Clinical trial NCT03930446
Conditions: Alcohol Drinking Binge Drinking Drinking Behavior Substance-Related Disorders Ethanol Physiological Effects of Drugs Central Nervous System Depressants
Sponsor: University of Chicago
Start date: 2016-01-01; Completion date: 2019-05-30
Enrollment: 80 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
To evaluate the relationship of extraversion to both the acute subjective and behavioral effects of alcohol, and the neural reactivity to the anticipation of reward.

Detailed description:

Arms: arm 1: Subjects will receive 4 color-coded beverages in green or blue cups, containing ethanol (0.2 g/kg per dose, total dose 0.8 g/kg). arm 2: Subjects will receive 4 color-coded beverages in green or blue cups, containing placebo (Juice).
Interventions: intervention 1: Ethanol intervention 2: Placebo
Intervention descriptions: intervention 1: The 0.8 g/kg body weight dose of oral alcohol (190-proof ethanol) will be divided into 4 servings of 0.2 g/kg each. The 0.8 g/kg dose is equivalent to 4 standard drinks, where a standard drink is defined as one 12 oz beer, one 5 oz glass of wine, or one 1.5 oz shot of 80 proof alcohol. Women will receive a reduced dose (0.68 g/kg) to account for sex differences in total body water intervention 2: The placebo beverage will consist of the cranberry or orange juice plus 1% alcohol added as a taste mask. All beverages will be sprayed with an alcoholic mist to provide a strong alcoholic scent.

Protocol documents:
Prot_SAP_000.pdf: 
Protocol Name: Disinhibition and alcohol reward (called “Behavioral tendencies and 
responses to drugs” on the consent form for blinding purposes) 
Identifiers: NCT03930446   Unique Protocol ID: IRB16-0015 
 
Date: 10/6/2015 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
Protocol Name: Disinhibition and alcohol reward (called “Behavioral tendencies and 
responses to drugs” on the consent form for blinding purposes) 
Principal Investigator: Harriet de Wit, Ph.D. 
Co-Investigators: Jessica Weafer, PhD and Royce Lee, MD 
 
Study Location: The University of Chicago Medical Center 
Version Date: October 6, 2015 
Background and Aims: Poor inhibitory control is a known risk factor for alcohol dependence. 
Prospective studies show associations between poor inhibitory control in childhood and alcohol 
use disorders in adolescence and adulthood (Dawson et al., 2010; McGue et al., 2001). 
Additionally, greater impulsive action on the stop task in a sample of heavy drinkers (N=380) 
prospectively predicted the development of alcohol dependence 4 years later (Rubio et al., 
2008). In laboratory animals, drug-naïve mice bred to be high alcohol preferring exhibit higher 
levels of impulsive action compared to non-alcohol preferring lines (Bowers and Wehner, 2001; 
Logue et al., 1998; Wilhelm et al., 2007). Together these studies suggest that poor inhibitory 
control plays a causal role in alcohol abuse. 
 
Greater sensitivity to alcohol’s rewarding effects has also been associated with risk for 
abuse. In early studies, we showed that stimulant effects of alcohol were associated with 
alcohol choice in a controlled laboratory setting (Chutuape and de Wit, 1994; de Wit et al., 
1987). More recently, we showed that a greater stimulant response to alcohol was prospectively 
associated with increased binge drinking at a 2 year follow-up (King et al., 2011). Moreover, 
individuals who are genetically at increased risk for alcohol abuse (i.e., Family History Positive) 
also report greater positive, stimulant-like effects of alcohol (Newlin & Thompson, 1990; Quinn & 
Fromme, 2011), providing further support for the link between sensitivity to alcohol reward and 
propensity for excessive use.  
 
Initial reports have investigated associations between impulsive personality and 
response to alcohol. These suggest that individuals scoring higher on self-report measures of 
impulsivity also report greater stimulation and less sedation after drinking, and that this 
association is stronger at higher doses (Hendershot et al., 2013; Leeman et al, 2013). These 
promising new findings further emphasize the need to probe this association with a behavioral 
measure of impulsive action. 
 
 
Study Aim: To examine the degree to which impulsive action predicts rewarding effects 
of alcohol. In this study we will examine the degree to which impulsive action predicts 
sensitivity to the rewarding effects of alcohol in healthy adults. To attain this objective, we will 
test the working hypothesis that individuals high in impulsive action, but matched on drinking 
history, will report significantly greater euphoria and arousal after alcohol than those low in 


impulsive action, and that they will exhibit greater preference for alcohol over placebo in a 
choice test. We will test our working hypotheses by comparing individuals high and low in 
impulsive action in both subjective reward and choice for alcohol vs placebo. The primary 
measures of euphoria and arousal with alcohol will be BAES Stimulation (see below), as well as 
ARCI A (arousal) and MBG (euphoria), and DEQ Drug Liking. The measure of choice will be the 
choice for alcohol over placebo and the number of alcohol servings consumed on the last 
session. Successful completion of this study will provide important information regarding the 
degree to which poor inhibitory control is linked to alcohol reward, as measured by both 
subjective and behavioral measures. Taken together with our other concurrent study with 
amphetamine, it will also provide information about the generalizability of associations between 
poor inhibitory control (i.e., impulsive action) and drug reward. Further, evidence that individuals 
with poor inhibitory control are more sensitive to the rewarding effects of alcohol, a drug that is 
often co-abused with stimulant drugs, will set the stage for future studies to examine 
neurobiological substrates underlying poor inhibitory control and both stimulant and alcohol 
reward. This will provide valuable information regarding potential risk factors for poly-drug abuse 
in these individuals. 
 
Research Design and Methods: 
Design: The study will use a between-subjects design to test two measures of reward 
(subjective effects and drug choice) in participants pre-selected based on their performance on 
the stop task (Logan et al., 1997), a standardized measure of impulsive action. Participants will 
be eligible to participate if they score in the upper (stop reaction time > 325ms; N=30) or lower 
(stop reaction time < 270ms; N=30) quartiles on stop task performance (calculated from over 
500 previous subjects in our lab) during the screening session. Subjects will then participate in a 
5-session choice procedure, consisting of 4 sampling sessions and one choice session. During 
the sampling sessions, participants will consume beverages containing 0.8 g/kg ethanol (divided 
into 4 servings of 0.2 g/kg each) or a matching placebo under double blind conditions. During 
the choice session, they will choose the beverage they prefer, and drink the number of servings 
(from 1-4) they prefer. The primary outcome measures are subjective ratings of stimulation, 
drug liking, “euphoria”, and “arousal” (see below) on the sampling sessions, and choice and 
number of servings of alcohol or placebo on the choice session. 
Participants: Healthy male and female volunteers, aged 21-29, will be recruited by posters, 
advertisements, and word-of-mouth referrals. Participants will provide consent under Protocol 
#13681B to undergo the screening procedure, which will include an EKG, physical exam, 
clinical psychiatric interview, and stop task performance. Participants will be moderate drinkers 
(7-30 drinks per week) who report at least one binge drinking episode (5 or more drinks on a 
single occasion for men; 4 for women) in the last month. Asian subjects who report a 
pronounced ‘flushing’ reaction will be excluded. Subjects who smoke >5 cigarettes/day will be 
excluded to avoid acute nicotine effects or withdrawal during the sessions. Additional exclusion 
criteria include any serious medical problems, Axis I psychiatric disorders including substance 
dependence (APA, 1994), pregnancy or lactation (females), lack of a high school education, and 
lack of fluency in English. Women not currently using hormonal contraceptives will only be 
tested during the follicular phase (days 1-14; White et al., 2002). We will monitor participant 


characteristics throughout the study to ensure that the high and low impulsive groups are 
matched on sex, race, education, SES, alcohol drinking, cigarette smoking, and other drug use.  
 
Qualifying participants will provide informed consent during an orientation session. They will 
agree to abstain from alcohol for 24 hours and other recreational drugs for 2 days before each 
session, to get normal amounts of sleep, and to consume their usual amounts of caffeine and 
nicotine prior to each session. For the sampling and choice sessions, they will also be asked to 
fast 4 hours prior. They will be told that breath and urine samples will be obtained on each 
session to verify abstinence. For blinding purposes they will be told that the beverages used in 
the study may contain a stimulant, sedative/tranquilizer, alcohol, or placebo. 
 
Procedure: Sessions will be conducted in the afternoons, in comfortable rooms at the Human 
Behavioral Pharmacology Laboratory. At each visit, participants will provide breath (Alco-sensor 
III, Intoximeters, St. Louis, MO) and urine (ToxCup, Branan Medical Co. Irvine, CA) samples to 
detect recent drug use or pregnancy (women; Aimstrip, Craig Medical Vista, CA). Positive 
pregnancy tests will result in exclusion and positive drug tests will result in rescheduling or 
exclusion. All sessions will be conducted from 3 pm to 8 pm, and will be separated by at least 
48 hours but no more than 7 days. Upon arrival pre-beverage mood and vital signs will be 
recorded, and beverage administrations will occur 30 min after arrival, at 3:30pm. Mood and 
vital signs will be recorded every 30 minutes post-beverage administration. Between 
measurements in the laboratory, participants may read or watch movies from an approved list, 
but will not be allowed to sleep or have access to internet or cell phones. Data collection will end 
at 8pm and participants will be provided with a snack and discharged providing they pass a 
sobriety test and breath alcohol concentrations are below 0.02mg% (as per NIAAA guidelines). 
If BrAC is above 0.02%, BrAC samples will be collected every 15 minutes until BrAC is below 
0.02mg% after which participants will be allowed to leave. However, participants will not be 
allowed to drive themselves home. If using public transportation, participants will be 
accompanied by a lab member to the bus stop, and funds for public transportation will be given, 
if needed. If they are getting picked up, a lab member will wait with them until their ride arrives. 
Participants will be made aware of these travel requirements at their orientation session. In 
addition, we will confirm travel arrangements with the participant prior to drink administration at 
each of the sampling and choice sessions.  
Orientation Session: Subjects will attend an orientation session during which study procedures 
are explained, and trait impulsive action is re-assessed. They will read and sign the consent 
form, complete self-report questionnaire measures of personality, and perform the stop task. 
Subjects will also perform additional behavioral impulsivity tasks, including a go/no-go task and 
a delay discounting task, to determine the specificity of these effects to impulsive action and the 
stop task. Finally, they will complete a sweet taste test to examine associations between alcohol 
reward and a non-drug reward.  
Sampling Sessions: During the four sampling sessions, subjects will undergo the pre-session 
screening procedures described above, and then on each of four sessions they will receive 4 
color-coded beverages in green or blue cups, containing alcohol (0.2 g/kg per dose, total dose 


0.8 g/kg) or placebo. Within each session all the beverages will contain either alcohol or 
placebo, and the alcohol or placebo sessions will be scheduled in alternating order, with the 
initial drug randomized. For each subject the alcohol beverages will be in cups of one color, and 
the placebo in cups of the other color. Alcohol and placebo color-coding will be randomized 
across subjects. Subjects will be told that the drug and dose in each color will be the same on 
both days, and instructed to pay close attention to the color of the beverage container and to 
associate the color with how the drug makes them feel. 
Choice Session: During the choice session, subjects will undergo pre-session screening and  
then complete an alcohol purchase task in which they choose between varying amounts of 
money and each color cup. The subject will then choose the color of the beverage cup they 
prefer (i.e., green or blue) to ingest and the number of servings they would like to consume (1-
4). Mood and physiological measures will be obtained at regular intervals but the primary 
outcome measures will be whether they choose alcohol over the placebo, and the number of 
servings they choose to drink. 
Measures:  
Stop Task (Logan et al., 1997) measures behavioral inhibition of a prepotent response. 
Participants are required to respond as quickly as possible when a ‘go’ target appears and to 
inhibit that response when a ‘stop’ signal (an auditory tone) occasionally occurs. The duration of 
the delay to presentation of the stop signal following the go signal is adjusted until the 
participant is able to successfully inhibit the response on 50% of trials. The final mean delay of 
the stop signal, based on this 50% success rate criterion, is subtracted from the mean go 
reaction time, providing the stop reaction time (stop RT), which is the primary measure of 
impulsive action.  
The go/no-go task requires participants to respond as quickly as possible to ‘go’ stimuli and to 
withhold responses to ‘no-go’ stimuli. The dependent measure of interest is the number of 
inhibitory failures to no-go stimuli.  
The delay discounting task requires participants to choose between a series of small 
hypothetical monetary rewards available immediately and large hypothetical monetary rewards 
available after a delay. A preference for smaller, sooner rewards over larger, later rewards is 
indicative of steeper discounting (i.e., greater impulsivity). 
The Sweet Taste Test (Kampov-Polevoy et al., 1997) is a measure of preference for sweetness. 
Participants taste 5 concentrations of sweet solutions, and they rate each solution in terms of 
sweetness and pleasantness.  
Biphasic Alcohol Effects Scale (BAES; Martin et al., 1993) is a 14-item measure on which 
subjects rate the degree to which they feel subjective stimulant and sedative responses to 
alcohol on 11-point Likert-type scales.  
Drug Effects Questionnaire (DEQ) consists of questions on a visual analogue scale that are 
sensitive to the effects of drugs. Subjects are asked to rate the extent they feel a drug effect, 


whether they like the drug effect, and if they would want to take more of the drug if given the 
choice. Scales range from ‘none’ to ‘a lot’. 
Addiction Research Center Inventory (ARCI; Martin et al., 1971) is a 49-item true-false 
questionnaire that is a standardized measure of drug effects. We will focus on two empirically 
derived scales that measure drug-induced “euphoria” (morphine-benzedrine group: MBG) and 
stimulant-like effects (amphetamine: A). 
Cardiovascular Measures will include heart rate (HR) and blood pressure (BP). 
End of Session Questionnaire: subjects guess which drug they received, say if they would take 
the drug again in a recreational setting, and how much they would pay to take the drug again in 
a recreational setting. 
Drug Choice (last session): Subjects will be given a choice of which color beverage to ingest 
(i.e., alcohol or placebo; green or blue color cups) and the number of servings they wish to 
ingest (1-4) during the choice session. Choice for alcohol or placebo and the total number of 
servings (1-4) will provide the measures of drug choice. This is a standardized procedure used 
in this and other laboratories (Evans et al, 1996). The amount of money they are willing to pay in 
the drug purchase task provides a secondary measure of drug choice. 
Drugs: The 0.8 g/kg body weight dose of oral alcohol (190-proof ethanol) will be divided into 4 
servings of 0.2 g/kg each. The 0.8 g/kg dose is equivalent to 4 standard drinks, where a 
standard drink is defined as one 12 oz beer, one 5 oz glass of wine, or one 1.5 oz shot of 80 
proof alcohol. Women will receive a reduced dose (0.68 g/kg) to account for sex differences in 
total body water (Frezza et al., 1990; Sutker et al., 1983). Previous research using this adjusted 
dose has produced equivalent breath alcohol concentrations (BrACs) in men and women 
(Roche et al., 2015; Weafer and Fillmore, 2012). This dose was chosen because it is well-
tolerated and produces reliable increases in subjective response measures and alcohol choice 
(Doty and de Wit, 1995; de Wit et al., 1987; Weafer et al., in press). With this dose we expect 
breath alcohol levels to return to 0.02mg% within about 4 hours (i.e., by 7:30pm). Subjects will 
be discharged at 8pm. To provide a context, the legal limit for driving is 0.08mg%. The individual 
alcohol servings will be served in a 10% solution by volume with either cranberry juice or orange 
juice, depending on the subject’s preference. The placebo beverage will consist of the cranberry 
or orange juice plus 1% alcohol added as a taste mask. All beverages will be sprayed with an 
alcoholic mist to provide a strong alcoholic scent. Beverages will be served in opaque (color-
coded) lidded cups, and subjects will have a total of 15 min to consume the servings.  
Statistical analyses: First, we will check that the high and low impulsive groups are matched 
on sex, race, education, SES, cigarette smoking, alcohol drinking and other drug use. To test 
the hypothesis that individuals high in impulsive action will report significantly greater stimulation 
and euphoria after alcohol than those low in impulsive action, we will conduct 2 (Group) X 2 
(Drug) mixed design analyses of variance (ANOVA), with dose order and sex included as 
covariates, for each of the subjective response measures (i.e., BAES, ARCI, and DEQ). Group 
(high or low impulsive action) will be the between-subjects factor, and will be determined at the 
orientation session (see above). The dependent measures of subjective stimulation and 


euphoria will be calculated as area under the curve (AUC). An average AUC across the two 
alcohol sessions will be calculated, and an average AUC across the two placebo sessions will 
be calculated. If the overall F-test for the group X drug interaction is significant (p<.05), post hoc 
paired t-tests will be used to test for drug effects (relative to placebo) in the high and low 
impulsive action groups separately. To test the hypothesis that high impulsive individuals will 
exhibit greater preference for alcohol over placebo compared to low impulsive individuals, we 
will compare choice for alcohol or placebo in high and low impulsive individuals. We will perform 
a chi-square analysis to determine if the high impulsive action group is comprised of a higher 
number of choosers compared to the low impulsive action group, and a between-groups t test to 
see if the high impulsive action group chooses a greater number of alcohol servings than the 
low impulsive action group.  
Sample size determination: Estimations of sample size were derived from our preliminary data 
with d-amphetamine. Between groups (high vs. low impulsive action) t tests for subjective 
response measures of Elation and Vigor (AUC; 20 mg vs. placebo) suggest a medium effect 
size (d=.60-.68). N=60 subjects would provide 80% power (alpha = .05) to detect a difference 
between high and low impulsive individuals. 
 
HUMAN SUBJECTS 
Risks to subjects: 
a. Human subjects involvement and characteristics: Subjects in this study will be male and 
female adults, aged 21-29 years of any race or ethnicity, as long as they are fluent in English 
and meet other inclusion criteria. No special classes of vulnerable individuals will be included. 
Children younger than 21 will not be included because of ethical considerations and because 
the measures to be used are not validated for children. Subjects will undergo psychiatric and 
medical screening before participating, including a face-to-face interview with a trained 
interviewer to determine health history, current and lifetime recreational drug use history, and 
current and past psychiatric problems, according to DSM-V criteria. Subjects will also complete 
the MAST (Selzer, 1971) to detect alcohol problems, the SCL-90 and BDI to assess psychiatric 
symptoms, and women will complete a questionnaire concerning their menstruation history. 
Potential subjects will obtain an electrocardiogram and be examined by a physician. Exclusion 
criteria are: abnormal electrocardiogram, any current medical condition requiring medication or 
for which alcohol is contraindicated; any current Axis I psychiatric disorder (APA, 1994) 
including Substance Dependence, except Nicotine Dependence, any history of psychosis; less 
than high school education; lack of fluency in English; night shift work. Women who are 
pregnant or lactating will be excluded. 
b. Sources of materials: Data collected will consist of demographic data obtained at intake, 
subjective (self-report), behavioral (e.g., task performance), and physiological measures (e.g., 
heart rate), and personality measures. 


c. Potential risks: The risks to subjects are minimal. The drug used may produce side effects, 
including constipation, drowsiness, coordination problems, memory loss, tiredness, depression, 
dizziness or faintness, rapid heart rate, raised blood pressure, restlessness, dry mouth, changes 
in sex drive, double or blurred vision, confusion, slurred speech, shakiness or tremor, headache 
and nausea or muscle weakness. We have administered the proposed dose of alcohol in 
previous studies with no adverse effects. There is no evidence that alcohol administration in the 
laboratory increases drinking outside the laboratory. For the proposed study we will recruit 
subjects who report moderate drinking. Subjects will not be allowed to leave the lab unless their 
blood alcohol level is less than 0.02mg% and they will be informed not to drive after the 
sessions. Other risks involve risks of confidentiality. Confidentiality is strictly maintained by 
laboratory personnel, and records are kept in a secure location. Subjects will be fully debriefed 
following the study. 
Adequacy of protection against risks: 
a. Recruitment and informed consent: Subjects will be recruited from the university and 
surrounding community by posters, advertisements in the student newspaper and online, and 
word-of-mouth referrals. At the time of the initial screening interview and again during the 
orientation session preceding the study subjects will be required to read the consent form and 
may ask any questions they may have about it. After the study has been fully explained and 
questions have been answered by the Principal Investigator and/or Research Assistant, and 
before the first session, the subject will sign the consent form. Subjects agree in the consent not 
to take other drugs for 24 hours before each session. Women agree that they are not pregnant 
and not planning to become pregnant. Subjects will be informed that BrAC levels and urines will 
be obtained before each session.  
b. Protection against risk: To protect against, or minimize any possible risks, we follow these 
procedures: Subjects will be carefully screened to exclude those who are physically or 
psychiatrically at risk (see above). 
The study will be conducted in a laboratory located in a hospital, where emergency assistance 
(including the psychiatry resident on-call and a psychiatrist connected with the study) is close at 
hand. Subject files containing confidential information are maintained in a locked cabinet in the 
PI’s office. Only personnel directly connected with the study have access to this information, 
and these individuals are instructed in the importance and procedures for maintaining 
confidentiality. Data collected in the study are identified by subject codes only, and no data will 
be published in a form by which the subject can be identified 
Potential benefits: The minimal risks to subjects are justified by the knowledge to be gained 
regarding the behavioral processes related to drug use. Knowledge about the risk factors for 
drug abuse in at-risk individuals (i.e., individuals with poor behavioral control) will inform our 
understanding of the development and treatment of drug abuse. Subjects will benefit from the 
information obtained during the screening procedure (e.g., physical examination and 
electrocardiogram, as well as psychiatric screening). This is particularly beneficial to individuals 
who are excluded during the screening because of some previously undiagnosed condition. 
These individuals are referred for treatment. Subjects are paid for their participation. They may 


also request information about their performance and responses during the study. Smokers and 
individuals with other psychiatric disorders will be referred for treatment following their 
participation.