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DRUGS,
ADDICTION,
AND THE
BRAIN
GeorGe F. Koob
The Scripps Research Institute,
La Jolla, CA, USA

Michael a. arends
The Scripps Research Institute,
La Jolla, CA, USA

Michel le Moal
University of Bordeaux and Neurocentre Magendie Inserm U862,
Bordeaux, France

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Preface
Addiction is a brain disease that afflicts In this context, we have conceptualized addic-
millions of individuals, costs society enormously tion as a three-stage cycle – binge/intoxication,
in terms of medical and social expense, and withdrawal/negative affect, and preoccupation/
causes an untold amount of suffering among anticipation – that worsens over time and
those with the disease and their loved ones. One involves allostatic-like changes in the brain
of the most compelling arguments that addiction incentive salience, reward, stress, and execu-
is a biological disorder comes from advances in tive function systems. Allostasis is defined
our understanding of the brain in the context as stability with change and refers to a break
of addiction. The study of the neurobiology of with normal homeostatic processes that can
addiction has also taught us much about how lead to overt pathology and on the way gen-
the brain works, particularly in the domains of erate prolonged pathophysiology known as
reward, motivation, and emotions. addiction.
This textbook is an effort to bring the neuro- This book is divided into three major parts.
biology of addiction to a didactic level for uni- Chapters 1–3 outline basic information that the
versity and college students. We envision this reader will need to interpret and place in con-
book as serving as material for upper-division text the specific discussions of each major drug
college courses, Masters and Ph.D. graduate class. Chapter 1 defines the concept of addic-
programs, and seminars on the neurobiology tion from a historical perspective and includes
of addiction. We also envision this book as a discussions of the new diagnostic criteria
resource for those in the medical field, includ- defined by the American Psychiatric Associa-
ing pharmacists and addiction treatment tion’s Diagnostic and Statistical Manual of Men-
professionals, to help them to gain a basic tal Disorders, 5th edition (DSM-V). Chapter 2
understanding of the neurobiology of addic- defines basic neurobiological concepts relevant
tion. We are convinced that a better under- to addiction and provides an overall summary
standing of the disorder by both professionals of the neurobiology of addiction. Chapter 3
and patients will allow them to better under- outlines animal models of various aspects of
stand addiction processes and the challenges the addiction cycle and their reliability and
of recovery. validity.
The book is organized on the basis of con- Chapters 4–8 outline in detail the major
cepts that have guided our research in the field classes of drugs of abuse using a standard
for some time, but particularly the concept that format for each chapter: Definitions; History
addiction is a chronically relapsing disorder of Use; Use, Abuse and Addiction; Medical
characterized by: Uses; Behavioral and Physiological Effects;
(i) A compulsion to seek and take drugs, Pharmacokinetics; Behavioral Mechanism of
(ii) Loss of control over drug intake, and Action; and Neurobiological Effects divided
(iii) Emergence of a negative emotional state into the binge/intoxication, withdrawal/nega-
(e.g., dysphoria, anxiety, and irritability) tive affect, and preoccupation/anticipation stages.
that defines a motivational withdrawal The neurobiology section follows the out-
syndrome when access to the drug is line of the three stages of the addiction cycle
prevented. so readers can explore the similarities and

vii
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viii PREFACE

differences between each drug class. Each over 40 years of different but complementary
chapter includes a history of how the use of basic research from the Koob and Le Moal labo-
the drug evolved. In addition to the neurobio- ratories in the domains of the motivation and
logical mechanism of action, a section on the pathophysiology of motivation. Students will
behavioral mechanism of action is provided to receive a rich but catholic view of the neuro-
demonstrate a unifying and integrating princi- biology of addiction that will stimulate future
ple of order and predictability at the behavioral interest in the field and hopefully drive excite-
level for a given drug. Although the addiction ment to gain further knowledge.
process for each drug class has certain common
neurobiological elements, each class of drugs is
also unique and engages the addiction cycle at ACKNOWLEDGMENTS
different points.
Finally, the third section of the book, repre- All of the figures in this book were redrawn
sented by Chapter 9, is an attempt to translate from their original sources by Janet Hightower
the neurobiology of addiction to the realm of the of The Scripps Research Institute Biomedical
pharmacotherapeutic treatment of addiction. Graphics department. We are always grate-
This chapter explores the mechanisms of action ful for her efforts. We thank Lisa Romero for
of known approved treatments of addiction, assistance with proof processing. We would
again within the construct of the three stages of also like to extend our deep appreciation to
the addiction cycle. the following colleagues for providing encour-
We provide many opportunities for read- agement, suggestions, references, figures, and
ers to relate the concepts herein with the real their own personal interpretations: R. Adron
world of individuals with addiction by includ- Harris, Barbara Mason, Mandy McCracken,
ing various case histories and studies of addic- Elizabeth D’Amico, Joel Schlosburg, Ami
tion. We also provide references for the data Cohen, Tom Eissenberg, Scott Edwards, Ken
presented in the figures and tables and various Warren, Antonio Noronha, Olivier George, and
suggestions for further reading so that students Pietro Sanna.
may pursue certain topics of interest in more
depth. This book takes a unique approach to George F. Koob
the study of the neurobiology of addiction, Michael A. Arends
guided by a conceptual framework honed from Michel Le Moal

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C H A P T E R

1
What is Addiction?
O U T L I N E

Definitions of Addiction 1 Vulnerability to Addiction 11

Drug Use, Drug Abuse, and Drug Addiction 1
Neuroadaptational Views of Addiction 20
Diagnostic Criteria for Addiction 4
Behavioral Sensitization 20
Frequency and Cost of Addiction 5
Counteradaptation and Opponent Process 21
Patterns of Addiction 6
Motivational View of Addiction 22
The “Dependence” View of Addiction 7
Allostasis and Neuroadaptation 25
Psychiatric View of Addiction 8
Psychodynamic View of Addiction 8 Summary 26
Social Psychological and Self-Regulation
Suggested Reading 27
Views of Addiction 11

DEFINITIONS OF ADDICTION drug use, the loss of control over limiting drug
intake, and the emergence of chronic compul-
Drug Use, Drug Abuse, and Drug sive drug seeking that characterize addiction.
Historically, three types of drug use have been
Addiction
delineated:
Drug addiction, formerly known as substance
1) Occasional, controlled, or social use,
dependence (American Psychiatric Association,
2) Drug abuse or harmful use, and
1994), is a chronically relapsing disorder that is
3) Drug addiction as characterized as either
characterized by:
Substance Dependence (Diagnostic and
1) A compulsion to seek and take a drug, Statistical Manual of Mental Disorders, 4th
2) Loss of control in limiting intake, and edition [DSM-IV]) or Dependence (see
3) Emergence of a negative emotional state below, and Tables 1.1 and 1.2).
(e.g., dysphoria, anxiety, irritability) when
More current descriptions have elaborated a
access to the drug is prevented.
continuum of behavioral pathology, from drug
The occasional but limited use of an abus- use to addiction, in the context of substance use
able drug is clinically distinct from escalated disorders.

Drugs, Addiction, and the Brain

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2 1. WHAT IS ADDICTION?

TABLE 1.1 DSM-5, DSM-IV, and ICD-10 Diagnostic Criteria for Abuse and Dependence
DSM-5 DSM-IV ICD-10

DEPENDENCE
A problematic pattern of substance use A maladaptive pattern of substance use, Three or more of the following have
leading to clinically significant impairment leading to clinically significant impairment been experienced or exhibited at
or distress, as manifested by at least two of the or distress as manifested by three or more of some time during the previous year
following occurring within a 12 month period the following occurring at any time in the
same 12-month period
1. Tolerance is defined by either of the 1. Need for markedly increased 1. Evidence of tolerance, such
following: a) a need for markedly amounts of a substance to achieve that increased doses are
increased amounts of substance to intoxication or desired effect; or required in order to achieve
achieve intoxication or desired effect markedly diminished effect with effects originally produced by
b) a markedly diminished effect with continued use of the same lower doses.
continued use of the same amount of amount of the substance.
substance.
2. Withdrawal is manifested by either of 2. The characteristic withdrawal 2. A physiological withdrawal
the following: a) the characteristic syndrome for a substance or use state when substance
withdrawal syndrome for substance or of a substance (or a closely related use has ceased or been
b) substance is taken to relieve or avoid substance) to relieve or avoid reduced as evidenced by:
withdrawal symptoms. withdrawal symptoms. the characteristic substance
withdrawal syndrome,
or use of substance (or a
closely related substance) to
relieve or avoid withdrawal
symptoms.
3. There is persistent desire or 3. Persistent desire or one or more 3. Difficulties in controlling
unsuccessful efforts to cut down or unsuccessful efforts to cut down or substance use in terms of
control substance use. control substance use. onset, termination, or levels
of use.
4. Substance is often taken in larger 4. Substance used in larger amounts or None
amounts or over a longer period than over a longer period than the person
was intended. intended.
5. Important social, occupational, or 5. Important social, occupational, or 4. Progressive neglect of
recreational activities are given up or recreational activities given up or alternative pleasures or
reduced because of substance use. reduced because of substance use. interests in favor of substance
use; or
6. A great deal of time is spent in 6. A great deal of time spent in A great deal of time spent in
activities necessary to obtain activities necessary to obtain, to activities necessary to obtain,
substance, use substance, or recover use, or to recover from the effects of to use, or to recover from
from its effects. substance used. the effects of substance use.
7. Continued substance use despite 7. Continued substance use despite 5. Continued substance use
having persistent or recurrent social or knowledge of having a persistent or despite clear evidence of
interpersonal problems caused recurrent physical or psychological overtly harmful physical or
or exacerbated by the effects of problem that is likely to be caused or psychological consequences.
substance. exacerbated by use.
None None 6. A strong desire or sense of
compulsion to use
substance.

Continued

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DEfINITIONS Of ADDICTION 3
TABLE 1.1 DSM-5, DSM-IV, and ICD-10 Diagnostic Criteria for Abuse and Dependence—cont’d
DSM-5 DSM-IV ICD-10

ABUSE
A maladaptive pattern of substance use A pattern of substance use that is
leading to clinically significant impairment causing damage to health.
or distress, as manifested by one (or more)
of the following occurring with a 12 month
period
8. Substance use is continued despite 1. Recurrent substance use resulting in The damage may be physical or
knowledge of having a persistent or a failure to fulfill major role mental. The diagnosis requires that
recurrent physical or psychological obligations at work, school, or home. actual damage should have been
problem that is likely to have been caused to the mental or physical
caused or exacerbated by substance health of the user
9. Recurrent use in situations in which it 2. Recurrent substance use in situations
is physically hazardous in which use is physically hazardous.
None 3. Recurrent substance-related legal
problems.
10. Recurrent substance use resulting in a 4. Continued substance use despite
failure to fulfill major role obligations having persistent or recurrent social
at work, school or home or interpersonal problems caused or
exacerbated by the effects of the drug.
11. Craving or a strong desire or urge to None None
use alcohol (or other substance)

TABLE 1.2 Estimated Number and Percentage of Persons of the US Population Aged 12 and Older (N = 258 Million)
Who Ever Used Alcohol, Tobacco, Cannabis, Cocaine, Heroin, or Prescription Opioids, the Number
and Percentage Who Used these Drugs in the Last Year, the Number and Percentage Who Ever Showed
Dependence (DSM-IV Criteria; See Text) in the Last Year, and the Number and Percentage Who Showed
Abuse or Dependence (DSM-5 Criteria; See Text) in the Last Year
Last-Year Use with Last-Year Use with
Ever Used Last-Year Use Dependence Abuse or Dependence
Drug Millions % Millions % Millions % Millions %

Cocaine 36.9 14.6 3.9 1.5 0.58 14.5 0.82 21.1

Stimulants 20.4 7.2 2.7 1.0 0.25 9.3 0.33 12.9

Methamphetamine 11.9 4.6 1.0 0.4 – – – –

Heroin 4.2 1.7 0.6 0.2 0.37 57.0 0.43 65.5

Analgesics 34.2 13.5 11.1 4.3 1.4 12.7 1.8 16.5

Alcohol 211.7 82.1 170.4 65.9 7.8 4.6 16.7 9.8

Tobacco 173.9 67.5 81.9 31.8 – – – –

Cigarettes* 161.8 62.8 67.1 26.1 22.9 34.2 22.9 34.2

Cannabis 107.8 42.0 29.7 11.5 2.6 8.8 4.2 13.9

* There is no abuse category for cigarettes, so the third and fourth columns of the table are identical.
Data from Substance Abuse and Mental Health Services Administration, National Survey on Drug Use and Health, 2011

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4 1. WHAT IS ADDICTION?

Diagnostic Criteria for Addiction edition of the DSM (DSM-IV) and ICD-10, with
the exception of the removal of “committing
The diagnostic criteria for addiction, as illegal acts” and the addition of a new “craving”
described in the DSM, have evolved from the criterion. For example, rather than differentiat-
first edition published in 1952 to DSM-IV, with ing “alcoholics” and “alcohol abusers,” the new
a shift from an emphasis on the criteria of tol- classification Substance Use Disorder on Alco-
erance and withdrawal to other criteria which hol encompasses individuals who are afflicted
are more directed at compulsive use. The crite- by the disorder to different degrees, from “mild”
ria for Substance Use Disorders outlined in the (e.g., a typical college binge drinker who meets
DSM-IV closely resemble those outlined in the two criteria, such as alcohol is often taken in
International Statistical Classification of Diseases larger amounts or over a longer period than
and Related Health Problems (ICD-10) for Drug was intended and there is a persistent desire or
Dependence (World Health Organization, 1992; unsuccessful efforts to cut down or control alco-
Table 1.1). The DSM-5 was published in 2013 hol use) to “severe” (e.g., a classic person with
(American Psychiatric Association, 2013). In alcoholism who meets six or more criteria, such
this, the criteria for drug addiction have changed as a great deal of time spent in activities neces-
both conceptually and diagnostically. The new sary to obtain alcohol, use alcohol, or recover
diagnostic criteria for addiction merge the abuse from its effects, recurrent alcohol use resulting in
and dependence constructs (i.e., substance a failure to fulfill major role obligations at work,
abuse and substance dependence) into one con- school, or home, alcohol use despite knowledge
tinuum that defines “substance use disorders” of having a persistent or recurrent physical or
on a range of severity, from mild to moderate to psychological problem, continued alcohol use
severe, based on the number of criteria that are despite persistent social or interpersonal prob-
met out of a total of 11. The severity of a sub- lems, tolerance, and withdrawal).
stance use disorder (addiction) depends on how The terms Substance Use Disorder and Addic-
many of the established criteria are met by an tion will be used interchangeably throughout
individual. Mild Substance Use Disorder is the this book to refer to a usage process that moves
presence of 2–3 criteria, moderate is 4–5 criteria, from drug use to addiction as defined above.
and severe is six or more criteria. These criteria Drug addiction is a disease and, more precisely,
remain basically the same as in the previous a chronic relapsing disease (Figures 1.1 and 1.2).

FIGURE 1.1 Last-year use with abuse or dependence (data from Substance Abuse and Mental Health Services Administration,
National Survey on Drug Use and Health, 2011; see Table 1.2).

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DEfINITIONS Of ADDICTION 5
FIGURE 1.2 Stages of addiction to drugs
of abuse. Drug taking invariably begins with
social drug taking and acute reinforcement and
often, but not exclusively, moves in a pattern of
use from escalating compulsive use to depen-
dence, withdrawal, and protracted abstinence.
During withdrawal and protracted abstinence,
relapse to compulsive use is likely to occur
with a repeat of the cycle. Genetic factors, envi-
ronmental factors, stress, and conditioning all
contribute to the vulnerability to enter the cycle
of abuse/dependence and relapse within the
cycle. [Taken with permission from Koob GF, Le
Moal M. Neurobiology of Addiction. Academic
Press, London, 2006.]

The associated medical, social, and occupa- tobacco, 32% of the population used tobacco in the
tional difficulties that usually develop during last year. For cannabis, 13.9% of last-year users met
the course of addiction do not disappear after the criteria for Substance Abuse or Dependence on
detoxification. Addictive drugs produce changes cannabis. For cocaine, 21.1% of last-year users met
in brain circuits that endure long after the person the criteria for Substance Abuse or Dependence on
stops taking them. These prolonged neurochem- cocaine. For heroin, 65.5% of last-year users met
ical and neurocircuitry changes and the associ- the criteria for Substance Abuse or Dependence on
ated personal and social difficulties put former heroin.
patients at risk of relapse, a risk that is > 60% The cost to society of drug abuse and drug
within the first year after discharge. addiction is prodigious in terms of both the
direct costs and indirect costs associated with
secondary medical events, social problems, and
Frequency and Cost of Addiction loss of productivity. In the United States alone,
A shortcut for examining the frequency of sub- illicit drug use and addiction cost society $161
stance use disorders is to utilize a combination of billion per year in 2011. Alcoholism cost society
the percentage of individuals who have drug abuse $223 billion per year in 2012, and nicotine addic-
and drug dependence as defined by the DSM-IV, tion costs society $155 billion. In terms of health
since no data are yet available for the frequency of burden, alcohol and tobacco use are in the top 10
substance use disorders based on the DSM-5 cri- greatest risk factors for loss of years to disease
teria. Combining the old drug abuse and depen- and disability.
dence criteria yields an approximate percentage Much of the initial research into the neu-
of 15% (38.6 million people as of 2011) for the U.S. robiology of drug addiction focused on the
population who are 12 or older who suffered from acute impact of drugs of abuse (analogous to
Substance Use Disorders for alcohol, tobacco, or comparing no drug use to drug use). The focus
illicit drugs in the last year (Table 1.2). For alco- has shifted to chronic administration and the
hol, 9.8% of last-year users met the criteria for acute and long-term neuroadaptive changes
Substance Abuse or Dependence on Alcohol. For that occur in the brain. Sound arguments have

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6 1. WHAT IS ADDICTION?

been made to support the hypothesis that drug taking, intense initial intoxication, the
addictions are similar to other chronic relaps- development of profound tolerance, escalation
ing disorders, such as diabetes, asthma, and in intake, and profound dysphoria, physical dis-
hypertension, in their chronic relapsing nature comfort, and somatic withdrawal signs during
and treatment efficacy (for further reading, see abstinence (Box 1.1). Intense preoccupation with
McLellan et al., 2000). Current neuroscientific obtaining opioids (craving) develops and often
drug abuse research seeks to understand the precedes the somatic signs of withdrawal. This
cellular and molecular mechanisms that medi- preoccupation is linked to stimuli associated
ate the transition from occasional, controlled with obtaining the drug, stimuli associated with
drug use to the loss of behavioral control over withdrawal, and internal and external states of
drug seeking and drug taking that defines stress. A pattern develops in which the drug
chronic addiction. must be administered to avoid the severe dys-
phoria and discomfort of abstinence.
Alcohol substance use disorder or alco-
Patterns of Addiction holism follows a somewhat different pattern
Different drugs produce different patterns of of drug taking that depends on the sever-
addiction, with an emphasis on different com- ity of the disorder. The initial intoxication is
ponents of the addiction cycle. Opioids are a less intense than opioids, and the pattern of
classic drug of addiction, in which an evolving drug taking often is characterized by binges
pattern of use includes intravenous or smoked of alcohol intake that can be daily episodes or

BOX 1.1

Jimmy pulls out of the graveled driveway she probably is going to the next group session.
onto the smooth asphalt surface of the road. It Dennis’ heart begins to pound – gripped by a
feels so good to drive again after the long months flood of memories about the car, where he and
in “rehab.” No heroin use in over 6 months. ‘‘Not Diana had shared so much cocaine. A wave of
bad,” he congratulates himself. But as he takes intense feeling rushes from the tip of his toes,
the exit to the old neighborhood, his bowels up to his head and back down again. Thoughts
begin to growl. He breaks out in sweat, gripping racing, desire coursing through his body, he
the steering wheel and trying to ignore the raw, turns away from the road home, into the night.
acid taste in the back of his throat. Yawning, eyes As he approaches the familiar buying corner, he
watering, he feels mounting panic, and the desire can taste the cocaine in the back of his throat.
for drugs begins to burn in the pit of his stomach, He is sweating heavily now, ears ringing. “Just
“So much for good intentions,” be mutters, turn- a taste,” he bargains with himself, “just a taste is
ing toward a familiar alley and the drug that will all I’m going to buy.”
make everything right again.
Dennis leaves his cocaine therapy group From: Childress AR, Hole AV, Ehrman RN, Robbins SJ,
McLellan AT, O’Brien CP, Cue reactivity and cue reactivity
full of energy. “I’ve got 30 days clean, and now interventions in drug dependence. In: Onken LS, Blaine JD,
I’m going for 90!” he yells to a buddy as they Boren JJ (Eds.), Behavioral Treatments for Drug Abuse and
enter their cars. As he leaves the parking lot, a Dependence (series title: NIDA Research Monograph, vol.
137), National Institute on Drug Abuse, Rockville MD, 1993,
familiar white sedan is pulling in – Diana’s car; pp. 73–95.

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