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 Cocaine and
Methamphetamine
Dependence
Advances in Treatment
This page intentionally left blank
 Cocaine and
Methamphetamine
Dependence
Advances in Treatment

Edited by

Thomas R. Kosten, M.D.

Thomas F. Newton, M.D.
Richard De La Garza II, Ph.D.
Colin N. Haile, M.D., Ph.D.

Washington, DC
London, England
Note: The authors have worked to ensure that all information in this book is accurate
at the time of publication and consistent with general psychiatric and medical standards,
and that information concerning drug dosages, schedules, and routes of administration is
accurate at the time of publication and consistent with standards set by the U.S. Food and
Drug Administration and the general medical community. As medical research and prac-
tice continue to advance, however, therapeutic standards may change. Moreover, specific
situations may require a specific therapeutic response not included in this book. For these
reasons and because human and mechanical errors sometimes occur, we recommend that
readers follow the advice of physicians directly involved in their care or the care of a mem-
ber of their family.
Books published by American Psychiatric Publishing (APP) represent the findings, con-
clusions, and views of the individual authors and do not necessarily represent the policies
and opinions of APP or the American Psychiatric Association.
Disclosure of interests: All authors affirm that they have no competing financial interests
or affiliations relative to the content of this book.

Copyright © 2012 American Psychiatric Association

ALL RIGHTS RESERVED
Manufactured in the United States of America on acid-free paper
15 14 13 12 11 5 4 3 2 1
First Edition
Typeset in Helvetica and Berkeley
American Psychiatric Publishing
A Division of American Psychiatric Association
1000 Wilson Boulevard
Arlington, VA 22209-3901
www.appi.org

Library of Congress Cataloging-in-Publication Data

Cocaine and methamphetamine dependence : advances in treatment / edited by Thomas
R. Kosten ... [et al.]. — 1st ed.
p. ; cm.
Includes bibliographical references and index.
ISBN 978-1-58562-407-2 (pbk. : alk. paper)
I. Kosten, Thomas R.
[DNLM: 1. Cocaine-Related Disorders—therapy. 2. Amphetamine-Related Disorders—
therapy. 3. Behavior Therapy. 4. Psychotropic Drugs—therapeutic use. WM 280]
LC classification not assigned
615.7'88—dc23
2011025966
British Library Cataloguing in Publication Data
A CIP record is available from the British Library.

If you would like to buy between 25 and 99 copies of this or any other American Psychiatric Publishing title,
you are eligible for a 20% discount; please contact Customer Service at [email protected] or 800-368-5777.
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 Contents

Contributors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii
Foreword . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix
Herbert D. Kleber, M.D.

1 Epidemiology and Psychiatric Comorbidity . . . . . 1

Thomas R. Kosten, M.D.
Thomas F. Newton, M.D.

2 History, Use, and Basic Pharmacology of

Stimulants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Colin N. Haile, M.D., Ph.D.

3 Diagnoses, Symptoms, and Assessment . . . . . . . 85

Thomas R. Kosten, M.D.

4 Behavioral Interventions . . . . . . . . . . . . . . . . . . 105

Jin H. Yoon, Ph.D.
Rachel Fintzy, M.A.
Carrie L. Dodrill, Ph.D.

5 Pharmacotherapy. . . . . . . . . . . . . . . . . . . . . . . . 143
Thomas F. Newton, M.D.
Richard De La Garza II, Ph.D.
Ari D. Kalechstein, Ph.D.
6 Polydrug Abuse . . . . . . . . . . . . . . . . . . . . . . . . . 155
Richard De La Garza II, Ph.D.
Ari D. Kalechstein, Ph.D.

7 HIV and Other Medical Comorbidity . . . . . . . . 175

Valerie A. Gruber, Ph.D., M.P.H.
Elinore F. McCance-Katz, M.D., Ph.D.

8 Summary and Future Directions. . . . . . . . . . . . 193

Thomas F. Newton, M.D.
Colin N. Haile, M.D., Ph.D.

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205
 Contributors
Richard De La Garza II, Ph.D.
Associate Professor of Psychiatry, Neuroscience, and Pharmacology, Baylor
College of Medicine and Michael E. DeBakey Veterans Affairs (VA) Medical
Center; Research Director and Associate Professor, Departments of Psychiat-
ric Oncology and Behavioral Science, University of Texas M.D. Anderson
Cancer Center, Houston, Texas

Carrie L. Dodrill, Ph.D.

Psychologist, Michael E. DeBakey VA Medical Center, Houston, Texas

Rachel Fintzy, M.A.

Project Director, UCLA Integrated Substance Abuse Programs, David Geffen
School of Medicine, University of California, Los Angeles

Valerie A. Gruber, Ph.D., M.P.H.

Clinical Professor, Department of Psychiatry, University of California, San
Francisco

Colin N. Haile, M.D., Ph.D.

Assistant Professor, Menninger Department of Psychiatry and Behavioral
Sciences, Baylor College of Medicine and Michael E. DeBakey VA Medical
Center, Houston, Texas

Ari D. Kalechstein, Ph.D.

Adjunct Associate Professor, Menninger Department of Psychiatry and Behav-
ioral Sciences, Baylor College of Medicine and Michael E DeBakey VA Medical
Center, Houston, Texas

Herbert D. Kleber, M.D.

Professor, Department of Psychiatry, Columbia University, and Director, Di-
vision of Substance Abuse, New York State Psychiatric Institute, New York,
New York

vii
viii Cocaine and Methamphetamine Dependence

Thomas R. Kosten, M.D.

J.H. Waggoner Chair and Professor of Psychiatry, Pharmacology and Neuro-
science, Baylor College of Medicine; Professor of Psychiatry and Epidemiol-
ogy, M.D. Anderson Cancer Center; and Director, VA National Substance
Use Disorders Quality Enhancement Research Initiative (QUERI), Houston,
Texas

Elinore F. McCance-Katz, M.D., Ph.D.

Professor, Department of Psychiatry, University of California, San Francisco

Thomas F. Newton, M.D.

Professor, Menninger Department of Psychiatry and Behavioral Sciences and
Department of Pharmacology, Baylor College of Medicine and Michael E.
DeBakey VA Medical Center, Houston, Texas

Jin H. Yoon, Ph.D.

Assistant Professor, Menninger Department of Psychiatry and Behavioral
Sciences, Baylor College of Medicine, Houston, Texas
 Foreword

This book provides a comprehensive summary of what a clinician needs

to know about stimulant dependence and its treatment in order to move be-
yond the basics of this complex disorder as presented in The American Psychi-
atric Publishing Textbook of Substance Abuse Treatment (Galanter and Kleber
2008). The textbook covers the material that a general psychiatrist or pri-
mary care physician needs for appropriate referral and initial management
of patients with these complex disorders, for which no U.S. Food and Drug
Administration (FDA)–approved pharmacotherapies yet exist, but treat-
ments for these disorders are evolving rapidly. The present volume more
closely examines stimulant abuse and its changing epidemiologies and treat-
ment models.
As outlined in Chapter 1 of this volume, cocaine, methamphetamine
(METH), and amphetamine (AMPH) abuse and dependence differ substan-
tially in geographic distribution among North American cities and rural ar-
eas, as well as in Europe and Asia. The Philippines have the world’s highest
rates of AMPH abuse, with estimates that over 2.9% of the population are
abusers (Ahmad 2003).
The criminal justice responses to these stimulant epidemics have pro-
duced some enlightened and humane linkages between the criminal justice
system and treatment, such as “drug courts,” where judges order legally su-
pervised treatment for stimulant abusers rather than sending them to prison.
Treatment has also been introduced into the prisons themselves and includes
options for reducing the duration of imprisonment through work-release
programs. These legal innovations are critical for the estimated 1.6 million
current (on any given day) cocaine abusers and 502,000 current METH
abusers (2009 estimates; Substance Abuse and Mental Health Services Ad-
ministration 2010b). Another intervention initiated by the criminal justice
system rapidly reduced small clandestine METH laboratories from more
than 16,000 in 2004 to about 5,000 by 2007 as law enforcement efforts to
control supplies of the ephedrine precursors and to find and destroy these
laboratories were effective. These efforts increased the price of METH by

ix
x Cocaine and Methamphetamine Dependence

over 80% while its purity decreased by 26%, and the indicators in almost all
metropolitan areas showed stable or reduced METH use (although there ap-
peared to be somewhat of a rebound in METH availability during 2008).
Despite such efforts, there is still a steady number of new users and ca-
sualties from stimulant use: the 30-day prevalence of cocaine abuse among
eighth, tenth, and twelfth graders increased more than twofold between
1991 and 1998 and recently increased again in 2009 and 2010 (Johnston et
al. 2010).
Overall, cocaine dependence complications are common, being involved
in one of every three drug-related emergency department visits, and cocaine
has substantial social and economic impacts on those afflicted (McLellan et
al. 2000; Substance Abuse and Mental Health Services Administration
2010b). Moreover, from 2007 through 2009, the United States had 2.5 mil-
lion cocaine abusers using regularly, and in 2007 only 809,000 of them re-
ceived treatment (Substance Abuse and Mental Health Services Administra-
tion 2010c). Coroners’ reports (Graham and Hanzlick 2008; Kaye et al.
2008) relate stimulants to the direct cause of death in 25% of cocaine over-
doses and 68% of METH overdoses, or identify stimulant use as an anteced-
ent of cardiovascular or other medical problems, leading to death, in another
20% of these abusers.
The epidemiology of stimulant abuse is changing because of the increase
in pharmaceutical abuse attributable to several factors: 1) increasing num-
bers of prescriptions have led to greater availability; 2) attention to this form
of abuse by the media and in advertising on television and newspapers has
stimulated adolescents’ interest in it; 3) easy access through family and
friends has made this type of abuse cheap and attractive; and 4) lack of
proper monitoring of adolescents and of disappearance of drugs in the home
or elsewhere has led to underrecognition of addiction (Substance Abuse and
Mental Health Services Administration 2010a).
Cocaine and METH abuse and dependence frequently co-occur with
other major (i.e., Axis I) mental illnesses, especially schizophrenia, major
depression (Hughes et al. 1986), and posttraumatic stress disorder (PTSD)
(Jacobsen et al. 2001). Many types of drug use are more common among pa-
tients with mental illnesses than among the general population. Patients
with mood and anxiety disorders are at less risk for smoking and perhaps for
stimulant abuse than patients with schizophrenia, but patients with any of
these comorbid disorders smoke at higher rates than control subjects, and
many biological and social factors are involved. Psychotic symptoms second-
ary to METH abuse may not abate after the METH use has stopped and may
be associated with heavy alcohol use.
Chapter 2, on the complex pharmacology of stimulants, is outstanding,
although not readily summarized in a brief Foreword.
Foreword xi

Chapter 3, on symptoms and diagnosis, introduces the plan for DSM-5 to

drop the distinction between abuse and dependence, which is a useful
change in considering stimulants. In addressing teenage drug use informa-
tion reports, the author emphasizes the limitations of self-reports; even if
anonymous or confidential, they can lead to underreporting because respon-
dents will still give socially acceptable but untruthful answers, such as
“I don’t” use drugs. A recent study in teens found that hair specimens were
52 times more likely to identify cocaine use compared with self-report. Fur-
thermore, parent hair analyses for cocaine use were 6.5 times more likely to
indicate drug use than was parental self-report (Delaney-Black et al. 2010).
The SBIRT (Screening, Brief Intervention, and Referral to Treatment), a na-
tional program for screening and brief interventions with drug abusers, in-
dicates that such urine screening in emergency departments has particularly
high yields for detection and for reductions in health care utilization with
even a single 10- to 15-minute intervention focused on the substance abuse.
Subjective and behavioral responses to stimulants, including both toler-
ance of and sensitization to behavioral effects, are also detailed in Chapter 3.
Sensitization for AMPH-induced psychosis may persist despite long periods
of abstinence and may be characterized by delusions, paranoid thinking, and
stereotyped compulsive behavior. Dependence and withdrawal syndromes
are reviewed, and treatments for the range of stimulant complications are
considered (Gay 1982).
A comprehensive assessment of the patient involves the management of
aberrant behaviors such as intoxication, violence, suicidality, impaired cog-
nitive functioning, and uncontrolled affective displays. Suicidal ideation may
be intense but may clear within hours. In the case of intoxication, blood and
urine tests can help to determine the relevant stimulant(s) involved, as well
as to identify withdrawal from another drug that is masked or exacerbated by
concurrent stimulant dependence. Differences in developmental, gender,
and cultural presentations in the natural history of stimulant dependence are
also considered in Chapter 3.
The differential diagnosis of stimulant-induced intoxication and with-
drawal can require distinguishing these from a wide range of psychiatric dis-
orders, and up to a month of abstinence may be required for clear distinctions
to be made. However, the introduction of pharmacological treatments, such
as antidepressants, does not require such a lengthy delay. Thus, therapeutic
and diagnostic distinctions may require different time frames during evalua-
tions of the patient. For example, the symptoms of stimulant withdrawal fre-
quently overlap with those of depressive disorders, and this diagnosis can be
particularly difficult to distinguish from protracted withdrawal, which can in-
clude sleep and appetite disturbance as well as dysphoria that mimics affec-
tive disorders. A clinical vignette addresses whether a patient with stimulant
xii Cocaine and Methamphetamine Dependence

dependence in remission with a confirmed diagnosis of residual attention

deficit disorder should be given a trial of methylphenidate.
Chapter 3 closes with a review of biomarkers for stimulant, and particu-
larly cocaine, dependence. These biomarkers include abnormalities in neu-
rotransmitter receptors and transporters that have been noted in animal
models and confirmed in human neuroimaging studies of both the dopamine
(DA) and serotonin (5-HT) neurotransmitter systems (Volkow et al. 1990),
although none of these neuroimaging, neurohormone, or genetic biomarkers
have entered general clinical use.
Later chapters focus on treatment and emphasize that the most impor-
tant component of stimulant treatment involves behavioral therapies, often
in combination with adjunctive medications (see Chapters 4 and 5). Al-
though no medications have been FDA approved for use in stimulant depen-
dence, a range of candidate medications, with varying mechanisms of action,
have shown some efficacy. Distinguishing among the effectiveness of avail-
able behavioral treatments based on outcome has been difficult. A large
multisite study showed little difference between drug counseling and two
more intensive behavioral therapies, cognitive and supportive-expressive;
however, these therapies retain patients in treatment and can lead to absti-
nence (Crits-Christoph et al. 1999). Overall, these therapies form the plat-
form for any pharmacotherapy in order to engage the patient and facilitate
more long-term changes, including prevention of relapse (Carroll 1997; Car-
roll et al. 2000).
Contingency management (CM) procedures are given significant atten-
tion in this book. The authors emphasize that effective CM requires treat-
ment providers to identify an appropriate target as well as a method for
assessing the occurrence of the target behavior. Additionally, treatment pro-
viders must choose appropriate and effective reinforcers and decide the op-
timal way to deliver those reinforcers. Positive contingencies have been used
to initiate abstinence and prevent relapse, and this approach has been quite
successful for managing individuals who abuse cocaine or AMPH (Higgins et
al. 1994b, 2000a, 2000b; Petry 2005; Silverman et al. 1996; Weinstock et al.
2007). The goal of this approach has been to decrease behavior maintained
by drug reinforcers and increase behavior maintained by nondrug reinforcers
by presenting rewards contingent on documented drug abstinence (positive
contingencies) and withdrawing privileges contingent on documented drug
use (negative contingencies).
Studies illustrate how positive CM procedures facilitate initial abstinence
in cocaine-dependent persons. In a 24-week study (Higgins et al. 1994a), co-
caine-dependent individuals were randomly assigned to receive either behav-
ioral treatment without incentives or behavioral treatment with incentives
(i.e., vouchers exchangeable for goods and services) during weeks 1–12. Then,
Foreword xiii

during weeks 13–24, clients in both groups received a $1.00 lottery ticket for
every drug-free urine sample, in addition to behavioral treatment. The group
that received the incentives showed significantly greater treatment retention
and longer duration of continuous abstinence than the group not receiving
the incentives. In a 12-week clinical trial among methadone-maintained co-
caine abusers (Silverman et al. 1996), the CM group also achieved signifi-
cantly longer duration of sustained cocaine abstinence than control subjects.
Overall, these findings suggest that incentives contingent on drug abstinence
can be a powerful intervention tool for facilitating cocaine abstinence in co-
caine- and methadone-maintained cocaine abusers.
Recent studies have further reinforced that abstinence-based incentive
procedures are efficacious in improving retention and associated abstinence
outcomes in substance abusers. CM interventions implemented in commu-
nity-based settings, for example, have been successful in improving reten-
tion and associated abstinence outcomes (Petry 2005). Combining CM with
pharmacotherapies such as bupropion may significantly improve treatment
outcomes for cocaine addiction as well (Poling et al. 2006). There is, how-
ever, a significantly higher cost associated with the incentives group versus
usual-care group (Olmstead et al. 2010). In order to determine the cost-
effectiveness of implementing CM to improve patient outcomes in real-
world situations, researchers need to determine threshold values for patient
outcomes in substance abuse treatment.
As discussed in Chapter 4, cognitive-behavioral therapy (CBT) is also an
efficacious intervention for the treatment of stimulant abuse. CBT for stim-
ulant abuse includes functional analyses to determine the client’s historical
and current triggers for drug use, along with skills training in the manage-
ment of drug cravings, effective drug-refusal techniques, and general prob-
lem-solving and decision-making strategies. Computerized delivery of CBT
may effectively address issues commonly associated with regular in-person
therapy sessions, such as scarcity of qualified mental health professionals in
less populated regions, scheduling problems, transportation issues, and fi-
nancial constraints.
In a recent pilot study, CBT was examined in conjunction with pharma-
cotherapy to evaluate length of treatment, drug-free urinalyses, and reduc-
tion of alcohol and cocaine craving. Although subjects who received CBT
remained in treatment longer than subjects who received CBT and either di-
sulfiram or naltrexone, the combination treatment groups achieved signifi-
cantly greater reductions in cocaine-positive urinalyses (Grassi et al. 2007).
In a study comparing CBT with CM, CM was found to be efficacious during
treatment application. While CM may be useful in engaging substance users,
retaining them in treatment, and helping them achieve abstinence, CBT has
comparable longer-term outcomes (Rawson et al. 2006). Results of previous
xiv Cocaine and Methamphetamine Dependence

research also suggest that cognitive deficits predict low retention in outpa-
tient CBT treatment programs for cocaine dependence (Aharonovich et al.
2003, 2006). Future studies should examine the potential impact of differ-
ences in cognitive functioning on treatment outcomes and should test group
counseling approaches, which offer various assumptions and models to
match the needs of specific individuals.
The complex pharmacology and pharmacodynamics of cocaine’s action,
from the molecular to the behavioral level, is described in Chapter 5 as a foun-
dation for a review of current pharmacotherapies (see also Chapter 2 for a dis-
cussion of basic neuropharmacology of stimulants). A key concept for acute
reinforcement and euphoria is that different forms of cocaine and AMPH dif-
fer in their addictive potency based on how quickly the drug traverses the
blood-brain barrier and affects key limbic circuits. Chronic stimulant abuse
induces aberrant synaptic plasticity on brain circuits linked to reward learn-
ing as well as on other brain circuits. Specifically, cocaine-dependent individ-
uals have decreased DA synthesis, reduced endogenous DA levels, blunted
stimulant-induced DA release, reduced D2/D3 receptor availability, and in-
creased DA transporter and cortical norepinephrine (NE) transporter levels.
These abnormalities have been shown in human neuroimaging studies of lim-
bic brain areas related to DA neurotransmission. Furthermore, vulnerable
phenotypes prone to develop cocaine dependence are being noted in both
neuroimaging and genetic studies. These abnormalities are defining the brain
disease substrate of cocaine dependence and helping researchers to identify
appropriate targets for treatment. Newer clinical studies have switched their
focus from DA to the NE and glutamate (GLU) neurotransmitter systems in
order to develop new pharmacotherapies. A substantial number of clinical tri-
als have identified compounds that theoretically may correct deficiencies in
neural circuits and attenuate the reinforcing effects of cocaine in cocaine-
dependent individuals. Some compounds also appear to block drug cue–
induced craving that relates to relapse. These medications include DA releasers
such as sustained-release formulations of medications used to treat attention-
deficit/hyperactivity disorder; mixed DA reuptake inhibitors (modafinil); DA
precursors (L-dopa); NE synthesis blockers (disulfiram); and drugs that po-
tentiate GLU neurotransmission (N-acetylcysteine). The difficulty of defin-
ing the appropriate therapeutic target to produce positive clinical results, as
well as the cost of development, has led to inadequate involvement by the
pharmaceutical industry. Although some agonist therapies have shown prom-
ising results, it remains controversial whether their potential abuse liability
would outweigh their possible clinical efficacy.
Chapter 6 covers polydrug abuse. Substance abuse comorbidity is com-
mon with alcohol, marijuana, and opiates. Common psychiatric comorbidity
includes depression, psychosis, and personality disorders.
Foreword xv

Medical comorbidity and HIV are addressed in Chapter 7. A substantial

problem with medical comorbidity is that despite evident extreme examples
of health problems resulting from cocaine or METH use, these comorbid
conditions often are not credible to users. Many well-controlled studies link
stimulant use to a number of medical problems, some of which are fatal.
Knowledge of these problems can help stimulant users and health care pro-
viders respond to symptoms earlier, but the denial of these major medical
complications among the stimulant users is a significant challenge.
The list of complications begins with stimulant overdose (Centers for
Disease Control and Prevention 2010), which manifests initially with symp-
toms such as agitation, increased heart rate, and hyperthermia (Kosten and
Kleber 1988). Hyperthermia is particularly lethal through progression to
rhabdomyolysis and renal failure. Long-term stimulant use increases the risk
of hypertension, atherosclerosis, vasospasm, thrombosis formation, myocar-
dial infarction, and stroke. Rarely, vasoconstriction can also cause corneal ul-
cers and scarring, resulting in blindness. Smoking crack or METH harms the
lungs, exacerbates asthma and chronic obstructive pulmonary disease, and
increases vulnerability to tuberculosis. Cocaine and especially METH can
cause gum disease and tooth decay via vasoconstriction, dehydration, re-
duced salivary flow, poor dental hygiene, and poor diet. Cocaine and METH
use can lead to dehydration and nutritional deficiencies that result in dry,
itchy skin. In addition, some users have tactile or visual hallucinations in-
volving their skin (e.g., feeling bugs under their skin) that exacerbates dam-
age to the skin through their picking at it (Gawin and Ellinwood 1988).
Behavioral complications of chronic stimulants extend from the neonatal
and pediatric periods to older adulthood (Delaney-Black et al. 2010). Chil-
dren who are exposed prenatally to cocaine or METH are at increased risk for
neurobehavioral problems and should receive regular developmental and
mental health assessments and referrals as needed. Cocaine and METH use is
associated with increased risk of violence toward and from intimate partners,
even after other risk factors are taken into account. Unprotected sex and the
resuse of previously used needles, syringes, and possibly pipes can transmit
HIV and hepatitis C virus. Poor skin hygiene when injecting can result in in-
fections of the skin (abscesses), heart (endocarditis), or other organs. The
adulterant levamisole, found in most cocaine, can result in neutropenia and
life-threatening infections. Finally, cocaine and possibly METH increase HIV
disease progression, even after taking into account other risk factors. To re-
duce this disparity, it is important to engage stimulant users in HIV care and
addiction treatment as early as possible.
The continued high levels of cocaine and METH/AMPH abuse and the
destructive effects of such abuse call for renewed efforts to improve treat-
ment results. This comprehensive volume brings together what is known
xvi Cocaine and Methamphetamine Dependence

about these drugs and points the way to such improvement. As such, it is an
important contribution to the addiction field.

Herbert D. Kleber, M.D.

Professor of Psychiatry and Director, Division of Substance Abuse,
Columbia University, New York, New York

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