Vulnerability for Alcohol Use Disorder

Vulnerability for Alcohol Use Disorder and Rate of Alcohol Consumption Joshua L. Gowin, Ph.D., Matthew E. Sloan, M.D., M.Sc., Bethany L. Stangl, Ph.D., Vatsalya Vatsalya, M.D., M.Sc., Vijay A. Ramchandani, Ph.D.

Objective: Although several risk factors have been identified for alcohol use disorder, many individuals with these factors do not go on to develop the disorder. Identifying early phenotypic differences between vulnerable individuals and healthy control subjects could help identify those at higher risk. Binge drinking, defined as reaching a blood alcohol level of 80 mg%, carries a risk of negative legal and health out- comes and may be an early marker of vulnerability. Using a carefully controlled experimental paradigm, the authors tested thehypothesis that risk factors foralcoholusedisorder, including family history of alcoholism, male sex, impulsivity, and low level of response to alcohol, would predict rate of binging during an individual alcohol consumption session.

Method: This cross-sectional study included 159 young so- cial drinkers who completed a laboratory session in which they self-administered alcohol intravenously. Cox proportional

hazards models were used to determine whether risk factors for alcohol use disorder were associated with the rate of achieving a binge-level exposure.

Results:Agreaterpercentageofrelativeswithalcoholism(hazard ratio: 1.04, 95% CI=1.02–1.07), male sex (hazard ratio: 1.74, 95% CI=1.03–2.93), and higher impulsivity (hazard ratio: 1.17, 95% CI=1.00 to 1.37) were associated with a higher rate of binging throughout the session. Participantswith all three risk factors had the highest rate of binging throughout the session compared with the lowest riskgroup(hazard ratio:5.27,95%CI=1.81–15.30).

Conclusions: Binge drinking may be an early indicator of vulnerability to alcohol use disorder and should be carefully assessed as part of a thorough clinical evaluation.


Alcohol use disorder has a lifetime prevalence of nearly one in three individuals intheUnitedStates (1).An importantgoal is to identify at-risk individuals prior to the development of this disorder so that they canbe targeted for early intervention.One way to determine early phenotypic differences in those at risk is to examine behavior at the level of an individual drinking session. For example, the rate of drinking and total alcohol exposuremay differ between those at high and low risk. These parameters, however, are difficult to quantify in the field be- cause of the lack of instruments that can continuously and accurately monitor blood alcohol concentration. Furthermore, asking individuals to report details about their rate of con- sumption does not account for variability in absorption and metabolism (2) and would likely be inaccurate because in- toxication impairs recall (3). Despite these measurement difficulties, there is evidence that the rapid consumption of large quantities of alcohol leading to a blood alcohol con- centration of 80 mg%, defined as binge drinking (4), affects psychological and physical well-being. Binge drinking is associatedwith greater riskof negativehealth consequences

(e.g., myocardial infarction) and legal trouble (5, 6). Binge drinking may signify an innate preference for higher brain alcohol exposure and may begin before an individual meets criteria for an alcohol use disorder, but this hypothesis has never been empirically tested.

Onemethod to assess alcohol consumption that overcomes many of these measurement difficulties is intravenous alcohol self-administration (7). This method has shown good test- retest reliability and external validity (8, 9) and has been employed in pharmacological (10) and genetic studies (11). Intravenous alcohol self-administration has several advan- tages over oral self-administration. Whereas oral adminis- tration at fixed doses can result in up to threefold variability in alcohol exposure between individuals as a result of phar- macokinetic differences (12, 13), intravenous administration standardizes alcohol exposure by bypassing gastrointestinal absorption and first-pass metabolism. Interindividual differ- ences in alcohol distribution and elimination are accounted for by using an infusion algorithm that adjusts for age, sex, height, and weight (2). Accordingly, each infusion increases

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alcohol levels by a fixed quantity, allowing the infusion software to provide continuous esti- mates of blood alcohol levels that closely track brain alcohol exposure (14) and breathalyzer readouts(15).Theseestimatescanthenbeusedto measurean individual’s total alcohol exposure, as wellashowquicklytheindividualreachesabinge level of exposure. This paradigm also eliminates specific cues associated with oral alcoholic bev- erages, including taste, smell, and appearance.As a result, intravenous self-administration should be driven primarily by alcohol’s pharmacody- namic effects, such as dopamine release in the nucleus accumbens (16). This method is there- fore ideal to determine whether preference for higher alcohol exposure is evident prior to the development of alcohol use disorder among in- dividuals with biological risk factors.

The DSM-5 lists the following genetic and physiological risk factors for alcohol use dis- order (17): family history of alcoholism (18), male sex (1), impulsivity (19), absence of acute alcohol-related skin flush (20), pre-existing schizophrenia or bipolar disorder (21), and low level of response toalcohol (22).Although these factorsmarkedly increase the risk of developing alcohol use disorder, it remains unclear how they affect the likelihood of risky drinking patterns prior to disorder onset. In the present study, we examined the largest community sample to date of young adult social drinkers using intravenous alcohol self-administration. We investigated whetherthegeneticandphysiological riskfactors listed inDSM-5 (except for skinflush and comorbid psychiatric disorders, which were exclusion criteria) were associated with the rate of binge- level exposure during an individual drinking session. We hy- pothesized that individuals at higher risk for developing an al- cohol use disorder would exhibit a preference for higher brain alcohol exposure as demonstrated by higher rates of binging throughout thesessionandhigher levelsof totalalcoholexposure.


Participant Characteristics A total of 162 social drinkers between the ages of 21 and 45 were recruited through newspaper advertisements and the National Institutes of Health (NIH) Normal Volunteer Office (for detailed demographic information, seeTable 1 and Tables S1–S3 in the data supplement accompanying the online version of this article). To be included, participants must have consumed at least five drinks on one occasion at one point in their life. Participants completed a telephone screen and sub- sequently completedan in-personassessment at theNIHClinical Center in Bethesda, Md. The study protocol was approved by theNIHAddictions Institutional ReviewBoard, and participants were enrolled after providing written, informed consent.

Participants were excluded if they met any of the fol- lowing 10 exclusion criteria: 1) nondrinker; 2) lifetimehistory

ofmood, anxiety, or psychotic disorder; 3) current or lifetime history of substance dependence (including alcohol and nicotine); 4) recent illicit use of psychoactive substances; 5) history of acute alcohol-related skin flush; 6) regular to- bacco use (.20 uses/week); 7) history of clinically significant alcohol withdrawal; 8) lifetime history of suicide attempts; 9) current or chronic medical conditions, including cardiovascular conditions, requiring inpatient treatment or frequent medical visits; or 10) use of medications that may interact with alcohol within 2weeks prior to the study. Femaleswere excluded if they were breastfeeding or pregnant or if they intended to become pregnant.

All participants were assessed for psychiatric diagnoses, history of acute alcohol-related skin flush, drinking history, andother risk factors foralcoholusedisorder.Diagnoseswere assessed by the StructuredClinical Interview forDSM-IVAxis I disorders (23). History of acute alcohol-related skin flush was assessedusingtheAlcoholFlushingQuestionnaire(24).Drinking history was assessed using the Alcohol Use Disorder Identifi- cation Test (25). Two participants were excluded from this analysisbecause theywereheavydrinkersbasedon theTimeline Followback Interview (.20drinks/week formales,.15 drinks/ week for females). One participant was excluded because software failure caused the session to be terminated prior to minute 20 of the alcohol self-administration session, resulting in a final sample size of 159 participants.

Alcohol Use Disorder Risk Factor Measures Family history. Participants completed the Family Tree Questionnaire (26) to identify first- and second-degree rel- atives who may have had alcohol-related problems. They subsequently completed the family history assessment plus

TABLE 1. Characteristics of the Sample by Sex

Characteristic Male (N=86) Female (N=73)

Mean SD Mean SD

Age (years) 26.4 5.2 25.8 5.0 Family history densitya,b 3.6 8.5 2.6 6.9 Delay discountinga,c –4.7 1.8 –4.5 1.7 Level of alcohol responsed,e 4.8 2.1 3.7 1.7 Alcohol Use Disorder Identification Test score 5.8 2.5 5.1 2.8

N % N %

Family history positive 17 19.8 11 15.1 Current alcohol abusea 2 2.4 2 2.7

a Dataweremissing for someparticipants (family history, N=158; delay discounting, N=134; current alcohol abuse, N=158).

b Family history density was obtained by dividing the number of first- and second-degree relatives withanalcoholusedisorderby the total numberoffirst- andsecond-degree relatives; it is reported as a percentage. The value displayed represents themean and SD for thewhole sample (see Table S1 in the online data supplement for family history density in the family history positive group).

c Delaydiscounting isabehavioralmeasureof impulsivity inwhichparticipantschoosebetweensmaller immediate or larger delayed rewards; values are reported as the natural logarithmof the discounting constant, k; lower values of ln(k) indicate lower degrees of delay discounting and less impulsivity.

d Level of alcohol response is derived from the Self-Rating of the Effects of Alcohol form, assessing response during the first five drinking occasions; the final score represents the mean of the number of drinks needed to achieve four possible intoxication-related outcomes, with a higher number indicating a lower level of response to alcohol.

e Male and female participants showed statistically different distributions for level of alcohol re- sponse using the Mann-Whitney test (Zu=3.7, p,0.01).

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individual assessment modules of the Semi-Structured As- sessment for Genetics of Alcoholism for all identified relatives (27). This assessment is widely used in family history-based studies, including large genetic studies, such as the Collabo- ration on the Genetics of Alcoholism (28). If no information was available about a relative, then that relativewas scoredas a 0. Relatives with a known history of alcohol-related problems werescoredasa1.Afamilyhistorydensityscorewascalculated by dividing the number of relatives with alcohol problems by the total number of first- and second-degree relatives. One participant did not complete this measure, and his value was imputedwith the samplemedian of 0 given that family history density was not normally distributed (Shapiro-Wilk test: p,0.001). We conducted all models with and without this participant and found that his exclusion did not alter our findings, and thus we report the results with this participant included.

Behavioral impulsivity. Participants completed a delay dis- counting task (29), which is a well-validated measure of behavioral impulsivity that has a robust association with alcohol use disorder (30, 31). During this task, participants chose between smaller immediate rewards or $100 re- ceived after a delay (e.g., $90 now or $100 in 7 days). Im- mediate rewards ranged in value from $0 to $100, and delay periods ranged from 7 to 30 days. The degree of discount- ing delayed rewards, k, can be calculated using the equation developed by Mazur et al. (32). Since k values were not normally distributed, they were normalized using a loga- rithmic transformation and reported as ln(k). Lower values of ln(k) suggest less impulsivity and lower degrees of dis- counting. A portion of the sample did not complete this task (N=25), and missing values of ln(k) were imputed with the sample mean.

Level of response to alcohol. Participants also completed the Self-Rating of the Effects of Alcohol form (33). This in- strument assesses response to alcohol during the first five drinking occasions of a person’s life, their heaviest drinking period, and their most recent drinking period. For each period, it asks how many drinks it took for them to feel different, to feel dizzy, to begin stumbling, and to pass out. The final score represents the mean of the number of drinks needed to achieve each outcome, with a higher number of drinks indicating a lower level of response to alcohol. We focused on the first five drinking occasions in the present analyses to reduce the potentially confounding impact of tolerance.

Intravenous Alcohol Self-Administration Participants were instructed not to drink alcohol in the 48 hours prior to study procedures. Upon arrival, they provided a breathalyzer reading to confirm abstinence. Participants also provided a urine sample that was tested for illicit drugs and, for females, pregnancy; bothhad to benegative to proceed with the study session. After the participant ate a

standardized (350 kcal) meal, an intravenous catheter was inserted into a vein in the forearm. Self-administration was conducted using the computer-assisted alcohol infusion systemsoftware,whichcontrolled the rateof infusionof 6.0% v/v alcohol in saline for each individual using a physiologi- cally based pharmacokinetic model for alcohol distribu- tion andmetabolism that accounts for sex, age, height, and weight (2).

The alcohol self-administration session consisted of a 25-minuteprimingphase anda 125-minute free-accessphase. During the first 10minutes of the priming phase, participants were required to push a button four times at 2.5-minute intervals. Each button press resulted in an alcohol infu- sion that raised blood alcohol concentration by 7.5 mg% in 2.5 minutes, such that participants achieved a peak con- centration of approximately 30mg%atminute 10. During the next 15 minutes, the button remained inactive while par- ticipants experienced the effects of the alcohol. Atminute 25, the free-access phasebegan, andparticipantswere instructed to “try to recreate a typical drinking session outwith friends.” Participants could self-administer ad libitum, but they had to wait until one infusion was completed before initiating another. Blood alcohol concentration was estimated con- tinuously by the software based on infusion rate and model- estimated metabolism, and a readout was provided at 30-second intervals. Breath alcohol concentration was also obtained via breathalyzer at 15-minute intervals to confirm the software-calculated estimates; these readings were en- tered into the software to provide the model feedback, and the infusion rate was automatically adjusted accordingly (2). Software estimates of blood alcohol concentration were used to determine whether a participant reached binge- level exposure, defined as achieving an estimated blood alcohol concentration greater than 80mg% (4). A limit was imposed such that estimated blood alcohol concentration could not exceed 100 mg% to prevent adverse events due to intoxication.

Statistical Analysis To examine whether risk factors for alcohol use disorder were predictors of rate of binging throughout the free- access phase of the intravenous alcohol self-administration session, we plotted Kaplan-Meier survival curves and conductedCoxproportional hazardsmodels.Wegenerated the following four Kaplan-Meier survival curves using binary variables (Figure 1): 1) male compared with female; 2) family-history positive compared with negative; 3) high compared with low impulsivity (median split); and 4) high compared with low level of response to alcohol (median split). For the Cox proportional hazards analyses, the outcome variable was time to binge (estimated blood al- cohol concentration of 80 mg%), and participants were censored when they reached a binge or ended the session early (one participant). For the initial Cox proportional hazards model, five independent variables were included: sex was coded as a binary variable (0 for females, 1 for

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males), and delay discounting, family history density, level of response to alcohol, and age were entered as continuous variables.

To determine whether faster rate of consumption translated into greater overall exposure to alcohol, we cal- culated the area under the curve for the estimated breath alcohol concentration by time plot during the free-access phase of the session. Three individuals ended the session early due to software malfunction or adverse events (at minutes 59, 88.5, and 99.5); thus, in order to generate the area under the curve for these participants, we imputed values for

the remainder of the session by carrying their last observed alcohol concentration forward. To confirm the validity of this approach, we applied the same imputation procedure for 20 random participants starting at minute 59 and found that the imputed values correlated highly with the actual values (Spearman’s rho.0.9).WeconductedMann-Whitney tests to compare area under the curve distributions for each risk factor, as area under the curve valueswere not normally distributed (Shapiro-Wilk test: p,0.05). For these analy- ses, we used the binary categorical risk factors described above.

FIGURE 1. Cumulative Probability of Achieving Binge-Level Exposure by Each Alcohol Use Disorder Risk Factora

Time (minutes)

1200 20 40 60 80 100

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