ARTICLES
Subjective Responses to Alcohol in the Development
and Maintenance of Alcohol Use Disorder
Andrea King, Ph.D., Ashley Vena, Ph.D., Deborah S. Hasin, Ph.D., Harriet deWit, Ph.D., Sean J. O’Connor, M.D.,
Dingcai Cao, Ph.D.
Objective: Alcohol use disorder (AUD) remains an urgent
public health problem. Longitudinal data are needed to
clarify the role of acute subjective responses to alcohol in
the development and maintenance of excessive drinking
and AUD. The authors report on 10 years of repeated
examination of acute alcohol responses in the Chicago
Social Drinking Project.
Methods: Young adult drinkers (N5190) participated in
an initial alcohol challenge (0.8 g/kg of alcohol com-
pared with placebo) that was repeated 5 and 10 years
later. They were also assessed on drinking behavior and
AUD symptoms at numerous intervals across the decade.
Retention was high, as 184 of the 185 (99%) nonde-
ceased active participants completed the 10-year follow-
up, and 91% (163 of 179) of those eligible for alcohol
consumption engaged in repeated laboratory testing
during this interval.
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 sub-
sequent 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 character-
ize 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,
See related features: Editorial by Dr. Ray and colleagues (p. 483), CME course (online and p. 571) and Video by Dr. Pine (online).
560 ajp.psychiatryonline.org
Results: At the end of the decade, 21% of participants met
criteria for past-year AUD. Individuals who reported the
greatest alcohol stimulation, liking, and wanting at the initial
alcohol challenge were most likely to have developed AUD
10 years later. Further, alcohol-induced stimulation and
wanting increased in reexamination testing among those
with the highest AUD symptoms as the decade progressed.
Conclusions: Initial stimulant and rewarding effects of al-
cohol predicted heavy alcohol use, and the magnitude of
these positive subjective effects increased over a 10-year
period in those who developed AUD compared with those
who did not develop the disorder. The findings demon-
strate systematic changes in subjective responses to alco-
hol over time, providing an empirical basis for prevention,
early intervention, and treatment strategies.
Am J Psychiatry June 2021; 178:560–571;doi: 10.1176/appi.ajp.2020.20030247
sensitization, or an increased drug effect with repeated expo-
sure, has also been linked to addiction (13, 14). Although both
tolerance and sensitization are integral components of neuro-
biological 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 inten-
sive and require high retention rates. Yet the knowledge from
such investigations is necessary to adequately test the transla-
tional significance of animal models of addiction to humans
(17) and thus to inform empirically based strategies for pre-
vention, early intervention, and treatment. Whether the excit-
atory, euphoric, or sedating effects of alcohol increase,
decrease, or remain constant over time in problem drinkers
represents an unresolved issue in clinical psychiatry.
Am J Psychiatry 178:6, June 2021

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, pre-
dicted progression of AUD symptoms 5–6 years after the ini-
tial 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 per-
sistently greater stimulation, wanting, and liking after con-
suming 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 partici-
pants were just entering their fourth decade of life, which
may not have been sufficient to fully examine AUD develop-
ment. In addition, the previous study focused mainly on
heavy drinkers and did not allow for an integrated examina-
tion 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 consump-
tion 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 ses-
sions 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 Inter-
net advertisements and word-of-mouth referrals. Initial
Am J Psychiatry 178:6, June 2021
SUBJECTIVE RESPONSES TO ALCOHOL IN ALCOHOL USE DISORDER
inclusion criteria were age between 21 and 35 years, weight
between 110 and 210 pounds, good general health, not preg-
nant or lactating, no current or past major medical or psy-
chiatric 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 medi-
cal 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 com-
fortable 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, objec-
tive breath tests confirmed recent alcohol abstinence, and a
urine sample was collected for women to verify nonpreg-
nancy. 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 por-
tions and, in the presence of the research assistant, con-
sumed 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 (N53), who were pregnant or
nursing (N53), or who were abstinent from alcohol (N53)
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. Reex-
amination sessions were scheduled for the same month as the
initial testing; the mean interval from participants’ initial
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KING ET AL.
session was 61 months (SD53.0) to the year-5 session and 122
months (SD53.7) 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 assess-
ments, 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 con-
sumed, 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 physiologi-
cal 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 sur-
veys 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 (AUD1) or absence (AUD2) of the disor-
der in the last year of follow-up. Twenty-one percent of par-
ticipants (N539) met DSM-5 criteria for AUD at year 10,
forming the AUD1 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
AUD2 group. Of these, 124 reported no AUD symptoms,
and 21 reported one symptom. A review of the preceding 10
years revealed that the AUD1 group showed more AUD
symptoms than the AUD2 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 sub-
group analysis was based on DSM-IV symptom counts
562 ajp.psychiatryonline.org
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 crite-
rion 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 sub-
group (N5103), an intermediate AUD symptom subgroup
(N562), and a high AUD symptom group (N519). The AUD
symptoms across these subgroups corresponded to the fre-
quency 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 classifi-
cations 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 sub-
group, 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 AUD1 and AUD2 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 concentra-
tion 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 Question-
naire) 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 con-
ducted in the main analysis to examine subgroup, time, and
phase effects and their interactions. All generalized estimat-
ing 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
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 SUBJECTIVE RESPONSES TO ALCOHOL IN ALCOHOL USE DISORDER

FIGURE 1. Mean alcohol use disorder (AUD) symptom count and heavy drinking occasions per month across 10 years of follow-up
in a study of the subjective responses to alcohol in the development and maintenance of AUDa

A
6 14

Heavy Drinking Occasions per Month

12
5

10
AUD Symptom Count

8
3
6

2
4

1 2

0 0
Initial 1 2 4 5 6 8 10 Initial 1 2 4 5 6 8 10
AUD+ at year 10
Follow-Up Year Follow-Up Year
AUD– at year 10
B
6 14

12
Heavy Drinking Occasions per Month
5

10
AUD Symptom Count

8
3
6

2
4

1
2

0 0
Initial 1 2 4 5 6 8 10 Initial 1 2 4 5 6 8 10
Follow-Up Year High AUD symptom count Follow-Up Year
Intermediate AUD symptom count
Low AUD symptom count

a
Panel A depicts results for the presence of AUD (AUD1 group) or the absence of AUD (AUD2 group) as determined at year 10, and panel B
depicts results for AUD symptom subgroups. Data shown are mean values, and error bars indicate standard error. The left panel depicts AUD
symptoms at each follow-up interval for each group, and the right panel depicts the frequency of binge drinking during follow-up. As shown
in panel A, the AUD1 and AUD2 groups were identified based on AUD symptom counts per DSM-5 at year 10 of follow-up. As shown in
panel B, three trajectory subgroups were identified based on symptom counts from DSM-IV criteria for alcohol abuse and alcohol dependence
(0–11 symptoms possible) over 10 years of follow-up, and symptom counts were ascertained during initial testing and at years 1, 2, 4, 5, 6, 8,
and 10 (dotted lines represent model fits). Because the study began before DSM-5 was released, symptom counts for years 1–5 were based
on the 11 criteria for DSM-IV alcohol abuse and dependence (as reflected in the Structured Clinical Interview for DSM-IV). For unity, these
DSM-IV criteria also were used for the follow-up in years 6–10 for trajectory analysis. Notably, only one symptom is different between the cri-
teria for DSM-IV alcohol abuse and dependence compared with those for DSM-5 AUD.

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 labora-
tory reexamination sessions were conducted in 156 and 163
participants, respectively. These rates represent 88% and
91% of the 178 and 179 participants eligible for reexamina-
tion at each phase, respectively.
The AUD1 and AUD2 groups at 10 years did not differ on
most demographic characteristics; however, as expected, the
AUD1 group reported heavier alcohol consumption and

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KING ET AL.

TABLE 1. Demographic and clinical characteristics of groups with alcohol use disorder (AUD) (AUD1) and without AUD (AUD2) at
year 10 at initial and year 10 testing in a study of the subjective responses to alcohol in the development and maintenance of AUD
AUD1 at Year 10 (N539) AUD– at Year 10 (N5145)
Significance
Characteristic Initial Testing Year 10 Testing Initial Testing Year 10 Testing Testing
N % N % N % N %
Male 25 64 – – 75 52 – – ns
Whitea 32 82 – – 108 74 – – ns
Family history of AUDb 7 18 – – 35 24 – – ns
Married or living with partner 3 8 17 44 20 14 98 68 ns
Nicotine dependencec 6 15 10 26 3 2 6 4 Group, p,0.01
Substance dependencec 3 8 1 3 1 1 0 0 ns
Mean SD Mean SD Mean SD Mean SD
Age (years) 24.6 3.0 34.6 3.0 25.9 3.2 35.9 3.2 ns
Education (years) 15.5 1.7 16.4 2.1 16.2 1.8 17.7 3.0 ns
Beck Depression Inventory score 4.1 3.3 6.5 5.7 2.2 2.6 3.2 3.8 ns
Spielberger State Anxiety t score 49.2 8.9 51.8 7.8 43.6 6.8 46.6 5.9 ns
AST (U/L) 21.7 6.7 21.0 5.3 22.6 9.5 20.5 10.4 ns
ALT (U/L) 20.1 10.6 22.1 11.3 22.1 17.2 21.5 16.8 ns
Drinking days in past monthd 14.3 6.9 20.6 6.3 9.7 5.1 15.0 6.9 Group, p,0.05
Heavy drinking days in past 7.5 4.5 13.7 6.6 3.5 4.3 4.9 4.9 Group-by-phase
monthd interaction, p,0.01
Alcohol problemse 11.3 5.0 18.7 6.2 6.8 4.6 8.6 5.4 Group-by-phase
interaction, p,0.01
AUD symptoms during follow-upe – – 4.5 1.8 – – 1.2 1.5 Group, p,0.001
a
Race was provided by participants from a list of options consistent with National Institutes of Health classifications.
b
Family history of AUD was defined as having one biological primary or two or more biological secondary relatives with AUD.
c
Nicotine dependence and substance dependence were determined using the Structured Clinical Interview for DSM-IV (SCID), indicating the number of
participants who met past-year criteria at year 1 and during any follow-up time point across 10 years.
d
From the timeline follow-back calendar for the month preceding initial testing and maxima across follow-up time points for days that any alcohol was
consumed and days with heavy drinking, defined as $5 drinks per occasion for men and $4 drinks for women, based on the standard definition of one
drink (i.e., 12 oz. of beer, 5 oz. of wine, or 1.5 oz. of liquor).
e
From the Alcohol Use Disorders Identification Test and the SCID, indicating the past year at initial testing and mean scores or the number of 11 DSM-IV
symptoms met across follow-up time points for 10 years.

more drinking problems than the AUD2 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 aver-
age 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: x255.78, df58, p50.672). 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 sub-
stantially differ across the testing phases.
In terms of subjective response, alcohol produced mark-
edly different effects in the 10-year AUD1 and AUD2 groups.
These differences were evident starting at the initial testing
phase and increased further over the course of the reexamina-
tion phases (Figure 2). Overall, the AUD1 group exhibited
increasing sensitivity for pleasurable alcohol responses during
the decade of participation, while the AUD2 group showed
low initial levels on these measures with little to no change
through the testing phases. Specifically, alcohol produced ini-
tially higher stimulation in the AUD1 group relative to the
AUD2 group during the early portion of the breath alcohol
concentration curve, and stimulation level increased in inten-
sity through the reexamination phases (group-by-time-by-
phase interaction, p50.016; Table 3). Alcohol also initially
increased ratings of motivational salience (wanting) in the
AUD1 group relative to the AUD2 group across the entire
breath alcohol concentration curve, and wanting also
increased in intensity through the reexamination phases
(group-by-phase interaction, p50.001). Initial hedonic reward
(liking) from alcohol was also higher in the AUD1 group
(p50.017), and this effect increased through reexamination,
but the escalation was not statistically significant (group-by-
phase interaction, p50.104). 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 AUD1 and AUD2
groups (Figure 3). Relative to the low AUD symptom sub-
group, the intermediate and high AUD symptom subgroups
exhibited initially heightened alcohol stimulation, wanting,

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 SUBJECTIVE RESPONSES TO ALCOHOL IN ALCOHOL USE DISORDER

TABLE 2. Characteristics of alcohol use disorder (AUD) symptom trajectory subgroups at initial testing and year 10 testing in a
study of the subjective responses to alcohol in the development and maintenance of AUD
Low AUD Symptom Intermediate AUD High AUD Symptom
Group (N5103) Symptom Group (N562) Group (N519)
Initial Year 10 Initial Year 10 Initial Year 10 Significance
Characteristic Testing Testing Testing Testing Testing Testing Testing
N % N % N % N % N % N %
Male 48 47 – – 40 65 – – 12 63 – – ns
Whitea 75 73 – – 50 81 – – 15 79 – – ns
Family history of 28 27 – – 10 16 – – 4 21 – – ns
AUDb
Married or living 15 15 71 69 6 10 37 60 2 10 7 37 ns
with partner
Nicotine 2 2 3 3 4 6 6 10 3 16 7 37 Group, p,0.05
dependencec
Substance 0 0 0 0 1 2 0 0 3 16 1 5 ns
dependencec
Mean SD Mean SD Mean SD Mean SD Mean SD Mean SD
Age (years) 26.2 3.3 36.2 3.3 24.8 3.0 34.7 3.0 25.3 2.9 35.3 2.9 ns
Education (years) 16.4 1.8 18.0 3.2 15.9 1.5 17.0 1.8 15.1 2.2 15.6 2.2 Group-by-phase
interaction,
p,0.05
Beck Depression 1.8 2.3 2.9 3.2 3.2 3.3 4.0 3.6 5.1 3.8 9.1 6.2 Group-by-phase
Inventory score interaction,
p,0.001
Spielberger State 50.1 12.7 46.5 4.6 49.6 10.1 48.2 6.9 49.2 11.4 53.4 8.2 Group-by-phase
Anxiety t score interaction,
p,0.001
AST (U/L) 22.2 4.8 19.3 7.4 22.5 6.8 22.8 12.9 23.0 7.7 20.8 6.5 ns
ALT (U/L) 21.9 11.9 19.6 14.6 21.2 9.5 24.6 17.8 22.1 14.0 22.9 14.6 ns
Drinking days in past 8.0 4.3 13.3 6.8 13.6 5.5 18.8 5.7 15.4 7.1 22.8 5.5 Group-by-phase
monthd interaction,
p,0.01
Heavy drinking days 2.0 3.4 3.0 3.8 6.9 4.0 10.0 4.5 9.0 4.6 16.7 6.9 Group-by-phase
in past monthd interaction,
p,0.01
Alcohol problemse 5.0 3.3 6.4 3.8 11.0 4.3 14.4 4.8 12.4 5.4 21.9 6.2 Group-by-phase
interaction,
p,0.01
AUD symptoms – – 0.5 0.7 – – 2.9 1.4 – – 6.1 1.3 Group, p,0.001
during follow-upe
a
Race was provided by participants from a list of options consistent with National Institutes of Health classifications.
b
Family history of AUD was defined as having one biological primary or two or more biological secondary relatives with AUD.
c
Nicotine dependence and substance dependence were determined using the Structured Clinical Interview for DSM-IV (SCID), indicating the number of
participants who met past-year criteria at year 1 and during any follow-up time point across 10 years.
d
From the timeline follow-back calendar for the month preceding initial testing and maxima across follow-up time points for days that any alcohol was
consumed and days with heavy drinking, defined as $5 drinks per occasion for men and $4 drinks for women, based on the standard definition of one
drink (i.e., 12 oz. of beer, 5 oz. of wine, or 1.5 oz. of liquor).
e
From the Alcohol Use Disorders Identification Test and the SCID, indicating the past year at initial testing and mean scores or the number of 11 DSM-IV
symptoms met across follow-up time points for 10 years.

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 (r50.14, p50.06), and
sedation (r520.17, p,0.05).
On secondary measures, alcohol increased feel-drug rat-
ings during the rising breath alcohol concentration limb
(time, p50.026; see Table S1 in the online supplement); this
response became more intense through the reexamination
phase for the AUD1 group (group-by-phase interaction,
p50.004). 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 supple-
ment). For all analyses, there were no sex differences.

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FIGURE 2. Subjective alcohol responses during initial testing and at 5-year and 10-year reexaminations in alcohol use disorder
(AUD) groups as determined at year 10 in a study of the development and maintenance of AUDa

Initial Testing Year 5 Year 10

25 25 25
AUD+ at year 10
20 AUD– at year 10 20 20

15 15 15
Stimulation

10 10 10

5 5 5

0 0 0

–5 –5 –5
–30 0 30 60 120 180 –30 0 30 60 120 180 –30 0 30 60 120 180
25 25 25

20 20 20

15 15 15
Sedation
Change Between Alcohol and Placebo Session Scores

10 10 10

5 5 5

0 0 0

–5 –5 –5
–30 0 30 60 120 180 –30 0 30 60 120 180 –30 0 30 60 120 180
50 50 50

40 40 40

30 30 30

20 20 20
Liking

10 10 10

0 0 0

–10 –10 –10

–20 –20 –20

–30 0 30 60 120 180 –30 0 30 60 120 180 –30 0 30 60 120 180
50 50 50

40 40 40

30 30 30
Wanting

20 20 20

10 10 10

0 0 0

–10 –10 –10

–20 –20 –20

–30 0 30 60 120 180 –30 0 30 60 120 180 –30 0 30 60 120 180
Time (minutes) Time (minutes) Time (minutes)

a
Data shown are mean values, with error bars indicating standard error, of the change in scores (alcohol session scores minus placebo session
scores) for the four primary subjective response measures at each time point and at each testing phase for the presence of AUD (AUD1
group) at year 10 (N539) or the absence of AUD (AUD2 group) at year 10 (N5145). The AUD1 and AUD2 groups were identified based on
AUD symptom counts per DSM-5 at year 10 of follow-up. The y-axis ranges for liking and wanting differ slightly given the range of values and
because liking is based on a scale with the midpoint as neutral. Details on the statistical testing are provided in Table 3.

566 ajp.psychiatryonline.org Am J Psychiatry 178:6, June 2021

 SUBJECTIVE RESPONSES TO ALCOHOL IN ALCOHOL USE DISORDER

TABLE 3. Summary of a generalized estimating equation analysis of primary alcohol response outcomes in groups with alcohol use
disorder (AUD) (AUD1) and without AUD (AUD2) at year 10 and in AUD symptom trajectory subgroupsa
Primary
Outcome b SE p b SE p b SE p b SE p b SE p b SE p
AUD group-by-phase AUD group-by-time AUD group-by-time-
AUD group Time Phase interaction interaction by-phase interaction
Stimulation 1.126 2.192 0.607 –4.089 4.383 0.351 –0.037 0.137 0.788 –0.305 0.289 0.292 6.027 6.300 0.339 2.541 0.987 0.010
Sedation –1.980 1.958 0.312 1.885 0.373 <0.001 –0.030 0.099 0.760 –0.182 0.210 0.385 –1.250 0.789 0.113 0.159 0.124 0.198
Wanting 5.534 6.093 0.364 –2.819 1.172 0.016 –0.830 0.332 0.012 2.203 0.702 0.002 –1.367 2.368 0.564 0.268 0.371 0.470
Liking 11.454 4.691 0.015 –8.699 0.996 <0.001 –0.574 0.282 0.042 1.091 0.598 0.068 –1.463 2.016 0.468 –0.148 0.316 0.639
AUD symptom group-
AUD symptom AUD symptom group- AUD symptom group- by-time-by-phase
trajectory subgroups Time Phase by-phase interaction by-time interaction interaction
Stimulation 0.759 1.380 0.582 –9.354 7.061 0.185 0.326 0.297 0.273 –0.281 0.176 0.111 5.104 3.820 0.181 1.818 0.600 0.002
Sedation –0.927 1.270 0.465 1.822 0.812 0.025 0.123 0.216 0.569 –0.125 0.128 0.328 –0.133 0.479 0.781 –0.001 0.075 0.991
Wanting 10.741 3.792 0.005 –4.727 2.475 0.056 –1.959 0.733 0.008 1.054 0.433 0.015 1.033 1.456 0.478 –0.090 0.229 0.693
Liking 8.712 2.972 0.003 –8.215 2.079 <0.001 –1.194 0.616 0.052 0.567 0.364 0.119 –0.553 1.223 0.651 –0.075 0.192 0.696
a
Data are results from a generalized estimating equation analysis and include the cubic term for stimulation and linear terms for sedation, wanting, and
liking as the best fit for these four variables. For stimulation, the three-way interaction of AUD group by time by phase and of AUD group by time-
squared by phase were also significant. All generalized estimating equations analyses controlled for baseline AUD count, breath alcohol concentration,
sex, race, and family history of alcoholism. Boldface indicates statistical significance.

DISCUSSION neuroadaptations in the circuits mediating motivational

AUD is phenotypically complex (41), and a better under-
standing 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 find-
ings: first, heightened sensitivity to the pleasurable effects of
alcohol (stimulation, liking, and wanting) in young adult-
hood preceded the development of AUD through middle
age; and second, sensitivity to alcohol stimulation and want-
ing increased across repeated testing over a decade in per-
sons who developed AUD. Trajectory analyses of AUD
symptom progression over follow-up confirmed these find-
ings 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 cor-
tisol did not predict AUD development. Taken together,
these findings support the idea that the positive stimulating
and motivating effects of alcohol increase during the devel-
opment and maintenance of AUD. The findings do not sup-
port 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 motiva-
tional (“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 behav-
ioral 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
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 cen-
tral tenet of this theory.
There has been substantial disagreement among clini-
cians 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 with-
stand a higher breath alcohol concentration than inexperi-
enced 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 tol-
erance. The well-controlled findings from the present study
are not consistent with the notion of robust chronic toler-
ance of alcohol’s subjective effects, so anecdotal patient
reports of lessened effects of alcohol over time may be influ-
enced 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

Am J Psychiatry 178:6, June 2021 ajp.psychiatryonline.org 567

KING ET AL.

FIGURE 3. Subjective alcohol responses during initial testing and at 5-year and 10-year reexaminations in alcohol use disorder
(AUD) symptom trajectory subgroups in a study of the development and maintenance of AUDa

Initial Testing Year 5 Year 10

25 25 25
Symptom count
20 High AUD 20 20
Intermediate AUD
15 Low AUD 15 15
Stimulation

10 10 10

5 5 5

0 0 0

–5 –5 –5

–10 –10 –10

–30 0 30 60 120 180 –30 0 30 60 120 180 –30 0 30 60 120 180

25 25 25

20 20 20

15 15 15
Change Between Alcohol and Placebo Session Scores

Sedation

10 10 10

5 5 5

0 0 0

–5 –5 –5

–10 –10 –10

–30 0 30 60 120 180 –30 0 30 60 120 180 –30 0 30 60 120 180

40 40 40

30 30 30

20 20 20

10 10 10
Liking

0 0 0

–10 –10 –10

–20 –20 –20

–30 –30 –30

–30 0 30 60 120 180 –30 0 30 60 120 180 –30 0 30 60 120 180

60 60 60

50 50 50

40 40 40

30 30 30
Wanting

20 20 20

10 10 10

0 0 0

–10 –10 –10

–20 –20 –20

–30 0 30 60 120 180 –30 0 30 60 120 180 –30 0 30 60 120 180

Time (minutes) Time (minutes) Time (minutes)

a
Data are shown as mean values, with error bars indicating standard error, for low AUD symptom count (N5103), intermediate AUD symptom
count (N562), and high AUD symptom count (N519) trajectory groups at the initial and reexamination phases. Subjective response data are
change scores (alcohol session scores minus placebo session scores) at each time point. The y-axis ranges for liking and wanting differ
slightly given the range of values and because liking is based on a scale with the midpoint as neutral. Details on the statistical testing are pro-
vided in Table 3.

568 ajp.psychiatryonline.org Am J Psychiatry 178:6, June 2021


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 neuroim-
aging 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 dif-
ficult to reconcile the contrasting findings, given the differ-
ences 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 symp-
tom counts for alcohol abuse and dependence. Thus, symp-
tom 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 concen-
tration 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 consequen-
ces. 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
Am J Psychiatry 178:6, June 2021
SUBJECTIVE RESPONSES TO ALCOHOL IN ALCOHOL USE DISORDER
this issue is recent collaborative work by the first author
(A.K.) and international colleagues showing that older ado-
lescent heavy drinkers exhibit sensitivity to alcohol stimula-
tion 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 AUD1 group was modest. How-
ever, using two similar but not overlapping outcome
approaches may ameliorate concerns about sample size.
Comparing the AUD1 and AUD2 groups at year 10 pro-
vided a practical clinical endpoint used by clinicians, and
notably, 64% of AUD1 subjects met DSM-IV alcohol depen-
dence at some point through follow-up, compared with 7%
in the AUD2 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 exces-
sive drinking was beyond the scope of this article, persons in
the AUD1 group had a higher likelihood of seeking advice
or help with drinking or of seriously considering getting help
relative to the AUD2 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. How-
ever, the study results were not consistent with the allostasis
model of a progressive deficit in reward. In terms of preven-
tion of alcohol problems, rather than a sole focus on toler-
ance, young adults might be informed that marked
stimulant-like, pleasurable, and appetitive effects after con-
suming 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.
AUTHOR AND ARTICLE INFORMATION
Department of Psychiatry and Behavioral Neuroscience, University of
Chicago, Chicago (King, Vena, deWit); Department of Epidemiology,
Mailman School of Public Health, and Department of Psychiatry, Col-
lege of Physicians and Surgeons, Columbia University, New York
(Hasin); Department of Psychiatry, Indiana University School of
ajp.psychiatryonline.org 569
KING ET AL.
Medicine, Indianapolis, and Department of Biomedical Engineering,
Purdue University, West Lafayette, Ind. (O’Connor); Department of
Ophthalmology and Visual Sciences, University of Illinois at Chicago,
Chicago (Cao).
Send correspondence to Dr. King (aking@bsd.uchicago.edu).
Presented in part at the 41st annual meeting of the Research Society on
Alcoholism, San Diego, June 16–20, 2018.
Supported by National Institute on Alcohol Abuse and Alcoholism
grants AA-013746 to Dr. King, AA-023839 to Dr. Cao, AA-07611 to Dr.
O’Connor, and AA-025309 to Dr. Hasin, and by NIDA grants
DA-043469 to Drs. Vena and deWit and DA-018652 to Dr. Hasin.
ClinicalTrials.gov identifier: NCT00961792.
The authors thank Patrick McNamara for project coordination, data
collection, and database management and Royce Lee, M.D., and Jon
Grant, M.D., for medical supervision and oversight.
Dr. King has served on an advisory board for Pfizer and as a consultant
to the Respiratory Health Association. The other authors report no
financial relationships with commercial interests.
Received March 3, 2020; revision received July 13 2020; accepted
August 10, 2020; published online Jan. 5, 2021.
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Continuing Medical Education Examination Questions: King et al.

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Association.
1. What theory purports that addiction involves the development of a deficit in reward
or change in aversive states and stress response?
a. Incentive-sensitization.
b. Tolerance.
c. Allostasis.
d. Disease model.
2. Heightened sensitivity to what response domain(s) increased across a decade of
repeated testing in persons developing alcohol use disorder?
a. Stimulation and wanting.
b. Sedation.
c. Cortisol and heart rate.
d. Attention bias.
3. How might the findings inform providers treating patients concerned about
exacerbations in drinking and symptoms of alcohol use disorder?
a. Inform patients that their adrenal response to alcohol is overactive.
b. Discuss that abstinence is the only way to cure addiction.
c. Tell patients that most people respond to alcohol the same way.
d. Discuss that experiencing more rewarding and stimulating responses may put
patients at risk for continued excessive drinking and addiction.

Am J Psychiatry 178:6, June 2021 ajp.psychiatryonline.org 571