REVIEWS AND OVERVIEWS
Addiction as a Coping Response: Hyperkatifeia, Deaths
of Despair, and COVID-19
George F. Koob, Ph.D., Patricia Powell, Ph.D., Aaron White, Ph.D.
Neuroadaptations that occur in response to repeated sub-
stance use diminish the euphoria that is produced by the
acute use of a drug and increase levels of physical and
emotional stress between drug use episodes. An individual
who struggles with addiction can be tempted to return to drug
use to reduce misery that is caused by use of the drug itself.
Recent developments, including an increase in “deaths of
despair” in the United States, increases in alcohol use by some
individuals as a result of the 2019 coronavirus disease
(COVID-19) pandemic, and limited availability of in-person
treatment and recovery support, raise concerns about the use
of alcohol and other drugs in an effort to cope with distress. In
this article, we examine the role of negative reinforcement in
the development of addiction, discuss neuroadaptations that
lead to increases in emotional and physical misery between
episodes of drug use, and explore how using substances to
cope with the emotional strain of social isolation and financial
uncertainty during the COVID-19 pandemic could contribute
to deaths of despair.
CONCEPTUAL FRAMEWORK OF ADDICTION
Alcohol Use Disorder as a Prototype Addiction
Alcohol use disorder (AUD) can be defined as a chronically
relapsing disorder that is associated with compulsive alcohol
drinking, the loss of control over intake, and the emergence of
a negative emotional state when alcohol is no longer available.
Patterns of alcohol use in AUD can range from intermittent
episodes of binge alcohol intake to prolonged heavy drinking
over longer periods that progresses to continual drinking for
fear of withdrawal. Comorbid affective disorders, a history
of trauma, and exposure to stressors increase the likelihood
of developing AUD (1, 2). Abstinence from such alcohol
binges or chronic high alcohol intake is characterized by a
withdrawal syndrome with severe emotional and somatic
symptoms and intense craving for alcohol. Negative emo-
tional states commonly trigger relapse (3, 4), and such neg-
ative emotional states can be driven by excessive alcohol
consumption itself. Like other substance use disorders, AUD
is now considered a spectrum disorder, as described in
Am J Psychiatry 177:11, November 2020
DSM-5 (5), which provides a framework for determining the
intensity of the disorder based on the number of symptoms
the individual presents.
Heuristic Framework for Addiction
A heuristic framework for studying addiction, characterized
by a three-stage cycle—binge/intoxication, withdrawal/
negative affect, and preoccupation/anticipation—provides a
starting point for exploring our theme in this article, namely,
the intersection between alcohol addiction, deaths of despair,
and social isolation that are caused by the COVID-19 pan-
demic (6, 7). Under this framework, dysregulation occurs in
three functional domains that reflect the three stages of the
addiction cycle: incentive salience/pathological habits in
the binge/intoxication stage, negative emotional states in
the withdrawal/negative affect stage, and executive func-
tion deficits in the preoccupation/anticipation stage. These
three domains and stages are hypothesized to be mediated
by three major neurocircuitry elements: basal ganglia, extended
amygdala, and prefrontal cortex, respectively (6). An individual
can enter the addiction cycle at any of these three stages (6)
(Figure 1).
For many years, positive reinforcement was postulated to
be the driving motivational construct in addiction. Sub-
stantial work focused on neural circuits that are engaged in
the positive hedonic effects of drugs. However, a growing
body of evidence also implicates negative reinforcement in
driving and maintaining addiction. Negative reinforcement
can be defined as an increase in the probability of a response
that is produced by the removal of an aversive event. In the
context of addiction, negative reinforcement can initially
draw an individual into unhealthy patterns of substance use
by reducing existing discomfort and, as addiction develops,
may subsequently manifest in continuing substance use in an
effort to reduce, terminate, or prevent the negative experi-
ence of drug withdrawal.
Hyperkatifeia and Negative Reinforcement
The term withdrawal can be defined simply as abstinence
from, or the removal of, chronic drug use, usually charac-
terized by signs and symptoms that are opposite to the acute
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ADDICTION AS A COPING RESPONSE

FIGURE 1. Conceptual framework for the neurobiological basis of substance use disordersa

Incentive Salience/Pathological Habits

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The framework involves a three-stage cycle—binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation. These three stages
involve dysregulations in three functional domains (incentive salience/habits, negative emotional states, and executive function) that are mediated by
three major neurocircuitry elements (basal ganglia, extended amygdala, and prefrontal cortex, respectively). The negative emotional state of drug
withdrawal, termed hyperkatifeia, can be facilitated and exacerbated by non-drug-related allostatic loads, such as genetics, epigenetics, childhood
trauma, and psychiatric comorbidity, in addition to excessive drinking. Hyperkatifeia in turn drives the negative reinforcement source of motivation for
compulsive-like alcohol seeking and using. Hyperkatifeia can drive impulsivity via negative urgency that is associated with relapse in the preoccupation/
anticipation stage and then a return to the binge/intoxication stage. Hyperkatifeia can also drive the malaise of protracted abstinence that sets up a return
to the binge/intoxication stage via craving and relapse in the preoccupation/anticipation stage. (Figure modified from Koob GF, Arends MA, Le Moal M:
Drugs, Addiction, and the Brain. San Diego, Academic Press, 2014.)

positively perceived effects of the drug (7). Withdrawal from
drugs of abuse is one of 11 criteria that are used to diagnose
substance use disorder in DSM-5 and one of six criteria that
are used to diagnose substance dependence in ICD-10 (8).
Historically, and still embedded in current thinking about
addiction, withdrawal is inextricably linked to physical or
somatic signs (9). For many drugs, however, including al-
cohol, the key components of withdrawal that motivate
further use are such symptoms as anxiety, dysphoria, pain,
irritability, sleep disturbances, and general malaise. Although
some of these symptoms can be linked directly to physical
disturbances, such as gastrointestinal distress, most of them
involve changes in brain reward and stress systems (10–13).
The emergence of negative emotional symptoms following re-
peated substance use has a theoretical basis in opponent pro-
cess theory as proposed by Solomon and Corbit (14), whereby
counteradaptations occur in which the initial acute hedonic ef-
fectsofa drugare opposed byhomeostatic changes in systemsthat
mediate these primary hedonic effects. As a result, with repeated
drug taking, tolerance develops to the hedonic effects, and a
greater amount and more frequent use of the previously re-
warding drug are needed to maintain or approach euthymia.
Expanding this concept beyond adaptations that coun-
teract the initial rewarding effects of a drug, others have
argued that the opponent process that underlies withdrawal
involves the recruitment of brain stress systems (11, 15). Al-
cohol and other substances can initially dampen stress-
related brain function and reduce emotional discomfort,
but the resulting neuroadaptations subsequently lead to the
need for escalating doses and the emergence of an augmented
state of emotional discomfort when the drug wears off. To
capture the essence of the negative emotional state that is
associated with drug withdrawal, the term hyperkatifeia was
introduced. Hyperkatifeia (derived from the Greek katifeia
for dejection or negative emotional state) is defined as an
increase in intensity of the constellation of negative emo-
tional or motivational signs and symptoms of withdrawal
from drugs of abuse (16). This overactive negative emotional

1032 ajp.psychiatryonline.org Am J Psychiatry 177:11, November 2020


state is also hypothesized to sensitize with repeated drug
exposure and withdrawal and drive an increase in the role of
negative reinforcement in maintaining substance use as ad-
diction develops (17).
Validation of the Negative Emotional State Domain in
Alcohol Use Disorder
Advances in the social psychology of self-regulation, neuro-
biological advances, and imaging studies led to the framework
of the three domains that are outlined above—executive
function, incentive salience, and negative emotionality—each
linked to different phases of the addiction cycle. One ex-
trapolation of this work is that these elements form the core
functional elements of AUD and as such provide new neu-
roclinical measures, termed the Addictions Neuroclinical
Assessment (ANA), to differentiate patients who meet clinical
criteria for addiction for the same agent while differing in
etiology, prognosis, and treatment response (18). As a result,
this framework could lead to a better understanding of the
mechanisms that provoke and maintain addiction. Indeed, a
study evaluated the utility of the ANA for translation to a
clinical framework and showed that the three neurofunctional
domains were validated using a factor analysis of a deeply
phenotyped clinical sample (19). Subsequent studies analyzed
the ANA approach specifically for the negative emotionality
domain in a treatment-seeking AUD sample and showed that a
one-factor model was an excellent fit for all assessments in this
domain. This negative emotionality domain was time and sex
invariant and was associated with drinking patterns and
reasons to drink (20). Another study, using a multilevel growth
model analysis of data from the Prospective Study sample
of the Collaborative Study on the Genetics of Alcoholism,
found that positive reinforcement that was associated with
alcohol consumption did not differ as a function of alcohol
dependence, but negative reinforcement that was associated
with alcohol consumption became stronger as alcohol de-
pendence developed (21).
Collectively, these results suggest that in AUD, the neg-
ative emotionality domain, reflecting symptoms that are
associated with hyperkatifeia, plays an important role in the
addiction cycle, a role at least equal to that of incentive sa-
lience, pathological habits, and craving. Although hyper-
katifeia is most likely to manifest during the withdrawal/
negative affect stage, it can also infiltrate other stages of the
addiction cycle to promote or facilitate impulsivity (negative
urgency), craving, and relapse (Figure 1).
Negative Urgency, Protracted Abstinence, and Relapse
Classically, individuals with AUD may start with recreational
use of the drug during the binge/intoxication stage and
progress to the withdrawal/negative affect stage as negative
reinforcement evolves and impaired functioning of the
frontal cortex progresses, facilitating reemergence of a binge
despite aversive consequences (Figure 1). However, our
hypothesis is that a significant amount of alcohol misuse
develops because negative emotional states from other
Am J Psychiatry 177:11, November 2020
KOOB ET AL.
sources can drive alcohol seeking and use and may be an
initial starting point for entering the addiction cycle via
self-medication (22) (Figure 1). Thus, we suggest that
entrance into the three-stage cycle at any stage can engage
neuroadaptations that lead to hyperkatifeia; conversely,
hyperkatifeia can contribute to all three stages of the ad-
diction cycle (Figure 1).
Negative Urgency
Negative urgency is an emotion-based trait that is charac-
terized by a tendency to act rashly and impulsively when
experiencing unusually strong negative emotions (23, 24).
The trait is associated with a higher likelihood of problematic
risk taking, including the early initiation and escalation of
alcohol and other drug use (25, 26), and an increase in alcohol
consumption in response to negative mood (27–29). Negative
urgency may be an early risk factor for substance use dis-
orders and has been hypothesized to be an endophenotype for
alcohol and tobacco addiction (23, 27). The negative emo-
tional symptoms that are associated with hyperkatifeia and
the withdrawal/negative affect stage may elicit intense urges
that are moderated or mediated by negative urgency (24).
Additionally, impairments in executive control that are as-
sociated with negative urgency may decrease the capacity to
resist urges to pursue substance use in the preoccupation/
anticipation stage, such that an episode of use occurs rapidly
and without forethought of potential harm despite actual
consequences (19, 24) (Figure 1).
Protracted Abstinence
Withdrawal symptoms can persist past the acute withdrawal
phase that follows the binge/intoxication stage and continue
through the preoccupation/anticipation stage (30). By one
estimate, 75% of people who experience alcohol withdrawal
have symptoms that endure beyond the acute withdrawal
phase (31, 32). This extended period is termed protracted
abstinence or protracted withdrawal and begins approx-
imately 1 week after the resolution of physical withdrawal
signs. For patients with AUD who experience protracted
withdrawal, such symptoms as hypohedonia, anxiety, and
sleep disturbances typically abate within 3–6 weeks but can
persist for longer periods in a more subtle form. These
subtle changes in affective processing could be sufficient to
lead to craving and relapse under stressful circumstances
(30, 33). Human laboratory studies and clinical trials
demonstrate the strength of this interaction and suggest
that cue reactivity, combined with a negative emotional
overlay, can predict the efficacy of medications for treating
AUD (34–36).
Relapse
In the preoccupation/anticipation (craving) stage, both en-
vironmental factors and internal states are hypothesized to
contribute to relapse (6). External factors include priming
doses of the drug, drug-associated cues, and exposure to
stressors. Internal factors include malaise, a state of stress, or
ajp.psychiatryonline.org 1033
ADDICTION AS A COPING RESPONSE
interoceptive cues, many of which can be subsumed under
the hyperkatifeia construct (see above).
Stress is a major determinant of relapse and vulnerability
to relapse in individuals with AUD (3, 4, 37–39). Exposure
to negative affect, stress, or withdrawal-related distress also
increases alcohol craving (34, 40, 41). For example, in a
prospective study of patients with AUD who were enrolled in
a 12-week outpatient study, high stress-induced craving was
associated with a significantly shorter time to alcohol relapse,
a higher mean number of drinks per week, a lower percentage
of days abstinent, and lower rates of complete abstinence over
the study duration (40). These results suggested that stress-
related increases in alcohol craving are associated with
poorer alcohol treatment outcomes, supporting the use of
stress-induced craving as a predictor of alcohol relapse
propensity (40).
Neurobiology of Hyperkatifeia
Hyperkatifeia has been hypothesized to be mediated by
profound changes in the brain reward and stress systems,
providing a basis of an additional source of motivation for
alcohol misuse via negative reinforcement (7). As tolerance
and withdrawal develop, reward function decreases and is
mediated by acute losses of function of dopamine, serotonin,
and endogenous opioid systems and neuroadaptations in the
g-aminobutyric acid/glutamate systems (7). Such a hypo-
hedonia component of hyperkatifeia has been termed a
within-system neuroadaptation to excessive alcohol intake,
in which alcohol reward circuits are compromised (6, 10).
Perhaps even more compelling for the development and
persistence of hyperkatifeia are between-system neuro-
adaptations (6, 10). Brain stress systems, such as corticotropin-
releasing factor, glucocorticoids, norepinephrine, dynorphin,
vasopressin, hypocretin, and substance P, and neuroimmune
systems are recruited by excessive alcohol consumption,
producing aversive or stress-like states, also contributing
to hyperkatifeia (7). There is also evidence that deficits in
stress-buffering systems, such as neuropeptide Y, nociceptin,
endocannabinoids, and oxytocin, may also contribute to
hyperkatifeia (7). Molecular mechanisms that are involved in
the withdrawal/negative affect stage can contribute to mo-
lecular loading on within- and between-system neurocircuit
adaptations (42). Many of these neurochemical neuro-
adaptations continue into protracted abstinence and parallel
neurochemical neuroadaptations that are associated with
acute withdrawal (7).
HYPERKATIFEIA, DEATHS OF DESPAIR, AND
IMPLICATIONS FOR THE COVID-19 PANDEMIC
Deaths of Despair
After increasing for decades, life expectancy in the United
States began to decline around 2014. The decline was driven
in part by what Case and Deaton (43, 44) referred to as
“deaths of despair”—deaths from drug and alcohol overdoses,
1034 ajp.psychiatryonline.org
liver disease, and suicide. These deaths are linked to de-
clining quality of life, including declines in emotional and
physical well-being, financial difficulties, and serious
mental illness. Increases in deaths of despair began in the
late 1990s among non-Hispanic white men and women in
midlife (43, 45). However, such deaths are now increasing
among people in midlife across racial and ethnic groups
(46–48).
As discussed previously, alcohol can temporarily dampen
negative emotional states, providing short-term relief and
powerful reinforcement for continued use. Over time, neu-
roadaptations reduce the relief that is provided by alcohol and
increase emotional misery between episodes of use. Alcohol
plays a prominent role in deaths of despair and contributes
to an estimated 15% of all drug overdoses (49, 50), 26% of
suicides (51), and 50% of deaths from liver diseases (52).
Deaths in the United States that involve alcohol are in-
creasing, having doubled from 1999 to 2017 (53, 54), as are
rates of alcohol-related emergency department visits and
hospitalizations.
Alcohol Consumption During the Pandemic:
Disinhibition and Disease
The COVID-19 pandemic can be considered a major stressful
event that affects daily life for people throughout most of the
world. Mental health experts fear that the stress, uncertainty,
and trauma of the pandemic could precipitate a mental health
crisis in the United States and elsewhere (55). Alcohol use
could escalate during the pandemic, leading to a greater
treatment need and a greater burden of alcohol on public
health. Combining available data on alcohol sales, including
both on-premise (e.g., bars and restaurants) and off-premise
(e.g., liquor and grocery stores) locations, during the pan-
demic suggests that sales increased roughly 5% overall in
March 2020 but returned to near pre-pandemic levels in May
2020 (56). Sales data do not indicate whether some people are
drinking more. A recent survey by the Research Triangle
Institute found that roughly 40% of respondents reported an
increase in alcohol use during the pandemic, whereas 30%
reported a decrease (57). Another survey suggested that
greater COVID-related distress was associated with larger
increases in alcohol use (58).
Coping With Stress: Psychosocial Side Effects of
COVID-19
Physical distancing during the pandemic has also restricted
social interaction. Given that social interaction is a powerful
reinforcer for humans, the lack of it can contribute to
loneliness, dysphoria, depression, and malaise. As a result,
social isolation could serve as a source of stress that motivates
drinking to cope. Using alcohol to dampen emotional misery
is a form of misregulation in the domain of self-regulation (59)
and tends to make people more miserable once the alcohol
wears off and motivated to drink again to fix a problem that is
now caused or exacerbated by alcohol itself. Drinking to cope
with negative emotions places an individual at a higher risk of
Am J Psychiatry 177:11, November 2020

developing AUD (60, 61). Therefore, alcohol drinking is not a
safe or sustainable solution for the emotional strain that many
people are experiencing during the pandemic.
The physical distancing that has been imposed during
the pandemic may be particularly challenging for people
who are in recovery from AUD. As noted above, stress
and negative affect are major triggers of relapse (1–4).
Although there are options for one-on-one sessions
through telehealth or participation in online mutual sup-
port groups (https://www.niaaa.nih.gov/alcohol-and-covid-19;
https://alcoholtreatment.niaaa.nih.gov), face-to-face therapy
sessions and in-person mutual support group meetings that are
often critical for successful treatment and recovery are un-
available to most people right now, highlighting a current
challenge to treatment.
Alcohol is a well-known social lubricant and decreases
inhibitions in interactions with both friends and strangers
(62, 63). It also impairs decision making, threat detection, and
impulse control, which could have an impact on adherence to
guidelines on physical distancing and mask wearing, po-
tentially increasing spread of the SARS-CoV-2 virus that
causes COVID-19. In addition to potentially increasing viral
transmission, there are reasons to suspect that excessive
alcohol use can increase the risk of infection with SARS-CoV-
2 and decrease the body’s defense system via mechanisms
that are similar to the interaction between alcohol and acute
respiratory distress syndrome (64, 65).
CONCLUSIONS
Using AUD as a prototype, we argue that negative emotional
states play an often overlooked but key role throughout the
addiction cycle. In some cases, the misuse of alcohol is an
attempt to mitigate misery and as such provides entry into the
addiction cycle. For other individuals who are already ex-
periencing AUD, the hyperkatifeia of alcohol and other drug
withdrawal extends long past the acute physical (often so-
matic) manifestations of withdrawal and perpetuates AUD.
Such negative emotional states in addiction fit an allostatic
view, manifested as a break with normal reward and stress
regulation (66). Allostasis is defined as an attempt to maintain
hedonic stability through change. The loss of reward func-
tion, gain of stress system function, and loss of executive
control progressively produce an allostatic load that mani-
fests as an allostatic state (i.e., the hyperkatifeia of acute and
protracted withdrawal). These changes can ultimately lead to
the pathological state of addiction. The ongoing COVID-19
pandemic has resulted in social isolation, the loss of loved
ones, the loss of livelihood, and drinking to cope, thereby
exacerbating negative emotional states for many. The fear,
dysphoria, and social isolation of COVID-19 could greatly
augment allostatic load in the domain of addiction. Because
the pandemic began against the backdrop of increases in
deaths of despair in the United States, it is possible that in-
creases in pandemic-related stress combined with elevated
Am J Psychiatry 177:11, November 2020
KOOB ET AL.
substance use could fuel an increase in mortality from over-
doses, suicide, and alcohol-related liver disease. The pandemic
challenges us to develop new ways to meet the expanding needs
of the etiology, diagnosis, prevention, and treatment of addiction
and avert a looming crisis in the addiction field.
AUTHOR AND ARTICLE INFORMATION
National Institute on Alcohol Abuse and Alcoholism, Bethesda, Md. (all
authors); National Institute on Drug Abuse, Bethesda, Md. (Koob).
Send correspondence to Dr. Koob (george.koob@nih.gov).
The authors thank Janet Hightower for generating the artwork for this
article, and Michael Arends for his assistance with manuscript preparation.
Dr. Powell holds stock in Pfizer, Inc. The other authors report no financial
relationships with commercial interests.
Accepted September 17, 2020.
Am J Psychiatry 2020; 177:1031–1037; doi: 10.1176/appi.ajp.2020.
20091375
REFERENCES
1. McCaul ME, Hutton HE, Stephens MA, et al: Anxiety, anxiety
sensitivity, and perceived stress as predictors of recent drinking,
alcohol craving, and social stress response in heavy drinkers. Alcohol
Clin Exp Res 2017; 41:836–845
2. Strine TW, Dube SR, Edwards VJ, et al: Associations between ad-
verse childhood experiences, psychological distress, and adult al-
cohol problems. Am J Health Behav 2012; 36:408–423
3. Marlatt G, Gordon J: Determinants of relapse: implications for the
maintenance of behavioral change, in Behavioral Medicine:
Changing Health Lifestyles. Edited by Davidson P, Davidson S. New
York, Brunner/Mazel, 1980, pp 410–452
4. Marlatt GA: Relapse prevention: introduction and overview of the model, in
Relapse Prevention: Maintenance Strategies in the Treatment of Addictive
Behaviors.EditedbyMarlatt GA,GordonJR.London,Guilford,1985,pp3–70
5. American Psychiatric Association: Diagnostic and Statistical Manual
of Mental Disorders, 5th ed. Washington, DC, American Psychiatric
Association, 2013
6. Koob GF, Le Moal M: Drug abuse: hedonic homeostatic dysregu-
lation. Science 1997; 278:52–58
7. Koob GF: Neurobiology of opioid addiction: opponent process, hyper-
katifeia, and negative reinforcement. Biol Psychiatry 2020; 87:44–53
8. World Health Organization: International Statistical Classification
of Diseases and Related Health Problems, 10th revision. Geneva,
World Health Organization, 1992
9. Himmelsbach CK: Symposium: Can the euphoric, analgetic, and
physical dependence effects of drugs be separated? IV: With reference
to physical dependence. Federation Proceedings 1943; 2:201–203
10. Koob GF, Bloom FE: Cellular and molecular mechanisms of drug
dependence. Science 1988; 242:715–723
11. Koob GF, Le Moal M: Addiction and the brain antireward system.
Annu Rev Psychol 2008; 59:29–53
12. Baker TB, Piper ME, McCarthy DE, et al: Addiction motivation
reformulated: an affective processing model of negative re-
inforcement. Psychol Rev 2004; 111:33–51
13. Baker TB, Morse E, Sherman JE: The motivation to use drugs: a
psychobiological analysis of urges. Nebr Symp Motiv 1986; 34:257–323
14. Solomon RL, Corbit JD: An opponent-process theory of motivation,
I: temporal dynamics of affect. Psychol Rev 1974; 81:119–145
15. Koob GF: A role for brain stress systems in addiction. Neuron 2008;
59:11–34
16. Shurman J, Koob GF, Gutstein HB: Opioids, pain, the brain, and
hyperkatifeia: a framework for the rational use of opioids for pain.
Pain Med 2010; 11:1092–1098
ajp.psychiatryonline.org 1035
ADDICTION AS A COPING RESPONSE
17. Ahmed SH, Koob GF: Transition to drug addiction: a negative re-
inforcement model based on an allostatic decrease in reward func-
tion. Psychopharmacology (Berl) 2005; 180:473–490 [erratum: 2012;
220:247]
18. Kwako LE, Momenan R, Litten RZ, et al: Addictions Neuroclinical
Assessment: a neuroscience-based framework for addictive disor-
ders. Biol Psychiatry 2016; 80:179–189
19. Kwako LE, Schwandt ML, Ramchandani VA, et al: Neurofunctional
domains derived from deep behavioral phenotyping in alcohol use
disorder. Am J Psychiatry 2019; 176:744–753
20. Votaw VR, Pearson MR, Stein E, et al: The Addictions Neuroclinical
Assessment negative emotionality domain among treatment-seekers
with alcohol use disorder: construct validity and measurement in-
variance. Alcohol Clin Exp Res 2020; 44:679–688
21. Cho SB, Su J, Kuo SI, et al: Positive and negative reinforcement
are differentially associated with alcohol consumption as a
function of alcohol dependence. Psychol Addict Behav 2019; 33:
58–68
22. Koob GF, Nestler EJ: The neurobiology of drug addiction.
J Neuropsychiatry Clin Neurosci 1997; 9:482–497
23. Cyders MA, Smith GT: Emotion-based dispositions to rash action:
positive and negative urgency. Psychol Bull 2008; 134:807–828
24. Zorrilla EP, Koob GF: Impulsivity derived from the dark side:
neurocircuits that contribute to negative urgency. Front Behav
Neurosci 2019; 13:136 [erratum: 2019; 13:188]
25. Smith GT, Cyders MA: Integrating affect and impulsivity: the role of
positive and negative urgency in substance use risk. Drug Alcohol
Depend 2016; 163(suppl 1):S3–S12
26. Stautz K, Cooper A: Impulsivity-related personality traits and ad-
olescent alcohol use: a meta-analytic review. Clin Psychol Rev 2013;
33:574–592
27. VanderVeen JD, Plawecki MH, Millward JB, et al: Negative urgency,
mood induction, and alcohol seeking behaviors. Drug Alcohol De-
pend 2016; 165:151–158
28. Um M, Hershberger AR, Cyders MA: The relationship among de-
pressive symptoms, urgency, and problematic alcohol and cannabis
use in community adults. Addict Behav 2019; 88:36–42
29. Tran J, Teese R, Gill PR: UPPS-P facets of impulsivity and alcohol use
patterns in college and noncollege emerging adults. Am J Drug
Alcohol Abuse 2018; 44:695–704
30. Mason BJ: Emerging pharmacotherapies for alcohol use disorder.
Neuropharmacology 2017; 122:244–253
31. Caputo F, Cibin M, Loche A, et al: The recognition and management
of protracted alcohol withdrawal may improve and modulate the
pharmacological treatment of alcohol use disorder. J Psychopharmacol
(Online ahead of print, July 10, 2020)
32. Semel J, Semel T: Post-Acute Withdrawal Syndrome (PAWS). Los
Angeles, University of California, Semel Institute for Neuroscience and
Human Behavior, UCLA Dual Diagnosis Program, 2020. https://
www.semel.ucla.edu/dual-diagnosis-program/News_and_Resources/
PAWS
33. Heilig M, Egli M, Crabbe JC, et al: Acute withdrawal, protracted
abstinence, and negative affect in alcoholism: are they linked? Addict
Biol 2010; 15:169–184
34. Mason BJ, Light JM, Escher T, et al: Effect of positive and negative
affective stimuli and beverage cues on measures of craving in non
treatment-seeking alcoholics. Psychopharmacology (Berl) 2008;
200:141–150
35. Mason BJ, Light JM, Williams LD, et al: Proof-of-concept human
laboratory study for protracted abstinence in alcohol dependence:
effects of gabapentin. Addict Biol 2009; 14:73–83
36. Mason BJ, Quello S, Goodell V, et al: Gabapentin treatment for al-
cohol dependence: a randomized clinical trial. JAMA Intern Med
2014; 174:70–77
37. Brown SA, Vik PW, Patterson TL, et al: Stress, vulnerability, and
adult alcohol relapse. J Stud Alcohol 1995; 56:538–545
1036 ajp.psychiatryonline.org
38. Sinha R, Fox HC, Hong KA, et al: Enhanced negative emotion and
alcohol craving, and altered physiological responses following
stress and cue exposure in alcohol dependent individuals. Neuro-
psychopharmacology 2009; 34:1198–1208
39. Koob GF, Mason BJ: Existing and future drugs for the treatment of
the dark side of addiction. Annu Rev Pharmacol Toxicol 2016; 56:
299–322
40. Higley AE, Crane NA, Spadoni AD, et al: Craving in response to stress
induction in a human laboratory paradigm predicts treatment out-
come in alcohol-dependent individuals. Psychopharmacology (Berl)
2011; 218:121–129
41. Cooney NL, Litt MD, Morse PA, et al: Alcohol cue reactivity, negative-
mood reactivity, and relapse in treated alcoholic men. J Abnorm Psychol
1997; 106:243–250
42. Kyzar EJ, Pandey SC: Molecular mechanisms of synaptic remodeling
in alcoholism. Neurosci Lett 2015; 601:11–19
43. Case A, Deaton A: Rising morbidity and mortality in midlife among
white non-Hispanic Americans in the 21st century. Proc Natl Acad
Sci USA 2015; 112:15078–15083
44. Case A, Deaton A: Mortality and morbidity in the 21st century.
Brookings Pap Econ Act 2017; 2017:397–476
45. Shanahan L, Hill SN, Gaydosh LM, et al: Does despair really kill? A
roadmap for an evidence-based answer. Am J Public Health 2019;
109:854–858
46. Gaydosh L, Hummer RA, Hargrove TW, et al: The depths of despair
among US adults entering midlife. Am J Public Health 2019; 109:
774–780
47. Woolf SH, Chapman DA, Buchanich JM, et al: Changes in
midlife death rates across racial and ethnic groups in the United
States: systematic analysis of vital statistics. BMJ 2018; 362:
k3096
48. Woolf SH, Schoomaker H: Life expectancy and mortality rates in the
United States, 1959–2017. JAMA 2019; 322:1996–2016
49. Warner M, Trinidad JP, Bastian BA, et al: Drugs most frequently
involved in drug overdose deaths: United States, 2010–2014. Natl
Vital Stat Rep 2016; 65:1–15
50. Tori ME, Larochelle MR, Naimi TS: Alcohol or benzodiazepine
co-involvement with opioid overdose deaths in the United States,
1999–2017. JAMA Netw Open 2020; 3:e202361
51. Ertl A, Sheats KJ, Petrosky E, et al: Surveillance for violent deaths:
National Violent Death Reporting System, 32 states, 2016. MMWR
Surveill Summ 2019; 68:1–36
52. Yoon YH, Chen CM: Liver cirrhosis mortality in the United States:
national, state, and regional trends, 2000–2015 (Surveillance Report,
vol 111). Bethesda, Md, National Institute on Alcohol Abuse and
Alcoholism, 2018 (https://pubs.niaaa.nih.gov/publications/
surveillance111/Cirr15.htm)
53. White AM, Castle IP, Hingson RW, et al: Using death certif-
icates to explore changes in alcohol-related mortality in the
United States, 1999 to 2017. Alcohol Clin Exp Res 2020; 44:
178–187
54. Esser MB, Sherk A, Liu Y, et al: Deaths and years of potential life lost
from excessive alcohol use: United States, 2011–2015. MMWR Morb
Mortal Wkly Rep 2020; 69:981–987
55. Türközer HB, Öngür D: A projection for psychiatry in the post-
COVID-19 era: potential trends, challenges, and directions. (Online
ahead of print, July 17, 2020)
56. Alcohol Sales During the COVID-19 Pandemic (Surveillance Report
COVID-19). Bethesda, Md, National Institute on Alcohol Abuse and
Alcoholism, 2020. https://pubs.niaaa.nih.gov/publications/surveil-
lance-covid-19/COVSALES.htm
57. Barbosa CB, Cowell AJ, Dowd WN: How has drinking behavior
changed during the COVID-19 pandemic? Research Triangle
Park, NC, Research Triangle Institute, 2020. https://www.rti.
org/sites/default/files/covid19_alcohol_survey_webinar_slides_
071420.pdf
Am J Psychiatry 177:11, November 2020

58. Rodriguez LM, Litt DM, Stewart SH: Drinking to cope with the
pandemic: the unique associations of COVID-19-related perceived
threat and psychological distress to drinking behaviors in American
men and women. Addict Behav 2020; 110:106532
59. Baumeister RF, Heatherton TF, Tice DM: Losing Control: How and
Why People Fail at Self-Regulation. San Diego, Academic Press, 1994
60. Clay JM, Parker MO: The role of stress-reactivity, stress-recovery, and
risky decision-making in psychosocial stress-induced alcohol consump-
tion in social drinkers. Psychopharmacology (Berl) 2018; 235:3243–3257
61. Blaine SK, Sinha R: Alcohol, stress, and glucocorticoids: from risk to
dependence and relapse in alcohol use disorders. Neuropharma-
cology 2017; 122:136–147
Am J Psychiatry 177:11, November 2020
KOOB ET AL.
62. Sayette MA, Creswell KG, Dimoff JD, et al: Alcohol and group
formation: a multimodal investigation of the effects of alcohol on
emotion and social bonding. Psychol Sci 2012; 23:869–878
63. Kirchner TR, Sayette MA, Cohn JF, et al: Effects of alcohol on group
formation among male social drinkers. J Stud Alcohol 2006; 67:
785–793
64. Boé DM, Vandivier RW, Burnham EL, et al: Alcohol abuse and
pulmonary disease. J Leukoc Biol 2009; 86:1097–1104
65. Simou E, Britton J, Leonardi-Bee J: Alcohol and the risk of pneumonia:
a systematic review and meta-analysis. BMJ Open 2018; 8:e022344
66. Koob GF, Le Moal M: Drug addiction, dysregulation of reward, and
allostasis. Neuropsychopharmacology 2001; 24:97–129
ajp.psychiatryonline.org 1037