Subjective Responses to Alcohol in the Development and Maintenance of Alcohol Use Disorder

Heavy drinking is increasing among U.S. adults (1–3) and remains a major preventable contributor to disability and mortality worldwide (4). It is also a strong predictor of subsequent alcohol use disorder (AUD) (5, 6), which carries additional serious consequences for health and functioning (7). Given the global burden of alcohol misuse, identifying factors that increase the susceptibility to the development and maintenance of AUD is a critical public health need (8).

One way to examine vulnerability to AUD is to characterize acute subjective responses to alcohol at different stages of development of the disorder (9). Two large studies have found that greater initial stimulation and reward responses to alcohol (10, 11), as well as lesser intoxicating and sedating responses (12), predict future drinking problems through young adulthood. These acute responses may change with chronic heavy drinking as a result of neuroadaptations that produce either tolerance or sensitization. Tolerance, or a diminished response to the same dose of a drug after repeated use, is a diagnostic criterion for AUD. Conversely, sensitization, or an increased drug effect with repeated exposure, has also been linked to addiction (13, 14). Although both tolerance and sensitization are integral components of neurobiological theories of the development and progression of addiction (14–16), most of the empirical evidence for these theories has been based on studies using animal models.

Examination of adaptive responses to alcohol in humans requires rigorous longitudinal investigations in persons who develop AUD or progress in severity of the disorder. Such prospective, repeated-measurement studies of acute alcohol responses are challenging, as they are time and labor intensive and require high retention rates. Yet the knowledge from such investigations is necessary to adequately test the translational significance of animal models of addiction to humans (17) and thus to inform empirically based strategies for prevention, early intervention, and treatment. Whether the excitatory, euphoric, or sedating effects of alcohol increase, decrease, or remain constant over time in problem drinkers represents an unresolved issue in clinical psychiatry.

In the Chicago Social Drinking Project, we undertook such an analysis in our first cohort and documented that, compared with lighter drinkers, young adult heavy drinkers were more sensitive to the stimulating, motivating (“wanting”), and rewarding (“liking”) effects of alcohol and were less sensitive to its sedative effects (10). Although stimulation and sedation were inversely correlated (18), we found that higher alcohol stimulation, wanting, and liking, and not lower sedation, predicted progression of AUD symptoms 5–6 years after the initial alcohol challenge in heavy drinkers (11). Further, when participants were retested with alcohol 5–6 years later, heavy drinkers who developed more AUD symptoms reported persistently greater stimulation, wanting, and liking after consuming alcohol (at both the initial test and 5 years later), whereas light drinkers did not report experiencing these euphoric and motivating responses (19). However, the testing was limited to a 5-year reexamination period when participants were just entering their fourth decade of life, which may not have been sufficient to fully examine AUD development. In addition, the previous study focused mainly on heavy drinkers and did not allow for an integrated examination of the trajectory of both light and heavy drinkers.

We now report on a more comprehensive and extended 10-year follow-up and reexamination of acute responses to alcohol in the Chicago Social Drinking Project. We shift the analytical focus to examine differences in the acute responses to alcohol, based on who, among the entire sample, did or did not manifest AUD after a decade of natural drinking. The approach comprises a three-phase assessment: initial, 5-year, and 10-year examinations of alcohol responses from young adulthood through middle age. We evaluated the existence of adaptive changes in subjective responses to alcohol consumption in the development and progression of addiction. Our goal was to determine whether AUD is marked by increases, decreases, or no change in sensitivity to alcohol’s stimulating, motivating, rewarding, or sedating effects.

Methods

The Chicago Social Drinking Project is a multicohort, double-blind study with repeated, within-subject laboratory assessments of acute responses to alcohol compared with placebo, combined with long-term follow-up of drinking behaviors and AUD symptoms. The study was approved by the University of Chicago institutional review board, and participants provided written informed consent. Testing sessions were conducted at the Clinical Addictions Research Laboratory at the University of Chicago. Participants attended initial laboratory sessions from March 2004 to July 2006. They underwent regular follow-up interviews and were invited to participate in identical double-blind alcohol and placebo reexaminations 5 and 10 years later (see the CONSORT diagram in Figure S1 in the online supplement).

Initial Screening and Enrollment

Recruitment was conducted through local media and Internet advertisements and word-of-mouth referrals. Initial inclusion criteria were age between 21 and 35 years, weight between 110 and 210 pounds, good general health, not pregnant or lactating, no current or past major medical or psychiatric disorders, including DSM-IV alcohol and substance dependence (other than nicotine), and no current use of any psychotropic medications. Participants were included if they met criteria for being either a high- or low-risk drinker. This distinction was defined by a predominant adult pattern of drinking (and minimally for the past 2 years). High-risk, heavy drinkers reported weekly binge drinking of ≥5 drinks for men, ≥4 drinks for women, and regular consumption of 10–40 drinks per week. Low-risk, light drinkers reported rare or no binges and regular consumption of 1–5 drinks per week. These criteria were based on established high- and low-risk drinking guidelines (20, 21) and were consistent with previous studies (22–25). Candidates underwent medical and psychiatric screening to determine eligibility for an alcohol challenge (for details, see the supplemental methods section of the online supplement).

Laboratory Procedures

At each of the three testing phases, participants attended two individual 4- to 5-hour laboratory sessions, one with alcohol, and the other with placebo, in randomized order and under double-blind conditions. Sessions were conducted in a comfortable living room–like environment, separated by at least 24 hours. The sessions were identical except for the alcohol content of the beverage, 0.8 g/kg of alcohol (adjusted for sex), or placebo with a 1% alcohol taste mask. Upon arrival, objective breath tests confirmed recent alcohol abstinence, and a urine sample was collected for women to verify nonpregnancy. Subjective, objective, and alcohol breath tests were obtained throughout the session (for more details, see the supplemental methods section in the online supplement).

Starting at experimental time 0, the participant received the beverages in lidded, clear plastic cups in two equal portions and, in the presence of the research assistant, consumed each portion over two 5-minute periods, separated by a 5-minute rest (22, 23, 26). The alternative substance paradigm (27) was employed to reduce expectancy effects by informing each participant that the beverage may contain a stimulant, sedative, alcohol, placebo, or a combination of these substances. At the end of each approximate 4-hour session, when breath alcohol concentration was <0.04 g/dL (28), the participant was transported home by a car service.

Identical procedures and instructions were followed for the 5- and 10-year laboratory testing reexamination phases. For ethical reasons, participants who had major medical or psychiatric contraindications (N=3), who were pregnant or nursing (N=3), or who were abstinent from alcohol (N=3) were not eligible for the final 10-year reexamination sessions. As nearly half (49%) of the sample no longer resided in the area, transportation to Chicago, lodging accommodations, and other per diem expenses were provided as warranted. Reexamination sessions were scheduled for the same month as the initial testing; the mean interval from participants’ initial session was 61 months (SD=3.0) to the year-5 session and 122 months (SD=3.7) to the year-10 session.

Outcome and Measures

In the testing sessions, measures were obtained before beverage consumption and repeated 30, 60, 120, and 180 minutes after consumption. To maintain blinding, the alcohol breath tests (Alco-Sensor IV, Intoximeter; St. Louis) displayed 0.000 g/dL during real-time assessments, and the actual values were downloaded later. The primary dependent measures were scores on the stimulation and sedation subscale of the 14-item Biphasic Alcohol Effects Scale (29) and responses to two items from the Drug Effects Questionnaire (100-mm visual analogue scale) for hedonic reward (“do you LIKE the effect you are feeling now?”) and motivational salience (“would you like MORE of what you consumed, right now?”) (30, 31). The surveys instructed participants to focus on their current mood state and did not reveal the beverage content (32). Stimulation, sedation, liking, and wanting were examined across the breath alcohol concentration curve by subtracting the placebo from the alcohol response at each time point. Secondary measures were general drug (the “feel-drug” item of the Drug Effects Questionnaire) and physiological responses, including heart rate and salivary cortisol measures.

Follow-Up Assessments

After each participant’s initial testing, follow-up assessments were conducted at 1, 2, 4, 5, 6, 8, and 10 years. No subject was lost to follow-up (i.e., unreachable throughout this decade of participation), reflecting our protocol to attain strong retention (33). Continuous participation was strong (185 of 189 living participants), with four study dropouts. The follow-up assessments included Internet or mailed surveys and a telephone or in-person administration of the Structured Clinical Interview for DSM-IV to determine AUD symptoms. The main outcome from these assessments was the presence (AUD+) or absence (AUD−) of the disorder in the last year of follow-up. Twenty-one percent of participants (N=39) met DSM-5 criteria for AUD at year 10, forming the AUD+ group. Of these, 20 met criteria for mild AUD, 10 for moderate AUD, and nine for severe AUD. The remaining 79% did not meet AUD criteria and formed the AUD− group. Of these, 124 reported no AUD symptoms, and 21 reported one symptom. A review of the preceding 10 years revealed that the AUD+ group showed more AUD symptoms than the AUD− group and reported heavier drinking (Figure 1A and Table 1).

In addition to the AUD group classifications based on the 10-year follow-up, we employed a complementary approach to determine trajectory subgroups based on the growth and progression (or regression) in AUD symptom severity throughout all follow-up time points (10, 11, 19). The subgroup analysis was based on DSM-IV symptom counts because DSM-5 was not yet developed when the follow-up assessments were initiated in 2005. This trajectory analysis (34) included a zero-inflated Poisson mixture model with a cubic trajectory for each subgroup. The number of trajectory groups was determined by the Bayesian information criterion using 2ln(B₁₀) ≥ 10 as strong evidence for rejecting the null model. This analysis showed that a three-trajectory group model best fit the data: a low AUD symptom subgroup (N=103), an intermediate AUD symptom subgroup (N=62), and a high AUD symptom group (N=19). The AUD symptoms across these subgroups corresponded to the frequency of heavy drinking across follow-up (Figure 1B). Of note, the classifications of individuals in the AUD symptom trajectory subgroup were fairly stable, relative to the classifications of initial heavy drinkers in the 5-year analysis (11). Eighty-one percent of the participants remained in their respective low, intermediate, and high AUD symptom subgroup, while 15% moved by one category to the next higher symptom group and 4% changed to the next lower group. Demographic and drinking characteristics for the AUD symptom subgroups are shown in Table 2.

Statistical Analysis

Demographic and drinking characteristics were compared between the AUD+ and AUD− groups by t tests and chi-square tests, as appropriate. Acute alcohol responses were analyzed by generalized estimating equation models (35) that included group, time, and phase, with the latter two variables treated as continuous variables. To assess potential nonlinearity over time, models for each alcohol response included linear, square, and cubic terms of time. Results revealed that stimulation only (and not sedation, liking, or wanting), as measured by the Biphasic Alcohol Effects Scale, required the second- and third-order polynomial terms. This is consistent with previous work showing rapid increases in stimulation during the ascending breath alcohol concentration limb, followed by an inflection point and sharp declines during the descending breath alcohol concentration limb (10). Generalized estimating equation models were also used for secondary measures, including general subjective response (the “feel-drug” item of the Drug Effects Questionnaire) and physiological effects (heart rate and cortisol secretion), which are sensitive to alcohol (36–38). The AUD symptom subgroups were assessed on alcohol responses in generalized estimating equation models similar to those conducted in the main analysis to examine subgroup, time, and phase effects and their interactions. All generalized estimating equation models adjusted for age, race, education, family history of alcoholism (39), breath alcohol concentration (as a time-varying covariate), and the number of baseline AUD symptoms.

Results

Participant retention in the Chicago Social Drinking Project was high, with 99% (184 of 185) of the nondeceased active participants completing follow-up at 10 years (i.e., 184 out of 190 participants from the original sample, or 97%; see Figure S1 in the online supplement). The 5-year and 10-year laboratory reexamination sessions were conducted in 156 and 163 participants, respectively. These rates represent 88% and 91% of the 178 and 179 participants eligible for reexamination at each phase, respectively.

The AUD+ and AUD− groups at 10 years did not differ on most demographic characteristics; however, as expected, the AUD+ group reported heavier alcohol consumption and more drinking problems than the AUD− group at the 10-year reexamination and at the initial testing phase (Table 1). Across the test phases, the groups did not differ significantly on average breath alcohol concentration (see Figure S2A in the online supplement), with both showing a rapid rising breath alcohol concentration limb that reached peak level 60 minutes after the initiation of the beverage consumption, followed by a slow breath alcohol concentration declining limb (group-by-time-by-phase interaction: χ²=5.78, df=8, p=0.672). Thus, while reflecting individual variability in alcohol pharmacokinetics as they relate to oral administration (40), the mean values of breath alcohol concentration of the AUD groups did not substantially differ across the testing phases.

In terms of subjective response, alcohol produced markedly different effects in the 10-year AUD+ and AUD− groups. These differences were evident starting at the initial testing phase and increased further over the course of the reexamination phases (Figure 2). Overall, the AUD+ group exhibited increasing sensitivity for pleasurable alcohol responses during the decade of participation, while the AUD− group showed low initial levels on these measures with little to no change through the testing phases. Specifically, alcohol produced initially higher stimulation in the AUD+ group relative to the AUD− group during the early portion of the breath alcohol concentration curve, and stimulation level increased in intensity through the reexamination phases (group-by-time-by-phase interaction, p=0.016; Table 3). Alcohol also initially increased ratings of motivational salience (wanting) in the AUD+ group relative to the AUD− group across the entire breath alcohol concentration curve, and wanting also increased in intensity through the reexamination phases (group-by-phase interaction, p=0.001). Initial hedonic reward (liking) from alcohol was also higher in the AUD+ group (p=0.017), and this effect increased through reexamination, but the escalation was not statistically significant (group-by-phase interaction, p=0.104). Finally, both groups showed increases in alcohol-induced sedation, but this effect did not differ by group or test phase (group-by-phase interaction, p>0.385). Reanalyzing the data based on DSM-IV criteria for alcohol dependence yielded similar results.

As with the AUD groups, for the AUD symptom groups, breath alcohol concentration curves did not differ across subgroups (see Figure S2B in the online supplement). For alcohol responses, a similar pattern of results emerged for the AUD symptom subgroups as for the AUD+ and AUD− groups (Figure 3). Relative to the low AUD symptom subgroup, the intermediate and high AUD symptom subgroups exhibited initially heightened alcohol stimulation, wanting, and liking. For alcohol stimulation and wanting, these responses were potentiated through the reexamination phases (i.e., augmented across the decade of participation), with liking remaining elevated but not increasing further as the decade progressed (Figure 3). Further, initial subjective responses to alcohol significantly predicted the frequency of heavy drinking through follow-up; this behavioral outcome was used in our previous work (10), and associations were evident over the decade for liking and wanting (all r values, 0.19; all p values, <0.01), stimulation (r=0.14, p=0.06), and sedation (r=−0.17, p<0.05).

On secondary measures, alcohol increased feel-drug ratings during the rising breath alcohol concentration limb (time, p=0.026; see Table S1 in the online supplement); this response became more intense through the reexamination phase for the AUD+ group (group-by-phase interaction, p=0.004). Alcohol-induced heart rate and cortisol increases did not differ by group or across test phases (see Table S1 and Figure S3 in the online supplement). The same results were observed when based on an analysis of AUD symptom subgroups (see Table S1 and Figure S4 in the online supplement). For all analyses, there were no sex differences.

Discussion

AUD is phenotypically complex (41), and a better understanding of factors that increase vulnerability to sustained excessive drinking is crucial for effective prevention, early intervention, and treatment development (42). The present study provides the first repeated assessment of acute alcohol responses in the same people across a substantial 10-year period of adulthood. The results comprise two main findings: first, heightened sensitivity to the pleasurable effects of alcohol (stimulation, liking, and wanting) in young adulthood preceded the development of AUD through middle age; and second, sensitivity to alcohol stimulation and wanting increased across repeated testing over a decade in persons who developed AUD. Trajectory analyses of AUD symptom progression over follow-up confirmed these findings by demonstrating amplification of alcohol stimulation and wanting as a function of AUD severity across a decade. Notably, physiological responses such as heart rate and cortisol did not predict AUD development. Taken together, these findings support the idea that the positive stimulating and motivating effects of alcohol increase during the development and maintenance of AUD. The findings do not support the idea that low sensitivity to alcohol increases the risk for AUD (12) or that a reward deficit stage emerges in the progression to addiction (43).

The study results are consistent with the central tenet of the incentive-sensitization theory, namely, that motivational (“wanting”) but not hedonic (“liking”) processes become sensitized in the progression to addiction (14). In our study, the individuals who developed AUD over the 10-year period reported increases in wanting alcohol over time, while liking of alcohol remained high and stable over time. The incentive-sensitization theory is based on behavioral and pharmacological studies in rodents demonstrating wanting and liking as distinct components of reward and mediated by separate neural systems. In the animal studies, repeated exposure to the drug produced incremental neuroadaptations in the circuits mediating motivational salience, rendering them hypersensitive to the drug and its associated stimuli (14, 44). Until now, however, this idea had not been examined in a longitudinal manner in humans. Although cross-sectional studies of the continuum of alcohol use severity support this idea (45–49), to our knowledge, our study, which includes repeated alcohol challenge testing in the same participants over an extensive period, provides the first longitudinal support for the central tenet of this theory.

There has been substantial disagreement among clinicians and researchers as to whether AUD is progressive, what behavioral or subjective changes occur in response to alcohol over extended periods of use, and what processes underlie neuroadaptive changes that result from chronic drinking. It is known that chronic exposure to alcohol leads to pharmacodynamic tolerance such that users can withstand a higher breath alcohol concentration than inexperienced drinkers before experiencing stupor, coma, and eventual death (50). Although tolerance to the subjective effects of alcohol is a hallmark symptom of AUD, it has been challenging to track the development of such tolerance in humans. In a similar vein, it has been difficult to document the progressive stages of allostasis, another construct believed to contribute to the disorder.

Several issues are relevant when reconciling the results of the present study with existing theory. First, retrospective patient reports suggesting the need for more alcohol to get the same effects as compared with when one first started drinking regularly are not sufficient support for chronic tolerance. The well-controlled findings from the present study are not consistent with the notion of robust chronic tolerance of alcohol’s subjective effects, so anecdotal patient reports of lessened effects of alcohol over time may be influenced by factors other than acute alcohol response. Second, studies of chronic exposure to alcohol derived from animal models of addiction, while providing critical information about the behavioral and physiological correlates of consumption (51), are not able to shed light on changes in the euphoric effects of drinking in humans and how these change over time. Third, some theories of addiction, such as allostasis, indicate development of a deficit in reward or a change in aversive states and stress responses. Although our data do not provide support for this idea, it is possible that this putative stage requires more than a decade to develop or that it exists only in excessive drinkers prone to negative affect or extremely aversive withdrawal. Alternatively, while certain tenets of the allostasis theory may relate to animal models, they may not translate to manifestations of AUD as observed within the demographic characteristics of our study sample. Importantly, our within-subject, longitudinal findings demonstrated that the perceived pleasurable effects of alcohol are not diminished as AUD severity progressed during a 10-year period. However, cross-sectional neuroimaging studies suggest that heavy drinkers relative to lighter social drinkers exhibit reduced activation of the nucleus accumbens after alcohol infusion (52–54). Although it is difficult to reconcile the contrasting findings, given the differences in samples and methodologies, we may speculate that other neurobiological substrates (i.e., the basal ganglia) or circuits underlie the persistent positive subjective response to alcohol. Nevertheless, this possibility highlights the need for studies employing both neurobiological techniques and validated subjective measures.

The Chicago Social Drinking Project has several strengths, including a prospective design with alcohol and placebo testing at three phases, outstanding retention, and determination of drinking and AUD symptoms from early to middle adulthood. Most notably, we were able to attain near-perfect retention of participants across the decade. The inclusion of dual follow-up outcomes, that is, categorical AUD diagnosis and trajectory analyses of symptom growth over time, provides a powerful picture of the development of alcohol problems (55). Relatedly, as this longitudinal study began in 2004, nearly a decade before the 2013 release of DSM-5, the trajectory analysis was based on DSM-IV symptom counts for alcohol abuse and dependence. Thus, symptom counts may have been “undercounts,” and the actual symptom count severity may well have been higher if DSM-5 were available because DSM-IV included the item for legal problems, which was determined to have infrequent endorsement (56), and did not include the item for craving, which is more often endorsed (57).

The study also has limitations. First, the standardized body weight–adjusted and sex-adjusted fixed dose of alcohol was chosen to produce a sharp rise in breath alcohol concentration to minimize variability. However, this procedure did not allow for other clinically relevant aspects of drinking, including both self-paced drinking and choice to drink in the presence of both alcohol and other reinforcers or consequences. Second, we were not able to test participants younger than 21 years of age, and it is possible that alcohol-related changes had already occurred before the participants enrolled in the Chicago Social Drinking Project. Relevant to this issue is recent collaborative work by the first author (A.K.) and international colleagues showing that older adolescent heavy drinkers exhibit sensitivity to alcohol stimulation with heightened tonic wanting (58), so prospective studies with younger participants, perhaps in locations where adolescent drinking is permitted, would be valuable in determining the earliest precipitants of adaptive responses to alcohol. Third, although our sample developed AUD at a higher rate than that of 12.7% in the general population (1), the final sample size of the AUD+ group was modest. However, using two similar but not overlapping outcome approaches may ameliorate concerns about sample size. Comparing the AUD+ and AUD− groups at year 10 provided a practical clinical endpoint used by clinicians, and notably, 64% of AUD+ subjects met DSM-IV alcohol dependence at some point through follow-up, compared with 7% in the AUD− group. The AUD symptom trajectory construct provided a data-driven approach, affording consistency with our previous work (11, 19). All of the participants in the high AUD symptom subgroup met alcohol dependence through follow-up, compared with 26% and 0% in the intermediate and low AUD symptom groups, respectively. Although an examination of consequences and distress related to excessive drinking was beyond the scope of this article, persons in the AUD+ group had a higher likelihood of seeking advice or help with drinking or of seriously considering getting help relative to the AUD− group (49% compared with 8%).

In sum, this study is the most extensive repeated human testing study of its kind, examining the adaptive processes underlying the development and maintenance of AUD. Alcohol-induced subjective stimulation increased over time, and euphoric processes did not wane as AUD symptoms emerged. Instead, these effects either stayed the same or increased, challenging the notion that conventional chronic tolerance to alcohol’s subjective effects plays a key role in escalation of excessive drinking. The findings are consistent with the incentive-sensitization theory, as alcohol wanting increased across a decade in persons developing AUD. However, the study results were not consistent with the allostasis model of a progressive deficit in reward. In terms of prevention of alcohol problems, rather than a sole focus on tolerance, young adults might be informed that marked stimulant-like, pleasurable, and appetitive effects after consuming alcohol are risk factors for the development and maintenance of addiction. Finally, pharmacological and behavioral interventions focused on reducing positive rewarding effects and motivational salience during acute alcohol consumption may be crucial in future medication development and treatment of AUD.