUDY POPULATION
FEMALE 
ENROLL-
MENT
MALE 
ENROLL-
MENT
TOTAL
ENROLL- 
MENT
FEMALE 
COMPLETERS
MALE 
COMPLETERS
TOTAL
COMPLETERS
APPROVED
CEILING
33
67
100
25
50
75
NIH TARGETED/PLANNED ENROLLMENT

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Sex/Gender
ETHNIC CATEGORY
Females
Males
Total
Hispanic or Latino
1
3
4**
Not Hispanic or Latino
32
64
96
Ethnic Category: Total of All Subjects*
33
67
100*
RACIAL CATEGORIES
American Indian/Alaska Native
0
1
1
Asian
1
1
2
Native Hawaiian or Other Pacific Islander
0
0
0
Black or African American
21
43
64
White
11
22
33
Other
0
0
0
Racial Categories: Total of All Subjects*
33
67
100*
*The “Ethnic Category: Total of All Subjects” must be equal to the “Racial Categories: total of All
4. Recruitment plan
Recruiting
Recruitment through the NIDA Office of the Clinical Director will be done by the NIDA-IRP 
recruitment contractor, MMG, and under certain circumstances, materials may be developed by other 
contractors as well. Alternatively, we may develop our own ads or contract these services ourselves. All 
advertising methods will comply with the most current regulations (NIH and OHSRP SOPs and 
guidelines, as well as FDA guidelines for FDA-regulated research) and the NIDA policy on recruitment 
materials.
The recruitment contractor may alter the ads in minor ways without prospective IRB review and 
approval; see below for a list of these types of changes. Other than that, modifications to these materials 
will be submitted to the IRB for approval as protocol amendments.
The following changes may be made to recruitment materials with no prospective review and approval by 
the IRB:

Contact phone numbers

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
Color change to graphics

Overall size, but all content will be increased or decreased proportionately

Addition of tear-off phone number tags to an approved ad or flyer

Color or font of the text, but any color change will replace all the text of a certain color. No new 
emphasis will be created.
All of these changes will be made to the most recently approved recruitment materials and submitted to 
the IRB annually at the time of continuing review.
Screening methods
Screening for this study will be conducted under protocol 06-DA-N415. Data from participants 
who enroll in this protocol and collected under protocol 06-DA-N415 will be shared and analyzed as part 
of this protocol.
The following measures will determine study eligibility:
Screening
Medical
(1) a 90-day timeline follow-back calendar for 
alcohol use
(1) medical history and physical examination,
(2) the Alcohol Use Disorders Identification Test
(AUDIT),
(2) breath sample for measurement of blood
alcohol level;
(3) the Addiction Severity Index (ASI),
(3) urine sample for drug testing and, for females, 
pregnancy testing
(4) Structured Clinical Interview for DSM Disorders 
(SCID) with counselor’s evaluation or Mini 
International Neuropsychiatric Interview (M.I.N.I.)
(4) blood sample for the following laboratory tests:
(a) NIDA chemistry 2 panel,
(b) serum magnesium (Mg++),
(c) complete blood count with differential (CBC 
w/diff),
(d) hepatitis B surface antigen, with reflex hepB 
panel if positive, and
(e) hepatitis C antibody.
(5) the Clinical Institute Withdrawal Assessment 
for Alcohol, Revised (CIWA-Ar),
Observation of urine collection for screening under protocol 06-DA-N415 will follow the same 
procedures as observation of urine collection in the 6 laboratory visits in this protocol: urine collection 
for screening will be observed at random and if a participant provides a sample with attempted tampering.

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Consent documents and process
Participants applying for the study and meeting its eligibility criteria will be asked to give 
informed consent. Consent will be obtained only by the investigators and coinvestigators named on this 
protocol, all of whom have completed NIH's electronic course in human-research ethics, and all of whom 
are qualified to answer questions about the study. Any study candidate who has questions or concerns 
about medical aspects of the study will be offered a chance to talk with the study physician before signing 
consent. After the consent form is read to or by the applicant, he/she will take and sign a 12-item quiz to 
ensure that he/she understands the protocol. The quiz may be done on paper or electronically in 
CDW/HuRIS. A score of 80% will be considered passing; if the score is lower than that, the quiz will be 
readministered once. The process will be documented in the CDW by the investigator who obtains 
consent. The consent form contains all required elements. Participants may sign the consent form on 
paper or electronically in CDW/HuRIS. Regardless of consent method, participants will be given 
hardcopies of their signed consent forms.
5. Justification for exclusion of vulnerable populations
Justification for the exclusion of children under 18 including neonates
Children under 18 will not be included because many of the measures to be administered in this 
study are not validated for use with children. Furthermore, it is illegal to administer alcohol to individuals 
under the age of 18.
Justification for the exclusion of pregnant women and human fetuses
A safe threshold for fetal alcohol exposure has not been established (“Administering Alcohol in 
Human Studies” <http://www.niaaa.nih.gov/Resources/ResearchResources/job22.htm>). Therefore, 
pregnant women and human fetuses will not be included.
Justification for the exclusion of other vulnerable populations
Individuals who are cognitively impaired to the extent that they cannot give informed consent or 
cannot give self-reports appropriately will be excluded. Self-report is a central outcome measure; 
including participants who cannot do it would invalidate the study. Including participants who cannot 
give informed consent cannot be justified for this study.
6. Evaluation of Risks/Discomforts and Benefits ratio
This study is more than minimal risk. The risks to participants are generally small and transient, 
and are outweighed by the potential benefits for treatment of substance-use disorders.

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Potential benefits
Direct benefits:
Participants are not expected to receive any direct benefit.
Indirect benefits:
The generalizable knowledge gained may benefit society by providing data on a potential intervention 
for substance use disorders.
Potential risks
Risks associated with alcohol consumption:
There are physical, psychological, and social risks associated with alcohol consumption (Wood & 
Sher, 2000). Physical risks include gastrointestinal distress, headache, flushing reactions; psychological 
risks include unwanted or excessive intoxication, embarrassment from impaired performance or 
disinhibited behavior; social risks include behavioral disinhibition leading to socially inappropriate 
action, censure from those who believe it is morally wrong to consume alcohol (e.g., for religious 
reasons), and legal sanctions (e.g., for public intoxication or driving while intoxicated).
Risks associated with cue exposure:
Alcohol cue presentation during the laboratory sessions is meant to cause craving for alcohol. 
Participants may experience stress and/or negative affect during these sessions, or may object to the 
eliciting of emotions by an experimental manipulation. The risk and discomfort with these procedures is 
related to their intended effects.
Risks associated with urine collection:
Participants may experience embarrassment from being observed while giving urine samples; this 
risk is minimized by having the observation always occur through a one-way mirror, by a staff member of 
the same sex as the participant.
Risks associated with GMA data collection:

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Carrying the portable electronic devices may be a burden to participants. There is a risk of loss of 
confidentiality associated with carrying information on alcohol use on and location on smartphones.
Carrying these devices may increase the likelihood of being robbed.
Other inconveniences:
Participants will need to spend time in the laboratory, including time for the experimental 
procedures and time BAC to return to a safe level. Participants will be compensated for their time (see 
Compensation section for details).
Alternative treatments and procedures
This protocol will not provide treatment for drinking problems and is not intended for people who 
want or need such treatment. Participants or study applicants who indicate a desire for treatment at any 
point, or who, in the investigators’ judgment, need treatment, will be referred for treatment rather than 
being enrolled or continued in the protocol.
Procedures for protecting against or minimizing any potential risks
Protecting against or minimizing risks associated with alcohol consumption:
We will not serve alcohol to people who do not drink regularly in their daily lives. We will not 
include those seeking treatment for their alcohol use, and we will not serve alcohol to people who are 
seeking to become alcohol abstinent on their own (i.e., without participation in a formal treatment 
program). Participants will have access to a limited amount of alcohol in each session, and the amount of 
alcohol available in each session is similar to or less than what participants report typically consuming on 
their own. When presented with an alcohol-containing beverage, participants will not be pressured to 
drink more of the beverage, or to drink it more rapidly than they wish to. Physical and psychological 
risks are also minimized by the availability of both medical staff and trained psychological counselors.
Participants will be able to contact medical staff and counselors during and between laboratory visits. 
Social risks are minimized by (1) the safeguarding of personally identifiable information according to 
standard NIH policies, which are designed to prevent breach of privacy at a level considered sufficient for 
sensitive healthcare data, and (2) requesting that participants remain in the laboratory until their BAC has 
fallen to an acceptable level and until participants can pass a pre-discharge sobriety test.

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Protecting against or minimizing risks associated with cue exposure:
Responses will be closely monitored and managed during and after the challenge sessions by 
trained staff. Participants will be debriefed, and standard CBT techniques for coping with cravings will 
be used when necessary.
Protecting against or minimizing risks associated with urine collection:
Any observation of urine collection will be performed through a one-way mirror by a staff 
member who is the same sex as the participant.
Protecting against or minimizing risks associated with GMA data collection:
We will reduce the burden of carrying the portable electronic devices by providing participants 
carrying cases with belt clips. The risk of loss of confidentiality associated with carrying information on 
alcohol use on and location on smartphones will be minimized because the smartphones will have only 
coded identification numbers on them and will be password-protected. Many people now carry electronic 
devices, including smartphones, every day, and so it is not likely that the risk of robbery is substantially 
increased over the usual risks. We have issued smartphones or handheld computers to approximately 300 
participants in prior studies without having encountered this problem. Similarly, all cell phones in the 
state of Maryland are now required to have position-tracking devices; therefore, risks from location 
tracking are similar to those of using a standard cell phone. All information we collect will be protected 
under an NIH-issued Certificate of Confidentiality.
Provisions for ensuring that necessary medical or professional intervention is available
Medical intervention will be provided by the Medical Advisory Investigator or nursing staff 
associated with the Treatment Section. Participants will also have access to trained psychological 
counselors. Participants will be able to contact medical staff and counselors during and between 
laboratory visits.
7. Subject monitoring
Parameters to be monitored

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BAC will be measured at the start of sessions 2-6 and then every 20 min after completion of study 
session tasks until BAC ≤0.01% and participant may be discharged home by taxi or public transportation 
as described in “Study design” above.
Criteria for individual subject withdrawal
A participant will be withdrawn from the study if he or she:

so requests, or withdraws consent.

misses and does not reschedule any of the study visits.

is unable or unwilling to complete study measures.

does not complete at least 75% of GMA entries in two consecutive weeks.

loses or damages two GMA smartphones.

arrives at session with a BAL > 0 in more than two sessions

develops any exclusionary condition or medical problem for which, in the MAI’s medical 
judgment, it is in the participant’s best interest to be withdrawn from the study.

develops any other conditions for which, in the investigators’ opinion and following adequate 
safety review, it is in the participant’s best interest to be withdrawn from the study.

becomes or is found to be pregnant or unwilling to practice required contraception.

shows an emergence or worsening of clinically significant psychiatric symptoms such as 
psychosis, low mood, suicidal ideation or behavior, anxiety, agitation, or disorientation.
8. Conflicts of interest
NIH guidelines on conflict of interest have been distributed to all investigators. There are no 
conflicts of interest to report.
M. Protection of Participants’ Privacy and Confidentiality
1. Methods used to identify and contact potential participants
Identification and contacting of potential participants will occur according to the recruiting plan 
described in this protocol.
2. Settings in which an individual will interact with an investigator
During laboratory visits, research activities will be conducted in private rooms located in 
restricted-access areas of the NIDA BRC. Outside of the laboratory visits, participants can contact

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investigators by telephone. Investigators will not initiate contact with participants outside of the 
laboratory visits unless a need arises to give new safety information or notify participants of an 
unexpected need to reschedule a visit.
3. Appropriateness of all personnel present for research activities
Only those personnel needed for the conduct of research activities will be present for research 
activities.
4. Methods used to obtain information about subjects and the nature of the requested information
Methods used to obtain information about subjects
Information about participants will be collected by self-report, by interview with an investigator, 
or through the collection of biological samples (blood, urine).
The nature of the requested information
The requested information is necessary for the successful conduct of the study or the 
interpretation of its results. It consists of: (1) information necessary to individualize the experimental 
tasks used during the laboratory sessions, (2) the study’s primary and secondary outcome measures, (3) 
demographic information that could affect the study’s outcome measures, or (4) other information about 
the participant that could affect the study’s outcome measures. In the latter case, this information consists 
of measures of psychological processes related to drinking alcohol or soft-drinks or obtaining other 
rewards, home environment, or mental imagery, which are essential features of the laboratory sessions 
and/or GMA data collection.
5. Information that may be obtained about individuals other than those enrolled in the study
We will not obtain identifiable private information about individuals other than those enrolled in 
the study. For demographic purposes, three study questionnaires ask about members of participants’ 
families: (1) participants are asked whether they are married, (2) participants are asked about their total 
family income, (3) participants are asked about their family history of alcohol use. In all cases, the other 
individuals are identified only in relation to the enrolled participant and by the type of relation (e.g., 
sister, cousin). We will not collect the other individuals’ names, dates of birth, addresses past or present, 
social security numbers, biometric information, or other identifiable private information. Individuals who 
are not enrolled in the study are not human subjects.
6. Justification for the amount of personal information required
The amount of personal information required is appropriate. Only the personal information 
needed for the successful conduct of the study or the interpretation of its results is collected.

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N. Study Agents/Interventions
Only commercially produced and packaged alcohol and soft-drink beverages will be used. The 
beverages will be chosen based on participants’ preferences and regularly consumed beverages to 
maximize the relevance of the study procedures to the participants’ normal alcohol consumption patterns.
There is no gene therapy and no FDA-regulated device or drug in this study.
O. Plan for Reporting Unanticipated Problems and Adverse Events
Reportable events will be tracked and submitted to the IRB as outlined in Policy 801.
P. Data and Safety Monitoring
1.
Data and safety will be monitored by the Principal investigator and MAI.
2.
A DSMB is not necessary for this study, which is unblinded and occurring at a single site. 
a. Monitoring mechanism: The Principal Investigator is responsible for data and safety
monitoring, and will work with the MAI to examine the adverse event data for safety 
concerns. The Lead Associate Investigator and Associate Investigators on the project will 
examine data for integrity and report to the PI.
b. Frequency: Data will be examined once a year at the time of the continuing review. Adverse 
event data will be examined as new events occur weekly.
c. Criteria for stopping the study: We will stop the study after we complete data collection from 
our target number of completers (n=75). We will stop the study sooner than that if there are 
more than 10 SAEs that are probably or 5 SAEs that are definitely attributed to study 
participation.
d. Advanced plans for interim/futility analyses: Interim analyses will not be conducted.
e. Information to be monitored:
1. Participant Safety: We will continually monitor adverse events for serious situations. 
Yearly, we will conduct an assessment of all adverse events to understand the risks that may 
be associated with the study.
2. Study Demographics: We will monitor recruiting and enrollment data to assure the 
consistency of our efforts with enrolling a diverse population representative of Baltimore City 
and its surrounding counties.

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3. Data Quality: We will review the data at the completion of each of the first 5 participants 
and at the end of completion of each 10 participants thereafter for data integrity as it relates to 
primary outcome measures.
f. Communication: The Lead Associate Investigator and Associate Investigators will bring safety 
and data integrity concerns to the PI. Safety and data integrity concerns will be immediately 
brought to the attention of the IRB and the Clinical Director via problem reports.
Q. Clinical Monitoring Plan
Not applicable.
R. Data/Records Management
For medical records and research data: All participants’ records generated by the NIDA/IRP 
staff will be accessible to authorized NIDA/IRP staff only and will be kept in locked files or password- 
protected electronic files (i.e., NIDA/IRP’s Clinical Data Warehouse; CDW, a Microsoft SQL Server 
database). Data will be kept in password-protected computers. All data forms will be identified by ARC 
number; participant names and ARC numbers will not appear together on paper forms except where 
mandated by federal or NIH policy (as on signed consent forms). The key that links ARC numbers with 
participants' names will be kept by the principal investigator in a locked filing cabinet in a locked room.
For stored samples: Samples will be stored using codes that we assign. Samples will be kept in 
freezers in a restricted-access area of the BRC. All access to that part of the BRC requires an NIH badge 
and is automatically logged. Samples may be used for other research projects with participant’s written 
consent. The samples will be coded with non-identifying information and the code kept at NIDA.
No clinically usable genotype data will be generated during the course of this study and no 
Clinical Laboratory Improvement Act-certified (CLIA-certified) genotyping acceptable for diagnostic or 
insurance purposes will be performed.
A Certificate of Confidentiality will be obtained prior to initiation of the study. To the extent 
legally possible, NIDA/IRP will not release participants' information without participants' explicit 
consent. However, in the event of a medical emergency, pertinent information will be provided to 
attending physicians.
1. Quality assurance
To ensure the validity and integrity of the data, the majority of data will be 
collected directly by participant self-entry into computers, and we will create and use

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checklists and standard operating procedure (SOP) manuals for data collection.
2. Relationship to other protocols
Data from participants who enroll in this protocol and that was collected through screening under 
protocol 06-DA-N415 will be shared and analyzed as part of this protocol. It is expected that behavioral 
and physiological data obtained from this protocol may be combined and/or compared with those 
obtained in other IRP protocols. Additionally, behavioral, physiological, and genetic data obtained from 
other IRP protocols may be combined and/or compared with those obtained in this protocol. This will 
allow us to better understand commonalities and differences in genotypes and phenotypes across different 
drug-using cohorts and healthy controls.
3. Data-sharing description
We share information with researchers outside the NIH in two ways. Most commonly, we have 
specific partnerships with other researchers. Also, we may put data into one or more scientific databases, 
where it is stored along with information from other studies. Researchers can then study the information 
combined from many studies to learn even more about health and disease.
We will share some protocol data with our scientific research partners inside or outside the NIH. 
Research partners outside the NIH sign an agreement with the NIH to share data. This agreement 
indicates the type of data that can be shared and what can be done with those data.
Some health information collected under this protocol may be placed into one or more scientific 
databases after it has been stripped of identifiers such as name, address or account number, so that it may 
be used for future research on any topic and shared broadly for research purposes. A researcher who 
wants to study the information must apply to the database and be approved. Researchers with an approved 
study may be able to see and use the data from this protocol, along with that from many other studies. We 
do not expect any direct benefits for participants resulting from in the use of protocol data and 
information, though new discoveries that may help other people could occur. The Principal Investigator 
is open to answering any questions about how this data may be used.
Participants may stop participating in this study at any time. They may subsequently decide to 
withdraw permission for the use of their individual data, specimens and health information for additional 
or future research at any time. If they choose, we will destroy their data. However, it may not be possible 
to withdraw or delete materials or data once they have been shared with other researchers.
4. Technology transfer
There are no Technology Transfer agreements needed for this study.

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S. Compensation
Volunteers will be compensated for time and research-related inconveniences. All participants 
will be offered at the experimenters’ expense either a taxi ride to and from the laboratory or payment for 
public transportation fares for all sessions involving drinking an experimental beverage. For public 
transportation fare payments, we will request receipts from participants documenting their fares and pay 
participants for the indicated amounts. Participants may, however, be using longer-term or multi-ride 
electronic pass systems (e.g., monthly unlimited ride cards) that do not provide ride-by-ride tickets or 
receipts with ride-by-ride pricing information. If participants do not possess individual receipts, we will 
provide payments to cover the cost of a 1-day pass or 1 round trip fare on each public transportation 
system used by the participant. An experimenter will establish the transportation systems used in 
discussion with participants about their routes, verified by transportation schedules, maps, and/or route 
planners showing the connections between participants’ point of origin and the BRC. Transportation by 
taxi and public transportation payments may be combined to provide rides by taxi to/from public 
transportation service locations (e.g., train stations).
Amount of compensation (hourly rate, inconvenience units and maximum for study):
1.
Session 1: 5 hours, compensated at $20/hour, for a total of $100.00
2.
Sessions 2-5: 6 . 0 hours, compensated at $20/hour, for a total of $120.00 per session
3.
Session 6: 8.5 hours, compensated at $20/hour, for a total of $170.00
4.
Compensation for GMA data collection: $80.00 for answering ≥ 82.0% of random 
prompts, $100.00 for return of the smartphone in working condition
5.
Follow-up contact by telephone:  1 hour, compensated at $20/hour, for a total of $20.00
6.
If a participants’ first cue script development session does not produce appropriate 
material (described above), he/she will be asked revise or replace the material either by 
telephone contact or by returning to the laboratory on a separate day. This will take ≤ 
1hour, and participants will be compensated $20.00 for doing so (not included in total 
compensation amount below).
7.
If a blood draw for any visit is unsuccessful due to technical, processing, or laboratory 
error, a participant may be asked to return on a separate day for repeat draw and will be 
compensated $20 (not included in total compensation amount below).

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The total amount of compensation if the participant completes all experimental events is $950.00. The 
total maximum compensation does not include compensation for imagery script revision or repeat blood 
draw if needed.

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